Abstracts and Case Studies for the College of American Pathologists 2020 Annual Meeting (CAP20 Virtual)

Rong Chen, MD ([email protected]); Cristina Magi-Galluzzi, MD, PhD; Fei Fei, MD; Sameer Al Diffalha, MD. Department of Pathology, University of Alabama at Birmingham.

Context: Malakoplakia is an acquired inflammatory condition. We reviewed all cases of malakoplakia diagnosed at our institution during the past 15 years.

Design: Gross and microscopic features of all cases diagnosed as malakoplakia from 2005 to 2019 were reviewed. Clinical history and demographic characteristics were obtained and analyzed.

Results: Eighteen cases were identified. Most occurred in women (78%) and all in adults (range, 31–87 years of age). Half of the patients were white, 44% were African American, and 6% were “other.” Four cases (22%) presented in the setting of organ transplants and 4 (22%) with malignancy (2 colon cancers, 1 chronic lymphocytic leukemia, 1 lymphoma). Other clinical settings included systemic lupus erythematosus (1 case, 6%), diabetes mellitus (2 cases, 11%), and recurrent infection (4 cases, 22%); no significant medical history was noted for the remaining patients. Four patients had positive results for microbiologic cultures. One-third presented with a masslike lesion; 61% (11/18) involved the genitourinary tract, 28% (5/18) gastrointestinal tract, 6% (1/18) abdominal soft tissue, and 6% (1/18) vagina. Seven of 18 (39%) had antibiotic treatment upon diagnosis. Two cases (11%) underwent resection of the mass/plaquelike lesions, while other cases were treated supportively. In 11 patients (61%) with follow-up, malakoplakia resolved after treatment (Figure 1).

Conclusions: Malakoplakia is a rare disorder occurring in a wide age range, more commonly in women, with no significant racial prevalence. Most patients with malakoplakia have some type of immunosuppression. While genitourinary and gastrointestinal tracts are the most common sites, other anatomic locations can be involved. Accurate diagnosis and appropriate treatment are important to avoid recurrence.

Ali Samani, BS¹; Samieh Khosravinia, MD¹; Amir Samani, MD, PhD² ([email protected]). ¹Department of Research, Dr Amir Samani Medicine Professional Corporation, Toronto, Ontario, Canada; ²Department of Pathology, Humber River Hospital, Toronto, Ontario, Canada.

Patients with hemoglobin SC (HbSC) may suffer from complications of several organs such as retina, bone, kidney, and spleen. However, a literature search (PubMed and Google search) do not show any report on gastrointestinal (GI) complications for these patients. We report on an ischemic colitis as a major GI complication for HbSC. A 62-year-old woman was admitted to the emergency department of our hospital with chief complaint of right abdominal pain. CT scan showed thickening of the ascending colon approximately 8.5 cm in length. Subsequent colonoscopy showed an apple core lesion in the ascending colon with a circumferential bowel thickening and a narrowed lumen suggestive of malignancy. Mucosal biopsy of the lesion showed granulation tissue. A right hemicolectomy was performed. By microscopic examination, features of ischemic colitis were evident (Figure 2, A). However, the blood vessels were full of RBCs morphologically similar to sickle cells (Figure 2, B and C). Our patient was not known to have hemoglobinopathy. Upon review of peripheral blood smear, some features of HbC disease were recognized (Figure 2, D). Subsequent electrophoresis identified HbSC disease. This patient has been followed up in our hospital for the last 7 years. Except for minor episodes of abdominal pain, she has been free from other GI complications. Ischemic colitis can be seen in HbSC disease. The sickled RBCs in blood vessels of affected tissue may be a clue for this diagnosis in previously undiagnosed patients.

Hussam Abu-Farsakh, MD; Faten Al Fares, MD ([email protected]); Altaf Ljmail, MSc. Department of Pathology, First Medical Lab, Amman, Jordan.

Context: Esophageal squamous papillomas (ESPs) are related to human papillomavirus (HPV) infection or to chronic mucosal irritation from esophagitis or Barrett esophagus. They can progress to squamous cell carcinoma. In this study, we examined the expression of PD-L1 in HPV-related ESPs.

Design: We retrieved 8 cases of ESPs that presented in the years 2014–2019 from our laboratory archives (Figure 3, A) and that proved to be HPV positive by immunohistochemistry (IHC). Eight cases of esophageal tissue, not having squamous papilloma, were also retrieved as a control group. PD-L1 IHC was performed on all cases along with the control group. The age range for the ESPs was from 9 to 42 years. One case showed invasive well-differentiated squamous carcinoma adjacent to a squamous papilloma (Figure 3, B).

Results: HPVIHC was positive in all cases of ESPs with a nuclear staining pattern (Figure 3, C). PD-L1 was expressed in only 3 cases of ESPs. The expression was seen predominantly in the basal layer in 25% to 30% of the cells (Figure 3, D). The case with squamous carcinoma showed focal positivity for PD-L1 in the ESP component (30% of cells) and in the carcinoma component (25% of the cells). No immunostaining for HPV or PD-L1 was seen in the control group.

Conclusions: ESPs that are HPV related have a modest increase in PD-L1 expression, compared to the normal squamous epithelium. PDL1 expression may be seen in squamous carcinoma arising from HPV-related ESPs. The significance of PD-L1 expression in ESPs may affect the mode of therapy and requires further testing.

Fei Fei, MD ([email protected]); Vishnu Reddy, MD; Chirag R. Patel, MD; Deepti Dhall, MD; Goo Lee, MD; Mengjun Xiong, MD; Sameer Al Diffalha, MD. Department of Pathology, The University of Alabama at Birmingham.

Context: MEITL is a rare primary and highly aggressive intestinal T-cell lymphoma derived from intraepithelial lymphocytes. The diagnosis of MEITL is very challenging and the clinical outcome of patients with MEITL is very poor. The aim of the present case series is to highlight the pathology, diagnosis, and clinical course of patients with MEITL.

Design: A retrospective chart review from 2009 through 2019 was performed and 4 patients diagnosed with MEITL were identified. Data regarding age, sex, ethnicity, clinical presentation, treatment, patients' outcome, and pathologic features were reviewed.

Results: The mean age of the 4 patients was 68.3 years and all patients were male. The clinical presentations were nonspecific including abdominal pain, weight loss, diarrhea, and small-intestine perforation. The pathologic features include transmural infiltration of sheets of relatively monotonous atypical small to medium-sized lymphoma cells. The lymphoma cells were positive for CD3, CD8, and CD56, and negative for CD4 and CD5, with Ki-67 ranging from 50% to 90%. One patient had relapse 3 months after completion of 6 cycles of CHOP regimen and expired 8 months after diagnosis. One patient's disease progressed after 2 cycles of EPOCH regimen. Unfortunately, 2 consult cases had no clinical history provided and no corresponding follow-up. The clinical and pathologic features for the 4 patients are summarized in the Table.

Conclusions: MEITL is a very rare primary intestinal T-cell lymphoma with distinctive clinical and pathologic features. The diagnosis is extremely challenging, and the optimal management remains undetermined.

Brian K. Cox, MD, MAS ([email protected]); Bonnie Balzer, MD, PhD; Stacey Kim, MD; Brent Larson, DO; Maha Guindi, MD; Kevin Waters, MD, PhD. Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, California.

Context: PNI is observed in almost all cases of PDCA and is correlated with recurrence and poor prognosis. Studies show that PDCA induces neural remodeling, plasticity, and density. We assessed WSIs for evidence of neurotropism and nerve enlargement in PDCA.

Design: The tumor bed, neoplastic glands, nerves, and PNI were manually annotated on WSIs of representative sections from 11 PDCA resections and were compared to a control group of nerve annotations from 11 nonneoplastic pancreas slides. WSIs were generated by using the Aperio ScanScope Turbo slide scanner. Expected PNI was calculated as follows: Perineural Invasion (exp) = (Gland Area/Tumor Bed Area) × Nerve Number. Spearman correlation was used to examine the validity of our ×estimation of expected PNI. A sign test was used to compare observed versus expected PNI. An independent samples t test was used to compare nerve caliber in PDCA to the nonneoplastic pancreas.

Results: A total of 4273 glands and 1113 nerves were annotated. PDCA cases averaged 388 neoplastic glands and 35 nerves. Observed PNI highly correlated with expected PNI (q = 0.81; P = .003). Observed PNI exceeded expected PNI in 9 of 11 cases (82%), and the average number of observed PNI instances per case (4.27) was greater than expected (3.52). The mean nerve diameter in PDCA was 125 μm, significantly greater than that seen in the nonneoplastic controls (75 μm; P < .001).

Conclusions: Using this method of DIA to examine the characteristics of PNI in PDCA suggests that while PNI itself does not modify nerve diameter, the PDCA microenvironment significantly increases nerve caliber. The correlation of expected PNI with observed PNI suggests that PNI may be explained by chance collisions.

Dongwei Zhang, MD, PhD; Roula Katerji, MD; Michael Drage, MD, PhD; Aaron Huber, MD; Xiaoyan Liao, MD, PhD ([email protected]). Department of Pathology, University of Rochester Medical Center, Rochester, New York.

Context: Malignant tumors occur in less than 0.5% of all surgically excised hernia sacs and the clinicopathologic features are not fully understood.

Design: Cases were collected between 2003 and 2019 at our institution. Immunohistochemical (IHC) studies with a panel of markers were performed to facilitate diagnosis.

Results: Twenty-three patients were identified, consisting of 9 women and 14 men, with an average age of 69.7 years (range, 36–93). Most of the tumor-containing hernia sacs were ventral/periumbilical (n = 14, 61%). Clinically, 17 patients (74%) carried a prior or current diagnosis of malignancy, andtumorsinherniasac were thesamebymorphology. The remaining 6 cases (26%) were of unknown origin. A panel of IHC markers was applied: specifically, SATB2/CDX2 positivity for colorectal origin and CK7 positivity/SMAD4 expression loss for pancreatobiliary origin. The final classification was as follows: 10 gastrointestinal adenocarcinomas (5 colorectal, 3 appendiceal, 2 gastroesophageal junction), 7 gynecologic carcinomas (6 ovarian, 1 uterine), 5 pancreatobiliary carcinomas, and 1 gastrointestinal stromal tumor. While female patients predominantly had gynecologic primary (7/9, 78%), gastrointestinal primary was the most common (9/14, 64%) among male patients. Fifteen patients (65%) died of disease after a median follow-up of 237 days, while 5 patients (22%), all with gastrointestinal primary, were alive after a median follow-up of 672 days.

Conclusions: This case series, the largest reported to date, establishes that gastrointestinal, gynecologic, and pancreatobiliary adenocarcinomas are the most common primary metastatic to the hernia sac, portending a poor prognosis. Clinical, radiographic findings, and selective IHC studies are helpful to determine the site of origin.

Lucy Wang, DO¹ ([email protected]); Michael Rosman, MD²; Michael Toth, BS³; Ira Jacobson, MD²; Neil D. Theise, MD.¹ Departments of ¹Pathology and ²Medicine, New York University Medical Center, New York; ³Department of Analytics, Michael Toth Analytics, New York, New York.

Context: Recent reports indicate that keratin 19–demonstrated loss of canals of Hering (CoH) may be the earliest identifiable PBC lesion, so-called minimal change PBC (mcPBC). This criterion has been applied in our institution since early 2017. This retrospective chart review is a preliminary data set that is being followed by retroactive keratin 19 IHC on all liver biopsy specimens (LBx) from 2000 to 2019 and review of changes in clinical criteria of LBx for PBC over that time.

Design: Retrospective search of our pathology database identified LBx from 2000–2016 (early period) and 2017–2019 (later period) in 3 categories of clinical-pathologic correlation (CPC): clinically suspected PBC/LBx confirmation, clinically suspected PBC/no LBx confirmation, and clinically unsuspected PBC/LBx PBC diagnosis. Scheuer stage of PBC was assessed (with stage 0 used for mcPBC). Statistical analyses were performed by using Fisher exact test comparing LBx.

Results: Results summarized in the Table (P < .006) showed that there was an increase in diagnostic LBx, most of which was attributable to addition of mcPBC criteria (44% of cases in later period). Scheuer stage in diagnostic LBx showed statistically significant differences (P < 3.8 × 10⁻⁷): early-year cases range from stage 1 to 4 (median 3) and later-year cases range from 0 to 4 (median 1), also indicating effects of mcPBC diagnosis.

Conclusions: Changes in diagnostic criteria and clinical decisions about when to obtain LBx have changed PBC CPCs. Addition of LBx criteria of near total loss of CoH increases confirmation of PBC, identifies cases of unsuspected PBC, and results in earlier PBC stage at diagnosis.

Jacobson is a consultant with AbbVie, Alea, Arbutus, Arrowhead, Assembly Biosciences, Bristol Myers Squibb, Gilead, Intercept, Janssen, Merck, Novo Nordisk, and Siemens. Jacobson has received grant or research support from Assembly Biosciences, Bristol Myers Squibb, Durect, Eli Lilly, Enanta, Genfit, Gilead, Janssen, and Merck.

Minqian Shen, MD, PhD¹ ([email protected]); Xiaoqiong Wang, MD, PhD¹; Scott Robertson, MD, PhD¹; Daniel Roberts, MD¹; Clifton Fulmer, MD¹; Pablo Bejarano, MD²; Daniela Allende, MD.^{1 1}Department of Pathology, Cleveland Clinic, Cleveland, Ohio; ²Department of Pathology, Cleveland Clinic Florida, Weston, Florida.

Context: Pancreatic ductal adenocarcinoma (PDAC) typically presents in older patients with low survival rate. Tumor heterogeneity is common in PDAC, which may have prognostic impact and be associated with molecular profiles. The significance and reproducibility of these findings in outlier PDAC populations (young adults and long-term survivors) remain unknown.

Design: Retrospective searches of pathology databases identified 9 PDAC cases in young adults (≤45 years) and 4 PDAC cases with longer survival (≥60 months' survival) from 2007–2017. A control population of 18 typical PDAC cases was included. All H&E slides were reviewed by hepatopancreaticobiliary pathologists and semiquantitatively scored (%) according to published study guidelines (Kalimuthu et al, 2019).

Results: Tumor heterogeneity (2 or more patterns) was common in all groups (29/30, 96.7%), with most cases demonstrating a combination of different “glandular forming” (Figure 4, A and B) and “nonglandular forming” (NGF) (Figure 4, C and D) patterns. Greater than 40% of NGF morphology was noted in 6 of 9 younger patients (66.7%), 1 of 4 long-term survival patients (25%), and 6 of 18 controls (33.3%). The presence of ≥40% of NGF in younger adults and long-term survivors was not statistically different from controls (P = NS). Long-term survivors showed an average 37.7% of NGF morphology, similar to controls (32.3%).

Conclusions: Younger adults with PDAC with ≥40% of NGF morphology are not different from matched PDAC controls. However, this morphologic classification associated to outcome was not reproducible in our cohort of long-term survivors, suggesting other drivers of outcomes in such cases.

Roula Katerji, MD¹ ([email protected]); Dongwei Zhang, BMed, PhD¹; Laura Bratton, MD²; Qi Yang, MS¹; Diana Agostini-Vulaj, DO¹; Christa L. Whitney-Miller, MD¹; Xiaoyan Liao, BMed, PhD.¹¹Department of Pathology, University of Rochester, New York; ²Department of Pathology, Ochsner Health System, Louisiana.

Context: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at advanced stages with liver metastases. We evaluated a panel of immunohistochemical markers in diagnosing metastatic PDAC and compared it to cholangiocarcinoma, which often shares a similar immunoprofile with PDAC.

Design: Cases of metastatic adenocarcinoma to liver, in the context of a pancreatic mass and absence of other lesions, were collected. Relevant clinical information and histopathologic data were collected. A tissue microarray comprising 54 cases of cholangiocarcinoma was used as a control.

Results: A total of 70 patients with biopsy-proven PDAC metastatic to liver were identified. Immunohistochemically, the metastatic PDACs were positive for CK7 and CK19, while negative for PAX8 and essentially negative for TTF1, SATB2, and GATA3. CDX2 and CK20 were variably expressed. p53 overexpression was observed in 45% of cases, and Ki-67 was focally increased in 65% of cases. SMAD4 was lost in 90% of PDACs but only lost in 24% of cholangiocarcinomas (P < .001). MUC5AC was expressed in similar portions of PDAC and cholangiocarcinoma cases (75% versus 66.6%; P > .05). Interestingly, MUC5AC-negative PDAC showed high-grade cytology and poor differentiation, whereas MUC5AC expression did not correlate with tumor grading in cholangiocarcinoma. The degree of tumor differentiation did not play a role in overall survival.

Conclusions: A selected panel of immunomarkers (CK7, CK19, SATB2, SMAD4) can assist in diagnosing metastatic PDACs to the liver. Loss of nuclear SMAD4 is highly sensitive and specific, especially to distinguish PDAC from cholangiocarcinoma. The role of MUC5AC in PDAC differentiation and survival may warrant further workup.

Lucas DO Buchanan, DO¹; Hansini Laharwani, MD² ([email protected]); Sara Iqbal, MD³; Charu Subramony, MD²; Pegah Hosseini-Carroll, MD.³ Departments of ¹Medicine, ²Pathology, and ³Gastroenterology, University of Mississippi Medical Center, Jackson.

Drug-induced liver injury (DILI) is a common cause of liver injury and failure. It has an incidence of 14 to 19 per 100 000 cases and is responsible for 5% of hospital admissions for jaundice. Injury from dietary and herbal supplements is increasing. Our patient is a 44-year-old man with no medical history who presented to an outside hospital after 2 weeks of worsening fatigue and jaundice. He had decreased appetite, nausea, vomiting and a 40-pound weight loss during the last month. On admission to our facility, ALT and AST were mildly elevated to 53 U/L and 64 U/L, respectively. His alkaline phosphatase was 312 and total bilirubin was 26.86 with a direct bilirubin of 19.01. Viral, autoimmune, and other causes of liver injury were ruled out. Endoscopic retrograde cholangiopancreatography revealed no stricture, obstruction, or mass. Liver biopsy was performed with subsequent pathology suggesting DILI. He reported no medication use but admitted to taking whey protein (Universal Super Whey) supplementation daily for several months. About a month before symptom onset he had increased his usage, consuming a minimum of 5 scoops up to 3 times a day. While no active ingredients of Universal Super Whey are on the NIH liver toxicology list, there have been a few documented cases of whey protein–induced liver injury. When faced with DILI from an unknown source, protein supplementation, including whey protein, should be considered (Figure 5).

Pooja Dhorajiya, MD ([email protected]); Gabriel Levi, MD; Swan Thung, MD. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.

Lymphoepithelioma-like carcinomas (LELCs) are tumors strongly associated with EBV that occur in a wide variety of anatomic sites. They most frequently show an undifferentiated epithelial component with dense lymphoplasmacytic infiltration. LELCs are exceptionally rare in the liver and can present as lymphoepithelioma-like hepatocellular carcinomas (LELHCCs) or lymphoepithelioma-like cholangiocarcinomas (LELCCs). Fewer than 25 cases of LELCC have been described and their natural behavior is not well understood. We report a case of a 74-year-old woman with a 3.2-cm incidental hepatic mass in segment 8. On biopsy, it showed epithelial proliferation of ductal cells with minimal cytologic atypia, admixed with abundant lymphoplasmacytic infiltrate (Figure 6, A). EBER and CK19 immunostains were strongly positive (Figure 6, B). Diagnosis of atypical lymphoepithelial lesion was rendered. The patient was advised to undergo surgical resection but elected observation with surveillance imaging, which 3 years later revealed a 4.1-cm mass. Serum AFP, CEA, and CA 19-9 levels were within normal limits. The patient underwent radiotherapy. Two years later, a peripancreatic mass was found on surveillance imaging. Biopsy specimen revealed a similar-appearing neoplasm to the initial biopsy, except the epithelial component was now overtly malignant with significant nuclear pleomorphism, architectural disarray, desmoplastic stroma, and necrosis (Figure 6, C). EBER was again strongly positive within the epithelial cells, consistent with LELCC (Figure 6, D). This case report illustrates the natural behavior of an LELCC with corresponding histopathologic progression. It highlights the slow progression of a bland LELCC to a highly malignant tumor and underscores a prompt treatment of these lesions when encountered.

Mohammed Alsomali, MD¹ ([email protected]); Wei Chen, MD, PhD²; Rachel Pearlman, MS, LGC³; Amy Lehman, MAS⁴; Heather Hampel, MS, LGC³; Deborah Knight, MS²; Wendy Frankel, MD.^{2 1}Department of Pathology, King Fahad Specialist Hospital, Dammam, Saudi Arabia; Departments of ²Pathology, ³Internal Medicine, and ⁴Biostatistics, The Ohio State University Wexner Medical Center, Columbus.

Context: Microsatellite instability (MSI) occurs in 15% of colorectal carcinomas (CRCs), with Lynch syndrome (LS) accounting for 3%. Conventional adenoma (CAd) and sessile serrated adenoma (SSA) are precursors to CRC. We compared polyps in microsatellite stable (MSS) and MSI CRC resections, and among MSI CRCs due to LS, MLH1 hypermethylation, and double somatic (DS) mismatch repair mutations.

Design: Slides and pathology reports from 67 MSI CRCs and 291 MSS CRCs from 2013–2016 were reviewed. Mismatch repair status was previously identified by immunohistochemistry and MSI PCR. Etiology for mismatch deficiency was elucidated by using MLH1 methylation, germline testing, and tumor sequencing. The number of polyps found grossly and microscopically was assessed for CAds, SSAs, and hyperplastic polyps.

Results: In MSS CRCs, 1 to 5 polyps, 6 to 10 polyps, and >10 polyps were identified in 25%, 1%, and 6% versus 24%, 6%, and 0% in MSI, respectively. CAds, SSAs, and hyperplastic polyps were identified in 21%, 2%, and 14% of MSS, compared to 24%, 10%, and 1% of MSI, respectively (Table). In MSI, we found CAds in 32% of methylated CRCs, 12% of LS, and 15% of DS. SSAs were identified in 19% of methylated MSI and not in LS or DS, while hyperplastic polyps were seen in 6% of LS cases and not in methylated or DS.

Conclusions: Only MSS contained >10 polyps. Similar proportions of MSS and MSI contained polyps and CAds, but SSAs were seen more often in MSI owing to MLH1 methylation. LS CRC patients may have polyps; this should not exclude LS or favor MSS over MSI.

Hampel is a consultant with 23andMe, a shareholder of Genome Medical, and on the scientific advisory boards for Genome Medical, Invitae, and Promega.

Yi-Hsuan Ho, MD ([email protected]); Anna F. Li, MD, PhD. Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan.

Context: Colorectal neuroendocrine carcinoma and mixed adenocarcinoma–neuroendocrine carcinoma are rare entities with poor prognosis. Early death after diagnosis is still noted despite clear surgical margins and aggressive chemotherapy. Therefore, we explored the possibilities of using PD-1/PD-L1 inhibitors as an adjunct treatment option by testing PD-L1 staining in surgical specimens and at the same time tried to find adverse prognostic factors in such patients.

Design: The study included 11 colorectal neuroendocrine carcinoma and 5 mixed adenocarcinoma-neuroendocrine carcinoma resection specimens collected in our institute during a 9-year span. Clinicopathologic data were retrospectively reviewed. PD-L1 (clone SP263, Roche Ventana) was stained on whole slides and combined positive score was assessed at a cutoff of ≥1. Synaptophysin and Ki-67 double staining was performed to confirm diagnosis. P53, RB1, and P16 immunostains were also applied for correlation study and survival analysis.

Results: All statistical analyses were evaluated for the entire 16 cases because there was no significant profile difference between neuroendocrine carcinoma and mixed adenocarcinoma–neuroendocrine carcinoma subgroups. PD-L1 immunoreactivity was seen in 56% of cases and associated with P53 overexpression (Fisher exact test, P = .005). Significantly lower rates of survival, using Kaplan-Meier analysis and log-rank test, were noted in patients with metastasis (P = .03), perineural invasion (P = .02), and Ki-67 labeling index >55% (P = .005). Metastasis and perineural invasion were also statistically significant in multivariable analysis. Neither P16 overexpression nor RB1 loss significantly influenced survival.

Conclusions: PD-L1 immunostaining can be observed in colorectal neuroendocrine carcinoma and mixed adenocarcinoma–neuroendocrine carcinoma and is correlated with P53 overexpression. Metastasis, perineural invasion, and Ki-67 labeling index >55% are associated with poorer prognosis.

Kiran G. Manjee, MBBS ([email protected]); Thomas Cibull, MD; Thanh Lan, MD. Department of Pathology & Laboratory Medicine, NorthShore University Health System, Evanston, Illinois.

Context: NKX3.1 is a specific marker for primary and metastatic prostatic adenocarcinoma. Recently, NKX3.1 expression was observed in a case of metastatic gastroesophageal adenocarcinoma. This study was undertaken to further investigate the expression of NKX3.1 in esophageal and gastroesophageal adenocarcinoma (E/GE-ADC), as this has not been reported in the literature.

Design: H&E-stained sections from 42 primary and 23 metastatic E/GE-ADCs from 2004–2009 (34 patients with no history of prostatic adenocarcinoma) were reviewed. Four-micrometer-thick formalinfixed, paraffin-embedded sections were immunolabeled with a prediluted rabbit polyclonal NKX3.1 antibody (BioCare Medical) according to established protocol. NKX3.1 staining was scored as weak, moderate, or strong in a focal or diffuse pattern. Strong is defined as the intensity seen in normal prostate control. Focal and diffuse are defined as <50% or ≥50% of the tumor nuclei, respectively.

Results: Six cases (9%) of E/GE-ADC (from 4 patients) showed NKX3.1 expression: 3 esophageal biopsy, 1 esophagectomy, 1 lymph node metastasis, and 1 cutaneous metastasis. The biopsy cases were weak diffuse (n = 1) and weak focal (n = 2). The esophagectomy was moderate focal (Figure 7, A and B). The lymph node metastasis was weak focal. The cutaneous metastasis was strong diffuse (Figure 7, C and D). Incidentally, variable positivity was also seen in benign esophageal submucosal glands in 3 specimens.

Conclusions: NKX3.1 shows spurious positivity in both primary and metastatic E/GE-ADC. Although predominantly weak-moderate in intensity, this aberrant immunolabeling can be strong and diffuse in rare cases, which may cause considerable diagnostic challenges, especially in the metastatic setting.

Diane A. Chen, MD ([email protected]); Anne Koehne de Gonzalez, MD; Ladan Fazlollahi, MD; Stephen Lagana, MD; Helen Remotti, MD. Department of Pathology, Columbia University Medical Center, New York, New York.

Context: Neuroblastoma (NB), Wilms tumor (WT), and hepatoblastoma (HB) are common intra-abdominal pediatric malignancies that pose diagnostic challenges in advanced metastatic disease. Albumin in situ hybridization (ISH) and immunostaining (IHC) for HepPar, arginase, glypican-3, β-catenin, PAX8, GATA3, and glutamine synthetase (GS) may be useful in the differential diagnosis. The aim of this study was to determine the utility of this panel in clinical practice.

Design: Tissue microarrays including 26 HB, 44 NB, and 30 WT cases were constructed. Albumin RNA ISH and IHC for HepPar, arginase, glypican-3, β-catenin, GATA3, PAX8, and GS were performed.

Results: Twenty six of 26 HBs (100% sensitivity/specificity) were albumin RNA ISH and arginase IHC positive. HepPar was positive in 22 HBs (85%), 0 NB (0%), and 1 WT (3%). β-Catenin was positive in 15 HBs (58%), while negative in 100% NBs and WT. GATA3 was positive in 1 HB (4%), 40 NBs (91%), and 14 WTs (47%). GATA3 staining was primarily localized to tubular epithelium in WT. PAX8 was positive in 28 WTs (93%) and negative in 100% of HBs and NBs. GS was positive in 30 HBs (88%), 43 NBs (98%), and 30 WTs (100%) (Table).

Conclusions: Albumin RNA ISH and arginase IHC are the most sensitive and specific hepatocellular differentiation markers for HB. HepPar is less sensitive (85%). Nuclear positivity of β-catenin is observed in HB, with limited sensitivity (58%). PAX8 is specific and sensitive (93%) for WT. GATA3 is most sensitive for NB but also stains WT epithelium. GS staining is seen across all 3 tumors, lacking specificity.

Paige A. Peterson, MD¹ ([email protected]); Daniel Olson, DO.^{2 1}Department of Pathology, University of Colorado Hospital, Aurora; ²Department of Pathology, Rocky Mountain Regional VA Medical Center, Aurora, Colorado.

A 67-year-old man with a past medical history of testicular diffuse large B-cell lymphoma was found to have lesions involving the pancreatic tail, spleen, and liver on full body CT scan for metastatic disease. Radiographically, the lesions were consistent with metastatic diffuse large B-cell lymphoma. The patient underwent R-CHOP treatment. A mid-treatment FDG PET/CT scan demonstrated that only the pancreatic tail mass failed to improve on treatment (hypermetabolic; max SUV 5.5), which prompted a CT-guided biopsy. Microscopic examination of the pancreatic tail mass showed nests of round to spindled uniform cells with smudgy chromatin, intranuclear cytoplasmic inclusions, and associated chunky brown/black intracellular and extracellular pigment (Figure 8). The tumor was positive for CK AE1/3, CD56, chromogranin, cyclin D1, SOX10 (rare positive cells), and synaptophysin, while negative for β-catenin, CD45, and CK7. Ki-67 labeling index was low (<3%). These findings are consistent with a pigmented well-differentiated neuroendocrine tumor. This tumor is an extremely rare variant referred to as pigmented “black” neuroendocrine tumor of the pancreas. Reviewing the medical literature, there are no reports describing the metabolic status of this tumor on FDG PET/CT scan. This case reports a rare and interesting variant of neuroendocrine tumor of the pancreas in the setting of a clinical and radiographic mimicker of metastatic diffuse large B-cell lymphoma. Although rare, recognition of this entity is needed as it can mimic a variety of neoplasms and pose diagnostic challenges.

Grant Williams, MD¹ ([email protected]); Lynn Messer-smith, DO¹; Jamie Lombardo, MD¹; Devin Broadwater, MD¹; Phillip Bohan, MD²; Robert Chick, MD²; Annelies Hickerson, MD²; Jessica Cindass, MD²; George Peoples, MD³; Guy Clifton, MD²; Robert Brady, MD.¹ Departments of ¹Pathology and ²Surgery, SAUSHEC, San Antonio, Texas; ³Department of Surgery, Cancer Insight, San Antonio, Texas.

Context: Therapies targeting programmed death ligand-1 (PD-L1) are used to treat multiple types of cancer, including colorectal cancer. Various studies have examined rates of PD-L1 concurrence between biopsy and resection with mixed results. One explanation for low concurrence is tumor heterogeneity of PD-L1 expression. Routine practice involves staining 1 representative section of tumor resection, which may miss areas of PD-L1 positivity.

Design: A total of 96 patients with matched endoscopic biopsies and resected colorectal adenocarcinoma diagnosed between 2006 and 2016 were selected for review. PD-L1 immunohistochemistry staining of tumor cells was interpreted per manufacturer guidelines. Twelve cases with PD-L1–positive biopsy and PD-L1–negative resection were identified and additional sections of tumor were stained for PD-L1.

Results: Initial PD-L1 positivity on biopsy and matched resection showed 66% concurrence (κ = 0.26). When 58 additional tumor sections (mean, 4.8/case) were stained in the 12 false-positive cases, 16 of the blocks (28%) from 5 different cases had PD-L1 positivity. This decreased the number of false-positive cases to 7 and changed the concordance rate to 71% (κ = 0.40). This also increased the positive predictive value of PD-L1 on biopsy from 58% to 75%. The negative predictive value remained 70%.

Conclusions: Standard practice of testing colorectal cancer for PDL1 positivity involves staining 1 representative section of the resection. In cases where there is PD-L1 positivity on biopsy, staining multiple additional sections of tumor from resection will increase the PPV and increase concurrence rate between biopsy and resection. If PD-L1 is positive on biopsy, staining multiple tumor sections at resection may be warranted.

Bartlomiej L. Radzik, MD ([email protected]); Pouyan Kheirkhah-Rahimabad, MD; Elizabeth Wiley, MD. Department of Pathology, University of Illinois at Chicago.

Gallbladder adenocarcinoma (GBC) is a rare malignancy affecting 2 per 100 000 people per year in the United States whose prevalence favors females of Native American, East Asian, and Northern Indian descent. GBC is often found incidentally upon evaluation of cholelithiasis and is associated with painful jaundice in advanced disease. Mismatch repair protein (MMRp) expression is directly correlated to increased survival. Further, MMRp deficiency in GBC, patterns of expression, and their clinical associations remain poorly characterized. We describe the case of a 70-year-old African American woman with a past medical history of colon cancer treated with partial colectomy, and endometrial carcinoma treated with hysterectomy and bilateral oophorectomy, who presented for cholecystectomy due to cholelithiasis. Histopathologic evaluation revealed multiple foci of adenocarcinoma in situ and vascular invasion. Evaluation was hindered owing to gangrenous cholecystitis and transmural necrosis. MMRp testing demonstrated mismatch repair protein deficiency and P53 staining <2% of tumor nuclei, leading to a diagnosis of Lynch syndrome in herself and her immediate family. Diagnosing GBC and its in situ components has many pitfalls. However, once the diagnosis was made, MMRp testing led to an otherwise undiagnosed case of familial Lynch syndrome. In a patient with multiple carcinomas, including rare tumors such as GBC, testing for Lynch syndrome should become a standard practice in histopathologic diagnosis and workup.

Preeti Behl, MD¹ ([email protected]); Chukwuyejulumafor Nwanze, MD¹; Byron Crawford, MD¹; Yukihiro Nakanishi, MD, PhD.^{2 1}Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana; ²Department of Pathology, Moffitt Cancer Center, Tampa, Florida.

Rosai-Dorfman disease (RDD) is a histiocytic proliferative disorder that commonly involves the cervical lymph nodes. Extranodal involvement occurs in 40% of the cases, most commonly involving bone, skin, soft tissue, central nervous system, salivary glands, and respiratory tract. Gastrointestinal tract involvement is very rare, with only 10 cases previously reported. We herein report a case of extranodal RDD presenting as a rectal polyp in a HIV patient. A 50-year-old woman with a medical history of HIV underwent a screening colonoscopy, which demonstrated a 3-cm broad-based, protruding submucosal mass in the rectum. The mass was completely excised transanally. Histologic examination showed colonic tissue with a submucosal infiltrate consisting of numerous small mature lymphocytes, plasma cells, neutrophils, and abundant histiocytes demonstrating mild cytologic atypia with prominent emperipolesis. Focal mucosal involvement was also identified. The histiocytes demonstrated positivity for CD68 and S100, consistent with the diagnosis of extranodal RDD. Laboratory testing revealed an elevated C-reactive protein level of 4.1 mg/dL and iron deficiency anemia. Tests for antinuclear antigen, rheumatoid factor, erythrocyte sedimentation rate, and quantitative IgG were within normal limits. No additional treatment was given. Follow-up examination of the patient did not reveal any lymphadenopathy or systemic symptoms and no recurrence. The exact etiology of RDD is not well understood, but some evidence exists to suggest that viral infections such as Epstein-Barr virus and human herpesvirus 6 play a role in its pathogenesis. Very few cases associated with HIV infection have been reported, suggesting the possibility of association with HIV infection.

Lucy Wang, DO ([email protected]); Oliver Szeto, MD. Department of Pathology, New York University Medical Center, New York.

Kaposi sarcoma (KS) is an angioproliferative neoplasm caused by human herpesvirus-8 (HHV-8) that most commonly presents on the skin. In addition to the well-known subtypes of KS, there is a fifth subtype that is rare and underrecognized called nonepidemic KS. Nonepidemic KS affects men who have sex with men (MSM) who are both HIV negative and immunocompetent. So far, in the literature cases of nonepidemic KS have only presented on the skin. We report an unusual case of nonepidemic KS arising in the anorectum in a 39-year-old healthy MSM man who is both HIV negative and immunocompetent. Colonoscopy revealed a nodular and ulcerated lesion located in the anorectum. Microscopic sections showed a nodular spindle cell proliferation infiltrating the rectal lamina propria and submucosa. The spindle cells had mild to moderate nuclear pleomorphism, eosinophilic cytoplasm, visible nucleoli, and indistinct cell borders in a background of hemorrhage (Figure 9, A). Numerous extravasated red blood cells and scattered hyaline globules were seen (Figure 9, B) and occasional mitotic figures were noted. Immunohistochemically, the spindle cells stained positively for HHV-8 (Figure 9, C) and ERG, and negatively for SOX-10, MNF116, and DOG-1. Ki-67 proliferative index showed approximately 20% proliferation activity. PAS-D stain highlighted the hyaline globules (Figure 9, D). Based on morphologic and immunohistochemical findings, diagnosis of KS involving rectal tissue was made. Kaposi sarcoma located in the gastrointestinal tract is very unusual and therefore should be included in the differential diagnosis of a spindle cell proliferation found in the gastrointestinal tract, regardless of a patient's HIV status.

Bicong Wu, MD ([email protected]); Matthew Yeh, MD, PhD; Deepti Reddi, MD. Department of Pathology, University of Washington, Seattle.

In rare instances, hepatocellular carcinoma (HCC) and yolk sac tumor (YST) have overlapping histologic features. Although α-fetoprotein is a frequent serum marker for HCC, elevated α-fetoprotein has been reported in most YST patients. SALL4, a nuclear zinc finger transcription factor, is reported as a highly sensitive and specific marker for primary and metastatic gonadal and extragonadal YST. We present a case of HCC expressing SALL4 by immunohistochemistry. The patient is a 73-year-old white woman with a history of cirrhosis secondary to non–alcoholic steatohepatitis, with a segment 8, enlarging 4.8-cm ill-defined heterogenous mass demonstrating arterial enhancement and washout on imaging. Laboratory studies showed elevated α-fetoprotein (21 303 ng/mL). Biopsy of the liver showed background bridging fibrosis surrounding regenerative nodules (Figure 10, A). The neoplastic cells consisted of columnar and epithelioid cells with dense chromatin, eosinophilic cytoplasm, areas of glandular architecture, and focal area of neoplastic cells lining the central vascular core (Figure 10, B). Immunohistochemically, the neoplastic cells were strongly positive for CAM 5.2, SALL4 (Figure 10, C), Glypican 3 (Figure 10, D), α-fetoprotein, arginase-1 (variable), and CK19 (focal) while negative for CK7, CK20, ER, GATA-3, CDX-2, hepar-1, lung adeno cocktail, synaptophysin, PAX8, Hercep, and WT-1. Although strong immunoreactivity of SALL4 is characteristic of YST, ≥25% of neoplastic cells with SALL4 expression is reported in up to 7% of HCC cases. Our case highlights the potential pitfall when using SALL4 in distinguishing HCC and YST, especially with limited biopsy material. Clinical correlation including patient's age and background liver disease may be helpful.

Anna Sarah Erem, BSc¹ ([email protected]); Karolin E. Ginting, MD²; Timothy S. Braverman, MD³; Shyam S. Allamaneni, MD.^{2 1}Department of Pathology, Saba University School of Medicine, the Bottom, Saba, Netherlands Antilles; ²Department of Surgery, the Jewish Hospital-Mercy Health, Cincinnati, Ohio; ³Department of Pathology, the Jewish Hospital - Mercy Health, Cincinnati, Ohio.

Solitary fibrous tumor (SFT) of the liver is extremely rare, and those positive for cytokeratin are even rarer, with outcomes that are difficult to assess. Most SFTs are benign, with a very low recurrence/metastatic rate. We present the case of a 79-year-old woman who presented with SFT of the liver. Histologic evaluation at the time of the first surgery showed bland spindle cells with focal hemangiopericytic growth pattern, and areas of hypercellularity and hypocellularity (Figure 11, A and B). The tumor cells were positive for vimentin, BCL-2, CD99 (Figure 11, C), and STAT6 (Figure 11, D) (expected for SFT), but negative for CD34 and focally positive for cytokeratin (unexpected for SFT). In assessing the malignant potential, no necrosis, significant nuclear pleomorphism, or infiltrative margins were observed, but the tumor had plentiful mitoses and increased proliferative activity by Ki-67 staining. Using these factors, the tumor was diagnosed as a borderline SFT with a medium risk of metastasis. Three years later, the patient was admitted for small-bowel obstruction, and multiple liver lesions were detected on CT scan. Core biopsies of these lesions showed pathology and immunohistochemistry similar to those at initial diagnosis, with the exception that the tumor was cytokeratin negative. The patient then underwent chemotherapy. Though surgical excision is the most effective therapy, borderline malignant SFTs require close ongoing monitoring. Prompt tissue diagnosis and chemotherapy were the mainstay treatment in this case. However, current literature suggests that antiangiogenic therapy may be more effective than chemo-radiation.

Tuyet Hong T. Tran, DO¹ ([email protected]); Cathy Q. Fan, MD, MBBS²; Seymour Katz, MD¹; Suparna A. Sarkar, MD, PhD.^{1 1}Department of Pathology, New York University Langone Medical Center, New York; ²Department of Pathology, Northwell Health, East Hills, New York.

Gastrointestinal clear cell sarcoma (CCS)/malignant gastrointestinal neuroectodermal tumor (GNET) is a rare sarcoma with neuroectodermal differentiation and characterized by EWSR1 fusion translocations. This aggressive neoplasm is most commonly localized to the small intestine, stomach, and colon, and shows a predilection for young adults (median age, 33 years). The median survival is 10 months with metastasis to liver and lymph nodes. We present a case of small-bowel CCS/GNET in a 29-year-old patient with synchronous multiple liver metastasis. His medical history was significant for Hodgkin lymphoma (stage IIB, status post chemotherapy) with no current evidence of active disease and ulcerative colitis, while taking vedolizumab with good control. He presented with iron deficiency anemia and underwent a colonoscopy that was unremarkable. He then underwent a capsule endoscopy that caused a small-bowel obstruction leading to a small-bowel segmental resection. Gross examination revealed a 3.5×2.0-cm circumferential, centrally ulcerated, polypoid, firm mass. Microscopic examination highlighted a malignant neoplasm infiltrating the full thickness of the small intestinal wall in a nested pattern. Tumor cells had oval to polygonal nuclei, prominent nucleoli, and clear cytoplasm (Figure 12). Tumor cells were immunoreactive for SOX-10, EMA, vimentin, and negative for S100, HMB-45, Melan-A, CD117, DOG1, chromogranin, synaptophysin, SMA, desmin, CAM 5.2, and AE1/AE3. FISH analysis was remarkable for EWSR1 break-apart rearrangement. Biopsy of hepatic lesions was consistent with metastatic CCS/GNET. To our knowledge this is the first case of CCS/GNET in the setting of chronic inflammatory bowel disease, and the demonstration of EWSR1 gene rearrangement was key to the diagnosis.

Irene Chen, MD ([email protected]); Dongwei Zhang, BMed, PhD; Xiaoyan Liao, BMed, PhD. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.

Vanishing bile duct syndrome (VBDS) is a group of acquired disorders characterized by paucity/loss of intrahepatic bile ducts. Etiologies include medications, autoimmune diseases, infection, and neoplasms. We report a unique case of acute onset rapid progressive VBDS in a 33-year-old woman with a history of systemic lupus erythematosus and lupus nephritis (class IV/V) managed with Cellcept and Medrol. She presented initially with increased nausea and vomiting, and was noted to have elevated liver enzymes. She was given intravenous ceftriaxone and metronidazole but developed jaundice and worse cholestatic pattern of liver function tests. Imaging studies revealed no biliary abnormalities or lesions. Serology was positive for anti–ds DNA but negative for ANA, anti-mitochondria, and F-actin antibodies. Liver biopsy was performed and revealed centrilobular cholestasis with nearly complete absence of intralobular bile ducts. There was mild portal inflammation, portal and periportal fibrosis, but no features of primary biliary cholangitis, primary sclerosing cholangitis (PSC), or autoimmune hepatitis. A diagnosis of VBDS was made, favoring drug induced. The patient underwent liver transplant a year later. The explant liver showed continuous VBDS with no advanced fibrosis. Interestingly, there was multifocal replacement of mediumsized bile ducts with obliterating fibrosis, a single hilar large bile duct with xanthogranulomatous inflammation, and 1 rare residual small bile duct with periductal fibrosis, findings suggestive of PSC. Acute VBDS in a lupus patient, overlapping with drug-induced injury and late-onset PSC, has not been previously reported. This unique case demonstrates the complexity of an autoimmune disease compromising the hepatobiliary system, the mechanism of which is yet to be understood.

Preeti Behl, MD¹ ([email protected]); Byron Crawford, MD¹; Yukihiro Nakanishi, MD, PhD.^{2 1}Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana; ²Department of Pathology, Moffitt Cancer Center, Tampa, Florida.

Pyloric gland adenomas (PGAs) are rare benign adenomas most often seen in the stomach. Very rarely they arise in extragastric sites such as duodenum, gallbladder, bile ducts, esophagus, and rectum. Their recognition is important because of the high rate of malignant transformation ranging from 12% to 30%. We report a case of 6-mm pyloric gland adenoma with focal high-grade dysplasia arising in the duodenum. The patient is a 77-year-old man with a past medical history of gastroesophageal reflux disease. He presented to the clinic with dysphagia. Upper gastrointestinal endoscopy revealed a gastroesophageal junction stenosis and a 6-mm sessile nodule in the duodenal bulb, which was biopsied. Histologic examination of the duodenal nodule showed a pyloric gland adenoma with low and focal high-grade dysplasia, characterized by closely packed adenoma glands with characteristic foamy, ground-glass cytoplasm and basally located uniform nuclei. The dysplastic cells were diffusely positive for MUC6, focally positive for MUC5AC, MUC2, CK7, CD56, chromogranin, NSE, and CDX2, and negative for CK20. No invasive carcinoma or associated gastric heterotopia was identified on the submitted biopsy specimen. Further management of the patient was not performed as he was lost to follow-up. Although PGAs with high-grade dysplasia have been reported to be significantly larger in size than PGAs with low-grade dysplasia, our current case shows focal high-grade dysplasia in a 6-mm PGA. Therefore, it is important for both pathologists and clinicians to correctly diagnose this entity to provide appropriate management and surveillance of these patients.

Fernando Alekos Ocampo Gonzalez, MD ([email protected]); Joanna Solarewicz, DO; Lin Cheng, MD; Paolo Gattuso, MD. Department of Pathology, Rush University Medical Center, Chicago, Illinois.

Context: Pancreas is an uncommon site for metastasis. Limited, small studies exist on this topic. We reviewed secondary malignancies of pancreas in our institution to better understand this uncommon situation and broaden our differential diagnosis.

Design: Our database was searched for secondary neoplasms of pancreas. Clinical data and pathologic reports were reviewed. Primary malignancies anatomically continuous with pancreas and neuroendocrine tumors were excluded.

Results: Among 1137 cases of pancreatic malignancies in our database, 36 cases (3.2%) were identified as secondary. Diagnoses were made by fine-needle aspiration in 11 (31%), biopsy in 8 (22%), and resection in 17 (47%) and included 19 metastatic carcinomas (14 renal, including 9 clear cell and 5 other subtypes; 2 liver including 1 hepatocellular and 1 fibrolamellar; 1 pulmonary, 1 breast, and 1 squamous cell); 14 lymphoproliferative diseases (10 diffuse large B-cell lymphomas, 2 classic Hodgkin lymphomas, 1 follicular lymphoma, and 1 posttransplant lymphoproliferative disease); 2 sarcomas (1 undifferentiated sarcoma and 1 Ewing sarcoma); and 1 malignant melanoma.

Conclusions: In our study, 3.2% of pancreatic malignancies were secondary. Most common was metastatic renal cell carcinoma (39%), likely direct extension. Only 3 metastatic carcinomas (8%) were from remote sites, presumably from an unfavorable microenvironment for seeding. The second most common secondary malignancy was lymphoma, with the most common subtype being diffuse large B-cell lymphoma. Ten of 14 lymphoma cases (71%) were diagnosed on FNA or biopsy, preventing unnecessary surgery. Differential diagnosis for small round blue cell tumor in pancreas should include Ewing sarcoma; clinical/cytogenetic data can help in diagnosing.

Ayesha Siddique, MD ([email protected]); Saverio Ligato, MD. Department of Pathology and Laboratory Medicine, Hartford Hospital, Hartford, Connecticut.

Context: Several risk factors have been recognized as predictors of lymph node metastasis (LNM) in malignant polyps (pT1). The Japanese Society for Cancer of the Colon and Rectum (JSCCR) has identified depth of submucosal invasion (DSI) (≥1000 μm) and high tumor budding (TB) at the invasive front as predictors of LNM. The International Tumor Budding Consensus Conference (ITBCC) agreed aTB ≥5 is predictive of LNM in pT1s. Most of these studies were performed on surgically resected pT1s or a mix of polypectomies and resections. Our aim was to validate these predictors of LNM, with a focus on TB and DSI exclusively in endoscopically resected polypectomies (ERPs).

Design: ERPs with pT1 and subsequent resections from 2009 to 2018 were included. Age, sex, polyp location, polyp size, polyp configuration, invasive tumor size, DSI, TB, grade, lymphovascular invasion (LVI), poorly differentiated clusters (PDCs), and TNM on follow-up were documented. TB was assessed according to the ITBCC. We used cutoff values of 3 and 5 TBs, and DSI was measured according to the JSCCR criteria. The χ² test was used to compare the risk factors of cases with and without LNMs.

Results: Of 52 ERPs (M:F = 1.4:1; age, 60.8 ± 11.1 years) 6 (11.5%) had LNMs. Neither high TB with a cutoff of 3 or 5 nor DSI ≥1000 μm or ≥2000 μm was associated with LNMs. We did not find associations with the PDCs, LVI, grade, and LNMs (Table).

Conclusions: In our study of ERPs neither TB nor DSI were reliable predictors of LNMs. The association of TB and DSI with LNMs needs to be revisited in a larger series of ERPs.

Qingzhao Zhang, MD, PhD¹ ([email protected]); Huili Li, MD, PhD¹; Guoli Chen, MD, PhD²; Zhaohai Yang, MD, PhD.^{3 1}Department of Pathology, Penn State Health Medical Center, Hershey, Pennsylvania; ²Department of Pathology, Geisinger Medical Center, Danville, Pennsylvania; ³Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Context: Immunohistochemistry (IHC) markers such as CDX2 and CK20 are used in confirming the site of origin for metastatic colorectal carcinomas (CRCs). This study aims to investigate whether there are differences in marker expression between MMR-deficient and MMR-proficient CRCs.

Design: Twenty-nine MMR-deficient and 88 MMR-proficient CRC cases were identified. IHC for CK7, CK20, CDX2, CEA, EpCAM, and SATB2 was performed on tissue microarray slides and subsequently reviewed. The expression of each marker was scored, and the cases were categorized into 3 groups: strong and diffusely positive (>50%); weak and/or focal positive (<50%); and negative. The χ² test was used.

Results: The MMR-deficient tumors presented with significantly reduced CK20 staining with 62.1% negative and 17.2% focal/weak, while 8% of MMR-proficient cases were negative and 17% were focal/weak for CK20 (P < .01; Table). CDX2 staining was negative and focal/weak in 3.4% and 2.3% of MMR-proficient cases, respectively. The MMR-deficient group showed decreased CDX2 expression with negative staining in 6.9% and focal/weak staining in 27.6% of cases, compared to the MMR-proficient group (P < .01). MMR-deficient tumors had less SATB2 expression with 17.2% negative and 31% focal/weak positive versus MMR-proficient tumors with 14.8% negative and 6.8% focal/weak (P < .01). CK7 was negative in most tumors with no difference between the 2 groups. There were marginal differences in EpCAM (P = .05) and CEA (P = .06) staining with reduced expression of EpCAM and CEA in MMR-deficient tumors.

Conclusions: MMR-deficient CRCs have reduced expression of CK20, CDX2, and SATB2. Caution should be taken during workup of the primary site for an MMR-deficient CRC.

Emad Ababneh, MBBS ([email protected]); Daniela Allende, MD; Xuefeng Zhang, MD. Department of Pathology and Laboratory Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.

Context: Well-differentiated small intestinal neuroendocrine tumors (NETs) are classified into 3 grades on the basis of proliferative index (Ki-67 and/or mitotic count). We aim to investigate whether grade 1 (G1) and grade 2 (G2), using current classification, are different in association with lymph node (LN) metastasis and/or distant metastasis (DM).

Design: All resections of G1 and G2 NETs of the small intestine (2002–2019) were retrieved. Clinicopathologic features were recorded. Grading was based on 2019 WHO criteria. Tumor extension was staged by using AJCC 8th edition. Regression analyses were performed to identify factors affecting outcome. P values <.05 were considered statistically significant.

Results: A total of 128 cases (G1, 81; G2, 47) were included. Ninety-six had LN metastasis and 47 had DM. Disease-free survival was associated with LN metastasis (Cox proportional hazards ratio, 3.4; 95% CI, 1.0–11.2; P = .04) and DM (Cox proportional hazards ratio, 24.1; 95% CI, 5.7–101.1; P < .01). Multivariate logistic regression models showed no statistically significant difference in the probability of LN metastasis, DM, or disease-free survival between G1 and G2 NETs (P = .89, .09, and .78, respectively). High tumor stage showed significant association with LN and DM (pT4 versus pT1, P < .01 for LN metastasis, and P = .03 for DM). Sampled LN number was related to the probability of LN metastasis (P < .01). To achieve a predicted probability of LN metastasis, at least 12 LNs need to be examined (Table).

Conclusions: In small intestinal NETs, G1 and G2 tumors show no statistically significant difference in LN metastasis or DM after adjusting for other factors. LN sampling (≥12) is important for detecting LN metastasis.

Jim C. Lee, MD, MPH ([email protected]); Saverio Ligato, MD. Department of Pathology, Hartford Hospital, Hartford, Connecticut.

Context: ORISE Gel is a recently introduced synthetic submucosal lifting agent injected to facilitate the endoscopic resection of small mucosal gastrointestinal (GI) lesions. Recently, a few reports have described the histopathologic features in surgical specimens in the GI tract following the injection of this gel. We report our experience with the identification of this procedure-related artifact and potential mimickers.

Design: All subjects who underwent endoscopic mucosal resection or submucosal dissection with ORISE injection (January 2019–January 2020) were included in this study. H&E slides from all cases, including those who underwent subsequent resection, were reviewed. Mucicarmine, Trichrome, Alcian blue, and Congo red stains were performed on selected cases.

Results: On day 0 of the ORISE injection, H&E sections from 19 cases showed no significant histopathologic changes. In 1 case, a pale, grayish, indistinct and amorphous material was identified in the submucosa (Figure 13, A). Four of 19 cases underwent segmental resection (2 for colonic tubular adenoma, 1 for colonic adenocarcinoma, 1 for gastric adenocarcinoma) owing to failure of ORISE to lift or completely remove the lesion. Examination of these specimens identified submucosal globules and ribbons of a homogeneous, amorphous, and eosinophilic material surrounded by a foreign-body giant cell reaction resembling amyloid. However, Congo red was negative, and Trichrome showed light-blue staining (Figure 13, B through D). Mucicarmine and Alcian blue were negative. The average interval between ORISE injection and segmental resection was 49.8 days.

Conclusions: We want to raise awareness among pathologists of the histopathologic changes caused by injection of ORISE in GI tract specimens and avoid misinterpretation of this artifact.

Subhashree Mallika Krishnan, DO ([email protected]); Ping Zhang, MD, PhD; Zhenhong Qu, MD, PhD. Department of Pathology, Beaumont Health, Royal Oak, Michigan.

Context: Histologically, the hallmark of active eosinophilic esophagitis (EoE) is the presence of intraepithelial eosinophils (iEos). Recently, studies have evaluated the etiologic role of intraepithelial mast cells (iMCs) in pathogenesis of EoE and residual disease. We aimed to evaluate diagnostic and prognostic value of iMCs in EoE by its prevalence in esophageal biopsy cases in association with presence of iEos and/or lymphocytes.

Design: Esophageal biopsy cases were prospectively reviewed for presence of iEos, lymphocytes, and/or iMCs. An experienced gastroenterology pathologist at our institution quantitated the number of inflammatory cells. Immunohistochemistry (CD117) was used to highlight iMCs. Unpaired Student t test was used to analyze data with statistically significant P value of <.05.

Results: Thirty-one esophageal biopsy cases were examined. Eighteen (study group) cases had iEos and iMCs, with clinical diagnosis of EoE in 14 of these cases (Figure 14, A). The remaining 13 cases (control group) had intraepithelial lymphocytes (Figure 14, C) without any significant presence of iEos or iMCs, with clinical diagnosis of lymphocytic/reflux esophagitis. Unpaired Student t test showed statistically significant (P value = .001) number of iMCs (mean iMCs, 40.1 ± 6.1) in the study group compared to control group (mean iMCs, 3.1 ± 1.4; Figure 14, B and D). Thus, increased iMCs were found to be associated with increased iEos during active EoE, and treated EoE with reduced iEos. In contrast, increased iMCs were not associated with other studied diseases.

Conclusions: We conclude that iMCs can be used as a surrogate marker for diagnosis of EoE. Further studies are needed to determine prevalence of iMCs in residual disease, which can have clinical impact.

Sepideh Madahian, MD ([email protected]); Richard Judelson, MD; Jacob Bledsoe, MD. Department of Pathology, UMass Memorial Health Care, Worcester, Massachusetts.

Context: Basaloid anal squamous cell carcinoma (SCC) is morphologically heterogeneous and may mimic other tumors. We received outside slides from a biopsy of an anal mass that was originally diagnosed as neuroendocrine carcinoma on the basis of morphology and expression of CD56 (Figure 15, A and B). However, further workup with pancytokeratin, P16, P40 (Figure 15, C), P63 (Figure 15, D), and HPV genotyping revealed the tumor to be HPV-related poorly differentiated basaloid SCC. Therefore, we retrospectively investigated the incidence of CD56 expression in anal SCC, a potential diagnostic pitfall.

Design: Forty-four basaloid anal SCC cases with known HPV 16/18 status (Cervista Invader Assay, Hologic) were identified from 2000–2019. The H&E and immunohistochemical stains of all cases were reviewed to confirm the original diagnosis. Additional immunohistochemical stains for CD56 (123C3, Agilent, Santa Clara, California), chromogranin (polyclonal, ThermoFisher, Waltham, Massachusetts), and synaptophysin (SP11, ThermoFisher) were evaluated and scored as negative, focal (≤25% cells staining), or diffusely (>25%) positive.

Results: Of the 44 cases, 1 (2%) showed focal and 2 (5%) showed diffuse CD56 positivity. All were negative for chromogranin and synaptophysin. There was no association with HPV status. Three of the cases had basaloid morphology with palisading, including 1 with focal adenoid cystic-like features.

Conclusions: Basaloid anal SCC infrequently demonstrates CD56 expression. However, such tumors are often poorly differentiated without keratinization, and CD56 expression may result in misdiagnosis as a neuroendocrine carcinoma. Therefore, in this location, an immunohistochemical panel that includes squamous cell markers and HPV studies is needed to avoid misdiagnoses.

Rabia Zafar, MD¹ ([email protected]); Patrick N. Costello, MD.^{2 1}Department of Pathology, East Tennessee State University, Johnson City; ²Department of Pathology, Johnson City Medical Center/Watauga Pathology Associates, Johnson City, Tennessee.

Leukocyte chemotactic factor-2 (ALECT-2) amyloidosis is a rare systemic disease, shows marked predilection for Hispanic/Middle Eastern ethnicity, and can involve kidney, adrenal gland, and liver. It can progress to renal failure. We report a case of a 38-year-old Hispanic woman with a history of dyslipidemia who presented with intermittent liver enzyme elevation. A liver biopsy specimen showed normal architecture and normal distribution of portal tracts with patchy mononuclear infiltrate. There was mild steatosis, involving zone 2–3 with mild ballooning degeneration. Globules of homogenous pale pink material were found in zone 3 steatotic areas, adjacent to central veins, and in periportal area. Some were present within hepatocytes or engulfed by macrophages. Congo red stain was weakly positive but there was typical apple-green birefringence under polarized light. Special stains for iron, PAS/diastase, trichrome, elastic, and copper stain were negative. These globular deposits showed features consistent with globular amyloidosis. The subtype of amyloidosis was confirmed by liquid chromatography with tandem mass spectrometry (LC MS/MS) as being of ALECT-2 type. Liver involved by ALECT-2 type amyloidosis shows characteristic globular deposits in periportal/perivenular areas. In our case, there was a paucity of globules. Congo red stain was also only weakly positive. Pathologists should consider ALECT-2–associated amyloidosis when the characteristic pattern of globular amyloid deposition is seen on H&E. The false-positive rate of ALECT-2 immunostain is high; diagnosis is best made by LC-MS/MS to ensure specificity. Making the correct diagnosis of this rare entity is essential for the correct management of the patient.

Jiayun Fang, MD ([email protected]); Jiaqi Shi, MD. Department of Pathology, University of Michigan, Ann Arbor.

Granular cell tumor (GCT) is a predominantly benign neoplasm that may occur anywhere in the body, including the gastrointestinal tract. However, only a handful of cases have been reported in the pancreas. We present a case of a 39-year-old woman with a history of recurrent pancreatitis and abdominal pain for 1 year. Computed tomography scan revealed a heterogeneous mass in the pancreatic tail, measuring 32 × 26 mm, and endoscopic retrograde cholangiopancreatography identified a stricture. Fine-needle aspiration showed atypical cells. These findings were clinically suggestive of intraductal papillary mucinous neoplasm versus adenocarcinoma, leading to a recommendation for distal pancreatectomy, splenectomy, and wedge gastric resection. Grossly, no distinct masses were identified within the pancreas, but the pancreatic duct was dilated to a diameter of 0.8 cm. Microscopically, a 0.4-cm neoplasm surrounding a pancreatic duct branch composed of plump cells with abundant amphophilic, granular cytoplasm, and small nuclei was identified. These findings were consistent with GCT (Figure 16, A and B). Background pancreatitis was present (Figure 16, C). Fewer than 10 intrapancreatic granular cell tumors have been reported in the literature. In more than half of the previously reported cases, adenocarcinoma was the primary clinical impression, leading to surgical management, with a third undergoing a Whipple procedure. Most GCTs are benign and do not require radical surgery for removal. Owing to the rarity of pancreatic GCT, recognition of this benign neoplasm via imaging and fine-needle aspiration remains challenging, but critical for appropriate patient management.

Regina Kwon, MD, MPH¹ ([email protected]); Jialing Huang, MD, PhD¹; Kiyoko Oshima, MD, PhD¹; Lysandra Voltaggio, MD¹; Ying Wang, MD, PhD²; Elizabeth Montgomery, MD¹; Danielle Hutchings, MD.¹ Departments of ¹Pathology and ²Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Microvillus inclusion disease is a rare autosomal recessive disease presenting as intractable secretory diarrhea in infancy. Patients require total parenteral nutrition and the only curative treatment is small-bowel transplant. Most cases have been associated with alterations in the MYO5B gene, located on chromosome 18 (18q21.1). MYO5B encodes myosin Vb, a motor protein involved in intracellular transport and epithelial cell surface polarity. We report the findings in a 5-day-old female infant, born at full term, who presented with metabolic acidosis, respiratory distress, and persistent watery stools. The prenatal course was unremarkable other than dilated bowel loops on ultrasonography. No history of consanguinity was reported by the parents. Upon admission, treatment with parenteral nutrition was initiated with some clinical improvement. Endoscopy revealed edematous, friable duodenal mucosa with nodularity of the bulb. Biopsies showed partial duodenal villous atrophy. There was no increase in inflammation or apoptosis. Goblet cells, Paneth cells, and plasma cells were normal in number and distribution. CD10 immunostain and periodic acid–Schiff/Alcian blue stain highlighted patchy loss of the normal brush border and CD10⁺ intracytoplasmic inclusions in surface enterocytes. A duodenal specimen submitted for electron microscopy was suboptimal for evaluation but did show nonspecific villus injury. Whole exome sequencing (trio) identified 2 likely pathogenic variants (in trans)in MYO5B: loss of a splice acceptor site (c.3277-2A>G) and deletion of exons 24–27. STX3 and STXBP2 genes were intact. To our knowledge, both MYO5B alterations represent novel pathogenic variants leading to microvillus inclusion disease.

Joshua T. Nguyen, BS ([email protected]); Katsiaryna Laziuk, MD; Deepthi Rao, MD. Department of Pathology, University of Missouri, Columbia.

Phrygian cap is a benign congenital abnormality of the gallbladder with a 4% incidence rate. The abnormality occurs when the fundus involutes into the body of the gallbladder. This anatomic variant is usually of no clinical importance other than to not mistake it for any significant pathology. The Phrygian cap is most commonly identified on ultrasonography, CT, cholescintigraphy, or MRI and can be mistaken for false thickening. The reported cases of Phrygian cap gallbladders are usually diagnosed incidentally on radiologic imaging. Past reported cases very rarely provide histologic characteristics of the entity. The patient is a 25-year-woman who presented to the hospital for right upper quadrant pain. Subsequent CT scan identified thickening of the gallbladder and on ultrasonography showed cholelithiasis and early cholecystitis. Owing to her symptoms and imaging, she underwent a laparoscopic cholecystectomy. Grossly, the gallbladder was filled with yellow-green gallstones and was found to have a 2-cm, in greatest dimension, Phrygian cap. Histologically, the gallbladder was found to have chronic cholecystitis. The section of the Phrygian cap showed a mucosal fold with a disorganized muscle layer lined by benign gallbladder epithelium. These findings are most consistent with the diagnosis of a Phrygian cap. Although Phrygian caps of the gallbladder are usually clinically insignificant, this anatomic variant should be in the differential diagnosis when evaluating masses in the gallbladder or liver.

Mohamed A. Yakoub, MD, PhD¹ ([email protected]); Steven Gilday, MD, PhD¹; Angel Munoz, MD.^{2 1}Department of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio; ²Department of Pathology, Cincinnati VA Medical Center, Cincinnati, Ohio.

Lifting agents are used intraoperatively to facilitate the endoscopic resection of intramucosal and/or submucosal neoplasms. ORISE gel, which is approved by the US Food and Drug Administration (FDA), with its density can maintain submucosal lifting for longer durations than normal saline. Histopathologic findings following lifting agents' submucosal injection have not been heavily investigated in the literature given its recent development. We report a case of a 55-year-old man who was referred to University of Cincinnati Medical Center after colonoscopy finding of semipedunculated polyp in the sigmoid colon, which was endoscopically resected. ORISE gel was injected to achieve complete polyp resection. Histopathologic findings of the polyp showed invasive moderately differentiated adenocarcinoma invading the submucosa without involving the resection margin (Figure 17, A). Five weeks later, the patient underwent sigmoid colon resection for assessment of potential nodal disease given the sessile nature of the polyp and the relatively limited margin on the polypectomy resection. Gross examination of the polypectomy resection site revealed a 2.2×1.4-cm yellow, firm, sessile polypoid-like lesion with flattening of the mucosal folds, extending into the submucosa through the muscularis propria. Histopathologic findings showed abundant amorphous hyaline-like material with robust foreign-body–type giant cell reaction, extending into the submucosa and muscularis propria (Figure 17, B). Ancillary studies showed nonreactivity to mucicarmine or Congo red stains (Figure 17, C and D). Endoscopic and gross findings of lifting agent granuloma can be mistakenly diagnosed as recurrent carcinoma. Clinical history together with microscopic examination and ancillary special stains can help make the diagnosis.

Juwairiya Arshi, MD ([email protected]); Joshua Nguyen, DO; Feng Yin, MD, PhD. Department of Pathology and Anatomical Sciences, University of Missouri at Columbia.

Russell bodies are eosinophilic globular intracytoplasmic accumulations of nondegradable immunoglobulins in plasma cells. The first case of Russell body gastritis was reported in 1998, and since then about 39 cases have been reported, of which only 2 involved the esophagus. Gastric antrum is the most commonly reported location, and pathologic conditions associated with Russell body include autoimmune conditions, monoclonal gammopathy of undetermined significance, multiple myeloma, and signet ring cell carcinoma. We report the case of a 41-year-old man with history of gastroesophageal reflux disease. The patient received treatment for Candida esophagitis a month earlier. Esophagogastroduodenoscopy showed a patch of salmon-colored esophageal mucosa from 35 to 38 cm, as well as mild erythema in the gastric body and antrum. Biopsy from distal esophagus showed cardiac-type columnar mucosa with intestinal metaplasia, consistent with Barrett esophagitis. There was diffuse infiltration of plasma cells filled with Russell bodies within the lamina propria. Gastric cardia biopsy showed gastric antral mucosa with mild chronic inactive gastritis and diffuse infiltration of plasma cells with Russell bodies. No evidence of intestinal metaplasia was identified in gastric biopsy. On both biopsies, the Russell bodies within the plasma cells demonstrated immunopositivity for CD138 and were negative for cytokeratin AE1/AE3 stain. Periodic acid–Schiff stain highlighted Russell bodies containing plasma cells within the lamina propria (Figure 18, A through D). There was no evidence of Helicobacter pylori organisms on immunohistochemical stain. In summary, we present the first case of Russell body Barrett esophagitis in conjunction with Russell body gastritis.

Kavitha Juvvala, MD¹ ([email protected]); Jagmohan Sidhu, MD.² Departments of ¹Internal Medicine and ²Pathology, UHS Hospitals, Johnson City, New York.

Mantle cell lymphoma (MCL) is a rare subgroup of non-Hodgkin lymphomas that shows an aggressive disease course with frequent involvement of regional lymph nodes and/or other organs. MCL can have small cell, blastoid, marginal zonelike, and pleomorphic morphology, and usually has CD5⁺/CD10⁻/CD19⁺/CD20⁺/CD22⁺/CD23⁻/CD43⁺/CD79a⁺/cyclin D1⁺/SOX11⁺immunophenotype. Most cases have t(11;14)(q13;32). Blastoid variant of MCL (BVMCL) is composed of lymphoid cells with variable size and shape, frequent mitotic figures, oval to irregular nuclear contours, pale cytoplasm, and prominent nucleoli. Primary isolated gastric MCL and secondary gastric MCL are extremely rare. We are reporting a case of gastric presentation of secondary BVMCL. An 85-year-old woman presented after a fall without gastrointestinal symptoms. Laboratory findings showed marked normocytic normochromic anemia. CT scan of thorax/abdomen/pelvis showed multiple enlarged upper abdomen, mesenteric, and retroperitoneal lymph nodes. Upper GI endoscopy showed nonbleeding erosive gastropathy. A gastric biopsy showed a lamina proprial, diffuse, architecture-destructive, large nucleolated, and mitotically active lymphoid cell infiltration. These cells had CD20⁺/CD5⁺/CD10⁻/CD23⁻/BCL2⁺/BCL1⁺/SOX1/Ki-67⁺(almost 100%) immunophenotype. A diagnosis of BVMCL was made. She expired before the treatment started. MCL presentation as primary or secondary gastric neoplasm is an extremely rare clinical situation. Our case is the first case of gastric presentation of secondary BVMCL. Chemotherapy, radiation therapy, or targeted therapy may be used, but our patient expired soon after the diagnosis and, therefore, no treatment could be instituted. The short survival of our patient was not a surprise because of the dire prognosis of MCL.

Harsimar Kaur, MBBS ([email protected]); Kevan Salimian, MD, PhD. Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell responses. Mutations inthisimmune checkpointprotein have recently been reported in patients with common variable immunodeficiency (CVID) and autoimmunity. We report a case of a 14-year-old male with CVID, recurrent sinusitis and pneumonia, chronic diarrhea, and severe malabsorption syndrome previously diagnosed as Crohn disease. Next-generation sequencing revealed a CTLA4 heterozygous variant of unknown significance, c.436G>A; p.G146R. Concurrent Sanger sequencing showed that both parents were negative for this change, suggesting the mutation arose de novo in the patient. Gastrointestinal biopsies showed an absence of Paneth cells and patchy goblet cell loss in the small bowel, parietal cell loss in the stomach, and prominent intraepithelial apoptoses and intraepithelial lymphocytosis throughout the gastrointestinal tract. Plasma cells were identified; however, only about two-thirds of patients with CVID lack plasma cells. The patient was diagnosed with autoimmune gastropathy and enterocolopathy secondary to immune dysregulation syndrome associated with de novo CTLA4 mutation, and treatment with abatacept (a CTLA-4 immunoglobulin fusion protein) was initiated, resulting in successful resolution of the patient's sinusitis and diarrhea with improved weight gain. Thus, while autoimmune enteropathy can mimic IBD, the recognition of this condition is important, since new treatment options such as abatacept and bone marrow transplant can be offered in refractory conditions.

Bebu Ram, MBBS¹ ([email protected]); Justin Snow, MD²; Yan Shi, MD²; Jonathan Melamed, MD²; Allen Leung, MD.^{2 1}Department of Pathology, NYUniversity Winthrop Hospital, Mineola, New York; ²Department of Pathology, Bellevue Hospital Center, New York, New York.

Inflammatory myofibroblastic tumor (IMT) is a rare spindle cell neoplasm with a relatively indolent course. The cytologic diagnosis of IMT is challenging owing to rarity and morphologic overlap with other mesenchymal neoplasms and only a few reports in the cytology literature. We present a case of ALK-negative IMT sampled by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). A 44-year-old man with history of HIV was found to have a 17-cm intra-abdominal mass in the perigastric region adherent to the stomach and liver. EUS-FNA of the mass showed a hypercellular specimen consisting of multiple spindle cell fragments intermixed with inflammatory cells. Some neoplastic cells had markedly enlarged and vesicular nuclei with prominent nucleoli. No mitosis or necrosis was identified. Given the location and cytomorphologic findings, spindle cell neoplasm was diagnosed with a differential diagnosis that included IMT and GIST. However, immunohistochemical studies revealed that the neoplastic cells were negative for ALK-1, CD117, and DOG-1 but focally positive for smooth muscle actin. Histologic examination of the subsequent surgically resected mass showed that the tumor consisted of loosely arranged spindle cells with occasional ganglion-like nuclei in a fibroinflammatory background. Despite negativity for ALK-1, the morphology and immunohistochemistry findings were consistent with IMT. This case highlights the diagnostic challenge of IMT in cytology in the absence of ALK expression. Literature shows 50% of IMTs express ALK and/or demonstrate ALK gene rearrangements. When encountering a spindle cell lesion with prominent inflammatory component, a high index of suspicion along with use of ancillary studies can be helpful in making the diagnosis of IMT (Figure 19).

Anusha Vemuri, BS ([email protected]); Lawrence C. Kenyon, MD, PhD; Manju Ambelil, MD. Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania.

Solid pseudopapillary neoplasm (SPN) of the pancreas, representing approximately 3% of pancreatic tumors, typically occurs in young women. Although SPNs are considered tumors of low malignant potential, 10% to 15% of patients develop metastasis/recurrence. We present the case of a 30-year-old woman with recurrent and metastatic SPN for which she underwent debulking 15 years after primary resection. At 14 years of age, the patient had a distal pancreatectomy and splenectomy for blunt abdominal trauma following a cheerleading accident. Pathology showed a ruptured SPN with no significant atypia and a negative resection margin. The patient was followed up with serial imaging that showed peritoneal implants after 8 years. Subsequently, the implants have grown in size and multiple new lesions were noted in the pancreas surgical bed. An exploratory laparotomy with limited pancreatectomy and peritonectomy was performed. Histology demonstrated various proportions of solid and pseudopapillary areas with eosinophilic hyaline globules and myxoid changes. Tumor demonstrated nuclear expression of β-catenin and cytoplasmic immunoreactivity for CD10 (Figure 20). Multiple metastatic SPN foci ranging from 0.3 to 5.4 cm were identified in the omentum, falciform ligament, cul-de-sac, right paracolic gutter, and broad ligament. No lymph node metastases were identified. Immunohistochemical expression for mismatch-repair proteins was retained. A Pan-cancer 42-gene mutation panel revealed a CTNNB1 gene mutation. Tumor size, stage, muscular vessel invasion, partial resection, and the presence of an undifferentiated component are reported important predictors of disease-specific survival in SPN. Recurrence of this patient's SPN may have been the result of rupture and surgical intervention with local seeding of tumor cells.

Jane Lee, MD ([email protected]); Deyali Chatterjee, MD. Department of Pathology & Immunology, Washington University, St Louis, Missouri.

Context: Diffuse lymphoplasmacytic cholecystitis (LC) and follicular cholecystitis (FC) are histologic entities that have both been shown to be associated with distal biliary obstruction. This study explores factors to determine why some gallbladders develop FC while others develop LC in apparently similar clinical settings.

Design: The histology of 55 gallbladders associated with Whipple procedure (2018–2019) for malignant neoplasms involving the pancreatic head region were reviewed and classified as chronic cholecystitis (CC), LC, or FC, according to previously established histologic criteria. Relevant clinical information was obtained from the patient chart.

Results: The pertinent clinicopathologic information is detailed in the Table. When compared to LC cases, FC cases were associated with a higher mean age, larger mean tumor size, greater incidence of neoadjuvant therapy, longer time interval between diagnosis of cancer to resection, and a greater degree of distal biliary obstruction manifested by higher total bilirubin and alkaline phosphatase levels at the time of diagnosis. Gallbladders featuring only CC, expectedly, had significantly less distal biliary obstruction and had lower incidence of neoadjuvant therapy, as compared to LC/FC.

Conclusions: FC is much rarer in frequency than LC. Both are associated with distal biliary obstruction, even though a high percentage of both LC and FC cases were stented until resection after an interval, indicating that relief of obstruction did not revert the histologic manifestations. Our study also shows for the first time the clinicopathologic differences between FC and LC cases.

Abdullah Osme, MD ([email protected]); Rachael N. Nakfoor, MD; Min Cui, MD, PhD. Department of Pathology, University Hospitals Cleveland Medical Center/Case Western Reserve University School of Medicine, Cleveland, Ohio.

Context: Metastatic liver lesions usually form a radiographically detectable mass. Non–mass-forming metastatic liver lesion that initially presents with liver failure is uncommon.

Design: We present a case series of patients who underwent random liver biopsy for acute liver function abnormality. Clinical histories and radiographic, microscopic, and immunohistochemical findings were examined.

Results: Eight cases (3 men, 5 women; age range, 49–84 years) of metastatic carcinoma to the liver with no radiologically detectable masses were identified. Patients presented with new-onset elevated liver function enzymes and underwent liver biopsy to evaluate for the underlying condition. Six of 8 cases had a malignancy history: 3 lobular carcinoma of breast, 1 ductal carcinoma of breast, 1 urothelial carcinoma, and 1 small cell carcinoma of the prostate. For the 2 cases with no prior malignant history, metastatic urothelial carcinoma and hepatocellular carcinoma were diagnosed from morphology and immunohistochemistry studies. Microscopic evaluation revealed nests and sheets of infiltrating malignant cells involving sinusoidal spaces and portal tracts in the biopsy samples (Figure 21, A through D).

Conclusions: Radiologically undetectable liver metastases with diffuse hepatic sinusoidal infiltrations are uncommon. This case series emphasizes the importance of liver biopsy in workup of patients with liver function abnormality and no radiologically detectable lesion, including cases with no prior malignant history. Certain types of carcinoma such as breast carcinoma and urothelial carcinoma composed the majority of cases (6/8) in this study with this unusual metastatic pattern.

Ibrahim Abukhiran, MBBS ([email protected]); Andrew M. Bellizzi, MD; Anand Rajan, MBBS. Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City.

Context: Digital image analysis (DIA) programs have different customizable analysis parameters (CAPs) that can be modified by users. We sought to characterize the sensitivity of Ki-67 percentage to the available CAPs in Halo DIA software (Indica Labs, New Mexico).

Design: Twenty cases of gastrointestinal neuroendocrine tumor (GI-NET) were included. Whole Ki-67 IHC slides were digitally scanned at ×20 (0.24 lm/pixel). CAPs chosen to be tested were as follows: nuclear contrast threshold (NCT); minimum nuclear optical density (NOD); minimum nuclear size (Min-NS); maximum nuclear size (Max-NS); and nuclear segmentation aggressiveness (NSA). We changed each parameter independently from the rest by using the following values: −50%, −25%, default value, +25%, +50%. Five hot spot areas, 0.24 mm² each (equivalent to ×40 objective lens), were scored for Ki-67%.

Results: Except for NCT, all CAPs behaved uniformly. Ki-67% and H-Score were most sensitive to change in NCT (+), Min-NS (−), NSA (−), and NOD (−), in descending order. Changing the Max-NS had no effect on the Ki-67%-PI or the H-Score. Changing NCT yielded extreme Ki-67% values (from −30% to +1062%), with mixed effects on Ki-67% and H-score (Figure 22).

Conclusions: In Halo DIA software, changing the CAPs can lead to a significant change in the Ki-67% used for grading of NETs. Nuclear contrast threshold (positive correlation) and Min-NS (negative correlation) are the 2 parameters with the highest impact. Therefore, when using DIA programs for routine clinical practice, modifying the CAPs must be done with caution, as these changes can overestimate or underestimate the true (biologic) grade of NETs.

Maria Gonzalez, MD¹; Allison Kerper² ([email protected]). Departments of ¹Pathology and ²College of Medicine, University of Illinois at Chicago.

Context: Incidence and mortality of young-onset colorectal cancer (CRC), defined as onset at less than age 50 years, have increased in recent years. While racial/ethnic disparities in the incidence and outcomes of CRC have been widely studied, there have been few studies comparing specific pathologic parameters among these groups. This study identifies these disparities among young-onset CRC patients at our institution.

Design: Patients with CRC resected from January 2016 to February 2020 were divided into 4 groups: white/non-Hispanic or Latino (N-HL); black/N-HL; Asian/N-HL; and other/Hispanic or Latino. Tumor location, grade, stage, size, and mutations were compared.

Results: There were 26 patients with young-onset CRC. Most were black/N-HL (n = 10), with an equal number of white/N-HL and other/Hispanic or Latino (n = 7), and the fewest were Asian/N-HL (n = 2). The average age was youngest in the other/Hispanic or Latino group (37) and oldest in the Asian/N-HL group (46). Most cases were located in the rectum and were stage IV (Table). Of the 12 patients aged 40 years or younger, there was a female predominance (n = 9). Two of these tumors displayed microsatellite instability. Five had KRAS mutations, most commonly in black/N-HL and white/N-HL patients. Of the 14 patients aged 41 to 49 years, there was a male predominance (n = 10). All had microsatellite stable tumors. Four had KRAS mutations, most commonly in black/N-HL patients.

Conclusions: This study demonstrates differences in presentation and pathologic parameters of young-onset CRC patients among racial/ethnic groups. The number of young-onset tumors located in the rectum suggests a role for early screening for CRC via rectosigmoidoscopy in certain populations.

Dana Balitzer, MD¹ ([email protected]); Sarah Umetsu, MD, PhD.^{2 1}Department of Pathology, San Francisco Veterans Affairs, San Francisco, California; ²Department of Pathology, University of California San Francisco.

Context: Transarterial chemoembolization (TACE) is a widely used treatment for hepatocellular carcinoma (HCC) and may result in nontarget embolization of the cystic artery. The goal of our study is to evaluate the pathologic effects of preoperative HCC therapies on the gallbladder.

Design: Retrospective review identified representative cases of hepatectomy with cholecystecomy (n = 67) with a preoperative diagnosis of HCC. Clinical data, gross descriptions, and histologic analysis were performed and cases were categorized by preoperative therapy for HCC including no preoperative therapy (n = 15), radiofrequency ablation (n = 10), or TACE (n = 42).

Results: Demographic data were similar between the groups (average age, 62.4 years; 79% male patients). Cases treated with preoperative TACE therapy had thicker gallbladder walls than cases without any preoperative therapy (average, 0.2 cm versus 0.1 cm; P = .009). Mucosal hyperplasia (25%), deep and/or extensive Rokitanksy-Aschoff sinuses (22.4%), and transmural inflammation (26.9%) were seen regardless of preoperative therapy. Of the cases with preoperative TACE therapy, 9.5% had demonstrable foreign material in histologic sections of gallbladder wall, all of which were after treatment for right-sided HCC and associated with histologic features of mucosal hemorrhage and foreign-body giant cells. No dystrophic calcifications, dysplasia, or carcinoma was seen in any of the cases.

Conclusions: Histologic features suggestive of acalculous chronic cholecystitis are frequently seen in cirrhotic livers explanted for HCC regardless of preoperative therapy. Livers treated with TACE for HCC have significantly thicker gallbladder walls. Distinct histologic features after right-sided TACE, including mucosal hemorrhage, extracellular hemosiderin, and chemoembolic material, are seen in a minority of cases.

Shivani Sharma, DNB, DCP¹; Aditya Tayal, DNB¹ ([email protected]); Sarita Prasad, DNB¹; Mallika Dixit, DNB¹; Dipanjan Panda, MD²; Sambit Mohanty, MD, FRCpath.^{3 1}Department of Pathology and Laboratory Medicine, CORE Diagnostics, Gurugram, India; ²Department of Oncology, Indraprastha Apollo Hospital, Delhi, India; ³Department of Pathology and Laboratory Medicine, CORE Diagnostics, Gurugram, India; Advanced Medical Research Institute, Bhubaneswar, India.

Kaposi sarcoma (KS) remains one of the most common cancers in immunocompromised individuals and is associated with significant morbidity and mortality. Primary visceral KS in the absence of cutaneous lesions presenting with gastrointestinal symptoms has rarely been reported. We present a case of gastric KS in an immunocompromised young individual. Our patient, a 35-year-old Indian man, presented with upper abdominal pain and dyspepsia. He had a history of renal transplant and was receiving immunosuppressants. An upper gastrointestinal endoscopy revealed multiple hyperemic gastroduodenal mucosal nodules (Figure 23, A). The biopsy revealed histologically unremarkable gastric foveolar epithelium. The lamina propria was expanded and edematous with spindle to plump moderately atypical cells and small nucleoli in a few of them. Columns of red cells and some attempted vessels were observed. Mitotic figures were present (Figure 23, B). The lesional cells exhibited a CD34⁺/CD31⁺(Figure 23, C)/D2-40⁺(Figure 23, D) phenotype and were immunonegative for myogenic, epithelial, and markers of gastrointestinal stromal tumor (CD117 and DOG1). HHV-8 immunostaining was performed on the basis of clinical history, histomorphology, and endothelial phenotype of the lesional cells, which revealed a diffuse and strong nuclear immunoreactivity. A diagnosis of KS was rendered. PET-CT failed to demonstrate additional lesions and the systemic cutaneous survey was within normal limits. Although a rarity, primary gastrointestinal presentation of a KS should be considered in the differential diagnosis of dyspepsia, abdominal pain, and gastrointestinal hemorrhage, particularly in an immunocom-promised individual. Awareness and accurate diagnosis have significant therapeutic and prognostic implications. Furthermore, it prevents prolonged diagnostic dilemma.

Mehran Taherian, MD¹ ([email protected]); Joyce M. Paterson, MD¹; Amarpreet Bhalla, MD.^{2 1}Department of Pathology, University at Buffalo, New York; ²Department of Pathology, Albert Einstein/Montefiore Medical Center, Bronx, New York.

Context: Differentiation of steatosis and steatohepatitis can be challenging. p62 is an autophagy receptor involved in oligomerization and aggregation of ubiquitinated substrates and is a component of Mallory-Denk bodies. This study aims to evaluate expression of p62 in fatty liver disease for diagnostic and prognostic utilization.

Design: Biopsy specimens of fatty liver disease received between 2016–2019 were reviewed. The cases were categorized as unremarkable (group A, n = 5), steatosis (group B, n = 9), and steatohepatitis (group C, n = 15). The percentage of steatosis, balloon cells, presence of inflammation, Mallory-Denk bodies, NAS (Nonalcoholic Fatty Liver Disease Activity Score), and stage were noted. p62 immunostaining was performed, and a scoring scale was created.

Results: The p62 immunostaining score was 0 in group A, varied from 0 to 1 in group B, and 2 to 4 in group C. p62 immunostaining highlighted higher number of balloon cells in the hotspots, in comparison to H&E. The staining intensity was variable. The scoring is described in the Table. In general, cases with advanced fibrosis yielded higher number of balloon cells in the hotspots, and a higher score and intensity of immunostaining. There was a significant positive correlation of p62 scoring with stage (r = 0.833, P < .001). No significant correlation was present between percentage of steatosis and p62 score.

Conclusions: Identification of dark brown staining with aggregate formation (score 2–4) by p62 immunostain highlights “true balloon cells” in fatty liver disease. p62 expression may be used to distinguish steatohepatitis from steatosis. Advanced-stage steatohepatitis is associated with higher p62 score.

Eleanor Abreo, MD¹ ([email protected]); Lewis Hassell, MD¹; Dale Brannon, MD²; William M. Tierney, MD³; Laura Fischer, MD.⁴ Departments of ¹Pathology, ²Nuclear Medicine, ³Gastroenterology, and ⁴Surgery, University of Oklahoma Health Sciences Center, Oklahoma City.

A 59-year-old man with a history of Barrett esophagus and intramucosal adenocarcinoma status post endoscopic mucosal resection presented 3 months later for endoscopic surveillance (Figure 24, A). Recurrent high-grade dysplasia was found on biopsy with possible invasion into the muscularis propria as noted on endoscopic ultrasonography (Figure 24, B). PET/CT also demonstrated a PET-avid area in the distal esophagus but could not differentiate between inflammation or recurrent carcinoma. The patient underwent minimally invasive esophagectomy and the pathology specimen revealed a white, well-circumscribed mass underneath the esophageal epithelium, but no surface tumor was apparent. Microscopically, the mass was an extensive foreign body reaction involving submucosa, muscularis, and a regional lymph node (Figure 24, C and D). Multiple giant cells were seen engulfing a blocky, acellular, hyaline pink substance creating a mass effect involving submucosa, muscularis, and a regional lymph node. While Barrett with high- and low-grade dysplasia was present as well, there was no evidence of residual invasive or in situ adenocarcinoma. When an endoscopic mucosal resection is performed, the endoscopist creates a submucosal fluid cushion via lifting agent to separate the mucosa from the muscularis propria. This patient's prior endoscopic mucosal resection used ORISE Gel (Boston Scientific, Marlborough, Massachusetts) as a lifting agent. This agent can create a foreign body reaction on subsequent radiographic and histopathologic examination, potentially leading to overstaging and hence overtreatment.

Denise Gamble, DO ([email protected]); O. H. Iwenofu, MD; Martha Yearsley, MD; Wei Chen, MD, PhD. Department of Pathology, The Ohio State University Wexner Medical Center, Columbus.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition in which individuals are at increased risk for developing cutaneous leiomyomas, early-onset multiple uterine leiomyomas, and aggressive type 2 papillary renal cell cancer. This condition is caused by mutations in the fumarate hydratase gene (FH), which inactivates the enzyme and changes the functions of the tricarboxylic acid (TCA/Krebs) cycle. Hepatic adenoma is not classically associated with HLRCC. Here we report a case of hepatic adenoma with atypical cells that show loss of FH expression in a patient with HLRCC. A young female in her 20s with a history of genetic mutation of FH (HLRCC) had an enlarging liver mass that was biopsied. Liver core biopsies demonstrated a well-differentiated hepatocellular neoplasm consistent with inflammatory-type hepatic adenoma. Interestingly, the neoplasm contained scattered highly atypical epithelioid cells with irregular nuclei (Figure 25, A and B). On immunohistochemistry, these atypical cells were positive for vimentin (Figure 25, C), showed loss of expression of FH (Figure 25, D), and were negative for all other markers tested (cytokeratin AE1/3, CK7, E-cadherin, MOC31, HepPar-1, arginase, glutamine synthetase, β-catenin, smooth muscle actin, desmin, CD68, CD163, S100, Melan-A, Ki-67, CD61, serum amyloid A, ERG, and GFAP). To the best of our knowledge, this case represents the first report of FH-deficient atypical cells identified in a hepatic adenoma. Of note, cytologic atypia is well documented in FH-deficient leiomyomas of the uterus. Awareness of such cells is important in the setting of FH deficiency and not to mistake them as malignancy.

Caroline I. Mullins Underwood, MD ([email protected]); Avani A. Pendse, MD, PhD. Department of Pathology, Duke University Health System, Durham, North Carolina.

Pretransplant screening of donor livers uses frozen section evaluation of biopsy specimens to predominantly assess for steatosis, (infectious) hepatitis, and fibrosis. Thorough histologic examination using special stains is rarely available before transplant. With increasing demand, there is rising concern for unrecognized conditions that are not reliably identifiable via frozen section assessment alone. We present a case of undiagnosed α₁-antitrypsin deficiency (A1AT-d) resulting in donor liver cirrhosis along with literature review. A 17-year-old male underwent orthotropic liver transplant for autoimmune hepatitis-induced end-stage liver disease. The transplant was complicated by cirrhosis (Figure 26, A) portal hypertension, and thrombosis of the portal, superior mesenteric, and right popliteal veins. Subsequently, he received a multivisceral stomach, liver, small-bowel, and colon transplant. The first cirrhotic donor liver explant showed intracytoplasmic PAS-positive diastase-resistant globules in hepatocytes (Figure 26, B and C), suggestive of A1AT-d, and confirmed by positive A1AT immunohistochemistry (Figure 26, D). A1AT level, 2 weeks prior, was 63 mg/dL (normal: 90–200 mg/dL). Literature review revealed only 3 cases of donor livers with A1AT-d, all diagnosed after transplant and appropriately monitored with no complications. With this example, we aim to increase awareness of rare, yet significant diseases in donor livers that may adversely affect graft function and outcome. The frequency of missing a significant diagnosis such as A1AT-d at pretransplant assessment is likely to rise with increased use of extended criteria donors. More research is necessary to determine if the current screening guidelines are adequate.

Megan E. Dibbern, MD ([email protected]); Edward B. Stelow, MD; Anne M. Mills, MD. Department of Pathology, University of Virginia School of Medicine, Charlottesville.

Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare cause of chronic colonic ischemia that typically affects the rectosigmoid colon of older adult men. Patients often present with progressive abdominal pain and diarrhea refractory to medical treatment. There is commonly a disconnect between clinical findings, which are suggestive of inflammatory bowel disease, and pathologic findings, which support an ischemic etiology. Although surgical resection is curative, treatment is often delayed owing to misdiagnosis. Recognition of characteristic biopsy findings of arteriolized capillaries, subendothelial fibrin deposits, and perivascular hyalinization can facilitate earlier definitive treatment for patients. We report the case of a 34-year-old man who presented with 1 month of progressively worsening abdominal pain, diarrhea, and 30-pound weight loss. Imaging studies showed inflammatory changes of the rectosigmoid colon suggestive of colitis. Mucosal biopsies showed small vessels with thrombosis, thickened capillary walls, and prominent hyalinization (Figure 27, A); however, definitive diagnosis was not rendered until rectosigmoid colectomy. Microscopic examination revealed diffuse submucosal vascular changes, including clustered, dilated, or “arteriolized” capillaries; subendothelial hyaline deposits; and fibrin thrombi (Figure 27, B). Medium-sized to large mesenteric veins showed marked myointimal hyperplasia and compressed slitlike lumina, with sparing of the mesenteric arteries (Figure 27, C), highlighted by Verhoeff–van Gieson staining (Figure 27, D). These microscopic findings confirmed the diagnosis of IMHMV. The patient's symptoms resolved entirely after resection.

Nicole Duff, BS¹ ([email protected]); Ryan Buyting, MS¹; Tsetan Dolkar, MD.^{2 1}School of Medicine, Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada; ²Department of Pathology and Laboratory Medicine, Saint John Regional Hospital, Saint John, New Brunswick, Canada

A 33-year-old man with longstanding Crohn colitis, status post abdominal colectomy and end ileostomy at age 13 years, presented with anal stenosis and incontinence of mucus from the defunctioned rectal stump after being lost to follow-up 7 years prior. Digital rectal examination revealed a firm circumferential mass corresponding to the area of anal stenosis. A rectal MRI identified a rectal mass extending into the mesorectal fat. Initial biopsies showed rectal mucosa with high-grade dysplasia in a background of severe active chronic proctitis. The dysplastic glands were unevenly distributed and were accompanied by an inflammatory milieu similar to lamina propria. Repeated deeper biopsies showed low-grade glands within the thick muscle bundles, as well as calcified glands, and more bland small round glands within thick muscle bundle and fat without desmoplastic response. Although highly suggestive of malignancy, the patient was reluctant to proceed with an abdominoperineal resection without a definite malignant diagnosis. Expert external consultation was sought and diagnosis of low-grade tubuloglandular adenocarcinoma was rendered. It is an uncommon adenocarcinoma seen in the setting of IBD, characterized by well-differentiated tubular and circular glands lined by a single layer of cuboidal epithelium with absent to minimal stromal desmoplasia. The subsequent resection showed similar histology to the biopsies but also had areas with higher cytologic grade. This case serves as a reminder, especially to those practicing in a community setting, to keep this uncommon entity in the differential diagnoses when assessing for malignancy in IBD in small biopsy samples (Figure 28).

Withdrawn.

Ifeyinwa M. Asuzu, MD ([email protected]); Kingsley E. Ebare, MD; Jocelyn Villanueva, MD. Department of Pathology and Laboratory Medicine, Staten Island University Hospital, Staten Island, New York.

Primary gallbladder carcinomas are rare aggressive malignancies affecting elderly women with coexisting cholelithiasis most likely via the chronic inflammation/metaplasia/dysplasia/carcinoma pathway. Diagnosis in most cases is unsuspected, with early-stage lesions coming to light because of inflammatory symptoms related to coexistent cholelithiasis or cholecystitis. Radiologic findings in early-stage carcinomas are often subtle, mimicking those of acute or chronic cholecystitis. The tumor is often fundal and reported to arise in epithelium of adenomyomatous hyperplasia. We present a case of early-stage adenocarcinoma of the gallbladder in an elderly woman who had cholecystectomy due to chronic cholecystitis, cholelithiasis, and gallstone pancreatitis. Laboratory tests revealed raised serum total bilirubin, liver transaminases, and alkaline phosphatase levels. Computerized tomography showed adenomyomatosis of the gallbladder fundus, cholelithiasis, and pancreatitis. Gross examination of the gallbladder revealed an intact gallbladder containing black stones. There was a 1.5-cm firm nodule in the fundus that contained a unilocular cyst cavity filled with a friable tan-white mass. Microscopy demonstrated superficial adenocarcinoma (intestinal type) arising in an intracystic neoplasm, invasive to lamina propria (pT1a) with extensive background fundal adenomyomatous hyperplasia. The patient is currently monitored by interval radiologic examination and is alive and well 1 year after diagnosis. We advocate that gallbladders be thoroughly examined with the correct approach to margins to adequately assess any incidental carcinoma in the right clinical and demographic setting. We also call for increased surveillance for gallbladder carcinomas in elderly women with symptoms suggestive of acute and chronic cholecystitis especially if they have long-standing gallstones (Figure 30).

Lei Sun, MD ([email protected]); Juwairiya Arshi, MD; Feng Yin, MD. Department of Pathology, University of Missouri at Columbia.

Context: Hyperplastic polyp of the esophagus is an uncommon benign lesion and is characterized by hyperplasia of either squamous mucosa or foveolar columnar mucosa, or both. Its association with gastroesophageal reflux disease has been reported. However, there is limited evidence in the literature on its association with intestinal metaplasia.

Design: Three cases of esophageal hyperplastic polyp with intestinal metaplasia were reviewed at our institution. The clinical, endoscopic, and histopathologic findings were collected.

Results: In our case series, the mean age was 56.6 years. Two patients were male, and 1 patient was female. Endoscopically, all the cases presented with an esophageal nodular lesion. Histology from these biopsies showed hyperplastic, cystically dilated foveolar epithelium, inflamed lamina propria, and focal intestinal metaplasia. Patient 1 had a history of gastroesophageal reflux disease. Patient 2 had concurrent Barrett esophagus and an incidental finding of squamous papilloma near the polyp. Patient 3 had a history of esophagitis and presented with a 2.5-cm esophageal nodule on endoscopy, and the biopsy demonstrated mild epithelial atypia but indefinite for dysplasia.

Conclusions: In conclusion, we present 3 cases of esophageal hyperplastic polyp with focal intestinal metaplasia. All the cases had a prolonged history of esophagitis. Even though no definitive dysplasia was identified in our series, we propose a possible correlation of hyperplastic polyp with intestinal metaplasia. Further studies are needed to test whether hyperplastic polyp of the esophagus could undergo metaplasia-dysplasia sequence.

Wenchang Guo, MD ([email protected]); Whayoung Lee, MD; Di Lu, MD; Xiaodong Li, MD; Vishal Chandan, MD. Department of Anatomic Pathology, University of California - Irvine, Orange.

Context: GATA3 is a marker for carcinomas of mammary or urothelial origin and is routinely used in surgical pathology. Adeno-carcinoma of the gallbladder (GB) is often diagnosed at a late stage. The diagnosis of GB carcinoma is challenging and often requires a multidisciplinary approach. In one autopsy series, more than 90% of gallbladder carcinomas showed metastasis to organs such as liver, lung, and brain. GATA3 expression in GB adenocarcinomas has not been evaluated in detail. The aim of this study was to evaluate GATA3 expression in adenocarcinomas of the GB.

Design: Thirty-one surgically excised GB adenocarcinomas were retrospectively selected from 2000 to 2018. One full-thickness tumor section from each case was stained with GATA3. Moderate to strong intensity nuclear staining of GATA3 in 5% or more of the tumor was considered as positive.

Results: Five of 31 cases (16%) showed GATA3 positivity. Three cases showed patchy staining within the tumor (10%–30%, moderate intensity staining) and 2 cases showed diffuse staining (>50%, strong intensity). Of the 5 positive cases, 2 were well differentiated, 1 moderately differentiated, and 2 poorly differentiated; 3 showed lymph node metastasis at the time of diagnosis and 1 was directly invading into the liver.

Conclusions: GATA3 expression is seen in 16% of GB adenocarcinomas. GATA3 positivity within a tumor does not exclude a GB adenocarcinoma. Awareness of this finding is important when interpreting immunostain results on small biopsy samples from a malignant lesion of uncertain origin, mainly to avoid misdiagnosis as mammary or urothelial carcinoma.

Aljunaid Alhussain, MD ([email protected]); Vijay Kumar, MD; William Daley, MD. Department of Pathology, University of Mississippi Medical Center, Jackson.

Skin metastases from colorectal carcinoma are rare and usually appear within 2 years after resection of the primary tumor. They typically signify widespread disease with poor prognosis. Frequency of skin metastasis has been reported to be 2.3% to 6%. Interestingly, according to a 2008 Taiwanese study, the rate of cutaneous metastasis is 0.81%, suggesting a remarkable difference in frequencies between white and Taiwanese patient populations. We present a case of a 44-year-old white man with a perianal skin polyp 5 months after resection of a colonic adenocarcinoma. The polyp was excised and sent for pathology. Microscopic examination showed a polypoidal focus of adenocarcinoma (Figure 31, A and B) with unremarkable surrounding skin. Immunohistochemical studies were positive for CK20 and CDX2 (Figure 31, C and D), and negative for CK7, consistent with a colonic primary. Metastatic colonic carcinoma can assume a variety of morphologic appearances. It usually presents as violaceous to flesh-colored painless nodules, single or multiple. Histologic features, in general, resemble those of the primary tumor, but in some cases appear more anaplastic than the primary tumor. Skin metastases from colorectal adenocarcinoma often present simultaneously with metastases to the liver, peritoneum, and lung. The most frequent site of cutaneous metastasis is abdominal skin, often involving surgical incision scars. Uncommon reported sites of skin metastasis include scalp, face, nose, and genitalia. Wide local excision of the cutaneous metastatic lesion is the preferred treatment option in isolated lesions. Our patient is doing well 2 months after polyp resection with no evidence of other metastatic disease.

Weihua Song, MD, PhD ([email protected]); Gerard Morvillo, DO; Hueizhi Wu, MD, PhD. Department of Pathology, State Island University Hospital, Northwell Health, Staten Island, New York.

Granular cell tumor (GCT) is now recognized as a benign neoplasm, although rarely its malignant counterpart is seen. There is no universal agreement on the cell origin. However, it is now generally believed that it arises from Schwann cells. GCT can occur anywhere in the body, and the most common sites include tongue, skin, and subcutaneous tissue. Gastrointestinal tract involvement has been documented, and the usual sites include esophagus, stomach, and colon. Granular cell tumor in the cecum is rare. To our knowledge, only 17 cases of GCT in the cecum have been reported. Here, we present a case of GCT that occurred in the cecum of a 52-year-old woman. She had laparoscopic sigmoidectomy for adenocarcinoma of the sigmoid colon. Laparoscopic cecectomy was performed for the incidental finding of a cecal submucosal nodule. The GCT was removed by laparoscopic resection. Macroscopic examination showed a rubbery tan-white submucosal nodule, 2 cm in the largest dimension. Microscopic examination revealed strikingly extensive hyalinization and focal calcification of the stroma (Figure 32, A and B). Bland polygonal neoplastic cells with eosinophilic granular cytoplasm, small nuclei, and inconspicuous nucleoli were seen (Figure 32, C). The neoplastic cells were immunoreactive for S100 (Figure 32, D), CD68, inhibin-α, neuron-specific enolase, and vimentin. The tumor cells were negative for EMA, neurofilament protein, and desmin. Tumor cells were positive on periodic acid–Schiff diastase stain. The above findings are consistent with GCT. The extensive hyalinization and focal calcification of the stroma indicate a tumor with a long-standing process and associated reactive changes.

Ali Samani, Bsc¹; Jennifer McCall²; Amir Samani, MD² ([email protected]). ¹Department of Research, Amir Samani Medicine Professional Corporation, Toronto, Ontario, Canada; ²Department of Pathology, Humber River Hospital, Toronto, Ontario, Canada.

Schwann cell hamartoma of the colon has been well documented and studied; however, there is only 1 case report in the literature (Pathology. 2018;50[4]:480–482) for the Schwann cell hamartoma of gallbladder. Herein, we report the expression of SOX-10 and calretinin in 2 cases of Schwann cell hamartoma of gallbladder. Cholecystectomies were performed for a 61-year-old man and an 80-year-old woman with complaints of pain episodes. Gallbladders were submitted in toto for microscopic examination, showing chronic cholecystitis and cholelithiasis. The lamina propria in both cases showed clusters of unencapsulated spindle cells with low nuclear pleomorphism and no mitotic activity. The size of clusters varied between 0.01 mm and 2.2 mm. In contrast to nerve bundles in subserosa, there was no ganglion cells associated with the spindle cells in the lamina propria. The spindle cell clusters were seen in 10% to 20% of total tissue with no special pattern of distribution. Using immunohistochemistry, spindle cells were diffusely positive for S100, synaptophysin, and CD56, confirming neural origin. Immunostains for CD34 and FXIII-A were inconsistent. Further immunostains showed diffuse staining for SOX-10 (nuclear) and calretinin (mainly cytoplasmic), confirming the Schwann cell origin of the lesions and strongly arguing against diagnosis of neurofibroma (Figure 33, A through D).

Aljunaid Alhussain, MD ([email protected]); Charulochana Subramony, MD. Department of Pathology, University of Mississippi Medical Center, Jackson.

Mixed neuroendocrine-nonneuroendocrine tumors have been described in the gallbladder, but very rarely have been described in the liver. Here, we present a case of a 58-year-old woman who presented with abdominal pain and weight loss. Imaging studies showed a large hepatic mass involving segments 5 and 6 of the liver (Figure 34, A). Further studies showed no evidence of primary tumor outside the liver. Subsequently the tumor was surgically resected. Gross examination showed an ill-defined mass measuring 18 cm in greatest dimension with solid and cystic areas (Figure 34, B). Histologic sections revealed epithelial neoplasm consisting of uniform cells with neuroendocrine cytologic features. The cells formed small tubules and large glandular structures (Figure 34, C). Areas with more solid and nested configuration were also present. The gallbladder was not involved by the tumor. The tumor was positive for chromogranin, synaptophysin (Figure 34, D), CD56, CK7, mucicarmine, and albumin-ISH, and negative for CA 19-9, Hep-Par 1, arginase, CDX2, TTF-1, PAX-8, and trypsin. Electron microscopy showed neurosecretory granules along the luminal surface, which along with immunohistochemical profile, confirms the neuroendocrine lineage of the tumor. In addition, positivity for CK7, mucicarmine, and albumin-ISH suggests a primary hepatic glandular component. It is difficult to classify this tumor with currently available criteria. Further study is also needed to identify the optimal therapy for this tumor. The patient remained cancer-free at follow-up 6 months after surgery.

Jamie J. Shah, BA¹ ([email protected]); Nella Fernandez, MD.^{2 1}Department of Clinical Medicine, Kansas City University of Medicine and Biosciences, Kansas City, Missouri; ²Department of Pathology, Lee Memorial Health System, Fort Myers, Florida.

IgG4-related autoimmune pancreatitis (IRAP) is a unique entity that can mimic a pancreatic mass on clinical presentation. Typically, IRAP presents as diffuse enlargement of the pancreas on imaging studies. CA 19-9 is used as a tumor marker for pancreatic and biliary tract cancers, but levels can also be increased in inflammatory conditions and cholestasis. We report a case of IRAP misdiagnosed as suspected pancreatic adenocarcinoma. A 76-year-old man presented with a 3-week history of abdominal pain and diarrhea. Significant laboratory results showed elevated serum levels of lipase (598 IU/L), AST (200 IU/L), ALT (444 IU/L), total bilirubin (6.7 mg/dL), and alkaline phosphatase (229 IU/L). Magnetic resonance cholangiopancreatography showed a 2.6×2.4-cm pancreatic head mass. Subsequently, serum CA 19-9 was elevated to 134 U/mL. Owing to clinical concern for malignancy, a pancreaticoduodenectomy was performed. Histopathology on the surgical specimen was consistent with IRAP, showing multifocal lymphoplasmacytic infiltrate, periductal fibrosis, and obliterative phlebitis. Immunohistochemistry for CD138, IgG, and IgG4 demonstrated increased IgG4-positive plasma cells highlighting more than 60 per high-power field and an IgG4:IgG plasma cell ratio of 54%. Correct diagnosis of IRAP through biopsy and steroid therapy can significantly improve outcomes, obviate unnecessary surgical intervention, and reduce high relapse rates in the absence of steroid treatment. This case highlights potential diagnostic pitfalls associated with considering elevated levels of serum tumor markers in isolation during the evaluation of pancreatic malignancies. IRAP should be considered in the setting of cholestasis due to a pancreatic mass with the histologic findings discussed above.

Mark J. Zivney, MD ([email protected]); Christina Arnold, MD; Antonio Galvao Neto, MD. Department of Pathology, University of Colorado School of Medicine, Aurora.

We present an extremely rare case of a 41-year-old woman who was referred to our institution with biopsy-proven gastrointestinal stromal tumor (GIST) of the gastric body and 5 months of ineffective imatinib therapy. Slides were reviewed at our institution and additional molecular testing was performed. No mutations in KIT or PDGFRA genes were identified, which prompted discontinuation of imatinib and initiation of a new clinical trial drug, Xmab18087. After no clinical response to both treatments, she ultimately underwent extensive surgical resection. Unlike typical GISTs, this gastric GIST was multinodular with metastases to the lymph nodes, diaphragm, and liver. Tumor sections showed a distinctive plexiform architecture, immunopositivity for CD117 and DOG1, and more importantly and characteristically, loss of expression for succinate dehydrogenase (SDH), confirming the diagnosis of SDH-deficient GIST (Figure 35, A through D). GISTs more commonly have a male predominance, peak incidence at 60 to 65 years, KIT or PDGFRA mutations (80%–85%), and well-circumscribed borders; they lack lymphovascular invasion or metastases, and are usually responsive to imatinib. In contrast, SDH-deficient GISTs are extremely rare (comprising 5%–7.5% of all GISTs) and are characterized by female predominance, younger age of onset, and wild-type KIT and PDGFRA; they often have lymphovascular/lymph node invasion, metastases, and are unresponsiveness to imatinib. While these distinct clinical, gross, and histologic features are often misdiagnosed, they should prompt the GI pathologist and moreover the general surgical pathologist to consider the uncommon diagnosis of SDH-deficient GIST. Furthermore, pathologists should be aware of their unique biologic behavior and possible association with genetic syndromes (ie, Carney triad or Carney-Stratakis syndrome).

Alanna Wu, BS¹; Xiaolin Wu, MD² ([email protected]). ¹Department of Biology, Indiana University, Bloomington; ²Department of Pathology, IUHealth Ball Memorial Hospital, Muncie, Indiana.

The Epstein-Barr virus (EBV) is the first herpesvirus related to human malignancy. EBV-associated carcinoma is characterized by lymphoepithelioma morphology and EBV infection of tumor cells. Schistosomiasis is the second most common parasitic infection of humans. Rare cases of schistosomiasis-related cholangiocarcinoma have been reported. Here, we report the first case of EBV-associated intrahepatic cholangiocarcinoma in concomitant chronic schistosomiasis. The 69-year-old asymptotic female patient was from Susong, Anhui, China, an area previously endemic for Schistosoma japonicum infections. She was found to have a liver mass by ultrasonography during a routine physical examination; follow-up MRI and PET/CT scans confirmed a primary liver malignancy. Her liver enzymes were within normal limits. A partial hepatectomy with lymph node dissection was performed. The gross examination showed a 3-cm mass with satellite nodules. Microscopically, the neoplastic cells, arranged in nests and cords, had prominent nucleoli and abundant eosinophilic cytoplasm (Figure 36, A). The tumor was infiltrated by numerous lymphocytes and plasma cells. Of note, there were abundant calcified Schistosoma ova in the portal tracts and the carcinoma (Figure 36, B). Immunostains showed that the malignant cells were positive for CK7 and CK19 (Figure 36, D), and negative for P63, CK20, arginase-1, and Hepar1. In situ hybridization of EBV (EBER) showed diffuse positivity (Figure 36, C). Postsurgical recovery was uneventful; however, 9 months later, CT showed multiple liver masses. Six cycles of cisplatin and gemcitabine reduced the tumor size significantly. Unfortunately, the patient died 2 years later. This unique case highlights the role of infections in carcinogenesis.

M. Suzanne Bloomquist, MD ([email protected]); Vijayalakshmi Padmanabhan, MD; Shilpa Jain, MD. Department of Pathology, Baylor College of Medicine, Houston, Texas.

Programmed death 1 (PD-1) is an immune checkpoint and negative regulator of T-cell function. Pembrolizumab (KEYTRUDA) is an antibody to PD-1, now FDA approved in the treatment of many solid tumor types. Lower gastrointestinal symptoms are well-known side effects of these drugs; however, upper gastrointestinal tract involvement, including gastritis and associated histopathologic lesions, is still being newly described. We report a case of a 49-year-old woman with metastatic non–small cell lung cancer, and receiving pembrolizumab therapy for the past 24 months, who presented to the gastroenterologist with nausea and vomiting. On endoscopy, a gastric ulcer was noted along the lesser curvature and erythema seen in antrum and body. On histologic examination at 1 and 2 years after treatment initiation, biopsies showed severe pan-gastritis. The stomach body showed complete atrophy of parietal and chief cells with diffuse expansion of lamina propria by lymphoplasmacytic infiltrate, prominent eosinophils, and lymphoid follicles (Crohn-like reaction; Figure 37, C and D). The antrum showed similar inflammation with multifocal intestinal metaplasia (Figure 37, A and B). The surface epithelium showed intraepithelial neutrophils and patchy lymphocytes. Helicobacter pylori, herpes, and cytomegalovirus immunostains were negative. Synaptophysin was negative for enterochromaffin-like cell hyperplasia. Despite negative H pylori stool antigen, the patient received treatment for H pylori and continued taking pembrolizumab after the first biopsy. This case is presented to define the histologic features of isolated gastric injury associated with the chronic use of anti–PD-1 therapy, leading to diffuse atrophy. Recognition of histopathologic features of adverse effects is crucial for pathologists in order to guide clinician management.

Roula Katerji, MD ([email protected]); Diana Agostini-Vulaj, DO; Aaron R. Huber, DO. Department of Pathology, University of Rochester, New York.

Context: Gastric neuroendocrine tumors (GNETs) are uncommon gastric neoplasms that usually present in middle-aged adults as asymptomatic gastric polyps and account for less than 2% of all gastric malignancies. Multifocal GNETs are even less common, unless arising in the setting of atrophic/autoimmune gastritis. Guidelines have not been established for grading multifocal primary GNETs with respect to whether all or only 1 lesion should be stained with Ki-67. We evaluated the utility of staining multifocal GNETs with Ki-67.

Design: Retrospectively we searched for all cases of multifocal GNETs between January 2005 and January 2020. We identified 7 patients with multifocal GNETs for a combined total of 15 primary lesions. Clinicopathologic data were obtained. Ki-67 immunohistochemical staining was performed on all 15 primary lesions. The proliferation index was manually counted from 1 photographed hotspot per tumor.

Results: Five cases were WHO grade 1 with Ki-67 of less than 3% and 2 cases were WHO grade 2 with Ki-67 of >3% and <20%; only 1 case had 3 foci of tumor. All patients were female with a mean age of 56 years. The background stomach demonstrated atrophic/autoimmune gastritis in all. Patients presented either with anemia or as an incidental finding detected during sleeve gastrectomy. The number of tumor cells counted was between 175 and 1088, and the mean difference for Ki-67 between tumors of the same case was 0.5% (0.01%–0.9%), which did not change the grade of any case (Table).

Conclusions: In patients with multifocal GNETs, only staining 1 lesion—preferably the largest—with Ki-67 should serve to grade almost all cases accurately.

Sarah K. Daley, MD¹ ([email protected]); Neha Varshney, MD¹; Belinda Sun, MD, PhD¹; Joy Liau, MD²; Achyut K. Bhattacharyya, MD¹; Diego R. Martin, MD, PhD.² Departments of ¹Pathology and ²Medical Imaging, University of Arizona, Tucson.

Context: Pancreatic duct adenocarcinoma (PDAC) is usually lethal, increasing in incidence, and estimated to become the second leading cause of cancer-related mortality by 2030. Improved outcomes have been reported with the latest neoadjuvant chemotherapeutic (NCT) regimens, surgical procedures, and molecular genetics. Our study aims to identify characteristic histopathologic and radiologic features that correlate with NCT treatment effects.

Design: Twelve patients with PDAC and NCT, followed by surgical resection, were identified between 2013 and 2019. Patients were imaged by magnetic resonance imaging (MRI) prior, during, and after NCT. Histologic parameters from surgical specimens were documented by 2 pathologists and MRI tumor features noted by 2 radiologists. Treatment effects were scored with CAP standards.

Results: Two patients had near complete responses (score 1), 6 had partial responses (score 2), and 4 had no response (score 3). Following NCT, both vascularization and desmoplastic reaction presented with significant differences among PDACs with score 1, score 2, and score 3 therapy response. Average neovascularization/vascular proliferation index per high-power field was as follows: score 1 = 8.5, score 2 = 4.5, and score 3 = 0.88. All cases showed ranges of desmoplastic reaction with the most extensive reaction observed in PDAC with no response. Posttreatment gadolinium contrast-enhanced MRI showed increased arterial phase enhancement (representing tissue vascularity) greatest in score 1 (high responders) versus score 3 (nonresponders), measured as relative enhancement change.

Conclusions: The degree of neovascularization/innate-vascularization and desmoplastic reaction correlates to the NCT response of PDAC, and with contrast-enhanced MRI. Our results indicate that MRI tumor bed features may serve as a radiomic biomarker for histologic characteristics of tumor response.

Tom Z. Liang, MD¹ ([email protected]); Yuna Gong, MD.^{2 1}Department of Pathology, LAC + USC Medical Center, Los Angeles, California; ²Department of Pathology, Keck Medical Center of USC, Los Angeles, California.

Paneth cell–rich carcinoma arising from the gastroesophageal junction is a rare entity with only 1 reported case in the literature. We report a case of an 80-year-old woman with a history of acid reflux managed by proton-pump inhibitors who presented with dysphagia, epigastric pain, and fatigue. An esophagogastroduodenoscopy was performed and showed a 1.6-cm mass at the gastroesophageal junction. Endoscopic mucosal resection of the mass demonstrated a moderately differentiated adenocarcinoma arising in the background of intestinal metaplasia with extensive dysplasia showing both intestinal and pyloric differentiation (Figure 38, A through C). A subset of tumor cells had abundant cytoplasm with coarse eosinophilic granules, reminiscent of Paneth cells. Immunohistochemical and special stains demonstrated strongly positive cytoplasmic staining for lysozyme antibody (Figure 38, D) and periodic acid–Schiff with diastase digestion, and negative staining for synaptophysin in tumor cells, supporting Paneth cell differentiation. To date, this is only the second case of Paneth cell–rich carcinoma arising from the GEJ and the first reported case seen in association with intestinal metaplasia. In addition, while intestinal (conventional) type of dysplasia is a common sequela of long-standing Barrett esophagus, pyloric-type dysplasia has only been reported in a handful of case reports in this region. We herein report a novel case of Paneth cell–rich carcinoma of the GEJ with first reported association with both intestinal metaplasia and pyloric-type dysplasia.

Daniel L. Shen, MD ([email protected]); Wendy Liu, MD. Department of Pathology, Case Western Reserve University - University Hospitals Cleveland Medical Center, Cleveland, Ohio.

Metastatic small intestinal neuroendocrine tumors (SNETs) are rare neoplasms that present with frequent distant metastasis and poor prognosis. Despite their aggressive behavior, SNETs are rarely symptomatic and are frequently found on incidental examination. Lymphangiomas commonly present as a benign proliferation of lymphatic vessels involving the skin, head, or neck of children. However, lymphangiomas may rarely be found intra-abdominally in adults. The etiology of lymphangiomas in the adult population is poorly understood. To our knowledge, there have been no previous case reports of metastatic neuroendocrine tumors with concomitant finding of lymphangioma. We present a case study of a 65-year-old woman with incidentally discovered mesenteric lymphadenopathy and filling defect on computed tomography. Ultrasound-guided biopsy of affected lymph nodes confirmed carcinoma of unknown origin. After 6 cycles of chemotherapy regimen and persistent mesenteric lymphadenopathy, the involved segment of small bowel was resected. On gross examination of resection specimen, 2 distinct types of mucosal lesions were noted. Multiple firm lesions were revealed to be the sites involved by SNETs. The second lesion type was soft and raised and was diagnosed as lymphangiomas on light microscopy. The presence of a lymphatic-invasive neoplasm presents an interesting possibility for the pathogenesis of lymphangiomas in the adult population. Identification of noncongenital lymphangiomas may provide a hint to clinicians to search for possible causes of lymphatic obstruction, which, in rare cases like this, may represent an underlying malignancy (Figure 39).

Sarah K. Daley, MD ([email protected]); Neha Varshney, MD; Tiffany Morrison, MD; Belinda Sun, MD, PhD. Department of Pathology, University of Arizona, Tucson.

Adenomyomatous hyperplasia of the pancreas is a rare benign condition in the pancreas that presents most commonly as acute pancreatitis. Very rarely, it presents as obstructive jaundice showing a pancreatic mass on radiology, raising concerns for malignancy and often leading to aggressive treatments like a Whipple procedure, which has a high mortality and morbidity rate. Grossly, adenomyomatous hyperplasia appears as a nodular lesion and microscopically it shows smooth muscle and epithelial cells. We report a challenging case of an 80-year-old man with a past medical history of ulcerative colitis who presented with symptoms of obstructive jaundice with an elevated CA 19-9 level (461 U/mL). On imaging, a pancreatic head mass with thickened common bile duct was noted. Endoscopic retrograde cholangiopancreatography was attempted but was unsuccessful. Owing to the high concern for neoplasm, a pancreatoduodenectomy (Whipple procedure) was performed. Macroscopic examination showed an illdefined, pale, firm 3.2-cm lesion surrounding a markedly indurated ampulla that also appeared involved by the lesion. Histologic examination showed proliferating bile ducts with thick bundles of muscle confirmed with SMA and trichrome stains, leading to periductal fibrosis and cholangitis causing stricture of the bile duct and ampulla (Figure 40). No high-grade dysplasia or malignancy was identified. These findings are consistent with adenomyomatous hyperplasia of the distal common bile duct. Although adenomyomatous hyperplasia of the pancreas is rare, this case highlights the pitfalls for patients presenting with pancreatic masses. Pathologists, gastroenterologists, and surgeons must consider adenomyomatous hyperplasia as a benign mimicker of pancreatic neoplasms to avoid unnecessary surgical procedures.

Smitha Mruthyunjayappa, MD ([email protected]); Chirag Patel, MD; Goo Lee, MD, PhD; Leona Council, MD; Upender Manne, PhD; Sameer Al Diffalha, MD. Department of Pathology, University of Alabama, Birmingham.

Context: Mucinous cystic neoplasm of the liver (MCN) is a rare, benign hepatic tumor seen almost exclusively in women. The most recent World Health Organization classification of MCN in 2010 defined it as cyst-forming epithelial neoplasm associated with ovarian-type subepithelial stroma and usually demonstrating no connection with the bile ducts. Steroidogenic factor-1 (SF-1) regulates genes involved in the adrenal and gonadal development and in the biosynthesis of their hormones. The immunoreactivity of steroid-related factors in these subepithelial stromal cells in MCNs of liver has not been studied earlier. The aim of this study is to highlight the pathology, diagnosis, clinical course, and the use of SF-1 immunohistochemistry in patients with MCN of liver.

Design: Retrospective search between 2010 and 2019 at University of Alabama, Birmingham, yielded 5 cases.

Results: The clinicopathologic characteristics are mentioned in the Table. Histologically, all the cases showed a cyst lined by intestinal, pseudopyloric, or gastric foveolar-type epithelium that often forms papillae, surrounded by characteristic dense ovarian-type stroma. All the cases showed positivity for SF-1 IHC in the stroma.

Conclusions: MCN should be managed with complete surgical resection, as conservative techniques are associated with high recurrence rates. Nearly 20% of the patients undergo malignant transformation, hence periodical surveillance imaging is recommended in the postoperative period. SF-1 IHC can be used over ER, PR in challenging cases.

Vincent Francis P. Castillo, MD¹ ([email protected]); Daphne C. Ang, MD¹; Narciso S. Navarro Jr, MD²; Derick V. Cabahug, MD.² Departments of ¹Pathology and ²Surgery, St. Luke's Medical Center - Global City, Taguig City, Philippines.

Echinococcosis is caused by ingestion of a cestode of the genus Echinococcus. Humans are accidental intermediate hosts, where the parasite can form hydatid cyst in liver. The cyst may rupture into the peritoneum spontaneously or secondary to trauma or surgical procedure. Although this parasitic infection is considered to be a significant public health issue worldwide, it is relatively rare in the Philippines and may not be included as one of the considerations in patients presenting with hepatic and/or peritoneal cyst. We describe a case of a 49-year-old man who had a history of hepatic cyst 2 years before admission, s/p excision, and diagnosed as simple cysts. Recurrence was then noted 2 years after the surgery in the form of multiple cysts in the liver and peritoneum (Figure 41, A and B). Microscopic examination of the cyst wall revealed an outermost layer composed of fibrovascular tissue with lymphocytic infiltrates, a middle layer of acellular laminated membrane, and a thin, nucleated layer (Figure 41, C). Attached on the wall were few protoscolices with refractile hooklets and round suckers (Figure 41, D). The histologic features were diagnostic of echinococcal cyst. A review of previous slides showed few fragments of laminated membrane, which were suggestive of a hydatid cyst. This case report emphasizes the importance of inclusion of this parasitic disease in the differential diagnosis of hepatic cyst to avoid misdiagnosis and offer optimal therapeutic management.

Aditya Tayal, DNB¹ ([email protected]); Shivani Sharma, DNB, DCP¹; Lata Kini, MD¹; Rahul Katara, PhD¹; Atul Peters, DNB, FMAS, FIAGES, FASMBS, FALS²; Sambit Mohanty, MD, FRCpath.^{3 1}Department of Pathology and Laboratory Medicine, CORE Diagnostics, Gurugram, India; ²Department of Bariatric, Minimal Access, & General Surgery, Max Smart Super Specialty Hospital, Delhi, India; ³Department of Pathology and Laboratory Medicine, CORE Diagnostics, Gurugram, India; Advanced Medical Research Institute, Bhubaneswar, India.

Accurate diagnosis of gastrointestinal stromal tumor (GIST) is important, since imatinib mesylate significantly inhibits these tumors. The diagnosis of GIST is heavily reliant on KIT immunoreactivity. However, recently a subset of GISTs has been detected with PDGFRA mutation rather than KIT mutation. We report the case of a 56-year-old Indian woman who presented with abdominal pain. CT scan revealed a mass in the lesser curvature of the stomach. The mass had solid, cystic, and hemorrhagic areas. On morphology, the mass appeared well circumscribed with tumor cells arranged predominantly in sheets. The tumor cells were spindled to epithelioid with hyperchromatic nuclei, inconspicuous nucleoli, and moderate to scant cytoplasm. The mitotic count was 11/50 high-power-field. The tumor cells were negative for pancytokeratin, S100, CD117, CD45, HMB-45, CD34, and PAX8. INI1 was preserved in the tumor. There was strong and diffuse immunoreactivity for vimentin, SMA, desmin, and DOG1. A diagnosis of GIST was rendered. Molecular studies revealed the tumor was negative for all gain-of-function mutations for KIT, whereas deletion mutations of PDGFRA exon 18 (C2534-2543 and HDSN845-848) were detected. Although histopathology, CD117 (CKIT) immunohistochemistry, and gain-of-function mutation remain the gold standards for diagnosis of GIST, the index case highlighted the importance of DOG1 in the diagnostic immunopanel and complete mutational analysis for the prognostic and predictive workup of a GIST. Most importantly, PDGFRA-mutated GISTs that harbor sensitive mutations may benefit from imatinib therapy, however, remain undiagnosed as based on KIT negativity by immunohistochemistry and molecular study, when DOG1 immunostain is not included in the diagnostic workup.

Ali Afsari, MD¹ ([email protected]); Mallory Williams, MD²; Tammey J. Naab, MD.¹ Departments of ¹Pathology and ²Surgery, Howard University Hospital, Washington, District of Columbia.

Atrophic visceral myopathy is a pathologic diagnosis characterized by atrophy of the smooth muscle layers of the viscera with intact ganglia. Rarely it has been reported as a cause of acute large-bowel pseudo-obstruction. Small-bowel pseudo-obstruction has been reported in the context of scleroderma and mixed connective tissue disease in adults and in inherited muscular dystrophy or primary visceral myopathy in younger ages. A 50-year old woman with history of cesarean section and hysterectomy presented with abrupt onset of severe crampy abdominal pain. A CT scan of the abdomen and pelvis was performed that showed a closed loop bowel obstruction. She subsequently underwent a resection of 17 cm of small bowel and primary end-to-side anastomosis. The serosal surface appeared slightly dusky and the mucosal surface appeared normal. Segmental atrophy of muscularis externa (internal circular muscle and outer longitudinal muscle) with neural proliferation, submucosal edema, lymphangiectasia, focal mild serosal fibrosis, and focal submucosal hemorrhage were the histologic findings. Adhesions were not present. This case is an unusual presentation of pseudo-obstruction. Although the patient had multiple surgical procedures in the past, there is no evidence of ischemic enteritis seen in the specimen submitted to explain the small-bowel obstruction. To date, the patient has no evidence of scleroderma or mixed connective tissue disease. This case highlights the need to look carefully for any deviation from normal histology in order to explain symptoms of obstruction and also to bring attention to an unusual cause of pseudo-obstruction.

Sameer Chhetri Aryal, MD ([email protected]); Zhiqiang Wang, MD; Laura Favazza, DO. Department of Pathology and Laboratory Medicine, Henry Ford Hospital, Detroit, Michigan.

Malignant mimics of the diseased gallbladder are clinically complicated, and the role of pathology, especially frozen section diagnosis, is crucial for best patient care. Xanthogranulomatous cholecystitis is one such rare entity. We report our experience with a 78-year-old man weighing 303 pounds who was transferred to us because of aborted cholecystectomy due to “extremely firm and masslike” malignant appearance. On admission, results of laboratory workup were mildly abnormal and imaging features, including ultrasound and CT scan, suggested acute cholecystitis. Surgery was indicated for cholecystectomy with possible hepatic resection and portal lymphadenectomy. Received for frozen section were 2 fragments of thickened gallbladder wall, and 1 representative section was submitted for frozen section. An eventual nonmalignant frozen section diagnosis facilitated the completion of the surgical procedure. Three additional parts were received for permanent sections, which were composed of periportal adipose tissue and the rest of the gallbladder. Microscopically, the luminal surface exhibited an admixture of blood, cholesterol clefts, and mixed inflammation with foci of microabscess. The mucosa was largely depleted, and the wall was replaced with granulation tissue, proliferative myofibroblasts, and diffusely infiltrative pigment and lipid-laden macrophages. The macrophages extended to pericholecystic adipose tissue in a similar diffuse and infiltrative pattern, which was best highlighted with CD163 immunostains (Figure 42, A and B). In summation, the diffusely infiltrative foamy histiocytes, the hallmark feature in xanthogranulomatous cholecystitis, resemble signet ring cells and are diagnostically challenging at frozen section. Awareness of the entity and its clinical presentation is important. Our case is exemplary and contributes to the literature.

Jonathan Galassi, MD ([email protected]); Alia Nazarullah, MD. Department of Pathology, University of Texas Health Science Center, San Antonio.

Malignant gastrointestinal neuroectodermal tumor or clear cell sarcoma–like tumor of the gastrointestinal tract is a rare, aggressive neoplasm arising within the walls of the stomach, and small or large bowel. These tumors consistently show rearrangements involving the EWSR1 gene, express S100, and lack melanocytic markers. Misdiagnosis and/or delay in diagnosis is due to nonspecific morphologic and immunophenotypic features that overlap with other tumors. We report a case of a 27-year-old woman with a 3-month history of abdominal distension and weight loss. Computed tomography of the abdomen revealed ascites, retroperitoneal lymphadenopathy, omental nodularity, and a 19-cm intra-abdominal mass with evidence of metastatic disease to the liver. Histologically, the omental nodules consisted of spindled and epithelioid cells with scant eosinophilic cytoplasm, vesicular chromatin, and inconspicuous nucleoli, featuring pseudopapillary architecture and occasional pseudorosettes. Immunohistochemical studies showed diffuse expression of S100, SOX10, and CD56 (Figure 43, A through D), while lowand high-molecular-weight keratins, HMB-45, MART1, CD117, DOG1, CD99, FLI-1, synaptophysin, and chromogranin were negative. The differential diagnosis included melanoma, neuroendocrine tumor, gastrointestinal stromal tumor, synovial sarcoma, and malignant peripheral nerve sheath tumor. Recognizing this entity, and possible origin of the mass from the small-bowel wall, led to EWSR1 (22q12)rearrangement testing via fluorescence in situ hybridization. EWSR1 rearrangement was detected, with a fusion partner of ATF1 identified via next-generation sequencing, confirming the diagnosis. Cases of younger adults with intra-abdominal masses, tumoral S100 expression, lack of melanocytic markers, and variable neuroendocrine immunophenotype should trigger consideration of this rare entity, followed by EWSR1 mutation testing.

Areeba H. Rizvi, MD ([email protected]); Abdullah Thayyil, MD; Anas Mohamed, MD; Kim R. Geisinger, MD. Department of Pathology and Laboratory Medicine, East Carolina University/Vidant Medical Center, Greenville, North Carolina

Context: Hirschsprung disease (HD) is an intestinal motility disorder due to an embryonic failure of neural crest cells' migration. The diagnosis is based on the absence of ganglion cells in the Auerbach and Meissner plexuses in colorectal biopsies, usually without associated inflammatory infiltrate. Recognition entails prompt surgical correction with subsequent clinical improvement. A recent study presented 3 cases of “eosinophilic myenteric ganglionitis” clinically simulating HD, in which ganglion cells were present with concentrated eosinophilic infiltrates.

Design: Patients with clinical diagnosis of HD in a 36-month period were retrospectively identified. Those with histologic confirmation and improvement following corrective surgeries were excluded. Our final cohort included 18 patients with clinical presentations resembling HD but with ganglion cells identified on the initial or repeated colorectal biopsies.

Results: Among the 18 patients (ranging in age from 2 months to 15 years), ganglion cells were seen on the initial pathologic examination of 16 patients, including 1 with eosinophilic infiltrates; these patients failed to meet the diagnostic criteria of HD. The remaining 2 patients had no ganglion cells identified on the initial biopsies, but their symptoms persisted after surgical correction. Repeated biopsies revealed eosinophils infiltrating among the ganglion cells, and 1 of these was also found to have peripheral eosinophilia.

Conclusions: We demonstrate that eosinophilic ganglionitis, an apparent rare entity, can sometimes mimic HD. In such patients, remission may be achieved with dietary modification and conservative management, and surgical intervention may not be necessary. A larger-scale study to further explore the significance, management, and prognosis of pediatric intestinal eosinophilic ganglionitis is underway.

Caroline Bsirini, MD¹ ([email protected]); Sohaib Abu-Farsakh, MD²; Roula Katerji, MD¹; Mark Ettel, MD¹; Laura Bratton, MD³; Jennifer Findeis-Hosey, MD¹; Aaron Huber, DO¹;Diana Agostini-Vulaj, DO.¹¹Department of Pathology, University of Rochester, New York; ²Department of Pathology, Indiana University, Bloomington; ³Department of Pathology, Ochsner Health System, New Orleans, Louisiana.

Context: Carbonic anhydrase IX (CAIX) is a zinc-containing metalloenzyme that regulates tumor acid-base balance, allowing tumor survival in a hypoxic environment. This marker has been under investigation in different tumors owing to its possible prognostic and therapeutic implications. Studies on CAIX expression in pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CC) are limited. We aim to evaluate CAIX immunohistochemical expression and its prognosis in PDAC and CC.

Design: Slides from tissue microarrays containing 219 PDACs and 54 CCs were analyzed by using a monoclonal antibody against CAIX. Percentage and staining intensity of tumor cells were recorded. CAIX staining expression was interpreted as high if positive in ≥10% of tumor cells. Clinicopathologic features were evaluated. Statistical analyses were performed by using Fisher exact, log-rank, and t tests (P value <.05 considered statistically significant).

Results: High CAIX expression was present in 44 of 219 PDACs (20%) and 16 of 54 CCs (30%). Survival was significantly better in PDACs with high CAIX expression than those with low/no expression (P = .01). No significant clinicopathologic differences were otherwise seen in PDACs with high versus low/no CAIX expression. While there was no significant difference in survival for CCs with high CAIX expression (P = .49), CAIX-high cases demonstrated larger tumor size (P = .04) and lower N stage (P = .049).

Conclusions: Our study shows a prognostic implication of CAIX immunohistochemical expression in PDACs with better survival in high-expression tumors. While no statistically significant survival difference was identified in CC cases, higher CAIX expression was associated with larger tumor size and lower N stage.

Daniela M. Bertel-Rodriguez, MD; Berlly L. Diaz-Gomez, MD; Marcela Mejia-Arango, MD ([email protected]). Department of Pathology and Laboratories, Fundación Santa Fe de Bogotá, Colombia

Lymphoepithelioma-like carcinomas (LELCs) associated with Epstein-Barr virus (EBV) have been described in different locations; most are of nasopharyngeal or gastric origin. An intense stromal peritumoral and intratumoral lymphocytic infiltration, and positive in situ hybridization for EBV, are characteristic. Metastatic LELC of unknown primary is rarely described outside the head and neck region. We present the case of a 58-year-old man with an incidental finding of multiple adenomegalies adjacent to pancreas tail and splenic hilum, up to 36 mm in diameter (Figure 44, A), and associated discrete thickening of the gastric greater curvature. A distal pancreatectomy and splenectomy were performed. Histopathologic study showed lymph node metastatic involvement by a poorly differentiated carcinoma, composed of sheets of large, pleomorphic cells in a syncytial pattern, associated with a dense intratumoral lymphocytic infiltrate (Figure 44, B). Immunohisto-chemistry showed positivity for CDX2 (Figure 44, C) and CK20, and in situ hybridization for EBV detection (EBER-1) was positive in tumor cells (Figure 44, D). The findings were consistent with a metastatic LELC of probable gastric origin. After multiple gastric biopsies and a diagnostic mucosectomy, only some atypical cell nests in lamina propria of the corpus were observed. Gastric LELC presenting as an unknown primary is a rare event but must be considered in the differential diagnosis of carcinomas with a rich lymphocytic infiltrate. Preoperative diagnosis of gastric LELC is difficult; most cases are diagnosed pathologically after radical surgery. Gastric LELC has demonstrated a better survival, suggesting that extensive inflammatory infiltrate contributes to a low risk of tumor spread and better prognosis.

Donghwa Baek, MD ([email protected]); Mary R. Schwartz, MD; Alberto G. Ayala, MD; Jae Y. Ro, MD, PhD. Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas.

Micropapillary adenocarcinoma is a morphologically and clinically distinct subtype of colorectal adenocarcinoma. Although it is estimated to comprise 5% to 20% of colorectal adenocarcinomas, this subtype has not been described in association with colorectal mucinous adenocarcinoma. Mucinous micropapillary carcinoma has been described in breast, lung, and stomach (first case reported by our group). Breast and lung tumors have worse behavior than pure mucinous and nonmucinous adenocarcinomas, respectively, with higher risk of nodal metastasis. Our gastric case also had a nodal metastasis. A 46-year-old man with a family history of colon cancer was found to have a 6-cm hepatic flexure mass at screening colonoscopy. No metastases were identified on preoperative workup. A right hemicolectomy was performed. The tumor grossly invaded into subserosal fat. Microscopic examination showed a mucinous adenocarcinoma with a papillary growth pattern. Small groups of tumor clusters were detached from leading edges of papillae, floating in mucin pool, and showed a typical appearance of micropapillary carcinoma (ie, lack of fibrovascular cores, inverted nuclear polarity, and narrow cellular clusters). No lymphovascular or perineural invasion was identified. No metastatic carcinoma was identified in 26 lymph nodes. The tumor showed loss of MLH1 and PMS2 by immunohistochemistry and microsatellite instability with polymerase chain reaction. MLH1 promotor methylation was not detected. No local recurrence or distant metastasis has been found postoperatively for 6 months. To the best of our knowledge, this is the first reported case of mucinous micropapillary adenocarcinoma of the colon. The pathologic and clinical significance awaits more cases with long-term follow-up (Figure 45, A through D).

Katrina Krogh, MD¹ ([email protected]); Farres Obeidin, MD¹; Audrey Deeken-Draisey, MD²; Ryan Jones, MD, PhD³; Juehua Gao, MD¹; Guang-Yu Yang, MD, PhD.^{1 1}Department of Pathology, Northwestern Memorial Hospital Feinberg School of Medicine, Chicago, Illinois; ²Department of Pathology, Advocate Health Care, Decatur, Illinois; ³Department of Pathology, Tempus Labs, Chicago, Illinois.

Context: Superficial spreading squamous cell carcinoma (SS-SCC) of the esophagus is a distinct, little-studied subset of squamous cell carcinoma morphologically defined by diffuse, circumferential endoscopic abnormality, and histologically confirmed in situ/superficially invasive carcinoma. The molecular alterations in SS-SCC are not well known. Here, we used next-generation sequencing and immunohistochemistry to analyze the dominant genetic alterations in SS-SCC.

Design: We identified a unique single-institution cohort of 8 SS-SCC cases. Using a next-generation sequencing 22-gene panel, we analyzed genetic alterations in the following genes: FBXW7, KRAS, EGFR, BRAF, PIK3CA, AKT1, ERBB2, PTEN, NRAS, STK11, MAP2K1, ALK, DDR2, CTNNB1, MET, TP53, SMAD4, FGFR3, NOTCH1, ERBB4, and FGFR1/2. Tested mutations included known and likely pathologic mutations, based on dbSNP and COSMIC databases. Immunohistochemical analysis with p53 and Ki-67 was performed and correlated with mutation status.

Results: In our cohort, all SS-SCC cases endoscopically showed circumferential keratinization (Figure 46, A) and histopathologically demonstrated superficial invasion (Figure 46, B). Clinically, the patient age was 55 to 77 years (median, 66 years) and female to male ratio was 1.7:1. Sequencing revealed that 75% (6/8) of cases carried missense TP53 mutations and 12.5% (1/8) had FGFR3 mutations. Immunohistochemistry demonstrated aberrant nuclear accumulation of mutant p53 in all TP53-mutated cases (Figure 46, D), and these correlated highly with high Ki-67 (>40%) (Figure 46, C). High Ki-67 was also seen in the FGFR3-mutated case. Overall, high Ki-67 was seen in 87.5% (7/8) of cases.

Conclusions: Missense TP53 gene mutations are the early and dominant genetic alterations driving SS-SCC. p53 and Ki-67 coimmunostaining can be used as a surrogate for TP53 mutation. Mutant p53 may be a potential therapeutic target for this unique malignancy.

Phoenix D. Bell, MD, MS ([email protected]); Aaron R. Huber, DO. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.

Context: Intestinal perineurioma (IP) is almost invariably associated with serrated epithelium (SE). BRAF V600E mutations have been identified within the SE of IP. To our knowledge, there is only 1 case report describing a single IP that showed positive cytoplasmic staining in the SE and negative staining in the IP by BRAF immunohistochemistry. We sought to further evaluate the significance of BRAF V600E mutations in IP by using IHC in a larger cohort of patients.

Design: Sixty-nine IP cases were available for IHC evaluation. All cases were evaluated for the BRAF V600E mutation in the SE and IP by using the BRAF V600E antibody (clone VE1, Roche Ventana). Cytoplasmic staining was categorized as positive or negative in the IP component and weak, moderate, or strong in the SE component.

Results: The IP component was negative by BRAF V600E IHC in 97% (67/69) of cases. Two cases were equivocal. IP was associated with SE in 93% (64/69), of which 94% (60/64) were positive by BRAF IHC: 50% (30/60) weak cytoplasmic staining, 37% (22/60) moderate cytoplasmic staining, and 13% (8/60) strong cytoplasmic staining.

Conclusions: Our results show that the SE associated with IP is positive for BRAF V600E by IHC, while the IP component is negative. These findings are in concordance with prior studies showing the presence of BRAF V600E mutations in IP via molecular techniques. Further, our findings support the hypothesis that the SE is the neoplastic component of the polyp, while the IP component is reactive or part of a hybrid mixed epithelial and mesenchymal–type polyp.

Fareed Rajack, MD ([email protected]); Tammey J. Naab, MD. Department of Pathology, Howard University Hospital, Washington, District of Columbia.

Synovial sarcoma (SS) rarely occurs in the gastrointestinal tract, usually presenting in the extremities. We report a case of a 63-year-old woman with a 1-month history of early satiety, epigastric pain, and weight loss. CT revealed a 10-cm complex intra-abdominal cystic lesion (level of umbilicus). Past medical history was significant for a gastric SS diagnosed 13 years previously when she underwent distal gastrectomy, gastrojejunostomy, and right hemicolectomy owing to a 3.5-cm subserosal gastric mass composed of short spindle cells growing in solid sheets with absence of paranuclear vacuoles. Negative CD117 and CD34 ruled against gastrointestinal stromal tumor. AE1/3 was focally positive. SS, monophasic spindle cell type, was diagnosed after molecular studies revealed SYT-SSX1 fusion. Resection of the recurrent 10-cm tumor revealed a gelatinous, necrotic, partially cystic mass adherent to the transverse colon and ileocolic anastomosis but sparing distal stomach. The short spindle cell neoplasm showed prominent myxoid change and invaded muscular walls of ileum and colon. It was positive for BCL2 and AE1/3 and negative for CD34. FISH revealed split signal of SS18 (SYT, 11q11.2) in 74% of cells, confirming recurrent SS. Synovial sarcoma can recur years later, often with lung metastases. The largest series of 10 gastric SSs, including initial presentation of our case, reported 2 fatalities, one with large size (8 cm) and the other having a poorly differentiated component. Our case is unusual because of late intra-abdominal recurrence; it emphasizes importance of reviewing past medical history and recognizing classic histology of SS.

Oluwadamilare Ajayi, MBChB ([email protected]); Jiang Wang, MD, PhD. Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio.

Intrahepatic cholangiocarcinoma is a relatively uncommon primary malignancy of the liver. We present a case of thyroid-like intrahepatic cholangiocarcinoma, a recently described variant of cholangiocarcinoma with fewer than 5 cases previously reported in the English literature. A 46-year-old white woman presented with abdominal pain and jaundice. CT scan revealed a 6.5-cm enhancing mass within the left common hepatic duct. Left hepatectomy showed a tan-white ill-defined tumor. Microscopically, the tumor was composed of predominantly thyroid follicle–like architectures with focal trabecular patterns reminiscent of a thyroid follicular neoplasm (Figure 47, A). These follicular structures contained eosinophilic “colloid-like” secretion and small vacuoles and were lined by cuboidal cells with round, large crowded nuclei (Figure 47, B). The tumor cells were positive for CK7 (Figure 47, C), and negative for thyroid markers TTF-1, thyroglobulin, and PAX8 (Figure 47, D), colonic markers CK20 and CDX2, hepatocellular marker Arginase-1, breast marker GATA3, and neuroendocrine markers synaptophysin and chromogranin. The patient had no known history of thyroid carcinoma. Unlike the other reported cases in the literature, the background liver was cirrhotic at the time of diagnosis. Awareness of this histologic variant of intrahepatic cholangiocarcinoma in the absence of a primary thyroid is necessary to avoid the misdiagnosis of a metastatic thyroid follicular carcinoma.

Michelle Lin, MD¹ ([email protected]); Mary Schwartz, MD¹; Suzanne Crumley, MD¹; Sudha Kodali, MD²; Robert McFadden, MD²; Chukwuma Egwim, MD²; Victor Ankoma-Sey, MD²; David Victor, MD²; Mukul Divatia, MD.¹ Departments of ¹Pathology and Genomic Medicine and ²Internal Medicine, Houston Methodist Hospital, Houston, Texas.

Context: Congestive hepatopathy (CH) is frequently observed in liver biopsies of patients with congestive heart failure. In CH, the degree of fibrosis is often widely variable, rendering its interpretation challenging. In addition, studies of fibrosis in biopsies of CH are scant. Our objectives were to assess the heterogeneity of fibrosis in liver biopsies showing CH, as well as to study the association of fibrosis with clinical indicators of disease severity.

Design: We selected 56 liver biopsies showing CH from 54 patients with congestive heart failure. Fibrosis was assessed by using the following staging system: stage 0 (no fibrosis), stage 1 (centrizonal fibrosis), stage 2A (mild portal fibrosis), stage 2B (at least moderate portal fibrosis), stage 3 (bridging fibrosis), and stage 4 (cirrhosis). Heterogeneous fibrosis was defined as at least a 2-stage difference within the biopsy cores. Relevant clinical data were obtained from the electronic medical record. Statistical analysis was performed by using 1-way ANOVA or χ² testing.

Results: Twenty eight of 56 biopsies (50%) showed heterogeneous fibrosis. Thirty-nine biopsies (69.6%) showed at least focally advanced (stage 3 or 4) fibrosis; of those, 24 showed heterogeneous fibrosis with areas of advanced fibrosis. No association of fibrosis with right atrial pressure, hepatic venous pressure gradient, bilirubin, or albumin was observed.

Conclusions: Our results demonstrate a markedly increased prevalence of heterogeneous fibrosis in liver biopsies showing CH, and an especially high frequency of heterogeneous fibrosis in the setting of advanced fibrosis. We recommend thoroughly documenting the spectrum and severity of fibrosis in liver biopsies with CH for optimal clinical management.

Shivani Sharma, DNB, DCP¹; Lata Kini, MD¹; Aditya Tayal, DNB¹ ([email protected]); Rahul Katara, PhD¹; Mohit Kumar, PhD¹; Vivek Gupta, MS²; Sambit Mohanty, MD, FRCpath.^{3 1}Department of Pathology and Laboratory Medicine, CORE Diagnostics, Gurugram, India; ²Department of Surgery, Ravindra Hospital, Hisar, India; ³Department of Pathology and Laboratory Medicine, CORE Diagnostics, Gurugram, India; Advanced Medical Research Institute, Bhubaneswar, India.

The oncogenic drivers responsible for gastrointestinal stromal tumor (GIST) primarily include mutations involving KIT. Anaplastic lymphoma kinase (ALK) overexpression is observed in inflammatory myofibroblastic tumors (IMTs), which not infrequently comes as a morphologic differential of a GIST. GIST can be distinguished from IMTs by a CD117⁺/DOG⁺/ALK1⁻ immunoprofile. Recently, we came across a case of GIST with diffuse and strong immunoreactivity for ALK1 along with the classic immunohistochemical repertoire of a GIST. A 49-year-old Indian man presented with abdominal pain and mass of 1-year duration. Computed tomography revealed an ileal mass that measured 5 cm in maximum dimension. The mass was multilobulated with tan-yellow cut surfaces. Histomorphology showed a cellular and mildly pleomorphic spindle cell neoplasm with intersecting fascicular pattern of arrangement. Mitosis was 3/10 high-power-field. A provisional diagnosis of spindle cell neoplasm was rendered. The tumor had a CD117⁺/DOG1⁺/SMA⁺/CD34⁻/desmin⁻/S100⁻immunoprofile. ALK1 was diffusely and strongly positive within the tumor. The tumor had an exon 11 (V560D) mutation in the CKIT gene, whereas ALK break-apart FISH assay was negative. This is the second case reported of a GIST with ALK expression. The mechanism underlying ALK expression is still unknown, with ALK rearrangement being excluded in the index case. In addition, ALK may be a potential therapeutic target for patients with GIST, particularly when the tumor is inherently imatinib resistant or they develop resistance to imatinib during the course of therapy. Further studies are warranted to elucidate the mechanism and significance of ALK expression in these tumors.

Robert Propst, DO ([email protected]); Yan Chen Wongworawat, MD, PhD; Evelyn Choo, MD; Camilla Cobb, MD; Anwar Raza, MD. Department of Pathology, Loma Linda University Medical Center, Loma Linda, California.

We present the first known case of metastatic prostate adenocarcinoma presenting as acute appendicitis with a concurrent high-grade appendiceal mucinous neoplasm (HAMN), along with early presentation of a secondary primary malignancy 8 years after radiation therapy. A 70-year-old man presented with recurrent high-grade prostate adenocarcinoma with extraprostatic extension 4 years after initial radiation therapy. He subsequently received radical prostatectomy and salvage proton radiation. Two years later, he presented to the emergency department with right lower quadrant pain. A CT scan showed a perforated appendix and intra-abdominal abscess, for which he was treated with interval appendectomy. Histologic analysis revealed metastatic prostate adenocarcinoma of the appendiceal wall and mesoappendix, with associated perineural and lymphovascular invasion. Additionally, an incidental HAMN was also present with mucin extending to the muscularis mucosae. Four months later, he presented with persistent abdominal pain and rapid weight loss. Abdominal CT scan revealed a 6.1-cm rectal mass, and biopsy revealed a high-grade postradiation spindle cell sarcoma. The patient opted for palliative care. There have been no other reported cases of metastatic prostate adenocarcinoma presenting as acute appendicitis with a concomitant HAMN. Postradiation secondary primary malignancies are also commonly seen at least 10 years after radiation therapy, whereas our patient developed a postradiation secondary primary malignancy 8 years after his initial and subsequent proton radiation therapy. This case illustrates that epidemiology and a thorough clinical history should always be considered when evaluating older patients with clinical signs and symptoms of acute appendicitis, particularly patients with a history of malignancy.

Isma Perveze, MD ([email protected]); Alan Lu, BA; Deepthi Rao, MD; Feng Yin, MD. Department of Pathology, University of Missouri-Columbia.

Human papillomavirus (HPV) is the most common sexually transmitted agent in the United States. The oncogenic potential of HPV and its association with squamous cell carcinoma of the lower anogenital tract is well established. However, there is only 1 recent peer-reviewed case series of HPV-associated primary adenocarcinoma of the vagina, vulva, and anorectum with characteristic papillary or villoglandular architecture. We describe a case of a 78-year-old man who presented with a 1-month history of severe perianal pain and hematochezia. Rectal examination revealed an ulcerated mass at the anorectal junction, concerning for malignancy. The patient underwent anoscopic core biopsy of the lesion. The biopsy demonstrated fragments of malignant tumor with villoglandular architecture and focal prominent extracellular mucin. A diagnosis of moderately differentiated adenocarcinoma was made. Immunohistochemical studies showed that the tumor cells were positive for CK7, CK20, and CDX2. Notably, p16 was also strongly positive in tumor cells. Morphologically and immunohistochemically these findings were consistent with an HPV-related primary adenocarcinoma of the anorectum. The patient is currently undergoing neoadjuvant chemoradiotherapy. This case adds to the spectrum of HPV-associated cancers and serves as an important reminder to consider the possibility of HPV-related disease when a neoplastic lesion is encountered at the lower anogenital tract with typical morphology and immunoprofiles.

Miao Tian, MD, PhD ([email protected]); Karen Matsukuma, MD, PhD. Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento.

Context: Acute appendicitis is commonplace, and corresponding histologic findings (eg, full thickness acute inflammation, periappendicitis) are typical. On occasion, a different pattern of inflammation in which lymphocytes are the predominant inflammatory component both within the mucosa and subserosa is seen. Our initial observations suggested that this “lymphoid predominant” pattern corresponded with retrocecal location of the appendix.

Design: We evaluated a randomized set of 156 appendectomy specimens consisting of 52 retrocecal and 104 nonretrocecal appendices (classified from operative findings). Histologic sections of each appendectomy were scored for pattern of inflammation as follows: (1) mural extent of acute inflammation and (2) presence of prominent extramural lymphoid aggregates (“lymphoid predominant” group). Patient age, sex, and symptom duration were also tabulated.

Results: Nineteen percent (29/156) of cases were categorized as lymphoid predominant. No correlation was seen between the lymphoid-predominant pattern and retrocecal location (P = .88) or with symptom duration (P = .42). However, a strong correlation between the lymphoid-predominant pattern and early acute appendicitis (defined as neutrophilic inflammation extending no more than focally into the muscularis propria) was seen (P < .001).

Conclusions: We have identified a pattern of chronic inflammation in the appendix that correlates with histologic evidence of early acute appendicitis. Despite the central role of lymphocytes in the chronic inflammatory response, in the setting of clinical acute appendicitis, prominent extramural lymphoid aggregates are paradoxically associated with findings of early acute appendicitis.

Roula Katerji, MD ([email protected]); Jennifer J. Findeis-Hosey, MD; Aaron R. Huber, DO. Department of Pathology, University of Rochester, New York.

Esophageal mucosal injury from doxycycline is well known to occur; however, gastric mucosal doxycycline-induced injury (GMDII) is rare and potentially underrecognized. To our knowledge, there are only 14 cases in the English literature of GMDII. Herein, we present an additional 2 cases of GMDII in an attempt to increase awareness of this type of medication-induced injury among practicing pathologists. Case 1: A 93-year-old man with multiple medical problems presented with melena and an esophagogastroduodenoscopy was performed that demonstrated “gastropathy” within the gastric body. The patient was taking oral doxycycline after a recent second toe amputation. Case 2: An 83-year-old man with multiple medical problems was admitted for anemia and pneumonia. An esophagogastroduodenoscopy was performed that demonstrated an ulcer of the gastroesophageal junction extending into the proximal cardia of the stomach. The patient was receiving oral doxycycline for pneumonia. In both cases, the gastric mucosa demonstrated changes of reactive gastropathy, active inflammation, superficial mucosal necrosis, and a peculiar pattern of vascular injury with concentric fibrinoid-like material within the superficial capillaries (Figure 48). Iron stains (both cases) were negative and Von Kossa stain (case 1) was negative. GMDII is uncommon and may be easily overlooked if one is not aware of the characteristic histologic features that include superficial mucosal necrosis and vascular degenerative changes. Recognition of this unusual pattern of superficial vascular injury by the pathologist and correlation with the clinical history and endoscopic findings should lead to the correct diagnosis.

Evan Stern, DO ([email protected]); Kumarasen Cooper, MBChB, DPhil; Robin Collingwood, MD. Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare low-grade sarcoma that most commonly arises in the soft tissues of the lower extremity and is characterized by multiple EWSR1 translocations. SEFs have been rarely reported within extraskeletal sites. We present the case of a 66-year-old man with a right colon mass found on routine screening colonoscopy. Hematoxylin-eosin–stained sections of the mass showed cells with small to medium-sized bland nuclei and clear cytoplasm, which infiltrate in cords and nests (Figure 49, A through C) within a background of dense hyalinized fibrosis. The tumor cells show positivity for MUC4 (Figure 49, D) by immunohistochemistry, and an EWSR1 rearrangement was identified by fluorescence in situ hybridization. Based on the histologic morphology, immunophenotype, and molecular studies, a diagnosis of SEF was rendered. The SEF histologic pattern can often be confused for an epithelial or hematolymphoid malignancy when arising in an atypical site, as in this case. Further confounding this diagnosis, multiple cytokeratins can be expressed within the tumor cells and other stains commonly expressed in sarcomas (smooth muscle actin and desmin) are usually negative. Although rare, a diagnosis of SEF should be considered in gastrointestinal tumors that display this unique morphology and staining pattern.

Katrina Krogh, MD ([email protected]); Samuel Weinberg, MD, PhD; Jie Liao, MD; Guang-Yu Yang, MD, PhD. Department of Pathology, Northwestern Memorial Hospital Feinberg School of Medicine, Chicago, Illinois.

Context: We previously showed in a cohort of human immunodeficiency virus–positive (HIV⁺) patients that highly active antiretroviral therapy (HAART) could slow the progression of anal squamous dysplasia. Here, we determined whether immunity alterations in intraneoplastic immune cells (T cells, B cells, natural killer cells) in human papillomavirus (HPV)/HIV–coinfected patients play a critical role in dysplasia progression. Given the probable significance of immune cell regulation in the pathogenesis of HIV-related tumors, we performed multiple color-immunofluorescence (IF) analysis on anal biopsies in HIV-positive patients before and after HAART.

Design: Anal dysplasia biopsies from 20 HIV-positive patients were collected before and after HAART. Slides were graded from anal intraepithelial neoplasia-1 (AIN-1) to AIN-3. IF was performed for immune cell subsets (CD3, CD4, CD8, CD20, CD56) by using specific fluorescent probes. Hybridization signals were scored and analyzed for trends in tumor immune response.

Results: Median age pre HAART was 42 years (100% male). Average HIV duration was 11.1 years (0.5–27.9), viral load (VL) was 36,724 copies/mL (36–208,087), and CD4⁺was 234 cells/mm³ (8–601). Post HAART, average therapy duration was 2.4 years (0.2–8.4), VL was 78 copies/mL (0–819), and CD4⁺was 394 cells/mm³ (36–1015). Preliminary IF data show that the proportion of all immune cell probes, particularly CD8⁺/CD3⁺and CD56⁺/CD3⁻ cells, increased in dysplastic lesions after HAART. Further IF analysis will be performed to better characterize the cohort.

Conclusions: The local immune cell subsets in anal dysplasia biopsies are altered after HAART. Specifically, an increase in cytotoxic T cells (CD8⁺/CD3⁺) and natural killer cells (CD56⁺/CD3⁻) in HIV-positive patients appears critical to inhibiting dysplasia progression.

Weihua Song, MD, PhD¹ ([email protected]); Indraneil Mukherjee, MBBS, MD²; Joel Lanceta, MD¹; Kokila Mody, MD.¹ Departments of ¹Pathology and ²Minimal Invasive Surgery, State Island University Hospital, Northwell Health, Staten Island, New York.

Calcifying fibrous tumor (CFT), a rare benign neoplasm with a predilection for children and young adults, usually arises in the subcutaneous and deep soft tissues including pleura and peritoneum. CFT of the gastrointestinal tract is exceedingly rare. Therefore, it raises a diagnostic challenge and it is prone to be confused with other spindle cell lesions more commonly encountered in the small bowel. Here we present a case of CFT arising in the small intestine that caused intestinal intussusception. A 29-year-old woman presented to the emergency room with cramping lower abdominal pain, nausea, and vomiting. Abdominal computerized tomography showed a 2.3-cm nodule in the small bowel. Small-bowel segmental resection was performed for the nodular lesion and related intussusception. Macroscopically the lead point of the intussusception corresponded to an unencapsulated submucosal firm nodule. The nodule was ovoid and measured 2.3 × 1.8 × 1.5 cm, protruding into the luminal spaces, with a short stalk present (Figure 50, A). The cut surface was white with a whorled pattern. Microscopically, the lesion was composed of extensive hyalinized collagen arranged in a concentric whorled pattern. Bland fibroblasts, lymphoplasmacytic infiltration, mast cells, and dystrophic calcifications were seen (Figure 50, B through D). Because the involvement of gastrointestinal tract by CFT is extremely rare, it is likely to be confused with more common spindle cell lesions including leiomyoma and gastrointestinal stromal tumors (GISTs) among others. The distinction of such entity from others such as GIST imposes a different implication and can lead to different clinical management.

Abiye T. Kassa, MD¹ ([email protected]); Charles Howell, MD²; Tammey Naab, MD.¹ Departments of ¹Pathology and ²Internal Medicine, Howard University Hospital, Washington, District of Columbia.

The histopathologic diagnosis of well-differentiated hepatocellular carcinoma (HCC) can be challenging because of its close resemblance to benign conditions. Immunohistochemistry and reticulin stains are very helpful in such cases. A 68-year-old man with a BMI of 21.7 and a history of prostatic adenocarcinoma who was receiving leuprolide presented with yellowish discoloration of the skin for 2 months and right upper quadrant abdominal pain for 2 weeks. History was negative for alcohol use, liver disease, or diabetes mellitus. Complete metabolic panel, CEA, CA 19-9, and AFP levels were within normal results. Hepatic CT and ultrasound imaging showed a 4-cm solid subcapsular heterogeneous mass in the right lobe. Liver biopsy showed hepatocytes with abundant steatosis as well as arteries not paired with bile ducts, and atypical mitotic figures. Reticulin was partially lost. Glypican-3 and HepPar-1 were diffusely positive (Figure 51, A through D). This case highlights the need for careful histologic evaluation of benign-appearing liver biopsies that resemble steatosis or steatohepatitis. In such cases, the other differential diagnoses to consider include hepatic adenoma, focal nodular hyperplasia, steatohepatitic HCC, and lipid-rich conventional HCC. In our case, the overall findings were consistent with well-differentiated conventional HCC with abundant steatosis. Given the absence of conventional risk factors associated with nonalcoholic fatty liver disease and HCC, the abundant steatosis seen in this case could be related to the leuprolide therapy. Leuprolide has been associated with metabolic syndrome and nonalcoholic fatty liver disease. Hence, the leuprolide might have initiated the metabolic syndrome–steatosis–nonalcoholic steatohepatitis–HCC sequence in this case.

Neha Varshney, MD ([email protected]); Sarah K. Daley, MD. Department of Pathology, University of Arizona, Tucson.

Submucosal lifting agents are routinely used by gastroenterologists to expand the submucosal space, helping to lift gastrointestinal mucosal lesions from the muscular layer, aiding their resection for polyps. We describe an interesting case of a 73-year-old woman with history of adenomatous polyps who presented with an endoscopically unresectable ascending colon polyp. At colonoscopy, she was noted to have multiple polyps, including an unresectable sessile lesion located in the proximal ascending colon that encompassed one-fourth of the colon circumference. Resection of this lesion was attempted after raising it with ORISE, a lifting agent, but was unsuccessful. Subsequently, a right hemicolectomy was performed that showed a subtle, sessile 0.2-cm polypoid lesion. Upon histologic review, amorphous submucosal nodular deposits were identified with surrounding giant cell reaction that spared blood vessels (Figure 52). The specimen was negative for dysplasia or malignancy. Differential diagnosis in this case included amyloidosis; however, Congo red and elastin stains were negative. Gouty tophus was also suggested. Subsequently, it was learned that during colonoscopy, a submucosal lifting agent was used, and it was then concluded that the amorphous submucosal deposits were remnants of ORISE, a submucosal lifting gel. With endoscopic resection techniques becoming a more common procedure for managing premalignant and early-stage gastrointestinal cancers, submucosal lifting agents will be used more often. Pathologists, gastroenterologists, and surgeons need to be aware of the gross and histologic findings of submucosal lifting agents so that the correct diagnosis can be rendered to reduce unnecessary clinical procedures and subsequent tissue workup.

Azin Mashayekhi, MD¹ ([email protected]); Jon D. Wilson, MD²; Eric U. Yee, MD.^{1 1}Department of Pathology, University of Arkansas for Medical Sciences, Little Rock; ²Department of Pathology, Arkana Laboratories, Little Rock, Arkansas.

Context: Epithelial inclusions (EIs) in cholecystectomy specimens have been reported to occur at a surprisingly high rate and were initially believed to represent the opportunistic protozoan Cystoisospora belli. More recent studies based on formalin-fixed, paraffin-embedded tissues have shown that these EIs contain no molecular or ultrastructural evidence of this parasite. Our aim was to further characterize these EIs by transmission electron microscopy, using nonprocessed tissue to potentially enable better ultrastructural resolution.

Design: We identified 4 cholecystectomy specimens that had EIs on H&E examination and retrieved nonprocessed, discarded tissue from these cases. We subjected tissue to fixation in glutaraldehyde at 4°C after standard formalin fixation and performed transmission electron microscopy on all samples.

Results: Ultrastructural examination of all 4 specimens showed small, relatively well-circumscribed, perinuclear cytoplasmic aggregates composed of finely granular to fibrillar material that appeared similar to those described in recent studies. These aggregates lacked a capsule and any organized internal structures/organelles, thereby showing no ultrastructural evidence of C belli organisms or any other infectious microorganism (Figure 53).

Conclusions: Our study represents the largest cohort of EIs to date analyzed by electron microscopy and confirms that EIs do not represent C belli organisms. Although we could not provide further insight into the nature of these EIs, our method has not been previously attempted in this context and did enable better morphologic clarity of EIs on ultrastructural examination. Our findings may help future research into this phenomenon.

John Diks, MD ([email protected]); Yang Liu, MD; Kristina Loukeris, MD. Department of Pathology, SUNY Downstate Health Sciences University, Brooklyn, New York.

Malakoplakia is a rare chronic granulomatous inflammation characterized by accumulation of macrophages and usually involving the urinary tract. It may affect many organs including the lung, brain, skin, vagina, adrenal glands, pancreas, bone, and gastrointestinal tract. We present a case of a 63-year-old woman with past medical history of hypertension, appendix rupture, CVA with left-sided residual weakness, status post kidney transplant, and atrial fibrillation. The patient underwent colonoscopy for colorectal cancer screening (Figure 54, A). Biopsies of a cecal mass confirmed the diagnosis of adenocarcinoma. The patient had a right hemicolectomy and the specimen was received fresh and consisted of terminal ileum, cecum, ascending colon, and appendix. Upon opening, a tan-brown, fungating, solid mass was identified in the cecum, measuring 3.5 × 3 cm and occupying the whole cecum. Serial sections revealed that the mass abutted the ileocecal valve and appeared to grow into the appendiceal orifice and grossly invaded the pericolonic fat. Microscopic examination showed cecal adenocarcinoma adjacent to appendicular orifice malakoplakia with aggregates of granular histiocytes with Michaelis-Gutmann bodies (Figure 54, C), which was histochemically confirmed with periodic acid–Schiff and CD68 (Figure 54, D). One year prior, the patient had an appendiceal rupture and abscess. At the same time, the patient had a pelvic wash that revealed inflammatory cells with histiocytes and Michaelis-Gutmann bodies but was not identified as malakoplakia (Figure 54, B).

Lei Sun, MD ([email protected]); Joshua Nguyen, MD; Feng Yin, MD; Deepthi Rao, MD. Department of Pathology, University of Missouri at Columbia.

Context: Granular cell tumors (GCTs) in the gastrointestinal (GI) tract account for only 1% to 2% of all GCTs. Colonic GCTs are even rarer. This study aims to examine the clinicopathologic feature of colonic GCTs.

Design: A retrospective study of colonic GCTs was conducted at our institute and 6 cases were retrieved from the years 2007 to 2020. The clinical history, endoscopic findings, and histopathologic features were collected.

Results: The study group consisted of 4 women and 2 men with a mean age of 50.5 years (range, 38–61 years). Four patients were white, 1 was African American, and 1 was Hispanic. Endoscopically, these tumors commonly present with polypoid lesions with a mean size of 5 mm (ranging from 2 to 8 mm). Four patients had concurrent nonspecific GI symptoms and 2 were incidental findings on routine endoscopic screening. None of the patients had a history of colonic malignancy. The most common endoscopic finding was a single firm polypoid nodule, and the locations include ascending colon (2 cases), cecum (3 cases), and descending colon (1 case). The tumors were within the submucosa (50%) or lamina propria (50%). Immunohistochemically the tumor cells were positive for S100.

Conclusions: Colonic GCTs are rare tumors with similar features shared by GCTs in other locations. Most of the patients in our series were white. It is important to be aware of this rare mesenchymal soft tissue tumor with a polypoid presentation in the lower GI tract.

Juwairiya Arshi, MD ([email protected]); Deepthi Rao, MD. Department of Pathology and Anatomical Sciences, University of Missouri at Columbia.

Hepatoblastoma (HB) is a rare malignant neoplasm noted in the pediatric population. The term congenital hepatoblastoma (CHB) is used when HB is detected antenatally to 3 months of age. However, <10% of cases are diagnosed in the neonatal period. Based on a literature review, CHB is noted to be the least common neonatal hepatic lesion and is associated with poor prognosis. It is associated with Li Fraumeni syndrome, Beckwith-Wiedemann syndrome, familial colonic polyposis, or small-for-gestational-age babies. It is a challenging diagnosis and αfetoprotein is elevated in these patients. A large liver mass was noted in a newborn female and a right liver lobectomy was performed on the third day of life. The tumor was 10.5 cm in the greatest dimension and cut surfaces revealed lobulated, hemorrhagic, friable, and necrotic tumor. Microscopic sections revealed HB with predominantly epithelial fetal growth pattern composed of cords of uniform neoplastic hepatocytes with moderate amounts of eosinophilic cytoplasm, which was associated with prominent hematopoiesis. The tumor showed mesenchymal component with spindle cell morphology and areas of prominent osteoid production. Vascular invasion was present. There was complete remission following the surgery and chemotherapy. The patient was followed up with no recurrence until 8 years of age. In summary, malignant neoplasms are extremely rare in the neonatal population and often not considered during neonatal evaluation. Our case highlights the importance of considering malignancies on the list of differential diagnoses during neonatal evaluation. Further, our case represents mixed epithelial and mesenchymal type of CHB with complete remission.

Matthew Parke, DO ([email protected]); Felicia D. Allard, MD; Bobby Boyanton, MD; Eric U. Yee, MD. Department of Pathology, University of Arkansas for Medical Sciences, Little Rock.

Context: The Campylobacter-like organism (CLO) test, standard histology, and immunohistochemistry (IHC) are common methods used to detect Helicobacter pylori infection. Our objective was to compare the performance of CLO test to standard histology and IHC for the detection of H pylori in a pediatric population.

Design: We retrospectively searched one institution's database for patients diagnosed with H pylori gastritis detected by either CLO test, IHC, and/or visible H pylori organisms on routine H&E. We then calculated the performance characteristics of the CLO test as compared to IHC and H&E.

Results: Of 7466 gastric biopsies performed between 2015 and 2019, H pylori was detected in 108 cases (1.45%). In the same period, 4449 CLO tests were performed, and 74 cases were positive (1.66% of total CLO tests). Of the 108 H pylori cases, 87 (81%) had a CLO test performed: 74 were positive (85%) and 13 were negative (15%). All 13 CLO-negative cases were confirmed positive for H pylori with IHC. Of the 108 cases, only 1 (0.93%) was diagnosed with CLO alone. Based on these data, the sensitivity and specificity for CLO is 85% and 100%, respectively. H&E alone had a sensitivity of 58.3%, while H&E combined with IHC showed a sensitivity of 99.1%.

Conclusions: In our pediatric patient population, CLO testing led to the additional detection of only 1 case during a 5-year period. Given the lower sensitivity of the CLO test as compared to H&E and IHC and the cost of the test, our data call into question the routine use of CLO testing in the pediatric population.

Yee is a consultant with PathAI.

Ahmed M. Alhusseiny, MD ([email protected]); Roxanne R. Florence, MD. Department of Pathology, Baystate Medical Center, Springfield, Massachusetts.

Takotsubo cardiomyopathy (broken heart syndrome, apical ballooning syndrome) is an increasingly recognized condition most common in postmenopausal women that usually occurs after a profound psychological or physical stressor. Signs/symptoms mimic acute myocardial infarction. On ventriculogram, acute mid to apical left ventricular systolic dysfunction with apical ballooning is observed, resembling a takotsubo (Japanese octopus fishing pot). Significant coronary artery disease is absent. Excessive activation of the sympathetic nervous system is the favored etiology. Most recover in hours to weeks, and when death occurs it is usually secondary to cardiogenic shock or arrhythmias. We present a rare case with death from myocardial rupture. A 63-year-old woman with hypertension and hypothyroidism presented with 5 hours of radiating chest pain, arm numbness, and burping. Electrocardiogram showed lateral nonspecific ST-T wave abnormalities, and troponin and CK-MB levels were elevated at 1.62 ng/mL and 130.1 ng/mL, respectively. Cardiac catheterization with ventriculography revealed a large area of apical akinesis in the distal 2/3 of the ventricle consistent with Takotsubo cardiomyopathy. A 70% stenosis of the left circumflex artery was thought unrelated to ventriculogram findings. She expired 41 hours after presentation. Autopsy revealed a 1.1-cm rupture in the inferior aspect of the posterior-lateral left ventricle. Necrotic myocytes, acute inflammation, and hemorrhage adjacent to the rupture and subendocardial contraction bands in the lateral left ventricle were observed microscopically. The left circumflex artery had moderate luminal stenosis. History of a preceding stressor was unknown. This case highlights a rare fatal consequence of Takotsubo cardiomyopathy.

Karleen Meiklejohn, MD ([email protected]); Bruce Parks, MD. Department of Pathology, University of Arizona/Banner University Medical Center - Tucson.

Congenital pulmonary lymphangiectasia is divided into primary and secondary forms, which are related to thoracic duct obstruction and congenital heart defects/discrete syndromes, respectively. This disease is rare, though incidence is not clearly defined, and most cases are sporadic. Congenital pulmonary lymphangiectasia is typically discovered at birth but it is known to be associated with nonimmune fetal hydrops as well as congenital chylothorax. The mortality rate for this condition ranges from 50% to 98% of live-born infants. We present a case of a newborn (0-day-old) girl (blood type B positive) born to a 25-year-old gravida 2, para 1 woman (blood type O negative) who received appropriate Rh-immunoglobulin treatment as part of routine prenatal care. An ultrasound examination performed at 36 weeks' gestation showed effusions and edema with normal fetal heart tones. Owing to the discovery of fetal hydrops, the mother underwent induction of labor. Delivery was complicated by severe shoulder dystocia. After delivery the patient was handed off to neonatology with an Apgar score of 0 with no heart rate and no respiration. Despite resuscitation efforts, no recovery was achieved, and the infant was pronounced deceased. Examination of tissue sections of the lung at autopsy showed edematous connective tissue in a pleural and interlobular distribution with dilated lymphatic channels, consistent with congenital pulmonary lymphangiectasia. The immediate cause of death was determined to be birth trauma, with an underlying cause of death being fetal hydrops secondary to pulmonary lymphangiectasia. Based on a lack of any identifiable anatomic defects, this case is likely a primary congenital pulmonary lymphangiectasia (Figure 55).

Jaffar Khan, MBBS ([email protected]); Rong Fan, MBBS; Joe Curran, MD; Khaleel Al-Obaidy, MBBS. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis.

Williams syndrome (WS), also known as Williams-Beuren syndrome, is a rare genetic disorder characterized by infantile hypercalcemia, short stature, a varying degree of mental retardation, elfin-like facial features, and cardiovascular abnormalities including systemic hypertension, aortic hypoplasia, coarctation of the aorta, and valvular heart disease (aortic and pulmonic stenosis, mitral valve prolapsed, or bicuspid aortic valve). Most WS cases are sporadic, while few are familial. Both sporadic and familial cases are due to deletion of chromosome 7 (7q11.23). We present an autopsy case of a 16-day-old male infant born to a 25-year-old mother with history of WS. Prenatal echocardiogram showed supravalvular aortic stenosis and pulmonary stenosis. The postnatal course was complicated by feeding difficulties and desaturation. Gross autopsy findings included generalized edema, macrocephaly with short neck, and multiple facial anomalies (mandibular hypoplasia, depressed nasal bridge, long philtrum, ear malformation, and wide mouth). The heart was hypertrophied with obstructed ventricles and rudimentary, hypoplastic aortic root. An enlarged, dilated, and tortuous left ureter was a unique finding to this case, in addition to variation in the renal arteries' size and a small-bowel outpouching located 33 cm from the ileocecal valve. Cytogenetic analysis revealed deletion of chromosome 7 (7q11.23). In conclusion, most WS cases are sporadic, a few are familial and are inherited as an autosomal dominant. Ureteric abnormalities seen in this case are extremely rare and it is unclear whether this constitutes a defining feature of this syndrome or not, but it is worth investigating (Figure 56).

Meagan Chambers, MD, MS, MSc¹ ([email protected]); Jody E. Hooper, MD.^{2 1}Department of Pathology, University of Washington, Seattle; ²Department of Pathology, Johns Hopkins University, Baltimore, Maryland.

Context: Rapid autopsies are urgent postmortem tissue collection procedures usually carried out within specialized academic centers to support cancer research. Identified barriers to entry for new rapid autopsy programs include (1) a central and metropolitan location; (2) a distinguished cancer center; and (3) extensive research infrastructure and funding. Herein, we conduct a review of various collaborative models proposed to overcome these obstacles, emphasizing the importance of community-based approaches to these programs.

Design: A comprehensive rapid autopsy search was conducted with PubMed and EMBASE. A title, abstract, and full text review was undertaken with special attention to models and resources for rapid autopsy programs in nonacademic settings.

Results: Of 234 articles explicitly mentioning a rapid autopsy protocol, 21 described their program protocol in detail. Of these, 5 emphasized collaborative models. Two articles detailed specific approaches using local medical examiner's offices, which had the benefits of increasing their source area and sharing 24-hour staffing and transportation infrastructure. A different approach for smaller institutions (academic or private/community practices) was to partner with a major existing program, acting as a referral network. Notably, this type of referral structure for patients can connect motivated donors to a biobanking repository, bringing meaning to their death.

Conclusions: Some rapid autopsy advocates have explicitly acknowledged the need for community-based participation in order to expand access to these important procedures. This paper reviews the latest approaches to extending the emerging rapid research autopsy model to a community-based environment.

Maryam Aghighi, MD¹ ([email protected]); Ali Rashidbaigi, MD¹; Yong Kang, MD, PhD.^{2 1}Department of Pathology, RWJBarnabas Health, Livingston, New Jersey; ²Department of Pathology, Robert Wood Johnson University Hospital, New Brunswick, New Jersey.

Arrhythmogenic right ventricular cardiomyopathy is a rare disease associated with genetic factors and characterized by prominent fatty infiltration, fibrosis, and focal inflammation in the right ventricular wall, causing cardiac arrhythmia and sudden death in young adults. Increased fat distribution in heart can occur in varying degree depending on age and sex. Pure right ventricular fatty infiltration has been reported, but its relationship with cardiac arrhythmia and sudden death has yet to be established. An unresponsive 76-year-old woman with ventricular tachycardia arrived at the emergency department unconscious, pulseless, apneic, without audible heart sounds, with dilated and fixed pupils. After several rounds of advanced cardiac life support, the patient was pronounced dead. Autopsy revealed a dilated right ventricle with gross right ventricular fatty infiltration. Neuropathologic examination revealed hypoxic/ischemic encephalopathy with diffuse mild cerebral edema, secondary to systemic hypoxia. Serial sections of the heart demonstrated extensive myocardial fatty infiltrations with myocardial atrophy, limited to the right ventricle shown (Figure 57). Rare case of sudden death due to pure fatty infiltration of right ventricles has been reported, but the relationship of pure fatty infiltration and cardiac arrhythmia has not been established. Whether pure right ventricular myocardial fatty infiltration should be classified into arrhythmogenic right ventricular cardiomyopathy is controversial. Our case showed pure extensive myocardial fatty infiltrations, limited to the right ventricle, in an elderly female patient who clinically had ventricular tachycardia without family history. Further studies are needed to clarify arrhythmogenic right ventricular cardiomyopathy diagnosis criteria and the pathogenesis of pure right ventricular myocardial fatty infiltration.

Stephanie M. Bryant, MD ([email protected]); Rohin Mehta, MD. Department of Pathology, SUNY Upstate Medical University, Syracuse, New York.

Rhizopus spp are fungal organisms ubiquitous in the environment that may cause sinus infections in diabetic patients and disseminated infection in neutropenic patients. These fungal species are normally killed by phagocytosis and oxidative metabolites of neutrophils. A 14-year-old adolescent girl with combined variable immunodeficiency and autoimmune hepatitis, receiving antirejection pharmacotherapy for bone marrow and liver transplants, was admitted with neutropenia and gram-negative bacteremia. Her prolonged hospital course was complicated by pneumonia, persistent bacteremia, and multiorgan failure. She was noted to have widening of the mediastinum on repeated chest radiographs during hospitalization. At autopsy, white plaques and nodules in the mediastinum (Figure 58, A) extended from the midtrachea to the hila of the lungs and into the pericardium. Plaques were seen around the aortic root, ascending aorta, epicardium, and superficial myocardium. Antemortem blood and bronchoalveolar lavage specimens, finalized in the days following death, were positive for Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and Rhizopus. Histology showed angioinvasion by zygomycetes with extensive soft tissue necrosis (Figure 58, B). Zygomycotic forms were seen filling penetrating coronary artery branches (Figure 58, C) with downstream contraction band necrosis (Figure 58, D). A high index of suspicion for mediastinal and cardiac zygomycosis, although rare, should be maintained in profoundly neutropenic patients with mediastinal changes on imaging.

Monica H. Miyakawa-Liu, MS¹ ([email protected]); Dana Troxclair, MD²; Ellen Connor, MD, PhD.^{2 1}Ochsner Clinical School, University of Queensland, New Orleans, Louisiana; ²Coroner's Office, Jefferson Parish Forensic Center, Jefferson, Louisiana.

Diagnosis of zoonosis can be challenging in autopsy settings particularly in the setting of limited investigative and clinical history. This case demonstrates a collaboration between the Jefferson Parish Coroner's Office and the Louisiana State University School of Veterinary Medicine to identify a fatal case of rat bite fever in a 24-year-old decedent who quickly decompensated following presentation to the emergency department. Recent history included 2 days of diarrhea and vomiting, skin mottling, and bilateral lower extremity arthralgia. On presentation, she was hypotensive with thrombocytopenia, lactic acidosis, and renal failure. She rapidly decompensated and was pronounced dead despite aggressive resuscitation efforts. The Jefferson Parish Coroner's Office assumed jurisdiction, where a postmortem examination revealed hemorrhagic lungs, diffuse cerebral edema, and acute tubular necrosis. Gram-negative bacilli were identified on peripheral blood smear and within the renal tubules. However, blood cultures were negative. Through additional conversations with the family, it was discovered that the decedent owned numerous exotic pets, including various rodents. Therefore, the School of Veterinary Medicine was consulted to assist with bacterial identification. On the basis of their recommendation, Streptobacillus moniliformis was identified by polymerase chain reaction. This case demonstrates a fatal case of rat bite fever in an immunocompetent adult, whereas previous reports of such fatalities have been limited to children. The diagnosis is best made with broad spectrum polymerase chain reaction, which is not readily available to autopsy facilities. Additionally, this is a unique case where veterinary medicine played a pivotal role in the diagnosis by offering insight into zoonotic infectious diseases.

Amanda Herrmann, MD, PhD ([email protected]); Brenda Mai, MD; Amanda Tchakarov, MD. Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, Houston.

We present a case of anencephaly with diaphragmatic hernia in an infant with 22q11.2 microduplication. The decedent was born to a 29-year-old gravida 1, para 0 mother with no significant medical history. During an ultrasonography performed at 14 weeks, the fetus was diagnosed with left-sided diaphragmatic hernia and anencephaly. Whole genome microarray on amniotic fluid revealed a 22q11.2 microduplication. The infant died shortly after birth at 31 weeks' gestation. Autopsy confirmed anencephaly with a complete absence of calvarium and gross brain tissue (Figure 59, A and B). Also confirmed was a diaphragmatic hernia with herniation of abdominal viscera into the left pleural cavity (Figure 59, C), bilateral pulmonary hypoplasia, and cardiac dextroposition (Figure 59, D). Microscopic examination of skull contents revealed primitive neuroglial tissue and ganglion cells with a prominent vascular proliferation. All other organs were histologically unremarkable. This case represents the first description of a neural tube defect and diaphragm malformation possibly resulting from 22q11.2 microduplication. This duplication of 30 to 40 genes with unknown function manifests as developmental delays, learning disabilities, and often no abnormality. Deletion at this same locus results in the well-described 22q11.2 deletion (DiGeorge) syndrome. Studies into the effects of changes to genes in this region of chromosome 22 are still underway to determine the role these genes play in these syndromes and the effects they have on normal anatomic development. Our case adds to the literature describing the phenotypic changes resulting from alteration in copy numbers at this specific locus, and points to the importance of these select genes for development of different organ systems.

Chase Middleton, MD¹; Hansini Laharwani, MD¹ ([email protected]); Andrew Biesemier, BS²; Kris Adams, MD.¹ Departments of ¹Pathology and ²School of Medicine, University of Mississippi Medical Center, Jackson.

Inborn errors of bile acid synthesis are rare disorders that account for 1% to 2% of all cholestatic disorders in children. We present a case of a 12-day old female infant born at 39 weeks' gestational age with hypertonia and hypotonia, hyponatremia, elevated creatine, renal insufficiency, hematuria, and persistent abnormalities in liver function. Her medical course was complicated and progressive respiratory distress prompted intubation. Pulmonary hemorrhage was suspected, with death occurring on day 12 of life. At autopsy, the liver showed hepatic necrosis with biliary proliferation and giant cell hepatitis, severe cholestasis, and residual regenerative nodules (Figure 60, A through D). Viral serologies were negative. Gestational alloimmune liver disease was considered but genetic testing was recommended. Chromosomal microarray demonstrated a 3.73% absence of heterozygosity and the baby's parents reported being distantly related. Whole exome sequencing identified a homozygous variant of ACOX2 c461_464delCAGA, which was inherited from both parents. The ACOX2 gene encodes peroxisomal branched-chain acyl-CoA oxidase, which is part of bile acid synthesis. This particular variant is predicted to result in protein truncation and plays a crucial role in the biosynthesis of bile acids. In this case, the novel homozygous variant was associated with severe progressive liver disease and death. Inborn errors of bile acid synthesis are rare but can have severe presentations in the neonatal period. Thus, it is very important to rule out inborn errors of bile acid synthesis in cases with idiopathic and early onset of severe cholestasis and multiorgan failure.

Caroline Simon, MD ([email protected]); Raja Rabah-Hammad, MD. Department of Pathology, University of Michigan, Ann Arbor.

Pulmonary veno-occlusive disease (PVOD) is a rare form of fatal pulmonary vascular disease resulting in pulmonary hypertension. Familial and sporadic cases are described. Most commonly it has been seen secondary to other conditions; however, PVOD rarely presents without predisposing conditions. The presentation is nonspecific, and the diagnosis requires a biopsy. The prognosis is poor, the only definitive treatment being lung transplant. Here we present 2 autopsy cases of PVOD with superimposed viral pneumonia diagnosed at autopsy. Case 1: An 8-month-old girl was admitted with cough, labored breathing, and hypoxia. Viral PCR testing was positive for RSV. She improved with treatment and was discharged. She re-presented 3 days later with respiratory distress and hypoxia and expired. Case 2: A 22-month-old girl with recurrent episodes of hypoxia associated with URIs presented to the ER at an OSH and was diagnosed with human metapneumovirus. She was discharged home on oxygen. The next morning, she collapsed and expired. Both patients developed viral pneumonia and expired. During autopsy, the lungs of 1 decedent showed diffuse mottling of the pleura, increased vascular markings, and firm congested parenchyma. Histologically, both patients had features of PVOD, including dilation and arterialization of septal veins with thrombi of various ages. Preseptal venules with loose intimal and luminal fibrosis were noted. RSV and HMPV may cause a wide spectrum of disease, including flulike symptoms, bronchitis, and pneumonitis. Risk factors associated with severe infection include prematurity, young age, preexisting infection, and underlying disease. PVOD is a rare condition that requires a high index of suspicion for accurate/timely diagnosis.

Fahd Hussain, MD¹ ([email protected]); Hansini Laharwani, MD¹; Kristen Roberts, BS²; Kristen Adams, MD.¹ Departments of ¹Pathology and ²Medicine, University of Mississippi Medical Center, Jackson.

Methylene blue has been used as an effective therapeutic agent for various clinical entities including the treatment of methemoglobinemia, ifosfamide-induced encephalopathy, hepatopulmonary syndrome, and as a dye in diagnostic procedures. It has also been used as a pressor agent for catecholamine-refractory circulatory shock. Methylene blue is known to give bluish discoloration to skin, mucosa, and urine. Discoloration of internal organ tissues has been reported in very few cases in the literature. We report a case of a 30-year-old woman with past medical history of lupus anticoagulant syndrome and chronic thromboembolic pulmonary hypertension who presented to the emergency room with abdominal pain and shortness of breath. Imaging studies identified a large pericardial effusion and she underwent pericardiocentesis with removal of 1000 mL of fluid. Her hospital course was complicated by persistent altered mentation, respiratory failure, and hypotension, which became refractory to catecholamines, necessitating the use of methylene blue. Despite maximum medical therapy, our patient's medical condition continued to decline, and she ultimately went into cardiac arrest. Autopsy examination was requested by family. Upon opening the cranial vault, there was extensive bluish discoloration of the brain surface (Figure 61, A through C). The blue color relatively spared the dura, optic and cranial nerves, and deep white matter on coronal section, contrasting with the intense discoloration in cortical and subcortical gray matter (Figure 61, D). Methylene blue–associated brain discoloration is a rare and unusual entity that must be kept in mind in cases when one encounters a green-blue discolored brain.

Cara Bornstein, MD ([email protected]); Knarik Arkun, MD. Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, Massachusetts.

Erdheim-Chester disease is a rare, non–Langerhans cell histiocytosis in which histiocytes proliferate and accumulate in various organs and tissues with associated fibrosis. The most common sites of involvement are long bones, retroperitoneum, large vessels, heart, lungs, orbits, central nervous system, and skin. Presently there is no genetic or infectious basis found but it can be associated with mutations (BRAF, NRAS, KRAP, ARAF, PIK3CA,and MAP2K1). We report an autopsy case of a 54-year-old man with no past medical history who presented with acute onset of chest and back pain. He was found to have a late presentation STEMI and a decreased ejection fraction. Imaging showed circumferential inflammation around the aorta, extensive soft tissue thickening involving the thoracic aortic arch, the major aortic branch vessels through the common iliac vessels, and bilateral perinephric thickening. Clinical suspicion was high for Erdheim-Chester disease owing to the characteristic radiographic findings. At autopsy we found a dense white infiltrate and marked thickening around the aorta, renal arteries, and thickened and indurated perinephric fat encasing kidneys and adrenal glands. Microscopically, affected tissues demonstrated sclerosing fibrosis and inflammation, including lymphocytes, markedly increased histiocytes, and giant cells. There was extensive multiorgan involvement including aorta, coronary vessels with myocardial infarction, prostate, testes, renal arteries, and retroperitoneal tissue. Histiocytes were S100 and CD1a negative, and CD68 and CD163 positive, consistent with non–Langerhans cell histiocytes. This case highlights the importance of a high index of suspicion to recognize uncommon presentations of rare disease and autopsy to confirm the diagnosis.

Elizabeth O. Ferreira, MD¹ ([email protected]); Marc R. Del Bigio, MD, PhD, FRCPC¹; Patrick Frosk, MD, PhD, FRCPC, FCCMG²; Jason Morin, MD, FRCPC.¹ Departments of ¹Anatomic Pathology and ²Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.

GLRX5 (glutaredoxin 5) is a mitochondrial protein that is essential for cellular redox homoeostasis and lipoic acid synthesis. Rare case reports of pathogenic GLRX5 mutations have been associated with sideroblastic anemia and nonketotic hyperglycinemia with progressive spasticity and cavitating leukoencephalopathy. We report a case of a child with cardiomyocyte abnormalities in the context of a homozygous GLRX5 variant. This 11-month-old female of Dutch-German Mennonite descent was born at full term with features of Pierre-Robin sequence and laryngomalacia. At 2 months, she underwent a bilateral distraction osteogenesis procedure. Seizure activity 1 week postoperatively prompted metabolic screening, which demonstrated nonketotic hyperglycinemia. Targeted genetic testing of the glycine cleavage system was unrevealing. Whole exome sequencing demonstrated a homozygous variant in GLRX5 (c.208A>G, p.Ser70Gly). Two months after the whole exome sequencing, the infant died following aspiration. Autopsy demonstrated cardiomegaly (87.3g; >95th percentile for weight) and concentric left ventricular hypertrophy. Light microscopic examination of cardiomyocytes demonstrated numerous areas of PAS-negative and iron-negative cytoplasmic clearing (Figure 62, A). Electron microscopy of cardiomyocytes showed a mixture of membrane-bound vacuoles and non–membrane-bound areas of cytoplasmic clearing with abnormally swollen mitochondria and intact myofibrils (Figure 62, B). Neuropathologic examination demonstrated severe cerebral white matter degeneration most marked in the periventricular regions (Figure 62, C and D; HLA-DR). Cytologic abnormalities suggested a possible oligodendrogliopathy and secondary axonal damage. This first reported case of a GLRX5 mutation with both neurologic and cardiac manifestations may be the result of mitochondrial degeneration secondary to ineffective mitochondrial iron-sulfur cluster transfer.

Evi Abada, MD, MS¹ ([email protected]); Bernadino B. Pacris, MD²; Ljubisa J. Dragovic, MD.²¹Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan; ²Oakland County Medical Examiner's Office, Pontiac, Michigan.

According to the Centers for Disease Control and Prevention, more than 36% of households in the United States own at least 1 dog. Although these creatures have become integral members of many families, the increasing rate of dog-related fatalities are fast becoming a huge public health concern. We present the case of a healthy 4-year-old boy who was mauled by an unprovoked pitbull whom his family was pet-sitting. The dog had no significant histories of aggressive attacks. Despite adequate and aggressive resuscitative efforts, the boy died a few hours later from his injuries. Autopsy revealed multiple wounds and lacerations (Figure 63, A and B) to the front, back, and sides of the neck, measuring up to 3½ inches in length, with puncture of the right carotid artery. Additional lacerations (Figure 63, C) were seen on the chest, face, and extremities, measuring up to 2½ inches. There was a linear cutting wound on the forehead measuring up to 6 inches in length. Soft tissue hemorrhages were seen around the hyoid bone. Paw imprints were seen on the cervical vertebrae and chest. There were no significant intracranial hemorrhages (Figure 63, D). The boy's cause of death was determined to be sharp force trauma to the neck with significant blood loss. In summary, dog-related attacks may be unprovoked and injuries resulting from such attacks may be too severe, defying medical intervention and ultimately result in death. Precautionary measures should be taken to protect children and other at-risk individuals while in the company of dogs to minimize fatal attacks.

Dalia Ibrahim, MD, MSc ([email protected]); Amira Gohara, MD. Department of Pathology, University of Toledo Medical Center, Toledo, Ohio.

Hypertrophic cardiomyopathy is a heterogeneous disease with a number of phenotypes. We present the rarest phenotype (1% of all cases), the midventricular obstructive type. It is characterized by hypertrophy in the mid portion of the left ventricle involving the papillary muscles, resulting in systolic intraluminal obstruction of the mid-ventricle. Our patient is a 41-year-old man who died suddenly while hiking. He had no past medical history except for hyperlipidemia. He had no history of hypertension, with documented repeated normal blood pressure readings, or family history of cardiac problems, sudden death, or death at young age. On autopsy examination, his heart weighed 540 g. The left ventricle was concentrically hypertrophied, 1.8 cm in thickness, with prominent papillary muscles and small lumen (Figure 64). The interventricular septum measured 1.8 cm in thickness, with increased subaortic wall thickness (Figure 64). Microscopic examination revealed myocyte hypertrophy with boxcar-like nuclear enlargement and interstitial fibrosis. There was myocardial fiber disarray (Figure 64). Intramural vessels showed dysplastic changes with medial thickening and narrowing of the lumen (Figure 64). Genetic cardiomyopathy panel testing on paraffin-embedded sections was negative; testing on whole blood is preferred but the body was embalmed before autopsy. The immediate cause of death was hypertrophic cardiomyopathy leading to pulmonary edema with potential complications as arrhythmias and low cardiac output. This case highlights the importance of light microscopy in the diagnostic process despite negative genetics. It also underscores the cruciality of adopting better strategies to identify the disease, since sudden death occurs frequently in those where diagnosis is missed during life.

Anas Mohamed, MD ([email protected]); Abdullah Thayyil, MD; Karen L. Kelly, MD. Department of Pathology and Laboratory Medicine, East Carolina University/Vidant Medical Center, Greenville, North Carolina.

Polymer grafts are used in endovascular procedures. Reports of polymer graft embolization are few in the literature. We report a case of fatal simultaneous polymer graft material and cholesterol embolization to multiple organs. A 76-year-old woman underwent an endovascular repair with polymer graft for thoracoabdominal aortic aneurysm. On day 2, she developed somnolence and hypotension. Her serum creatinine acutely increased, and she developed lactic acidosis. Her condition deteriorated despite treatment and she died on day 7. Autopsy findings included intact polymer grafts extending from left subclavian artery to the bifurcation of abdominal aorta. Multiple hepatic (Figure 65, A), renal, and splenic infarcts were noted. The intestines were dusky and friable. Microscopic examination showed widespread embolization of nonrefractile, nonpolarizable, foreign material in the glomeruli (Figure 65, B) and arterioles of both kidneys. Sections from spleen, pancreas, stomach (Figure 65, C, van Gieson stain), and intestines showed the same material in the arteries and arterioles, with acute ischemic changes in the surrounding areas. Multiple cholesterol emboli were also present in these organs separately or combined with polymer (Figure 65, D). Microscopic examination of the organs supplied by the arteries arising proximal to the graft (brain and heart) revealed no embolized material or infarcts. The downstream distribution pattern of the embolized foreign material suggests that the synthetic graft is the source. The final diagnosis was death from systemic complications of endovascular aortic repair procedure. Simultaneous cholesterol and polymer graft embolization has not been previously reported. Polymer embolization is an underrecognized cause of organ failure and death.

Jessica Snider, MD ([email protected]); Nicholas I. Batalis, MD. Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston.

Adult T-cell leukemia/lymphoma (ATLL) is a rare, aggressive lymphoid neoplasm closely linked to HTLV-1 infection. The most aggressive form is fatal within weeks to months and even with treatment many patients quickly have relapse. Death often occurs from overwhelming infiltration by leukemic cells, opportunistic infections, and/or hypercalcemia. Although ATLL commonly involves the spleen, there has only been 1 reported case of fatal splenic rupture. We report an additional case of fatal splenic rupture in a 65-year-old man with schizophrenia. At presentation, white blood cell count was 229 000/lL and arterial lactate was 6 mmol/L. Peripheral smear showed characteristic flower cells (Figure 66, A) and flow cytometry was positive for CD2, CD3, CD4, CD5, and CD25, consistent with ATLL. HTLV-1 was positive. Chemotherapy was initiated, but he decompensated with hypotension, lethargy, and acidosis with arterial lactate more than 20 mmol/L, and expired. Autopsy findings included marked splenomegaly, weighing 1290 g; splenic infarcts up to 5 cm; a 15-cm ruptured subcapsular splenic hematoma (Figure 66, B) and associated 4-L hemoperitoneum. Gentle manipulation led to additional capsular rupture. Widespread infiltration of all organs by ATLL was observed microscopically and most pronounced in the splenic parenchyma, highlighted by diffuse CD3 staining (Figure 66, C and D). Hematologic malignancies frequently involve the spleen but rarely cause pathologic splenic rupture. Most of these ruptures occur unexpectedly with no apparent trauma, as in this case. Patients with ATLL have a high mortality risk. Early detection of splenic rupture can facilitate an emergency splenectomy, an option that may lead to better outcomes.

Joy O. Edegbe, MD¹ ([email protected]); Jordan Colson, MD¹; Atif Ahmed, MD²; Uttam Garg, PhD.²¹Department of Pathology, University of Missouri, Kansas City; ²Department of Pathology, Children's Mercy Hospital, Kansas City, Missouri.

Primary hyperoxaluria (PH) represents a group of rare autosomal recessive inherited disorders of glyoxylate metabolism (Figure 67, A) that lead to recurrent oxalate kidney stones, nephrocalcinosis, and failure to thrive. In the pediatric population, the disease is very rare and accounts for only 1% to 2% of children with end-stage renal disease. Although mortality is high, autopsy findings are rarely ever reported. We report a fatal case of PH in a male infant and describe the autopsy findings. At 4 months of age, the patient presented with seizures, pallor, poor feeding, and acute kidney injury. Laboratory analysis revealed anemia, metabolic acidosis, hyperoxalemia, and hyperoxaluria. Bilateral kidney calcifications were detected by ultra-sonography. The presence of compound heterozygous pathogenic variants in AGXT, c.508G>A (p.Gly170Arg) and c.33dupC (p.Lys12Glnfs*156) by blood exome sequencing confirmed the diagnosis of PH type 1. Management of his multiple comorbidities included hemodialysis and orthotopic liver transplant that was complicated by hemorrhagic shock, coagulopathy, and graft failure necessitating a second transplant. Postoperative course was characterized by respiratory failure, coagulopathy, and progressive neurologic decline culminating in death. The autopsy revealed hepatosplenomegaly and small kidneys with extensive bilateral crystal depositions (Figure 67, B). Both lungs had multiple thrombi involving small and medium-sized blood vessels. A large subdural hematoma, global hypoxic ischemia, extensive cerebral atrophy, and periventricular leukomalacia were present. Although a pediatric autopsy of PH type 1 has been previously reported, this is the first genetically confirmed case resulting in massive coagulation events and infant death.

Jonathan N. Wilcock, DO ([email protected]); Pamela C. Gibson, MD; Juli-Anne Gardner, MD; Katherine A. Devitt, MD. Department of Pathology, the University of Vermont Medical Center, Burlington.

A 78-year-old man with a history of nonspecific autoimmune polyarticular arthritis was transferred from an outside hospital with worsening pancytopenia. Laboratory analysis revealed a hemoglobin of 9.3 g/dL, platelet count 28 000/cmm, white blood cell count 620/cmm with absolute neutrophil count 200/cmm, lactate dehydrogenase 13 297 U/L, D-dimer 4170 ng/mL, and haptoglobin <7 mg/dL. There was no current or prior erythrocytosis. Imaging revealed mild splenomegaly and mesenteric lymphadenopathy. Bone marrow biopsy was nonspecific with patchy cellularity, dysplastic changes, and areas of fibrosis. His mental status and coagulopathy worsened, and he died within days. Autopsy revealed peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) involving bones, lymph nodes, lungs, and bowel. Bone marrow involvement was extensive but patchy, with adjacent fibrosis. Next-generation sequencing of the bone marrow was positive for mutations in JAK2 T514M exon 12, TET2, and ZRSR2. This patient had PTCL, NOS, an exceedingly rare JAK2 exon 12 mutation, and no history of erythrocytosis or elevated hemoglobin to suggest a myeloproliferative neoplasm. Aberrations in the JAK/STAT pathway are common in T-cell neoplasms, and JAK1 and JAK3 mutations have been described in PTCL, NOS. However, JAK2 exon 12 mutations are fairly specific for polycythemia vera and have not been reported in this setting. TET2 and ZRSR2 are nonspecific mutations often seen in myeloid disorders, although TET2 has also been reported in T-cell lymphomas. This case represents a previously undescribed mutation in PTCL, NOS.

Joel Lanceta, MD ([email protected]); Anupma Agarwal, MD; Monika Wrzolek, MD, PhD. Department of Pathology, Northwell Health-Staten Island University Hospital, Staten Island, New York.

Hereditary transthyretin amyloidosis (ATTR) is a rare systemic disorder caused by a mutant form of transthyretin, a liver-synthesized transport protein, which causes the protein to misfold and accumulate as amyloid deposits. Here, we present a case of an 84-year-old African American woman admitted for worsening heart failure, lymphedema, and dyspnea who died from septic shock. Autopsy showed cardiomegaly with a waxy, diffuse appearance of the myocardium. Microscopy revealed extensive extracellular deposition of an amorphous eosinophilic material in the heart and lungs (Figure 68, A and B), with multifocal vascular deposits at other sites (including gastrointestinal tract, bladder, and leptomeninges). Congo red stain confirmed amyloid deposits in the heart and lungs (Figure 68, C and D). Liquid chromatography–tandem mass spectrometry performed on formalinfixed, paraffin-embedded heart tissue showed a peptide profile consistent with transthyretin. Additionally, the mass spectrometry detected a mutation in the transthyretin protein (Val122lle), an ATTR mutation prevalent in approximately 3% to 4% of African Americans. This case highlights how novel molecular techniques, combined with traditional postmortem examination, assist in cases where clinical diagnosis is challenging. ATTR is often underdiagnosed, since its cardiac symptoms are usually attributed to more common conditions, such as hypertension. ATTR should be considered as a cause for heart failure in elderly African Americans. Diagnosis of cardiac ATTR, if known, has implications for treatment options. In addition, since this patient had the mutated form of transthyretin, the autopsy findings have significant implications for her family members. The family was informed and referred for genetic counseling.

Charles E. Middleton, MD¹ ([email protected]); Lakshmi Ramachandran Nair, MD¹; Macy Cummins, BA²; Megan K. Dishop, MD³; Kristen Adams, MD.¹ Department of ¹Pathology and ²School of Medicine, University of Mississippi Medical Center, Jackson; ³Department of Pathology, Phoenix Children's Hospital, Phoenix, Arizona.

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a lethal, neonatal developmental lung disorder that results in abnormal alveolar air-blood barriers for gas exchange, leading to severe hypoxemia and pulmonary hypertension. Although usually fatal in the first weeks of life, longer survival has been reported. Our case involves ACDMPV in a 3-month-old female infant delivered by emergency cesarian section at 39 weeks' gestation. CT chest scan showed multiple subpleural and parenchymal cysts, diffuse ground glass appearance, and subsegmental atelectasis. Her medical course was complicated, requiring intubation and treatment in NICU with severe refractory pulmonary hypertension that eventually led to her demise. At autopsy, the lungs showed pleural cobblestoning and incomplete lobation (Figure 69, A). Microscopic examination revealed pulmonary hypertensive arteriopathy, maldeveloped acini, and dilated broncho-pulmonary shunt vessels (Figure 69, B and D). Peripheral cystic remodeling and septal fibrosis were consistent with extended survival (Figure 69, C). Molecular genetic analysis revealed a previously undescribed variant in ACDMPV. The patient was heterozygous for FOXF1 gene sequence variant designated c.223T>C, which is predicted to result in the amino acid substitution p.Tyr75His. ACDMPV is a rare lung disease with poor prognosis and almost 100% mortality within the first month of life. This pattern of disease may be seen in the setting of FOXF1 mutations or deletions. The previously undescribed genetic variant found in this patient warrants further investigation. The significance of this novel mutation is unclear. Future studies examining the relationship between this and other mutations with regard to prognosis should be performed.

Denisse Leza Rincon, MD¹ ([email protected]); Kevin E. Fisher, MD, PhD¹; Alexander Vargas-Hernandez, PhD²; Lisa R. Forbes-Satter, MD²; Nahir Cortes-Santiago, MD, PhD.¹ Departments of ¹Pathology & Immunology and ²Pediatrics, Baylor College of Medicine, Houston, Texas.

We report a case of fetal hydrops and neonatal anasarca with disseminated hypereosinophilia associated with STAT5B p.N642H gain-of-function mutation. Our case involves a 2-day-old female, born at 29 2/7 weeks' gestation to a 31-year-old gravida 2, para 1 mother, who was delivered by emergent C-section owing to concerns for Mirror syndrome coupled with prenatal imaging showing fetal hydrops and pulmonary hypoplasia. Her postnatal course was complicated by refractory hypotension, hypoxemia, and peripheral eosinophilia (11.3 × 10³/lL, 38%) and she subsequently died on her second day of life. Trio whole exome sequencing obtained before death demonstrated a de novo, heterozygous STAT5B c.1924A>C p.N642H mutation. Postmortem examination showed anasarca with multicompartment effusions and pulmonary hypoplasia. All major organs demonstrated prominent eosinophilia with variable associated extramedullary hematopoiesis. The bone marrow showed largely myeloid precursors with striking eosinophil predominance. Somatic STAT5B gain-of-function mutations are reported in adult hematologic malignancies with eosinophilia and recently in 2 pediatric patients with early-onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. In our case, the early onset of disseminated eosinophilia suggests germline inheritance or a somatic mutation in utero. These findings highlight an expanding role for STAT5B in eosinophil homeostasis and underscore the importance of temporal acquisition of the mutation in the clinical presentation and outcome. To our knowledge, this is the youngest patient reported with STAT5B gain-of-function mutation. Our data together with cases detailed in the literature highlight the heterogeneity in presentation of STAT5B gain-of-function diseases as well as the importance of STAT5B in hematopoiesis. Molecular diagnostics has been invaluable for identification and characterization of these rare disorders.

Alexander R. Gross, MD¹ ([email protected]); Nada M. Mohamed, MD²; Varun M. Badami, MD²; Haroon Ahmed, MD²; Matthew J. Zdilla, DC¹; Jeffrey A. Vos, MD.¹ Departments of ¹Pathology, Anatomy, and Laboratory Medicine and ²Pulmonary Critical Care and Sleep Medicine, WVUniversity Health Sciences, Morgantown, West Virginia.

Context: Bronchoalveolar lavage (BAL) is an often used, and difficult to standardize, clinical diagnostic procedure. Obstacles to reproducibility include clinical setting, disease process, and a naturally variant, anatomically complex lung. For example, between 2 patients, aspiration from the same left upper lobe, third-order bronchus could involve different bronchial, and alveolar, distributions. In fact, yet unstudied is what precise lung anatomy is involved during a BAL.

Design: Within a bronchus in each lobe of refrigerated, explanted human lungs, a mini-BAL cannula was wedged. Forty milliliters of novel, gelatinized, barium sulfate suspension was injected and allowed to set, before cannula removal. The lungs were dissected to characterize airways/lung parenchyma involved by gelatinized fluid (Figure 70, A and B).

Results: Lung parenchyma involved by gelatinized fluid varied by lobe, and bronchial order. At lowest-order branching was a single third-order bronchus that conveyed fluid into lateral segment alveoli comprising 10% of the lobe of the right lower lobe. At highest-order branching were multiple eighth-order bronchi that conveyed fluid into medial segment alveoli comprising 12% of the left upper lobe. Percentage of lobe involved ranged from 9% in the left lower lobe to 26% in the right upper lobe.

Conclusions: Characterization of the anatomy involved by BAL is possible with the novel fluid described here. In our specimen, the most influential finding is that the BAL fluid filled into the parenchyma at significantly different bronchial orders in each lobe; bronchial branching correlates with segmental anatomy. Further adaptation of this technique may help investigate the BAL procedure.

Alaaeddin Alrohaibani, MD ([email protected]); Christopher Corless, MD; Jessica Davis, MD; Peter Stenzel, MD, PhD. Department of Pathology, Oregon Health and Science University, Portland.

Nuclear protein in testis (NUT) carcinoma is a rare, aggressive malignant neoplasm that has a predilection for midline structures and occurs chiefly in young adults and children. The cell of origin is unknown; however, a germ cell origin has been suggested because of the tumor's typical midline occurrence (similar to teratomas) and its pathognomonic NUTM1 gene fusions. The NUT protein is normally expressed only in the testis. NUT carcinoma with ovarian involvement has been reported only twice, and autopsy reports of fatal NUT carcinoma are likewise rare. An 11-year-old girl presented with cough and pleuritic chest pain. She was found to have no breath sounds on the left side, and a computed tomography scan showed total obstruction of the left mainstem bronchus and near total collapse of the left lung. Biopsy of the lung mass was consistent with NUT carcinoma. She died 8 weeks after presentation. At autopsy, the tumor filled the left pleural cavity and occluded the left bronchus. The right ovary was almost entirely replaced by tumor (Figure 71). The left ovary was unaffected. Molecular studies revealed the presence of a chimeric mRNA consistent with a BRD4-NUTM1 gene fusion: (chromosome 19: 15364963 – chromosome 15: 34640170). To our knowledge, this is only the third case of NUT carcinoma with ovarian involvement. The autopsy findings could be explained by an ovarian origin of a NUT carcinoma with extensive pulmonary metastases, which would be consistent with a germ cell origin for this cancer.

Yuan Huang, MD, PhD ([email protected]); Kurt B. Hodges, MD; Jiang Wang, MD, PhD. Department of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio.

Acute liver failure is rarely the cause of death in systemic immunoglobin light chain (AL) amyloidosis. Herein we describe a case of systemic AL amyloidosis with severe liver involvement in a 61-year-old woman. On admission, her laboratory values showed cholestatic liver injury with unusually high total bilirubin/direct bilirubin (38.9/25 mg/dL) and modest increase of alkaline phosphatase (225 IU/L). Viral and autoimmune markers were negative. Liver biopsy demonstrated diffuse and marked deposition of eosinophilic amorphous substance in sinusoidal spaces (Figure 72, A). Congo red staining revealed apple-green birefringence on polarizing microscopy consistent with amyloidosis, which is represented in Figure 72, B. In addition to severe liver injury, she also developed acute renal injury with blood urea nitrogen measuring 42 mg/dL and serum creatinine level at 6.62 mg/dL, and rapid cardiac involvement of amyloidosis. Progressive left ventricular hypertrophy with significant wall thickening from 1.4cmtomore than2.8 cm wasdepictedonserial echocardiograms during a period of 1 month. She progressed to multiorgan failure and died 1 week after admission. Postmortem examination showed systematic amyloidosis with marked involvement of liver, heart (Figure 72, C) and kidney, with additional adrenal gland and bone marrow amyloid deposition. Bone marrow examination showed 20% κ-restricted plasma cells consistent with primary amyloidosis (Figure 72, D). Mass spectrometry confirmed AL subtype of amyloidosis. In summary, this is a rare case of primary AL amyloidosis presenting with acute liver failure with unusually high bilirubin level.

Juan Carlos Alvarez Moreno, MD ([email protected]); Michael Pagacz, MD; Odille Mejia, MD; Kei-Shing Oh, MD; Ana Maria Medina, MD. Department of Pathology, Mount Sinai Medical Center, Miami Beach, Florida.

Collecting duct carcinoma is a rare neoplasm of the kidney, accounting for only 1% to 2% of renal tumors. These tumors arise from the principal cells of the renal collecting ducts of Bellini. Most patients eventually have lymph node involvement and metastases to lungs, liver, bone, adrenal glands, and brain. We present a case of a 48-year-old woman who came to the hospital with a clinical presentation suggestive of pneumonia. One week later her symptoms worsened. A CT chest and abdominal imaging showed bilateral pulmonary infiltrates, retroperitoneal lymphadenopathy, and left hydroureteronephrosis. She expired after developing acute respiratory failure. An autopsy was performed that revealed 150 cc of chylopericardium (Figure 73, a); bilateral reticular pattern on the surfaces of the lungs; neck, mediastinal, and retroperitoneal lymphadenopathy; and a 5.1-cm left kidney mass located in the medulla of the mid portion (Figure 73, b). The kidney tumor was poorly differentiated with a predominantly rhabdoid appearance and with focal tubule formation. The cells showed abundant eosinophilic cytoplasm, occasional mucin vacuoles, nuclear pleomorphism, and hyperchromasia (Figure 73, c). The immunoprofile showed positivity for Pax-8 and CK7, while CD10 was negative. The mucin vacuoles were highlighted by positive staining with Alcian blue and mucicarmine. These findings supported the diagnosis of a rhabdoid collecting duct carcinoma. The lungs showed diffuse subpleural lymphangitic spread of the carcinoma (Figure 73, d). We report a rare case of chylopericardium due to lymphangitic carcinomatosis from a 5.1-cm rhabdoid collecting duct carcinoma that was not suspected clinically or radiologically, highlighting the important role of autopsies.

Ellie S. Hong, MD¹ ([email protected]); Daniel Olson, DO.^{2 1}Department of Pathology, University of Colorado, Aurora; ²Department of Pathology and Laboratory Medicine, VA Eastern Colorado Healthcare System, Aurora.

An 81-year-old man presented to the emergency department with malaise and productive cough with hemoptysis. Five days prior, he was diagnosed with pneumonia and treated with antibiotics without improvement. Social history was significant for alcohol abuse. During the prior month, he experienced night sweats, shortness of breath, and a 10-pound unintentional weight loss. Chest CT scan revealed a peripheral consolidation with areas of lucency in the right upper lobe of lung. He was admitted and given broad-spectrum antibiotics. The patient further deteriorated and was transitioned to comfort care. At autopsy, gross examination of the right upper lobe of lung revealed a 7.5 × 6.0 × 5.5-cm necrotic cavitary lesion (Figure 74, A). Microscopic examination of the lesion revealed thick-walled, septated, and acute angle branching fungal elements (Figure 74, B) with associated polarizable crystals (compatible with calcium oxalate crystals), parenchymal destruction, and angioinvasion. Fungal dissemination to the left lung, bilateral kidneys, and bilateral adrenal glands was present. The histologic features in conjunction with the calcium oxalate crystals suggested Aspergillus niger as the causative organism. Aspergillus is a fungus that can cause a spectrum of disease from allergic bronchopulmonary aspergillosis, aspergilloma, chronic necrotizing aspergillosis, to invasive bronchopulmonary aspergillosis. Chronic necrotizing aspergillosis has a progressive course with vague respiratory and constitutional symptoms that can mimic tuberculosis, malignancy, and typical pneumonias. With immune status change, disease can progress to invasive bronchopulmonary aspergillosis, which has a mortality rate up to 70%. Recognition of this entity is crucial for prompt and appropriate antifungal treatment.

Matthew S. Dinehart, MD, MEd ([email protected]); Kirsten Threlkeld, MD; Ronald J. Bryant, MD; Juli-Anne Gardner, MD; Katherine A. Devitt, MD. Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington.

We present the case of a 68-year-old man with multiple medical problems, transferred from an outside hospital for presumed septic shock due to bacterial peritonitis. Past medical history included cirrhosis, acute kidney injury, nephrectomy, chronic anemia, recurrent cholangitis, hypertension, vascular disease, pancreatic resection, and chronic back pain. CBC was notable for hemoglobin 9 g/dL, platelet count 72 000/cmm, and white blood cell count 41 510/cmm with 41% neutrophils, 38% monocytes, 12% lymphocytes, 5% immature granulocytes, and 4% blasts. Imaging revealed multiple fluid collections in the abdomen with presumed spontaneous bacterial peritonitis, and a notable lack of splenomegaly and lymphadenopathy. The patient expressed wishes for comfort care and died 2 weeks later. Autopsy revealed dense infiltration of atypical immature cells surrounding and infiltrating all organs, within vessels, and replacing all lymph nodes. The cells were CD3 and CD20-negative, myeloperoxidase-positive, with a marked proliferation rate. The morphologic and immunohisto-chemical features were diagnostic of extensive involvement of acute myeloid leukemia. The underlying diagnosis of acute myeloid leukemia with extensive extramedullary involvement was masked by a complicated medical history and septic presentation. Sepsis classically causes markedly elevated WBC counts as well as atypical cellular morphology. In addition, the promonocytes and monoblasts of AML with monocytic differentiation are morphologically challenging to differentiate from mature monocytes; however, recognition of these populations is critical under these circumstances. This case highlights the difficulty of diagnosing AML in septic patients and the importance of additional definitive diagnostic testing in these patients, as the clinical presentation can mask the underlying diagnosis.

Quinlan R. Carlson, BS¹ ([email protected]); William Lainhart, PhD, D(ABMM).^{2 1}College of Medicine and ²Department of Pathology and Medicine, University of Arizona College of Medicine, Tucson.

Context: Infection is a significant cause of mortality worldwide, yet the value of microbiologic studies in the autopsy setting is controversial owing to the unclear correlation with causative pathogens and the effects of confounding variables. The objective of this project is to review culture data from autopsy cases, and to assess the potential impact of contamination, postmortem interval, and other variables on culture outcomes.

Design: Antemortem and postmortem culture data from autopsies performed from 2018–2019 (n = 195) were assessed for number of organisms, species, specimen type, and postmortem interval.

Results: Of autopsy cases with postmortem cultures ordered (n = 179), 168 (93.9%) were positive for at least 1 organism, and 11 (6.1%) were negative. The number of distinct organisms isolated per case ranged from 0 to 11 (mean, 3.1). Postmortem interval ranged from 5.6 to 335.0 hours. There was no statistically significant correlation between the number of organisms isolated and the postmortem interval (lung [R² = 0.0081], blood [R² = 0.0005], and all specimens [R² = 0.0022]). Eighty-seven cases (48.6%) had positive antemortem culture data available. Of these, 24 (27.6%) had postmortem cultures isolating at least 1 organism in common with antemortem culture; 63 (72.4%) found either different organisms or had no growth.

Conclusions: The lack of correlation between postmortem interval and number of organisms isolated, alongside a high average number of organisms isolated per case, suggests that contamination, not postmortem transmigration, is a major confounder of microbiologic culture results in autopsy practice. Thoughtful clinical decision-making is necessary to determine when to use cultures in autopsy and how to interpret them.

Madhavi Pandiri, MD ([email protected]); Jonathan K. Freeman, MD. Department of Pathology, UMMS-Baystate Medical Center, Springfield, Massachusetts.

ATTR amyloidosis occurs owing to misfolding of transthyretin. There are 2 types of ATTR amyloidosis: hereditary ATTRv, caused by mutations of the transthyretin gene, and wild-type ATTRwt, which is acquired with age and in which ATTR mutations are not present. We report a case of a 79-year-old man with a history of bradycardia and complete heart block referred to surgery for aortic stenosis and coronary artery disease. During aortic valve replacement and coronary artery bypass grafting, surgeons noted extreme tissue fragility, which led to an intraoperative rupture of the right ventricular wall, with inability to hold sutures. Efforts attempting bovine patch repair and extracorporeal oxygenation proved futile and the patient died shortly after leaving the operating room. Autopsy demonstrated previously undiagnosed amyloidosis with extensive involvement of the heart. Grossly, the heart was stiff and heavy, typical of widespread infiltration by amyloid (Figure 75, A). Histologically, right ventricular rupture occurred in an area with a particularly dense infiltrate (Figure 75, B). Congo red staining confirmed amyloid deposits (Figure 75, C) that were birefringent under polarized light (Figure 75, D). Further testing by liquid chromatography–tandem mass spectrometry detected a peptide profile consistent with ATTR (transthyretin)–type amyloid protein, most consistent with age-related amyloidosis. Sequencing the TTR genes and genetic counseling would be recommended if clinical suspicion persists for the hereditary form. In summary, this is a dramatic case of undiagnosed amyloidosis resulting in death from cardiac surgery, emphasizing the need for clinicians and pathologists to remain vigilant with an appropriate index of suspicion, especially in the elderly.

Sarah Glogowski, DO ([email protected]); Alireza Salem, MD; Joseph Guileyardo, MD. Department of Pathology, Baylor University Medical Center, Dallas, Texas.

Ehlers-Danlos syndromes are a group of connective tissue disorders divided into 13 subtypes on the basis of specific genetic alterations. Symptoms can range from increased skin elasticity and joint hypermobility to defective vasculature formation, putting patients at increased risk for spontaneous rupture and internal bleeds. Here we present a case of a 42-year-old woman with a complex medical history including abdominal vessel rupture and carotid-cavernous fistula. No connective tissue disorders were identified on previous genetic testing. Leading to the current hospitalization, she fell unconscious during a jog and was subsequently discovered to have a splenic artery rupture, requiring emergent ligation and splenectomy. Operative notes reported difficulty performing their procedures secondary to increased tissue friability. Despite clinical improvement, a few days postoperatively she abruptly developed cardiovascular collapse. Attempted resuscitation including extracorporeal membranous oxygenation catheter insertion was unsuccessful and an autopsy was requested. During evisceration, dissecting instruments were seldom needed as even gentle traction would cause tissue separation. A postmortem aortopathy panel was performed by massive parallel sequencing and confirmed by Sanger sequencing, which found a COL3A1 c.3005G>A; p.Gly1002Asp variant. To date, this mutation has not been reported in medical literature, gene specific databases, or general population databases. This variant causes alterations to a highly conserved glycine residue in the triple helical domain, disrupting the formation of collagen helices and causing connective tissue instability. While previous testing was negative, the results provided by the autopsy identified a specific genetic variant that her family, as well as others, now can be tested for.

Joseph M. Curran, MD ([email protected]); Lan Zheng, MD, PhD; Ashley S. Inman, MD. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis.

Primary hyperoxaluria type 1 is a rare autosomal recessive genetic disorder occurring in 0.11 to 0.26 per 100 000 live births. The inherited disorder causes an overproduction of oxalate, secondary to a deficiency of hepatic enzymes, which in turn leads to deposition of calcium oxalate crystals in the kidneys. The earliest symptom of affected individuals is urolithiasis. Renal damage is caused by a combination of tubular toxicity from oxalate, obstruction by calculi, and nephrocalcinosis. Additional damage occurs when the glomerular filtration rate decreases, and the kidneys are subsequently unable to effectively excrete the oxalate that they receive. The oxalate is consequently deposited in many tissues (systemic oxalosis), particularly within the skeleton. We report a case of a 46-year-old woman with a history of nephrolithiasis as early as age 2 years. Her kidney function declined, resulting in end-stage renal disease necessitating hemodialysis. She presented for a scheduled liver and kidney transplant. An orthotopic, whole liver transplant was performed, complicated by an intraoperative increase in serum lactate and coagulopathy. While in the intensive care unit she remained unstable and continued to be anemic despite multiple transfusions. Unfortunately, despite maximal therapy she died. At autopsy, calcium oxalate crystals brilliantly birefringent to polarized light were identified systemically within the kidneys (Figure 76, A), cardiac muscle (Figure 76, B), skeletal muscle, and within the skeleton (Figure 76, C). The severity of calcium oxalate crystal accumulation within the bone marrow displaced the hematopoietic cells, likely contributing to her severe anemia.

Joseph M. Curran, MD ([email protected]); Bianca N. Puello Yocum, MD; Ryan F. Relich, PhD; Ashley S. Inman, MD. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis.

Hepatitis A is the most common acute viral hepatitis worldwide with roughly 1.5 million cases annually. It is typically a benign self-limiting disease with few or no extrahepatic manifestations. Fulminant hepatic failure is an extremely uncommon complication of hepatitis A, occurring in only 0.14% to 0.35% of hospitalized cases. Acute renal injury due to cholemic nephropathy is likely due to epithelial cell damage and tubular obstruction caused by bile casts. We report the case of an otherwise healthy 54-year-old man with a history significant for atrial flutter and diabetes mellitus. After a week-long vacation in Florida he reported fatigue, vomiting, and jaundice. A hospital admission revealed elevated liver enzymes, elevated bilirubin, and a positive hepatitis A IgM. After receiving supportive care, he was discharged home. A few weeks later he presented with worsening jaundice and fatigue. He continued to deteriorate with fulminant liver failure, hepatic encephalopathy, acute renal failure, anemia, and thrombocytopenia. Despite maximal therapy he died. At autopsy, the liver parenchyma demonstrated diffuse cholestasis. The kidneys were a marked green discoloration (Figure 77, A); the renal pyramids appeared darker (Figure 77, B) likely due to the increased concentration of bilirubin. Linear green streaks within the cortex correlate histologically as numerous bile casts (Figure 77, C and D), highlighted by Hall bilirubin stain (Figure 77, D). Bile cast nephropathy, an incompletely understood entity, is commonly underestimated but is a significant cause of renal failure in liver disorders with jaundice. Diagnosis requires a high index of suspicion in patients with hyperbilirubinemia and concomitant acute renal insufficiency.

Doaa Atwi, MD ([email protected]); Beth Raju, MD; Michael L. Magguilli, MD, MS. Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City.

Ischemic heart disease is the leading cause of death worldwide and usually secondary to a significant obstruction of a coronary artery due to atherosclerotic disease. Other causes include hypoperfusion, shock, hypoxemia, or increased demand. We report a case of a 55-year-old man with past medical history of congenital rubella syndrome and aortic stenosis status post mechanical valve replacement who presented to the emergency department with upper respiratory symptoms. The patient expired 1 day after admission, and an autopsy was requested. Approximately 8 weeks prior, the mechanical aortic valve was replaced with a bioprosthetic valve. Surgical complications required aortic root replacement and a 2-vessel coronary artery bypass graft to the left anterior descending and right coronary artery, from which the patient recovered and was discharged. Autopsy findings revealed patent grafts and native coronaries, along with a subacute myocardial infarction with acute extension in the lateral left ventricle. It is favored that the metabolic demands of the myocardium were pushed beyond the capability of the retrograde flow and collateral circulation from the left anterior descending coronary artery bypass grafts to adequately perfuse the left circumflex artery's zone of perfusion. The subacute myocardial infarction likely manifested as upper-respiratory–like symptoms, but ultimately resulted in cardiogenic shock and death.

Erik L. Handberg, MD ([email protected]); Christopher Corless, MD, PhD; Peter Stenzel, MD, PhD. Department of Pathology, Oregon Health & Science University, Portland.

Bile duct adenomas (BDAs) have been controversial lesions because of uncertainty regarding their incidence, their nature (being reactive, hamartomatous, or neoplastic), and their malignant potential. Two recent studies showed that BDAs frequently harbor a BRAF V600E mutation. One study found the mutation in 8 of 15 consecutively accessioned tumors. Another study found the mutation in 7 of 8 BDAs that were discovered in livers of patients with α₁-antitrypsin deficiency. We performed an autopsy on a 53-year-old man who died from a myocardial infarction and had 4 separate BDAs (Figure 78) and no underlying liver disease. Sequences of DNA from these lesions showed BRAF V600E mutations in 2 of the 4 tumors. We then compared the tumors by immunohistochemistry for expression of markers that have previously been shown to differ in benign versus malignant biliary epithelial lesions. The expression of Ki-67, P53, CD56, and BCL2 was assessed for each of the 4 BDAs. We found no difference between the tumors with the V600E mutation and those without the mutation. Our results provide no evidence for a malignant potential in BDAs with BRAF V600E mutation.

Joseph M. Curran, MD ([email protected]); Bianca N. Puello Yocum, MD; Ashley S. Inman, MD. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis.

Nontraumatic aortic rupture is catastrophic but relatively rare with an associated high mortality rate of 50% to 97% with patients often dying within 6 hours after rupture. Owing to anatomic relationships, rupture of the descending aorta typically causes a left hemothorax. We report the case of a 61-year-old man with a remote history of a trauma-induced thoracic aortic aneurysm status post endovascular graft repair. A few days before his death he reported chest pain and hemoptysis. On the day of his death he expectorated roughly 800 mL of blood. A chest radiograph showed a pleural effusion (Figure 79, A). An inserted chest tube returned copious amount of blood. Despite aggressive resuscitation efforts, he died. At autopsy a rupture of the 5.2-cm aortic aneurysm was identified at the proximal portion of the descending thoracic aorta near the distal aspect of the intraluminal endograft. The rupture was associated with a false lumen created between the distal aspect of the intraluminal endograft (Figure 79, B and C) and the aortic intimal layer filled with organizing thrombus (Figure 79, C). A hemothorax within the left pleural space with 1000 mL of bloody fluid and clotted blood was seen. Blood was identified within the larynx, trachea, and bilateral bronchi. An aortic aneurysm that ruptures into the lung parenchyma can lead to acute and massive hemoptysis. This case exemplifies the extremely high mortality rate associated with aortic rupture, even when circulation is initially restored, and the need of a high index of suspicion on presentation.

Hansen Lam, MD ([email protected]); Matthew S. Shapiro, MD; Alexandros Polydorides, MD. Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Acute lung injury (ALI) is a rare and fatal complication of transcatheter arterial chemoembolization (TACE) therapy for hepato-cellular carcinoma (HCC). TACE has been used since the 1970s to prolong survival of patients with HCC who are nonsurgical candidates, and traditionally involves injection of ionized oil emulsion loaded with chemotherapeutics. More recent advancements in TACE delivery methods have developed drug-eluting beads loaded with chemotherapeutic agents (DEB-TACE). Scattered case reports with limited discussion regarding histologic changes have shown that ALI remains a possible life-threatening complication, the mechanism of which remains poorly understood. We present a case of ALI, with histologic findings of diffuse alveolar damage, associated with DEB-TACE therapy in a 68-year-old woman with HCC. The patient completed treatment with Adriamycin-loaded DEB-TACE and 2 days later experienced acute onset dyspnea, hypoxia, with subsequent expiration the same day. On autopsy, all lung lobes demonstrated diffuse alveolar damage in acute exudative phase, with prominent hyaline membranes, and associated beadlike foreign material found within the nearby pulmonary vasculature. The liver showed hepatocellular carcinoma with areas of necrosis associated with beadlike foreign material that histologically matched those found in the pulmonary vasculature. To the authors' knowledge, this is the first case report of ALI associated with DEB-TACE in the United States (Figure 80).

Anna-Karoline Israel, MD ([email protected]); Nicole Pecora, MD, PhD; Caroline Dignan, MD. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.

Invasive fungal infections, especially in immunocompromised patients, are associated with a high mortality rate. Here, we describe the case of a 20-year-old Hispanic man with disseminated Blastoschizomyces capitatus infection diagnosed postmortem. The patient had a history of B-cell acute lymphoblastic leukemia (ALL) and presented to the hospital with clinical signs of infection, leukocytosis, thrombocytopenia, and neutropenia. Treatment with antibiotics was initiated and relapse ALL diagnosed. Blood cultures from an indwelling medication port grew C dubliniensis, and caspofungin was appropriately added to the treatment regimen. The patient's clinical status deteriorated, and he developed cognitive decline, and hypovolemic shock with metabolic and respiratory acidosis. Despite resuscitative efforts the patient expired. Autopsy revealed widespread tan to red-brown targetoid lesions involving most of his internal organs, including heart and lungs bilaterally. Histologically these lesions demonstrated areas of coagulative necrosis with abundant fungal organisms. Postmortem blood and lung cultures, as well as antemortem blood cultures that turned positive after the patient had died, identified B capitatus. Blastoschizomyces capitatus exists throughout the environment and can colonize human skin and the gastrointestinal and upper respiratory tracts. It was first recognized as a pathogen 30 years ago and has the potential to cause infections in both immunocompetent and immunocompromised individuals. It is intrinsically resistant to echinocandins and more commonly affects individuals with hematologic malignancies and neutropenia, or taking cytotoxic chemo-therapy or corticosteroids. Symptoms are nonspecific and pose a diagnostic challenge. Suspicion for this rare cause of invasive fungal disease is crucial in guiding appropriate treatment.

Raheel Ahmed, MD ([email protected]); Kurt Hodges, MD; Divya Sharma, MD. Department of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio.

Herpes simplex virus (HSV) hepatitis is a rare complication of herpes infection resulting in geographic necrosis and is usually fatal. Only 1% of acute liver failure is attributed to HSV hepatitis. It usually affects pregnant women or immunocompromised patients and is often clinically unsuspected, since it is not diagnosed until autopsy owing to nonspecific clinical features. It is caused by HSV-1 or HSV-2. Microscopically, there is geographic necrosis with viable and nonviable areas distributed in a patchy, seemingly random fashion. Classic nuclear features of herpes infection (margination, multi-nucleation, molding) are seen within the hepatocytes. The clinical history for this case report involves a 71-year-old woman with a history of cirrhosis status post liver transplant. Laboratory studies showed evidence of acute liver injury with elevated liver enzymes concerning for transplant rejection. Subsequently, the patient was treated with steroids. Three weeks later, the patient's clinical condition deteriorated, and the patient died 2 days later. The major autopsy findings included disseminated HSV infection with acute HSV necrotizing hepatitis. The presence of HSV viral infection in the liver was confirmed by immunohistochemical staining. Therefore, the cause of death was disseminated HSV infection with necrotizing HSV hepatitis. HSV hepatitis is typically diagnosed at autopsy via histologic and immunohistochemical analysis of liver tissue as seen in this case. The treatment includes empiric antiviral therapy or liver transplant. The prognosis is a rapid downhill clinical course with acute liver failure and is usually fatal, as in this case, owing to extensive hepatic necrosis (Figure 81).

Joanna Solarewicz, DO ([email protected]); Fernando Alekos Ocampo Gonzalez, MD; Abdullah Almajnooni, MD; Anas Alabkaa, MD; Ritu Ghai, MD. Department of Pathology, Rush University Medical Center, Chicago, Illinois.

Context: Metastasis of malignant tumors to the heart is an uncommon finding in autopsy studies, with rates ranging from <1% to 12% in large-scale studies. It is commonly associated with widespread metastatic disease. Here we reviewed the rate of cardiac metastases identified on autopsy at our institution.

Design: We searched our autopsy database from 2005–2019 for all autopsies performed. For the final analysis, we excluded limited autopsies (those without trunk examination) and fetal autopsies. We separated all cases with metastases among cases with proven malignancy, and those with cardiac metastases. For all identified cases, slides of heart tissue were re-reviewed to confirm the original diagnosis.

Results: A total of 1562 cases were found, of which 175 were excluded as limited and 334 as fetal autopsies. No data were available for 29 cases. Of the remaining 1024 cases, 270 cases had proven malignancy, with 195 showing metastasis of any kind, among which 33 (17.8%) presented with cardiac metastases. In descending order, the primary site of origin was lung, hematologic, kidney, breast, liver, pancreas, soft tissue, gastrointestinal, and gynecologic. Most metastases were identified in the pericardium, with myocardium and epicardium following. No cases showed endocardial metastases.

Conclusions: Our study showed a higher than average rate (17.8%) of cardiac metastases. This could be explained by the academic and tertiary nature of our medical center, as well as falling rates of autopsy with more severe cases being studied. Cardiac metastases appear to be associated predominantly with widespread metastatic disease, with no cases of isolated cardiac metastasis identified.

Esraa E. Mohamed, MBBCH ([email protected]); Shobha Parajuli, MD; Diping Wang, MD. Department of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio.

Lipomatous hypertrophy of the interatrial septum (LHIS) is a rare cardiac lesion characterized by thickening of the interatrial septum (>2 cm), sparing the fossa ovalis, and histology of adipose tissue interspersed by hypertrophic myocytes. A 63-year-old obese woman with history of hypertension, diabetes, and severe aortic stenosis collapsed outside of her house and soon expired. Autopsy showed left ventricular hypertrophy, coronary artery disease, aortic stenosis, multiple old infarcts, and recent ischemic changes in the heart. In addition, thickening up to 3 cm of the interatrial septum was seen, with sparing of the fossa ovalis. Cut section showed yellow, lobulated soft tissue without a capsule. Histologic examination revealed mature adipose tissue and brown fat with interspersed hypertrophic myocytes and irregularly arranged collagen bundles (Figure 82). These findings are consistent with LHIS. Although LHIS was first identified in patients with sudden death by autopsy and reportedly associated with potentially fatal supraventricular arrhythmias, most cases of LHIS were incidentally identified in patients without significant antemortem cardiac symptoms. Searching literature published since 1990, we identified 54 reported autopsy cases of LHIS. Among them, only 3 cases (5.6%) had previous cardiac arrhythmia documented and LHIS was considered as an important contributor to the patient's death. Most of the deaths were attributed to other conditions, especially other cardiovascular diseases. Given the significant other cardiac findings and the statistics obtained from literature, we conclude that LHIS in our patient likely represents an incidental finding rather than the main cause of the patient's death.

Yamac Akgun, MD ([email protected]); Nicolas Millan, MD; Ali Saad, MD. Department of Pathology, Jackson Memorial Hospital, Miami, Florida.

Kasabach-Merritt syndrome (KMS) is a consumptive, potentially life-threatening coagulopathy marked by platelet sequestration and severe thrombocytopenia associated with rapidly proliferating vascular neoplasms such as Kaposiform hemangioendothelioma, tufted angiomas, and rarely congenital hemangiomas. KMS associated with infantile hemangioma is rare. We describe a rapidly fatal case of KMS in a patient with massive hepatic infantile hemangioma. The patient was a 4-week-old full-term male infant who was admitted with acute liver failure and severe respiratory distress. Laboratory tests revealed evidence of consumption coagulopathy. Imaging of the abdomen showed heterogeneously nodular liver parenchyma. The patient rapidly deteriorated and succumbed to his refractory consumptive coagulopathy. At autopsy, the liver was almost completely replaced by multiple dark red nodules. Histologic examination revealed an infiltrative vascular lesion composed of vascular spaces lined by plump endothelial cells. There were no anastomosing vascular channels. The endothelial cells were positive for Glut-1 by immunostains. These features were consistent with juvenile hemangiomas. Despite recent advances, the management of KMS remains challenging especially in extreme cases like ours. In our case, perhaps liver transplant was the only therapeutic option but the patient rapidly deteriorated and an intracranial hemorrhage complicated the clinical course. In relatively stable patients, therapeutic modalities have included surgery, corticosteroids, and medications causing vasomodulation such as β-blockers and sildenafil.

Rhonda Mittenzwei, MD ([email protected]); Elizabeth Pavlisko, MD. Department of Pathology, Duke University Medical Center, Durham, North Carolina.

Right-sided aortic arch is an exceedingly rare congenital anomaly of the aortic arch and the arch vessels, occurring in approximately 0.04% to 0.1% of autopsy series. Two primary classification systems are used to type the arrangements of arch vessels: the Edwards system (1964) and the Adachi-Williams-Nakagawa system (1935). A literature review of the topic yielded only 1 case report of a right-sided aortic arch in an infant, and no case reports of intrauterine fetal demise associated with right-sided aortic arch. Herein, we present autopsy findings from a 33-week-old fetus, stillborn at 34 weeks, in which right-sided aortic arch was suspected on fetal echocardiography. Autopsy revealed an anomaly most compatible with a Type N configuration by the Adachi-Williams-Nakagawa system, and a Type III configuration by the Edwards system. The heart (Figure 83) exhibited a normal aortic root and pulmonary trunk; however, congenital absence of the brachiocephalic artery was noted. Instead, the right common carotid and right subclavian arteries independently arose from the aortic arch (Figure 83, A). Additionally, the left subclavian artery arose from a large caliber patent ductus arteriosus in association with a retroesophageal aortic segment (Figure 83, B), effectively creating a ring around the trachea and esophagus. An ostium secundum atrial septal defect was also identified. Cytogenetic testing revealed a normal male karyotype. These unique findings, identified in a stillborn fetus at autopsy, broaden the scope of knowledge about right-sided aortic arch and its associated arch vessel anatomy, and may elucidate the possibility of particular configurations being symptomatic or associated with death.

Mazen Osman, MD ([email protected]); Mariam P. Alexander, MD; Marie C. Aubry, MD; Anja C. Roden, MD; Dong Chen, MD. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder with a prevalence of 1 to 2 in 1 million individuals worldwide. It is characterized by the presence of oculocutaneous albinism, platelet dysfunction, granulomatous colitis, and pulmonary fibrosis. Here we report the autopsy findings of the patient's native and transplanted lungs. The decedent was a 43-year-old man diagnosed with HPS with compound heterozygous mutations of HPS1 (a frameshift mutation, c.1189delC, and a 1.8-kb deletion). Electron microscopy of platelets showed the absence of dense bodies (Figure 84, A). He had bilateral lung transplant due to progressive pulmonary fibrosis. Three years later, following multiple episodes of viral infections, he developed and succumbed to acute respiratory failure. Grossly, the pleural surface of his native lungs demonstrated a cobblestone appearance involving all lobes. The cut surface showed peripheral fibrosis with apical sparing. Histologically, there was organizing diffuse alveolar damage, and chronic fibrosing interstitial lung disease with usual interstitial pneumonia–like pattern (Figure 84, B). His posttransplant lungs revealed bilateral fibrinous exudates, and multinodular bronchocentric consolidations in the upper and lower lobes with targetoid lesions. Histologically, the pulmonary allograft showed acute and subacute bronchopneumonia with focal hemorrhage (Figure 84, C), and acute and chronic organizing fibrinous pneumonia with focal fibrosis. There was ungradable acute rejection and airway inflammation, in addition to chronic airway and vascular rejection (Figure 84, D). To the best of our knowledge, this is the first case report documenting autopsy findings in a patient with HPS status post lung transplant.

Areeba H. Rizvi, MBBS, MD¹ ([email protected]); John T. Fallon, MD, PhD¹; Marwan Majeed, MD, MPH¹; Priya S. Kishnani, MD, MBBS²; Karen L. Kelly, MD.¹¹Department of Pathology, East Carolina University/Vidant Medical Center, Greenville, North Carolina; ²Department of Medical Genetics, Pediatrics, Duke University Medical Center, Durham, North Carolina.

Pompe disease (PD), a rare type of glycogen storage disease (type 2), manifests as multiorgan accumulation of intralysosomal glycogen stemming from a deficiency of the enzyme acid α-glucosidase (GAA). The infantile-onset form of PD carries the worst prognosis, characterized by symptoms shortly after birth, always leading to cardiomyopathy. Enzyme replacement therapy with alglucosidase alfa has revolutionized management and increased life expectancy. Timely screening and intervention play a pivotal role in modern health care. We present a case of PD in a 3-month-old infant who presented to the ED with respiratory distress and peripheral cyanosis. The mother, a 17-year-old African-American female, reported her infant as having an upper respiratory infection. Chest radiography revealed cardiomegaly. EKG was indicative of biventricular hypertrophy. The infant rapidly succumbed to cardiopulmo-nary arrest secondary to congestive heart failure. Autopsy demonstrated marked cardiomegaly with biventricular hypertrophy and compression of the left lung. Hematoxylin-eosin–stained heart sections revealed diffuse clear, vacuolated myocytes. PAS and PAS-diastase staining was consistent with glycogen deposition on frozen heart section. Snap-frozen myocardium was sent for assessment of glycogen content and enzyme activity. A blood-spot card was sent for single-exon GAA testing. Despite expert recommendations, screening newborns for PD in North Carolina has been delayed owing to anticipated screening cost increase. However, ED visits warranting critical care may cost up to $20,000. We therefore emphasize the unmet need of early diagnosis and treatment of PD.

Joseph Krenzer, DO ([email protected]); Erin Brooks, MD; Xiaofei Zhang, MD, PhD. Department of Pathology, University of Wisconsin - Madison.

Ruvalcaba-Myhre-Smith syndrome (RMSS) is a rare autosomal dominant disorder. Although several dozen cases have been reported in the medical literature, the exact prevalence is unknown. Adding to the confusion are the multiple different names the syndrome has been previously known by. The phenotypic presentation can be quite variable, but some of the most commonly documented manifestations are intestinal hamartomas, macrocephaly, lipomas, hemangiomas, and thyroid issues. Males often have penile lentigines. Approximately 60% of all cases result from germline PTEN gene mutations. We report the case of a 36-year-old man with RMSS who expired of congestive heart failure. Autopsy was notable for morbid obesity (BMI, 59.3), numerous acrochordons and hyperpigmented cutaneous regions, cardiomegaly (630 g), megalencephaly (brain weight, 2070 g), multiple submucosal colonic lipomas (0.2–1.0 cm), and a multinodular thyroid gland. Review of medical records revealed clinical manifestations of RMMS had been detected during childhood; genetic testing approximately 9 years before his death was positive for the PTEN gene mutation. Distinction between RMMS and Cowden syndrome can be challenging, as the diseases show partial clinical overlap and identical PTEN mutations have been described in both. However, clinical manifestations of RMSS are typically present from birth or become apparent in early childhood as in the current case. Morbid obesity with heart failure has not previously been reported in association with RMMS; further study is needed to determine whether such manifestations are linked to the syndrome, lifestyle factors, or a combination of both.