Context.—

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is an uncommon disorder with germline-inactivating mutations in the fumarate hydratase (FH) gene. The kidney cancers that develop in patients with HLRCC are often unilateral and solitary, with a potentially aggressive clinical course; morphologic identification of suspicious cases is of the utmost importance.

Objective.—

To review classic morphologic features of HLRCC-associated renal cell carcinoma, the reported morphologic spectrum of these tumors and their mimics, and the evidence for use of immunohistochemistry and molecular testing in diagnosis of these tumors.

Data Sources.—

University of Michigan cases and review of pertinent literature about HLRCC and the morphologic spectrum of HLRCC-associated renal cell carcinoma.

Conclusions.—

Histologic features, such as prominent nucleoli with perinucleolar halos and multiple architectural patterns within one tumor, are suggestive of HLRCC-associated renal cell carcinoma. However, the morphologic spectrum is broad. Appropriate use of FH immunohistochemistry and referral to genetic counseling is important for detection of this syndrome.

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), also referred to as Reed syndrome,14  is a rare familial cancer disorder caused by a germline mutation in the fumarate hydratase (FH) gene (Figure 1). In contrast to most other types of hereditary renal cell tumors, HLRCC-associated renal cell carcinoma (RCC) is often unilateral and solitary.1  It is crucial to recognize the importance of renal masses in patients with HLRCC because a significant proportion of lower-stage tumors may metastasize.5,6  Previous reports indicate that many patients die within 5 years of diagnosis.7  Approximately 20% to 35% of patients with germline FH mutations develop RCC.8,9  Given the highly aggressive nature of these tumors, annual surveillance in patients with known HLRCC should begin at age 10 years,2,10,11  and surgical removal of even small renal tumors is recommended.5,12  There is not yet a standard therapy for patients with metastatic RCC associated with germline FH mutations. Patients may be treated with tyrosine kinase inhibitors or mechanistic target of rapamycin (mTOR) inhibitors.13  Yamasaki et al14  reported a case in which treatment with 2-deoxy-d-glucose was administered as a glycolysis inhibitor; however, the treatment was unsuccessful. Only a subset of these tumors has been determined to be positive for programmed death ligand 1 (PD-L1) by polymerase chain reaction and/or immunohistochemistry; targeted immunotherapy may be helpful in such occasional cases.15  The FH-deficient tumor growth has been documented to be reduced in mouse models via lactate dehydrogenase-A inhibition.16  Current phase II clinical trials include vandetanib (kinase inhibitor with activity against vascular endothelial growth factor receptor [VEGFR], epidermal growth factor receptor [EGFR], and RET-tyrosine kinase) in combination with metformin (http://clinicaltrials.gov NCT02495103), guadecitabine (SGI-110, DNA methyl transferase inhibitor) (http://clinicaltrials.gov NCT03165721), and bevacizumab (VEGF inhibitor) and erlotinib (tyrosine kinase inhibitor with activity against EGFR) (http://clinicaltrials.gov NCT01130519); the results from those studies may influence management of HLRCC-associated RCC in the future.

Figure 1

Germline fumarate hydratase mutations. Schematic representation of fumarate hydratase (FH) protein, indicating its functional Pfam (protein families) Database (European Molecular Biology Laboratory, Heidelberg, Germany) domains lyase (green) and fumarase (Fum; red). The FH germline mutation positions and types reported in ClinVar (National Center for Biotechnology Information, Bethesda, Maryland) as pathogenic or likely pathogenic are indicated as lollipops. Of the 46 mutation calls, 18 are nonsense mutations (black) and 28 are missense events (purple). Schematic representation was generated with the mutation mapper tool in cBioPortal (cBioPortal for Cancer Genomics, http://www.cbioportal.org).

Figure 1

Germline fumarate hydratase mutations. Schematic representation of fumarate hydratase (FH) protein, indicating its functional Pfam (protein families) Database (European Molecular Biology Laboratory, Heidelberg, Germany) domains lyase (green) and fumarase (Fum; red). The FH germline mutation positions and types reported in ClinVar (National Center for Biotechnology Information, Bethesda, Maryland) as pathogenic or likely pathogenic are indicated as lollipops. Of the 46 mutation calls, 18 are nonsense mutations (black) and 28 are missense events (purple). Schematic representation was generated with the mutation mapper tool in cBioPortal (cBioPortal for Cancer Genomics, http://www.cbioportal.org).

Close modal

The extrarenal manifestations of HLRCC tend to present clinically in patients younger (during their third decade) than those with HLRCC-associated RCC.7,8  Those manifestations include leiomyoma of the skin (Figure 2, A and B) and uterus. The presence of multiple cutaneous leiomyomata is considered a sufficient cause to perform germline testing for FH mutations.17,18  Cutaneous leiomyomata also need to be followed because of the possibility of the tumor transforming into leiomyosarcoma.19,20  Although uterine leiomyomata are fairly common in the general population, patients with HLRCC tend to have hysterectomies for symptomatic leiomyomata approximately 10 years (often by the age of 30 years) earlier than other women have them.7,21  Uterine leiomyomata are a highly penetrant feature of HLRCC and may show nuclear features similar to those seen in HLRCC-associated RCC (Figure 2, C and D), as well as increased cellularity, nuclear pleomorphism, and the presence of eosinophilic globular cytoplasmic inclusions.2225  There have been reports of the development of uterine leiomyosarcoma in patients with HLRCC at a younger age.26  Various adrenal manifestations have been reported in such patients, including adrenal cortical hyperplasia,2729  pheochromocytoma,30  and very rarely, adrenal cortical carcinoma.31  Testicular Leydig cell tumors have been reported in patients with HLRCC,32  although the specificity of that association needs confirmation by additional studies.

Figure 2

Manifestations of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). The cutaneous leiomyomata (A) seen in patients with HLRCC usually do not show distinct morphologic features but often demonstrate loss of fumarate hydratase (FH) expression by immunohistochemistry (B). The epidermis and adnexal structures serve as positive internal controls. C, Uterine leiomyomata in HLRCC may show atypical features and often show nuclear features reminiscent of HLRCC-associated renal cell carcinoma (RCC), although usually not as well developed as those depicted here. D, The FH expression is lost in neoplastic cells. E, The HLRCC-associated RCC often show papillary and tubular growth patterns. F, Classically, HLRCC-associated RCC show foci with prominent inclusion-like nucleoli and perinucleolar halos (hematoxylin-eosin, original magnifications ×100 [A and E], ×200 [F], and ×400 [C and F-inset]; original magnifications ×100 [B] and ×400 [D]).

Figure 2

Manifestations of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). The cutaneous leiomyomata (A) seen in patients with HLRCC usually do not show distinct morphologic features but often demonstrate loss of fumarate hydratase (FH) expression by immunohistochemistry (B). The epidermis and adnexal structures serve as positive internal controls. C, Uterine leiomyomata in HLRCC may show atypical features and often show nuclear features reminiscent of HLRCC-associated renal cell carcinoma (RCC), although usually not as well developed as those depicted here. D, The FH expression is lost in neoplastic cells. E, The HLRCC-associated RCC often show papillary and tubular growth patterns. F, Classically, HLRCC-associated RCC show foci with prominent inclusion-like nucleoli and perinucleolar halos (hematoxylin-eosin, original magnifications ×100 [A and E], ×200 [F], and ×400 [C and F-inset]; original magnifications ×100 [B] and ×400 [D]).

Close modal

The clinical features currently considered to be definitional for HLRCC include either the presence of multiple biopsy-proven cutaneous piloleiomyomas or the presence of 2 of the following minor criteria: (1) surgical treatment for symptomatic uterine leiomyomas before age 40 years, (2) type 2 papillary RCC before age 40 years, or (3) first-degree family member who meets 1 of these criteria.11  Germline mutational testing for FH is necessary for confirmation of HLRCC in a proband or suspected family.

The HLRCC-associated RCC was originally described as papillary RCC or, less commonly, collecting duct carcinoma (CDC).7,8,20,29,33  The initial series8  of 4 high-grade kidney tumors in a family with HLRCC demonstrated areas of papillary architecture, abundant cytoplasm, and large nuclei with inclusion-like eosinophilic nucleoli. One tumor had admixed tubulopapillary architecture (similar to that shown in Figure 2, E), and another had admixed solid, cystic, and sarcomatoid areas. It was later proposed that a notable morphologic feature of these tumors was the large nucleus with a prominent inclusion-like nucleolus and perinucleolar halo (Figure 2, F).34  Although helpful, those nuclear features may be present only in scattered cells in some cases (Figure 3, A and B). In a more recent series of renal tumors from 9 patients with germline FH mutations, papillary architecture predominated in only one-third of cases.35  Fibrovascular cores in these tumors were often edematous or hyalinized, and micropapillary structures were often present. All tumors showed mixed architectural patterns, including tubulopapillary, solid (Figure 3, C and D), and cystic (often with intracystic papillary/tubulopapillary structures). Morphologic overlap with collecting duct carcinoma was common (Figure 3, E and F), with infiltrative carcinoma and inflammation involving desmoplastic stroma. In tubulocystic regions of HLRCC-associated RCC, prominent nucleoli were sometimes seen. Sarcomatoid growth has been described in at least 2 HLRCC-associated RCCs. The widely metastatic HLRCC-associated RCC previously described in a “rapid autopsy” case report36  from our institution showed the classic nuclear features even in the sarcomatoid and rhabdoid components (Figure 4, A through D). A large subset of RCC cases with tubulocystic and associated dedifferentiated collecting duct carcinoma-like areas (“tubulocystic carcinoma with poorly differentiated foci,” similar to those shown in Figure 5, A and B) have been demonstrated to show somatic FH deficiency, and some cases have been confirmed to be associated with HLRCC.37,38  A low-grade oncocytic variant of HLRCC-associated RCC with morphologic resemblance to succinate dehydrogenase (SDH)-deficient RCC (similar to that shown in Figure 5, C and D) has been recently reported.39  Rarely, HLRCC-associated RCCs may be entirely cystic (Figure 5, E and F). A recent study comparing 24 renal tumors from known carriers of the FH mutation to 12 type 2 papillary RCCs from patients with wild-type FH demonstrated that a multiplicity of architectural patterns (including papillary, tubulopapillary, tubulocystic, sarcomatoid, and rhabdoid) within the same tumor was more specific for HLRCC-associated RCC than was the presence of prominent nucleoli with perinucleolar halos.40  Selected entities in the differential diagnosis for HLRCC-associated RCC are presented in the Table. Based on the current literature, the uninvolved kidney in patients with HLRCC may show cysts lined by eosinophilic to clear epithelium with somewhat similar nuclear features.2,40,41 

Figure 3

Morphologic spectrum of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)–associated renal cell carcinoma (RCC). A and B, In some cases of HLRCC-associated RCC, the nuclear features are poorly developed. C, Some cases of HLRCC-associated RCC show papillary and solid growth patterns reminiscent of solid papillary RCC. D, This example shows the prominent inclusion-like nucleoli with prominent perinucleolar halos that are classic for HLRCC-associated RCC. In addition, HLRCC-associated RCC may mimic collecting duct carcinoma with neoplastic tubules demonstrating an infiltrative growth pattern (E); however, fumarate hydratase expression is lost in HLRCC-associated RCC (F) but retained in healthy kidney (F, inset) (hematoxylin-eosin, original magnifications ×200 [A and E], ×400 [B and D], and ×100 [C]; fumarate hydratase, original magnifications ×400 [F] and ×200 [F, inset]).

Figure 3

Morphologic spectrum of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)–associated renal cell carcinoma (RCC). A and B, In some cases of HLRCC-associated RCC, the nuclear features are poorly developed. C, Some cases of HLRCC-associated RCC show papillary and solid growth patterns reminiscent of solid papillary RCC. D, This example shows the prominent inclusion-like nucleoli with prominent perinucleolar halos that are classic for HLRCC-associated RCC. In addition, HLRCC-associated RCC may mimic collecting duct carcinoma with neoplastic tubules demonstrating an infiltrative growth pattern (E); however, fumarate hydratase expression is lost in HLRCC-associated RCC (F) but retained in healthy kidney (F, inset) (hematoxylin-eosin, original magnifications ×200 [A and E], ×400 [B and D], and ×100 [C]; fumarate hydratase, original magnifications ×400 [F] and ×200 [F, inset]).

Close modal
Figure 4

Rapid autopsy for hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). A, A rapid autopsy performed at the University of Michigan on a patient with known HLRCC syndrome (PMID 24625422) demonstrated a 12.5-cm, tan-white, multinodular mass involving most of the left kidney and invading the perinephric and renal sinus fat. B, Histologically, the primary tumor showed sarcomatoid areas with plump spindled cells displaying prominent nucleoli and perinucleolar halos. A metastasis in the pancreas (C, with preserved pancreatic acini indicated by the red arrow) demonstrated rhabdoid cells and multinucleated tumor giant cells with prominent nucleoli and perinucleolar halos (D) (hematoxylin-eosin, original magnifications ×200 [B and C] and ×400 [D]).

Figure 4

Rapid autopsy for hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). A, A rapid autopsy performed at the University of Michigan on a patient with known HLRCC syndrome (PMID 24625422) demonstrated a 12.5-cm, tan-white, multinodular mass involving most of the left kidney and invading the perinephric and renal sinus fat. B, Histologically, the primary tumor showed sarcomatoid areas with plump spindled cells displaying prominent nucleoli and perinucleolar halos. A metastasis in the pancreas (C, with preserved pancreatic acini indicated by the red arrow) demonstrated rhabdoid cells and multinucleated tumor giant cells with prominent nucleoli and perinucleolar halos (D) (hematoxylin-eosin, original magnifications ×200 [B and C] and ×400 [D]).

Close modal
Figure 5

Morphologic spectrum of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)-associated renal cell carcinoma (RCC). A, The HLRCC-associated RCC may show prominent tubulocystic and microcystic growth pattern, with poorly differentiated areas (red arrow). Although there is some morphologic resemblance to tubulocystic carcinoma in focal areas, presence of poorly differentiated foci (B) should prompt consideration of HLRCC and evaluation of fumarate hydratase (FH) status (B-inset, loss of FH expression by IHC). Rare cases of HLRCC-associated RCC have low-grade oncocytic morphology (C) resembling succinate dehydrogenase-deficient RCC; however, FH expression is lost in such HLRCC-associated RCC (D). The HLRCC-associated RCC may have an entirely cystic architecture (E) with patchy prominent nucleoli (F) and loss of FH expression in the neoplastic cells (F-inset) (hematoxylin-eosin, original magnifications ×20 [A], ×200 [B and C], ×10 [E], and ×400 [F]; FH, original magnifications ×200 [B-inset and D] and ×400 [F-inset]).

Figure 5

Morphologic spectrum of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)-associated renal cell carcinoma (RCC). A, The HLRCC-associated RCC may show prominent tubulocystic and microcystic growth pattern, with poorly differentiated areas (red arrow). Although there is some morphologic resemblance to tubulocystic carcinoma in focal areas, presence of poorly differentiated foci (B) should prompt consideration of HLRCC and evaluation of fumarate hydratase (FH) status (B-inset, loss of FH expression by IHC). Rare cases of HLRCC-associated RCC have low-grade oncocytic morphology (C) resembling succinate dehydrogenase-deficient RCC; however, FH expression is lost in such HLRCC-associated RCC (D). The HLRCC-associated RCC may have an entirely cystic architecture (E) with patchy prominent nucleoli (F) and loss of FH expression in the neoplastic cells (F-inset) (hematoxylin-eosin, original magnifications ×20 [A], ×200 [B and C], ×10 [E], and ×400 [F]; FH, original magnifications ×200 [B-inset and D] and ×400 [F-inset]).

Close modal

Differential Diagnoses for Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)–associated Renal Cell Carcinoma (RCC)

Differential Diagnoses for Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)–associated Renal Cell Carcinoma (RCC)
Differential Diagnoses for Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)–associated Renal Cell Carcinoma (RCC)

Overall, HLRCC-associated RCC is relatively enriched for renal tumors, which morphologically demonstrate a mixture of different growth patterns within the same tumor, including tubulopapillary, cystic, and/or solid areas, as well as those with sarcomatoid and/or poorly differentiated components; such tumors, when encountered within pathology/clinical practice, are optimal candidates for further workup at the clinical, immunohistochemical, and/or molecular level to confirm or rule out the possibility of an association with HLRCC.

Immunohistochemical Evaluation/Markers

The 2 immunohistochemical biomarkers that show a high correlation with the diagnosis of HLRCC-associated RCC are fumarate hydratase (FH) and S-(2-succino)-cysteine (2SC). Inactivating mutations in the FH gene lead to loss of fumarate hydratase expression within tumor cells. Cytoplasmic and granular (mitochondrial) expression is considered a positive result; neoplastic cells can be considered to have absent FH expression if there is an appropriate positive internal control in blood vessels, inflammatory cells, or other nonneoplastic cells.35,42  The high level of fumarate in tumor cells leads to aberrant succination of cellular proteins, which is a stable chemical modification that can be detected with the 2SC antibody (available only in a research setting at the time of this publication). Neoplastic cells that stain positively for 2SC expression generally show strong cytoplasmic and nuclear expression, with negative staining in the background healthy renal parenchyma.35,42  A FH/2SC+ immunophenotype in a renal tumor morphologically suspicious for HLRCC-associated RCC should be regarded as a strong trigger to perform further clinical workup and germline mutational testing in an index patient without a previously established diagnosis of HLRCC. Cytokeratin 7 (CK7) and Ulex europaeus agglutinin-1 are generally reported to be negative in HLRCC-associated RCC,34  but these observations are considered to be relatively nonspecific.

Although a renal tumor with FH/2SC+ immunophenotype carries a strong correlation with the presence of the FH mutation at the germline level, the type of FH mutation itself may determine whether FH protein loss can be detected by immunohistochemical evaluation. A small subset of patients with HLRCC-associated RCC may demonstrate equivocal results or retain FH expression within the tumor; a correlated finding reported in the literature is that tumors from patients with FH missense mutations may show equivocal or retained FH expression because of alteration in protein-antibody interactions.25,43 

Immunohistochemical evaluation of FH and 2SC on cutaneous or uterine leiomyoma specimens may be helpful in identifying patients who should undergo further clinical workup or germline mutation testing for HLRCC.23,25,4345  Another group has suggested molecular screening of uterine leiomyoma tissue.46  Although absent FH expression aids in the detection of patients with HLRCC, uterine leiomyomata may be FH deficient in both syndromic and sporadic settings.47 

Molecular Underpinnings of HLRCC

The autosomal-dominant HLRCC syndrome has germline-inactivating mutations in the FH gene (1q42.3–q43).3,7,29,48  The loss of FH function leads to increased levels of intracellular fumarate, which is considered an oncometabolite and has been shown to mediate various proteomic and epigenetic events. Competitive inhibition of prolyl-hydroxylase domain-containing proteins ultimately affects the stability of proteins such as the transcription factor hypoxia-induced factor 1 (HIF1).49,50  Such events lead to succinylation of several proteins, including KEAP1, a component of the cullin 3 E3 ubiquitin ligase, thereby disrupting its regulation of nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 is a key regulator of antioxidant response genes, such as AKR1B10, whose overexpression has been previously shown in HLRCC.5156  Competitive inhibition of multiple α-ketoglutarate–dependent dioxygenases, including histone demethylases, and the TET family of 5-methlycytosine hydroxylases results in decreased histone and DNA demethylation.57  Inhibition of TET has been attributed to the DNA-hypermethylation phenotype of HLRCC. The Cancer Genome Atlas RCC cases with hypermethylation included a subset with loss of FH expression.58  Although molecular aberrations in HLRCC continue to unfold, methods for translating those findings to the clinical practice still need to be determined. Although immunohistochemical assessment can be helpful in classifying RCC, FH-deficient RCC is rarely seen sporadically. Definitive confirmation of HLRCC can be achieved by testing the patient for a germline FH mutation.

Type 2 Papillary RCC

Many examples of HLRCC-associated RCC demonstrate enrichment for papillary architecture; therefore, HLRCC-associated RCC was frequently regarded as type 2 papillary RCC in the past.34,59  Type 2 papillary RCC is characterized by pseudostratified high-grade epithelium with abundant eosinophilic cytoplasm and nuclear anaplasia (Figure 6, A and B). Up to 58% of type 2 papillary RCC may have prominent nucleoli with perinucleolar halos.40  Papillary architecture is the dominant pattern in papillary RCC, although tubular and solid architecture are not uncommon and glomerulations may be seen in approximately 20% of cases, especially those with type 1 morphology.60  Papillary RCC often has a well-defined tumor capsule and lacks extensive infiltration. There is clear prognostic importance in accurately classifying these tumors because papillary RCC is generally considered to have a more-favorable prognosis than clear cell RCC or HLRCC-associated RCC has, and metastatic disease is fairly uncommon at presentation in papillary RCC.1,6164 

Figure 6

Differential diagnosis. Type 2 papillary renal cell carcinoma (RCC) can show a solid growth pattern with prominent nucleoli (A), which may raise concern for hereditary leiomyomatosis and RCC syndrome (HLRCC)–associated RCC; however, fumarate hydratase (FH) expression is retained in papillary RCC (B). Both TFE3-translocation RCC (C) and TFEB-amplified RCC (D) can show prominent, papillary architecture with prominent nucleoli. E, Collecting duct carcinoma is an infiltrative tumor that can show prominent nucleoli with poorly developed halos that may raise concern for HLRCC-associated RCC. F, Clear cell RCC (F) can show prominent pseudopapillary growth and prominent nucleoli similar to HLRCC-associated RCC; however, carbonic anhydrase IX shows diffuse membranous staining in clear cell RCC (inset) (hematoxylin-eosin, original magnifications ×200 [A, C, D, and F] and ×400 [E]); original magnification ×200 [B]; original magnification ×200 [F-inset]).

Figure 6

Differential diagnosis. Type 2 papillary renal cell carcinoma (RCC) can show a solid growth pattern with prominent nucleoli (A), which may raise concern for hereditary leiomyomatosis and RCC syndrome (HLRCC)–associated RCC; however, fumarate hydratase (FH) expression is retained in papillary RCC (B). Both TFE3-translocation RCC (C) and TFEB-amplified RCC (D) can show prominent, papillary architecture with prominent nucleoli. E, Collecting duct carcinoma is an infiltrative tumor that can show prominent nucleoli with poorly developed halos that may raise concern for HLRCC-associated RCC. F, Clear cell RCC (F) can show prominent pseudopapillary growth and prominent nucleoli similar to HLRCC-associated RCC; however, carbonic anhydrase IX shows diffuse membranous staining in clear cell RCC (inset) (hematoxylin-eosin, original magnifications ×200 [A, C, D, and F] and ×400 [E]); original magnification ×200 [B]; original magnification ×200 [F-inset]).

Close modal

Although HLRCC-associated RCC and type 2 papillary RCC demonstrate extensive morphologic overlap, some features help discriminate between those 2 entities. The HLRCC-associated RCC, when compared with papillary RCC, more commonly shows a variety or a mixture of diverse architectural patterns within the same tumor.40  In contrast to papillary RCC, HLRCC-associated RCC is markedly infiltrative and lacks the relative circumscription generally associated with true papillary RCC. Immunohistochemical evaluation can aid in the distinction as well. Papillary RCC is usually stains diffusely positive for CK7 and AMACR expression, whereas those markers are commonly negative in HLRCC-associated RCC. Sporadic papillary RCC often demonstrates trisomy of chromosomes 7 and 17, with loss of chromosome Y. Hereditary papillary renal carcinoma syndrome–associated cases, as well as a minor subset of sporadic papillary RCC, have been demonstrated to harbor activating mutations of the MET oncogene.65  Although the hypoxia pathway–associated genes can be somewhat turned on and overexpressed in HLRCC-associated RCC (see the narrative above in the molecular section), HLRCC-associated RCC in general shows limited to negative carbonic anhydrase IX expression. However, significantly, in contrast to papillary RCC, HLRCC-associated RCC demonstrates a loss of FH expression by IHC in most cases.

Melanogenesis-Associated Transcription Factor Family Aberration–Associated RCC

Similar to HLRCC-associated RCC, both TFE3-translocation RCC and TFEB-amplified RCC tend to be high-grade tumors with mixtures of architectural patterns, including papillary. The classic appearance of TFE3-translocation RCC is a tumor with a papillary architecture and cells with voluminous clear to eosinophilic cytoplasm and numerous psammoma bodies (Figure 6, C).66,67  Much like HLRCC-associated RCC, TFE3-translocation RCC has been reported to have morphologic features overlapping with several other RCC subtypes.6873  High-grade RCCs, which demonstrate subnuclear clearing, with linear nuclear array and nuclear pseudoinclusions, have been reported to be enriched in TFE3 genomic aberrations.73,74  Although not yet included in the World Health Organization classification of renal tumors, TFEB-amplified RCC has been recognized as an emerging entity. Most reported cases of TFEB-amplified RCC show predominant papillary architecture with high-grade features and an oncocytic phenotype (Figure 6, D).68,7577  Although the diagnosis of translocation-associated carcinoma should always be entertained in a renal tumor that demonstrates a relative underexpression of cytokeratins or epithelial markers by immunohistochemistry, cytokeratin expression (focal or diffuse) can be present in these tumors, and lack of cytokeratin expression generally does not serve as a very faithful tool in delineating these entities diagnostically. Immunohistochemical stains for evaluating TFE3 and TFEB protein expression exist but are technically challenging to perform and suffer from fixation and other issues78,79 ; fluorescence in situ hybridization (FISH), in contrast, is a useful tool for accurate classification of these tumors.70,71  TFE3-translocation RCC and TFEB-amplified RCC, like HLRCC-associated RCC and clear cell RCC, are potentially aggressive subtypes of RCC.68,7477,8082 

The melanogenesis-associated transcription factor (MITF) aberration–associated RCC and HLRCC-associated RCC have been reported to show broad and overlapping morphologic spectrums. Helpful features to aid in the diagnosis of TFE3-translocation RCC include the presence of dual (eosinophilic and clear) cytoplasmic tones and psammoma bodies, as well as identification of TFE3 rearrangement by FISH. TFEB-amplified RCC generally demonstrates high-grade oncocytic cells with papillary architecture and will show TFEB amplification by FISH. At the morphologic level, HLRCC-associated RCCs are enriched for the features described in the preceding sections including a spectrum or mixture of diverse morphologic patterns within the same tumor. When MITF aberration–associated RCCs and HLRCC-associated RCCs are in the differential diagnosis for high-grade tumors with prominent nucleoli and papillary architecture, immunohistochemical and molecular assessment can be helpful because HLRCC-associated RCC, unlike the MITF aberration–associated RCC, demonstrates loss of FH expression by IHC and does not show MITF aberrations by FISH.

Collecting Duct Carcinoma

CDC comprises one of the major differential diagnoses for HLRCC-associated RCC at the clinical, morphologic, and immunohistochemical levels. Collecting duct carcinoma, like HLRCC-associated RCC, tends to occur in younger patients.1  Approximately 50% of patients with CDC have metastatic disease at the time of presentation, and the clinical course can be rapid with many patients dead of disease within 2 years.83  Collecting duct carcinoma is a medulla-centered tumor, although large tumors can involve the cortex secondarily and mimic cortical tumors. Similar to HLRCC-associated RCC, CDC shows multiple architectural patterns with an infiltrative growth pattern and occasional multinodularity.6,84  Per the 2016 World Health Organization (Geneva, Switzerland) classification of renal tumors,1  diagnostic criteria supporting the diagnosis of CDC include medullary involvement, predominant tubular morphology, desmoplastic stromal reaction, high-grade cytology, an infiltrative growth pattern, and the absence of other RCC or urothelial carcinoma. Growth patterns described in CDC include tubular, solid, acinar, papillary, cribriform, and signet ring. Collecting duct carcinoma tends to demonstrate a desmoplastic stroma and associated inflammation (Figure 6, E). Tubular dysplasia is often seen in the kidney parenchyma adjacent to CDC. At the immunohistochemical level, CDC generally stains positive for PAX8, high–molecular-weight cytokeratin, CK7, and carcinoembryonic antigen and has negative p63 expression.84,85  Interestingly, a recent Foundation Medicine (Cambridge, Massachusetts) study demonstrated that nearly one-third of CDCs have genomic alterations in NF2, indicating that mTOR inhibitors may be beneficial for treatment of a subset of CDCs.86 

Because of the immense morphologic overlap, some examples of HLRCC-associated RCC were originally classified as CDC in the literature; however, FH immunohistochemistry and certain morphologic features coupled with genetic testing (as necessary) can aid in the accurate classification of these tumors. Morphologically, HLRCC-associated RCC often demonstrates hyalinized fibrovascular cores, rather than the delicate or absent fibrovascular cores of CDC. Although a tubulopapillary growth pattern is common in both HLRCC-associated RCC and CDC, intracystic papillary and tubulocystic growth is more often seen in HLRCC-associated RCC.6,84  The presence of prominent nucleoli with classic perinucleolar halos is also more indicative of the possibility of an association with HLRCC. In both entities, cytologic features are high grade, with marked pleomorphism and brisk mitotic activity. In contrast to CDC, HLRCC-associated RCC is usually negative for CK7 expression,34  and FH expression is lost in most HLRCC-associated RCCs.

One can hypothesize that a small subset of CDCs might demonstrate the loss of FH protein expression because of a somatic FH genomic aberration. Hence, clinical evaluation and germline testing is very important in patients who demonstrate RCC with CDC-like morphology and FH protein loss as assessed by immunohistochemistry. Germline mutational testing in such cases should correctly categorize the patients into the HLRCC subgroup versus those with a somatic FH mutation.

High-Grade Clear Cell RCC

Despite its name, high-grade clear cell RCC tends to have eosinophilic cytoplasm and may demonstrate papillary or pseudopapillary architecture (Figure 6, F), thus, presenting itself as a mimic to HLRCC-associated RCC and other high-grade renal tumor subtypes. Although pseudopapillary architecture and focal true papillary architecture are acceptable for the diagnosis of clear cell RCC, a prominent papillary architecture should prompt consideration of other diagnoses, including papillary RCC and HLRCC-associated RCC. Even high-grade clear cell RCC usually retains the delicate (“racemose”) vascular network, at least focally. Clear cell RCC is typically positive for pancytokeratin and carbonic anhydrase IX (CAIX, diffuse membranous), and negative for AMACR and CD117. Often, CAIX expression can be appreciated in perinecrotic areas in other tumors, but diffuse membranous reactivity is generally not seen in HLRCC-associated RCC. CK7 can be focally positive in cystic and/or fibrotic areas of clear cell RCC87  but is usually negative in HLRCC-associated RCC. Clear cell RCC is the most common subtype of RCC, as well as the most aggressive of the common subtypes of RCC, with an overall 5-year survival of 75%.1,61,88  Most clear cell RCCs show band 3p copy number losses at the molecular level. von Hippel-Lindau syndrome confers predisposition to the development of clear cell RCC.1 

To summarize, clear cell RCC and HLRCC-associated RCC are both aggressive neoplasms that can show a papillary or pseudopapillary architecture. Clear cell RCC often shows diffuse membranous positivity for CAIX and retains FH expression. Most examples of clear cell RCC retain the characteristic, delicate vascular network, at least focally, and do not show a significant proportion of true papillary architecture. In contrast, HLRCC-associated RCC shows the loss of FH expression and lacks diffuse positivity for CAIX expression.

Tubulocystic Carcinoma With Poorly Differentiated Foci

In 2016, Smith and colleagues37  reported a series of 29 tubulocystic carcinomas with poorly differentiated foci of infiltrative adenocarcinoma and demonstrated that RCCs with that morphology are enriched for FH deficiency. Tubulocystic RCC (when “pure”) is a relatively rare and well-circumscribed tumor, classically composed of small- to intermediate-sized, sometimes dilated, tubules (Figure 7, A) with a single layer of flat, hobnail, cuboidal, or columnar epithelium with uniform, large nuclei and prominent nucleoli (Figure 7, B) and frequently fibrotic stroma; no solid or papillary areas are present. Renal cell carcinoma with tubulocystic tumors with poorly differentiated foci of infiltrative adenocarcinoma morphology, in contrast, has a component of classic tubulocystic carcinoma-like morphology, in addition to poorly differentiated foci with infiltrative adenocarcinoma or collecting-duct type features and focal papillary growth. Tubulocystic RCC, when pure, is thought to have low malignant potential82 ; however, patients with tubulocystic carcinomas with poorly differentiated foci of infiltrative adenocarcinoma morphology have more aggressive disease than do those with pure tubulocystic RCC.89 

Figure 7

Differential diagnosis. Tubulocystic carcinoma is a well-circumscribed tumor composed of tubules and cystic spaces (A), lined by cuboidal cells with prominent central nucleoli (B), which may prompt consideration of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)–associated renal cell carcinoma (RCC), particularly if areas of poor differentiation are present. Succinate dehydrogenase (SDH)-deficient RCC (C) shows cells with uniform nuclei, fine chromatin, and flocculent eosinophilic cytoplasm, with occasional inclusions arranged in nests (similar to a rare, low-grade, oncocytic variant of HLRCC-associated RCC) but demonstrates loss of SDH subunit B expression by immunohistochemistry (D) and retained fumarate hydratase (FH) expression (not shown). Renal cell carcinoma, type unclassified (E), may show morphologic overlap with high-grade RCCs, including HLRCC-associated RCC and translocation RCC; however, this case showed retained FH expression by immunohistochemistry (F) and lacked TFE3 or TFEB aberrations by fluorescence in situ hybridization (not shown) (hematoxylin-eosin, original magnifications ×100 [A], ×400 [B], and ×200 [C and E]; original magnification ×100 [D]; original magnification ×200 [F]).

Figure 7

Differential diagnosis. Tubulocystic carcinoma is a well-circumscribed tumor composed of tubules and cystic spaces (A), lined by cuboidal cells with prominent central nucleoli (B), which may prompt consideration of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)–associated renal cell carcinoma (RCC), particularly if areas of poor differentiation are present. Succinate dehydrogenase (SDH)-deficient RCC (C) shows cells with uniform nuclei, fine chromatin, and flocculent eosinophilic cytoplasm, with occasional inclusions arranged in nests (similar to a rare, low-grade, oncocytic variant of HLRCC-associated RCC) but demonstrates loss of SDH subunit B expression by immunohistochemistry (D) and retained fumarate hydratase (FH) expression (not shown). Renal cell carcinoma, type unclassified (E), may show morphologic overlap with high-grade RCCs, including HLRCC-associated RCC and translocation RCC; however, this case showed retained FH expression by immunohistochemistry (F) and lacked TFE3 or TFEB aberrations by fluorescence in situ hybridization (not shown) (hematoxylin-eosin, original magnifications ×100 [A], ×400 [B], and ×200 [C and E]; original magnification ×100 [D]; original magnification ×200 [F]).

Close modal

Renal cell carcinoma that demonstrates a tubulocystic growth pattern with associated poorly differentiated foci should prompt consideration of HLRCC-associated RCC. The HLRCC-associated RCC, in contrast to the more-indolent pure tubulocystic RCC, often shows an overtly invasive phenotype with a mixture of different growth patterns. From an immunohistochemical perspective, pure tubulocystic RCC demonstrates positive CK7, AMACR, and FH expression, whereas tubulocystic RCC with poorly differentiated foci consistent with HLRCC-associated RCC is negative for FH expression in most cases.37,38,90 

SDH-Deficient RCC

Succinate dehydrogenase–deficient RCC may show some overlapping morphologic features with the low-grade oncocytic variant of HLRCC-associated RCC in a few cases. The SDH-deficient RCC is classically described as an oncocytic carcinoma with predominantly solid or nested architecture (Figure 7, C) and sometimes having a minor component of tubular or microcystic growth pattern.39,91  The neoplastic cells show uniform cytology, polygonal shape, fine chromatin and inconspicuous nucleoli (“neuroendocrine features”), and flocculent/vacuolated eosinophilic cytoplasm with occasional inclusions of pink hyaline material.39  Intratumoral mast cells are commonly seen, and benign renal tubules may be entrapped at the periphery of the tumor. The neoplastic cells are positive for PAX8 expression, variably positive for EMA (delicate membranous pattern), CAM 5.2, and AE1/AE3 and are generally negative for CK7 and CD117 expression.91  Characteristically, the neoplastic cells show loss of SDHB protein expression by immunohistochemistry (Figure 7, D) because of mitochondrial complex II instability resulting from mutation of SDHA, SDHB, SDHC, or SDHD.91  A recent study39  reported a series of 4 RCCs with similar morphology but strong and diffuse SDHB expression, consistent with an intact SDH complex. Those cases were negative for FH expression and positive for 2SC by immunohistochemistry. Such data indicate that a subset of HLRCC-associated RCC might demonstrate a relatively lower-grade morphology that is also enriched for oncocytic features. Such FH-deficient, relatively low-grade oncocytic tumors may have a more-favorable outcome, based on the current (albeit limited) data.

Although some instances of HLRCC-associated RCC show a morphology that is nearly identical to that of SDH-deficient RCC, based on the limited data presented in the literature, the distinction should be faithfully resolved by immunohistochemical evaluation. The HLRCC-associated RCCs interrogated so far demonstrate retained SDHB expression and absent FH expression, compared with the absent SDHB expression and retained FH expression in SDH-deficient RCC.

Together, FH and SDH are involved in pathways that respond to metabolic stress within the kidney and are known to have a central role in the mitochondrial tricarboxylic acid cycle, which is coupled to energy production through oxidative phosphorylation. Mutations in both FH and SDH can result in dysregulation of metabolic pathways involved in oxygen or energy sensing, suggesting that kidney cancers associated with such genomic aberrations result from a dysfunctional metabolic state within the cell. In that context, the morphologic overlap of low-grade oncocytic RCC shared by SDH-deficient carcinomas and FH-deficient HLRCC-associated RCC in a few cases can otherwise be defined by disparate classic phenotypes. It is interesting (but maybe not surprising) that metabolic insults resulting from mutational dysfunction of 2 distinct but mutually cooperative genes (FH and SDH in this context) can uncommonly result in tumors with a common morphologic phenotype.

RCC, Type Unclassified

If a primary RCC does not fit well into a well-described World Health Organization category based on morphologic, immunophenotypic, and/or molecular grounds, it is best to assign it to the RCC, type unclassified, category for more-accurate prognostication and guidance of therapy. Figure 7, E and F, demonstrates an example of a high-grade RCC with retained FH expression, absent CAIX expression, and the absence of MITF aberrations by FISH (not shown), which falls best under the RCC, type unclassified, category. Recent literature highlights the fact that even RCCs correctly assigned to the type unclassified category demonstrate distinct molecular subsets with implications for potential targeted therapy.92  The Chen et al92  molecular analysis of 62 high-grade primary RCCs with unclassified histology demonstrated that approximately three-quarters of cases fell into molecularly distinct subsets. One subset of RCC with unclassified histology demonstrated NF2 loss and dysregulated Hippo-YAP signaling, and was associated with a poor prognosis; potential future therapies in such cases may interfere with YAP activity. Another subset of RCC with unclassified histology demonstrated mTORC1 hyperactivity and more-favorable prognosis; patients with such tumors may benefit from treatment with mTOR inhibitors. The worst prognosis in the cohort was observed in the 4 FH-deficient RCCs with unclassified histology. Of note, although 3 patients were confirmed to have germline FH mutations, the fourth had a somatic FH alteration. Further studies are needed to elucidate the clinical behavior of RCC with somatic FH alterations in comparison to HLRCC-associated RCC.

A Practical Surgical Pathology Diagnostic Approach

In general, HLRCC-associated RCC has an aggressive clinical course, with frequent metastases and subsequent death. As such, the identification of patients with HLRCC-associated RCC is important because those patients and their families should undergo regular clinical assessment and genetic evaluation and counseling.

The morphologic spectrum of HLRCC-associated RCC is broad and overlaps with multiple other entities including clear cell RCC, papillary RCC, tubulocystic RCC with poorly differentiated foci, CDC, SDH-deficient RCC, and translocation RCC. Histologic features in a high-grade RCC, such as prominent nucleoli with perinucleolar halos (particularly when diffuse), are considered suggestive of HLRCC-associated RCC. Appropriate use of FH immunohistochemistry coupled with a clinical workup and referral to genetic counseling, as outlined above, is important for detection of this syndrome. Until a germline FH mutation has been confirmed, the diagnosis of FH-deficient RCC is most appropriate for renal tumors with loss of FH protein expression upon immunohistochemistry.

On a day-to-day basis, for a pathologist who is presented with a renal tumor with some or all of the morphologic features described above, FH immunohistochemical evaluation along with other markers (especially CK7 and CAIX) can be a good starting point for a diagnostic workup. For patients with a previously unestablished diagnosis, communication with a patient's urologist and/or medical oncologist about the clinical stigmata and the patient's personal and family history is extremely important because these data might further indicate clues to an association with HLRCC syndrome. Loss of FH protein expression in renal tumors upon immunohistochemistry is considered a good trigger for launching germline mutational testing and a thorough clinical evaluation for patients who might harbor HLRCC that has not otherwise been proven. In that context, a small subset of patients with HLRCC-associated RCC may demonstrate preserved or reduced FH protein expression (instead of the completely absent immunoexpression); hence, thorough communication with the clinician about strongly suspicious RCC morphology (for HLRCC, even with retained or equivocal FH loss) is paramount, so that appropriate clinical and/or genetic testing may be performed.

The above discussion underscores the essential role of the surgical pathologist in the early recommendation of genetic consultation for patients harboring tumors in the morphologic and clinical spectrum described above. There is ample evidence now that the genomic/molecular classification of renal tumors is becoming increasingly important because it may allow for a clinically useful, algorithmic subdivision based on predicted response to treatment and a more-accurate risk assessment for small renal masses.93  Recognition and correct classification of these RCC subtypes are very important for accurate risk stratification and therapeutic management.

1
Fleming
S
,
Amin
MB
,
Storkel
S.
Collecting duct carcinoma
.
In
:
Moch
H
,
Humphrey
PA
,
Ulbright
TM
,
Reuter
VE
,
eds
.
WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed
.
Lyon, France
:
IARC Press;
2016
:
29
30
.
World Health Organization Classification of Tumours; vol 8
.
2
Lehtonen
HJ
,
Kiuru
M
,
Ylisaukko-oja
SK
, et al.
Increased risk of cancer in patients with fumarate hydratase germline mutation
.
J Med Genet
.
2006
;
43
(
6
):
523
526
.
3
Udager
AM
,
Mehra
R.
Morphologic, molecular, and taxonomic evolution of renal cell carcinoma: a conceptual perspective with emphasis on updates to the 2016 World Health Organization Classification
.
Arch Pathol Lab Med
.
2016
;
140
(
10
):
1026
1037
.
4
Reed
WB
,
Walker
R
,
Horowitz
R.
Cutaneous leiomyomata with uterine leiomyomata
.
Acta Derm Venereol
.
1973
;
53
(
5
):
409
416
.
5
Grubb
RL
III
,
Franks
ME
,
Toro
J
, et al.
Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer
.
J Urol
.
2007
;
177
(
6
):
2074
2079
.
6
Ohe
C
,
Smith
SC
,
Sirohi
D
, et al.
Reappraisal of morphologic differences between renal medullary carcinoma, collecting duct carcinoma, and fumarate hydratase-deficient renal cell carcinoma
.
Am J Surg Pathol
.
2018
;
42
(
3
):
279
292
.
7
Toro
JR
,
Nickerson
ML
,
Wei
MH
, et al.
Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America
.
Am J Hum Genet
.
2003
;
73
(
1
):
95
106
.
8
Launonen
V
,
Vierimaa
O
,
Kiuru
M
, et al.
Inherited susceptibility to uterine leiomyomas and renal cell cancer
.
Proc Natl Acad Sci U S A
.
2001
;
98
(
6
):
3387
3392
.
9
Tickoo
SK
,
Reuter
VE
.
Differential diagnosis of renal tumors with papillary architecture
[
published correction appears in
Adv Anat Pathol
.
2015
;
22
(
4
):
281
].
Adv Anat Pathol
.
2011
;
18
(
2
):
120
132
.
10
van Spaendonck-Zwarts
KY
,
Badeloe
S
,
Oosting
SF
, et al.
Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age: implications for surveillance
.
Fam Cancer
.
2012
;
11
(
1
):
123
129
.
11
Smit
DL
,
Mensenkamp
AR
,
Badeloe
S
, et al.
Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis
.
Clin Genet
.
2011
;
79
(
1
):
49
59
.
12
Metwalli
AR
,
Linehan
WM
.
Nephron-sparing surgery for multifocal and hereditary renal tumors
.
Curr Opin Urol
.
2014
;
24
(
5
):
466
473
.
13
Menko
FH
,
Maher
E
,
Schmidt
LS
, et al.
Hereditary leiomyomatosis and renal cell cancer (HLRCC). Renal cancer risk, surveillance, and treatment
.
Fam Cancer
.
2014
;
13
(
4
):
637
644
.
14
Yamasaki
T
,
Tran
TA
,
Oz
OK
, et al.
Exploring a glycolytic inhibitor for the treatment of an FH deficient type 2 papillary RCC
.
Nat Rev Urol
.
2011
;
8
(
3
):
165
171
.
15
Alaghehbandan
R
,
Stehlik
J
,
Trpkov
K
, et al.
Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) expression in fumarate hydratase-deficient renal cell carcinoma
.
Ann Diagn Pathol
.
2017
;
29
(
1
):
17
22
.
16
Xie
H
,
Valera
VA
,
Merino
MJ
, et al.
LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer
.
Mol Cancer Ther
.
2009
;
8
(
3
):
626
635
.
17
Stewart
L
,
Glenn
G
,
Toro
JR
.
Cutaneous leiomyomas: a clinical marker of risk for hereditary leiomyomatosis and renal cell cancer
.
Dermatol Nurs
.
2006
;
18
(
4
):
335
341
.
18
Stewart
L
,
Glenn
GM
,
Stratton
P
, et al.
Association of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer
.
Arch Dermatol
.
2008
;
144
(
12
):
1584
1592
.
19
Henley
ND
,
Tokarz
VA
.
Multiple cutaneous and uterine leiomyomatosis in a 36-year-old female, and discussion of hereditary leiomyomatosis and renal cell carcinoma
.
Int J Dermatol
.
2012
;
51
(
10
):
1213
1216
.
20
Wei
MH
,
Toure
O
,
Glenn
GM
, et al.
Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer
.
J Med Genet
.
2006
;
43
(
1
):
18
27
.
21
Keshavarz
H
,
Hillis
SD
,
Kieke
BA
,
Marchbanks
PA
.
Hysterectomy surveillance—United States, 1994–1999
.
MMWR Morb Mortal Wkly Rep
.
2002
;
51
(
SS05
):
1
8
.
22
Sanz-Ortega
J
,
Vocke
C
,
Stratton
P
,
Lineham
WM
,
Merinjo
MJ
.
Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome
.
Am J Surg Pathol
.
2013
;
37
(
1
):
74
80
.
23
Reyes
C
,
Karamurzin
Y
,
Frizzell
N
, et al.
Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry
.
Mod Pathol
.
2014
;
27
(
7
):
1020
1027
.
24
Garg
K
,
Tickoo
SK
,
Soslow
RA
,
Reuter
VE
.
Morphologic features of uterine leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report
.
Am J Surg Pathol
.
2011
;
35
(
8
):
1235
1237
.
25
Joseph
NM
,
Solomon
DA
,
Frizzell
N
,
Rabban
JT
,
Zaloudek
C
,
Garg
K.
Morphology and immunohistochemistry for 2SC and FH aid in detection of fumarate hydratase gene aberrations in uterine leiomyomas from young patients
.
Am J Surg Pathol
.
2015
;
39
(
11
):
1529
1539
.
26
Ylissaukko-oja
SK
,
Kiuru
M
,
Lehtonen
HJ
, et al.
Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients
.
Int J Cancer
.
2006
;
119
(
2
):
283
287
.
27
Matyakhina
L
,
Freedman
RJ
,
Bourdeau
I
, et al.
Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical Cushing syndrome: a clinical and molecular genetic investigation
.
J Clin Endocrinol Metab
.
2005
;
90
(
6
):
3773
3779
.
28
Shuch
B
,
Ricketts
CJ
,
Vocke
CD
, et al.
Adrenal nodular hyperplasia in hereditary leiomyomatosis and renal cell cancer
.
J Urol
.
2013
;
189
(
2
):
430
435
.
29
Tomlinson
IP
,
Alam
NA
,
Rowan
AJ
, et al
Multiple Leiomyoma Consortium
.
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer
.
Nat Genet
.
2002
;
30
(
4
):
406
410
.
30
Udager
AM
,
Magers
MJ
,
Goerke
DM
, et al.
The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes
.
Hum Pathol
.
2018
;
71
(
1
):
47
54
.
31
Guo
X
,
Chen
H
,
Fu
H
,
Wu
H.
Hereditary leiomyomatosis and renal cell carcinoma syndrome combined with adrenocortical carcinoma on 18F-FDG PET/CT
.
Clin Nucl Med
.
2017
;
42
(
9
):
692
694
.
32
Carvajal-Carmona
LG
,
Alam
NA
,
Pollard
PJ
, et al.
Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations
.
J Clin Endocrinol Metab
.
2006
;
91
(
8
):
3071
3075
.
33
Alam
NA
,
Rowan
AJ
,
Wortham
NC
, et al.
Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency
.
Hum Mol Genet
.
2003
;
12
(
11
):
1241
1252
.
34
Merino
MJ
,
Torres-Cabala
C
,
Pinto
P
,
Linehan
WM
.
The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome
.
Am J Surg Pathol
.
2007
;
31
(
10
):
1578
1585
.
35
Chen
YB
,
Brannon
AR
,
Toubaji
A
, et al.
Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry
.
Am J Surg Pathol
.
2014
;
38
(
5
):
627
637
.
36
Udager
AM
,
Alva
A
,
Chen
YB
, et al.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a rapid autopsy report of metastatic renal cell carcinoma
.
Am J Surg Pathol
.
2014
;
38
(
4
):
567
577
.
37
Smith
SC
,
Trpkov
K
,
Chen
YB
, et al.
Tubulocystic carcinoma of the kidney with poorly differentiated foci: a frequent morphologic pattern of fumarate hydratase–deficient renal cell carcinoma
.
Am J Surg Pathol
.
2016
;
40
(
11
):
1457
1472
.
38
Smith
SC
,
Trpkov
K
,
Mehra
R
, et al.
Is tubulocystic carcinoma with dedifferentiation a form of HLRCC/fumarate hydratase–deficient RCC [abstract]?
Mod Pathol
.
2015
;
28
(
suppl 2
):
260A
.
39
Smith
SC
,
Sirohi
D
,
Ohe
C
, et al.
A distinctive, low-grade oncocytic fumarate hydratase-deficient renal cell carcinoma, morphologically reminiscent of succinate dehydrogenase-deficient renal cell carcinoma
.
Histopathology
.
2017
;
71
(
1
):
42
52
.
40
Muller
M
,
Guillaud-Bataille
M
,
Salleron
J
, et al.
Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma from kidney tumors without FH gene alteration
[
published online ahead of print
February
6,
2018]
.
Mod Pathol
. doi:.
41
Pollard
PJ
,
Spencer-Dene
B
,
Shukla
D
, et al.
Targeted inactivation of FH1 causes proliferative renal cyst development and activation of the hypoxia pathway
.
Cancer Cell
.
2007
;
11
(
4
):
311
319
.
42
Trpkov
K
,
Hes
O
,
Agaimy
A
, et al.
Fumarate hydratase–deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome
.
Am J Surg Pathol
.
2016
;
40
(
7
):
865
875
.
43
Carter
CS
,
Skala
SL
,
Chinnaiyan
AM
, et al.
Immunohistochemical characterization of fumarate hydratase (FH) and succinate dehydrogenase (SDH) in cutaneous leiomyomas for detection of familial cancer syndromes
.
Am J Surg Pathol
.
2017
;
41
(
6
):
801
809
.
44
Buelow
B
,
Cohen
J
,
Nagymanyoki
Z
, et al.
Immunohistochemistry for 2-succinocysteine (2SC) and fumarate hydratase (FH) in cutaneous leiomyomas may aid in identification of patients with HLRCC (hereditary leiomyomatosis and renal cell carcinoma syndrome)
.
Am J Surg Pathol
.
2016
;
40
(
7
):
982
988
.
45
Llamas-Velasco
M
,
Requena
L
,
Adam
J
,
Frizzell
N
,
Hartmann
A
,
Mentzel
T.
Loss of fumarate hydratase and aberrant protein succination detected With S-(2-Succino)-cysteine staining to identify patients with multiple cutaneous and uterine leiomyomatosis and hereditary leiomyomatosis and renal cell cancer syndrome
.
Am J Dermatopathol
.
2016
;
38
(
12
):
887
891
.
46
Martinek
P
,
Grossmann
P
,
Hes
O
, et al.
Genetic testing of leiomyoma tissue in women younger than 30 years old might provide an effective screening approach for the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC)
.
Virchows Arch
.
2015
;
467
(
2
):
185
191
.
47
Harrison
WJ
,
Andrici
J
,
Maclean
F
, et al.
Fumarate hydratase–deficient uterine leiomyomas occur in both the syndromic and sporadic settings
.
Am J Surg Pathol
.
2016
;
40
(
5
):
599
607
.
48
Lehtonen
HJ
.
Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics
.
Fam Cancer
.
2011
;
10
(
2
):
397
411
.
49
Isaacs
JS
,
Jung
YJ
,
Mole
DR
, et al.
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability
.
Cancer Cell
.
2005
;
8
(
2
):
143
153
.
50
Pollard
PJ
,
Briere
JJ
,
Alam
NA
, et al.
Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations
.
Hum Mol Genet
.
2005
;
14
(
15
):
2231
2239
.
51
Alderson
NL
,
Wang
Y
,
Blatnik
M
, et al.
S-(2-succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate
.
Arch Biochem Biophys
.
2006
;
450
(
1
):
1
8
.
52
Bardella
C
,
El-Bahrawy
M
,
Frizzell
N
, et al.
Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status
.
J Pathol
.
2011
;
225
(
1
):
4
11
.
53
Kansanen
E
,
Kuosmanen
SM
,
Leinonen
H
,
Levonen
AL
.
The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer
.
Redox Biol
.
2013
;
1
(
1
):
45
49
.
54
Adam
J
,
Hatipoglu
E
,
O'Flaherty
L
, et al.
Renal cyst formation in Fh1-deficient mice is independent of the HIF/PHD pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling
.
Cancer Cell
.
2011
;
20
(
4
):
524
537
.
55
Ooi
A
,
Wong
JC
,
Petillo
D
, et al.
An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma
.
Cancer Cell
.
2011
;
20
(
4
):
511
523
.
56
Yang
M
,
Soga
T
,
Pollard
PJ
,
Adam
J.
The emerging role of fumarate as an oncometabolite
.
Front Oncol
.
2012
;
2
(
85
):
1
7
.
57
Xiao
M
,
Yang
H
,
Xu
W
, et al.
Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors
[
published correction appears in
Genes Dev
.
2015
;
29
(
8
):
887
].
Genes Dev
.
2012
;
26
(
12
):
1326
1338
.
58
Chen
F
,
Zhang
Y
,
Senbabaoglu
Y
, et al.
Multilevel genomics-based taxonomy of renal cell carcinoma
.
Cell Rep
.
2016
;
14
(
10
):
2476
2489
.
59
Tickoo
SK
,
Reuter
VE
.
Kidney tumors and tumor-like conditions
.
In
:
Amin
MB,
McKenney
JK,
Tickoo
SK,
et al,
eds
.
Diagnostic Pathology: Genitourinary
.
Salt Lake City, UT
:
Amirsys
;
2010
:
1.1
1.247
.
60
Warrick
JI
,
Tsodikov
A
,
Kunju
LP
, et al.
Papillary renal cell carcinoma revisited: a comprehensive histomorphologic study with outcome correlations
.
Hum Pathol
.
2014
;
45
(
6
):
1139
1146
.
61
Amin
MB
,
Amin
MB
,
Tamboli
P
, et al.
Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases
.
Am J Surg Pathol
.
2002
;
26
(
3
):
281
291
.
62
Delahunt
B
,
Cheville
JC
,
Martignoni
G
, et al
Members of the ISUP Renal Tumor Panel
.
The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters
.
Am J Surg Pathol
.
2013
;
37
(
10
):
1490
1504
.
63
Delahunt
B
,
Eble
JN
.
Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors
.
Mod Pathol
.
1997
;
10
(
6
):
537
44
.
64
Sukov
WR
,
Lohse
CM
,
Leibovich
BC
,
Thompson
RH
,
Cheville
JC
.
Clinical and pathological features associated with prognosis in patients with papillary renal cell carcinoma
.
J Urol
.
2012
;
187
(
1
):
54
59
.
65
Sweeney
P
,
El-Naggar
AK
,
Lin
SH
,
Pisters
LL
.
Biological significance of c-met overexpression in papillary renal cell carcinoma
.
J Urol
.
2002
;
168
(
1
):
51
55
.
66
Argani
P
,
Antonescu
CR
,
Illei
PB
, et al.
Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents
.
Am J Pathol
.
2001
;
159
(
1
):
179
192
.
67
Argani
P
,
Antonescu
CR
,
Couturier
J
, et al.
PRCC-TFE3 renal carcinomas: morphologic, Immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(x;1)(p11.2;q21)
.
Am J Surg Pathol
.
2002
;
26
(
12
):
1553
1566
.
68
Argani
P
,
Olgac
S
,
Tickoo
SK
, et al.
Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum
.
Am J Surg Pathol
.
2007
;
31
(
8
):
1149
1160
.
69
Zhong
M
,
DeAngelo
P
,
Osborne
L
, et al.
Translocation renal cell carcinomas in adults: a single-institution experience
.
Am J Surg Pathol
.
2012
;
36
(
5
):
654
662
.
70
Green
WM
,
Yonescu
R
,
Morsberger
L
, et al.
Utilization of a TFE3 break-apart FISH assay in a renal tumor consultation service
.
Am J Surg Pathol
.
2013
;
37
(
8
):
1150
1163
.
71
Rao
Q
,
Williamson
SR
,
Zhang
S
, et al.
TFE3 break-apart FISH has a higher sensitivity for Xp11.2 translocation associated renal cell carcinoma compared with TFE3 or Cathepsin K immunohistochemical staining alone: expanding the morphologic spectrum
.
Am J Surg Pathol
.
2013
;
37
(
6
):
804
815
.
72
Argani
P
,
Zhong
M
,
Reuter
V
, et al.
TFE3-fusion variant analysis defines specific clinicopathologic associations among Xp11 translocation cancers
.
Am J Surg Pathol
.
2016
;
40
(
6
):
723
737
.
73
Xia
Q
,
Wang
Z
,
Chen
N
, et al.
Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement
.
Mod Pathol
.
2016
;
30
(
3
):
416
426
.
74
Skala
SL
,
Xiao
H
,
Udager
AM
, et al.
Detection of 6 TFEB-amplified renal cell carcinomas and 25 renal cell carcinomas with MITF translocations: systematic morphologic analysis of 85 cases evaluated by clinical TFE3 and TFEB FISH assays
.
Mod Pathol
.
2018
;
31
(
1
):
179
197
.
75
Argani
P
,
Reuter
VE
,
Zhang
L
, et al.
TFEB-amplified renal cell carcinomas: an aggressive molecular subset demonstrating variable melanocytic marker expression and morphologic heterogeneity
.
Am J Surg Pathol
.
2016
;
40
(
11
):
1484
1495
.
76
Gupta
S
,
Johnson
SH
,
Vasmatzis
G
, et al.
TFEB-VEGFA (6p21.1) co-amplified renal cell carcinoma: a distinct entity with potential implications for clinical management
.
Mod Pathol
.
2017
;
30
(
7
):
998
1012
.
77
Williamson
SR
,
Grignon
DJ
,
Cheng
L
, et al.
Renal cell carcinoma with chromosome 6p amplification including the TFEB gene: a novel mechanism of tumor pathogenesis?
Am J Surg Pathol
.
2016
;
41
(
3
):
287
298
.
78
Udager
AM
,
Alva
A
,
Mehra
R.
Current and proposed molecular diagnostics in a genitourinary service line laboratory at a tertiary clinical institution
.
Cancer J
.
2014
;
20
(
1
):
29
42
.
79
Mosquera
JM
,
Dal Cin
P
,
Mertz
KD
, et al.
Validation of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinomas
.
Diagn Mol Pathol
.
2011
;
20
(
3
):
129
137
.
80
Sukov
WR
,
Hodge
JC
,
Lohse
CM
, et al.
TFE3 rearrangements in adult renal cell carcinoma: clinical and pathologic features with outcome in a large series of consecutively treated patients
.
Am J Surg Pathol
.
2012
;
36
(
5
):
663
670
.
81
Hora
M
,
Urge
T
,
Trávníček
I
, et al.
MiT translocation renal cell carcinomas: two subgroups of tumours with translocations involving 6p21 [t (6; 11)] and Xp11.2 [t(X;1 or X or 17)]
.
Springerplus
.
2014
;
3
(
245
):
1
9
.
82
Srigley
JR
,
Delahunt
B
,
Eble
JN
, et al
ISUP Renal Tumor Panel. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia
.
Am J Surg Pathol
.
2013
;
37
(
10
):
1469
1489
.
83
Tokuda
N
,
Naito
S
,
Matsuzaki
O
, et al.
Collecting duct (Bellini duct) renal cell carcinoma: a nationwide survey in Japan
.
J Urol
.
2006
;
176
(
1
):
40
43
.
84
Gupta
R
,
Billis
A
,
Shah
RB
, et al.
Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship
.
Am J Surg Pathol
.
2012
;
36
(
9
):
1265
1278
.
85
Kobayashi
N
,
Matsuzaki
O
,
Shirai
S
,
Aoki
I
,
Yao
M
,
Nagashima
Y.
Collecting duct carcinoma of the kidney: an immunohistochemical evaluation of the use of antibodies for differential diagnosis
.
Hum Pathol
.
2008
;
39
(
9
):
1350
1359
.
86
Pal
SK
,
Choueiri
TK
,
Wang
K
, et al.
Characterization of clinical cases of collecting duct carcinoma of the kidney assessed by comprehensive genomic profiling
.
Eur Urol
.
2016
;
70
(
3
):
516
521
.
87
Mai
KT
,
Kohler
DM
,
Belanger
EC
,
Robertson
SJ
,
Wang
D.
Sporadic clear cell renal cell carcinoma with diffuse cytokeratin 7 immunoreactivity
.
Pathology
.
2008
;
40
(
5
):
481
486
.
88
Pantuck
AJ
,
Zisman
A
,
Belldegrun
AS
.
The changing natural history of renal cell carcinoma
.
J Urol
.
2001
;
166
(
5
):
1611
1623
.
89
Zhao
M
,
Teng
X
,
Ru
G
, et al.
Tubulocystic renal cell carcinoma with poorly differentiated foci is indicative of aggressive behavior: clinicopathologic study of two cases and review of the literature
.
Int J Clin Exp Pathol
.
2015
;
8
(
9
):
11124
11131
.
90
Azoulay
S
,
Viellefond
A
,
Paraf
F
, et al.
Tubulocystic carcinoma of the kidney: a new entity among renal tumors
.
Virchows Arch
.
2007
;
451
(
5
):
905
909
.
91
Williamson
SR
,
Eble
JN
,
Amin
MB
, et al.
Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma
.
Mod Pathol
.
2015
;
28
(
1
):
80
94
.
92
Chen
Y-B
,
Xu
J
,
Skanderup
AJ
, et al.
Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets
.
Nat Commun
.
2016
;
7
:
13131
. doi: .
93
Hakimi
AA
,
Voss
MH
.
Genomic classifiers in renal cell carcinoma
.
Eur Urol
.
2018
;
73
(
5
):
770
771
.

Author notes

The authors have no relevant financial interest in the products or companies described in this article.

Presented in part at the New Frontiers in Pathology meeting; October 19–21, 2017; Ann Arbor, Michigan.