Renal Medullary Carcinoma

Clinical signs and symptoms of patients with either sickle cell trait or disease frequently involve the kidney. Berman⁴  originally described 6 sickle cell nephropathies, including gross hematuria, papillary necrosis, nephritic syndrome, renal infarction, inability to concentrate the urine, and pyelonephritis.

Typically, the presentation of RMC is that of a young male patient of African or Mediterranean descent, with hematuria and/or flank pain. Most patients are younger than 20 years, and childhood cases show a male predominance.¹  Some patients may have suspected renal abscess or urinary tract infection and may present without a clinically recognizable mass.⁵  Systemic symptoms, such as weight loss, fatigue, or parasthesias, may be present depending on the extent of disease. This is a result of the aggressive nature of the malignancy, with most patients having metastatic disease at the time of presentation. After metastasis to the regional lymph nodes, the most common sites are the liver and lungs, followed by bone and the adrenal glands.⁶ 

The fact that gross hematuria is often the primary presenting symptom of RMC can be problematic for the clinician because sickle cell carriers commonly have painless gross hematuria secondary to the effects of sickled erythrocytes within the kidney medulla. The low oxygen tension, hypertonicity, and low pH within the medulla promote hemoglobin S polymerization, causing vascular stagnation and secondary ischemia and infarction. Baig et al⁷  argue that urine cytology and imaging are appropriate for patients with sickle cell disease or trait who present with persistent or recurrent renal symptoms, such as hematuria.

Fine-needle aspiration of either the primary kidney tumor or a metastasis will show features of a high-grade carcinoma with loosely cohesive groups of cells in a background of scattered individual cells. Tumor cells typically have irregular nuclei with membrane grooves and 1 prominent or several smaller nucleoli. The chromatin is often coarse or vesicular in nature, and the cytoplasm is frequently vacuolated. It is composed of either a single large vacuole or multiple smaller vacuoles which tend to indent the nucleus (Figure 1). Fragments of fibrous connective tissue can be identified in the background. Cytology from pelvic washings may reveal similar findings, with large atypical cells arranged in sheets, loosely cohesive groups, and/or single cells with irregular nuclei with coarse chromatin. Although these cytologic findings are nonspecific, fine-needle aspiration of the primary renal neoplasm in the right clinical setting can lead to the appropriate diagnosis of RMC.⁸ 

The tumor has a predilection for the right kidney (3:1) and has been reported to range in size from 2 to 18 cm, with an average diameter of 7.4 cm. It is characteristically an ill-defined and poorly circumscribed mass that often occupies most of the renal medulla, with infiltration into the renal pelvis as well as perinephric and renal sinus adipose tissues. Small satellite nodules are commonly encountered in the renal cortex. The consistency is usually firm or rubbery, and the cut surface appears tan to gray, with variable amounts of cystic change, hemorrhage, and necrosis. Occasionally, RMC may be mucoid, cavitary, or well-circumscribed and lobulated.^1,5,9 

At low power, the histology of RMC is that of a high-grade carcinoma exhibiting many different architectural patterns. The most characteristic finding is that of a reticular or cribriform pattern, with spaces of variable sizes, reminiscent of a testicular yolk sac tumor of reticular type (Figure 2). Other common patterns are adenoid cystic, sarcomatoid, and microcystic, with the last of these usually accompanied by micropapillations. Davis et al¹  also describe areas of poorly differentiated solid sheets of cells present in most of the cases, sometimes as the dominant or only pattern. Less common patterns include tubular, trabecular, or discrete gland formations.

A striking desmoplastic stromal response (Figure 3) as well as a prominent mixed inflammatory infiltrate are distinctive features of RMC. Acute inflammation, both infiltrative and abscess-forming, is almost universal and is sometimes supplemented by small-sized lymphocytes. Dense bands of lymphoplasmacytic infiltrate can be observed at the periphery of the tumor or around satellite nodules (Figure 4).

Hemorrhage and extensive necrosis are frequently present. The necrosis pattern is most commonly suppurative, resembling microabscesses within the epithelial aggregates. Other necrosis patterns that may be seen are ischemic, geographic, and comedo-type.

Davis et al¹  comment that satellite nodules are very frequently found in the renal cortex or adjacent peripelvic soft tissue, often representing venous or lymphatic invasion. In their study, tumors at the time of surgery were commonly in the later stages of disease, and where lymph node examination was possible, lymph node metastasis was always documented. All tumors contained lymphatic or vascular invasion or often both.¹ 

At high power, the tumor cells typically have moderately pleomorphic nuclei with nuclear grooves and clear or vesicular chromatin, and they contain 1 or more prominent nucleoli (Figure 5). Eosinophilic cytoplasm is common, with cytoplasmic lumina described in some cases. Mitotic rate is highly variable, in 1 study ranging from 0 to 24 per 10 high-power fields.⁵  Rao et al⁶  describe all of the tumors as poorly differentiated, with Fuhrman nuclear grade 4. The cells may have a squamoid appearance along with intercellular bridging, although keratinization has not been described. Plasmocytoid appearance or rhabdoid appearance with cytoplasmic inclusions is occasionally encountered. Sickled red blood cells are almost always present.^1,5,6,9 

Because of the rarity of RMC as a diagnostic entity, immunohistochemical stains have traditionally been found to provide nominal assistance in its diagnosis. The literature mentions only small numbers of cases, leading to inconsistency in various published immunohistochemical patterns for RMC, and therefore should be interpreted with caution.

Renal medullary carcinoma may be positive for low–molecular weight cytokeratin 8,18 (CAM 5.2), pancytokeratin (AE1/AE3), vimentin, paired box 8 protein (PAX-8), epithelial membrane antigen (EMA), hypoxia-inducible factor (HIF), and vascular endothelial growth factor (VEGF).⁵  Gupta et al¹⁰  report that RMC may be positive for cytokeratin 7 (CK7) in up to 71% of 13 cases and positive for Ulex europaeus agglutinin 1 (UEA-1) in up to 55% of cases. Cytokeratin 34β E12 (34βE12) staining has been reported as ranging from negative to positive in up to 29% of cases.^5,10  Cytokeratin 20, paired box 2 protein (PAX-2), and carcinoembryonic antigen (CEA) stain variably.^5,10 

More recently, staining for a germ cell tumor marker, octamer-binding transcription factor 3/4 (OCT3/4), has shown positivity in most cases. OCT3/4 staining was notably absent in all cases of collecting duct carcinoma (CDC) and urothelial carcinoma. However, caution must be exercised when using this marker, particularly in the setting of metastatic disease, because the presence of OCT3/4 staining in a poorly differentiated neoplasm may represent a germ cell tumor. Another marker for germ cell tumors, sal-like protein 4 (SALL4), was found to be negative in all cases.⁶ 

Significantly, RMC has been shown to have a complete loss of tumor suppressor gene integrase interactor 1 (INI1), also known as switch/sucrose nonfermentable (SWI/SNF)–related, matrix-associated, actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) or Brahma-related gene 1/human Brahma (BRG1/hBRM)-associated factor 47 (BAF47). Loss of INI1/SMARCB1 nuclear staining in RMC (Figures 6 and 7) is similar to that seen in the malignant rhabdoid tumor of the kidney.^11–13  In contrast, all RCCs or urothelial cell carcinomas, including those with rhabdoid features, expressed INI1.¹³ 

The hallmark of RMC has been shown to be loss of INI1/SMARCB1 expression, explaining the negative INI1 by immunohistochemistry as noted above.^11,12,14  Loss of INI1 has been linked to downregulation of p16INK4a and upregulation of cyclin D1, promoting unregulated progression through the cell cycle.¹⁵ 

Calderaro et al¹⁶  have recently shown that there is a hemizygous deletion of the 22q11.2 region containing the SMARCB1 gene, with a second hit consisting of an interchromosomal balanced translocation disrupting the SMARCB1 sequence and leading to its inactivation. All 4 sickle cell disease patients included in their study showed translocations with different partner chromosomes, suggesting that genetic alterations in SMARCB1 induce a loss of function as opposed to a de novo function.^16,17  The SMARCB1 locus had a homozygous deletion in the 1 young patient with normal hemoglobin in this same study, suggesting the diagnosis of unclassified RCC with medullary phenotype.^2,16  In an investigation by Carlo et al,¹⁷  fluorescent in situ hybridization analysis of 10 RMC tissue samples showed a loss of heterozygosity with concurrent translocation in 8 patients and a biallelic loss of INI1 in the remaining 2 patients. The same study also showed that no mutations of SMARCB1 were identified through next-generation sequencing.¹⁷  The only recurrently mutated genes (DNA Polymerase Epsilon, Catalytic Subunit, and MTOR) were found in samples without a matched germ line control. These findings were interpreted as likely “variants of unknown significance” based on allele frequency and American College of Medical Genetics criteria.¹⁷ 

Additionally, rearrangement of chromosome 8 resulting in a loss of 8p and a gain of 8q can be observed, as well as gains of chromosomes 7, 8, 10, and 11; losses of chromosomes 9 and 13; additional unknown material on 10p; a deletion of 7q; and a dicentric chromosome composed of 13q and 21q.^11,12  Rare instances of ABL gene amplification or translocation have also been described.¹⁶ 

Wartchow et al¹⁸  describe 3 cases of RMC in which electron microscopy plays an important role in diagnosis. The 3 cases have a virtually identical ultrastructural appearance that is different from other pediatric renal tumors. Consistent with histologic findings, the most striking feature is the presence of large intracytoplasmic lumina, which contain projections of multiple long, slender microvilli. The length of the microvilli is particularly specific for RMC. An additional finding specific for RMC is electron-dense, finely filamentous luminal contents.¹⁸ 

If the patient has no documented history of sickle cell trait or disease, hemoglobin electrophoresis may be used to evaluate for the presence of hemoglobin S. If no concomitant hemiglobinopathy is identified in a patient with histologic and immunohistochemical findings consistent with RMC, it is recommended that the tumor be diagnosed as “unclassified renal cell carcinoma with medullary phenotype.”^2,19 

Collecting duct carcinoma of the kidney can appear similar histologically to RMC, especially because of its high-grade features, robust desmoplastic reaction, and a pronounced inflammatory infiltrate. However, the former occurs predominantly in older adults, with a mean age of 55 years, whereas presentation of RMC in patients older than 40 years is extremely uncommon.²⁰  Additionally, CDC usually displays a tubular or a tubulopapillary pattern, as opposed to the predominantly reticular pattern of RMC. Ohe et al²¹  describe a study of 100 cases in which a multinodular infiltrating papillary pattern was statistically significantly more likely to be associated with CDC than with RMC. According to Gupta et al,¹⁰  immunohistochemistry may be of limited use: 34βE12 has been reported to be positive in 26% of CDCs and 29% of RMCs. In the same study, UEA-1 was positive in 75% of CDCs and 55% of RMCs, and CK7 was positive in 44% of CDCs and 71% of RMCs.¹⁰  Both tumors have been reported to be vimentin positive in 100% of cases.¹⁰  PAX-2 staining has been reported as variable in RMCs and positive in up to 26% of cases in CDCs, and CK20 staining has been reported as variable in RMCs and positive in only 8% of CDCs.^5,10  Therefore, there is a clear need for immunohistochemical stains that reliably differentiate between these 2 entities.

Expression of OCT3/4 is typically absent in CDC and may be present in RMC.^6,21  INI1/SMARCB1 staining is lost in RMC but present in 21 of 22 CDCs¹²  and in all other subtypes of RCCs, even those with histologic rhabdoid features.¹³  Molecular studies have shown CDC to demonstrate variable chromosomal aberrations, with loss of heterozygosity in 1q, 6p, 8p, 9p, and 21q; loss of Y; and monosomies 1, 6, 14, 15, and 22 all being reported.¹⁷  Concerning SMARCB1, infrequent truncating mutations were found in 18% of CDCs in a series.²¹  In comparison, loss of SMARCB1 through a combination of hemizygous deletions and translocations or through homozygous deletions is an invariable finding in molecular analysis of RMC.^12,15,17 

Urothelial carcinoma of the renal pelvis shares morphologic and cytogenetic features with RMC; however, the 2 entities can be differentiated on the basis of immunohistochemical testing with PAX-8 (negative in urothelial carcinoma and positive in RMC), as well as loss of INI1 staining in RMC.^6,11  Urothelial carcinoma is usually negative for OCT3/4 expression, whereas OCT3/4 is expressed in some cases of RMC.^6,21  Additionally, urothelial carcinoma generally occurs in an older patient cohort, whereas RMC affects a younger patient population.^6,11 

Another renal tumor recently reported in pediatric patients with history of sickle cell trait is anaplastic lymphoma kinase–related RCC (ALK-rearrangement RCC). Immunohistochemistry will reveal intact INI1/SMARCB1 and strong ALK positivity, whereas in RMC, INI1/SMARCB1 staining will be lost and the tumor will be negative for ALK expression.¹⁵  The specific molecular finding in pediatric ALK-rearrangement RCC patients with a history of sickle cell trait is Vinculin (VCL)–ALK fusion.¹⁵  The diagnosis of ALK-rearrangement RCC should be strongly considered in a patient with sickle cell trait or disease and a renal mass with intact SMARCB1 and ALK rearrangement.

Malignant rhabdoid tumor of the kidney can have a very similar morphologic presentation to RMC; however, the former occurs in patients younger than 3 years. Both tumors show loss of INI1 expression.¹⁷  Although rhabdoid tumors mostly show SMARCB1 deletions or mutations, RMC harbors hemizygous SMARCB1 deletions with concurrent translocations or homozygous deletions.¹⁷ 

Fumarate hydratase (FH)–deficient RCC is an emerging diagnostic entity associated with hereditary leiomyomatosis and RCC syndrome. These tumors demonstrate germ line mutations in the gene encoding FH that lead to loss of FH expression, in addition to demonstrating induction of S-(2-succino)-cysteine (2SC).²¹  Fumarate hydratase–deficient RCC shows varied histologic patterns overlapping with those of RMC. The Ohe et al²¹  study showed that cribriform and reticular/yolk sac–like patterns favored the diagnosis of RMC, and intracystic papillary and tubulocystic patterns favored that of FH-deficient RCC. Immunohistochemical studies revealed both tumor types to be positive for PAX8 in the vast majority of cases; however, FH-deficient RCC did not lose SMARCB1 expression compared with RMC.²¹  Additionally, FH-deficient RCC was negative for OCT3/4 expression in all 25 cases, whereas OCT3/4 was expressed in 39% of 33 cases of RMC.²¹  Lastly, loss of FH and induction of 2SC would be expected in FH-deficient RCC but not in RMC.

Renal medullary carcinoma has been reported to stain for pancytokeratin, vimentin, CAM5.2, and PAX-8; however, other subtypes of RCC may also show positivity for 1 or more of these immunohistochemical markers.^5,22  As mentioned above, other subtypes of RCCs, unlike RMC, retain expression of the INI1 protein. Additionally, RMC generally affects a younger patient population.

Renal medullary carcinoma is a notoriously aggressive malignancy and has been found to be resistant to many conventional chemotherapeutic agents. Iacovelli et al²³  describe a total of 166 patients in a pooled analysis of all reported cases of RMC in MEDLINE from 1995 to 2013. A total of 98% of cases had sickle cell trait, and local or regional lymph nodes were involved in 71% of cases. The overall survival at diagnosis was 4.0 months in patients with metastases and 17.0 months in patients without metastatic disease.²³  Notably, patients receiving platinum-paclitaxel-gemcitabine therapy show prolonged survival (12 months) compared with those receiving topoisomerase inhibitor therapy (7 months) or methotrexate-vinblastine-doxorubicin-cisplatin therapy (4 months, approaching statistical significance at P = .058). The authors recommend radical nephrectomy to be considered as initial treatment because of improved overall survival (6 months versus 3 months), as well as for symptom management and definitive diagnosis. The benefit of radical nephrectomy is not statistically significant in patients with metastatic disease.²³ 

Maroja Silvino et al²⁴  report the treatment response of 5 patients with RMC in Brazil, also noting that the longest time to disease progression is achieved with platinum-based chemotherapy. The biologic agent sunitinib was administered to 2 patients without response. Amjad et al²⁵  report 1 case of near-complete response to dose-dense methotrexate-vinblastine-doxorubicin-cisplatin therapy, describing 16 months of progression-free survival after consolidation nephrectomy and retroperitoneal lymph node dissection.

A controversial area of investigation involves the programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1). Beckermann et al²⁶  report a case of complete response of recurring metastatic RMC to PD-1 inhibitor nivolumab 9 months after initiation of therapy. PD-L1 was expressed in 23% of tumor cells in this patient. Sodji et al²⁷  later note that PD-L1 levels may not correlate with the amount of response to nivolumab. In their study of 2 patients with RMC, response to nivolumab was observed only in the patient whose tumor had the lowest rate of PD-L1 expression, present in 25% of tumor cells. Unfortunately, that response was temporary because her disease progressed after more than 15 months of nivolumab therapy. There was no response in the second patient, in whom 60% of tumor cells expressed PD-L1.²⁷ 

The role of antiangiogenic therapy in the treatment of RMC is a promising area of research, with some authors showing that bevacizumab, particularly in combination with chemotherapy, may offer prolonged survival.^28,29  Batra²⁸  shares a case report of a maintenance antiangiogenic regimen of bevacizumab and temozolomide during a period of 6 months, which was followed by a sustained remission for 42 months. In a study of 9 RMC patients, Johnson et al²⁹  show that bevacizumab-based therapy had a median survival of 5.8 months longer (18.5 versus 12.7 months).

Another area of ongoing research targets enhancer of Zeste homologue (EZH2), which is the catalytic subunit of the polycomb repressive complex 2 (PRC2). EZH2 catalyzes lysine residue methylation on histone H3; aberrant EZH2 methylation has been linked to the development of malignancy.^17,30  Because SWI/SNF plays a role in PRC2 regulation, loss of SMARCB1 expression leads to overactivation of PRC2.³⁰  Preclinical data show that EZH2 inhibition leads to apoptosis and differentiation in cell lines with SMARCB1 expression loss and may play a role in the treatment of RMC.³⁰ 

There is a rare report of a pediatric patient in Brazil remaining disease-free at 8 years after nephrectomy with early detection of a well-circumscribed tumor restricted to the kidney.³¹  Prognosis of RMC in general remains extremely poor; however, additional research into the roles of antiangiogenic therapy, PD-1, and EZH2 inhibitors may prove fruitful.