Case of the Month: Kidney

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2016, case 11, and is a renal cell carcinoma with rhabdoid differentiation.

This is a 13.8 cm renal cell carcinoma with rhabdoid features, a rare subset of “unclassifiable” adult renal cell carcinoma with poorly-differentiated epithelioid or rhabdoid morphology. It is classified as grade 4 by the International Society of Urologic Pathology and Fuhrman grading, and is associated with a dismal prognosis. The rhabdoid morphology is thought to most likely represent a high-grade variant of clear cell renal cell carcinoma, but may possibly arise from papillary type 2 or sarcomatoid types. Some pathologists also consider “rhabdoid” to be synonymous with “sarcomatoid” features, although in other series those tumors with spindled sarcomatoid morphology have even worse prognoses. Necrosis, marked lymphoid response, focal myxoid change, large nuclei with large cherry red nucleoli and eccentric cytoplasm and brisk mitotic activity, including atypical forms are typically present.

This tumor extends into the renal sinus and perirenal fat, has positive margins, and is associated with lymphovascular invasion. All lymph nodes are negative. The pathologic staging is pT3a, pN0. Targeted therapy (tyrosine kinase inhibitors, VEGF inhibitors, mTOR inhibitors) or cytokine therapy is per clinical recommendation.

By immunohistochemistry, these tumors can coexpress vimentin, pan-cytokeratin (AE1/AE3), EMA, CK18, CAIX, focal RCC, rare CD10, PAX2, PAX8, and CD117, with variable to negative CK7. These tumors are usually negative for CK20, CK5/6, desmin, SMA, and CD68. Prognostic markers, p53 and Ki-67, are usually elevated. The current tumor is strongly positive for p53, vimentin, CD10, PAX8 (supportive of renal cell carcinoma in this male), and INI-1 is retained. Tumor cells are negative for CAIX (which would be positive in clear cell renal cell carcinoma), CK7 (which would be positive in papillary renal cell carcinomas), pan-cytokeratin, EMA, RCC, CD30, desmin, SMA, Ksp-cadherin, S100 protein, Melan-A, HMB45, TFE-3, PAX-2, and NSE. The molecular mutations are common to other renal cell carcinomas, mostly clear cell type, including mutations in tumor-suppressor genes BAP1 or PBRM1 located on chromosome 3p, and those with increased copy numbers of these genes. In one study, loss of 11p specific to rhabdoid differentiation in renal cell carcinoma was identified.

The differential diagnosis includes rhabdoid tumor of the kidney (RTK), a rare, aggressive, and lethal neoplasm of young children usually younger than 5 years, composed of large cells with vesicular chromatin, prominent nucleoli, and hyaline intracytoplasmic inclusions. RTK coexpress vimentin, pan-cytokeratin, EMA and lose INI1; CD34 is usually negative. These patients also get PNET-like tumors of the CNS. The bi-allelic inactivation of hSNF5/INI-1 tumor suppressor gene on the long arm of chromosome 22 is the molecular hallmark of RTK. The age of the patient and retention of INI-1 and other immunostains exclude RTK in the current patient.

The background of marked lymphocytes raises the question of an anaplastic large cell lymphoma (ALCL) or other high-grade hematolymphoid neoplasm, which have rarely been reported in the kidney. Some ALCL can exhibit rhabdoid features by morphology. While lymphoma can be primary in the kidney usually as an EBV related lymphoma in post-transplant lymphoproliferative disorder in an immunosuppressed host, secondary lymphoma of the kidney is thirty times more common, usually diffuse large B cell lymphoma subtype. The immunophenotype and lack of CD30 or other lymphoid markers exclude this diagnosis. Of interest, ALK translocations have rarely been reported in pediatric renal cell carcinoma of unclassified type.

Epithelioid angiomyolipoma (AML), often found in association with tuberous sclerosis (TS), could be considered in the differential diagnosis. These tumors can have nuclear atypia, pleomorphism, mitoses, necrosis, and even vascular invasion, yet are usually benign. AML is part of the PEComa myomelanocytic family. By molecular analysis, allelic loss of chromosomal arm 16p (TS2 containing region) is noted in classic, epithelioid, and sarcomatoid AML. The current tumor, however, appears clearly malignant and the immunophenotype, including negative desmin and HMB45 exclude AML.

Pleomorphic undifferentiated sarcoma previously known as malignant fibrous histiocytoma (MFH) is rare in the kidney and, while nuclear pleomorphism and rhabdoid features can be observed in MFH, the sprinkling of lymphocytes and dirty appearing necrosis favor a carcinoma or melanoma variant over sarcoma. Likewise, primary pleomorphic rhabdomyosarcoma of the kidney in an adult has been reported as a sporadic case; however, pleomorphic rhabdomyosarcoma itself is a controversial entity, with most cases of pleomorphic skeletal muscle differentiation representing heterologous features in a dedifferentiated liposarcoma or carcinosarcoma. The absence of desmin and actin (and presumably myoregulatory proteins) also excludes rhabdomyosarcoma.

Xp11.2 translocation tumors resulting in gene fusions involving the TFE3 gene are more common in younger patients with psammoma-like calcifications, a packeted arrangement of tumor cells, and more indolent behavior; TFE3 immunostain was negative in the current tumor.

Solid papillary renal cell carcinoma type 2 is excluded by the higher nuclear grade, eosinophilic cytoplasm, negative pan-cytokeratin and CK7 immunostains in this case. On the other hand, very high-grade solid papillary carcinomas may also have sarcomatoid and rhabdoid features.

There are many other tumors in the differential diagnosis that are excluded by older patient age, morphology and phenotype. High-grade urothelial carcinoma with plasmacytoid features is not favored by location and negative CK5/6. Favorable histology Wilms tumor can have filamentous cytoplasmic inclusions and rarely macronucleoli but is excluded by patient age and morphology. Rhabdoid melanoma is excluded by the negative S100 protein, as well as negative melanoma markers. Congenital mesoblastic nephroma might have been considered in a child, yet this is an adult. Oncocytoma with eosinophilic cytoplasm and prominent nucleoli is excluded by the solid growth pattern and the fact that this tumor is clearly malignant.

1. Which of the following is the best answer regarding renal cell carcinoma with rhabdoid features?
   1. It is different from high-grade clear cell carcinoma, grade 4.
   2. It is different from primary renal pleomorphic rhabdomyosarcoma.
   3. It is the same as rhabdoid tumor of the kidney.
   4. It is the same as type 2 papillary carcinoma with plasmacytoid features.
   5. It is the same as Xp11.2 translocation carcinoma.
2. Which of the following is not usual for renal cell carcinoma with rhabdoid features?
   1. Favorable prognosis
   2. Molecular event similar to clear cell renal cell carcinoma but with increased gene copy numbers
   3. Pleomorphic cells with eosinophilic cytoplasm and large eosinophilic nucleoli
   4. Poor outcome even after treatment
   5. Usual coexpression of vimentin, EMA, RCC, CD10, PAX8
3. Which of the following is true?
   1. Anaplastic large cell lymphoma has never been reported in the kidney.
   2. If angiomyolipoma had rhabdoid features it would mean that it is malignant.
   3. One does not need immunostains to classify a pleomorphic tumor in the kidney.
   4. Pleomorphic rhabdomyosarcoma is common in the kidney and other anatomic sites.
   5. Solid papillary renal cell carcinoma type 2 could have rhabdoid features.

1. Dalfior D, Eccher A, Gobbo S, et al. Primary pleomorphic rhabdomyosarcoma of the kidney in an adult. Ann Diagn Pathol. 2008;12(4):301-303.
2. Fanburg-Smith JC, Hengee M, Hengee UR, Smith JSC, Miettinen M. Extrarenal rhabdoid tumors of soft tissue: A clinicopathologic and immunohistochemical study and a review of the literature. Ann Diagn Pathol. 1998;2(6):351-362.
3. Furlong MA, Mentzel T, Fanburg-Smith JC. Pleomorphic rhabdomyosarcoma in adults. A clinicopathologic study of 38 cases with emphasis on morphologic subtypes and recent skeletal muscle specific markers. Modern Pathol. 2001;14(6):595-603.
4. Keylock JB, Fanburg-Smith JC, Alaggio R, Barton JH, Sesterhenn IS. Renal angiomyolipoma in the first two decades of life: a clinicopathologic study of 44 cases. Modern Pathol. 2009;22(1)175A. Presented in Boston, MA at USCAP meeting, April, 2009.
5. Makhlouf HR, Ishak KG, Shekar R, Sesterhenn IA, Young DY, Fanburg-Smith JC. Melanoma markers in angiomyolipoma of the liver and kidney: a comparative study. Arch Pathol Lab Med. 2002;126(1):49-55.
6. Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012;44(7):751-759.
7. Perrino CM, Hucthagowder V, Evenson M, Kulkarni S, Humphrey PA. Genetic alterations in renal cell carcinoma with rhabdoid differentiation. Hum Pathol. 2015;46(1):9-16.
8. Sugawara E, Togashi Y, Kuroda N, et al. Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method. Cancer. 2012;118(18):4427-4436.
9. Venizelos ID, Rombis V, Tulupidis S, Garipidou V. Primary anaplastic large cell lymphoma of the kidney. Leuk Lymphoma. 2003;44(2):353-355.
10. Weeks DA, Beckwith JB, Mierau GW, Zuppan CW. Renal neoplasms mimicking rhabdoid tumor of kidney. A report from the National Wilms' Tumor Study Pathology Center. Am J Surg Pathol. 1991;15(11):1042-1054.
11. Yang X, Xi C, Jin J, et al. Adult renal cell carcinoma with rhabdoid differentiation: incidence and clinicopathologic features in Chinese patients. Ann Diagn Pathol. 2015;19(2):57-63.
12. Zhang BY, Cheville JC, Thompson RH, et al. Impact of rhabdoid differentiation on prognosis for patients with grade 4 renal cell carcinoma. Eur Urol. 2015. [Epub ahead of print]

2016
Julie C. Fanburg-Smith, MD
Surgical Pathology Committee
Sibley Memorial Hospital of Johns Hopkins Medicine/ICMD
Washington DC

1. It is different from primary renal pleomorphic rhabdomyosarcoma. (b)
2. Favorable prognosis (a)
3. Solid papillary renal cell carcinoma type 2 could have rhabdoid features. (e)