Renal cell carcinoma in tuberous sclerosis complex

Abstract

Renal cell carcinoma (RCC) occurs in 2% to 4% of patients with tuberous sclerosis complex (TSC). Previous reports have noted a variety of histologic appearances in these cancers, but the full spectrum of morphologic and molecular features has not been fully elucidated. We encountered 46 renal epithelial neoplasms from 19 TSC patients and analyzed their clinical, pathologic, and molecular features, enabling separation of these 46 tumors into 3 groups. The largest subset of tumors (n=24) had a distinct morphologic, immunologic, and molecular profile, including prominent papillary architecture and uniformly deficient succinate dehydrogenase subunit B (SDHB) expression prompting the novel term "TSC-associated papillary RCC (PRCC)." The second group (n=15) were morphologically similar to a hybrid oncocytic/chromophobe tumor (HOCT), whereas the last 7 renal epithelial neoplasms of group 3 remained unclassifiable. The TSC-associated PRCCs had prominent papillary architecture lined by clear cells with delicate eosinophilic cytoplasmic thread-like strands that occasionally appeared more prominent and aggregated to form eosinophilic globules. All 24 (100%) of these tumors were International Society of Urological Pathology (ISUP) nucleolar grade 2 or 3 with mostly basally located nuclei. Tumor cells from 17 of 24 TSC-associated PRCCs showed strong, diffuse labeling for carbonic anhydrase IX (100%), CK7 (94%), vimentin (88%), and CD10 (83%) and were uniformly negative for SDHB, TFE3, and AMACR. Gains of chromosomes 7 and 17 were found in 2 tumors, whereas chromosome 3p deletion and TFE3 translocations were not detected. In this study, we reported a sizable cohort of renal tumors seen in TSC and were able to identify them as different morphotypes, which may help to expand the morphologic spectrum of TSC-associated RCC.

Figure 1

Morphologic features of TSC-associated - papillary RCC. A, B (patient 6, tumor 11); C, D (patient 9, tumor 28); E (patient 8, tumor 22); F (patient 6, tumor 10). A, C: On low power, tumors predominantly displayed complex branching papillary structure; B, D: On high power, the clear cytoplasm often contained delicate thread-like eosinophilic strands which occasionally aggregated to form eosinophilic globules (arrow); E: Fibrotic stroma and cystic changes were common; F: Tumor cells with clear cytoplasm were admixed with tumor cells with fine granular eosinophilic cytoplasm.

Figure 2

TSC-associated papillary RCC with prominent papillary structure. A-F (patient 5, tumor 8) A: On low power, the main tumor nodule was surrounded by thick fibrous stroma; B: On high power, the papillae were lined by large clear cells with fine eosinophilic cytoplasmic thread-like strands. The nuclei oriented towards the basement membrane; C-F: Immunohistochemical stains showed that tumor cells were strongly and diffusely positive for CK7, CD10 and CA-IX; and negative for SDHB.

Figure 3

SDHB immunohistochemical staining. A, D (patient 5, tumor 8); B, E (patient 8, tumor 27); C, F (patient 8, tumor 24); G-I: Control tumors, G (patient 4, tumor 4); H (patient 10, tumor 30); I (patient 5, tumor 7). A-C: Tumor cells from TSC-associated papillary RCC showed completely negative staining for SDHB; D, E, F: Lower magnification of the tumors displayed in A, B, and C, respectively, demonstrated strong granular cytoplasmic staining in adjacent normal renal tubules, serving as an internal positive controls; G-I: Examples of SDHB positive renal epithelial tumors in TSC patients, showing a staining pattern that was both cytoplasmic and distinctly granular representing a mitochondrial pattern, was considered positive.

Figure 4

TSC-associated papillary RCC with prominent compact nested growth pattern showed similar cytological and immunological features. A-C: (patient 7, tumor 12); D-F: (patient 8, tumor 21); G-I: (patient 8, tumor 21). A: The only focus of tumor cells exhibiting papillary architecture in background of nested growth; B: Higher magnification of the papillary growth pattern of A (arrow); C: Higher magnification of left upper corner of A (arrowhead), showing the compact nested architecture consisting of clear cells with fine eosinophilic thread-like strands; D: Solid cell nests were surrounded by loose hyalinized stroma; E: Tubules with small blunt papillae tufted into the luminal space; F: On high power, clear cells with eosinophilic strands formed compact nests. G-I: Immunohistochemical stains showed that tumor cells were strongly and diffusely positive for CK7 and CA-IX, and negative for SDHB.

Figure 5

Histologic features of hybrid oncocytic/chromophobe tumors (HOCTs). A: (patient 18, tumor 45); B: (patient 5, tumor 7); C: (patient 12, tumor 35); D: (patient 18, tumor 46). A, B: Pattern 1 with polygonal tumor cells containing abundant eosinophilic cytoplasm and centrally placed, round nuclei with perinuclear clearing ; C: Pattern 2 with mosaicism of areas with features characteristic of oncocytoma and chromophobe RCC. D: Nested and tubular architecture with cells comprised of abundant eosinophilic cytoplasm typical of an oncocytoma with more irregular, folded nuclei.

Figure 6

TSC-associated renal tumors with unusual features remain unclassified. A-C: (patient 4, tumor 4, 5, 6); D-F: (patient 11, tumor 33, 32, 34); G-I: (patient 17, tumor 40).