Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients

Abstract

Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis.

FIGURE 1

Although many of the tumors demonstrated cystic change, which was often profound (A, 85 mm tumor from the right kidney of patient 9), this was not a constant finding, and some neoplasms were solid (B, 2 solid tumors, 90 and 28 mm, from the left kidney of patient 21).

FIGURE 2

The tumors were well circumscribed (A) and only occasionally separated from the adjacent kidney by a pseudocapsule (B). C and D, Cystic change was commonly appreciated histologically, and the cystic spaces contained pale eosinophilic fluid (hematoxylin and eosin).

FIGURE 3

The tumor cells had eosinophilic cytoplasm but lacked the granularity associated with true oncocytes. In some cases the eosinophilic cytoplasm was dense (A), but in most cases (B and C) it had a pale and wispy, almost flocculent, appearance. In some tumors (D) the combinations of flocculent cytoplasm and frequent intracytoplasmic inclusions imparted a bubbly appearance to many of the tumor cells (hematoxylin and eosin).

FIGURE 4

Serial sections stained with hematoxylin and eosin (A and C) and SDHB IHC (B and D). Frequently entrapped benign tubules were noted at the edge of the tumors. SDHB IHC demonstrates positive staining in the internal controls (including the entrapped benign tubules) but all the neoplastic cells are negative.

FIGURE 5

In this case with higher-grade nuclear features and early dedifferentiation, the intracytoplasmic inclusions are more subtle (arrows) and were identified only after a careful search (hematoxylin and eosin).

FIGURE 6

Cases with variant morphology. One case demonstrated morphology reminiscent of conventional clear cell renal carcinoma of ISUP nucleolar (nuclear) grade 3 (A and B). C and D, A second case demonstrated a papillary architecture with prominent nucleoli, reminiscent of type 2 papillary renal carcinoma (hematoxylin and eosin).

FIGURE 7

Representative photomicrographs from the primary tumor (A and B) and the vertebral metastasis (C and D) of case 10. The primary tumor demonstrated stereotypical low-grade features with ISUP nucleolar (nuclear) grade 2. In the metastasis documented 30 years later, the tumor demonstrated high-grade nuclear features but still showed negative staining for SDHB. As the patient had a contralateral renal tumor, which was unbiopsied at the time of metastatic disease, this may represent spread from a second primary tumor (hematoxylin and eosin).