Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases

Abstract

Hybrid oncocytic/chromophobe tumors (HOCT) of the kidney have been described in patients with Birt-Hogg-Dubé syndrome (BHD) and in association with renal oncocytosis without BHD. HOCT in patients without evidence of BHD or renal oncocytosis is exceedingly rare, and these cases have been poorly characterized. We have identified and studied 14 cases of HOCT from previously diagnosed renal oncocytomas (398 cases) and chromophobe renal cell carcinomas (351 cases) without evidence of BHD or renal oncocytosis. Immunohistochemical, ultrastructural, and molecular genetic studies analyzing numerical chromosomal changes, loss of heterozygosity for chromosome 3p, and mutation status of VHL, c-kit, PDGFR, and folliculin (FLCN) genes were performed. HOCTs were identified in nine men and five women (age range 40-79 years). The size of tumors ranged from 2 to 11 cm. All tumors displayed a solid alveolar architecture and were composed of cells with abundant granular eosinophilic oncocytic cytoplasm with perinuclear halos. Occasional binucleated neoplastic cells were present, but irregular, hyperchromatic, wrinkled (raisinoid) nuclei were absent. The cytoplasm contained numerous mitochondria of varying sizes, but only sparse microvesicles with amorphic lamellar content were found. Tumors were positive for CK7 (12/14), AE1-AE3 (14/14), anti-mitochondrial antigen (14/14), E-cadherin (11/13), parvalbumin (12/14), and epithelial membrane antigen (14/14). Tumors were generally negative for racemase, CK20, CD10, and carboanhydrase IX. Interphase fluorescence in situ hybridization revealed multiple chromosomal losses and gains with a median of four (range 1-9) chromosomal aberrations per case. Monosomy of chromosome 20 was common and found in 7 of 14 cases. Monosomy of chromosomes 6 and 9 was present in 4 of 14 cases each, of which two cases displayed monosomy for both chromosomes 6 and 9. Polysomy of chromosomes 10, 21, and 22 was found in 4/14 cases each, of which one case displayed polysomy for all these three chromosomes. No pathogenic mutations were found in the VHL, c-kit, PDGFR, and folliculin (FLCN) genes. (1) We have shown that hybrid oncocytic/chromophobe tumors of the kidney do occur, albeit rarely, outside the Birt-Hogg-Dubé syndrome and without associated renal oncocytosis. (2) These tumors constitute a relatively homogenous group with histomorphologic features of both chromophobe renal cell carcinoma and renal oncocytoma. (3) Sporadic hybrid oncocytic/chromophobe renal tumors are characterized by multiple numerical aberrations (both mono- and polysomies) of chromosomes 1, 2, 6, 9, 10, 13, 17, 21, and 22 and lack of mutations in the VHL, c-kit, PDGFRA, and FLCN genes. (4) The tumors seem to behave indolently as no evidence of malignant behavior was documented in our series, although admittedly, the follow-up was too short to fully elucidate the biological nature of this rare neoplasm. At worst, these tumors could have a low malignant potential, which only can be found out with longer follow-up.

Glycogen: A must have storage to survive stressful emergencies

“…[38][39][40][41][42][43][44][45][46][47][48][49][50][51] BHD is caused by germline mutations in the BHD gene, which encodes FLCN, a 64KDa protein, expressed in most tissues. 52 Since the discovery of the FLCN gene, diverse FLCN-related cellular functions have been reported.…”

“…57 The AMPK-dependent regulation of hyperosmotic stress that we observed in C. elegans is a very interesting aspect in regards to BHD disease, which is mostly manifested by enlarged renal cysts and tumors in all mammalian models including rats, mice, dogs, and men. [40][41][42]44,48 Since the kidney is an organ chronically exposed to hyperosmotic stress, it is possible that the BHD renal tumors and cysts are formed because of an increased resistance to hyperosmotic conditions, which could lead to DNA damage. In support of this, loss of FLCN and VHL, which are both renal tumor suppressor genes, predispose to renal clear cell carcinomas which are glycogen-rich tumors.…”

Papillary renal cell carcinoma embedded in an oncocytoma: Case report of a rare combined tumour of the kidney

“…4 Sometimes RCC arises within an oncocytoma. 5 However, the combination of oncocytoma and papillary RCC, 2 renal neoplasms of different origin, is very rare.…”

“…[1][2][3] There are reports on renal tumours with hybrid features between chromophobe renal cell carcinoma (RCC) and oncocytoma, both thought to arise from the distal tubular epithelium. 4 Sometimes RCC arises within an oncocytoma. 5 However, the combination of oncocytoma and papillary RCC, 2 renal neoplasms of different origin, is very rare.…”

Renal cell neoplasm of oncocytosis: a type of unclassified renal cell carcinoma

“…In contrast, the findings of immunohistochemistry indicated several positive factors for chromophobe renal cell carcinoma, whereas there were no results suggestive of oncocytoma. Consequently, hybrid oncocytoma/chromophobe renal cell carcinoma [9], so called hybrid tumor, was ruled out. According to these biological characteristics, this tumor could be considered to stay midway between oncocytoma and chromophobe renal cell carcinoma (Table 1).…”