2021-09/ March 1
Contributor: Athanase Billis

A woman in her mid-40s with a kidney tumor underwent radical nephrectomy.


1. What is the correct diagnosis?

a) Fumarate hydratase-deficient renal cell carcinoma

b) Renal medullary carcinoma

c) Papillary renal cell carcinoma

d) Tubulocystic renal cell carcinoma

e) Collecting duct carcinoma

1. Fumarate hydratase-deficient renal cell carcinoma

The most frequent and extensive architectural pattern was papillary (Fig. 1A) and intracystic papillary (Fig. 1B). Some of the papillary stalks were enlarged by fibrosis (Fig. 1A). Ductal (Fig. 2A) and solid areas (Fig. 2B) were seen in some areas and a tubulocystic-like area in only one focus (Fig 3). The nuclei were pleomorphic and in some areas showed very prominent eosinophilic nucleoli with perinucleolar halo reminiscent of viral inclusion (Fig. 4). Immunohistochemistry for fumarate-hydratase was negative (Fig. 5). The internal control was positive vascular endothelial cells.

Fumarate-hydratase deficient renal cell carcinoma is a rare and aggressive tumor. The patient had bone metastasis at the time of diagnosis. It can be sporadic or associated to hereditary leiomyomatosis. This latter syndrome is inherited as an autosomic dominant condition with incomplete phenotype penetrance, and germline mutations in the fumarate-hydratase (FH, 1q42.3-q43) gene. Due to the inactivation of fumarate-hydratase, there is a high level of fumarate substrate, resulting in an aberrant succination of cellular proteins forming high levels of [S-(2-succino)-cysteine (2SC)] residues, which can be detected by immunohistochemistry. A combination of FH-/2SC+ in immunohistochemistry has a high sensibility and specificity. The patients are at risk for the development of uterine and skin leiomyomas and renal cell cancer. This patient had a previous history of hysterectomy due to leiomyomas, and it is likely her kidney cancer was associated with the hereditary leiomyomatosis.

The main differential diagnoses of this tumor are collecting duct carcinoma, medullary renal cell carcinoma, and papillary renal cell carcinoma. Areas of tubulocystic-like carcinoma may be seen in fumarate-deficient renal cell cancer. The reticular pattern of medullary renal cell carcinoma (reminiscent of the yolk sac tumor of the testis) is a peculiar pattern of this tumor, but ductal and solid areas may be present as well as in collecting duct carcinoma and fumarate-hydratase deficient carcinoma. An important clue for the diagnosis of medullary renal cell carcinoma is presence of sickled red blood cells.

Papillary renal cell carcinoma, particularly type 2, is the most important differential diagnosis. Prominent and enlarged fibrotic papillary stalks instead of presence of xanthomatous macrophages and the tendency to have papillary intracystic growth favors fumarate-hydratase deficient carcinoma. Macronucleoli with clear halo reminiscent of viral inclusion are a frequent and peculiar finding in this tumor but most of the times are focal and similar morphology may be seen in other tumors.

1. Merino MJ, Torres-Cabala C, Pinto P, Linchan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol 2007;31:1578-85.

2. Chen Y-B, Brannon A R, Toubaji A, Dudas ME, Won HH, Al-Ahmadie HA et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol 2014;38:627-37.

3. Trpkov K, Hes O, Agaimy A, Bonert M, Martinek P, Magi-Galluzzi C et al. Fumarate hydratase-deficient renal cell carcinoma is strongly correlated with fumarate hydratase mutation and hereditary leiomyomatosis and renal cell carcinoma syndrome. Am J Surg Pathol 2016;40:865-75.

4. Smith SC, Trpkov K, Chen Y-B, Mehra R, Sirohi D, Ohe C et al. Tubulocystic carcinoma of the kidney with poorly differentiated foci: A frequent morphologic pattern of fumarate hydratase-deficient renal cell carcinoma. Am J Surg Pathol 2016;40:1457-72.

5.Ohe C, Smith SC, Sirohi D, Divatia M, Peralta-Venturina M et al. Reappraisal of morphologic differences between renal medullay carcinoma, collecting duct carcinoma, and fumarate hydratase-deficient renal cell carcinoma. Am J Surg Pathol 2018;42:279-92.

6. Kuroda N, Tsutsui M, Iguchi M, Nobuoka E, Uehara T, Sonobe Y et al. Fumarate hydratase-deficient renal cell carcinoma: A clinicopathological study of seven cases including hereditary and sporadic forms. Ann Diagn Pathol 2020;49:151599.

Athanase Billis
State University of Campinas (Unicamp)


kidney; fumarate hydratase-associated renal cell carcinoma