Microscopic description:

The tumor cells are arranged in papillary and tubulo-cystic pattern with voluminous eosinophilic cells and characteristic macronuclei at places with surrounding clear halos. Hyalinized cores are seen.

Immunohistochemistry was positive for vimentin, PAX 8, SDH and negative for CK7, CAIX, CD10, ALK1, and FH.

FISH for TFE3 gene rearrangement was negative.

Discission:

FH Renal Cell Carcinoma (FH-RCC) is a rare and aggressive subtype of renal cell carcinoma associated with fumarate hydratase gene mutations.

FH-RCC is linked to Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) syndrome, characterized by painful cutaneous leiomyomas and uterine leiomyomas in affected individuals.

FH-RCC overlaps morphologically with papillary RCC, collecting duct carcinoma, and tubular-cystic RCC. Immunohistochemistry for FH/2SC and GATA3 can aid in the identification and differential diagnosis of FH-deficient RCC.

Prognosis varies based on the grade of the tumor, with high-grade FH-RCC being highly aggressive, prone to metastasis, and having a poor prognosis. Low-grade FH-deficient RCC presents with oncocytic morphology and has a more favorable outcome.

Importance of recognition of this tumor lies in the fact a genetic counselling should be initiated for the patient’s family.

Therapeutic approaches for FH-RCC are still under investigation, with early-phase studies showing promise with erlotinib and bevacizumab. However, further research is needed to explore potential therapeutic targets and improve treatment options for this aggressive subtype of renal cell carcinoma.

References:

Zhang W, Chu J, Zou YW, et al. [Clinicopathological characteristics of fumarate hydratase-deficient renal cell carcinoma]. Zhonghua Bing Li Xue Za Zhi. 2019;48(2):120-126. doi:10.3760/cma.j.issn.0529-5807.2019.02.009

Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol. 1973;53(5):409-416.

Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA. 2001;98(6):3387-3392. doi:10.1073/pnas.051633798

Tomlinson IPM, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406-410. doi:10.1038/ng849

Joseph NM, Solomon DA, Frizzell N, Rabban JT, Zaloudek C, Garg K. Morphology and immunohistochemistry for 2SC and FH aid in detection of fumarate hydratase gene aberrations in uterine leiomyomas from young patients. Am J Surg Pathol. 2015;39(11):1529-1539. doi:10.1097/PAS.0000000000000520

Trpkov K, Hes O, Agaimy A, 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(7):865-875. doi:10.1097/PAS.0000000000000617

Smith SC, Trpkov K, Chen Y-B, 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(11):1457-1472. doi:10.1097/PAS.0000000000000719

Hamza A, Sirohi D, Smith SC, Amin MB. Low-grade Oncocytic Fumarate Hydratase-deficient Renal Cell Carcinoma: An Update on Biologic Potential, Morphologic Spectrum, and Differential Diagnosis With Other Low-grade Oncocytic Tumors. Adv Anat Pathol. 2021;28(6):396-407. doi:10.1097/PAP.0000000000000321

Moch H, Amin MB, Berney DM, et al. The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol. 2022;82(5):458-468. doi:10.1016/j.eururo.2022.06.016

CASE IMAGES