2021-38/ September 20
Contributors: Michelle S. Hirsch, Mark Carter

A woman in her early 30s presented with pelvic pain, and a 2.0 cm kidney mass was incidentally found.


1. What is the correct diagnosis?

a. Oncocytoma

b. Succinate-dehyrogenase deficient RCC

c. Fumarate hydratase-deficient RCC

d. Eosinophilic, solid and cystic RCC

e. Chromophobe RCC

2. Is there an associated gene mutation with this tumor?

a. No, no specific gene mutation

b. Yes, succinate dehydrogenase (SDH)

c. Yes, fumarate hydratase (FH)

d. Yes, tuberous sclerosis complex (TSC)

e. Yes, p53

3. What is the correct follow-up for this patient?

a. None, it is a benign tumor

b. Genetic evaluation

c. Routine imaging, including the contralateral kidney

d. Evaluation of parents/siblings/children

e. Answer choices b – d

1. c
2. c
3. e

1. Fumarate hydratase-deficient RCC
2. Yes, fumarate hydratase (FH)
3. Answer choices b-d

Fumarate hydratase (FH)-deficient renal cell carcinomas (RCCs) are typically high grade RCCs that present as part of the autosomal dominant disorder, Hereditary Leiomyomatosis and RCC Syndrome (HLRCC). HLRCC occurs secondary to a mutation in the FH gene, resulting in uterine and dermal leiomyomata and kidney tumors. However, it should be noted that a significant proportion of FH-deficient leiomyomata occur secondary to a somatic FH mutation, whereas as most FH-deficient kidney tumors are associated with a germline mutation.

The majority of FH-deficient RCCs have characteristic histological findings, including: papillary, tubulopapillary and solid architectures, an infiltrative growth pattern, and high grade cytology with eosinophilic cytoplasm, and nuclei with large, prominent nucleoli and perinucleolar halos. Cytoplasmic vacuolization may be present. Tumor size can vary, and some patients present with metastatic disease. Rarely, FH-deficient RCC can present with low grade features/cytology. These tumors still demonstrate solid, nested, tubular and cystic growths patterns, but demonstrate lower grade cytologic features, and have a more favorable prognosis. However, close follow-up (including the contralateral kidney) is advised, as additional low and/or high grade FH-deficient tumors can occur in these patients, with the latter having a poor prognosis. Patients and family members require a genetic work-up follow an FH-deficient RCC diagnosis.

The differential diagnosis for the high grade FH-deficient RCC includes papillary RCC and collecting duct RCC. In contrast, the differential diagnosis for the low grade FH-deficient RCCs includes a variety of ‘pink tumors’, including oncocytoma, chromophobe RCC, succinate-dehydrogenase (SDH) deficient RCC, and tumors associated with a tuberous sclerosis complex (TSC)-mutation, such as eosinophilic, solid and cystic (ESC) RCC.

Immunohistochemistry can be used to distinguish tumors in the differential diagnosis of a low grade FH-deficient RCC. FH is negative (i.e., lost) and 2SC is expressed in FH-deficient RCCs (as was seen in this case); the opposite is true in all other RCC subtypes. CK7 (scattered cells) and CD117 are expressed in oncocytoma, diffuse CK7 and CD117 are expressed in chromophobe RCC, SDHB is negative (i.e., lost) in SDH-deficient RCC (SDH was intact in this case), and CK20 is expressed in the majority of ESC RCCs (CK20 was negative in this case).

1. Smith SC, Sirohi D, Ohe C, McHugh JB, Hornick JL, Kalariya J, Karia S, Snape K, Hodgson SV, Cani AK, Hovelson D, Luthringer DJ, Martignoni G, Chen YB, Tomlins SA, Mehra R, Amin MB. A distinctive, low-grade oncocytic fumarate hydratase-deficient renal cell carcinoma, morphologically reminiscent of succinate dehydrogenase-deficient renal cell carcinoma. Histopathology. 2017 Jul;71(1):42-52.

2. Gupta S, Swanson AA, Chen YB, Lopez T, Milosevic D, Kipp BR, Leibovich BC, Thompson RH, Herrera-Hernandez L, Cheville JC, Jimenez RE. Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC. Hum Pathol. 2019 Sep;91:114-122.

Michelle S. Hirsch
Brigham and Women’s Hospital & Harvard Medical School

Mark Carter
Kaiser Foundation Hospital, Baldwin Park (Southern California Permanente Medical Group)


Fumarate hydratase-deficient RCC