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Fumarate hydratase-deficient renal cell carcinoma: an oncology care institutional experience
Meenakshi Kamboj1, Gurudutt Gupta1, Sunil Pasricha1
1Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute & Research Centre, Delhi, India.
Abstract:
Renal cell carcinoma (RCC) accounts for 2% of all cancer cases worldwide, and majority are sporadic. The latest World Health Organization (WHO) classification of renal cell tumors (fifth edition, 2022) has molecularly defined renal tumor entities, which includes fumarate hydratase (FH)-deficient RCC. FH-deficient RCC is an aggressive carcinoma caused by pathogenic alterations in FH gene, seen in 15% of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) syndrome. These tumors occur more frequently at a younger age and present at an advanced stage, carrying a dismal prognosis. We report a series of 10 cases of FH-deficient RCC. The mean age was 49.8 years, and all cases presented in advanced stages (III and IV). Morphologically, the cases had varied architectural patterns with characteristic eosinophilic macronucleoli and perinucleolar halo. On immunohistochemistry (IHC), all showed diffuse nucleo-cytoplasmic expression of S-(2-succino)-cysteine (2-SC), with loss of FH in seven cases. FH-deficient RCCs are aggressive neoplasms and can be diagnosed using specific IHC markers (FH and 2-SC). These patients should undergo germline testing for FH gene mutation, genetic counseling, and surveillance of family members.
Insights
Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is an aggressive cancer linked to FH gene alterations. Immunohistochemistry markers like FH and S-(2-succino)-cysteine (2-SC) aid in diagnosing this rare but dangerous tumor.
Area of Science:
- Oncology
- Pathology
- Genetics
Background:
- Renal cell carcinoma (RCC) represents 2% of global cancer diagnoses, with most cases being sporadic.
- The 2022 WHO classification identifies fumarate hydratase (FH)-deficient RCC as a distinct molecular entity.
- FH-deficient RCC arises from FH gene alterations, is associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome, and presents aggressively.
Purpose of the Study:
- To report a series of 10 FH-deficient RCC cases.
- To describe the morphological and immunohistochemical features of FH-deficient RCC.
- To highlight diagnostic markers and clinical management recommendations for FH-deficient RCC.
Main Methods:
- Retrospective case series analysis of 10 FH-deficient RCC patients.
- Morphological evaluation of tumor architecture and cellular features.
- Immunohistochemistry (IHC) for FH and S-(2-succino)-cysteine (2-SC) expression.
Main Results:
- The 10 cases presented with advanced stage (III/IV) disease, with a mean age of 49.8 years.
- Morphological findings included varied architectural patterns and characteristic eosinophilic macronucleoli with perinucleolar halos.
- IHC revealed diffuse nucleo-cytoplasmic 2-SC expression in all cases and FH loss in seven cases.
Conclusions:
- FH-deficient RCC is an aggressive neoplasm requiring accurate diagnosis.
- Immunohistochemistry for FH and 2-SC are valuable diagnostic tools.
- Patients diagnosed with FH-deficient RCC should be considered for germline FH mutation testing, genetic counseling, and family member surveillance.
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