Subtitle: A case-based guide to FH-deficient leiomyoma (fumarate hydratase-deficient leiomyoma): the morphological clues, FH and 2SC immunohistochemistry, the link with hereditary leiomyomatosis and renal cell carcinoma (HLRCC), and FH-deficient RCC, with 10 MCQs for NEET SS, FRCPath and MD/DNB Pathology residents.
Author: PathologyMCQ Editorial Board
Category: Gynaecological and Renal Pathology
Last Updated: October 2026
Read Time: 6 minutes
At-a-Glance: FH-Deficient Leiomyoma
- The answer: the mutation is in fumarate hydratase (FH), and the syndrome is HLRCC (hereditary leiomyomatosis and renal cell carcinoma).
- Clues on H&E in FH-deficient leiomyoma: large nuclei with prominent orangeophilic nucleoli and perinucleolar halos, eosinophilic cytoplasmic globules, staghorn vessels and alveolar oedema.
- IHC: loss of FH and positive 2SC (S-(2-succino)-cysteine).
- Why it matters: germline FH mutation carries a risk of an aggressive FH-deficient renal cell carcinoma.
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The Case: Which Gene Is Mutated in This Uterine Leiomyoma?
A uterine leiomyoma shows the features below. Which gene is mutated, and which syndrome is it associated with? Look at the nuclei before reading on, as you would in a pathology board review question.
Next step: FH and 2SC immunohistochemistry, and a comment recommending genetic counselling.
How Do You Recognise FH-Deficient Leiomyoma? Morphological Clues on H&E
FH-deficient leiomyoma is recognised by enlarged nuclei with prominent orangeophilic nucleoli and perinucleolar halos, eosinophilic cytoplasmic globules, staghorn vessels and alveolar-pattern oedema.
- Nuclei: enlarged, with prominent eosinophilic to orangeophilic nucleoli and a perinucleolar halo (viral inclusion-like).
- Cytoplasm: eosinophilic, rhabdoid-like globules.
- Vessels: staghorn (haemangiopericytoma-like) vessels.
- Stroma: alveolar-pattern oedema.
- Architecture: cellular with chain-like or slit-like nuclear arrangement; scattered bizarre nuclei may occur.
- Mitoses are usually low and tumour cell necrosis is absent, which separates it from leiomyosarcoma.
For the differential diagnosis of uterine smooth muscle tumours with atypia and mitoses, see uterine leiomyosarcoma: WHO criteria →
FH and 2SC Immunohistochemistry in FH-Deficient Leiomyoma
On immunohistochemistry, FH-deficient leiomyoma shows loss of FH with positive 2SC (S-(2-succino)-cysteine) staining.
| Stain | FH-deficient | FH-proficient |
|---|---|---|
| FH | Lost (cytoplasmic staining absent; internal controls retained) | Retained granular cytoplasmic staining |
| 2SC | Positive (nuclear and cytoplasmic) | Negative |
| Interpretation | Supports FH deficiency; germline testing recommended | Does not exclude missense mutations with retained protein |
Some FH missense mutations retain protein expression, so 2SC is more sensitive than FH loss. A combination of both is recommended.
What Is HLRCC? Hereditary Leiomyomatosis and Renal Cell Carcinoma and FH-Deficient RCC
HLRCC (hereditary leiomyomatosis and renal cell carcinoma, also called Reed syndrome) is an autosomal dominant syndrome caused by a germline FH mutation. It presents with cutaneous leiomyomas, early-onset uterine leiomyomas and a risk of aggressive FH-deficient renal cell carcinoma.
- Inheritance: autosomal dominant germline FH mutation (1q43).
- Skin: multiple, often painful cutaneous piloleiomyomas.
- Uterus: multiple, early-onset leiomyomas.
- Kidney: FH-deficient RCC: solitary, aggressive, metastasises early even when small. Papillary, tubulocystic, solid or cribriform architecture with macronucleoli and perinucleolar halos. WHO 2022 prefers the name FH-deficient renal cell carcinoma over HLRCC-associated RCC, and the entity includes tumours with somatic as well as germline FH alterations.
- Surveillance: annual renal MRI is recommended for carriers, starting at about 8 years of age (GeneReviews: FH tumour predisposition syndrome).
For all hereditary renal cancer syndromes, see hereditary renal carcinoma syndromes → For the WHO 2022 update on renal tumours, see WHO 2022 renal tumours →
Molecular Subgroups of Uterine Leiomyoma: MED12, HMGA2 and FH-Deficient Leiomyoma
Uterine leiomyomas fall into distinct molecular subgroups. FH-deficient leiomyoma is one of the smaller subgroups but the most important to recognise, because of its link with HLRCC.
| Subgroup | Approximate frequency | Clues |
|---|---|---|
| MED12 mutated | About 70% | Ordinary leiomyomas |
| HMGA2 rearranged | About 10% | Often large, solitary; cellular or lipoleiomyoma-like |
| FH-deficient | Under 2% (higher in young women) | Macronucleoli with halos, eosinophilic globules, staghorn vessels |
| COL4A5/COL4A6 deletion | Rare | Alport syndrome with diffuse leiomyomatosis |
Tweetorial: Fumarate Hydratase Mutation Case Thread
Test Yourself: 10 FH-Deficient Leiomyoma and HLRCC MCQs
FH-deficient leiomyoma and HLRCC: 10 MCQs
Morphology, IHC, genetics and renal cancer, with instant explanations.
More pathology MCQs for postgraduate residents: the gynaecological pathology MCQ bank →
Exam Pearls: FH-Deficient Leiomyoma and HLRCC
- Macronucleoli with perinucleolar halos in a leiomyoma: think FH deficiency.
- FH loss and 2SC positivity confirm it.
- Germline FH mutation: HLRCC (Reed syndrome).
- HLRCC triad: cutaneous leiomyomas, uterine leiomyomas, aggressive FH-deficient RCC.
- WHO 2022 name: FH-deficient renal cell carcinoma (preferred over HLRCC-associated RCC).
- Commonest leiomyoma driver: MED12.
- FH and SDH are both Krebs cycle enzymes.
This topic is useful revision for NEET SS Pathology preparation, FRCPath Part 1 and Part 2 preparation, MD/DNB Pathology exam preparation and APCP board preparation. MD Pathology and DNB Pathology residents can use the MCQs above as pathology board review questions for histopathology board examination preparation.
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Preparing for NEET SS, FRCPath or an MD/DNB Pathology exam?
Related reads: Hereditary renal carcinoma syndromes → · Emerging renal tumours, WHO 2022 →
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References
- WHO Classification of Tumours Editorial Board. Female Genital Tumours. 5th ed. IARC; 2020.
- Gupta S, Swanson AA, Chen YB, et al. Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening. Hum Pathol. 2019;91:114–122.
- Joseph NM, Solomon DA, Frizzell N, et al. 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;39:1529–1539.
- Menko FH, Maher ER, Schmidt LS, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. 2014. Publication record.
- GeneReviews®. FH Tumor Predisposition Syndrome (Hereditary Leiomyomatosis and Renal Cell Cancer). NCBI Bookshelf NBK1252. ncbi.nlm.nih.gov/books/NBK1252.
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