Fumarate hydratase (FH) deficiency in uterine leiomyomas: recognition by histological features versus blind immunoscreening

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a rare autosomal dominant disease caused by germline mutations in the fumarate hydratase (FH) gene. Affected individuals develop cutaneous and uterine leiomyomas and aggressive RCC. To date, only few publications described the frequency and morphology of FH-deficient uterine leiomyomas. We reviewed 22 cases collected over 8 years from routine and consultation files based on distinctive histological features. In addition, we screened 580 consecutive uterine leiomyomas from 484 patients, 23 extra-uterine and 8 uterine leiomyosarcomas, and 6 leiomyomas with bizarre nuclei for FH loss using immunohistochemistry (IHC) on tissue microarrays (TMAs). All 22 FH-deficient cases were suspected on H&E sections and confirmed by FH IHC. Patients' ages ranged from 25 to 70 years (median 36). Seventeen patients had multiple nodules (2-14) measuring up to 11.8 cm. None of the patients had stigmata or family history of the HLRCC syndrome. Histologically, all FH-deficient tumors showed consistent and reproducible features as reported previously. FH loss was detected in 2/534 evaluable leiomyomas (0.4%), but in none of leiomyosarcomas. Two of six leiomyomas with bizarre nuclei were FH-deficient. FH-deficient uterine leiomyomas are rare in routine material (= 0.4%). They can be reliably identified or suspected by consistent morphological features. Our data showed predictive morphology to be superior to blind IHC screening for detecting them. The relationship of FH-deficient uterine smooth muscle tumors to the HLRCC syndrome needs further clarification.

Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants

“…The COL4A5/COL4A6 deletion positive UL subtype constitutes about 2% (12). We and other estimated that FH deficient UL subtype makes up 0.4% to 1.6% of all ULs (13,14).…”

“…We included 13 FH deficient ULs with sufficient high-quality DNA from a previously described cohort of 22 prospectively diagnosed tumors collected from routine surgical pathology (n = 10) or consultation files (n = 3) of one of the authors (A.A.) (13). The histopathological characteristics of theses ULs have been reviewed by an experienced pathologist and analyzed by immunohistochemistry for FH in all 13 cases (as described previously (13)) and…”

“…We recently showed that FH deficient ULs can reliably be suspected based on consistent morphological features and confirmed by FH immunohistochemistry (IHC) (13). Based on this cohort, we now analyzed 13 ULs with available tumor DNA by targeted panel sequencing to investigate their somatic variant spectrum for both small genetic (single nucleotide variants: SNVs, base insertions or deletions: indels) and copy number variants (CNVs).…”

High grade infiltrative adenocarcinomas of renal cell origin: New insights into classification, morphology, and molecular pathogenesis

“…Histologically they show increased cellularity, eosinophilic cytoplasm, prominent vascularity in a staghorn “hematopericytoma”‐like pattern, and scattered bizarre nuclei, some with the nucleolar prominence and perinucleolar findings as described for the renal tumors, some multinucleate . Variable stromal edema has been described, as has schwannoma‐like nuclear palisading . In particular, it seems that a significant subset of atypical or bizarre leiomyomas show FH deficiency …”

“…48,49 Variable stromal edema has been described, as has schwannoma-like nuclear palisading. 50,51 In particular, it seems that a significant subset of atypical or bizarre leiomyomas show FH deficiency. 52,53 One of the challenges of dealing with this syndrome, from the surgical pathologist's standpoint, is that tumors with morphologic and cytologic features very suggestive of the syndrome seem to come to sign-out without available documentation of any personal or family history of the syndrome or any data regarding presence or absence of its stigmata.…”