Multiple cutaneous and uterine leiomyomata with features of benign metastasing leiomyomatosis: a novel mutation of the fumarate hydratase gene

Gilhooley, Eimear; Fahy, C.; Hanrahan, Emer O.; Keane, Michael P.; Swan, Niall; Lally, Aoife

doi:10.1111/ced.13332

Cited by 4 publications

(2 citation statements)

References 4 publications

(5 reference statements)

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“…BML is a rare disease in which women with a previous history of UL develop smooth muscle tumors outside the uterus. 24 Further studies with additional samples are warranted to verify the possible contributions of ATRX, ALT, and/or FH to BML pathogenesis. 18 The clinical course of BML is typically indolent, although rare malignant transformation has been reported.…”

Section: Discussionmentioning

confidence: 99%

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Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas

Ahvenainen

Mäkinen

Nandelstadh

et al. 2018

Cancer

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BACKGROUND: Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype. METHODS: To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs. RESULTS: A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres. CONCLUSIONS: These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential. Cancer 2018;124:4650-4656.

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Section: Discussionmentioning

confidence: 99%

“…One BML patient with a germline FH mutation has been reported, but the FH status of the tumors is not known. 24 Further studies with additional samples are warranted to verify the possible contributions of ATRX, ALT, and/or FH to BML pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas

Ahvenainen

Mäkinen

Nandelstadh

et al. 2018

Cancer

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Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases

Yin,

Wei,

Al Shamsi

et al. 2024

Virchows Arch

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Leiomyoma is the most prevalent benign tumor of the female reproductive system. Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5–2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.

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Lung metastases and subsequent malignant transformation of a fumarate hydratase -deficient uterine leiomyoma

Ahvenainen

Khamaiseh

Alkodsi

et al. 2022

Experimental and Molecular Pathology

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Multiple cutaneous and uterine leiomyomata with features of benign metastasing leiomyomatosis: a novel mutation of the fumarate hydratase gene

Cited by 4 publications

References 4 publications

Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas

Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas

Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases

Lung metastases and subsequent malignant transformation of a fumarate hydratase -deficient uterine leiomyoma

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