Two Subtypes of Atypical Leiomyoma

Ubago, Julianne M.; Zhang, Qing; Kim, Julie; Kong, Beihua; Wei, Jian Jun

doi:10.1097/pas.0000000000000646

Cited by 31 publications

(22 citation statements)

References 14 publications

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“…Furthermore, we expanded on previous observations and demonstrated that leiomyomas with bizarre nuclei with an aberrant FH/2SC immunoprofile are genetically distinct from those with a normal FH/2SC staining pattern, with somatic FH genetic alteration restricted to the former and TP53 and/or RB1 alterations significantly more frequent in the latter. The concept of two subtypes of leiomyomas with bizarre nuclei has also been recently described by Ubago et al 39 in which their type I atypical leiomyomas were more likely to show “hereditary leiomyomatosis and renal cell carcinoma syndrome features,” whereas type II atypical leiomyomas had a higher rate of TP53 and MED12 mutations. It should be noted that one of the cases harboring a somatic FH missense mutation coupled with loss of the wild-type allele (SCU14T) retained FH expression while also being 2SC-positive.…”

Section: Discussionmentioning

confidence: 82%

“…Other studies have identified that these features can also be seen in sporadic leiomyomas. 35 – 39 In a morphological-based study by Alsolami et al, 35 six pathologists evaluated a series of 30 uterine leiomyomas (19 from patients with germline-proven hereditary leiomyomatosis and renal cell carcinoma syndrome and 11 sporadic) for the above described features; however, interobserver variability was poor for most parameters. Another study observed at least one of these morphologic findings in 92% (11/12) of uterine leiomyomas from non-hereditary leiomyomatosis and renal cell carcinoma syndrome patients, but for their two leiomyomas from patients with germline-proven mutations, only one showed all of the “hereditary leiomyomatosis and renal cell carcinoma syndrome features”.…”

Section: Discussionmentioning

confidence: 99%

“… 47 , 50 , 52 , 54 , 55 , 61 , 63 – 66 In five studies leiomyomas with bizarre nuclei were specifically evaluated for MED12 mutations and were found in up to 25% of tumors. 39 , 47 , 50 , 53 , 61 Two studies detected somatic MED12 mutations in a small subset of leiomyomas from patients with germline-proven hereditary leiomyomatosis and renal cell carcinoma syndrome; however, loss of heterozygosity for the FH allele was not identified in any of these tumors. 53 , 59 Similarly, Liegl-Atzwanger et al 61 found MED12 and FH somatic mutations to be mutually exclusive in their series of leiomyomas, leiomyomas with bizarre nuclei, and leiomyosarcomas.…”

Section: Discussionmentioning

confidence: 99%

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Leiomyoma with bizarre nuclei: a morphological, immunohistochemical and molecular analysis of 31 cases

et al. 2017

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Leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome and leiomyomas with bizarre nuclei often show overlapping morphological features, in particular cells with prominent eosinophilic nucleoli, perinucleolar halos and eosinophilic cytoplasmic inclusions. While hereditary leiomyomatosis and renal cell carcinoma syndrome is defined by fumarate hydratase (FH) germline mutations, resulting in S-(2-succino)-cysteine (2SC) formation, it is unknown if leiomyomas with bizarre nuclei show similar alterations. In this study, we evaluated the morphology and FH/2SC immunoprofile of 31 leiomyomas with bizarre nuclei. DNA from tumor and normal tissues from 24 cases was subjected to massively parallel sequencing targeting 410 key cancer genes. Somatic genetic alterations were detected using state-of-the-art bioinformatics algorithms. No patient reported a personal history of renal neoplasia or cutaneous leiomyomas, but one had a family history of renal cell carcinoma while another had a family history of uterine leiomyomas. Aberrant FH/2SC expression was noted in 17 tumors (16 FH-negative/2SC-positive, 1 FH-positive/2SC-positive). On univariate analysis, staghorn vessels, eosinophilic cytoplasmic inclusions, diffuse distribution of prominent eosinophilic nucleoli with perinucleolar halos and an “alveolar pattern of edema” were associated with an abnormal immunoprofile, but only staghorn vessels remained significant on multivariate analysis. Massively parallel sequencing analysis (n=24) revealed that 13/14 tumors with aberrant FH/2SC immunoprofile harbored somatic FH somatic genetic alterations, including homozygous deletions (n=9), missense mutations coupled with loss of heterozygosity (n=3), and a splice site mutation (n=1), whereas no somatic FH mutations/deletions were found in tumors with normal immunoprofile (n=10; p<0.0001). Leiomyomas with bizarre nuclei with normal FH/2SC staining pattern more frequently harbored TP53 and/or RB1 alterations than those with aberrant FH/2SC immunoprofile (60% vs 14%; p=0.032). These data demonstrate that leiomyomas with bizarre nuclei are morphologically and genetically heterogeneous, and that hereditary leiomyomatosis and renal cell carcinoma syndrome-related morphologic features, abnormal FH/2SC staining, and somatic FH mutations/deletions can be seen in a subset of sporadic tumors.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Leiomyoma with bizarre nuclei: a morphological, immunohistochemical and molecular analysis of 31 cases

et al. 2017

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“…For those cases with mixed type I and II nuclear features, we defined cases as either type I or II when over 70% of the tumor cells appeared to show nuclear features favoring one or another. The detailed description of type I and II characterization has been outlined in a previous study 13 .…”

Section: Methodsmentioning

confidence: 99%

“…Historically, many sporadic SMT-FH were diagnosed as LM-BN due to the significant nuclear atypia 11, 12 . LM-BN also present with a wide range of histologic features 1, 3, 4 and in our set of tumors originally diagnosed as LM-BN, nearly half showed nuclear features similar to SMT-FH 9, 10 and we therefore defined them as type I LM-BN 13 . This suggests that many uterine smooth muscle tumors with atypical histology diagnosed as LM-BN may be related to FH alterations/mutations.…”

Section: Introductionmentioning

confidence: 98%

Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei

Zhang

Poropatich²,

Ubago³

et al. 2018

International Journal of Gynecological Pathology

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Leiomyoma with bizarre nuclei (LM-BN), is a variant of uterine smooth muscle tumor with atypical histologic features. Although some LM-BN share several significant genetic alterations with leiomyosarcoma, including p16 and p53, the underlying tumorigenesis of LM-BN remains largely unknown. As we previously reported, LM-BN can be divided into 2 subtypes, type I and type II, based on different nuclear features. Type I LM-BN have similar histologic features as uterine smooth muscle tumors with fumarate hydratase (FH) alterations. In this study, we examined FH expression and FH mutations in 77 LM-BN (40 type I cases and 37 type II cases). FH expression was examined by immunohistochemistry using S-(2-succino)-cysteine antibodies (2SC, a protein modification associated with FH inactivation and subsequent fumarate accumulation) and FH antibodies (FH gene products). Seventy-two LM-BN tumors underwent Sanger sequencing to detect FH mutations. We found that 51% (39/77) of LM-BN showed FH alterations detected by immunohistochemistry with both 2SC and FH. Mutational analysis showed that 21% (15/72) of LM-BN harbored FH gene mutations. Further analysis revealed that 85% (34/40) of those with FH alterations were type I LM-BN while 19% (7/37) were type II LM-BN. Our findings suggest that over half of histologically diagnosed LM-BN may be related to FH alterations or FH mutations and the majority of these have the characteristic histologic features of type I LM-BN.

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Hereditary leiomyomatosis and renal cell carcinoma syndrome associated uterine smooth muscle tumors: Bridging morphology and clinical screening

Garg

Rabban

2020

Genes Chromosomes & Cancer

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Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome that results from germline mutation in the fumarate hydratase (FH) gene and is associated with an increased risk for smooth muscle tumors of the uterus and skin and renal cell carcinoma. HLRCC associated RCC develop in up to 25% of patients, often presenting in the fourth decade and are high stage, aggressive tumors with poor clinical outcome. Most women with HLRCC develop large and bulky uterine smooth muscle tumors (USMT) in the second to third decade, thus presenting the ideal opportunity for early detection of HLCC to enable timely implementation of surveillance for their RCC risk. However, the concept of screening women with USMT for HLRCC is challenging given that HLRCC is rare but USMT are common. In addition, FH deficiency in USMT can also result from sporadic FH gene aberrations, unrelated to HLRCC, further complicating any potential screening process. Recent studies show that tumor morphology can be used to identify FH deficiency in USMT and thereby direct patients to formal genetic counseling. The low magnification clues of staghorn shaped blood vessels and alveolar pattern should prompt for high magnification examination for eosinophilic cytoplasmic inclusions and oval nuclei containing prominent eosinophilic macronucleoli surrounded by a halo. Additional clues include Schwannoma‐like growth and chain‐like distribution of the tumor cells. Although immunostains exist for FH and 2SC, their role is limited in the presence of well‐developed FH deficient morphology. The prevalence of germline pathogenic mutation in FH among women with USMT with FH deficient morphology is as high as 50% in some studies, with somatic FH mutation accounting for the remainder. Therefore, morphologic evaluation of USMT for features of FH deficiency can serve as a screening tool for HLRCC syndrome by triaging patients to formal hereditary risk assessment.

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Two Subtypes of Atypical Leiomyoma

Cited by 31 publications

References 14 publications

Leiomyoma with bizarre nuclei: a morphological, immunohistochemical and molecular analysis of 31 cases

Leiomyoma with bizarre nuclei: a morphological, immunohistochemical and molecular analysis of 31 cases

Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei

Hereditary leiomyomatosis and renal cell carcinoma syndrome associated uterine smooth muscle tumors: Bridging morphology and clinical screening

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