Current Morphologic Criteria Perform Poorly in Identifying Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome-associated Uterine Leiomyomas

Alsolami, S; El‐Bahrawy, Mona; Se, Kalloger; Aldaoud, Najla; Pathak, T; Chung, Chia Min; Mulligan, Anna Marie; Ip, Tomlinson; Pj, Pollard; Cb, Gilks; McCluggage, W. Glenn; Clarke, Blaise A.

doi:10.1097/pgp.0000000000000091

Cited by 24 publications

(22 citation statements)

References 23 publications

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“…FH deficiency has been shown to be overrepresented in leiomyomas with bizarre nuclei and some of the morphologic features typical for these tumors have been associated with FH mutations [42, 44–47]. Even though morphologic features alone lack robustness to separate sporadic and HLRCC-associated ULs [48–50], the possibility of an underlying germline FH mutation should be considered in patients with ULs with bizarre nuclei. Clinical features such as the severity of symptoms, number of tumors within the uterus, age at diagnosis, and possible family history of ULs can be evaluated, and patients should be examined for possible cutaneous leiomyomas.…”

Section: Resultsmentioning

confidence: 99%

Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors

Mäkinen¹,

Kämpjärvi²,

Frizzell³

et al. 2017

Mol Cancer

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Uterine smooth muscle tumors range from benign leiomyomas to malignant leiomyosarcomas. Based on numerous molecular studies, leiomyomas and leiomyosarcomas mostly lack shared mutations and the majority of tumors are believed to develop through distinct mechanisms. To further characterize the molecular variability among uterine smooth muscle tumors, and simultaneously insinuate their potential malignant progression, we examined the frequency of known genetic leiomyoma driver alterations (MED12 mutations, HMGA2 overexpression, biallelic FH inactivation) in 65 conventional leiomyomas, 94 histopathological leiomyoma variants (18 leiomyomas with bizarre nuclei, 22 cellular, 29 highly cellular, and 25 mitotically active leiomyomas), and 51 leiomyosarcomas. Of the 210 tumors analyzed, 107 had mutations in one of the three driver genes. No tumor had more than one mutation confirming that all alterations are mutually exclusive. MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression. Highly cellular leiomyomas displayed the least amount of alterations leaving the majority of tumors with no known driver aberration. Our results indicate that based on the molecular background, histopathological leiomyoma subtypes do not only differ from conventional leiomyomas, but also from each other. The presence of leiomyoma driver alterations in nearly one third of leiomyosarcomas suggests that some tumors arise through leiomyoma precursor lesion or that these mutations provide growth advantage also to highly aggressive cancers. It is clinically relevant to understand the molecular background of various smooth muscle tumor subtypes, as it may lead to improved diagnosis and personalized treatments in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0672-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors

Mäkinen¹,

Kämpjärvi²,

Frizzell³

et al. 2017

Mol Cancer

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“…[48][49][50] However, these features are not easily reproducible and it has been shown that leiomyomas with bizarre nuclei that are not associated with this syndrome can also show absence of staining for FH (Figure 4d) with positive S2C in the same cells, indicating that the above morphologic features are not diagnostic of this syndrome. 48,51 Thus, absence of staining should be used as a "triage" for further genetic testing but not as a diagnostic tool in this scenario. Finally, avoid using the term atypical leiomyoma for a leiomyoma with bizarre nuclei/symplastic leiomyoma as this term is used in the most recent WHO classification as a synonym of smooth muscle tumor of uncertain/low malignant potential.…”

Section: Tumor Cell Necrosismentioning

confidence: 99%

Practical issues in uterine pathology from banal to bewildering: the remarkable spectrum of smooth muscle neoplasia

Oliva

2016

Modern Pathology

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Among mesenchymal tumors of the uterus, smooth muscle neoplasms are most common. The wide morphologic spectrum, especially within the category of leiomyomas, is responsible for diagnostic problems more frequently with leiomyosarcoma (including mitotically active, apoplectic, and leiomyoma with bizarre nuclei) but also with endometrial stromal tumors. In the former scenario, clinical information, gross appearance as well as strict utilization of morphologic criteria including cytologic atypia, mitotic activity, and tumor cell necrosis are clues in establishing the correct diagnosis. It is important to keep in mind that mitotic rate thresholds vary for the different subtypes of leiomyosarcoma. Of note, p16 should be used with caution in supporting a diagnosis of leiomyosarcoma as it is often positive in leiomyomas with bizarre nuclei and leiomyomas with apoplectic change (in the latter most frequently and more intense near areas of necrosis). MED12 mutations have also a very limited role in this differential diagnosis. Endometrial stromal tumors are by far, less common than smooth muscle tumors, but can be confused with leiomyosarcomas if they are associated with an undifferentiated uterine sarcoma and the low-grade component is overlooked or they have a myxoid/fibroblastic morphology. The differential diagnosis may be confounded if the latter is associated with a high-grade endometrial stromal sarcoma. It is important to highlight that CD10 is not a reliable marker in these differentials and should be used as a part of a panel of antibodies that also includes desmin and h-caldesmon. Two other recently categorized tumors in the uterus that merit special mention are PEComa and inflammatory myofibroblastic tumor as they enter in the differential diagnosis of smooth muscle tumors. PEComa may be part of the tuberous sclerosis syndrome and may show either a predominantly epithelioid or spindle morphology or combination thereof. Rarely, it may contain melanin pigment. There is variable positivity for HMB-45, MelanA, MiTF, and CathepsinK, and some tumors have been shown to express TFE-3 especially when associated with "clear cell" morphology. Patients with adverse outcome have tumors with ≥ 2 of the following features: ≥ 5 cm, infiltration, high-grade cytologic features, mitotic rate ≥ 1/50 high-power fields, necrosis, or lymphovascular invasion. Inflammatory myofibroblastic tumor is important to recognize as it often mimics myxoid smooth muscle tumors, either benign or malignant. The presence of an associated lymphoplasmacytic infiltrate should alert to that possibility and ALK studies (immunostain or FISH) are helpful in establishing this diagnosis. These tumors can behave in a malignant manner if large, associated with abundant myxoid change, brisk mitotic rate or show tumor cell necrosis.

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“…It has previously been suggested that uterine leiomyomas arising in the setting of germline FH mutation may show distinctive morphologic features including prominent nucleoli with perinucleolar clearing, hypercellularity, symplastic-type nuclear atypia, a hemangiopericytomatous vascular pattern, cytoplasmic globules, and stromal edema. 7 , 10 , 11 However, the significance and specificity of these features has recently been questioned, 8 and it seems that morphology alone will be inadequate to identify HLRCC-associated uterine leiomyomas prospectively. 10 …”

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confidence: 99%

“… 7 , 10 , 11 However, the significance and specificity of these features has recently been questioned, 8 and it seems that morphology alone will be inadequate to identify HLRCC-associated uterine leiomyomas prospectively. 10 …”

mentioning

confidence: 99%

“…14 , 15 This lack of specificity is a significant problem in a screening test for a rare entity. Although there is some evidence that 2SC IHC may be useful to identify HLRCC-associated uterine leiomyomas, 10 others have found it less useful. 8 Perhaps most importantly, to our knowledge, IHC for 2SC is not commercially available and, therefore, cannot be deployed in the routine surgical pathology laboratory.…”

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confidence: 99%

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Fumarate Hydratase–deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings

Harrison

Andrici

Maclean

et al. 2016

American Journal of Surgical Pathology

111

138

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Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.

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Current Morphologic Criteria Perform Poorly in Identifying Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome-associated Uterine Leiomyomas

Cited by 24 publications

References 23 publications

Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors

Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors

Practical issues in uterine pathology from banal to bewildering: the remarkable spectrum of smooth muscle neoplasia

Fumarate Hydratase–deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings

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