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

Abstract

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.

Primary Leiomyoma of the Visceral Pleura: An Unexpected Occurrence

“…Genetic studies have demonstrated that metastatic lung lesions belong to the same malignant cellular lineage as those from the uterine leiomyomas and have the ability to develop new mutations during tumoral evolution (26). Another disease in which leiomyoma is present is hereditary leiomyomatosis, which is a dominant autosomal hereditary illness associated with in vivo 35: 2457-2463 (2021) increased risk of multiple uterine and skin leiomyomas, renal cancer and pulmonary lymphangiomyomatosis manifesting as chylothorax (27).…”

Gene of the month: FH

“…that may raise suspicion as to their underlying pathogenesis. 40 FH-deficient leiomyomata are more likely than other leiomyomata to present with symplastic-type nuclear atypia, misinterpretation of which may result in erroneous classification as leiomyosarcoma. 37 38 41 More specific features include hemangiopericytoma-like ('staghorn') blood vessels, 'alveolartype' stromal oedema, eosinophilic cytoplasmic globules and large, eosinophilic nucleoli (figure 4); none of these features in isolation show perfect diagnostic accuracy, but their conspicuous presence within a tumour should prompt further consideration that one is dealing with an FH-deficient tumour, particularly in a young patient.…”

“…35 42 FH-deficient leiomyomata of the uterus are not specifically associated with an increased risk of malignancy, however, their identification is extremely important as by recognising the characteristic phenotype and/or confirming FH-deficiency by IHC or molecular testing, pathologists can recommend germline testing for FH mutations so as to identify patients that may benefit from routine screening for HLRCC-associated RCC. 40…”

Das FH-defiziente Nierenzellkarzinom erweitert das Spektrum der papillären Tumoren in der Niere

“…1 d, e) sowie uterinen (Abb. 1 f, g) Leiomyomen [ 20 ]. Eine Screeningstudie auf FH-Defizienz zeigte dabei in uterinen Leiomyomen eine breite Schwankung von Prävalenzen, je nach morphologischem Spektrum.…”

“…Ein immunhistochemischer FH-Expressionsverlust kann einen aufkommenden Verdacht untermauern, wobei wie auch in FH-defizienten NZK die Expression in einzelnen Fällen erhalten sein kann. Dies lässt sich zum Beispiel durch pathogene Mutationen erklären, die zu einem Funktionsverlust führen, allerdings das Epitop des verwendeten Antikörpers nicht betreffen [ 20 ]. Weiterhin eröffnet sich in der Folge die Schwierigkeit des korrekten klinischen Managements.…”