Hereditary Leiomyomatosis And Renal Cell Carcinoma Research Articles

Genetic Testing by Cancer Site

This review article discusses hereditary cancer predisposition syndromes with uterine manifestations. Lynch syndrome accounts for 2% to 3% of endometrial cancers. The identification of endometrial cancer patients at risk for Lynch syndrome is discussed, as are the characteristics of Lynch syndrome-associated endometrial cancer and the screening and prevention options for women at risk for Lynch syndrome-associated endometrial cancer. Endometrial cancer associated with PTEN hamartoma tumor syndrome (also known as Cowden syndrome) is also discussed. HLRCC (hereditary leiomyomatosis and renal cell carcinoma), which has an associated high risk of symptomatic uterine leiomyomas, is reviewed.

Familial renal cancer as an indicator of hereditary leiomyomatosis and renal cell cancer syndrome

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a hereditary condition which typically presents with cutaneous and uterine leiomyomata. Papillary type II renal cell carcinoma and other less common histologic subtypes of renal cancer have been reported in HLRCC. We describe the case of a 31-year-old man in which the pathology review of his renal carcinoma and a positive family history of renal carcinoma allowed for the identification of a pathogenic mutation in the FH gene (c.698G>A;p.R233H) confirming the diagnosis of HLRCC. Recognition of this syndrome allowed for appropriate surveillance as well as identification of at-risk family members. Pathology review is essential for accurate diagnosis of a hereditary cancer syndrome in the setting of familial renal cancer.

Morphologic Features of Uterine Leiomyomas Associated With Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome

Patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome are prone to develop smooth muscle tumors of the uterus and skin and also renal carcinomas. The morphologic features of renal tumors that arise in the setting of HLRCC are well described, the hallmark feature being the presence of prominent eosinophilic nucleoli surrounded by a clear halo. Renal tumors associated with HLRCC are aggressive and often present late with high-stage disease. Early detection of patients with HLRCC could lead to surveillance for renal carcinomas. Women with HLRCC often present at a young age with uterine leiomyomas and frequently undergo hysterectomy as a result. HLRCC associated uterine leiomyomas show nuclear features similar to those described in HLRCC associated renal tumors. Therefore, presence of these nuclear features in uterine smooth muscle tumors may aid in early detection of HLRCC, resulting in surveillance for renal carcinoma. We present a case of a 32-year-old woman who underwent hysterectomy for uterine fibroids and subsequently presented 5 years later with high-stage renal carcinoma. Histologic evaluation of uterine leiomyomas and renal carcinoma revealed identical nuclear features, that is, prominent nucleoli with perinucleolar halos, raising the possibility of HLRCC. Subsequent testing confirmed a fumarate hydratase mutation. The presence of above-described nuclear features in uterine leiomyomas should raise the possibility of HLRCC.

22. Hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report

Background Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome characterised by cutaneous and uterine leiomyoma and renal cell carcinoma. The kidney tumours are typically described as having features of type 2 papillary carcinoma; however, other types of renal cell cancers have also been reported. The tumours tend to be aggressive, with frequent and early nodal and distant metastases despite the often small size of the primary tumour. Case report We present an unusual case of HLRCC in a 53-year-old male who was referred to a Family Cancer Service with a strong personal and family history of renal cancer. He was diagnosed at age 31 with a ‘Grawitz tumour’. The histology of his renal cell carcinoma was reviewed following recognition of HLRCC in the family. The patient’s tumour had solid and cystic areas with tubulopapillary architecture. The tumour cells had a moderate amount of eosinophilic cytoplasm, with Fuhrman nuclear grade 3. Many of the nuclei showed prominent eosinophilic nucleoli, with a clear halo surrounding the nucleolus. No invasion of the renal capsule or vessels was seen. Initially no underlying genetic cause for renal cancer in the family was found. The family history then evolved with a female relative developing both cutaneous and uterine leiomyoma and her dermatologist suspected HLRCC as the cause. A New Zealand Family Cancer Clinic arranged genetic testing of an affected relative and a causative germline mutation was identified in the fumarate hydratase (FH) gene [p.Gly354Arg (G354R)]. Genetic testing for our patient was then arranged and this confirmed he had inherited the family mutation in the FH gene. He remains disease free. His offspring are being tested. Conclusion This case report reviews the molecular genetics of HLRCC and the pathological features of renal cell carcinoma, with discussion on possible characteristic histological features that may help to alert the pathologist to the possibility of a familial cancer syndrome.

Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes

Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p < 0.001), thyroid (5/10 versus 15/106, p < 0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.

The Morphologic Spectrum of Kidney Tumors in Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) Syndrome

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome characterized by the development of cutaneous and uterine leiomyomas as well as renal tumors. The mutation of this condition has been identified in the fumarate hydratase (FH, 1q42.3-q43) gene. The histology of the renal cancers has not been well described or illustrated because of the newness of the syndrome. We reviewed 40 renal tumors resected from 38 patients belonging to HLRCC families with proven fumarate hydratase germline mutation. Patients ranged in age from 17 to 75 years of age. Tumors were unilateral in all but 2 cases. The size of the tumors varied between 2.3 and 20 cm and there was no laterality preference. Several different architectural patterns were recognized: papillary (25 cases), tubulo-papillary (8 cases), tubular (2 cases), and solid (1 case). Mixed patterns were also present in 4 cases. The most important histologic feature of these neoplasms, which we believe to be the hallmark of the HLRCC tumors, is the presence of a characteristic large nucleus with a very prominent inclusion like orangiophilic or eosinophilic nucleolus, surrounded by a clear halo. Immunohistochemical studies did not provide a specific marker for these tumors, however, loss of heterozygosity at 1q32 and 1q42-44 was frequently found. These tumors are associated with poor prognosis and frequent spread to regional lymph nodes. At the moment, morphology is the best tool to recognize these tumors. Proper diagnosis of this syndrome by the pathologist may assist in early detection of these tumors.

Aberrant expression of apoptosis proteins and ultrastructural aberrations in uterine leiomyomas from patients with hereditary leiomyomatosis and renal cell carcinoma

To examine differences between sporadic and familial uterine leiomyomata related to expression of apoptosis-related proteins and tumor ultrastructure. Expression of apoptosis-related proteins was measured by immunohistochemistry. Tumor ultrastructure was evaluated by transmission electron microscopy. Human genetics laboratory. Patients confirmed for hereditary leiomyomatosis and renal cell carcinoma (HLRCC), and anonymous archival sporadic leiomyoma patients. Samples for electron microscopy were collected from myomectomy and hysterectomy with informed consent. Other samples were archival. Intensity of immunohistochemistry staining and evaluation of electron micrographs. Immunohistochemistry revealed increases in expression of antiapoptotic Bcl-2 and the proliferation factor proliferating cell nuclear antigen (PCNA) in both sporadic and HLRCC uterine leiomyomata. Furthermore, we observed an increase in antiapoptotic Bcl-x and a concurrent decrease in proapoptotic Bak solely in HLRCC leiomyomas. We also observed ultrastructural alterations in HLRCC and sporadic leiomyomas, particularly pertaining to extracellular matrix and intermediate filament aggregation. The observed alterations in expression of apoptosis-related proteins indicate a shift in both HLRCC and sporadic leiomyomas to increased resistance to apoptosis compared with myometrium, which appears to be stronger in HLRCC leiomyomas. The changes observed in HLRCC leiomyomas appear to be related to activation of the hypoxia pathways. The results suggest not only a partial overlap in the pathogenic mechanism of the two tumor types, but also intriguing differences.

The Genetics of Uterine Leiomyomata

The genetics of many complex diseases, including hypertension, diabetes, and asthma, are receiving intense investigation and beginning to have therapeutic relevance. Family medical history can be a critical source of information for providing optimal patient care. For gynecologists, knowledge of cancer susceptibility genes such as BRCA1 and BRCA2 and the genetic syndrome hereditary nonpolyposis colorectal cancer (Lynch syndrome II) affects how patients are screened for ovarian and endometrial cancers. Similarly, identification of mutations in the fumarate hydratase (FH) gene that lead to a syndrome called hereditary leiomyomatosis and renal cell carcinoma (HLRCC) will impact screening and treatment of women with uterine leiomyomas. Hereditary leiomyomatosis and renal cell carcinoma syndrome is particularly relevant to clinicians and patients because of the resulting increased risk of malignant disease for both the affected woman and her family. The goals of this article are to summarize the evolving genetic information concerning uterine leiomyomas, including hereditary leiomyomatosis and renal cell carcinoma syndrome, and to discuss the clinical importance of these findings. The current role of family medical history and future implications of genes relevant to leiomyoma biology will be reviewed.