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Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome.
Am J Surg Pathol. 2013 Jan; 37(1):74-80.AJ

Abstract

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome in which affected individuals are predisposed to the development of multiple leiomyomas of the skin and uterus and aggressive forms of kidney cancer. Affected individuals harbor a germline heterozygous loss-of-function mutation of the fumarate hydratase (FH) gene. Uterine leiomyomas are present in up to 77% of women with this syndrome. Previous studies have shown that inactivation of the FH gene is unusual for nonsyndromic leiomyomas. Therefore, it might be possible to distinguish 2 genetic groups of smooth muscle tumors: the most common group of sporadic uterine leiomyomas without FH gene inactivation and the more unusual group of HLRCC leiomyomas in patients who harbor a germline mutation of FH, although the exact prevalence of hereditary HLRCC is unknown. We reviewed the clinical, morphologic, and genotypic features of uterine leiomyomas in 19 HLRCC patients with FH germline mutations. Patients with HLRCC syndrome were younger in age compared with those with regular leiomyomata. DNA was extracted by microdissection, and analysis of loss of heterozygosity (LOH) at 1q43 was performed. Uterine leiomyomas in HLRCC have young age of onset and are multiple, with size ranging from 1 to 8 cm. Histopathologically, HLRCC leiomyomas frequently had increased cellularity, multinucleated cells, and atypia. All cases showed tumor nuclei with large orangeophilic nucleoli surrounded by a perinucleolar halo similar to the changes found in HLRCC. Occasional mitoses were found in 3 cases; however, the tumors did not fulfill the criteria for malignancy. Our study also showed that LOH at 1q43 was frequent in HLRCC leiomyomas (8/10 cases), similarly to what has been previously found in renal cell carcinomas from HLRCC patients. LOH is considered to be the second hit that inactivates the FH gene. We conclude that uterine leiomyomas associated with HLRCC syndrome have characteristic morphologic features. Both, uterine leiomyomas and renal cell carcinoma share some morphologic nuclear changes and genotypic features in HLRCC patients. The specific morphologic features of the uterine leiomyomas that we describe may help in the identification of patients who may be part of the hereditary syndrome.

Authors+Show Affiliations

Translational Surgical Pathology, National Institutes of Health, Bethesda, MD 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23211287

Citation

Sanz-Ortega, Julian, et al. "Morphologic and Molecular Characteristics of Uterine Leiomyomas in Hereditary Leiomyomatosis and Renal Cancer (HLRCC) Syndrome." The American Journal of Surgical Pathology, vol. 37, no. 1, 2013, pp. 74-80.
Sanz-Ortega J, Vocke C, Stratton P, et al. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol. 2013;37(1):74-80.
Sanz-Ortega, J., Vocke, C., Stratton, P., Linehan, W. M., & Merino, M. J. (2013). Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. The American Journal of Surgical Pathology, 37(1), 74-80. https://doi.org/10.1097/PAS.0b013e31825ec16f
Sanz-Ortega J, et al. Morphologic and Molecular Characteristics of Uterine Leiomyomas in Hereditary Leiomyomatosis and Renal Cancer (HLRCC) Syndrome. Am J Surg Pathol. 2013;37(1):74-80. PubMed PMID: 23211287.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. AU - Sanz-Ortega,Julian, AU - Vocke,Cathy, AU - Stratton,Pamela, AU - Linehan,William Marston, AU - Merino,Maria J, PY - 2012/12/6/entrez PY - 2012/12/6/pubmed PY - 2013/2/13/medline SP - 74 EP - 80 JF - The American journal of surgical pathology JO - Am. J. Surg. Pathol. VL - 37 IS - 1 N2 - Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome in which affected individuals are predisposed to the development of multiple leiomyomas of the skin and uterus and aggressive forms of kidney cancer. Affected individuals harbor a germline heterozygous loss-of-function mutation of the fumarate hydratase (FH) gene. Uterine leiomyomas are present in up to 77% of women with this syndrome. Previous studies have shown that inactivation of the FH gene is unusual for nonsyndromic leiomyomas. Therefore, it might be possible to distinguish 2 genetic groups of smooth muscle tumors: the most common group of sporadic uterine leiomyomas without FH gene inactivation and the more unusual group of HLRCC leiomyomas in patients who harbor a germline mutation of FH, although the exact prevalence of hereditary HLRCC is unknown. We reviewed the clinical, morphologic, and genotypic features of uterine leiomyomas in 19 HLRCC patients with FH germline mutations. Patients with HLRCC syndrome were younger in age compared with those with regular leiomyomata. DNA was extracted by microdissection, and analysis of loss of heterozygosity (LOH) at 1q43 was performed. Uterine leiomyomas in HLRCC have young age of onset and are multiple, with size ranging from 1 to 8 cm. Histopathologically, HLRCC leiomyomas frequently had increased cellularity, multinucleated cells, and atypia. All cases showed tumor nuclei with large orangeophilic nucleoli surrounded by a perinucleolar halo similar to the changes found in HLRCC. Occasional mitoses were found in 3 cases; however, the tumors did not fulfill the criteria for malignancy. Our study also showed that LOH at 1q43 was frequent in HLRCC leiomyomas (8/10 cases), similarly to what has been previously found in renal cell carcinomas from HLRCC patients. LOH is considered to be the second hit that inactivates the FH gene. We conclude that uterine leiomyomas associated with HLRCC syndrome have characteristic morphologic features. Both, uterine leiomyomas and renal cell carcinoma share some morphologic nuclear changes and genotypic features in HLRCC patients. The specific morphologic features of the uterine leiomyomas that we describe may help in the identification of patients who may be part of the hereditary syndrome. SN - 1532-0979 UR - https://www.unboundmedicine.com/medline/citation/23211287/Morphologic_and_molecular_characteristics_of_uterine_leiomyomas_in_hereditary_leiomyomatosis_and_renal_cancer__HLRCC__syndrome_ L2 - http://dx.doi.org/10.1097/PAS.0b013e31825ec16f DB - PRIME DP - Unbound Medicine ER -