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Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients.
Am J Surg Pathol. 2015 Nov; 39(11):1529-39.AJ

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant syndrome that results from mutations in the fumarate hydratase (FH) gene. Patients with HLRCC are at risk for smooth muscle tumors of the uterus and skin as well as renal tumors. The renal cell carcinomas associated with HLRCC are usually high stage at presentation, aggressive, and have poor clinical outcomes. Therefore these patients and family members would benefit from early identification and appropriate surveillance. In small studies, HLRCC-associated uterine leiomyomas have been noted to display characteristic morphologic features including eosinophilic cytoplasmic inclusions, prominent eosinophilic nucleoli, and perinucleolar halos. Limited data suggest that positive staining for 2-succinocysteine (2SC) and loss of staining for FH by immunohistochemistry (IHC) can help with identification of HLRCC. The aim of this study was to evaluate the ability of morphology and IHC for FH and 2SC to help identify HLRCC in young patients with uterine smooth muscle tumors. We identified 194 evaluable uterine leiomyomas from women less than 40 years of age. We found FH gene aberrations by mutation analysis in 5 cases, a 2.6% incidence. Of these 5 cases, 4 displayed the characteristic morphologic features outlined above, whereas 1 did not. All 5 tumors with FH gene abnormalities showed positive staining for 2SC, whereas no FH gene aberrations were found in the 2SC-negative cases. Loss of FH staining was seen in 2 of the 5 cases, 1 with frameshift mutation and the other with homozygous deletion, whereas the remaining 3 cases with missense FH gene mutations were FH positive. Our study shows that morphologic features can be helpful for detection of HLRCC in uterine leiomyomas, although they may not be present in every case. IHC for 2SC and FH can be helpful: presence of positive staining for 2SC is sensitive and specific for detection of FH gene aberrations, whereas loss of staining for FH is specific but not sufficiently sensitive, as cases with missense mutations in the FH gene can show retained staining.

Authors+Show Affiliations

*Department of Pathology, University of California San Francisco, San Francisco, CA †University of South Carolina School of Medicine, Columbia, SC.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Evaluation Study
Journal Article

Language

eng

PubMed ID

26457356

Citation

Joseph, Nancy M., et al. "Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients." The American Journal of Surgical Pathology, vol. 39, no. 11, 2015, pp. 1529-39.
Joseph NM, Solomon DA, Frizzell N, et al. Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients. Am J Surg Pathol. 2015;39(11):1529-39.
Joseph, N. M., Solomon, D. A., Frizzell, N., Rabban, J. T., Zaloudek, C., & Garg, K. (2015). Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients. The American Journal of Surgical Pathology, 39(11), 1529-39. https://doi.org/10.1097/PAS.0000000000000520
Joseph NM, et al. Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients. Am J Surg Pathol. 2015;39(11):1529-39. PubMed PMID: 26457356.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients. AU - Joseph,Nancy M, AU - Solomon,David A, AU - Frizzell,Norma, AU - Rabban,Joseph T, AU - Zaloudek,Charles, AU - Garg,Karuna, PY - 2015/10/13/entrez PY - 2015/10/13/pubmed PY - 2016/1/27/medline SP - 1529 EP - 39 JF - The American journal of surgical pathology JO - Am. J. Surg. Pathol. VL - 39 IS - 11 N2 - Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant syndrome that results from mutations in the fumarate hydratase (FH) gene. Patients with HLRCC are at risk for smooth muscle tumors of the uterus and skin as well as renal tumors. The renal cell carcinomas associated with HLRCC are usually high stage at presentation, aggressive, and have poor clinical outcomes. Therefore these patients and family members would benefit from early identification and appropriate surveillance. In small studies, HLRCC-associated uterine leiomyomas have been noted to display characteristic morphologic features including eosinophilic cytoplasmic inclusions, prominent eosinophilic nucleoli, and perinucleolar halos. Limited data suggest that positive staining for 2-succinocysteine (2SC) and loss of staining for FH by immunohistochemistry (IHC) can help with identification of HLRCC. The aim of this study was to evaluate the ability of morphology and IHC for FH and 2SC to help identify HLRCC in young patients with uterine smooth muscle tumors. We identified 194 evaluable uterine leiomyomas from women less than 40 years of age. We found FH gene aberrations by mutation analysis in 5 cases, a 2.6% incidence. Of these 5 cases, 4 displayed the characteristic morphologic features outlined above, whereas 1 did not. All 5 tumors with FH gene abnormalities showed positive staining for 2SC, whereas no FH gene aberrations were found in the 2SC-negative cases. Loss of FH staining was seen in 2 of the 5 cases, 1 with frameshift mutation and the other with homozygous deletion, whereas the remaining 3 cases with missense FH gene mutations were FH positive. Our study shows that morphologic features can be helpful for detection of HLRCC in uterine leiomyomas, although they may not be present in every case. IHC for 2SC and FH can be helpful: presence of positive staining for 2SC is sensitive and specific for detection of FH gene aberrations, whereas loss of staining for FH is specific but not sufficiently sensitive, as cases with missense mutations in the FH gene can show retained staining. SN - 1532-0979 UR - https://www.unboundmedicine.com/medline/citation/26457356/Morphology_and_Immunohistochemistry_for_2SC_and_FH_Aid_in_Detection_of_Fumarate_Hydratase_Gene_Aberrations_in_Uterine_Leiomyomas_From_Young_Patients_ L2 - http://dx.doi.org/10.1097/PAS.0000000000000520 DB - PRIME DP - Unbound Medicine ER -