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Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry.

Reyes C, Karamurzin Y, Frizzell N, Garg K, Nonaka D, Chen YB, Soslow RA - Mod. Pathol. (2013)

Bottom Line: High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells but not in normal tissues or tumors unassociated with hereditary leiomyomatosis and renal cell carcinoma syndrome.Two of three tested patients had germline fumarate hydratase mutations.Smooth-muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

ABSTRACT
Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to a somatic fumarate hydratase mutation. Germline mutations account for the hereditary leiomyomatosis and renal cell carcinoma syndrome, which predisposes for cutaneous and uterine leiomyomas and aggressive renal cell carcinomas. Altered fumarate hydratase leads to fumarate accumulation in affected cells with formation of S-(2-succino)-cysteine, which can be detected with the polyclonal antibody. High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells but not in normal tissues or tumors unassociated with hereditary leiomyomatosis and renal cell carcinoma syndrome. We hypothesized that S-(2-succino)-cysteine-positive leiomyomas, indicating fumarate hydratase aberration, have morphologic features that differ from those without S-(2-succino)-cysteine positivity. Hematoxylin and eosin-stained slides of uterine smooth-muscle tumors were prospectively analyzed for features suggesting hereditary leiomyomatosis and renal cell carcinoma syndrome, such as prominent eosinophilic macronucleoli with perinucleolar halos, yielding nine cases. Germline genetic testing for fumarate hydratase mutations was performed in three cases. A detailed morphological analysis was undertaken, and S-(2-succino)-cysteine immunohistochemical analysis was performed with controls from a tissue microarray (leiomyomas (19), leiomyosarcomas (29), and endometrial stromal tumors (15)). Of the nine study cases, four had multiple uterine smooth muscle tumors. All cases had increased cellularity, staghorn vasculature, and fibrillary cytoplasm with pink globules. All cases had inclusion-like nucleoli with perinuclear halos (7 diffuse, 1 focal). All showed diffuse granular cytoplasmic labeling with the S-(2-succino)-cysteine antibody. Two of three tested patients had germline fumarate hydratase mutations. Only one leiomyoma from the tissue microarray controls was immunohistochemically positive, and it showed features similar to other immunohistochemically positive cases. Smooth-muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity. Although the features described are not specific for the germline fumarate hydratase mutation or the hereditary leiomyomatosis and renal cell carcinoma syndrome, their presence should suggest fumarate hydratase aberration. Identifying these cases is an important step in the diagnostic workup of patients with possible hereditary leiomyomatosis and renal cell carcinoma.

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(A) S-(2-succino)-cysteine-positive leiomyoma from the tissue microarray, showing staghorn vasculature and increased cellularity. (B) Many nuclei show optical clearing (arrow) and small, eosinophilic nucleoli (arrowhead).
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Figure 6: (A) S-(2-succino)-cysteine-positive leiomyoma from the tissue microarray, showing staghorn vasculature and increased cellularity. (B) Many nuclei show optical clearing (arrow) and small, eosinophilic nucleoli (arrowhead).

Mentions: All the lesions demonstrated diffuse granular cytoplasmic labeling with S-(2-succino)-cysteine, but staining was absent in the eosinophilic globules and adjacent normal myometrium, when available for evaluation (Figure 5). S-(2-succino)-cysteine staining of the 63 tissue microarray cases revealed equivocal staining in one leiomyosarcoma, but repeat staining in a complete section of this tumor was negative. Only one leiomyoma was diffusely positive with S-(2-succino)-cysteine. This patient was 44-year-old at presentation. She complained of heavy vaginal bleeding and increasing pelvic pressure. The patient did not report a significant family cancer history and was not noted to have any cutaneous lesions. Hysterectomy revealed multiple leiomyomas, measuring 0.2 cm to 8.5 cm, all with a white and whorled appearance on gross examination. Sections of the largest leiomyoma revealed SMT-FH features, but macronucleoli were not easily found (Figure 6). Sections of several smaller leiomyomas did not reveal SMT-FH features. The remaining 61 cases, including endometrial stromal tumors, leiomyomas, and leiomyosarcomas, were completely negative for S-(2-succino)-cysteine staining. Review of the original slides did not reveal any histologic features suggestive of SMT-FH.


Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry.

Reyes C, Karamurzin Y, Frizzell N, Garg K, Nonaka D, Chen YB, Soslow RA - Mod. Pathol. (2013)

(A) S-(2-succino)-cysteine-positive leiomyoma from the tissue microarray, showing staghorn vasculature and increased cellularity. (B) Many nuclei show optical clearing (arrow) and small, eosinophilic nucleoli (arrowhead).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4048336&req=5

Figure 6: (A) S-(2-succino)-cysteine-positive leiomyoma from the tissue microarray, showing staghorn vasculature and increased cellularity. (B) Many nuclei show optical clearing (arrow) and small, eosinophilic nucleoli (arrowhead).
Mentions: All the lesions demonstrated diffuse granular cytoplasmic labeling with S-(2-succino)-cysteine, but staining was absent in the eosinophilic globules and adjacent normal myometrium, when available for evaluation (Figure 5). S-(2-succino)-cysteine staining of the 63 tissue microarray cases revealed equivocal staining in one leiomyosarcoma, but repeat staining in a complete section of this tumor was negative. Only one leiomyoma was diffusely positive with S-(2-succino)-cysteine. This patient was 44-year-old at presentation. She complained of heavy vaginal bleeding and increasing pelvic pressure. The patient did not report a significant family cancer history and was not noted to have any cutaneous lesions. Hysterectomy revealed multiple leiomyomas, measuring 0.2 cm to 8.5 cm, all with a white and whorled appearance on gross examination. Sections of the largest leiomyoma revealed SMT-FH features, but macronucleoli were not easily found (Figure 6). Sections of several smaller leiomyomas did not reveal SMT-FH features. The remaining 61 cases, including endometrial stromal tumors, leiomyomas, and leiomyosarcomas, were completely negative for S-(2-succino)-cysteine staining. Review of the original slides did not reveal any histologic features suggestive of SMT-FH.

Bottom Line: High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells but not in normal tissues or tumors unassociated with hereditary leiomyomatosis and renal cell carcinoma syndrome.Two of three tested patients had germline fumarate hydratase mutations.Smooth-muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

ABSTRACT
Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to a somatic fumarate hydratase mutation. Germline mutations account for the hereditary leiomyomatosis and renal cell carcinoma syndrome, which predisposes for cutaneous and uterine leiomyomas and aggressive renal cell carcinomas. Altered fumarate hydratase leads to fumarate accumulation in affected cells with formation of S-(2-succino)-cysteine, which can be detected with the polyclonal antibody. High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells but not in normal tissues or tumors unassociated with hereditary leiomyomatosis and renal cell carcinoma syndrome. We hypothesized that S-(2-succino)-cysteine-positive leiomyomas, indicating fumarate hydratase aberration, have morphologic features that differ from those without S-(2-succino)-cysteine positivity. Hematoxylin and eosin-stained slides of uterine smooth-muscle tumors were prospectively analyzed for features suggesting hereditary leiomyomatosis and renal cell carcinoma syndrome, such as prominent eosinophilic macronucleoli with perinucleolar halos, yielding nine cases. Germline genetic testing for fumarate hydratase mutations was performed in three cases. A detailed morphological analysis was undertaken, and S-(2-succino)-cysteine immunohistochemical analysis was performed with controls from a tissue microarray (leiomyomas (19), leiomyosarcomas (29), and endometrial stromal tumors (15)). Of the nine study cases, four had multiple uterine smooth muscle tumors. All cases had increased cellularity, staghorn vasculature, and fibrillary cytoplasm with pink globules. All cases had inclusion-like nucleoli with perinuclear halos (7 diffuse, 1 focal). All showed diffuse granular cytoplasmic labeling with the S-(2-succino)-cysteine antibody. Two of three tested patients had germline fumarate hydratase mutations. Only one leiomyoma from the tissue microarray controls was immunohistochemically positive, and it showed features similar to other immunohistochemically positive cases. Smooth-muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity. Although the features described are not specific for the germline fumarate hydratase mutation or the hereditary leiomyomatosis and renal cell carcinoma syndrome, their presence should suggest fumarate hydratase aberration. Identifying these cases is an important step in the diagnostic workup of patients with possible hereditary leiomyomatosis and renal cell carcinoma.

Show MeSH
Related in: MedlinePlus