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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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S-(2-succino)-cysteine-positive leiomyoma showing a neurilemmoma-like growth pattern.
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Figure 4: S-(2-succino)-cysteine-positive leiomyoma showing a neurilemmoma-like growth pattern.

Mentions: In cases in which normal myometrium was available for comparison, low-power examination revealed that all SMT-FHs showed slightly increased cellularity and a different refractile quality owing to increased fibrillarity. All cases showed staghorn vasculature at low power (Figure 1). Five cases initially gave the impression of a diffusely epithelioid neoplasm owing to the presence of round nuclei, and in 4 cases, this feature was present only focally. Despite the presence of round nuclei, the tumor cells were fusiform in shape, not epithelioid. Nuclear atypia was severe and diffuse in 2 cases, moderate in 3, and mild in the remaining 4. Multinucleation was present in 5 cases, but only focally. The mean mitotic index was 3-4/10 HPF, and only one case showed atypical scattered forms. In all 9 cases, high-power evaluation revealed a characteristic fibrillary cytoplasm that in some areas aggregated to form pink globules (Figure 2). Eight cases showed the characteristic inclusion-like nucleoli, eosinophilic nucleoli with perinuclear halos diffusely throughout the lesion, but this was only evident at 20x magnification and was generally not appreciable at 4x (Figure 3). One case showed these nuclear features only focally. All cases contained tumor cells with round and vesicular nuclei, sometimes resembling “Orphan Annie nuclei” with optical clearing, with or without a small eosinophilic nucleolus. These were more prevalent than cells with macronucleoli and perinucleolar clearing. In patients with multiple leiomyomata and available slides, the leiomyomata did not necessarily appear morphologically similar. Some of the leiomyomata showed more easily appreciated SMT-FH features than others. Three cases showed a “neurilemmoma-like” growth pattern (Figure 4).


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)

S-(2-succino)-cysteine-positive leiomyoma showing a neurilemmoma-like growth pattern.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: S-(2-succino)-cysteine-positive leiomyoma showing a neurilemmoma-like growth pattern.
Mentions: In cases in which normal myometrium was available for comparison, low-power examination revealed that all SMT-FHs showed slightly increased cellularity and a different refractile quality owing to increased fibrillarity. All cases showed staghorn vasculature at low power (Figure 1). Five cases initially gave the impression of a diffusely epithelioid neoplasm owing to the presence of round nuclei, and in 4 cases, this feature was present only focally. Despite the presence of round nuclei, the tumor cells were fusiform in shape, not epithelioid. Nuclear atypia was severe and diffuse in 2 cases, moderate in 3, and mild in the remaining 4. Multinucleation was present in 5 cases, but only focally. The mean mitotic index was 3-4/10 HPF, and only one case showed atypical scattered forms. In all 9 cases, high-power evaluation revealed a characteristic fibrillary cytoplasm that in some areas aggregated to form pink globules (Figure 2). Eight cases showed the characteristic inclusion-like nucleoli, eosinophilic nucleoli with perinuclear halos diffusely throughout the lesion, but this was only evident at 20x magnification and was generally not appreciable at 4x (Figure 3). One case showed these nuclear features only focally. All cases contained tumor cells with round and vesicular nuclei, sometimes resembling “Orphan Annie nuclei” with optical clearing, with or without a small eosinophilic nucleolus. These were more prevalent than cells with macronucleoli and perinucleolar clearing. In patients with multiple leiomyomata and available slides, the leiomyomata did not necessarily appear morphologically similar. Some of the leiomyomata showed more easily appreciated SMT-FH features than others. Three cases showed a “neurilemmoma-like” growth pattern (Figure 4).

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