Uterine tumors resembling ovarian sex cord tumors

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1 ORIGINAL ARTICLE Diverse Phenotypic Profile of Uterine Tumors Resembling Ovarian Sex Cord Tumors An Immunohistochemical Study of 12 Cases Laurence de Leval, MD, PhD,* Gkeok Stzuan Diana Lim, FRCPA, FRCPath,w David Waltregny, MD, PhD,* and Esther Oliva, MDz Background: Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare neoplasms thought to be of putative endometrial stromal origin and solely composed of sex cord elements. Our study aimed to delineate the immunophenotype of these tumors and to verify whether their morphology reflects true sex cord-like differentiation. Design: Representative paraffin blocks from 12 UTROSCTs were selected after confirmation of the diagnosis. Cords and/ or trabeculae were seen in all tumors, whereas tubules, diffuse areas, and a retiform pattern were present in 9, 6, and 2 cases, respectively. Tumors were stained for sex cord (inhibin, calretinin, WT1, and melan-a), epithelial (KL1 and epithelial membrane antigen), and smooth muscle markers (smooth muscle actin, desmin, smooth muscle myosin heavy chain, h-caldesmon, and histone deacetylase-8), CD10, HMB45, S100, and CD117. Intensity and percentage of staining were recorded. Results: Six out of 12 tumors were positive for sex cord markers (inhibin 3 of 12, calretinin 4 of 12, WT1 4 of 12, and melan-a 3 of 11) with 4 tumors coexpressing more than one marker. Half of the UTROSCTs showed positivity for KL1, with 2 tumors coexpressing epithelial membrane antigen. All but one tumor expressed one or more smooth muscle markers, with smooth muscle actin, desmin and histone deacetylase-8 being most commonly expressed. CD10 was positive in 6 of 12 tumors, CD117 in 4 of 12, and S100 in 2 of 11 tumors, whereas HMB45 was negative in 11 tumors tested. Conclusions: UTROSCTs have a diverse immunohistochemical profile often coexpressing sex cord, epithelial, and smooth muscle markers. The expression of smooth muscle markers in these tumors does not imply a smooth muscle origin as endometrial and sex cord stromal tumors are not infrequently positive for these markers. Positivity for sex cord markers supports a true sex cord/steroid phenotype. Although the immunohistochemical profile of these tumors overlaps with that From the *Department of Pathology, C.H.U. Sart-Tilman, Liège, Belgium; wdepartment of Pathology, National University Healthcare System, Singapore; and zdepartment of Pathology, The Massachusetts General Hospital, Boston, MA. Correspondence: Esther Oliva, MD, Department of Pathology, The Massachusetts General Hospital, 55 Fruit Street, Warren 2, Boston MA ( eoliva@partners.org). Copyright r 2010 by Lippincott Williams & Wilkins of endometrial stromal tumors with sex cord-like differentiation as well as ovarian sex cord stromal tumors, the origin of UTROSCT remains uncertain. Key Words: UTROSCT, immunohistochemistry, differentiation, sex cord, epithelial, smooth muscle (Am J Surg Pathol 2010;34: ) Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare uterine neoplasms first reported by Clement and Scully in In the original contribution, the authors classified neoplasms predominantly or exclusively composed of sex cord-like elements (group II tumors) as UTROSCTs, whereas tumors showing overt endometrial stromal differentiation were classified as endometrial stromal tumors (ESTs) with sex cord-like differentiation (group I tumors). This morphological distinction is of clinical importance as UTROSCTs usually behave in a benign fashion 14 whereas the presence of sex cord-like differentiation in ESTs does not affect prognosis, the latter being related to the demarcation of the tumor from the surrounding myometrium. 6 Since the original series, much interest has been devoted to the origin of UTROSCTs, and there has been conflicting immunohistochemical and ultrastructural findings regarding their histogenesis. Variable evidence for stromal, 14,23,31 epithelial, 23 smooth muscle, 61 and true sex cord differentiation 8,31,41,45 has been presented. Recent studies suggest that these tumors may be polyphenotypic 36,37,39 holding true sex cord differentiation, yet no consensus has been reached. In line with its controversial origin, in the current World Health Organization classification, UTROSCTs are placed in the miscellaneous category of tumors of the uterine corpus. 64 In this study we investigated the immunohistochemical expression of sex cord, epithelial, and smooth muscle markers in a series of 12 UTROSCTs. The aims of our study were: (1) to delineate the immunophenotype of these tumors, (2) to verify whether their morphology reflects true sex cord-like differentiation, and (3) to identify if their immunohistochemical profile is helpful Am J Surg Pathol Volume 34, Number 12, December

2 de Leval et al Am J Surg Pathol Volume 34, Number 12, December 2010 in the differential diagnosis with other uterine tumors with overlapping morphological features, not an uncommon problem specially when dealing with small biopsy specimens. MATERIALS AND METHODS Ten tumors were kindly provided by Dr R.E. Scully, and 2 were obtained from the consultation files of one of us. The electronmicroscopic and molecular results of 12 and 11 of these cases have been previously published. 31,86 For each case, a representative paraffin block was selected after evaluation and confirmation of the diagnosis based on the most recent World Health Organization classification. 64 Clinical, gross, and microscopic features of the tumors were recorded when available. Immunohistochemical staining was performed for inhibin, calretinin, WT1, melan-a, KL1, epithelial membrane antigen (EMA), smooth muscle actin (SMA), desmin, smooth muscle myosin heavy chain (SMMHC), h-caldesmon, histone deacetylase-8 (HDAC8), CD10, CD117, S100, and HMB45. The source and conditions for each antibody are summarized in Table 1. Staining was performed using the avidin-biotin complex kit (LSAB, Dako, Glostrup, Denmark). Intensity (1+, 2+, 3+) and percentage of stained tumor cells were recorded. Neoplasms were considered negative when <1% of the tumor cells were immunoreactive. Internal tissue controls were used when available. For inhibin, calretinin, melan-a, CD117, and HMB45, external controls were systematically used. RESULTS Clinical and Pathological Features The clinical and pathological features of the 12 UTROSCTs are summarized in Table 2. The tumors occurred in patients ranging in age from 29 to 59 (median 50) years. Five patients presented with abnormal vaginal bleeding; 3 tumors were incidentally diagnosed in patients who underwent hysterectomy for other causes and in 1 patient, the tumor was incidentally discovered on routine gynecologic examination. The initial presentation was not known in the other 3 patients. The tumors ranged in size from 3 to 10 (median 5.5) cm. Five tumors were intramural, 4 presented as submucosal/polypoid masses, and 1 was subserosal. On sectioning, 9 tumors had a solid cut surface and 1 was solid and cystic. No information regarding gross findings was available in 2 cases. Microscopically, 6 tumors had an infiltrative growth into the adjacent myometrium and 4 were well circumscribed. The margin could not be evaluated in 2 cases. All tumors had cords and/or trabeculae (Figs. 1A, B), this being the predominant pattern in 10 tumors; hollow or solid (Fig. 1C) tubules were seen in 9 cases and it was the predominant pattern in 2, whereas a diffuse/solid growth (Fig. 1D) was seen in 6 neoplasms. A retiform pattern was TABLE 1. Source and Conditions of Antibodies Antibody Clone Source Pretreatment Working Dilution Smooth muscle 1A4 Dako, Glostrup, Water bath at 951C for 40 min in 10 mm citrate 1:400 ON 41C a-actin Denmark buffer (ph6) Desmin D33 Dako Pressure cooker 10 min in EDTA buffer (ph9) 1:600 1 h RT Smooth muscle HSM-V Sigma, Saint Louis, Water bath at 371C for 20 min in trypsin/ 1:2500 ON 41C myosin heavy chain MO PBS+water bath at 951C for 40 min in 10 mm citrate buffer (ph6) H-caldesmon h-cd Dako Water bath at 371C for 20 min in trypsin/ 1/100 ON 41C PBS+water bath at 951C for 40 min in 10 mm citrate buffer (ph6) HDAC8 T-19 Santa Cruz, CA Water bath at 951C for 40 min in 10 mm citrate 1:200 ON 41C buffer (ph6) Pancytokeratin KL1 KL1 Immunotech Pressure cooker 5 min in EDTA buffer (ph9) 1: h RT Epithelial E29 Dako Pressure cooker 5 min in EDTA buffer (ph9) 1:20 1 h RT membrane antigen Inhibin R1 Dako Pressure cooker 5 min in EDTA buffer (ph9) 1:200 1 h RT Calretinin 2 E7 Immuno Vision Microwave 23 min 500 W in Citrate buffer (ph 6) 1:300 1 h RT WT1 6F-H2 Dako Pressure cooker 5 min in EDTA buffer (ph9) 1:50 1 h RT CD10 56C6 Novocastra, Pressure cooker 5 min in EDTA buffer (ph9) 1:10 1 h RT Newcastle upon Tyne, UK Human melanosome HMB-45 Dako Microwave at 500 W for 23 min in 10 mm citrate 1:200 1 h RT (HMB45) buffer (ph6) Melan-A A103 Novocastra Microwave at 500 W for 23 min in 10 mm citrate 1:25 1 h RT buffer (ph6) S100 Polyclonal Dako Pressure cooker 5 min in EDTA buffer (ph9) 1: h RT CD117 Polyclonal Dako None 1:50 1 h RT HDAC indicates histone deacetylase-8; ON, overnight; PBS, phosphate-buffered saline; RT, room temperature r 2010 Lippincott Williams & Wilkins

3 Am J Surg Pathol Volume 34, Number 12, December 2010 Diverse Profile of Uterine Tumors Resembling TABLE 2. UTROSCTs: Clinicopathological Features Case Age (y) Presentation Treatment Gross Interface Cords/ Trabeculae Tubules Solid/ Diffuse Retiform 1 NA NA NA Polypoid NA + 2 NA NA NA Polypoid Pushing Asymptomatic TAHBSO 10 cm subserosal Infiltrating cystic 4 NA NA NA NA NA Abnormal vaginal Curettage NA Infiltrating + + bleeding 6 59 Asymptomatic TAHBSO 4 cm Intramural Infiltrating Asymptomatic uterine TAHBSO 6 cm Intramural Infiltrating + + mass on physical examination 8 52 Asymptomatic VH 4 cm Intramural Pushing , Focal 9 43 Abnormal vaginal TAHBSO 3 cm Submucosal Infiltrating + + bleeding Abnormal vaginal bleeding TAHBSO 8 cm Intramural Pushing + + +, Extensive Abnormal vaginal TAH 5 cm Submucosal Infiltrating + + bleeding Abnormal vaginal bleeding polypoid TAHBSO 10 cm Intramural Pushing NA indicates not available; TAH, total abdominal hysterectomy; TAHBSO, total abdominal hysterectomy and bilateral salpingo-oophorectomy; UTROSCTs, uterine tumor resembling ovarian sex cord tumors; VH, vaginal hysterectomy. present in 2 of 12 tumors (Fig. 1E), being extensive in 1. Ten neoplasms had minimal amount of intervening stroma and 2 displayed moderate hypocellular stroma. Most cells had variable amounts of eosinophilic cytoplasm with vacuolated cells being present in 2 tumors. The nuclei ranged from round-to-oval, had vesicular chromatin, and small-to-inapparent nucleoli. Mitotic activity was low, ranging from <1 to 5/10 high-power fields. No areas of conventional endometrial stromal neoplasia or vascular invasion were identified. Necrosis was present in 1 tumor. Immunohistochemical Findings The immunohistochemical profile for the individual markers is summarized in Table 3 and coexpression profiles are shown in a diagram (Fig. 2). Smooth Muscle Markers Eleven of the 12 tumors stained for SMA with a reactivity of 2 to 3+ in 9 of them. All but one tumor showed extensive staining (>60% in 10 and 30% in 1). Desmin was positive in 10 out 12 cases; the staining was usually 2+ and always present in at least 30% of the tumor cells. h-caldesmon was expressed in 3 out of 12 tumors (1 with 2+ staining in >90% of tumor cells and 2 with 3+ in <5% of tumor cells). HDAC8 displayed mostly 1+ reactivity in <5% to 100% of the tumor cells in 5 cases, whereas 2+ reactivity and very focal 3+ staining was seen in 2 and 1 tumors, respectively. SMMHC was positive in 3 out of 12 neoplasms; 1 tumor showed 3+ positivity in <5% of tumor cells whereas the other 2 displayed extensive (70% and 90%) 1+ positivity. In total, 11 of 12 tumors were positive for at least 1 of the smooth muscle markers tested. When excluding SMA, desmin was the most frequent marker expressed (10 of 12) (Fig. 3). Epithelial Markers Six out of 12 tumors showed 2 to 3+, KL1 staining in 10% to 100% of the tumor cells. Two of them were also positive (1+) for EMA in <5% of the tumor cells. EMA staining could not be performed in 1 case (Fig. 4). Sex Cord Markers One+ to 2+ positivity for inhibin was noted in 3 out of 12 tumors, staining 90%, 40%, and <5% of the cells, respectively; the staining mostly seen in the vacuolated cells in the latter. Four out of 12 neoplasms showed 2+ nuclear and cytoplasmic positivity for calretinin in 10% to 75% of the tumor cells. Among the 2 tumors with vacuolated cells, 1 showed calretinin expression in both vacuolated and nonvacuolated cells whereas the other was only positive in the nonvacuolated cells. Expression of WT1 was noted in at least 40% of the tumor cells in 4 out of 12 cases, with intensity ranging from 1+ to 3+. In 2 of them, only cytoplasmic staining was detected. Three out of 11 tumors displayed 1+ to 2+ melan-a positivity (<5% in 2 cases both restricted to vacuolated cells, and 70% in 1 case). In total, 6 of 12 neoplasms were positive for one or more sex cord markers, but overall, the degree of positivity was not striking (Fig. 5). r 2010 Lippincott Williams & Wilkins

4 de Leval et al Am J Surg Pathol Volume 34, Number 12, December 2010 FIGURE 1. Morphologic patterns in uterine tumors resembling ovarian sex cord tumors: Anatomizing cords (A), trabeculae (B), solid tubules, some containing lipidized cells (C), diffuse growth (D), and retiform pattern (E). Other Markers CD10 was positive in 6 of 12 tumors (1+ to 3+ in 30% to 100% of cells) and CD117 in 4 of 12 neoplasms (1 to 2+, up to 100%). S100 was only positive in 2 of 11 cases tested (1+ in both) whereas HMB45 was negative in all 11 tumors tested (Fig. 6). DISCUSSION Since the initial study of UTROSCTs by Clement and Scully in there have been several attempts to further characterize the histogenesis of these unusual uterine neoplasms. 8,16,31,33,36,37,39,41,45,56,61,65,68 Whereas ESTs with foci of sex cord-like elements are thought to r 2010 Lippincott Williams & Wilkins

5 Am J Surg Pathol Volume 34, Number 12, December 2010 Diverse Profile of Uterine Tumors Resembling TABLE 3. UTROSCTs: Immunohistochemical Results Smooth Muscle Markers Epithelial Markers Sex Cord Markers Miscellaneous SMA DESMIN H-CALD SMMHC HDAC8 KL1 EMA Inhibin Calretinin WT1 Melan-A CD10 HMB45 S-100 CD117 Case % 1+60% 1+70% 2+ 55% Case % 2+90% 3+40% Case % 2+50% 2+ >70% 1+40% (CP) 2+40% 1+ <10% Case % 2+60% 1+80% 3+100% NA 2+40% 2+75% 3+100%(NUC) NA 2+30% NA NA Case % 3+30% 3+ <5% 3+ <5% 3+ <5% 2+40% 1+<5% 1+<5% 2+20% 1+60% (NUC) 2+<5% 2+60% 1+10% Case % 2+60% Case % 3+100% 1+50% 2+ 45% Case % 2+35% 3+ <5% 1+ <5% 2+60% Case % 2+50% 2+10% 2+10% 1+<5% 1+ <5% Case % 1+>90% 2+ >90% 1+ 90% % 1+60% 1+90% 1+90% 2+>90% (CP) 1+70% 3+100% % % Case % Case % 1+45% 1+ 45% 1to2+80% Total 11/12 10/12 3/12 3/12 8 /12 6/12 2 /11 3/12 4/12 4/12 3/11 6/12 0/11 2/11 4/12 CP indicates cytoplasmic; EMA, epithelial membrane antigen; H-CALD, h-caldesmon; HDAC8, histone deacetylase-8; NA, not available; NUC, nuclear; SMA, smooth muscle actin; SMMHC, smooth muscle myosin heavy chain. Sex cord markers Smooth muscle markers Epithelial markers FIGURE 2. Shared expression of epithelial, smooth muscle, and sex cord-like markers in uterine tumors resembling ovarian sex cord tumors. be essentially ESTs, the true nature of pure UTROSCTs remains enigmatic. Different studies have suggested evidence for either stromal, 14,23,31 epithelial, 23 smooth muscle, 59 and true sex cord differentiation. 8,31,41,45 Arecent immunohistochemical study advocates for a polyphenotypic profile of these tumors hypothesizing that they may arise from pluripotent mesenchymal cells. 37 Amorerecent ultrastructural study of 13 UTROSCTs has shown that these tumors display epithelial and sex cord-like differentiation but no smooth muscle differentiation, also supporting a polyphenotypic profile. 31 Yet another study has shown that UTROSCTs do not exhibit the t(7,17) (most frequent translocation) seen in ESTs. 86 Given the rarity of these neoplasms, only a small number of cases have been thoroughly characterized, mostly as single case reports, with only a few series reported, the largest being the one presented herein. In this study, we applied a large panel of antibodies to test for the expression of sex cord, epithelial, smooth muscle, endometrial stromal, and other markers in a series of 12 UTROSCTs. Our findings confirm that UTROSCTs have a diverse immunohistochemical profile as indicated by the coexpression of sex cord, epithelial, and smooth muscle markers in one-third of the cases. Evidence of smooth muscle differentiation in UTROSCTs has been demonstrated by several investigators with variable positivity for different smooth muscle markers. 8,36,37,39,45,46,68 All but one UTROSCTs (11 of 12) in this series were positive for at least one smooth muscle marker, SMA and desmin being the 2 most commonly expressed (11 of 12 and 10 of 12, respectively). Our results parallel those reported by Oliva et al, 68 r 2010 Lippincott Williams & Wilkins

6 de Leval et al Am J Surg Pathol Volume 34, Number 12, December 2010 FIGURE 3. Expression of smooth muscle markers in uterine tumors resembling ovarian sex cord tumors. Actin (A), desmin (B), smooth muscle myosin heavy chain (C), h-caldesmon (D), and histone deacetylase-8 (E) are expressed by the tumor cells. Hurrell and McCluggage, 36 and Irving et al 37 in terms of the frequency of SMA and desmin expression, which was seen in at least 60% of the cases, in contrast to the series reported by Krishnamurthy et al 45 in which only 2 of 7 tumors were positive for muscle markers. It must be emphasized, however, that the smooth muscle a-isoform of actin lacks diagnostic specificity as this marker is widely expressed in benign and neoplastic endometrial stromal cells, 10,22,26,50,66,68,76 and can also be expressed in sex cord stromal tumors of the ovary. 15,47,70,72,77,80,92 Similarly, the intermediate filament desmin, although being more specific than actin, may be expressed in r 2010 Lippincott Williams & Wilkins

7 Am J Surg Pathol Volume 34, Number 12, December 2010 Diverse Profile of Uterine Tumors Resembling FIGURE 4. Expression of epithelial markers in uterine tumors resembling ovarian sex cord tumors. The neoplastic cells are positive for keratin (A) and epithelial membrane antigen (B). ESTs 22,26,66,68,76 and has been occasionally reported to be positive in epithelial tumors and in sex cord stromal tumors of the ovary. 15,72,77,80,92 h-caldesmon, a cytoplasmic protein that regulates cellular contraction through its interactions with actin and tropomyosin, has been validated as a more specific marker of smooth muscle FIGURE 5. Expression of sex cord markers in uterine tumors resembling ovarian sex cord tumors. Neoplastic cells show variable positivity for calretinin (A), WT-1 (B), inhibin (C), and melan-a (D). r 2010 Lippincott Williams & Wilkins

8 de Leval et al Am J Surg Pathol Volume 34, Number 12, December 2010 FIGURE 6. A uterine tumor resembling an ovarian sex cord tumor shows immunoreactivity for CD10 (A) and CD117 (B). It is weakly positive for S100 (C). differentiation than desmin in the differential diagnosis of uterine mesenchymal tumors, being negative in most ESTs, except those showing smooth muscle differentiation. 17,66,71,76,95 However, h-caldesmon has not been widely assessed in UTROSCTs. Among all cases evaluated in the literature, only 1 of 12 showed diffuse but weak h-caldesmon positivity. 16,36,68 We found expression of h-caldesmon in 3 tumors, with extensive staining seen only in one of them. SMMHC, a highly specific marker in the delineation of smooth muscle and myoepithelial cells in normal human tissues 52 is also helpful in our experience, in the classification of mesenchymal tumors of the uterus, with a similar sensitivity as that of h-caldesmon or desmin and a very high specificity. 17 However, some ESTs have been reported to show faint to moderate SMMHC staining. 2 We have recently demonstrated that HDAC8, a class I HDAC with mainly a cytosolic distribution, represents a novel and reliable marker of smooth muscle differentiation in normal tissues and uterine mesenchymal tumors, with ESTs being positive only when they show areas of smooth muscle differentiation. 17 In this study, 67% of UTROSCTs were positive for HDAC8. Amongst the smooth muscle markers tested in this study, it appears that desmin and HDAC8 were the 2 markers most commonly expressed after actin. The fact that most UTROSCTs express to some extent smooth muscle markers may suggest early smooth muscle differentiation in these tumors. In addition, McCluggage et al, 59 reported one EST with sex cord-like differentiation with electronmicroscopic evidence of smooth muscle differentiation in the latter areas. The cells in the sex cord-like component were surrounded by prominent external lamina and had abundant intermediate filaments and subplasmalemmal densities. However, they lacked characteristic cytoplasmic dense bodies and thin microfilaments as seen in smooth muscle tumors. The finding of sex cord-like areas juxtaposed to areas of smooth muscle differentiation in ESTs may suggest that in fact these 2 components represent morphologic variations of similar lineage. Furthermore, other tumors in the female genital tract, specifically sex cord stromal tumors of the ovary frequently show basal lamina around some groups of cells and they also contain aggregates of filaments, basal lamina, and pinocytic vesicles. 20 Gupta et al 31 studied the ultrastructural features of 13 UTROSCTs and found no evidence of smooth muscle differentiation in any of their tumors. Epithelial differentiation was present in 2 neoplasms and prominent lipid droplets correlated with positivity for sex cord markers in 2 cases. Fifty percent of UTROSCTs in our series were positive for cytokeratin, with minimal coexpression of EMA in 2 cases. Similar findings have been reported in the literature, with the majority of tumors being positive for different keratins but much less frequently for EMA (6 of 15). 8,16,33,34,36,37,39,45,58,65,68,89 90,93 However, it is well known that keratins may also be expressed in conventional ESTs, myometrium, and smooth muscle tumors. 1,9,14,19,22,37,38,68 Thus its utility in the differential diagnosis and usefulness in elucidating the line (s) of differentiation of these tumors is very limited. EMA, another well-known marker of epithelial differentiation, can also be expressed in smooth muscle tumors, more frequently in the epithelioid variant and more commonly in those that originate in the uterus. 38 Conversely, EMA is not usually expressed in ESTs with or without sex cordlike differentiation. 35,60 Finally, sex cord tumors of the ovary will also frequently express keratins but only rarely EMA. 97 These observations argue against a pure epithelial line of differentiation of UTROSCTs. Fifty percent of the UTROSCTs in this series displayed positivity for sex cord markers, with calretinin and WT1 being the most frequently expressed. Calretinin r 2010 Lippincott Williams & Wilkins

9 Am J Surg Pathol Volume 34, Number 12, December 2010 Diverse Profile of Uterine Tumors Resembling TABLE 4. Differential Expression of Smooth Muscle, Epithelial, Stromal, and Sex Cord Markers (Used in This Study) in SMT, EST [Conventional, With Smooth Muscle Differentiation and With SCLD], UTROSCTs and Sex Cord Tumors of the Ovary SMT 2,4,8,21,22,25,27,29,32, 43,48,61,69,75,81,82,90, 92,100,105,115 EST-Conventional 1,2,8,9,10,13,15,16,21, 22,25,26,27,29,32,33,59, 61,69,75,81,82,92,95,100, ,106,115 EST-SM 7,15,34,52,53,60,61,64,73, 77,79,111 EST-SCLD 3,8,34,35,47,59,65,85,91, 95,112 UTROSCT 5,8,12,14,24,27,30,31,36, 40,42,44,46,47,50,56,57, 63,67, 69,70,74,76,81, 84,97,99,101,102,109 Ovarian sex cord tumors 6,11,17-20,23,28,37,38, 39,41,45,49,51,54,55,58, 62,66,69,71,72,78,80,83, 86 89,93 96,98,104,107, 108,110,113, /314 (93.9%) 68/140 (48.6%) Smooth Muscle Epithelial Stromal Sex Cord Actin Desmin Caldesmon SMMHC HDAC8 Keratin EMA CD10 Inhibin Calretinin Melan-A WT-1 28/33 (84.8%) 14/14 (100%) 20/49 (40.8%) 33/71 (46.5%) 341/375 (90.9%) 75/202 (37.1%) 38/44 (86.4%) 19/27 (70.4%) 20/79 (25.3%) 27/76 (35.5%) 256/282 (90.8%) 6/123 (4.9%) 6/6 (100%) 1/15 (6.7%) 46/54 (85.2%) 3/19 (15.8%) 42/45 (93.3%) 32/157 (20.4%) 0/9 (0%) 32/127 (25.2%) 2/16 (12.5%) 19/29 (65.5%) 0/3 (0%) 0/3 (0%) 48/72 (66.7%) 211/413 (51.1%) 10/49 (20.4%) 1/34 (2.9%) 77/243 (31.7%) 151/164 (92.1%) 0/16 (0%) 6/9 (66.7%) 0/12 (0%) 3/4 (75.0%) 11/32 (34.4%) 9/244 (3.7%) 18/30 (60.0%) 37/89 (41.6%) 0/60 (0%) 50/61 (81.2%) 0/43 (0%) 0/14 (0%) 32/44 (72.7%) 3/14 (21.4%) 24/50 (48.0%) 560/614 (91.2%) 3/4 (75.0%) 23/24 (95.8%) 170/209 (81.3%) 1/3 (33.3%) 17/20 (85.0%) 41/59 (69.5%) 5/6 (83.3%) 25/33 (75.8%) Full reference list available online. EMA indicates epithelial membrane antigen; EST, endometrial stromal tumor; HDAC8, histone deacetylase-8; SCLD, sex cord-like differentiation; SMT, smooth muscle tumors; SMMHC, smooth muscle myosin heavy chain; UTROSCTs, uterine tumors resembling ovarian sex cord tumors. r 2010 Lippincott Williams & Wilkins

10 de Leval et al Am J Surg Pathol Volume 34, Number 12, December 2010 is a calcium-binding protein expressed by theca interna cells, hilus cells, stromal cells, ovarian surface epithelium, and mesothelial cells. 12,54 It is widely used as a marker for sex cord stromal tumors and steroid cell tumors of the ovary as it has higher sensitivity although less specificity than inhibin in the diagnosis of these tumors. 18,57,63,81 Calretinin has also been reported to be positive in the majority of UTROSCTs reported in the literature, 16,34,36,37,39,65,89 sex cord-like elements of ESTs 37,81 as well as non-neoplastic endometrial stromal cells of the superficial functionalis layer in the proliferative phase, and all stages of the secretory phase. 55 Calretinin positivity has been reported much less frequently in low-grade Mu llerian adenosarcomas 85 and it has only occasionally been tested in smooth muscle tumors. 73,81 Pusiol and coworkers 73 reported 2 leiomyomas with tubules that exhibited weak immunoreactivity for calretinin. In a study by Shah et al, leiomyosarcomas (including 7 from the uterus), showed focal strong staining for calretinin and positive staining has also been reported in other types of mesenchymal tumors such as lipomas and liposarcomas. 13 WT1 is expressed during the development of the urogenital system and it is detected in the metanephros and mesonephros, spleen, gonads, and mesothelium in fetuses. 30,49 This antibody is also detected in Wilms tumors, desmoplastic small round cell tumors, mesotheliomas, and ovarian carcinomas (more commonly serous and transitional cell types) but can also be expressed in sex cord tumors of the ovary. 4,7,18,25,29,32,51,96 Finally, it has been reported that normal endometrial stromal as well as endometrial stromal neoplasms and uterine smooth muscle tumors may also express WT1. 2 Studies on WT1 expression by UTROSCTs in the literature are scarce. Hurrel and McCluggage 36 as well as Sutak and coworkers 89 reported WT1 positivity in 4 of 4 and 1 of 1 tumors, respectively. The frequency of WT1 positivity was lower in this study (25%), which may be secondary to differences in staining protocols. Inhibin, the most specific marker of sex cord stromal tumors of the ovary, 44,57,75,87 is typically negative in conventional ESTs, but areas of sex cord-like differentiation in these tumors may express this marker. 8 Conversely, inhibin expression has not been reported in smooth muscle tumors of the uterus or other organs 81 and only rare sarcomas (liposarcomas and angiosarcomas) or carcinomas have been reported positive for this marker. 56,61,79 Melan-A is a marker that has been shown to stain steroid-producing cells in the gonads, 88 adrenal cortex, 11 and areas of sex cord-like differentiation in ESTs, indicating a specialized gonadal stromal phenotype. 6 Expression of melan-a, mostly seen in tubules lined by cells with abundant vacuolated cytoplasm, supports the presence of a cell type with a steroid phenotype as seen in sex cord stromal tumors of the ovary. In contrast to ovarian sex cord stromal tumors, which typically diffusely express inhibin, calretinin, and WT-1 and only occasionally express smooth muscle markers, the majority of UTROSCTs in this series that expressed sex cord markers also showed positivity for smooth muscle markers, suggesting that there may be other factors (uterus vs. ovary and endometrial stroma vs. specialized ovarian stroma) that may play a role in defining the type or degree of differentiation of these tumors. Rare positivity of calretinin and absence of inhibin expression (the most specific markers of sex cord differentiation) in conventional smooth muscle tumors of the uterus argues against pure smooth muscle differentiation of UTROSCTS, as do the most recent ultrastructural findings. 31 Even though when comparing expression of sex cord markers in ESTs with sex cord-like differentiation and UTROSCTs it has been shown, that in general, there is less expression of inhibin, CD99, melan-a, and calretinin in the former group, 8,33,37,39,45,53,56,65,67,68,90 it is important to note that these markers are not helpful in this differential diagnosis as there is significant overlap. The most helpful feature is to identify areas of conventional endometrial stromal neoplasia, which should be negative for sex cord stromal markers. Half of the UTROSCTs in this series were positive for CD10. This membranous enzyme expressed in endometrial stroma and in most tumors of endometrial stromal origin, is also expressed in a substantial proportion of uterine smooth muscle tumors and other mesenchymal and epithelial tumors of the gynecologic tract. 68 Of note, CD10 is also expressed in luteinized ovarian stromal cells and sex cord stromal tumors of the ovary. 71 Although UTROSCTs frequently express smooth muscle markers, they typically do not express HMB45 36 and only occasionally express melan-a. 36,37,45 HMB45 is a melanocytic marker shown to be positive in uterine PEComas 93 that is used in differentiating these tumors from epithelioid smooth muscle tumors. However, there is some controversy to whether smooth muscle tumors may also express this antibody and to what extend and consequently if this marker can be used as surrogate marker of PEComa. 82,84 HMB45 has not been reported in ovarian sex cord stromal tumors or EST with sex cord-like differentiation. Melan-A is also expressed in PEComas 24 and it can also be positive in smooth muscle tumors of the uterus. 69 However to date, no melan-a positivity has been reported in conventional ESTs. Table 4 highlights the expression of smooth muscle, epithelial, endometrial stromal, and sex cord markers used in this study for UTROSCTs in tumors considered in this differential diagnosis including smooth muscle tumors, ESTs (conventional, with smooth muscle differentiation and with sex cord-like differentiation), and sex cord tumors of the ovary. S100, a marker of neural differentiation can also be detected in some sex cord-stromal tumors of the ovary and testis 3,74,91 and smooth muscle tumors of the uterus 40 although its significance is unclear. No S100 expression has been detected in previously reported UTROSCTs. 35,89 In our study, only 2 tumors showed weak S100 staining. In rare instances, this marker may be useful to distinguish between UTROSCTs and melanoma or nerve sheath tumors occurring in the uterus, which are typically positive for S ,28,42,62,83,94 Finally, UTROSCTs should be added to the list of CD117 (c-kit) positive tumors. CD117 (c-kit) is a r 2010 Lippincott Williams & Wilkins

11 Am J Surg Pathol Volume 34, Number 12, December 2010 Diverse Profile of Uterine Tumors Resembling transmembrane tyrosine kinase receptor protein, commonly used in the diagnosis of gastrointestinal stromal tumors, 78 that can also be expressed in benign and malignant endometrial epithelium, smooth muscle tumors, 5,21 and ESTs of the uterus. 27,43,48 CD117 expression was previously studied in a series of 7 UTROSCTs, but no significant staining was found in those cases. 68 In this study, 33% of UTROSCTs stained for CD117 and 1 case even showed diffuse staining of the tumor cells. However, unlike gastrointestinal stromal tumors, all 4 positive cases also showed coexpression of smooth muscle and/or sex cord markers. In conclusion, this study supports the finding that UTROSCTs are a unique group of uterine neoplasms that exhibit diverse immunohistochemical characteristics, often coexpressing sex cord, epithelial, and smooth muscle markers. 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