Advances in Anatomic Pathology:
WT1 Expression in the Female Genital Tract
Bárcena, Carmen MD; Oliva, Esther MD
Pathology Department, Massachusetts General Hospital, Boston, MA
The authors have no funding or conflicts of interest to disclose.
Reprints: Esther Oliva, MD, Pathology Department (Warren 2), Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (e-mail: email@example.com). All figures can be viewed online in color at http://www.anatomicpathology.com.
The Wilms tumor gene 1 (WT1) has been reported in normal tissues and many neoplasms of the female genital tract. This review discusses WT1 expression in the female genital tract and its potential utility in the differential diagnosis of neoplasms that occur at this location. WT1 is of value in the differential diagnosis of synchronous serous carcinomas arising in the ovary/fallopian tube/peritoneum and endometrium, as strong WT1 positivity in both tumors points toward an extrauterine origin. In addition, WT1 can be used to distinguish sex cord stromal tumors (WT1 positive) from endometrioid carcinomas (OECs). WT1 expression is not helpful in the differential diagnosis of ovarian serous carcinomas (OSCs) and transitional carcinomas, as both are typically positive and has limited value in the distinction of serous tumors arising in the ovary/fallopian tube/peritoneum from mesotheliomas. WT1 is also not helpful to differentiate small cell carcinoma of hypercalcemic type from juvenile granulosa cell tumor, a common diagnostic problem. Intra-abdominal desmoplastic round cell tumor reacts to WT1 (C-terminal) in contrast to all other tumors discussed which helps to separate this rare tumor from most other small round cell tumors that may involve, primarily or secondarily, the ovary with the exception of small cell carcinoma of hypercalcemic type that typically reacts with the N-terminal of WT1.
The Wilms tumor 1 (WT1) gene, first cloned in 1990, is located on the short arm of chromosome 11 at p13.1,2 WT1 encodes a transcription factor with a C-terminus that has 4 zinc finger motifs and a N-terminus with a proline-glutamine-rich DNA-binding domain and it is localized in the nucleus of the cells.1,2 WT1 regulates the expression of several genes implicated in cellular proliferation and development. In addition, it plays an important role in tissue differentiation, especially of the urogenital tract.3 WT1 was first identified as a tumor suppressor gene mutated in hereditary Wilms tumor.1,2 Subsequent studies have also shown that WT1 mutations are involved in the development of sporadic Wilms tumors.4 However, more recently, WT1 has been reported to have a potential oncogenic effect in breast cancer5–8 and acute leukemia.9 Finally, several studies have hypothesized that WT1 may play a crucial role in the normal mesenchymal-epithelial transition as it has been shown in the kidney leading to nephron formation from renal mesenchyme.10–12
Two antibodies are routinely used in immunohistochemistry against WT1, C-19 (polyclonal) directed against the C-terminus and 6F-H2 (monoclonal) against the N-terminus. It has been reported that 6F-H2 has a more homogenous, stronger, and higher rate of nuclear reactivity when compared with C-19 with the exception of the intraabdominal desmoplastic small round cell tumor.13
In the human embryo, WT1 is important in the development of the urogenital system, spleen, and mesothelial derivatives.3 In adults, it is highly expressed in mesothelial cells, glomerular podocytes and mesangial cells of the kidney, Sertoli cells of the testis, and hematopoietic stem cells.14 Up to date, WT1 expression has been reported in adult leukemia,15,16 Wilms tumor,17 mesotheliomas,18–21 non-small cell carcinoma of the lung,22 soft tissue smooth muscle tumors of mullerian type,23,24 and intraabdominal desmoplastic small round cell tumor 25 besides a wide range of tumors that occur in the female genital tract (discussed below). Many other tumors including breast, gastric, colorectal, pancreaticobiliary, lung, and prostate carcinoma as well as clear cell and papillary carcinomas of the kidney, transitional cell carcinoma of the urinary tract, astrocytomas, soft tissue sarcomas [primitive neuroectodermal tumors (PNET), rhabdomyosarcoma, nongynecologic leiomyosarcoma (LMS), malignant peripheral nerve sheath tumor, angiosarcoma, clear cell sarcoma], osteosarcoma, malignant melanoma, and islet cell tumor have been reported to have only cytoplasmic positivity for WT1,26,27 but this type of staining is considered nonspecific.
WT1 EXPRESSION IN NORMAL TISSUES OF THE FEMALE GENITAL TRACT
In the ovary, WT1 is expressed in stromal cells, granulosa cells, and surface epithelium.23,28 In the uterus, it has been reported in the myometrium28 and endometrial stromal cells (Fig. 1A).14,29 Mesothelial cells from the pelvic peritoneum also express WT1.19 In contrast, cervical and endometrial glands and squamous epithelium are WT1 negative. Trophoblast cells are also negative for this marker.
WT1 EXPRESSION IN EPITHELIAL TUMORS OF THE OVARY
Surface epithelial-stromal tumors of the ovary account for approximately 60% of all ovarian neoplasms, OSC being the most common, as it represents 80% to 90% of all primary ovarian carcinomas.30 The diagnosis of OSC is usually straightforward; however, it may be difficult in those cases in which the morphologic appearance is unusual or nonspecific (predominant solid growth, cells with clear cytoplasm, reticular growth with hyaline globules, pseudoglandular architecture, or rare squamous differentiation) or when it is necessary to rule out metastases from other locations of the female genital tract or most commonly from breast carcinoma (as these patients have high frequency of BRCA 1 or 2 mutations) or gastrointestinal and pancreatobiliary carcinomas.
Comparing among ovarian serous tumors, Shimizu et al21 did not find significant differences in WT1 expression between OSC and serous borderline tumors and no significant differences in WT1 expression have been found between low-grade and high-grade OSC.31,32 The differential diagnosis of OSC and transitional cell carcinoma of the ovary (TCC-O) may be important for prognostic purposes. Although they are treated with the same chemotherapeutic protocols, some investigators have found that TCC-O are associated with a better response to treatment when compared to OSC33–36; however, these findings have not been corroborated by other investigators.37,38 From the histopathologic point of view, both may show diffuse or papillary growths, slit-like spaces, microcysts, pseudoglandular differentiation, bizarre tumor giant cells, and high-grade nuclear features. Often times, these two cell types coexist and it is not infrequent to find transition areas.39 In a study of 100 TCC-O, Eichhorn and Young39 found 16 neoplasms to show a serous component comprising more than 10% of the tumor. There has been some controversy about the immunohistochemical profile of TCC-O (being similar to transitional cell carcinomas of the urinary tract or to OSC). It has been shown that TCC-O typically expresses CK7 and WT1 (Fig. 2A), an immunohistochemical profile that closely overlaps with that seen in OSC (Fig. 2B). Therefore, immunohistochemistry is not helpful in distinguishing these 2 subtypes of surface epithelial carcinomas.40 In contrast to urinary tumors, TCC-O are negative for uroplakin III, CK20, and p63 as occurs with serous carcinomas, whereas transitional cell carcinomas of the urinary tract are CK7, CK20, p63, and uroplakin III positive but WT1 negative.41,42
The differential diagnosis of OSC (low and high grade) often also includes endometrioid carcinomas. Low-grade serous carcinoma or even serous borderline tumors should be differentiated from low-grade OEC with a predominant papillary or cribriform growth. However, the latter typically shows slender papillae lined by columnar epithelium lacking the arborizing architecture, budding of individual or clusters of tumor cells, nests, or small papillae present in the ovarian stroma seen in low-grade serous tumors, whereas may show glandular differentiation, squamous metaplasia, mucinous differentiation, adenomatofibromatous background, or areas of endometrioid borderline tumor.43 When an OEC is high grade, either by showing diffuse growth or high-grade cytologic atypia, it raises the differential diagnosis with a high-grade OSC. Features favoring OEC include presence of clear-cut glandular differentiation (cells with nuclear polarity and luminal border), squamous metaplasia, and/or endometriosis. The characteristic profile of OEC includes estrogen receptor (ER), progesterone receptor (PR), β-catenin positivity,44–47 and absent or minimal WT1 expression.21,48 However, ER and PR are also commonly positive in OSC and therefore not helpful in this differential diagnosis49 and poorly differentiated endometriod carcinomas are β-catenin negative.50 In contrast to OEC, most primary ovarian (as well as primary peritoneal and tubal) serous carcinomas exhibit diffuse WT1 nuclear positivity.21,31,51,52 Al-Hussaini et al31 reported 36 of 38 (94.7%) OSCs to be positive for WT1, whereas all primary ovarian and uterine OECs were negative for this marker (13 of 13 OECs and 7 of 7 uterine OECs, respectively). Thus, in problematic cases, WT1 staining may be used to distinguish between a high-grade serous and a high-grade OEC. Diffuse and strong WT1 positivity favors serous whereas nuclear β-catenin positivity favors OEC.45–47,53 Moreover, p16 (p16INK4A) can also be helpful in this differential diagnosis as it is more likely to be diffusely and strongly positive in serous than in OECs.54,55
The presence of clear cells in an ovarian tumor always raises the possibility of clear cell carcinoma (CCC). However, when the differential diagnosis is between CCC and high-grade serous carcinoma with clear cells, lack of typical architectural patterns seen in CCC and absence of an adenofibromatous background or endometriosis should point toward the diagnosis of serous carcinoma. When unclear or in small specimens, a panel of immunohistochemical stains may help in this differential diagnosis. These include WT1, hepatocytic nuclear factor-1, and ER. In a large series comparing 237 CCC and 200 high-grade OSC, WT1 was the best maker for high-grade OSC (79.9% sensitivity and 97.4% specificity) whereas hepatocytic nuclear factor-1 showed the highest sensitivity (82.5%) and specificity (95.2%) for CCC.56
High-grade OSC with a solid growth pattern can be mistaken with an undifferentiated carcinoma (UC). The latter is a diagnosis of exclusion and is defined as a poorly differentiated carcinoma composed of solid groups or sheets of noncohesive cells, lacking glands or papillae.57–60 Large areas of necrosis with islands of perivascular viable tumor cells are frequently observed.60 Finding papillae, micropapillae, and slit-like spaces may point toward the diagnosis of OSC.60 Immunohistochemistry may help as in contrast to OSC, UC typically is negative or shows minimal expression for epithelial markers 60 and WT1.43,61
It is important to ascertain the origin of serous carcinomas that can also arise from the endometrium, fallopian tube, or peritoneum, as those originating from the endometrium show a poorer response to cisplatin-based chemotherapy.62 Endometrial serous carcinomas (SC-U) commonly extend to extrauterine sites including the ovary and conversely OSC may extend to the uterus. Although the latter often shows invasion from the serosa into the outer myometrium, in some instances, tumor may travel through the fallopian tube and implant in the endometrium, being impossible to be certain about the origin of the tumor. Synchronous primary tumors of the endometrium and ovary are found in 10% of women with ovarian cancer and 5% of women with endometrial cancer,63 synchronous serous carcinomas being much less frequent than synchronous endometrioid carcinomas.57 Besides the unusual finding of a precursor lesion such as serous borderline tumor in the ovary, intratubal carcinoma in situ, or intraepithelial carcinoma in the endometrium, immunohistochemical markers used to help to determine the origin of a serous carcinoma include WT1, ER, PR, and p53.64–67 Typically, WT1 shows strong and diffuse nuclear positivity in serous carcinomas arising in the ovary, peritoneum, and fallopian tube, whereas SC-U are usually negative or show much less intense positivity for this marker.20,31,51,68 Goldstein and Uzieblo51 found that 29 of 30 (97%) OSCs were WT1 positive whereas all (18 of 18) SC-U were WT1 negative. Al-Hussaini et al31 reported WT1 positivity in 36 of 38 (94.7%) OSCs but 20 of 25 SC-U were negative for WT1, 2 tumors showed weak or moderate positivity, respectively, and only 1 tumor was strongly positive. The investigators concluded that WT-1 is useful in distinguishing OSC from SC-U. Other investigators have found some WT1 expression in SC-U, although the differences of staining between ovarian and uterine tumors have been significant in these studies.48,69,70 Thus, WT1 staining may be helpful in discriminating endometrial versus nonendometrial origin of a serous carcinoma but has no value in distinguishing OSC from tumors arising in the fallopian tube or peritoneum.
A common problem in patients with BRCA1/2 and a prior history of breast cancer that present with a new ovarian or peritoneal growth is to determine whether the tumor is a metastasis or new primary as serous carcinomas often occur in patients with BRCA1/2.71 Furthermore, metastases of ovarian carcinoma to the breast have been reported,72,73 being serous carcinoma the most frequent ovarian/peritoneal neoplasm metastasizing to that site.74–76 Even though in most instances both tumors look histologically different, there are occasions when this differential diagnosis is very difficult especially if the tumor has a papillary or diffuse growth. A correct diagnosis is crucial because of therapeutic and prognostic implications.77 Although there is overlap in their immunohistochemical profile, both typically being CK7+, CK20−, and hormonal receptors positive,78–81 most ovarian carcinomas are also positive for WT1, CA125, 82,83 and PAX8,84,85 whereas the majority of breast carcinomas are negative for these markers83 and approximately half of them are positive for gross cystic disease fluid protein-15 (GCDFP-15) and mammoglobin.82,83 Kanner et al82 found all breast carcinomas to be WT1 negative whereas GCDFP-15 and mammoglobin were positive in 8 of 21 and 14 of 21 of these tumors, respectively. However, several studies have shown focal nuclear WT1 immunoreactivity in a minority of breast carcinomas including micropapillary carcinomas (up to 10%).77,83,86,87 Positive WT1 and CA125 immunoreactivity and lack of expression of GCDFP-15 and mammoglobin appear to be the most predictive combination for the diagnosis of OSC.
As a final remark, low-grade OSC with intraluminal mucin and high-grade OSC with microcysts and signet ring cells must be differentiated from ovarian mucinous carcinomas of intestinal type, metastatic mucinous carcinomas of the gastrointestinal and pancreatobiliary tract carcinomas. Although rare, poorly differentiated pancreatic carcinoma with widespread omental or peritoneal involvement may mimic a serous carcinoma. WT1 may be helpful as it is typically negative in ovarian mucinous carcinomas43 and pancreatobiliary carcinomas.18 In the largest study comparing OSC and pancreatobiliary carcinomas, Goldstein et al18 found all 64 pancreaticobiliary adenocarcinomas to be WT1 negative.
WT1 EXPRESSION IN MESOTHELIAL TUMORS
Although the diagnosis of malignant mesothelioma is usually straightforward, the differential diagnosis with serous carcinomas arising in the ovary or the peritoneum can be challenging due to histologic and immunohistochemical similarities. More common scenarios include when malignant mesothelioma presents as an ovarian mass,88 a serous borderline tumor is associated with peritoneal implants, a low-grade serous carcinoma is associated with metastases in the peritoneum (especially when the prior clinical history is not known), or when low-grade or high-grade serous carcinomas metastasize to the pleura. Numerous studies have attempted to use a variety of immunohistochemical antibodies in this differential diagnosis, but none have shown good enough sensitivity or specificity.27,89–96 WT1 (Fig. 3), calretinin, CK5/6, and D2-40 are positive in more than 90% of mesotheliomas97; however, they may also be expressed in approximately 90%, 10%, 25% and 65% of OSC, respectively.94 WT1 positivity in mesothelioma has been reported to range from 43% to 90% 97–100 but it is also positive in the vast majority high-grade OSC,21,31,51,94,101 low-grade OSC, and serous borderline tumors.21,31,32 Recently, PAX8 has been shown to be highly sensitive and specific for the diagnosis of serous tumors.102 In a recent study by Laury et al,102 PAX8 staining was seen in 99% of high-grade OSC and 100% of low-grade OSC and serous borderline tumors; however, only 74% of these neoplasms (188 of 254) showed positivity in greater than 50% of tumor cells with intensity ranging from strong to weak. In contrast, only 2 of 23 (9%) of peritoneal malignant mesotheliomas showed focal and/or weak staining while all pleural malignant mesotheliomas were negative. Strong PAX8 staining seems to be highly specific (P<0.00001) in the distinction of serous carcinoma from malignant mesothelioma and thus a better discriminator than WT1.
Adenomatoid tumor, a benign mesothelial proliferation, is most frequently present in the uterus, fallopian tube, and ovarian hilus.103–107 Its diagnosis is based on the typical morphologic appearance and usually is straightforward. In the uterus, they are frequently associated with smooth muscle hypertrophy and they may be mistaken for leiomyomas. WT1, although initially thought to be a mesothelial marker, it also stains uterine smooth muscle, thus, not helping in this distinction.108,109 Calretinin expression in the neoplastic mesothelial cells is useful in this differential diagnosis.104 Rarely, when these tumors have a prominent signet ring cell component, they could be confused with a metastatic signet ring cell adenocarcinoma110 or tumors with microcystic pattern and signet ring cells including epithelial and sex cord stromal tumors.111–114 WT1 may be helpful in the differential diagnosis with a metastatic adenocarcinoma with signet ring cells, as the latter does not show positivity for this marker, whereas WT1 has no value in the differential with sex cord stromal tumors as the latter are also often WT1 positive.23,115
WT1 EXPRESSION IN MESENCHYMAL TUMORS OF THE UTERUS
Although the differential diagnosis of uterine smooth muscle and endometrial stromal tumors (EST) is usually straightforward, overlapping morphologic characteristics between both groups of neoplasms are encountered, in particular if ESTs have smooth muscle metaplasia, sex cord-like differentiation, epithelioid cells, fibrous and myxoid appearances, and vascular invasion mimicking smooth muscle tumors or when highly cellular leiomyoma mimicks a EST.116–121 The latter is a common problem as both tumors show diffuse high cellularity, prominent vasculature, and may have irregular borders.118 In this scenario, it is important to establish the correct diagnosis for therapeutic and prognostic purposes. WT1 is not helpful in this differential diagnosis as the scant literature has shown significant overlapping results. Sumathi et al122 reported that 11 of 19 EST in their study were WT1 positive (nuclear) (Fig. 1B), but only 4 cellular or highly cellular leiomyomas also had nuclear positivity (4 of 14). In contrast, Agoff et al123 reported no differences in WT1 expression between low-grade ESS and cellular leiomyomas as WT1 positivity was seen in 9 of 10 and 9 of 9 of these tumors, respectively. Therefore, WT1 should not be considered a discriminatory marker in the differential diagnosis of EST and cellular leiomyomas. Other immunohistochemical stains, particularly CD10, h-caldesmon, and desmin, are more helpful in this distinction.117,122–130
WT1 is expressed in uterine LMSs,109,131,132 ranging from approximately 8% to 50%; however, a very limited number of high-grade endometrial sarcomas tested (defined by marked cytologic atypia and ≥10 mitoses/10 high power fields) were all negative (0 of 4).123 To the best of our knowledge, nuclear WT1 expression has not been reported in other sarcomas that may occur in the uterus or in the rest of the female genital tract including rhabdomyosarcoma, angiosarcoma, malignant peripheral nerve sheath tumor, and others.
WT1 may be helpful in establishing soft tissue versus gynecologic origin of a smooth muscle tumor. Deavers et al109 found WT1 positivity in the vast majority of benign smooth muscle tumors and in 60% of gynecologic LMS (12 of 20) but in none of the nongynecologic smooth muscle tumors. In another recent study, Carvalho et al131 reported WT1 expression in 23% and 43% uterine and retroperitoneal LMS, respectively. The investigators noted that WT1-positive tumors also had ER expression and concluded that WT1 and ER may be used in conjunction to delineate the origin of a smooth muscle tumor. In contrast, Lee et al132 studied the expression of WT1 and ER in 245 LMS (including 102 of gynecologic origin) and 49 uterine leiomyomas, and found WT1 positivity in only 8% (weak to moderate) and 0% of gynecologic and nongynecologic LMS, respectively. They also noted positivity in 67% of uterine leiomyomas. ER positivity was observed in 3% and 50% of nongynecologic and gynecologic LMS, respectively. All uterine leiomyomas were ER positive. The investigators concluded that WT1 is not valuable to determine the gynecologic origin of LMSs.
Uterine tumors resembling ovarian sex cord stromal tumors (UTROSCT) are uncommon neoplasms first described by Clement and Scully in 1976.133 They are considered by the most recent WHO classification to be of uncertain histogenesis although in the past they have been related to ESTs.57 These tumors show a broad spectrum of morphologies but essentially recapitulate the appearance of sex cord stromal tumors of the ovary. In general, these neoplasms have a variable immunophenotype, not infrequently with coexpression of epithelial, stromal, smooth muscle, and sex cord markers.134–145 The diagnosis is based on their microscopic characteristics and immunohistochemistry is only of limited value in the differential diagnosis with other uterine epithelial-like tumors, most commonly ESTs with extensive sex cord-like differentiation and epithelioid smooth muscle neoplasms. Studies of WT1 expression in these tumors are scant. Hurrell and McCluggage140 and Sutak et al146 reported WT1 positivity in 100% of UTROSCT studied (4 and 1 tumors, respectively). In contrast, De Leval et al136 reported lower frequency of WT1 positivity (approximately 33%, 4 of 12 tumors). As discussed earlier, ESTs with or without extensive sex cord-like differentiation and smooth muscle tumors are commonly WT1 positive; thus, this marker is not helpful in this distinction. Inhibin, the most specific marker of sex cord stromal tumors of the ovary,147–150 calretinin,135,140–142,146,151 and melan A,152 may be more helpful as not infrequently are positive in areas with sex cord-like differentiation but negative in pure ESTs and in smooth muscle tumors.140,146 Finally, OEC with a sex cord-like pattern can be mistaken for a UTROSCT especially those with sertoliform features153,154 which may even show overlapping immunohistochemical characteristics including WT1, inhibin, CD99, calretinin, and melan A expression.153,155 However, UTROSCTs are usually positive for at least 1 smooth muscle marker (desmin) and are not associated with areas of classic OEC.136
WT1 IN MIXED TUMORS OF THE FEMALE GENITAL TRACT
Low grade Mullerian/mesodermal adenosarcomas (MA) are rare mixed mesenchymal and epithelial neoplasms that occur most frequently in the uterus but can also be encountered at extrauterine sites.156–159 These tumors are composed of benign or at most atypical epithelium, most commonly of endometrioid type and a low malignant mesenchymal component, often resembling that of an EST. Thus, not surprisingly, the immunohistochemical profile of these tumors is similar to that observed in ESTs. Soslow et al160 studied WT1 expression in 35 MA (7 with sarcomatous overgrowth) and found WT1 moderate positivity in 25% to 75% of cells in 22 of 27 conventional MA but only in 2 of 7 MA with sarcomatous overgrowth. The stromal cells also expressed ER, PR, CD10, SMA, and AE1/AE3 and desmin to a lesser degree. Compared with MA without sarcomatous overgrowth, MA with sarcomatous overgrowth showed loss of WT1, ER, PR, and CD10. The most common differential diagnosis of MA is with polypoid endometriosis and low-grade ESS showing glandular differentiation.161–163 In these scenarios, immunohistochemistry has limited value due to significant overlap in the immunophenotype of these lesions. All are positive for WT1122,123,164 besides ER,165,166 PR,165,166 and CD10128,165–167 among others.
Most malignant Mullerian mixed tumors (MMMT) (carcinosarcomas) originate from the endometrium and rarely from extrauterine sites such as the ovary, fallopian tube, cervix, vagina, and peritoneum. Even though, this tumor has a biphasic growth having malignant epithelial and stromal components, it is now classified among epithelial malignant tumors.57 WT1 expression in MMMT of the female genital tract has been rarely studied. To date, among 61 MMMT studied in the literature, 28 have shown WT1 positivity.27,168–171 The largest study up to date170 analyzed WT1 expression in 16 MMMT of endometrial (10), ovarian (5) and peritoneal (1) origin. The malignant epithelium was mostly serous/clear cell (62.5%) and the remainder endometrioid or undifferentiated. The mesenchymal component was homologous in 9 (56.3%) and heterologous in 7 (43.7%) tumors. Only 5 of 16 (38.5%) MMMT showed nuclear WT1 positivity. Four (66.7%) and 1 (14.3%) of the homologous and heterologous MMMT were WT1 positive, respectively. The endometrial tumors mostly showed strong stromal cytoplasmic staining, whereas the ovarian and peritoneal tumors mostly showed strong WT1 nuclear/cytoplasmic positivity in the epithelial and stromal compartments. Coosemans et al168 found only 1 of 12 MMMT with nuclear expression. In contrast, Dupont et al169 in a study of WT1 expression in endometrial carcinomas found 7 (70%) of 10 MMMT to be positive in both epithelial and mesenchymal components.
WT1 EXPRESSION IN SEX CORD STROMAL TUMORS
Sex cord stromal tumors (SCSTs) are uncommon neoplasms that account approximately for 8% of all primary tumors of the ovary.172 The diagnosis of sex cord stromal tumors is based on clinicopathologic characteristics; however, problematic cases may require immunohistochemistry. Some studies have shown immunohistochemical overlap between sex cord stromal tumors and ovarian epithelial tumors (typically endometrioid tumors), including expression of pan-cytokeratin, low-molecular weight cytokeratin, vimentin, muscle markers, ER, and PR, limiting the diagnostic utility of these markers.151,173–188 Recently, WT1 has been shown to be a sensitive marker for sex cord stromal tumors.23,115 In a large study, Zhao et al189 analyzed the expression of WT1 and other sex cord stromal lineage markers (inhibin, calretinin, steroidogenic factor-1/SF-1, CD99, and MART-1) in 127 sex cord stromal tumors, comprising 32 adult granulosa cell tumors, 27 Sertoli cell tumors, 18 Sertoli-Leydig cell tumors, 25 steroid cell tumors, and 25 fibromas/fibrothecomas. They found WT1 expression in all (78% to 100%) but steroid cell tumors and concluded that WT1 was a highly sensitive marker for most types of SCSTs. Among the other sex cord stromal markers, SF-1 was expressed in 100% of cases including steroid cell tumors, whereas inhibin and calretinin were expressed in all tumor types but with lower frequency (56% to 100% and 36% to 100%, respectively). CD99 was expressed in all tumor groups (32% to 88%) except in fibromas/fibrothecomas, and MART-1 was only expressed in steroid cell tumors. The investigators concluded that the most helpful sex cord stromal markers for the differential diagnosis with non sex cord stromal tumors were WT1, inhibin, calretinin, and SF-1. In another study, Zhao et al115 showed that WT1 was diffusely expressed in almost all Sertoli cell tumors (96%) but it was negative in carcinoids (22 cases); with a small group of endometrioid tumors (16% of endometrioid borderline tumors, 13% of well differentiated OECs, 25% of sertoliform OECs) being WT1 positive. In contrast to Sertoli cell tumors, WT1-positive endometrioid tumors including the sertoliform variant of OEC, usually exhibited focal expression. Therefore, they concluded that this marker is useful for the distinction of Sertoli cell tumor from carcinoid and endometrioid tumors. In contrast to these studies, Deavers et al151 found a lower frequency of WT1 expression in SCSTs. They reported that 39 (74%) SCSTs were WT1 positive, most commonly Sertoli-Leydig cell tumors. All of them also expressed calretinin and 45 (85%) were inhibin positive. Therefore, the investigators concluded that WT1 has limited value in the diagnosis of SCSTs compared with calretinin and inhibin that seemed to be more sensitive.
WT1 EXPRESSION IN SMALL ROUND “BLUE” CELL TUMORS
Ovarian small cell carcinoma of hypercalcemic type (OSCCHT) is a rare neoplasm that most commonly occurs in young women and in two-thirds of patients is associated with hypercalcemia.172 It is predominantly composed of small cells with scant cytoplasm; however, 40% of tumors display large eosinophilic cells (large cell variant).190 The differential diagnosis is wide and often includes sex cord stromal tumors and neoplasms belonging to the family of “small round cell tumors,” whereas the “large cell” variant should be differentiated most frequently from UC and melanoma.191 Often, SCCHT is mistaken with a juvenile granulosa cell tumor (JGCT) because both neoplasms occur in young women, have cells with brisk mitotic activity and show follicle-like spaces. Clinical signs in favor of JGCT are estrogenic manifestations and normal calcemia. Morphologically, JGCT may have a nodular growth, typically is associated with a myxomatous background, have cells with more abundant eosinophilic cytoplasm and nuclear pleomorphism, and are associated with a theca cell component. OSCCHT is typically strongly positive for WT1101 (Fig. 4) as also seen in granulosa cell tumors.151,189 Thus, this marker is not helpful in this differential diagnosis. The most helpful markers include EMA and inhibin.101,184 The former when positive supports the diagnosis of SCCHT whereas the latter is typically positive in granulosa cell tumors.
Another blue round cell tumor typically positive for WT1 is the intra-abdominal desmoplastic small round cell tumor (IADSRCT),13,25,192–194 which may occur in female individuals and can be misdiagnosed as an ovarian small cell carcinoma of hypercalcemic type. In contrast to the latter, IADSRCT is associated with extensive peritoneal and omental involvement and even though ovarian involvement can be bilateral, typically it does not form a predominant ovarian mass.190,195,196 Microscopically, IADRSCT lacks follicles and typically has a prominent desmoplastic stroma. In selective cases immunohistochemistry may be helpful in this differential diagnosis. Although both tumors are positive for WT1, IADSRCT is characteristically reactive with antibodies against the C-terminal13,25,192–194 in contrast to OSCCHT, which shows nuclear positivity with antibodies against the N-terminal.101 Morever, IADSRCT may be positive for neural (synaptophisin, NSE, and leu7) and mesenchymal (desmin) markers.25,197 The most helpful marker in this distinction is desmin, as Ordoñez25 reported positivity in 39 of 39 IADSRCT whereas OSCCHT were typically negative.
Other small round cell tumors that occasionally involve the ovaries of young women include neuroectodermal tumors (PNETs),198–200 rhabdomyosarcoma,201 metastatic neuroblastoma,202 and metastatic round cell sarcomas.203,204 Barnoud et al192 analyzed the expression of WT1 (antibody C-19) in 71 small round cell tumors considered in the differential diagnosis of IADSRCT and found nuclear WT1 positivity in 10 of 14 (71%) nephroblastomas, rare and focal in 2 of 17 rhabdomyosarcomas, and no expression in Ewing/PNETs, neuroblastomas, and rhabdoid tumors of the kidney.
WT1 staining often times is not diagnostic and should be integrated with other immunohistochemical markers and morphologic features.WT1 is positive in both serous and transitional carcinomas of the ovary, and thus it is not helpful in the differential diagnosis. However, WT1 will be helpful in determining the origin of a transitional cell carcinoma, as transitional cell carcinomas from the urinary tract are negative for WT1.
WT1 may be of value in separating OSCs and OECs, because this is diffusely positive in almost all OSCs but negative or only focally positive in most OECs.
In the presence of synchronous serous carcinomas in the ovary/fallopian tube/peritoneum and endometrium, strong WT1 positivity in both tumors will point toward an extrauterine origin.
In the differential diagnosis of malignant mesothelioma with ovarian or peritoneal involvement versus OSC, WT1 should be used as part of a panel of antibodies that includes PAX8, calretinin, CK5/6, and D2-40.
In mesenchymal tumors of the uterus, WT1 positivity is not useful for the differentiation of EST from cellular leiomyomas, as both are WT1 positive or in the differential diagnosis of UTROSCTs from EST and smooth muscle tumors.
WT1 can be used to determine the origin of a smooth muscle tumor in conjunction with ER as only gynecologic LMSs and uterine leiomyomas are commonly WT1 and ER positive.
WT1 has limited value for the distinction of mullerian adenosarcoma from polypoid endometriosis and low-grade ESS with glandular differentiation, as all are typically positive for this marker.
WT1 is a very sensitive marker of sex cord stromal tumors (except steroid cell tumors); however, it should be used as part of a panel of antibodies including inhibin, calretinin, SF-1 when an OEC or a carcinoid tumor enters the differential diagnosis.
WT1 cannot be used to separate a small cell carcinoma of hypercalcemic type and juvenile granulosa cell tumor, as both are typically positive. Therefore, an immunohistochemical panel including EMA and inhibin, should be used for this differential diagnosis.
The differential diagnosis between small cell carcinoma of hypercalcemic type and intraabdominal desmoplastic small round cell tumor is usually based on morphology. Even though both tumors are WT1 positivity, it important to remember that they react with different antibodies against WT1. Small cell carcinoma is reactive with antibodies against the N-terminal whereas intraabdominal desmoplastic small round cell tumor reacts with antibodies against the C-terminal.
When dealing with a small round blue cell tumor, WT1 may be helpful in differentiating a small cell carcinoma of hypercalcemic type or intraabdominal desmoplastic small round cell tumor (both WT1 positive), from other small round cell tumors that may involve the ovary (typically negative except Ewing sarcoma).
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