Offman, Saul L. MD; Longacre, Teri A. MD
Clear cell carcinoma of the female genital tract can arise in the ovary, endometrium, and cervical-vaginal region, as well as in peritoneal and other extrauterine, extraovarian sites. Despite morphologic similarities (Table 1), the clinical and biological features of these tumors often differ with respect to primary site. Misdiagnosis of clear cell carcinoma at all of these sites, either on frozen sections or permanent sections, is one of the more common errors in gynecologic pathology. Accurate diagnosis is important because of the poor response to platinum-based chemotherapy for advanced-stage disease and increased risk of thromboembolism.
This review discusses the clinical, histologic, and immunohistologic features of female genital tract clear cell carcinomas; highlights recent molecular developments; addresses areas of potential diagnostic confusion; and presents solutions for these diagnostic problems where they exist. Wherever gray areas persist, a patient management–based approach is proposed.
OVARIAN CLEAR CELL CARCINOMA
Ovarian clear cell carcinoma occurs at a slightly younger median age compared with high-grade serous carcinoma (55 vs. 64 y).1 Although many consider it to be rare, it is the second most common type of epithelial ovarian cancer in the current series, accounting for approximately 15% of cases (70% of ovarian cancers have high-grade serous histology).2,3 Clear cell carcinoma is likewise second only to serous carcinoma for ovarian cancer–related deaths.2 There is an unexplained increased prevalence of clear cell carcinoma in Japan (up to 25%) relative to western countries, even though the overall incidence of ovarian carcinoma in Japan is relatively low.4,5 Clear cell carcinoma is also more common in Asians living in the United States.1 Clear cell carcinoma is confined to 1 or both ovaries at presentation [International Federation of Gynecology and Obstetrics (FIGO) stage I] in 56% of cases, as compared with serous carcinoma, which is confined to the pelvis in only 19% of cases.1 The ovarian tumors are unilateral (>95%) and when of high stage, do not appear to respond well to standard platinum-based chemotherapy. There is an increased risk of thromboembolism (2.5-fold) compared with other ovarian epithelial cancers at presentation and, possibly, throughout the course of the disease.6–8 Rates as high as 40% to 42% have been reported.7,8 Clear cell morphology is also the most common histologic subtype seen in cases of paraneoplastic hypercalcemia in gynecologic malignancies.9 This tumor type has been observed in association with Lynch syndrome.10,11
Approximately 50% to 70% of cases of ovarian clear cell carcinoma are associated with pelvic endometriosis and/or ovarian endometriosis.12,13 A 3-fold relative risk for ovarian clear cell carcinoma has been reported in patients with endometriosis, but larger studies are required to confirm this risk level.14
Stage is the single most important prognostic factor in ovarian clear cell carcinoma. Within stage I tumors, preoperative capsule rupture, surface involvement, and positive ascitic fluid impart a poorer prognosis.15 Tumor macroarchitecture has also been suggested to influence behavior.16 Specifically, cystic architecture may be more favorable than adenofibromatous architecture, but this finding has yet to be confirmed in large-scale studies with detailed pathologic review.16 Improved prognosis has also been reported for those tumors that are associated with endometriosis, but this has not been confirmed when clear cell carcinomas are classified on the basis of strict histologic criteria.17–20
Poor responsiveness to platinum-based chemotherapy has been shown in high-stage disease, resulting in poor overall and disease-specific survival.1,4,6,21–23 A subset of patients with FIGO stage I tumors will be cured by surgery alone, but it is unclear which features equate with this favorable outcome. At present, consideration for “surgery-only” regimens should only be offered to patients with bilateral salpingo-oophorectomy and complete surgical staging demonstrating FIGO stage IA disease. Future studies are required to determine which low-stage patients will benefit from adjuvant therapy, with both chemotherapy and radiation currently playing a role in advanced disease. Regimens focused specifically at treating clear cell carcinoma are still relatively early in investigation.24 To date, there is no convincing evidence that grading ovarian clear cell carcinoma stratifies outcome.
Ovarian clear cell carcinoma is diagnosed correctly in only 44% of intraoperative consultations.25 Misdiagnosis occurs because the architectural patterns in clear cell carcinoma (Table 1) are also commonly encountered in other histologic subtypes and because these other tumors frequently harbor clear cells (Table 2).
Most clear cell carcinomas are unilateral. The tumors may be solid, but more commonly the sectioned surface reveals a thick-walled unilocular or multilocular cystic lesion with multiple solid, yellow nodules protruding into the cyst (Fig. 1). Cystic spaces may contain watery, mucinous fluid, or brownish “chocolate-colored” fluid when associated with endometriosis. Endometriosis may be grossly evident as patches of brownish discoloration, either within the cyst wall or in surrounding tissues. The mean size of ovarian clear cell carcinoma is 15 cm, although these tumors may measure up to 30 cm.
Clear cell adenocarcinoma is composed of glycogen-containing cells and hobnail cells. The glycogen-containing cells are polyhedral with abundant clear cytoplasm, although many tumors will contain a mixture, or sometimes even a predominance of cells with granular eosinophilic cytoplasm (Fig. 2). This so-called oxyphilic variant of clear cell carcinoma is often a source of diagnostic confusion; identification of more typical patterns of clear cell carcinoma may assist in the diagnosis of this variant. The glycogen-rich cytoplasm is periodic acid-Schiff positive and diastase sensitive, although diastase-resistant material may be focally present along the apical cell membranes. Nuclei are often eccentrically placed, with rounded to angulated contours, hyperchromasia, and mostly inconspicuous nucleoli. Hobnail cells possess relatively scant cytoplasm and enlarged, bulbous, hyperchromatic nuclei that protrude into tubule and cyst lumens (Fig. 2C). Cysts and/or glands lined by bland, flattened cuboidal cells as seen in clear cell adenofibromas (Fig. 1C), and occasionally signet ring-like cells, also referred to as “targetoid cells” when they contain inspissated mucin within vacuoles (Fig. 2D), may be encountered.
Architectural patterns include tubulocystic, papillary, solid, and mixtures thereof (Fig. 3). Tubulocystic areas include variably sized tubules and cysts that are lined predominantly by flat to cuboidal cells with variable atypia and scattered hobnail cells. The tubules and cysts contain mucin, but intracytoplasmic mucin is not a common feature of the lining cells. Papillary areas contain morphologically variable papillae that are most commonly small and round in comparison with those in serous carcinoma. The papillae are also generally more orderly and less cellular than in serous carcinoma. The fibrovascular cores may be filled with either fibromatous, myxoid, spherule-like mucoid, or hyalinized basement membrane–type material; sometimes they exhibit so-called “empty” cores (Fig. 4).25 Solid areas are composed of sheets of polyhedral cells, usually with clear cytoplasm, separated by thin septa of hyalinized, fibrovascular stroma. It is not uncommon for nonspecific poorly differentiated areas to be present. An accompanying inflammatory infiltrate, with prominence of plasma cells, is sometimes evident. Microcalcifications and psammoma bodies can be seen in clear cell carcinomas; up to 25% of cases contain eosinophilic hyaline bodies. Areas of clear cell carcinoma can merge with benign and/or borderline regions, calling attention to the need to thoroughly sample those lesions in which a malignant component is not identified on initial evaluation. Mixed subtypes of surface-epithelial carcinomas are occasionally encountered; a secondary component of endometrioid carcinoma is most common. Rarely, mixtures of serous carcinoma and clear cell carcinoma may be seen, but most putative mixed tumors are in reality serous carcinomas with clear cytoplasm (Fig. 5).26
By definition, only clear cell carcinoma (vs. borderline clear cell tumors) exhibits high-grade nuclear features, although a spectrum of nuclear atypia may be present. All clear cell carcinomas are considered to be of high grade. Mitotic figures are relatively uncommon compared with other ovarian carcinomas; however, their presence may be helpful in the differential diagnosis with benign and borderline clear cell lesions.
Benign and borderline clear cell lesions are exceedingly rare, and their presence should cue the pathologist to submit additional tissue for evaluation. Moderate to severe nuclear atypia, mitotic activity, confluent tubular growth, or stromal invasion (even microinvasion) in a clear cell lesion, all warrant a diagnosis of malignancy.27
Ovarian clear cell carcinomas with typical morphologic findings will not require immunohistochemistry to establish a diagnosis. However, when immunohistochemistry is used, the differential keratin profile is reliably CK7+/CK20−, although CK7 may be focal in approximately 10% of cases.28–31 Clear cell tumors will also stain positively for cytokeratins and epithelial membrane antigen (EMA) and may stain with other epithelial markers such as Leu-M1, carcinoembryonic antigen (CEA), and CA125.28,29,32,33 In general, clear cell carcinomas are negative for estrogen receptor (ER), progesterone receptor (PR), and WT1 (Table 3). Hepatocyte nuclear factor (HNF)-1β is a relatively new marker that has been utilized in clear cell carcinoma.34,36–38 HNF-1β is a transcription factor responsible for glucose metabolism and antiapoptosis and is normally expressed in hepatic, gastrointestinal, pancreatic, and renal tissues.45 HNF-1β is also strongly expressed in secretory endometrium, yolk sac tumors, and the majority of endometriotic tissues associated with clear cell carcinoma.36 PAX8 has emerged as a powerful marker of müllerian tract lineage in tumors of unknown origin. This observation holds true for clear cell carcinoma, where it has been shown to be positive for PAX8 in 76% to 100% of cases (Table 3).40–44
Immunohistochemical markers that are usually negative in ovarian clear cell carcinoma, but have utility in the differential diagnosis of specific mimics include glypican-3 (yolk sac tumor),31 OCT3/4 (dysgerminoma),46 and CD10 (renal cell carcinoma).30,42
Until recently, knowledge of the molecular changes triggering the development of ovarian clear cell carcinoma has been relatively limited. The molecular alterations seen in high-grade serous carcinoma, such as ubiquitous TP53 mutations, somatic and germline BRCA mutations, and complex karyotypes and chromosomal instability, are uncommon in clear cell carcinoma.47–49 These latter differences may account for the relative chemoresistance documented in these tumors.4,6,21,22 Clear cell carcinomas are strongly associated with endometriosis,12,13 but they typically lack expression of hormonal markers (ER, PR).34 This may suggest less hormonal impact during oncogenesis for clear cell carcinoma.50
The link with endometriosis has been utilized as a starting point for the investigation of potential molecular events in the development of clear cell carcinoma. The most important alterations to be identified include ARID-1 A, PIK3CA, and HNF-1β mutations (Table 4).37,38,51–54,56 ARID1A encodes the protein BAF250a, which is integral in the SWI-SNF chromatin remodeling complex. ARID1A mutations are seen in 40% to 60% of ovarian clear cell carcinomas, but not in high-grade serous carcinomas (Table 4). In general, loss of BAF250a expression correlates with mutational status. ARID1A mutations and BAF250a loss are also seen in contiguous endometriotic lesions but not in endometriosis at distant sites. PIK3CA mutations are seen in about 40% of clear cell tumors, the majority of which (71%) are also ARID1A deficient, suggesting that these mutations frequently coexist.52
Because of the papillary architecture and high-grade cytology in some clear cell carcinomas, distinction between clear cell carcinoma and serous carcinoma can be difficult (Table 5) (Fig. 5).57 Serous carcinomas are typically bilateral, whereas clear cell carcinomas are almost always unilateral, even when of high stage. Endometriosis is more commonly associated with clear cell carcinoma. On microscopy, papillae in serous carcinoma are large, irregular, and have hierarchical branching, in contrast to the small, round, and more simplified papillae in clear cell carcinoma. Papillae in clear cell carcinoma are also lined by a single layer of cells, without the characteristic stratification and budding seen in serous carcinoma. In most cases, clear cell carcinoma does not exhibit the degree of mitotic activity observed in serous carcinomas. The presence of psammoma bodies is not necessarily helpful as they can be found in both entities; however, an abundance would seem to favor serous carcinoma. Although the classic composite immunophenotype in ovarian clear cell carcinoma is ER−/WT1−/p53−/HNF-1β+, a more limited panel of WT1, ER, and HNF-1β is most discriminatory in the differential diagnosis.34 Serous carcinomas tend to express ER and WT1, whereas clear cell carcinomas typically do not express these markers (or if they do, typically they will express only 1 of the 2 markers).
Many high-grade ovarian carcinomas appear to contain areas of mixed serous and clear cell differentiation. A recent study examining these more problematic tumors showed that ovarian tumors with an apparent mixed serous and clear cell component exhibited significant interobserver variability in diagnosis, but a similar immunophenotype that resembled pure serous carcinomas. These data suggest that most tumors with apparent mixed serous-clear cell histology represent serous carcinomas with clear cytoplasm and should be classified separately from classic clear cell carcinoma.26
Serous Borderline Tumor
Clear cell carcinomas with prominent papillary architecture may also be misdiagnosed as serous tumors of low malignant potential, leading to delayed staging and treatment (Fig. 6).58,59 The diagnostic confusion arises in part due to similar age at presentation and in part due to the low level of mitotic activity present in many clear cell carcinomas. Features favoring clear cell carcinoma include unilateral presentation, coexistent endometriosis, simple papillae with nonhierarchical branching, focal high-grade nuclear features, monomorphous cell population (compared with serous tumors containing a mix of ciliated pink cells and columnar cells), and the presence of more typical clear cell carcinoma patterns elsewhere in the tumor. The presence of endometriosis, although not specific, should always prompt consideration for papillary clear cell carcinoma. Problematic cases may warrant immunohistochemistry with ER and WT1: serous tumors express both markers, whereas clear cell carcinomas typically express neither.
Endometrioid Carcinoma With Secretory or Clear Cell Change
Clear cell adenocarcinoma is usually distinguished from endometrioid carcinoma with secretory change by the presence of hobnail cells with high-grade nuclei (Table 6). However, clear cell and endometrioid carcinoma may be intermixed in some cases; distinguishing these mixed cases from endometrioid tumors with cytoplasmic clearing can be difficult. Although most cytoplasmic clearing is typified by vacuoles confined to a supranuclear or infranuclear location recapitulating secretory endometrium (secretory carcinoma), other forms of clear cell change can be more variable with regard to the quality and location of the vacuoles.60 Cytoplasmic clearing in these tumors may be due to accumulation of glycogen (squamous differentiation), lipid, mucin, or other substances. Features favoring endometrioid carcinoma include relatively uniform neoplastic cells with ovoid to columnar shape, squamoid differentiation, and cribriform architecture (Fig. 7A, B). These features contrast with the polyhedral-shaped clear cells and hobnail cells in clear cell carcinoma. Endometrioid carcinoma with areas of clear cell change must also be distinguished from true mixed endometrioid and clear cell carcinomas. The “clear cell” and “non–clear cell” areas tend to merge into one another in the former tumor, whereas a bona fide mixed endometrioid and cell carcinoma should exhibit well demarcated foci of each tumor type with characteristic cytology and architectural patterns. Endometrioid carcinomas show similar CK7+/CK20− expression to clear cell carcinoma. In contrast, they are typically positive for ER and less commonly positive for HNF-1β, although variable staining patterns may be present in endometrioid tumors.60
Yolk Sac Tumor
Clear cell carcinoma may be difficult to distinguish from yolk sac tumor, particularly when it occurs in a younger patient. Yolk sac tumors are recognized by the presence of papillae with central blood vessels (Schiller-Duval bodies), elevated serum α-fetoprotein (AFP) and a more prominent reticular pattern (Fig. 7C). The expression of CK7 in the absence of AFP staining in clear cell carcinoma has been exploited in the differential diagnosis of yolk sac tumor; however, almost 30% of clear cell carcinoma may express AFP, and staining with this marker is often patchy, even in yolk sac tumors (Table 7).31 A CK7+/EMA+ phenotype highly favors clear cell carcinoma over yolk sac tumor; however, one must be careful not to over interpret CK7+ enteric glands and other mixed elements in a germ cell tumor as evidence for clear cell carcinoma. Glypican-3 is strongly and diffusely expressed in 97% of yolk sac tumors, but this staining pattern is seen in 17% of clear cell carcinomas.31 The novel zinc finger transcription factor SALL4 is also expressed in nearly all yolk sac tumors and in <10% of clear cell carcinoma.32 SALL4 is a nuclear protein and is also expressed in dysgerminoma, embryonal carcinoma, choriocarcinoma, and teratoma. HNF-1β is strongly expressed by both and is not useful in this differential diagnosis.
Clear cell carcinomas with an extensive solid pattern may be difficult to distinguish from dysgerminoma in younger patients; however, the cells in dysgerminoma tend to be rounder with centrally positioned nuclei and multiple, often prominent, nucleoli (Fig. 7D), whereas those in clear cell carcinoma are more polyhedral in contour and usually possess nuclei that are eccentric with inconspicuous to small nucleoli. When an inflammatory infiltrate is present in clear cell carcinoma, it usually consists of a predominance of plasma cells, in contrast to the prominent lymphocytic infiltrate in dysgerminoma. Clear cell carcinomas strongly express keratin and EMA, whereas dysgerminoma expresses little or no keratin or EMA. Placental alkaline phosphatase (PLAP) may be useful in this differential diagnosis, but only tumors exhibiting PLAP staining that is strong and diffuse should be interpreted as supporting a diagnosis of dysgerminoma, as clear cell carcinomas may express PLAP in a patchy or weak pattern. OCT3/4 is the more sensitive and specific marker for dysgerminoma in this differential diagnosis.
Renal Cell Carcinoma
Metastatic renal cell carcinoma involving the ovary is uncommon but may be initially misdiagnosed as primary ovarian clear cell carcinoma. Renal cell carcinomas are typically associated with a more extensive sinusoidal vascular stromal framework than is seen in clear cell carcinoma; hobnail cells are not seen. Immunohistochemistry is somewhat limited, but PAX2 may be useful [positive in renal cell (>75%); usually negative in ovarian clear cell (<10%)].30,42 PAX8 and HNF-1β have no utility as they are positive in both. Active exclusion—that is, imaging studies, immunohistochemistry, etc—should be performed when there is (1) a history of renal cell carcinoma; (2) suspicion of a retroperitoneal mass; (3) family history or renal cell carcinoma or evidence of hereditary renal cell carcinoma syndrome (von Hippel-Lindau, Birt-Hogg-Dubé, or possibly, hereditary leiomyomatosis); or (4) unusual distributional features.
Juvenile Granulosa Cell Tumor
Sex-cord stromal tumors, particularly juvenile granulosa cell tumor may be confused with clear cell carcinoma, on both macroscopic and microscopic examinations. Juvenile granulosa cell tumor is distinguished from clear cell carcinoma by the presence of large follicle-like cysts containing pale-staining, often basophilic, fluid; glandular structures and true papillae are absent. Juvenile granulosa cell tumors also express inhibin and calretinin, and although some may express keratin (and in rare cases, EMA), the expression is generally never as extensive as is seen in most clear cell carcinomas. Estrogenic manifestations may also be present.
Steroid Cell Tumor
Clear cell carcinomas may be mistaken for steroid cell tumors due to their prominent yellow coloration on macroscopic examination and their prominent cytoplasmic clearing on microscopic examination (Fig. 7E); however, most steroid cell tumors have uniform nuclei and lack papillae. Steroid cell tumors are strongly positive for cytokeratin, but these tumors can be distinguished from clear cell carcinoma by their positive reactions with inhibin, calretinin, and SF-1.
Other Miscellaneous Lesions
Papillary clear cell cystadenoma is rare, usually arises in the broad ligament, is typically associated with von Hippel-Lindau syndrome, and is benign.65 The papillary architecture and clear cytoplasm can pose a problem on frozen sections (Fig. 7F), especially if there is no history of von Hippel-Lindau syndrome, but the nuclei are bland, the lesion is small, and other patterns associated with clear cell carcinoma are not seen.
Primary ovarian mucinous carcinoma may occasionally be difficult to distinguish from clear cell carcinoma on frozen sections, particularly as both tend to be unilateral. Most mucinous carcinomas can be identified by the presence of gastrointestinal differentiation: gastric-type glands, goblet cells, etc.
Krukenberg tumors may exhibit tubulocystic patterns and clear cells, whereas clear cell carcinoma may have signet ring-like cells (Fig. 2D). Distribution of disease suggestive of metastasis (eg, bilaterality, extensive lymphovascular space invasion, micronodular pattern) and lack of architectural patterns typically seen in clear cell carcinoma are helpful distinguishing features.
Arias-Stella reaction is discussed in the section on uterine clear cell carcinoma.
UTERINE CLEAR CELL CARCINOMA
Uterine clear cell carcinoma is distinctly uncommon, comprising only 2% to 5% of endometrial carcinomas.66–69 It is considered to be a type II estrogen-independent, nonendometrioid carcinoma on the basis of the proposed dualistic model of endometrial carcinoma.50,61,70 Patients are usually postmenopausal, tend to be older than those with endometrioid carcinoma, but slightly younger than those with uterine serous carcinoma, presenting at a median age of 66 to 68 years.67,69,71 As with uterine serous carcinomas, African American women are more commonly affected. Despite its designation as a high-grade carcinoma, disease is confined to the uterus (stages I to II) in the majority of cases.69 Myometrial invasion is present in approximately 80% of cases and lymphovascular space invasion in approximately 25%.72 Radiation and tamoxifen have been implicated in a subset of these tumors; unlike their cervico-vaginal counterpart, there is no association with diethylstilbestrol (DES).73,74
Pathologic stage and patient age are the most important prognostic factors in uterine clear cell carcinoma.69 Clear cell carcinoma has a propensity for extrauterine spread and is considered to have a worse prognosis than endometrioid carcinoma.69,75 Late stage/recurrent uterine clear cell carcinoma has poor progression-free survival and poor overall survival when compared with endometrioid carcinoma and, possibly, even serous carcinoma.76 Unlike studies on their ovarian counterparts, these observations are not attributed to poorer response to chemotherapeutic regimens.
The natural history and optimal treatment in uterine clear cell carcinoma is not clearly defined. Clear cell carcinoma relapses in the pelvis, para-aortic nodes, and often at distant extrapelvic sites such as the upper abdomen, lungs, or bone. Relapses occur beyond the pelvis more commonly than with endometrioid carcinoma. The standard first line therapy for uterine clear cell carcinoma is total abdominal hysterectomy with bilateral salpingo-oophorectomy and comprehensive surgical staging, with some patients possibly benefitting from adjuvant chemoradiation.75 As with its ovarian counterpart, there is an associated increased risk of thromboembolic events, particularly with higher-stage disease, and there are also rare reports of an association with paraneoplastic hypercalcemia.77,78 A subset has been associated with Lynch syndrome. The data concerning this endometrial histologic subtype are limited by the fact that many of the earlier studies of endometrial serous and clear cell carcinoma combined these 2 histologic subtypes.
Uterine clear cell carcinoma most often forms soft, fleshy masses that involve the endometrial surface, in an indistinct pattern similar to that seen in endometrioid carcinoma. Friable, polypoid masses and tumor confined entirely to an endometrial polyp may also be seen (Fig. 8).79
Uterine clear cell carcinoma shares many histomorphologic features with its ovarian counterpart. Architecturally, the classic tubulocystic, papillary, solid, and mixed patterns are seen (Fig. 3). Papillae are distinct, due to the presence of eosinophilic basement membrane–type material within the connective tissue cores or edematous, so-called “empty” cores (Fig. 4B). Although variable, the characteristic neoplastic cells are polyhedral in shape and contain relatively large amounts of clear to eosinophilic cytoplasm, typically with eccentrically placed nuclei. A subset of hobnail cells and relatively bland, flattened cuboidal cells with minimal cytoplasm may also be present (Fig. 2). The voluminous cytoplasm seen in a subset of the neoplastic cells is because of abundant glycogen; however, a periodic acid-Schiff diastase stain can also highlight intraluminal mucin, or in some cases, inspissated eosinophilic mucin droplets within vacuoles of signet ring-like or “targetoid cells.” Intracytoplasmic mucin is otherwise not seen. Cytology is high grade in most cases with enlarged nuclei and macronucleoli, and mitotic figures are present. As in the ovary, clear cell carcinoma is not assigned a FIGO grade; it is high grade by definition, due to its aggressive clinical behavior. Psammoma bodies may be present in 10% of cases, particularly in papillary areas. Extracellular hyaline bodies have also been noted.80,81
A possible precursor lesion for uterine clear cell carcinoma has been described.82 The precursor cells are distributed among glands and surface epithelium in areas adjacent to the carcinomatous components. They are present as isolated cells or cell clusters with variable clear to eosinophilic cytoplasm and nuclear atypia. These lesions are presently of uncertain clinical significance. It is noteworthy that endometrial hyperplasia has been seen associated with some cases of clear cell carcinoma.61
The immunohistochemical profile of uterine clear cell carcinoma is not as well described as it is for endometrioid and serous carcinomas. In general, clear cell carcinoma is positive for cytokeratins (including CAM5.2 and CK34βE12) and exhibits a CK7+/CK20− cytokeratin profile in the majority of cases. Other epithelial markers such as Leu-M1 and CEA may also be positive, as is vimentin.28 Uterine clear cell carcinoma is usually negative or only weakly positive for hormonal receptors ER and PR, and approximately 50% are positive for p16.61–63 p53 expression has been shown to be greater in uterine clear cell carcinomas than in endometrioid carcinomas, but lower as compared with serous carcinomas, although rates of positivity vary.61,63 Expression of HNF-1β has been observed in uterine clear cell carcinoma, but is also seen in secretory and gestational endometrium, and other extrauterine neoplasms, namely yolk sac tumor and clear cell renal cell carcinoma.34,36,37 Although it has been suggested that HNF-1β may be an excellent marker for clear cell carcinoma, a recent study demonstrated substantial numbers of serous (60%) and endometrioid (35%) carcinomas that also expressed HNF-1β, and this has been our experience with this marker.37,64
Uterine clear cell carcinoma is considered a type II estrogen-independent, nonendometrioid tumor in the dualistic model of endometrial carcinoma.50,61,70,83,84 However, TP53 mutations are less common in uterine clear cell carcinoma (30% to 40%) than in serous carcinoma (90%). In addition, the frequency of both microsatellite instability and PTEN alterations is higher in clear cell carcinoma (15% and 30%) as compared with serous carcinoma (<5% and 10%), but lower as compared with endometrioid carcinoma (20% to 40% and 35% to 50%).83 As with ovarian clear cell carcinoma, mutations of the ARID1A gene (BAF250a protein loss) have been identified in a subset of uterine cases (23% to 26%); however, unlike their ovarian counterpart, a subset of serous carcinomas also demonstrate BAF250a loss.56,85
Many neoplasms and tumor-like lesions of the uterus and cervix possess clear cells that may mimic clear cell carcinoma (Table 1). These entities include serous and endometrioid carcinomas, mesenchymal tumors such as epithelioid leiomyosarcoma and perivascular epithelioid cell tumors (PEComas), non-neoplastic conditions such as endometrial clear cell metaplasia and Arias-Stella reaction, and clear cell carcinoma arising in the cervico-vaginal region. Metastatic clear cell renal cell carcinoma to the uterus is uncommon but is an additional diagnostic consideration and is discussed in the previous section.
The histomorphologic patterns observed in uterine clear cell carcinoma may overlap with those seen in serous carcinoma, including the presence of marked nuclear atypia, hobnail and “eosinophilic” cells, cellular dyshesion, and papillary and simple glandular architectural patterns (Table 8).80,81,86 Both tumors occur in postmenopausal women, often in the setting of atrophic endometria. Although prototypical forms can usually be distinguished, this differential becomes problematic in the cases of serous carcinoma that possess clear cells (Fig. 5).87 Helpful features to distinguish clear cell carcinoma may include the presence of eosinophilic intracytoplasmic globules, papillae with simple, rounded contours and hyalinized or “empty” connective tissue cores, and less cellular tufting and micropapillae (Figs. 2–4). In contrast, uterine serous carcinoma may exhibit more complex architecture, including large and irregularly shaped papillae that show significant stratification, budding, and frequent micropapillae. Cells in clear cell carcinoma typically have sharp cell borders and voluminous cytoplasm in contrast to the high nuclear to cytoplasmic ratios seen in serous carcinoma.
Hybrid morphology, or so-called clear cell carcinoma with serous features (or vice versa) is sometimes present, in addition to composite tumors with mixtures of both tumor types.61 Assignment to one or the other groups in these situations is highly subjective and not reproducible. From a primary disease management standpoint, this distinction may be of no significance, as both are clinically aggressive, high-grade tumors and are staged in a similar manner. That said, the presence of a bona fide clear cell component should be diagnosed as such (either pure or mixed), given the potential increased risk for thromboembolism. There are currently no reliable markers available to distinguish between uterine clear cell and serous carcinomas. They both show weak to negative expression with ER and PR, and although strong and diffuse p53 or p16 expression would favor serous carcinoma, these markers can also be expressed in uterine clear cell carcinoma. Ki67 index appears to be higher in serous carcinoma as compared with clear cell carcinoma, but comparative studies have been based on tumors with classic morphology, and the utility of this in the problematic tumor is uncertain.61,62 WT1 is not reliably expressed in serous tumors of the uterus.34,88
Endometrioid carcinomas of the female genital tract may exhibit prominent cytoplasmic clearing; this is most commonly encountered in (1) “secretory carcinoma”; (2) endometrioid tumors with glycogenated squamous metaplastic cells; and (3) endometrioid tumors with clear cells, not otherwise specified (Fig. 7A, B) (Table 6).60,81,86,89 The distinction between secretory carcinoma and clear cell carcinoma is based foremost on cytology and the presence or absence of other distinctive architectural patterns seen in clear cell carcinoma. Carcinomas with glycogenated squamous metaplastic cells will almost always have other areas of typical squamous metaplasia, as will most cases of endometrioid carcinomas with clear cells, not otherwise specified. In general, features favoring an endometrioid tumor are relative maintenance of ovoid to columnar shape of tumor cells, presence of squamous metaplasia, cribriform architecture, and absence of the typical architectural patterns and high-grade cytology as seen in clear cell carcinoma.
Diagnostic difficulty often arises when a neoplasm with endometrioid features merges with solid areas that contain a component with clear cell morphology. In this situation, the distinction between a mixed endometrioid and clear cell carcinoma, and an endometrioid carcinoma with clear cells can be quite subjective, particularly when the endometrioid component is of high grade. As this distinction is particularly difficult on a limited endometrial sampling, the possibility of a clear cell carcinoma should be mentioned in the report to guide surgical management. The use of immunohistochemistry is limited in this setting.61–63
Many uterine clear cell carcinomas may also be mixed with endometrioid carcinomas, and these tumors appear to have a similar prognosis to pure clear cell carcinoma, although this phenomenon is not well studied.80,90 In this scenario, we diagnose both components and assign an overall grade reflective of the higher-grade clear cell component.
Epithelioid smooth muscle tumors and some PEComas with prominent cytoplasmic clearing (Fig. 9A) may mimic a clear cell carcinoma in limited uterine samplings.91,92 Features favoring a mesenchymal lesion include a myometrial-based tumor, absence of a glandular component, presence of spindle cell areas, and absence of characteristic clear cell carcinoma morphology. Reactivity with smooth muscle markers and HMB45 in the case of PEComa would also favor these diagnoses. A potential pitfall in this scenario is relying on cytokeratin or p16 positivity to point toward carcinoma, as these markers can also be positive in epithelioid smooth muscle tumors.93,94
Other tumors that may rarely contain clear cells but that do not typically pose a diagnostic difficulty include endometrial stromal tumors, placental site trophoblastic tumor, and alveolar soft part sarcoma.81
Clear cell change may be prominent in both secretory and nonsecretory (clear cell metaplasia) endometria; however, there should not be architectural or cytologic atypia. Pseudopapillary patterns may be present, but true papillae or solid patterns as seen in clear cell carcinoma are absent. Endometrial hyperplasias may also display cells with cytoplasmic clearing, but are distinguished by adjacent areas of more typical endometrial hyperplasia with or without squamous morules. Most hyperplasias should express ER and/or PR.
Arias-Stella reaction is notable for nucleomegaly and bizarre nuclei, features that can be mistaken for those of clear cell carcinoma (Fig. 9B).86 Women with Arias-Stella reaction are usually in their reproductive years, pregnant or have a history of recent pregnancy, or have been treated with hormonal therapy. In contrast, most women with uterine clear cell carcinoma are postmenopausal. Occasionally, Arias-Stella-like reaction is seen in postmenopausal women. In this situation, the distinction between Arias-Stella and clear cell carcinoma may be problematic. However, the cells in Arias-Stella reaction are either not mitotically active or feature only rare mitotic figures and the nuclei show degenerative features with pseudoinclusions. Glandular or tubulocystic architecture may be seen in Arias-Stella, but papillary architecture is absent. A mass lesion is absent and an accompanying stromal predecidual reaction is helpful when present (Fig. 9B). Most importantly, other typical patterns of clear cell carcinoma are not seen.
Reactive clear or hobnail cells may be seen in association with stromal breakdown or areas of infarction. These changes are typically focal, are seen in the context of other reactive changes such as syncytial metaplasia, and are present within a spectrum of otherwise benign cellular alterations.
Cervical Clear Cell Carcinoma
Cervical clear cell carcinoma has historically been linked to in utero DES exposure.73,95 Exposure to this teratogen is now almost nonexistent; however, primary cervical tumors still occur. The histologic and immunophenotypic features are not dissimilar from those that arise in the endometrium, and assigning a primary site is not possible without clinical correlation and imaging studies.
CERVICO-VAGINAL CLEAR CELL CARCINOMA
The association between cervico-vaginal clear cell carcinoma and in utero DES exposure was convinicingly documented in the 1970s when these lesions began to be noted disproportionately in young women.95 Exposed individuals develop clear cell carcinoma at a peak age of 19 years, although the increased risk persists in later years, necessitating continued follow-up. Non–DES-associated cases occur over a wide age range, affecting pediatric to postmenopausal populations. The overall incidence of daughters exposed to DES is approximately 1/1000.96 The rarity of this lesion even in this exposed population suggests that DES is an incomplete carcinogen. Other risk factors implicated in the development of cervico-vaginal clear cell carcinoma include history of spontaneous abortion or premature births in the patients’ mothers.97 More recent cases of cervico-vaginal clear cell carcinoma are predominantly non–DES associated (Fig. 10). When they occur in the cervix, they have the same prognosis when controlled for stage as the usual cervical carcinoma. Although the literature is conflicting, neither DES nor non-DES cervical clear cell cancers appear to have a strong association with high-risk human papillomavirus.98–100
DES-associated clear cell carcinoma typically arises in the anterior upper third of the vagina (2/3) or ectocervix (1/3). In contrast, non–DES-associated cancers develop predominantly in the endocervix and/or ectocervix (Fig. 10).101 Vaginal lesions are associated with adenosis in 90% of cases, suggesting that adenosis (atypical adenosis) may represent a precursor lesion. Vaginal bleeding is a common presentation, although many small tumors are asymptomatic, requiring exfoliative cytology for detection.
Low-stage vaginal clear cell carcinoma is most commonly treated with radical hysterectomy, partial or complete vaginectomy, and lymphadenectomy, although combinations of less extensive surgery and radiotherapy may also be used.102 Vaginal lesions progress primarily through local invasion or lymphatic spread. The overall recurrence rate is 25%, most occurring within 3 years after therapy.
Stage is the most important prognostic marker. The 5-year survival for FIGO stage I cancers approaches 100%. Non–DES-associated cancers have lower 5-year survival rates (69%) compared with DES-associated cancers (84%).98,103 However, non–DES-associated cervical cancers appear to have a similar prognosis as compared with stage-matched usual cervical adenocarcinomas.
Lesions are typically polypoid, nodular, or papillary, but may also be flat or ulcerated. Cervico-vaginal clear cell carcinomas have a similar appearance to those in the ovary and endometrium with tubulocystic, papillary, solid, and mixed growth patterns (Fig. 3). The cytologic features are also similar (Fig. 2). Adenosis, which may be atypical, is often discovered adjacent to the carcinoma in DES-associated tumors.
Immunohistochemical features do not appear dissimilar to those in the uterine corpus.
The differential diagnosis of cervico-vaginal clear cell carcinoma includes serous carcinoma, yolk sac tumor, and alveolar soft part sarcoma (Fig. 11A). The differential with Arias-Stella reaction has also been discussed (see non-neoplastic conditions under endometrial clear cell carcinoma). Microglandular hyperplasia usually occurs in the cervix but occasionally occurs in the vagina within areas of adenosis. Microglandular hyperplasia consists of tightly packed glands without intervening stroma and may be confused with glandular portions of clear cell carcinoma (Fig. 11B). These lesions typically lack the degree of nuclear atypia seen in clear cell carcinoma and contain mucin, often forming subnuclear vacuoles. Mesonephric remnants may also mimic clear cell carcinoma at low magnification, but again lack nuclear atypia when assessed at high magnification.
PERITONEAL CLEAR CELL CARCINOMA
Peritoneal clear cell carcinoma is rarely encountered. Less than 10 cases have been described in the English literature.104–110 Associations with and without endometriosis have been reported, but the association is not nearly as strong as with ovarian clear cell carcinoma. At least 1 reported case may have represented a metastasis from low-stage endometrial clear cell carcinoma, whereas another may have been associated with ovarian endometriosis with possible transfer to the peritoneum.106 The morphologic features are similar to those that occur elsewhere in the female genital tract.
The authors wish to acknowledge Norm Cyr for assistance in figure preparation.
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