Morphologic, Immunophenotypic, and Molecular Features of Epithelial Ovarian Cancer

February 16, 2016
Preetha Ramalingam, MD

This review focuses on the clinicopathologic and molecular features of epithelial ovarian cancer, with specific attention to genetic predisposition, morphologic challenges, immunohistochemistry, and molecular features.

Epithelial ovarian cancer comprises a heterogeneous group of tumors. The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor. While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively resistant to chemotherapy. It is now well-accepted that high-grade and low-grade serous carcinomas represent distinct entities rather than a spectrum of the same tumor type. While they are similar in that patients present with advanced-stage disease, their histologic and molecular features are entirely different. High-grade serous carcinoma is associated with TP53 mutations, whereas low-grade serous carcinomas are associated with BRAF and KRAS mutations. Endometrioid and clear cell carcinomas typically present as early-stage disease and are frequently associated with endometriosis. Mucinous carcinomas typically present as large unilateral masses and often show areas of mucinous cystadenoma and mucinous borderline tumor. It must be emphasized that primary mucinous carcinomas are uncommon tumors, and metastasis from other sites such as the appendix, colon, stomach, and pancreaticobiliary tract must always be considered in the differential diagnosis. Lastly, transitional cell tumors of the ovary, specifically malignant Brenner tumors, are quite uncommon. High-grade serous carcinoma often has a transitional cell pattern, and adequate sampling in most cases shows more typical areas of serous carcinoma. Immunohistochemical markers are routinely employed in the diagnosis of epithelial ovarian carcinomas. However, molecular testing of these tumors, unlike in endometrial carcinoma, is not routinely used in clinical practice.

Introduction

Ovarian cancer is the second most common cancer of the female genital tract. In the United States, it is responsible for more cancer deaths than all other gynecologic tumors.[1] Malignant epithelial tumors are the most common type of ovarian cancer and comprise almost 90% of cases.[2-4] The treatment of ovarian cancer has been based mainly on tumor grade and stage, but it is now apparent that the histologic subtype is just as important in patient management. The various histologic subtypes are different in terms of risk factors, precursor lesions, clinical course, patterns of spread, molecular genetics, response to conventional chemotherapy, and prognosis.[2-4] Hence, it is imperative to accurately subtype these tumors based primarily on morphology and immunohistochemistry tests, when necessary. We now know that high-grade serous carcinoma (HGSC), the most common subtype of epithelial ovarian carcinoma, is a different disease from low-grade serous carcinoma (LGSC). HGSC presents in older women and responds at least initially to chemotherapy but has a worse overall prognosis than LGSC. In contrast, LGSC presents in younger women and does not respond well to chemotherapy but has a better prognosis.[5-8] Endometrioid adenocarcinoma (EC) and clear cell carcinoma (CCC) typically present as stage I/II disease and are frequently associated with pelvic endometriosis. Lastly, mucinous carcinoma (MUC) of the ovary is a fairly uncommon disease if metastasis has been excluded, and its outcome is highly variable, based on stage at presentation and type of invasion.[9-11] This review focuses on the clinicopathologic and molecular features of epithelial ovarian cancer, with specific attention to genetic predisposition, morphologic challenges, immunohistochemistry, and molecular features.

Hereditary Ovarian Cancer

In young women with HGSC or CCC, the possibility of hereditary conditions such as BRCA1 or BRCA2 mutations or Lynch syndrome must be considered. While the majority of ovarian cancers are sporadic, family history is one of the strongest risk factors. Of these hereditary conditions, breast and ovarian cancer syndrome associated with germline mutations in the BRCA1 and BRCA2 tumor suppressor genes, and hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) associated with germline mutations in the DNA mismatch repair genes, are the most studied to date.[12] Overall, approximately 10% of ovarian cancers are hereditary; 90% of these hereditary tumors are associated with BRCA mutations and the remainder are related predominantly to HNPCC syndrome.[12] Two large meta-analyses have shown that the cumulative risk of developing ovarian cancer is higher in patients with BRCA1 mutations compared with those with BRCA2 mutations. Antoniou et al performed a meta-analysis on 22 studies and found that the cumulative risk for ovarian cancer was 39% in patients with BRCA1 mutation and 11% in patients with BRCA2 mutation, by the age of 70 years.[13] Chen and colleagues reviewed 10 studies and estimated the cumulative risk to be 40% for BRCA1 mutation carriers and 18% for BRCA2 mutation carriers, again by 70 years of age.[14] Studies have shown the incidence, clinical features, and outcomes of ovarian cancer to be different in patients with BRCA1 mutation compared with BRCA2 mutation carriers and patients with sporadic ovarian cancers.[15-18] Patients with BRCA-related ovarian cancers have been shown to present at a more advanced disease stage, but they respond better to platinum-based chemotherapy and have longer disease-free intervals and overall survival compared with patients with sporadic cancers.[17,18] Reitsma et al, in a study of 55 cases of BRCA1 mutation carriers and 16 cases of BRCA2 mutation carriers, found that patients with BRCA2 mutations tended to have longer time to first relapse and fewer relapses.[19] BRCA2 mutation carriers had longer disease-free and overall survival compared with BRCA1 mutation carriers; however, the authors noted that these findings were not statistically significant, perhaps due to small sample size.[19] In terms of histologic subtype, tumor grade, and International Federation of Gynecology and Obstetrics (FIGO) stage, no significant differences have been reported between BRCA1 and BRCA2 mutation carriers.[18-20]

With regard to ovarian cancer in Lynch syndrome patients, several series have been published.[21-27] In separate studies, Bonadona et al and Engel et al reported a lifetime ovarian cancer risk of 8% in patients with Lynch syndrome.[25,26] Watson et al analyzed Lynch syndrome registries in Denmark, Holland, Finland, and the United States, reporting a 6.7% overall risk of ovarian cancer among these patients.[27] Watson et al also found that these patients were diagnosed with ovarian cancer at a younger age than the general population (mean age at diagnosis, 43 years vs 59 years) and that 22% of these patients presented with synchronous endometrial cancer.[27] Screening and surveillance for patients with hereditary ovarian cancer has been a challenge, and currently there are no definite recommendations based on randomized prospective data.[23] There are no reliable screening methods for ovarian cancer, since cancer antigen 125 (CA-125) is highly nonspecific for ovarian cancer, and radiologic evaluation is neither feasible nor sensitive. In patients with BRCA1/2 mutations or deleterious mutations associated with Lynch syndrome who have completed childbearing, risk-reducing prophylactic hysterectomy with bilateral salpingo-oophorectomy (BSO) in the former, and BSO in the latter, are typically recommended.[23] Meta-analysis of 10 studies by Rebbeck et al showed an approximately 80% reduction in ovarian and fallopian tube cancer in patients who underwent risk-reducing BSO.[28] The current National Comprehensive Cancer Network guidelines recommend risk-reducing BSO in women “ideally between 35 and 40 years, and upon completion of childbearing, or individualized based on earliest age of onset of ovarian cancer in the family.”[29]

Overview of Common and Uncommon Subtypes of Epithelial Ovarian Cancers

Of the most common histologic subtypes of ovarian cancer, serous carcinoma occurs most often, followed by CCC and EC, which are diagnosed with almost equal frequency. Seidman et al found that among 220 consecutive patients with surface epithelial carcinoma, almost 80% of cases of intra-abdominal carcinomatosis were of serous histology, especially when peritoneal carcinomas, carcinosarcomas, and mixed carcinomas with serous component were included.[30] Thus, it is now well-established that serous carcinomas represent the majority of advanced-stage ovarian cancers. The second most common subtype has been variable between EC and CCC.[4,31,32] In the previously described study by Seidman et al, CCC was found to be the second most common ovarian carcinoma, followed by EC.[32] The reason for these differences could be overlapping features between HGSC and EC. Primary ovarian MUC, previously considered to be the second most common epithelial ovarian tumor, is now known to be much less common, because the majority of these tumors represent metastases.[33] Familiarity with the morphologic spectrum of metastatic tumors in the ovary and use of immunohistochemistry has resulted in a marked decrease in the reported incidence of primary ovarian MUCs.[33-35] Other subtypes include transitional cell carcinomas, mixed carcinomas, and undifferentiated carcinomas. Less common are tumors such as squamous cell carcinoma, papillary thyroid carcinoma, sebaceous carcinoma, and carcinoid tumors that are typically associated with mature cystic teratomas; these tumor types are beyond the scope of this review. Briefly, the management of ovarian carcinoma has evolved significantly in the past decade-from primary definitive surgery and debulking followed by chemotherapy, to treating patients with neoadjuvant chemotherapy, especially in the setting of miliary disease that cannot be optimally debulked.[36,37] Pathologic review of post-treatment resections poses some problems-including typing of tumors that have undergone therapy-related changes, such as marked atypia and clear cell changes, as well as identifying minimal residual disease in the presence of inflammation and necrosis.

Ovarian Serous Carcinoma

HGSCs are characterized by papillary (Figure 1A), glandular, solid, and transitional (Figure 1B) patterns. The diagnosis of HGSC is typically straightforward, especially when there is a predominantly papillary pattern with associated psammoma bodies. The solid pattern can cause difficulty in distinguishing HGSC from EC. However, morphologic features such as glands that are slit-like rather than smooth/round, with prominent cellular budding and bizarre nuclei, are more typical of serous carcinoma. ECs, on the other hand, are associated with squamous differentiation, adenofibromatous background, and endometriosis. Furthermore, staining for the Wilms tumor 1 (WT1) protein, a characteristic immunohistochemical marker of serous neoplasms, can assist in making the correct diagnosis, since ECs are typically negative or only weakly positive for this marker.[38] Other useful immunohistochemical markers include p16 and p53, both of which are more likely to be diffusely and strongly positive in HGSC rather than EC.[39,40]

As previously noted, it is now well-established that HGSC and LGSC represent two distinctly different disease entities rather than grades of the same tumor.[3,6-8,41-43] Serous carcinomas were traditionally graded as well-differentiated, moderately differentiated, and poorly differentiated. However, in 2004 Malpica et al proposed a two-tier grading system that assesses only nuclear atypia and mitotic activity; this approach has since been found to be highly reproducible and is now fairly widely accepted.[42,44] Based on this system, HGSCs are characterized by marked nuclear pleomorphism (nuclei 3 times the size of others) and mitotic activity of > 12 mitoses per 10 high-power fields. LGSC, on the other hand, is characterized by tumor cells with relative nuclear uniformity, absence of nuclear pleomorphism, and mitotic activity typically < 12 mitoses per 10 high-power fields. The tumors are generally characterized by micropapillae surrounded by clear spaces (Figure 1C); however, glandular, macropapillary, and single cell patterns can also be seen.

Although HGSCs are thought to arise from the ovarian surface epithelium or cortical inclusion cysts, no definite precursor lesions have been identified. There is emerging evidence that the majority of ovarian HGSCs arise from the epithelium of the fimbrial end of the fallopian tube.[45-49] Evidence for this lies in the detection of serous tubal intraepithelial carcinoma (STIC) in the fallopian tubes of asymptomatic BRCA mutation–positive women,[50] as well as identifying STIC in patients with advanced-stage ovarian cancer.[51] Recent studies suggest the presence of a dualistic model of HGSC-that is, patients whose tumors had a pseudoendometrioid morphology that was less likely to be associated with STIC vs patients whose tumors had a more classic morphology that was frequently associated with STIC.[52] This is an evolving area of investigation, and it would be reasonable to suggest that at least a subset of ovarian and pelvic HGSCs arise from the fallopian tube epithelium.

Conversely, LGSC is thought to arise from preexisting cystadenoma or serous borderline tumor (SBT) that eventually progresses to invasive carcinoma. While the majority of typical SBTs do not show frankly invasive carcinoma, microinvasion is not uncommon. In some reports, LGSC has been associated with SBT in up to 60% of cases.[53] There are important considerations regarding the micropapillary pattern in SBT: While some authors propose using the term “micropapillary serous carcinoma,” most acknowledge that the micropapillary pattern must be noted in the patient report rather than labeling it as a carcinoma, given that this pattern is frequently associated with bilateral ovarian involvement, surface involvement, and peritoneal implants.

Although patients with low-grade neoplasms usually have recurrences that are low-grade tumors, we have encountered cases of LGSC either coexisting with HGSC or recurring as HGSC. Boyd and McCluggage have reported seven cases of LGSC that either coexisted with HGSC or recurred as either HGSC or undifferentiated carcinoma.[5] Close examination of the tumor is recommended, since the areas of HGSC may be focal or admixed with areas resembling SBT.

In most cases, immunohistochemical stains are not necessary for making a diagnosis of either HGSC or LGSC. However, they are useful in the assessment of post-therapy specimens, in which CCC is often considered in the differential diagnosis, or when a diagnosis must be made using small biopsies. As previously mentioned, most patients with peritoneal carcinomatosis are likely to receive neoadjuvant chemotherapy, so establishing a diagnosis of a Müllerian/gynecologic primary based on a limited biopsy is becoming standard practice. Typically only a small amount of tumor is present in these biopsies, and numerous immunohistochemical tests are often performed to exclude other entities. Both HGSCs and LGSCs have some overlapping characteristics, as well as some distinct immunophenotypic features. Both tumor types are positive for paired box gene 8 (PAX8) and WT1 expression, as well as estrogen receptor (ER) and progesterone receptor (PR) expression. When the morphologic features are suggestive of serous carcinoma, use of these four markers is sufficient to establish the diagnosis in most cases, and an extensive panel of immunomarkers is usually not necessary. In small biopsies, mesothelioma can enter the differential diagnosis; PAX8, MOC-31, Ber-EP4, and ER are useful markers because they are positive in HGSC but not in mesotheliomas.[54-56] In small-core biopsies with limited tumor, accurate grading may not be possible in some cases. Immunohistochemical stains for p16, p53, and Ki-67 are helpful, since HGSCs show diffuse staining for p16 and p53 and an elevated Ki-67 proliferation index, whereas LGSCs show patchy staining for p16, wild-type staining for p53, and a low Ki-67 proliferation index.[38,57,58] This panel is also helpful in detecting focal HGSC in the background of a tumor that is predominantly an LGSC. The immunophenotypes of the major epithelial ovarian cancer types are summarized in Table 1.

The molecular features of HGSC and LGSC are distinctly different. HGSC is associated with TP53 mutations or p53 dysfunction in almost all cases. Ahmed et al identified TP53 mutations in almost 97% of 145 patients with HGSCs.[59] In mutation-negative cases, p53 dysfunction associated with copy number gain in MDM2 or MDM4 was noted, or the cases were excluded because they represented LGSCs or other malignancies. Therefore, the mutation status in these tumors almost approached 100%. LGSC is typically associated with mutations in either KRAS or BRAF, but mutations in HER2 have also been reported.[42,60,61] Mutations of KRAS and BRAF are mutually exclusive; only one of these mutation types is present in a given tumor.

Lastly, from a clinical standpoint, although LGSC presents in younger women and is resistant to chemotherapy, overall survival is better than that of patients who have HGSC.[7,8,41,62] While HGSC responds well to chemotherapy initially, patients frequently experience recurrence and succumb to the disease. Recent Gynecologic Oncology Group 10-year follow-up data suggest improved survival with intraperitoneal chemotherapy in optimally debulked patients with HGSC who still had gross residual disease (< 1.0 cm).[63]

Endometrioid Adenocarcinoma

EC of the ovary is usually associated with endometriosis or an endometrioid adenofibroma/borderline tumor. It typically presents as a unilateral mass confined to the ovary-that is, as stage I disease. The diagnosis of EC in the majority of cases is based on the presence of back-to-back glands rather than infiltrative invasion (Figure 1D). Several characteristic histologic features are seen in EC, including squamous morules, mucinous differentiation, clear cell change, spindle morphology, and secretory change, with the latter sometimes mimicking CCC. The most important differential diagnosis for EC is metastatic colonic adenocarcinoma; the distinction between these two cancers can be made with immunohistochemical stains, since EC is positive for cytokeratin 7 (CK7), PAX8, ER, and PR, while colonic adenocarcinoma is positive for cytokeratin 20 (CK20) and caudal-type homeobox 2 (CDX2) protein. Of note, CDX2 can be positive in the squamous morules of EC.[64] Distinguishing high-grade EC from HGSC can be difficult, especially when the tumor is predominantly solid. Immunostains for WT1, p53, and p16 are helpful; these markers are usually diffusely and strongly positive in HGSC, while WT1 staining is negative in EC, which also shows patchy staining for p16 and wild-type staining for p53.[38,39,58,65-67]

Lastly, it is important to mention the concept of de-differentiated carcinoma, which is the presence of an undifferentiated carcinoma adjacent to a low-grade EC.[68] These tumors are often misdiagnosed as EC, FIGO grade 3. The entity was first described by Silva and colleagues, who found that the presence of the undifferentiated carcinoma component in ovarian and endometrial endometrioid carcinoma, regardless of the percentage, conferred a much worse prognosis.[69,70] In the ovary, such tumors may represent the far end of the spectrum of HGSC carcinoma or can be associated with low-grade EC. Undifferentiated carcinoma is characterized by the presence of discohesive, monotonous cells resembling lymphoma. Recognizing the morphologic features of these tumors-particularly when associated with low-grade EC-is important, given that these patients have a significantly worse prognosis. Undifferentiated carcinoma can express neuroendocrine markers, but the staining is typically less than 10%. Diffuse staining for neuroendocrine markers favors diagnosis of a high-grade neuroendocrine carcinoma.[71] EC, especially when confined to the ovary, has an excellent prognosis. If patients have been adequately staged, close follow-up is an acceptable therapeutic option.

Approximately 10% of patients with ovarian cancer present with synchronous endometrial tumors.[72-74] These can represent metastasis from the ovary or endometrium to either site, or may be synchronous ovarian and endometrial primaries. Histologic features that favor synchronous primaries include: (1) histologic dissimilarity of tumors, (2) noninvasive or superficially invasive endometrial tumor, (3) no lymphovascular space invasion, (4) no surface involvement in the ovarian tumor, (5) presence of ovarian endometriosis, and (6) absence of spread of either tumor type to other sites. Conversely, a deeply invasive myometrial tumor with lymphovascular invasion, bilateral multinodular ovaries with hilar and surface involvement, or direct extension to adnexa and absence of ovarian endometriosis would favor a diagnosis of metastasis from the endometrial primary. Despite these established criteria for diagnosis, in some cases it is not possible to determine the primary site with certainty.[73] In such cases the pathologist can, at best, favor one site over another, and can explain the challenges precluding definite distinction between metastasis and synchronous ovarian and endometrial primaries. Soliman and colleagues found that patients with synchronous endometrial and ovarian primaries had distinct clinical characteristics, such as younger age, nulliparity, obesity, and premenopausal status.[73] They also found that patients with synchronous primaries had an excellent overall survival approaching 10 years, especially when both tumors had endometrioid histology.

Ovarian ECs are most commonly associated with somatic mutations of the catenin β1 (CTNNB1) and phosphatase and tensin homolog (PTEN) genes.[75] When compared with endometrial EC, ovarian ECs have a similar frequency of CTNNB1 abnormalities, but microsatellite instability and PTEN alterations are less common.

Clear Cell Carcinoma

CCC comprises approximately 10% of ovarian carcinomas. CCCs are often associated with endometriosis, similar to EC. They are rarely bilateral, and patients usually present with stage I or II disease. Histologically, CCCs are characterized by solid, papillary, and tubulocystic patterns (Figure 2A). The papillae are typically short with hyalinized fibrovascular cores and are lined by hobnail cells with clear cytoplasm (Figure 2B). The nuclei of CCC are usually uniformly atypical, with large nucleoli; notably, bizarre atypia is not frequently identified in HGSC.[3,4,76] The diagnosis of CCC is challenging because both EC and HGSC can have prominent clear cell change, particularly in the solid and papillary areas. Studies have shown that tumors with clear cell change without the characteristic architectural pattern of CCC likely represent either EC or HGSC.[77,78] Clear cell change is also a common histologic feature associated with therapy effect; therefore, careful consideration of architectural and cytologic features is necessary prior to making a diagnosis of CCC. Immunohistochemical stains may be helpful in the differential diagnosis. CCCs are typically negative for WT1 and ER staining, whereas HGSCs are positive for both markers and ECs are positive for ER. Other markers that have recently been reported to be positive in CCC include hepatocyte nuclear factor-1 beta (HNF1β) (Figure 2C) and napsin A (Figure 2D).[79-83] In a study of 279 ovarian tumors, Fadare et al found HNF1β and napsin A to be expressed in 92% and 82%, respectively, of 65 cases of CCC; in 7% and 1%, respectively, of 101 serous carcinomas; and in 37% and 5.3%, respectively, of 19 patients with EC.[79] While HNF1β was a highly sensitive marker, its specificity was low. The converse was true of napsin A. In our experience, use of a panel of markers that includes WT1, ER, HNF1β, and napsin A is optimal when trying to establish a diagnosis of CCC and exclude it from other tumors with clear cell change.

The most common molecular genetic alterations in ovarian CCC include somatic inactivating mutations of AT-rich interactive domain 1A (ARID1A), activating mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and deletion of PTEN. The latter suggests that an aberrant PI3K/PTEN pathway plays a role in the development of CCC.[84,85] Wiegand and colleagues showed that ARID1A mutations were present in 55 of 119 (46%) ovarian CCCs.[86] In their study, two cases showed ARID1A mutations and loss of BAF250a expression in tumor, as well as contiguous foci of atypical endometriosis but not in distant endometriosis; therefore, they postulated that ARID1A mutations represent an early event in transformation of endometriosis to carcinoma.

Although the outcome for early-stage CCC is favorable, patients with advanced-stage disease have a poor prognosis. Additionally, CCC does not respond well to conventional chemotherapy, further contributing to poor overall outcomes.

Mucinous Carcinoma

As previously mentioned, primary ovarian MUC is now known to be an uncommon tumor. The reason for overdiagnosis of primary ovarian MUC in the past was the lack of a means to reliably distinguish them from metastatic tumors, particularly from the gastrointestinal tract. Improved understanding of the gross, morphologic, and immunohistochemical features of primary and metastatic mucinous tumors of the ovary over the past few decades has now resulted in a much lower reported incidence of primary MUC, estimated to be approximately 3%.[4,32,33] From a gross examination perspective, primary MUC is usually considered when the patient presents with a large unilateral mass. Metastasis is considered with bilateral small multinodular ovaries. However, unilateral large tumors can represent metastasis from the appendix, colon, and pancreas, rather than ovarian primaries; therefore, careful histologic evaluation is necessary.

Ovarian MUCs often show a spectrum of changes that include areas resembling cystadenoma and borderline tumor. MUCs can show two patterns of invasion, namely expansile type (Figure 3A) and infiltrative type (Figure 3B). The expansile pattern is characterized by the presence of back-to-back glands, with minimal to no intervening stroma measuring at least 5 mm in one dimension. In addition, there is no evidence of stromal invasion or desmoplastic reaction. Infiltrative invasion is characterized by the presence of infiltrating glands with associated desmoplasia.

Histologically, there are two major types of MUC and mucinous borderline tumor (MBT): intestinal and endocervical. The intestinal type often has goblet cells but this is not required for diagnosis, since the epithelium may resemble pancreatic- or gastric-type epithelium. Endocervical MBT is much less common than the intestinal type, and its malignant counterpart, seromucinous carcinoma (SMC), is even less common. The revised World Health Organization (WHO) Classification of Tumours of the Female Reproductive Organs defines SMC as “a carcinoma composed predominantly of serous and endocervical-type mucinous epithelium” and states that “foci containing clear cells and areas of endometrioid and squamous differentiation are not uncommon.”[87] SMC is a relatively newly described entity. The largest series was recently reported by Taylor et al.[88] The authors found that almost half of the 19 cases they studied occurred in women younger than 40 years of age, and (unlike intestinal-type MUC) the tumors were bilateral in one-sixth of cases. The tumors were composed of endocervical-like mucinous, endometrioid, and eosinophilic “indifferent” (serous-like) cells. However, hobnail cells, squamous cells, clear cells, and signet ring cells were also identified in a subset of cases. An acute inflammatory infiltrate is often seen within the epithelium. These tumors are frequently associated with endometriosis.

Distinguishing primary from metastatic MUC can be particularly challenging on the basis of morphology alone. Histologic features such as intraluminal necrotic debris are characteristic of metastatic colonic carcinoma, and the presence of pseudomyxoma ovarii/peritonei is almost always associated with an appendiceal primary (Figure 3C). Immunohistochemical stains can be helpful in distinguishing primary MUC, intestinal type, from metastases (Table 2). CK7 and CK20 are often employed in this differential, since primary ovarian MUCs are typically diffusely positive for CK7 and only focally positive for CK20, but the converse is true for metastasis from the appendix and lower gastrointestinal tract.[29,32,89,90] CDX2 is often positive in ovarian MUCs and limits its utility in this differential.[90] Right-sided microsatellite unstable colonic adenocarcinomas can be diffusely positive for CK7 and negative for CK20, and this must be taken into consideration when interpreting these stains.[91] Distinguishing primary ovarian MUC from pancreaticobiliary tract primary can be quite challenging due to overlapping morphologic features (Figure 3D) and is often a diagnosis of exclusion.[92,93] Both aforementioned tumors are positive for CK7 and negative for CK20, thus other markers are necessary. Ovarian MUCs can be positive for PAX8 and ER; however, the low sensitivity of these markers limits their utility. Similarly, while expression of SMAD4 or DPC4 is lost in about 50% of pancreatic cancers, ovarian MUCs typically retain expression of this marker. Thus, SMAD4 is useful only when there is negative staining in the tumor cells.[92] Despite several immunomarkers now available, in some cases it is not possible to distinguish primary from metastatic tumors, and correlation with clinical and radiologic findings becomes necessary to determine the primary site. Endocervical-type/SMC ovarian tumors have a Mullerian phenotype, in that they are diffusely positive for PAX8, ER, and PR. The main differential diagnosis for SMC is EC. However, EC can have significant mucinous differentiation, and in this case, the distinction is both challenging and somewhat arbitrary.[88] Both SMC and EC arise in the background of endometriosis, and in many cases the diagnosis of malignancy is made based on the presence of back-to-back glands, similar to the expansile pattern of invasion in MUC, rather than on destructive stromal invasion. In the few case series reported, the prognosis of stage I SMC appears to be favorable; however, patients with advanced-stage disease are expected to have a worse outcome.[88,94,95]

Molecular alterations in ovarian mucinous neoplasms are limited primarily to KRAS mutations, which can be seen in benign, borderline, and carcinoma components within the same tumor.[96-98] Stage I MUC, intestinal type, has a favorable prognosis overall; however, recurrences have been reported. Advanced-stage ovarian MUCs are uncommon but nevertheless respond poorly to chemotherapy and usually have an adverse outcome. The infiltrative type of invasion, even when focal, has a much worse prognosis than the expansile pattern of invasion; thus, the importance of tumor sampling cannot be overemphasized.[99]

Transitional Cell Tumors

Transitional cell neoplasms comprise approximately 1% to 2% of ovarian tumors. They are broadly classified as benign, borderline, and malignant Brenner tumor; and transitional cell carcinomas (TCCs).[100,101] Malignant Brenner tumor is characterized by the presence of epithelium resembling urothelial neoplasms and shows the presence of stromal invasion. Most importantly, when diagnosing this subtype, areas of benign Brenner tumor must be identified and metastasis from the urinary tract should be excluded.[100,101] TCC, on the other hand, is now widely considered to be a variant of HGSC and is typically positive for WT1, further supporting this impression.[100] Furthermore, similar to HGSC, TCCs typically overexpress p53 and p16 and are ER-positive. Patients with malignant Brenner tumors usually present with stage I disease and have excellent 5-year survival; in contrast, survival rates for patients with TCCs are similar to those for advanced-stage HGSCs.[102]

Published reports indicate that malignant Brenner tumors show activation of the PI3K/AKT signaling pathway through epidermal growth factor receptor (EGFR), while TCCs are high-grade tumors with p53 mutations.[103]

Conclusions

In summary, epithelial ovarian neoplasms are a heterogeneous group of tumors, with subtypes that have distinct clinicopathologic and molecular features. Familiarity with the unique morphologic features of each subtype, as well as overlapping microscopic features, will allow accurate diagnosis. Problematic areas in diagnosis usually involve distinguishing HGSC from high-grade EC, undifferentiated carcinoma, and tumors with clear cell change. In challenging cases, judicious use of immunohistochemical stains is recommended. The need for accurate histologic typing is particularly important in the current era of personalized therapy, in which many patients are participating in clinical trials that often have histologic type as a selection criterion. Unlike endometrial cancer, molecular testing of ovarian cancer is not currently part of routine practice; however, ongoing research and clinical trials may identify actionable biomarkers in the future.

Financial Disclosure:The author has no significant financial relationship with the manufacturer of any product or provider of any service mentioned in this article.

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