Ovarian cancer is heterogeneous disease, and it contains several histological subtypes.
EOC accounts for over 90% of primary ovarian tumors and can be classified into distinct morphologic categories: serous, mucinous, endometrioid, clear cell, transitional cell (Brenner tumors), mixed, and undifferentiated type ().
Pathology of Epithelial Ovarian Tumors
Papillary serous histology accounts for 75% of ovarian cancers, and its histological pattern simulates the lining of the fallopian tube. High-grade, poorly differentiated tumors are the majority and are macroscopically indistinguishable from other epithelial tumors. This histologic variant is often associated with concentric rings of calcification known as psammoma bodies. Although no universal grading schema exists for ovarian serous carcinoma, a 2-tiered system (low-grade vs high-grade) has received increasing acceptance.35,36
Histopathologic grade is of prognostic significance35
and may also be of predictive value in that low-grade tumors appear less responsive to chemotherapy than high-grade tumors.37-39
Studies aimed at identifying a precursor lesion within the ovary have been largely unsuccessful. Based on the observation of a high rate of tubal intraepithelial changes (TICs) in high-risk women undergoing RRSO, it has been hypothesized that many apparent ovarian or primary peritoneal carcinomas may be of fallopian tube origin. Recent studies have documented that up to 59% of high-grade pelvic (nonuterine) serous carcinomas are associated with serous TICs. This is consistent with the hypothesis that the fallopian tube is the source of a majority of these tumors.40
There is increasing evidence that the pathogenesis of low-grade serous carcinomas and of serous tumors of low malignant potential (LMP; discussed later in this section) involves similar genes and pathways, and is distinct from that of high-grade serous carcinomas.41-43
Low-grade serous carcinomas and LMP serous tumors are characterized by a young age at diagnosis and a prolonged natural history.39
The clinical behavior of LMP tumors that recur as low-grade invasive serous carcinomas appears similar to that of newly diagnosed low-grade serous carcinomas.37
Other studies have shown that LMP tumors often coexist with low-grade serous carcinomas, and when they recur, frequently do so as low-grade serous carcinomas.44,45
These findings have led some to hypothesize that low-grade serous ovarian carcinomas represent the natural progression of an undetected serous ovarian tumor of LMP. However, there is no definitive evidence that low-grade serous carcinomas always arise from LMP tumors, and whether the 2 entities represent a continuum of tumor progression remains unproven. Although there are ongoing trials specifically for low-grade ovarian cancers, at present, low-grade and high-grade invasive serous ovarian tumors are treated similarly.
Mucinous tumors histologically resemble endocervical epithelium. They tend to be the largest epithelial ovarian neoplasms, with a median diameter of 18 to 20 cm, but tend to remain confined to the ovaries. Pseudomyxoma peritonei, a clinical syndrome characterized by accumulation of a gelatinous ascites, may be present. Furthermore, primary ovarian mucinous tumors can be difficult to distinguish from metastatic mucinous tumors from the appendix, colon/rectum, cervix, or pancreas. Primary tumors tend to be large and unilateral.46
Platinum-based first-line chemotherapy seems to be less effective for mucinous compared with nonmucinous EOCs.47-49
Current trials are examining whether chemotherapy regimens that include agents (such as capecitabine, oxaliplatin, and bevacizumab) with activity against GI cancers may be more effective in mucinous ovarian cancers.
Endometrioid tumors closely resemble the components of endometrial cancer and they appear to have an improved survival compared with serous adenocarcinoma, regardless of disease stage or response to platinum-based therapy.50
Patients with ovarian clear cell cancer frequently have a clinical history of endometriosis. Clear cell carcinomas tend to have a higher percentage of stage I disease than advanced stage disease. This suggests that clear cell carcinomas may have more symptoms when confined to the ovary and are thus more easily diagnosed at an early stage, or that they have a lower propensity for spread. In support of the former theory, clear cell carcinomas may be associated with a large pelvic mass.51,52
Recurrences are more frequent than with other histologies, and the response rate to platinum- and taxane-based regimens is lower.47,52,53
Nevertheless, at this time, clear cell cancers are still treated similarly to other EOCs.
Brenner tumors can be benign or malignant. Benign Brenner tumors are small, solid masses comprised of nests of transitional epithelium within the fibrous stroma. Intermediate Brenner tumors are comprised of proliferating cells of LMP. These are generally unilateral and multicystic, with a good prognosis. Malignant Brenner tumors are comprised of frankly malignant cells with atypical features and invasive characteristics.
Transitional cell carcinomas represent less than 1% of ovarian cancers. Although some series have reported an improved outcome for ovarian transitional cell carcinoma, a recent Gynecologic Cancer Intergroup (GCIG) study reported that, when controlled for other prognostic factors, the outcome for patients with transitional cell carcinoma did not differ significantly from that for patients with serous carcinoma.54
Undifferentiated carcinoma refers to tumors with no discernible histologic differentiation or only minor areas of differentiation.
Mixed carcinomas are those containing 2 or more distinct histologic types of cancer, with each subtype involving at least 10% of the tumor mass. The presence of serous carcinoma or sarcoma as one of the components worsens the prognosis.55
Noninvasive borderline tumors or LMP tumors are a heterogeneous group of lesions defined histologically by atypical epithelial proliferation without stromal invasion and represent approximately 10% of ovarian epithelial tumors. The majority of borderline tumors are serous. Patients tend to be younger, and 75% have stage I disease. In general, these patients have an excellent prognosis, and the tumors can be treated conservatively in women who wish to preserve fertility or are pregnant at the time of diagnosis. The overall risk of recurrence after conservative surgery varies from 7% to 30%, and recurrences are typically again LMP, not invasive malignancies. TAH-BSO is recommended for women who are not planning pregnancy or have advanced disease and staging is recommended to rule out invasive implants. Use of adjuvant chemotherapy is controversial.
Primary peritoneal carcinoma (papillary serous carcinoma of the peritoneum) is closely associated with, but distinct from, EOC.56-58
Histologically, this tumor is indistinguishable from papillary serous ovarian carcinoma, but morphologic distinctions have been described. The criteria established by the GOG to define primary peritoneal carcinoma are: 1) ovaries normal in size; 2) extraovarian involvement greater than ovarian involvement; 3) predominantly serous histology; and 4) ovarian surface involvement of less than 5 mm in depth and width. Primary peritoneal carcinoma is surgically staged according the FIGO/TNM staging system. The pattern of spread is similar to that in women with EOC.59,60
Women with papillary serous carcinoma of the peritoneum are treated similarly to those with EOC. Optimal surgical cytoreduction may be more difficult to achieve in the setting of widespread peritoneal disease without a predominant ovarian or pelvic mass. Chemotherapy regimens and response rates are similar to EOC.61
Non-EOCs account for 3% to 7% and include germ cell tumors, sex cord-stromal tumors, carcino-sarcoma (malignant mixed mullerian tumors), and small cell tumors. They differ from EOC in their biology and treatment. The ovary can also be involved by metastatic disease, especially from breast cancer or Krukenberg tumors (mucin-producing, neoplastic signet ring cells involving the ovarian stroma) from the GI tract.