Jeffrey D. Seidman

The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin.

Advances over the past decade suggest a need to reassess the distribution of ovarian surface epithelial tumors. A series of 220 consecutive invasive ovarian carcinomas, including carcinosarcomas and peritoneal carcinomas, was reviewed. Notable findings include: 7% of tumors were carcinosarcomas; 22% of cases of peritoneal serous carcinomatosis were of peritoneal origin; <3% of cases were mucinous carcinomas; and only one malignant Brenner tumor (0.5%) and no pure transitional cell carcinomas were identified. If peritoneal carcinomas, carcinosarcomas, and mixed carcinomas with a serous component are combined with serous carcinomas, this group accounts for 78% of all cases and 87% of advanced stage cases, suggesting a greater uniformity to epithelial ovarian cancer than previously appreciated.

Primary and metastatic mucinous adenocarcinomas in the ovaries: Incidence in routine practice with a new approach to improve intraoperative diagnosis

Mucinous carcinomas are reported to comprise 6–25% of ovarian carcinomas (mean 12%), but recent refinements in the interpretation of histologic features of noninvasive and metastatic mucinous carcinomas suggest that this may be an overestimate. Mucinous carcinomas in the ovaries are commonly metastatic, but the proportion of primary versus metastatic mucinous carcinomas in unselected patients is unknown. To evaluate the histologic-type distribution of ovarian surface epithelial carcinomas, a consecutive series of 124 ovarian carcinomas was reviewed using uniform current criteria. Microinvasive and intraepithelial carcinomas and carcinomas arising in germ cell and stromal tumors were excluded. To evaluate the proportions of primary and metastatic tumors among the mucinous carcinomas, 52 consecutive mucinous carcinomas from nonreferral patients were reviewed. Three of 124 primary ovarian carcinomas were pure mucinous carcinomas (2.4%). Among 52 cases of mucinous carcinomas in the ovaries, 40 (77%) were metastatic and 12 (23%) were primary. Among the 12 primary mucinous tumors, three were atypical proliferative mucinous tumors with microinvasion and nine were invasive mucinous carcinomas. Among the 40 metastatic mucinous tumors, 18 (45%) were from the gastrointestinal tract, 8 (20%) were pancreatic, 7 (18%) were gynecologic malignancies (5 cervical, 2 endometrial), 3 (8%) were from the breast, and 4 (10%) were of unknown primary site. A simple rule that classifies all bilateral mucinous carcinomas as metastatic, unilateral mucinous carcinomas <10 cm as metastatic, and unilateral mucinous carcinomas ≥10 cm as primary correctly classified 90% of the neoplasms. This algorithm for distinguishing primary and metastatic mucinous carcinomas in the ovary can be used at the time of intraoperative consultation to guide surgical management. After careful exclusion of noninvasive, microinvasive, and metastatic tumors, pure mucinous adenocarcinoma primary in the ovary appears to be substantially less common than previously reported.

Subclassification of serous borderline tumors of the ovary into benign and malignant types: A clinicopathologic study of 65 advanced stage cases

Poor outcome in serous borderline tumors (SBT) of the ovary is limited to patients with advanced stage disease. This study was designed to determine whether there are histologic features among advanced-stage SBTs (International Federation of Gynecology and Obstetrics [FIGO] stages II and III) that predict behavior. The 65 cases in the study were divided into three groups: typical SBTs, with noninvasive implants (51 cases), SBTs with invasive implants (three cases), and a recently described tumor, designated micropapillary serous carcinoma (MPSC) (11 cases), a proliferative serous ovarian neoplasm that often lacks destructive infiltrative growth but appears to behave as a low-grade invasive carcinoma. When the tumor lacks infiltrative growth, as it did in the 11 cases in this series, it qualifies as a borderline tumor. After censoring nontumor deaths, the 5- and 10-year actuarial survival rates were 98% for SBTs with noninvasive implants, 33% for SBTs with invasive implants, and 81% at 5 years and 71% at 10 years for MPSCs. The mean follow-up was 100 months. Two (4%) of 51 patients with SBTs with noninvasive implants subsequently developed invasive carcinoma, and one (2%) died of carcinoma. In contrast, two (67%) of three women with SBTs accompanied by invasive implants developed invasive carcinoma, and both died of disease. Finally, of the 11 patients with MPSC, seven (64%), all of whom had invasive implants, developed recurrences of invasive carcinoma and/or died of tumor. MPSCs had significantly higher rates of mortality (p < 0.001) and recurrence as invasive carcinoma (p < .002) than SBTs with noninvasive implants. The recognition that SBTs can be divided into benign and malignant subtypes provides the basis for replacing the borderline category. The benign subgroup is composed of typical SBTs, including those with noninvasive implants for which the term atypical proliferative serous tumor is appropriate. In contrast, tumors displaying a micropapillary growth pattern (MPSC) and SBTs with invasive implants should be classified as carcinomas and treated accordingly.

Differences in Tumor Type in Low-stage Versus High-stage Ovarian Carcinomas

Although there are recognized differences in the type of ovarian carcinomas between those tumors diagnosed at low versus high stage, there is a lack of data on stage distribution of ovarian carcinomas diagnosed according to the current histopathologic criteria from large population-based cohorts. We reviewed full slide sets of 1009 cases of 2555 patients diagnosed with ovarian carcinoma that were referred to the British Columbia Cancer Agency over a 16-year period (1984 to 2000). On the basis of the reviewed cases we extrapolated the distribution of tumor type in low-stage (I/II) and high-stage (III/IV) tumors. We then compared the frequencies with those seen in a large hospital practice. The overall frequency of tumor types was as follows: high-grade serous—68.1%, clear-cell—12.2%, endometrioid—11.3%, mucinous—3.4%, low-grade serous—3.4%, rare types—1.6%. High-grade serous carcinomas accounted for 35.5% of stage I/II tumors and 87.7% of stage III/IV tumors. In contrast, clear-cell (26.2% vs. 4.5%), endometrioid (26.6% vs. 2.5%), and mucinous (7.5% vs. 1.2%) carcinomas were relatively more common among the low-stage versus high-stage tumors. This distribution was found to be very similar in 410 consecutive cases from the Washington Hospital Center. The distribution of ovarian carcinoma types differs significantly in patients with low-stage versus high-stage ovarian carcinoma when contemporary diagnostic criteria are used, with consistent results seen in 2 independent case series. These findings reflect important biological differences in the behavior of the major tumor types, with important clinical implications.

Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 179 cases.

Coordinate expression profiles for cytokeratins 7 and 20 (CK7 and CK20) are useful for distinguishing certain types of adenocarcinomas but use for distinction of primary and secondary mucinous tumors in the ovary is limited due to the existence of a number of tumor types exhibiting overlapping CK7/CK20 immunoprofiles; the use of staining distribution patterns in the distinction of tumors with shared profiles has not been evaluated in detail. We report analysis of both coordinate expression profiles and staining distribution in 179 rigorously classified mucinous tumors in the ovary, including 53 primary tumors [35 atypical proliferative (borderline) mucinous tumors of gastrointestinal type and 18 invasive mucinous carcinomas] and 126 secondary tumors [28 colorectal adenocarcinomas, 54 appendiceal tumors (23 adenocarcinomas, 31 low-grade adenomatous mucinous tumors associated with pseudomyxoma peritonei), 14 pancreatic adenocarcinomas, 8 endocervical adenocarcinomas, 5 gastric adenocarcinomas, 4 gallbladder/biliary tract adenocarcinomas, and 13 adenocarcinomas of unknown primary sites). A CK7+/CK20+ immunoprofile was the most common profile in primary ovarian tumors (74%), upper gastrointestinal tract tumors (78%), and endocervical tumors (88%) but was occasionally observed in lower intestinal tract tumors (colorectal: 11%; appendiceal: 13% of low-grade tumors, 35% of carcinomas). A CK7–/CK20+ immunoprofile was the most common profile in lower intestinal tract tumors (79%) and was uncommon in upper gastrointestinal tract tumors (9%), rarely seen in primary ovarian tumors (4%), and not seen in endocervical tumors. A CK7+/CK20− profile was observed in some primary ovarian (23%), upper gastrointestinal tract (13%), and endocervical tumors (13%) but not in lower intestinal tract tumors. For CK7+ tumors, staining distribution was very frequently diffuse (>50% of tumors cells positive) in primary ovarian, upper gastrointestinal tract, and endocervical tumors, whereas staining distribution was often focal (<50% of tumors cells positive) when present in colorectal and appendiceal carcinomas but not in low-grade appendiceal tumors. For CK20+ tumors, staining distribution was variable but often focal in primary ovarian tumors and nonlower intestinal tract tumors, whereas the pattern was almost always diffuse in lower intestinal tract tumors. Immunohistochemical staining distribution can supplement CK7/CK20 coordinate expression profiles to distinguish subsets of primary ovarian and metastatic lower intestinal tract mucinous tumors having overlapping immunoprofiles but neither coordinate expression profiles nor staining distribution distinguishes primary ovarian tumors from the nonlower intestinal tract metastases.

Interobserver and intraobserver variability of a two-tier system for grading ovarian serous carcinoma.

Although grading has been demonstrated to be an important prognostic factor in ovarian serous carcinoma, there is no system universally used to perform this task. A few years ago, we proposed a two-tier system for grading ovarian serous carcinoma that is based primarily on the assessment of nuclear atypia (uniformity vs. pleomorphism) in the worst area of the tumor. Tumor grade in this two-tier system is correlated with survival. After being used by numerous pathologists and trainees at The University of Texas M.D. Anderson Cancer Center (MDACC) for 15 years, we have observed that this system is user-friendly and reproducible. We undertook this study to evaluate the interobserver and intraobserver variability among a group of 7 gynecologic pathologists and 2 general surgical pathologists using this grading system. A total of 80 cases of ovarian serous carcinoma, 40 low-grade and 40 high-grade, were circulated twice among these pathologists. Slides with examples of low-grade and high-grade serous carcinoma were sent with the unknowns. A website was used to provide diagnostic criteria, images of examples of ovarian low-grade and high-grade carcinoma, and a log form to facilitate data entry. Statistical analysis demonstrated an overall κ statistic among the different observers of 0.909. The intergrader κs ranged from 0.717 to 1.000 in the first round of the review and from 0.701 to 1.000 in the second round. Eight of the participants had an intragrader κ ranging from 0.775 to 1.000 (excellent agreement), whereas a single participant had an intragrader κ of 0.725 (good agreement). This study demonstrates that the two-tier grading system (the MDACC grading system) for ovarian serous carcinoma on the basis of the assessment of nuclear atypia is easy to learn and is highly reproducible. These findings would support its universal use, which would be beneficial for the standardization of clinical trials and protocols, thus facilitating the understanding of this disease and investigation into the treatment of patients affected by these tumors.

Association of mucinous tumors of the ovary and appendix. A clinicopathologic study of 25 cases.

Twenty-five patients with mucinous tumors of the ovary and appendix were studied. The average age of the patients was 52 years, and the ovarian and appendiceal tumors were discovered synchronously in all but two cases. The majority had either a pelvic mass or abdominal or pelvic pain. A high frequency of bilateral ovarian tumors (11/25), and right-sided predominance for the unilateral ovarian tumors (nine right, five left) were found. Four patients had ovarian mucinous carcinomas, 10 had mucinous tumors of low malignant potential, 10 had mucinous cystadenomas, and one had a mucinous cyst. Pseudomyxoma ovarii was present in 22 cases. Twenty-two of 24 appendices were grossly abnormal. There were six appendiceal mucinous adenocarcinomas, 10 mucinous tumors of uncertain malignant potential, seven mucinous cystadenomas, one hyperplastic polyp, and one mucocele. Twelve patients had ovarian and appendiceal tumors of similar malignant potential, nine had appendiceal tumors with more aggressive morphologic features than the corresponding ovarian tumor, and four had ovarian tumors with more aggressive morphologic features than the appendiceal tumor. Eighteen patients had peritoneal involvement by mucinous epithelium admixed with mucus (nine localized, nine diffuse). Immunoperoxidase reactions for four epithelial antigens in 15 cases showed complete concordance between ovarian and appendiceal lesions in only five cases and were not helpful in determining the site of origin of the peritoneal tumor. Our findings suggest an independent origin of the ovarian and appendiceal tumors in most cases and do not favor an origin in a single site. Furthermore, it is proposed that the peritoneal lesions may arise de novo as part of a multifocal neoplastic process.

Immunohistochemical expression of CDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7.

Recent studies have demonstrated conflicting results regarding the value of CDX2 for distinguishing primary ovarian mucinous tumors from metastatic mucinous carcinomas in the ovary. Utility of coordinate expression of cytokeratins 7 and 20 is restricted to distinction of ovarian mucinous tumors from lower gastrointestinal tract metastases and data comparing coordinate expression of all three markers is limited. Immunohistochemical studies were performed to compare expression of CDX2 and cytokeratin 20, both markers of intestinal differentiation, in conjunction with coordinate expression of cytokeratin 7, in 90 mucinous tumors involving the ovary: 42 primary ovarian mucinous tumors (31 atypical proliferative (borderline) mucinous tumors (gastrointestinal type), 11 mucinous carcinomas) and 48 metastatic mucinous carcinomas of upper (pancreaticobiliary tract: 14; stomach: five) and lower (colon and rectum: 25; appendix: four) gastrointestinal tract origin. Primary ovarian tumors expressed CDX2 (40%) less frequently than cytokeratin 20 (83%) (P<0.0001). CDX2 expression in primary ovarian tumors (40%) was lower than CDX2 expression in metastatic carcinomas of both upper (74%; P=0.016) and lower gastrointestinal tract origin (90%; P<0.0001). Cytokeratin 20 expression was similar in primary ovarian tumors (83%) and metastases of upper (89%; P=0.071) and lower gastrointestinal tract origin (93%; P=0.29). Thus, as a single marker CDX2 offers some advantage over cytokeratin 20 because it is less frequently positive in primary ovarian tumors. In the almost universally cytokeratin 7-positive primary ovarian tumors and metastases of upper gastrointestinal tract origin, CDX2 coordinate expression was less common in primary ovarian tumors (36%) than in metastases of upper gastrointestinal tract origin (63%) (P=0.022) whereas cytokeratin 20 coordinate expression was identical in both tumor types (79%). In the almost universally cytokeratin 7-negative metastases of lower gastrointestinal tract origin, coordinate expression of CDX2 (83%) and cytokeratin 20 (86%) were equivalent (P=1.00). CDX2 was comparable to cytokeratin 20 in distinguishing metastases of lower gastrointestinal tract origin (usually cytokeratin 7-negative and CDX2/cytokeratin 20 positive) from primary ovarian tumors and metastases of upper gastrointestinal tract origin (usually cytokeratin 7-positive and CDX2/cytokeratin 20 variable). CDX2 provided some advantage over cytokeratin 20 for distinguishing primary ovarian mucinous tumors from metastases of upper but not lower gastrointestinal tract origin; however, the advantage in the former was limited due to the occurrence of shared coordinate expression profiles in both tumor types. Cytokeratin 7 provides the predominant discriminatory value among these markers yet is limited to distinction of primary ovarian tumors from metastases of lower gastrointestinal tract origin.

Mucinous tumors arising in ovarian mature cystic teratomas: Relationship to the clinical syndrome of pseudomyxoma peritonei

&NA; Recent studies have redefined pseudomyxoma peritonei (PMP) as a specific clinicopathologic syndrome in which mucinous ascites is accompanied by peritoneal lesions characterized by bland to low‐grade adenomatous mucinous epithelium intimately associated with pools of extracellular mucin and fibrosis, diagnosed pathologically as disseminated peritoneal adenomucinosis (DPAM). Most recent studies support an appendiceal rather than ovarian origin for virtually all cases of PMP/DPAM in women. Peritoneal mucinous tumors with the histologic features of carcinoma (peritoneal mucinous carcinomatosis, PMCA) are also rarely ovarian in origin and are distinguished from DPAM, even though they may produce abundant mucin, because PMCA and DPAM are pathologically and prognostically distinct. We report three cases of PMP (mucinous ascites) associated with ruptured mucinous tumors arising in ovarian mature cystic teratomas. Two tumors contained bland to low‐grade adenomatous mucinous epithelium associated with dissecting mucin, identical to the mucinous tumors that secondarily involve the ovaries and peritoneum in PMP/DPAM derived from ruptured appendiceal mucinous adenomas. The third was composed of both low‐grade adenomatous tumor and areas of mucinous carcinoma. In all cases the appendices were microscopically normal. The mucinous ascites associated with the low‐grade tumors contained only a few fragments of detached bland mucinous epithelium in one and none in the other. The mucinous ascites associated with the higher‐grade tumor contained one fragment of atypical mucinous epithelium. All three mucinous tumors were cytokeratin 20‐positive and cytokeratin 7‐negative, consistent with a lower gastrointestinal tract‐type rather than primary ovarian‐type mucinous tumor immunophenotype. Mucinous tumors arising in ovarian mature cystic teratomas are morphologically and immunohistochemically consistent with gastrointestinal tract‐type mucinous tumors, which likely arise from gut elements of the teratoma. Rupture can on rare occasions produce mucinous ascites containing very scant mucinous epithelium, but additional follow‐up will be required to determine whether these ovarian tumors ever lead to recurrent disease accompanied by the characteristic peritoneal lesions of DPAM or PMCA. Such tumors probably represent the only cases of ovarian origin of PMP.

A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells

Ovarian carcinomas are thought to arise from cells of the ovarian surface epithelium by mechanisms that are poorly understood. Molecules associated with neoplasia are potentially immunogenic, but few ovarian tumor antigens have been identified. Because ovarian carcinomas can elicit humoral responses in patients, we searched for novel tumor antigens by immunoscreening a cDNA expression library with ovarian cancer patient serum. Seven clones corresponding to the homeobox gene HOXB7 were isolated. ELISAs using purified recombinant HOXB7 protein revealed significant serologic reactivity to HOXB7 in 13 of 39 ovarian cancer patients and in only one of 29 healthy women (P < 0.0001). Ovarian carcinomas were found to express HOXB7 at markedly higher levels than normal ovarian surface epithelium, suggesting that immunogenicity of HOXB7 in patients could be associated with its elevated expression in ovarian carcinomas. Overexpression of HOXB7 in immortalized normal ovarian surface epithelial cells dramatically enhanced cellular proliferation. Furthermore, HOXB7 overexpression increased intracellular accumulation and secretion of basic fibroblast growth factor, a potent angiogenic and mitogenic factor. These results reveal HOXB7 as a tumor antigen whose up-regulated expression could play a significant role in promoting growth and development of ovarian carcinomas.