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.
The treatment of complex atypical hyperplasia (CAH) and well-differentiated endometrioid carcinoma (WDC) by progestin therapy has been shown to be a safe alternative to hysterectomy. Accurate assessment for regressive changes induced by the progestins is critical to successful treatment. However, there are few studies detailing the histopathologic changes associated with progestin therapy. A total of 44 patients with CAH or WDC, treated with oral progestins or a progesterone or levonorgestrel-releasing intrauterine device, were followed by endometrial biopsy and/or curettage at 3 to 6 month intervals for a maximum of 25 months. The pretreatment and posttreatment endometrial samples were evaluated for response to treatment and for the histologic features of gland-to-stroma ratio, architectural abnormalities [back-to-back glands and confluency (cribriform and/or papillary patterns)], glandular cellularity, mitotic activity, cytologic atypia, and cytoplasmic changes. Histologic changes seen in progestin-treated endometria included a decreased gland-to-stroma ratio, decreased glandular cellularity, decreased to absent mitotic activity, loss of cytologic atypia, and a variety of cytoplasmic changes including mucinous, secretory, squamous, and eosinophilic metaplasia. Architectural changes tended to resolve later in the course of treatment. Some architectural abnormalities, specifically cribriform and papillary patterns, were induced by progestins mimicking progression. Twelve (67%) of 18 women with CAH had complete resolution, 2 (11%) regressed to complex hyperplasia without atypia, and 4 (22%) demonstrated persistent disease over a median follow-up period of 11 months. Eleven (42%) of 26 women with WDC had complete resolution and 15 (58%) had persistent disease over a median follow-up period of 12 months. Three instances of disease progression occurred, presumably only after discontinuing progestin treatment. Only persistent architectural abnormalities and/or cytologic atypia in the 7 to 9-month biopsies were predictive of treatment failure, with a trend for cytologic atypia to be the most powerful predictor. These findings indicate that progestin therapy should be continued for no less than 6 months to accurately assess treatment response. A modified classification for progestin-treated lesions of the endometrium is proposed.
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%) (Po0.0001). CDX2 expression in primary ovarian tumors (40%) was lower than CDX2 expression in metastatic carcinomas of both upper (74%; P ¼ 0.016) and lower gastrointestinal tract origin (90%; Po0.0001). Cytokeratin 20 expression was similar in primary ovarian tumors (83%) and metastases of upper (89%; P ¼ 0.071) and lower gastrointestinal tract origin (93%; P ¼ 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 ¼ 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 ¼ 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.
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