Multivariate survival analysis of clinicopathologic features in surgical stage I endometrioid carcinoma including analysis of HER-2/neu expression.

OBJECTIVE: We previously described vascular invasion-associated changes, defined as the presence of vascular invasion or perivascular lymphocytic infiltrates, as key prognostic indicators in stage I endometrioid carcinoma. The current study was undertaken to examine the prognostic value of HER-2/neu expression in relation to other factors, including vascular invasion-associated changes, in surgical stage I endometrioid carcinoma. STUDY DESIGN: Seventy-one patients with surgical stage I endometrioid carcinoma treated by hysterectomy and followed up were randomly chosen for retrospective analysis of prognostic indicators including standard clincopathologic features, deoxyribonucleic acid ploidy, and HER-2/neu expression. The latter was examined by an objective computerized quantitative immunohistochemical system. RESULTS: By univariate analysis many factors were found to correlate with outcome, including age, tumor grade, depth of invasion, ploidy, HER-2/neu expression, and vascular invasion-associated changes. By multivariate analysis only vascular invasion-associated changes, aneuploidy, and HER-2/neu overexpression were found to independently correlate with survival. Stratification of patients on the basis of these three features revealed survival rates of 100%, 92%, and 60% when none, one, and two or three features were present, respectively. CONCLUSION: This study suggests that HER-2/neu expression correlated with outcome independent of other factors in endometrial carcinoma and may aid in estimating prognosis. The prognostic value of HER-2/neu overexpression independent of vascular invasion suggests that this factor may operate by increasing the ability of tumor cells to grow at a distal site once vascular invasion occurs.

Image analysis quantification in hormone receptor assay of mucinous carcinoma of the breast. Comparison with biochemical analysis.

Mucinous carcinoma (MC) of the breast is characterized by abundant extracellular mucin and by variable epithelial cellularity. Since some MCs are extremely hypocellular, we questioned the validity of biochemical (BIO) assays in these tumors. We analyzed paraffin-embedded tissue from 34 cases of MC of the breast for quantitative estrogen receptor (ER) and progesterone receptor (PR) using immunohistochemistry (IHC) on the Cell Analysis System CAS-200. Of the 34 cases, 31 (91%) were positive for ER, whereas 18 (53%) were positive for PR. In 21 cases the quantitative ER and PR were assayed biochemically by a dextran-coated charcoal method. Using the BIO results as the "true" values, the sensitivity of IHC for ER and PR was 100% and 78%, and the specificity was 13% and 64%, respectively. The low specificity of the values obtained by IHC was attributed to the fact that eight cases were "falsely" false positive (negative by BIO and positive by IHC) for ER and/or PR. Review of the histologic patterns of all 21 cases showed that 7 of the 8 falsely false positive cases were significantly hypocellular (epithelial cellularity 5-20%) as compared to the remaining cases (epithelial cellularity 20-75%). We conclude that immunohistochemical analysis of ER/PR status using image analysis in MC is a sensitive method, with the ability to detect receptor content when their concentration might be too low to be demonstrated by the conventional method as a result of sparse cellularity.

Ovarian endometriotic cysts. An analysis of cytologic atypia and DNA ploidy patterns.

Cytologic atypia may be seen in the glandular epithelium that lines ovarian endometriotic cysts. The significance of this atypia has not been fully elucidated. The authors studied the morphologic appearance and DNA ploidy of the glandular epithelium from 36 ovarian endometriotic cysts by image analysis on formalin-fixed paraffin-embedded tissue sections. In 29 of the cases the corresponding endometrium proper also was studied. The DNA content was diploid in all eutopic endometrium and in the lining epithelium of all endometriotic cysts without atypia or with only mild cytologic atypia. DNA aneuploidy was observed in 3 of 6 endometriotic cysts with severe atypia. Our findings indicate that mild cytologic atypia in the glandular epithelium of endometriotic cysts is associated with normal DNA ploidy patterns, whereas severe atypia may be associated with aneuploidy. These findings support the hypothesis that cytologic atypia represents the precursor lesion for the invasive epithelial malignancy that may arise in ovarian endometriotic cysts.

Significance of papillary (villoglandular) differentiation in endometrioid carcinoma of the uterus.

The frequency, topography, and significance of papillary (villoglandular) differentiation were examined in 142 cases of endometrioid (typical) carcinoma of the endometrium. Forty-four (31%) of the 142 cases showed papillary differentiation, including eight carcinomas limited to the endometrium and 36 cases with myometrial invasion. In 24 (67%) of the 36 cases with myometrial invasion, papillary differentiation was found in both the endometrial component of the carcinoma and in tumor invading the myometrium. In the remaining 12 cases, papillary differentiation was found in the endometrial component but not in tumor invading the myometrium, which showed either glandular or solid growth patterns. When patients were divided into two groups based on the presence or absence of papillary differentiation, regardless of its location, the two groups did not differ in prognosis or frequency of pathologic changes associated with outcome. In the subgroup of patients with tumors showing myometrial invasion, however, endometrioid carcinomas displaying papillary differentiation in the myometrium were associated with a higher frequency of vascular invasion (p = 0.007), a higher rate of lymph node metastasis (p = 0.001), and worse outcome (p = 0.05) compared with carcinomas showing myometrial invasion in the form of glandular or solid patterns regardless of the presence or absence of papillary differentiation in the endometrium. The results of the present study suggest that papillary differentiation is of significance in endometrioid carcinoma. If these findings can be confirmed, a separate designation for these tumors as "papillary endometrioid carcinomas" or "villoglandular endometrial carcinomas" would be helpful if use of these terms was limited to endometrioid carcinomas manifesting papillary differentiation in the myometrium.

Role of DNA content determination by image analysis in confirmation of dysplasia in Barrett's esophagus.

Progression to cancer in Barrett's esophageal columnar metaplasia is classically heralded by the presence of epithelial dysplasia. Differentiation of reactive epithelial atypia and mild dysplasia from severe dysplasia, however, may often be difficult especially with limited biopsy material. We performed DNA content analysis of 11 cases of Barrett's esophagus showing variable reactive atypia, 24 cases of Barrett's with low- and high-grade dysplasia, and 30 cases of Barrett's with invasive adenocarcinoma (BCA) using Feulgen-stained paraffin sections and the CAS 200 image analyzer. The mean DNA index of the uniformly diploid BE was 1.06. The 1.26 mean DNA index for the low-grade Barrett's esophagus with dysplasia, 1.62 for high grade, and 1.88 DI for BCA were significantly greater than for variable reactive atypia (P < 0.004) but not different from each other. Six BCA cases (20%) were diploid; 24 cases (80%) were aneuploid. Mean survival of diploid BCA at 20.4 mo was nearly double the survival of 10.6 mo for aneuploid BCA. However, this difference was not statistically significant (P < 0.21) and survival at 3 yr was identical for all BCA cases. Tumor grade, stage, and lymph node status did not significantly correlate with ploidy pattern. Thus, although DNA analysis does not seem to predict ultimate outcome in BCA, aneuploidy and high DNA index are associated with Barrett's esophagus with dysplasia and BCA and may be of significant value in the differentiation from variable reactive atypia in small biopsies.

Nuclear DNA content and clinical follow-up in resected pancreatic adenocarcinoma.

Nuclear DNA content was determined by image analysis of paraffin-embedded tissue sections in 20 cases of resected pancreatic ductal adenocarcinoma. Seven cases (35%) showed a diploid pattern; 13 (65%) were aneuploid. Mean survival time of patients with diploid tumors was significantly greater (17 months) than for patients with aneuploid carcinomas, 7.5 months (P < .03, Kaplan-Meier and Cox univariate analysis). Patient age, grade of differentiation, primary tumor size and lymph node status did not correlate significantly with ploidy pattern and survival. In four cases atypical hyperplasia/adenocarcinoma in situ was present in the main duct epithelium at the pancreatectomy resection line. These intraductal foci were uniformly diploid. We conclude that despite the uniform fatality of pancreatic cancer, adenocarcinomas with aneuploid patterns pursue a significantly more rapid and aggressive clinical course than do diploid tumors and that the atypical intraductal epithelial foci that may accompany resected specimens from invasive adenocarcinoma are DNA diploid, may represent noninvasive precursor lesions and are of uncertain clinical significance.

Histologic and ultrastructural features of experimental duodenal ulcers in Sprague-Dawley rats.

The histologic and ultrastructural features of a time sequence study of the development, evolution, and healing of acetic acid-induced experimental duodenal ulcer are presented. Duodenal ulcers produced by serosal application of acetic acid featured microvascular injury with progressive disintegration of the tips of the mucosal villi and subtotal necrosis of the duodenal wall. At 3 days ulcers transformed into a chronic state with regenerating epithelium originating from the crypts of the intact bordering mucosa extending toward the center of the ulcers. By 21 days healed ulcers were covered by distorted duodenal surface mucosa. We conclude that this reproducible and standardized model of duodenal ulcer features vascular injury as the earliest microscopic event, that ischemic necrosis leads to ulceration, and that the chronic phase bears morphologic resemblance to human duodenal ulcer.

Evaluation of prognostic indicators in squamous carcinoma of the vulva including nuclear DNA content.

The prognostic value of clinical and pathologic features including tumor ploidy status was evaluated in 43 randomly selected primary invasive squamous carcinomas of the vulva in which the lesion was totally excised and a lymph node dissection performed. By both univariate and multivariate analysis, survival most closely correlated with the number of involved lymph nodes. In the subgroup of patients with negative lymph node dissections, outcome was also found to correlate with tumor diameter but not with any other feature studied including nuclear DNA content. Both the FIGO surgical staging system and stratification of patients by Gynecologic Oncology Group (GOG) risk groups provided valuable methods of estimating prognosis with survival rates of 100%, 80%, 59%, and 25% for FIGO stages I, II, III, and IV, respectively, and rates of 100%, 75%, 56%, and 42% for GOG groups of minimal, low, intermediate, and high risk. Subdivision of patients with FIGO Stage III disease based on tumor diameter and the number of involved lymph nodes appeared to be of prognostic value with a survival rate of 67% when tumor diameter was below 8 cm and less than three lymph nodes were involved but only 50% when either value was above the cut-off point. This study suggests that DNA ploidy status is not a prognostic value in vulvar squamous carcinoma, but the results support the value of utilizing the number of involved lymph nodes for prognosis assessment. The latter feature in combination with tumor size may be useful in the subdivision of FIGO Stage III patients into prognostic subgroups.