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When it comes to prognostic relevance, the most popular systems for grading ovarian cancer fail to make the grade, say the authors. They urge universal acceptance of a simplified--and more consistent--approach. [ABSTRACT FROM AUTHOR]

The field of gynaecological pathology has grown from its infancy to a mature subspecialty over the last 50 years. What discoveries have led the way in this evolution? On the basis of personal experience and a survey of expert gynaecological pathologists, the following discoveries have been most impactful: (i) identification of the role of human papillomavirus in the aetiology of carcinoma of the lower genital tract; (ii) the emergence of international classification systems for gynaecological cancers (with cervical adenocarcinoma being the most recent example of this); (iii) the development of reliable immunohistochemistry as a diagnostic adjunct; (iv) discoveries around the aetiology and the relationship between serous carcinoma of the tube/ovary and the endometrium; and (v) identification of the role of oestrogen in the development of endometrial carcinoma and histological recognition of the precursor lesion atypical hyperplasia/endometrial intraepithelial neoplasia, and how recognition of the role of diethylstilboestrol in the aetiology of vaginal clear cell carcinoma led directly to this discovery. The history of each discovery and how it changed diagnostic pathology will be discussed in this review., (© 2019 John Wiley & Sons Ltd.)

Endometrial polyps are very common benign endometrial lesions, but their pathogenesis is poorly understood, except for a few studies indicating the possibility of benign stromal neoplasm. Although the histopathological diagnosis of endometrial polyp on a surgical specimen is straightforward, it is often difficult to differentiate endometrial polyp from endometrial hyperplasia on a biopsy or curettage specimen. Presently, there is no immunohistochemical marker helpful in this differential diagnosis. In this study, we examined p16 expression in 35 endometrial polyps and 33 cases of endometrial hyperplasia that included 16 simple hyperplasias, 14 complex atypical hyperplasias, and 3 complex hyperplasias without atypia. Stromal p16 expression differed significantly between the two groups; it was seen in 31 (89 %) endometrial polyps, but in only 1 (3 %) endometrial hyperplasia. The percentage of p16-positive stromal cells ranged from 10 to 90 % (mean, 47 %) and the positive cells tended to be distributed around glands. Six cases of endometrial hyperplasia within an endometrial polyp were also examined and all cases showed stromal p16 expression. There was no difference in glandular p16 expression between endometrial polyps 33 (94 %) and hyperplasia 27 (82 %). The p16-immunoreactivity was mostly confined to metaplastic epithelial cells in both groups. Stromal p16 expression might be a peculiar characteristic of endometrial polyp and constitute a useful marker for the diagnosis, especially in fragmented specimens from biopsy or curettage. Stromal p16 expression might be a reflection of p16-induced cellular senescence, which has been documented in several benign mesenchymal neoplasms.

Context: Endometrial tissue specimens are commonly encountered in daily practice. It is well known that a number of problematic diagnostic scenarios occur relative to these specimens., Objective: To emphasize practical aspects of endometrial specimen handling and reporting, with selected comments on common diagnostic pitfalls, including (1) the diagnosis of endometrial intraepithelial carcinoma in atrophic endometrial biopsy specimens, (2) evaluation of adequacy of endometrial sampling specimens, (3) problems in diagnosing and measuring the depth of myometrial invasion in endometrial carcinoma, (4) the question of metastasis versus independent primaries in concurrent carcinomas of endometrium and one or both ovaries, (5) the problematic differential diagnoses between type 1 (primarily endometrioid) and type 2 (primarily serous) adenocarcinomas, and (6) atypical hyperplasia and proposed classification systems for its replacement., Data Sources: Published literature, consensus statements, and personal experience., Conclusions: A systematic approach to the handling and reporting of endometrial specimens reduces the potential for omission and error. Recognition of diagnostic pitfalls and practical approaches to their resolution help improve quality.

Peritumoral retraction artefact appears in tissue sections as an empty space partially or completely encircling a nest of tumor cells, usually in conformity with the rounded or angular outline of that particular nest. The present study was designed to test this finding in a large series of cases and to quantify the appearance of peritumoral retraction artefact in, in situ and infiltrating duct carcinoma of the breast. We examined 199 cases of infiltrating duct carcinoma (IDC) and 188 cases of ductal carcinoma in situ (DCIS). Of the total of 387 cases, 111 were core needle biopsies, whereas the others were larger resections. In each specimen, retraction was evaluated on hematoxylin and eosin-stained slides as negative, 1+ (1% to 25% of tumor showing retraction), 2+ (26% to 50%), 3+ (51% to 75%), or 4+ (76% to 100%). Overall, peritumoral retraction was noted in 168 of 199 cases (84.4%) of IDC, versus 30 of 188 cases (16%) of DCIS (P < 0.0001). Peritumoral retraction scored as 2+ or greater (26% to 50%) was seen in only 1 of 188 DCIS specimens, compared with 77 of 199 IDC. Thus, peritumoral retraction artefact appears to be a significant finding seen during the evaluation of hematoxylin and eosin specimens for the diagnosis of carcinoma. We discuss the possibility that this phenomenon might represent true prelymphatic space involvement rather than a fixation artefact.

Objective: Difficulties in detecting cervical adenocarcinoma early are well known. We report a detailed pathology review of cervical adenocarcinoma subtypes, comparing growth patterns and appearance of non-neoplastic epithelium to inform possible clues for disease progression and early detection., Methods: This analysis includes 154 women aged 18-69 years and diagnosed with incident in situ or invasive adenocarcinoma (AC), adenosquamous (AS), or other rare cervical glandular tumors from 1992-1996 in six U.S. medical centers. A pathology review panel evaluated histological features from original diagnostic slides., Results: Higher tumor grade (P < 0.001) and vascular invasion (P = 0.002) were more common in AS compared to AC. Adenocarcinoma in situ (AIS) was also more common among AC than AS (P = 0.002). Among AC with cervical intraepithelial carcinoma (CIN), AIS and cribriform patterns were more common than AC without CIN (P = 0.01). Further, non-endometrioid AC had higher tumor grade (P = 0.01) and stromal responses (P = 0.02) than endometrioid AC. Finally, although microglandular hyperplasia is historically thought to be related to oral contraceptive (OC) use, our data do not support this notion., Conclusion(s): AS appears to be either diagnosed later or histologically more aggressive than AC, and among AC subtypes, there are distinct histologic characteristics. Further research is needed to identify precursor lesions for early detection of AC and particularly for AS where AIS may not be a common precursor.

Background: Most gynecologists determine therapy based on current International Society of Gynecologic Pathologists (ISGP)/World Health Organization classification of endometrial hyperplasia, the reproducibility of which has been questioned. The Gynecologic Oncology Group (GOG) initiated a protocol to assess the efficacy of hormonal therapy of atypical endometrial hyperplasia (AEH). Primary goals of the first phase (Part A) were to prospectively determine reproducibility of referring institution's pathologist's diagnosis of AEH by a panel of 3 gynecologic pathologists and to determine reproducibility of diagnoses by panel members., Methods: Three hundred six women were entered on this protocol with a referring institution's pathologist diagnosis of AEH based on biopsy or curettage. Available slides were assessed independently and interpreted by each of a panel of 3 gynecologic pathologists who used International Society of Gynecologic Pathologists (ISGP)/World Health Organization criteria. The majority diagnosis was based on diagnostic concordance by at least 2 of the 3 panelists., Results: The referring institution's pathologist's diagnosis of AEH was supported by the majority of the panel in only 38% of cases. Overall kappa value for the panel diagnosis of AEH was 0.28. The majority diagnosis was adenocarcinoma in 29%, cycling endometrium in 7%, and nonatypical hyperplasia in 18% of cases. Unanimous agreement for any diagnosis was reached among all 3 of the panel in 40% of cases. For the panel, paired kappa values for any diagnosis ranged 0.34-0.43, with an overall kappa value of 0.40., Conclusion: Reproducibility of referring institution's pathologists' diagnosis of AEH by a panel of gynecologic pathologists is poor. Both underestimation and overestimation of the severity of the lesion are very common. The level of reproducibility among subspecialist panel members for diagnosis of AEH in these specimens also is poor. Better criteria and better sampling are needed to improve reproducibility of this diagnosis, particularly if it is to be used for clinical decisions., (Copyright 2006 American Cancer Society.)

Previous work suggests that cervical cancer may aggregate in families. We evaluated the association between a family history of gynecological tumors and risk of squamous cell and adenocarcinomas of the cervix in 2 studies conducted in Costa Rica and the United States. The Costa Rican study consisted of 2,073 women (85 diagnosed with CIN3 or cancer, 55 diagnosed with CIN2 and 1,933 controls) selected from a population-based study of 10,049 women. The U.S. study consisted of 570 women (124 with in situ or invasive adenocarcinomas, 139 with in situ or invasive squamous cell carcinomas of the cervix and 307 community-based controls) recruited as part of a multicentric case-control study in the eastern part of the United States. Information on family history of cervical and other cancers among first-degree relatives was ascertained via questionnaire. Information on other risk factors for cervical cancer was obtained via questionnaire. Human papillomavirus (HPV) exposure was assessed in both studies using broad spectrum HPV L1-based PCR testing of exfoliated cervicovaginal cells and in Costa Rica by additional testing of plasma collected from participants for antibodies against the L1 protein of HPV types 16, 18, 31 and 45 by ELISA. A family history of cervical cancer in a first-degree relative was associated with increased risk of squamous tumors in both studies (odds ration [OR] = 3.2 for CIN3/cancer vs. controls; 95% confidence interval [CI] = 1.1-9.4 in Costa Rica; OR = 2.6 for in situ/invasive squamous cell carcinoma cases vs. controls, 95% CI = 1.1-6.4 in the Eastern United States study). These associations were evident regardless of whether the affected relative was a mother, sister or daughter of the study participant. Furthermore, observed effects were not strongly modified by age. In Costa Rica, the effect persisted in analysis restricted to HPV-exposed individuals (OR = 3.0; 95% CI = 1.0-9.0), whereas in the Eastern United States study there was evidence of attenuation of risk in analysis of squamous carcinoma cases restricted to HPV positive women (OR = 1.4; 95% CI = 0.29-6.6). No significant association was observed between a family history of cervical cancer in a first-degree relative and adenocarcinomas (OR = 1.3; 95% CI = 0.43-3.9). History of gynecological tumors other than cervical cancer in a first-degree relative was not significantly associated with risk of disease in either study. These results are consistent with a role of host factors in the pathogenesis of squamous cell cervical cancer, although familial aggregation due to shared environmental exposures cannot be ruled out., ((c) 2005 Wiley-Liss, Inc.)

Eosinophilic cell change is one of the most common endometrial metaplasias occurring in both non-neoplastic and neoplastic endometrium. Its phenotypic characteristics have not still been fully clarified. We examined expression of mucin core proteins in a total of 95 distinct histological areas of endometrial specimens comprising 39 benign nonhyperplastic endometria, 14 endometrial hyperplasias, and 42 endometrial carcinomas. Eosinophilic cell change was very common, seen in 27 endometrial areas (28%); mucinous metaplasia (28%) and ciliated (tubal) change (31%), were also frequently seen. Eosinophilic cell change was more frequently seen in endometrial hyperplasia and carcinoma than in benign nonhyperplastic endometrium. In endometrial carcinomas, eosinophilic cell change was frequently associated with mucinous metaplasia and the two types of metaplastic cells were occasionally intermingled in a single neoplastic gland. A total of 23 (85%) of 27 eosinophilic cell changes and 18 (72%) of 25 mucinous metaplasias showed MUC5AC expression. These frequencies of MUC5AC expression did not differ significantly among benign non-hyperplastic endometrium, endometrial hyperplasia and endometrial carcinoma. Totally, 15 (52%) of 29 ciliated (tubal) changes and two (100%) of two surface syncytial changes, which showed cytoplasmic eosinophilia at least focally, also expressed MUC5AC. Most of the endometrial changes characterized by cytoplasmic eosinophilia may be subtypes of immature mucinous metaplasia which express a mucin core protein but are not fully glycosylated.

Intratumoral aromatase is a therapeutic target for the treatment of post-menopausal estrogen-dependent breast cancers. Therefore, reliable methods should be developed for routine application for the detection of intratumoral aromatase. Immunohistochemistry (IHC) is considered one of the most suitable methods in this regard. A multi-centre collaborative group has been established to generate and validate new aromatase monoclonal antibodies. We have selected two monoclonal antibodies, #677 against native aromatase protein and F2 against formalin-fixed protein for this purpose. With these two monoclonal antibodies 43 cases of invasive ductal carcinoma, which had been previously assayed for aromatase activity by product isolation methodology, were immunostained in three laboratories in UK, USA and Japan and independently evaluated by three pathologists (H.S., T.A. and S.G.S.). Staining of malignant epithelium, adipose tissue, normal/benign and stromal compartments of the tumors were assessed by estimating the proportion of positive staining cells and the relative intensity of staining in this fashion. Immunoreactivity could be detected in each component of the tissue specimens but a significant positive correlation with biochemical activity was detected only in malignant epithelium stained with 677 not in other components with #677 and not in any of the components. Staining using F2 as a primary antibody did not produce a positive correlation in any components with aromatase activity. These results suggest that we now have a monoclonal antibody against aromatase (#677) which may be used to stain archival materials. A methodology and scoring system is recommended whereby staining significantly correlates with aromatase activity of the resected tissue specimens of breast cancer.

Signet ring cell carcinoma and glassy cell carcinoma are both rare histological subtypes of uterine cervical cancer. This report is of a case of uterine cervical carcinoma arising in a 29-year-old woman who had major components of signet ring cell carcinoma and glassy cell carcinoma within the same tumor. Histochemical and immunohistochemical analyses, including high and low molecular weight cytokeratins, p63 and MUC5AC, additionally demonstrated the squamous and adenocarcinomatous differentiation in the neoplastic cells, which showed otherwise unclassifiable morphology on the haematoxylin-eosin sections. A wide range of differentiation described above supports the speculation that glassy cell carcinoma may arise from the multipotential immature cells that can differentiate into both squamous and glandular cells. It would be precise to classify this tumor as adenosquamous carcinoma. Although adenosquamous carcinoma is not a rare histological subtype in the uterine cervix, it should be necessary to report the presence of glassy cells and signet ring cells when present because the presence of both components is associated with an unfavorable clinical behavior.

Intratumoral aromatase is a potential therapeutic target for the treatment of postmenopausal estrogen-dependent breast cancers. Therefore, reliable methods should be developed for routine application for the detection of intratumoral aromatase. A multi-center collaborative group has been established to generate and validate new aromatase monoclonal antibodies (MAbs). A recombinant GST-aromatase fusion protein was expressed in baculovirus and the purified protein was used for immunization of mice either as a native or formalin-fixed antigen. Hybridomas were generated using standard techniques and screened biochemically prior to immunohistochemistry (IHC) evaluation in human placenta, ovary and breast cancer tissues. Twenty-three MAbs selected by biochemical assays were further evaluated by IHC of paraffin-embedded tissue sections including normal ovary, and placenta, and a small series of 10 breast carcinomas. Of the 23 MAbs, 2 (clones 677 and F2) were determined to specifically stain cell types known to express aromatase in normal tissues. In breast carcinomas staining of malignant epithelium, adipose tissue, normal/benign and stromal compartments was detected. IHC was performed and independently evaluated by three pathologists (HS, TJA and SGS), each using the same evaluation criteria for staining intensity and proportion of immunopositive cells. With these two MAbs, interpathologist and intralaboratory variations were minimal in comparison with differences which could be detected between tissue specimens and antibodies.

Squamous cell carcinoma is the most common malignant cervical tumor, but the incidence of adenocarcinomas has been rising during the past few decades. This article discusses the epidemiology and pathogenesis of the squamous cell carcinoma, its clinical and histologic features, including microinvasive carcinoma, its histologic grade, and variant tumors. The prognostic impact of these features and the differential diagnosis are also covered. The second portion of this article is devoted to the glandular tumors of the cervix, including adenocarcinoma in situ and invasive adenocarcinoma and its variants. The differential diagnosis of these tumors with tumor like glandular lesions is given special attention. Finally, less common malignant cervical tumors are covered, with an emphasis being placed on their significance.

The differential diagnosis of endocervical glandular lesions can be very difficult, and the interobserver agreement on borderline cases can be low. We are proposing a new scoring system to aid in the reproducibility of the diagnosis of noninvasive endocervical glandular lesions. The total of 67 diagnostically difficult cases were independently reviewed by five pathologists. After the completion of the first round review, a consensus diagnosis was reached for each lesion by all participants. This consensus diagnosis was used as the reference diagnosis. According to the consensus, the lesions included 21 benign/reactive conditions, 7 endocervical glandular dysplasias, and 39 adenocarcinomas in situ. During the second round review, all cases were assessed using the new scoring scheme, according to which separate scores from 0 to 3 were given to each lesion for: 1) nuclear atypia, 2) stratification, and 3) sum of mitoses/apoptoses (counted in the two most active glands, and the average number used). These three scores were then added to result in the total score (0-3 = benign; 4-5 = endocervical glandular dysplasia; 6-9 = adenocarcinoma in situ). Complete agreement between all observers in the first round review was seen in 35 of 67 cases (52.2%), kappa = 0.565. This agreement improved in the second round with the use of the scoring scheme: 52 of 67 cases (77.6%), kappa = 0.705. If the benign and endocervical glandular dysplasia diagnostic categories were combined, the overall agreement in the second round review would be 63 of 67 cases (94%), meaning that the scheme affords accurate distinction between adenocarcinoma in situ and lesser lesions. We propose applying this new scoring scheme to the diagnosis of noninvasive endocervical glandular lesions to improve interobserver agreement. The use of this scheme will result in more consistency of data in series from different institutions and will allow uniformity on the issue of adenocarcinoma in situ precursor lesions.

Two cases of lobular breast carcinoma metastatic to an endometrial polyp are described. Both patients had been treated with tamoxifen and presented with abnormal uterine bleeding. Histology of endometrial biopsy in both cases showed typical tamoxifen-associated endometrial polyps with focal subtle stromal infiltration by metastatic lobular breast carcinoma. This was confirmed by positive immunohistochemical staining with cytokeratin epithelial markers. Metastatic breast carcinoma may rarely involve tamoxifen-associated endometrial polyps. Because primary endometrial carcinomas may also arise within tamoxifen polyps, these should be extensively sampled. We briefly review polypoid uterine lesions that may occur secondary to tamoxifen therapy.

Objective: Although human papillomavirus causes essentially all cervical carcinoma, cofactors may differ by cancer histologic type. We examined human papillomavirus genotypes and sexual and reproductive risk factors for cervical adenocarcinoma and squamous cell carcinoma., Study Design: One hundred twenty-four women with adenocarcinoma, 139 women with squamous cell carcinoma, and 307 control subjects participated in this case-control study. Logistic regression analyses were performed to calculate odds ratios and CIs., Results: Human papillomavirus 18 was associated most strongly with adenocarcinoma (odds ratio, 105; 95% CI, 23-487). Human papillomavirus 16 was associated most strongly with squamous cell carcinoma (odds ratio, 30; 95% CI, 12-77). More than three lifetime sexual partners was a risk factor for adenocarcinoma (odds ratio, 2.1; 95% CI, 1.1-4.0) and squamous cell carcinoma (odds ratio, 3.0; 95% CI, 1.6-5.9). Even being pregnant was associated inversely with adenocarcinoma (odds ratio, 0.4; 95% CI, 0.2-0.8). Five or more pregnancies was associated with squamous cell carcinoma (odds ratio, 2.2; 95% CI, 0.9-5.4)., Conclusion: The relative importance of human papillomavirus genotypes 16 and 18 and the reproductive co-factor differences suggest distinct causes for cervical adenocarcinoma and squamous cell carcinoma.

The insufficient state of knowledge concerning the biology of endocervical glandular lesions is compounded by the lack of universal diagnostic criteria for recognizing endocervical glandular dysplasia. This study addressed the issue of diagnostic reproducibility of noninvasive endocervical glandular lesions and tested the proposed new scoring scheme designed to improve this reproducibility. We have shown that the application of this scheme has significantly improved interobserver agreement in all diagnostic categories. Moreover, the results of this study lend support to the recommendation not to diagnose endocervical glandular dysplasia in the clinical setting, although this category can be still reliably separated out for research purposes. Application of our scoring scheme will bring uniformity to the diagnosis of noninvasive endocervical glandular lesions and allow the study of a precursor to endocervical adenocarcinoma

Several studies have reported on the use of antibodies to monoclonal carcinoembryonic antigen (CEA) and vimentin (VIM) to distinguish between adenocarcinomas of endometrial (EM) and endocervical (EC) origin, with variably enthusiastic results. It is still unclear whether site of origin or pathway of differentiation (endometrioid [em] versus mucinous [m]) is more important in predicting immunohistochemical differences. In the present study, paraffin blocks from adenocarcinomas of known origin were retrieved and immunostained with monoclonal antibodies to VIM and CEA, as well as cytokeratins (CK) 4, 18, and 20, estrogen receptor (ER), and progesterone receptor (PR). Positivity was scored on a scale from 0 to 12, with emphasis on the pattern of differentiation (tumors with mixed patterns received separate scores for the em and m foci). Mean CEA scores for emEM (n = 27), mEM (17), mEC (10), and emEC (6) were 0.4, 0.9, 5.1, and 1.2, respectively. VIM scores were 6.9, 1.3, 0, 4.4; ER, 5.7, 4.2, 0, 1.6; PR, 7.6, 2.8, 0.1, 6.0; CK4, 9.2, 4.4, 8.5, 10.6; CK18, 6.4, 3.4, 5.5, 8.4; CK20, 0.7, 0, 0.5, 0.4. Both site and differentiation influenced these results, with the latter more important for VIM and PR, the former for ER, both for CEA (only mEC was frequently strongly positive), and neither for the CKs studied. No one stain or combination reliably distinguished endometrial from endocervical origin. The only immunostaining pattern that might identify a site of origin with more accuracy than hematoxylin & eosin evaluation alone is the combination of high VIM and ER scores in an endometrioid carcinoma, suggesting with about 95% accuracy in this series an endometrial origin of the tumor.

To evaluate the significance of mitotic activity and apoptosis in the differential diagnosis of endocervical glandular lesions, we examined the frequency of mitoses and apoptosis in 89 endocervical glandular lesions from 78 patients, which consisted of benign reactive changes (7 cases), lobular or diffuse laminar endocervical glandular hyperplasia (4), microglandular hyperplasia (3), tunnel clusters (7), nabothian cysts (2), mesonephric remnants (3), tubal metaplasia (3), endocervical glandular dysplasias (including atypical tubal metaplasia) (EGD) (7), adenocarcinoma in situ (AIS) (31), microinvasive adenocarcinoma (7), frankly invasive adenocarcinoma (12), and minimal deviation adenocarcinoma (3). Mitotic index (MI; mitotic figures per 1000 cells) was significantly higher in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma than any other lesions examined. Microinvasive adenocarcinoma showed the highest MI. Apoptosis was detected consistently and frequently in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma. AIS showed the highest apoptotic index (AI; apoptoses per 1000 cells). Frequent apoptotic bodies and mitotic figures are a common feature of endocervical glandular malignancies (except for minimal deviation adenocarcinoma) and are an important feature that can facilitate their differentiation from benign and borderline lesions. High MI in microinvasive adenocarcinoma might aid the distinction of microinvasive adenocarcinoma from AIS. Although both MI and AI of EGD were between those of benign reactive changes and of AIS, MI and AI alone are not sufficient to differentiate EGD from benign reactive changes. MI and AI are not helpful in the differential diagnosis between minimal deviation adenocarcinoma and its benign mimics.

Context: The endometrium is an intrinsically dynamic tissue with great capability for regeneration and proliferation; consequently, there is some overlap between features seen in benign, premalignant, and malignant lesions. This leads to marked intrabiopsy, interbiopsy, and interobserver variability., Objective: We studied the specificity and sensitivity of computerized image analysis of molecular markers to evaluate its potential use as a diagnostic tool., Design: Specimens from 100 patients were examined and the following histologic diagnoses were assigned: proliferative endometrium (n = 10), secretory endometrium (n = 10), endometrial hyperplasia (n = 40; 30 with no atypia, 10 with atypia), and carcinoma (n = 40; 20 endometrioid, 10 serous, and 10 clear cell). All cases were evaluated immunohistochemically for p53 and proliferating cell nuclear antigen (PCNA) expression. Computerized image analysis was performed with a CAS 200 digital analyzer., Results: Expression of p53 was found only in carcinomas (65%) and endometrial hyperplasia with atypia (30%). Expression of p53 was higher in the poor prognostic categories (serous carcinoma and clear cell carcinoma) than in endometrioid carcinoma. In endometrioid carcinoma, p53 expression correlated with grade. Proliferating cell nuclear antigen showed a similar pattern of results to p53 in the various carcinoma subtypes and endometrioid carcinoma grades. Endometrial hyperplasia PCNA values were the lowest among all the groups. Both carcinomas and proliferative endometrium showed higher glandular and stromal PCNA values, significantly different from endometrial hyperplasia with atypia. In proliferative endometrium, stromal PCNA was the highest among all of the groups. The p53 and PCNA results correlated with each other for carcinoma., Conclusions: Computerized image analysis correlates well with the established morphologic groups of endometrial pathology and yields results consistent with previous studies. Owing to its higher degree of sensitivity, computerized image analysis is of potential use in cases of diagnostic dilemmas and can help objectively allocate the case in the correct category (e.g., proliferative endometrium vs. endometrial hyperplasia, endometrial hyperplasia with atypia vs. endometrioid carcinoma). It is particularly useful in the evaluation of stromal changes.

Hyaline globules (HG) have been observed in a large variety of unrelated categories of tumors and benign tissues. Different explanations for their formation have been proposed, varying according to tumor type and anatomic location. We have studied 80 tumor cases containing HG, by light microscopy, electron microscopy, immunohistochemical stains for various plasma proteins, and in situ DNA-end labeling for apoptosis. On light microscopy, HG were invariably related to areas of increased apoptosis and often contained apoptotic nuclear fragments. The HG stained as expected, with variable intensity with acidic stains. Most cells containing HG stained with immunohistochemical stains for all plasma proteins examined (alpha-1-antitrypsin, ferritin, C3, kappa and lambda light chains, and IgG), indicating an increased plasma membrane permeability. A morphologic change associated with the increased permeability was cytoplasmic blebbing. In the HG themselves, immunohistochemical stains for the plasma proteins were either diffusely positive or stained only the periphery of the larger HG. Double stains for apoptosis and plasma proteins confirmed the increased plasma membrane permeability to proteins of apoptotic cells in general and cells containing HG in particular. Free hyaline globules were often linked to the extracellular matrix by fibrin fibrils. Ultrastructurally, the HG appeared as phagosomes/secondary lysosomes or areas of cytoplasmic condensation surrounded by rough endoplasmic reticulum whorls. These were always associated with intense cytoplasmic blebbing. We conclude that HG reflect stages of cell injury, which in most instances relate to apoptotic cell death. They are specifically associated with the cytoplasmic blebbing and condensation typically seen in this form of cell death. These phenomena are accompanied by plasma protein influx (insudated plasma) and formation of distinct intracellular "hyalinized" cellular fragments. With cell fragmentation, the HG become extracellular and are likely to be ultimately disposed of by a process of "remodeling" and incorporation into the extracellular matrix, followed by collagenization. The latter process partly occurs by the initial linking of all components (HG, collagen fibers, cellular fragments, etc.) by a network of fibrin. The process of formation of HG follows a stereotypical pathway independent of cell type. Because it results mostly from apoptotic cell death, it is more pronounced in rapidly growing tumors or posttreatment. We propose the term thanatosomes for the entire spectrum of HG to emphasize their relationship to cell death. HUM PATHOL 31:1455-1465., (Copyright 2000 by W.B. Saunders Company)

The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least some gastric cancers. APC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B, respectively. We evaluated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.

Background: E (epithelial)-cadherin, the cell adhesion molecule also considered a potential invasion/metastasis suppressor, is mutationally inactivated in nearly half of all undifferentiated-scattered (diffuse-type) gastric carcinomas. In addition, silencing of E-cadherin by CpG methylation within its promoter region has been reported in several gastric carcinoma cell lines. We investigated the methylation status of the E-cadherin promoter region in 53 primary human gastric carcinomas., Methods: Hypermethylation of the E-cadherin promoter was determined by utilizing methylation-specific polymerase chain reaction (PCR)-single-strand conformation polymorphism (MSP-SSCP) analysis followed by direct sequencing of PCR products. Expression of E-cadherin was studied by western blot analysis. All statistical tests were two-sided., Results: Hypermethylation of the E-cadherin promoter was evident in 27 (51%) of 53 primary gastric carcinomas examined by MSP-SSCP. It occurred more frequently in carcinomas of the undifferentiated-scattered type (in 15 [83%] of 18) than in other histologic subtypes (in 12 [34%] of 35) (P =.0011, Fisher's exact test), and it was present at similar rates in early (in six [60%] of 10) versus advanced (in 21 [49%] of 43) carcinomas (P =.73, Fisher's exact test). Methylation occurring at all cytosine-guanosine sequences (CpGs) near the transcriptional start site was confirmed in six of six tumors examined by bisulfite-DNA sequencing, including two early gastric carcinomas. In addition, loss or diminished expression of E-cadherin was confirmed by western blotting in four of the six tumor tissues demonstrating hypermethylation., Conclusions: The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis.

The prevalence and clinical significance of mucosal epithelial proliferation or hyperplasia of the fallopian tube are controversial in the few studies reported. Some authors have retrospectively examined "routine" sections (one or two submitted from each tube), whereas others have prospectively blocked the entire tubes. In the current study, we prospectively studied a total of 168 tubes from 98 women who had various indications for salpingectomy and compared the diagnosis in an initial single section (to simulate the usual practice) with that in the remainder of the entirely sectioned and submitted tube (mean total number of sections, 9.0). Some degree of mucosal epithelial proliferation was found in 83% of all tubes examined, with no difference between the tubes removed for routine tubal ligation and those in women who had benign ovarian lesions, malignant gynecologic tumors, uterine leiomyomata, or benign tubal lesions (salpingitis or ectopic pregnancy). Mucosal epithelial proliferation graded as more than mild, however, was seen in only 4.5% of the otherwise normal ligated tubes versus 35 to 46% of tubes associated with the other lesions. When the initial sections were compared with the subsequent ones, the diagnosis was identical in 96 tubes (57%). In the other 72 tubes (43%), the difference in diagnosis was never greater than one grade (no, mild, moderate, severe mucosal epithelial proliferation), with the diagnosis more often upgraded (50 tubes) than downgraded (22 tubes) in the additional sections. It is concluded that there is no reason to submit an entire tube for histologic examination to detect clinically significant lesions, and the usual practice of submission of one or two sections is clinically appropriate.

The differential diagnosis of endometrial hyperplasia and well-differentiated endometrioid adenocarcinoma is complicated not only by the resemblance of these lesions to each other, but also by their tendency to be overdiagnosed (particularly hyperplasia) on the background of polyps, endometritis, artifacts, and even normally cycling endometrium. Atypical hyperplasia may also be overdiagnosed when epithelial metaplastic changes occur in simple or complex hyperplasia without atypia. Low-grade adenocarcinomas are best recognized by architectural evidence of stromal invasion, usually in the form of stromal disappearance, desmoplasia, necrosis, or combinations of these findings between adjacent glands. Endometrioid adenocarcinomas are usually Type 1 cancers associated with manifestations of endogenous or exogenous hyperestrogenic stimulation and a favorable prognosis. Subtypes include adenocarcinomas with squamous differentiation and secretory, ciliated cell and villoglandular variants. Rules and pitfalls in the grading of endometrioid adenocarcinomas and the estimation and reporting of myometrial invasion are presented.

Objective: To report a case of secondary amenorrhea and infertility caused by an inhibin-B-producing ovarian fibrothecoma., Design: Case report., Setting: Academic medical center., Patient: A 37-year-old woman with a 2-year history of secondary amenorrhea and infertility., Intervention(s): Operative removal of a 5-cm ovarian fibrothecoma., Main Outcome Measure(s): Luteinizing hormone, FSH, E2, inhibin-B, TSH, and prolactin measured preoperatively and postoperatively. Immunostaining of tumor cells for inhibin and LH., Result(s): Preoperative hormone levels were as follows: FSH, 1.7 mIU/mL; LH, 23.4 mIU/mL; E2, 31 pg/mL; and inhibin B, 1,154 pg/mL. Three weeks postoperatively, the FSH was 1.5 mIU/mL, LH decreased to 7.1 mIU/mL, E2 increased to 276 pg/mL, and inhibin-B decreased to 17 pg/mL. The fibrothecoma did not stain for LH but was strongly positive for inhibin. Regular menstrual cycles resumed 28 days postoperatively., Conclusion(s): Inhibin-B produced by an ovarian tumor profoundly suppressed FSH levels and resulted in secondary amenorrhea and infertility. Use of sensitive and specific immunoassays for inhibin-A and -B may aid in the differential diagnosis of hormonally active ovarian tumors.

The histopathologic grade of ovarian epithelial carcinoma has generally been found to be of prognostic significance, but the grading system used has varied among published reports, and often has not been specified at all. The major proposed grading systems are reviewed, and a new system is proposed, which is modeled on the Nottingham system of breast cancer grading and is designed to be applied to all invasive epithelial carcinomas of the ovary. Results obtained in studies using this system are presented. When grading is compared with histopathologic typing of ovarian carcinoma, the latter is less valuable in predicting survival but better at predicting tumor responsiveness to chemotherapy, and can also suggest the chemotherapeutic agents to be used. Thus, both grade and type should be specified in the surgical pathology report for any ovarian carcinoma.

To assess the hypothesis that oral contraceptives (OCs) increase the risk of cervical adenocarcinomas, we conducted a six-center case-control study of 124 patients with adenocarcinomas, 139 with squamous cell carcinomas, and 307 population controls. Women between the ages of 18 and 69 who were newly diagnosed with cervical adenocarcinomas between 1992 and 1996 were eligible. Healthy female controls and a second case group of incident cervical squamous cell carcinomas were matched to the adenocarcinoma cases. All participants were interviewed regarding OCs, other risk factors for cervical carcinoma, and utilization of cytological screening, and a PCR-based test determined HPV genotype of cervical samples for both case groups and controls. Use of OCs was positively and significantly associated with adenocarcinomas and positively but weakly associated with squamous cell carcinomas. Associations between OCs and invasive adenocarcinomas (n = 91), squamous cell carcinoma in situ (n = 48), and invasive squamous cell carcinomas (n = 91) disappeared after accounting for HPV infection, sexual history, and cytological screening, but a positive association remained between current use of OCs and cervical adenocarcinoma in situ (n = 33). This association persisted after stratification by screening and sexual history and after restriction according to HPV status, but small numbers made it difficult to exclude detection bias, selection bias, or residual confounding by HPV as potential explanations Current OC use was associated with cervical adenocarcinomas in situ, but we saw no other evidence that OCs independently increase the risk of cervical carcinomas.

Currently, molecular pathology plays a limited role in improving patient outcome in gynecologic oncology. However, molecular investigation is providing important insights into the epidemiology, pathogenesis, and progression of female genital cancers. Future roles should include prediction of poor outcome in low-risk cases, more accurate staging of multifocal tumors, identification of new precursor lesions, and prediction of response to specific therapeutic regimens. Gene therapy of some malignant tumors may become important in the near future. In the immediate future, however, the most significant role of molecular pathology may be in the screening and triage of putative cervical cancer precursors and in the possible prophylaxis of these lesions by means of a vaccine or vaccines against human papillomaviruses.

We present a case of a 62-year-old G0P0 Caucasian woman who developed endometrial adenocarcinoma, FIGO grade 2, endometrioid type, after receiving tamoxifen for 2 years following a diagnosis of invasive carcinoma and ductal carcinoma in situ of the breast. An incidental finding in the hysterectomy specimen was numerous endometriotic foci involving the submucosa, subserosa, and serosa of the cervix; lower uterine segment serosa; and bilateral ovaries. Polypoid structures, similar to the endometrial polyps occurring in tamoxifen-treated patients, were observed to arise from endometriotic foci in the serosa of the cervix and bilateral ovaries. We have found only one similar report in the literature. Since these structures do not fit the definition of "polyp," we suggest "basaloma" as an alternative. We also review all cases of tamoxifen-associated endometriosis reported in the world literature and cases of polypoid endometriosis occurring in non-tamoxifen-treated patients. Of 12 reported cases of tamoxifen-associated endometriosis, 4 occurred in premenopausal women, 1 in a perimenopausal women, and 7 in postmenopausal women, of whom none had a known history of endometriosis. The endometriotic foci gave rise to a spectrum of lesions which included epithelial metaplasias, simple and complex hyperplasias, polypoid lesions, and 2 cases of endometrioid carcinomas., (Copyright 1999 Academic Press.)

The effect of cautery artifact on the ability to accurately diagnose dysplasia and predict abnormal follow-up in large loop excision specimens of the transformation zone (LLETZ) has not been adequately addressed in the pathology literature. One hundred consecutive conization specimens with cytologic and/or histologic follow-up were studied. Indications for the procedure were high-grade squamous intraepithelial lesion (on Pap smear and/or biopsy) in 64 cases, low-grade squamous intraepithelial lesion in 28, atypical squamous cells of unknown significance (ASCUS) in 3, atypical glandular cells of unknown significance in 2, adenocarcinoma in situ, squamous carcinoma in situ, and invasive squamous carcinoma in 1 each. Twenty-four specimens were cold-knife conizations (CKCs) and 76 LLETZs. All LLETZs had at least 1+ artifact, and in 46 cases (61%) it interfered with at least one aspect of evaluation. In 21 cases (28%), 1+ artifact interfered only with margin assessment. In 25 cases (33%), there was 2+ or 3+ artifact precluding not only margin assessment, but also diagnosis and grading of dysplasia. Of the 43 LLETZs received in more than one piece, 33 (77%) had interfering artifact, and in 21 (49%) it was 2+ or 3+, at least focally interfering with diagnosis and grading. In contrast, of 33 LLETZs received in a single piece, only 13 (39%) had interfering artifact, which was 2+ or 3+ in 4 (12%), (p < 0.05). Positive follow-up (including ASCUS, favor dysplasia, and ASCUS, not otherwise specified) was found in 6 of 7 CKCs with positive margins (86%), 10 of 16 LLETZs with positive margins (63%), and 4 of 7 LLETZs with unassessable margins (57%). In cases with negative cone margins, positive follow-up was found in 2 of 17 CKCs (12%), and 18 of 53 LLETZs (34%), p < 0.05; a higher frequency of interfering artifact (p < 0.05) was seen in these cases. LLETZ margin status and postprocedure endocervical curettage (ECC) specimens were not good predictors of residual disease, unlike margin status in CKC. Post-CKC ECC was a better predictor of subsequent abnormal follow-up than post-LLETZ ECC (p < 0.05). The presence of interfering artifact was only rarely mentioned in the original pathology report. In conclusion, the status of margins is a better predictor of abnormal follow-up in CKC than in LLETZ specimens. Fragmentation of the specimen is an additional factor, compounding the inevitable artifact. Postprocedure ECC is not a useful indicator of residual dysplasia. The pathologist should not hesitate to comment on specimen adequacy in surgical pathology reports.

Endocervical adenocarcinoma in situ (AIS) is currently classified as having endocervical, endometrioid, or intestinal differentiation or admixtures of these patterns. Tubal metaplasia (TM) of endocervical mucosa has been considered a benign lesion that may be confused with AIS but has no malignant potential. In recent years, an increasing number of cases in which TM not only coexists with AIS, but also possesses atypia with transitions between ordinary TM, atypical TM, and AIS with residual tubal morphology have been reviewed by the authors, largely in consultation material. The clinical and pathologic features of 11 cases showing tubal and other types of AIS arising in a background of TM are reported. It cannot be assumed that all ciliated tubal epithelium in the cervix is benign and possesses no premalignant potential. The relationship of atypical TM (dysplasia) to tubal-type AIS must be defined, and the latter pattern should be added to the known types of differentiation of cervical AIS.

Many reports describe an increased frequency and unusual features of endometrial polyps and carcinomas in women treated with tamoxifen (TMX) for breast cancer. Postmenopausal women with endometrial polyps were identified by computer search of pathology files from 1990 to 1996. Medical records were reviewed, and patients were divided into three groups: 28 receiving TMX for breast cancer, 23 receiving hormone replacement therapy (HRT), and 28 untreated controls (UC). Cumulative doses (CDs) of TMX were calculated. Histologic slides of polyps were reviewed blindly and evaluated for size, metaplasias, vascularity, fibrosis, and inflammation. Carcinomas were found in 3 TMX, no HRT, and 1 UC patient. Atypical hyperplasias were found in 1 TMX, 0 HRT, and 1 UC patient. Mean polyp size was larger in the TMX group (2.9 cm) than in the HRT (1.05 cm) and UC (1.35 cm) groups, and stromal fibrosis was more prominent in TMX-related and larger polyps. Mucinous metaplasias were observed more frequently in the patients receiving TMX. No other differences were noted. The two TMX patients in whom low-grade carcinomas developed and the one with atypical hyperplasia had independent risk factors. CDs for these patients were 32.9, 36.5, and 17.6 g, respectively. A high-grade carcinoma developed in a TMX patient without constitutional risk factors at a CD of 94.9 g. On the basis of a literature review and these results, low-grade carcinomas developing after relatively low CDs of TMX may be at least partially attributable to other risk factors. The association between poorly differentiated and nonendometrioid tumors with higher TMX CDs is still speculative, but the current study suggests that they may be related to TMX. A statistically significant increase in the frequency of thyroid replacement use by TMX patients is also noted.

Large-core (14g) needle biopsy (CNB) of the breast is a new diagnostic modality increasingly being used to evaluate patients with mammographic abnormalities. Two hundred twenty-four CNBs were performed on 198 patients. Surgical follow-up was available in 64 cases (28.6%). Overall concordance rate was 93.8% (60 of 64 cases). Of the four discordant cases, two were diagnosed as atypical ductal hyperplasia (ADH) on CNB; on excision, these cases showed cribriform ductal carcinoma in situ (DCIS); two remaining cases, diagnosed on CNB as ADH versus DCIS, showed invasive carcinoma (DCIS with invasive component and infiltrating cribriform carcinoma, respectively) on excisional biopsy. Malignancy, primary (52) or metastatic (5), was identified in 57 cases (25.4%); 47 of these patients underwent surgical excision, and the diagnosis was confirmed in all of these cases. Of 51 cases with radiographic evidence of microcalcifications, 48 (94%) had microcalcifications in the CNB: 30 (62.5%) were benign, 11 (22.9%) were malignant, and 7 (14.6%) were diagnosed as ADH. In the remaining three cases (1.3%), only benign breast tissue without microcalcifications was seen, and the lesion was considered to have been missed. Biopsy specimens were obtained from 173 lesions because of the presence of a mass: 125 (72.3%) were benign, 45 (26%) were malignant, and 3 (1.7%) were diagnosed as ADH. Follow-up was available in 118 patients with benign lesions: all were mammographically stable or decreased at 6 or 12 months; no follow-up was available for the remaining patients. CNB of the breast is a highly sensitive (96.9%) and specific (100%) technique for management of patients with mammographic abnormalities. The histologic findings should be correlated with the mammographic appearance, and an attempt should be made to achieve a specific diagnosis in all lesions, particularly masses. The diagnosis of ADH should always prompt excisional biopsy because of a high frequency of false-negative results caused by sampling errors or underestimation.

Objective: Because there is no universally accepted grading system for ovarian epithelial carcinoma, we attempted to compare the prognostic utility of the individual components used in some systems--both architectural and cytologic features, as well as mitotic activity and histologic tumor type--to determine which of these components fit best with survival., Methods: We studied 461 patients with invasive ovarian carcinoma who had uniform treatment, complete clinical data including staging and follow-up, and slides available for review. Each tumor was assigned a histologic subtype, architectural grade (based on whether the predominant pattern was glandular, papillary or solid), nuclear grade, mitotic count, and FIGO grade (based on the system for endometrial carcinoma). These features were compared with each other and with tumor stage and survival., Results: The architectural grade, nuclear grade, and mitotic count were independent variables both in stage I/II and stage III/IV disease. Each of them correlated with survival for most combinations of histologic type and stage. By multivariate analysis, in stage I/II cancer, nuclear grade and architectural grade were significantly correlated with survival, mitotic count showed only a trend, and FIGO grade did not correlate. In stage III/IV disease, nuclear grade, architectural grade 3, and mitotic count were significant, and FIGO grade was not., Conclusion: The new architectural grading system proposed worked better than the FIGO system in this study. Furthermore, it could be applied to all histologic subtypes of carcinoma. The nuclear grade and mitotic count were also independent of each other, correlated with survival, and could be utilized for all histologic types. These data support the development of a grading system which combines these architectural, nuclear, and mitotic features and can be applied regardless of the histologic type of carcinoma, modeled after the Nottingham system for grading of breast carcinoma.

Background: Most published series of ovarian carcinoma find a correlation between histologic grade and survival, but the grading system used commonly is not specified, and several different systems exist, some of which use different criteria for different histologic types. However, several studies have shown marked interobserver variability in distinguishing among the histologic types of ovarian carcinoma. The authors attempted to derive a universal grading system for all invasive ovarian carcinomas (IOC), based on the Nottingham system for grading all types of mammary carcinoma., Methods: The authors studied 461 patients with IOC of different histologic types and clinicopathologic stages who were treated in a uniform manner between 1980 and 1994 with surgery and cisplatin-based chemotherapy. All slides were reviewed and the tumors graded as follows: Architectural pattern (predominant): Glandular = 1, Papillary = 2, and Solid = 3; Nuclear pleomorphism: Slight = 1, Moderate = 2, and Marked = 3; Mitotic activity (mitotic figures per 10 high-power fields [1 HPF = 0.345 mm2]) in most active region: 0-9 = 1, 10-24 = 2, and > or = 25 = 3; Grade 1 = total score (adding three values obtained earlier) 3-5, Grade 2 = 6 or 7, and Grade 3 = 8 or 9., Results: Tumor grade correlated with survival in both early and advanced stage disease and for all major histologic types of IOC except clear cell carcinoma (CCC). Results for CCC approached but did not reach clinical significance. By multivariate analysis, only this tumor grade and performance status were significant in Stage I/II IOC. For Stage III/IV tumors, the new tumor grade also was significant, as were performance status, residual tumor size, response to chemotherapy, and mucinous (unfavorable) or transitional cell (favorable) histologic type. International Federation of Gynecology and Obstetrics grade (based primarily on architectural features) did not correlate significantly with survival except in Stage III/IV serous and Stage I/II mucinous carcinomas., Conclusions: The new grading system reported is simple, reproducible (among the current study authors), and useful for all histologic types and clinical stages of IOC. Further testing for reproducibility and clinical utility is recommended.

This study evaluates the applicability of the published cytologic criteria in the categorization of proliferative breast lesions by assessing the diagnostic accuracy and interobserver reproducibility of a panel of experts. Twelve breast fine-needle aspiration (FNA) specimens of biopsy-proven nonproliferative breast lesion (NPL) (1 case), proliferative lesions without atypia (PL) (7 cases), proliferative lesion with atypia (PLA) (1 case), and low-nuclear grade ductal carcinoma in situ (DCIS) (3 cases) were selected. Six FNAs were Papanicolaou (PAP) and 6 were Diff-Quik-stained (DQ). Six expert cytopathologists classified the smears using a summary of published criteria as a guideline. All 6 participants rendered the same cytologic diagnosis in 2/12 (16%) cases. The agreement among the 6 raters was low (Kappa = 0.35). Cytohistologic correlation was achieved in 26/72 (36%) FNA diagnoses. The correlation of the PAP-stained cases was better than the DQ: 17/36 (47%) PAP and 9/36 (25%) DQ correlated. Improving the correlation was achieved by amalgamation of NPL and PL into "low risk" and PLA and DCIS into "high risk" categories: 47/72 (65%) FNA diagnoses then correlated with histology [29/36 (81%) PAP and 18/36 (50%) DQ]. We conclude that the cytologic criteria of proliferative breast lesions need to be further defined and assessed. Consideration should be given to minimizing the number of diagnostic categories and adopting a terminology that has a direct effect on patient management.

We studied the immunolocalization of cyclins D1 and E and their corresponding partner cyclin dependent kinases (cdk), cdk4 and cdk2 in 41 cases of human breast malignancy (21 invasive ductal carcinomas and 19 invasive lobular carcinomas) and examined the correlation of the labeling indexes among these cyclins, cdks, Ki67, estrogen receptor (ER) and progesterone receptor (PR). Cyclin D1 immunoreactivity was observed exclusively in the nuclei of tumor cells in 27/41 (65%) of the cases examined. Immunoreactivity for cyclin E and cdk2 was detected in all the cases and observed in the nuclei of both carcinoma and non-carcinoma cells. cdk4 immunoreactivity was detected in 39/41 (95%) cases and found in carcinoma and non-carcinoma cells. In all carcinomas examined, a significant correlation was observed only between Ki67 and cyclin D1 (p = 0.0037). However, when examining only invasive ductal carcinomas, a significant correlation was detected between Ki67 and cyclin D1 (p = 0.0069), Ki67 and cdk2 (p = 0.0043) and cyclin D1 and cdk4 (P = 0.0024). Only cyclin D1 correlated with the pathologic stages of the disease and histological grades of invasive ductal carcinoma. Among these cyclins and cdk, overexpression of cyclin D1 is considered to play an important role in the development of human breast malignancy through abnormal proliferation. No significant correlation was observed between steroid receptor status and any of cyclins and cdks examined. Cyclin D1 and cdk2 expression correlated with cell proliferation (Ki67) and cyclin D1 expression with expression of cdk4 in invasive ductal carcinoma but not invasive lobular carcinoma. Cyclin E expression did not correlate with cell proliferation, cyclin D1 or cdks possibly due to deregulation of its expression. These results also indicate different patterns of cyclin D1, cyclin E, cdk2 and cdk4 expression between invasive ductal and lobular carcinoma of human breast.

Telomerase activity has been detected in a broad range of human cancers and its expression could be an important step in tumor progression. Here, telomerase activity by the telomeric repeat amplification protocol in cases of benign endometrium, endometrial hyperplasia, and endometrial adenocarcinoma was tested. Telomerase expression was detected in 13 of 14 cases of proliferative phase endometrium, in 7 of 12 cases of secretory phase endometrium, but was not detected in any of 7 cases of atrophic endometrium. Three of three cases with evidence of luteal phase defect and one of four cases of chronic endometritis also expressed telomerase activity. Hyperplastic endometrium was positive for telomerase in 13 of 17 cases. Telomerase activity was detected in 40 of 48 cases of endometrial adenocarcinoma, which included 36 of 43 cases of endometrioid adenocarcinoma and four of five cases of papillary serous carcinoma. The detection of telomerase in endometrial adenocarcinoma was not associated with either architectural grade, myometrial invasion, or stage. There was statistically significant association, however, between telomerase activity in benign atrophic endometrium versus any endometrial abnormality in women 52 years of age or older.