The most important discoveries of the past 50 years in gynaecological pathology.

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.

Stromal p16 expression differentiates endometrial polyp from endometrial hyperplasia.

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.

Karyometry in atypical endometrial hyperplasia: a Gynecologic Oncology Group study.

OBJECTIVES: Treatment for atypical endometrial hyperplasia (AEH) is based on pathologic diagnosis. About 40% of AEH is found to be carcinoma at surgery. This study's objective is to derive an objective characterization of nuclei from cases diagnosed as AEH or superficially invasive endometrial cancer (SIEC). METHODS: Cases from GOG study 167A were classified by a central pathology committee as AEH (n=39) or SIEC (n=39). High resolution digitized images of cell nuclei were recorded. Features of the nuclear chromatin pattern were computed. Classification rules were derived by discriminant analysis. RESULTS: Nuclei from cases of AEH and SIEC occupy the same range on a progression curve for endometrial lesions. Cases of AEH and SIEC both comprise nuclei of two phenotypes: hyperplastic characteristics and premalignant/neoplastic characteristics. The principal difference between AEH and SIEC is the percentage of premalignant/neoplastic nuclei. When this percentage approaches 50-60% superficial invasion is likely. SIEC may develop already from lesions at the low end of the progression curve. CONCLUSIONS: AEH comprises cases which may constitute a low risk group involving <40% of AEH cases. These cases hold a percentage of <20% of nuclei of a preneoplastic phenotype. AEH cases from the central and high end of progression have >40% of nuclei of preneoplastic phenotype. Nuclei of the preneoplastic phenotype in AEH lesions are almost indistinguishable from nuclei in SIEC, where this percentage exceeds 60%. The percentage of nuclei of the preneoplastic phenotype in AEH esions might serve as criterion for assessment of risk for the development of invasive disease.

The endometrium.

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.

Artefact as the pathologist's friend: peritumoral retraction in in situ and infiltrating duct carcinoma of the breast.

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.

Pathological characteristics of cervical adenocarcinoma in a multi-center US-based study.

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.

Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study.

BACKGROUND: Adenocarcinoma of the endometrium is the most common gynecologic malignancy in the United States, accounting for approximately 36,000 diagnoses of invasive carcinoma annually. The most common histologic type, endometrioid adenocarcinoma (EC), accounts for 75-80% of patients. The objective of this work was to estimate the prevalence of concurrent carcinoma in women with a biopsy diagnosis of the precursor lesion, atypical endometrial hyperplasia (AEH). METHODS: This prospective cohort study included women who had a community diagnosis of AEH. Diagnostic biopsy specimens were reviewed independently by three gynecologic pathologists who used International Society of Gynecologic Pathologists/World Health Organization criteria. Study participants underwent hysterectomy within 12 weeks of entry onto protocol without interval treatment. The hysterectomy slides also were reviewed by the study pathologists, and their findings were used in the subsequent analyses. RESULTS: Between November 1998 and June 2003, 306 women were enrolled on the study. Of these, 17 women were not included in the analysis: Two patients had unreadable slides because of poor processing or insufficient tissue, 2 patients had only slides that were not endometrial, the slides for 5 patients were not available for review, and 8 of the hysterectomy specimens were excluded because they showed evidence of interval intervention, either progestin effect or ablation. In total, 289 patients were included in the current analysis. The study panel review of the AEH biopsy specimens was interpreted as follows: 74 of 289 specimens (25.6%) were diagnosed as less than AEH, 115 of 289 specimens (39.8%) were diagnosed as AEH, and 84 of 289 specimens (29.1%) were diagnosed as endometrial carcinoma. In 5.5% (16 of 289 specimens), there was no consensus on the biopsy diagnosis. The rate of concurrent endometrial carcinoma for analyzed specimens was 42.6% (123 of 289 specimens). Of these, 30.9% (38 of 123 specimens) were myoinvasive, and 10.6% (13 of 123 specimens) involved the outer 50% of the myometrium. Among the women who had hysterectomy specimens with carcinoma, 14 of 74 women (18.9%) had a study panel biopsy consensus diagnosis of less than AEH, 45 of 115 women (39.1%) had a study panel biopsy consensus diagnosis of AEH, and 54 of 84 women (64.3%) had a study panel diagnosis of carcinoma. Among women who had no consensus in their biopsy diagnosis, 10 of 16 women (62.5%) had carcinoma in their hysterectomy specimens. CONCLUSIONS: The prevalence of endometrial carcinoma in patients who had a community hospital biopsy diagnosis of AEH was high (42.6%). When considering management strategies for women who have a biopsy diagnosis of AEH, clinicians and patients should take into account the considerable rate of concurrent carcinoma.

Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study.

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.

Eosinophilic cell change of the endometrium: a possible relationship to mucinous differentiation.

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.

Family history as a co-factor for adenocarcinoma and squamous cell carcinoma of the uterine cervix: results from two studies conducted in Costa Rica and the United States.

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.

Combined signet ring cell and glassy cell carcinoma of the uterine cervix arising in a young Japanese woman: a case report with immunohistochemical and histochemical analyses.

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.

Borderline ovarian tumors: key points and workshop summary.

This article documents major points of agreement and disagreement among experts invited to participate in a Borderline Ovarian Tumor Workshop held in Bethesda, MD, on August 27-28, 2003. It is suggested that controversies related to the diagnosis and management of these tumors are often related to lack of data in the literature (small numbers of cases, unreported or unclear criteria for diagnosis and follow-up, insufficient length of follow-up, etc), and specific recommendations are made for further investigation and for reporting of data in future studies.

Pathology of cervical cancer.

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.

Proposal of a new scoring scheme for the diagnosis of noninvasive endocervical glandular lesions.

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.

Comparison of human papillomavirus genotypes, sexual, and reproductive risk factors of cervical adenocarcinoma and squamous cell carcinoma: Northeastern United States.

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.

Symposium part 3: Should pathologists diagnose endocervical preneoplastic lesions "less than" adenocarcinoma in situ?: Point.

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

Immunohistochemical staining in the distinction between primary endometrial and endocervical adenocarcinomas: another viewpoint.

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.

Mitotic activity and apoptosis in endocervical glandular lesions.

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.