Human leukocyte antigen class I and II haplotypes and risk of cervical cancer.

Human leukocyte antigen (HLA) variations may affect immune response to human papillomavirus infection and subsequent cervical neoplasia risk. We investigated the frequency and relationship between HLA-A-B and HLA-A-B-DR haplotypes among women with cervical cancer/high-grade lesions (n=365) and cytologically normal population controls (n=681) within three cervical neoplasia studies in the US and Costa Rica. Notable differences in haplotype frequencies were observed; the HLA-A*01-B*08 haplotype occurred in >5% of US Caucasians but in <1% of Costa Ricans. The most prevalent HLA-A*24-B*40-DR*04 haplotype in Costa Rica (5%) was found in <1% of US Caucasians. No HLA haplotype was significantly associated with cervical neoplasia, suggesting that individual allele associations reported to date (e.g. HLA-DR*13) are not likely explained by underlying haplotypes.

Associations between smoking and adenocarcinomas and squamous cell carcinomas of the uterine cervix (United States).

OBJECTIVES: Few studies of smoking and cervical carcinoma have addressed the rare cervical adenocarcinomas or used DNA-based tests to control for human papillomavirus (HPV) infection. METHODS: This multicenter case-control study included 124 adenocarcinoma cases, 307 community controls (matched on age, race, and residence to adenocarcinoma cases), and 139 squamous carcinoma cases (matched on age, diagnosis date, clinic, and disease stage to adenocarcinoma cases). Participants completed risk-factor interviews and volunteered cervical samples for PCR-based HPV testing. Polychotomous logistic regression generated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for both histologic types. RESULTS: Eighteen percent of adenocarcinoma cases, 43% of squamous carcinoma cases, and 22% of controls were current smokers. After control for HPV and other questionnaire data, adenocarcinomas were consistently inversely associated with smoking (e.g. current: OR = 0.6, 95% CI 0.3-1.1; > or = 1 pack per day: OR = 0.7, 95% CI 0.4-1.3), while squamous carcinomas were positively associated with smoking (e.g. current: OR = 1.6, 95% CI 0.9-2.9; > or = 1 pack per day: OR = 1.8, 95% CI 1.0-3.3). Results in analyses restricted to HPV-positive controls were similar. CONCLUSION: Smoking has opposite associations with cervical adenocarcinomas and squamous carcinomas. Although both histologic types are caused by HPV and arise in the cervix, etiologic co-factors for these tumors may differ.

Variance in the interpretation of cervical biopsy specimens obtained for atypical squamous cells of undetermined significance.

We sought to determine whether the variability in dysplasia rates in cases of atypical squamous cells of undetermined significance (ASCUS) reflects variability in interpretation of cervical biopsy specimens. In phase 1, 124 biopsy specimens obtained because of a cytologic diagnosis of ASCUS were reviewed independently by 5 experienced pathologists. Diagnostic choices were normal, squamous metaplasia, reactive, indeterminate, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL). The rate of dysplasia ranged from 23% to 51%. All pathologists agreed in 28% of cases. In 52% of cases, the diagnoses ranged from benign to dysplasia. The overall interobserver agreement was poor. In phase 2, 60 cervical biopsy specimens (21 obtained for ASCUS, 22 for LSIL, and 17 for HSIL) were evaluated using the same diagnostic choices. Agreement was better in biopsies performed for HSIL and LSIL compared to those for ASCUS. Intraobserver reproducibility in the interpretation of biopsies performed for ASCUS ranged from poor to excellent. We conclude that variability in the interpretation of biopsy specimens plays an important role in the differences in rates of dysplasia reported for the follow-up of ASCUS.

Glandular lesions of the uterine cervix.

During the past 20 years, pathologists have more carefully examined and more precisely classified glandular lesions of the endocervix, largely reflecting increased concerns about the diagnosis and pathogenesis of adenocarcinoma of the cervix. This review of glandular lesions of the cervix focuses on the following six issues surrounding the histologic diagnosis of the more common types of adenocarcinoma of the endocervix and their mimics: (1) the classification and recognition of preinvasive glandular lesions, (2) the distinction of invasive from preinvasive adenocarcinoma, (3) the definition and significance of microinvasive adenocarcinoma, (4) the epidemiology and pathogenesis of adenocarcinoma, (5) the identification and behavior of the more common subtypes of invasive adenocarcinoma, and (6) the recognition of benign lesions that mimic adenocarcinoma It is the author's opinion that most in situ and invasive adenocarcinomas of the cervix can be recognized and distinguished from benign mimics. In contrast, glandular dysplasia and microinvasive adenocarcinoma of the cervix are currently ill-defined and irreproducible terms that should not be used for diagnostic purposes. Although only brief descriptions of the biologic behavior of the various lesions and their therapy are included in this review, certain variants of endocervical adenocarcinoma have distinctive behaviors and should be classified appropriately to provide prognostication and help to guide therapy.

Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an unusual polyposis syndrome that has enjoyed a rich and somewhat confusing history. Mucocutaneous pigmentation and diffuse gastrointestinal hamartomas are the hallmark features of this autosomal dominant inherited condition. Peutz-Jeghers syndrome is now also recognized as a cancer predisposition syndrome. In this review, we highlight the historical aspects of PJS polyposis with special emphasis on its extraintestinal manifestations, particularly genital tract tumors. A PJS management scheme for clinicians is included.

Significance of true surgical pathologic staging: a Gynecologic Oncology Group Study.

OBJECTIVE: The object of the study was to determine the true surgical pathologic disease extent in patients with clinical stage II adenocarcinoma of the endometrium. STUDY DESIGN: As part of a Gynecologic Oncology Group surgical pathologic protocol of patients with adenocarcinoma of the endometrium, patients with clinical stage II cancers were evaluated. Among >1000 patients with early stage disease entered into this protocol group study, 148 were in clinical stage II. All patients underwent abdominal hysterectomy, bilateral salpingo-oophorectomy, and selective pelvic and para-aortic lymphadenectomy as the primary therapy. Surgical pathologic material was evaluated to determine true extent of disease. RESULTS: Only 66 of 148 (45%) of patients in clinical stage II had cancer in the cervix. Fifty-seven patients had disease limited to the upper fundus and 25 had disease extending into the lower uterine segment but not into the cervix. Among the 66 patients with disease in the cervix, only 35 had disease limited to the uterus whereas 31 patients had extrauterine disease (lymph nodes, adnexa, etc). Thus among 148 patients with diagnoses of clinical stage II disease only 35 (24%) in fact had true surgical stage II cancer. CONCLUSION: Clinical diagnosis of stage II adenocarcinoma of the uterus is a poor reflection of true surgical stage II cancer. Only when true extent of disease is known can optimally definitive therapy be determined.

A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study.

OBJECTIVE: The objective of this study was to evaluate the benefits and risk of adjuvant pelvic radiotherapy aimed at reducing recurrence in women with Stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. METHODS: Two hundred seventy-seven eligible patients were entered with at least two of the following risk factors: >1/3 stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Of 277 patients, 137 were randomized to pelvic radiotherapy (RT) and 140 to no further treatment (NFT). RESULTS: Twenty-one (15%) in the RT group and 39 (28%) in the NFT group had a cancer recurrence, 18 of whom were vaginal/pelvic in the RT and 27 in the NFT group. In the RT group, of 18 (13%) who died, 15 died of cancer. In the NFT group, of the 30 (21%) who died, 25 died from cancer. Life table analysis indicated a statistically significant (47%) reduction in risk of recurrence (relative risk = 0.53, P = 0.008, one-tail) among the RT group, with recurrence-free rates at 2 years of 88% versus 79% for the RT and NFT groups, respectively. Severe or life-threatening (Gynecologic Oncology Group grade 3 or 4) urologic adverse effects occurred in 4 (3.1%) in the RT group and 2 (1.4%) in the NFT group; 3 (2.3%) and 1 (0.7%) hematologic; 4 (3.1%) and 0 gastrointestinal (GI); and 1 (0.8%) and 0 neurologic, respectively. One patient's death was attributable to grade 4 GI adverse effects. CONCLUSIONS: Adjuvant pelvic radiotherapy following radical surgery reduces the number of recurrences in women with Stage IB cervical cancer at the cost of 6% grade 3/4 adverse events versus 2.1% in the NFT group.

Reproducibility of the histopathological classification of vulvar squamous carcinoma and intraepithelial neoplasia.

Invasive vulvar carcinoma has been shown to be etiologically heterogeneous on the basis of pathological, virological, and epidemiological criteria. Human papillomavirus-related invasive vulvar carcinoma has basaloid or warty morphology and has adjacent basaloid or warty intraepithelial neoplasia. Invasive carcinoma unrelated to human papillomavirus is a keratinizing squamous carcinoma that may have adjacent squamous hyperplasia. We provided to 3 pathologists for their review and pathological diagnoses stained tissue sections from 95 patients with vulvar carcinoma. The reproducibility for grading individual categories of intraepithelial lesions was only fair (kappa values of 0.31-0.43). The reproducibility was better (moderate to good; kappa values of 0.58-0.59) for grading individual categories of invasive carcinomas. The agreements improved when the basaloid and warty categories were combined. Good agreement was achieved (kappa values of 0.55-0.79) in distinguishing human papillomavirus-related lesions from those unrelated to human papillomavirus; all three reviewers agreed on this classification for 67% of the cases. The intrareviewer agreement was of the same order as interreviewer agreement. Difficulties in differentiating between some lesions (e.g., a warty carcinoma with little atypia from a well- to moderately differentiated keratinizing squamous carcinoma) and concurrent occurrence of human papillomavirus-related lesions and those lesions unrelated to human papillomavirus in a patient may account for some of the discrepancies in the histopathological diagnoses of vulvar carcinoma.

Villoglandular adenocarcinoma of the endometrium: a clinicopathologic study of 61 cases: a gynecologic oncology group study.

Papillary endometrioid or villoglandular adenocarcinoma (VGA) is a relatively common type of endometrial adenocarcinoma, but studies describing its behavior have yielded conflicting results. Patients with a component of VGA were identified in a review of 819 women entered in a Gynecology Oncology Group Study (Protocol 33) of clinical stages I and II endometrial adenocarcinoma. Cases with coexisting foci of serous or clear cell carcinoma were excluded from further consideration. Of the 61 cases that formed the study sample, there were 24 with pure villoglandular differentiation and 37 who were admixed with typical endometrioid adenocarcinoma (EA). The general clinicopathologic features of patients with pure and mixed VGA are compared with 469 patients with pure EA. The VGAs were better differentiated (grade 1 or 2--97% of VGA versus 74% EA, p = 0.001). but they were not significantly different with respect to median age, depth of invasion, or frequency of nodal spread. Six of the 61 patients with VGA died of their tumor. The disease-specific survival rate at 3 years for VGA is 94% (95% confidence interval: 0.88-0.99) compared with 88% (95% CI: 0.86-0.91) for EA. Two of the patients who died had pure villoglandular tumors and four had mixed villoglandular and endometrioid carcinoma. In view of the frequent admixture of VGA and EA and their generally similar biological characteristics, with a prognosis similar to that of typical EA, we conclude that VGA should be considered a variant of EA.

DNA content is an independent prognostic indicator in endometrial adenocarcinoma. A Gynecologic Oncology Group study.

The identification of prognostic variables is an important aspect of managing and counseling women with endometrial adenocarcinoma. The surgical stage, age, cell type, depth of myometrial invasion, and histologic grade have all been previously demonstrated to be related to prognosis. Several reports have indicated that tumor ploidy as determined by flow cytometry with fresh or fixed cells removed from paraffin blocks of endometrial adenocarcinomas can contribute to the assessment of prognosis. To verify the significance of DNA content in endometrial adenocarcinoma, we conducted an historical cohort study on a subgroup of women from a Gynecologic Oncology Group (GOG) protocol of early clinical stage disease. Flow cytometry was performed at one facility on cells extracted from blocks obtained from several GOG member institutions. Blocks were submitted for 293 of 933 eligible patients. Ninety-two histograms were of good quality, with 55 interpreted as diploid and 37 as aneuploid. One hundred sixty-two histograms were technically suboptimal, of which 137 were considered probably diploid, 13 probably aneuploid, and 12 unacceptable due to high background noise. Of the commonly accepted prognostic variables, only depth of invasion was significantly related to the ploidy status. There was no discernable difference in survival between patients with diploid and patients with probable diploid and probable aneuploid tumor types. Incorporation of the flow cytometry data into a proportional hazards regression model adjusted for age and surgical stage revealed a significant increased risk of disease-related death (relative risk, 4.1; 95% confidence interval, 2.3 to 7.3) for patients with aneuploid tumor type as compared to patients with diploid tumor type. This study confirms the prognostic significance of ploidy determination by flow cytometry and also indicates some of the difficulties of retrospectively applying this technology to cooperative group studies.

Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. A Gynecologic Oncology Group study.

OBJECTIVE: Our purpose was to evaluate the risk factors and prognosis in patients with stage IA squamous cell carcinoma of the cervix and 3 to 5 mm of invasion. STUDY DESIGN: From 1981 to 1984 the Gynecologic Oncology Group conducted a prospective clinicopathologic study of patients with stage I carcinoma of the cervix. A selective study group that was previously defined and reported included patients with squamous cell carcinoma of the cervix who were treated with radical hysterectomy and pelvic lymphadenectomy and who had disease confined to the uterus, with or without microscopically positive lymph nodes. RESULTS: One hundred eighty-eight patients had invasion of 3, 4, or 5 mm as determined by central pathology review. Patients who satisfied the 3 to 5 mm invasion definition of the current stage IA2 classification of the International Federation of Gynecology and Obstetrics (1995) are the subject of this report. CONCLUSIONS: Patients with stage IA2 carcinoma of the cervix who have 3 to 5 mm of invasion present on conization with no invasion in the hysterectomy specimen are at very low risk for lymph node metastases, recurrences, or death caused by cancer.

An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: a Gynecologic Oncology Group study.

The influence of cell type on recurrence-free interval (RFI) and survival after radical hysterectomy for patients with Stage IB carcinoma of the cervix was investigated. Patients with Stage IB carcinoma of the cervix (>3-mm invasion) underwent a radical hysterectomy and pelvic lymphadenectomy. Patients with involved paraaortic nodes or gross extracervical disease were excluded. Of 813 evaluable patients, 645 had squamous, 104 with adenocarcinoma, and 64 had adenosquamous cell type. The time to failure and the following clinical/pathologic characteristics were compared among the three cell types: age, Gynecologic Oncology Group performance status (PS), gross versus occult tumor, histologic grade, depth of invasion, node status, uterine extension, parametrial extension, surgical margins, and capillary-lymphatic space (CLS) involvement. A Cox proportional hazards model was used to compare the patients with adenosquamous and adenocarcinoma to those with squamous while adjusting for prognostic factors. The median age was 40 years (range, 21-87). Pelvic nodes were involved in 119 (15%) of patients. There were no significant differences between cell types in distributions of the following factors: age, PS, positive nodes, depth of invasion, uterine extension, surgical margins, or parametrial extension. There were statistically significant differences between cell types with regards to grade (P < 0.001), gross versus occult primary status (P = 0.016), and CLS involvement (P = 0.005). There was no statistically significant difference detected between cell types in crude comparisons of RFI (P = 0.29); however, there was a difference in survival (P = 0.02) with shorter survival seen in the adenosquamous cell type. After adjusting for CLS involvement, PS, depth of invasion, and clinical tumor size, survival remained worse for patients with adenosquamous primaries when compared to squamous carcinoma (P = 0.02) and adenocarcinoma (P = 0.007). In conclusion, no statistically significant differences were seen in RFI among cell types; however, in patients with Stage I carcinoma of the cervix overall survival after radical hysterectomy may be slightly worse for those with adenosquamous cell type.

Pathologic models to predict outcome for women with endometrial adenocarcinoma: the importance of the distinction between surgical stage and clinical stage--a Gynecologic Oncology Group study.

BACKGROUND: Numerous pathologic factors have been identified as important in predicting outcome for women with endometrial adenocarcinoma. However, most patients have a mixture of good and bad factors. For these women, the prognosis is uncertain, and it is often unclear whether postoperative therapy is indicated. METHODS: Using univariate and multivariate analysis, we investigated the pathologic factors commonly reported to be of prognostic significance, using data from 819 patients with clinical Stages I and II endometrial adenocarcinoma from a Gynecologic Oncology Group study. Since the clinical stage frequently underestimated the surgical stage, models that designate the relative risk associated with each of the variables were created for both clinical and surgical Stage I and 11 patients. RESULTS: We confirmed the importance of age, depth of myometrial invasion, and to a lesser degree, histologic grade, and cell type, as independent prognostic variables. CONCLUSIONS: The relative risk of death can be determined using a simple multiplicative calculation, and the absolute risk can be estimated by inspection of the accompanying figures. These data can be used to provide patients with prognostic information and to help determine the need for postoperative adjuvant therapy.

The immunohistochemical discrimination of endometrioid adenocarcinomas.

Carcinomas of endometrioid histology frequently arise in the endometrium, ovary, and endocervix and involve the pelvic tissues in women. Adenocarcinomas of psuedoendometrioid morphology developing in the colon also frequently involve the ovary. The authors retrospectively examined 97 adenocarcinomas from the uterus, cervix, ovary, and colon to ascertain whether the site of origin could be determined by using a battery of antibodies with the immunoperoxidase method on formalin-fixed tissue. This study was restricted to tumors with endometrioid morphology. There were 27 endometrial, 16 ovarian, 23 endocervical adenocarcinomas, and 31 psuedoendometrioid colonic adenocarcinomas. The battery of antibodies included vimentin (V), monoclonal carcinoembryonic antigen (mCEA), and monoclonal CEA D-14. V-positive cells were defined by the presence of a crisp paranuclear band of staining, and CEA-positive cells showed irregular or diffuse cytoplasmic staining. V diffusely decorated 22 of 27 (81.4%) of endometrial tumors, 3 of 23 (13%) of endocervical tumors, (rare, focal staining), diffusely stained 5 of 16 (31.3%) of ovarian tumors, and was rare and focal in 2 of 31 (6.4%) of colon tumors. Both CEA antibodies were negative for cytoplasmic staining in both endometrial and ovarian tumors, but decorated from 65.2% (CEA D-14) to 95.6% (monoclonal CEA) of endocervical tumors and from 83.8% (CEA D14) to 90.3% (mCEA) of colonic tumors. The authors conclude that endometrioid adenocarcinomas developing in endometrium and ovary are most often strongly V positive and CEA negative, which greatly aids in distinguishing them from endometrioid or pseudoendometrioid tumors arising in endocervix and colon, which are only rarely, and very focally V and CEA positive. The antibodies do not allow for discrimination between endocervical and colonic tumors. CEA D-14 offered no immunodiagnostic superiority over mCEA. These results support the use of immunohistochemistry is assisting in the distinction of endometrial from endocervical primary sites in curettage specimens and in metastatic sites.

The utility of the revised International Federation of Gynecology and Obstetrics histologic grading of endometrial adenocarcinoma using a defined nuclear grading system. A Gynecologic Oncology Group study.

BACKGROUND: The histologic grade of endometrial adenocarcinoma is related to the aggressiveness of the tumor and probability of death from disease. However, the ideal system for assignment of histologic grade remains controversial. In 1988, the International Federation of Gynecology and Obstetrics (FIGO) revised its recommendations for grading typical endometrial adenocarcinoma, such that grade is determined primarily by the architecture of the tumor and secondarily modified in the presence of "notable nuclear atypia"; this phrase, however, has never been defined, and therefore the prognostic validity of this system is unknown. METHODS: Seven hundred and fifteen women with clinical Stage I and occult Stage II endometrial adenocarcinomas (excluding serous or clear cell type) entered on a Gynecologic Oncology Group protocol, and those treated by total abdominal hysterectomy, bilateral salpingo-oophorectomy, and selective pelvic and para-aortic lymph node sampling formed the study population. All cases were centrally reviewed and assigned an architectural grade and a nuclear grade using specific criteria. The FIGO grade was then determined. The various grading methods were examined based on ability to stratify patients into groups with differing rates of disease progression and relative survival at five years. RESULTS: The architectural grade, nuclear grade, and FIGO grade of tumors each were used to separate patients into groups with statistically significant different rates of progression of disease and relative survival. The FIGO modification of architectural grade resulted in the reassignment of 44 patients into a higher grade. The outcome for these 44 was worse than for the remaining patients in the initial grade but was similar to the group into which they were moved. CONCLUSIONS: If clearly specified criteria for architectural and nuclear grading are used and "notable nuclear atypia" is defined as grade 3 nuclei, the 1988 FIGO grading system has prognostic utility. The authors recommend this system as the standard method for the grading of typical endometrial adenocarcinoma.

The prognostic value of nuclear versus architectural grading in endometrial adenocarcinoma: a Gynecologic Oncology Group study.

The pathologic grade of endometrial adenocarcinoma is widely recognized as an important prognostic and therapeutic indicator. However, disagreement persists about the optimal method of determining grade. The pathology committee of the Gynecologic Oncology Group employs a system based on the proportion of tumor in glandular array; this system is both reproducible and predictive of outcome. Others have suggested that grading based on nuclear pleomorphism and the size of nucleoli provides better prognostication. We compared the three-level architectural grading system (AG) with a two-level nuclear grading system (NG) to determine reproducibility and prognostic value in 88 cases of stage 1 endometrial adenocarcinoma. Three pathologists made independent assessments of grade by each method. The division of tumors by architectural arrangement was superior for predicting survival (83%, 73%, and 44%, AG, p = 0.005; vs. 79% and 61%, NG, p = 0.14) and equivalent to nuclear grading for prediction of recurrence. Both systems were moderately reproducible (k = 0.49, AG; k = 0.57, NG). Assessment of NG was more tedious than that of AG. Subdivision of architectural grade based on high nuclear atypia, as recommended in current, International Federation of Gynecology and Obstetrics guidelines, did not improve prognostication. Because grading based on nuclear pleomorphism does not provide prognostic information superior to that resulting from architectural grading, we do not advocate its use in routine surgical pathology practice.