Mucin production in carcinomas of the uterine cervix

The histological types of the cervical carcinoma effect the incidence, prognosis and the treatment methods. One hundred and eighty-seven cases selected randomly among the cervical carcinoma were stained with mucicarmen, alcian blue, PAS, and PAS with diastase to identify the presence of intracellular mucin. One hundred and seventy-two squamous carcinoma were examined and 27.3% (47 cases) of them were shown to contain some degree intracellular mucin (nine cases which were originally diagnosed squamous carcinoma after the application of mucin stains to the tumors, reclassified as adenosquamous carcinoma because of demonstrated widespread intracellular mucus). Of the 14 adenocarcinomas, 13 were mucin positive. Mucin-positive tumors (independent of histological type) had metastasized to the lymph nodes in 23 of 60 cases (38.3%), in contrast to mucin-negative tumors which had metastasized in 24 of 127 cases (18.9%). The application of mucin stains can assist in the classification of poorly differentiated lesions as well as help in the planning of management and in the prognosis.     

Reducing the burden of glandular carcinomas of the uterine cervix

Widespread use of the Papanicolaou test for the screening of cervical cancers has lead to a significant decline in overall incidence and mortality rates over the past 3 decades. When different histologic types of cervical cancers are considered and trends are reexamined, it becomes apparent that observed declines are reflective of squamous cell carcinomas predominantly; the rates for adenocarcinomas continue to rise. This rise in incidence may be due to the greater difficulty in screening for glandular precursor lesions that often arise high within the endocervical canal. Reducing the incidence and mortality rates that are associated with adenocarcinomas can be accomplished by using improved screening techniques and large-scale implementation of cervical cancer vaccines that target the predominant oncogenic human papillomavirus types that are associated with adenocarcinoma.     

The prognosis of adenosquamous carcinomas of the uterine cervix.

OBJECTIVES: Firstly, to identify a cohort of women with invasive adenosquamous carcinomas of the uterine cervix, including mucin-producing squamous cell carcinomas. Secondly, to compare the biological characteristics and behaviour of a cohort of adenosquamous carcinomas with a cohort of non-mucin-producing squamous cell carcinomas. DESIGN: Histological review, retrospective survival analysis. SETTING: Regional multidisciplinary gynaecological oncology service. SUBJECTS: 161 cases of stage 1B and above invasive cervical carcinoma presenting between 1 January 1980 and 31 July 1987. Thirty nine women with adenosquamous carcinomas were compared with 103 women with non-mucin-producing squamous cell tumours. RESULTS: Inclusion of routine stains for mucin in the assessment of histological material resulted in the reclassification of 38 (24%) of the cases, including the identification of 31 mucin-producing squamous cell carcinomas. The survival with adenosquamous tumours was significantly worse than with squamous cell cancers (P = 0.006), 5-year survival rates being 52% and 75% respectively. Multivariate analysis showed that this effect was explained by differences in clinical stage, pelvic lymph node metastasis and vascular invasion by tumour. CONCLUSIONS: The application of routine mucin stains to cervical tumours identifies a group of previously unrecognized adenosquamous cancers. Tumours so identified are likely to pursue a more aggressive clinical course associated with a poorer survival when compared to non-mucin-producing squamous carcinomas.     

Reproducibility of classification in non-squamous cell carcinomas of the uterine cervix

OBJECTIVE: Reproducibility of histopathologic classification systems is of major importance for their utility in daily practice and in research. The reproducibility of histologic classification of non-squamous carcinomas (non-SCC) of the uterine cervix was evaluated, using population-based material from two 5-year periods in Norway. METHODS: Histologic slides from 388 tumors were reviewed by three experienced pathologists and analyzed for inter- and intraobserver agreement on histological subtypes and grade. RESULTS: Kappa values of inter- and intraobserver agreement were moderate to substantial for all major adenocarcinoma subgroups (endocervical, endometrioid, clear cell, or serous carcinoma), and fair to poor for mixed carcinomas and adenocarcinomas not otherwise specified (NOS). Interobserver agreement on villoglandular and adenosquamous carcinomas was poor, and the distinction of adenocarcinoma in situ from well-differentiated carcinoma proved difficult. Reproducibility of the high-risk subgroups of small cell and undifferentiated carcinomas was acceptable from a statistical point of view (kappa values >0.50). However, the authors agreed upon the diagnosis of small cell carcinomas and undifferentiated carcinomas only in 2/3 of these high-risk diagnoses. Patients with high-risk diagnoses showed significantly lower overall survival than patients with non-high-risk diagnoses (P < 0.001). This inferior survival was independent of whether the reviewers had agreed on the high-risk diagnosis or not. CONCLUSION: Clinicians should be aware of the potential inconsistencies of histopathologic diagnoses. No histopathological classification system will ever be perfectly reproducible. Future histopathologic classification of the uterine cervix should emphasize the distinction between groups of particularly low or high prognostic risks.     

Structure, treatment and success of treatment in invasive carcinomas of the uterine cervix

At the University Hospital Gynecological Department in Zagreb 1666 cancers of the uterine cervix were treated in the period of 4 years [1969--1972]. Among them were only 309 carcinomas in situ, the remaining 1357 were invasive. The distribution by stages was as follows: IA--75, IB--223, II--326, III--611, IV--122. Such unfavourable groups of cervical cancers proceed from the fact that cancer in situ and the early cancer stage I are often treated in other institutions; only the patients with advanced cancer, a poor general condition and those with various accompanying diseases are concentrated in the above quoted institution where there are technical possibilities and a team of surgeons and radiotherapists well educated in the treatment of cervical cancer. The authors present a five-year survival achieved by surgical, radiological, as well as by a combined method of treatment. The total cure rate for stage I was 87.6%, for stage II 64,4%, for stage III 34.4% and for stage IV 6.6%.     

Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix

INTRODUCTION: Exogenous hormones may influence the development of cervical adenocarcinomas. Incidence rates of adenocarcinomas and use of noncontraceptive hormones have increased since the 1970s, but few studies have investigated this potential relationship. METHODS: We conducted a multicenter case-control study of 124 women with adenocarcinomas, 139 women with squamous cell carcinomas matched on age, diagnosis date, clinic, and stage of disease (in situ or invasive) to adenocarcinoma cases, and 307 healthy community controls who were also matched on age, ethnicity, and residence to adenocarcinoma cases. Participants completed in-person interviews regarding exogenous hormone use before diagnosis and other risk factors and volunteered cervical samples for human papillomavirus (HPV) testing via a PCR-based method. Odds ratios (ORs) with 95% confidence intervals (CIs) estimated relative risks. RESULTS: Only 13 adenocarcinoma cases (10.5%), 7 squamous carcinoma cases (5%), and 20 controls (6.5%) had used noncontraceptive hormones for menopausal symptoms, irregular periods, or disease prevention; most use was short-term, former use. Ever-use was associated with adenocarcinomas (OR = 2.1, 95% CI 0.95-4.6) but not squamous carcinomas (OR = 0.85, 95% CI 0.34-2.1). No trends were seen with duration of use or ages at first use, but unopposed estrogens were positively associated with adenocarcinomas (OR = 2.7). Unopposed estrogens remained associated with adenocarcinomas (OR = 2.0) when analyses were restricted to the HPV-positive controls. Menopausal status was not associated with adenocarcinomas or squamous carcinomas and did not modify the other associations. CONCLUSION: Although small numbers warrant tentative conclusions, exogenous estrogens, especially unopposed estrogens, were positively associated with adenocarcinomas. Noncontraceptive hormones were negatively but weakly associated with squamous carcinomas.     

Overexpression of the c-Met/HGF receptor and its prognostic significance in uterine cervix carcinomas

OBJECTIVE: The purpose of this study is to evaluate the significance of the c-Met/hepatocyte growth factor receptor expression in invasive cervical carcinoma. METHODS: Ninety-Four patients with FIGO stage 1B disease, treated primarily with surgery, were studied immunohistochemically. Of the cases, 67 were squamous carcinoma and 27 were nonsquamous (10 were adenocarcinoma, 15 were adenosquamous carcinoma, and 2 were indifferentiated carcinoma). Immunohistochemically stained c-Met slides of primary malignancies were evaluated blindly of clinical outcome and other histopathological factors. RESULTS: Overexpression of c-Met was found in 56 of 94 specimens. Primary tumors which show recurrences were found to be c-Met overexpressors. Univariate survival analysis (Kaplan-Meier) showed that c-Met overexpression is significantly correlated with disease-free survival. Moreover the diameter of the primary tumor, deep cervical stromal invasion, presence of metastatic lymph node, number of metastatic lymph nodes and c-Met overexpression were significantly correlated with overall 5-year survival. Furthermore multivariant analysis with Cox regression showed that the presence of metastatic lymph node and immunopositivity for c-Met are significantly correlated with overall survival, while c-Met overexpression was found to be an independent variable for disease-free survival. CONCLUSION: These results reveal that c-Met oncogene overexpression is an important parameter for disease progression, recurrence, and survival in early-stage invasive uterine cervix carcinomas.     

Sebaceous glands in the uterine cervix: two new cases

The authors report on two new cases of sebaceous glands in the uterine cervix. This extremely rare histological observation was found on biopsy specimens of the uterine cervix because of unclear colposcopic findings and of recurrent CIN II. The etiology of this entity is discussed including a brief review of the medical literature.     

Adjuvant radiotherapy in carcinomas of the uterine cervix: the prognostic value of hemoglobin levels

Anemia has been associated with a poorer treatment response and reduced survival in women undergoing primary radiotherapy (RT) or radiochemotherapy for advanced cervical carcinoma. This study aimed to determine the influence of anemia on outcome in patients with cervical carcinoma undergoing adjuvant RT. Medical records were reviewed for 183 cervical cancer patients who had received adjuvant RT because of risk factors after radical surgery (n= 109) or inadequate primary surgery (simple hysterectomy; n= 74). Kaplan-Meier and Cox regression analyses were used to study hemoglobin levels before and during adjuvant RT in relation to recurrence-free and overall survival. Hemoglobin values > or =11 g/dL were considered normal, while those <11 g/dL indicated anemia. Hemoglobin levels before RT influenced significantly overall survival and recurrence-free survival across the whole group (overall survival--log rank(all patients)= 7.5; df = 1; P= 0.006). However, subgroup analysis showed that the observed difference was mainly due to the group of women who had undergone inadequate primary surgery (overall survival--log rank(inadequate surgery)= 10.8; df = 1; P= 0.001). Multifactorial regression analyses comparing hemoglobin before RT with grading and tumor stage confirmed the prognostic value of hemoglobin values. Maintaining normal hemoglobin values before and during adjuvant RT seems to be important, especially in patients who have had inappropriate simple hysterectomy, which may resemble a therapeutic situation.     

Plasma proteomic profiling for detecting and differentiating in situ and invasive carcinomas of the uterine cervix

The objective of this study was to identify multiple plasma protein markers that might be characteristic of in situ and invasive cervical cancers. Plasma samples obtained from patients with in situ cervical cancer (carcinoma in situ [CIS], n= 32), from patients with early invasive cervical cancer without lymph node metastasis (squamous cell carcinoma [SCC], n= 60), and from age-matched disease-free controls (n= 37) were analyzed by cation-exchange protein chips and surface-enhanced laser desorption and ionization time-of-flight mass spectrometry. A classification tree defined by six protein peaks could discriminate 84 of the 92 cancers (CIS and SCC) and 36 of the 37 controls, with 91% sensitivity and 97% specificity. In comparing the CIS and SCC samples, two protein peaks with Mr values of 6586.41 and 3805.68 were able to classify 55 of the 60 SCC and 31 of the 32 CIS samples, with 92% sensitivity and 97% specificity. This study demonstrates for the first time the feasibility of differentiating in situ and invasive cervical cancers through plasma protein profiling. Identification of the proteins different in invasive and in situ cancer may be of great value in the understanding of cervical cancer invasion and in the development of novel therapeutic intervention.     

CA 125 in normal tissues and carcinomas of the uterine cervix,endometrium and fallopian tube

Summary The study deals with the occurrence of cancer antigen 125 (CA 125) in the normal and neoplastic uterine cervix, endometrium and fallopian tube and its applicability as a tumour marker. CA 125 concentrations were measured in 52 secretion specimens, in cytosol fractions of 97 tissue biopsies and in serum from 47 women with nonmalignant disorders and from 334 patients with carcinomas. High quantities of CA 125 (780-454860 U/ml) were detected in cervical mucus, intra-uterine and tubal fluid, exceeding those in the corresponding serum samples by factors of up to 2000. CA 125 concentrations were 9–53 fold higher in cytosol fractions of normal and neoplastic glandular epithelia of the endocervix and endometrium than in those of cervical squamous epithelia and the cervical wall. Despite similarly high antigen concentrations in normal glandular epithelia and adenocarcinomas serum levels elevated to above 65 U/ml were only found in patients with malignant tumours. The positivity rates in serum increased with tumour extent and were 0–43% for primary and 63–79% for recurrent cervical, endometrial and tubal adenocarcinomas. During long-term follow-up, CA 125 serum concentrations were concordant with the clinical course in 10 out of 11 patients with progressive carcinomas. According to these results, the release of CA 125 into the peripheral blood is apparently dependent on the infiltrative growth and the mass of the tumour rather than on, the local tissue concentrations. The clinical use of CA 125 is limited to the detection of advanced adenocarcinomas of the Müllerian duct.Presented in part at the 46. Tagung der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe, Sept. 1986, Düsseldorf/FRGDedicated to Prof. Dr. A. Bolte, Köln, for his 60th birthday