False-negative Papanicolaou smears from women with cancerous and precancerous lesions of the uterine cervix

The occurrence from 1980 to 1989 of false-negative Papanicolaou smears in women with cancerous and precancerous lesions of the uterine cervix was studied. The 4,781 cases of cancer (2,814 invasive carcinomas and 593 carcinomas in situ) and precancerous lesions (418 severe dysplasias, 748 moderate dysplasias and 208 mild dysplasias) included 70 cases (1.5%) with false-negative smears. These 70 cases included 43 invasive carcinomas (61.4%), 17 carcinomas in situ and adenocarcinomas in situ (24.2%), and 10 dysplasias (14.4%); all were diagnosed histologically. The mean age of women with false-negative smears was 44.1 +/- 13.7 years. Review of the original cytologic samples showed a screening error in 41 cases (58.5%), an interpretation error in 2 cases (2.9%) and a sampling error in 27 cases (38.6%). Methods for eliminating false-negative smears are discussed.     

Discrimination between precancerous and cancerous lesions of the uterine cervix by DNA measurements on tissue sections

Morphologically typical uterine cervical biopsies were separated into normal cervices, condylomas and cervical intraepithelial neoplasias (CIN) grades I, II and III. At least 100 nuclei per lesion were measured on 4 micron Feulgen-stained sections using a Zeiss microspectrophotometer, with a variant of the plug method used to compute the nuclear DNA content. DNA distribution histograms were then decomposed into subsets of diploid, tetraploid, octoploid and aneuploid cells. The decomposition, which assumed a log-normal model of polydiploidy distribution, led to the identification of six indices: (1) the percentage of diploid cells, (2) the percentage of tetraploid cells, (3) the percentage of octoploid cells, (4) the percentage of aneuploid cells with DNA contents less than tetraploidy, (5) the percentage of aneuploid cells with DNA contents between tetraploidy and octaploidy and (6) the percentage of aneuploid cells with DNA contents greater than octoploidy. These indices, along with the mean nuclear radius, the 5c exceeding rate and the 2c deviation index, generated a nine-dimensional space. Two methods of discriminant analysis on this space showed discriminating powers of 78.22% and 87.13%, respectively, as compared to the original diagnoses. The most discriminating variable in both analyses appeared to be the percentage of octoploid cells.     

Nuclear DNA analysis of koilocytic and premalignant lesions of the uterine cervix.

Cervical biopsy samples were taken from 79 patients who had various grades of cervical intraepithelial neoplasia or who showed evidence, in the form of koilocytosis, of human papillomavirus infection of the uterine cervix and from 10 women with normal cervices. The DNA content of the cells in the samples was analysed by flow cytometry. Analysis of the data obtained showed that the biopsy samples from women with cervical intraepithelial neoplasia and human papillomavirus lesions contained significantly more dividing cells (31.2% of cells from human papillomavirus lesions with no cervical intraepithelial neoplasia and 33.06%, 29.89%, and 31.76% of cells from cervical intraepithelial neoplasia grades I, II, and III, respectively) than those from women with normal cervices (21.6%). The proportion of aneuploid samples from the group who showed evidence of human papillomavirus infection only (18.2%) did not differ significantly from the group with cervical intraepithelial neoplasia grade III (21.2%). Aneuploidy and an increased rate of cellular proliferation are recognised characteristics of malignancy. These results therefore support the view that human papillomavirus plays an important part in the aetiology of cervical carcinoma and are relevant to the clinical management of patients.     

Histochemical methods in the diagnosis of precancerous states and early forms of cancer of the uterine cervix.

Histochemical characteristics of displasia, various forms of the cancer in situ and initial invasive cancer together with histochemical criteria for differential diagnoses of these processes are given.     

Verrucous carcinoma of the uterine cervix. A case report

The cytohistopathologic features of a verrucous cervical carcinoma are reported. The presence in a cervical smear of two distinct types of dyskaryotic cells, with regularity of size and shape, and of occasional vacuolated cells set in a bright, eosinophilic background should suggest the lesion. With the cytologic suggestion and the typical warty clinical appearance of the tumor, an accurate preoperative diagnosis may be established.     

Sister chromatid exchanges in patients with precancerous and cancerous lesions of cervix uteri

Summary The frequency of sister chromatid exchanges (SCEs) was studied in leucocytes from 46 patients with cervical carcinoma, 89 precancerous lesions, and 43 age-matched control women. The frequency of SCEs was found to be 10.15 ±2.49 in cancer, 8.83±2.15 in precancerous lesions, and 7.55±2.24 in controls. The analyses of SCE data revealed a highly significant (P<0.001) increase in precancerous and cancerous lesions compared to controls. The intra-chromosomal distribution of SCEs revealed a random increase in various chromosomal groups in patients with cancer and dysplasia compared to controls. The mean SCE level among various groups of precancerous lesions according to severity of pathological condition did not show significant differences. However, 70.8% of dysplasia cases revealed SCE levels higher than the average in controls. The increased frequencies of SCEs in the majority of cancer patients and a few, precancerous lesions indicate that individuals with high SCE levels may be at a high risk of developing cancer. Thus the usefulness of SCE levels as a preclinical marker to identify the high risk group of dysplasias needs to be ascertained by follow-up studies; these are in progress.     

DNA-cytometric diagnosis of prospective malignancy in borderline lesions of the uterine cervix

Interactive DNA cytometry was used for the diagnosis of prospective malignancy in 48 smears with borderline lesions (mild and moderate dysplasias) of the uterine cervix. In addition, 183 smears with benign squamous epithelia, 38 with carcinoma in situ and 7 with invasive squamous carcinoma were also measured. Nuclear Feulgen-DNA measurements were performed using various methods, and the resulting data were analyzed by an algorithm for a DNA-cytophotometric diagnosis of malignancy. The results were compared with the data on follow-up and subsequent histologic studies in these cases. There was no false-positive diagnosis in the 183 benign smears and only 1 false-negative diagnosis in the 76 histologically proven squamous-cell carcinomas, which yields a specificity of 100% and a sensitivity of 98.6%. The sensitivity for the detection of subsequent histologically proven malignancy in cases with cytologically mild or moderate dysplasia amounted to 97%. In 13 borderline cases, there was a mean interval of 21 months between the taking of the cytologic smear on which the DNA diagnosis of malignancy was made and the date on which the histologic confirmation of malignancy was made. In 17% of the cytologically dysplastic cases, the DNA diagnosis of malignancy was not verified by subsequent histologic investigation. These results indicate that interactive DNA cytometry is able to detect prospective malignancy in smears from borderline lesions of the uterine cervix with a high sensitivity.     

Adenoid basal lesions of the uterine cervix: evolving terminology and clinicopathological concepts

The epithelial proliferations that are designated adenoid basal carcinoma (ABC) in the current classification from the World Health Organization represent <1% of all cervical malignancies. These lesions may be associated, and occasionally show morphologic transitions with, conventional cervical malignancies. The determination of the precise frequency with which these so-called ABCs show this association is hampered by the inherent selection bias in the reported cases. However, this frequency appears to be substantial (>15%). The biologic course of ABCs that are associated with separate malignancies is largely dependent on the clinicopathologic parameters of the associated malignancies. Morphologically pure lesions, in contrast, have largely been associated with favorable patient outcomes, as none of the 66 reported patients have experienced tumor recurrence, metastases or tumor-associated death, irrespective of the modality of treatment. Although the finding of genome integrated high-risk human papillomavirus (HPV) types and p53 alterations in adenoid basal lesions (ABL) argue in support of their neoplastic nature, we identified no lines evidence that suggest an inherent malignancy for morphologically pure lesions. The finding of morphologic transitions between ABLs and conventional malignancies and shared HPV types in these areas, suggest that ABLs have some malignant potential. However, the precise magnitude of this potential is not readily quantifiable and should not dictate the management of morphologically pure lesions that are entirely evaluable. ABLs continue to occupy a unique position in human oncology in which the term carcinoma (without an in-situ suffix) is applied to a tumor that has not been shown to recur, metastasize or cause death. We concur with a previous proposal that the term ABC should be discarded and replaced with Adenoid Basal Epithelioma (ABE). In our opinion, there is insufficient evidence at present time to expose patients with morphologically pure lesions to the ominous implications – social, psychological, medical, financial – of a "carcinoma" diagnosis. Morphologically impure lesions should not be designated ABC or ABE. Furthermore, given the uncertainties regarding the frequency with which ABE are associated with separate malignancies, we suggest that the ABE designation only be applied when the tumor in question is entirely evaluable e.g in a hysterectomy specimen or in an excisional biopsy with negative margins. Otherwise, the generic designation Adenoid Basal Tumor is preferable. This approach strikes an appropriate balance between the need to prevent over-treatment of pure lesions on one hand, and the need to ensure that the lesions are indeed pure on the other.     

P-cadherin expression in glandular lesions of the uterine cervix detected by liquid-based cytology

OBJECTIVE: To study P-cadherin aberrant expression as a possible marker for cervical adenocarcinomas in cytological samples. METHODS: We studied P-cadherin immunoexpression in liquid-based cervical cytology samples of biopsy-proven cervical lesions. RESULTS: We found a statistically significant correlation between P-cadherin expression and a cytological diagnosis of malignancy, either glandular or squamous (P < 0.0001). Twenty-two of 33 malignant cases showed P-cadherin membrane staining. None of the 30 benign cases tested showed membrane staining, but three of them displayed an aberrant nuclear P-cadherin expression. CONCLUSIONS: We concluded that P-cadherin can be used to discriminate between malignant and benign cervical cytological specimens, but not to discriminate glandular from squamous lesions.     

Pseudotumoral tuberculosis of the uterine cervix. Cytologic presentation

The cytologic presentation of a case of pseudotumoral tuberculosis of the uterine cervix is described. The presence in cervicovaginal smears of epithelioid cells arranged in clusters mixed with Langhans' giant cells was highly suggestive of tuberculosis. This diagnosis was confirmed by the detection of acid-fast bacilli in histologic preparations and cultures from biopsy specimens.     

The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix.

Recently, mast cell tryptase has been identified as another potent proangiogenic factor in tumors, along with fibroblast and vascular endothelial growth factors. Its role has been studied in a number of cancers, including carcinoma of the uterine cervix, with discordant results. Our aim was to study the expression of tryptase and bFGF in mast cells (MCs) during development of neoangiogenesis in premalignant and malignant lesions of the cervix. Biopsy specimens from 21 patients without cancer and from 63 patients with dysplasias and squamous cell carcinomas were used. They were stained with Alcian blue-safranin O (ABSO) and immunostained with specific antibodies against factor VIII, CD105, tryptase, and bFGF. Tryptase-positive mast cells increased with tumor progression and were close to newly formed blood vessels. Vascularization showed a linear increase from dysplasia to invasive cancer. We suggest that MC tryptase may upregulate neoangiogenesis in carcinogenesis of the uterine cervix.     

Excision of precancerous lesions of the lip

A method of surgical treatment of precancerous lesions of the lip, by excision of the vermilion border and the advancement of the inner mucosa of the lip to cover the defect, satisfactorily removes the entire lesion and restores normal tissue to the lip surface.     

Co-overexpression of bcl-2 and c-myc in uterine cervix carcinomas and premalignant lesions

To establish the role of co-overexpression of bcl-2 and c-myc protooncogenes in uterine cervix carcinogenesis, we examined 138 tissue samples of low grade cervical squamous intraepithelial lesions (SIL), high grade SIL, portio vaginalis uteri (PVU) carcinoma in situ and PVU carcinoma invasive, stage IA-IIA (study group) and 36 samples without SIL or malignancy (control group). The expression of bcl-2 and c-myc was detected immunohistochemically using a monoclonal antibody. Fisher’s exact test (P<0.05) was used to assess statistical significance. Overexpression of bcl-2 was found to increase in direct relation to the grade of the cervical lesions. High sensitivity was of great diagnostic significance for the detection of these types of changes in the uterine cervix. On the basis of high predictive values it can be said that in patients with bcl-2 overexpression there is a great possibility that they have premalignant or malignant changes in the uterine cervix. Co-overexpression of bcl-2 and c-myc oncogenes was found only in patients with PVU invasive carcinoma (6/26-23.0%). Statistically significant difference was not found in the frequency of co-overexpression in patients with PVU invasive carcinoma in relation to the control group (Fisher’s test; P=0.064). The method's sensitivity of determining these oncogenes with the aim of detecting PVU invasive carcinoma was 23%, while specificity was 72.2%. On the basis of high predictive values (100%), speaking in statistical terms, it can be concluded that all patients with co-overexpression of bcl-2 and c-myc oncogenes will have PVU invasive carcinoma. We confirmed in our research that co-overexpression of bcl-2 and c-myc oncogenes was increased only in PVU invasive carcinoma. However, a more extensive series of samples and additional tests are required to establish the prognostic significance of bcl-2 and c-myc co-overexpression in cervical carcinogenesis.     

Immunohistochemical localization of glutathione S-transferase in preneoplastic and neoplastic lesions of the human uterine cervix

A mouse monoclonal antibody and a rabbit polyclonal antibody prepared against the placental form of the enzyme glutathione S-transferase (GST-pi) were used to immunohistochemically stain normal and neoplastic human uterine cervical tissues from 88 cases. Of 65 cases of preneoplastic squamous lesions and invasive carcinomas of the cervix, 94% stained with the monoclonal antibody and 100% with the polyclonal antibody. In the 23 benign tissues, staining of ectocervical squamous epithelium was generally not observed; however, areas of reserve-cell hyperplasia, immature squamous metaplasia and adjacent endocervical cells did show staining (68% with the monoclonal antibody and 95% with the polyclonal antibody). Many of the positive tissue types showed a variety of staining patterns and intensities. These findings do not support the concept that GST-pi staining can be used to distinguish preneoplastic lesions of the cervix from benign reactive or proliferative processes. These results are of interest in the investigation of cervical carcinogenesis since GST-pi may be involved in an early stage of neoplastic transformation of the cervical epithelium. The correlation of these findings with the results of human papillomavirus testing and DNA content analysis should be of interest in determining the relationship of this enzyme to cervical neoplasia.