Ulf Stendahl

Type-Specific Persistence of Human Papillomavirus DNA before the Development of Invasive Cervical Cancer

BACKGROUND Infection with the human papillomavirus (HPV) has been established as a cause of cervical cancer, but the association between a positive test for HPV DNA and the risk of the subsequent development of invasive cervical cancer is unknown. METHODS In a study of women who participated in a population-based screening program for cancer of the cervix in Sweden from 1969 to 1995, we compared the proportion of normal cervical smears (Pap smears) that were positive for HPV DNA among 118 women in whom invasive cervical cancer developed an average of 5.6 years later (range, 0.5 month to 26.2 years) with the proportion of HPV DNA-positive smears from 118 women who remained healthy during a similar length of follow-up (controls). The control women were matched for age to the women with cancer, and they had had two normal Pap smears obtained at time points that were similar to the times of the baseline smear and the diagnosis of cancer confirmed by biopsy in the women with cancer. RESULTS At baseline, 35 of the women with cancer (30 percent) and 3 of the control women (3 percent) were positive for HPV DNA (odds ratio, 16.4; 95 percent confidence interval, 4.4 to 75.1). At the time of diagnosis, 80 of the 104 women with cancer for whom tissue samples were available (77 percent) and 4 of the 104 matched control women (4 percent) were positive for HPV DNA. The HPV DNA type was the same in the base-line smear and the biopsy specimen in all of the women with cancer in whom HPV DNA was detected at base line. None of the control women had the same type of HPV in both smears. CONCLUSIONS A single positive finding of HPV DNA in a Pap smear confers an increased risk of future invasive cervical cancer that is positive for the same type of virus as identified earlier.

A population-based prospective study of Chlamydia trachomatis infection and cervical carcinoma

Persistent human papillomavirus (HPV) infection is an established cause of cervical cancer, but the role of other sexually transmitted agents, most notably Chlamydia trachomatis, has not been well defined. The women participating in the population‐based cervical cancer screening program in Västerbotten county of Northern Sweden were followed up for up to 26 years to identify 118 women who developed cervical cancer after having had a normal Pap smear (on average 5.6 years later; range 0.5 months–26 years). As controls, we selected another 118 women who were matched by birth cohort, time‐point of sampling of the baseline normal smear and who had a normal smear at the time when the corresponding case was diagnosed with cancer. The Pap smears and cervical cancer biopsies were analyzed by PCR for C. trachomatis DNA and for HPV DNA. At baseline, C. trachomatis DNA was present in 8% of cases but not among any one of the controls. The relative risk for cervical cancer associated with past C. trachomatis infection, adjusted for concomitant HPV DNA positivity, was 17.1 (95% CI 2.6–∞).The presence of C. trachomatis and of HPV were not interrelated. Whereas C. trachomatis was primarily found in specimens taken many years before cancer diagnosis, HPV DNA was associated with a short lag time before cancer diagnosis. Whereas most women who were HPV DNA‐positive in the prediagnostic smear were also positive for the same virus in the cervical cancer biopsy, none of the women were positive for C. trachomatis in both the prediagnostic smear and in the subsequent cervical cancer. In conclusion, a prior cervical C. trachomatis infection was associated with an increased risk for development of invasive cervical cancer.

Genetic alterations in cervical carcinomas: Frequent low-level amplifications of oncogenes are associated with human papillomavirus infection

The development of cervical carcinoma is closely associated with HPV infection. However, other genetic alterations also play an important role. In this study, we analyzed copy number alterations of several oncogene loci in a panel of 84 cervical tumors. Sixty‐five (77%) tumors were HPV DNA‐positive, and most were infected with type 16 or type 18 or both. The oncogenes studied include PIK3CA at 3q26.3, TERT at 5p15.33, C‐MYC at 8q24, CCND1 at 11q13.3, ERBB2 at 17q21.2 and locus region 20q13.2. Amplification of 1 or more genes was detected in 55 (65%) cases using interphase FISH. PIK3CA was amplified in 43% of tumors, followed by TERT (33%), 20q13.2 (30%), ERBB2 (29%), C‐MYC (25%) and CCND1 (12%). Most tumors showed low‐level amplification with 3–7 copies of these genes, and complex changes involving 3 or more genes occur more frequently in tumors at advanced stages. Increased protein expression of c‐erbB2 and c‐myc was observed in tumors with the corresponding gene amplification. Oncogene alterations were found more often in HPV‐infected cases, particularly for C‐MYC and TERT. These findings indicate that HPV‐associated cervical carcinomas bear frequent alterations of these genes, which may have critical biologic impact on the development and progression of carcinoma of the uterine cervix.

Haptoglobin Groups in Ovarian Carcinoma

Haptoglobin groups were determined in 182 patients with primary ovarian carcinoma. Previously reported associations could not be confirmed. A significant excess of HP2-1 was observed among patients with a family history of cancer.

LRIG1 and squamous epithelial uterine cervical cancer: correlation to prognosis, other tumor markers, sex steroid hormones, and smoking

The aim is to evaluate LRIG1 as a prognosis predictor and correlations to cofactors in squamous cell cervical cancer. LRIG1 expression was studied in 128 cervical carcinomas and was compared with expression of nine other tumor markers. Smoking history was registered and pretreatment serum estradiol and progesterone levels were evaluated in 79 women. At clinical stage IB, 58% of the tumors showed LRIG1 expression, but there was a decline by increasing stage (33% in stage IV). Ninety percent of women with stage IB cancer and LRIG1 positivity survived, as compared to 64% without expression (P = 0.02). LRIG1 expression did not predict prognosis in advanced stages, but in stage IIA there was a marked relative difference, with 75% survival in tumors expressing LRIG1, as compared to 43% in those without. No correlation was found between LRIG1 and the other nine tumor markers studied. A high serum progesterone and smoking correlated to absent LRIG1 expression. We conclude that LRIG1 appears to be a significant prognosis predictor in early-stage cervical cancer, independent of the other tumor markers that were studied. Diminished expression in advanced stages and the inverse correlation to serum progesterone and smoking indicates that LRIG1 is a tumor suppressor in cervix.

Carcinoma of the cervix in the African setting.

Carcinoma of the cervix is the commonest female malignancy in sub‐Saharan Africa today. A brief description of its prevalence and distribution is given. Kenyan data is then used to illustrate the predominance of advanced disease in mostly premenopausal women (70%) of high parity. Follow up is characteristically poor and treatment results, although difficult to calculate with accuracy, are also poor. These are compared to FIGO statistics. Against this background aspects peculiar to the tumor, patient and treatment facilities in Africa are cited and discussed with reference to current relevant literature.

Pretreatment serum levels of CA-125, carcinoembryonic antigen, tissue polypeptide antigen, and placental alkaline phosphatase, in patients with ovarian carcinoma, borderline tumors, or benign adnexal masses: Relevance for differential diagnosis☆

Pretreatment serum levels of the antigens CA-125, tissue polypeptide Antigen (TPA), carcinoembryonic antigen (CEA), and placental alkaline phosphatase (PLAP) were determined in samples from 295 women with adnexal masses. At laparotomy 48% of patients had epithelial ovarian carcinoma, 9% had tumors of low malignant potential, and 8% suffered from malignancies of other kinds. The sensitivity of CA-125 with 35 U/ml as the cutoff was 88% in women with ovarian carcinoma, but 74% among those with limited disease and 58% in borderline malignancy. Only 6 of 17 mucinous ovarian carcinomas were detected. Specificity was 83%. CEA was elevated above 5.0 micrograms/liter in 15 of 17 patients with mucinous ovarian cancer. TPA detected advanced stages of malignancy, but the sensitivity was low, 53%, in cases with limited disease. PLAP was elevated in 46% of ovarian carcinoma patients. For detecting malignancy overall, the use of a parallel combination of the CA-125 and CEA assays was more sensitive than use of CA-125 as a single marker. This test combination may be of value in the diagnosis of adnexal masses. The predictive value of a positive result was 90%, and that of a negative result, 76%.

Pretreatment serum levels of CA-125, carcinoembryonic antigen, tissue polypeptide antigen, and placental alkaline phosphatase in patients with ovarian carcinoma: Influence of histological type, grade of differentiation, and clinical stage of disease

Pretreatment serum levels of the tumor-associated antigens CA-125, tissue polypeptide antigen (TPA), carcinoembryonic antigen (CEA), and placental alkaline phosphatase (PLAP) were analyzed in 142 patients with epithelial ovarian carcinoma, and related to clinical and histopathological parameters. In a linear multiple regression model CA-125 serum levels were profoundly influenced by the type of tumor, i.e., mucinous or nonmucinous. Clinical stage also had significant impact, whereas grade of differentiation did not, when the other two factors were taken into account. CEA levels were also dependent mainly on histological type. Mucinous tumor cases had high levels. Only clinical stage or tumor burden had a significant impact on TPA levels. PLAP levels were significantly influenced by histological type of tumor and by grade of differentiation but not by clinical stage. The dependence of CA-125 levels upon clinical stage was evident only in nonmucinous tumors. Furthermore, size of the primary tumor was not important for the CA-125 value, in contrast to FIGO stage. Thus CA-125 is primarily a sensitive indicator of disseminated disease in ovarian carcinoma patients. On the basis of the CA-125 level it was possible to predict the extent of disease with an overall accuracy of 55%. If TPA and CEA levels were also considered, the predictive accuracy was 63%.

Cryosurgical treatment of cervical intraepithelial neoplasia with follow-up of five to eight years

During 1972 to 1974, 181 women of different ages with cervical intraepithelial neoplasia were treated with cryosurgery. Of these, 170 have now been observed for 5 to 8 years. Treatment failures total 16%, but when the different age groups are considered the results are seen to be much better in young women less than 30 years of age, with only a 12% rate of failure, whereas older women have almost twice as many failures. One patient, 45 years of age, developed an early invasive cancer, but in her case pretreatment diagnosis may have been correct. Our conclusions are that cryosurgery is an easy and effective method of treating cervical intraepithelial neoplasia in young women, provided that the diagnosis prior to therapy is correct. Furthermore, we stress that after treatment the status of the patient must be checked with vaginal smears over a long period and also that at lease one endocervical curettage and directed biopsies of the vaginal cervix should be done as a control.

LRIG2 in contrast to LRIG1 predicts poor survival in early-stage squamous cell carcinoma of the uterine cervix

Abstract Background. The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises LRIG1, 2, and 3. LRIG1 negatively regulates growth factor signaling and is a proposed tumor suppressor. In early stage uterine cervical carcinoma, expression of LRIG1 is associated with good survival. Less is known about the function and expression of LRIG2; it has not been studied in cervical carcinoma, previously. Materials and methods. LRIG2 expression was studied by immunohistochemistry in 129 uterine cervical squamous cell carcinomas and 36 uterine cervical adenocarcinomas. Possible associations between LRIG2 immunoreactivity and patient survival were evaluated. Results. In early-stage squamous cell carcinoma (stages IB–IIB), high expression of LRIG2 was associated with poor survival (Kaplan-Meier, log-rank, p=0.02). The 10-year survival rate for patients with high expression of LRIG2 was 60%, compared to 87% in patients with low expression (odds ratio 0.22, 95% CI 0.07–0.64). In multivariate analysis including the previously studied tumor suppressor LRIG1 and clinical stage, LRIG2 emerged as an independent prognostic factor (odds ratio 0.22, 95% CI 0.09–0.50). For patients with both high expression of LRIG2 and low expression of LRIG1, the 10-year survival rate was only 26% compared to 66% for the remaining study population. There was no correlation between LRIG2 expression and prognosis in the limited adenocarcinoma series. Discussion and conclusion. LRIG2 appears to be a significant predictor of poor prognosis in early-stage squamous cell carcinoma of the uterine cervix. A combination of high LRIG2 expression and low LRIG1 expression identified women with a very poor prognosis.