Pretreatment serum squamous cell carcinoma antigen: a newly identified prognostic factor in early-stage cervical carcinoma.

PURPOSE: To investigate the prognostic value of pretreatment serum squamous cell carcinoma antigen (SCC-ag) levels in patients with cervical squamous cell carcinoma in relation to well-established conventional risk factors. PATIENTS AND METHODS: Sera from 653 women treated for squamous cervical cancer between 1978 and 1994 were analyzed for the presence of SCC-ag and related to clinicopathologic characteristics and patient outcome using univariate and multivariate analyses. RESULTS: Increased pretreatment SCC-ag levels correlated strongly with unfavorable clinicopathologic characteristics (International Federation of Gynecology and Obstetrics [FIGO] stages IB to IV [P < or = .00005]; stages IB and IIA: tumor size [P = .0236], deep stromal infiltration [P = .00009], and lymph node metastasis [P = .0001]). After multivariate analysis, elevated pretreatment serum SCC-ag levels (P = .001), lesion size (P = .043), and vascular invasion by tumor cells (P = .001) were independent predictors for the presence of lymph node metastases. In Cox regression analysis, controlling for SCC-ag, lesion size, grade, vascular invasion, depth of stromal infiltration, and lymph node status only the initial SCC-ag level had a significant independent effect on survival (P = .0152). Even in node-negative patients, the risk of recurrence was three times higher if the SCC-ag level was elevated before therapy. CONCLUSION: The determination of pretreatment serum SCC-ag level provides a new prognostic factor in early-stage disease, particularly in patients with small tumor size. In future trials to assess the value of new treatment strategies, pretreatment serum SCC-ag levels can be used to help identify patients with a poor prognosis.

Clinical value of routine serum squamous cell carcinoma antigen in follow-up of patients with early-stage cervical cancer.

PURPOSE: To investigate the contribution to recurrence detection and survival of serum squamous cell carcinoma antigen (SCC-ag) analysis in the follow-up of early-stage cervical cancer patients. PATIENTS AND METHODS: Follow-up data were evaluated in patients with early-stage squamous cell cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy with or without radiotherapy. Routine serum SCC-ag determination was performed at each follow-up visit. RESULTS: Recurrent disease occurred in 35 (16%) of 225 patients and was preceded or accompanied by serum SCC-ag elevation 26 times (sensitivity, 74%). In five (14%) of these 35 patients, elevated serum SCC-ag was the first measured clinical indicator. Desite salvage therapy, all five patients died of disease. In the other 31 patients (21 with serum SCC-ag elevation), either symptoms and/or positive signs led to recurrence detection. Median survival time after recurrence was worse (9 months; range, 2 to 112+) for patients with an elevated serum SCC-ag value at recurrence in comparison with patients with normal serum SCC-ag values (20 months; range, 4 to 96; P <.01). In 23 of the 190 patients without recurrences, serum SCC-ag values became falsely elevated. In 16 of these 23 patients, the repeat sample after 6 weeks showed a normal SCC-ag, and in seven patients benign (especially skin) disorders were found. CONCLUSION: Serum SCC-ag analysis results in earlier recurrence detection in a small proportion (14%) of patients but did not contribute to better survival. As long as treatment possibilities for recurrent cervical cancer patients are not improved, serum SCC-ag analysis should not be carried out in routine follow-up.

Antibodies to human papillomavirus type 16 E7 related to clinicopathological data in patients with cervical carcinoma.

AIMS: To investigate the correlation between antibodies to the transforming protein E7 of human papillomavirus (HPV) type 16 and clinicopathological indices in women with cervical squamous carcinoma. METHODS: A synthetic peptide of the HPV type 16 E7 protein (amino acids 6 to 35) was used to screen sera from 29 children, 130 women with cervical intraepithelial neoplasia, 443 women with cervical cancer, and 222 controls, for antibodies against this viral antigen. Bivariate and multivariate analyses were used to investigate the correlation between the serological status in the pretreatment sera and clinicopathological indices (size of the lesions, histological grade, stomal infiltration, vascular invasion, and nodal spread). Survival analysis was done using the Cox regression model for all FIGO stages and stages IB and ILA. RESULTS: Cervical carcinoma patients had a significantly higher prevalence of antibodies to synthetic peptide E7/6-35 than women with cervical intraepithelial neoplasia (17.7% v 7%, p < 0.005) or controls (17.7% v 11%, p < 0.05). Bivariate analysis of the data on the presence of anti-E7/6-35 antibodies in the pretreatment sera from these patients and clinicopathological indices showed a significant correlation between the presence of anti-E7/6-35 antibodies and the size of the lesion (p = 0.0009), histological grade (p = 0.0031), and lymph node metastasis (p = 0.01). 0.011). In addition, the Cox regression model, analysing four risk factors which can be determined before treatment, showed a significant correlation between the presence of anti-E7/6-35 antibodies and a worse prognosis (p = 0.003). Survival analysis revealed that both for all FIGO stages (p = 0.0005) and for stages IB and IIA alone (p = 0.0021), anti-E7/6-35 positive patients before treatment had a significantly shorter life expectancy. CONCLUSIONS: The presence of antibodies against E7/6-35 in pretreatment sera from patients with cervical carcinoma correlates with the size of the lesions, lymph node involvement, and a worse prognosis.

Detection of HPV-16 DNA by PCR in histologically cancer free lymph nodes from patients with cervical cancer.

The prognostic value of detection of human papillomavirus (HPV) type 16 DNA in histologically cancer free lymph nodes was assessed in left obturator lymph nodes from cervical cancer patients with HPV-16 positive primary tumours. HPV-16 DNA was detected by polymerase chain reaction in 12 of 35 patients with histologically cancer free lymph nodes. Of these 12 patients, only one developed a recurrence, suggesting HPV-16 DNA detection in cancer free lymph nodes has no prognostic value.

Tumor markers CA 125, squamous cell carcinoma antigen, and carcinoembryonic antigen in patients with adenocarcinoma of the uterine cervix.

Between 1978-1987, 439 patients with primary cervical carcinoma were admitted to our department. Seventy-seven patients (17.5%) had cervical adenocarcinoma and are reviewed in this retrospective study. Serial serum samples of these 77 patients were analyzed for cancer antigen 125 (CA 125), squamous cell carcinoma antigen, and carcinoembryonic antigen. Before treatment, only elevated serum CA 125 levels varied directly with the clinical stage of disease. In stages IB and II disease (International Federation of Gynecology and Obstetrics [FIGO]), the incidence of elevated serum CA 125 levels was highest in patients with adenosquamous tumor. Serum marker levels, measured 3 months after therapy, concurred with the treatment results. At that time, 17 of the 23 cases (74%) with at least one elevated serum marker level either had residual disease (N = 9) or developed recurrent disease during follow-up (N = 8), compared with six of the 40 cases (15%) with normal serum marker levels (P less than .001). Increasing serum marker levels during follow-up coincided with or preceded the clinical detection of recurrent disease. Tumor relapse, clinically located in the vaginal vault, occurred concomitant with a rise of at least one serum marker level in six of the seven cases (86%). All 15 patients with abdominal recurrence showed elevation of CA 125. In progressive disease, very high serum CA 125, squamous cell carcinoma antigen, and carcinoembryonic antigen levels were determined in patients with adenosquamous tumor, whereas patients with adenocarcinoma demonstrated only high CA 125 levels. We conclude that all three markers are important for monitoring patients with cervical adenocarcinoma.

CA 125 in serum and tumor from patients with uterine sarcoma.

Serial serum samples of 33 patients with primary sarcoma of the uterus were analyzed for CA 125 and frozen tissue sections of tumor from 23 patients were tested for this antigen. Before treatment, 12 of 30 evaluable patients showed serum CA 125 levels> 16 Uml-1 (40%). There was no relationship between serum CA 125 level and the histologic subtype. Patients with serum CA 125> 16 Uml-1 showed extrauterine tumor sites in 67% of the cases versus 33% in patients with normal CA 125 determinations (P = 0.026). In (FIGO) stages I and II, elevated serum CA 125 levels prior to surgery were associated with a poor prognosis (P = 0.043). Patients with recurrent or progressive disease demonstrated serum CA 125 levels> 16 Uml-1 in 14 of the 20 cases (70%). Sarcoma cells were completely negative for CA 125, whereas positivity was observed in the epithelial component of mixed Müllerian tumors. The source of the elevated serum CA 125 levels in patients with uterine sarcoma may be stimulated mesothelial cells.

CA 125: a useful marker in endometrial carcinoma.

In a retrospective study 121 patients with endometrial cancer were examined. In addition, 20 primary endometrial adenocarcinomas were tested immunohistochemically for CA 125. All tumor tissues were demonstrated to contain CA 125. However, only 25% of 110 patients had elevated CA 125 levels in serum before treatment. The incidence of elevated CA 125 serum levels increased with higher tumor staging up to 55% and 86% in surgical Stages III and IV, respectively. In Stage I and II disease (International Federation of Gynecology and Obstetrics) elevated serum levels before treatment correlated with the presence of tumor tissues outside the uterine body or outside the uterus, respectively, as was determined histopathologically after operation. In addition a close correlation between elevated levels and vessel invasion of tumor cells was revealed. Serum levels of CA 125 paralleled the clinical course of disease. Tumor recurrence in the abdomen can be preceded by an increase of serum CA 125 levels.

Serum CA 125 levels in patients with a provisional diagnosis of pelvic inflammatory disease. Clinical and theoretical implications.

In 50 patients with a provisional diagnosis of pelvic inflammatory disease (PID), CA 125 concentrations in serum were measured before laparoscopy and during hospitalization, using an enzyme immunoassay. The findings at laparoscopy were graded on the basis of the extent of inflammatory peritoneal involvement (grades 0-3; normal observations having a score of 0). On admission, 66% of the patients had serum CA 125 concentrations in excess of the cut-off value of 16 U/ml (range: 20-1300 U/ml). The serum CA 125 concentration before laparoscopy correlated with the extent of inflammatory peritoneal involvement (eta = 0.74). The predictive value of an elevated serum CA 125 level to indicate the presence of salpingitis (grades 1-3) was 97%. However, the predictive value of a normal CA 125 level indicating normal observations at laparoscopy (grade 0) was only 47%. During treatment and follow-up, the serum CA 125 concentration returned gradually to normal levels. It was concluded that the finding of an elevated serum CA 125 level confirms the diagnosis of peritoneal involvement in patients with a clinical diagnosis of PID.

Adenocarcinoma of the uterine cervix. Prognostic significance of pretreatment serum CA 125, squamous cell carcinoma antigen, and carcinoembryonic antigen levels in relation to clinical and histopathologic tumor characteristics.

The prognostic value of the pretreatment serum CA 125, squamous cell carcinoma antigen (SCC), and carcinoembryonic antigen (CEA) levels in relation to tumor type, vascular invasion by tumor cells, and lymph node metastases was investigated in 77 patients with cervical adenocarcinoma. In Stage IB (International Federation of Gynecology and Obstetrics [FIGO]), the five-year actuarial survival of patients with pretreatment serum CA 125 levels greater than 16 U/ml was 52.4% versus 95.6% when normal serum CA 125 levels were determined (P less than 0.01). Pretreatment serum SCC or CEA levels had no substantial prognostic value. In Stage IB (FIGO), 42% of the patients with elevated serum CA 125 levels had lymph node metastases versus 4% when normal levels were found (P = 0.012). The presence of vascular invasion (P = 0.01) or lymph node metastases (P = 0.001) was associated with an increased risk for recurrent disease. Adenosquamous tumors showed a higher incidence of vascular invasion (P = 0.05) and a higher incidence of elevated serum CA 125 levels (P = 0.03). Particularly in Stage II, adenosquamous tumors were found to have a poorer prognosis than adenocarcinomas (P = 0.0566). We conclude that in cervical adenocarcinoma serum CA 125 is an important prognostic factor and an implicit indicator of tumor virulence.

Follow-up of antibody responses to human papillomavirus type 16 E7 in patients treated for cervical carcinoma.

A synthetic peptide comprising amino acids 6-35 of HPV-16 E7 was used in an ELISA to screen sera taken from 31 cervical carcinoma patients. Sera obtained before and during treatment, and in follow-up, were tested for the presence of antibodies to this peptide. Sixteen patients with negative pretreatment serum determination remained negative during treatment and follow-up. Of the 15 patients with positive pretreatment sera, 12 showed a decrease in anti-E7 6-35 antibody level during treatment. During follow-up an increase in anti-E7/6-35 antibody level was observed in 6 out of 7 patients with progressive or recurrent disease, whereas all patients who remained in complete remission showed stable or further decreasing antibody levels. During the course of disease of the 15 seropositive patients, serum anti-E7/6-35 antibody levels were compared with serum squamous cell carcinoma antigen (SCC-Ag) profiles, a clinically useful tumor marker in the management of cervical cancer patients. Similar patterns were observed in 10 out of 15 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Humoral immune response against proteins E6 and E7 in cervical carcinoma patients positive for human papilloma virus type 16 during treatment and follow-up.

To investigate the humoral immune response to transforming proteins E6 and E7 of human papillomavirus type 16 before and after treatment and during follow-up, consecutive serum samples from 36 cervical cancer patients whose tumours were found to contain human papillomavirus type 16 DNA by use of the polymerase chain reaction were tested using in vitro translated proteins E6 and E7 in a radioimmunoprecipitation assay and in an E7 synthetic peptide enzyme immunoassay. Antibody levels against E6 and E7 as measured by radioimmunoprecipitation assay showed a nearly identical pattern. Seronegative patients remained seronegative throughout treatment and follow-up. Seropositive patients showed either a decrease in antibody level or stable antibody levels during treatment. In contrast to patients without evidence of disease at the end of the study, the majority of patients with recurrent disease showed increasing antibody levels during the follow-up period. These results indicate that, in patients who are seropositive before treatment antibody levels against E6 and E7 of human papillomavirus type 16 after treatment are closely linked to treatment response. The use of the more sensitive radioimmunoprecipitation assay did not lead to a better correlation of antibody levels with clinical disease status of the patients than the use of the enzyme immunoassay.

The effect of abdominal surgery on the serum concentration of the tumour-associated antigen CA 125.

The CA 125 assay is used to monitor the course of disease in women with adenocarcinoma of the genital tract. We measured serum CA 125 levels longitudinally in three different groups of patients who had normal serum CA 125 levels (less than or equal to 16 U/ml) before extensive intraperitoneal abdominal surgery (group 1, second-look laparotomy in 28 women with ovarian cancer; group 2, radical hysterectomy in 42 patients with cervical cancer; group 3, 13 men and one woman who had aortic surgery for atherosclerotic occlusive disease or aneurysm formation). Following surgery, rising serum CA 125 levels were observed in 69 out of the 84 patients (82%), irrespective of the primary diagnosis, type of operation or sex. The highest levels were found during the second week after the operation (range 3-336 U/ml) and decreased gradually thereafter, to become normal at 8 weeks after surgery. It was concluded that abdominal surgery interferes with the specificity of CA 125 as a tumour marker during the early postoperative period.

Cancer of the uterine cervix: sensitivity and specificity of serum squamous cell carcinoma antigen determinations.

Between 1978 and 1989, 451 patients with cervical squamous cell carcinoma were referred to our department, of whom 143 experienced persistent or recurrent disease. Serial serum samples of the patients were analyzed for the presence of squamous cell carcinoma antigen (SCC). The incidence of elevated pretreatment serum SCC levels ranged from 37% in stage IB (N = 173) to 90% in stage IV (N = 19). Multivariate analysis showed that deep stromal infiltration and lymph node metastases were associated with significantly higher serum SCC levels. Serum SCC trends correlated with the course of disease: after treatment the sensitivity (percentage positive results in patients with persistent disease) was 79% and the specificity (percentage negative results in patients with no evidence of disease) was 91%. During follow-up, the sensitivity of the assay was 85.5% in patients with recurrent disease. However, the positive predictive value of a single serum SCC value greater than 2.5 ng/ml for tumor recurrence was only 49%. This figure rose to 76% when two consecutive elevations were determined. Stage and pretreatment serum SCC level were the only factors found to influence survival, using Cox's regression analysis with five pretreatment variables.

The tumor marker CA 125 is a common constituent of normal cervical mucus.

The presence of the tumor marker CA 125 was studied in the cervices of healthy women. Immunohistochemical staining of normal cervical tissue demonstrated the presence of CA 125 in the tall columnar cells of the endocervical epithelium but not in the ectocervical squamous epithelium. We measured very high levels of CA 125 in liquefied cervical mucus from women with regular menstrual cycles. At midcycle, levels ranged from 14,200 to 153,000 U/ml (n = 13) in cervical mucus, while normal levels less than 35 U/ml were found in the corresponding serum samples. Levels of CA 125 in cervical mucus are comparable to the high levels found in cyst fluids from ovarian tumors (median 24,600 U/ml, n = 25). When secretion of cervical mucus was stimulated by ethinyl estradiol, equally high levels were found (7900 to 138,000 U/ml, n = 10). We conclude that the tumor marker CA 125 is synthesized and secreted by normal endocervical cells. Apparently an effective barrier exists between the endocervical mucosa and the circulation.

Elevated levels of squamous cell carcinoma antigen in patients with a benign disease of the skin.

Squamous cell carcinoma antigen (SCC), formerly referred to as TA-4, is a tumor marker for SCC of the uterine cervix. Based on the findings in a patient with complete remission after treatment for cervical carcinoma, the authors decided to analyze the sera from patients with benign dermatoses. It was found that 83% (25/30) of the patients with psoriasis and 80% (12/15) of the patients with eczema had SCC levels in excess of the cut-off value of 2.5 ng/ml. In psoriasis the serum SCC level correlated positively with the body surface area affected by the disease (r = 0.64). Seven patients with miscellaneous skin disorders, all with an inflammatory component, showed high serum SCC levels as well. Thus the existence of an inflammatory skin disease or a hyperkeratotic skin disease with an inflammatory component interferes with the usefulness of the SCC antigen as a tumor marker in SCC of the uterine cervix.

Relation between HPV-16 serology and clinico-pathological data in cervical carcinoma patients: prognostic value of anti-E6 and/or anti-E7 antibodies.

To investigate the clinical significance of the enhanced sensitivity of antibody detection by radio immunoprecipitation assays (RIPA), using in vitro translated HPV-16 E6 and E7 proteins, over synthetic-peptide enzyme-linked immunosorbent assay (ELISA), RIPA for HPV-16 E6 and E7 were performed. The results obtained with E6 and E7 RIPA were related to clinico-pathological data from cervical carcinoma patients positive for HPV type 16 DNA in their primary tumour. The data obtained with E6 and E7 RIPA were then compared to the results obtained using the E7/6-35 synthetic-peptide ELISA. The prevalence of antibodies to E6, E7, E6 and/or E7 and E6 and E7, as determined by RIPA, was significantly higher in cervical cancer patients than in both controls and cervical intraepithelial neoplasia patients. Odds ratios, calculated for cervical carcinoma patients versus controls, ranged from 7.4 to 15.4. Antibodies to E6 and/or E7 were largely restricted to patients with HPV DNA in their primary tumour. Analysis of the relation between prevalence of antibodies to E6 and E7 and clinico-pathological parameters was limited to 85 patients positive for HPV-16 DNA. The strongest relation with clinico-pathological data, such as lesion size, lymph node involvement, and prognosis, was found for E7 synthetic-peptide ELISA, whereas E6 and E7 RIPA did not reach significance. The significance of these findings is discussed.

Comprehensive study of several general and type-specific primer pairs for detection of human papillomavirus DNA by PCR in paraffin-embedded cervical carcinomas.

We have compared the efficacies of three general primer pairs for the detection of human papillomavirus (HPV) DNA in formaldehyde-fixed paraffin-embedded carcinomas. The use of these primer pairs leads to underestimates of the HPV prevalence (GP5/6, 61.1%; CPI/IIG, 57.4%; MY09/11, 46.9%; combined, 72.8%). The efficacy of each primer pair seemed to be inversely correlated to the length of the amplimer produced. By using newly developed type-specific primer pairs (amplimer length, approximately 100 bp), an increase in HPV DNA detection (87.6%) was found.

The clinical value of squamous cell carcinoma antigen in cancer of the uterine cervix.

A review is given of the clinical use and interpretation of serum tumor marker levels during the treatment of patients with cancer of the uterine cervix. Pretreatment serum squamous cell carcinoma (SCC) antigen provides a new prognostic factor in early stage squamous cell carcinoma of the uterine cervix. Elevated serum values of SCC antigen at the time of diagnosis of stage IB and IIA cervical cancer indicate a 3 x increased risk of tumor recurrence, independent of tumor diameter, grade or the presence of lymph node metastases. High pretreatment SCC antigen levels could therefore be used to select 'high-risk' patients for adjuvant therapy. Measurement of the serum SCC antigen levels provides a means of monitoring the effect of therapy. During the postoperative follow-up of patients with localized cancer of the uterine cervix the measurement of SCC antigen can lead to the early detection of recurrent disease when curative therapy is still an option. The profile of serum SCC antigen parallels the response to radiotherapy and provides a way of evaluating the effectiveness of chemotherapy. Serial measurements after surgery and during radio- and chemotherapy demonstrate that SCC antigen is a more sensitive marker for recognizing tumor progression or recurrence than CYFRA-21.1, TPS or CEA. When following up patients with a pure adenocarcinoma of the cervix measurements of serum CA 125 and CEA are preferred over SCC antigen measurements.