Ovarian cancer is usually found at a late stage when the prognosis is often bad. Relative survival rates decrease with tumor stage or grade, and the 5-year survival rate for women with carcinoma is only 38%. Thus, there is a great need to find biomarkers that can be used to carry out routine screening, especially in high-risk patient groups. Here, we present a large-scale study of 64 tissue samples taken from patients at all stages and show that we can identify statistically valid markers using nonsupervised methods that distinguish between normal, benign, borderline, and malignant tissue. We have identified 217 of the significantly changing protein spots. We are expressing and raising antibodies to 35 of these. Currently, we have validated 5 of these antibodies for use in immunohistochemical analysis using tissue microarrays of healthy and diseased ovarian, as well as other, human tissues.

The goal of this retrospective study concerning primary carcinoma of the vagina (PCV) was to analyze clinical and histopathologic prognostic factors in one of the largest known material, which comprised 314 patients. PCV is a rare disease, and the majority of published studies are based on small materials; therefore, the established knowledge concerning prognostic factors is insufficient. Routine treatment is based on irradiation with risk for undertreatment or overtreatment, which leads to unnecessary complications in the absence of prognostic factors. The overall 5-year disease-specific survival rate in this study was 45% and in stage I 75%. In the univariate statistical analysis, several factors correlated significantly with disease-specific survival. However, in the multivariate analysis, there were only three factors that independently could predict poor survival—high age at diagnosis, large tumors (≥4 cm), and advanced stage. Common background factors with no prognostic significance were prior hysterectomy, other gynecological malignancies, and pelvic irradiation. In conclusion, this study has elucidated three strong prognostic factors that might be considered in the choice of therapy and also for modification of the FIGO guidelines. Increased knowledge concerning complementary biologic markers to discriminate between low- and high malignant tumors is however of great importance.

Background: The presence of human papillomavirus (HPV), the HPV type and viral load in early stage cervical carcinoma were investigated in order to elucidate whether any of these factors were important for clinical outcome. Patients and Methods: Twelve patients who were disease-free 5 years after diagnosis were matched and compared with 12 patients who died within 2 years. The presence of HPV, HPV type and viral load in their tumours was examined by PCR. Results: The distribution and load of HPV was similar in the 2 patient groups. HPV-16 was, however, significantly more common in tumours of the surviving patients than in those of patients who died (88.9% and 18.2%, respectively, p=0.0152). Conclusion: HPV-16 was significantly more common in early stage carcinomas of patients surviving more than 5 years in comparison to early stage carcinomas of patients with a poor prognosis.

The aim was to determine whether specific gains of chromosome 3q and laminin-5γ2-chain expression can improve early detection of invasive capacity in precancerous and squamous cell carcinoma of the vulva (VSCC). Six VSCC and three precancerous lesions were studied. Multicolor fluorescence in situ hybridization (FISH) probe sets were applied to nuclei suspensions prepared from archival material using the Hedley method. The probe panel consists of the centromers of chromosome 7, chromosome 3, and the TERC gene residing on the long arm of chromosome 3. Laminin-5γ2-chain immunohistochemical analysis was performed on corresponding specimens and was expressed only in the VSCC. The genome-specific FISH analysis revealed 3q amplification in 43% of the nuclei analyzed for the VSCC and 22% of the nuclei for the precancerous lesions. Low-level 3q amplifications were found in precancerous lesions with an average fold increase of 1.15 for 3q. The invasive lesions showed higher average fold increases for 3q, averaging 1.32. Laminin-5γ2-chain protein was expressed only in VSCC, whereas 3q gains were observed both in precancerous lesions and in VSCC, indicating that gain of chromosome 3q is an early and consistent event during carcinogenesis of VSCC.

The objective to this retrospective study of 341 cases of primary carcinoma of vagina (PCV) diagnosed between 1956 and 1996 was to find whether epidemiological, clinical, and histopathological variables were related to the age at diagnosis of patients with PCV. The univariate statistical analysis showed that younger age at diagnosis significantly correlated with a history of cervical dysplasia, hysterectomy, gynecological infections, and tumors located in the upper part of the vagina, whereas older age at diagnosis significantly correlated with late menarche and exophytically growing tumors. In the multivariate regression analysis, the remaining independent predictors were a history of cervical dysplasia and age at menarche. Further, parity ≥4 as well as nulliparity, smoking, and unstable marital status were more common among patients with PCV than among those in the general Swedish female population. This study indicates that the etiology of vaginal carcinoma may be age related. In young patients, the disease seems to be etiologically related to cervical neoplasia and thus human papillomavirus (HPV) dependent. However, in the most common age group, the older patients, there might be another (probably non-HPV-related) etiology associated with hormonal factors and trauma to the vagina.

Expression of the laminin-5 γ2-chain in carcinoma cells has been implicated in tumor invasion. The aim was to investigate the expression and prognostic significance of the In-5 γ2-chain compared with clinicopathological factors and tumor cell DNA ploidy in endometrial carcinoma. Histological specimens from 80 endometrial carcinomas were examined with respect to immunohistochemical In-5 γ2-chain expression and correlated to the clinicopathological characteristics, DNA ploidy, and survival. Sixty-eight of 80 investigated cases were judged to be positive for the In-5 γ2-chain. Ln-5 γ2-chain did not show any correlation to stage, histopathological subtype, grade, and DNA ploidy. In univariate analyses, advanced stage (p<0.001), nonendometrioid carcinoma (p=0.030), low grade (p<0.001), aneuploid tumors (p<0.001), and In-5 γ2-chain expression (p=0.017) were highly associated with poor survival. Aneuploid tumors in combination with strong In-5 γ2-chain expression were significant predictors (p<0.001) of poor prognosis. In multivariate analyses including stage, histopathological subgroup, grade, DNA ploidy, and In-5 γ2-chain expression, all lost their significant prognostic information except for stage (p<0.001) and grade (p<0.05). Ln-5 γ2-chain expression and DNA ploidy both as a single parameter and in combination were demonstrated to be significant prognostic factors in univariate analysis. However, stage and grade provided more useful clinical information beyond histopathological subgroup, DNA ploidy, and In-5 γ2-chain expression. The results also indicate that In-5 γ2-chain expression is upregulated during the progression of endometrial carcinoma.

During recent decades it has become apparent that there are two types of vulvar disease: the classic type found in elderly women with unicentric and unifocal lesions, and the type found in younger women, in which precancerous and invasive changes develop in the anogenital lower tract in a multicentric and multifocal fashion, often over a long period of observation. The laminin-5 gamma 2 chain is an extracellular protein that is a component of the basement membrane. Recently its expression has been recognized as a marker in cervical cancer that permits identification of invasive capacity. The aim of our study was to determine if laminin-5 gamma 2 chain antibody can act as a sensitivity marker of invasive capacity in precancerous and invasive carcinoma in women with uni- and multifocal changes in the anogenital tract. The result showed that all patients in the older group of women with invasive carcinoma of the vulva had moderate to high positive expression of the laminin-5 gamma 2 chain. In the group of younger patients with multifocal precancerous changes observed over long periods, most of the patients with vulva intraepithelial neoplasia (VIN) 3 showed laminin-5 gamma 2 chain positivity already in the precancerous changes, and all of them developed invasivity during the period of observation. Normal epithelium without atypia was mostly negative or of low immunoreactivity of laminin-5. In conclusion, positive laminin-5 gamma 2 chain expression seems to indicate the invasiveness potential of precancerous lesions and is also expressed in all investigated invasive carcinomas of the anogenital tract.

Primary fallopian tube carcinoma is a rare, aggressive gynecological cancer; little is known about its cause. Previous studies have indicated that p53 immunopositivity is correlated with short-term survival in primary fallopian tube carcinoma. We examined p53 and p21/WAF1 immunostaining and TP53 mutation in exons 5 to 8 by single-stranded conformation polymorphism and constant denaturant gel electrophoresis in nine cases of primary fallopian tube carcinoma and their metastases/recurrences from patients who survived for between a few months and more than 20 years after diagnosis. We found that 1.) p53 immunopositivity without detectable p21/WAF1 immunostaining did not correlate with TP53 mutations in the conserved domains; 2.) mutations in TP53 occurred in two metastases/recurrences but not in their corresponding primary tumors; 3.) in two cancers, a TP53 mutation was observed in the primary tumor but not in the metastases/recurrences; 4.) constant denaturant gel electrophoresis seems to be more sensitive than single-stranded conformation polymorphism in detecting TP53 mutations; and 5.) in the nine cases studied, p53 immunoreactivity and/or TP53 mutation analysis did not correlate with tumor progression, survival, or response to treatment.

The purpose of this experiment was to investigate the expression and the prognostic impact of the gamma2 subchain of laminin-5 in vaginal malignancies. The outcome of the rare disease primary carcinoma of the vagina is poor and little is known about prognostic markers. The gamma2 chain of laminin-5, an epithelial basement membrane protein, is thought to play a crucial role in tumor cell adhesion, migration, and proliferation, and may thus be an additive potential marker. Archival, paraffin-embedded sections were stained immunohistochemically with an antibody against the gamma2 chain of human laminin-5 protein. The material consisted of 59 cases of primary vaginal malignancies, subdivided into short- and long-time survivors. All invasive malignancies of epithelial origin were positively stained with the antibody against the gamma2 chain. High expression of the gamma2 chain correlated significantly in an univariate analysis with short-time survival (P = 0.041), but in the multivariate analysis only age and tumor size were independent prognostic factors. A significant intercorrelation between large tumors and high gamma2 chain immunoreactivity was found (P = 0.003). These results indicate that laminin-5gamma2 subchain expression in primary vaginal carcinomas is of prognostic impact. However, in a multivariate analysis only patient age and tumor size had independent prognostic value.

Among 2,895 malignant ovarian tumor cases referred to Radiumhemmet, Stockholm from 1975 through 1995, 36 were certified to be malignant mixed müllerian tumors. The overall prognosis was poor with only 18% five-year actuarial survival (median survival 16.6 months). Five patients are still surviving after 75, 68, 117, 121, and 168 months, respectively. Fifteen women treated with melphelan, doxorubicin (adriamycin) and cisplatin (MAP) had a five-year actuarial survival of 33.3% and a median survival of 19.8 months. In a multivariate analysis taking into account stage, age, radiation, type of chemotherapy, histopathologic type and completeness of surgery, the most important predictors for survival were stage (stages I-II vs stages III-IV, P < 0.05), histopathologic type (homologous vs heterologous, P < 0.05), and type of chemotherapy (MAP or CAP vs other types, P < 0.05). We concluded that homologous tumor and chemotherapy containing cisplatin, doxorubicin, and melphalan, as well as early stage of the tumor, provided the optimal survival rate.

Primary fallopian tube carcinoma (PFTC) is a rare and highly aggressive tumor. Twelve cases of PFTC (stages IA to IV) were analyzed by comparative genomic hybridization. The most consistent DNA gain was mapped to chromosome arm 3q in 11 of 12 cases. In six cases, the gain of 3q was present as a high level copy number increase (amplification) with a consensus region mapped to 3q26.2-qter. In the 12 cases, other frequent gains were located on chromosome arms 1q (in 11 cases), 2q (in 10), 7q (in 9), 8q (in 9), 5p (in 8), 6p (in 7), 12p (in 7), and 14q (in 6). Frequent copy number losses occurred on chromosome arms 16q (in 8 cases), 22q (in7), 6q (in 6). 8p (in 6), 18q (in 6), Xq (in 6), 1p (in 5), and 17p (in 5). All chromosomes were involved in chromosomal aberrations and the average number of copy alterations per case was 19.7. None of the 12 carcinomas revealed the presence of human papillomavirus (HPV) genomes. All of the cases exhibited crude aneuploidy. Strong p53 immunoreactivity could be observed in 10 of 12 cases while p21/WAF1 expression was low or undetectable. These results indicate that PFTC is a genomically highly unstable cancer, an observation that is in agreement with the poor prognosis associated with this tumor. A high frequency of 3q-gains has also been observed in HPV-related carcinomas of the uterine cervix. However, none of the PFTC was HPV related, suggesting that the 3q-gain is independent from HPV DNA.

An unusually aggressive case of endometrial cancer in a 30 year old woman is presented. The patient experienced abnormal uterine bleeding, at times requiring blood transfusions, for almost half a year before the diagnosis was revealed. For obvious reasons there is a reluctancy to perform invasive examinations in young women. The diagnostic options are discussed.

Tumour angiogenesis (antifactor VIII-related antigen antibody), p53 overexpression (DO-1) and proliferative activity (MIB-1) were immunohistochemically analysed for the prediction of long-term survival in 113 patients with squamous cervical carcinoma. The median follow-up time was 82 months (range 72-99). In early stages (IB-IIA), neovascularisation was significantly related to tumour size. Significantly more patients in stage IIA had high tumour vascularity compared to stage IB (P < 0.01) but no significant difference was found between early and advanced stages (IIB-IVB) of cervical carcinoma. p53 overexpression was correlated to the stage of disease (P < 0.01). No relationship was found between tumour angiogenesis, p53 overexpression or MIB-1 and pelvic lymph node metastases, histological subtype or differentiation. Tumours with more than 50% p53 overexpression was significantly correlated with survival in the univariate analysis, but no independent predictive value was found. It is concluded that immunohistochemically detectable p53 overexpression as measured by DO-1 and proliferative activity as measured by MIB-1 seems of no clinical value for the prediction of long-term survival in squamous cervical carcinoma. The predictive value of tumour angiogenesis for survival outcome has still to be determined in squamous cervical carcinoma.

Malignant mixed Mullerian tumors (MMMT) of the fallopian tube are extremely rare and account for less than 4% of all MMMT. The most common site of origin for MMMT is the endometrium followed, in decreasing order, by the vagina, cervix and ovary. To date less than 60 cases of MMMT in the fallopian tube have been reported. The prognosis is poor. We report nine cases of fallopian tube MMMT treated during the period 1923-1994. Analysis of ploidy, p53, tumor angiogenes and cell proliferation did not help to discriminate long and short time survivors. Three cases receiving complete therapy including surgery, chemotherapy and external radiation belong to the long-survival group. Our conclusion is that MMMT represent clinically and biologically highly malignant tumors. Thus aggressive treatment comprising complete surgery, chemotherapy and external radiation seems to be necessary in order to improve survival both in early and advanced stage patients.

The usefulness of adjuvant therapy in early ovarian cancer is a matter of controversy and there is a need for predictive methods to distinguish between low and high risk patients. Specimens from 95 early-stage ovarian cancer patients have been analysed for conventional clinical variables as well as for the biological markers-DNA content, MIB-1, p53, WAF-1-and correlated to survival. Prognostic significance achieved in univariate analysis could be improved by using a score based on several biological markers. Using a score based on DNA content, MIB-1, p53 and WAF-1, a significant predictor could be achieved with the aim of determining the postsurgical therapy. By using this tool, it is hoped that adjuvant therapy can be avoided for one-third of the patients with early-stage ovarian cancer

Short- and long-time survivors among patients with primary fallopian tube carcinoma (PFTC) were studied with respect to prognosis predicting factors. Within the Radiumhemmets series 35 patients died within 2 years and they were compared with 27 patients surviving 8 years or more. All tumours were aneuploid. The two groups had different p53 immunoreactivity (P = 0.05). The prognostic influence of FIGO stage, proliferative activity (MIB-I), tumor angiogenesis (F8) and p53 immunoreactivity was studied in all stages. MIB-1, F8, and p53 immunoreactivity showed no significant correlation to survival. FIGO stage was significantly correlated to survival (P = 0.001). Increasing proliferative activity correlated to poor survival in a multivariate analysis of stage I (P = 0.015). Nine out of 19 stage I patients are still alive with a median survival of 22 years (11–32). Six of the survivors (66%) did not receive chemotherapy and underwent incomplete surgery. Two patients in stage IV are still alive after 12 and 13 years respectively. The only difference in biological parameters in the two survival groups was the absence of p53 mutations in the long-time survivors.

Nuclear DNA content and p53 immunoreactivity were determined in 53 cases of primary fallopian tube cancer (PFTC). All tumors showed a distinctly aneuploid DNA distribution pattern, whereas p53 immunoreactivity was observed in 51% of the cases. If the patients were divided into two groups according to survival time, p53 immunoreactivity was present in 40% of the tumors from patients surviving for more than 8 years and in 65% of tumors from patients who died within 2 years. This difference was not statistically significant (P=0.438). Patient survival was significantly correlated to the clinical stage (FIGO) (P=0.0009).

A case of primary carcinoid of the ovary in association with an imitation of appendix vermicularis is presented. These elements were thus parts of a mature teratoma. In the other ovary a granulosa cell tumour with a similar morphology was found. Following surgery no additional treatment was administered and the patient is well 13 years after the diagnosis.