Vera M. Abeler

Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients.

Aims:  To determine the frequency and survival of the various types of uterine sarcoma in the total population of Norway and evaluate histopathological prognostic factors in order to identify risk groups.

Differentiation of Human Embryonal Carcinomas In vitro and In vivo Reveals Expression Profiles Relevant to Normal Development

Embryonal carcinoma is a histologic subgroup of testicular germ cell tumors (TGCTs), and its cells may follow differentiation lineages in a manner similar to early embryogenesis. To acquire new knowledge about the transcriptional programs operating in this tumor development model, we used 22k oligo DNA microarrays to analyze normal and neoplastic tissue samples from human testis. Additionally, retinoic acid-induced in vitro differentiation was studied in relevant cell lines. We identified genes characterizing each of the known histologic subtypes, adding up to a total set of 687 differentially expressed genes. Among these, there was a significant overrepresentation of gene categories, such as genomic imprinting and gene transcripts associated to embryonic stem cells. Selection for genes highly expressed in the undifferentiated embryonal carcinomas resulted in the identification of 58 genes, including pluripotency markers, such as the homeobox genes NANOG and POU5F1 (OCT3/4), as well as GAL, DPPA4, and NALP7. Interestingly, abundant expression of several of the pluripotency genes was also detected in precursor lesions and seminomas. By use of tissue microarrays containing 510 clinical testicular samples, GAL and POU5F1 were up-regulated in TGCT also at the protein level and hence validated as diagnostic markers for undifferentiated tumor cells. The present study shows the unique gene expression profiles of each histologic subtype of TGCT from which we have identified deregulated components in selected processes operating in normal development, such as WNT signaling and DNA methylation.

A retrospective study of 370 borderline tumors of the ovary treated at the norwegian radium hospital from 1970 to 1982. A review of clinicopathologic features and treatment modalities

Methods. Three‐hundred seventy patients with borderline tumors treated between 1970 and 1982 at the Norwegian Radium Hospital were analyzed retrospectively for clinicopathologic features, treatment, and survival characteristics.

Analysis of prognostic factors in stage I epithelial ovarian carcinoma : importance of degree of differentiation and deoxyribonucleic acid ploidy in predicting relapse

OBJECTIVES Our purpose was to identify prognostic factors in stage I epithelial invasive ovarian carcinoma. STUDY DESIGN The traditional clinical and pathologic prognostic variables and deoxyribonucleic acid ploidy were analyzed in a group of 290 patients. RESULTS A multivariate analysis identified degree of differentiation as the most powerful prognostic indicator of disease-free survival, followed by deoxyribonucleic acid ploidy and, finally, International Federation of Gynecology and Obstetrics (1986) stage. Tumors with clear cell carcinoma elements were not graded, and in this subgroup International Federation of Gynecology and Obstetrics (1986) stage was the most important prognostic characteristic. When the effects of the three most important factors were accounted for in graded tumors, then none of the following were prognostic: histologic type, dense adhesion, extracapsular growth, ascites, rupture during surgery, International Federation of Gynecology and Obstetrics (1973) stage, size of tumor, and age and type of adjuvant treatment. None of 77 patients with well differentiated deoxyribonucleic acid diploid tumors had relapses. CONCLUSION Deoxyribonucleic acid ploidy is an important new independent prognostic factor in stage I ovarian carcinoma.

Clear cell carcinoma of the endometrium: A histopathological and clinical study of 97 cases

In a histopathologic review of 1985 cases of endometrial carcinoma 97 patients (4.9%) had clear cell carcinoma (CCC). Mean age at diagnosis was 65.3 years. The crude 5- and 10-year survivals for all stages were 42.3 and 30.9%, respectively. Fifty-nine percent of the patients in surgicopathological stage I and 27% in stage II survived 5 years. Myometrial infiltration and vessel invasion were important prognosticators. Ninety percent of the patients with intramucosal tumors survived 5 years, in contrast to only 15% of the patients with deep myometrial infiltration. Seventeen percent of the patients with vessel invasion survived 5 years, in contrast to 49% of the patients without this finding. CCC is one of the most aggressive subtypes of endometrial carcinoma.

Clear cell carcinoma of the endometrium: Prognosis and metastatic pattern

To establish the prognosis, metastatic pattern, sites of treatment failure, and effect of various treatment modalities, a large series of patients with endometrial clear cell carcinomas (ECCC) was analyzed.

Endometrial adenocarcinoma in Norway. A study of a total population

Fifteen hundred sixty‐six patients with adenocarcinoma of the endometrioid type (AC) were studied. These accounted for 78.9% of all 1985 patients with confirmed endometrial carcinoma diagnosed in Norway in the period 1970 through 1978. Four hundred and sixty‐nine patients (29.9%) had well‐differentiated tumors, 677 (43.2%) were moderately and 420 (26.8%) poorly differentiated. Eighty‐one percent of the patients had surgicopathologic Stage I disease, 11% Stage II, 6% Stage III, and 2% Stage IV. Mean age at diagnosis was 62.1 years (range, 36 to 91). The crude 5‐year and 10‐year survival rates for all patients were 74.1% and 62.2%, respectively. Five‐year crude survival was 86.8% for Grade 1 and 58.3% for Grade 3 tumors. The 5‐year crude survival for patients with intramucosal tumors was 88.7% as opposed to 46.9% for patients with tumors infiltrating to the serosa. Sixty‐six percent of the patients with vessel invasion survived for 5 years in contrast to 88.6% for patients without vessel invasion. Histologic grade, myometrial infiltration, vessel invasion, and lymphocyte reaction surrounding the tumor were strongly interrelated. Multivariate analysis showed that the age of the patient at the time of diagnosis was the most important single prognostic factor. Disregarding age, survival in operated patients was more dependent on the depth of myometrial invasion than on grade and stage of disease.

Randomized trial comparing cisplatin with radioactive phosphorus or whole-abdomen irradiation as adjuvant treatment of ovarian cancer

In this study, 347 patients with epithelial ovarian cancer without residual tumor after primary laparotomy, were assigned randomly to receive either intraperitoneal instillation of radioactive phosphorus (32P) or six courses of cisplatin (50 mg/m2. Patients randomized to receive 32P with extensive intraperitoneal adhesions were treated with whole‐abdomen irradiation instead of 32P (n = 28). The median follow‐up was 62 months. Crude and disease‐free survival were similar in all groups. Late bowel complications occurred more often in patients treated with 32P compared with the cisplatin group. The estimated 5‐year crude survival rate was as high as 95% in patients with borderline or well‐differentiated tumors in Stage I. It is suggested that these patients can be treated adequately by operation alone. Patients with moderately or poorly differentiated cancers in Stage I disease had a 5‐year crude survival rate of 75%. In these patients, the relapse risk was high enough to warrant postoperative treatment. The efficacy of adjuvant treatment in this subgroup of patients can only be established in a prospective randomized study comparing postoperative adjuvant treatment with a no‐treatment arm. Because of the high number of late bowel complications after 32P treatment, it was recommended that cisplatin be used as standard adjuvant treatment for subsequent controlled studies.

Randomized study on adjuvant chemotherapy in stage I high-risk ovarian cancer with evaluation of DNA-ploidy as prognostic instrument

Summary Purpose: Adjuvant chemotherapy versus observation and chemotherapy at progression was evaluated in 162 patients in a prospective randomized multicenter study. We also evaluated DNA-measurements as an additional prognostic factor. Patients and methods: Patients received adjuvant carboplatin AUC 7 every 28 days for six courses (n - 81) or no adjuvant treatment (n = 81). Eligibility included surgically staged and treated patients with FIGO stage I disease, grade 1 aneuploid or grade 2 or 3 non-clear cell carcinomas or clear cell carcinomas. Disease-free (DFS) and disease-specific (DSS) survival were end-points. Results: Median follow-up time was 46 months and progression was observed in 20 patients in the treatment group and 19 in the control group. Estimated five-year DFS and DSS were 70% and 86% in the treatment group and 71% and 85% in the control group. The hazard ratio was 0.98 (95% confidence interval (95% CI): 0.52-1.83) regarding DFS and 0.94 (95% CI: 0.37-2.36) regarding DSS. No significant differences in DFS or DSS could be seen when the log-rank test was stratified for prognostic variables. Therefore, data from both groups were pooled for the analysis of prognostic factors. DNAploidy (P = 0.003), extracapsular growth (P = 0.005), tumor rupture (P = 0.04), and WHO histologic grade (P = 0.04) were significant independent prognostic factors for DFS with P < 0.0001 for the model in the multivariate Cox analysis. FIGO substage (P = 0.01), DNA ploidy (P < 0.05), and histologic grade (P = 0.05) were prognostic for DSS with a P-value for the model < 0.0001. Conclusions: Due to the small number of patients the study was inconclusive as regards the question of adjuvant chemotherapy. The survival curves were superimposable, but with wide confidence intervals. DNA-ploidy adds objective independent prognostic information regarding both DFS and DSS in early ovarian cancer.

Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers

BackgroundOvarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia.ResultsWe examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2γ) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13–40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH.ConclusionThis study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females.