Inhibin-alpha, -betaA and -betaB subunits in uterine non-endometrioid carcinomas: Prognostic significance and clinical implications
Introduction
Endometrial cancer has become the most frequent gynaecologic malignancy in the Western World.1, 2, 3 An incidence of 15–20 to 100,000 women per year has been estimated with a life time risk to develop this type of cancer being approximately 2.5%.4 Meanwhile, several prognostic factors like histological type, histologic grade, surgical stage, pelvic lymph node involvement and myometrial invasion have been established.1, 2
Meanwhile, endometrial cancer has been described as consisting of two different clinicopathological categories with distinct biological and molecular characteristics.2, 5, 6, 7 Type I endometrial cancers are the most common histopathological form, being usually endometrioid adenocarcinomas, well-differentiated with a more favourable outcome compared to endometrial cancer of the second group.1, 2, 3, 4, 5, 6 Contrarily, type II endometrial cancers are often of the non-endometrioid type, poorly differentiated with a poor prognosis.6, 7, 8 These observations lead to the postulation of a dualistic model for the molecular carcinogenesis in endometrial carcinomas,7 although common characteristics of these groups of endometrial cancer exist. The carcinogenesis of type I endometrial carcinomas is thought to be due to oestrogenic risk factors,1, 2, 7 demonstrating genetic alterations like mutations in PTEN and K-ras.7 Type II cancers more often exhibit p53 mutations,9 HER-2/neu amplification10 and chromosomal instability.7
Inhibins and activins are secreted polypeptides, representing a subgroup of the TGF-β superfamily of growth and differentiation factors.11, 12, 13 Inhibins are heterodimers that consist of an α-subunit and one of two possible β-subunits (βA or βB), resulting in the formation of either inhibin A (α–βA) or B (α–βB), respectively. On the contrary, activins are homodimers of β-subunits linked by a disulphide bond, leading to the formation of activin A (βA–βA), activin B (βB–βB) or activin AB (βA–βB).11, 12, 13 The inhibin-subunits have been primarily detected in endocrine tumours14 and their differential expression has suggested an important role in malignant cell transformation in human endometrium.15, 16, 17
Interestingly, TGF-β has been recognised as a tumour suppressor in premalignant stages of carcinogenesis with an additional dual role as a pro-oncogene in later stages of the disease, leading to metastasis.18 The tumour suppressive activity of the inhibin-α subunit was first identified after functional deletion of the inhibin-α gene in male and female mice, resulting in primary gonadal sex cord-stromal tumours.19, 20 Recently, a significantly lower inhibin-α expression in well-differentiated adenocarcinomas compared to normal and hyperplastic endometrial tissue was demonstrated.21, 22 These results also led to the hypothesis that inhibin-α might be a tumour suppressor with crucial functions in endometrial carcinoma development.16 This assumption is underlined by demonstrating that inhibin-α subunit was an independent prognostic parameter in a large cohort analysis of human endometrial carcinomas.17 However, the prognostic significance and clinical implications of the inhibin-α, -βA and -βB subunits in non-endometrioid cancers are still quite unclear.
Section snippets
Tissue samples
Pathological and surgical records of 41 patients who have been operated in the 1st Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Munich, between 1990 and 2002 were reviewed for this retrospective analysis. The evaluated patient group has been previously well characterised.17, 23 In a previous large cohort study 302 endometrial cancer specimens were analysed for the expression of the inhibin-α, -βA and -βB subunits, including 265 endometrioid adenocarcinoma and 37
Clinicopathological characterisation
The clinicopathological features of the endometrial carcinomas are summarised in Table 1. The median patient’s age at the time of diagnosis was 65.98 years (range, 45.83–88.37 years). Twenty-four (58.5%) and 3 (7.3%) patients were diagnosed in FIGO stages I and II, respectively, while 13 (31.7%) patients had FIGO stage III and 1 patient (2.4%) presented with metastatic disease (FIGO IV). Pelvic and/or para-aortic lymph node sampling was performed for 32 patients (78%) while 6 patients (14.6%)
Discussion
Endometrial cancer is the most frequent gynaecologic malignancy in the Western World.1, 2, 4 Although more than 50% of patients with endometrial carcinoma are diagnosed with FIGO stage I, as many as 20% die of their disease.3 This is an unusual situation, compared to other solid tumours, and may reflect the failure of current diagnostic methods for identifying endometrial cancer patients with a poor prognosis. Especially non-endometrioid carcinomas pose a problem, since they are mostly poorly
Conflict of interest statement
The author declares that he has no competing interests. He received once a lecture fee in the year 2006 with the title ‘Endometrial cancer and inhibin-subunits’.
Acknowledgements
The author would like to thank Dr. S. Worbs, Dr. N. Shabani, Mrs. C. Kuhn, Mrs. S. Kunze, Mrs. S. Schulze, Dr. D. Dian, Dr. A. Gingelmaier, Dr. C. Schindlbeck, Dr. A. Bruning, Dr. U. Jeschke, Prof. H. Sommer and Prof. K. Friese for their help in conducting the primary study. Additionally we would like to thank Prof. D. Hölzel – Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University Munich and Mr. M. Schmidt of the Munich Tumor Registry for supplying the
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