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PTEN as a Molecular Marker to Distinguish Metastatic From Primary Synchronous Endometrioid Carcinomas of the Ovary and Uterus

Ricci, Romeo M.D.; Komminoth, Paul M.D.; Bannwart, Fridolin M.D.; Torhorst, Joachim M.D.; Wight, Edward M.D.; Heitz, Philipp U. M.D.; Caduff, Rosmarie F. M.D.

Diagnostic Molecular Pathology: June 2003 - Volume 12 - Issue 2 - pp 71-78

The distinction between two primary carcinomas on the one hand and a metastatic disease on the other hand in patients suffering from synchronous endometrioid carcinomas of the uterus and ovary is difficult. Exclusive histopathologic analysis appears to be insufficient and sometimes misleading. The tumor suppressor PTEN was found to be important in early neoplastic transformation in endometrioid carcinomas of the uterus. In this study, we screened synchronous endometrioid carcinomas of the uterus and ovary of 10 patients for loss of heterozygosity using seven different microsatellite markers at 10q23.3 and for mutations in the entire coding region of PTEN. Point mutations or microdeletions/insertions were found in six patients. Allelic loss at 10q23.3 was detected in eight patients. Based on conventional histology, a metastatic disease was diagnosed in seven patients and a concomitant uterine and ovarian carcinoma in three patients. After molecular analysis, the histopathologic diagnosis of three patients had to be revised. Histopathology represents the standard method to process tumor specimens from these patients. Nevertheless, mutation screen for PTEN and LOH analysis at 10q23.3 provide helpful genetic tools to establish a correct final diagnosis, which is important in view of prognosis and therapeutic implications.

The differential diagnosis of two independent primary carcinomas versus metastatic disease in synchronous endometrioid carcinomas of the uterus and ovary is established by defined histologic criteria. Tumor size, extension of tumor mass, predominance and limit in one organ, and vascular invasion are used as guidelines (1). In some patients, histopathology is difficult to interpret. However, an adequate staging has prognostic and therapeutic implications for the patient. The prognosis of patients with two independent primary endometrioid carcinomas (stage I) is better compared with patients suffering from metastatic disease (2–4).

The PTEN (phosphatase and tensin homolog deleted from chromosome 10) tumor-suppressor gene, also known as MMAC1 (mutated in multiple advanced cancers) or TEP1 (TGFβ-regulated and epithelial cell-enriched phosphatase) is located on chromosome 10q23.3. Germline PTEN mutations have been found in about 80% of patients suffering from one of three related autosomal dominant disorders: Cowden disease (5,6), Lhermitte-Duclos disease (7,8), and Bannayan-Zonana syndrome (6).

Loss of heterozygosity (LOH) at 10q23.3 is a very common event in many primary tumors (9). Somatic deletions or mutations have been identified in a large number of tumors, including glioblastomas (10–12), prostate cancer (10–14), hepatocellular carcinomas (15), bladder cancer (16), malignant melanomas (17), and primary breast carcinomas (18,19). PTEN appears to be the most frequent (30%–60%) inactivated tumor suppressor gene involved in carcinogenesis of endometrioid uterine carcinomas (10,20–24). Importantly, a complete loss of PTEN function in the early stage of neoplastic transformation of the endometrium (2,25–28) identified PTEN as a crucial tumor suppressor of the uterus. Genetic alterations in this locus may be required early in development of uterine carcinomas. Although less frequently, PTEN was found to be also involved in the pathogenesis of endometrioid ovarian tumors (29,30). Similar to endometrioid cancers of the uterus, PTEN inactivation was described as an early event in the development of ovarian cancers (31). A high incidence of PTEN mutations and 10q23.3 LOH in patients with synchronous endometrioid carcinomas of the uterus and ovary have been reported in a previous study (32).

A complete loss of PTEN function in early stage tumors appears to be unique for endometrial and ovarian cancers. On the other hand, inactivation of only one PTEN allele plays an important role in cell survival and proliferation in the endometrium, because heterozygosity for PTEN can cause endometrial neoplasia and lymphoproliferative disorders in mice (33,34). Moreover, it was shown, that DNA mismatch repair deficiency accelerates endometrial tumorigenesis in PTEN heterozygous mice (35). Therefore, PTEN haploinsufficiency contributes to early selection and expansion of cells during transformation. At later stages in tumor progression, complete loss of PTEN function and additional mutations in other genes could exacerbate the transformed phenotype and lead to metastatic growth (36). Interestingly, hemizygous PTEN deletions in breast cancer lead to a lack of expression at the protein level (19), indicating again that haploinsufficiency might be sufficient to cause a substantial inactivation of the protein. Overall, these findings support a fundamental role for PTEN in the control of endometrial epithelial growth/proliferation.

In the current study, we examined 10 different synchronous endometrioid carcinomas of the uterus and ovary for mutations of PTEN and LOH at the loci flanking the PTEN gene to determine the origin of the synchronous tumors at the molecular level. We found frequent allelic losses at 10q23.3 and mutations of the PTEN gene in these carcinomas and identified PTEN as an important molecular marker that may contribute to a reliable differentiation between a metastatic disease and a process of two independent tumors.

From the Department of Pathology (R.R., P.K., P.U.H., R.F.C.) and Department of Gynecology and Obstetrics (E.W.), University of Zurich, Switzerland; Institute of Pathology, City Hospital Triemli, Zurich, Switzerland (F.B.); Department of Pathology, University of Basel, Switzerland (J.T.); and Institute of Pathology, Kantonsspital, Baden, Switzerland (P.K.).

Address correspondence and reprint requests to Dr. Rosmarie F. Caduff, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland (e-mail:

© 2003 Lippincott Williams & Wilkins, Inc.