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Glandular premalignant (EIN) and malignant (carcinoma) neoplasms of the endometrium may be associated with discrete regions of squamous differentiation, but these squamous areas are rarely clinically aggressive. We have previously showed that the squamous elements lack estrogen and progesterone receptors and are mitotically quiescent, in contrast to the adjacent receptor positive proliferative neoplastic glands. It is unclear whether these squamous elements are part of the neoplastic process which have undergone aberrant differentiation, or a reactive change of adjacent normal tissues. We used unique somatic mutations of the PTEN gene as a clonal marker to determine the lineage relationships between glandular and squamous elements of endometrial neoplasms. Laser capture microdissection of the squamous and glandular components of 1 EIN and 2 endometrial carcinomas was used to isolate DNA from each of these distinctive elements. PTEN mutations were detected by PCR amplification of all 9 exons, followed by DGGE and direct sequencing. Different somatic PTEN mutations were seen in the lesional tissues of different patients. Within each patient, however, the matched squamous and glandular elements demonstrated identical PTEN mutations. The squamous elements seen in endometrial glandular precancers and carcinoma are integral components of the neoplastic clone, and thus part of the neoplastic process itself. Squamous differentiation is accompanied by reduced mitotic activity and inability to respond to sex hormones, making this functionally inert subpopulation an unlikely participant in estrogen-driven lesion progression. The mechanism for initiation of squamous differentiation in these glandular lesions is currently unknown, but may represent a viable target for future differentiation therapy.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]