Faculty Bibliography

We discovered that pigment epithelium-derived factor (PEDF)-null mice have endometrial hyperplasia, the precursor to human type I endometrial cancer (ECA), which is etiologically linked to unopposed estrogen (E2), suggesting that this potent antiangiogenic factor might contribute to dysregulated growth and the development of type I ECA. Treatment of both ECA cell lines and primary ECA cells with recombinant PEDF dose dependently decreased cellular proliferation via an autocrine mechanism by blocking cells in G1 and G2 phases of the cell cycle. Consistent with the known opposing effects of E2 and progesterone (Pg) on endometrial proliferation, Pg increases PEDF protein synthesis and release, whereas E2 has the converse effect. Using PEDF luciferase promoter constructs containing two Pg and one E2 response elements, E2 reduced and Pg increased promoter activity due to distal response elements. Furthermore, E2 decreases and Pg increases PEDF secretion into conditioned media (CM) by both normal endometrial stromal fibroblasts (ESFs) and cancer-associated fibroblasts (CAFs), but only CM from ESFs mediated growth-inhibitory activity of primary endometrial epithelial cells (EECs). In addition, in cocultures with primary EECs, Pg-induced growth inhibition is mediated by ESFs, but not CAFs. This is consistent with reduced levels of Pg receptors on CAFs surrounding human malignant glands in vivo. Taken together, the data suggest that PEDF is a hormone-regulated negative autocrine mediator of endometrial proliferation, and that paracrine growth inhibition by soluble factors, possibly PEDF, released by ESFs in response to Pg, but not CAFs, exemplifies a tumor microenvironment that contributes to the pathogenesis of ECA.

Marjolin's ulcers typically result from long-term chronic inflammation of a squamous surface, most often related to burns and other scars. This report describes a squamous cell carcinoma arising from the pleural surface in a patient with a chronically neglected Eloesser flap.

We previously reported that aberrant TGF-beta/Smad2/3 signaling in endometrial cancer (ECA) leads to continuous ubiquitylation of p27kip 1 (p27) by the E3 ligase SCF-Skp2/Cks1 causing its degradation as a putative mechanism involved in the pathogenesis of this cancer. In contrast, normal intact TGF-beta signaling prevents degradation of nuclear p27 by SCF-Skp2/Cks1 thereby accumulating p27 to block Cdk2 for growth arrest. Here we show that in ECA cell lines and normal primary endometrial epithelial cells, TGF-beta increases Cdh1 and its binding to APC/C to form the E3 ligase complex that ubiquitylates Cks1 and Skp2 prompting their proteasomal degradation and thus, leaving p27 intact. Knocking-down Cdh1 in ECA cell lines increased Skp2/Cks1 E3 ligase activity, completely diminished nuclear and cytoplasmic p27, and obviated TGF-beta-mediated inhibition of proliferation. Protein synthesis was not required for TGF-beta-induced increase in nuclear p27 and decrease in Cks1 and Skp2. Moreover, half-lives of Cks1 and Skp2 were extended in the Cdh1-depleted cells. These results suggest that the levels of p27, Skp2 and Cks1 are strongly or solely regulated by proteasomal degradation. Finally, an inverse relationship of low p27 and high Cks1 in the nucleus was shown in patients in normal proliferative endometrium and grade I-III ECAs whereas differentiated secretory endometrium showed the reverse. These studies implicate Cdh1 as the master regulator of TGF-beta-induced preservation of p27 tumor suppressor activity. Thus, Cdh1 is a potential therapeutic target for ECA and other human cancers showing an inverse relationship between Cks1/Skp2 and p27 and/or dysregulated TGF-beta signaling.

Placental mesenchymal dysplasia (PMD), a rare condition of pregnancy, is characterized by placentomegaly and grape-like vesicles similar to molar pregnancy. It is associated with a fetus and therefore often clinically misdiagnosed as a partial mole. There is strong association of PMD with fetal growth restriction and Beckwith- Wiedemann syndrome (BWS), but it is also seen with live birth of normal-appearing fetuses. Maternal serum alpha- fetoprotein is elevated and beta-HCG levels are normal to increased in PMD. There are occasional case reports where a twin pregnancy consisted of 1 complete mole and 1 fetus with PMD. There are no case reports of a PMD without fetus. We present the first case of PMD that was not associated with fetus and was clinically diagnosed as complete hydatidiform mole. A 17-year-old girl with 10-week intrauterine pregnancy had beta-HCG level of 49,000 mIU/mL and a characteristic "snowstorm" pattern without any fetus on ultrasound. Complete mole was diagnosed and D&C was performed. Macroscopically red-brown tissue with grape-like vesicles without identifiable fetal tissue was seen. Entire specimen was submitted for microscopic examination. Characteristic histologic features of PMD, namely enlarged chorionic villi with central cisterns and fibromuscular vessels at the periphery without any trophoblast hyperplasia, were seen. No fetal or embryonic tissue was seen microscopically. No fetal RBCs were seen in the chorionic villous vessels. Immunostain for p57 was positive in trophoblast and villous stromal cells. Diagnosis of PMD was made based on histologic findings and positive p57 immunostain. The patient's HCG came down to 22 mIU/mL 1 week post D&C. PMD is associated with a fetus and clinically presents as partial mole. Ours is the first case in literature in which PMD did not have associated fetal tissue and was clinically diagnosed as complete mole. Complete mole was ruled out by positive p57 immunostaining and lack of trophoblast hyperplasia. Diagnosis of PMD was based on characteristic histologic findings

Extraneural ependymomas are rare tumors that occur in sacrococcygeal, pelvic and extra pelvic regions. While sacrococcygeal extraneural ependymomas are equally distributed among males and females, pelvic and extra pelvic ependymomas have been exclusively reported in women, mainly of child bearing age. We present a case of extraneural, pelvic ependymoma that showed clinical response to GnRH therapy with its immunohistochemical and electron microscopic analysis, and an overview of primary extraneural ependymomas based on a review of all such cases published in English literature.

Retroperitoneal schwannoma is a rare tumor that is often misdiagnosed as malignancy due to a concerning appearance on cross-sectional imaging. Pathology and immunohistochemistry form the gold standard for diagnosis; as such, local excision is the treatment of choice for this disease. We present two cases of juxta-adrenal ancient schwannoma that were treated with adrenalectomy and discuss the current literature regarding this entity.

Ganglioneuromas are uncommon, benign, and highly differentiated tumors arising from sympathetic ganglia. Common sites for these tumors include the paraspinal region of the retroperitoneum and posterior mediastinum. We report a case of a retropharyngeal ganglioneuroma, a rare occurrence, emphasizing its key imaging characteristics.