Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer.

We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression.

A rare soft tissue tumor masquerading as a parathyroid adenoma in a patient with birt-hogg-dubé syndrome and multiple cervical endocrinopathies.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder that presents with renal tumors, pulmonary cysts with spontaneous pneumothoraces, and skin hamartomas. We present a case of a 67-year-old female with multiple endocrinopathies and a history of BHD syndrome. In 2011, a thyroidectomy with a four-gland parathyroidectomy was performed for toxic multinodular goiter (TMNG) and parathyroid hyperplasia. On frozen section, a tumor was identified next to a hypercellular parathyroid. After being worked up, this tumor was determined to be an adult rhabdomyoma. This represents the first time that both TMNG and parathyroid hyperplasia have been present in a BHD patient. Additionally, this is the first adult rhabdomyoma reported in a patient with BHD syndrome. Adult rhabdomyomas have no reported associations; however, potential colocation of the mutation in BHD syndrome and translocation in adult rhabdomyomas on chromosome 17p suggests a possible connection. Further work is needed to better understand this connection.

Do black (dark) lymph-node metastases in papillary thyroid carcinoma suggest more advanced or aggressive disease?

BACKGROUND: In some patients, papillary thyroid carcinoma (PTC) lymph-node metastases are noted to be black (dark) in color at the time of surgical removal. The goal of this project was to determine histological, genetic, and clinical features that are associated with regional black PTC metastasis. METHODS: Fifteen patients with black PTC metastases (black-PTC) were compared to a control cohort of 15 patients with nonblack PTC metastasis (nonblack PTC). Each sample was evaluated for the histological characteristics, BRAF V600E mutational status, and associated patient clinical data. RESULTS: The degree of cystic degeneration (80% vs. 27%, p=0.004), percent hemosiderin deposition (20% vs. 6%, p=0.001), and presence of classical variant (100% vs. 67%, p=0.018) were significantly greater in black PTC than nonblack PTC (α=0.05). Other results were not significantly different. CONCLUSION: This study demonstrates that black compared to nonblack metastases have a greater degree of cystic degeneration and hemosiderin deposition leading to discoloration, and a trend toward an increased incidence in BRAF V600E mutations. This study is the first of its kind to describe the clinical, pathological, and genetic features associated with black PTC lymph-node metastasis.

Dedifferentiated epithelial-myoepithelial carcinoma: analysis of a rare entity based on a case report and literature review.

Dedifferentiated epithelial-myoepithelial carcinoma (DEMC) is very rare salivary gland neoplasm with only anecdotal reports. We present an analysis of DEMC, based on a case and review of literature. Our patient, an 85-year-old woman, presented with a submandibular mass of 5 years duration that was increasing in size over a 5-week period. Histologically, there were areas of typical epithelial-myoepithelial carcinoma, with dedifferentiation of both components, manifesting morphologically as salivary duct carcinoma and areas of myoepithelial carcinoma. A review of literature revealed 21 previously reported cases of DEMC. DEMC occurs at an average age of 72 years, most often in the parotid gland (72%) followed by submandibular gland (17%). Dedifferentiation more often involves the epithelial component (13/15 cases) than the myoepithelial component (5/15 cases). Although typical epithelial-myoepithelial carcinomas are fairly indolent (average disease-free survival of 11.34 years), dedifferentiation confers a poor prognosis (survival reported from 1 to 72 months).

A comparative study of cell cycle mediator protein expression patterns in anaplastic and papillary thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive and rapidly fatal neoplasm. The aim of this study was to identify a limited cell cycle associated protein expression pattern unique to ATC and to correlate that pattern with clinical outcome. This represents one of the largest tissue micro-array projects comparing the cell cycle protein expression data of ATC to other well-differentiated tumors in the literature. Tissue microarrays were created from 21 patients with ATC and an age and gender matched cohort of patients with papillary thyroid carcinoma (PTC). Expression of epidermal growth factor receptor, cyclin D1, cyclin E, p53, p21, p16, aurora kinase A, opioid growth factor (OGF), OGF-receptor, thyroglobulin and Ki-67 was evaluated in a semi-quantitative fashion. Differences in protein expression between the cohorts were evaluated using chi-square tests with Bonferroni adjustments. Survival time and presence of metastasis at presentation were collected. The ATC cohort showed a statistically significant decrease (p < 0.05) in thyroglobulin expression and statistically significant increases (p < 0.05) in Ki-67 and p53 expression as compared with the PTC cohort. A trend toward loss of p16 and p21 expression was noted in the ATC cohort. A trend toward decreased survival was noted with p21 expression. These data indicate disruption of the normal cell cycle with aberrant expression of multiple protein markers suggesting increased proliferative activity and loss of control of cell cycle progression to G1 phase. These findings support the assertion that ATC may represent the furthest end of a continuum of thyroid carcinoma dedifferentiation.

Expression of opioid growth factor (OGF)-OGF receptor (OGFr) axis in human nonmedullary thyroid cancer.

BACKGROUND: Although thyroid cancers are readily treatable with surgery and radioactive iodine, there are problems in managing recurring, as well as locally advanced, thyroid cancer. The opioid growth factor (OGF) and its receptor, OGF receptor (OGFr), form a tonically active, autocrine-paracrine loop that serves to inhibit cell proliferation in a wide variety of normal and abnormal cells and tissues. In the present study we examined the presence and distribution of OGF and OGFr in nonmedullary thyroid cancer, including papillary, follicular, and anaplastic, as well as thyroid tissue from patients with nonmalignant disease. METHODS: Patient samples of thyroid cancers and goiter were collected at the time of resection and processed for immunohistochemistry of OGF and OGFr, as well as pharmacological binding assays for OGFr. RESULTS: Both peptide and receptor were detected in the cytoplasm and nucleus of all nonmedullary thyroid cancers, as well as in goiter. Specific and saturable binding of OGFr was found in all thyroid samples. CONCLUSIONS: The finding that a potent negative growth regulator and its receptor are present in nonmedullary thyroid cancers and thyroid tissues from patients with nonmalignant disease lead us to suggest that the OGF-OGFr axis serves as a regulator of cell proliferation in these tissues. Moreover, modulation of this biological system may be used to treat progression of nonmedullary thyroid neoplasias.