Increased expression of CYP24A1 correlates with advanced stages of prostate cancer and can cause resistance to vitamin D3-based therapies.

A major limitation of exogenous vitamin D3 administration for the treatment of prostate cancer is the marginal, if any, clinical efficacy. We dissected the basis for the resistance to the vitamin D3 antitumor properties and specifically examined the effect of its major catabolic enzyme, CYP24A1, in prostate cancer. Local CYP24A1 expression levels and the effect of selective modulation were analyzed using tissue microarrays from needle core biopsy specimens and xenograft-bearing mouse models. CYP24A1 mRNA was elevated in malignant human prostate tissues compared to benign lesions. High CYP24A1 protein levels were seen in poorly differentiated and highly advanced stages of prostate cancer and correlated with parallel increase in the tumor proliferation rate. The use of CYP24A1 RNAi enhanced the cytostatic effects of vitamin D3 in human prostate cancer cells. Remarkably, subcutaneous and orthotopic xenografts of prostate cancer cells harboring CYP24A1 shRNA resulted in a drastic reduction in tumor volume when mice were subjected to vitamin D3 supplementation. CYP24A1 may be a predictive marker of vitamin D3 clinical efficacy in patients with advanced prostate cancer. For those with up-regulated CYP24A1, combination therapy with RNAi targeting CYP24A1 could be considered to improve clinical responsiveness to vitamin D3.

Leptomeningeal carcinomatosis as initial presentation in adenocarcinoma of lung with signet ring cell features: an autopsy case report.

Signet ring cell (SRC) features are rare but well-recognized cytological changes of pulmonary adenocarcinoma (PA). PA with SRC features (PA-SRC) is frequently associated with anaplastic lymphoma kinase (ALK) gene rearrangement, and recognition of PA-SRC may be important for the administration of targeted treatment. To the authors' knowledge, leptomeningeal carcinomatosis (LMC) as an initial presentation of PA-SRC has not yet been reported. We report an autopsy case from a 59-year-old female who presented with intractable headache for 6 weeks and died of LMC as a result of metastatic PA-SRC. Premortem brain MRI showed nonspecific leptomeningeal enhancement. At autopsy, a tan rubbery mass was found in the hilar area of the right lung, which also surrounded the lower trachea and carotid arteries. A right posteromedial middle lobe mass was also found. Leptomeninges were slightly thickened, without discrete masses. Microscopic examination of the lung mass and leptomeninges showed solid sheets and nests of malignant cells with pleomorphic nuclei and frequent SRC features which comprised 50% of the mass. Immunohistochemically, the tumor cells demonstrated strong diffuse expression of cytokeratin (CK)-7, TTF-1, and napsin-A. Immunostains for CK-20 and ALK were negative. These features were consistent with PA-SRC. It has been reported that approximately 70% of PAs demonstrate ALK gene rearrangement when SRCs comprised >10% of the tumor cells. The presence of SRCs can be indicative of a lung primary and, because of frequent ALK gene rearrangement in PA-SRC, proper recognition of PA-SRC may be important in determining whether further testing is advisable (e.g., ALK immunostaining and/or ALK gene rearrangement).

Benign salivary gland tissue inclusion in a pulmonary hilar lymph node from a patient with invasive well-differentiated adenocarcinoma of the lung: a potential misinterpretation for the staging of carcinoma.

Benign epithelial and nonepithelial inclusions have been found in lymph nodes in multiple body sites. These inclusions have been seen in cervical, axillary, mediastinal, abdominal, and pelvic lymph nodes. They appear as benign epithelial, parathyroid, decidual, mesothelial, angiolipomatous, nevus cells, or Tamm-Horsfall protein. Although heterotopic salivary gland tissue is not infrequent in paraparotid lymph nodes, it has only been described in lymph nodes of the pulmonary hilum once. A 68-year-old woman with gastric lymphoma now in remission presented for routine follow-up and was found to have a lung mass. After a fine needle aspiration biopsy diagnosis of adenocarcinoma, lobectomy and lymph node dissection were performed. Histological sections of lung demonstrated a well-differentiated adenocarcinoma and one lymph node, which displayed a subcapsular nest of well-formed salivary glands occupying approximately one third of the nodal tissue. The inclusion was composed of acinar cells of both serous and mucinous types, but ductal type of cells were not seen. Identification of heterotopic tissue in lymph nodes is of great importance for patient management. Misdiagnosing benign glandular inclusions for metastasis could potentially lead to incorrect tumor staging. Benign salivary gland tissue inclusions should be considered in the differential diagnosis when evaluating for metastatic adenocarcinoma. The salivary gland inclusion in pulmonary hilar lymph node may be histogenetically related to the minor salivary glands, which are located within the bronchial submucosa.