Expression of SOCS1 and the downstream targets of its putative tumor suppressor functions in prostate cancer.

BACKGROUND: Suppressor of cytokine signaling 1 (SOCS1) is considered a tumor suppressor due to frequent epigenetic and micro-RNA-mediated repression of its gene expression in diverse cancers. In prostate cancer (PCa), elevated expression of miR-30d that targets SOCS1 mRNA is associated with increased risk of disease recurrence. SOCS1 can mediate its tumor suppressor functions by diverse mechanisms such as inhibiting the JAK-STAT signaling pathway, promoting the tumor suppressor functions of p53, attenuating MET receptor tyrosine kinase signaling and blocking the oncogenic potential of the cell cycle inhibitor p21CIP1 (p21). Here, we studied the expression of SOCS1 and the downstream targets of its putative tumor suppressor functions (p53, MET and p21) in human PCa specimens to evaluate their significance as markers of disease prognosis. METHODS: Tissue microarrays were constructed of 78 archived prostatectomy specimens that were grouped according to the recommendations of the International Society of Urological Pathology (ISUP) based on the Gleason patterns. SOCS1, p53, MET and p21 protein expression were evaluated by immunohistochemical staining alongside the common prostate cancer-related markers Ki67, prostein and androgen receptor. Statistical correlations between the staining intensities of these markers and ISUP grade groups, local invasion or lymph node metastasis were evaluated. RESULTS: SOCS1 showed diffuse staining in the prostatic epithelium. SOCS1 staining intensity correlated inversely with the ISUP grade groups (ρ = -0.4687, p <0.0001) and Ki67 (ρ = -0.2444, p = 0.031), and positively with prostein (ρ = 0.3511, p = 0.0016). Changes in SOCS1 levels did not significantly associate with those of p53, MET or p21. However, p21 positively correlated with androgen receptor expression (ρ = -0.1388, p = 0.0003). A subset of patients with regional lymph node metastasis, although small in number, showed reduced SOCS1 expression and increased expression of MET and p21. CONCLUSIONS: Our findings suggest that evaluating SOCS1 and p21 protein expression in prostatectomy specimens may have a prognostic value in identifying the aggressive disease. Hence, prospective studies with larger numbers of metastatic PCa specimens incorporating clinical correlates such as disease-free and overall survival are warranted.

Napsin-A Immunohistochemistry in the Diagnosis of Pulmonary Alveolar Proteinosis.

CONTEXT.­: The diagnosis of pulmonary alveolar proteinosis (PAP) relies on a limited set of stains, namely hematoxylin-eosin and periodic acid-Schiff-diastase (PAS-D), demonstrating abundant alveolar material representing mostly surfactant. As cells harboring surfactant also express Napsin-A (pneumocytes and macrophages), we hypothesized that it would also be expressed within alveoli in PAP. OBJECTIVE.­: To evaluate the sensitivity and specificity of Napsin-A in the diagnosis of PAP. DESIGN.­: A 12-year retrospective case control study was designed to identify cases of PAP and potential histologic mimics (intra-alveolar fibrin, pulmonary edema, diffuse alveolar damage, and alveolar mucinosis). PAS-D staining and Napsin-A immunohistochemistry were performed. Distribution and intensity were evaluated by using a semiquantitative 3-point scale. Positivity was defined as 2+ intensity score, regardless of distribution. RESULTS.­: Eleven cases of PAP and 46 control cases were identified. Napsin-A showed positivity in all PAP cases and 3 of 12 cases of edema. Among positive cases, all those with a 2+ distribution were PAP cases, with heterogeneous (1+) staining in all cases of edema. PAS-D showed positivity in all cases of PAP and most controls, except cases of edema. Sensitivity and specificity of Napsin-A for PAP were 100% and 94%, respectively, and of PAS-D for PAP, 100% and 21%, respectively. Double positivity for Napsin-A and PAS-D was 100% specific and sensitive for PAP. CONCLUSIONS.­: This study is the first to demonstrate that Napsin-A is highly specific for the diagnosis of PAP, more so than PAS-D. It also shows that the combined positivity of Napsin-A and PAS-D is 100% specific and sensitive for PAP.

Testing for BAP1 loss and CDKN2A/p16 homozygous deletion improves the accurate diagnosis of mesothelial proliferations in effusion cytology.

BACKGROUND: A number of ancillary tests have been developed that aid in the diagnosis of mesothelioma in cytology specimens. The aim of this retrospective study was to determine whether testing for BAP1 and CDKN2A/p16 status in effusion specimens preceding the tissue diagnosis of mesothelioma would improve diagnostic accuracy and allow an earlier diagnosis of malignancy. METHODS: The study cohort included 99 matched cytology fluid specimens from 74 patients with a surgical specimen diagnosis of malignant mesothelioma (67 epithelioid, 7 biphasic, 55 pleural, and 19 peritoneal). BAP1 immunohistochemistry and p16 fluorescence in situ hybridization (FISH) were performed retrospectively. RESULTS: BAP1 or p16 FISH testing revealed a loss in 7 of 18 (39%) samples originally categorized as benign/reactive, 20 of 33 (61%) interpretable samples categorized as atypical, and 10 of 14 (71%) cases suspicious for mesothelioma. In some cases, the diagnosis of mesothelioma could have been made up to 9 months before biopsy. Similarly, loss of BAP1 or p16 was found in 28 of 30 (93%) samples categorized as malignant, with some cases diagnosable up to 6 months before biopsy. Overall, loss of BAP1 and/or CDKN2A/p16 homozygous deletion would change the diagnostic interpretation in 37 of 60 (62%) (P = .07) effusion specimens, particularly in pleural effusions (32 of 48 samples) (P = .002). The sensitivity of morphologic interpretation alone was 30.3%; however, adding testing for BAP1 and p16 resulted in an increase in sensitivity to 68.7%. (P < .0001). CONCLUSION: These findings suggest that routine use of BAP1 immunochemistry and p16 FISH as adjunctive tests improves the diagnostic accuracy of cytology specimens and potentially allows an earlier diagnosis of malignant mesothelioma.