Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate.

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.

Do Nonseminomatous Germ Cell Tumors of the Testis With Lymphovascular Invasion of the Spermatic Cord Merit Staging as pT3?

The staging of testicular nonseminomatous germ cell tumors (NSGCTs) with lymphovascular invasion (LVI) of the spermatic cord in the absence of cord parenchymal involvement remains controversial. Our previous study showed that tumors with spermatic cord LVI present at a higher clinical stage than tumors with LVI confined to the testis (pT2). We compared NSGCTs with LVI of the spermatic cord without direct involvement of the spermatic cord soft tissues to pT3 tumors to help clarify the appropriate staging of this histologic finding. A retrospective, multi-institutional review was performed to identify cases of NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord. The clinical-pathologic findings were compared with NSGCTs with spermatic cord soft tissue invasion (pT3). We identified 38 pT2 NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord and 89 pT3 tumors. There were no significant differences in patient age, tumor size, or clinical stage at presentation between the 2 groups. There were no significant differences in dominant histologic subtype, rete testis invasion, hilar soft tissue invasion, or margin status. There were no significant differences in disease recurrence/progression (P=0.63), recurrence/progression after chemotherapy (P=0.35), or death (P=0.51) between patients with only spermatic cord LVI versus patients with cord soft tissue invasion. In patients with pT2 NSGCTs according to the current staging, LVI in the spermatic cord without cord soft tissue invasion is comparable with pT3 tumors in terms of clinical stage at presentation as well as disease recurrence and survival.

Anti-glutamate receptor 2 as a new potential diagnostic probe for prostatic adenocarcinoma: a pilot immunohistochemical study.

Diagnoses of prostatic carcinoma (PC) have increased with widespread screening. While the use of α-methylacyl coA racemase and high molecular weight cytokeratins have aided in distinguishing benign mimics from malignancy, their sensitivity and specificity are limited. We studied 6C4, a monoclonal antibody to glutamate receptor 2, an excitatory amino acid receptor subunit distributed throughout the central nervous system, on benign prostatic epithelium, high-grade prostatic intraepithelial neoplasia, and PC. Ten cases with post-atrophic or adenosis-like prostate glands were also stained with prostatic intraepithelial neoplasia 4, an immunostain cocktail against α-methylacyl coA racemase, p63, and high molecular weight cytokeratin, in parallel with 6C4. Immunoreactivity for 6C4 was graded as negative (0% to 10%), +1 (11%% to 50%), and +2 (>50%). Malignant epithelium was classified by Gleason patterns. Gleason patterns 4 and 5 were subdivided into cribriform or noncribriform type. Its utility in distinguishing postatrophic or adenosis-like glands from prostate cancer, both of which show absence of basal cells on prostatic intraepithelial neoplasia 4 immunostain, was also investigated. Our results revealed a statistically significant difference in staining of benign secretory prostatic epithelium, high-grade prostatic intraepithelial neoplasia, and low Gleason pattern carcinomas. The results also showed 6C4 is a sensitive marker in separating basal cell negative postatrophic or adenosis-like glands from prostate carcinoma. In addition, there was a statistically significant difference between staining of cribriform versus noncribriform Gleason pattern 4 and 5 carcinomas. A limited number of lymph node metastases from cribriform and noncribriform carcinomas were studied, and they stained the same as the primary tumor in the majority of cases. In conclusion, our preliminary data demonstrated potential utility of 6C4 in the pathologic evaluation of PC.