Faculty Bibliography

Atypical intraductal cribriform proliferations of the prostate (AIP) are loose cribriform proliferations of luminal cells that exhibit greater architectural complexity and/or nuclear atypia than high-grade prostatic intraepithelial neoplasia (HGPIN), but lack the diagnostic criteria for intraductal carcinoma (IDC). The significance of AIP has not been formally established. We compared the clinical, morphologic, and immunohistochemical characteristics of AIP with classic IDC in 310 radical prostatectomy specimens that were received over an 18-month period. Of the 310 cases, 46 cases had AIP only (n=10), IDC only (n=6), or AIP coexisting with IDC (n=30). The ERG status of all 46 AIP/IDC cases was identical to the nearby acinar carcinoma, contrasted to just 3 cases of HGPIN (7%, P<0.01). The degree of uniform phosphatase and tensin homolog (PTEN) loss in 34 selected cases was identical in AIP and IDC (66.7%). No foci of HGPIN showed uniform PTEN loss; there was only 38% concordance of PTEN expression pattern between HGPIN and the nearby acinar carcinoma, unlike AIP and IDC (77% and 81%, respectively, P<0.01). AIP-associated and/or IDC-associated carcinoma (n=46) showed a higher stage and grade compared with acinar-only carcinoma (n=264, P<0.01). AIP-associated carcinoma had similar clinicopathologic features as IDC-associated carcinoma, including preoperative prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis (n=36, P>0.05). In conclusion, AIP shares similar ERG/PTEN immunoprofiles and exhibits similar clinical behavior as IDC, warranting immediate repeat biopsy when AIP is identified on biopsy, as is recommended in the most recent WHO Classification of Tumours of the Urinary System and Male Genital Organs, 2016.

Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development, as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here, we show that TPL2 overexpression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically, activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK, mTOR, NF-kappaB, and p38 MAPK leads to TPL2-mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly, TPL2 overexpression is required for iTPL2 TG-driven SCC and KA-like cSCC tumor maintenance, validating TPL2 as a possible drug target for the treatment of SCC/KA. Finally, we verified that TPL2 is overexpressed in human cutaneous metastatic SCC and KA clinical specimens compared with normal skin. Taken together, our results establish TPL2 as an oncogenic driver in SCC/KA development. Cancer Res; 76(22); 1-11. (c)2016 AACR.

Significant differences, including epidemiologic, clinical, pathologic and genetic, exist between Asian and Caucasian prostate cancer. Detailed pathologic data are, however, scarce. We studied in detail and compared the pathological features of prostate cancer in radical prostatectomy specimens in 228 patients (117 Japan, 111 US). Japanese prostate cancer had a higher Gleason grade group (mean 2.67 vs. 2.42 US, P < 0.05), but lower pathological stage (72 % pT2 and 28 % pT3 vs 55 % pT2 and 45 % pT3 US, P < 0.05). Japanese cancer showed significantly more tumor foci (3.8 vs 2.9 US, P < 0.05), and higher incidence of bilateral significant disease (81.3 % vs. 66.7 % US, P < 0.05). The dominant tumor nodules in Japanese cases had higher Gleason grade group (mean 2.73 vs. 2.40 US, P < 0.05). The incidence of intraductal carcinoma was significantly higher in Japanese patients (35.3 % vs. 12.6 % US, P < 0.01), which was independent of Gleason score (7: 30.9 % Japan vs 11.8 % US, P < 0.01; >/= 8: 87.5 % Japan vs 28.6 % US, P < 0.01) and tumor stage (pT2: 24.1 % Japan vs 6.6 % US, P < 0.01; pT3: 62.9 % Japan vs 20 % US, P < 0.01). These findings demonstrate distinct pathological features in prostate cancer between Japanese and Caucasian patients, and may have important diagnostic and therapeutic implications.