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There are few pathologic or molecular studies of penile precancerous lesions, and the majority refers to lesions associated with invasive carcinomas. Penile Intraepithelial Neoplasia (PeIN) is classified in two morphologically and distinctive molecular groups, non-HPV and HPV-related with special subtypes. The primary purpose of this international series was to classify PeIN morphologically, detect HPV genotypes and determine their distribution according to PeIN subtypes. A secondary aim was to evaluate the p16

Our objective was to evaluate the pathologic features and clinical outcomes in cases of invasive penile squamous cell carcinoma (SCC) and the association with p16 immunohistochemistry (IHC) and human papilloma virus (HPV) in situ hybridization (ISH). A retrospective multi-institutional database search was conducted for invasive SCC of the penis diagnosed between 2007 and 2018 that had undergone surgical resection. Pathologic features, p16 IHC, and HPV ISH were investigated with clinical outcomes. A total of 102 patients were included in the study. The average age was 63 ± 13.3 years. Based on histology, 46% of tumors displayed an HPV-related subtype, whereas p16 was positive in 52% of all cases. Tumor histology correlated well with p16 positivity (P .001), and p16 IHC accurately predicted the presence of HPV in 25/26 (96%) cases. On multivariate analysis, perineural invasion was associated with local disease recurrence (P = .02), whereas lymphovascular invasion was associated with progression to metastatic disease (P = .002) and increased overall mortality (P = .02). Urethral involvement was also associated with increased overall mortality (P = .02). In addition, HPV-related tumors based on histologic features correlated with lower rates of metastatic disease (P = .007). HPV is a common cause of penile SCC and can be diagnosed by tumor histology and confirmed by overexpression of p16 on IHC. The presence of lymphovascular invasion, perineural invasion, and urethral involvement are poor prognostic indicators, whereas HPV-related tumors based on histology may have lower risk for metastatic disease.

The differential diagnosis of glandular lesions of the bladder/urinary tract can be challenging because of significant morphologic and immunohistochemical overlap between primary lesions and metastasis/direct extension from adjacent organs. Special AT-rich sequence-binding protein 2 (SATB2), encoded on chromosome 2q32-33, is a recently described DNA-binding protein involved in osteoblast lineage commitment and expressed in colorectal and appendiceal neoplasms. In this study, we hypothesized that immunohistochemistry for SATB2 may be of value in distinguishing primary adenocarcinoma of the bladder/urinary tract and urothelial carcinoma with glandular differentiation from gastrointestinal and endocervical primaries. Intensity and distribution of SATB2 nuclear labeling were semiquantitatively scored and compared with those of CDX2. The study included 43 primary adenocarcinomas of the bladder/urinary tract, 20 urothelial carcinomas with glandular differentiation, 26 adenocarcinomas of the uterine cervix, and 22 colorectal adenocarcinomas involving the bladder. Positive SATB2 immunostaining was observed in 21 of 43 (49%) primary bladder/urinary tract adenocarcinomas, in 17 of 22 (77%) colorectal adenocarcinomas, and in the glandular component of 4 of 18 (22%) urothelial carcinomas with glandular differentiation. SATB2 was negative in 25 of 26 endocervical adenocarcinomas and showed focal weak immunostaining (1+) in 1 of 26 (4%). The results were not significantly different from those seen with CDX2. We conclude that SATB2 immunohistochemistry is not useful in supporting urothelial versus gastrointestinal or endocervical origin in the differential diagnosis of glandular lesions of the bladder/urinary tract.

Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI-2) is a scaffolding protein that links cell adhesion molecules, receptors, and signaling molecules to the cytoskeleton and maintains the architecture of cell junctions. MAGI-2 gene rearrangements have recently been described in prostate cancer. We studied the immunohistochemical expression of MAGI-2 protein in prostate tissue. Seventy-eight radical prostatectomies were used to construct 3 tissue microarrays consisting of 512 cores, including benign tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma, Gleason patterns 3 to 5. Immunohistochemistry for phosphatase and tensin homologue (PTEN) and double-stain MAGI-2/p63 was performed and analyzed by visual and image analysis, the latter as percent of analyzed area (%AREA), and mean optical density multiplied by %AREA (STAIN). By visual and image analysis, MAGI-2 was significantly higher in adenocarcinoma and HGPIN compared with benign (benign versus HGPIN P < .001; benign versus adenocarcinoma, P < .001). HGPIN and adenocarcinoma did not significantly differ by either modality. Using visual intensity to distinguish benign tissue and adenocarcinoma, a receiver operating curve yielded an area under the curve of 0.902. A STAIN threshold of 1470 yielded a sensitivity of 0.66 and specificity of 0.96. There was a significant correlation between PTEN and MAGI-2 staining for normal and benign prostatic hyperplasia, but this was lost in HGPIN and cancer. We conclude that MAGI-2 immunoreactivity is elevated in prostate cancer and HGPIN compared with normal tissue, and suggest that MAGI-2 may contribute to prostate carcinogenesis. This is the first report of MAGI-2 staining by immunohistochemistry in prostate cancer.

Antibody-mediated rejection (ABMR) is implicated in 45% of renal allograft failure and 57% of late allograft dysfunction. Peritubular capillary C4d is a specific but insensitive marker of ABMR. The 2013 Banff Conference ABMR revised criteria included C4d-negative ABMR with evidence of endothelial-antibody interaction. We hypothesized that endothelial activation and lymphangiogenesis are increased with C4d-negative ABMR and correlate with intragraft T-regulatory cells and T-helper 17. Seventy-four renal transplant biopsies were selected to include (a) ABMR with C4d Banff scores ≥2 (n = 35), (b) variable microvascular injury and C4d score 0-1 (n = 24), and (c) variable microvascular injury and C4d score = 0 (n = 15). Controls included normal preimplantation donor kidneys (n = 5). Immunohistochemistry for endothelial activation (P- and E-selectins [SEL]), lymphangiogenesis (D2-40), T-regulatory cells (FOXP3), and T-helper 17 (STAT3) was performed. Microvessel and inflammatory infiltrate density was assessed morphometrically in interstitium and peritubular capillaries. All transplants had significantly higher microvessel and lymph vessel density compared with normal. Increased expression of markers of endothelial activation predicted transplant glomerulopathy (P-SEL, P = .003). Increased P-SEL and D2-40 were associated with longer interval from transplant to biopsy (P = .005). All 3 markers were associated with increased interstitial fibrosis, tubular atrophy, and graft failure (P-SEL, P < .001; E-SEL, P = .0011; D2-40, P = .012). There was no association with the intragraft FOXP3/STAT3 ratio. We conclude that endothelial activation and lymphangiogenesis could represent a late response to injury leading to fibrosis and progression of kidney damage, and are independent of the intragraft FOXP3/STAT3 ratio. Our findings support the therapeutic potential of specifically targeting endothelial activation.

We have observed a predominantly mesangial non-immunoglobulin A immune complex mesangial glomerulopathy (MG) in renal transplants with mesangial deposits by immunofluorescence and electron microscopy. Clinicopathological features of 28 patients with MG were analyzed and compared with 28 transplant controls, matched for age, sex, ethnicity, donor type, estimated glomerular filtration rate, and interval from transplant to biopsy. Indications for biopsy in the MG group were allograft dysfunction in 64%, allograft dysfunction/proteinuria in 29%, and proteinuria in 7%. Biopsy indications in controls were allograft dysfunction (61%), allograft dysfunction/proteinuria (18%), proteinuria (14%), and delayed graft function (7%). Most MG cases had mild mesangial hypercellularity with endocapillary proliferation in 2 and crescents in 2 without fibrinoid necrosis. Immunoglobulin M-dominant deposits were present in 83%, and immunoglobulin G was dominant in 17% with mesangial deposits in 93% of cases by electron microscopy. Compared with controls, MG had higher Banff interstitial inflammation score (i) (P = .036) and was associated with concurrent acute T-cell-mediated rejection (P = .023), but not with acute or chronic antibody-mediated rejection. MG patients and controls had similar prevalence of polyomavirus nephropathy and Epstein-Barr virus infection. At follow-up, most MG patients had stable estimated glomerular filtration rate with no or stable proteinuria. Disease-specific graft survival was not different in MG versus controls. We conclude that, in view of the apparent self-limited nature of this lesion, additional treatment may not be required in these patients. Awareness of this lesion may thus spare patients unwarranted further intervention.