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AIMS Atypical intraductal proliferation (AIP) of the prostate is histologically worse than high-grade prostate intraepithelial neoplasia, but lacks the diagnostic criteria of intraductal carcinoma of the prostate (IDC-P). The aim of this study was to compare the clinicopathological and molecular characteristics (ERG overexpression and PTEN loss) of AIP and IDC-P in core needle biopsies. METHODS AND RESULTS One hundred and six [84 (5.6%) of 1480 consecutive and 22 retrospectively collected] cases met the criteria: AIP only (2.4%), IDC-P only (1.3%), and IDC-P coexisting with AIP (2%). Invasive adenocarcinoma [prostate adenocarcinoma (PCa)] was present in 96% and 97% cases of AIP and IDC-P, respectively. The mean number of glands/focus and the largest gland diameter for AIP and IDC-P were 7.6 (range, 2-27) and 11.7 (range, 1-51), and 0.59 mm (range, 0.2-1.1 mm) and 0.75 mm (range, 0.2-1.8 mm), respectively. For AIP, loose cribriform architecture was the most common (93%) morphology. IDC-P-associated PCa had more aggressive pathology, including the highest combined Gleason score (GS), high-grade GS ≥ 4 + 3, and largest percentage involvement of core by PCa and percentage positive cores, than AIP-associated PCa (P

In the above-referenced commentary,1 Murali Varma raises two valid concerns regarding implications for communication from the message of our study2. First, introducing a term ”Atypical Intraductal Proliferation (AIP)” or “low-grade intraductal carcinoma (IDC-P)” for which there are no well-defined morphological cut-offs or criteria and, second, for the risk of overtreatment. In this author's experience which is based on current2 and previous studies,3-6 AIPs represent significant lesions and must be distinguished from HGPIN. Morphologically, the vast majority of AIPs present with cribriform morphology which have been increasingly recognized as significant lesions. This article is protected by copyright. All rights reserved.

Aims Patients who have undergone prostate radiation are at increased risk for developing urothelial carcinoma. Radiation changes can cause significant cytological atypia in benign prostate glands that may mimic pagetoid spread of urothelial carcinoma. GATA3 is a common marker for differentiating prostatic adenocarcinoma from urothelial carcinoma. The aim of this study was to investigate the expression of GATA3 in the epithelium of irradiated benign and malignant prostate tissue. Methods and results We performed a retrospective review of prostate cases with radiation atypia. GATA3 staining was performed on benign prostate tissue with and without radiation atypia, as well as on residual/recurrent prostatic adenocarcinoma after radiation therapy. PIN4 immunohistochemical (IHC) staining was performed on prostate tissue with radiation atypia to confirm the presence of both basal and luminal cells. We identified 31 cases with benign prostate glands containing radiation atypia. The average time between treatment with radiation therapy and the surgical procedure was 10 years (range 5-20 years). PIN4 IHC staining confirmed the presence of basal and luminal cells in benign prostate glands with radiation atypia. Thirty-one of 31 (100%) cases of benign prostate tissue with radiation atypia showed staining for GATA3 in both basal and luminal cells. Eight of eight (100%) cases of benign prostate glands without radiation atypia and no inflammatory changes showed GATA3 positivity limited to basal cells. GATA3 was negative in 12/12 (100%) cases of prostatic adenocarcinoma after radiation therapy. Conclusion Benign prostate glands with radiation atypia show diffuse positivity for GATA3. This staining pattern, along with the cytological atypia resulting from radiation, can mimic urothelial carcinoma.

Carvalho J C, Thomas D G, McHugh J B, Shah R B & Kunju L P (2012) Histopathology 60, 597–608 p63, CK7, PAX8 and INI-1: an optimal immunohistochemical panel to distinguish poorly differentiated urothelial cell carcinoma from high-grade tumours of the renal collecting system Aims: High-grade, poorly differentiated, infiltrative carcinomas involving the renal sinus region often pose challenging differential diagnostic considerations, specifically differentiation of urothelial carcinoma (UC) from renal cell carcinoma (RCC) subtypes. Accurate classification, especially the distinction of UC from RCC, is critical, as therapeutic approaches differ. Methods and results: Cluster analysis was performed on immunohistochemical data from 18 invasive UCs, six CDCs, two RMCs, 18 type 2 papillary renal cell carcinomas (PRCCs) and 20 high-grade clear cell renal cell carcinomas (CRCCs) using a broad panel of traditional and novel immunohistochemical markers. The initial analysis with all antibodies segregates almost all the RCCs (45 of 46, 98%) from all the UCs based on the lack of expression of p63 in all (100%) RCCs, along with predominant strong expression of paired box gene 8 (PAX8) and vimentin, predominant lack of expression of high molecular weight cytokeratin (HMCK) and CK7 and variable expression of RCC, CD10, CA1X and PAX2. All the UCs cluster together with strong, diffuse reactivity for p63, predominant reactivity for CK7 and high molecular weight kininogen (HMWK), and absent to minimal staining with PAX8, RCC antigen, PAX2, alpha-methylacyl-CoA racemase (AMACR), carbonic anhydrase IX (CAIX) and vimentin. After removing antibodies with significant overlap and/or minimal impact, a second analysis with a limited panel including p63, CK7, vimentin, integrase interactor 1 (INI-1) and PAX8 was performed. Again, the majority of UCs cluster into one group and p63 positivity separates all UCs from RCCs. Conclusions: Lack of INI-1 expression, noted exclusively in RMCs, segregates RMCs into a separate cluster. PAX8 is rarely positive (17%) in UC, is commonly expressed in CDC, RMC, PRCC and CRCC and is superior to PAX2.

Carvalho J C, Wasco M J, Kunju L P, Thomas D G & Shah R B (2011) Histopathology58, 169–179 Cluster analysis of immunohistochemical profiles delineates CK7, vimentin, S100A1 and C-kit (CD117) as an optimal panel in the differential diagnosis of renal oncocytoma from its mimics Aims: To develop an immunohistochemical strategy for distinguishing renal oncocytoma (RO) from the eosinophilic variant of chromophobe (ChRCC), and papillary (PRCC) and clear cell (CRCC) renal cell carcinoma containing eosinophilic cytoplasm in core biopsy specimens. Methods and results: Cluster analysis was performed on immunohistochemical data from 21 RO, 16 ChRCC, 16 CRCC and 20 PRCC patients. A panel of CK7, C-kit, S100A1 and vimentin clustered into four groups. Cluster A (94% ChRCC) expressed C-kit and CK7 and lacked S100A1 and vimentin. Cluster B (95% RO) expressed C-kit, S100A1, focal CK7 (single or small clusters of cells) and lacked vimentin. Cluster C comprised a mixture of PRCC and CRCC with no expression of C-kit or CK7 and variable S100A1 and vimentin. PRCC with strong expression of CK7 clustered into group D. A panel of S100A1 (positive) and focal CK7 expression distinguished RO from ChRCC with 91% sensitivity and 93% specificity. A panel of vimentin (negative) and C-kit (positive) distinguished RO from CRCC with 83% sensitivity and 86% specificity and RO from PRCC with 79% sensitivity and 88% specificity. Conclusions: Hierarchical cluster analysis is an effective approach to analyse high-volume immunohistochemical data to generate an optimal panel in the differential diagnosis of oncocytoma from its mimics.

Aim : Studies using a monoclonal (P504S) and a polyclonal antibody (p-AMACR) to α-methylacyl-CoA racemase (AMACR) have shown variable expression in prostate cancer (PCa). The goal is to compare the sensitivity of both antibodies in PCa and evaluate their utility in the work-up of atypical prostate needle biopsies (NBXs). Methods and results : A tissue microarray (TMA) with 248 samples of benign prostate, high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa samples, 20 NBXs with minute PCa and 32 NBXs with ‘atypical’ foci were stained with P504S and p-AMACR. Ninety percent of PCa (76/76 TMA, 16/20 NBXs) showed predominantly strong p-AMACR expression while 87% (65/69 TMA, 16/20 NBXs) showed variable P504S expression (sensitivity 90% versus 87%, P = 0.10). In HGPIN, P504S and p-AMACR were positive in 77% and 91% of samples, respectively. In the ‘atypical’ NBXs group, 53% were classified as PCa, 12% benign and 35% atypical, suspicious for PCa, after review of the basal marker. Of atypical, suspicious for PCa, P504S/p-AMACR helped convert the diagnosis to PCa in 5/11 (45%) cases, where, despite negative basal cell markers, morphology was less than optimal. Conclusions : Differences between P504S and p-AMACR appear marginal and clinically insignificant. AMACR is negative in a subset of unequivocal minute PCa with both antibodies. However, when utilized in proper context, AMACR may offer significant advantage in converting an ‘atypical’ diagnosis to PCa where morphology and basal markers are less than optimal in resolving the diagnosis.

High-grade, poorly differentiated, infiltrative carcinomas involving the renal sinus region often pose challenging differential diagnostic considerations, specifically differentiation of urothelial carcinoma (UC) from renal cell carcinoma (RCC) subtypes. Accurate classification, especially the distinction of UC from RCC, is critical, as therapeutic approaches differ.Cluster analysis was performed on immunohistochemical data from 18 invasive UCs, six CDCs, two RMCs, 18 type 2 papillary renal cell carcinomas (PRCCs) and 20 high-grade clear cell renal cell carcinomas (CRCCs) using a broad panel of traditional and novel immunohistochemical markers. The initial analysis with all antibodies segregates almost all the RCCs (45 of 46, 98%) from all the UCs based on the lack of expression of p63 in all (100%) RCCs, along with predominant strong expression of paired box gene 8 (PAX8) and vimentin, predominant lack of expression of high molecular weight cytokeratin (HMCK) and CK7 and variable expression of RCC, CD10, CA1X and PAX2. All the UCs cluster together with strong, diffuse reactivity for p63, predominant reactivity for CK7 and high molecular weight kininogen (HMWK), and absent to minimal staining with PAX8, RCC antigen, PAX2, alpha-methylacyl-CoA racemase (AMACR), carbonic anhydrase IX (CAIX) and vimentin. After removing antibodies with significant overlap and/or minimal impact, a second analysis with a limited panel including p63, CK7, vimentin, integrase interactor 1 (INI-1) and PAX8 was performed. Again, the majority of UCs cluster into one group and p63 positivity separates all UCs from RCCs.Lack of INI-1 expression, noted exclusively in RMCs, segregates RMCs into a separate cluster. PAX8 is rarely positive (17%) in UC, is commonly expressed in CDC, RMC, PRCC and CRCC and is superior to PAX2.

To develop an immunohistochemical strategy for distinguishing renal oncocytoma (RO) from the eosinophilic variant of chromophobe (ChRCC), and papillary (PRCC) and clear cell (CRCC) renal cell carcinoma containing eosinophilic cytoplasm in core biopsy specimens.Cluster analysis was performed on immunohistochemical data from 21 RO, 16 ChRCC, 16 CRCC and 20 PRCC patients. A panel of CK7, C-kit, S100A1 and vimentin clustered into four groups. Cluster A (94% ChRCC) expressed C-kit and CK7 and lacked S100A1 and vimentin. Cluster B (95% RO) expressed C-kit, S100A1, focal CK7 (single or small clusters of cells) and lacked vimentin. Cluster C comprised a mixture of PRCC and CRCC with no expression of C-kit or CK7 and variable S100A1 and vimentin. PRCC with strong expression of CK7 clustered into group D. A panel of S100A1 (positive) and focal CK7 expression distinguished RO from ChRCC with 91% sensitivity and 93% specificity. A panel of vimentin (negative) and C-kit (positive) distinguished RO from CRCC with 83% sensitivity and 86% specificity and RO from PRCC with 79% sensitivity and 88% specificity.Hierarchical cluster analysis is an effective approach to analyse high-volume immunohistochemical data to generate an optimal panel in the differential diagnosis of oncocytoma from its mimics.