Prostatic Acinar Adenocarcinoma Research Articles

Foamy Gland Variant of Prostatic Adenocarcinoma (FGVPA), diagnostic pitfalls: A case report and literature review

A transurethral resection of prostate (TURP) specimen was received from a 72-year-old male who presented with a recent history of urinary tract infection and increased serum prostate specific antigen (PSA) of 15 ng/mL. There was an atypical glandular proliferation of which a predominant population demonstrated abundant pale xanthomatous cytoplasm with small hyperchromatic nuclei and inconspicuous nucleoli. A minor component of conventional prostatic acinar adenocarcinoma was identified focally in the background. Immunohistochemistry was used to confirm the diagnosis of adenocarcinoma. FGVPA is a rare variant, with foamy cytoplasm due to intracytoplasmic vesicles not lipid or neutral mucin, and usually with small pyknotic nuclei with minimal atypia. Gleason scoring is performed by the underlying architectural pattern. Immunohistochemistry of basal cell markers and AMACR are often used to confirm a diagnosis of prostatic adenocarcinoma; however, it is to be noted that variants of prostate cancer including FGVPA are labelled with AMACR in only 60–70% of cases. It is important for the pathologist to be aware of FGVPA as in its pure form can easily be missed especially on needle core biopsy. The differential diagnoses of benign mimics with clear cytoplasm include xanthoma, Cowper’s glands, clear cell cribriform hyperplasia and mucinous metaplasia.

Mucinous Prostate Cancer Shows Similar Prognosis to Typical Prostate Acinar Carcinoma: A Large Population-Based and Propensity Score-Matched Study.

Background: Mucinous prostate cancer (PCa) is an extremely rare form of prostate malignancy. To date, the limited knowledge of its biology and outcomes stems from mostly small, single institution experiences. We analyzed the Surveillance, Epidemiology, and End Results (SEER) database to explore the incidence and treatment of mucinous PCa together with its prognostic factors to gain relatively large and consolidated insights.Methods: Age-adjusted incidence (AAI) rates were evaluated over time. Propensity score matching (PSM) and Kaplan–Meier analyses were used to compare the prognosis between mucinous PCa and typical prostate acinar adenocarcinoma. We assessed cancer-specific survival (CSS) and overall survival (OS) after patient stratification according to summary stage and treatment choice. Cox hazards regression analysis was performed to determine independent predictors of CSS and OS.Results: The AAI in 2016 was 0.24 per million. Patients with mucinous PCa had similar CSS and OS to matched individuals with typical prostate acinar adenocarcinoma. In terms of treatment, 65.3% of mucinous PCa patients underwent surgery, and 23.9% received radiation therapy. Patients who underwent surgery had longer survival (CSS, p = 0.012; OS, p < 0.001), and patients who received radiation therapy had similar survival to those who did not receive radiation therapy (CSS, p = 0.794; OS, p = 0.097). A multivariate Cox analysis for CSS and OS showed that older age (CSS: HR: 4.982, p = 0.001; OS: HR: 4.258, p < 0.001) and distant stage (CSS: HR: 40.224, p < 0.001; OS: HR: 9.866, p < 0.001) were independent prognostic factors for mucinous PCa patients.Conclusions: Mucinous PCa has an extremely low AAI. Analysis of its outcomes indicates that it is not a more malignant tumor as previously suspected. Mucinous PCa shows a similar prognosis to typical prostate acinar carcinoma. Surgery was associated with prolonged survival. An older age at diagnosis and distant stage was associated with poor survival.

Prostatic Ductal Adenocarcinoma Controlled for Cancer Grade and Tumor Volume Does Not Have an Independent Effect on Adverse Radical Prostatectomy Outcomes Compared to Usual Acinar Prostatic Adenocarcinoma

To study if prostatic ductal adenocarcinoma (PDA) controlled by Grade Group (GG), PSA, and tumor volume (TV) is an independent predictor of adverse radical prostatectomy (RP) outcomes. One-hundred and twenty-eight PDA and 1141 acinar continuous RPs were studied. Each tumor nodule (TN) was individually graded, staged, and its TV measured. Univariate analysis (UVA) identified features associated with lymph node metastasis (LN+), extraprostatic extension (EPE), positive surgical margins (SM+), and seminal vesicle invasion (SV+). We then assessed PDA effect on RP outcomes in a multivariate analysis (MVA). In 127 cases PDA was present in 1 TN and no TN was pure PDA. One-hundred and twenty-three cases had PDA in TNs with highest grade, stage, and TV. Patients with PDA were older (65 vs 63 years, P < 0.001), had higher GG (P < 0.001), and LN+ (6.3% vs 2.7%, P=0.049). Controlling these variables by GG eliminated statistical significance. Overall, there were 3249 separate TNs (129 PDA and 3120 acinar). In UVA, PDA predicted EPE (92/124 vs 517/3045), SV+ (28/1129 vs 116/3,120), and SM+ (51/129 vs 296/3120), all P < 0.001. In MVA, PDA lost its effect on EPE (OR=0.88, P=0.64), SM+ (OR=0.86, P=0.5), and SV+ (OR=0.99, P=0.98). Controlled for grade and TV, PDA was not an independent predictor of adverse RP outcomes, but former 2 were. Hence, higher GG and TV associated with PDA TNs may be predictive of adverse RP outcomes rather than PDA by itself. These conclusions may be used in preoperative risk stratification and definitive therapy planning when PDA is identified on needle biopsy.

Prostatic Ductal Adenocarcinoma Masquerading as a Rectal Mass: A Case Report

Abstract Objective The approach to a patient presenting with a rectal mass who has a history of bright red blood per rectum (BRBPR) renders a wide range of differential diagnoses. The clinical reasoning to suspect prostatic ductal adenocarcinoma (PDA) in a patient with BRBPR without a classical clinical presentation is highly unlikely. The incidence of PDA is rare with only 0.4% to 0.8% in pure ductal origin. Methods A 71-year-old African American male presented with 3-month history of watery, bloody diarrhea and a recent history of BRBPR with unintentional weight loss. Patient underwent colonoscopy, which showed a large polyp 10 cm from the anal verge, measuring 7 cm. The unclear history of this patient contributed to an initial impression of a colorectal cancer leading to a biopsy of the colonic mass. Results An erroneous diagnosis of tubulovillous adenoma was rendered initially. Further workup showed a large mass originating from the prostate area that was seen penetrating the colorectal region on an abdominal CT scan. The patient’s serum prostate-specific antigen (PSA) level was alarmingly high (4,800 ng/mL) and a subsequent prostate biopsy showed PDA. The colonic biopsy was reviewed again by a genitourinary pathologist and a correct diagnosis was rendered. Conclusion The role of pathology in diagnosing PDA is crucial as patients with PDA can have normal digital rectal examination (DRE) as well as a normal serum PSA level (less than 4.0 ng/mL). Majority of PDAs originate from periurethral prostatic ducts. The unique presentation of primary prostate pathology offers appreciation into the approach and workups to diagnose PDA. Diagnosing PDA can be challenging due to its more aggressive nature of PDA compared to prostatic acinar adenocarcinoma. The clinical reasoning and pathological findings from this rare case can aid clinicians and pathologists to establish the diagnosis of PDA in a timely and efficient manner.

Rare Variant of Carcinoma Prostate Masquerading as Benign Prostatic Hyperplasia

Prostatic ductal adenocarcinoma, is an uncommon entity in the spectrum of prostatic carcinoma. Clinically it is different from common prostatic acinar adenocarcinoma. It is usually more aggressive than prostatic acinar adenocarcinoma. We are presenting a case report on prostatic ductal adenocarcinoma, a cystic variant of prostatic carcinoma in a 55-year-old man who complained of obstructive urinary symptoms with mildly raised prostate-specific antigen (PSA). On further evaluation in our radiology department a cystic lesion with enhancing polypoidal soft tissue component was noted in prostatic parenchyma. Histopathology confirmed the diagnosis of ductal adenocarcinoma.

34BetaE12 and Alfa-Methylacyl Coenzyme A Racemase (AMACR) Antibodies Better Than p63 Antibody Distinguish Normal and Neoplastic Glands in Prostatic Tissue With Thermal Artifacts.

The occurrence of inked margins with crush artifact derived from the electrocauterization in radical prostatectomy and/or the presence of crushed areas with distorted glands in prostatic samples after transurethral resection of prostate (TURP) can induce a significant interobserver variability during histopathologic evaluation of specimens. The specific immunostaining for basal cell markers 34BetaE12 and p63 and for alfa-methylacyl coenzyme A racemase (AMACR) in neoplastic cells is commonly used as an ancillary tool to establish benign and malignant glands. In this study we carried out the immunohistochemical reactions for p63, 34BetaE12, and AMACR on 3 different and successive paraffin sections to discriminate malignant and benign prostatic glands, distorted and crushed by the thermal artifacts in 60 radical prostatectomies and 50 TURP samples. All prostatic acinar adenocarcinoma showed the loss of basal cell markers and expression of AMACR, whereas p63 failed to stain the basal cell layer in benign crushed prostatic glands. The same cauterized glands were steadily positive for 34BetaE12. The high percentage of p63 false negative cases in benign distorted and crushed glands could be explained by the thermal artifacts which might cause lack of p63 antigenicity. In contrast, the antigenicity of 34BetaE12 and AMACR seem not to be affected by cautery artifacts. Thus, in cauterized suspicious prostatic glands an immunohistochemistry panel including, p63, 34BetaE12, and AMACR or only 34BetaE12 is recommended. In addition, after the first evaluation with only p63, we suggest that a separate and confirmatory staining for 34BetaE12 is strongly recommended.

Prognostic Significance of High Androgen Receptor Expression in Prostatic Acinar Adenocarcinoma

Background:Quantitative immunohistochemical expression of Androgen receptor (AR) has not been evaluated as a prognostic biomarker of prostate cancer in our population, therefore in the current study we aimed to evaluate the association of AR expression in prostatic acinar adenocarcinoma with various prognostic parameters like tumor quantification, Gleason score, WHO grade group and perineural invasion.Methods:Total 121 cases of biopsy proven prostatic acinar adenocarcinoma were selected from records of pathology department archives from January 2013 till December 2017. Hematoxylin and eosin stained slides and paraffin blocks were retrieved and new sections were cut where necessary. Slides of all cases were reviewed by two senior histopathologists and pathologic characteristics like Gleason score, WHO grade, tumor quantification, perineural and lymphovascular invasion were evaluated. Androgen receptor immunohistochemistry was applied on all cases.Results:Low AR expression was noted in 53 cases (43.8%) while high AR expression was seen in 68 cases (56.2%). Significant association of AR expression was noted with total Gleason score, WHO grade and percentage of tissue involvement (tumor quantification). Univariate binary logistic regression showed patients with low Gleason scores (scores 6,7 or 8) and low WHO grade (grade 1, 2 or 3) were less likely to express high AR expression in comparison to high Gleason score (score 9) and high WHO grade group (grade 5) respectively. Similarly, cases with low tissue involvement by carcinoma (<50%) were less likely to show high AR expression in comparison to cases with >50% tissue involvement by carcinoma.Conclusion:Significant association of AR expression was noted with total Gleason score, WHO grade and percentage of tissue involvement (tumor quantification) which are among the most important markers of tumor progression; therefore we suggest that AR expression should be performed in patients with prostatic adenocarcinoma for prognostic stratification of the patients.

The Association of Invasive Cribriform Lesions With Adverse Prostatic Adenocarcinoma Outcomes: An Institutional Experience, Systematic Review, and Meta-analysis.

Recent studies and a few reviews suggest that presence of invasive cribriform lesions (ICLs) in prostatic acinar adenocarcinoma correlates with adverse outcomes. However, a systematic review with meta-analysis on this correlation is currently lacking. To compare the likelihood of adverse outcomes by the status of ICLs in prostatic acinar adenocarcinoma with the meta-analysis of high-quality published data and institutional experience. PubMed, Scopus, manually searched references, and institutional data. Observational retrospective case-control studies or prospective cohort studies of adverse outcomes stratified by the status of ICLs were selected. Study quality was analyzed. The prevalence of adverse outcomes stratified by the status of ICLs was extracted. Eighty-five cases were reviewed. Extraprostatic extension, seminal vesicle invasion, and regional lymph node metastasis were observed in 18 (45%), 14 (35%), and 7 (17.5%) of the 40 cases with cribriform lesions, respectively. These features were observed in 4 (8.9%), 1 (2.2%), and 0 (0%) of the 45 cases without ICLs. During the follow-up, biochemical prostate-specific antigen recurrence, local recurrence, and metastasis/disease-specific death were documented in 7 (17.5%), 2 (5%), and 2 (5%) of the 40 cases with ICLs. These poor outcomes were found in 6 (13.3%), 1 (2.2%), and 1 (2.2%) of the 45 cases without ICLs. Meta-analysis revealed a significant increase in the risk of adverse outcomes in patients who had ICLs relative to those who did not (odds ratio, 3.95; 95% CI, 2.61-5.97; I2 = 53%; Z = 6.52; P < .01). These results suggest that presence of ICLs is associated with adverse outcomes.

Intraductal growth pattern in prostate acinar adenocarcinoma on core biopsy – an important feature for your report

Intraductal growth pattern in prostate acinar adenocarcinoma on core biopsy – an important feature for your report

Prognostic utility of epidermal growth factor receptor (EGFR) expression in prostatic acinar adenocarcinoma

BackgroundEpidermal growth factor receptor (EGFR) is potential prognostic biomarker expressed in many human cancers. Prognostic significance of EGFR immunohistochemical expression has not been established in prostatic acinar adenocarcinoma, therefore we aimed to evaluate the frequency of expression of EGFR in prostatic adenocarcinoma and its association with other prognostic parameters.MethodsThe study included 123 cases of biopsy proven prostatic acinar adenocarcinoma treated at Liaquat National hospital, Karachi from January 2013 till December 2017. Paraffin blocks of all cases were retrieved; sections were cut and stained with haematoxylin and eosin. Pathologic characteristics including tumor quantification, WHO grade group, gleason score, perineural and lymphovascular invasion were evaluated. EGFR immunohistochemistry (IHC) was performed on all tissue blocks.ResultsMean age of the patients included in the study was 69.05 ± 8.68 years. High gleason scores i.e. 8 & 9 were noted in 22% (27 cases) and 22.8% (28 cases) respectively. Similarly, 22.8% (28 cases) showed WHO grade group 5. 52.8% (65 cases) had > 50% tissue involvement by carcinoma and perineural invasion was seen in 37.4% (46 cases). Positive EGFR expression was noted in 18.7% (23 cases), while 81.3% (100 cases) showed negative EGFR expression. Significant association of EGFR expression was noted with gleason score (p-value = < 0.001), WHO grade (p = < 0.001), tumor quantification (p = 0.007) and perineural invasion (p = < 0.001). Moreover, significant association of EGFR expression was also seen with disease recurrence and Her2neu over expression. Patients with low gleason scores (score 6 and 7) and lower grade group (1, 2 & 3) were less likely to have positive EGFR expression as compared to patients with high gleason score (score 9) and higher grade group (5). Similarly, patients with perineural invasion were more likely to have positive EGFR expression.ConclusionWe found a relatively low EGFR expression in our patients with prostatic adenocarcinoma; however, its association with poor prognostic parameters like high gleason score, higher grade group, perineural invasion, higher tissue involvement by cancer and disease recurrence signifies its importance as a prognostic parameter in prostatic acinar adenocarcinoma.

Skene’s Glands Adenocarcinoma

Skene's (periurethral) gland adenocarcinoma is very rare, with only 7 cases reported in the literature. This is the first series of cases on this entity. We describe the histologic, immunohistochemical, and clinical findings of 4 patients with Skene's gland adenocarcinoma retrieved from the Johns Hopkins Urologic Pathology Consult Service from 1984 to 2017. The average age at diagnosis of the 4 women was 74.5 years (range, 61 to 87 y). Tumors were treated by limited resections with negative margins. Tumor size ranged from 1.0 to 2.0 cm (mean, 1.5 cm). Average follow-up time was 40.7 months (range, 4 to 132 mo). Three of our cases were morphologically consistent with prostatic acinar adenocarcinoma with variable cribriform, fused, and poorly formed glands, analogous to Gleason score 4+4=8. Of these, one had mixed ductal features with neoplastic cells showing papillary carcinoma with columnar cytology. These 3 lesions were positive for PSA, P501S, NKX3.1, and AMACR. Focal goblet cells positive for CK20 and negative for prostatic markers were seen in one of these cases, suggesting intestinal differentiation (although negative for CDX2 and SATB2). A fourth case had glandular and papillary formations with pseudostratified columnar epithelium and mucin secretion, showing positivity for CK7, ER, and P16, and negativity for prostatic markers, suggesting serous differentiation (although negative for PAX8 and WT1). PIN4 cocktail confirmed the origin in preexisting paraurethral glands in 3 of the cases. All patients were alive and free of recurrence or metastatic disease at the time of last follow-up. Because of the rarity of Skene's gland adenocarcinomas, there is no consensus regarding their treatment. Our findings demonstrate that Skene's gland adenocarcinomas recapitulate morphologies and immunohistochemical markers seen in prostatic adenocarcinoma. However, it is unknown whether applying the same grading criteria for prostatic adenocarcinomas to Skene's gland adenocarcinoma is valid given the small number of cases with variable treatment and limited follow-up.

Prostatic Adenocarcinoma With Focal Pleomorphic Giant Cell Features: A Series of 30 Cases.

Prostatic adenocarcinoma with focal pleomorphic giant cell features is rare with the only prior series consisting of 6 cases. From 2005 to 2018, we identified 29 cases from our consult service and 1 case from our own institution. Men ranged in age from 39 to 90 years (median=75.5). Diagnostic specimens consisted of needle biopsies (n=13); transurethral resections (n=7), urethral/bladder biopsies (n=8), radical prostatectomy (n=1), and orchiectomy (n=1). In all cases, there was usual acinar prostatic adenocarcinoma, where the highest grade in all cases was Gleason score 9 to 10 (Grade Group 5). On average, 68% of the involved cores had cancer with a maximum percent of cancer averaging 55%; on average, transurethral resections had 85% of the area involved by cancer. Areas of cancer showing pleomorphic giant cell features were focal (<5%). Two of the needle biopsies showed extraprostatic extension. The radical prostatectomy had seminal vesicle invasion and positive margins with lymphovascular invasion. Prostatic adenocarcinoma with focal pleomorphic giant cell features is always accompanied by extensive usual acinar prostate adenocarcinoma where the highest grade in all cases was Gleason score 9 to 10 (Grade Group 5). Although the pleomorphic component is focal, it can mimic urothelial carcinoma. IHC can be misleading as PSA staining is often negative or focal in both the pleomorphic and usual prostatic adenocarcinoma components. NKX3.1 is the most sensitive prostate marker, but was still focal in 1 usual prostatic adenocarcinoma and negative in 2 pleomorphic components. Prostatic adenocarcinoma with focal pleomorphic giant cell features has a dismal prognosis. In men with no prior diagnosis of prostate adenocarcinoma and >1-year follow-up, 7/19 (37%) were dead at a median of 8 months after diagnosis. Of the 7 men with a prior history of prostate adenocarcinoma, 4/7 (57%) were dead at a median of 7 months after diagnosis of recurrent prostate adenocarcinoma with pleomorphic giant cell features.

Immune infiltrates and PD-L1 expression in treatment-naïve acinar prostatic adenocarcinoma: an exploratory analysis

Tumour-induced immunosuppression plays a role in the development and progression of cancer. Of interest is the interaction between programmed death-1 and programmed death ligand-1 (PD-L1) which can be targeted through...

Clinical significance and EZH2, ERG and SPINK1 protein expression in pure and mixed ductal adenocarcinoma of the prostate.

Although ERG and SPINK1 molecular alterations have been studied in acinar and ductal adenocarcinoma of the prostate, EZH2 expression has not been previously evaluated in ductal adenocarcinoma. We collected cases of pure and mixed ductal adenocarcinoma of the prostate and evaluated clinical significance and EZH2, ERG, and SPINK1 protein expression. We investigated 61 ductal adenocarcinomas, 22 pure and 39 mixed ductal/acinar. Except for tumor growth pattern, none of the clinical parameters studied significantly differed between pure and mixed tumors. Thirty-five percent of ductal adenocarcinomas were organ confined, 15% displayed seminal vesicle invasion. Lymph node and distal metastasis occurred in 13% and 24% of cases, respectively; 34% of patients experienced biochemical failure, 7% died of disease. Ninety-eight percent of tumors expressed EZH2; in 80% of cases >50% of tumor cells were positive. ERG and SPINK1 were expressed in 20% and 36% of cases, respectively. There was no difference in protein expression between pure and mixed ductal adenocarcinomas. ERG expression tended to be lower, and SPINK1 higher than reported for acinar tumors. Biochemical failure, metastasis and death did not differ between EZH2, ERG, and SPINK1 positive and negative patients, nor between <50% versus >50% expression of SPINK1 and EZH2, respectively. Pure and mixed ductal adenocarcinomas have similar clinical behavior and molecular alterations. Higher EZH2 and SPINK1 protein expression, compared to acinar prostatic adenocarcinoma, might account for the more aggressive clinical course of ductal adenocarcinoma.

Prostate Ductal Adenocarcinoma.

Prostate ductal adenocarcinoma (PDA) is a rare subtype of prostate adenocarcinoma that shows more aggressive behavior than conventional prostatic acinar adenocarcinoma. PDA demonstrates similar clinical and paraclinical features such as prostatic acinar adenocarcinoma; therefore, clinical distinction of the 2 entities is very difficult (if not impossible) and histopathology plays an important role in the diagnosis of the disease. This review discusses all the necessary information needed for the diagnosis and prognosis of PDA including the morphologic features of PDA, an introduction about the known variants of PDA with helpful hints in grading of each variant, tips on differential diagnosis of PDA from the common morphologic mimickers, a detailed discussion on the value of immunohistochemistry in the diagnosis of PDA, and pathologic features that are helpful in determining the outcome.

The Gleason pattern 4 in radical prostatectomy specimens in current practice - Quantification, morphology and concordance with biopsy

The upgrading of a prostate acinar adenocarcinoma grade group 1 (GG1) between needle biopsy and prostatectomy is common. The extent of high-grade tumor and cribriform morphology are currently suggested as prognostic factors. We reviewed 159 prostatectomy specimens from a private laboratory and an academic/public institution in Salvador, Bahia. Tumors signed as GG1 at biopsy were upgraded in 59% of all cases. These tumors showed a low frequency of non-focal extraprostatic extension (one case, 3%), extensive positive surgical margins (two cases, 6%) and seminal vesicle invasion (one case, 3%). Among GG2 and GG3 tumors at prostatectomy, the percentage of Gleason pattern 4 (Gp4) involving the gland at ≤1%, 2-5% and >5% was associated with extensive extraprostatic extension (9%, 8% and 42%, respectively) and seminal vesicle invasion (1%, 10% and 31%, respectively). The volume of Gp4 of ≤1ml, >1 to 2ml and >2ml was associated with extensive extraprostatic extension (8%, 26% and 38%, respectively), seminal vesicle invasion (2%, 21% and 33%, respectively) and non-focal positive surgical margins (12%, 26% and 29%, respectively). Some GG2 tumors (~20%) indeed showed at least one measurement of Gp4 higher than one quarter of GG3 carcinomas. Cribriform morphology showed no significant associations for other adverse pathologic prognostic factors. Upgrading from GG1 to GG2 is associated with a very low frequency of morphologic features associated with poor prognosis. Routine quantification of Gp4 is feasible in radical prostatectomy products and seems to better stratify tumors regarding the association with other morphologic parameters of prognostic importance.

Abstract 3394: CGP identifies largely non-overlapping high tumor mutational burden and HRD genomic alterations in 721 clinically advanced prostate acinar adenocarcinoma cases

Abstract Background: Effective therapies for the management of castrate resistant prostate cancer are lacking. We performed comprehensive genomic profiling (CGP) on advanced prostate carcinomas (PC) in the course of clinical care to identify genomic alterations that could suggest benefit from targeted, immune- and PARP inhibitor therapeutic strategies. Methods: DNA was extracted from 40 microns of FFPE specimen from 721 clinically advanced PC cases. CGP was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of over 500X. All four classes of genomic alterations (GA) - base substitutions, insertions and deletions, gene fusions, and copy number alterations (amplifications and losses) - were identified. Results: Of the 721 PC patients - men with median age of 65 (range 34 - 88) - CGP was performed on 335 (46.5%) prostate specimens and 386 (53.5%) specimens from metastatic sites. The most common genes altered were TP53 (N=336, 46.6%), PTEN (N=254, 35.2%), TMPRSS2-ERG (N=214, all fusions, 29.7%), AR (N=173, 24%), and MYC (N=105, 14.6%). Median tumor mutational burden (TMB) for this series was 3.6 mut/Mb (range 0 - 305). AR and MYC amplifications were enriched in metastatic tumors compared to primary tumors (p &amp;lt; 0.001 for both). Alterations characteristic of homologous recombination deficiency (HRD) were found in &amp;gt;15% of cases, including homozygous deletions and truncating mutations in BRCA2 in 79 (11%) samples, as well as truncating mutations in ATM in 41 (5.7%) samples, with only 3 samples possessing alterations in both genes. Cases with these HRD-relevant alterations possessed overall higher genomic loss of heterozygosity (LOH) content than did those without (p = 0.02). HRD and non-HRD cases had median TMB of 4.8 versus 2.7 mut/Mb, respectively, and mean TMB of 10.4 versus 4.0 mut/Mb (p &amp;lt; 0.01). Only 2.6% of non-HRD cases were TMB-high (20 mut/Mb or more), versus 8.4% of HRD cases, a small but significant enrichment in the latter. Conclusions: CGP for advanced PC cases identifies largely non-overlapping TMB-high and HRD positive cases, suggesting benefit from immunotherapeutics and PARP inhibitors respectively. Further investigation will assess whether HRD pathway alterations result in genomic LOH in the context of a hypermutated tumor, and enrichment or exclusivity with other GA in prostate carcinoma. Citation Format: Ninad Dewal, Yuting He, Richard J. Lee, Alexa B. Schrock, Jon Chung, Christopher Hoimes, Zachary R. Chalmers, Garrett M. Frampton, James X. Sun, Primo N. Lara, Neeraj Agrawal, Paul Matthew, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, Siraj M. Ali. CGP identifies largely non-overlapping high tumor mutational burden and HRD genomic alterations in 721 clinically advanced prostate acinar adenocarcinoma cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3394. doi:10.1158/1538-7445.AM2017-3394

BRCA1/2 reversion mutations in prostate cancer identified from clinical tissue and liquid biopsy samples.

5024 Background: Prostate tumors with genomic alterations (GA) in BRCA1 or BRCA2 ( BRCA) may be sensitive to treatment with PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) can arise that may restore BRCA function and underlie reduced sensitivity to PARPi or platinum (Pt)-based therapy. Comprehensive genomic profiling (CGP), using either tissue or liquid biopsies, can detect the variety of clinically relevant revGA that can arise. Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for 1911 patients with predominantly relapsed, refractory or metastatic prostate carcinoma was analyzed by hybrid-capture, next-generation sequencing for all classes of GA: base substitutions, indels, rearrangements, and copy number changes. RevGA were any GA that could restore the reading frame if in cis with a nonsense or frameshift (fs) GA. Results: 216/1911 (11.3% ± 1.4%) tumors had ≥1 deleterious BRCA GA. Of these, 7 samples harbored potential revGA in BRCA1 (1) or BRCA2 (6): prostate acinar adenocarcinoma (5), neuroendocrine carcinoma (1), or undifferentiated carcinoma (1). Of these, 2 samples were liquid biopsies (blood), 4 were FFPE tissue samples (liver), and 1 sample was a bone marrow core biopsy. All samples with revGA were metastases. Potential revGA were of 3 types: overlapping indel (4), compensatory fs (2), and missense (1). One case harbored 2 revGA, an overlapping indel and a compensatory fs. Alteration frequencies for TMPRSS2 (fusions), PTEN, and AR were similar with or without BRCA mutations; revGA-positive samples had a modest increase in PTEN alterations (42.9% vs 33.8%, NS). The frequency of CDK12 alterations was significantly reduced in BRCA-mutated tumors (0.9% vs 6.9%, p = 0.00002). Clinical histories for patients with reversion mutations will be presented. Conclusions: CGP of 1911 prostate carcinomas reveals ≥1 deleterious BRCA1/2 in 11.3% of samples. From these, a series of 7 cases, all metastases, with co-occurring potential revGA were identified. Although rare, revGA can be acquired during treatment and may underlie resistance to PARPi or Pt-based therapy. BRCA revGA can be detected from both tissue and liquid biopsies.

SOCS3 Immunohistochemical Expression Seems to Support the 2005 and 2014 International Society of Urological Pathology (ISUP) Modified Gleason Grading System.

In the 2014, The International Society of Urological Pathology (ISUP) consensus conference update the grading of prostate, last revised in 2005. In this study we evaluate the SOCS3 immunohistochemical protein expression in different Gleason prostatic adenocarcinoma: classical Gleason grade 3, classical Gleason grade 3 upgraded to Gleason grade 4 according to the ISUP modifications and classical and modified Gleason grade 4. The major conclusions were: (i) Cribriform glands should be assigned a Gleason pattern 4, regardless of morphology; (ii) Glomeruloid glands should be assigned a Gleason pattern 4, regardless of morphology; (iii) Grading of mucinous carcinoma of the prostate should be based on its underlying growth pattern rather than all as pattern 4; and (iv) Intraductal carcinoma of the prostate without invasive carcinoma should not assigned Gleason grade and a comment about aggressive carcinoma probably associated should be made. In a recent report we analyzed the methylathion status of cytokine signaling (SOCS) proteins 3 (SOCS3) gene and the consequences of promoter hypermethylation on mRNA and protein expression in a collection of prostate cancer and benign prostate hyperplasia (BPH) and for the first time we demonstrated that a hypermethylation of SOCS3 with a significant reduction of its mRNA and protein expression identifies a subgroup of prostate cancer with a more aggressive behavior. Moreover we demonstrated that the immunohystochemical analysis of SOCS3 protein expression in prostatic cancer biopsies may provide a useful and easier method than SOCS3 methylation analysis to individuate in cancer with intermediate-high grade Gleason score a subgroup of prostate cancer with a more aggressive behavior. A total of 148 radical prostatectomy with diagnosis of prostatic acinar adenocarcinoma were stratified into three different categories on the basis of Gleason grade: (i) Twenty-six prostatic adenocarcinoma with classical and modified Gleason grade 3; (ii) Fifty seven prostatic adenocarcinoma with classical Gleason grade 3 upgraded to Gleason grade 4 by 2005 and 2014 ISUP Consensus Conference; and (iii) Sixty five prostatic adenocarcinoma with classical and modified Gleason grade 4. Immunohistochemical analysis for SOCS3 was performed and SOCS3 staining intensity were evaluated by two pathologists in three different ways on the basis of the intensity of cytoplasmatic staining: positive (intense cytoplasmatic staining in more than 50% of neoplastic cells) (+), negative (absence of cytoplasmatic staining in more than 50% of neoplastic cells) (-), weakly positive (weak cytoplasmatic staining in more than 50% of neoplastic cells (+/-). In the group of prostatic adenocarcinoma Gleason grade 3 we found that SOCS3 positivity (+) were observed in 19 out of 26 cases (73.1%); in 5 out of 26 prostatic adenocarcinoma the neoplastic glands showed weak intensity SOCS3 staining (+/-) (19.2%), while in only two cases we found SOCS-3 negativity (-) (7.7%); in the group of cases with prostatic adenocarcinoma with Gleason grade 4, 16 out 65 cases (24.6%) showed SOCS3 positivity (+); 18 out 65 cases (27.7%) SOCS3 weakly positive (+/-), and in 31 cases (47.7%) SOCS3 negative staining (-) were observed. Interestingly, the group of prostatic adenocarcinoma with histological Gleason 3 pattern upgraded to Gleason 4 pattern according to the 2005 and 2014 ISUP modified grading system, showed SOCS3 positivity (+) in 16 out of 57 cases (28%), in 16 out 57 cases (28%) a weakly positive for SOCS3 (+/-) were observed, while 25 cases (44%) showed negative SOCS3 staining (-). In this study we demonstrated a significant association of SOCS3 positivity (+) with prostatic carcinoma classical Gleason pattern 3 (P < 0.0001), while SOCS3 negative pattern (-) or SOCS3 weakly positive pattern (+/-) were associated to prostatic carcinomas with Gleason pattern 3 upgraded to Gleason pattern 4 (P = 0.0002) and with classical Gleason pattern 4. The significant difference of SOCS3 immunohistochemical expression between classical Gleason grade 3 and Gleason grade 4 upgraded to grade 4 seems to support the definitions and the modifications of Gleason grade 4 of the 2005 and the 2014 International Society of Urological Pathology (ISUP). The hypoexpression of SOCS3 protein in glomeruloid glands could support the hypothesis that from molecular point of view this growth pattern could be different from classical Gleason pattern 3 and biologically more closely to Gleason pattern 4, confirming the conclusions of the 2014 ISUP Conference assigning a Gleason pattern 4 to glomeruloid glands regardless of morphology. Prostate 77: 597-603, 2017. © 2017 Wiley Periodicals, Inc.

The Missing Link in the Diagnostic Pathway of Prostate Cancer.

Prostate cancer is one of the most common cancers in the Western world. It is among the leading causes of cancer related death. While its incidence and survival increased significantly during the last few decades in Denmark, the mortality rate did not change for patients younger than 80year old. Development of new techniques, such as multiparametric MRI, helps to increase the accuracy of diagnosis. However, a missing link in the diagnostic pathway may result in mistreatment if an acinar adenocarcinoma of prostate is transformed into a neuroendocrine phenotype such as small cell carcinoma.