Focal Neuroendocrine Differentiation Research Articles

Prostate cancer with BRCA2 pathogenic mutation: a clinicopathological analysis

Objective: To analyze the clinicopathological features of prostate cancers with BRCA2 pathogenic mutations, and the association between BRCA2 pathogenic mutation and clinicopathological characteristics. Patient survivals were also examined. Methods: Clinicopathological data of 249 prostate cancer patients who underwent genetic testing in West China Hospital of Sichuan University, Chengdu, China from June 2014 to August 2021 were collected. A retrospective analysis of histopathological morphology, clinicopathological characteristics, and patient survivals was conducted. Results: The genetic testing in the 249 prostate cancer patients showed a pathogenic mutation of DNA damage repair gene (DRG) in 73 cases (73/249, 29.3%), including 22 cases (8.8%) with BRCA2 pathogenic mutation and 51 cases with pathogenic mutations of other DRG. Among the 22 patients with BRCA2 pathogenic mutation, 14 patients (5.6%) harbored germline mutations and 8 patients (3.2%) somatic mutations. Their ages ranged from 48 to 91 years, with a median of 67 years. Seventeen patients (77.3%) had distant metastasis, including 16 cases with bone metastasis and 1 case with multiple metastases. Thirteen patients (59.1%) were castration-resistant prostate cancer. The histological type was mainly classical prostatic acinar adenocarcinoma, including 16 cases (72.7%) with intraductal carcinoma of the prostate (IDC-P). Six cases (27.3%) showed focal neuroendocrine differentiation. Perineural/vascular invasion and extraprostatic extension were seen in 11 cases (50.0%) and 8 cases (36.4%), respectively. The Gleason scores of 19 patients (86.4%) were≥8. IDC-P was more commonly found in patients with BRCA2 germline pathogenic mutation than those with BRCA2 somatic pathogenic mutation, other DRG pathogenic mutation or no-DRG pathogenic mutation (P=0.002). With a total follow-up time of 189 months, the median overall survival (OS) was 132.3 months. Patients with DRG pathogenic mutation had shorter OS than those with no-DRG pathogenic mutation (P=0.040). The OS of patients with BRCA2 germline pathogenic mutation did not significantly differ from that of patients with BRCA2 somatic pathogenic mutation, other DRG pathogenic mutation or no-DRG pathogenic mutation (P=0.216). Conclusions: The presence of BRCA2 gene pathogenic mutation is common in the prostate cancers with high Gleason grade, advanced clinical stage, and castration resistance. IDC-P is more commonly noted in cases with BRCA2 germline pathogenic mutation than those without. Patients with DRG pathogenic mutation have shorter OS than those with no-DRG pathogenic mutation, but there is no significant association between BRCA2 pathogenic mutations and OS.

THU527 Metastatic Adenocarcinoma Of The Colon Concealing An ACTH Secreting Neuroendocrine Differentiated Cluster: A Lethal Zebra Within A Trojan Horse

Abstract Disclosure: M. Velasquez: None. S. Shekhar: None. R.M. Goyal: None. Background: Ectopic ACTH secreting tumors are responsible for almost 10% of all cases of Cushing Syndrome. Tumors associated with this entity are most commonly small cell lung, thymic, and pancreatic neuroendocrine tumors. Few cases of colon adenocarcinoma with paraneoplastic ACTH secretion have been reported. They are associated with poor outcomes. Clinical case: A 57-year-old previously healthy male presented with shortness of breath and hypertension. CTA of the chest revealed metastatic liver lesions. CT abdomen and pelvis confirmed metastatic liver lesions with an apple core colonic mass consistent with a primary malignancy. Liver biopsy showed well-differentiated neuroendocrine tumor; tumor cells were negative for CK20, chromogranin, and CD56 but positive for CK7 and synaptophysin. The Ki-67 index was 30%. He was not evaluated for paraneoplastic hormonal secretion and the colonic mass wasn’t biopsied at that time. Ga-DOTATATE scan was negative for somatostatin uptake. He was started on carboplatin-etoposide + dexamethasone (three doses of 4mg each). Two months later presented with large bowel obstruction. Colonoscopy was performed and histopathology demonstrated colonic adenocarcinoma with focal neuroendocrine differentiation with positive CDX2 and negative CK7 and CK20. Synaptophysin was diffusely positive with sparse chromogranin positivity. ACTH stain of the colonic biopsy was negative. Chemotherapy was switched to FOLFORINOX and dexamethasone (one dose of 12mg). After two weeks of being on this regimen, he developed refractory hypokalemia and metabolic alkalosis and was sent to the emergency department. Vitals signs were within normal limits except for mildly elevated blood pressure. Physical examination remarkable for redness of his truncal skin. He did have changes in his handwriting, 0/3 three-word recall, and reduced short term memory. Primary team performed a morning cortisol that was elevated, and endocrinology was consulted. Two repeated 8AM cortisol level and a serum ACTH were found to be elevated. An 8mg overnight dexamethasone suppression test revealed an increase in cortisol. MRI brain showed no evidence of intracranial abnormalities. Refractory hypokalemia due to ectopic ACTH-dependent Cushing syndrome was diagnosed warranting treatment with ketoconazole. Unfortunately, he developed septic shock which led to his demise. Conclusion: This case illustrates a paradoxical rise in serum cortisol levels after dexamethasone suppression test suggesting the presence of positive feedback effects of exogenous corticosteroids on tumor’s ACTH release/production. Recognition of this syndrome is critical to avoid unnecessary use of exogenous glucocorticoids since they could trigger paraneoplastic Cushing syndrome in these patients. Presentation: Thursday, June 15, 2023

Abstract A068: Prostate luminal progenitors as the cell-of-origin for androgen receptor-independent prostate cancer

Abstract In the recent years, we have witnessed the emergence of androgen receptor (AR)-independent prostate cancer (AIPC) with the clinical use of second-generation androgen deprivation therapy, namely Enzalutamide and Abiraterone. Unluckily, treatment options for the end-stage AIPC patients are mainly palliative but not curable. However, the cellular origin and mechanisms involved in the evolution of AIPCs remain unclear. Previously, we have discovered that AR is not required for the survival and maintenance of progenitor property of CA stration- R esistant N kx3.1-expressing cells (CARNs), thus highlighting the AR-independent nature of this luminal progenitor subset. Interestingly, AR-deleted CARNs demonstrate gene expression profile that is highly similar to human neuroendocrine prostate cancer (NEPC), a subtype of AIPC. Moreover, upon Pten deletion and mutated Kras activation, AR-deleted CARNs can generate tumors exhibiting focal neuroendocrine differentiation, indicating the ability of CARNs to serve as a cell-of-origin for NEPC. Based on these observations, we hypothesize that AR-independent prostate luminal progenitor subsets are capable of initiating AIPC upon oncogenic transformation, while the transformed cells represent distinct subsets in AIPC that possess cancer stem cell property. In our latest assessments, we have validated the ability of CARNs to initiate NEPC using a novel genetically-engineered mouse model of prostate cancer. Moreover, we have established tumor organoids from CARNs-initiated AIPC, which are capable of generating allografts in both immunodeficient and immunocompetent mice, implying their immune-evading capability. Lastly, we have performed small molecule library screening on the transformed CARNs-derived tumor organoids to identify effective treatment options for AIPC. Taken together, our study has provided novel insights into the cellular origin of AIPCs. Consequently, targeting these prostate luminal progenitors-initiated tumor cells as well as their molecular property may serve as novel therapeutic strategies to overcome AR independence in prostate cancer. Citation Format: Chee Wai Chua. Prostate luminal progenitors as the cell-of-origin for androgen receptor-independent prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A068.

Large Cell Neuroendocrine Carcinoma of the Prostate Gland: A Review and Update

It has been documented that the 2016 World Health Organization’s histological classification of prostate cancer has included well-differentiated carcinoid tumours and small- or large-cell poorly differentiated tumours within the category of neuroendocrine tumours. Up to May 2021, only 20 cases of large-cell neuroendocrine tumours of the prostate gland (LCNTPs) had been reported within the literature, among which are nine cases of primary tumours. LCNTPs are a rare histological entity whose evolutive profile and therapeutic potential do differ from those of conventional adenocarcinoma of the prostate gland. Primary neuroendocrine tumours of the prostate gland could be pure or associated with an adenocarcinoma component. Mixed forms of large cell neuroendocrine cancers of the prostate gland (LCNECPs) tend to associated with better prognosis when diagnosed early at a localized stage. Nevertheless, most cases of (LCNTPs) at the time of initial diagnosis could tend to be advanced, locally advanced or metastatic. Even though LCNECPs that are diagnosed initially tend to primary prostate cancers that may be pure primary prostate cancers, few large LCNECPs have been found to be metastatic large cell neuroendocrine carcinomas that had metastasised from other sites of the body for example the lung. Primary LCNECP does tend to manifest similarly to primary adenocarcinoma of prostate gland with lower urinary tract symptoms, haematuria, or signs of obstruction of the upper urinary tract or inability to empty the urinary bladder. Cases of primary LCNECP that manifest tend also to be associated with symptoms related to the sites of the metastases. Serum prostate specific antigen levels tend to be slightly elevated with cases of primary LCNECP, but the levels generally tend not to be as high as most cases of advanced, locally advanced or metastatic primary adenocarcinomas of the prostate gland. Diagnosis of LCNECPs tend to be made pursuant to the undertaking of histopathology and immunohistochemistry staining studies of specimens of the prostate that had been obtained from prostate biopsies, trans-urethral reception of prostate specimens or prostatectomy specimens. The microscopy histopathology examination features of LCNECP the prostate gland have been summarized as follows: (a) Microscopy histopathology examination of LCNECP gland does tend to demonstrate large islands or sheets of tumour cells. (b) Large tumour cells with prominent neuroendocrine features such as salt and pepper chromatin and small nucleoli tend to be visualised upon microscopy examination of specimens of the prostate tumour. (c) High grade features such as lack of glandular formation, frequent mitoses and apoptotic bodies and tumour necrosis tend to be frequent findings upon microscopy examination of specimens of LCNECP. Immunohistochemistry staining features of LCNECP include: (a) At least one of the ensuing neuroendocrine tumour markers should be demonstrated upon immunohistochemistry staining including exhibition of positive immunohistochemistry staining for: chromogranin A, synaptophysin, neuron specific enolase, and CD56 may be positive: It has been stated that immunohistochemistry staining studies may exhibit positive staining in cases of LCNECP with utilization of the following: o TTFI tends to be positive in less than 50% of cases of LCNECP. o Positive AMACR immunohistochemistry staining, but this may be focal or weaker than for adenocarcinoma of the prostate gland. o Positive markers including: PSA, PSMA, NKX3.1 prostein (P501S) tend to be negative in majority of cases of LCNECP, but they could be focally positive in a small subset of the tumours. It has been iterated that in cases of LCNECP, immunohistochemistry staining studies tend to demonstrate negative staining for the ensuing markers: • Urothelial markers such as GATA3, p63, and high molecular weight cytokeratins such as CK5 / 6. • CD99. • Carcinoid tumour of the prostate gland. • PNET/Ewing sarcoma of the prostate gland. • Adenocarcinoma of the prostate gland with focal neuroendocrine differentiation. • Urothelial carcinoma with neuroendocrine differentiation. A high index of suspicion is required in order to diagnose early cases of primary large cell neuroendocrine carcinomas by undertaking early biopsies of prostate glands in all patients who have significant lower urinary tract symptoms if their serum prostate specific antigen (PSA) levels are slightly high or high even if they are commenced on Tamsulosin in an attempt to help improve the symptoms of voiding. There is no consensus opinion on the best management of LCNECP, therefore, there is an urgent need for the establishment of a global multi-centre trial related to various management options for the disease in order to ascertain the best options of management for LCNECP. gland.

Hepatoid carcinoma and related entities of the extrahepatic bile duct: A clinicopathological study of four cases.

Hepatoid carcinoma or related entities (HPC/RTs) are extremely rare, especially in the extrahepatic bile duct (EHBD). Only a few case reports have been published. We analyzed the clinicopathological features of HPCs/RTs in EHBD. HPC/RT of extrahepatic cholangiocarcinoma (eCCA) cases were selected based on the histological characteristics and immunohistochemical detection of spalt-like transcription factor 4 (SALL4) and/or alpha-fetoprotein (AFP). Four HPC/RT cases arose in the distal but not in the perihilar EHBD. The four patients with HPC/RT included one female and three males with a median age of 77 years. There are various macroscopic types of HPC/RT. The predominant histological features were two solid-type carcinomas that mimicked hepatocellular carcinoma and two well-differentiated tubular adenocarcinomas. Immunohistochemically, SALL4 and glypican-3 were expressed in all cases, and AFP was expressed in one case. Cancer cell phenotypes included intestinal, pancreatobiliary, and mixed pancreatobiliary and intestinal types. Focal neuroendocrine differentiation and severe perineural and lymphovascular invasions were also observed. HPC/RT recurred in two patients within 2 years, and one patient died 13 months postoperatively. It is suggested that the HPC/RT of EHBD shares common characteristics with HPC/RT arising in various organs, and has some unique characteristics. HPC/RT of EHBD might be more aggressive than conventional eCCA.

Investigation of the Prognostic Significance of Neuroendocrine Differentiation in Gleason Score 7 to 10 Prostate Adenocarcinoma in Patients With Distant Metastasis After Definitive Radiotherapy.

We investigated the prognostic implications of neuroendocrine differentiation (NED) in prostate adenocarcinoma detected by chromogranin A (CgA) in patients who developed distant metastasis (DM) after radiotherapy. Patients with Gleason score 7 to 10 conventional acinar prostate adenocarcinoma treated with definitive radiotherapy and with core biopsy CgA staining completed were reviewed. Patients who developed DM, defined as disease beyond the primary tumor or pelvic lymph nodes, underwent detailed chart review. Statistical analysis included Kaplan-Meier estimates and descriptive statistics to compare based on quantification of CgA staining. Thirty-five patients had confirmed DM. Twenty-five patients had less than 1% of cells staining positive for CgA, and 10 patients had more than 1%. Median overall survival (OS) time was 3.26 and 1.04 years, respectively (P = .52). Median cause-specific survival (CSS) was 6.15 and 1.04 years, respectively (P = .21). Fifty-six percent of patients with CgA less than 1% died of prostate cancer compared with 90% of those with CgA more than 1% (P = .059). There were no significant differences in sites of metastatic disease or administration of systemic therapies. No significant differences in OS and CSS were observed based on NED detected by CgA. Reduced median survival time and increased cancer-related death in cases with focal NED generates the hypothesis of inferior outcomes among patients with documented DM.

Single-cell analysis supports a luminal-neuroendocrine transdifferentiation in human prostate cancer

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore other intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.

Acinic cell carcinoma of the parotid gland with neuroendocrine differentiation

Acinic cell carcinoma (ACC) is a malignant salivary gland tumor characterized by tumor cells displaying acinar features. Usually presenting as a slow-growing tumor, ACC, however, may show dedifferentiation to a higher grade including neuroendocrine carcinoma. In addition, ACC may rarely show focal neuroendocrine differentiation without any frank evidence of neuroendocrine carcinoma. We describe such a case of ACC of the parotid gland in a 65-year-old female, which showed neuroendocrine differentiation. The diagnostic clues, immunohistochemistry panel, and prognostic and treatment aspects are also presented.

Clinicopathological features of 50 mismatch repair (MMR)-deficient endometrial carcinomas, tested by immunohistochemistry: A single institutional feasibility study, India

There are few comprehensive studies from Asia on clinicopathologic features of mismatch repair (MMR)-deficient endometrial carcinomas, including rarely from our country.One hundred and four cases of endometrial carcinomas were tested for four MMR proteins by immunohistochemistry.Among 50 MMR-deficient (MMRd) tumors(48%), age-range was 27–68 years(median = 53) and tumor size(n = 34) varied from 1.2–10 cm(average = 4.6). Lower uterine segment(LUS) was involved in 21/31 cases(67.7%). Histopathologically, all cases were endometrioid adenocarcinomas(EMACs), of FIGO grade 2(low-grade)(18 cases) and 3(high-grade)(32 cases), displaying de-differentiated, undifferentiated and lymphoepithelioma(LE)-like patterns, in 24 cases(48%). Tumor infiltration ≥ half of myometrium was seen in 30/44 cases (68.1%); lymphovascular emboli in 19/43 cases(44.1%); and lymph node metastasis in 7/22(31.8%) cases. Uncommonly, clear cell component(n = 2) and focal neuroendocrine differentiation (n = 2) were observed. Immunohistochemically, tumor cells showed paired loss of MLH1 and PMS2 in 33(66%) and MSH2 and MSH6 in 14(28%) cases, along with loss of MSH2 and PMS2, in two and a single case, respectively. Nine patients(18%) were treated for another cancer and 9/33(27.2%) disclosed familial history of cancer. MSH2 was the most frequently lost MMR protein in those cases. Additionally, tumor cells displayed ER positivity in 41/50 cases(82%), PR in 38/41cases(92.6%) and wild-type p53 staining in 24/28 cases(85.7%). Tumor with LE-pattern showed PDLI immunoexpression.Certain clinicopathologic features suggestive for MMRd associated ECs, such as relatively large-sized tumors, involving LUS; especially high-grade, infiltrative EMACs, with undifferentiated/de-differentiated, and LE-like patterns; showing deep muscle invasion, frequent PR immunoexpression and invariably, wild-type p53 immunostaining can be useful in screening cases of Lynch syndrome. This constitutes the first report on these tumors from our country.

2661 A Rare Case of Poorly Differentiated Lung Carcinoma With Duodenal Metastasis

INTRODUCTION: Lung cancer metastasis to the gastrointestinal (GI) tract is uncommon, with the duodenum being particularly rare. We present a unique case of a 61-year-old male with a history of lung cancer, who was found to have a metastatic mass on esophagogastroduodenoscopy (EGD) that was histologically similar to his lung cancer, ultimately being a diagnosis of poorly differentiated carcinoma (PDC) with focal neuroendocrine differentiation (FND). CASE DESCRIPTION/METHODS: 61-year-old male presented with 1 month of worsening dizziness, fatigue, and early satiety. On physical exam, he was tachycardic with a blood pressure of 92/60. Labs were notable for a Hgb of 7.2 (baseline of 12). Of note, 6 months prior, he was having hemoptysis and was found to have a left apical lesion on computerized tomography (CT) scan of the chest. Results from a fine needle aspiration (FNA) of the mass showed PDC that was weakly positive for CK-7, and synaptophysin on immunohistochemical staining (IHCS); thus, he was started on chemoradiation therapy. His EGD showed an oozing ulcer in the third portion of the duodenum with heaped up borders. Bipolar cautery was performed, and biopsies were obtained which showed PDC, histologically and immunohistochemically similar to his previous lung biopsy. The patient’s Hgb continued to drop during the hospital course requiring multiple transfusions, and ultimately, a gastroduodenal artery embolization. He was eventually discharged after monitoring his hemodynamics, with close outpatient follow up, as he wanted to pursue continued medical management. DISCUSSION: The results of the lung FNA showed sheets of atypical cells with focal necrosis, and prominent nucleoli being dispersed without a specific pattern, consistent with a diagnosis of PDC with FND. IHCS was weakly positive (very few scattered cells) for CK-7, and synaptophysin but negative for CK-20, P63, TTF-1, chromogranin, and CDX2. The duodenal mass biopsy showed PDC with IHCS negative for CK-7, synaptophysin, CK-20, P63, P40, Napsin-A, P40, CDX-2, TTF-1, chromogranin, calretinin, CD20, and CD3; making it histologically similar to his previous lung biopsy. The IHCS of both biopsies could not identify a specific type of carcinoma and histological analysis only showed areas of FND; highlighting the unique aspect of this case. Treatment of duodenal metastasis is challenging and depends on many variables. He was deemed a poor surgical candidate due to his comorbidities/metastatic disease and eventually had a palliative embolization.

Neuroendocrine carcinoma of the prostate (review of the literature)

Neuroendocrine neoplasia (NEC) of the prostate gland is a rather rare extrapulmonary neuroendocrine carcinoma and makes up only 0.5 to 1% of all malignant neoplasms of this localization. NEC of the prostate gland is a tumor of epithelial origin, histologically and immunohistochemically identical to analogues in the lungs and digestive system. When stained with hemotoxylin-eosin, neuroendocrine cells cannot always be visualized; they are best recognized by the immunohistochemical method of investigation using specific markers. Currently, a number of neuroendocrine markers are used, the expression of which may indicate a neuroendocrine nature. Androgen neuroendocrine cells themselves are independent and do not cause an increase in the concentration of prostate-specific antigen. Prostate NECs are represented by some histological forms according to WHO classification (2015): 1. Adenocarcinoma with focal neuroendocrine differentiation. 2. Well-differentiated neuroendocrine tumor. 3. Small cell neuroendocrine cancer is a high - grade tumor with high malignant potential. 4. Large cell neuroendocrine cancer is a high - grade tumor. Due to the rarity of NEC of the prostate, a specific algorithm for diagnosis and treatment has not been developed, as a rule, they are similar to methods of other malignant forms of prostate cancer and neuroendocrine tumors.

Alfa-Fetoprotein-Producing Female Primary Urethral Adenocarcinoma with Neuroendocrine Differentiation

We report an extremely rare case of an alpha-fetoprotein- (AFP-) producing female primary urethral adenocarcinoma with neuroendocrine differentiation (NED). The patient was a 65-year-old woman with a 2-year history of urinary frequency and voiding difficulty. Enhanced computed tomography showed an approximately 3.0×5.0-cm mass around the proximal urethra and bladder neck. Of examined tumor markers, serum AFP was elevated (48.3 ng/mL), while others including carcinoembryonic antigen were within a normal range. Transurethral resection of the tumor led to a diagnosis of carcinosarcoma of the urethra, with a radical cystourethrectomy and ileal conduit formation subsequently performed. The pathological assessment was poorly differentiated adenocarcinoma in the urethra. Immunostaining showed tumor cells strongly positive for AFP. In addition, some cancer cells were positive for CD56, chromogranin A, and synaptophysin, indicating focal NED. The tumor was finally diagnosed as an AFP-producing urethral adenocarcinoma with NED. Serum AFP was immediately normalized after surgery and no sign of tumor recurrence has been noted 2 years postoperatively.

Swinging inferior turbinate approach to the nasolacrimal duct

ABSTRACTPurpose: To report a case of a lacrimal sac tumour identified at the time of endoscopic dacryocystorhinostomy and describe a swinging inferior turbinate approach to the nasolacrimal duct (NLD) to facilitate an en-bloc excision of the lacrimal drainage apparatus.Methods: An 88-year-old male presented with a 6-month history of epiphora and mucocele. Endonasal DCR was performed for nasolacrimal duct obstruction (NLDO). Intraoperatively, a biopsy was performed of abnormal appearing lacrimal sac mucosa, following opening of the lacrimal sac. Subsequent definitive management was performed via a combined external and endoscopic approach using a swinging inferior turbinate approach to the NLD to facilitate an en-bloc excision of the lacrimal drainage apparatus, without removal of the bony medial wall of the maxillary sinus.Results: The excised lacrimal drainage showed insitu and invasive squamous cell carcinoma of the canaliculi and lacrimal sac with focal divergent neuroendocrine and sebaceous differentiation. There was no local tumour recurrence or metastatic spread at 3 months of follow-up.Conclusions: We describe a swinging inferior turbinate approach to the NLD to facilitate an en-bloc excision of the lacrimal drainage apparatus, without entering the maxillary sinus. We believe this modified technique is a useful option to consider in the management of tumours of the lacrimal drainage apparatus.

Focal Neuroendocrine Differentiation of Conventional Prostate Adenocarcinoma as a Prognostic Factor after Radical Prostatectomy: A Systematic Review and Meta-Analysis.

The biologic and prognostic value of focal neuroendocrine differentiation (NED) in conventional prostate adenocarcinoma (PC) patients who undergo radical prostatectomy (RP) remains controversial. In this systematic review and meta-analysis, we assessed the association of focal NED in conventional PC with oncological outcomes after RP. A literature search using PubMed, Scopus, Web of Science, and Cochrane Library was conducted on December 2018 to find relevant studies according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We used a fixed-effect model to analyze the impact of focal NED in RP specimen on progression-free survival defined by biochemical recurrence (BCR). A total of 16 studies with the outcomes of disease progression and survival were eligible. No patient in these studies received androgen deprivation therapy prior to RP. Eleven studies found no significant correlation between focal NED and outcomes of interest, while five studies reported a significant association of focal NED assessed by immunohistochemical chromogranin A or serotonin staining with BCR or survival. Focal NED was associated with higher BCR rates after RP with a pooled HR of 1.39 (95% CI 1.07‒1.81) in five studies. No heterogeneity was reported in this analysis (I2 = 21.7%, p = 0.276). In conclusion, focal NED in conventional PC is associated with worse prognosis after RP. Its presence should be reported in pathologic reports and its true clinical impact should be assessed in well-designed prospective controlled studies.

Correlation of focal neuroendocrine differentiation in prostate cancer with the parameters of predictive value

Background/Aim. Neuroendocrine (NE) cells are one of the epithelial populations in the prostate. It is well-known that the focal neuroendocrine differentiation (FNED) in prostate cancer (PC) is an aggressive subtype that most commonly evolves from preexisting PC which does not respond to hormone therapy (androgen independed PC). The incidence and clinical importance of FNED in PC is not clearly understood because of conflicting results in the studies, and evaluation of FNED is not routinely performed in clinical practice. The aim of the present study is to determine the importance of FNED presence in the examined prostate changes with special reference to the relationship of FNED degree in PC with some parameters of predictive value [Gleason score, preoperative serum total prostata specific antigen (PSA) value, tumor volume and tumor stage]. Methods. The study included the biopsy material from 100 untreated consecutive prostate pathological changes: 70 PC, 20 prostatic intraepithelial neoplasia (PIN) and 10 benign prostatic hyperplasia (BPH). The patients with PIN and BPH were the control groups. A block containing part of the main bulk of pathological change was chosen as representative based on hematoxylin-eosin appearance, and a section of this block was immunohistochemically stained for the tissue PSA (to mark prostatic secretory cells) and chromogranin A, serotonin and synaptophysin (to mark NE cells). Results. We found a very pronounced degree of FNED differentiation in 16 (22.9%) PC. Ten (62.5%) of them had Gleason score ? 7, the average serum PSA level was 32.62 ? 30.80 ng/mL, average tumor volume was 43.18 ? 31.45 mL and 6 (37.5%) of this PC were detected in D clinical stage with distant hematogenous metastases. The FNED is negatively correlated with the serum PSA level, Gleason score and clinical stage positively correlated with the tumor volume, but without statistically significant differences. Conclusion. The FNED has no significant role in the prognosis of PC.

Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation.

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer.

136 Eyelid Metastasis From Bladder Small Cell Carcinoma

Metastases to the eyelids are rare. The primary neoplasms are more frequently in breast, skin, digestive, and urological systems. There are very few reports related to bladder carcinomas. We present a unique case of small neuroendocrine cell carcinoma of the bladder metastatic to the eyelid. A 83-year-old man was treated for a high-grade superficial urothelial bladder carcinoma in August 2013 with endoscopic resection and intravesical BCG. In November 2014, he had an in situ bladder carcinoma (CIS). In November 2015, he presented a small cell neuroendocrine carcinoma in the bladder with invasion of muscular wall and areas of in situ carcinoma with focal neuroendocrine differentiation (immunostains positive for synaptophysin and partial for chromogranin A). In October 2016, he developed a skin metastasis of the back. In January 2017, a resective biopsy from a left superior eyelid nodule revealed a small cell carcinoma. The immunohistochemical reactions showed that tumor cells were positive for synaptophysin, chromogranin A, and CD56, and negative for cytokeratin 20. Metastases to the eyelids are rare. This is the first reported case of small cell neuroendocrine carcinoma of bladder metastasizing to the eyelid. The patient had a history of high-grade superficial urothelial carcinoma, later a CIS, and then the small cell neuroendocrine carcinoma. In the study, we need to discard Merkel cell carcinoma.

A bioinformatics-to-clinic sequential approach to analysis of prostate cancer biomarkers using TCGA datasets and clinical samples: a new method for precision oncology?

Biomarker-driven cancer therapy has met with significant clinical success. Identification of a biomarker implicated in a malignant phenotype and linked to poor clinical outcome is required if we are to develop these types of therapies. A subset of prostate adenocarcinoma (PACa) cases are treatment-resistant, making them an attractive target for such an approach. To identify target molecules implicated in shorter survival of patients with PACa, we established a bioinformatics-to-clinic sequential analysis approach, beginning with 2-step in silico analysis of a TCGA dataset for localized PACa. The effect of candidate genes identified by in silico analysis on survival was then assessed using biopsy specimens taken at the time of initial diagnosis of localized and metastatic PACa. We identified PEG10 as a candidate biomarker. Data from clinical samples suggested that increased expression of PEG10 at the time of initial diagnosis was linked to shorter survival time. Interestingly, PEG10 overexpression also correlated with expression of chromogranin A and synaptophysin, markers for neuroendocrine prostate cancer, a type of treatment-resistant prostate cancer. These results indicate that PEG10 is a novel biomarker for shorter survival of patients with PACa. Also, PEG10 expression at the time of initial diagnosis may predict focal neuroendocrine differentiation of PACa. Thus, PEG10 may be an attractive target for biomarker-driven cancer therapy. Thus, bioinformatics-to-clinic sequential analysis is a valid tool for identifying targets for precision oncology.

Molecular aspects of prostate cancer with neuroendocrine differentiation.

Neuroendocrine differentiation (NED), which is not uncommon in prostate cancer, is increases in prostate cancer after androgen-deprivation therapy (ADT) and generally appears in castration-resistant prostate cancer (CRPC). Neuroendocrine cells, which are found in normal prostate tissue, are a small subset of cells and have unique function in regulating the growth of prostate cells. Prostate cancer with NED includes different types of tumor, including focal NED, pure neuroendocrine tumor or mixed neuroendocrine-adenocarcinoma. Although more and more studies are carried out on NED in prostate cancer, the molecular components that are involved in NED are still poorly elucidated. We review neuroendocrine cells in normal prostate tissue, NED in prostate cancer, terminology of NED and biomarkers used for detecting NED in routine pathological practice. Some recently reported molecular components which drive NED in prostate cancer are listed in the review.

P1-6-3 - A Case of Prostate Cancer with Neuroendocrine Differentiation Treated with Everolimus Plus Octreotide

Prostate cancer recurrence in the absence of measurable levels of prostate-specific antigen (PSA) is rare. A 68-year-old man was diagnosed as Gleason 4 + 4 prostate cancer with PSA level of 16 ng/mL. After 6 months of androgen-deprivation therapy (ADT), a radical prostatectomy was performed. Three months later, he presented with paraplegia. PSA was below detectable levels. A bone scan revealed lesions at cervical and thoracic vertebrae, and he underwent emergency spinal laminectomy. A bone biopsy identified metastatic poorly differentiated neuroendocrine (NE) carcinoma (small cell carcinoma). CT confirmed growth development of the pelvic lesion and metastases in the liver, lungs, pancreas and multiple bones. Review of the original prostate cancer removed at prostatectomy showed foci of NE carcinoma within prostatic adenocarcinoma. Treatment with everolimus in combination with octreotide was initiated, but additional disease progression was observed. Whereas NE prostate cancer rarely arises de novo, ADT can promote progression of focal NE differentiation, which is more common. In the randomized phase III study in patients with advanced NE tumors, the combination of everolimus plus octreotide prolonged progression-free survival. To our knowledge, everolimus plus octreotide was used here in focal NE differentiation in prostatic adenocarcinoma for the first time and has never been reported in the literature. Focal NE differentiation in prostatic adenocarcinoma remain underdiagnosed and should be suspected in patients who experience symptoms with absent or low serum PSA as a possible escape mechanism from ADT.