Acinic Carcinoma Research Articles

72 Spatial whole transcriptome profiling of the tumor microenvironment in prostate carcinomas

BackgroundDespite years of studies and effort, the best strategies for treating prostate cancer and minimizing the complications of treatment remain unanswered questions. This gap in knowledge is partially due to the inability to dissect the complex heterogeneous tumor microenvironment (TME) and immune compartment. Spatially resolved molecular profiling of tumor sections will enhance our understanding of these complexities; However, it has been particularly challenging to do spatial molecular profiling in formalin-fixed paraffin-embedded (FFPE) tissues due to RNA degradation associated with this tissue-embedding method, which is routinely used in oncology workflows. The 10x Genomics Visium Spatial Gene Expression Solution for FFPE tissue overcomes these limitations, enabling spatial gene expression analysis of FFPE tissues combined with classical histology staining techniques such as Hematoxylin & Eosin (H&E) staining and immunofluorescence.MethodsWe used the 10x Genomics Visium Spatial Gene Expression Solution for FFPE tissue to analyze and resolve tumorigenic profiles in sections of normal and adenocarcinoma prostate samples. This assay incorporates ~5,000 molecularly barcoded, spatially encoded capture probes in spots over which the tissue is placed, imaged, and permeabilized. Imaging and sequencing data are processed together, resulting in a spatially resolved transcriptional readout.ResultsWe profiled the whole transcriptome in normal, invasive adenocarcinoma, and acinar cell carcinoma FFPE human prostate tissues. Unsupervised clustering of the whole transcriptome data from normal, invasive adenocarcinoma, and acinar cell prostate carcinoma FFPE sections enabled the identification of 2 different regions, which had a well defined spatial distribution within the tissues. Well known prostate gland and prostate-cancer markers were over-expressed in the corresponding healthy and cancerous portions of the tissue, validating the performance of this method. We found that, while in healthy tissues basal cells and luminal cells are spatially organized, this pattern is lost in tumor samples, where luminal cells are greatly expanded in the invasive carcinoma region and do not colocalize with basal cells. Moreover, T lymphocytes are dispersed throughout the whole tissue section in the adenocarcinoma, while plasma B cells are located in the peritumoral region which could impact prognosis.ConclusionsSpatial whole transcriptome analysis opens new opportunities for better understanding the TME which can not only help discover novel predictive tumor biomarkers, but also enable identifying cell type and tumor region specific drug targets.

Carboxypeptidase A1 (CPA1) immunohistochemistry is highly sensitive and specific for acinar cell carcinoma (ACC) of the pancreas

Abstract Introduction/Objective Introduction: Carboxypeptidase A1 (CPA1) is a zinc metalloprotease which is produced in pancreatic acinar cells and plays a role in cleaving C-terminal branched-chain and aromatic amino acids from dietary proteins. This study assessed the utility of immunohistochemical CPA1 staining for diagnosing pancreatic acinar cell carcinoma. Methods/Case Report Methods: A total of 15,680 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Results (if a Case Study enter NA) Results: CPA1 was strongly expressed in acinar cells of all normal pancreas samples but not in any other normal tissues. CPA1 immunostaining was detected in 100% of 11 pancreatic acinar cell carcinomas and one mixed acinar endocrine carcinoma (MAEC), but absent in 449 pancreatic ductal adenocarcinomas, 75 adenocarcinomas of the ampulla of Vater, and 11,739 other evaluable cancers from 128 different tumor entities. A weak to moderate diffuse staining of epithelial and stromal cells of cancer tissues immediately adjacent to non-neoplastic pancreatic acinar cells often occurred and was considered to be caused by diffusion of the highly abundant CPA1 from normal acinar cells that may have suffered some autolytic cell damage. Conclusion Our data show that CPA1 is a highly sensitive and largely specific marker for normal and neoplastic pancreatic acinar cells. CPA1 immunohistochemistry greatly facilitates the otherwise often difficult diagnosis of pancreatic acinar cell carcinoma.

Carboxypeptidase A1 (CPA1) Immunohistochemistry Is Highly Sensitive and Specific for Acinar Cell Carcinoma (ACC) of the Pancreas.

Carboxypeptidase A1 (CPA1) is a zinc metalloprotease that is produced in pancreatic acinar cells and plays a role in cleaving C-terminal branched-chain and aromatic amino acids from dietary proteins. This study assessed the utility of immunohistochemical CPA1 staining for diagnosing pancreatic acinar cell carcinoma (ACC). A total of 12,274 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types were interpretable by immunohistochemistry in a tissue microarray format. CPA1 was strongly expressed in acinar cells of all normal pancreas samples but not in any other normal tissues. CPA1 immunostaining was detected in 100% of 11 pancreatic ACCs and 1 mixed acinar endocrine carcinoma, but absent in 449 pancreatic ductal adenocarcinomas, 75 adenocarcinomas of the ampulla Vateri, and 11,739 other evaluable cancers from 128 different tumor entities. A weak to moderate diffuse staining of epithelial and stromal cells of cancer tissues immediately adjacent to non-neoplastic pancreatic acinar cells often occurred and was considered to be caused by the diffusion of the highly abundant CPA1 from normal acinar cells that may have suffered some autolytic cell damage. In conclusion, our data show that CPA1 is a highly sensitive and largely specific marker for normal and neoplastic pancreatic acinar cells. CPA1 immunohistochemistry greatly facilitates the otherwise often difficult diagnosis of pancreatic ACC.

Exome Sequencing of Pancreatic Acinar Carcinoma Identified Distinctive Mutation Patterns.

Pancreatic acinar cell carcinoma (ACC) is a rare pancreatic cancer. The advancement of treatment is hampered because of the limited knowledge of its molecular mechanism. Whole-exome sequencing was performed on DNA extracted from 11 pure ACC surgical samples. Potential germline variants were removed on the basis of polymorphic databases, alternative allele frequency, coverage depth, and Catalogue of Somatic Mutations in Cancer (COSMIC) annotations after variant calling procedure. Mutation profiles and signatures were assessed through the Mutational Patterns package. A median of 34 somatic mutations were detected (range, 19-60). Three novel recurrent small deletions were identified. Common pancreatic ductal adenocarcinoma mutations or neuroendocrine tumor mutants were not found. FAT atypical cadherin 4, mucin 5B, titin, and zinc finger homeobox 3 were consistently mutated across 4 independent ACC studies. A high contribution of COSMIC mutational signature 1 was seen in ACC, indicating deamination of 5-methylcytosine. The majority of the patients had COSMIC signatures 6, 15, or 20, relating to defective DNA mismatch repair. Six patients showed COSMIC mutational signature 10 because of the altered activity of DNA polymerase epsilon. Distinct mutational signatures pathways were found in ACC and targeting them may improve clinical outcome.

Abstract 413: Preclinical efficacy of platinum based chemotherapy regimens and targeted therapeutics in the first successful described patient derived xenograft model of mixed acinar neuroendocrine carcinoma of the pancreas

Abstract Background: Mixed acinar neuroendocrine carcinoma (MANEC) of the pancreas is an extremely rare histopathologic subtype. MANEC is an amphicrine malignancy composed of at least 25% of acinar cell carcinoma (PACC) and neuroendocrine carcinoma (pNET). No standard systemic treatment is available for MANEC and current recommendations are derived from standard of care for PACC or pNET. Platinum based regimens have been approved for PACC while targeted agents (sunitinib and everolimus) are approved for pNET. This study aimed to investigate the antitumor effect and toxicities of both platinum based and targeted agents on a successfully first described patient derived xenograft (PDX) of metastatic MANEC of the pancreas. Methods: Several generations of PDX from a surgically resected metastatic MANEC of the pancreas was histologically validated. PDX-MANEC tumors were heterotopically implanted into NOD/SCID mice and randomized into 6 groups (4 mice each) as in table 1. The study continued for 3 weeks. Antitumor efficacy was determined based on change in the tumor volume. Toxicity was assessed change in mice weights. Results: Table 1 shows the changes in tumor volume and mouse weight in all study arms compared to controls end point. Only FOLFIRINOX and gemcitabine/cisplatin arms revealed overall decrease in tumor volume lower than starting volume in controls. All arms other than sunitinib, led to decrease in overall tumor volume compared to control tumor volumes over time. All treatment arms led to lower trending mouse weights (toxicities) except sunitinib, however only the everolimus arm had statistical significance. Conclusion: Both platinum-based regimens and everolimus revealed significant tumor control. No synergistic effect observed in sunitinib/everolimus. Preclinical studies are undergoing to investigate other effective and less toxic therapeutics for MANEC. Table 1.Delta in tumor volumes of PDX-MANEC-P after multiple platinum-based chemotherapy regimens and targeted therapeutics from the standard of care for other pancreatic cancer subtypes including PACC and pNET.ControlFOLFIRINOXGemcitabine and CisplatinSunitinibEverolimusSunitinib and EverolimusDelta in tumor volume in mm3 at the study end (mean ± standard deviation)3225 ± 2054-609.3 ± 351.8-654.7 ± 92.561583 ± 950.3-178.1 ± 61.58-160.8 ± 86.55P value (column group vs. control)<0.0010.0030.0950.0010.001Delta in mice weight in grams at the study end (mean ± standard deviation)0.84 ± 1.68-1.26 ± 0.84-8.5 ± 1.630.86 ± 1.22-2.2 ± 1.61-1.42 ± 1.27P value (column group vs. control)0.058<0.0010.9810.0070.050 Citation Format: Amro M. Abdelrahman, Jennifer A. Yonkus, Roberto Alva-Ruiz, Jennifer L. Leiting, Nellie A. Campbell, Lewis R. Roberts, Michael L. Kendrick, David M. Nagorney, Sean P. Cleary, Travis E. Grotz, Gregory J. Gores, Jun Yin, Rondell P. Graham, Thorvardur R. Halfdanarson, Rory L. Smoot, Mark J. Truty. Preclinical efficacy of platinum based chemotherapy regimens and targeted therapeutics in the first successful described patient derived xenograft model of mixed acinar neuroendocrine carcinoma of the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 413.

Carboxypeptidase A1 (CPA1) immunohistochemistry is highly sensitive and specific for acinar cell carcinoma (ACC) of the pancreas

Carboxypeptidase A1 (CPA1) is a zinc metalloprotease which is produced in pancreatic acinar cells and plays a role in cleaving C-terminal branched-chain and aromatic amino acids from dietary proteins. This study assessed the utility of immunohistochemical CPA1 staining for diagnosing pancreatic acinar cell carcinoma. A total of 15,680 tumour samples from 132 different tumour types and subtypes as well as 8 samples each of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. CPA1 was strongly expressed in acinar cells of all normal pancreas samples but not in any other normal tissues. CPA1 immunostaining was detected in 100% of 11 pancreatic acinar cell carcinomas and one mixed acinar endocrine carcinoma (MAEC), but absent in 449 pancreatic ductal adenocarcinomas, 75 adenocarcinomas of the ampulla Vateri, and 11,739 other evaluable cancers from 128 different tumour entities. In conclusion, our data show that CPA1 is a highly sensitive and largely specific marker for normal and neoplastic pancreatic acinar cells. CPA1 immunohistochemistry greatly facilitates the otherwise often difficult diagnosis of pancreatic acinar cell carcinoma.

Survival Outcomes of Acinar Cell Pancreatic Cancer: A National Cancer Database Analysis.

Acinar cell pancreatic carcinomas (ACPCs) are rare neoplasms accounting for 1% to 2% of pancreatic tumors in adults. The objective of this study is to evaluate the benefit of chemotherapy in the adjuvant setting in resected ACPC and in the palliative setting for metastatic ACPC. Data were obtained from all US hospitals that contributed to the National Cancer Database between 2004 and 2014. Cases were identified using the histology code 8550. A total of 593 patients with ACPC were identified. The mean age was 64.4 years (range, 18-90 years), with a male preponderance (72.8%, n = 432). Localized stage disease comprised 52.3% (n = 310) of patients. Among localized ACPC patients, 88.0% (n = 191) underwent surgery and 50.6% (n = 91) received adjuvant chemotherapy. The 5-year overall survival in those who received adjuvant treatment was slightly higher than those who did not receive adjuvant treatment (46.7% vs 44.8%, P = 0.3271). Among advanced-stage ACPC patients, 67.6% received chemotherapy, which translated into improved 5-year overall survival compared with no chemotherapy (8.1% vs 0%, P < 0.0001). Chemotherapy in the palliative setting for advanced-stage ACPC patients was associated with improved survival. Adjuvant therapy did not translate into significant survival benefit.

Spontaneous Mammary Tumor with Concurrent Cavernous Hemangioma in Albino Mice- A Rare Case Report from Mizoram, India

Background: Mouse mammary tumor is a common neoplasm of the species. Mice is an established model for human breast cancer studies and in recent times for transgenic studies. Hemangiomas are tumors of blood vascular system. Hemangioma with breast cancer is reported in human beings. Presented study describes an unusual case of concurrent mouse mammary tumor and cavernous hemangioma from Mizoram, India.Methods: A mortality of 8 out of a colony of 25 female albino mice was observed due to mammary tumors. Dead mice were thoroughly necropsied and tissue samples were collected from different parts of each tumor mass and fixed in neutral buffered formalin. The fixed tissues were processed for hematoxylin and eosin staining by routine paraffin embedding, microtomy and staining protocol. Result: Gross examination revealed variable sized tumors on abdomen of affected mice. Histopathology revealed two different forms of mammary tumor viz, acinar and solid mammary carcinoma. Most peculiar finding was remarkable presence of large, endothelial lined cavernous spaces with presence of stagnant blood. These were diagnosed as cavernous hemangioma. Perusal of available literature did not reveal any report of cavernous hemangioma occurring with mouse mammary tumor, while it is found in other species including human beings.

Title: pancreatic\u2010type mixed acinar neuroendocrine carcinoma of the stomach: a case report and review of the literature

BackgroundThe majority of gastrointestinal tumors are adenocarcinomas. Rarely, there are other types of tumors, such as acinar cell carcinoma, and these are often called pancreatic-type acinar cell carcinomas. Among these tumors, some are differentiated into neuroendocrine components. A few of them are MiNENs.Case presentationThe patient was an 80-year-old male who was referred to our hospital for treatment of a pedunculated gastric tumor. It was 5 cm in diameter and detected in the upper gastric body with upper GI endoscopy conducted to investigate anemia. In the biopsy, although hyperplasia of gastric gland cells was noted, no tumor cells were found. Retrospectively, the diagnosis was misdiagnosed. An operation was arranged because bleeding from the tumor was suspected as a cause of anemia and because surgical resection was considered to be desirable for accurate diagnosis. Hence, laparoscopic and endoscopic cooperative surgery was performed. In the pathological examination, several types of epithelial cells that proliferated in the area between the mucosa and deep inside the submucosa were observed. These consisted of acinar-glandular/trabecular patterns and solid. A diagnosis of pancreatic-type acinar cell carcinoma of the stomach with NET G2 and G3 was made based on characteristic cellular findings and the results of immunostaining tests. Each of them consisted of more than 30% of the lesion; a diagnosis of pancreatic-type mixed acinar neuroendocrine carcinoma (pancreatic-type MiNEN) of the stomach or a type of gastric MiNEN was obtained. Anemia was resolved after the operation, and the patient was discharged from the hospital without perioperative complications.ConclusionsPancreatic-type ACC of the stomach that is differentiated into neuroendocrine tumors is very rare. Hence, we report this case along with a literature review.

Histologic variants of acinar prostate carcinomas: Clinicopathologic importance

Acinar carcinoma comprises more than 90% of prostatic adenocarcinomas and is characterized by a small gland proliferation with an infiltrative growth pattern. The numerous, variably-defined histological variants of prostatic adenocarcinoma can prove to be diagnostic challenges and show prognostic differences when compared to the usual acinar carcinoma, thus emphasizing the importance in accurate recognition. Variants of acinar prostatic adenocarcinoma include the atrophic, pseudohyperplastic, microcystic, foamy gland, mucinous (colloid), signet ring-like cell, pleomorphic giant cell, and sarcomatoid variants. The atrophic, pseudohyperplastic, microcystic, and foamy gland variants can be challenging to diagnose due to their deceptively benign appearance. While the atrophic, pseudohyperplastic, microcystic, and foamy gland variants usually present as low-grade malignancies (Gleason score 6-7), the mucinous (colloid), signet ring-like cell, pleomorphic giant cell, and sarcomatoid variants often present as high-grade malignancies (Gleason score &gt;7) and are usually associated with a worse prognosis. Small cell carcinoma is not considered as a variant of acinar carcinoma, is classified under neuroendocrine tumors, and is recommended not to be assigned a Gleason score. Small cell carcinoma is often preceded by a diagnosis of acinar adenocarcinoma, rarely presents as a de novo tumor, and, as in other organs systems has an aggressive clinical course. In this review article, we discuss variants of prostatic acinar carcinomas and briefly discuss small cell carcinoma. Awareness of variants of acinar prostate carcinoma and their clinicopathologic features is essential to rendering an accurate diagnosis and clinical management of patients with these tumors.

Presentation and outcome of mixed neuroendocrine non-neuroendocrine neoplasms of the pancreas

Background/objectivesMixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) of the pancreas and periampullary region are extremely rare and heterogeneous malignancies. Literature is sparse, clinical management is not standardized and little is known about survival outcomes. The aim of this study was to identify pathological and radiological features of MiNEN and assess the outcome of surgical management. MethodsPatients undergoing surgery for pancreatic and periampullary MiNEN between 2001 and 2019 were retrospectively analysed based on a prospective database. Histological, radiological and clinical features were assessed. Survival was analysed in a nested case-control study and matched-pair analyses with pure neuroendocrine neoplasms (pNEN) and ductal adeno- or acinar cell carcinomas of the pancreas. A literature review with focus on survival after surgical resection was additionally performed. ResultsOf 13 patients with MiNEN, 5 had acinar-MiNEN and 8 adeno-MiNEN. Two of 5 (40%) acinar-MiNEN and one adeno-MiNEN patients had liver metastases. All but one adeno-MiNEN (88%) showed preoperative radiological features of pancreatic adenocarcinoma, 3 of 5 (60%) acinar-MiNEN exhibited mainly neuroendocrine features. No surgical mortality was observed. The 5-year overall survival rate in all MiNEN was 40%. Five-year survival rate was 58% in adeno-MiNEN and comparable to that of matched ductal adenocarcinomas (36%) and pNEN (48%). Five-year overall survival rate was 20% in acinar-MiNEN, compared to 39% in acinar carcinoma patients and 59% in matched pNEN patients. ConclusionsMiNEN are rare and difficult to distinguish from pure adenocarcinoma or neuroendocrine neoplasm preoperatively. Surgical resection would therefore be the treatment of choice in localized tumors.

The cytologic and immunohistochemical findings of pancreatic mixed acinar-endocrine carcinoma.

The classification of epithelioid pancreatic neoplasms based on fine-needle aspiration (FNA) is important for proper management, as distinction of pancreatic neuroendocrine neoplasms from other similar appearing lesions can result in significantly different treatment. Mixed acinar-endocrine carcinomas (MAEC) are genetically related to acinar carcinomas and are treated as such. We reviewed cases of MAEC to better characterize their cytologic and immunohistochemical features. Eight FNAs of MAECs were identified and reviewed. A chart review for each case was conducted. All patients were male, 42-68 years of age, and presented with either Stage 3 or 4 disease. Smear backgrounds of all cases showed naked nuclei without significant necrosis. The smears were cellular with cells arranged in either three-dimensional (3D) clusters with intervening capillaries or singly dispersed. Acinar formation was a prominent feature. Cells were round to oval with small to moderate amounts of delicate cytoplasm. The nuclei were round to oval with mild to moderate anisonucleosis with granular chromatin and small nucleoli. Apoptotic bodies and mitoses were noted in most cases, with Ki67 indices of 10%-48%. All tumors, by definition, demonstrated expression of trypsin and synaptophysin with variable chromogranin expression (50%). The cytology of acinar cell carcinoma shares features with aspirates of other nonductal adenocarcinoma neoplasms of the pancreas. A clue to the diagnosis is that tumors show high Ki67 indices and a diagnosis of MAEC should be excluded anytime a diagnosis of Grade 2 or 3 well-differentiated neuroendocrine tumor or high-grade neuroendocrine carcinoma is in the differential.

Peculiarities of pathomorphological diagnostics of prostate gland adenosis and presentation of clinical case

Background. Atypical adenomatous hyperplasia (AAH) or adenosis of the prostate gland is a pseudoneoplastic process which according to its tissue-architectural and cytological morphological peculiarities often resemble small acinar adenocarcinoma. In modern specialized literature few clinical-morphological peculiarities related to both pathological processes AAH and prostate adenocarcinoma (PA) were described. First, the incidence of AAH increases with age, as does the incidence of PA. Second, AAH lesions are often multifocal, as is PA, and they are located very closely to cancer areas. Third, the incidence of AAH increases in the presence of cancer and, vice versa, cancer incidence increases in cases of diagnosed AAH. Fourth, there are numbers of morphological changes, typical for AAH, which are closely related to highly differentiated PA. Objective of current work is study, analysis and possibilities of application in practice of differential diagnostic criteria of AAH and small acinar carcinomas of the prostate. Methods. In the case proposed for consideration during primary histological examination of prostate gland biopsy taken from 74-year old man AAH was detected. Results and conclusion. However, certain pathomorphological signs more typical for prostatic carcinomas, as well as results of immunohistochemical examination more characteristic for malignant epithelial adenogenous tumors served as the basis for verification of prostatic adenocarcinoma.

Mixed Acinar-Neuroendocrine Carcinoma of the Stomach: A Case Report and Review of the Literature

Abstract Introduction/Objective Mixed Acinar Neuroendocrine Carcinoma (MACNEC) is rare and usually occurrs in the head of the pancreas. This is an epithelial neoplasm of the pancreas exhibiting both acinar and neuroendocrine differentiation. Each component must represent at least 30% of the tumor. Extrapancreatic acinar cell carcinoma arising in the stomach are also rare and represent &amp;lt;1% of all gastric neoplasms. Here we report a case of MACNEC arising in the stomach of a 60 yo female and we review the literature. Methods The specimen was formalin-fixed and paraffin embedded. 4-microns sections of the tumor block were stained for hematoxylin and eosin and immunostained for CAM5.2, Chromogranin, synaptophysin, trypsin, chymotrypsin, BCL10, HepPar1 and AFP using a Ventana Discovery XT automated system (Ventana Medical Systems, Tucson, Ariz) as per manufacturer’s protocol with proprietary reagents. Results The patient presented with heartburn and weight loss. An upper endoscopy revealed an ulcer along the stomach greater curvature. Endoscopic ultrasound revelaed an hypoechoic round mass involving the submucosa. Imaging showed no lesions in the pancreas. A stomach wedge resection was performed: a 1.2 x 0.6 x 0.5 cm. submucosal tan-brown mass was found. Microscopically the tumor had alternated solid/acinar areas with cords/ribbons neuroendocrine-like areas. Both components were immunohistochemically positive for keratin (CAM 5.2), chromogranin (diffuse), and synaptophysin (patchy). The trypsin, chymotrypsin and BCL10 immunostains were patchy and stained 30 to 40% of the tumor. The immunostains for HepPar-1 and AFP were negative. These results support the diagnosis of MACNEC. Pancreatic heterotopia was not identified in the tissue examined. The margins of resection were free of tumor. The tumor was staged as T1NXMX. The patient has been under close surveillance for 3 years and she has no radiographic evidence of tumor recurrence or metastases. Conclusion We found only 6 prior cases of MACNEC originating in the stomach. They had similar histopathologic and immunohistochemical features. In the absence of a pancreatic lesions, in this patient the tumor may have originated from ectopic pancreatic tissue or from a pluripotent stem cell in the stomach.

Abstract 817: Pancreatic acinar carcinoma - a rare entity with a targetable BRAF V600E mutation

Abstract Background: Pancreatic acinar carcinomas account for less than 1% of all pancreatic cancers and are considered genetically distinct entities form other pancreatic carcinomas. The pathogenesis of this malignancy is incompletely understood, and the efficacy of cytotoxic chemotherapy is not well defined especially in unresectable or metastatic disease. Methods: We identified one patient with pancreatic acinar carcinoma who was treated at our institution and was found to have a unique targetable pathogenic mutation on tumor sequencing. Results: A 64-year-old male patient was diagnosed with localized pancreatic acinar carcinoma during workup for epigastric pain. He underwent distal pancreatectomy with final pathology consistent with stage T3N0 acinar cell carcinoma without any adenocarcinoma component. He subsequently received six months of adjuvant chemotherapy with gemcitabine plus capecitabine, derived from evidence on pancreatic adenocarcinoma due to the size of his original tumor. Seven months after completion of adjuvant therapy, he was found to have local recurrence within the surgical bed and was treated with three cycles of systemic chemotherapy with FOLFIRINOX. During a following planned surgical resection, multiple liver lesions were seen intraoperatively, and surgery was aborted. Liver lesions were biopsied and hybrid capture next-generation sequencing was performed which revealed: a BRAF V600E gain of function mutation, CDKN2A loss as well as MYCN amplification. The patient declined further chemotherapy and his treatment was switched to Encorafenib (BRAF inhibitor) plus Binimetinib (MEK inhibitor). He attained a partial response to therapy at his first restaging CT scan after 2 months of therapy (-39% per RECIST 1.1). Both mass at the surgical bed as well as liver metastases were decreased in size. He tolerated treatment very well without significant adverse events (including no clinically significant rash). Conclusions: While BRAF rearrangements as described in the literature may occur in 15-23% of patients with acinar cell carcinoma of the pancreas, BRAF activating mutations and in particular the BRAF V600E substitution has not been reported. This particular substitution is commonly present in melanoma, hairy cell leukemia, Langerhans cell histiocytosis and less frequently in lung and colon cancer. A combination of BRAF and MEK inhibition may be used in patients with tumors harboring this activating mutation with variable efficacy across different histologies. In light of the rarity of acinar cell carcinomas of the pancreas and the lack of established systemic treatment guidelines, tumor sequencing should be considered if no other therapies are available. This is the first case reported in the literature of a patient with acinar cancer of the pancreas and BRAF V600E mutation where targeted therapy has shown an early response. Citation Format: Vaia Florou, Chris Nevala-Plagemann, Sean Mulvihill, Ignacio Garrido-Laguna. Pancreatic acinar carcinoma - a rare entity with a targetable BRAF V600E mutation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 817.

The Morphologic Spectrum of Castration-Resistant Prostate Cancer: Case Reports and Literature Review

Abstract Conventional acinar prostatic carcinomas are dependent on the androgen receptor (AR) to proliferate. Androgen deprivation therapy (ADT) is a common treatment for prostate cancers that have metastasized and is also being administered as first-line therapy with or without radiation therapy for intermediate- or high-risk disease. Cancers that recur after initially responding to ADT, or castration-resistant prostatic carcinomas (CRPCs), have a poor prognosis and are more likely to show divergent differentiation than de novo carcinomas. This review will present four cases of CRPC to highlight the morphologic spectrum, discuss effects of ADT on prostatic tumors, and discuss neuroendocrine prostatic tumors.

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.

Pancreatic Neoplasms With Acinar Differentiation: A Review of Pathologic and Molecular Features.

Pancreatic acinar lesions encompass a broad spectrum of malignant tumors and benign reactive processes affecting both adults and children, with clinical, pathologic, and molecular features that are distinct from more common ductal neoplasms. Accurate morphologic diagnosis and molecular assessment of these uncommon neoplasms is critical for effective patient care. To review the clinical, pathologic, and molecular features of pancreatic neoplasms with acinar differentiation, the most common of which is acinar cell carcinoma but which also includes mixed carcinomas with acinar components, cystic acinar lesions, and pancreatoblastoma. We assessed the current primary literature, as well as recently updated diagnostic manuals. Pancreatic acinar neoplasms are a morphologically and molecularly heterogeneous group of diseases that are characterized by acinar differentiation of at least a subset of the neoplastic cells, defined either morphologically (granular cytoplasm, single prominent nucleoli) or immunohistochemically. Squamoid nests are a key morphologic feature of pancreatoblastoma. Alterations in WNT signaling and chromosomal 11p loss are common molecular features of both acinar cell carcinoma and pancreatoblastoma. Targetable molecular alterations in acinar carcinoma include BRAF rearrangements and DNA repair defects, including mismatch repair deficiency and BRCA pathway defects. For practicing pathologists, morphologic recognition of such acinar neoplasms is critical, and in the future, molecular diagnostics to identify lesions susceptible to targeted therapy will likely form an important component of patient care.

Abstract B44: Clinical utility of semiquantitative evaluation of progesterone receptor immunohistochemistry in neuroendocrine tumors of the pancreas

Abstract Purpose: Progesterone receptor (PR) is expressed strongly in a subset of neuroendocrine cells in the pancreas. Tamoxifen has long been used in adjuvant endocrine therapy of steroid hormone receptor–positive breast cancer, and currently clinical trials are assessing its use in pancreatic neuroendocrine tumors (NET) that show variable PR expression. Prior studies have reported receptor status as “positive” or “negative,” using 1% or 10% positive nuclei as a cutoff. In this study, we assessed PR immunohistochemical expression in a cohort of NET and other pancreatic nonexocrine carcinomas. Theoretically, tumors with highest PR expression are more likely to respond to adjuvant tamoxifen. Experimental Design: Immunohistochemical staining for PR was performed on tissue microarrays of 54 well-differentiated neuroendocrine tumors of the pancreas and 8 poorly differentiated carcinomas of the pancreas, including 4 acinar cell carcinomas, 2 neuroendocrine carcinomas, and 2 small-cell neuroendocrine carcinomas. A minimum of 4 separate 2-mm tumor cores were sampled on each case. Results: PR expression in non-neoplastic pancreatic islets was used for positive control. PR staining was evaluated using a semiquantitative H-score method. Positive PR staining (defined as greater than 1%) was identified in 61% (33 of 54 cases) of well-differentiated NET (mean H-score 100) and 0% (0 of 8 cases) of poorly differentiated carcinomas of the pancreas. Of the 33 PR positive cases of well-differentiated NET, 3 cases had less than 10% nuclear staining (mean H-score 7), 8 cases had 10% to less than 50% nuclear staining (mean H-score 44), and 22 cases had 50% or greater nuclear staining (mean H-score 229). Conclusions: Based on these findings, we suggest analysis of NET tumor PR expression should include a quantitative or semiquantitative score rather than dichotomized immunohistochemical evaluation of hormone receptors, particularly in the evaluation of patients’ response to clinical trials with tamoxifen. High-grade endocrine and acinar carcinomas showed no PR expression and are less likely to derive benefit from adjuvant endocrine therapy. Citation Format: Sonya Purushothaman, Simona De Michele, Dorothy Low, Helen E. Remotti. Clinical utility of semiquantitative evaluation of progesterone receptor immunohistochemistry in neuroendocrine tumors of the pancreas [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B44.

Histopathology and Feline Pancreatic Lipase Immunoreactivity in Inflammatory, Hyperplastic and Neoplastic Pancreatic Diseases in Cats

The most common pancreatic diseases in cats are pancreatitis and exocrine pancreatic insufficiency (EPI). Non-invasive methods, such as serological quantification of feline pancreatic lipase immunoreactivity (fPLI), are often used in the diagnosis of pancreatitis. Previous studies have compared fPLI concentrations with histopathology, considered to be the gold standard for diagnosis of feline pancreatitis. However, fPLI concentrations in cats suffering from pancreatic tumours were rarely described. The aim of the present study was to determine the sensitivity and specificity of an in-house enzyme-linked immunosorbent assay (ELISA) for the quantification of fPLI in serum samples based on histopathological findings in cats diagnosed with various pancreatic diseases. Pancreatic biopsy samples from 80 cats were included. Five groups were defined on the basis of pancreatic histopathology: group 1, normal pancreas; group 2, nodular hyperplasia; group 3, mild pancreatitis; group 4, marked (moderate/severe) pancreatitis; and group 5, pancreatic neoplasia. Serum samples from all cats were tested by fPLI ELISA (<3.6μg/l normal, 3.6-5.3μg/l questionable, >5.3μg/l pancreatitis). In group 1 (n=19), serum fPLI values were within the reference interval in 74% of cases and in group 2 (n=9) in 78%. Cats with mild pancreatitis (n=23), marked pancreatitis (n=11) and pancreatic neoplasms (n=18) had significantly increased fPLI concentrations compared with group 1 (P=0.004/0.001/≤0.0001). Cats with nodular hyperplasia had significantly lower fPLI values than cats with marked pancreatitis (P=0.048) or tumours (P=0.002). Serum fPLI concentrations in group 3 were <3.6μg/l (n=6), 3.6-5.3μg/l (n=4) and >5.3μg/l (n=13). Calculated test sensitivity for mild pancreatitis was fPLI >3.5μg/l: 73.9% and fPLI >5.3μg/l: 56.5%. In group 4 (n=11), seven of nine cats (77.8%) with marked purulent pancreatitis had elevated fPLI. In group 4, a sensitivity of 81.8% was detected for fPLI >3.5μg/l and 63.6% for fPLI >5.3μg/l. Two cats with marked non-purulent pancreatitis had elevated fPLI, while two cats with marked purulent pancreatitis had normal fPLI values (<3.6μg/l). In group 5, one cat with pancreatic adenoma and one with pancreatic acinar carcinoma had normal fPLI concentrations. The other cats with pancreatic adenoma (solid, n=1; cystic, n=4) or carcinoma (solid, n=9; cystic, n=2) had elevated or high fPLI values (4.1 to >40μg/l, median 21.2μg/l), probably caused by additional inflammation. The results of the present study confirm the importance of detailed histopathological characterization for the interpretation of clinical signs and fPLI values in feline pancreatitis. Primary pancreatic neoplasms may also lead to elevated fPLI concentrations as there is concurrent pancreatitis in most cases. However, severe pancreatic diseases, such as chronic non-purulent pancreatitis or tumours without inflammation, may result in normal fPLI values.