Pancreatic acinar cell carcinoma (pACC) is a rare neoplasm of the exocrine pancreas. There is a dearth of information about tumor characteristics and patient outcomes. This study describes the clinical characteristics, genetic alterations, and survival outcomes of resected pACC.

Consecutive patients undergoing pancreatectomy for pathologically confirmed pACC from 1999 to 2022 across three high-volume pancreas surgery centers were analyzed. Patient demographics, tumor characteristics, treatment data, and genetic sequencing were obtained through retrospective abstraction.

A total of 61 patients with resected pACC were identified. Median overall survival (OS) was 73 months and median recurrence free survival was 22 months. Nine patients underwent resection for oligometastatic disease; median OS was not reached after a median follow-up of 31 months from date of metastasectomy. Adjuvant chemotherapy was administered in 67% of patients with FOLFOX/FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin, ± irinotecan) the most common regimen (58%). Sequencing data were obtained in 47 (77%) patients. A mutation in at least one of three core genes associated with the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, or PALB2) occurred in 26% (n = 12) with BRCA2 the most frequently identified. A mutation in any other "non-core" gene associated with DNA damage repair or the HRR pathway was identified in 45% (n = 21) with a high tumor mutational burden of > 10 mutations per megabase in 13%.

Resection of pACC is associated with favorable survival outcomes, even in the setting of oligometastatic disease. Mutations in the HRR pathway are common, providing opportunities for potential targeted therapeutic options.

Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic tumor with a heterogeneous clinical course and, except for radical surgery, limited treatment options. We present a comprehensive study encompassing whole-genome and RNA sequencing of 7 tumor samples from 3 metastatic PACC patients to further delineate its genomic landscape and potential therapeutic implications. Our findings reveal distinct signatures of homologous recombination deficiency (HRD) in patients harboring pathogenic germline BRCA1/2 and FANCL mutations, demonstrating favorable responses to poly (ADP-ribose) polymerase 1 (PARP) inhibitors with prolonged disease-free intervals. Additionally, we first describe structural variants in PACC, including BRCA1::TRIM47 fusion and another variant impacting FANCC, both events related to HRD, and we also identify alterations in the mitogen-activated protein kinase (MAPK) pathway, including RAF1 duplication as well as novel BRAF::SORBS2 and MAP7D2::SND1 gene fusions, offering potential targets for therapy. Our study underscores the importance of genome and transcriptome-wide profiling of PACC, to help guide personalized treatment strategies to improve patient outcomes.

Pediatric pancreatic acinar cell carcinoma (PACC) is an exceptionally rare and poorly understood malignancy with a challenging prognosis. Its clinical presentation is often atypical, and standardized treatment guidelines are currently unavailable. While genetic alterations in adult PACC have been studied to some extent, knowledge of genetic abnormalities in pediatric cases remains limited.

We report a case of pediatric PACC in a 7-year-old male presenting with a large, non-tender abdominal mass (11 cm x 11 cm) on the right side. Pathological and imaging evidence confirmed the diagnosis of PACC, with no lymph node infiltration or distant metastasis. Comprehensive genomic profiling by next-generation sequencing identified a non-canonical BRAF fusion with KMT2C at the DNA level and a classic SND1-BRAF fusion at the RNA level. The patient underwent surgical resection through a Whipple operation followed by six cycles of mFOLIRINOX chemotherapy and radiation therapy, achieving a favorable outcome up to now.

Next-generation sequencing has demonstrated significant value in identifying genetic fusions in pediatric PACC. In our case report, we identified both the classical SND1-BRAF fusion, commonly associated with PACC, and a previously unreported nonclassical BRAF-KMT2C fusion. These findings underscore the critical role of BRAF alterations as key drivers of oncogenesis in PACC. A multidisciplinary treatment strategy integrating surgery, chemotherapy, and radiation therapy offers a promising precedent for improving therapeutic outcomes and prolonging survival in pediatric PACC cases.

Pancreatic acinar cell carcinoma (PACC) is a rare and aggressive form of pancreatic cancer that originates in the acinar cells of the exocrine pancreas. In this study, we aimed to investigate the clinical and molecular characteristics of patients with PACC at our institution.

This was a retrospective study of patients with PACC seen at Mayo Clinic between 2002 and 2023. Baseline patient characteristics, tumor pathology, treatment strategies used, and survival outcomes were analyzed. Kaplan-Meier curves were estimated using newsurv macros in SAS.

The study included a total of 65 patients with PACC. The median age at diagnosis was 66 years. Almost half of the patients (48%) presented with resectable/borderline-resectable disease (n = 28). Five-year overall survival (OS) for resectable/borderline-resectable, locally advanced/unresectable, and metastatic disease were 72.0%, 21.6%, and 20.9%, respectively. Somatic and germline next-generation sequencing identified numerous potentially actionable targets including homologous recombination (43% somatic, 33% germline), RAF alterations (29% somatic), and mismatch repair (14% somatic).

Our findings underscore the heterogeneity and aggressive nature of PACC. Despite the improved prognosis for patients with resectable/borderline-resectable disease, OS remains poor, particularly for those with locally advanced or metastatic disease. The identification of actionable molecular targets in a significant proportion of patients highlights the potential for personalized therapeutic approaches. Future research should focus on tailored treatment strategies to exploit these molecular vulnerabilities, which may offer new options for improving outcomes in this rare malignancy.

RNF43 and ZNRF3 are recognized as important regulators of Wnt/β-catenin signaling by maintaining Wnt-receptors at minimal essential levels. In various cancer types, particularly gastrointestinal tumors, mutations in these genes lead to abnormal Wnt-dependent activation of β-catenin signaling. However, recent findings implicate RNF43/ZNRF3 also in the regulation of other tumor-related proteins, including EGFR, BRAF, and the BMP-signaling pathway, which may have important implications for tumor biology. Additionally, we describe in detail how phosphorylation and ubiquitination may finetune RNF43 and ZNRF3 activity. We also address the variety of mutations observed in cancers and the mechanism through which they support tumor growth, and challenge the prevailing view that specific missense mutations in the R-spondin and RING domains may possess dominant-negative activity in contributing to tumor formation.

Acinar cell carcinoma (ACC) and pancreatoblastoma (PBL) are rare pancreatic malignancies with acinar differentiation. Proteogenomic profiling of ACC and PBL revealed distinct protein expression patterns compared to pancreatic ductal adenocarcinoma (PDAC) and benign pancreas. ACC and PBL exhibited similarities, with enrichment in proteins related to RNA processing, chromosome organization, and the mitoribosome, while PDACs overexpressed proteins associated with actin-based processes, extracellular matrix, and immune-active stroma. Pathway activity differences in metabolic adaptation, epithelial-to-mesenchymal transition, and DNA repair were characterized between these diseases. PBL showed upregulation of Wnt-CTNNB1 and IGF2 pathways. Seventeen ACC-specific proteins suggested connections to metabolic diseases with mitochondrial dysfunction, while 34 PBL-specific proteins marked this pediatric cancer with an embryonic stem cell phenotype and alterations in chromosomal proteins and the cell cycle. This study provides novel insights into the proteomic landscapes of ACC and PBL, offering potential targets for diagnostic and therapeutic development.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic neoplasm. Recently, molecular analysis revealed that PACC shows a high frequency of the BRCA1/2 mutation and is likely to be considered a cancer associated with hereditary breast and ovarian cancer (HBOC). Hereditary cancers, including HBOC, are characterized by multifocal and/or metachronous tumors. However, no case reports exist of germline BRCA1-mutated synchronous and metachronous PACC.

A 58-year-old man was diagnosed with synchronous and metachronous PACC at the age of 56 and underwent two surgeries. Ten months after the second surgery, the patient developed multiple liver metastases. Gemcitabine plus nab-paclitaxel therapy was administered as first-line chemotherapy. After seven cycles, computed tomography examination revealed progressive disease (PD). Therefore, modified FOLFIRINOX (mFFX) was administered as second- line chemotherapy. After 19 cycles of mFFX, comprehensive cancer genomic profiling (CGP) identified a BRCA1 pathogenic variant that was confirmed to be germline origin. Accordingly, we treated the patient with olaparib; however, he was diagnosed with PD after 4 months. He subsequently died 5 years and 9 months after the initial surgery, and 3 years and 10 months after chemotherapy. Based on the genetic data of the patients, his family members received genetic counseling followed by cascade testing. Consequently, the same gBRCA1 pathogenic variant was detected in the son and his surveillance for HBOC-related cancers was initiated.

We diagnosed a 58-year-old man with a synchronous and metachronous PACC with germline BRCA1 pathogenic variant. Considering that PACC is likely to have BRCA1/2 mutations responsible for HBOC, we need to be aware of the possible presence of multifocal and/or metachronous tumors in patients with PACC. Additionally, patients with PACC should undergo genetic examinations, which would be beneficial in determining treatment strategies and health care for blood relatives.

Pancreatic cancer is one of the deadliest malignancies in humans and it is expected to play a bigger part in cancer burden in the years to come. Pancreatic ductal adenocarcinoma (PDAC) represents 85% of all primary pancreatic malignancies. Recently, much attention has been given to PDAC, with significant advances in the understanding of the mechanisms underpinning disease initiation and progression, along with noticeable improvements in overall survival in both localized and metastatic settings. However, given their rarity, rare histological subtypes of pancreatic cancer have been underappreciated and are frequently treated as PDAC, even though they might present non-overlapping molecular alterations and clinical behavior. While some of these rare histological subtypes are true variants of PDAC that should be treated likewise, others represent separate clinicopathological entities, warranting a different therapeutic approach. In this review, we highlight clinical, pathological, and molecular aspects of rare histological types of pancreatic cancer, along with the currently available data to guide treatment decisions.

Therapeutic approach used for pancreatic ductal adenocarcinoma is usually translated also for the rarer acinar counterpart, which shows a different mutational landscape nevertheless. While dMMR/MSI-H status is rare in the ductal histotype, it appears to be more prevalent in pancreatic acinar cell carcinoma (PACC).

We report the case of a patient with locally advanced MSI-H PACC in whom the treatment with the anti-PD-1 pembrolizumab, administered as third line, made possible surgical resection, achieving even an exceptional pathological complete response.

Treatment of PACC should be tailored based on the peculiar molecular features that distinguish PACC from ductal adenocarcinoma. Evaluation of potentially therapeutically targetable alterations should be mandatory in case of PACC diagnosis.

Complete remission of BRAF V600E-driven ACC CUP by BRAF/MEK inhibition underscores importance of precision oncology.

Pancreatic acinar cell carcinoma (PACC) is a rare form of pancreatic cancer that commonly harbors targetable alterations, including activating fusions in the MAPK pathway and loss-of-function (LOF) alterations in DNA damage response/homologous recombination DNA repair-related genes. Here, we describe a patient with PACC harboring both somatic biallelic LOF of NBN and an activating NTRK1 fusion. Upon disease progression following 13 months of treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), genomic analysis of a metastatic liver biopsy revealed the emergence of a novel reversion mutation restoring the reading frame of NBN. To our knowledge, genomic reversion of NBN has not been previously reported as a resistance mechanism in any tumor type. The patient was treated with, but did not respond to, targeted treatment with a selective NTRK inhibitor. This case highlights the complex but highly actionable genomic landscape of PACC and underlines the value of genomic profiling of rare tumor types such as PACC.

Pancreatic acinar cell carcinoma is a rare form (0.2-4.3%) of pancreatic neoplasm with unique clinical and molecular characteristics, which largely differ from pancreatic ductal adenocarcinoma. Pancreatic acinar cell carcinoma occurs more frequently in males and can occur in children. Serum lipase is elevated in 24-58% of patients with pancreatic acinar cell carcinoma. Pancreatic acinar cell carcinomas tend to be large at diagnosis (median tumour size: ~5 cm) and are frequently located in the pancreas head. Radiologically, pancreatic acinar cell carcinoma generally exhibits a solid appearance; however, necrosis, cystic changes and intratumoral haemorrhage can occur in larger lesions. Immunostaining is essential for the definitive diagnosis of pancreatic acinar cell carcinoma. Compared with pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma has a more favourable prognosis. Although radical surgery is recommended for patients with pancreatic acinar cell carcinoma who do not have distant metastases, the recurrence rate is high. The effectiveness of adjuvant therapy for pancreatic acinar cell carcinoma is unclear. The response to FOLFIRINOX is generally favourable, and some patients achieve a complete response. Pancreatic acinar cell carcinoma has a different genomic profile compared with pancreatic ductal adenocarcinoma. Although genomic analyses have shown that pancreatic acinar cell carcinoma rarely has KRAS, TP53 and CDKN2A mutations, it has a higher prevalence of homologous recombination-related genes, including BRCA1/2 and ATM, than pancreatic ductal adenocarcinoma, suggesting high sensitivity to platinum-containing regimens and PARP inhibitors. Targeted therapies for genomic alternations are beneficial. Therefore, genetic testing is important for patients with pancreatic acinar cell carcinoma to choose the optimal therapeutic strategy.

Pancreatic acinar cell carcinomas are rare malignant neoplasms. High-quality evidence about the best treatment strategy is lacking. We present the case of a 52-year-old male with a BRAFV600E -mutated PACC who experienced a complete remission after chemotherapy with BRAF-/MEK-inhibitors.

The patient presented with upper abdomen pain, night sweat, and weight loss. CT scan showed a pancreatic tumor extending from the pancreas head to body. Histological workup identified an acinar cell carcinoma. As the tumor was inoperable, chemotherapy with FOFIRNIOX was initiated and initially showed a slight regression of disease. The regimen had to be discontinued due to severe side effects. Molecular analysis identified a BRAFV600E mutation, so the patient was started on BRAF- and MEK-inhibitors (dabrafenib/trametinib). After 16 months, CT scans showed a near complete remission with a markedly improved overall health.

Studies suggest that up to one-fourth of PACCs carry a BRAF mutation and might therefore be susceptible to a BRAF-/MEK-inhibitor therapy. This offers a new therapeutic pathway to treat this rare but malignant neoplasm.

Pancreatic cancer represents one of the most lethal cancer types worldwide, with a 5-year survival rate of less than 5%. Due to the inability to diagnose it promptly and the lack of efficacy of existing treatments, research and development of innovative therapies and new diagnostics are crucial to increase the survival rate and decrease mortality. Nanomedicine has been gaining importance as an innovative approach for drug delivery and diagnosis, opening new horizons through the implementation of smart nanocarrier systems, which can deliver drugs to the specific tissue or organ at an optimal concentration, enhancing treatment efficacy and reducing systemic toxicity. Varied materials such as lipids, polymers, and inorganic materials have been used to obtain nanoparticles and develop innovative drug delivery systems for pancreatic cancer treatment. In this review, it is discussed the main scientific advances in pancreatic cancer treatment by nano-based drug delivery systems. The advantages and disadvantages of such delivery systems in pancreatic cancer treatment are also addressed. More importantly, the different types of nanocarriers and therapeutic strategies developed so far are scrutinized.

Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets.

PACC specimens (n = 51) underwent next-generation sequencing of DNA (n = 29) or whole exome (n = 22) and RNA (whole transcriptome, n = 29) at a commercial laboratory. We performed comparative analyses of a genomic cohort of pancreatic ductal adenocarcinomas (PDAC; n = 4,205). In parallel, we conducted a retrospective review of patients with PACC treated at Huntsman Cancer Institute (HCI).

The real-world dataset included samples from 51 patients with PACC. We found key molecular differences between pure PACC and PDAC, highlighting the unique characteristics of pure PACC. Major differences in PACC include lower MAPK signaling and less stromal cell abundance compared with PDAC. Pure PACC showed genomic loss-of-heterozygosity to largely coincide with mutations in BRCA1, BRCA2, and PALB2. Of the 7 patients treated at HCI, one had a tumor that harbored a BRAF-V600E mutation. Leveraging precision oncology, this patient is being treated with encorafenib plus binimetinib, achieving an exceptionally durable and ongoing complete response of more than 3 years.

There are major differences between PACC and PDAC, including downregulation of the MAPK signaling pathway, and less stromal cell abundance. In addition, genomic characterization of pure PACC revealed frequent targetable alterations, which can guide patient treatment.

Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic malignancy with unique clinical, molecular, and morphologic features. The long-term survival of patients with PACC is substantially better than that of patients with ductal adenocarcinoma of the pancreas. Surgical resection is considered the first choice for treatment; however, there is no standard treatment option for patients with inoperable disease. The patient with metastatic PACC reported herein survived for more than 5 years with various treatments including chemotherapy, radiotherapy, antiangiogenic therapy and combined immunotherapy.

Special subtypes of pancreatic cancer, such as acinar cell carcinoma (ACC), adenosquamous carcinoma (ASC), and anaplastic carcinoma of the pancreas (ACP), are rare, and so data on them are limited. Using the C-CAT database, we analyzed clinical and genomic characteristics of patients with these and evaluated differences on comparison with pancreatic ductal adenocarcinoma (PDAC) patients.

We retrospectively reviewed data on 2691 patients with unresectable pancreatic cancer: ACC, ASC, ACP, and PDAC, entered into C-CAT from June 2019 to December 2021. The clinical features, MSI/TMB status, genomic alterations, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) on receiving FOLFIRINOX (FFX) or GEM + nab-PTX (GnP) therapy as first-line treatment were evaluated.

Numbers of patients with ACC, ASC, ACP, and PDAC were 44 (1.6%), 54 (2.0%), 25 (0.9%), and 2,568 (95.4%), respectively. KRAS and TP53 mutations were prevalent in ASC, ACP, and PDAC (90.7/85.2, 76.0/68.0, and 85.1/69.1%, respectively), while their rates were both significantly lower in ACC (13.6/15.9%, respectively). Conversely, the rate of homologous recombination-related (HRR) genes, including ATM and BRCA1/2, was significantly higher in ACC (11.4/15.9%) than PDAC (2.5/3.7%). In ASC and ACP, no significant differences in ORR, DCR, or TTF between FFX and GnP were noted, while ACC patients showed a trend toward higher ORR with FFX than GnP (61.5 vs. 23.5%, p = 0.06) and significantly more favorable TTF (median 42.3 vs. 21.0 weeks, respectively, p = 0.004).

ACC clearly harbors different genomics compared with PDAC, possibly accounting for differences in treatment efficacy.

A 56-year-old man presented to our hospital for close examination of a mass in the portal vein. CT showed a homogeneously enhanced mass occupying the portal vein. No other lesions suggestive of a primary tumor were detected. Endoscopic ultrasound-guided fine-needle aspiration revealed that the tumor was pathologically acinar cell carcinoma (ACC) based on the positive staining for both BCL-10 and trypsin. He was diagnosed with an ectopic ACC developed in the portal vein. Because the tumor invaded secondary branches of the right intrahepatic portal vein and the superior mesenteric vein, it was considered surgically un-resectable. Therefore, chemotherapy with gemcitabine plus nab-paclitaxel (GEM + nab-PTX) was started. After 2 courses, CT showed progressive disease, so the regimen was switched to FOLFIRINOX. After starting treatment with FOLFIRINOX, the tumor shrank gradually. After 29 courses, CT scan eventually showed disappearance of the tumor and complete response was achieved. After 34 courses, the chemotherapy was discontinued. Since then, the patient has been recurrence-free for 5 years. Our English literature review yielded 6 cases, including this case, of un-resectable ACC in which complete response was achieved by chemotherapy. Our case suggest that platinum-based regimen might be an effective therapy for un-resectable ACC, including ectopic ACC.

Acinar cell carcinoma (ACC) of the pancreas is a malignant tumor of the exocrine cell lineage with a poor prognosis. Due to its rare incidence and technical difficulties, few authentic human cell lines are currently available, hampering detailed investigations of ACC. Therefore, we applied the organoid culture technique to various types of specimens, such as bile, biopsy, and resected tumor, obtained from a single ACC patient. Despite the initial propagation, none of these organoids achieved long-term proliferation or tolerated cryopreservation, confirming the challenging nature of establishing ACC cell lines. Nevertheless, the biopsy-derived early passage organoid developed subcutaneous tumors in immunodeficient mice. The xenograft tumor histologically resembled the original tumor and gave rise to infinitely propagating organoids with solid features and high levels of trypsin secretion. Moreover, the organoid stained positive for carboxylic ester hydrolase, a specific ACC marker, but negative for the duct cell marker CD133 and the endocrine lineage marker synaptophysin. Hence, we concluded the derivation of a novel ACC cell line of the pure exocrine lineage, designated HS-1. Genomic analysis revealed extensive copy number alterations and mutations in EP400 in the original tumor, which were enriched in primary organoids. HS-1 displayed homozygous deletion of CDKN2A, which might underlie xenograft formation from organoids. Although resistant to standard cytotoxic agents, the cell line was highly sensitive to the proteasome inhibitor bortezomib, as revealed by an in vitro drug screen and in vivo validation. In summary, we document a novel ACC cell line, which could be useful for ACC studies in the future.

Distinguishing grade 3 pancreatic neuroendocrine tumor (G3 PanNET) from neuroendocrine carcinoma (PanNEC) is a known diagnostic challenge, and accurate classification is critical because clinical behavior and therapies differ. Although current recommendations suggest that immunohistochemistry for p53, Rb, ATRX, and DAXX can distinguish most cases, some cases remain difficult to classify using this approach. In this study, we reviewed 47 high-grade neoplasms originally diagnosed as pancreatic neuroendocrine neoplasms. In addition to the currently recommended stains, we performed capture-based sequencing of approximately 500 cancer genes and immunohistochemistry for p16 and trypsin or chymotrypsin. Using an integrated molecular and clinicopathologic approach, 42 (89%) of 47 cases had a clear final diagnosis of either G3 PanNET (n = 17), PanNEC (n = 17), or mixed acinar-NEC (n = 8). The 17 G3 PanNETs demonstrated frequent alterations in MEN1 (71%), DAXX (47%), ATRX (24%), TSC2 (35%), SETD2 (42%), and CDKN2A (41%). Contrary to prior reports, TP53 alterations were also common in G3 PanNETs (35%) but were always mutually exclusive with CDKN2A alterations in this group. The 17 PanNECs demonstrated frequent alterations in TP53 (88%), cell cycle genes RB1 (47%), CCNE1/CCND1 (12%), CDKN2A (29%), and in KRAS (53%) and SMAD4 (41%); TP53 was coaltered with a cell cycle gene in 76% of PanNECs. Diffuse strong p16 staining was observed in 69% of PanNECs in contrast to 0% of G3 PanNETs. The 8 acinar-NECs had recurrent alterations in ATM (25%), APC (25%), and STK11 (25%). Five cases remained difficult to classify, 3 of which exhibited overlapping molecular features with alterations in MEN1 with or without ATRX, and RB1 with or without TP53, making it unclear whether to classify as PanNET or PanNEC. Our data demonstrate that molecular profiling and immunohistochemistry for p16 greatly improve the diagnostic accuracy of high-grade pancreatic neuroendocrine neoplasms and identify a subset of rare cases with overlapping features of both PanNET and PanNEC.

Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) represents an important molecular alteration with diagnostic, prognostic, and predictive value. The increasing interest toward this genetic alteration is given to the high response rate of MSI/dMMR tumors to immunotherapy. There are different cancers in the periampullary region that can harbor MSI/dMMR, and significant morphological-molecular correlates should be acknowledged in this district: (1) pancreatic ductal adenocarcinoma (PDAC): in this tumor category, the prevalence of MSI/dMMR is about 1-2%, and medullary and colloid variants are the most typically involved; (2) ampullary adenocarcinoma: here the prevalence of MSI/dMMR is up to 18%, and in this neoplastic group, MSI/dMMR is more commonly found in the intestinal subtype; (3) pancreatic acinar cell carcinoma: here the prevalence of MSI/dMMR is up to 14%; and (4) pancreatic and ampullary neuroendocrine carcinoma: in this tumor category, the prevalence of MSI/dMMR is up to 5-8%, and this molecular alteration should be assessed also in cases of mixed neuroendocrine-non-neuroendocrine neoplasms. Given the clinical importance of MSI/dMMR and its not-negligible prevalence among the different carcinomas arising in this district, its assessment should become part of the routine diagnostic workflow at least for the most typical histotypes. The test of choice is represented by immunohistochemistry for PDAC and ampullary carcinomas, and by direct molecular analyses including MSI-based polymerase chain reaction and next-generation sequencing for acinar cell and neuroendocrine carcinomas.

Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.

Acinar cell carcinoma (ACC) is a rare pancreatic malignancy with distinctive clinical, molecular, and morphological features. The long-term survival of ACC patients is substantially superior to that of pancreatic adenocarcinoma patients. As there are no significant patient series about ACCs, our understanding of this illness is mainly based on case reports and limited patient series. Surgical resection is the treatment of choice for patients with the disease restricted to one organ; however, with recent breakthroughs in precision medicine, medicines targeting the one-of-a-kind molecular profile of ACC are on the horizon. There are no standard treatment protocols available for people in which a total surgical resection to cure the condition is not possible. As a result of shared genetic alterations, ACCs are chemosensitive to agents with activity against pancreatic adenocarcinomas and colorectal carcinomas. The role of neoadjuvant or adjuvant chemoradiotherapy has not been established. This article aims to do a comprehensive literature study and present the most recent information on acinar cell cancer.

Pancreatic cancer and its rare subtype, acinar cell carcinoma (PACC), frequently harbor germline and/or somatic variants in homologous recombinant genes, including BRCA2. Individuals possessing germline pathogenic BRCA2 variants are known to have a higher risk of developing various cancers, including breast, ovarian, pancreatic, and bile duct cancers (BDCs). It has been reported that tumors positive for BRCA1/2 variants are sensitive to platinum-based agents. Thus, BRCA1/2 germline testing and comprehensive genomic profiling are recommended to identify genetic susceptibility and to indicate optimal targeted therapy. Here, we report familial occurrence of PACC and BDC associated with BRCA2; both tumors responded exceptionally well to platinum-based chemotherapy. A 37-year-old man was diagnosed with unresectable PACC with a germline BRCA2 variant. He was treated with oxaliplatin-containing chemotherapy and conversion surgery, and remains alive without tumor recurrence after more than 36 months. His father also possessed the identical germline BRCA2 variant and was diagnosed with extrahepatic BDC with lymph node metastases. The tumors showed marked shrinkage upon treatment with cisplatin-containing chemotherapy. Our cases underscore the importance of comprehensive genomic profiling and genetic testing for BRCA2 to ensure optimal therapeutic options for PACC as well as to identify high-risk individuals with various cancers in the family.

Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway.

To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without.

Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed.

BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 cases (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH.

This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.

Gene fusions involving R-spondin (RSPOfp) and RNF43 mutations have been shown to drive Wnt-dependent tumor initiation in colorectal cancer (CRC). Herein, we aimed to characterize the molecular features of RSPOfp/RNF43 mutated (mut) compared to wildtype CRCs to gain insights into potential rationales for therapeutic strategies.

A discovery cohort was classified for RSPOfp/RNF43 status using DNA/RNA sequencing and immunohistochemistry. An independent cohort was used to validate our findings.

The discovery cohort consisted of 7,245 CRC samples. RSPOfp and RNF43 mutations were detected in 1.3% (n=94) and 6.1% (n=443) of cases. We found 5 RSPO fusion events that had not previously been reported (e.g. IFNGR1-RSPO3). RNF43-mut tumors were associated with right-sided primary tumors. No RSPOfp tumors had RNF43 mutations. In comparison to wildtype CRCs, RSPOfp tumors were characterized by a higher frequency of BRAF, BMPR1A and SMAD4 mutations. APC mutations were observed in only a minority of RSPOfp-positive compared to wildtype cases (4.4 vs. 81.4%). Regarding RNF43 mutations, a higher rate of KMT2D and BRAF mutations were detectable compared to wildtype samples. While RNF43 mutations were associated with a microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) phenotype (64.3%), and a TMB {greater than or equal to}10 mt/Mb (65.8%), RSPOfp was not associated with MSI-H/dMMR. The validation cohort replicated our genetic findings.

This is the largest series of RSPOfp/RNF43-mut CRCs reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO/RNF43 and suggested potential alternative strategies to overcome the low clinical impact of Wnt-targeted agents and immunotherapy.

Pediatric solid neoplasms are rare and very different from those observed in adults. The majority of them are referred to as embryonal because they arise as a result of alterations in the processes of organogenesis or normal growth and are characterized by proliferation of primitive cells, reproducing the corresponding tissue at various stages of embryonic development. This review will focus on embryonal gastrointestinal pediatric neoplasms in adult patients, including pancreatoblastoma, hepatoblastoma, and embryonal sarcoma of the liver. Although they are classically considered pediatric neoplasms, they may (rarely) occur in adult patients. Hepatoblastoma represents the most frequent liver neoplasm in the pediatric population, followed by hepatocellular carcinoma and embryonal sarcoma of the liver; while pancreatoblastoma is the most common malignant pancreatic tumor in childhood. Both in children and adults, the mainstay of treatment is complete surgical resection, either up front or following neoadjuvant chemotherapy. Unresectable and/or metastatic neoplasms may be amenable to complete delayed surgery after neoadjuvant chemotherapy. However, these neoplasms display a more aggressive behavior and overall poorer prognosis in adults than in children, probably because they are diagnosed in later stages of diseases.

Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on "blastomas," which variably recapitulate the morphologic maturation of organs from which they originate. SIGNIFICANCE: In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.