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DNA Methylation Profiling Enables Accurate Classification of Nonductal Primary Pancreatic Neoplasms.Clinical Gastroenterology and... Jun 2024Cytologic and histopathologic diagnosis of non-ductal pancreatic neoplasms can be challenging in daily clinical practice, whereas it is crucial for therapy and...
BACKGROUND & AIMS
Cytologic and histopathologic diagnosis of non-ductal pancreatic neoplasms can be challenging in daily clinical practice, whereas it is crucial for therapy and prognosis. The cancer methylome is successfully used as a diagnostic tool in other cancer entities. Here, we investigate if methylation profiling can improve the diagnostic work-up of pancreatic neoplasms.
METHODS
DNA methylation data were obtained for 301 primary tumors spanning 6 primary pancreatic neoplasms and 20 normal pancreas controls. Neural Network, Random Forest, and extreme gradient boosting machine learning models were trained to distinguish between tumor types. Methylation data of 29 nonpancreatic neoplasms (n = 3708) were used to develop an algorithm capable of detecting neoplasms of non-pancreatic origin.
RESULTS
After benchmarking 3 state-of-the-art machine learning models, the random forest model emerged as the best classifier with 96.9% accuracy. All classifications received a probability score reflecting the confidence of the prediction. Increasing the score threshold improved the random forest classifier performance up to 100% with 87% of samples with scores surpassing the cutoff. Using a logistic regression model, detection of nonpancreatic neoplasms achieved an area under the curve of >0.99. Analysis of biopsy specimens showed concordant classification with their paired resection sample.
CONCLUSIONS
Pancreatic neoplasms can be classified with high accuracy based on DNA methylation signatures. Additionally, non-pancreatic neoplasms are identified with near perfect precision. In summary, methylation profiling can serve as a valuable adjunct in the diagnosis of pancreatic neoplasms with minimal risk for misdiagnosis, even in the pre-operative setting.
Topics: Humans; DNA Methylation; Pancreatic Neoplasms; Male; Female; Aged; Middle Aged
PubMed: 38382726
DOI: 10.1016/j.cgh.2024.02.007 -
Modern Pathology : An Official Journal... Feb 2007Although the majority of pancreatic neoplasms are infiltrating ductal adenocarcinomas or other neoplasms with ductal differentiation, neoplasms with acinar, endocrine,...
Although the majority of pancreatic neoplasms are infiltrating ductal adenocarcinomas or other neoplasms with ductal differentiation, neoplasms with acinar, endocrine, mixed, or uncertain differentiation constitute a diverse and distinctive group. The most common and best-characterized nonductal neoplasms are pancreatic endocrine neoplasm, acinar cell carcinoma, pancreatoblastoma, and solid pseudopapillary neoplasm. This review details the clinical and pathologic features of these nonductal neoplasms, highlighting diagnostic criteria including the use of specific immunohistochemical stains to define the cellular differentiation of the neoplasms.
Topics: Adenocarcinoma, Papillary; Adenoma, Islet Cell; Biomarkers, Tumor; Carcinoma, Acinar Cell; Carcinoma, Islet Cell; Humans; Pancreas; Pancreatic Neoplasms
PubMed: 17486055
DOI: 10.1038/modpathol.3800686 -
Cancer Jan 2004Pancreatic ductal adenocarcinomas (PDACs) are extremely rare before age 40 years. The objective of the current study was to determine whether the features of PDACs in... (Review)
Review
BACKGROUND
Pancreatic ductal adenocarcinomas (PDACs) are extremely rare before age 40 years. The objective of the current study was to determine whether the features of PDACs in patients age < 40 years differ from those in older patients. The authors reviewed the literature and their own files.
METHODS
The cases reported in the literature were evaluated to determine their precise diagnoses and characteristic features. In a series of 439 PDACs from the authors' files, tumors in patients age < 40 years were identified, and their clinicopathologic features and certain genetic features were compared with those in a selected group of patients age > 40 years.
RESULTS
Of 71 pancreatic carcinomas reported in patients age < 40 years, only 20 fully qualified as PDACs. The remaining tumors represented malignancies other than PDACs, such as pancreatoblastoma, solid-pseudopapillary neoplasms, acinar cell carcinomas, and endocrine tumors. PDACs in patients age < 20 years were the absolute exception and commonly were associated with risk factors such as Peutz-Jeghers syndrome, hereditary pancreatic cancer syndrome, and preceding radiotherapy. In the authors' series of patients, there were 6 PDACs and 4 PDAC variants in patients age < 40 years (0.2%), all in male patients. These tumors compared well with the PDACs in patients age > 40 years in their pathologic and molecular findings. Three patients were age < or = 20 years, and 2 of those patients had a mucinous component with MUC2 positivity.
CONCLUSIONS
The incidence of PDACs in patients age < 40 years was approximately 0.3%, and the incidence in patients age < 20 years was 0.1%. Their clinicopathologic findings were comparable to those in patients age > 40 years, but they seemed to include more variants, particularly mucinous carcinomas. In addition, PDACs in younger patients frequently appeared to be associated with genetic factors.
Topics: Adenocarcinoma; Adolescent; Adult; Age of Onset; Carcinoma, Pancreatic Ductal; Child; Female; Genetic Predisposition to Disease; Humans; Incidence; Male; Pancreatic Neoplasms; Risk Factors; Sex Factors
PubMed: 14692038
DOI: 10.1002/cncr.11860 -
Journal of Indian Association of... 2016Clinicoradiological and histopathological differentiation of pancreatoblastoma from hepatoblastoma can often be a challenge in clinical practice owing to their peculiar...
Clinicoradiological and histopathological differentiation of pancreatoblastoma from hepatoblastoma can often be a challenge in clinical practice owing to their peculiar resemblance. We report a case of a 4-year-old boy with a right hypochondriac region mass, which was diagnosed as hepatoblastoma on the basis of imaging, raised tumor marker, and biopsy; however, pancreatic origin of the mass was ascertained on exploration and pancreatoblastoma was confirmed on histopathology.
PubMed: 27046982
DOI: 10.4103/0971-9261.176969 -
Oncology Letters May 2015The present study describes the case of a 24-year-old patient who presented with obstructive jaundice and weight loss, and was diagnosed with pancreatoblastoma (PB)....
The present study describes the case of a 24-year-old patient who presented with obstructive jaundice and weight loss, and was diagnosed with pancreatoblastoma (PB). Abdominal imaging studies revealed a heterogenous lesion of the pancreatic head with dilatation of the common bile duct. The patient underwent pancreaticoduodenectomy, however, three months after surgery multiple liver and bone metastases were identified on follow-up computed tomography scans. Despite treatment with four cycles of systemic chemotherapy and five courses of radiofrequency ablation, the patient succumbed due to tumour dissemination 13 months after initial diagnosis. PB is a malignant tumour of the pancreas that typically occurs in the pediatric population. The aim of the present study was to highlight the aggressive behavior of this rare clinical entity, focusing on the pitfalls of pre-operative diagnosis and the lack of management strategy guidelines in adults. Preoperative diagnosis of PB based on radiographic features may be difficult, as the imaging characteristics are non-specific. Furthermore, cytology may also be misleading, as the neoplasm consists of multiple cell lines (acinar, ductal and neuroendocrine cells) and diagnosis depends largely on the identification of the distinctive histological characteristic of squamoid corpuscles, which present as nests of flattened cells with a squamous appearance. Despite the use of surgical resection and adjuvant chemoradiotherapy for the treatment of this malignancy, its aggressive nature means that PB is associated with a poor prognosis in adult patients.
PubMed: 26137059
DOI: 10.3892/ol.2015.3001 -
The American Journal of Surgical... May 2024The diagnosis of solid pseudopapillary neoplasm of the pancreas (SPN) can be challenging due to potential confusion with other pancreatic neoplasms, particularly...
The diagnosis of solid pseudopapillary neoplasm of the pancreas (SPN) can be challenging due to potential confusion with other pancreatic neoplasms, particularly pancreatic neuroendocrine tumors (NETs), using current pathological diagnostic markers. We conducted a comprehensive analysis of bulk RNA sequencing data from SPNs, NETs, and normal pancreas, followed by experimental validation. This analysis revealed an increased accumulation of peroxisomes in SPNs. Moreover, we observed significant upregulation of the peroxisome marker ABCD1 in both primary and metastatic SPN samples compared with normal pancreas and NETs. To further investigate the potential utility of ABCD1 as a diagnostic marker for SPN via immunohistochemistry staining, we conducted verification in a large-scale patient cohort with pancreatic tumors, including 127 SPN (111 primary, 16 metastatic samples), 108 NET (98 nonfunctional pancreatic neuroendocrine tumor, NF-NET, and 10 functional pancreatic neuroendocrine tumor, F-NET), 9 acinar cell carcinoma (ACC), 3 pancreatoblastoma (PB), 54 pancreatic ductal adenocarcinoma (PDAC), 20 pancreatic serous cystadenoma (SCA), 19 pancreatic mucinous cystadenoma (MCA), 12 pancreatic ductal intraepithelial neoplasia (PanIN) and 5 intraductal papillary mucinous neoplasm (IPMN) samples. Our results indicate that ABCD1 holds promise as an easily applicable diagnostic marker with exceptional efficacy (AUC=0.999, sensitivity=99.10%, specificity=100%) for differentiating SPN from NET and other pancreatic neoplasms through immunohistochemical staining.
Topics: Humans; Pancreatic Neoplasms; Pancreas; Carcinoma, Pancreatic Ductal; Neuroendocrine Tumors; Pancreatic Ducts; Biomarkers, Tumor; ATP Binding Cassette Transporter, Subfamily D, Member 1
PubMed: 38567813
DOI: 10.1097/PAS.0000000000002205 -
Seminars in Diagnostic Pathology Nov 2014Pancreatic neoplasms with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma, and carcinomas with mixed differentiation, are distinctive...
Pancreatic neoplasms with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma, and carcinomas with mixed differentiation, are distinctive pancreatic neoplasms with a poor prognosis. These neoplasms are clinically, pathologically, and genetically unique when compared to other more common pancreatic neoplasms. Most occur in adults, although pancreatoblastomas usually affect children under 10 years old. All of these neoplasms exhibit characteristic histologic features including a solid or acinar growth pattern, dense neoplastic cellularity, uniform nuclei with prominent nucleoli, and granular eosinophilic cytoplasm. Exocrine enzymes are detectable by immunohistochemistry and, for carcinomas with mixed differentiation, neuroendocrine or ductal lineage markers are also expressed. The genetic alterations of this family of neoplasms largely differ from conventional ductal adenocarcinomas, with only rare mutations in TP53, KRAS, and p16, but no single gene or neoplastic pathway is consistently altered in acinar neoplasms. Instead, there is striking genomic instability, and a subset of cases has mutations in the APC/β-catenin pathway, mutations in SMAD4, RAF gene family fusions, or microsatellite instability. Therapeutically targetable mutations are often present. This review summarizes the clinical and pathologic features of acinar neoplasms and reviews the current molecular data on these uncommon tumors.
Topics: Carcinoma; Carcinoma, Acinar Cell; Humans; Pancreatic Neoplasms
PubMed: 25441307
DOI: 10.1053/j.semdp.2014.08.003 -
Pediatric Reports May 2024Complete surgical resection in the context of a multimodal approach has been associated with excellent long-term survival in children diagnosed with pancreatoblastoma... (Review)
Review
Complete surgical resection in the context of a multimodal approach has been associated with excellent long-term survival in children diagnosed with pancreatoblastoma (PB). Traditionally, curative intent surgery for PB implies standard pancreatic resections such as pancreaticoduodenectomies and distal pancreatectomies with splenectomies, surgical procedures that may lead to significant long-term pancreatic functional deficiencies. Postoperative pancreatic functional deficiencies are particularly interesting to children because they may interfere with their development, considering their long life expectancy and the significant role of pancreatic functions in their nutritional status and growth. Thus, organ-sparing pancreatectomies, such as spleen-preserving distal pancreatectomies and central pancreatectomies, are emerging in specific tumoral pathologies in children. However, data about organ-sparing pancreatectomies' potential role in curative-intent PB surgery in children are scarce. Based on the literature data, the current review aims to present the early and late outcomes of pancreatectomies in children (including long-term deficiencies and their potential impact on the development and quality of life), particularly for PB, and further explore the potential role of organ-sparing pancreatectomies for PB. Organ-sparing pancreatectomies are associated with better long-term pancreatic functional outcomes, particularly central pancreatectomies, and have a reduced impact on children's development and quality of life without jeopardizing their oncological safety. The long-term preservation of pancreatic functions should not be disregarded when performing pancreatectomies for PB in children. A subset of patients with PB might benefit from organ-sparing pancreatectomies, particularly from central pancreatectomies, with the same oncological results as standard pancreatectomies but with significantly less impact on long-term functional outcomes.
PubMed: 38804376
DOI: 10.3390/pediatric16020033 -
The Journal of Pathology Mar 2014Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic...
Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole-exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations/carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations/tumour (range 12-189). The mean fractional allelic loss (FAL) was 0.27 (range 0-0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescence in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumours (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2 and PALB2 (one tumour each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumours (17%), BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%) and BAP1 in one (4%). Perhaps most importantly, we found that more than one-third of these carcinomas have potentially targetable genetic alterations, including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.
Topics: Acinar Cells; Biomarkers, Tumor; Carcinoma, Acinar Cell; Cell Differentiation; Chromosomes, Human; DNA Mutational Analysis; DNA, Neoplasm; Exome; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Mutation; Pancreatic Neoplasms; Phenotype
PubMed: 24293293
DOI: 10.1002/path.4310 -
Modern Pathology : An Official Journal... Sep 2020There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET...
There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was undertaken on 30 tumors comprising 25 'pure' acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1 gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RET or RAF1 fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Acinar Cell; Databases, Factual; Female; Gene Fusion; Gene Rearrangement; Humans; Male; Middle Aged; Pancreatic Neoplasms; Proto-Oncogene Proteins c-raf; Young Adult
PubMed: 32358589
DOI: 10.1038/s41379-020-0545-9