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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 -
BMJ Case Reports Apr 2020
Topics: Aged; Carcinoma, Acinar Cell; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Humans; Male; Mesenteric Veins; Neoadjuvant Therapy; Pancreatic Neoplasms; Thrombosis; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 32265211
DOI: 10.1136/bcr-2019-233884 -
Annals of Hepato-biliary-pancreatic... Feb 2020Pancreatoblastoma is a malignant exocrine pancreatic tumor that is usually present in childhood. We herein present one case of pediatric living donor liver...
Pancreatoblastoma is a malignant exocrine pancreatic tumor that is usually present in childhood. We herein present one case of pediatric living donor liver transplantation (LDLT) combined with spleen-preserving regional total pancreatectomy and portal vein homograft interposition in a 4-year-old boy with advanced pancreatoblastoma invading the portal and superior mesenteric veins. The size of the pancreatoblastoma was gradually reduced along systemic chemotherapy, thus we decided to perform surgery to remove it completely. A cold-stored fresh iliac vein homograft was prepared. Initially, a spleen-preserving distal pancreatectomy was performed. Thereafter, a completion regional total pancreatectomy was performed under superior mesenteric vein-vena cava bypass. A left liver graft from his mother was implanted according to the standardized procedures with portal vein interposition. This patient recovered uneventfully and is currently undergoing scheduled adjuvant chemotherapy. To our knowledge, this is the world-second case of pediatric LDLT for advanced pancreatoblastoma. Availability of fresh vein homografts is helpful to expand the indication of pediatric LDLT.
PubMed: 32181434
DOI: 10.14701/ahbps.2020.24.1.78 -
Cureus Jan 2020Pancreatoblastoma (PB) is a rare pancreatic neoplasm which arises when a group of pancreatic cells start to go through uncontrollable growth. The diagnosis of PB is...
Pancreatoblastoma (PB) is a rare pancreatic neoplasm which arises when a group of pancreatic cells start to go through uncontrollable growth. The diagnosis of PB is challenging due to its vague symptoms. The initial diagnosis is made by imaging, afterwards the management is usually by resection of the tumor with or without chemotherapy which depends on the size and grade of the tumor. We report a case of a nine-year-old girl who was diagnosed with pancreotoblastoma and underwent complete resection with chemotherapy.
PubMed: 32015939
DOI: 10.7759/cureus.6779 -
Archives of Pathology & Laboratory... Jul 2020Pancreatic acinar lesions encompass a broad spectrum of malignant tumors and benign reactive processes affecting both adults and children, with clinical, pathologic, and... (Review)
Review
CONTEXT.—
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.
OBJECTIVE.—
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.
DATA SOURCES.—
We assessed the current primary literature, as well as recently updated diagnostic manuals.
CONCLUSIONS.—
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.
Topics: Biomarkers, Tumor; Biopsy; Carcinoma, Acinar Cell; Cell Differentiation; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Molecular Diagnostic Techniques; Neoplasms, Complex and Mixed; Pancreatic Neoplasms; Phenotype; Predictive Value of Tests
PubMed: 31869246
DOI: 10.5858/arpa.2019-0472-RA -
Cancer Cytopathology Nov 2019Pancreatoblastoma (PBL) is a rare malignant pancreatic tumor seen predominantly in childhood, and its cytologic diagnosis remains challenging.
BACKGROUND
Pancreatoblastoma (PBL) is a rare malignant pancreatic tumor seen predominantly in childhood, and its cytologic diagnosis remains challenging.
METHODS
Twelve fine-needle-aspirations from 11 adults were analyzed.
RESULTS
In total, 6 men and 5 women (median age, 45 years; age range, 32-60 years) had tumors measuring a median 5.6 cm (range, 2.5-12 cm) located in the pancreatic head (n = 7) or tail (n = 4), including 3 with familial adenomatous polyposis (FAP)/FAP-related syndromes and 4 with metastasis at diagnosis. The median follow-up was 39.8 months (range, 0.8-348 months), and 5 patients died of disease. The original cytology diagnoses were: PBL (n = 2), neuroendocrine neoplasm (n = 2), poorly differentiated neuroendocrine carcinoma (n = 2), well differentiated neuroendocrine tumor (n = 1), poorly differentiated carcinoma (n = 2), "positive for malignancy" (n = 1), acinar cell carcinoma (n = 1), and epithelioid neoplasm with endocrine and acinar differentiation versus PBL (n = 1). Universal cytopathologic findings included hypercellularity; 3-dimensional clusters; and single, monotonous, blast-like cells that were from 1.5 to 2.0 times the size of red blood cells with high nuclear-to-cytoplasmic ratio, fine chromatin, small, distinct nucleoli, and a resemblance to well differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. Branching pseudopapillae (n = 7) and grooved nuclei (n = 3) raised the differential diagnosis of solid-pseudopapillary neoplasm, but with more atypia. Uncommon features included pleomorphism (n = 4) and numerous mitoses (n = 1). Squamoid morules were seen on smears (n = 5) or cell blocks (n = 6) in 70% of patients and were characterized by epithelioid cells with elongated, streaming nuclei, fine chromatin, absent nucleoli, and positive nuclear β-catenin (n = 6 of 8). The median Ki-67 index was 21% (range, 2%-70%), and neuroendocrine marker expression was common (100%), but acinar markers were variable (63%).
CONCLUSIONS
A combination of cytologic findings in PBL, including a predominant population of primitive blast-like cells, subtle squamoid morules, frequent neuroendocrine and variable acinar phenotype, should facilitate accurate cytologic diagnosis and distinction from common mimics.
Topics: Adenomatous Polyps; Adult; Biopsy, Fine-Needle; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Tumor Burden
PubMed: 31581358
DOI: 10.1002/cncy.22187 -
Modern Pathology : An Official Journal... Apr 2020Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may be under-recognized. In contrast to pancreatic ductal adenocarcinoma,...
Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may be under-recognized. In contrast to pancreatic ductal adenocarcinoma, most acinar cell carcinomas lack mutations in KRAS, DPC, CDKN2A or TP53, but appear to have a high incidence of gene rearrangements, with up to 20% reported to be driven by BRAF fusions. With the development of a new class of RET-specific tyrosine kinase inhibitors, which appear to have particularly strong activity against RET gene rearranged tumours, there is now considerable interest in identifying RET gene rearrangements across a wide range of cancers. RET rearrangements have been reported to occur at a very low incidence (<1%) in all pancreatic carcinomas. We postulated that given its unique molecular profile, RET gene rearrangements may be common in acinar cell carcinomas. We performed fluorescent in-situ hybridization (FISH) studies on a cohort of 40 acinar cell spectrum tumours comprising 36 pure acinar cell carcinomas, three pancreatoblastomas and one mixed acinar-pancreatic neuroendocrine tumour. RET gene rearrangements were identified in 3 (7.5%) cases and BRAF gene rearrangements in 5 (12.5%). All gene rearranged tumours were pure acinar cell carcinomas. Our findings indicate that amongst all pancreatic carcinomas, acinar carcinomas are highly enriched for potentially actionable gene rearrangements in RET or BRAF. FISH testing is inexpensive and readily available in the routine clinical setting and may have a role in the assessment of all acinar cell carcinomas-at this stage to recruit patients for clinical trials of new targeted therapies, but perhaps in the near future as part of routine care.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Acinar Cell; Databases, Factual; Europe; Female; Gene Rearrangement; Genetic Predisposition to Disease; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Pancreatic Neoplasms; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-ret; Young Adult
PubMed: 31558784
DOI: 10.1038/s41379-019-0373-y -
Tumori Aug 2019Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The...
INTRODUCTION
Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available.
METHODS
A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays.
CONCLUSIONS
We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.
Topics: Carcinoma, Acinar Cell; Carcinoma, Adenosquamous; Carcinoma, Pancreatic Ductal; Female; Humans; Immunohistochemistry; Italy; Male; Pancreatic Neoplasms; Retrospective Studies
PubMed: 30967031
DOI: 10.1177/0300891619839461 -
European Journal of Medical Genetics Jan 2020Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain...
Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain unclear. We report of an apparently non-syndromic infant with severe congenital hyperinsulinism (CHI) and diffuse pancreatic labelling by 18F*-DOPA-PET/CT leading to near-total pancreatectomy. The histology was atypical with pronounced proliferation of endocrine cells comprising >70% of the pancreatic tissue and a small pancreatoblastoma. Routine genetic analysis for CHI was normal in the blood and resected pancreatic tissue. At two years' age, Beckwith-Wiedemann Syndrome (BWS) stigmata emerged, and at five years a liver tumour with focal nodular hyperplasia and an adrenal tumour were resected. pUPD was detected in 11p15 and next in the entire chromosome 11 with microsatellite markers. Quantitative fluorescent PCR with amplification of chromosome-specific DNA sequences for chromosomes 13, 18, 21 and X indicated GW-pUPD. A next generation sequencing panel with 303 SNPs on 21 chromosomes showed pUPD in both blood and pancreatic tissue. The mosaic distribution of GW-pUPD ranged from 31 to 35% in blood and buccal swap to 74% in the resected pancreas, 80% in a non-tumour liver biopsy, and 100% in the liver focal nodular hyperplasia and adrenal tumour. MLID features included transient conjugated hyperbilirubinaemia and lack of macrosomia from BWS (pUPD6); and behavioural and psychomotor manifestations of Angelman Syndrome (pUPD15) on follow-up. In conclusion, atypical pancreatic histology in apparently non-syndromic severe CHI patients may be the first clue to BWS and multi-syndromal CHI from GW-pUPD. Variations in the degree of mosaicism between tissues explained the phenotype.
Topics: Beckwith-Wiedemann Syndrome; Child, Preschool; Chromosomes, Human; Congenital Hyperinsulinism; DNA Methylation; Female; Genetic Predisposition to Disease; Genome, Human; Genomic Imprinting; Humans; Mosaicism; Organ Specificity; Phenotype; Polymorphism, Single Nucleotide; Uniparental Disomy
PubMed: 30797057
DOI: 10.1016/j.ejmg.2019.02.004 -
Journal of Indian Association of... 2018Whipple's pancreaticoduodenectomy (WPD) is rarely required in children. However, WPD is the only option with pathologies involving the head of the pancreas requiring...
PURPOSE
Whipple's pancreaticoduodenectomy (WPD) is rarely required in children. However, WPD is the only option with pathologies involving the head of the pancreas requiring surgical excision. The objective of our study was to review our experience with WPD performed on children.
MATERIALS AND METHODS
A retrospective analysis of case records was conducted on all patients <18 years of age, who underwent WPD at our center over the last 20 years. Data regarding demographics, signs, and symptoms at presentation, diagnostic imaging and procedures, pathologic reports, surgical and medical treatment, and follow-up were collected to study the indications and safety and outcomes of WPD in children.
RESULTS
Five patients had been planned for a WPD during the study (1995-2015); but in one patient, the procedure was abandoned, the rest four patients formed the study group. Male to female ratio was 3:1. Median age at the time of surgery was 9 years (11 months-12 years). The most common presentation was obstructive jaundice (50%, 2/4). Radiological imaging was able to accurately predict the surgical procedure required in all except one case. The mean operating time was 205 min (180-240 min). There were no intraoperative complications. The mean intraoperative blood loss was 85 mL (20-150 mL). The youngest patient requiring WPD was an 11-month-old child. Oral feeding was established by the 7 postoperative day (range 5-7 days) in all cases. There were no cases of anastomotic leak or pancreatic or jejunal fistulae. One patient developed features of subacute intestinal obstruction after discharge and required re-exploration. There was no intra- or post-operative mortality.
CONCLUSION
WPD is safe and efficacious procedure in a selected group of children. The overall efficacy of surgical treatment combined with the relatively low severity of complications leads us to recommend WPD in children when indicated.
PubMed: 30443117
DOI: 10.4103/jiaps.JIAPS_35_18