Publications by authors named "Wenzel M Hackeng"

16 Publications

  • Page 1 of 1

A Parathyroid-Gut Axis: Hypercalcemia and the Pathogenesis of Gastrinoma in Multiple Endocrine Neoplasia 1.

Mol Cancer Res 2021 Mar 26. Epub 2021 Mar 26.

Pathology, UMC Utrecht.

Patients with multiple endocrine neoplasia 1 (MEN1) syndrome have a germline mutation in the MEN1 gene. Loss of the wildtype allele can initiate endocrine tumorigenesis. Microscopic and macroscopic pituitary, parathyroid, and pancreatic tumors (referred to as the 3 P's) show loss of the wildtype MEN1 allele up to 100%. In contrast, the duodenal gastrinoma pathogenesis in MEN1 syndrome follows a hyperplasia-to-neoplasia sequence. Gastrinomas have loss of heterozygosity of the MEN1 locus in <50%, and invariably coincide with linear, diffuse, or micronodular gastrin-cell hyperplasia. The factor initiating the gastrin-cell hyperplasia-to-neoplasia sequence is unknown. In this perspective, we argue that hypercalcemia may promote the gastrin-cell hyperplasia-to-neoplasia sequence through the calcium sensing receptor. Hypercalcemia is present in almost all patients with MEN1 syndrome due to parathyroid adenomas. We propose a parathyroid-gut axis, which could well explain why patients with MEN1 syndrome are regularly cured of duodenal gastrinoma after parathyroid surgery, and might cause MEN1 syndrome phenocopies in MEN1-mutation negative individuals with parathyroid adenomas. This perspective on the pathogenesis of the gastrin-cell hyperplasia and neoplasia sequence sheds new light on tumorigenic mechanisms in neuroendocrine tumors and might open up novel areas of gastrinoma research. It may also shift focus in the treatment of MEN1 syndrome related gastrinoma to biochemical prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-21-0073DOI Listing
March 2021

Genome Methylation Accurately Predicts Neuroendocrine Tumor Origin: An Online Tool.

Clin Cancer Res 2021 Mar 22;27(5):1341-1350. Epub 2020 Dec 22.

Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Purpose: The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors.

Experimental Design: Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort ( = 198 cases).

Results: NEN-ID predicted the origin of tumor samples with high accuracy (>95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community.

Conclusions: This DNA methylation-based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-3281DOI Listing
March 2021

The Impact of Clinical and Pathological Features on Intraductal Papillary Mucinous Neoplasm Recurrence After Surgical Resection: Long-Term Follow-Up Analysis.

Ann Surg 2020 Nov 17. Epub 2020 Nov 17.

Department of Surgery, Hepatobiliary and Pancreatic Surgery Section of the Division of Surgical Oncology, Johns Hopkins Hospital, Baltimore, MD.

Objective: This study aimed to identify risk factors for recurrence after pancreatic resection for intraductal papillary mucinous neoplasm (IPMN).

Summary Background Data: Long-term follow-up data on recurrence after surgical resection for IPMN are currently lacking. Previous studies have presented mixed results on the role of margin status in risk of recurrence after surgical resection.

Methods: A total of 126 patients that underwent resection for noninvasive IPMN were followed for a median of 9.5 years. Dedicated pathological and radiological reviews were performed to correlate clinical and pathological features (including detailed pathological features of the parenchymal margin) with recurrence after surgical resection. In addition, in a subset of 32 patients with positive margins, we determined the relationship between the margin and original IPMN using driver gene mutations identified by next-generation sequencing.

Results: Family history of pancreatic cancer and high-grade IPMN was identified as risk factors for recurrence in both uni- and multivariate analysis (adjusted hazard ratio 3.05 and 1.88, respectively). Although positive margin was not significantly associated with recurrence in our cohort, the size and grade of the dysplastic focus at the margin were significantly correlated with recurrence in margin-positive patients. Genetic analyses showed that the neoplastic epithelium at the margin was independent from the original IPMN in at least 9 of 32 cases (28%). The majority of recurrences (74%) occurred after 3 years, and a significant minority (32%) occurred after 5 years.

Conclusion: Sustained postoperative surveillance for all patients is indicated, particularly those with risk factors such has family history and high-grade dysplasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SLA.0000000000004427DOI Listing
November 2020

The Management of Neuroendocrine Tumors of the Lung in MEN1: Results From the Dutch MEN1 Study Group.

J Clin Endocrinol Metab 2021 Jan;106(2):e1014-e1027

Department of Endocrine Oncology, University Medical Center Utrecht, GA Utrecht, The Netherlands.

Introduction: Multiple endocrine neoplasia type 1 (MEN1)-related neuroendocrine tumors (NETs) of the lung are mostly indolent, with a good prognosis. Nevertheless, cases of aggressive lung NET do occur, and therefore the management of individual patients is challenging.

Aim: To assess tumor growth and the survival of patients with MEN1-related lung NETs at long-term follow-up.

Methods: The population-based Dutch MEN1 Study Group database (n = 446) was used to identify lung NETs by histopathological and radiological examinations. Tumor diameter was assessed. Linear mixed models and the Kaplan-Meier method were used for analyzing tumor growth and survival. Molecular analyses were performed on a lung NET showing particularly aggressive behavior.

Results: In 102 patients (22.9% of the total MEN1 cohort), 164 lesions suspected of lung NETs were identified and followed for a median of 6.6 years. Tumor diameter increased 6.0% per year. The overall 15-year survival rate was 78.0% (95% confidence interval: 64.6-94.2%) without lung NET-related death. No prognostic factors for tumor growth or survival could be identified. A somatic c.3127A > G (p.Met1043Val) PIK3CA driver mutation was found in a case of rapid growing lung NET after 6 years of indolent disease, presumably explaining the sudden change in course.

Conclusion: MEN1-related lung NETs are slow growing and have a good prognosis. No accurate risk factors for tumor growth could be identified. Lung NET screening should therefore be based on well-informed, shared decision-making, balancing between the low absolute risk of an aggressive tumor in individuals and the potential harms of frequent thoracic imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa800DOI Listing
January 2021

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Nat Commun 2020 08 14;11(1):4085. Epub 2020 Aug 14.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428044PMC
August 2020

The decisive role of molecular pathology in presumed somatic metastases of type II testicular germ cell tumors: report of 2 cases.

Diagn Pathol 2020 Jul 25;15(1):99. Epub 2020 Jul 25.

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Molecular diagnostics can be decisive in the differential diagnosis between a somatic metastasis of type II testicular germ cell tumor (TGCT) or a second primary carcinoma. This is in line with recent recommendations from the International Society of Urological Pathology, based on an international survey which showed that molecular testing is currently only performed by a minority of urological pathologists.

Case Presentations: This case report illustrates the necessity of molecular testing in two patients with a history of type II TGCT and a metastatic (retro) peritoneal carcinoma years later. The genetic hallmark of type II TGCT, chromosome 12p gain, was studied by fluorescence in situ hybridization and whole genome methylation profiling in case 1, and by single nucleotide polymorphism (SNP)-array in case 2. Next generation sequencing (NGS) was used to further explore clonality between the primary TGCT and peritoneal metastasis in case 2. In case 1, chromosome 12p gain was found in the primary type II TGCT and in the acinar cell carcinoma of the metastatic malignancy. In case 2, SNP array showed 12p gain in the epithelial component of the primary teratomatous TGCT but not in the peritoneal adenocarcinoma. Furthermore, NGS showed no mutations in the primary teratomatous TGCT but a KRAS and GNAS mutation in the peritoneal adenocarcinoma, suggestive of an appendicular origin.

Conclusions: Without the molecular data, both cases would have been regarded as a metastatic TGCT with development of somatic-type malignancy, which appeared a wrong diagnosis for case 2. These cases demonstrate the importance of molecular methods as an adjunct in today's pathology practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13000-020-01011-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382836PMC
July 2020

Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas.

Endocr Pathol 2020 Jun;31(2):108-118

Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12022-020-09611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250793PMC
June 2020

Assessment of ARX expression, a novel biomarker for metastatic risk in pancreatic neuroendocrine tumors, in endoscopic ultrasound fine-needle aspiration.

Diagn Cytopathol 2020 Apr 17;48(4):308-315. Epub 2019 Dec 17.

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: The transcription factors ARX and PDX1, and alternative lengthening of telomeres (ALT) were recently described as prognostic markers for resected non-functional pancreatic neuroendocrine tumors (PanNETs). ALT positive tumors with ARX expression relapse most often. Currently, tumor size is the only preoperative marker used to decide whether or not to operate, thus additional preoperative prognostic markers are needed. Therefore, it is critical to assess the performance of these biomarkers on preoperative cytologic specimens.

Methods: Endoscopic fine-needle aspiration cellblock material and corresponding surgical specimens of 13 patients with PanNETs were assessed for histology, immunohistochemical staining of ARX, PDX1, Synaptophysin, Ki67, and telomere-specific fluorescence in situ hybridization to detect ALT, and then associated with clinicopathological features. Scoring for ARX and PDX1 was performed blinded by two independent observers.

Results: Of the 13 surgical specimens, 8 were ARX+/PDX1-, 2 ARX-/PDX1+, and 3 ARX+/PDX1+. Concordance between cytologic and surgical specimens for ARX protein expression was 100%, whereas concordance for PDX1, ALT, and WHO tumor grade was 85%, 91%, and 73%, respectively. There was a perfect inter-observer agreement in ARX and PDX1 scoring.

Conclusion: ARX can reliably be determined in cytologic specimens and has low inter-observer variability. For cytology, false-positive PDX1 expression was observed, possibly due to contamination or sampling, while ALT had a false-negative case due to incomplete sampling. As previously observed, tumor grade is underestimated in cytologic specimens. Thus, ARX and ALT are the most promising markers to predict metastatic behavior in PanNETs, thereby warranting further validation in larger studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dc.24368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079001PMC
April 2020

Clear cell chondrosarcoma in Von Hippel-Lindau disease.

Fam Cancer 2020 01;19(1):41-45

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

A diagnosis of clear cell chondrosarcoma of the ulna was made in a patient with Von Hippel-Lindau disease (VHL). After surgery, genetic analysis of the tumor tissue showed loss of heterozygosity at the VHL gene locus. Immunohistochemical analysis confirmed loss of expression of the VHL protein in the tumor cells. In addition, abundant Cyclin D1 expression in the tumor was observed. Chondrosarcoma has been described before in a VHL patient and VHL protein expression has been correlated to tumor grade in a series of sporadic chondrosarcomas. In this report, we show that clear cell chondrosarcoma may be a rare but canonical VHL manifestation through a cell-autonomous mechanism involving somatic loss-of-heterozygosity of the VHL tumor suppressor gene. We discuss the relevance of this observation with regard to the pathogenesis of clear cell chondrosarcoma in the context of VHL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-019-00149-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026311PMC
January 2020

Well-differentiated Pancreatic Neuroendocrine Tumor in a Patient With Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM).

Am J Surg Pathol 2019 09;43(9):1297-1302

Departments of Pathology.

Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM), which is associated with an increased risk for pancreatic ductal adenocarcinoma and melanoma. CDKN2A is somatically inactivated in multiple neoplasms, raising the possibility that, although the data are not conclusive, germline CDKN2A mutation may also impose an increased risk for other neoplasms. We present a patient with a CDKN2A germline mutation (p16-Leiden mutation) and mosaicism for neurofibromatosis type 2, who presented with a small asymptomatic pancreatic lesion, detected during endoscopic ultrasound screening of the pancreas. After resection, the lesion was found to be a well-differentiated pancreatic neuroendocrine tumor (PanNET). Molecular analysis of the tumor showed somatic loss of the second allele, supporting a causal relation of the PanNET to the underlying FAMMM syndrome. Recent data, showing the association between certain single-nucleotide polymorphisms in the CDKN2A gene and an increased incidence for PanNET, further support a role for germline CDKN2A alterations in PanNET risk. We conclude that PanNETs can be a phenotypic expression of FAMMM syndrome. This can have implications for screening and for the diagnosis of pancreatic neoplasms in carriers of germline CDKN2A mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001314DOI Listing
September 2019

Pseudomyxoma Peritonei After a Total Pancreatectomy for Intraductal Papillary Mucinous Neoplasm With Colloid Carcinoma in Lynch Syndrome.

Pancreas 2019 01;48(1):135-138

Radiology, St Antonius Hospital, Nieuwegein, the Netherlands.

We report a case of pseudomyxoma peritonei (PMP) arising in a 62-year-old male patient with Lynch syndrome (LS). The patient's medical history included an adenocarcinoma of the colon for which a right hemicolectomy was performed and a pancreatectomy due to an intraductal papillary mucinous neoplasm (IPMN) with invasive colloid carcinoma. It was considered that the PMP could be a metastasis of the earlier colonic or pancreatic carcinoma. The pancreatic carcinoma, colon carcinoma, and PMP tissues were examined, and immunohistochemical and molecular analyses were performed to determine the PMP origin. Histopathologic examination revealed morphological similarities with the pancreatic colloid carcinoma, and further immunohistochemical and molecular analyses, including a shared GNAS mutation, confirmed the pancreatic origin of the PMP. In conclusion, this is a unique case of a patient with LS presenting with PMP originating from an IPMN with invasive colloid carcinoma, several years after pancreatectomy. The present case has important diagnostic implications. The IPMN should be considered as a rare extracolonic manifestation of LS, and pancreatic carcinoma origin should be considered in patients presenting with PMP. This case report highlights the added value of molecular diagnostics in daily pathology practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPA.0000000000001201DOI Listing
January 2019

Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis.

Histopathology 2017 Mar 13;70(4):549-557. Epub 2016 Dec 13.

Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.

Aims: Gastric pyloric gland adenomas (PGAs) are rare epithelial polyps that are found more commonly in autoimmune atrophic gastritis and familial adenomatous polyposis (FAP). Little is known about the morphology and genetics of PGAs in FAP. PGAs in FAP are studied morphologically and genetically. Findings in FAP-associated PGAs are compared to sporadic PGAs and related lesions such as oxyntic gland adenoma (OGA) to increase our understanding of these rare polyps.

Methods And Results: Seven PGAs and 18 fundic gland polyps (FGPs) from FAP patients were collected. KRAS and GNAS mutations were determined in six PGAs and 18 FGPs. Immunohistochemistry was applied on five PGAs to provide further confirmation of the histological subtypes and genetic alterations. Morphology of all PGAs was studied and compared to literature on sporadic PGAs and related lesions. All successfully sequenced PGAs (six of six) carried GNAS mutations and half of the successfully sequenced PGAs carried a KRAS mutation (three of six). Nuclear β-catenin was seen only in one PGA with focal high-grade dysplasia. Morphologically, PGAs in FAP showed overlapping features with OGA.

Conclusion: Familial adenomatous polyposis-associated PGAs have a similar genetic background as sporadic PGAs, i.e. KRAS and GNAS mutation. Based on morphological findings in FAP associated PGAs, it is hypothesized that PGAs and OGAs are closely related lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.13105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300963PMC
March 2017

Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis.

Hum Pathol 2016 10 21;56:93-100. Epub 2016 Jun 21.

Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address:

Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins. We identified aberrant Menin expression in 14 of 19 (74%) microadenomas, suggesting that alterations in Menin, at least a subset of which was likely due to somatic mutation, are early events in pancreatic neuroendocrine tumorigenesis. In contrast, none of the microadenomas met criteria for the alternative lengthening of telomeres phenotype (ALT) based on telomere FISH, a phenotype that is strongly correlated to ATRX or DAXX mutations. Two of 13 microadenomas (15%) were noted to have very rare abnormal bright telomere foci on FISH, suggestive of early ALT, but these lesions did not show loss of ATRX or DAXX protein expression by immunohistochemistry. Overall, these data suggest that loss of Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and ALT are relatively late events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2016.06.006DOI Listing
October 2016

Surgical and molecular pathology of pancreatic neoplasms.

Diagn Pathol 2016 Jun 7;11(1):47. Epub 2016 Jun 7.

Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Background: Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance.

Main Body: Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment.

Conclusion: This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13000-016-0497-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897815PMC
June 2016

Pancreatic adenocarcinoma pathology: changing "landscape".

J Gastrointest Oncol 2015 Aug;6(4):358-74

1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Pancreatic cancer is a devastating disease. At time of diagnosis the disease is usually advanced and only a minority of patients are eligible for surgical resection. The overall 5-year survival is 6%. However, survival of patients with early stage pancreatic cancer is significantly better. To improve the prognosis of patients with pancreatic cancer, it is essential to diagnose and treat pancreatic cancer in the earliest stage. Prevention of pancreatic cancer by treating noninvasive precursor lesions just before they invade tissues can potentially lead to even better outcomes. Pancreatic carcinogenesis results from a stepwise progression in which accumulating genetic alterations drive neoplastic progression in well-defined precursor lesions, ultimately giving rise to an invasive adenocarcinoma. A thorough understanding of the genetic changes that drive pancreatic carcinogenesis can lead to identification of biomarkers for early detection and targets for therapy. Recent next-generation sequencing (NGS) studies have shed new light on our understanding of the natural history of pancreatic cancer and the precursor lesions that give rise to these cancers. Importantly, there is a significant window of opportunity for early detection and treatment between the first genetic alteration in a cell in the pancreas and development of full-blown pancreatic cancer. The current views on the pathology and genetics of pancreatic carcinogenesis that evolved from studies of pancreatic cancer and its precursor lesions are discussed in this review.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3978/j.issn.2078-6891.2015.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502163PMC
August 2015