Pancreatic carcinoma, its variants and precursors: Overview of the current WHO classification.

Pancreatic carcinoma is a relatively common malignant tumor with increasing incidence and mortality. The tumor is usually diagnosed at an advanced stage and generally has a poor prognosis, with only 5% of patients surviving 5 years from the time of diagnosis. The stage of the disease at the time of diagnosis is a crucial factor for the prognosis; 25% of patients with localized tumors survive 3 years from diagnosis, compared to only 1% of those with generalized tumors. Radical surgical removal of the tumor (partial or total pancreatectomy) is a key factor in improving survival. Therefore, the topic is highly relevant to surgeons. Statistics on pancreatic carcinoma mainly focus on ductal adenocarcinoma, which is the most common and least favorable malignant tumor of the pancreas. This review focuses on ductal adenocarcinoma, its variants, and precancerous lesions. The article summarizes information from the latest WHO classification of 2019, which was released 11 years after the previous edition. Compared to the previous version, this new WHO classification introduced rather minor changes in the field of ductal adenocarcinoma. The delineation of rare variants of ductal adenocarcinoma is justified based on genetic and morphological similarities and clinical relevance, as individual subtypes significantly differ in prognosis. The article also includes a description of macroscopic and microscopic precursors of ductal adenocarcinoma and their definitions. Genetic and immunohistochemical differential diagnostic aspects are briefly discussed, as these are more relevant to pathologists than to surgeons.

PanIN or IPMN? Redefining Lesion Size in 3 Dimensions.

Pancreatic ductal adenocarcinoma (PDAC) develops from 2 known precursor lesions: a majority (∼85%) develops from pancreatic intraepithelial neoplasia (PanIN), and a minority develops from intraductal papillary mucinous neoplasms (IPMNs). Clinical classification of PanIN and IPMN relies on a combination of low-resolution, 3-dimensional (D) imaging (computed tomography, CT), and high-resolution, 2D imaging (histology). The definitions of PanIN and IPMN currently rely heavily on size. IPMNs are defined as macroscopic: generally >1.0 cm and visible in CT, and PanINs are defined as microscopic: generally <0.5 cm and not identifiable in CT. As 2D evaluation fails to take into account 3D structures, we hypothesized that this classification would fail in evaluation of high-resolution, 3D images. To characterize the size and prevalence of PanINs in 3D, 47 thick slabs of pancreas were harvested from grossly normal areas of pancreatic resections, excluding samples from individuals with a diagnosis of an IPMN. All patients but one underwent preoperative CT scans. Through construction of cellular resolution 3D maps, we identified >1400 ductal precursor lesions that met the 2D histologic size criteria of PanINs. We show that, when 3D space is considered, 25 of these lesions can be digitally sectioned to meet the 2D histologic size criterion of IPMN. Re-evaluation of the preoperative CT images of individuals found to possess these large precursor lesions showed that nearly half are visible on imaging. These findings demonstrate that the clinical classification of PanIN and IPMN fails in evaluation of high-resolution, 3D images, emphasizing the need for re-evaluation of classification guidelines that place significant weight on 2D assessment of 3D structures.

Is it resectable? A survey regarding tumor classification and vascular involvement.

INTRODUCTION: The anatomic location of the pancreas can result in involvement of major vasculature, which may act as a contraindication to resection. Several classification systems have been developed. We sought to discover the variations in the HPB community determining PDAC resectability. METHODS: The multiple-choice survey was distributed to all full members of the IHPBA. Questions were asked regarding demographics and clinical scenarios regarding tumor resectability. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. Most practiced in either Asia (n = 57,35.9%), North America (n = 52,32.7%), or Europe (n = 32,20.1%). Classification systems used to determine resectability were: NCCN (n = 42,26.3%), JPS (n = 35,21.9%), International consensus (n = 33,20.6%), AHPBA/SSO (n = 23,14.4%), Alliance (n = 3,1.9%), and other/no-classification (n = 23,14.5%). There was significant variation in the frequency of the most common answer within the scenarios (84.7%-33.5%). Participant concordance with their stated classification system found a median rate of 62.5%. Participant decision of tumor resectability was not dependent on their adopted classification system. CONCLUSION: When classifying PDAC resectability, there is significant variation between surgeons as to how they would classify a specific tumour, independent of the classification system they use. In addition, surgeons do not show high concordance with the definitions within that classification system.

An Illustrated Review of the Recent 2019 World Health Organization Classification of Neuroendocrine Neoplasms: A Radiologic and Pathologic Correlation.

ABSTRACT: Recent advances in molecular pathology and an improved understanding of the etiology of neuroendocrine neoplasms (NENs) have given rise to an updated World Health Organization classification. Since gastroenteropancreatic NENs (GEP-NENs) are the most common forms of NENs and their incidence has been increasing constantly, they will be the focus of our attention. Here, we review the findings at the foundation of the new classification system, discuss how it impacts imaging research and radiological practice, and illustrate typical and atypical imaging and pathological findings. Gastroenteropancreatic NENs have a highly variable clinical course, which existing classification schemes based on proliferation rate were unable to fully capture. While well- and poorly differentiated NENs both express neuroendocrine markers, they are fundamentally different diseases, which may show similar proliferation rates. Genetic alterations specific to well-differentiated neuroendocrine tumors graded 1 to 3 and poorly differentiated neuroendocrine cancers of small cell and large-cell subtype have been identified. The new tumor classification places new demands and creates opportunities for radiologists to continue providing the clinically most relevant report and on researchers to design projects, which continue to be clinically applicable.

Molecular Classification of Gastrointestinal and Pancreatic Neuroendocrine Neoplasms: Are We Ready for That?

In the last two decades, the increasing availability of technologies for molecular analyses has allowed an insight in the genomic alterations of neuroendocrine neoplasms (NEN) of the gastrointestinal tract and pancreas. This knowledge has confirmed, supported, and informed the pathological classification of NEN, clarifying the differences between neuroendocrine carcinomas (NEC) and neuroendocrine tumors (NET) and helping to define the G3 NET category. At the same time, the identification genomic alterations, in terms of gene mutation, structural abnormalities, and epigenetic changes differentially involved in the pathogenesis of NEC and NET has identified potential molecular targets for precision therapy. This review critically recapitulates the available molecular features of digestive NEC and NET, highlighting their correlates with pathological aspects and clinical characteristics of these neoplasms and revising their role as predictive biomarkers for targeted therapy. In this context, the feasibility and applicability of a molecular classification of gastrointestinal and pancreatic NEN will be explored.

Evidence for molecular subtyping in pancreatic ductal adenocarcinoma: a systematic review.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) patients exhibit varied responses to multimodal therapy. RNA gene sequencing has unravelled distinct tumour biology subtypes, forming the focus of this review exploring its impact on survival outcomes. METHODS: A systematic search across PubMed, Medline, Embase, and CINAHL databases targeted studies assessing long-term overall and disease-free survival in PDAC patients with molecular subtyping. RESULTS: Fifteen studies including 2731 patients were identified. Molecular subtyping was performed by RNA sequencing and Immunohistochemistry in 14 studies and by Mass Spectrometry in 1 study. Two main tumour subtypes were identified (classical and basal-like or squamous) with basal like associated with poorer outcomes. Further subtypes were identified in individual studies. Superior survival was seen with classical subtype in all other analyses that compared the classical and basal subtypes. High risk stromal subtypes were identified on further analysis of the stroma and were associated with a worse survival independent of the tumour subtype. CONCLUSION: Molecular subtyping of PDAC specimens can identify patients with high-risk tumour biology and poor survival outcomes. Routine subtyping is limited by the cost of RNA sequencing and the volume of raw data generated which has made its translation into routine clinical practice difficult.

DNA Methylation Profiling Enables Accurate Classification of Nonductal Primary Pancreatic Neoplasms.

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.

KRAS mutations in pancreatic cancer: could we talk about a risk factor for the development of thromboembolic phenomena?

The oncogenic KRAS mutation is associated with increased tissue factor expression and thus hypercoagulability. In this regard, numerous studies published in the last decade have shown that KRAS mutations are an important risk factor for the development of thromboembolic phenomena in neoplasms of the digestive tract, such as colorectal cancer. On the other hand, some recently published studies suggest that KRAS mutations are also associated with an increased risk of developing thromboembolic phenomena in pancreatic cancer. Based on these premises, we have conducted a single-centre retrospective study on a cohort of patients with pancreatic cancer. Our aim is to demonstrate whether there is an association between the presence of KRAS mutations in our cohort of pancreatic cancer patients and an increased risk of developing thromboembolic phenomena. (AU)

Cáncer de páncreas, un reto al sistema sanitario / Pancreatic cancer, a challenge to the health system

Fundamento: el cáncer de páncreas representa un serio problema de salud, por su elevada mortalidad. Un porciento considerable del diagnóstico de la enfermedad se hace en un estadio avanzado.Objetivo: actualizar los conocimientos sobre cáncer de páncreas, síntomas, signos de alarma, para lograr un umbral de sospecha más alto, dirigir al enfermo por los circuitos de atención resolutivos, y un diagnóstico más temprano. Métodos: la búsqueda de la información se realizó en el periodo de un mes, enero de 2018, se emplearon los siguientes descriptores: cáncer de páncreas, epidemiología, factores de riesgo, síntomas, signos. A partir de la información obtenida se realizó una revisión bibliográfica de 213 artículos publicados en las bases de datos MEDLINE, LILACS, BVS, Pubmed, SciELO Cuba, SciELO regional. El 62 porciento de los últimos cinco años, de ellas 54,8 porciento de los años 2017 y 2018.Desarrollo: se describen aspectos como la prevalencia y mortalidad del cáncer de páncreas según regiones del mundo, factores de riesgos, principales signos y síntomas de sospecha. Se hace referencia al uso de los marcadores tumorales. Sobrepasa el interés de este artículo aspectos del tratamiento y estadio clínico, muy específicos una vez realizado el diagnóstico. Conclusiones: la ausencia de síntomas específicos tempranos y el diagnóstico tardío del cáncer de páncreas hacen que los pacientes no tengan la oportunidad de recibir el tratamiento adecuado. Promover la sensibilización, tanto dirigida a profesionales sanitarios como población general, sobre las ventajas de la detección precoz, es una prioridad. Solo la alta sospecha clínica, la sensibilización de los profesionales de la atención y la conducción del paciente por el sistema pueden lograr un diagnóstico en fases tempranas de esta enfermedad(AU)

Background: pancreatic cancer represents a serious health problem due to its high mortality. A considerable percentage of the diagnoses is late, and advanced the disease. Objective: to update knowledge about pancreatic cancer, symptoms, warning signs, and an earlier diagnosis of pancreatic cancer. Methods: the search for the information was made in the period of one month, January 2018, the following descriptors were used: pancreatic cancer, epidemiology, risk factors, symptoms, signs. Based on the information obtained, a bibliographic review of 213 articles published in MEDLINE, LILACS, VHL, Pubmed, SciELO Cuba, SciELO regional databases was carried out. It was used 47 citations, 12 review articles, four doctoral theses, four international medical consensus conferences on pancreatic cancer, six methodological articles, 14 theoretical articles, two communications, five editorials and online press articles. 62 percent of the last five years, of them 54.8 percent of the years 2017 and 2018. Development: it is described aspects such as the prevalence and mortality of pancreatic cancer according to regions of the world, risk factors, main signs and symptoms of suspicion. Reference is made to the use of tumor markers. The interest of this article surpasses aspects of treatment and staging, very specific once the diagnosis has been made. Conclusions:the absence of specific early symptoms and the late diagnosis of pancreatic cancer mean that patients do not have the opportunity to receive adequate treatment. Promoting awareness, both directed to health professionals and the general population, about the advantages of early detection is a priority. Only the high clinical suspicion, the sensitization of the care professionals and the conduction of the patient through the system can achieve a diagnosis in early stages of this disease(AU)

Diagnosis and staging of pancreatic ductal adenocarcinoma

The management of pancreatic ductal adenocarcinoma (PDAC) is a major public health concern worldwide. Currently, most PDAC patients are diagnosed in advanced stages. The signs and symptoms of the disease, except for jaundice, are non-specific. Thus, the current challenge is to identify earlier those individuals for whom specific screening tools and specific treatments would be beneficial. On the basis of the recommendations of the group of experts of multiple medical specialties of the GALLgo Project, the patients with PDAC should be managed by a multidisciplinary team to assess the personal and family history, the best diagnostic and staging procedures and consider all important aspects for treatment decisions. In this article, the group of experts proposes strategies to shorten the diagnosis times in PDAC patients (AU)

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Validation of Group B Borderline Resectable Pancreatic Cancer: Retrospective Analysis

BACKGROUND/AIMS: Among borderline resectable pancreatic cancer (BRPC), group B BRPC patients have findings that are suggestive but not diagnostic of metastasis. In this study, we attempted to validate whether group B could truly be categorized as a borderline resectable group. METHODS: We placed the BRPC patients into group A or group B. The survival outcomes were compared between the groups. RESULTS: A total of 53 patients with pancreatic adenocarcinoma was classified as either group A or B borderline resectable. In group A, 23 (60.5%) of 38 patients underwent pancreatectomy after concurrent chemoradiotherapy or chemotherapy, but in group B, only five (33.3%) of 15 patients underwent pancreatectomy, mainly because of the progression of suspected distant metastasis. There was a significant difference in overall survival (OS) between group A and B patients (median OS, 21.2 months vs 10.2 months, respectively; p=0.007). Of the patients who underwent pancreatectomy, group B had a higher recurrence rate compared to group A (recurrence rate: 11 of 23 patients [47.8%] vs five of five patients [100%], respectively; p=0.033). CONCLUSIONS: This report is the first to validate the definition of BPRC. Group B had much worse outcomes, and whether group B BRPC can be categorized as BRPC together with group A is questionable.

Pancreatic Tumors: Emphasis on CT Findings and Pathologic Classification

Pancreatic tumors can be classified by their morphologic features on CT. The subtypes include solid tumors, mixed cystic and solid lesions, unilocular cysts, multilocular cystic lesions, and microcystic lesions. Endoscopic US and MRI can provide detailed information for classifying pancreatic lesions. Each subtype has different kinds of tumors and malignant potential, thus the classification can be useful for a better differential diagnosis and treatment planning. For this purpose, we suggest an appropriate modified classification system by using the imaging features of pancreatic tumors with an emphasis on CT findings and illustrate various findings of typical and atypical manifestations.

Primary Pancreatic Lymphoma in Korea-A Single Center Experience

The aim of this study was to report a single center experience of primary pancreatic lymphoma (PPL) in Korea. We analyzed the clinicopathological data from four PPL patients (three male, median age 36 yr) diagnosed from 1997 to 2007 at Seoul National University Hospital. The diagnoses were: diffuse large B cell lymphoma (n=2), Ki-1 (+) anaplastic large cell lymphoma (n=1), and Burkitt lymphoma (n=1). Presenting symptoms and signs were: abdominal pain (n=4), pancreatitis (n=2), weight loss (n=2) and abdominal mass (n=1). No patient underwent surgery. The Ann Arbor stages of the patients were: IEA (n=1), IIEA (n=1), and IVEB (n=2). Two patients underwent treatment. The stage IEA patient underwent chemotherapy and radiation therapy that resulted in a complete remission. The stage IVEB patient who underwent chemotherapy relapsed. This patient underwent subsequent peripheral blood stem cell transplantation and is alive at 30 months. Two patients (stages IVEB and IIEA) without treatment died at 0.8 and 7.0 months, respectively. For PPL patients, chemotherapy-based treatment, and addition of radiation therapy, if possible, may offer good prognosis.

Tumores endócrinos del páncreas / Endocrine tumors of the pancreas

Multiple endocrine neoplasia (MEN) is a rare familial disorder that affects multiple endocrine organs. it is inherited in an autosomal dominant pattern with variable penetrance. There are two distinct types of MEN. Dominantly inherited neoplasia are believed to occur from the recessive loss of tumor suppressor gene function. The first mutational event affects the germ cell, is hereditary, and predisposes to neoplasia. Because tumors occur in multiple organs in MEN, the second mutational evento probably occurs in common precursor cells, such as the amine precursor uptake and decarboxylation cells (APUD). The gene locus for tupe 1 MEN has been mapped to cromosome 11q. Type 1 organs affected: parathyroids, pancreas and pituitary. The gene locus for type 2 MEN is thought to be located for chromosome 10, (other organs). Fifty to 60 % of patients with type 1 MEN have pancreaticislet cell tumors. Insulinomas are tumors that originate in the beta cells of the islets of Langerhans, which compose the APUD system, the meaning of which is: A=Amino, P=Precursor, U=Uptake, D=Decarboxylation. The cells fo the APUD system have common cytochemical characteristics with the ability to secret polypeptides and amines. Symptoms are related to the peptide secreted by the tumor, and some tumors can produce multiple peptides. Gastrinomas comprise about 60 % of type 1 MEN-associated islet cell tumors. Gastric acid hypersecretion results from excess gstrin secretion and causes multiple gastric and duodenal ulcers (Zollinger-Ellison syndrome). The author describe an experience with this pathology with special reference to diagnostic methods, treatment, follow-up, laboratory studies and localization of the tumor.

Tumores endócrinos del páncreas / Endocrine tumors of the pancreas

Multiple endocrine neoplasia (MEN) is a rare familial disorder that affects multiple endocrine organs. it is inherited in an autosomal dominant pattern with variable penetrance. There are two distinct types of MEN. Dominantly inherited neoplasia are believed to occur from the recessive loss of tumor suppressor gene function. The first mutational event affects the germ cell, is hereditary, and predisposes to neoplasia. Because tumors occur in multiple organs in MEN, the second mutational evento probably occurs in common precursor cells, such as the amine precursor uptake and decarboxylation cells (APUD). The gene locus for tupe 1 MEN has been mapped to cromosome 11q. Type 1 organs affected: parathyroids, pancreas and pituitary. The gene locus for type 2 MEN is thought to be located for chromosome 10, (other organs). Fifty to 60 % of patients with type 1 MEN have pancreaticislet cell tumors. Insulinomas are tumors that originate in the beta cells of the islets of Langerhans, which compose the APUD system, the meaning of which is: A=Amino, P=Precursor, U=Uptake, D=Decarboxylation. The cells fo the APUD system have common cytochemical characteristics with the ability to secret polypeptides and amines. Symptoms are related to the peptide secreted by the tumor, and some tumors can produce multiple peptides. Gastrinomas comprise about 60 % of type 1 MEN-associated islet cell tumors. Gastric acid hypersecretion results from excess gstrin secretion and causes multiple gastric and duodenal ulcers (Zollinger-Ellison syndrome). The author describe an experience with this pathology with special reference to diagnostic methods, treatment, follow-up, laboratory studies and localization of the tumor.(AU)

Diagnóstico diferencial de las lesiones quísticas del páncreas / No disponible

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Neoplasias císticas do pâncreas / Cystic neoplasms of the pancreas

Os autores fazem uma revisão sobre neoplasias císticas do pâncreas , abrangendo sua classificação aspectos clinico- cirúrgicos diagnostico , assim como algoritmos de tratamento, seguimento e prognóstico

Neoplasias quísticas del páncreas. Manejo diagnóstico y terapéutico / cystic neoplasms of the pancreas. Diagnostic and therapeutic management

El manejo de las lesiones quísticas del páncreas interesa tanto al cirujano general y pancreático como a los especialistas en otras disciplinas: gastroenterología, medicina interna, endoscopia, radiología, anatomía patológica, etc. La mayoría de estas lesiones son seudoquistes inflamatorios. Las neoplasias quísticas suponen sólo un 10% del total de las lesiones quísticas del páncreas y un 1% de los tumores pancreáticos. El diagnóstico preoperatorio es crucial, dadas las diferencias en la historia natural del espectro de las lesiones: benignas, malignas y borderline. El cistadenoma seroso es una lesión benigna que no precisa resección quirúrgica, salvo cuando es sintomática. Las neoplasias mucinosas son lesiones premalignas que requieren mayoritariamente resección pancreática. A pesar de los avances en las técnicas de imagen, el diagnóstico definitivo se establece únicamente tras el estudio histológico de la pieza de resección. El riesgo que comporta la cirugía pancreática es un problema asociado al manejo apropiado de estos pacientes (AU)

Management of the cystic lesions of the pancreas is of interest to general and pancreatic surgeons and physicians of other disciplines: gastroenterology, internal medicine, endoscopy, radiology, pathology, etc. The majority of cystic lesions are inflammatory pseudo-cysts. Cystic neoplasms represents only 10%of cystic lesions of the pancreas and 1% of pancreatic tumours. Preoperative diagnosis is crucial given the differences in natural history of the spectrum of benign, malignant, and borderline lesions. Serous cystadenoma is a benign lesion that requires non-surgical management if there are no symptoms. Mucinous neoplasms are premalignant lesions that mainly require pancreatic resection. Despite improved radiographic imaging techniques, definitive diagnosis is only made after studying the resection sample. The pancreatic surgical risk isa problem for the appropriate management of these patients (AU)

Doença arterial obstrutiva periférica agravada pela utilização de gemcitabina para tratamento de neoplasia pancreática: relato de caso e revisão da literatura / Peripheral obstructive arterial disease worsened by use of gemcitabine for the treatment of pancreatic cancer: case report and review of the literature / Peripheral obstructive arterial disease worsened by use of gemcitabine for the treatment of pancreatic cancer: case report and review of the literature

Este estudo tem por objetivo relatar um caso de isquemia crítica de membro inferior associada a quimioterapia com gemcitabina. O relato descreve o caso de um paciente de 68 anos submetido a duodenopancreatectomia devido a tumor no pâncreas. Um mês depois da operação, o paciente realizou quatro sessões de quimioterapia com gemcitabina, durante um mês. Após 30 dias, o paciente desenvolveu sintomas de doença arterial obstrutiva periférica, e duas semanas depois, isquemia crítica do membro inferior direito. O exame por imagem demonstrou doença arterial difusa associada à oclusão femoropoplítea com reenchimento distal precário. O paciente foi submetido a uma tentativa de revascularização que, devido às condições locais, foi malsucedida, resultando na amputação do membro no nível da coxa.

We report a case of lower limb critical ischemia associated with chemotherapy with gemcitabine. This report presents a case of a 68-year-old man who underwent pancreatoduodenectomy due to pancreas tumor. One month later, the patient was submitted to four chemotherapy sessions with gemcitabine for 1 month. In addition, 30 days later he developed symptoms of peripheral arterial obstructive disease, and critical ischemia of the right lower limb 2 weeks later. An imaging study showed diffuse arterial disease associated with femoropopliteal occlusion and poor distal bed. The patient was submitted to a revascularization procedure, which was unsuccessful due to local conditions, resulting in above-knee amputation.