Critical considerations for the management of gastrointestinal mixed neuroendocrine non-neuroendocrine neoplasms and pure neuroendocrine carcinomas

Mixed neuroendocrine non-neuroendocrine neoplasms constitute rare tumors that are located mainly in the gastrointestinal(GI)tract and have high degrees of malignancy,and the frequency of these tumors has been increasing.They consist of a neuroendocrine neoplastic component with another component of adenocarcinoma usually and have a dismal prognosis.The rare GI pure neuroendocrine carcinoma is highly aggressive and requires complex and extensive management since a genetic distinction exists between it and GI non-neuroendocrine neoplasms,which are generally slow-growing lesions.The most common GI-mixed neuroendocrine non-neuroendocrine neoplasms are colorectal,followed by gastric,mainly in the gastroesophageal junction.Current imaging modalities of nuclear medicine and radiology play important roles in the accuracy of diagnosis.Liquid biopsy may contribute to early detection and timely diagnosis.Ultrasonography,either endoscopic or abdominal,is a technique that contributes to a diagnosis;additionally,contrast-enhanced ultrasonography is very helpful in followup appointments.Histopathology establishes a definite diagnosis and stage by evaluating the cell differentiation grade and the cell proliferation index Ki67.The genetic profile can be valuable in diagnosis and gene therapy.Surgical resection with wide lymphadenectomy,whenever possible,and adjuvant chemotherapy constitute the main therapeutic management strategies.Targeted therapy and immunotherapy achieve encouraging results.

Trends and hotspots in gastrointestinal neoplasms risk assessment: A bibliometric analysis from 1984 to 2022

BACKGROUND Gastrointestinal neoplasm(GN)significantly impact the global cancer burden and mortality,necessitating early detection and treatment.Understanding the evolution and current state of research in this field is vital.AIM To conducts a comprehensive bibliometric analysis of publications from 1984 to 2022 to elucidate the trends and hotspots in the GN risk assessment research,focusing on key contributors,institutions,and thematic evolution.METHODS This study conducted a bibliometric analysis of data from the Web of Science Core Collection database using the"bibliometrix"R package,VOSviewer,and CiteSpace.The analysis focused on the distribution of publications,contributions by institutions and countries,and trends in keywords.The methods included data synthesis,network analysis,and visualization of international collaboration networks.RESULTS This analysis of 1371 articles on GN risk assessment revealed a notable evolution in terms of research focus and collaboration.It highlights the United States'critical role in advancing this field,with significant contributions from institutions such as Brigham and Women's Hospital and the National Cancer Institute.The last five years,substantial advancements have been made,representing nearly 45%of the examined literature.Publication rates have dramatically increased,from 20 articles in 2002 to 112 in 2022,reflecting intensified research efforts.This study underscores a growing trend toward interdisciplinary and international collaboration,with the Journal of Clinical Oncology standing out as a key publication outlet.This shift toward more comprehensive and collaborative research methods marks a significant step in addressing GN risks.CONCLUSION This study underscores advancements in GN risk assessment through genetic analyses and machine learning and reveals significant geographical disparities in research emphasis.This calls for enhanced global collaboration and integration of artificial intelligence to improve cancer prevention and treatment accuracy,ultimately enhancing worldwide patient care.

Expanding role and scope of artificial intelligence in the field of gastrointestinal pathology

Digital pathology(DP)and its subsidiaries including artificial intelligence(AI)are rapidly making inroads into the area of diagnostic anatomic pathology(AP)including gastrointestinal(GI)pathology.It is poised to revolutionize the field of diagnostic AP.Historically,AP has been slow to adopt digital technology,but this is changing rapidly,with many centers worldwide transitioning to DP.Coupled with advanced techniques of AI such as deep learning and machine learning,DP is likely to transform histopathology from a subjective field to an objective,efficient,and transparent discipline.AI is increasingly integrated into GI pathology,offering numerous advancements and improvements in overall diagnostic accuracy,efficiency,and patient care.Specifically,AI in GI pathology enhances diagnostic accuracy,streamlines workflows,provides predictive insights,integrates multimodal data,supports research,and aids in education and training,ultimately improving patient care and outcomes.This review summarized the latest developments in the role and scope of AI in AP with a focus on GI pathology.The main aim was to provide updates and create awareness among the pathology community.

Prevalence of malignant neoplasms in celiac disease patients-a nationwide United States population-based study

BACKGROUND Celiac disease(CeD)is an autoimmune disorder triggered by the immune response to gluten in genetically predisposed individuals.Recent research has unveiled a heightened risk of developing specific malignant neoplasms(MN)and various malignancies,including gastrointestinal,lymphomas,skin,and others,in individuals with CeD.AIM To investigate the prevalence of MN in hospitalized CeD patients in the United States.METHODS Using data from the National Inpatient Sample spanning two decades,from January 2000 to December 2019,we identified 529842 CeD patients,of which 78128(14.75%)had MN.Propensity score matching,based on age,sex,race,and calendar year,was employed to compare CeD patients with the general non-CeD population at a 1:1 ratio.RESULTS Positive associations were observed for several malignancies,including small intestine,lymphoma,nonmelanoma skin,liver,melanoma skin,pancreas myelodysplastic syndrome,biliary,stomach,and other neuroendocrine tumors(excluding small and large intestine malignant carcinoid),leukemia,uterus,and testis.Conversely,CeD patients exhibited a reduced risk of respiratory and secondary malignancies.Moreover,certain malignancies showed null associations with CeD,including head and neck,nervous system,esophagus,colorectal,anus,breast,malignant carcinoids,bone and connective tissues,myeloma,cervix,and ovary cancers.CONCLUSION Our study is unique in highlighting the detailed results of positive,negative,or null associations between different hematologic and solid malignancies and CeD.Furthermore,it offers insights into evolving trends in CeD hospital outcomes,shedding light on advancements in its management over the past two decades.These findings contribute valuable information to the understanding of CeD’s impact on health and healthcare utilization.

Factors associated with gastrointestinal stromal tumor rupture and pathological risk:A single-center retrospective study

BACKGROUND Gastrointestinal stromal tumor(GIST)is a rare gastrointestinal mesenchymal tumor with potential malignancy.Once the tumor ruptures,regardless of tumor size and mitotic number,it can be identified into a high-risk group.It is of great significance for the diagnosis,treatment,and prognosis of GIST if non-invasive examination can be performed before surgery to accurately assess the risk of tumor.AIM To identify the factors associated with GIST rupture and pathological risk.METHODS A cohort of 50 patients with GISTs,as confirmed by postoperative pathology,was selected from our hospital.Clinicopathological and computed tomography data of the patients were collected.Logistic regression analysis was used to evaluate factors associated with GIST rupture and pathological risk grade.RESULTS Pathological risk grade,tumor diameter,tumor morphology,internal necrosis,gas-liquid interface,and Ki-67 index exhibited significant associations with GIST rupture(P<0.05).Gender,tumor diameter,tumor rupture,and Ki-67 index were found to be correlated with pathological risk grade of GIST(P<0.05).Multifactorial logistic regression analysis revealed that male gender and tumor diameter≥10 cm were independent predictors of a high pathological risk grade of GIST[odds ratio(OR)=11.12,95%confidence interval(95%CI):1.81-68.52,P=0.01;OR=22.96,95%CI:2.19-240.93,P=0.01].Tumor diameter≥10 cm,irregular shape,internal necrosis,gas-liquid interface,and Ki-67 index≥10 were identified as independent predictors of a high risk of GIST rupture(OR=9.67,95%CI:2.15-43.56,P=0.01;OR=35.44,95%CI:4.01-313.38,P<0.01;OR=18.75,95%CI:3.40-103.34,P<0.01;OR=27.00,95%CI:3.10-235.02,P<0.01;OR=4.43,95%CI:1.10-17.92,P=0.04).CONCLUSION Tumor diameter,tumor morphology,internal necrosis,gas-liquid,and Ki-67 index are associated with GIST rupture,while gender and tumor diameter are linked to the pathological risk of GIST.These findings contribute to our understanding of GIST and may inform non-invasive examination strategies and risk assessment for this condition.

Perspective on the practical indications of endoscopic submucosal dissection of gastrointestinal neoplasms

Endoscopic submucosal dissection (ESD) is a new endoluminal therapeutic technique involving the use of cutting devices to permit a larger resection of the tissue over the muscularis propria. The major advantages of the technique in comparison with polypectomy and endoscopic mucosal resection are controllable resection size and shape and en bloc resection of a large lesion or a lesion with ulcerative findings. This technique is applied for the endoscopic treatment of epithelial neoplasms in the gastrointestinal tract from the pharynx to the rectum. Furthermore, some carcinoids and submucosal tumors in the gastrointestinal tract are treated by ESD. To determine the indication, two aspects should be considered. The first is a little likelihood of lymph node metastasis and the second is the technical resectability. In this review, practical guidelines of ESD for the gastrointestinal neoplasms are discussed based on the evidence found in the literature.

Ultraslim endoscopy with flexible spectral imaging color enhancement for upper gastrointestinal neoplasms

AIM:To conduct a preliminary study on the effect of flexible spectral imaging color enhancement (FICE) used in combination with ultraslim endoscopy by focusing on the enhanced contrast between tumor and non-tumor lesions. METHODS: We examined 50 lesions of 40 patients with epithelial tumors of the upper gastrointestinal tract before endoscopic submucosal dissection using ultraslim endoscopy with conventional natural color imag ing and with FICE imaging. We retrospectively invest igated the effect of the use of FICE on endoscopic diagn osis in comparison with normal light. RESULTS: Visibility of the epithelial tumors of the upper gastrointestinal tract with FICE was superior to normal light in 54% of the observations and comparable to normal light in 46% of the observations. There was no lesion for which visibility with FICE was inferior to that with normal light. FICE visualized 69.6% of hyperemic lesions and 58.8% of discolored lesions better than conventional endoscopy with natural color imaging. FICE sign if icantly improved the visibility of lesions with hyp ere mia or discoloration compared with normocolored lesions. CONCLUSION: This study suggests that the use of FICE would improve the ability of ultraslim endoscopy to detect epithelial tumors of the upper gastrointestinal tract.

molecular pathology of intraductal papillary mucinous neoplasms of the pancreas

Since the first description of intraductal papillary mucinous neoplasms(IPMNs)of the pancreas in the eighties,their identification has dramatically increased in the last decades,hand to hand with the improvements in diagnostic imaging and sampling techniques for the study of pancreatic diseases.However,the heterogeneity of IPMNs and their malignant potential make difficult the management of these lesions.The objective of this review is to identify the molecular characteristics of IPMNs in order to recognize potential markers for the discrimination of more aggressive IPMNs requiring surgical resection from benign IPMNs that could be observed.We briefly summarize recent research findings on the genetics and epigenetics of intraductal papillary mucinous neoplasms,identifying some genes,molecular mechanisms and cellular signaling pathways correlated to the pathogenesis of IPMNs and their progression to malignancy.The knowledge of molecular biology of IPMNs has impressively developed over the last few years.A great amount of genes functioning as oncogenes or tumor suppressor genes have been identified,in pancreatic juice or in blood or in the samples from the pancreatic resections,but further researches are required to use these informations for clinical intent,in order to better define the natural history of these diseases and to improve their management.

Mixed neuroendocrine–nonneuroendocrine neoplasms of the gastrointestinal system:An update

Mixed neuroendocrine-nonneuroendocrine neoplasms(Mi NENs)of the digestive tract are a rare heterogeneous group of tumors that present many challenges in terms of diagnosis and treatment.Over the years,the diagnostic criteria,classification,and clinical behavior of these tumors have been the subjects of ongoing debate,and the various changes in their nomenclature have strengthened the challenges associated with Mi NENs.This review is performed to provide an understanding of the key factors involved in the evolution of the designation of these tumors as Mi NEN,highlight the current diagnostic criteria,summarize the latest data on pathogenesis and provide information on available treatments.Moreover,this work seeks to increase the awareness about these rare neoplasms by presenting the clinicopathological features and prognostic factors that play important roles in their behavior and discussing their different regions of origin in the gastrointestinal system(GIS).Currently,the Mi NEN category also includes tumors in the GIS with a nonneuroendocrine component and epithelial tumors other than adenocarcinoma,depending on the organ of origin.Diagnosis is based on the presence of both morphological components in more than 30%of the tumor.However,this value needs to be reconfirmed with further studies and may be a limiting factor in the diagnosis of Mi NEN by biopsy.Furthermore,available clinicopathological data suggest that the inclusion of amphicrine tumors in the definition of Mi NEN is not supportive and warrants further investigation.The diagnosis of these tumors is not solely based on immunohistochemical findings.They are not hybrid tumors and both components can act independently;thus,careful grading of each component separately is required.In addition to parameters such as the metastatic state of the tumor at the time of diagnosis and the feasibility of surgical resection,the aggressive potential of both components has paramount importance in the choice of treatment.Regardless of the organ of origin within the GIS,almost Mi NENs are tumors with poor prognosis and are frequently encountered in the elderly and men.They are most frequently reported in the colorectum,where data from molecular studies indicate a monoclonal origin;however,further studies are required to provide additional support for this origin.

Upper gastrointestinal barium evaluation of duodenal pathology: A pictorial review

Like other parts of the gastrointestinal tract(GIT), duodenum is subject to a variety of lesions both congenital and acquired. However, unlike other parts of the GIT viz. esophagus, rest of the small intestine and large intestine, barium evaluation of duodenal lesions is technically more challenging and hence not frequently reported. With significant advances in computed tomography technology, a thorough evaluation including intraluminal, mural and extramural is feasible in a single non-invasive examination. Notwithstanding, barium evaluation still remains the initial and sometimes the only imaging study in several parts of the world. Hence,a thorough acquaintance with the morphology of various duodenal lesions on upper gastrointestinal barium examination is essential in guiding further evaluation. We reviewed our experience with various common and uncommon barium findings in duodenal abnormalities.

Requirements for implementation of artificial intelligence in the practice of gastrointestinal pathology

Tremendous advances in artificial intelligence(AI)in medical image analysis have been achieved in recent years.The integration of AI is expected to cause a revolution in various areas of medicine,including gastrointestinal(GI)pathology.Currently,deep learning algorithms have shown promising benefits in areas of diagnostic histopathology,such as tumor identification,classification,prognosis prediction,and biomarker/genetic alteration prediction.While AI cannot substitute pathologists,carefully constructed AI applications may increase workforce productivity and diagnostic accuracy in pathology practice.Regardless of these promising advances,unlike the areas of radiology or cardiology imaging,no histopathology-based AI application has been approved by a regulatory authority or for public reimbursement.Thus,implying that there are still some obstacles to be overcome before AI applications can be safely and effectively implemented in real-life pathology practice.The challenges have been identified at different stages of the development process,such as needs identification,data curation,model development,validation,regulation,modification of daily workflow,and cost-effectiveness balance.The aim of this review is to present challenges in the process of AI development,validation,and regulation that should be overcome for its implementation in real-life GI pathology practice.

Gastrointestinal bleeding as initial presentation of extramedullary plasma cell neoplasms: A case report and review of the literature

BACKGROUND Plasma-cell neoplasms rarely involve the gastrointestinal tract and manifest as gastrointestinal bleeding. Plasmablastic myeloma is an aggressive plasma cell neoplasm associated with poor outcomes. A small number of cases with gastrointestinal involvement is reported in the literature and therefore high index of suspicion is essential for avoiding delays in diagnosis and treatment.CASE SUMMARY Our aim is to present our experience of a 70-year-old patient with a secondary presentation of plasmablastic myeloma manifesting as unstable upper gastrointestinal bleeding and to review the literature with the view to consolidate and discuss information about diagnosis and management of this rare entity. In addition to our case, a literature search(Pub Med database) of case reports of extramedullary plasma cell neoplasms manifesting as upper gastrointestinal bleeding was performed. Twenty-seven cases of extramedullary plasmacytoma(EMP) involving the stomach and small bowel presenting with upper gastrointestinal bleeding were retrieved. The majority of patients were males(67%). The average age on diagnosis was 62.7 years. The most common site of presentation was the stomach(41%), followed by the duodenum(15%). The most common presenting complaint was melena(44%). In the majority of cases, the EMPs were a secondary manifestation(63%) at the background of multiple myeloma(26%), plasmablastic myeloma(7%) or high-grade plasma cell myeloma(4%). Oesophagogastroscopy was the main diagnostic modality and chemotherapy the preferred treatment option for secondary EMPs.CONCLUSION Despite their rare presentation, upper gastrointestinal EMPs should be considered in the differential diagnosis of patients with gastrointestinal bleeding especially in the presence of systemic haematological malignancy.

A new breakthrough:ESD using a newly developed grasping type scissor forceps for early gastrointestinal tract neoplasms

Endoscopic submucosal dissection(ESD) has allowed the achievement of histologically curative en bloc resection of gastrointestinal neoplasms regardless of size,permitting the resection of previously non-resectable tumors.The ESD technique for treatment of early gastric cancer has spread rapidly in Japan and a few other Asian countries due to its excellent eradication rate compared to endoscopic mucosal resection.Although numerous electrosurgical knives have been developed for ESD,technical difficulties and high complication rates(bleeding and perforation) have limited their use worldwide.We developed the grasping type scissor forceps(GSF) to resolve such ESD-related problems.Our animal and preliminary clinical studies showed that ESD using GSF is a safe(no intraoperative complication) and technically efficient(curative en bloc resection rate 92%) method for dissection of early gastrointestinal tumors.The use of GSF is a promising option for performing ESD on early stage GI tract tumors both safely and effectively.

Conventional radiological strategy of common gastrointestinal neoplasms

This article summarizes the clinical characteristics and imaging features of common gastrointestinal(GI) neoplasms in terms of conventional radiological imaging methods. Barium studies are readily available for displaying primary malignancies and are minimallyor not at all invasive. A neoplasm may be manifested as various imaging findings, including mucosal disruption, soft mass, ulcer, submucosal invasion and lumen stenosis on barium studies. Benign tumors typically appear as smoothly marginated intramural masses. Malignant neoplasms most often appear as irregular infiltrative lesions on barium examination. Tumor extension to adjacent GI segments may be indistinct on barium images. Cross-sectional images such as computed tomography and magnetic resonance imaging may provide more accurate details of the adjacent organ invasion, omental or peritoneal spread.

Calcifying fibrous tumor of the gastrointestinal tract: A clinicopathologic review and update

Calcifying fibrous tumor(CFT)is a rare mesenchymal lesion that has been documented throughout the gastrointestinal tract.Gastrointestinal CFTs may occur at virtually any age,with a predilection for adults and for females.They occur most commonly in the stomach and the small and large intestines.CFTs are most often found incidentally,cured by local resection,and have a low risk of recurrence.Histology shows three characteristic features:Spindle cell proliferations within a densely hyalinized stroma,scattered calcifications,and lymphoplasmacytic inflammation.CFTs are immunoreactive for CD34,vimentin and factor XIIIa,helping to distinguish them from other benign mesenchymal neoplasms.The differential diagnosis of CFTs includes sclerosing gastrointestinal stromal tumor,leiomyoma,schwannoma,solitary fibrous tumor,inflammatory myofibroblastic tumor,plexiform fibromyxoma,fibromatosis,sclerosing mesenteritis,and reactive nodular fibrous pseudotumor.The pathogenesis of CFTs remains unclear,but some have hypothesized that they may be linked to IgG4-related disease,inflammatory myofibroblastic lesions,hyaline vascular type Castleman disease,sclerosing angiomatoid nodular transformation of the spleen,or trauma.

Pathologic complete response confirmed by surgical resection for liver metastases of gastrointestinal stromal tumor after treatment with imatinib mesylate

A 39-year-old male underwent distal gastrectomy for a high grade gastrointestinal stromal tumor(GIST) . Computed tomography(CT) and magnetic resonance imaging(MRI) 107 mo after the operation,revealed a cystic mass(14 cm in diameter) and a solid mass(9 cm in diameter) in the right and left lobes of the liver,respectively. A biopsy specimen of the solid mass showed a liver metastasis of GIST. The patient received imatinib mesylate(IM) treatment,400 mg/day orally. Following the IM treatment for a period of 35 mo,the patient underwent partial hepatectomy(S4 + S5) . The effect of IM on the metastatic lesions was interpreted as pathologic complete response(CR) . Pathologically verified cases showing therapeutic efficacy of IM have been rarely reported.

Bioenergetic alteration in gastrointestinal cancers:The good,the bad and the ugly

Cancer cells exhibit metabolic reprogramming and bioenergetic alteration,utilizing glucose fermentation for energy production,known as the Warburg effect.However,there are a lack of comprehensive reviews summarizing the metabolic reprogramming,bioenergetic alteration,and their oncogenetic links in gastrointestinal(GI)cancers.Furthermore,the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation.This review highlights the interplay between aerobic glycolysis,the tricarboxylic acid(TCA)cycle,and oxidative phosphorylation(OXPHOS)in cancer cells,as well as hypotheses on the molecular mechanisms that trigger this alteration.The role of hypoxia-inducible transcription factors,tumor suppressors,and the oncogenetic link between hypoxia-related enzymes,bioenergetic changes,and GI cancer are also discussed.This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy,particularly for GI cancers.Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy,the review categorizes these regulators into aerobic glycolysis/lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS.We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers,as well as the challenges posed by these drugs.Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments,although the diverse metabolic patterns present challenges for targeted therapies.Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes,address side effects,and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.

Three cases of jejunal tumors detected by standard upper gastrointestinal endoscopy:A case series

BACKGROUND In patients with obscure gastrointestinal bleeding,re-examination with standard upper endoscopes by experienced physicians will identify culprit lesions in a substantial proportion of patients.A common practice is to insert an adult-sized forward-viewing endoscope into the second part of the duodenum.When the endoscope tip enters after the papilla,which is a marker for the descending part of the duodenum,it is difficult to endoscopically judge how far the duodenum has been traversed beyond the second part.CASE SUMMARY We experienced three cases of proximal jejunal masses that were diagnosed by standard upper gastrointestinal endoscopy and confirmed with surgery.The patients visited the hospital with a history of melena;during the initial upper gastrointestinal endoscopy and colonoscopy,the bleeding site was not confirmed.Upper gastrointestinal bleeding was suspected;thus,according to guidelines,upper endoscopy was performed again.A hemorrhagic mass was discovered in the small intestine.The lesion of the first patient was thought to be located in the duodenum when considering the general insertion depth of a typical upper gastrointestinal endoscope;however,during surgery,it was confirmed that it was in the jejunum.After the first case,lesions in the second and third patients were detected at the jejunum by inserting the standard upper endoscope as deep as possible.CONCLUSION The deep insertion of standard endoscopes is useful for the diagnosis of obscure gastrointestinal bleeding.

European vs 2015-World Health Organization clinical molecular and pathological classification of myeloproliferative neoplasms

The BCR/ABL fusion gene or the Ph^1-chromosome in the t(9;22)(q34;q11)exerts a high tyrokinase acticity,which is the cause of chronic myeloid leukemia(CML).The1990 Hannover Bone Marrow Classification separated CML from the myeloproliferative disorders essential thrombocythemia(ET),polycythemia vera(PV)and chronic megakaryocytic granulocytic myeloproliferation(CMGM).The 2006-2008 European Clinical Molecular and Pathological(ECMP)criteria discovered 3variants of thrombocythemia:ET with features of PV(prodromal PV),"true"ET and ET associated with CMGM.The 2008 World Health Organization(WHO)-ECMP and 2014 WHO-CMP classifications defined three phenotypes of JAK2^(V617F)mutated ET:normocellular ET(WHO-ET),hypercelluar ET due to increased erythropoiesis(prodromal PV)and ET with hypercellular megakaryocytic-granulocytic myeloproliferation.The JAK2^(V617F)mutation load in heterozygous WHO-ET is low and associated with normal life expectance.The hetero/homozygous JAK2^(V617F)mutation load in PV and myelofibrosis is related to myeloproliferative neoplasm(MPN)disease burden in terms of symptomaticsplenomegaly,constitutional symptoms,bone marrow hypercellularity and myelofibrosis.JAK2 exon 12mutated MPN presents as idiopathic eryhrocythemia and early stage PV.According to 2014 WHO-CMP criteria JAK2 wild type MPL^(515)mutated ET is the second distinct thrombocythemia featured by clustered giant megakaryocytes with hyperlobulated stag-horn-like nuclei,in a normocellular bone marrow consistent with the diagnosis of"true"ET.JAK2/MPL wild type,calreticulin mutated hypercellular ET appears to be the third distinct thrombocythemia characterized by clustered larged immature dysmorphic megakaryocytes and bulky(bulbous)hyperchromatic nuclei consistent with CMGM or primary megakaryocytic granulocytic myeloproliferation.

PVSG and WHO vs European Clinical,Molecular and Pathological Criteria for prefibrotic myeloproliferative neoplasms

The Polycythemia Vera Study Group(PVSG),World Health Organization(WHO) and European Clinical,Molecular and Pathological(ECMP) classifications agree upon the diagnostic criteria for polycythemia vera(PV) and advanced primary myelofibrosis(MF). Essential thrombocythemia(ET) according to PVSG and 2007/2008 WHO criteria comprises three variants of JAK2V617 F mutated ET when the ECMP criteria are applied. These include normocellular ET,hypercellular ET with features of early PV(prodromal PV),and hypercellular ET due to megakaryocytic,granulocytic myeloprolifera-tion(ET.MGM). Evolution of prodromal PV into overt PV is common. Development of MF is rare in normocellular ET(WHO-ET) but rather common in hypercellular ET.MGM. The JAK2V617 F mutation burden in heterozygous mutated normocellular ET and in heterozygous/homozygous or homozygous mutated PV and ET.MGM is of major prognostic significance. JAK2/MPL wild type ET associated with prefibrotic primary megakaryocytic and granulocytic myeloproliferation(PMGM) is characterized by densely clustered immature dysmorphic megakaryocytes with bulky(bulbous) hyperchromatic nuclei,which are never seen in JAK2V617 F mutated ET,and PV and also not in MPL515 mutated normocellular ET(WHO-ET). JAK2V617 mutation burden,spleen size,LDH,circulating CD34+ cells,and pre-treatment bone marrow histopathology are mandatory to stage the myeloproliferative neoplasms ET,PV,PMGM for proper prognosis assessment and therapeutic implications. MF itself is not a disease because reticulin fibrosis and reticulin/collagen fibrosis are secondary responses of activated polyclonal fibroblasts to cytokines released from the clonal myeloproliferative granulocytic and megakaryocytic progenitor cells in ET.MGM,PV and PMGM.