In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a ...question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.
High-grade neuroendocrine neoplasms (World Health Organization WHO G3) of the pancreas include both well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine ...carcinoma (PD-NEC). According to the WHO classification scheme, the diagnosis of this group of tumors is based on both the histopathology of the tumor and the assessment of proliferation fraction. However, the former can be challenging due to the lack of well-defined histologic criteria, and the latter alone (ie, >20 mitoses/10 high-power fields or Ki67>20%) may not sufficiently distinguish WD-NETs from PD-NECs. Given the considerable differences in treatment strategies and clinical outcome, additional practical modalities are required to facilitate the accurate diagnosis of high-grade pancreatic neuroendocrine neoplasms. We examined 33 cases of WHO G3 neuroendocrine neoplasms of the pancreas and attempted to classify them into WD-NET, small cell PD-NEC (PD-NEC-SCC), and large cell PD-NEC (PD-NEC-LCC) or to designate them as “ambiguous” when an uncertain diagnosis was rendered by any of the observers or there was any disagreement in classification among the 3 observers. To simplify the interpretation, both PD-NEC-SCC and PD-NEC-LCC were considered together as PD-NECs in the final analysis. The initial approach was to assess microscopically a single morphologically challenging hematoxylin and eosin section from each case without the knowledge of Ki67 values, performed independently by 3 pathologists to assess the degree of diagnostic concordance, and then evaluate immunohistochemical staining for surrogate biomarkers of known genotypes of WD-NET and PD-NEC, respectively, and, lastly, complete a clinicopathologic review to establish a final definitive classification. Loss of DAXX or ATRX protein expression defined WD-NET, and abnormal p53, Rb, SMAD4 expression signified PD-NEC. When the chosen section displayed an element of WD histopathology, or other tumor sections contained WHO G1/G2 components, or there had been a prior established diagnosis of a primary WD-NET, the final diagnosis was rendered as a WD-NET with high-grade (G3) progression. If a component of conventional adenocarcinoma was present (in slides not seen in the initial review), the diagnosis was established as a combined adenocarcinoma and PD-NEC. All 3 pathologists agreed on the morphologic classification of 33% of the cases (6 WD-NET, 3 PD-NEC-SCC, and 2 PD-NEC-LCC), were conflicted on 2 cases between PD-NEC-SCC and PD-NEC-LCC, and disagreed or were uncertain on the classification for the remaining 20 cases (61%), which were therefore categorized as ambiguous. In the group of cases in which all pathologists agreed on the classification, the 6 WD-NET cases had either loss of DAXX or ATRX or had evidence of a WD-NET based on additional or prior pathology slides. The 7 PD-NEC cases had abnormal expression of p53, Rb, and/or SMAD4 or a coexisting adenocarcinoma. In the ambiguous group (n=20), 14 cases were established as WD-NETs, based upon loss of DAXX or ATRX in 7 cases and additional pathology evidence of high-grade progression from WD-NET in the other 7 cases; 5 cases were established as PD-NEC based upon abnormal expression of p53, Rb, and/or SMAD4; 1 case remained undetermined with normal expression of all markers and no evidence of entity-defining histologic findings in other slides. On the basis of the final pathologic classifications, the disease-specific survival was 75 and 11 months for the WD-NET and PD-NEC groups, respectively. Thus, we conclude that morphologic diagnosis of high-grade pancreatic neuroendocrine neoplasms is challenging, especially when limited pathologic materials are available, and necessitates better defined criteria. The analysis of both additional sections and prior material, along with an immunohistochemical evaluation, can facilitate accurate diagnosis in the majority of cases and guide the appropriate clinical management and prognosis.
Pathological evaluation of gallbladder neoplasia remains a challenge. A significant proportion of cases presents as clinically and grossly inapparent lesions, and grossing protocols are not well ...established. Among epithelial alterations, pseudo‐pyloric gland metaplasia is ubiquitous and of no apparent consequence, whereas goblet cell metaplasia and a foveolar change in surface cells require closer attention. Low‐grade dysplasia is difficult to objectively define and appears to be clinically inconsequential by itself; however, extra sampling is required to exclude the possibility of accompanying more significant lesions. For high‐grade dysplasia (‘high‐grade BilIN’, also known as ‘carcinoma in situ’), a complete sampling is necessary to rule out invasion. Designating in‐situ or minimally invasive carcinomas limited to muscularis or above as early gallbladder carcinoma (EGBC) helps to alleviate the major geographical differences (West/East) in the criteria for ‘invasiveness’ to assign a case to pTis or pT1. Total sampling is crucial in proper diagnosis of such cases. A subset of invasive GBCs (5–10%) arise from the intracholecystic neoplasm (ICN, ‘adenoma‐carcinoma sequence’) category. Approximately two‐thirds of ICNs have invasive carcinoma. However, this propensity differs by subtype. True ‘pyloric gland adenomas’ (> 1 cm) are uncommon and scarcely associated with invasive carcinoma. A distinct subtype of ICN composed of tubular, non‐mucinous MUC6+ glands intracholecystic tubular non‐mucinous neoplasm (ICTN) forms a localised pedunculated polyp. Although it is morphologically complex and high‐grade, it appears to be invasion‐resistant. Some of the invasive carcinoma types in the gallbladder have been better characterised recently with adenosquamous, neuroendocrine, poorly cohesive and mucinous carcinomas often being more advanced and aggressive.
Recently discovered DNAJB1-PRKACA oncogenic fusions have been considered diagnostic for fibrolamellar hepatocellular carcinoma. In this study, we describe six pancreatobiliary neoplasms with PRKACA ...fusions, five of which harbor the DNAJB1-PRKACA fusion. All neoplasms were subjected to a hybridization capture-based next-generation sequencing assay (MSK-IMPACT), which enables the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving ≥410 genes (n = 6) and/or to a custom targeted, RNA-based panel (MSK-Fusion) that utilizes Archer Anchored Multiplex PCR technology and next-generation sequencing to detect gene fusions in 62 genes (n = 2). Selected neoplasms also underwent FISH analysis, albumin mRNA in-situ hybridization, and arginase-1 immunohistochemical labeling (n = 3). Five neoplasms were pancreatic, and one arose in the intrahepatic bile ducts. All revealed at least focal oncocytic morphology: three cases were diagnosed as intraductal oncocytic papillary neoplasms, and three as intraductal papillary mucinous neoplasms with mixed oncocytic and pancreatobiliary or gastric features. Four cases had an invasive carcinoma component composed of oncocytic cells. Five cases revealed DNAJB1-PRKACA fusions and one revealed an ATP1B1-PRKACA fusion. None of the cases tested were positive for albumin or arginase-1. Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present. Moreover, considering DNAJB1-PRKACA fusions lead to upregulated protein kinase activity and that this upregulated protein kinase activity has a significant role in tumorigenesis of fibrolamellar hepatocellular carcinoma, protein kinase inhibition could have therapeutic potential in the treatment of these pancreatobiliary neoplasms as well, once a suitable drug is developed.
The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs ...defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67>20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of “hot spots.” The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.
Background Intraductal papillary mucinous neoplasms (IPMN) are being increasingly recognized as important precursors to pancreatic adenocarcinoma. Elucidation of the genetic changes underlying IPMN ...carcinogenesis may improve the diagnosis and management of IPMN. We sought to determine whether different histologic subtypes of IPMN would exhibit different frequencies of specific genetic mutations. Study Design Patients with resected IPMN-associated invasive carcinoma (IPMN-INV) between 1997 and 2012 were reviewed. Areas of carcinoma, high-grade dysplasia, and low-grade dysplasia were micro-dissected from each pathologic specimen. Targeted, massively parallel sequencing was then performed on a panel of 275 genes (including KRAS , GNAS , and RNF43 ). Results Thirty-eight patients with resected IPMN-INV and sufficient tissue for micro-dissection were identified. Median follow-up was 2.6 years. Mutations in GNAS were more prevalent in colloid-type IPMN-INV than tubular-type IPMN-INV (89% vs 32% respectively; p = 0.0003). Conversely, KRAS mutations were more prevalent in tubular-type than colloid-type IPMN-INV (89% vs 52%, respectively; p = 0.01). For noninvasive IPMN subtypes, GNAS mutations were more prevalent in intestinal (74%) compared with pancreatobiliary (31%) and gastric (50%) subtypes (p = 0.02). The presence of these mutations did not vary according to the degree of dysplasia ( GNAS : invasive 61%, high-grade 59%, low-grade 53%; KRAS : invasive 71%, high-grade 62%, low-grade 74%), suggesting that mutations in these genes occur early in IPMN carcinogenesis. Conclusions Colloid carcinoma associated with IPMN and its intestinal-type preinvasive precursor are associated with high frequencies of GNAS mutations. The mutation profile of tubular carcinoma resembles that of conventional pancreatic adenocarcinoma. Preoperative determination of mutational status may assist with clinical treatment decisions.
International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic ...intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other lesions. Consensus recommendations include the following(1) To improve concordance and to align with practical consequences, a 2-tiered system (low vs. high grade) is proposed for all precursor lesions, with the provision that the current PanIN-2 and neoplasms with intermediate-grade dysplasia now be categorized as low grade. Thus, “high-grade dysplasia” is to be reserved for only the uppermost end of the spectrum (“carcinoma in situ”–type lesions). (2) Current data indicate that PanIN of any grade at a margin of a resected pancreas with invasive carcinoma does not have prognostic implications; the clinical significance of dysplasia at a margin in a resected pancreas with IPMN lacking invasive carcinoma remains to be determined. (3) Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs. The term “incipient IPMN” should be reserved for lesions in this size with intestinal or oncocytic papillae or GNAS mutations. (4) Measurement of the distance between an IPMN and invasive carcinoma and sampling of intervening tissue are recommended to assess concomitant versus associated status. Conceptually, concomitant invasive carcinoma (in contrast with the “associated” group) ought to be genetically distinct from an IPMN elsewhere in the gland. (5) “Intraductal spread of invasive carcinoma” (aka, “colonization”) is recommended to describe lesions of invasive carcinoma invading back into and extending along the ductal system, which may morphologically mimic high-grade PanIN or even IPMN. (6) “Simple mucinous cyst” is recommended to describe cysts >1 cm having gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma to distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas.
Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting ...methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) 'eye-ball' estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson's correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) 'eye-balling' was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than 'eye-balling'. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. 'Eye-balling' produces highly inaccurate and unreliable results, and is not recommended for routine use.
Molecular profiling in cancer has identified potential actionable drug targets that have prompted attempts to discover clinically validated biomarkers to guide therapeutic decision-making and ...enrollment to clinical trials. We evaluated whether comprehensive genetic analysis of patients with pancreatic adenocarcinoma is feasible within a clinically relevant timeframe and whether such analyses provide predictive and/or prognostic information along with identification of potential targets for therapy.
Archival or prospectively acquired FFPE samples and matched normal DNA from
= 336 patients with pancreatic cancer were analyzed using a hybridization capture-based, next-generation sequencing assay designed to perform targeted deep sequencing of all exons and selected introns of 410 key cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.
The median time from protocol consent to reporting of the genomic results was 45 days with a median time from tissue delivery of 20 days. All genetic alterations identified were stratified based upon prior evidence that the mutation is a predictive biomarker of drug response using the MSKCC OncoKB classification. Three of 225 patients (1%) received a matched therapy based upon the sequencing results.
The practical application of molecular results to guide individual patient treatment is currently limited in patients with pancreatic adenocarcinoma. Future prospective molecular profiling efforts should seek to incorporate routine germline genetic analysis and the identification of DNA profiles that predict for clinical benefit from agents that target DNA damage repair and or immunotherapy.
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Cystic lesions of the pancreas are being recognized with increasing frequency and have become a more common finding in clinical practice because of the widespread use of advanced imaging modalities ...and the sharp drop in the mortality rate of pancreatic surgery. Consequently, in the past 2 decades, the nature of many cystic tumors in this organ has been better characterized, and significant developments have taken place in the classification and in our understanding of pancreatic cystic lesions.
To provide an overview of the current concepts in classification, differential diagnosis, and clinical/biologic behavior of pancreatic cystic tumors.
The authors' personal experience, based on institutional and consultation materials, combined with an analysis of the literature.
In contrast to solid tumors, most of which are invasive ductal adenocarcinomas with dismal prognosis, cystic lesions of the pancreas are often either benign or low-grade indolent neoplasia. However, those that are mucinous, namely, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, constitute an important category because they have well-established malignant potential, representing an adenoma-carcinoma sequence. Those that are nonmucinous such as serous tumors, congenital cysts, lymphoepithelial cysts, and squamoid cyst of pancreatic ducts have no malignant potential. Only rare nonmucinous cystic tumors that occur as a result of degenerative/necrotic changes in otherwise solid neoplasia, such as cystic ductal adenocarcinomas, cystic pancreatic endocrine neoplasia, and solid-pseudopapillary neoplasm, are also malignant and have variable degrees of aggressiveness.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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