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© 2021, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.The advancing edge profile is a powerful determinant of tumor behavior in many organs. In this study, a grading system assessing the tumor-host interface was developed and tested in 181 pancreatic neuroendocrine tumors (PanNETs), 63 of which were

Context.— The nature and associations of gallbladder (GB) “adenomyoma” (AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. Objective.— To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. Design.— Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. Results.— Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio = 1.9 (177:94) and mean size = 1.3 cm (range, 0.3–5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive (“adenomyomatosis”). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat-type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma was arising from AM (invasion was confined to AM, and dysplasia was predominantly in AM). Conclusions.— AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component; (ie, the name “adeno-myoma” is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flat-type high-grade dysplasia or carcinoma in situ and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.

Supplementary Figure 6 from Inactivation of Smad4 Accelerates KrasG12D-Mediated Pancreatic Neoplasia

PDF file - 981KB, Representative Immunohistochemistry for CHD7 Expression in Primary Tumor Tissue (S1). Network Analysis via MetaCore ExPlain Process Network Analysis for genes involved in CHK1, CDC25A, AURKB, PLK1, HUS1 pathway (S2). CHD7 Knockdown Causes Gemcitabine Sensitization (S3). Mice with Xenograft Tumors Showed No Significant Difference in Body Weight (S4). CHD7 Knockdown Effect on Cell Cycle (S5). Gemcitabine Does Not Significantly Change CHD7 Protein Levels in Cells (S6).

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall 5-year survival rate of KRAS are almost uniformly present in early-stage disease, with subsequent inactivating mutations in p16INK4A, p53, and SMAD4 occurring in more advanced lesions. In this study, we have tested whether the loss of Smad4 would cooperate with an activating KrasG12D mutation to promote progression to PDAC using the Pdx1-Cre transgenic system to activate KrasG12D and delete Smad4 in all pancreatic lineages including the ductal epithelium. Analysis of double-mutant mice showed that loss of Smad4 significantly accelerated the progression of pancreatic intraepithelial neoplasias (mPanIN) and promoted a high incidence of intraductal papillary mucinous neoplasia and active fibrosis compared with Pdx1-Cre;KrasG12D or Pdx1-Cre;Smad4lox/lox mice. Occasionally, double-mutant mice progressed to locally invasive PDAC with little evidence of metastases by 6 months of age and without the detectable loss of p53 or p16Ink4A expression or function. The loss of Smad4 only seemed to promote disease progression in the presence of the activated KrasG12D allele because we observed no abnormal pathology within the pancreata of 23 Pdx1-Cre;Smad4lox/lox animals that were analyzed up to 8 months of age. This indicates that Smad4 is dispensable for normal pancreatic development but is critical for at least partial suppression of multiple KrasG12D-dependent disease-associated phenotypes. [Cancer Res 2007;67(17):8121–30]

Supplementary Figure 1 from Inactivation of Smad4 Accelerates KrasG12D-Mediated Pancreatic Neoplasia

Supplementary Figure 1 from Notch1 Functions as a Tumor Suppressor in a Model of K-ras–Induced Pancreatic Ductal Adenocarcinoma

Supplementary Figure 3 from Inactivation of Smad4 Accelerates KrasG12D-Mediated Pancreatic Neoplasia

PDF file - 70KB

Supplementary Figure 4 from Inactivation of Smad4 Accelerates KrasG12D-Mediated Pancreatic Neoplasia

Supplementary Figure 2 from Inactivation of Smad4 Accelerates KrasG12D-Mediated Pancreatic Neoplasia

XLS file - 675KB, Full Results of Primary Gemcitabine Sensitivity Screen (S1). Known DNA Damage Response Genes Identified as Hits in Gemcitabine Sensitivity Screen (S2). Dysregulation, Differential Expression, and Literature RNAi Cross-Reference for Known DDR Genes and Select Hits (S3). Selected Top 15% of Gemcitabine Sensitivity Genes Tested on Secondary Screen (S4).

Supplementary Figure 5 from Inactivation of Smad4 Accelerates KrasG12D-Mediated Pancreatic Neoplasia

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment. Cancer Res; 74(10); 2677–87. ©2014 AACR.

K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation in murine models is sufficient to recapitulate the spectrum of lesions seen in human pancreatic ductal adenocarcinoma (PDAC). Recent studies suggest that Notch receptor signaling becomes reactivated in a subset of PDACs, leading to the hypothesis that Notch1 functions as an oncogene in this setting. To determine whether Notch1 is required for K-ras–induced tumorigenesis, we used a mouse model in which an oncogenic allele of K-ras is activated and Notch1 is deleted simultaneously in the pancreas. Unexpectedly, the loss of Notch1 in this model resulted in increased tumor incidence and progression, implying that Notch1 can function as a tumor suppressor gene in PDAC. Cancer Res; 70(11); 4280–6. ©2010 AACR.

The literature is highly conflicted on what percentage of pancreatic ductal adenocarcinomas (PDACs) arise in association with intraductal papillary mucinous neoplasms (IPMNs). Some studies have claimed that even small (Sendai-negative) IPMNs frequently lead to PDAC. Recently, more refined pathologic definitions for mucin-lined cysts were provided in consensus manuscripts, but so far there is no systematic analysis regarding the frequency and clinicopathologic characteristics of IPMN-mimickers, i.e., pseudo-IPMNs. In this study, as the first step in establishing frequency, we performed a systematic review of the pathologic findings in 501 consecutive ordinary PDACs, which disclosed that 10% of PDACs had associated cysts >= 1 cm. While 31 (6.2%) of these were IPMN or mucinous cystic neoplasm (MCN), 19 (3.8%) were other cyst types that mimicked IPMN (pseudo-IPMNs) per recent WHO/consensus criteria. As the second step of the study, we performed a comparative clinicopathologic analysis by also including our entire surgical pathology/consultation databases that was comprised of 60 IPMN-associated PDACs, 30 MCN-associated PDACs and 40 pseudo-IPMN-associated PDACs. We found that 84% of true IPMNs were pre-operatively recognized, whereas IPMN was considered in differential diagnosis of 33% of pseudo-IPMNs. Of the 40 pseudo-IPMNs, there were 15 secondary duct ectasias; 6 large-duct-type PDACs; 5 pseudocysts; 5 cystic tumor necrosis; 4 simple mucinous cysts; 3 groove pancreatitis-associated paraduodenal wall cysts; and 2 congenital cysts. Microscopically, pseudo-IPMNs had at least partial mucinous-lining mimicking IPMN but had smaller cystic (mean = 1.9 cm) and larger PDAC (mean = 3.8 cm) components compared to true IPMNs (cyst = 5.7 cm; PDAC = 2.0 cm). In summary, in this pathologically verified analysis that utilized refined criteria, 10% of PDACs were discovered to have cysts >= 1 cm, about two-thirds of which were IPMN/MCN but about one-third were pseudo-IPMNs. True IPMNs underlying the PDACs are often large and are already diagnosed pre-operatively as having an IPMN component, whereas only a third of the pseudo-IPMNs receive IPMN diagnosis by imaging and their cysts are smaller. At the histopathologic level, pseudo-IPMNs are highly prone to misdiagnosis as IPMN, which presumably accounts for much higher association of IPMNs with PDAC as reported in some studies. The subtle but salient characteristics of pseudo-IPMNs elucidated in this study should be combined with careful radiological/clinical correlation in order to exclude pseudo-IPMNs.

Context.— Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. Objective.— To investigate their morphologic, immunohistochemical, and molecular features. Design.— Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. Results.— The mean age at diagnosis was 69 years (42–81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). Conclusions.— Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.

The Gallbladder Reporting and Data System (GB-RADS) ultrasound (US) risk stratification is proposed to improve consistency in US interpretations, reporting, and assessment of risk of malignancy in gallbladder wall thickening in non-acute setting. It was developed based on a systematic review of the literature and the consensus of an international multidisciplinary committee comprising expert radiologists, gastroenterologists, gastrointestinal surgeons, surgical oncologists, medical oncologists, and pathologists using modified Delphi method. For risk stratification, the GB-RADS system recommends six categories (GB-RADS 0–5) of gallbladder wall thickening with gradually increasing risk of malignancy. GB-RADS is based on gallbladder wall features on US including symmetry and extent (focal vs. circumferential) of involvement, layered appearance, intramural features (including intramural cysts and echogenic foci), and interface with the liver. GB-RADS represents the first collaborative effort at risk stratifying the gallbladder wall thickening. This concept is in line with the other US-based risk stratification systems which have been shown to increase the accuracy of detection of malignant lesions and improve management. Graphical abstract: [Figure not available: see fulltext.].

Poorly cohesive carcinomas (PCCs) are neoplasms characterized by a dyshesive cell invasion pattern featuring single-cell or cord-like stromal infiltration. Although they have been extensively studied in the stomach and other digestive system organs, limited data regarding nonampullary small bowel poorly cohesive carcinomas (SB-PCCs) are hitherto available. The aims of our study were to analyze the clinicopathologic and immunophenotypical features of SB-PCCs (PCC pattern accounting for >50% of the neoplasm) and to compare them with small bowel adenocarcinomas (SBAs), not otherwise specified (SBAs-NOS) and with cancers with a histologically distinct PCC component accounting for 10% to 50% of the neoplasm (mixed-poorly-cohesive-glandular-SBAs). Fifteen SB-PCCs were identified and compared with 95 SBAs-NOS and 27 mixed-poorly-cohesive-glandular-SBAs. Most SB-PCCs (67%) were composed of

© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.There are highly conflicting data on relative frequency (2–32%), prognosis, and management of pT1b-gallbladder carcinoma (GBC), with 5-year survival ranging from > 90% in East/Chile where cholecystectomy is regarded as curative, versus < 50% in the West, with radical operations post-cholecystectomy being recommended by guidelines. A total of 473 in situ and invasive extensively sampled GBCs from the USA (n = 225) and Chile (n = 248) were re-evaluated histopathologically per Western invasiveness criteria. 349 had invasive carcinoma, and only 24 were pT1. Seven cases previously staged as pT1b were re-classified as pT2. There were 19 cases (5% of all invasive GBCs) qualified as pT1b and most pT1b carcinomas were minute (< 1mm). One patient with extensive pTis at margins (but pT1b focus away from the margins) died of GBC at 27 months, two died of other causes, and the remainder were alive without disease (median follow-up 69.9 months; 5-year disease-specific survival, 92%). In conclusion, careful pathologic analysis of well-sampled cases reveals that only 5% of invasive GBCs are pT1b, with a 5-year disease-specific survival of > 90%, similar to findings in the East. This supports the inclusion of pT1b in the “early GBC” category, as is typically done in high-incidence regions. Pathologic mis-staging of pT2 as pT1 is not uncommon. Cases should not be classified as pT1b unless extensive, preferably total, sampling of the gallbladder to rule out a subtle pT2 is performed. Critical appraisal of the literature reveals that the Western guidelines are based on either SEER or mis-interpretation of stage IB cases as “pT1b.” Although the prognosis of pT1b-GBC is very good, additional surgery (radical cholecystectomy) may be indicated, and long-term surveillance of the biliary tract is warranted.

The literature on liver cysts is highly conflicting, mostly owing to definitional variations. Two hundred and fifty-eight >= 1 cm cysts evaluated pathologically using updated criteria were classifiable as: I. Ductal plate malformation related (63%); that is, cystic bile duct hamartoma or not otherwise specified-type benign biliary cyst (35 with polycystic liver disease). These were female predominant (F/M=2.4), large (10 cm), often multifocal with degenerative/inflammatory changes and frequently misclassified as "hepatobiliary cystadenoma." II. Neoplastic (13%); 27 (10.5%) had ovarian-type stroma (OTS) and qualified as mucinous cystic neoplasm (MCN) per World Health Organization (WHO). These were female, solitary, mean age 52, mean size 11 cm, and 2 were associated with carcinoma (1 in situ and 1 microinvasive). There were 3 intraductal papillary neoplasms, 1 intraductal oncocytic papillary neoplasm, 1 cystic cholangiocarcinoma, and 2 cystic metastasis. III. Infectious/inflammatory (12%). These included 23 hydatid cysts (including 2 Echinococcus alveolaris both misdiagnosed preoperatively as cancer), nonspecific inflammatory cysts (abscesses, inflammatory cysts: 3.4%). IV. Congenital (7%). Mostly small (

Aims Intraductal tubulopapillary neoplasm (ITPN) of the pancreas is a recently recognized pancreatic tumor entity. Here we aimed to determine the most important features with a systematic review coupled with an integrated statistical approach. Methods and results PubMed, SCOPUS, and Embase were searched for studies reporting data on pancreatic ITPN. The clinicopathological, immunohistochemical, and molecular data were summarized. Then a comprehensive survival analysis and a comparative analysis of the molecular alterations of ITPN with those of pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) from reference cohorts (including the International Cancer Genome Consortium- ICGC dataset and The Cancer Genome Atlas, TCGA program) were conducted. The core findings of 128 patients were as follows: (i) Clinicopathological parameters: pancreatic head is the most common site; presence of an associated adenocarcinoma was reported in 60% of cases, but with rare nodal metastasis. (ii) Immunohistochemistry: MUC1 (>90%) and MUC6 (70%) were the most frequently expressed mucins. ITPN lacked the intestinal marker MUC2; unlike IPMN, it did not express MUC5AC. (iii) Molecular landscape: Compared with PDAC/IPMN, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, GNAS, and RNF43 were less altered in ITPN (P < 0.001), whereas MCL amplifications, FGFR2 fusions, and PI3KCA mutations were commonly altered (P < 0.001). (iv) Survival analysis: ITPN with a "pure" branch duct involvement showed the lowest risk of recurrence. Conclusion ITPN is a distinct pancreatic neoplasm with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for the enrichment of potential targets for precision oncology.

Among the mass-forming preinvasive (tumoral intraepithelial) neoplasms of the biliary tract, intraductal tubulopapillary neoplasms (ITPN-Bs) are increasingly being recognized as a separate category. By being intramucosal polypoid proliferations of dysplastic/neoplastic cells, they are highly similar to other members of the "intraductal neoplasms (IDNs)" category (namely, intraductal papillary neoplasms [IPNBs], and intraductal oncocytic papillary neoplasms [IOPNs]); however, they are distinguished by MUC6-expressing nonmucinous cells that lack intestinal differentiation and form striking tubular configuration. Their molecular/genetic profile is also proving to be different with frequent alterations in cell cycle and chromatin remodeling genes, which are quite uncommon in other IDNs and cholangiocarcinomas. Despite the conceptual overlaps, they are also very different from intracholecystic nonmucinous tubular neoplasms (ICTN) of the gallbladder with the latter being associated with Wnt/beta-catenin pathway alterations, and almost never invasive. In contrast, ITPN-Bs are invasive in an estimated 80% of the cases, although even invasive examples often exhibit a protracted course. Invasive carcinomas arising from ITPN-Bs are overall similar to cholangiocarcinomas (including small duct and large duct patterns) but also often have peculiar characteristics such as more nodular-compact (blunt invasion) pattern. Like other IDNs, the ITPN-Bs have also been classified in the past as intraductal-spreading type of cholangiocarcinomas (and they are still regarded as such in some publications). In small biopsies, they are prone to be mistaken as ordinary adenocarcinomas because of their tubular pattern and pancreatobiliary cytology although their relatively monotonous cytology and zones of back-to-back tubule formation can help in their correct identification. Clinical presentation of ITPN-Bs is generally similar to other intraductal neoplasms; however, in the intrahepatic component, they tend to be more nodular than cystic, and their snake-like intraductal growth pattern is often more striking. In the management (diagnosis and treatment) of these tumors that are in essence adenoma-carcinoma sequence, the invasive and noninvasive components ought to be evaluated separately. Minimally invasive examples are commonly curable, and even those more extensively invasive may have a surprisingly good prognosis. In summary, biliary ITPNs form a distinct category not only clinicopathologically, immunophenotypically, and molecular-wise but regarding their biological behavior as well.

Medullary carcinomas have not yet been fully characterized in the ampulla. Here, 359 ampullary carcinomas (ACs) were reviewed and 11 medullary type carcinomas (3%) were found and analyzed. In addition to diagnostic medullary pattern, six showed focal mucinous, and 8 had focal abortive gland-like formations. They occurred in younger patients (57 vs 65 y; p=0.02), had larger invasion size (mean, 3.2 vs 1.9 cm; p=0.01), formed nodular polypoid or plaque-like tumors, often lacked pre-invasive component. In addition to the lymphoplasmacytic infiltrates, they also had prominent eosinophils in 5/11 cases. Eight were papilla Vateri-NOS (not otherwise specified) tumors, two were ampullary-duodenal origin, one had a minor intra-ampullary papillary tubular neoplasm component, and none were ampullary-ductal. Although they had pushing-border infiltration, perineural and vascular invasion was common. They were strongly associated with DNA mismatch repair (MMR) protein deficient (7/11, 64%). The 5-yr survival rate (53%) appeared to be comparable with, and perhaps even better than that of non-medullary ACs (47%), although this did not reach statistical significance (p=0.47). Programed cell death ligand-1 (PD-L1) expression levels were assessed in 8, and all 4 that were MMR deficient were positive both by combined positive score (CPS) ≥1 and tumor proportion score (TPS) ≥1, and of the 4 MMR proficient cases, three were positive by CPS; two by TPS. Overall, only one of 8 available for analysis failed to show PD-L1 positivity by CPS. In contrast, non-medullary MMR-deficient carcinomas expressed PD-L1 in only 33% of tumors by CPS, and none by TPS. One medullary carcinoma was also EBV associated. Unlike "medullary carcinomas" of the kidney, INI1 was retained in all 8 cases tested. In conclusion, medullary carcinomas are 3% of ACs, have a strong association with MMR-D, and may be less aggressive despite their larger size. PD-L1 expression appears to be closely associated with medullary ACs regardless of MMR status, and thus targeted therapies can be considered for all medullary carcinomas of this site.

Summary Hepatoid tumors (HT) are rare neoplasms morphologically resembling hepatocellular carcinoma, which arise in several organs other than the liver. A comprehensive molecular profile of this group of neoplasms is still lacking. Genomic characterization of 19 HTs from different organs (three colon HTs, four esophagogastric HTs, four biliary HTs, six genitourinary HTs, two lung HTs) was performed using a multigene next-generation sequencing panel. NGS unraveled a composite molecular profile of HT. Their genetic alterations were clearly clustered by tumor site: (i) colorectal HT displayed microsatellite instability, high tumor mutational burden, mutations in ARID1A/B genes and NCOA4-RET gene fusion (2/3 cases); (ii) gastric HT had TP53 mutations (2/4); (iii) biliary HT displayed loss of CDKN2A (3/4) and loss of chromosome 18 (2/4); (iv) genital HT showed gain of chromosome 12 (3/6); (v) lung HT had STK11 somatic mutations (2/2). The only commonly mutated gene occurring in HT of different sites was TP53 (8/19 cases: colon 2, esophagogastric 2, biliary 2, genital 1, lungs 1). This study shows that most genetic alterations of HT were clustered by site, indicating that context matters. The novel potential targets for HT precision oncology are also clustered based on the anatomic origin. This study shed light on the biology of these rare cancers and may have important consequences for treatment decisions and clinical trial selection for HT patients.

The cause of most pancreatic and periampullary cancers (PAC) is unknown. Recently, anatomic variations such as pancreatobiliary maljunction have been recognized as risk factors, similar to Barrett-related gastro-esophageal cancers.Pre-operative MRI from 860 pancreatic/biliary resections, including 322 PACs, were evaluated for low-union (cystic duct joining the common hepatic duct inside of the pancreas or within 5 mm of the pancreatic border) RESULTS: Low-union, seen10% of the population, was present in 44% of PACs (73% distal bile duct/cholangiocarcinoma, 42% pancreatic head, and 34% ampullary). It was significantly lower(11%) in conditions without connection to the ductal system (thus not exposed to the ductal/biliary tract contents), namely mucinous cystic neoplasms and intrahepatic cholangiocarcinomas(p0.0001). Intra-pancreatic type low-union was seen in 16% of PACs versus 2% of controls(p0.0001).This study establishes an association between low-union and PACs, and points to an anatomy-induced chemical/bilious carcinogenesis. This may explain why most pancreas cancers are in the head. It is possible that the same chemical milieu, caused by conditions other than low-union/insertion, may also play a role in the remaining half of PACs. This opens various treatment opportunities including milieu modifications (chemoprevention), focused screening of at-risk patients, and early detection with possible corrective actions.

Background The significance of DNA mismatch repair (MMR) deficiency in ampullary cancers (ACs) has not been established. Methods In total, 127 ACs with invasive carcinomas measuring ≥3 mmthat had adequate tissue were analyzed immunohistochemically. Results MMR loss was detected in 18% of ACs (higher than in colorectal cancers). Twelve tumors with MLH1-PMS2 loss were negative for BRAF V600E mutation, suggesting a Lynch syndrome association. MMR-deficient tumors (n = 23), comparedwith MMR-intact tumors (n = 104), showed a striking male predominance (male:female ratio, 4.7). Although the deficient tumors had slightly larger invasion size (2.7 vs 2.1 cm), they also had more expansile growth and less invasiveness, including less perineural invasion, and they ultimately had lower tumor (T) classification and less lymph node metastasis (30% vs 53%; P = .04). More important, patients who had MMR-deficient tumors had better clinical outcomes, with a 5-year overall survival rate of 68% versus 45% (P = .03), which was even more pronounced in those who had higher Tclassification (5-year overall survival, 69% vs 34%; P = .04). MMR deficiencyhad a statistically significant association with medullary phenotype, pushing-border invasion, and tumor-infiltrating immune cells, and it occurred more frequently in ampullary-duodenal type tumors. Programed cell death-ligand 1 (PD-L1) levels analyzed in the 22 MMR-deficient ACs revealed that all medullary carcinomas were positive. Nonmedullary MMR-deficient carcinomas expressed PD-L1 in 33% of tumors cells according to the criteria for a combined positive score ≥1, but all were negative according to the tumor proportion score≥1 method. Conclusions In ACs, MMR deficiency is even more frequent (18%) than in colon cancer and often has a Lynch-suggestive profile, thus routine testing is warranted. Male gender, pushing-border infiltration, ampullary-duodenal origin, medullary histology, and tumor-related inflammation have a significantly higher association with MMR deficiency. MMR-deficient tumors have less aggressive behavior. PD-L1 expression is common in medullary-phenotype ACs, thus immunotherapy should be considered at least for this group.

Preinvasive tumor-forming gallbladder neoplasms that are composed of small, non-mucinous tubules with complex architecture remain a poorly characterized group. Here, we evaluated the clinicopathological characteristics of this entity. Twenty-eight examples were analyzed. Tumors were invariably pedunculated polyps with thin stalks, often presented as loosely attached intraluminal nodules, with cauliflower architecture (akin to cholesterol polyps) comprised of compact, back-to-back acinar-like, small tubular units with minimal/no cytoplasm showing variable complexity, creating a picture distinct from the other tubular type dysplasia in the gallbladder. Their limited stroma showed distinctive amorphous amyloid-like hyalinization (39%). While some had round nuclei with single prominent nucleoli, others exhibited slightly more elongated nuclei with washed out chromatin reminiscent of papillary thyroid carcinoma. Squamoid/meningothelial-like morules (71%) and subtle neuroendocrine cell clusters (39%) were frequent. The level of cytoarchitectural atypia qualified as high-grade dysplasia (HGD) in all cases, but none were invasive. The background mucosa showed no dysplasia, but cholesterolosis. The majority (n = 8/12) showed diffuse MUC6 expression and lacked MUC5AC expression. Based on these observations, 635 gallbladder carcinomas were re-analyzed for residual/adjacent lesions with entity-defining characteristics disclosed here, and none could be identified. Preinvasive tubular non-mucinous neoplasm of the gallbladder, which we propose to classify as intracholecystic tubular non-mucinous neoplasm, is a clinicopathologically discrete entity, which tends to occur in uninjured gallbladders and in association with cholesterol polyps. By being tubular, non-mucinous and MUC6-positive, it is akin to intraductal tubulopapillary neoplasms of pancreatobiliary tract, but it is also different in many other aspects. Although their cytoarchitectural complexity warrants an HGD/carcinoma classification, they do not show invasion and their distinct characteristics warrant their separate classification.

Significant improvements have taken place in our understanding of classification neuroendocrine neoplasms of the pancreas in the past decade. These are now regarded in three entirely separate categories: (I) neuroendocrine tumors (PanNETs) are by definition well differentiated, the pancreatic counterpart of carcinoids; (II) neuroendocrine carcinomas, which are poorly differentiated (PDNEC), the pancreatic examples of small cell carcinomas or large cell neuroendocrine carcinomas; (III) other neoplasms that have neuroendocrine differentiation or a distinct neuroendocrine component. PanNETs are by far the most common. They are now regarded as malignancies (albeit often curable when low grade and low stage) with the exception of minute incidental proliferations (tumorlets, or dysplastic-like changes) seen in the setting of some syndromes like MEN. PanNETs are staged based on their size, and for small T1 tumors, watchful waiting is now being considered, although these tumors are also known to show about 10% metastatic rate and/or progression, creating concerns about this approach. PanNETs are graded into 3, based on the proliferative activity, mostly based on the Ki-67 index, and also partly mitotic activity, although the latter seldom if ever is the determinant of the final grade. Neuroendocrine neoplasms with well differentiated morphology but Ki-67 >20% are now regarded as PanNET Grade 3 (G3); they have been shown to have a prognosis significantly worse than lesser grade PanNETs but still incomparably better than frank PDNECs, the latter typically has Ki-67 >50% (often much higher) and require platinum-based chemotherapy. There are also cases that are ambiguous between PanNET-G3 and PDNEC, and very rarely transformation of the former to the latter appears to occur. For low grade (G1/G2) PanNETs, more refined criteria to further prognosticate this group are needed. Morphologic variants being recognized may bring new perspectives to this group.

Better prognostication/stratification of pancreatic neuroendocrine tumors (PanNETs) is needed. In this detailed morpheomic study of 163 resected PanNETs, 11 unusual variants, some of which were not previously recognized, and others scarcely documented in the literature, were identified, and their pathologic characteristics were further analyzed. By behavior and clinicopathologic associations, these variants could be grouped into three prognostically different categories. I. More aggressive (20%). Included in this group were the variants that in average showed higher grade and stage and adverse outcome including oncocytic, plasmacytoid, lipid-rich and previously unrecognized hepatoid variants, which often had a more diffuse/broad-band growth pattern, with some also displaying discohesiveness. They were characterized by abundant cytoplasm and often had prominent nucleoli (as seen in metabolically active cells), thus the provisional name "metabolic cell phenotype." Because of their diversion from classical neuroendocrine cytomorphology, these variants created challenges on original diagnostic workup, particularly hepatoid examples, which revealed Arginase 1/Hep Par-1 expression in 50%. II. Less aggressive (10%). These cases either showed signs of maturation, including nested growth, paraganglioid pattern (which was previously unrecognized), and organoid PanNETs such as "ductulo-insular" growth, or showed symplastic/degenerative changes, and despite their paradoxically disconcerting histology, were more benevolent in behavior. III. Undetermined. There were other variants including mammary tubulolobular-like, pseudoglandular, peliotic, and sclerotic PanNETs, which although diagnostically challenging, their biologic significance could not be determined because of rarity or heterogeneous characteristics. Prognostic associations: Features that were significantly different in the more aggressive group than the less aggressive group were median size (5.0 vs 1.6 cm, p < 0.001), percentage of pT3+T4 cases (72% vs 12%, p < 0.001), Ki67 index (5.3% vs 2.3%, p = 0.001), % G2 and G3 cases (77% vs 27%, p < 0.001), and rate of lymph node and distant metastasis (96% vs 27%, p < 0.001). In stepwise logistic regression model using the 3 established prognosticators of T stage, size, and grade along with morphology, only aggressive-morphology (metabolic cell phenotype) was found to be associated with metastatic behavior with an odds ratio of 5.9 with 95% confidence interval (C.I.) 1.688 to 22.945 and p value 0.007. In conclusion, PanNETs display various morphologic patterns that are not only challenging and important diagnostically but appear to have biologic significance. Tumors with more diffuse growth of cells with nucleoli and abundant cytoplasm and/or discohesion (oncocytic, hepatoid, lipid-rich, plasmacytoid PanNETs), provisionally termed "metabolic cell phenotype," show aggressive characteristics and are an independent determinant of adverse outcome and thus may require closer post-surgical follow-up, whereas variants with more degenerative or mature features (ductuloinsular, pleomorphic, paraganglioma-like) appear to be more benevolent despite their more atypical and worrisome morphology.

Background. Endoscopic submucosal dissections (ESDs) allow removal of large gastrointestinal tumors and help patients avoid major oncologic surgery. In this study, the challenges and development of approaches toward successfully handling ESDs were analyzed in 279 colorectal specimens (114 rectal, 47 left, 118 right colonic; 90% adenoma with/without carcinoma). Methods. Each specimen was processed according to an established protocol including gross photography, mapping, and total submission for histopathologic examination. Results. Mean lesion size was 4.2 cm (range: 0.5-22 cm; 28% ≥5 cm; 6% ≥10 cm). Invasive carcinoma was present in 38 cases (14%), which had a mean overall tumor size of 3.8 cm (range: 1.1-17.5 cm), and mean largest size of the invasive component was 0.93 cm (range: 0.04-3 cm). Fifteen cases were staged as pT1a (submucosal invasion of

Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83–0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms. © 2022, The Author(s).

Pancreatoblastoma (PB) is a rare tumor of the pancreas. In case of metastases, the treatment options are sparse and targeted approaches are not developed. We here evaluate MCL1 amplification as a putative target in PB.Thirteen samples from adult (10/13) and pediatric patients (3/13) were collected. Three of these samples had been previously subjected to whole-exome sequencing (2 cases) or whole-genome sequencing (1 case) within a precision oncology program (NCT/DKTK MASTER), and this analysis had shown copy number gains of MCL1 gene. We established a fluorescence in situ hybridization (FISH) test to assess the copy number alterations of MCL1 gene in 13 formalin-fixed paraffin-embedded PBs, including the 3 cases assessed by genome sequencing. FISH analysis showed the amplification of MCL1 in 2 cases (both were adult PB), one of which was a case with the highest copy number gain at genomic analysis. In both cases, the average gene copy number per cell was ≥ 5.7 and the MCL1/1p12 ratio was ≥ 2.4. Our data support MCL1 as a putative target in PB. Patients with MCL1-amplified PB might benefit from MCL1 inhibition. Sequencing data is useful to screen for amplification; however, the established FISH for MCL1 can help to determine the level and cellular heterogeneity of MCL1 amplification more accurately.