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Open Access
Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications
(BMJ Publishing Group, 2020) Luchini, Claudio; Brosens, Lodewijk A. A.; Wood, Laura D.; Chatterjee, Deyali; Shin, Jae Il; Sciammarella, Concetta; Fiadone, Giulia; Malleo, Giuseppe; Salvia, Roberto; Kryklyva, Valentyna; Piredda, Maria L.; Cheng, Liang; Lawlor, Rita T.; Scarpa, Aldo; Adsay, Nazmi Volkan; Faculty Member; Koç University Hospital
Objective: recently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC). Design: PubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network -TCGA project). Results: overall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%-2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a KRAS/TP53 wild-type molecular background (p<0.01), with more common JAK genes mutations. Data on survival are still unclear. Conclusion: PDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.
Open Access
Gallbladder polyps: correlation of size and clinicopathologic characteristics based on updated definitions
(Public Library of Science, 2020) Baştürk, Olca; Reid, Michelle D.; Dursun, Nevra; Bağcı, Pelin; Saka, Burcu; Balcı, Serdar; Memiş, Bahar; Bellolio, Enrique; Araya, Juan Carlos; Roa, Juan Carlos; Tapia, Oscar; Losada, Hector; Sarmiento, Juan; Jang, Kee-Taek; Jang, Jin-Young; Pehlivanoğlu, Burçin; Taşkın, Orhun Çığ; Adsay, Nazmi Volkan; Erkan, Murat Mert; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Koç University Hospital; N/A; 286248; 214689
Background: different perspectives exist regarding the clinicopathologic characteristics, biology and management of gallbladder polyps. Size is often used as the surrogate evidence of polyp behavior and size of ≥1cm is widely used as cholecystectomy indication. Most studies on this issue are based on the pathologic correlation of polyps clinically selected for resection, whereas, the data regarding the nature of polypoid lesions from pathology perspective -regardless of the cholecystectomy indication- is highly limited. Methods: in this study, 4231 gallbladders -606 of which had gallbladder carcinoma- were reviewed carefully pathologically by the authors for polyps (defined as ≥2 mm). Separately, the cases that were diagnosed as “gallbladder polyps” in the surgical pathology databases were retrieved. Results: 643 polyps identified accordingly were re-evaluated histopathologically. Mean age of all patients was 55 years (range: 20–94); mean polyp size was 9 mm. Among these 643 polyps, 223 (34.6%) were neoplastic: I. Non-neoplastic polyps (n = 420; 65.4%) were smaller (mean: 4.1 mm), occurred in younger patients (mean: 52 years). This group consisted of fibromyoglandular polyps (n = 196) per the updated classification, cholesterol polyps (n = 166), polypoid pyloric gland metaplasia (n = 41) and inflammatory polyps (n = 17). II. Neoplastic polyps were larger (mean: 21 mm), detected in older patients (mean: 61 years) and consisted of intra-cholecystic neoplasms (WHO’s “adenomas” and “intracholecystic papillary neoplasms”, ≥1 cm; n = 120), their “incipient” version (<1 cm) (n = 44), polypoid invasive carcinomas (n = 26) and non-neoplastic polyps with incidental dysplastic changes (n = 33). In terms of size cut-off correlations, overall, only 27% of polyps were ≥1 cm, 90% of which were neoplastic. All (except for one) ≥2 cm were neoplastic. However, 14% of polyps <1 cm were also neoplastic. Positive predictive value of ≥1 cm cut-off -which is widely used for cholecystectomy indication-, was 94.3% and negative predictive value was 85%. Conclusions: approximately a third of polypoid lesions in the cholecystectomies (regardless of the indication) prove to be neoplastic. The vast majority of (90%) of polyps ≥1 cm and virtually all of those ≥2 cm are neoplastic confirming the current impression that polyps ≥1 cm ought to be removed. However, this study also illustrates that 30% of the neoplastic polyps are <1 cm and therefore small polyps should also be closely watched, especially in older patients.
Open Access
Histopathological tumour response scoring in resected pancreatic cancer following neoadjuvant therapy: international interobserver study (ISGPP-1)
(Oxford University Press (OUP), 2022) Janssen, Boris, V; van Roessel, Stijn; van Dieren, Susan; de Boer, Onno; Basturk, Olca; Brosens, Lodewijk; Campbell, Fiona; Chatterjee, Deyali; Chou, Angela; Doglioni, Claudio; Esposito, Irene; Feakins, Roger; Fuchs, Talia L.; Fukushima, Noriyoshi; Gill, Anthony J.; Hong, Seung-Mo; Hruban, Ralph H.; Kaplan, Jeffrey; Krasinkas, Alyssa; Luchini, Claudio; Shi, Chanjuan; Singhi, Aatur; Thompson, Elizabeth; Velthuysen, Marie-Louise F.; Besselink, Marc G.; Verheij, Joanne; Wang, Huamin; Verbeke, Caroline; Farina, Arantza; Adsay, Nazmi Volkan; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 286248
The ISGPP-1 study demonstrated that identifying the effect of neoadjuvant therapy in resected pancreatic cancer proved unreliable. The interobserver agreement for the current tumour response scoring (TRS) systems was suboptimal. A collaborative effort is required to develop an objective TRS system. Background Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems. Methods Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The accuracy in identifying the treatment effect was investigated in 60 patients (30 treatment-naive, 30 after neoadjuvant therapy (NAT)). The interobserver agreement for the College of American Pathologists (CAP) and MD Anderson Cancer Center (MDACC) tumour response scoring systems was assessed in 50 patients using intraclass correlation coefficients (ICCs). An ICC value below 0.50 indicated poor reliability, 0.50 or more and less than 0.75 indicated moderate reliability, 0.75 or more and below 0.90 indicated good reliability, and above 0.90 indicated excellent reliability. Results The sensitivity and specificity for identifying NAT effect were 76.2 and 49.0 per cent respectively. After NAT in 50 patients, ICC values for both tumour response scoring systems were moderate: 0.66 for CAP and 0.71 for MDACC. Conclusion Identification of the effect of NAT in resected pancreatic cancer proved unreliable, and interobserver agreement for the current tumour response scoring systems was suboptimal. These findings support the recently published International Study Group of Pancreatic Pathologists recommendations to score residual tumour burden rather than tumour regression after NAT.
Open Access
Inactivation of the Euchromatic Histone-Lysine N-Methyltransferase 2 pathway in pancreatic epithelial cells antagonizes cancer ınitiation and pancreatitis-associated promotion by altering growth and immune gene expression networks
(Frontiers, 2021) Urrutia, Guillermo; de Assuncao, Thiago Milech; Mathison, Angela J.; Salmonson, Ann; Kerketta, Romica; Zeighami, Atefeh; Stodola, Timothy J.; Pehlivanoglu, Burcin; Dwinell, Michael B.; Zimmermann, Michael T.; Iovanna, Juan L.; Urrutia, Raul; Lomberk, Gwen; Adsay, Nazmi Volkan; Faculty Member; School of Medicine; Koç University Hospital; 286248
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, painful disease with a 5-year survival rate of only 9%. Recent evidence indicates that distinct epigenomic landscapes underlie PDAC progression, identifying the H3K9me pathway as important to its pathobiology. Here, we delineate the role of Euchromatic Histone-lysine N-Methyltransferase 2 (EHMT2), the enzyme that generates H3K9me, as a downstream effector of oncogenic KRAS during PDAC initiation and pancreatitis-associated promotion. EHMT2 inactivation in pancreatic cells reduces H3K9me2 and antagonizes Kras(G12D)-mediated acinar-to-ductal metaplasia (ADM) and Pancreatic Intraepithelial Neoplasia (PanIN) formation in both the Pdx1-Cre and P48(Cre/+) Kras(G12D) mouse models. Ex vivo acinar explants also show impaired EGFR-KRAS-MAPK pathway-mediated ADM upon EHMT2 deletion. Notably, Kras(G12D) increases EHMT2 protein levels and EHMT2-EHMT1-WIZ complex formation. Transcriptome analysis reveals that EHMT2 inactivation upregulates a cell cycle inhibitory gene expression network that converges on the Cdkn1a/p21-Chek2 pathway. Congruently, pancreas tissue from Kras(G12D) animals with EHMT2 inactivation have increased P21 protein levels and enhanced senescence. Furthermore, loss of EHMT2 reduces inflammatory cell infiltration typically induced during Kras(G12D)-mediated initiation. The inhibitory effect on Kras(G12D)-induced growth is maintained in the pancreatitis-accelerated model, while simultaneously modifying immunoregulatory gene networks that also contribute to carcinogenesis. This study outlines the existence of a novel KRAS-EHMT2 pathway that is critical for mediating the growth-promoting and immunoregulatory effects of this oncogene in vivo, extending human observations to support a pathophysiological role for the H3K9me pathway in PDAC.
Open Access
Integrative characterization of intraductal tubulopapillary neoplasm (ITPN) of the pancreas and associated invasive adenocarcinoma
(Springer Nature, 2022) Mafficini, Andrea; Simbolo, Michele; Shibata, Tatsuhiro; Hong, Seung-Mo; Pea, Antonio; Brosens, Lodewijk A.; Cheng, Liang; Antonello, Davide; Sciammarella, Concetta; Cantu, Cinzia; Mattiolo, Paola; Taormina, Sergio, V; Malleo, Giuseppe; Marchegiani, Giovanni; Sereni, Elisabetta; Corbo, Vincenzo; Paolino, Gaetano; Ciaparrone, Chiara; Hiraoka, Nobuyoshi; Pallaoro, Daniel; Jansen, Casper; Milella, Michele; Salvia, Roberto; Lawlor, Rita T.; Scarpa, Aldo; Luchini, Claudio; Adsay, Nazmi Volkan; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Koç University Hospital; 286248
Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4 fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz-Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCH family genes and ERBB2, fusions involving RET and ERBB2, and RB1 disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53 mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCA alterations, ERBB2 and RET fusions, and ERBB2 amplification are novel targets in precision oncology. The TP53 mutation status can be used as a prognostic biomarker.
Open Access
Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumors
(Wiley, 2022) Paolino, G.; Esposito, I.; Hong, S.-M.; Baştürk, O.; Mattiolo, P.; Kaneko, T.; Veronese, N.; Scarpa, A.; Luchini, C.; Adsay, Nazmi Volkan; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Koç University Hospital; 286248
Aims: intraductal tubulopapillary neoplasm (ITPN)of the pancreas is a recently recognized pancreatictumor entity. Here we aimed to determine the mostimportant features with a systematic review coupledwith an integrated statistical approach.Methods and results: PubMed, SCOPUS, and Embasewere searched for studies reporting data on pancreaticITPN. The clinicopathological, immunohistochemical,and molecular data were summarized. Then a compre-hensive survival analysis and a comparative analysis ofthe molecular alterations of ITPN with those of pancre-atic ductal adenocarcinoma (PDAC) and intraductalpapillary mucinous neoplasm (IPMN) from referencecohorts (including the International Cancer GenomeConsortium- ICGC dataset and The Cancer GenomeAtlas, TCGA program) were conducted. The core find-ings of 128 patients were as follows: (i) Clinicopathologi-cal parameters: pancreatic head is the most commonsite; presence of an associated adenocarcinoma wasreported in 60% of cases, but with rare nodal metastasis.(ii) Immunohistochemistry: MUC1 (>90%) and MUC6(70%) were the most frequently expressed mucins. ITPNlacked the intestinal marker MUC2; unlike IPMN, it didnot express MUC5AC. (iii) Molecular landscape: Com-pared with PDAC/IPMN, the classic pancreatic driversKRAS,TP53,CDKN2A,SMAD4,GNAS,andRNF43were less altered in ITPN (P<0.001), whereasMCLamplifications,FGFR2fusions, andPI3KCAmutationswere commonly altered (P<0.001). (iv) Survival anal-ysis: ITPN with a “pure” branch duct involvementshowed the lowest risk of recurrence.Conclusion: ITPN is a distinct pancreatic neoplasmwith specific clinicopathological and molecular char-acteristics. Its recognition is fundamental for its clini-cal/prognostic implications and for the enrichment ofpotential targets for precision oncology.
Open Access
Ki-67 assessment of pancreatic neuroendocrine neoplasms: systematic review and meta-analysis of manual vs. digital pathology scoring
(Springer Nature, 2022) Luchini, Claudio; Pantanowitz, Liron; Asa, Sylvia L.; Antonini, Pietro; Girolami, Ilaria; Veronese, Nicola; Nottegar, Alessia; Cingarlini, Sara; Landoni, Luca; Brosens, Lodewijk A.; Verschuur, Anna V.; Mattiolo, Paola; Pea, Antonio; Mafficini, Andrea; Milella, Michele; Niazi, Muhammad K.; Gurcan, Metin N.; Eccher, Albino; Cree, Ian A.; Scarpa, Aldo; Adsay, Nazmi Volkan; Faculty Member; School of Medicine; Koç University Hospital; 286248
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.
Open Access
Löwenstein-Buschke: clinicopathologic analysis of 78 cases of large and giant condyloma acuminata of the anus
(Buluş Design, 2020) Pehlivanoğlu, Burçin; Reid, Michelle D.; Friedman, Theador; Lee, Michael; Tadros, Talaat S.; Bandyopadhyay, Sudeshna; Akinfolarin, Josephine; Baştürk, Olca; Taşkın, Orhun Çığ; Armutlu, Ayşe; Adsay, Nazmi Volkan; Faculty Member; Teaching Faculty; Koç University Hospital; 166686; N/A; 286248
Objective: the nature and clinicopathologic associations of Löwenstein-Buschke disease are unclear. Materials and methods: 78 anal condylomatous lesions (≥2 cm) were analyzed. Cases were classified based on size as "medium-large"(2-5 cm, n=59), "large" (5-10 cm, n=13) and "giant" ( > 10 cm, n=6). Results: patients were predominantly males (male/female=70/8). The mean age was 38 years (range:20-66). Two distinct lining types were recognized: 1) Epidermal type, typically lacking overt koilocytotic change, with associated invasive carcinoma in 8%; 2) Mucosal type, often manifesting koilocytotic change, with associated invasive carcinoma in 21%. Three types of high-grade dysplasia were discerned: 1) Basaloid, 8/9 showing high-grade dysplasia/carcinoma in-situ but non-invasive lesions; 2) Keratinizing, innocuous-appearing, but 5/6 was associated with invasion; 3) Giant cell, showing scattered individual bizarre cells, with 3/5 showing invasive carcinoma. Overall, invasion was found in 14% of the cases. The bulbous, broad-based destructive pattern characterizing verrucous carcinomas of the upper aerodigestive tract was not observed. A statistically significant trend existed between the incidence of invasion and size: 8.5% for medium-large, 23% for large, and 50% for giant (p=0.02). There was no discernable trend in the depth of invasion relative to condyloma size. Conclusions: our findings suggest that Löwenstein-Buschke lesions are mega versions of conventional condyloma. Being verrucoid, large and minimally invasive, they can be conceptually regarded as a form of verrucous carcinoma, but they do not display the histologic characteristics of verrucous carcinoma defined in the aerodigestive tract. They exhibit two types of linings: the mucosal type that often shows koilocytotic changes, and the epidermal type that can be difficult to recognize in biopsies. These lesions may be associated with invasive carcinoma, albeit limited in amount.
Open Access
Pancreatic neuroendocrine neoplasms: current state and ongoing controversies on terminology, classification and prognostication
(AME Publishing Company, 2020) Clarke, Callisia N.; Tsai, Susan; Evans, Douglas B.; Erkan, Murat Mert; Adsay, Nazmi Volkan; Taşkın, Orhun Çığ; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Koç University Hospital; 214689; 286248; N/A
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 Pa.nNFT 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 (G 1/G2) PanNETs, more refined criteria to further prognosticate this group are needed. Morphologic variants being recognized may bring new perspectives to this group.
Open Access
Pathologic evaluation of endoscopically resected non-ampullary duodenal lesions: a single center experience
(Buluş Design, 2020) Taşkın, Orhun Çığ; Meriçöz, Çisel Aydın; Aslan, Fatih; Adsay, Nazmi Volkan; Kapran, Yersu; Faculty Member; Faculty Member; Koç University Hospital; N/A; N/A; N/A; 286248; 168101
Objective: endoscopic resections are increasingly being used for superficial gastrointestinal lesions. However, application of these techniques in the duodenum remains challenging, due to the technical difficulties and high complication rates. This study projects a western tertiary center's experience in the endoscopic treatment and diagnostic workup of 19 cases of non-ampullary duodenal lesions. Material and method: specimens (12 endoscopic mucosal resections, 6 endoscopic submucosal dissections, and one endoscopic full-thickness resection) were processed following a strict protocol (photographed, mapped digitally and submitted totally) for histopathologic examination. Clinicopathologic characteristics, margin status and follow-up information were analyzed. Results: the mean age of the 16 patients was 52 years (range: 22-81). Mean lesion size was 1.4 cm (range: 0.3-3.6 cm) for all cases, 2 cm for endoscopic submucosal dissections and 1.1 cm for endoscopic mucosal resections. Mean number of blocks submitted was 4/case. Seven neuroendocrine tumors, 3 tubulovillous adenomas were diagnosed along with nine benign lesions. For endoscopic submucosal dissections, en-bloc and R0 resection rates were 100% (n=6/6) and 83% (n=5/6); for endoscopic mucosal resections, they were 92% (n=11/12) and 83% (n=10/12), respectively. Only one patient had procedure-related late perforation that was managed endoscopically. No mortality was encountered. Conclusion: duodenal endoscopic resections proved successful, safe and feasible methods in a tertiary center. The pathologist's role is to designate the accurate diagnosis, related histopathologic parameters and margin status. The gross protocol was found to be essential in evaluating specimen margins and orientation, as well as in size measurement. We recommend following a standardized approach including gross photography and digital mapping when handling these specimens, for both diagnostic and data collection purposes.
Open Access
Pure hepatoid tumors of the pancreas harboring CTNNB1 somatic mutations: a new entity among solid pseudopapillary neoplasms
(Springer, 2022) Mattiolo, Paola; Mafficini, Andrea; Lawlor, Rita T.; Marchegiani, Giovanni; Malleo, Giuseppe; Pea, Antonio; Salvia, Roberto; Piccoli, Paola; Sciammarella, Concetta; Santonicco, Nicola; Parisi, Alice; Silvestris, Nicola; Milella, Michele; Scarpa, Aldo; Luchini, Claudio; Adsay, Nazmi Volkan; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Koç University Hospital; 286248
Hepatoid tumors (HTs) represent a rare group of neoplasms that are histologically similar to hepatocellular carcinoma but arise outside the liver. The current World Health Organization classification recognizes the hepatoid morphology of pancreatic tumors only as a possible variant of pancreatic ductal adenocarcinoma (PDAC). Here, we describe two cases of ""pure"" HT of the pancreas showing common features and characterized by indolent biological behavior. These tumors were roundish nodules with pushing borders, hyaline globules, and pure hepatoid histology; they were diffusely positive for beta-catenin and LEF1 on immunohistochemistry. At next-generation sequencing, both neoplasms harbored only one pathogenic somatic mutation that affected the CTNNB1 gene at exon 3 and showed a loss of heterozygosity on chromosomes 18 and 21. By integrating macroscopic and microscopic features, along with their molecular profiles, we advocate that such tumors represent a distinct entity from PDAC and should be considered a new variant of solid pseudopapillary neoplasms. The recognition of this new neoplastic category may have immediate implications not only for tumor taxonomy but also for clinical practice.
Open Access
Whole exome sequencing of biliary tubulopapillary neoplasms reveals common mutations in chromatin remodeling genes
(Multidisciplinary Digital Publishing Institute (MDPI), 2021) Gross, Claudia; Engleitner, Thomas; Lange, Sebastian; Weber, Julia; Jesinghaus, Moritz; Konukiewitz, Bjoern; Muckenhuber, Alexander; Steiger, Katja; Pfarr, Nicole; Goeppert, Benjamin; Keller, Gisela; Weichert, Wilko; Kloeppel, Gunter; Rad, Roland; Esposito, Irene; Schlitter, Anna Melissa; Adsay, Nazmi Volkan; Faculty Member; School of Medicine; 286248
Simple summary: Intraductal tubulopapillary neoplasms (ITPN) have recently been described as rare precursor lesions of pancreatic ductal adenocarcinoma and cholangiocarcinoma. Despite a high number of associated invasive adenocarcinomas at the time of diagnosis, patients with ITPN tend to have a much better clinical outcome than those with classical pancreato-biliary adenocarcinoma. Furthermore, rare molecular studies of ITPN show an unexpected lack of hotspot mutations in common driver genes of pancreato-biliary adenocarcinoma, including KRAS. This article reports the first large comprehensive and comparative molecular study of pancreato-biliary ITPN. In the absence of KRAS mutations, we found a high genetic heterogeneity with enrichment in core signaling pathways, including putative actionable genomic targets in one-third of the cases. Whereas, pancreatic ITPN demonstrates a highly distinct genetic profile, differing from classical pancreatic carcinogenesis, biliary ITPN and classical cholangiocarcinoma share common alterations in key genes of the chromatin remodeling pathway, and therefore, appear more closely related than pancreatic ITPN and classical pancreatic ductal adenocarcinoma PDAC. The molecular carcinogenesis of intraductal tubulopapillary neoplasms (ITPN), recently described as rare neoplasms in the pancreato-biliary tract with a favorable prognosis despite a high incidence of associated pancreato-biliary adenocarcinoma, is still poorly understood. To identify driver genes, chromosomal gains and losses, mutational signatures, key signaling pathways, and potential therapeutic targets, the molecular profile of 11 biliary and 6 pancreatic ITPNs, associated with invasive adenocarcinoma in 14/17 cases, are studied by whole exome sequencing (WES). The WES of 17 ITPNs reveals common copy number variants (CNVs) broadly distributed across the genome, with recurrent chromosomal deletions primarily in 1p36 and 9p21 affecting the tumor suppressors CHD5 and CDKN2A, respectively, and gains in 1q affecting the prominent oncogene AKT3. The identified somatic nucleotide variants (SNVs) involve few core signaling pathways despite high genetic heterogeneity with diverse mutational spectra: Chromatin remodeling, the cell cycle, and DNA damage/repair. An OncoKB search identifies putative actionable genomic targets in 35% of the cases (6/17), including recurrent missense mutations of the FGFR2 gene in biliary ITPNs (2/11, 18%). Our results show that somatic SNV in classical cancer genes, typically associated with pancreato-biliary carcinogenesis, were absent (KRAS, IDH1/2, GNAS, and others) to rare (TP53 and SMAD4, 6%, respectively) in ITPNs. Mutational signature pattern analysis reveals a predominance of an age-related pattern. Our findings highlight that biliary ITPN and classical cholangiocarcinoma display commonalities, in particular mutations in genes of the chromatin remodeling pathway, and appear, therefore, more closely related than pancreatic ITPN and classical pancreatic ductal adenocarcinoma.