assification of Tumours « 5th Edition Digestive System Tumours Edited by the WHO Classification of Tumours Editorial Board We Wa) eo perteContents List of abbreviations Foreword 1 Introduction o tumours ofthe Gigestive system General introduction Gass'ation of neuroendocrine neoplasms ofthe digestive system ‘TNM staging o! wal-dierentated neureendoctine tumours ‘ofthe gastrointestinal tract 2 Tumours ofthe oesophagus WHO classtcaton of tumours of he oesophagus ‘TNA elaging of turours of the oasophagus Introduction Benign epithelia tumours and precursors ‘Squamous papiloms Barrett dysplasia Squamous dysplasia Malignant epthetal tunours ‘Adenocarcinama ofthe oesophagus and ‘casophagogastic junction NOS ‘Adenoid oystic carcinoma ‘Aaenosquamous and muccepidermod carcinomas ‘Squamous cell carcinoma NOS Unditierentated carcinoma Neuroendocrine neoplasms 3. Tumours ofthe stomach \WHO classification of tumours ofthe stomach ‘TNM staging of carcinomas of tre stomach Introduction Gastritis and metaplasia: precursors of gastric neoplasms Senign apthelal tumours and precursors Fund gland polyps Hypetpiasic polyps Dysplasia Intestinal-type adenoma, Foveolatype adenoma Pyfetc gland adenoma ‘Oxyntic gland adenoma Malignant epithelial tumours ‘Adenocarcinoma Squamous cel carcinoma ‘Adenosquamous carcinoma Unditferentated carcinoma, Gastobigsioma Nouraendocrine neoplasms 4 Tumours ofthe small intestine and ampul WHO classification ofturours ofthe small intestine ancampule TNM staging of carcinomas ofthe smal intestine “TNM staging of carcinomas ofthe ampulla of Valor Introduction Benign opitnalia tumours and precursors Non-ampullary adenoma Ampulity adenoma Malignant epithelial tumours Non-ampullary adenocarcinoma, ‘Ampullary adenocarcinoma Neuroandocrine nacpasme x x 13 4 6 20 23 2 2 100 wwe 108 a we 13 4 116 118 3 124 17 1 5 Tumours of the appendix WHO clasetieation of tumours of the eppencie ‘TNM staging of adenocarcinomas ofthe appendix Introduction Epithelial tumours ‘Sortated lasions and polyps Mucinous neoplasm Adenccarcinoma Goblet cll adenocarcinoma Neuroendocrine neoplasms 6 Tumours ofthe colon and rectum WHO classification of tumours of the colon and rectum TNM staging of carcinomas of the colon and rectum Introduction Benign epithelial tumours and precursors ‘Serrated lesions ang co'yps Conventional adenoma Inflammatory bowel dissase-associaled dysplasia Malignant epitiatal tumours ‘Adenocarcinoma Neuroendocrine neoplasms 7. Tumours ofthe anal canal WHO classification of tumours of the anal canal ‘TNM staging of tumours ofthe eral canal and perianal skin Introduction Benign epithelial tumours and precursors Inflammatory cloacogenic poiyp ‘Condyioma: ‘Squamous dysplasia (rtraepitholal neoplasia) Malignant epithelia tumours Squamous cel carcinoma, ‘Adenocarcinoma Neuroendocrine neoplasms 8 Tumours ofthe liver and intrahepatic bile ducts WHO classification of tumours ofthe lver and intrahepatic bite ducts TNM staging of tumours of the iver NM staging of tumours of he intrahepatic ble ducts Inrosuetion Benign hepatocellular tumours Focal nocular hyperpiasia of the liver Hepatocellular adenoma ‘Malignant hepatocellular tumours and precursors Hepatocellular carcinoma Hepatobiastoma ‘Benign biliary tumours and precursors Bile duct adenoma Bilary adenofivcoma Mucinous cystic neoplasm ofthe liver and biliary system Bilary inraepithelal neoplasia (see Ch. 9) Inttaductal papllary neoplasm of the ble ducts (coe.Cn.9) Matignert ily tumours Intrahepatic cholangiacarcinoma Combined hapatocaluar-chalengiocarcinoma and Unditferentiated primary iver carcinoma Hepatic neuroendocrine neopiasme 135 136 137 140 141 144 od 149 152 187 158 159 162 163 170 v4 wr 188 193 194 195 196 198 200 202 205 208 22 215 26 27 218 220 221 226 229 240 245 248 250 254n 9 Tumours of the gallbladder and extrahepatic bile ucts 265 ‘11 Haomnatolymphoid tumours ofthe digestive systom 873. WHO clasafieation of tumours ofthe gallbladder and WHO classtication of haematoymphaid tumours ‘extrahepatic bile ducts 268 ol the digestive system 374 TNM staging of tumours of the gatbladder 287 Introduction 36 TNM staging of turours of the perhe bile duots 268 Site-specific haematolymphaid tumours ‘TNM staging of tumours of the distal extrahepatic bile dvet 269 ‘Extvanadal marginal zone lymphoma of mucosa Irwroduction 270 ‘ass0olated lymphoid tisue (MALT ymphoma) S78. EBonign epithelia tumours and precursors ‘Duodenal-typefolicular lymphoma 383 Pylon gland adenoma ofthe galbiadder ont Entoropathy-associated T-cell lymphoma 386 Bilary inraepitnelal neoplesia 273 ‘Monomarphie epthelvopie intestinal T-cell lymphoma 390 Intracholecystic papilary neoplasm 276 Intestinal T-cell lymphoma NOS 393 Intraductal papilary neoplasm ofthe bile ducts 278 Ingolent T-cell ympnoproiterative disorder ofthe Gl tract 385 Muoinaus cystic neoplasm of the iver and biliary system Hopatosplonic T-cell ymphoma 207 (00 Ch. 8) EBV+ inflammatory folicular Genatic col sarcoma 399) Malignant epithelial tumours Haematolymphoid tumours occuring with some frequency Carcinoma ofthe gaioladder 283 inthe digestive system Carcinoma othe extrahepatic ble ducts 208 Diftuse large 8-col lymphoma 402 Neuroendocrine naoplasms of the Folicular ymphoma 406 ‘gallbladder and bile ducts 292 Marte cell lymphoma 408 Burt lymphoma au 410 Tumours of the pancreas 295 Plasmablastc lymphoma 415 WHO classifistion of tumours ofthe pancreas 298 Postranspiant ymphoproiferative disorders ar ‘TAM ctaging of carcinomas of the pancreas. par Extranodal NK/T-cellymphoma 420 Invoduetion 233, Systemic mastocylosis 423 Banign epithelial tumours and precursors Langechans cal histiocytosis 426 ‘Acinar cystic transformation 300 Folieuler dendritic cel sarcoma 428 ‘Sorous nooplasrns 303, Histiooytic sarcoma 430 intraepithelial neoplasia 307 Intraductal papilary mucinous neoplasm 310 12 Mesenchymal tumours ofthe digestive system 433 Intraductal onoocytic papilary neoplasm a5 WHO classification of mesenchymal tunours Intraductal tubulopapitary neoplasm 3i7 ‘of tne digestive system 434 Mucinous cystic neoplasm 319 ‘TNM staging of gastrointestinal strornal tumours 495 Maiignant epithelial tumours Introduction 436 Ductal adenocarcinoma 302 Gastointestinal somal tumour 499 Acinar cel carcinoma 333 Adipose issue and (myo)fibroblastc tumours Pancreatoblastoma 37 inflammatory myolibrobiastic tumour aaa Sold pseudopapliary neoplasm 340 Desmoid foromatosis 448, Nouraandoorine neoplasms Solitary fibrous tumour 408 Introduction 343 Lipoma 450 Non-tunctoning pancreatic neuroendocrine tumours 347. Inflammatory fibroid polyp 452 Functioning neuroendocrine tumours Ploxform fbrornyxoma 454 Tnauinera 353 ‘Smooth muscle and skeletal muscle tumours Gastrinoma, 355 Leiomyoma 455 viPoma 357 Leiomyosarcoma 458 Glcagonoma 388 Phabderyosarcoma 460 Somatestatinoma 381 Vascular and perivascular turnurs ACTH-praducing neuroendocrine turnour 363 Haemangioma, 462 ‘Serotonin-preducing neuroendocrine tumour 365 Eptheliod haemangicendotnelioma 466 Neuroendocrine carcinoma 367 kaposi satcoma: 463 MINENS 370 ‘Angiosarcoma’ at Glomus turour 473 Lymphangioma ang lymphangiomatosis a5 Neural tumours a7 479 Prineurioma 231 Gangioneuroma and gangioneuromatosis 483 Tumours of uncertain differentiation PEComa, including angomysipoma 485 ‘Mesenchiyral namarioma othe liver 485 Caletying nested stromal-epitnelal tumour ofthe iver 490, ‘Syrowal srcoma, 492 Gasicoinestinal clear coll sarcoma / matignant ‘gastrointestinal neuroectodermal tumour 494 mbryonal sarcoma ofthe iver 27449 Other tumours ofthe digestive system {WHO classification of other tumours ofthe digestive system Mucosal melanoma Germ cell tumours Metastases +4 Gonetie tumour syndromes ofthe digestive system Introcueton Lynch syndrome Familia! adenomatous polyposis 1 GAPPS and other fundic gland polyposes (thar adenomatous polyposes Seratad polyposis. Hereditary difuse gastric cancer Famili pancreatic cancer Juvenile polyposis syndrome Peute-sJeghors syndrome Cowden syndrome Other genetic tumour syncromes Contributors Doclaration of interests IARCIWHO Committe for ICD-O ‘Sources References ‘Subject index rovious volumes in the eerios 499 ‘500 502 504 506 st 512 515 522 526 529 532 535, 539) 52 505, Sar 550 851 557 636,List of abbreviations 30 ttvee-dimencional ABC activated B cell ‘ACG Asian Cancer Research Group ‘ADP adenosine diphosphate JCC ‘American Joint Cormitiea on Cancer ATP. ‘adenosine triphosphate a ‘confidence intarval ‘cimp (CpG island methylatoc phenotype NS: ccenral nervous system csF cerebrospinal fad cr ‘computed temegranhy MMR ‘mismatch repair-devicent DNA. deoxyribonucleic acid EBER EBV-encoded small RNA EBV Epstein-Barr vius EC ool enteroenromattin cot ECLoell ——_enteroctwomati-ika cot EHED ‘extrahopatic bile duct EMI ‘examurel vascular invasion ER estrogen receptor cus ‘endoscopic ulrasonography Foo. folicuiar dendrite col FOGPET —_18¥-iuoroceoxyglucose positron emission tomography FISH fluorescence in situ hybridization FNA fre-needie aspiration FNCLOC Fédération Natlonale des Centres de Lutta Conte lo Gancor ace (germina-centra B cll Gltact astoinestinal act apes apican-3 es (Utamine syrthetase HEE hasmatoxyin and eosin Hev hepatitis 8 virus rev hepatitis C vinss HV human immunadeficiency veus HPV. human papillomavirus IARC International Agency for Research on Cancer x Listof abbreviations te-11 ico iL vi Insight Ne ratio NK coll NSAID PAS PASD PCR PET PET-cr Pl pattern PR International Classification of Diseases, 11th Revision International iassicaton of Diseases for Oncology intraepthotal ymphocyte immunoglobulin intramural vascular invasion International Society for Gastrointestinal Heredltary Tumours inteligence quotient Japanese Gastric Cancer Association kio base par rmale-torfemale ato mucosa-associated lymphoid tissue ‘mass forming patter magnetic resonance imaging messenger rbonucteic acid rmeroeatoiite instabity rmiorosatolitestabity rnuclear-to-cyloplasmic ratio natural kiler cell ‘non-steroidal entéinflammatory dug potiodc acid-Schit ppotiodc acie-Schif with diastase polymerase chain reaction pasion emission tomography positon emission tomography-computed tomography periductal infiltrating pattern progesterone receptor ribonucleic acia somatic copy-number alteration succinate dehydrogenase Sunvellance, Epidemiology, and End Results Program Single nucleotide polymorphism ‘wanearierial chemosmibolzation The Cancer Genome Alles tumour, node, metastasis ‘umaur regression grace Union for international Cancer Contra! utravioletForeword The WHO Classification of Tumours, published as a series of books (also known as the WHO Blue Books), is an essential too! for standardizing diagnostic practice worldwide. The WHO classttication also serves as a vehicle forthe translation of cancer research into practice. The diagnostic criteria and standards these books contain are underpinned by evidence evaluated and debated by experts in the field. About 200 authors and editors participate in the production of each book, and they give their time freely fo this task. | am very grateful for their help; it's @ remarkable team effort. This frst volume of the fifth edition of the WHO Blue Books incorporates several important changes to the series as a whole. For example, this is the first WHO Blue Book to be led by an editorial board. The WHO Classification of Tumours Editorial Board is ‘composed of standing members nominated by pathology organizations and expert members selected on the basis of informed bib- llometric analysis. The diagnostic process 's increasingly multidisciplinary, and we are delighted thal several radiology and clinical experts have already joined us to address specific needs. The editorial board also includes a patient representative ‘The most conspicuous change to the format of the books in the fith ecition is that turnour types common to multiple systems are dealt with together — so there are separate chapters on haematolymphoid tumours and mesenchymal tumours. There Is also & Cchapter on genetic tumour syndromes. Genetic disorders are of increasing importance to diagnosis in individual patients, and the study of these disorders has undoubtedly informed our understanding of tumour biology and behaviour over the past 10 years. The inclusion of a chapter dedicated to genetic tumour syndromes reflects this importance. We have attempted to take a more systematic approach to the mulfaceted nature of tumour classification; each tumour type | described on the basis of its localization, clinical features, epidemiology, etiology, pathogenesis, histopathology, diagnostic. molecular pathology, staging, and prognosis and prediction, Where appropriate we have also included information on macroscopic appearance and cytology, as well as essential and desirable diagnostic criteria. This standardized, modular approactt is in part 10 ready the books to be accessible online, but italso enables us to call attention to areas in which there is litle information, and where serious gaps in our knowledge remain to be addressed. ‘The organization of the WHO Blue Books content now follows the normal progression from benign to malignant - a break with the fourth edition, but one we hope will be welcome, The volumes are still organized on the basis of anatomical site (digestive system, breast, soft tissue and bone, etc), and each tumour type is listed within a taxonomic classification that follows the format below, which helps to structure the books in a system- alic manner: + Site; e.g. stomach Category; ©.g, epithelial tumours + Family (class); 0.g. adenomas and other premalignant neoplastic lesions Type; eg. adenoma * Subtype; e.g. foveolar-type adenoma The issue of whether 2 given tumour type represents a distinct enlty rather than a subtype continues to exercise pathologists, and itis the topic of mary publications in the scientific literature. We continue to deal with this issue on a case-by-case basis, bul we believe there are inherent rules that can be applied. For example, tumours in which multiple histologicel patterns contain shared ‘truncal mutations are clearly of the same type, despite the differences in their appearance. Equally, genetic heterogeneity within the ‘same tumour type may have implications for treatment. A small shift in terminology as of this new edition is that the term "variant" in reference to a specific kind of tumour has been wholly superseded by "subtype", in an effort to more clearly differentiate this ‘meaning from that of “variant” in reference to @ genetic alteration. ‘The WHO Blue Books are much appreciated by pathologists and of increasing importance to cancer researchers. The new editorial board and | certainly hope that the series will continue to meet the need for standards in diagnosis and to faciliate the translation Of diagnastic research into practice worldwide. It is particularly important that cancers continue to be classified and diagnosed ‘accarding fo the sare standards internationally so that pationts can benefit rom multicentre clinical tals, as well as from the results of local trials conducted on different continents. GF Sle Gilink coe Head, WHO Classification of Tumours Group International Agency for Research on Cancer June 2019 Foreword xiIntroduction to tumours of the digestive system Geren van Suara Cements ra ore ete n eee Stem Tee ceIntroduction to tumours of the digestive system ‘The WHO classification of digestive system tumours presented in this volume of tne WHO Classification of Tumours series’ ith ‘dition reflects important advancements in our understanding (of tumours of the digestive system. For the fit time, certain ‘tumour types are defined as much by their moleculer pheno- type as their histological characteristics; however, histopatho- logical classification remains the gold standard tor diagnosis, inmost instances. The WHO Classification of Tumours sories is designed to be used worldwide, including those settings where a lack of tissue samples or of specific technical facilities limits the pathologist's abilty to rely on molecular testing, ‘Since the publication of the fourth-edition digestive system tumours volume in 2010 (975), there have bean important devel ‘opments in our understanding of the etiology and pathogen- ‘esis of many tumours. However, the extent to which this new information has altered clinical practice has been quite vari- able, For some of the tumours described in this volume, there is iltle molecular pathology in clinical use, despite the fact that we now have @ more detsiled understanding of their molecu lar pathogenesis, A tumour's molecular pathology, as defined for the purposes of this publication, concerns the molecular markers that are relevant to the tumour's diagnosss, biological behaviour, outcome, and treatment, rather than its molecular pathogenesis. The role of molecular pathology is expanding For some tumour entities, molecular analysis is now essential for establishing an acourate diagnosis. Some of these analyses require investigation of somatic (acquired) genetic alterations, ‘gene or protein expression, or even circulating tumour markers. For certain tumour types, specific analytical tests are needed to predict prognosis or tumour progression, and these tests are ‘carefully outlined in this volume. In the following paragraphs, ‘we have summarized some of the more notable changes since the fourth edition. More detalled descriptions can be found in the introductions to the chapters on each main tumour category andior in the tumour- specific sections themselves, In instances where the editorial board determined that there was insufficient evidence of the diagnostic or clinical relevance of new informa- tion about a particular tumour entity, the position held in the fourth edition has been maintained as the standard in the cur- rent volume, ‘There has been substantial progress in our understanding of the development of oesophageal neoplasia and the sequential neoplastic progression from inflammation to metaplasia (Barrett ‘oesophagus), dysplasia, and uliimately adenocarcinoma. This process is intialy driven by gasto-oesophageal reflux disease, ‘which leads to reprogramming of cell differentiation and prolt- eration in the oesophagus. The molecular pathway of cancer progression in the stom- ach is less clear. Most so-called epidemic gastric cancers are ‘now considered to be inflammation-driven, and their etiology 's characteristicaly environmental - usually related to Helico- ‘bacter pyfon infection. It is because of this infectious etiology 14 _Intraduetion to tumours of the digestive system Odze RD Paradis V Cree IA Rugge M Kiimstra DS ‘Sohirmacher P Nagtegaal ID that gastric cancer is included among the limited number of highly lethal but preventable cancers, Chronic gastric inflam- ‘mation leads to changes in the microenvironment (including the rmicrobiome) that result in mucosal atrophy/metaplasia, which may progress to neoplasia after further molecular alterations, Metaplastic changes in the upper Gl tract are well recognized 28 early cancer precursors, but their precise molecular mecha- nisms and the exact role of the progenitor cals in the oncogenic cascade are stil subjects of intense investigation ‘The pathogenesis of precursor lesions is lass clear in oesoph: fageal squamous carcinogenesis than in gastric carcinogen- esis. Environmental factors are believed to play en important role, but the mechanisms of neoplastic change as a result of specific factors, such as tobacco use and alcohol consump- tion, are poorly understood. For example, HPV infection was intially believed to play a key role in squamous carcinogenesis, but recent evidence suggests that there is no such association in most cases of oesophageal squamous cell carcinoma. This finding contrasts with our current knawiedge of the etiology and pathogenesis of anal squamous lesions, in which HPV infec tion does appear to play an important etiological role, driving (genetic alterations similar o thase seen in cervical cancer. ‘The pathogenesis of adenocarcinomas of the intestines (the small and large bowel and the appendix) is now much bet: ter delineated than it was a decade ago. The introduction of population-based screening for colorectal cancer has laid the foundation for a better understanding of neoplastic precur- sr lesions and the molecular pathways associated with each type of tumour. For example, our knowiedge of the molecular pathways and biological behaviour of conventional adenomas and serrated precursor lesions, including the recently renamed sessile serrated lesion (lormerly called sessile serrated polyp/ adenoma), has grown rapidly in the past decade, and this has enabled clinicians to provide tailored, evidence-driven soreening and surveillance programmes. Our understanding ‘of appendiceal lumours has also improved. For example, we row know that many tumours of the appendix develop via neo- plastic precursor lesions similar to those in the small and large intestines, and the biological potential and molecular pathways. of appendiceal tumours are therefore much better appreciated. Tne recently renamed goblet cell adenocarcinoma {formerly called goblet cell carcincidiearcinoma) of the appendix is a prime example of a tumour whose biological potential and his {ological characteristics have been better described, resulting in improvements in the pathological approach to these tumours. For some rare tumours, distinctive diver mutations have been Identiied, for example, the characteristic MALATI-GLI fusion gene in gastroblastoma and EWSA1 fusions in gastrointestinal Clear cell sarcoma and malignant gastrointestinal neuroecto- dermal tumour. In both examples, demonstration of the fusion (gene is now required for the diagnosis.One particulerly important change in the fith edition is in the classification of neuroendocrine neoplasms (NENs), which occur in multiple stes throughout the body. In this volume, NENs are covered within each organ-specific chapter, including the chap- ter on tumours of the pancreas, where detalled sections describ: ing each functioning and non-functioning subtype are provided. Previously, these neoplasms were covered in detail only in the ‘yolume on tumours of endocrine organs {1936}, The general prin- ciples guiding the classification of all NENs are presented in a separate introduction to this topic (Classification of neuroendo- Corne neoplasms of the digestive system, p. 16). To consolidate curincteased understanding of the genetics ofthese neoplasms, ‘2 gfoup of experts met for a consensus conference at the Inter rational Agency for Research on Cancer (IARC) in Novernber 2017 and subsequently published a paper in which they pro posed distinguishing between wol-ciferentiated neuroendoorine tumours (NETS) and poorly differentiated neuroendocrine carci- rnomas (NECs) in all sites where these neoplasms arise (2717 ‘Genomic data have also led to a change in the classification of mixed NENS, which are now grouped into the conceptual cate- ‘gory of ‘mixed neuroendocrine-non-neuroendocrine neoplasms. (MINENs)". Mixed acenoneuroendocrine carcinomas (MANECs}, ‘which show genetic alterations similar to those of adenocarcino- mas or NECs, rather than NETS, probably reflect clonal evolution within the turnours, which is rapidly growing area of interest. The study of these mixed carcinomas may also lead to an improved understanding of other facets of clonality in tumours ofthe diges- tive eystem and other parts of the body. Unfortunately, mixed tumours in other anatomical sites (e.g. ‘esophageal adenosquamous carcinoma and muooepider- moid carcinoma, as well as hepatic carcinomas with mixed hopatocolular and cholangiolar differentiation) also remain subjects of uncertainty. The relative importance of the vari- ‘ous lineages of cifferertiation within these neoplasms remains unknown, Its also uncertain how these neoplasms develop and how they should be treated clinically. These issues are a matter of debate because hard evidence is lacking, but improvements in the pathological criteria and classification of these neoplasms should help to standardize the diagnostic approach and facil- tate batter clinical and genomic research, There are certain terms in current day-to-day use about which ‘mary pathologists continue to disagree. The editorial board care~ fully considered our current understanding of carcinogenesis pathways when considering tho use of specific terms and defi- nitions. In general, the overall consensus was that established ferms, definitions, and criteria should not be changed unless there was strong evidence to support doing so and the proposed changes had clinical relevance, For some tumours, our under- standing ofthe progression from normal epithelium to metastatic ‘carcinoma remains inadequate. For example, in certain tumours the ine between benign and malignant can be ambiguous, and in some cases the distinction is more definitional than biological These are some of the many areas of tumour biology that need {0 be more fully investigated in the future, In the filth ecition, the terminology for precursors to invasive carcinoma in the Gl tract has been standardized somewhat, although the terms “dysplasia” and “intraepithelial neoplasia’ are both still considered acceptable for lesions in certain ana- tomical locations, in acknowledgement of their ongoing aiinical accepiance. For example, the term ‘dysplasia’ is preferred for i lesions in the tubular gut, whereas “intraepithelial neoplasia’ is preferred for those in the pancreas, gallbladder, and biliary tree. For all anatomical sites, however, a two-tiered system (low-grade vs high-grade) is considered the standard grading system for neoplastic precursor lesions. This has replaced the three-tiered dgrading scheme previously used for lasions in tne pancraatobil- lary system (267}. The term “carcinoma in situ" continues to be strongly discouraged in clinical practice for a variety of reasons, ‘most notabiy ts clinical ambiguly. This term is encompassed by the category of high-grade dysplasia / intraepithelial neoplasia ‘Genomic findings have helped to determine that some tumours, ‘such as pancreatic intraductal neoplasms (i, intraductal ‘oncocytic papillary neoplasm and intraductal tubulopapilary neoplasm) are distinct from pancreatic intraductal papillary mucinous neoplasms, and these tumours are now classified as separate entities. Additional clinical and genomi information has also helped in the identification of carcinoma subtypes that are distinct enough to warrant separate classification, Many refinements of the fourth-edition classification have been made concerning liver tumours, supported by novel molecular findings. For example, a comprehonsive picture of the molecular changes that occur in common hepatocellular carcinoma has recently emerged from large-scale molecular profling studies. Meanwhile, several rarer hepatocellular car- cinoma subtypes, which together may account for 20-30% of cases, have been defined by consistent morphomoleoular and Clinical features, with fiorolamellar carcinoma and its diagnos tic DNAJBI-PRKACA translocation being one prime example. Intrahepatic cholangiocarcinoma is now understood to be a dis- tinct entity with two very specific subtypes: a large duct type, which resembles extrahepatic cholangiocarcinoma, and a small duct type, which shares etiological, pathogenetic, and imaging characteristics with hepatocellular carcinoma. The two subtypes have vary different etiologies, molecular alterations, growth pat- tems, and clinical behaviours, exemplifying the conflict between anatomically and histogeneticallyipathogenetically based clas- stications. Clinical research and study protocols will need to incorporate these findings in the near future. Also supported by ‘molecular findings, the defintion of combined hepatocelluiar- Ccholangiocarcinoma and its distinction fram other entities have recently become clearer. Cholangioloceltular carcinoma is no longer considered a subtype of combined hepatoceliuiar-chol- angiocarcinoma, but rather a subtype of small duct intrahepatic Ccholangiocarcinama, meaning thal all intrahepatic carcinomas with a ductal or tubular phenotype are now included within the category of intrahepatic cholangiocarcinoma. A classic example of morphology-based molecular profiling leading to a new clas sification based on a combination of biological and molecular factors is the classification of hepatocelislar adenomas, which has gained a high degree of clinical relevance and has fueled the implementation of refined morphological crteria and molec- lar testing in routine diagnostics, In this fifth-edition volume, haematolymphoid tumours and ‘mesenchymal tumours that occur in the Gl tract, some of which are very distinctive, have been grouped together in their own separate chapters, 10 ensure consistency and avoid cuplica- tion. The importance of genetic tumour syndromes has also een highlighted in this edition by the'r inclusion in a dedicated ‘chapter, consolidating the increased knowledge of these disor ders in & way that we hope wll be helpful to all readers. Introduction to tumours of the digestive system 15Classification of neuroendocrine neoplasms of the digestive system General characteristics of NENS Neuroendocrine neoplasms (NENs) can arise in most epithelial ‘organs of the body and include many varieties, with widely dif- {ering etiologies, clinical features, morphological and genomic findings, and outcomes. Historically, NENs of the various ane- tomical sites have been classified separately, and although the various classification systems have shared some common features {1630}, differences in terminology and classification criteria between organ systems have caused considerable con- fusion. In 2018, WHO published a uniform classification frame- work for ail NENs (2717), based on a consensus conference held in November 2017. The key feature of this new, common classification is the istinction between well-dferentiated neu- roendocrine tumours (NETs), which were previously designated carcinoid tumours when occurring in the Gl tract, and poorly differentiated neuroendocrine carcinomas (NECs), which share with NETs the expression of neuroendocrine markers but are now known not to be closely related neoplasms. The morpho- logical classification of NEN& into NETS and NECs is supported by genetic evidence, as well as by clinical, epidemiological, histological, and prognostic differences. NETs are graded as G1, G2, or G3 on the basis of prolifera tive activity as assessed by mitotic rate and the Ki-67 proit- eration index ($431). Mitotic rates are to be expressed as the number of mitoses/2 min? (equalling 10 high-power fields at 40x magnification and an ocular field diameter of 0.5 mm) as deter- mined by counting in 50 fields of 0.2 mmr (ie. in a total area of 40 mm, although i is recognized that an accurate rate may not be possible to determine when only a small sample is available. ‘The Ki-67 proliferation index value is determined by counting ‘at least 500 cells in the regions of highest labelling (hotspots), which are identified at scanning magnification. In the event NET,Gt ow nero Wel teeniaad Iermedat NET Hon NEO, salt pe (SONEC) ee) c [NEC large celltyoe (LCNEC) a re nen Welersorytereines” Vile Kiimstra DS Kidppel & LaRosa S RindiG that the two proliferation indicators suggest different grades, the higher grage is assigned: generally, when there is discord- ance, its the Ki-67 proliferation index that indicates the higher (grade {2096}. NECs are considered high-grade by definition The current classification and grading system is largely based con the 2017 WHO classification of neoplasms of the neuroendo- cine pancreas (1936), which formally introduced the concept that wel-cfferentiated neoplasms could be high-grade {272}. In earlier classifications of both pancreatic and gastrointestinal NENs, the G3 category was considered to be synonymous with oor differentiation (i. NEC). However, after the publication of data related to pancreatic NETS (PanNETs), became clear that NETs of other organs can also have a proliferative cae in the G3 range (3256), juslfying the extension of the pancreatic classifi- cation system in the current edition of the WHO classification to NENs accurring throughout the Gl tract. ‘The rationale for a sharp separation of NETS and NECs into different families comes from a variety of sources. Although they share neuroendocrine differentiation based on immunolabelling for chromogranin A and synaptophysin, most NETS are mor- phologically distinct from NECs, which are subtyped as small cell NEC (SCNEO) and large cell NEC (LCNEC). NETs have an corgancid architecture (e.g. nests, cords, and ribbons), uniform ruclear features, coarsely stiooled chromatin, and minimal necrosis. NECs have a less nested architectural pattern, often growing in sheets, and they have either tightly packed fusitorm ‘clei with finely granular chromatin (SCNEC) or more-rounded, markedly atypical nuclei, sometimes with prominent nucleoti (LCNEC); necrosis is usually abundant. NETs may show grade progression, either within an individual tumour at presentation cor between different sites of isease (e.g, primary vs metasta- sis) during the course of tumour progression. The presence of asset and grading sora for neroendovine neoplasms (NEN ofthe rac an hapalopancoaoilry rans <2 <3 220 320% >20 >20% >20 > 20% >20 220% Varia Vast LLGNEG, age oat neuoandacine carcinoma; MINEN, rived nevoendootne-ron-newoendocie neoplasm; NEC, nowoondocrne carciname; NET, newendotine tnau SSCNEC smal cl neuverdosine canara. ‘Moe ae ce tba epressed asthe nurber of mitoses an eqaling 10 high-aower ets at 40 maghiteafon and an cel Hld ameter of 05m) as deterined by euntng in 0 ite of 0.2 rn (ie aol area of 10 mrt K-67 prolfration nox va is corrinod by counig a! lost 00 cas in tho regions ot gest bein Soi), whch are deni at scaring magncaon; tefl grade is asedonwrehever he wo polleaton indxes paces te nopasm inte figher gadecategory. Ponty dferertted NEOs ae not frmaly graded bu ae cosiered high rae by delta. n mas MNENs, both he reuerdoxtre and nor-neuoendocine congorens ar poty Ailerente, ard the navoendecrne component has olfeaion indexes inte sare range as oer NECS, ats corcetual algo alows fr the posstly atone or both camanets may be wel difereitx wren fesse, ech cargonent shoul therlre be grade separate. 16 Introduction to tumours of the digestive system—_— both low-grade and high-grade components within an individual NET provides strong evidence that the high-grade component remains a well-differentiated neoplasm. In contrast, NECs do rot commonly arise in association with NETs, but instead arise {rom precursor lesions that typically give rise to non-neuroendo- cine carcinomas of the respective organs, such as adenomas in the colorectum or squamous dysplasia in the oesophagus. NECs may also contain non-neuroendocine carcinoma ele. ‘ments such as adenocarcinoma or squamous call carcinoma, ‘Mixed neoplasms in which both components (neuroendocrine ‘and non-neuroendocrine) are substantial (each accounting for 530% of the neoplasm), are classified into the general category (of mixed neuroendocrine-non-neurosndociine neoplasms (MINENs), and they only exceptionally contain a well-differen tiated (NET) component in adcition to the non-neuroendocrine neoplasm. Emerging genomic data have provided further evi- dence that NETs and NECs are unrelated. In the pancreas in particular, frequent mutations in MENS, DAXX, and ATAX are etity-defining for woll-differentiated NETs {1463} and are not found in poorly differentiated NECs, which instead have muta- tions in TP53, RBS, and other carcinoma-associated genes {9632,1681,1682). Sporadic PanNETs are also associated with {germline mutalions in the DNA repair genes MUTYH, CHEK2, ‘and BRCAZ {3500} Even the G3 NETs ofthe pancreas retain the mutation profile of other wel-differentiated neoplasms, provid- ing @ means to cistinguish G3 NETS from NECs in challenging cases [3055,3253}. Genomic comparisons of NETs and NECs of other gastrointestinal sites are still emerging, NECs of these sites share frequent TP53 and RB1 mutations with NECs of the pancreas (and lung) (9577,1450), but extrapancreatic NETS ‘generally lack frequent recurrent mutations (233,961), reducing the value of genomic analysis for diagnostic purposes, although extrapancreatic NETs do share abnormalities in chromatin remodelling pathways with their pancreatic counterparts. There are also data supporting the distinction between GS NETs and NECs from a clinical perspective, The common response of NECs 10 platinum-containing chemotherapy (which is dramatic in the case of SCNECs) led to the standard use of these regimens for the treatment of NECs of diverse anatomi- cal origins (3153). However, it was recognized that a subset of pationts, probably patients who in fact had G3 NETS, failed to respond but paradoxically survived longer than the others (3104), Alternative approved therapies are available for some subsets of NETs {1716}; therefore, there is a clinical need to cis- tinguish NETs from NECs within the high-grade category. One differance between the current WHO classification and the fourth-edition classification of tumours of the pancreas con- ‘cerns the assignment of a grade for NECs. Previously, all NECs were graded G3, lke high-grade NETs. The current proposal is not to assign a grade to NECs (they are all high-grade by 20%, and values as high as 70-80% have been observed in some cases. Therefore, the Ki-67 proliferation index alone cannot be used to conclusively distinguish NETS from neuroendocrine carcinomas (NECs). ‘An important clinical distinction among NETs relates to their hormonal functionality, Functioning NETS are defined as those associated with characteristic clinical syndromes related to the abnormal production of hormones by the neoplasm. Clinically non-functioning NETs may also produce hormones, which can be detected in the serum or in the tumour cells using immuno- histochemistry, but the hormones do not result in clinical symp- toms, The nomenclature for functioning NETs often includes the name of the specific hormone causing the syndrome (insu- linoma, gastrinama, glucagonoma, ele). The pancreas gives rise to the greatest variety of functioning NETS (see Functioning pancreatic neurosndocrine tumours, 9. 363), Functioning gas- trin-producing NETS (gastrinomas) typically occur in the duo- enum, and NETs that cause carcinoid syndrome usually aise Introduction to tumours of the digestive system 17in the ileum, Most gastric NETs are non-functioning, although the conditions associated with hypergastrinaemia (includ ing gastrinomas themselves) can induce NETs composed of enterochromatfir-ike (ECL) cells in the oxyntic mucosa of the stomach. NETs of the bile ducts, liver, and colorectum are also usually non-functioning, Another characteristic feature of NETS is the expression of somatostatin receptors (in particule, abun- dant SSTR2), which can be detected by immunohisiochemistry ‘using functional radiographical imaging, such as octreoscan and 68Ga-DOTATOC/DOTATATE/DOTANOC PET-CT. NETs ‘are usually not detectable by FDG PET, with the exception of rare high-grade examples. Another distinctive clinical feature (of NETS is their indolent natural history. Although all NETs are ‘considered to be malignant neoplasms, early-stage NETs of all ‘anatomical sites have a low risk of metastasis if they are entirely removed, Larger or higher-grade NETs can metastasize and are difficult o treat, but survival for many years is still possible, even in advanced stages. The uniformity of the classification and grading system for {gastroenteropancreatic NETs presented in this volume should rot be interpreted as suggestive that NETs are a homogeneous {group of closely related neoplasms; this is far from the case. Each organ gives rise to different types of NETS, with differ- fent functionality, different histological features, and difterent genomic underpinnings. Certain types of NETs (e.g. pancre- atic and duodenal) occur commonly in patients with multiple endocrine neoplasia type 1 and are associated with frequent somatic mutations in MEN1, whereas other NETs (e.g. ileal and rectal) are not associated with this syndrome or with mutations in MEN. There are also prognostic differences amiong NETs of ifferent sites. These distinctive clinical features mean that the surgical and medical treatment of NETS is highly dependent on the site of origin, Attempts to determine the origin of NETs pre- senting with distant metastases can invalve bath radiographical ‘and pathological techniques (e.g. immunchistochemistry for site-specific transcription factors (3674). Poorly differentiated NENs: NECs Neuroendocrine carcinomas (NECs) are poorly differentiated epithelial neoplasms with morphological and. immunohisto- chemical features of neuroendocrine differentiation. NECs can bbe small cell NEC (SCNEC), which displays fusiform nuciet with finely granular chromatin, scant cytoplasm, and nuclear moulding, or large cell NEC (LCNEC), which has round nuciei, sometimes with prominent nucleoli, and moderate amounts of cytoplasm. All NECs are high-grade neoplasms Like neuroendocrine tumours (NETs), NECs can arise in most sites within the gastroenteropancreatic system and may be pure ‘or mixed with variable amounts of adenocarcinoma, squamous cell carcinoma, or other components. Previously, the term “neu- roendacrine carcinoma’ was also used for wal-cifferentiated NETs with evidence of malignant behaviour (12. metastasis), but in the current classification the term ‘carcinoma’ is reserved for poorly differentiated neoplasms. NECs are generally subclas- sifed as SCNEC or LCNEC; however, this distinction can be challenging at some sites within the Gl tract {2995). NECs are considered to be high-grade by definition, with a mitotic rate of > 20 miloses/2 mm® and a Ki-67 proliferation index of > 20% Inmost instances, these thresholds are eubstantialy exceeded: however, NECs may occasionally have a Ki-67 proliferation 18 Introduction to tumours of the digestive system index of 20-50%, especially after exposure to chemotherapy, 0 the Ki-67 proliferation index cannot be used to condlusively Cistinguish a NEC from a G3 NET {3283}. Necrosis is commonly extensive, Demonstration of neuroendocrine differentiation is necessary to confirm the diagnosis of NEC. For the diagnosis, of LCNEC, expression of either synaptophysin or chromogra- nin A must be present, The exact extent and intensity of staining required for the diagnosis have not yet been explicitly defined, bbut more than scattered positive cells should be present, and the morphology should also be suggestive of neuraendocrine differentiation NECs are somewhat more homogeneous among difer- ‘ent sites of origin than are NETS, The morphological patierns ‘overlap, as do the genomic alterations, which include common mutations in 7P53 and ABI. Additional organ-specific muta: tions that typify non-neuroendocrine carcinomas of the same site may also be found (3632,3587}. NECs lack mutations in the ‘genes most commonly involved in the pathogenesis of NETS. NECs are highly aggressive neoplasms, usually even more ‘0 than the more common types of carcinoma to arise at the same site, Advanced stage at presentation is common; there- fore, chemotherapy is often the primary therapeutic approach, and it may be the initial treatment choice even for surgically resectable cases (3153). Considerable evidence supports the {eaiment of extrapulmonary SCNEC with a platinur-containing regimen; anecdotal evidence of responses to similar regimens Jn LONECs nas promoted the widespread practice of treating all NECs with platinum-containing regimens, but there are no randomized clinical trials showing superior efficacy compared With the alternative regimens used for non-neuroendocrine car- cinomas. Defining the molecular basis for responsiveness to platinum remains an area of active investigation Mixed neoplasms: MINENs Mixed neurvendocrine-non-neurosndocrine neoplasms (MINENs) are mixed epithelial neoplasms in which a neuroendocrine component ig combined with neuroendocrine component, each of which is morphologically ‘and immunohistochemically recognizable as a discrete component and constitutes 2 30% of the neoplasm. ‘Most epithelial neoplasms in the Gi tract and hepatopan- creatobiliary system are classified as elther pure glandular or squamous neoplasms (or their precursors) or pute neuroen- docrine neoplasms (NENs). Glendular (and to a lesser extent squamous) neoplasms may have @ minor population of inter spersed neuroendocrine cells that can be identified by immu: nohistochemistry, but this finding does not affect the classi cation. Less commonly, epithelial neoplasms are composed of ‘uantitaively considerable neuroendocrine and non-neuroen docrine cell populations. Previously, when each component represented 2 30% of the neoplasm, these mixed neoplasms ‘were classified under the category of ‘mixed adenoneuroen- doctine carcinoma (MANEC)’. However, in recognition that the non-neuroendocrine component may not be adenocarcinoma, ‘and ‘0 reflect the possibilty that one or both components may not be carcinoma, the current term for this category is ‘mixed neuroendocrine-non-neuroendocrine neoplasm — (MiNEN)' MINEN Is regarded as a conceptual category of neoplasms rather than a specific diagnosis. Different types of MINENs arise in different sites throughout the gastroenteropancreatic system, |‘Box1.01 Specte subtypes of mixed neuroandacine-non-raucendotnaneplasrs (QWNEN ofthe Gl rac and hepelapaneesoiiary organs ‘oesophagus and oesophapogestis junction ‘Med SOD-NEC (SCNEC or LONEC) * Mes aderocarcinoma-NEG (SCNEC or LONEC) ‘Med xercarcinona NET (1240) Stomach Mas adenoercinons NEC (SCNEC or LONEG) + Mi alenocacnoma- NET {1758,1754) ‘Small intestine end ampulla = Mid aenocarnoma-NEC (SCNEC or LCNEC) ‘Appencic “Wied adenocarcinoma NEC (SONEC or LONEC) + aed agenecarcinona NET ‘Coon and rectum + Nie acenocarinoma-NEC (SONEC or LCNEC) Wise adenocarcinoma NET ‘Anal anal + Mised SOC-NEC (SCNEG or LCNEG) Ler ‘Med hepatoetircrcinoma-NEC ‘Med colangiocarcnoma NEC Galsadder and bie ducts * Med adenocarcinoma NEC (SCNEC or LENEC) Pancreas + Mixed dct carcinoma NEC (SCNEC or LONEC) + Wied dtl edoncarsiori-NET + Mixed acinar cel carcnoma-NEC (stnet components) + Mined iar el crcinoma- deta carcroma-NEC (dst components) NEG, lage col nuroendocine carcnoma; NEC, nowoendosine caténoma: NET, raroendornetunout SC, squamous ce carroma; SCNEC, smal cel euros seta cachama, land each should be diagnosed using site-specific terminology that reflects the neture of the components. Box 1.01 lists the specific neoplasms that are included inthe MINEN category, by anatomical site. For a neoplasm to qualily as MINEN, both components should be morphologically and immunchistochemicallyrecog- nizable, The presence of neuroendocrine aitferentition in the neuroendocrine component should be confirmed by immuno- labeling for synaptoptysin and/or chromogranin. In. MiNENS, arising inthe Gl tract and hepatopancreatobilary system, both Components ere usually carcinomas; therefore, the neuroendo- crine components usualy poorly diferentiated neuroendocrine ‘carcinoma (NEC) and can be either large cell NEC (LCNEC) ‘or small cell NEC (SCNEC). Rarely, the neuroendocrine com- ponent of a MINEN may be well differentiated. NENs can arise jn association with carcinoma precursors such as adenomas Of the tubular GI tract or intraductal or cystic neoplasms of the pancreas. However, neoplasms in which the non-neuroendo- Cerin component consists solely of a precursor (preinvasive) neoplasm are not considered MINENS. Similarly, independent neuroendocrine and non-neuroendocrine neoplasms arising in the same organ should not be classified as MINEN, even if they abut one another (true collision tumours), because the MINEN category applies only to neoplasms in which the two Components are presumed to be clonally related. Carcinomas Previously treated with neoadjuvant therapy should nat be ‘considered MINENS either, unless the diagnosis of MINEN is established based on a pretreatment specimen, because the neuroendocrine morphology exhibited by some treated carci omas may not have the same prognostic significance as that ‘s9en in a de nove component of NEC (2896, 2993}. By arbitrary convertion, each component should constitute > 30% of a neoplasm for the neoplasm to be included in the MINEN category; the presence of focal (< 30%) neuroendocrine cifferentiation may be mentioned in the diagnosis (in particular ‘when the component is poorly differentiated) but does not affect the diagnostic categorization. However, an important consid- ‘eration is the finding of focal (< 30%) SCNEC associated with ‘4 non-neuroendocrine neoplasm. Because of the clear clinical significance of SCNEC, even minor components should be ‘mentioned in the diagnosis. When feasible, the two components of MINENs should be graded individually; some data suggest that the grade of the neuroendocrine component correlates with prognosis [2163]. The non-neuroendocrine component should be classified as adenocarcinoma, acinar call carcinoma (in the Pancreas), squamous cell carcinoma, or any other definable tumour eategory as appropriate. In general, MINENs composed ‘of an adenocarcinoma with a NEC component, for which the designation MANEC can be retained, show poor prognosis (overlapping with that of pure NEC), independent of the non- Neuroendocrine component {2163}. MINENs composed of adenocarcinoma and neuroendocrine tumour (NET) have been reported, but their prognastie significance requires further study {1758,1754). The intensity and degree of the immunolabelling Of the neuroendocrine component for synaptophysin and chro mogranin A should be documented, Introduction to tumours of the digestive system 19TNM staging of well-differentiated neuroendocrine tumours of the gastrointestinal tract Rules for Classification This classiication system applies to well-diferentiated neuroendocrine lumours (carcinoid tumours and atypical Carcinoid tumours) ofthe gastointasinl tract, including the Pancreas. Neurcendocrine tumours ofthe lung should be Elassified according to criteria or carcinoma ofthe ung. Merkel ‘cell earcinoma of the skin has a soparate clacstication High-grade (Grade 3) neuraendocrine carcinomas are excluded ang should be classified according o crtola for cassifying Carcinomas atthe respective site Well-Differentiated Neuroendocrine Tumours (G1 and G2) - Gastric, Jejunum/lieum, Appendix, Colonic, and Rectal Regional lymph nodes ‘The regional lymph nodes correspond to those listed under the ‘approprate sites for carcinoma, TNM Clinical Classification ‘Stomach T= Primary Tumour TX Primary tumour cannot be assessed TO _No.vidence of primary tumour Ti Tumour invades mucosa or submucosa and 1 om or less in greatest dimension Te Tumour invades muscular propria or is more than 1 cm in greatest dimension 3 Tumour invades subserosa 4 Tumour perlorates visceral peritoneum (serosa) or invados other organs or adjacent structures Note Fr any T, ad (rn) for mutipte tumours. N—Rogional Lymph Nodes NX Regional iymoh nodes cannot be assesseo NO Novegional lrph node motastasis Ni Regional ymph node metastasis M- Distant Metastasis MO No distant metastasis Mi Oistant metastasis Mia Hepatic metastasis only MiB Extahopatic metastasis only Mic Hepatic and extranepatic metastases Well-Differentiated Neuroendocrine Tumours of the Gastrointestinal Tract Stage ‘sage! n no Mo Saget Is No Mo Stage t no Mo. Ary Nt Mo stage Ww aot Any mi ‘TNM Clinical Classification ‘Duodenal/Ampuliary Tumours ‘T= Primary Tumour TX Primary tumour cannot be assessed TO Noevidence of primary tumour TT Duodenal Tumour invacies mucosa or submucosa anc ‘Lem orless in greatest dimension Ampuilary: Tarmour 1 6m or less in greatost cimension and ‘confined within tho sphincter of Od 2 Duodenal Tumour invasos muscularis propria ors more than 1 om in greatest dimension ‘Ampuilary:Turmour invades trough sphincter nto ‘duodenal submucosa or musculars propria, or are than 41min greetest dimension 3. Tumour invades the pancteas or peripancreatic adioose tissue Té Tumour perlorates visceral pertoneum (serosa) or invades ‘ther organs Nate For any T, add () for multiple tumours. N—-Rogional Lymph Nodes NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis, Ni Regional lymph node metastasis M- Distant Metastasis MO No distant metastasis Ait Distant metastasis Mia Hepatic metastasis only Mtb Extrahepatic metastas's only Mie Hopatie and extrahopatic metastases Stage Stage n No Mo Sage I rs no Mo stage I a No MO. Any Nr Mo. siage at Bay mi ‘The infomation presented her has boon excerpted rom the 2077 TW clsssicaton of malgrant tumour, eight alton (408 32868) © 2017 UICC. Th nop dea fo spec Te quecions abouithe THM cassficaton = avnlabie at ips www ue organ 20 Introduction to tumours of the digestive system deskTNM ctnical Classification deunandioun Primary Tumour "Prey tumour eannot be assessec 10 Nosudense of primary tumour 71 Tumour rvades mucosa or suBmucose ard 1 cm or lessin rates! mension 72 Tumaur rades muscularis provi ois greater thant em in greatest cimansion 13. Tumour ivades through the musoulre propria into uboeroeal tissue wthou! penetration of oveying serosa {junto toa) 14 Tumour perforate visceral pertoneum (eres or ivades citer organs or adjacent sttuctures Note Fo any T, add (m) for multiple tumours N- Regional Lymph Nodes NX.” Regional lymph nodes cannot be assessed NO_ No regional mph node metastasis NI Less than 12 regional lymph node metastasis without mesenteric mass(es) greater than 2m in size 2 12ormore regional nodes andlor mesenteric mass(es) (greater than 2 om in maximum dimension M- Distant Metastasis MO No distant metastasis Mi Distant metastasss Mia Hepatic metastasis only Mtb Extrahepatic metastasis only Mic Hepatic and extrahepatic metastaces Stege ‘tage | n No Mo Stage I a3 No Mo ‘Stage I te aay Mo Boy Nin Mo. Stage Any any mi ‘TNM Clinical Classification Appendix Primary Tumour TX Primary tumour cannot be assessed TO Noewidence of primary tumour T! Tumour 2.om or less in grestest dimension 2 Tumour more than 2 em but not mare tnan 4 em in greatest dimension 73 Tumour more then 4 om or wih subserosal invasion oF involvement athe mesoanpencix Té Tumour periorates per toneum or ivades other adjacent ‘organs or stuctures, other than direct mural extonsion tw acjacent subsorose, © 9,, atdominel wall and skeleta musete® Notes "High-grade neuroendocrine carcinomas, mixed ‘agenoneuroendoctine carcinomas and gobiet cel carcinoid, are excluded and should ba clasaified according to erteria for classifying carcinomas. Tumour tha is adherent to other organs or structures, ‘macroscopically, is classfiod T4. However, no tumour is present inthe adhesion, microscopical, the tumour should be classified a p1t-3.8 appropriate N--Regional Lymph Nodes NX Ragional ymph nodes cannot be assessed NO Noregional iymon node metastasis Ni Regional lymph node metastasis MO No distant metastasis M1 Distant metastasis Mia Hepatic metastasis only Mtb Extrahepatic metastasis only Mic Hepatic and extrahepatic metastases [BTNM Pathological Classification The pT enc pN categories correspond to the T and N categories. NO. Histological examination a @ regional ymohadenectory ‘specimen wil ordinanly include 12 or more lymon nodes. IF the lymph nodes are negative, but the number orcinaily examined is not me, classy as pNO. pM — Distant Metastasis PMI Distant metastasis microscopically confirmed Note *pMO and pMX ere not valid categories. Stage lage! n No Mo. Stage rr NO. Mo Stage w No Mo oy Nt Mo Stage lv ny Any Me ‘The nfrmaton prosertd he has boon excerpt rom the 2017 THM classification of matgnant tumours ight ation 408 3386A].© 2017 UICG “Aha dest for epeciie Queens about Se TNM classifications avbiaiso at Ms antoesorgnm hep cs Introduction to tumours of the digestive system 21Nx No. Ni Mi ‘TNM Clinical Classification (Colon and Rectum T— Primary Tumour TX Primary tumour cannot be assessed TO No evidence of primary tumour 71 Tumour invades lamina propria or submucosa os no greater than 2 om in Sze Tia Tumourlese man tom in ize Tid Tumour for 2cminsze T2 Tumour invades muscularis propria or is greater then 2 om in size T3 Tumour invades subserosa, or pon-pertonealized pericollc or pervecal tissues T4 Tumour perloatas the visceral pertoneum or invades other organs Note For any T, add (m) for mutiple tumours, N- Regional Lymph Nodes gional lymph nodes cannot be assesses No regional lymph node metastasis, Regional ymph node meiasiasis M- Distant Metastasis MO No distant metastasie Distant metastasis Mia Hepatic metastasis only Mib Extrahepatic metastasis only Mic Hepatic and exahepatic metastases TNM Pathological Classification ‘The pT and pN categories correspond tothe T and N categories. pM - Distant Motastasis* PMI Distant metastasis microscopicaly confirmed Note pM and pK arent valid categories, Stage ‘Stage | n No Mo Siage IA r No wo i499 13 3 No Mo Siage lA 4 No Mo SiageliB—AnyT Nt Mo Siage Bayt ay me Well-Ditferentiated Neuroendocrine ‘Tumours ~ Pancreas (G1 and G2) ules for Classification ‘This classticaion system applies to well 95% of the ‘carcinoma composed of well-formed glands, Grade 2 (mod- ‘rately differentiated) is adenocarcinoma with 50-95% of the ‘carcinoma demonstrating glanduiar formation. Grade 3 (poorly differentiated) is adenocarcinoma with < 50% of the careinoma demonstrating glandular formation {1770}. |Immunohistochemistry and histochemistry esophageal adenocarcinoma has @ consistent cytokeratin ‘expression pattern of CKT+, CKI9+, and CK20~ (3258), which Tumours of the oesophagus 41does not distinguish it from gastric adenocarcinoma (812). PAS, Alcian blue, and mucicarmine are histochemical stains thet may identify mucin in poorly aifferentiated adenocarcinoma, Differential diagnosis hhcan be difficult to distinguish a poorly differentiated cinoma from a poorly differentiated squamous cell carcinoma in a biopsy of @ lower oesophageal tumour. Squamous cell carcinomas are strongly positive for CKSI6, p83 (often > 75% positive), and p40 (which is more specific than p63), whereas adenocarcinomas are strongly positive for CK7 (often > 7% positive) and negative for squamous markers. The diagnosis of Undifferentiated carcinoma should be considered for cases with {an equivocal immunonistocherical pattern and no morphologi cally identifiable squamous or glandular features. Some poorly Cssoptapealaderacarcroma. A Maoscopc appearance fir nad vant chemetrerapy B An exanple previously ees win preoperative chemeradi fn, shoning coz oal change athe a macrophages nthe ama, 42 Tumours of the eso agus 500 pm, poor aiferentation, lymphovascu lar invasion, and margin involverrent [2966]. The presence of duplicated and cistoried muscularis mucosae, which is @ con sistant finding in Barrett oesophagus, may ead to misinterpreta tion ofthe depth of invasion of carcinoma (1720), Regional lymph nodes are commonly the first sites of soread. The curent staging system for oesophageal aclenocan 50% caerama present system is favoured by some authors for pathological assess- ment because of ts better reprocuciblity (1786); tis system depends on the proportion of residual cancer cols presoct (600 Table 2.02 for more details) Trastuzuma, an antibody targeting tho human EGFR fem- ly member ERBE2 (HER2), is aporoved for the trearrent of advanced or metastatic adenocarcinoma of the osophago- g2stric junction in combination with ether chemotherapeutic agents (esplain and capectabineliverouraci, Lower oesoph- ageal adenocarcinoma should also be responsive to this ther apy [1684]. Ampiication of the ERBB2 gene (demonstrated by in stu hybriization) and the resuting overoxpression othe ERBB2 (HER2) protein (demonstrated by mmunohistochemis- try) in oesophageal adenacercinoma are predictive of response to ERBB? targeted therapy. The algorithm for ERBB2 tostng in vesoohageal adenocarcinoma varies across organizations some recommend performing both immunohistocherstry and in stu hybridization, whereas many others recornmend in sit hybridization only in the event of equivocal (2+) immunohisto- chemical fingings. The ERBB2 immunoscore is detined as 0 ‘1+ (faint), 2+ (weak to moderate), or 3+ (strong) on the basis of membrane staring {1884}. Oesophagagastric adenocarci- nomas that ere postive for EABB2 often show basolatoral orlat- eral memorane staining (unlike breast carcinomes, which often ‘show complete membrane staining) (1098). ‘The imenuno-oncology agent pembroizuma has shown promising eary results forthe tratment of advanced and meta- static esophagogastric junction adenocarcinoma {2589,3543}. High microsatelite instability and POL’ overexpression ae polental biomarkers for the response of cesophageal adeno- ‘arcinoma 0 immunotherapy (2567) Tumours of the oesophagus 43 feOesophageal adenoid cystic carcinoma Defirition ‘Adenoid oystio carcinoma of the oesophagus is a malignant ‘oesophageal epithelial tumaur of glandular differentiation with epi- thelial and mycepithlial cells in true glandular and pssudogian- ‘dular urna arranged in eribrifor, tubular, or solid architecture, ICD-0 coding ‘820013 Adenoid cystic carcinoma 1€D-11 coding 2B7OY & XHA302 Other specified malignant neoplasms of ‘oesophagus & Adenoid cystic carcinoma Related terminology None ‘Subtype(s) None Localization These carcinomas are most often located in the middle third of the oesophagus (2871,3773}. Clinical features ‘The most comiman symptom is dysphagia. Endoscopy and EUS are used to confirm the diagnosis and determine the extent of disease; the carcinoma appears as a protiudinglelevated or Ulcerative lesion. Radiological evaluation (CT, MRI, or PET) is sed to determine the clinical staging of the carcinoma, Epidemiology Oesophageal adenoid cystic carcinoma is uncommon, with only slignlly more than 100 reported cases {2871,3779,2578} Approximately half of these cases are from Asian populations {2871,3779,1118). Adenoid cystic carcinoma constitutes about 0.1% of all oesophageal malignancies (1525). It is more com- ‘mon in men, with an MiF ratio of 3.5:1 1 5:1 {2871,9779,2578), ‘and it most often ccours in the seventh decade of life (mean patient age: 65 years; range: 36-84 years) (2671,2578), Etiology Unknown Pathogenesis Unknown Macroscopic appearance Macroscopically, adenoid cystic carcinoma is either protruding of ulcerative (2871,3779,1118}. In the early stage, itotten located in the submucosa, with the mucosa stil intact. The lesions have ‘a mean size of 58 mm {867}, but they can be highly variable in size (3714,2083), 44 Tumours of the oesophagus Lam AK Histopathology ‘Adenoid cystic carcinoma consists of a mixture of epithelial ‘and myoepithelial ces in a variely of crbriform, tubular (glan- aula’), of solid patterns, The cxibriform pattem is character- ized by tumour cells forming cystic lumina, which contain either basophilic glycosaminogiycans that are Alcian biue— positive (true glands) or hyalinized basal lamina material that are PASD-posttive (pseudoglands). In both the oribritorm and tubular patterns, the glands are lined by inner epithelial and ‘outer myoepithelial celis, whereas the solid pattern shows no lumina, Perineural inftration and lymphovascular permeation fare common {2871}. Adenoid cystic carcinoma can coexist with squamous cell carcinoma or with dysplasia {carcinoma in situ (835). The myoepithelial cells in adenoid cystic carcinoma are positive for p63, S100, SMA, and calporin. The epithe- lial cells are positive for cytokeratin, CEA, and KIT (CD117) 19779,3274}. Besaloid squamous cell carcinoma may be con- sidered in the cifferential diagnosis, because it often has a pseudoglandular pattern similar to that of adenoid cystic car cinoma [1890}, However, adenoid cystic carcinoma rarely has squamous cells, central necrosis, or prominent mitotic figures, and basaloid squamous cell carcinoma is negative for SMA and $100. Cytology The cytological appearance of adenoid cystic carcinoma ars- ing in the oesophagus hes not been documented in the ltera~ ture Diagnostic molecular pathology Not clinically retevant Fig-215 Oesophageal eno cys carcinoma. The enbiorm pate. a —