L06 Bowel Neoplasms FINAL 2023.pdf

Neoplasms of the Bowel Dr Marcus Dabner Senior Lecturer UWA Anatomical Pathologist PathWest [email protected] Overview / Learning Objectives  Classification of mass lesions in the bowel:  Understand that many bowel neoplasms present as polyps and be able to provide a differential diagno...

Neoplasms of the Bowel Dr Marcus Dabner Senior Lecturer UWA Anatomical Pathologist PathWest [email protected] Overview / Learning Objectives  Classification of mass lesions in the bowel:  Understand that many bowel neoplasms present as polyps and be able to provide a differential diagnosis of the main types of epithelial polyps, including benign, pre-malignant (adenomatous polyps, serrated lesions/adenomas) and malignant (adenocarcinoma), as well as the non-epithelial polyps that may occur.  Discuss in detail the clinical relevance, pathological findings (macroscopic and microscopic), and pathogenesis of colorectal carcinoma, including the main pathways that lead to this event. o i.e. Understand the process of carcinogenesis in the setting of bowel cancer o Know the precursor lesions of colon adenocarcinoma o Name the main pathways and know the key genes involved o Be able to describe the adenoma-carcinoma sequence o Be aware of contributing factors such as familial cancer syndromes, chronic inflammation, epigenetics, diet, other risk factors  Understand the principles of how colorectal neoplasms may present clinically, including signs and symptoms and principles of staging.  Understand the principles of the national bowel cancer screening program.  Be aware of the common non-epithelial neoplasms of the large bowel (neuroendocrine tumours, lymphoma). Key Learning Points o What are the most important and common tumours that affect the bowel? o How does adenocarcinoma of the bowel develop and implications for management? o Rationale behind, and key points about, the national bowel cancer screening program. Neoplasms of the Bowel Part 1: Classification Dr Marcus Dabner Senior Lecturer UWA Anatomical Pathologist PathWest [email protected] Tumour types Remember that tumours may arise from any of the cells normally present, for example:  Mucosa  Epithelium: Adenomas (benign and/or pre-malignant), Carcinomas (malignant)  Submucosa  Nerves, Blood vessels, Lymphatics  Muscularis  Smooth muscle (leiomyoma, and rarely leiomyosarcoma)  Serosa  Mesothelium  Miscellaneous  Gastrointestinal stromal tumour (varying degrees of risk based on size, location, mitotic activity)  Neuroendocrine tumours (low grade and high grade) Regional Variation  Consider colon and rectum together; diseases are the same, treatment slightly different  Small bowel has more or less the same spectrum of diseases that happen, but adenocarcinoma MUCH less common in small bowel  Appendix also has more or less the same spectrum of diseases, but low-grade neuroendocrine tumours are more common in this site than elsewhere in the bowel and appendiceal carcinoma is relatively rare, and more likely to be mucinous or signet ring types than the rest of the large bowel. Bottom line: Colorectal adenocarcinoma is far and away the most important entity to discuss! Classification of bowel neoplasms (WHO 5th Edition, 2019)  Benign epithelial tumors and precursors   Hyperplastic polyp, microvesicular type Hyperplastic polyp, goblet cell  Serrated dysplasia, low grade8213/0  Serrated dysplasia, high grade8213/2  Adenomatous polyp, low grade dysplasia8210/0  Adenomatous polyp, high grade dysplasia8210/2  Tubular adenoma, low grade8211/0  Tubular adenoma, high grade8211/2  Villous adenoma, low grade8261/0  Villous adenoma, high grade8261/2  Tubulovillous adenoma, low grade8263/0     Gastrointestinal stromal tumour  Adipose tissue and (myo)fibroblastic tumours  Tubulovillous adenoma, high grade8263/2  Advanced adenoma  Glandular intraepithelial neoplasia, low grade8148/0  Glandular intraepithelial neoplasia, high grade8148/2  Malignant epithelial tumors  Adenocarcinoma, NOS8140/3    Adenoma-like adenocarcinoma8213/3  Micropapillary adenocarcinoma8262/3 Mucinous adenocarcinoma8480/3  Poorly cohesive carcinoma8490/3  Signet ring cell carcinoma8490/3  Medullary adenocarcinoma8510/3  Adenosquamous carcinoma8560/3  Carcinoma, undifferentiated, NOS8020/3  Carcinoma with sarcomatoid component8033/3  Mesenchymal tumours   Inflammatory myofibroblastic tumour  Desmoid fibromatosis  Solitary fibrous tumour  Lipoma  Inflammatory fibroid polyp  Plexiform fibromyxoma  Smooth muscle and skeletal muscle tumours  Leiomyoma  Leiomyosarcoma  Rhabdomyosarcoma  Vascular and perivascular tumours  Haemangioma  Epithelioid haemangioendothelioma (prev Vascular Tumours in Liver)  Kaposi sarcoma  Angiosarcoma  Glomus tumour  Lymphangioma and lymphangiomatosis Neural tumours  Schwannoma  Granular cell tumour  Perineurioma  Ganglioneuroma and ganglioneuromatosis  Site-specific haematolymphoid tumours  Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) involving the digestive tract  Duodenal-type follicular lymphoma  Enteropathy-associated T-cell lymphoma  Monomorphic epitheliotropic intestinal T-cell lymphoma  Intestinal T-cell lymphoma NOS  Indolent T-cell lymphoproliferative disorder of the GI tract  Hepatosplenic T-cell lymphoma  EBV+ inflammatory follicular dendritic cell sarcoma of the digestive tract Haematolymphoid tumours occurring with some frequency in the digestive system  Diffuse large B-cell lymphoma  Follicular lymphoma  Mantle cell lymphoma  Burkitt lymphoma  Plasmablastic lymphoma  Posttransplant lymphoproliferative disorders  Extranodal NK/T-cell lymphoma  Systemic mastocytosis  Langerhans cell histiocytosis  Follicular dendritic cell sarcoma  Histiocytic sarcoma Neuroendocrine tumors, NOS8240/3  Neuroendocrine tumor, grade 1 8240/3  Neuroendocrine tumor, grade 28249/3  Neuroendocrine tumor, grade 38249/3  L cell tumor8152/3  Glucagon-like peptide producing tumor8152/3  PP / PYY producing tumor8152/3  Enterochromaffin cell carcinoid8241/3 Tumours of uncertain differentiation     Haematolymphoid tumours PEComa, including angiomyolipoma Synovial sarcoma Gastrointestinal clear cell sarcoma / malignant gastrointestinal neuroectodermal tumour Other tumours of the digestive system  Mucosal melanoma of the digestive system  Serotonin producing carcinoid8241/3  Germ cell tumours of the digestive system  Neuroendocrine carcinoma, NOS8246/3  Digestive system metastases  Large cell neuroendocrine carcinoma8013/3  Small cell neuroendocrine carcinoma8041/3  Mixed neuroendocrine - nonneuroendocrine neoplasm (MiNEN)8154/3 Simplified Classification of Bowel Neoplasms   Epithelial Neuroendocrine   NET Grade 1 (formerly ‘carcinoid’)  Benign (low risk of malignancy)  Hyperplastic polyp  NET Grade 2 (may spread to nodes and through peritoneum, but slow growing)  Non-neoplastic polyps: hamatomatous, inflammatory polyps  NET Grade 3  Neuroendocrine carcinoma Mesenchymal  Benign and malignant tumours of adipose tissue, smooth muscle, blood vessels, lymphatics, nerves  Others  Metastases  Mucosal melanoma  Benign (potentially pre-malignant)  Sessile serrated lesion (serrated adenoma, serrated dysplasia)  Dysplastic adenoma (tubular, villous, tubulovillous), low and high grade  Lymphoma – virtually all are Non-Hodgkin Lymphoma, B or T cell  High grade B cell lymphomas  Diffuse large B cell lymphoma  Burkitt lymphoma  Malignant  Adenocarcinoma  Variants of adenocarcinoma  Low grade B Cell lymphomas  MALT Lymphoma (Extranodal Marginal Zone Lymphoma of MALT type)  Follicular lymphoma  Mantle cell lymphoma  Enteropathy associated T cell lymphoma (associated with Coeliac disease) Simplified Classification of Bowel Neoplasms  Epithelial  Benign (low risk of malignancy)  Hyperplastic polyp   Non-neoplastic polyps: hamatomatous, inflammatory polyps Neuroendocrine  NET Grade 1 (formerly ‘carcinoid’)  NET Grade 2 (may spread to nodes and through peritoneum, but slow growing)  NET Grade 3  Neuroendocrine carcinoma   Benign (potentially pre-malignant)  Sessile serrated lesion (serrated adenoma, serrated dysplasia)  Dysplastic adenoma (tubular, villous, tubulovillous), low and high grade    High grade B cell lymphomas      Variants of adenocarcinoma Benign and malignant tumours of adipose tissue, smooth muscle, blood vessels, lymphatics, nerves Lymphoma – virtually all are Non-Hodgkin Lymphoma, B or T cell  Malignant Adenocarcinoma Mesenchymal Diffuse large B cell lymphoma Burkitt lymphoma Low grade B Cell lymphomas  MALT Lymphoma (Extranodal Marginal Zone Lymphoma of MALT type)  Follicular lymphoma  Mantle cell lymphoma Enteropathy associated T cell lymphoma (associated with Coeliac disease)  Others  Metastases  Mucosal melanoma Ulcerated large bowel adenocarcinoma (adeno=gland forming, carcinoma = malignant epithelial tumour). Ulcerated is simply a descriptive term – it doesn’t reflect any fundamental difference in the nature of the lesion. Fungating large bowel adenocarcinoma. Fungating is also a descriptive term, meaning ‘mushroom-like’. Annular (ring-like) exophytic and obstructing small bowel adenocarcinoma with lymph node metastasis. Small bowel adenocarcinoma is similar to large bowel adenocarcinoma, however is much less common (for reasons we don’t fully understand). Large bowel non-Hodgkin lymphoma Metastatic ovarian carcinoma invading small bowel Colonic leiomyoma (=benign tumour of smooth muscle) Neoplasms of the Bowel Part 2: Bowel Cancer Epidemiology Dr Marcus Dabner Senior Lecturer UWA Anatomical Pathologist PathWest [email protected] What is Bowel Cancer?  Bowel cancer is…. o A malignant neoplasm of the bowel. (neoplasm=“new growth”, can be benign or malignant) (malignant= “tending to cause death”) o Generally taken to mean carcinoma (malignant epithelial tumour) of the large bowel (aka colorectal carcinoma) o Usually adenocarcinoma (gland forming) with a range of subtypes  Other less common types of cancer that occur in the bowel include… o Lymphomas, neuroendocrine tumours, GIST, sarcomas, metastases from other organs and ‘other’  Benign and intermediate grade tumours that occur in the bowel include…  Benign polyps (neoplastic - hyperplastic polyp; non-neoplastic - hamartomatous polyp, inflammatory polyp, others)  Pre-malignant polyps (tubular/tubulovillous/villous adenoma, sessile serrated lesion)  Adenocarcinoma of the small bowel is much less common but similar spectrum of tumours occur there Why is Bowel Cancer Important? Because it is… Common Curable if detected early Significant morbidity (illness) and mortality (deaths) due to bowel cancer How Important is it?  Bowel cancer accounts for approximately 17 000 new cancer diagnoses in AUS per year and 4000 cancer deaths (12.7% of cancers, 9.3% of cancer deaths)  Second most common cancer in men (behind prostate)  Second most common cancer in women (behind breast)  Lifetime risk of dying from bowel cancer is 1 in 46, of getting bowel cancer is about 1 in 10.  More common in men (55% of cases) than women (45%), and men are more likely to die if they get it http://www.aihw.gov.au/cancer/ Pope John Paul II Audrey Hepburn Elizabeth, The Queen Mother Terry Jones Charles M Schulz Ronald Reagan Francis Crick  Primarily a disease of older adults  Approx 10% are under 50, approx 5% under 40  Family history and genetic factors important  About 20% are hereditary cancers  Relative risk increases by approx 1.5x with 1 first degree relative affected,  3x with two or more first degree relatives.  If relative had bowel cancer under 45, RR is 5x.  Other risk factors:  Obesity  Diet high in processed meat, red meat, alcohol (i.e. high income countries, sedentary lifestyle)  Inflammatory bowel disease, esp Ulcerative colitis, is independently a risk factor  Risk of smoking is unclear  Interaction of associations is complex and isolated interventions don’t reduce risk much (i.e. risk reduction strategies require multiple things to be addressed at the same time, over many years).  Some benefit with long terms NSAIDS (low dose aspirin)  5 year survival has dramatically improved since the 1980s, (<50% to 74%)  Early detection and treatment  Identification of high risk individuals  New drugs (‘targeted therapy’) Fuchs et al, N Engl J Med 1994; 331:1669-1674 Currently in Australia: • More common in males than females (M going down, F going up) • Mortality gets worse as patient age increases • If you survive 5 years, you’re probably “cured” https://www.aihw.gov.au/reports/cancer-screening/national-bowel-cancer-screening-monitoring-2020/report-editions Survivorship  Not just survival, but overall health, living with and after, a cancer diagnosis.  Physical, psychosocial and economic issues.  Later effects of treatment, secondary cancers, quality of life. Neoplasms of the Bowel Part 3: Pathogenesis of bowel cancer Dr Marcus Dabner Senior Lecturer UWA Anatomical Pathologist PathWest [email protected] Ways of looking at bowel cancer  Type of tumour (90% are adenocarcinomas, 10% everything else)  Morphology (macroscopic and microscopic) – growth patterns / histological subtypes  Left side of colon vs right side of colon  Pathogenesis (which precursor lesion they develop from)  Molecular genetic pathway / signature; genomic classification  Targetable mutations (BRAF, KRAS, etc) Colon cancer carcinogenesis Remember that…  Cancers occur as a result of clonal expansion of a single mutant cell line  This occurs due to acquisition of multiple non-lethal genetic mutations (variations) or ‘hits’ (Knudson hypothesis)  Some people are more genetically susceptible  Some cells are more susceptible  Mutations impart additional abilities to cancer cells (immortality, survivability, invasiveness, etc)  These primarily occur in one of four classes of regulatory genes  Growth promoting proto-oncogenes (gain of function): b-catenin (cell signalling and growth via Wnt pathway), KRAS, BRAF (RAS/MAPK pathway)  Growth inhibiting tumour suppressor genes (loss of function): p53, APC  Genes that regulate cell death (pro-apoptotic)  Genes involved in DNA repair (e.g mismatch repair genes)  With many genes, both alleles must be affected before phenotype is altered  Carcinogenesis is therefore a multistep process at the genetic level, and this is reflected phenotypically as a progression of precursor lesions, as additional ‘hits’ occur, combined with changes in epigenetic signalling, tumour/immune system interactions.  The specific alterations and the order in which they occur are highly variable in CRC. How Does Colon Cancer Develop (precursors) Normal •Macroscopically normal •Histologically Normal •No genetic abnormalities Mucosa “Mucosa at risk” Adenoma Advanced Adenoma Carcinoma •Not well understood, field effect or localised “aberrant crypt focus” •Macroscopically normal •Histologically mild, hard to identify abnormalities •Associated with K-ras mutations, but poorly defined so far •Macroscopically small polyp •Histologically low grade dysplasia •Acquisition of additional mutations (APC, B-catenin etc) and overexpression of various growth factors •Larger, irregular polyps •High grade dysplasia / intramucosal carcinoma •Acquisition of additional mutations and overexpression of various growth factors Serrated Lesion/ Adenoma • • • Macroscopically small polyp Histologically serrated architecture Acquisition of additional mutations (e.g. BRAF) ? •Acquires ability to invade bowel wall and lymphovascular spaces •Becomes less well-differentiated •Acquisition of additional mutations and overexpression of various growth factors Mac Barnett and John Klassen (2014); Sam and Dave dig a hole Mechanisms of genetic change in colon cancers 1. Chromosomal instability resulting in high levels of somatic copy-number alterations and DNA gains/amplifications or losses/deletions (Chromosomal Instability Pathway / AdenomaCarcinoma Sequence) 2. Microsatellite instability (MSI) due to defective DNA mismatch repair (MMR), leading to high mutation rate (Usually MSI / serrated pathway, although note that MMR gene abnormalities are common in both other pathways as well). Most of these tumours show CpG island hypermethylation, with a smaller proportion having 3. Defective DNA polymerase proofreading, with a very high mutation rate, affecting large numbers of genes. Most of these are silent ‘passenger’ mutations, with some mutations occurring in driver genes (POLE pathway) Dysplasia  Dysplasia refers to cellular atypia in the absence of invasion  Dysplasia can occur in squamous or glandular epithelium  It reflects underlying cellular and molecular changes indicating changes in the cells that increase the risk of subsequent or concurrent development of cancer (i.e. through further ‘hits’)  Dysplasia is usually graded as low or high grade based on nuclear atypia (large, hyperchromatic, irregular nuclei, loss of polarity, increased mitotic activity) and architecture (complex, fused glands or disordered maturation from base to surface of epithelium, loss of villi, etc)  High grade dysplasia is on a morphological spectrum with carcinoma in situ but we don’t recommend the use of CIS in the GIT for….reasons.  In the GIT, dysplasia can occur in neoplasms (e.g. colon adenomatous polyps, pancreatic cystic neoplasms), or in association with chronic irritation or inflammation (e.g. in ulcerative colitis, GORD, occasionally in cholelithiasis) Terminology of Adenoma vs Dysplasia  In general, adenoma = benign epithelial neoplasm  However, in the tubular GIT, adenomas have pre-malignant potential (i.e. show dysplasia and/or molecular genetic changes in key cancer genes) but do not have all the properties required for malignancy  Adenoma-carcinoma sequence well understood in colon, increasingly understood in other sites  Long standing debate about terminology, best summarized as:  Should everything in the GIT with pre-malignant potential be called an adenoma?  Should we restrict the term adenoma only to dysplastic lesions?  Current WHO recommendation is:  In the tubular GIT, polyps with dysplasia are called adenomas, but not every polyp is dysplastic, and dysplasia can occur in non-polypoid mucosa (e.g. in ulcerative colitis)  In the rest of the GIT, presence of dysplasia DOES NOT get called adenoma (SIGH!!!!!) Dysplasia = morphology. Correlates well with underlying genetics, but not perfectly Some non-dysplastic polyps (serrated!) have similar implications for cancer risk www.pathologyoutlines.com Contributed by Kenrry Chiu, M.D High grade dysplasia: fused, back to back glands, nuclear atypia, loss of polarity, mucin depletion. Still identifiably glandular, basement membrane still present. Wikimedia commons https://commons.m.wikimedia.org/wiki/File:Colon_adenoma_with_highgrade_dysplasia,_very_high_mag.jpg “Serrated” Polyps  Colorectal neoplasms that have serrated / saw-tooth glands  Historically thought to be benign, we now know that a proportion of these lesions progress to cancer via the MSI/Serrated pathway (hard to know how many)  Types you should know: • Hyperplastic polyp: small, sessile (dome like) or flat lesion, serrated glands in superficial portion of crypt, often rich in goblet cells. More common in the left colon. Benign, or very low probability of progression to cancer. • Sessile serrated lesion (previously called sessile serrated adenoma): ill-defined, dome-like, small (<5mm), often have a mucus cap imparting a ‘cloud like’ appearance on endoscopy, serrations involve full depth of crypt, usually don’t have conventional dysplastic nuclei, but sometimes can, in which case it is termed a… • Traditional serrated adenoma: larger (5-10mm), exophytic polyp, serrated epithelium with conventional cytological features of dysplasia. Adenomatous Polyps  Colorectal neoplasms that have dysplastic glands (high grade dysplasia or low grade dysplasia)  Macroscopically: polypoid (pedunculated or sessile), flat or depressed. Size is important for determining risk – larger = higher risk (implies it has been there longer or is growing faster).  Adenomatous polyps are benign (usually 10+ years to develop into cancer, if at all – only about 5% will transform to cancer), but have mutations that place them along the pathway to cancer (usually WNT pathway, altering APC function). May also acquire mutations in P13K pathway, TP53, KRAS, SMAD4 and SMAD2.  KRAS appears to be important in progression to carcinoma (KRAS mutations in <10% of adenomas <1cm but in >50% of adenomas >1cm and >50% of invasive carcinomas).  P53 alterations also a late event: Present in 70-80% of cancers but rarely in adenomas.  Small ones can be removed endoscopically, large ones generally need surgery (endoscopic mucosal resection or gross total resection)  Types you should know (based on growth pattern): • Tubular • Tubulovillous • Villous: Slightly higher risk of malignancy, usually larger • Advanced: Are usually large, can’t be removed endoscopically, always show areas of high grade dysplasia, often have higher mutation burden and foci of early invasive carcinoma. Normal colon Adenoma Polypoid tubular adenoma with low grade dysplasia Adenoma Sessile tubulovillous adenoma with low grade dysplasia; Tubular adenoma with High grade dysplasia Normal colon Hyperplastic polyp Sessile serrated lesion Adenocarcinoma: Macroscopic: large, exophytic, obstructing, irregularly shaped, ulcerated and haemorrhagic surface, complexity caused by tortuous folds and fusion of glandular structures. Microscopic: infiltrative, irregular glands, variable architecture (can be solid, papillary, mucinous, tubular or a mix), often with desmoplastic stromal reaction and usually with intraluminal necrosis and inflammatory cells (‘dirty’ necrosis). High grade dysplasia / intramucosal carcinoma with early invasion Invasive adenocarcinoma: 1 and 2 – primary tumour, 3 – metastasis to lymph node ‘Adenoma-carcinoma’ Sequence – usually occurs in chromosomal instability pathway APC is a Tumour Suppressor Gene (TSG) that helps to downregulate bcatenin and Ecadherin (WNT signalling pathway) b-catenin is a protooncogene and up-regulates multiple growth pathways K-RAS is a protooncogene and upregulates growth factors p53 is a major TSG, regulates cell cycle and initiates senescence Loss Of Heterozygosity at 18q21 results in DCC loss (another TSG) SMAD proteins are signal transducers Telomerase prevents telomere shortening and loss of multiple DNA signals Others: 25-75% have normal alleles lost or silenced in other major cancer genes Robbins Pathologic Basis of Disease, 10th ed Serrated / Microsatellite Instability Pathway Robbins Pathologic Basis of Disease, 10th ed Defects in mismatch repair genes (MLH1, MSH2 and others) leads to microsatellite instability, which creates an environment allowing accelerated accumulation of mutations in numerous genes. Depending on the genes affected, this can lead to cancer. In the colon, this often includes BRAF (and less frequently KRAS), which can trigger the types of cancers that occur via the serrated pathway. Serrated Pathway Sessile serrated lesions (SSLs) have BRAF mutations and can develop de novo or possibly (dotted line) from microvesicular hyperplastic polyps (HPs). A key molecular event thought to precipitate the progression of SSL to malignancy is either MLH1 methylation, secondary to high levels of CpG island methylator phenotype (CIMP), progressing to mismatch repair (MMR)-deficient colorectal carcinoma, or TP53 mutation progressing to MMR-proficient colorectal carcinoma. Traditional serrated adenomas (TSAs) may develop de novo, possibly from SSL or from goblet cell HP (dotted lines). TSAs progress via the BRAF or KRAS pathway to high-grade dysplasia and MMR-proficient colorectal carcinoma. WNT signalling pathway activation occurs in all pathways through different mechanisms, at the transition to dysplasia. WHO Classification of Tumours of the Digestive System, 5th ed, 2019 Note that some genes are activated in more than one pathway - this demonstrates how different cellular changes can lead to the same outcome, and becomes important as it may impact whether a tumour will respond to a particular treatment. Now, let’s talk about the special cases of familial bowel cancer… Familial Colon Cancer 1 Most colon cancers are sporadic Undefined/unknown mutations explain the majority of CRC in familial settings Familial Colon Cancer 2 Familial Adenomatous Polyposis (FAP) Autosomal dominant (1 in 10 - 30 000) 20% of FAP cases are new germline mutations acquired during embryogenesis 100% risk of colon cancer by age 40 Mutation in APC gene at 5q21 (or rarely MYH gene) ‘Carpet’ of >100 adenomas increases probability of second, third hits Prophylactic total colectomy by age 25, screening of relatives Familial Colon Cancer 3 HNPCC (‘Lynch syndrome’ and variants) Autosomal dominant (1 in 600 - 2000) Fewer adenomatous polyps than FAP, more than sporadic cancers Mutations in mismatch repair gene(s) MLH1 or MSH2 (most) as well as MSH6, PMS2, and EPCAM Results in inherited microsatellite instability (MSI) Increased risk of bowel, endometrial, bladder, gastric and skin cancers “Amsterdam criteria” for genetic testing: 3 or more family members with CRC (at least one first degree), two successive generations, at least one before age 50, FAP excluded. “Bethesda criteria” for genetic testing: CRC <50 years, multiple CRC or other associated tumour, MSI-H histology <60 years, HNPCC diagnosed in first degree relative Full colonoscopy every 1-2 years from age 25, plus endometrial screening for women from age 25-35, bladder surveillance, gastroscopy F A P M a j o r HNPCC C o n t r i b u t o r y Conteduca, V et al, Int J Oncology, 2013, 43(4):973-984 Role of chronic inflammation  Chronic inflammation is associated with CRC in two ways  1) As a driver of dysplasia • Inflammatory bowel disease (UC > Crohn’s) increases the risk of bowel Ca due to repeated cycles of inflammation, ulceration and epithelial damage leading to increased turnover of epithelium • Faster turnover = higher chance of mutations occurring and reduced checking and repair of DNA errors = accelerates development of dysplasia and CRC  2) As a marker of the host response to cancer • CRC often triggers a florid host immune response. In general, more inflammation within a tumour (particular killer T cells) means the body has recognised the tumour as non-self and is attacking the tumour cells. • Possible implications for prognosis, and potential for immunotherapy Reconciling Pathways, Genetics, Genomics and Morphology 1. Chromosomal instability resulting in high levels of somatic copy-number alterations and DNA gains/amplifications or losses/deletions – 84% of CRC  Mostly correlated with development of cancer from conventional dysplastic adenomas  Majority of sporadic cancers on both left and right side of colon  Majority have mutations or alterations in APC (80%), TP53(60%) and KRAS(45%) plus many others.  Patients with FAP have a headstart and develop these cancers young 2. Microsatellite instability (MSI) due to defective DNA mismatch repair (MMR), leading to high mutation rate in a range of genes – 14% of CRC  Mostly correlates with development of cancer from serrated polyps  Subset of sporadic cancers and majority of cancers associated with Lynch syndrome  Most of these tumours show BRAF mutations and develop CpG island hypermethylation, with a smaller proportion having mutations in MMR genes (MLH1 in particular)  More likely to be right sided (more SSLs there) 3. Defective DNA polymerase proofreading, with a very high mutation rate, affecting large numbers of genes. Most of these are silent ‘passenger’ mutations, with some mutations occurring in driver genes (POLE pathway) - 3% of CRC Reconciling Pathways, Genetics, Genomics and Morphology The end result:  Most CRC arise from sporadic mutation of multiple cancer causing genes, while a subset arise from inherited mutations. Most familial cases are not well understood, but FAP and Lynch syndrome are both important in overall understanding of CRC carcinogenesis.  Most CRC, regardless of triggers, result in activation of the WNT, MAPK or PI3K pathways leading to growth promotion and anti-apoptosis, as well as inactivation of the TGF-b and/or p53 inhibitory pathways.  CRC is heterogenous in phenotype, genotype and pathogenesis, and covers the same spectrum of behaviour regardless of pathway, however pathway is relevant to treatment, risk for other family members and understanding of tumour biology Neoplasms of the Bowel Part 4: Clinicopathological features Dr Marcus Dabner Senior Lecturer UWA Anatomical Pathologist PathWest [email protected] What does a growing tumour in a hollow tube do? https://www.bowelcanceraustralia.org/bowel-cancer-staging Signs and symptoms of Colon Cancer 1  Early cancer  Usually asymptomatic  May have subtle blood loss in stool (melaena)  (chronic, insidious, painless)  From surface ulceration  May not be obvious http://www.lumen.luc.edu/lumen/meded/Pathology/images/gi21.jpg Signs and symptoms of Colon Cancer 2 - sequelae  Advanced cancer  Local Effects  Bowel obstruction (constipation/pain)  Perforation (peritonitis and tumour seeding)  Severe haemorrhage (anaemia, shock) (due to erosion of large vessels)  Systemic Effects  Spread to other organs  Direct invasion, lymphatic, haematogenous  Cachexia (Greek: “bad condition”) – nausea, vomiting, loss of appetite, loss of weight  (metabolic and systemic proinflammatory changes resulting in muscle and adipose tissue atrophy, loss of appetite, insulin resistance and others)  Paraneoplastic symptoms (hormone secretion) – uncommon except in some rare variants (e.g. neuroendocrine tumours) Sequelae Diagnosis of Colon cancer I  History and examination  Personal and Family History  Risk Factors (alcohol, ethnicity, processed diet, family history)  Clinical Symptoms  Asymptomatic  Altered blood in stool (melaena)  Pain/weight loss/bowel obstruction only when advanced  Clinical signs  Often nothing found (except low rectum – “if you don’t put your finger in it you’ll put your foot in it!”)  Palpable mass (advanced)  Investigations  Faecal occult blood testing  Imaging  Barium studies, ultrasound, CT scan  (virtual colonoscopy)  Endoscopy  Top and bottom  Pathology  Biopsy histopathology Diagnosis of Colon cancer II  If patient is symptomatic or has frank bleeding, Screening FOBT is not indicated – needs diagnostic colonoscopy +/- biopsy of any mass lesions identified  If asymptomatic but FOBT positive, referral for colonoscopy +/- biopsy  If small polyp found (usually adenomatous), can be removed via endoscopic resection  If large mass found, biopsied for histopathological confirmation  May be adenoma with low grade dysplasia, high grade dysplasia or carcinoma; or something else  If cancer or large adenomatous polyp, colectomy (removal of part of the bowel) plus lymph nodes Assessment and Management  Clinical and Pathological Assessment is aimed at defining in a particular cancer:  How advanced is it?  Has it, or is it likely to spread to other sites?  Does the patient need further treatment?  What is the likely prognosis?  TNM staging (see next slide):  Used for clinical management and research (comparing apples with apples, making predictions, directing resources)  T = Tumour  N = Lymph Nodes  M = Metastases  In general  Low stage = Local disease only: Resection = high chance of cure  Locally advanced: Cure possible but risk of spread ➢ Chemotherapy (+? Radiotherapy +? Targeted therapy)  High stage: Systemic disease: Resection to improve morbidity but lower chance of cure ➢ Chemotherapy to restrict tumour growth and increase survival Reminder: Ways that tumours spread  Blood  Lymphatics  Direct invasion  Transcoelomic (via body cavities) ALL OF THESE CAN HAPPEN IN BOWEL CANCER (i.e. it tends to spread to other body sites easily) Regional Lymph Nodes (N) NX Lymph nodes cannot be assessed N0 No regional lymph node metástases N1 Metastasis in 1–3 regional lymph nodes N1a Metastasis in one regional lymph node N1b Metastasis in 2–3 regional lymph nodes N1c Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues N2 Metastasis in four or more regional lymph nodes N2a Metastasis in 4–6 regional lymph nodes N2b Metastasis in seven or more regional lymph nodes Primary Tumour (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ: intraepithelial or invasion of lamina propria T1 Tumour invades submucosa T2 Tumour invades muscularis propria T3 Tumour invades through the muscularis propria into pericolorectal tissues T4a Tumour penetrates to the surface of the visceral peritoneum T4b Tumour directly invades or is adherent to other organs or structures Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis M1a Metastasis confined to one organ or site (e.g., liver, lung, ovary, nonregional node) M1b Metastases in more than one organ/site or the peritoneum Pathological examination of specimen – the critical role of pathology  Diagnosis of tumour type  Grading of tumour  TNM staging (extent of spread, node involvement, metastases)  Assessing margins  Providing prognostic information and guiding further treatment (is there lymphovascular invasion, is it MSI-H requiring genetic counselling/testing etc)  Pathologic findings  Macroscopic  Microscopic  Immunohistochemical (protein expression for MSI testing)  Molecular Genetic (KRAS, BRAF and other mutation analysis for targeted therapies) Multiple sporadic adenomas Adenocarcinoma arising in an adenoma (circled) – likely to be a sporadic case (i.e. nonfamilial), although several other adenomatous polyps are also present (arrow) Familial Adenomatous Polyposis – hundreds of polyps carpeting the large bowel Neoplasms of the Bowel Part 5: Screening Dr Marcus Dabner Senior Lecturer UWA Anatomical Pathologist PathWest [email protected] Why screen?  Screening refers to testing of an asymptomatic patient for disease or for a disease precursor  Benefits:  Reduction in mortality and morbidity (fewer than 40% of bowel cancers are detected early)  Cost-effective - Benefits to community of paying for lots of tests outweigh the costs of paying for treatment/years of life lost.  Procedures for early cancer easier, safer, cheaper than advanced cancer  Potential Risks/Costs:  Costly: More tests, more colonoscopies, more surgery = increased numbers of complications, unnecessary treatment + opportunity cost  False positives: May be positive in pts with blood loss from other causes e.g. upper GI, haemorrhoids, diverticular disease.  For a screening program to be worthwhile: 1. Disease has serious consequences 2. The disease must have a detectable preclinical period, before it becomes clinically apparent and during which it can be detected by the screening test. 3. Screening population has high prevalence of the condition 4. The test must be sensitive and specific - not too many false positive or false negative results 5. The test must be safe 6. Test is affordable and available 7. Effective treatment exists 8. Treatment is more effective when started earlier National Bowel Cancer Screening Program  Offered to general population (normal risk patients)  Looking for faecal occult blood (not visible) which is present due to microscopic haemorrhage from cancer or precursor lesions  Patient puts sample in containers and sends back to be tested  Has been shown to reduce mortality from CRC by up to 30% in screened patients  Immunochemical test for globin from blood  2 samples  Offered to >50 year olds  2 yearly Diagnostic and Management Algorithm Asymptomatic Symptomatic Over 50 years Any age Diagnostic Test Screening Test (FOBT) Positive (Colonoscopy with endoscopic biopsy) Negative No Treatment Continue screening program every 2 years Treatment (Endoscopic resection if adenoma) (Colectomy if adenocarcinoma) Further Treatment Based on Stage and molecular genetic testing (Chemotherapy) (Targeted therapy) (Occasionally radiotherapy) National Bowel Cancer Screening Program Outcomes  From 2017-2018, 5 million people were invited to participate.  42% elected to be screened (unchanged from previous 2 years), women > men (45% vs 40%), participate decreases with increasing rurality, 80% of those who previously participated were screened again.  Of those, 7% had a positive result warranting further assessment, of whom 66% reported a follow-up diagnostic assessment  1 in 30 participants who had a follow-up diagnostic assessment was diagnosed with a confirmed or suspected cancer (down from 1 in 26 in previous 2 years).  1 in 8 participants had an adenoma (up from 1 in 9, probably due to diagnostic drift in terms of serrated lesions being reclassified as adenomas).  Demonstrated benefit in reducing number of cancers presenting at late stage and small reduction in overall incidence of bowel cancer Review of Learning Objectives  Classification of mass lesions in the bowel:  Understand that many bowel neoplasms present as polyps and be able to provide a differential diagnosis of the main types of epithelial polyps, including benign, pre-malignant (adenomatous polyps, serrated adenomas) and malignant (adenocarcinoma), as well as the non-epithelial polyps that may occur.  Discuss in detail the clinical relevance, pathological findings (macroscopic and microscopic), and pathogenesis of colorectal carcinoma, including the main pathways that lead to this event. o i.e. Understand the process of carcinogenesis in the setting of bowel cancer o Know the precursor lesions of colon adenocarcinoma (adenomas, SSL) o Name the main pathways and know the key genes involved (A-C sequence; APC, p53, KRAS and MSI/serrated pathway; BRAF, MMR genes) o Be able to describe the adenoma-carcinoma sequence o Be aware of contributing factors such as familial cancer syndromes (FAP and Lynch syndrome), chronic inflammation, epigenetics, diet, other risk factors  Understand the principles of how colorectal neoplasms may present clinically, including signs and symptoms and principles of staging. (Mostly asymptomatic, FOBT, advanced tumours may invade, perforate, metastasise via blood, lymphatics, direct invasion or transcoelomic spread)  Understand the principles of the national bowel cancer screening program. (detection of FOB in asymptomatic individuals in at risk age group)  Be aware of the common non-epithelial neoplasms of the large bowel (neuroendocrine tumours, lymphoma). Summary  Colorectal adenocarcinoma is a major cause of morbidity and mortality in Australia  Adenomas are the precursor lesion in most colorectal carcinomas  Understanding multistep carcinogenesis is key to current and future treatment and research  Some cancers are familial, and these give important insights into the disease, and require different management processes  The National Bowel Cancer Screening program aims to use FOBT to identify patients with cancer or precursor lesions early  Pathological testing of tumours is required for diagnosis, staging and to guide management. Early diagnosis results in better outcomes and pathology is involved at every stage of the management of this disease References and Further Information  WHO Classification of Tumours of the Digestive System, 5th edition, IARC/WHO, 2019  Images from pathologyoutlines.com, WHO Classification of Tumours of the Digestive System and personal collection  Robbins Pathologic Basis of Disease, 10th edition (older editions still mostly accurate)  National Bowel Cancer Screening Program http://www.cancerscreening.gov.au/  Australian Institute of Health and Welfare (overall cancer statistics and NBCSP monitoring report 2020) www.aihw.gov.au/cancer/ https://www.aihw.gov.au/reports/cancer-screening/national-bowel-cancer-screening-monitoring-2020/report-editions  Pignone P.P, Flitcroft K.L et al: Costs and cost-effectiveness of full implementation of a biennial faecal occult blood test screening program for bowel cancer in Australia. MJA 2011.  Conteduca, V et al, Precancerous colorectal lesions, Int J Oncology, 2013, 43(4):973-984, http://www.spandidos-publications.com/10.3892/ijo.2013.2041#