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Neoplasms of the Gastrointestinal Tract Dr. M Jeffers Consultant Histopathologist AMNCH, Tallaght Objectives: GI tumour pathology tumour nomenclature and classification tumour aetiology and pathogenesis precursor lesions mechanisms of carcinogenesis in different tissues potential points for prevention / modification tumour growth and behaviour invasion metastasis tumour staging staging systems prognostic factors AMNCH Tallaght Useful links http://medstat.med.utah.edu/WebPath/webpath.html www.bmj.com : collected resources ABC of colorectal cancer ABC of the upper gastrointestinal tract: cancer of the stomach and pancreas AMNCH Tallaght Neoplasms Definition Epidemiology, Aetiology, Pathogenesis Morphology: Gross / Microscopic Clinical presentation and outcome Prognosis AMNCH Tallaght Nomenclature and Classification Nomenclature / Classification by histogenesis: Epithelial Mesenchymal Neuroendocrine Haematolymphoid Melanocytic AMNCH Tallaght Nomenclature and Classification Epithelial tumours: Benign: “adenoma” Malignant: “carcinoma” Adenocarcinoma Squamous carcinoma Small cell carcinoma AMNCH Tallaght Nomenclature and Classification Neuroendocrine tumours: Benign: “carcinoid” Malignant: neuroendocrine carcinoma small cell carcinoma AMNCH Tallaght Nomenclature and Classification Mesenchymal tumours: Benign: (tissue)oma lipoma, leiomyoma etc Malignant: (tissue)sarcoma liposarcoma, leiomyoma etc Gastrointestinal stromal tumour (GIST): benign low malignant potential malignant AMNCH Tallaght Nomenclature and Classification Haematolymphoid tumours: Bone marrow neoplasm (+/- circulating cells): leukaemia Lymph node / extranodal lymphoid cell tumour: lymphoma AMNCH Tallaght Neoplasms of the Gastrointestinal Tract Concepts: Carcinogenesis: Metaplasia/Dysplasia/Carcinoma sequence Adenoma/Carcinoma sequence Differentiation Invasion and Metastasis Tumour staging AMNCH Tallaght Tumour Aetiology and Pathogenesis: Carcinogenesis Various mechanisms operative in carcinogenesis in the GI tract: Intraepithelial neoplasia – Dysplasia – Carcinoma Metaplasia – Dysplasia - Carcinoma Adenoma - Carcinoma sequence Replicator error phenotype AMNCH Tallaght Intraepithelial neoplasia – carcinoma sequence Multistage process of carcinogenesis from normal through low grade intra-epithelial neoplasia (dysplasia) (RR 2.2) through high grade intra-epithelial neoplasia (dysplasia) (RR >60) to invasive carcinoma. Progressive development of architectural and cytological abnormality Progressive increase in relative risk of invasive carcinoma Useful model is squamous cell carcinoma of oesophagus. AMNCH Tallaght Intraepithelial neoplasia – carcinoma sequence: Oesophageal cancer Morphologic abnormality in dysplasia –carcinoma sequence in oesophageal mucosa reflects underlying genetic abnormality. p53 mutation low grade LOH 3p14 (FHIT) fragile histidine triad, tumour suppressor gene Cyclin D1 overexpression (11q13), 3p21 LOH C-myc, EGFR, HST1 overexpression invasive carcinoma AMNCH Tallaght Intraepithelial neoplasia – carcinoma sequence Normal oesophageal squamous mucosa p53 mutation High grade squamous dysplasia (carcinoma in-situ) FHIT LOH CYD1 Invasive squamous cell carcinoma c-myc, EGFR, HST1 AMNCH Tallaght Metaplasia – Dysplasia – Carcinoma Sequence Multistage process of carcinogenesis from Normal through Metaplastic columnar epithelium through Dysplasia in metaplastic epithelium low grade high grade to Invasive carcinoma Useful model is adenocarcinoma of oesophagus AMNCH Tallaght Metaplasia – Dysplasia – Carcinoma sequence: Oesophageal cancer Barrett’s oesophagus = columnar lined oesophagus Replacement of the squamous lining of the distal oesophagus by glandular mucosa in response to injury, most frequently gastro-oesophageal reflux metaplasia to gastric and intestinal type epithelium Stepwise progression of dysplasia in metaplastic epithelium leads to invasive malignancy: architectural and cytological abnormalities develop. Morphologic changes reflect underlying molecular genetic / cell cyle regulatory abnormalities AMNCH Tallaght Metaplasia – Dysplasia – Carcinoma sequence: Oesophageal cancer Normal Metaplasia FHIT alterations, CDKN2A hypermethylation Dysplasia rab11 abnormalities Low grade Ki67 abnormality High grade Invasive carcinoma APC mutation p53 mutation (different to scc) c-erbB2, EGFR AMNCH Tallaght Metaplasia – Dysplasia – Carcinoma sequence: Oesophageal cancer Normal oesophageal squamous mucosa Barrett’s oesophagus: metaplastic columnar and intestinal mucosa AMNCH Tallaght Metaplasia – Dysplasia – Carcinoma sequence: Oesophageal cancer Barrett’s oesophagus: low grade dysplasia FHIT Barrett’s oesophagus: high grade dysplasia Ki67 p53 Invasive adenocarcinoma APC AMNCH Tallaght The metaplasia dysplasia sequence: significance Intestinal metaplasia in the oesophagus is a marker of increased adenocarcinoma risk Risk of carcinoma is greatest with high grade dysplasia: concurrent carcinoma in up to 50% Many cases of high grade dysplasia will progress to invasive carcinoma over time Diagnosis of high grade dysplasia: Diagnosis of metaplasia: rebiopsy to exclude invasion consider surgery treat underlying conditions (GORD) surveillance endoscopy to identify dysplasia aiming to prevent cancers / detect cancer early AMNCH Tallaght Metaplasia – Dysplasia – Carcinoma sequence: Gastric cancer Chronic atrophic gastritis is a major risk factor for gastric carcinoma (intestinal type) Risk of malignant transformation is strongly linked to intestinal metaplasia and intra-epithelial neoplasia (dysplasia) Variety of processes may lead to atrophic gastritis: Helicobacter gastritis Auto-immune gastritis Metaplasia – dysplasia sequence acts as a final common pathway in development of malignancy AMNCH Tallaght H Pylori infection Nitrate reductase Gastritis iNOS expression Diet Nitrite Acid NO N2O 3 Ascorbic acid Cell damage (DNA, lipids, mitochondria etc) Apoptosis Atrophic gastritis Repair Metaplasia / dysplasia Nitrosamines Mutation Cancer AMNCH Tallaght Metaplasia – Dysplasia – Carcinoma sequence: Gastric cancer Chronic gastritis Intestinal metaplasia Dysplasia low grade high grade Invasive carcinoma AMNCH Tallaght Metaplasia – dysplasia - carcinoma sequence in the stomach Stomach: normal Stomach: chronic gastritis Stomach: atrophy and intestinal metaplasia AMNCH Tallaght Metaplasia – dysplasia - carcinoma sequence in the stomach Stomach: low grade dysplasia Stomach: high grade dysplasia Stomach: invasive adenocarcinoma AMNCH Tallaght The metaplasia dysplasia sequence: significance Most intestinal type gastric cancers develop on a background of atrophy, metaplasia and dysplasia. Predisposing factors for atrophy and metaplasia are known: chronic HP gastritis, auto-immune gastritis etc. Treatment of predisposing conditions, endoscopic surveillance of patients with documented metaplasia: strategies to reduce risk, detect cancer early. AMNCH Tallaght Colorectal carcinogenesis: the adenoma – carcinoma sequence Various epidemiological associations in colorectal carcinoma point to the important role of the adenoma as the precursor lesion of many cancers Morphological progression in colorectal carcinoma: Aberrant crypt focus Adenoma low grade dysplasia high grade dysplasia dysplastic ACF with APC mutation inactivation proto-oncogene activation: c-myc, ras suppressor gene inactivation: p53, p21, bax other abnormalities: BRCA, DCC, E-cad Carcinoma AMNCH Tallaght Methylation Defect Normal Epithelium Early Adenoma APC Carcinoma K-Ras p53 Smad4 ?? Intermediate Late Adenoma Adenoma Mismatch repair defect TGF, BAX Metastasis Carcinoma MSI + ?? Genetic Model for Sporadic Colorectal Carcinogenesis AMNCH Tallaght Adenomatous polyps of the colon Neoplastic polyps, precursors of carcinoma Architectural patterns: Tubular/Villous/Tubulovillous Gross presentation: sessile/pedunculated/flat adenoma Risk of malignancy size (ras), architecture, dysplasia AMNCH Tallaght Colon: tubular adenoma AMNCH Tallaght normal epithelium adenomatous epithelium AMNCH Tallaght Colon: villous adenoma AMNCH Tallaght Colon: villous adenoma AMNCH Tallaght Polyposis syndromes Sydromes characterised by multiple polyps in colorectum +/- elsewhere in GIT FAP:5q21 defect, multiple polyps, 100% lifetime risk of carcinoma HNPCC: MSH gene defect, fewer polyps, typical pattern of tumours Gardner: variant of FAP with skin and other lesions Turcot: association with CNS neoplasms AMNCH Tallaght Table 1. Intestinal polyposis syndromes Location Location of Type(s) of polyp Location of of polyp Gl cancer extraintestinal tumors AD lymphoid Adenoma; FGP, C, SI, ST C, SI AD AD Adenoma Hamartoma C C,SI,ST C C,SI,ST AD Juvenile C,SI,ST C,SI,ST Lipoma; fibroma; desmoid tumor; dental cysts; osteoma; carcinoma of thyroid and adrenal glands Central nervous system tumors Cancers of the breast, ovary, uterus, and testis None Syndrome Inheritance Gardner’s Turcot’s* Peutz-Jeghers Familial polyposis coli (familial adenomatous polyposis) Juvenile polyposis (one-third of cases) Cowden’s AD AD Cronkite-Canada Adenoma, FGP C, SI, ST C, SI None Hamartoma; C,SI inflammatory; ganglioneuroma; lipoma; lymphoid None Juvenile-like None C,SI,ST Colon (rare) Facial trichilemomas; oral mucosal papillomas; carcinoma of thyroid gland and breast None C,SI,ST C,SI,ST None C,SI,ST C,SI,ST None C Skin cancer: basal cell; squamous cell; sebaceous carcinoma None Attenuated familial polyposis coli** Hereditary flat Adenoma syndrome** Muir Torre syndrome AD Adenoma; FGP AD Adenoma; AD Adenoma Hereditary mixed polyposis syndrome AD Adenoma; juvenile; hyperplastic FGP C C C GI, gastrointestinal, AD, autosomal dominant, FGP, fundic gland polyp; C, colon; SI, small intestine; ST, stomach. *Some cases of Turcot’s syndrome have mutations in APC gene, Some cases of Turcot’s syndrome have germline mutations in mismatch repair genes (hMLH1 and hPMS2). **Attenuated familial polyposis coli and hereditary flat adenoma syndrome most likely are the same disorder, but they are listed separately in this table. Attenuated familial polyposis coli and hereditary flat adenoma syndrome are considered variants of familial polyposis coli. AMNCH Tallaght Familial adenomatous polyposis (FAP) Autosomal dominant condition characterised by numerous adenomatous polyps and high risk of progression to adenocarcinoma Germline mutation in APC gene (5q21-22) which encodes a 2843 aa polypeptide which acts as a negative regulator in the Wnt signalling pathway, regulates cellular -catenin concentration Lack of functional APC leads to accumulation of -catenin and consititutive expression of c-myc and cyclin D1 AMNCH Tallaght Colon: familial adenomatous polyposis AMNCH Tallaght Adenoma carcinoma sequence: significance and implications Mechanism underlying most colorectal carcinomas Identifiable precursor lesions in many cases: early detection of precursor lesions has obvious implications for early treatment and prevention of invasive disease Identification of families with germ-line mutations and significant polyposis syndromes offers significant preventive opportunities Tumour pathogenesis has direct implications on cancer management and prevention AMNCH Tallaght Colorectal carcinogenesis: the mismatch repair defect pathway Mechanism of carcinogenesis distinct from the adenoma – carcinoma sequence Tumours characterised by extensive nucleotide insertions / deletions in repeated sequences in tumour DNA: microsatellite instability (MSI) / DNA replication error (RER) Tumours with MSI are classified as MSI high-frequency (MSI-H) or MSI low frequency (MSI-L) These tumours arise through defects in the DNA mismatch repair mechanism, defects which may be sporadic or inherited Some sporadic tumours are MSI-H but most MSI-H tumours characteristic of hereditary non-polyposis colorectal carcinoma (HNPCC) AMNCH Tallaght HNPCC HNPCC: a syndrome characterised by inherited defects in DNA repair due to germline mutations of the relevant genes: (hMLH1, hMSH2) High frequency of colorectal carcinoma Extracolonic tumours in endometrium, stomach, ovary, brain, skin, small bowel Criteria for classification as HNPCC: Amsterdam criteria (+ revisions) Classical tumour characteristics: right sided, large, mucinous, low stage AMNCH Tallaght Hereditary Non-polyposis Colorectal Cancer Criteria: At least 3 relatives with a HNPCC associated cancer (colorectum/endometrium/small bowel/ureter/renal pelvis) Ones should be first degree relative of other two At least 2 successive generations involved At least one tumour diagnosed before 50 yrs of age Familial adenomatous polyposis should be excluded Tumours should be verified by histopathological examination AMNCH Tallaght MSI in colorectal cancer: diagnosis hMSH2: normal Normal tissue: hMSH2 expression hMSH2: tumour Loss of expression in MSI-H tumour AMNCH Tallaght Replicator error phenotype: implications Identification of MSI-H tumours confers a high probability of an inherited cancer Cancers can be screened for MSI status, confirmation of germ-line status required for definition of syndrome Careful family history combined with tumour characteristics can identify at-risk groups Early intervention and prevention opportunities Tumour pathogenesis impacts directly on patient management and prognosis. AMNCH Tallaght Carcinogenesis: review of mechanisms Various mechanisms operative in carcinogenesis in the GI tract: Intraepithelial neoplasia – Dysplasia – Carcinoma Metaplasia – Dysplasia - Carcinoma Adenoma - Carcinoma sequence Replicator error phenotype Various mechanisms implicated at different sites Significance in terms of identification of precursor lesions, treatment and prevention of cancer AMNCH Tallaght AMNCH Tallaght Differentiation Differentiation refers to the degree of maturation of tumour cells / tissues: what cell type / tissue type does the tumour grow in ? how closely does the tumour reproduce normal tissue architecture ? Tumours are described as: well differentiated moderately differentiated poorly differentiated Differentiation is closely related to tumour grade: well differentiated – low grade poorly differentiated – high grade AMNCH Tallaght Differentiation: colorectal carcinoma well differentiated moderately differentiated poorly differentiated AMNCH Tallaght AMNCH Tallaght Neoplasms of the Gastrointestinal Tract Classification of tumours: Anatomical Location Origin (Primary/Secondary) Behaviour (benign/uncertain/malignant) Histogenesis (epithelial/stromal/lymphoid etc) AMNCH Tallaght Tumours of the oesophagus Benign tumours rare: Leiomyoma Most are malignant and most are carcinomas Squamous cell carcinoma Adenocarcinoma AMNCH Tallaght Oesophageal carcinoma Approx 6% of GIT cancers 1996 Irish Cancer Registry data: 299 cases (1.4% of all cancers) 303 deaths (4.1% of all cancer deaths) AMNCH Tallaght Oesophageal carcinoma Histological types: Squamous cell carcinoma Adenocarcinoma (a/w Barrett’s oesophagus) Others Relative proportion of squamous and adenocarcinoma varies with geography Adenocarcinoma increasing incidence AMNCH Tallaght Oesophageal carcinoma Squamous carcinoma: Alcohol, Tobacco, Food, HPV Arise on background of dysplasia / in-situ carcinoma Varying differentiation well - poorly differentiated AMNCH Tallaght AMNCH Tallaght Normal Oesphagus AMNCH Tallaght Oesophageal squamous carcinoma AMNCH Tallaght Squamous cell carcinoma AMNCH Tallaght Oesophageal carcinoma Adenocarcinoma: Majority arise on a background of Barrett’s oesophagus. Metaplasia - Dysplasia - Carcinoma sequence Sequential acquisition of genetic abnormalities, oncogene activation, TSG inactivation Majority are intestinal type adenocarcinoma AMNCH Tallaght AMNCH Tallaght AMNCH Tallaght Oesophageal carcinoma Invasion through submucosa, muscularis and into soft tissue Metastasis to regional nodes, distant sites Most are advanced at diagnosis 5 year survival is poor (<30%) Early diagnosis improves outcome AMNCH Tallaght Tumours of the stomach Benign tumours are rare: Leiomyomas etc Malignant tumours: carcinoma >> lymphoma, stromal tumours, carcinoid tumours AMNCH Tallaght Gastric carcinoma Irish Cancer Registry Data 1996: 482 cases (2.3% of total cancers) 399 deaths (5.4% of total cancer deaths) Male : female 1.5:1 18 lymphomas in same time period AMNCH Tallaght Gastric carcinoma Pathogenesis: Chronic gastritis - metaplasia - dysplasia (H Pylori) Dietary factors, smoking Genetic factors (HNPCC) Dysplasia is a final common pathway in intestinal type tumours AMNCH Tallaght Gastric carcinoma Tumour pathology: 2 major types: Intestinal: Bulky masses / ulcers, glandular pattern Diffuse: infiltrative lesions, “signet-ring” cells AMNCH Tallaght Gastric tumour AMNCH Tallaght Gastric cancer: Linitis Plastica AMNCH Tallaght Normal stomach mucosa AMNCH Tallaght AMNCH Tallaght Gastric adenocarcinoma: diffuse type AMNCH Tallaght Gastric adenocarcinoma: signet ring cells AMNCH Tallaght Gastric carcinoma Late presentation is typical 6% present in stage I, 30% stage IV (of those staged) Prognosis is poor: Cumulative probability of survival 34% @ 1yr 20% @5yrs AMNCH Tallaght Gastric carcinoma Importance of Pathologic Staging: Early gastric carcinoma is disease limited to mucosa and submucosa, irrespective of nodal involvement 5ys is >90% with surgical resection Advanced gastric carcinoma is disease which invades the muscularis propria 5ys is <20% regardless of treatment AMNCH Tallaght Gastric carcinoma Patterns of disease spread: Direct invasion: stomach wall, adjacent structures local/regional/distant nodal metastases: lesser/greater curve, porta hepatis haematogenous dissemination: liver, lungs peritoneal spread (Krukenberg tumour of ovaries) AMNCH Tallaght Adenocarcinoma of the oesophago-gastric junction Adenocarcinoma which crosses the junction of oesophagus and stomach, regardless of where the tumour bulk lies (entirely above ogj: oesophageal carcinoma entirely below ogj: gastric carcinoma) Typically a tumour of older males Increasing in frequency (gastric carcinoma decreasing) Principal predisposing factor is GERD (not diet or HP gastritis) Typically present late AMNCH Tallaght Other tumours of the stomach Lymphoma: Low grade B cell MALT lymphoma clonal B cell process related to chronic H Pylori infection High grade B cell lymphoma Carcinoid tumours Stromal neoplasms tumours of muscle/nerve/vascular etc phenotype Metastases AMNCH Tallaght Stomach: large B cell lymphoma AMNCH Tallaght Carcinoid tumours of stomach 1. Atrophic gastritis / Pernicious anaemia hypochlorhydria, antral G cell hyperplasia, Gastrin , ECL cell 2. Sporadic (G cell or ECL) not a/w hypochlorhdyria 3. Fundic ECL tumours in patients with Zollinger-Ellison syndrome 4. Poorly differentiated small cell carcinoma AMNCH Tallaght AMNCH Tallaght Tumours of the small intestine Small bowel: 75% of GIT, 6% of GIT tumours Adenomas: majority occur in region of ampulla of Vater precursor of carcinoma in this location AMNCH Tallaght Tumours of the small intestine: Carcinoma Adenocarcinoma: Most occur in duodenum and jejunum Most probably arise from precursor adenoma Typical intestinal type adenocarcinomas May obstruct/perforate/bleed/spread AMNCH Tallaght Ampullary carcinoma AMNCH Tallaght Tumours of the small intestine: Carcinoid Tumour Carcinoid tumour: origin from endocrine (APUD/Kultchitsky cells) cells are neuroendocrine type, contain neurosecretory granules may produce hormone and cause carcinoid syndrome behaviour depends on depth of infiltration intra-mural: good prognosis, peritoneal involvement: poor prognosis AMNCH Tallaght Small intestinal carcinoid tumour AMNCH Tallaght Carcinoid tumour AMNCH Tallaght Tumours of the small intestine: Lymphoma Lymphoma: B cell lymphoma may be of MALT type or non-MALT T cell lymphoma associated with enteropathy (coeliac disease) AMNCH Tallaght AMNCH Tallaght Tumours of the small intestine: Stromal tumours Stromal tumours: Tumours derived from mesenchymal structures: muscle ,nerve, interstitial cells etc. Spectrum from benign-indeterminate-malignant Usually present as bulky masses with perforation / obstruction / haemorrhage Criteria for malignancy include size, necrosis, proliferation Most are Gastrointestinal Stromal Tumours (GIST) probably of interstitial cell origin c-kit (CD117) mutation AMNCH Tallaght Tumours of the appendix Carcinoid tumour: small, often at tip of appendix typical carcinoid / goblet cell carcinoid Mucinous neoplasms: mucinous cystadenoma mucinous cystadenocarcinoma May be associated with Pseudomyxoma Peritoneii AMNCH Tallaght Colorectal Tumours Polyps: Hyperplastic (metaplastic) Inflammatory, Juvenile, Hamartomatous Adenomatous Sporadic / Hereditary syndromes AMNCH Tallaght Colorectal cancer Risk factors / associations: Geography: industrialised societies Obesity, inactivity Diet: meat and refined carbohydrates family history adenomatous polyps (sporadic/familial syndromes) ulcerative colitis AMNCH Tallaght Colorectal Carcinoma >70% arise from adenomas adenoma incidence is ~ 30 -40% immediate family of affected patient: risk x 2-3 ~ 2% arise on a background of ulcerative colitis different genetic pathways to neoplasia: (1) adenoma - carcinoma sequence (2) hereditary non-polyposis mechanism (3) UC associated neoplasia AMNCH Tallaght Adenomatous polyps of the colon Neoplastic polyps, precursors of carcinoma Architectural patterns: Tubular/Villous/Tubulovillous Gross presentation: sessile/pedunculated/flat adenoma Risk of malignancy size (ras), architecture, dysplasia AMNCH Tallaght Colon: tubular adenoma AMNCH Tallaght Colon: adenomatous epithelium AMNCH Tallaght Colon: villous adenoma AMNCH Tallaght Colon: villous adenoma AMNCH Tallaght Colitis-associated neoplasia UC increases risk x 2-8 Risk increased with - duration of disease - extent of disease - presence of dysplasia neoplasm evolves from dysplasia rather than adenoma bcl-2 overexpression less frequent in UCAN APC gene mutations much less frequent in UCAN E-cadherin mutations more frequent in UCAN AMNCH Tallaght Colorectal carcinoma: Pathology Virtually all are adenocarcinomas Irish Cancer Registry 1996: 1784 cases (8.6% of all cancers, largest group apart from skin cancer), close to European average Crude incidence 40% > in males Age standardised incidence 75%> in males AMNCH Tallaght Colorectal carcinoma Left > right side Left side tend to be annular obstructing lesions Right side tend to be polypoid exophytic Intestinal type adenocarcinomas, range of differentiation: well- moderate –poor +/- mucinous, neuroendocrine differentiation Mucinous differentiation more common in right sided tumours, HNPCC association AMNCH Tallaght Colon: carcinoma AMNCH Tallaght Colon: carcinoma AMNCH Tallaght Colon: carcinoma AMNCH Tallaght Colon: adenocarcinoma AMNCH Tallaght Colorectal carcinoma Infiltrate into and through wall metastasize to regional nodes disseminate through blood to liver, distant sites prognosis is primarily dependent on stage Staging: Dukes’ A B C Dukes’ variants TNM Accurate staging depends on pathological examination of resected specimen in conjunction with clinical and radiological information AMNCH Tallaght Dukes’ A Dukes’ B Colon cancer: staging AMNCH Tallaght Dukes’ C Colon cancer: staging AMNCH Tallaght Colorectal carcinoma Stage at diagnosis: Stage 1: <20% Stage 4 >20% Cumulative survival probability: 1 yr 69%, 3yrs 51% 1yr: stage 1 90%, stage 4 30% 3yr: stage 1 80%, stage 4 10% AMNCH Tallaght Objectives: GI tumour pathology tumour nomenclature and classification tumour aetiology and pathogenesis precursor lesions mechanisms of carcinogenesis in different tissues potential points for prevention / modification tumour growth and behaviour invasion metastasis tumour staging staging systems prognostic factors AMNCH Tallaght