A Short Review Of Malignant Tumors Of Gi Tract Pathology. M.Farhadi,M.D,APCP Tehran,April 2013

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1 خداوند بخشنده مھربان بنام

2 A Short Review Of Malignant Tumors Of Gi Tract Pathology M.Farhadi,M.D,APCP Tehran,April 2013

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4 Anatomical Histopathology Of Gi Tract Squamous Epithelium Esophagus Stomach Columnar Epithelium Small Intestine Large Intestine Mucosal Anal Canal Submucosal Serosal * Lymphoid Tissue Smooth muscle,connective,endocrine Tissues

5 Prototypes Of Gi Tract Tumors Histopathology Squamous Cell Carcinoma Adenocarcinoma Malignant Lymphoma Carcinoid Tumor

6 Squamous Cell Carcinoma The highest rates are found in Asia (particularly in China and Singapore), Africa, and Iran. Lower socioeconomic status was associated with esophageal SCC in a large population-based study.

7 ESOPHAGEAL CARCINOMA RISK FACTORS Alcohol Cigarettes Nitrosamines Aflatoxins Plummer-Vinson syndrome (SCC) Barrett's oesophagus (adenoca.) Sites upper 20% ~ middle 50% ~ lower 20% ~

8 ESOPHAGEAL CARCINOMA HISTOLOGY Squamous cell carcinoma 90% Adenocarcinoma 10% Squamous Ca Adenoca.

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15 ESOPHAGEAL CARCINOMA SPREAD DIRECT into surrounding tissues LYMPHATIC to paraoesophageal, paratracheal and cervical node groups HAEMATOGENOUS to liver or lung PROGNOSIS POOR 70% dead within 1 year <10% 5-year survival

16 Gi-Adenocarcinoma

17 ADENOCARCINOMA-STOMACH INCIDENCE 2 nd commonest carcinoma worldwide East Asia, South America (Andes), Eastern Europe Declining incidence Age: m=f, young age: m>f

18 PATHOLOGY OF GASTRIC (MALIGNANT) TUMOURS: The gastric cancer may arise in the antrum (50%), the gastric body (30%), the fundus or oesophago-gastric juntion (20%).

19 The macroscopic forms of gastric cancers are classified by (Bormann classification) into:- 1. Polypoid or Proliferative 2. Ulcerating 3. Ulcerating/Infiltrating 4. Diffuse Infiltrating (Linnitus- Plastica)

20 Gastric Adenocarcinoma

21 Microscopically the tumours commonly adenocarcinoma with range of differentiation. The most useful to clinician and epidemiologist is Lauren Histological Classification: a. Intestinal gastric cancer b. Diffuse gastric cancer

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23 Early Gastric Cancer limited to Mucosa & Submucosa

24 Advanced Gastric Cancer extend to Muscularis properia

25 Helicobacter pylori & Gastric Cancer Class I carcinogen Countries with high gastric cancer incidence also have high Hp infection rates Hp predisposes to cancer by - production of potential carcinogens e.g. nitrosocompounds in hypochlorhydric y gastric juice and free radicals in inflammatory response - deficiency of anti-oxidants such as ascorbic acid in gastric juice - increased cell turnover stressing DNA repair mechanisms and perpetuating mutations

26 Stages in the development of gastric carcinoma normal gastric mucosa superficial gastritis H pylori atrophic gastritis Precancerous lesions intestinal metaplasia dysplasia carcinoma

27 SPREAD GASTRIC CARCINOMA Direct infiltration Duodenum, pancreas, colon, liver, spleen LYMPHATIC SPREAD Local and regional nodes Virchow's node HAEMATOGENOUS Liver, lungs TRANSCOELOMIC Omentum Mesentery Ovary (Krukenberg tumour)

28 PROGNOSIS GASTRIC CARCINOMA Early gastric cancer Mucosa/submucosa/LN negative: 85% 5 year survival Late gastric cancer Full thickness/ln negative 30% 5 year survival Full thickness/ln positive 5% 5 year survival

29 Gi-Lymphoma

30 SMALL BOWEL MALIGNANT LYMPHOMA B-cell origin (mucosa associated lymphoid tissue) Enteropathy associated T-cell lymphoma α-chain disease (IPSID)

31 GI-MALT LYMPHOMA H pylori and Gastric MALT Lymphoma Mucosa Associated Lymphoid Tissue arises in the stomach as a result of Hp infection Lymphoid follicle

32 Infiltrate of B cells Lympho-epithelial lesion

33 Distribution of GI Lymphoma 55-65% 20-35% 7-20% Courtesy of Dr. Alyssa Krasinskas

34 MALT MorphologyMantle zone Morphology Marginal zone Mantle zone Germinal center Reactive B-cell follicles with surrounding, expanded marginal zones of neoplastic cells (analogous to Peyer s patches) Neoplastic cells infiltrate mucosa widely, creating LELs Defined as at least three neoplastic cells, causing epithelial damage While usually easily found, LELs are not (on their own) diagnostic of MALT lymphoma/emzl Small/medium-sized lymphocytes with irregular nuclei (resembling centrocytes) and relatively abundant cytoplasm More cytoplasm gives a monocytoid appearance

35 Lymphoepithelial lesions Near total destruction of gland Infiltration by few neoplastic lymphocytes Monocytoid B-cells

36 Morphology (cont.) Cells may also be smaller, with less abundant cytoplasm Plasma cell differentiation present (in varying degree) in about 1/3 of cases Often most pronounced in the superficial (i.e., luminal) part of the mucosa Can be focal/scattered, or predominant (raising the differential diagnosis of extramedullary plasmacytoma and/or lymphoplasmacytic lymphoma (LPL) While plasmacytic differentiation is fairly common, paraproteins are not

37 Dutcher body MALT l h ith t i MALT lymphoma with extensive plasmacytic differentiation

38 Morphology (cont.) May colonize follicles, mimicking FL, or be diffuse Large/transformed (centroblast- or immunoblast-like) cells can vary in number If infiltrate t is diffuse and predominantly large cells, the appropriate diagnosis is DLBCL Report low-grade MALT lymphoma component, if present IPSID Similar, but usually with more pronounced plasma cell component (and a paraprotein, often)

39 Naked germinal centers

40 MALT Markers Immunophenotype IgM (less often IgG or IgA) positive with lightchain restriction (on flow cytometry) Immunohistochemical evidence of light chain restriction mostly associated with plasmacytic differentiation IPSID has α-heavy chain expression Positive: CD20, CD79a, CD43+/-, CD21, CD35 CD43 + in about 1/3-1/2 of cases Negative: CD5, CD10, CD23 Bottom line: no specific MALT/EMZL marker

41 Naked germinal center surrounded by lymphoma cells

42 Genetics Molecular MALT t(11;18)(q21;q21) API2/MALT1 gene fusion ~25% of gastric MALT lymphomas t(1;14)(p22;q32) ;q3 ) BCL10 deregulated by coming under control of Ig gene Some intestinal MALT lymphomas t(14;18)(q32;q21) MALT1/Ig fusion <5% of gastric MALT lymphomas Trisomy 3, 12, 18 (often associated with t(1;14) p53 mutation; methylation of p15 and p16 promoters Mutations of fas Owens SR Smith LB Molecular aspects of H pylori-related MALT lymphoma Owens SR, Smith LB. Molecular aspects of H. pylori related MALT lymphoma. Patholog Res Int Jan 24;2011:

43 MESENCHYMAL TUMOURS (GastroIntestinal Stromal Tumours, GIST) Stromal cell origin i (previously smooth muscle) Prognosis depends on size, necrosis, mitoses Also tumours of adipose tissue, nerves including autonomic (GANT) and blood vessels

44 Gi- Carcinoid Tumors

45 Neuroendocrine Tumors Neuroendocrine tumors come in two varieties: a) tumors of the endocrine organs (pancreas, adrenal) b) tumors of the dispersed endocrine cells ( GI tract, bronchopulmonary, C cells of the thyroid) Carcinoid refers to neuroendocrine tumors of the dispersed endocrine system ONLY

46 Classification of NE Tumors Well-differentiated NE tumors = Carcinoids Benign behavior or uncertain malignant potential Well-differentiated NE carcinomas (atypical carcinoids) Low-grade malignancy Poorly differentiated NE carcinomas (usually small cell) High-grade malignancy

47 GI Carcinoids Morphology Located in mucosa and submucosa Arise at the base of the crypts Nested growth pattern (insular, acinar, trabecular) Small uniform cells Round regular nuclei Finely stippled salt & pepper chromatin Lack of prominent nucleoli and mitotic activity Stain with neuroendocrine markers

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50 GI Carcinoids IHC Shared Neuroendocrine Markers Chromogranin Synaptophysin Specific Neuroendocrine Hormones Gastrin (G cells) Somatostatin (D cells) Serotonin (EC cells) Glucagon (L cells)

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52 GI Neuroendocrine Cells Distribution ib ti Gastric body: ECL (enterochromaffin-like) cells Histamine Antrum and Duodenum: G cells Gastrin Duodenum: D cells Somatostatin Bowel: EC (enterochromaffin) cells Serotonin Stomach and bowel: L cells Enteroglucagon

53 Behavior of GI Carcinoids by Site Foregut carcinoids Gastric (10%), duodenal (<5%). Generally low malignant potential Midgut carcinoids Ileal/Jejunal (25%). 60% malignant Appendiceal (40%). 1% malignant Hindgut carcinoids Rectal (20%), 15% malignant

54 GROSS PATHOLOGY CARCINOID TUMOUR Tumour of gut neuroendocrine cells, affecting appendix, ileum, rectum, stomach Yellow submucosal lesions May ulcerate or infiltrate

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56 COLORECTAL CARCINOMA Neoplastic Polyps (Adenomas) Almost all carcinomas arise from benign adenomas (polyps) The more polyps the greater the risk The larger the polyp the more likely it is to be malignant

57 National Bowel Cancer Screening Programme Almost all colorectal cancers arise from pre- existing adenomas Mostly sporadic, mostly middle-aged to elderly Screening introduced recently 60+ age group invited to provide stool for faecal occult lood test t (FOBT) If positive, colonoscopy to identify precursor lesions of adenoma

58 Molecular Pathology of Colorectal Neoplasia Outline Pathogenesis of colorectal neoplasia Adenoma-carcinoma carcinoma sequence Chromosomal instability Microsatellite instability Hypermethylation Serrated pathways Targeted therapies

59 GI NEOPLASIA Familial Adenomatous Polyposis (FAP) Autosomal dominant Chromosome 5 (APC GENE 5q21) Polyps from mid-teens onward Carcinoma inevitable ~15 years later Variants: Gardner s and Turcot syndromes Need for genetic counselling

60 How Does Colorectal Cancer Develop? Janne PA, Mayer RJ. N Engl J Med 2000;342:1960.

61 Molecular Pathology of Colorectal Neoplasia Colorectal carcinogenesis requires progression from normal mucosa to adenoma to carcinoma Adenoma-carcinoma sequence long accepted Molecular basis defined as molecular techniques evolved Many cancers associated with specific genetic changes at high frequency

62 The Adenoma - Carcinoma Sequence: 1 1 APC 2 3 K-ras Chromosomal Instability (50-85%) 4 SMAD2/4 p53 5

63 Typical Chromosomal Instability in a Colorectal Cancer: near-triploid SW403: an MSS colorectal cancer showing near-triploid pattern & unbalanced translocations (Dr MW Arends, Cambridge)

64 The Adenoma - Carcinoma Sequence: 2 1 APC 2 MSH2 MLH1 3 K-ras 4 TGFBIIR Bax Defective DNA Mismatch Repair Microsatellite Instability (15%) 5 Mutations in repetitive sequences

65 Molecular Pathology of Colorectal Microsatellite instability Neoplasia Change in length of repetitive sequences e.g. CACACA- Defects in mismatch repair genes Often near-diploid

66 Cancers in HNPCC

67 Molecular Pathology of Colorectal Neoplasia Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Autosomal dominant disease: Lynch Syndrome High risk of cancers of colon, rectum, endometrium, stomach, small intestine, hepatobiliary system, upper ureteric tract, ovary and brain Estimated 68 82% lifetime risk of colorectal cancer (CRC) HNPCC-related colon cancers present at an early age (mean age 45 years) Predominantly located in the proximal colon (60 70%) 70%), with approximately 10 30% developing synchronous or metachronous cancers

68 COLORECTAL CARCINOMA GROSS Ulcerating Polypoid/fungating

69 COLORECTAL CARCINOMA SPREAD Dukes Stage A above muscle layer 5 yr survival 95% Dukes Stage B into serosal fat, LN negative 66% 5 yr survival Dukes Stage C LN involvement 33% 5 yr survival

70 Staging of Colorectal Cancer

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