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![Juvenile
polyposis
coli
(1) Any number of
polyps in a patient with
family history, or (2)
≥3 polyps[*] without
family history. Polyps
are predominantly
colonic; small bowel
polyps, if present, are
few
Autosomal
dominant, but
family history in
only 20% to
50%
BMPR1A
mutation or
SMAD4 mutation
30% to 68% risk
of colorectal
carcinoma
Generalized
juvenile
polyposis
Polyps throughout
stomach, small bowel,
and colorectum,
usually numbering
from 50 to 200
Autosomal
dominant, but
family history in
only 20% to
50%
SMAD4 mutation
> BMPR1A
mutation
At least 55% risk
of gastrointestinal
carcinomas,
including 20%
upper tract
(stomach,
duodenum)
carcinomas](https://image.slidesharecdn.com/gipolyps-190320160428/85/Gi-polyps-30-320.jpg)
Uploaded byMadhumitha Udayakumar
Gi polyps
Gastrointestinal polyps can be classified based on their morphology and location. Inflammatory polyps are a type of benign polyp caused by inflammation in the gastrointestinal tract. They are usually asymptomatic but can sometimes cause bleeding. Microscopically, inflammatory polyps show features of inflammation, ulceration, and regeneration in the lamina propria. Hamartomatous polyps like juvenile polyps and Peutz-Jeghers polyps are genetic conditions characterized by the overgrowth of normal tissues. Juvenile polyps can occasionally harbor dysplasia and patients with juvenile polyposis have an increased cancer risk, requiring endoscopic surveillance.
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Gi polyps
- 1. Gastrointestinal polyps Presenter –Madhumitha U Moderator – Dr. DS Chauhan
- 2. • Is aclinical term or gross description of any circumscribed growth that projects above the surrounding mucosa Polyps
- 3. Sessile –base directly attached to the GIT wall. Pedunculated – mucosal stalk interposed b/w polyp & the wall (<5mm rarely ) Flat – height less than one half the diameter of the lesion. Depressed – likely to harbour high grade dysplasia or malignancy even if small. Endoscopic classification of polyps
- 5. • Highly prevalentin the older population. • If there is a family history of polyp or colon cancer. • Smoker / alcoholic • Overweight/ fatty food intake. Risk factors
- 6. • Mostly asymptomatic,until they grow to 2 cm in diam. • They can lead to bleeding, frank blood or microscopic bleeding. • Rarely present with a change in bowel habit. Clinical presentation
- 7. • Large polypin the rectum can present with tenesmus. • Large amount of mucus can also be passed. • Rarely a polyp will prolapse through the anus or act as an apex for an intussusception.
- 8. Polypoidal lesions Hyperplasia/ heterotropia Benignepithelial lesions Inflammatory lesions NEC tumors Mesenchymal tumors Lymphoid lesions Metastasis
- 9. Inflammatory Polyps • Etiology– ulcerative colitis, crohn’s disease, ischemia, infections, adjacent to ulcers, at surgical anastomotic sites. • Full thickness ulceration of mucosa, followed by inflammation & regeneration of the non-ulcerated epithelium. • Gross – solitary or numerous, <2 cm (giant inflm polyp) , sessile or pedunculated.
- 10. Classic microscopic features 1)Variable degree of fibromuscular hyperplasia of the lamina propria 2) Thickening, splaying, and vertical extension of the muscularis mucosae into the lamina propria 3) Crypt abnormalities (e.g., elongation, hyperplasia, architectural distortion, and serration) 4) Inflammation, ulceration, and reactive epithelial change
- 11. Giant filiform inflammatory poyp Diffuseinflammatory polyposis in ulcerative colitis
- 12. Surface erosion Distorted anddilated crypts with crypt abscess and cryptitis Mixed inflammatory infiltrate in lamina propria
- 13. 1. Bizarre enlargedstromal cells(pseudosarcomatous cells) 2. Often seen underneath areas of ulceration and granulation tissue
- 14. Inflammatory polyps 2˚to mucosal prolapse different spectra/stages of mucosal polyps • Inflammatory cap polyposis • inflammatory myoglandular polyp • diverticular polyps
- 15. Inflammatory cap polyposis •Limited to rectosigmoid and distal colon • Usually sessile and can be solitary to numerous • Histologically - eroded surface with a fibrinosuppurative inflammatory cap
- 16. Body of polyp– acute and chronic inflammation Proliferation of muscularis mucosae Fibromuscular obliteration of lamina propria Epithelial changes – goblet cell hyperplasia and tortuosity of glands
- 19. Inflammatory myoglandular polyp •Mainly located in distal colon, rarely seen in ileum • Solitary and usually pedunculated Histologically 1. Branching and dilated glands
- 20. 2. background ofradially proliferating smooth muscle 3. Surface is often eroded with a fibrinopurulent cap Treatment – directed at the underlying inflammatory condition / rarely,surgical excision when large or numerous polyps causing symptoms (bleeding or obstruction).
- 21.
- 22. Inflammatory fibroid polyp Occuringin small intestine, stomach and less commonly large intestine Gross – ranges from 1.5 to 13 cm in size Most often limited to submucosa, but can infiltrate the mucosa
- 23. Microscopically • Vascularized, fibromyxoidstroma • Abundant inflmmatory cells (eosinophils, lymphocytes, plasma cells, macrophages and mast cells ) • Spindle or stellate shaped stromal cells (fibroblasts ) arranged in an onion skin fashion around blood vessels.
- 24. • IHC –vimentin, CD34 (82-100%), SMA (25%). • Associated with activating PDGFRA mutaions 1. Exon 12 predominate in small intestinal lesions 2. Exon 18 in gastric lesions
- 25. Polypoidal mass expandingthe sub mucosa Bland, spindled cells arranged in onion skin fashion
- 26. Hamartomatous polyps • definedas overgrowths of cells and tissues native to the anatomic location in which they occur. • In the GI tract, hamartomas typically incorporate both stromal and epithelial components. • Hamartomas are most often solitary but may occur as part of a hamartomatous polyposis syndrome
- 27. • Peutz Jeghers •Juvenile polyp • Cowden syndrome • BannayanRiley-Ruvalcaba syndrome • Cronkhite Canada PTEN hamartoma tumor syndromes Types of Hamartomatous polyps
- 28. Juvenile Polyps &Juvenile Polyposis • Juvenile polyps occur in four distinct settings • Sporadic or isolated juvenile polyps are the most common type of colon polyp among patients in the first decade of life
- 29. Association Diagnostic CriteriaInheritance Genetics Risk of malignancy Sporadic <3 polyps; no family history of juvenile polyposis None Essentially none Juvenile polyposis of infancy Diarrhea, protein-losing enteropathy, bleeding, rectal prolapse, polyps from stomach through rectum (resembles adult Cronkhite-Canada syndrome) None De novo germline deletion of 10q encompassin g PTEN and BMPR1A Usually fatal before age 2 years from non- neoplastic complications
- 30. Juvenile polyposis coli (1) Any numberof polyps in a patient with family history, or (2) ≥3 polyps[*] without family history. Polyps are predominantly colonic; small bowel polyps, if present, are few Autosomal dominant, but family history in only 20% to 50% BMPR1A mutation or SMAD4 mutation 30% to 68% risk of colorectal carcinoma Generalized juvenile polyposis Polyps throughout stomach, small bowel, and colorectum, usually numbering from 50 to 200 Autosomal dominant, but family history in only 20% to 50% SMAD4 mutation > BMPR1A mutation At least 55% risk of gastrointestinal carcinomas, including 20% upper tract (stomach, duodenum) carcinomas
- 31.
- 32. 1. 5 ormore juvenile polyps in the colorectum 2. 1 juvenile polyp in the upper and one in the lower GI tract 3. any number of juvenile polyps and a family history of juvenile polyposis . Diagnostic criteria (any one)
- 33. Types of JP TypeA classical JP - found most frequently in isolated cases Type B atypical JP – seen mostly in patients with jps
- 34. Classical JP Pathological features Gross– mainly pedunculated, rarely sessile < 3cm in diameter Smooth glistening surface c/s cystic fluid filled spaces
- 35. Microscopically Cystically dilated andtortuous glands in an inflamed stroma Glands – well formed mucus secreting cells that may be flattened and attenuated Stroma – a/c and c/h inflammation & granulation tissue
- 36. Smooth surface with cysticallydilated glands Numerous cystically dilated glands with expanded laminpropria Irreguraly dilated gland lined by benign epithelium
- 37. larger, multilobulated, andvilliform, often giving the gross appearance of several polyps attached to a single stalk. Atypical JP Histologically, compared with typical cases, they contain less abundant lamina propria and greater epithelial overgrowth with many elongated, tortuous, and irregularly shaped crypts
- 38. Polyps with villiform architecture Epithelialovergrowth and less abundant stroma Crypt architectural distortion with crypt branching and dilatation
- 39. nonneoplastic However ,dysplasia - observed in 15 to 30 % of syndromic and rarely in non syndromic cases Foci of dysplasia - more frequently in atypical jp than in typical jp
- 40.
- 41. evaluation bypolyp type revealed a distinct pattern of dysplasia in polyps with a SMAD4 or BMPR1A Focal dysplasia in a SMAD4 setting was found only in type B polyps, BMPR1A setting focal dysplasia was seen in both type B and type A polyps All sporadic polyps were negative for dysplasia.
- 42. Treatment Upper andlower endoscopy - usually recommended by age 15 and repeated annually. Endoscopic polypectomies and histologic examination until the patient is free of polyps Prophylactic gastrectomy or colectomy if diffuse polyposis not be controlled by endoscopic polypectomy or a family history of GI carcinoma.
- 43. Peutz-Jeghers syndrome Rareautosomal dominant inherited disorder (1:8300-200000 live births) associated with a lifetime hazard for cancer up to 93% Germline mutation in the STK11 gene (Chr 19p13.3)
- 44. Diagnostic criteria a)=>2 histologically confirmed P-J polyps b) Any number of P-J polyps with a family history c) Prominent mucocutaneous pigmentation with a family history d) Any number of P-j polyps and mucocutaneous pigmentation
- 45. C/F –Age – second to third decade SI – obstruction & abd pain LI – bloody stools & prolapse
- 46. • occur throughoutthe GI tract, small bowel (65% to 95%) > colon (60%) > stomach (20% to 50%). • Involved bowel segments - 1 to 20 polyps • size varies from 0.5 to 3 cm in diameter • Well developed polyps in the small intestine and colon -pedunculated. Pathological features
- 47. Lobuar, pedunculated polypin the deuodenal mucosa
- 48. Microscopically • Glandular epitheliumresting on a branching smooth muscle derived from the muscularis mucosae. • In low power gives a “Christmas tree” or “arborescent like appearance”
- 49. • The overlyingmucosa is typically nondysplastic and maintains its normal architecture. • Unlike juvenile polyps, the mucosa has a normal ratio of lamina propria to epithelium and the crypts are not cystically dilated.
- 50. Branching smooth musclecore Over growth of epithelium with arborizing pattern
- 51. • Peutz-Jeghers polypsshow foci of epithelial misplacement, pseudoinvasion, or herniation of benign epithelium into the intestinal wall – enteritis cystica profunda
- 52. Histologic features pseudoinvasion carcinoma 1) Cellularatypia absent present 2) Hemosiderin depositon present absent 3) Deep mucinous cysts present absent 4) Desmoplastic response absent present Discriminators of pseudoinvasion and carcinoma
- 53. Somatic loss ofthe 19p13.3 allele Nondysplastic polyps and hamartoma formation Additional genetic alterations at loci such as TP53 and β-catenin Dysplasia and carcinoma Molecular alterations
- 54. Cancer risk inP-J syndrome
- 55. At 18 yearsonwards – 1. Colonoscopy & Upper endoscopy with either push enteroscopy or double contrast radiology of the entire small intestine every 2-3 years 2. Monthly breast self examination At 25 years onwards – 1. Semiannual clinical breast examination & annual mammography Pelvic examination & PAP smears / annual testicular examination. Pancreatic USG every 1-2 years S U R V E I L A N C E I N P J S
- 56. Cowden syndrome • Autosomaldominant hamartoma / neoplasia syndrome • Mutations in PTEN gene on chromosome 10q23 reported in 80- 85% families with this syndrome • Hamartomas in all 3 germ layers
- 57. • Mucocutaneous lesions– acral keratoses,Trichilemmoma • Fibroadenoma, breast CA • Thyroid-goitre, CA • Macrocephaly, cerebellar gangliocytoma, and genitourinary malformations • Recently, increased risks for endometrial carcinoma and renal cell carcinoma
- 58. Pathological features GIhamartomas - only 35% to 40% of patients most common esophageal manifestation is glycogenic acanthosis Most polyps resemble juvenile polyps and consist of cystically dilated, mucin-filled crypts set within an abundant lamina propria Colonic lipomas, fibrolipomas, fibromas, ganglioneuromas, and adenomas also reported in Cowden syndrome.
- 60. Cronkite – CanadaSyndrome Nonhereditary GI polyposis associated with alopecia, nail atrophy, hyperpigmentation of the skin.80% - 50 years old or more C/F – diarrhea, wt loss, anorexia, nausea, vomiting, weakness. Polyps all over GIT except esophagus. Histologically resemble JP, cystically dilated tortuous crypts filled with inspissated mucin embedded in an edematous & inflammed lamina propria.
- 61. Polypoidal structure withcystically dilated glands Dilated gland from the flat non-polypoidal mucosa
- 62. Treatment The mortality rateis high (50% to 60%). Death usually results from malnutrition, GI bleeding, or infection. aggressive nutritional support, antibiotics, corticosteroids, and/or surgical resection of symptomatic segments of the GI tract.
- 63. Overview of Hamartomatouspolyposis syndromes
- 64. Epithelial polyps • Hyperplastic/serrated •Conventional adenoma • Adenomatous polyposis syndrome • Adenomas and adenoma-like dysplasia-associated lesions or masses in inflammatory bowel disease
- 65. Hyperplastic / serratedpolyps Traditionally considered as non-neoplastic but some hyperplastic may show abnormal proliferation and maturation and may be sessile (SSA/Polyp). Recognised to have potential neoplastic nature Serrated pathway of carcinogenesis
- 66. Progression of adenomato carcinoma Conventional adenoma pathway accounts for approximately 70 to 80% of CRC Serrated pathway – 20 to 30% of all CRC.
- 68. The “serrated neoplasticpathway” describes the progression of serrated polyps, (most commonly SSAs and TSAs) to colorectal cancer. Their development can be divided into two distinct pathways, ◦ One that occurs on the right side of the colon ◦ One that occurs on the left side or distal bowel
- 71. Two examples ofBRAF V600E mutant colon carcinomas with strong VE1 immunoreactivity. The upper row shows a mucinous carcinoma and lower row a poorly differentiated gland-forming adenocarcinoma. Both tumors are MLH1-negative and mismatch repair-deficient.
- 73. Adenoma-carcinoma sequence Serrated pathways APC BRAF KRAS KRAS p53 h-MLH-I SMAD4 p16 MGMT Genetic Alterations
- 74. KRAS proto-oncogene • RASfamily genes • Point mutations of RAS family genes constitute the most common type of abnormality of proto oncogenes in human cancers • 90% of pancreatic adenocarcinomas and cholangiocarcinomas • 50% of colon, endometrial, and thyroid cancers
- 75. • RAS proteinsare members of a family of membrane-associated small G proteins that can bind GTP and GDP • normally flip back and forth between an excited signal-transmitting state in which they are bound to GTP and a quiescent state in which they are bound to GDP. • Stimulation of receptor tyrosine kinases by growth factors leads to exchange of GDP for GTP and subsequent conformational changes that generate active RAS
- 76. downstream kinasesphosphorylate and activate a number of cytoplasmic effectors as well as several transcription factors that turn on genes that support rapid cell growth. Normally : Activation of RAS is transient because RAS has an intrinsic GTPase activity that binds to active RAS and terminates signal transduction.
- 79. BRAF (member ofRAF kinase family • A serine/threonine protein kinase • Top of cascade of kinases belonging to MAPK family • Involved by gain-of-function mutations in various cancers • 100% of hairy cell leukemia,60% of melanoma
- 80. ◦ Like activatingRAS mutations, activating mutations in BRAF stimulate each of the downstream kinases and ultimately activate transcription factors. ◦ > 30 mutations recognised in the BRAF gene. ◦ V600E mutation = most common (90% of BRAF mutations). valine (V) to glutamatic acid (E)
- 81. A single, activating,point mutation in BRAF (V600E) Constitutive signaling of the mitogen-activated protein kinase or (MAPK) pathway Cell proliferation, survival, inhibition of apoptosis
- 82. When compared toCRCs arising from classical adenoma- carcinoma pathway tumors with CIMP-H/non MSI-H and non MSI-H CRCs with BRAF or KRAS mutations (arising from the serrated neoplasia pathway) show • Reduced survival • More aggressive • More resistant to adjuvant therapy
- 83. Classification of serratedcolonic polyps Non dysplastic serrated polyps 1) Normal architecture with normal proliferation • Microvesicular hyperplastic polyp • Goblet cell hyperplastic polyp • Mucin poor hyperplastic polyp 2) Abnormal architecture,abnormal proliferation • Sessile Serrated polyp (SSA)
- 84. Dysplastic serrated polyps •Traditional serrated adenoma • Serrated sessile polyp with dysplasia • Conventional adenoma with serrated architecture
- 85. Serrated Abundant mucin Columnar mucin secretingcells Goblet cells few No dysplasia Microvesicular hyperplastic polyp Grossly measure < 0.5 cm Histology – 1) irregular saw tooth or luminal serrated surface,pronounced in the upper portion of crypts. 2) Simple tubular architecture 3) Presence of abundant (microvesicular) mucin 4) Ki67 staining – limited to the lower half of the crypts
- 86. Serrations only at surface Abundant mucin Gobletcells +++ No dysplasia Goblet cell hyperplastic polyp Grossly measure < 0.5 cm, sessile lesion, mc – in left colon Histology – 1) Elongated crypts rich in goblet cells. 2) Serrations are of far lesser degree and limited to uppermost portions of crypts.
- 87. Mucin poor hyperplasticpolyp Serrations prominent at surface and crypts Absent mucin Goblet cells nil No dysplasia Least common type and usually sessile. Histology – 1) Prominent serrations, often runs entire length of the crypts. 2) Lack of mucin and absence of goblet cells. 3) Exhibit small cells with less cytoplasm, hyperchromatic nuclei and micropapillary architecture
- 88. • Sessile SerratedPolyp/adenoma are often larger than 0.5 cm and commonly seen in right side. • Endoscopically, smooth surface contour and often covered with mucus. • Other commonly used terminologies 1) Atypical hyperplastic polyp 2) Large hyperplastic polyp with architectural abnormalities. 3) Hyperplastic polyp with abnormal proliferation
- 89. Serrations exagerrated at deep partsof crypts Crypt disarray Inverted T/L Lateral growth No dysplasia Serrated sessile polyp (SSA) Histology – 1) Characterised by architectural changes such as a) Crypt branching and dilatation, b) Peculiar growth pattern – crypts grow parallel to muscular mucosa, creating an inverted T or L shape. 2) Prominent serrations at the base or throughout the crypt. 3) Ki 67 staining – irregular asymmetric and highly variable expressions
- 90. Dysplasia ++ Serrated sessilepolyp with dysplasia Prominent Serrations Crypt disarray Dysplasia 1) These lesions referred as mixed hyperplastic/ adenomatous polyps 2) Morphologically,these lesions may show discrete areas of hyperplastic change typical of MVP, show features of SSP combined with dysplasia
- 91. Prominent Serrations Dysplasia Dysplasia ++ Serrated sessilepolyp with dysplasia Sharp Junction
- 92. Traditional Serrated adenoma Prominent Serrations Dysplas ia Nuclearstratification Hypereosinophilic cytoplasm Filiform growth pattern seen in rectum 1) Grossly, tends to be pedunculated 2) Histology: prominent serrations, villiform growth pattern and hypereosinophilic epithelium with/without phenotypic evidence of dysplasia(either low or high grade).
- 93. Conventional adenoma withSerrated architecture Prominent Serrations Dysplasia Cigar shaped nucleus Nuclear stratification Mucin depletion1) Rarely,conventional adenoma show areas of architectural serrations but should be distinguished from TSA by nucleai features, 2) Develop through APC + KRAS fusion molecular pathway.
- 94. Serrated polyp, unclassified Distinction of HP from SSA/P and TSA is based mainly on architectural criteria Not all serrated lesions are easily classified, often because of sampling issues or poor orientation of the specimen. "serrated polyp, unclassified with/without dysplasia“ may be used
- 95. Serrated polyposis syndrome Rarely described entity with rapidly evolving diagnostic and molecular criteria due to increased risk of CRC. Diagnostic criteria of SPS were first defined by Burt and Jass in 2000 for the WHO. These criteria have been recently redefined this entity.
- 96. Diagnostic criteria (1) atleast 5 histologically confirmed serrated polyps located proximal to the sigmoid colon, of which atleast two are larger than 10 mm in diameter; (2) any number of serrated polyps located proximal to the sigmoid colon in a subject with a first-degree relative with SPS; or (3) More than 30 serrated polyps of any size distributed evenly throughout the colon.
- 97. Approximately, 1/3rdof SPS cases are associated with CRC SPS with BRAF mutations – cancer risk high SPS with KRAS mutation – little or no cancer risk
- 98.
- 99. The clinical importanceof serrated lesions of the colorectum Rev. gastroenterol. Perú v.33 n.2 Lima abr./jun. 2013 99
- 100. Conventional adenoma Morphologicallydefined as dysplastic clonal proliferation of epithelium. Grossly, classified as sessile or pedunculated. Microscopically, categorised as 1) tubular 2) tubulo-villous and 3) villous
- 101. Tubular adenoma 1) >75% of tubular architect ure 2) Low malignan cy risk ranging from 2 – 3%
- 102. Tubulovillous adenoma Villousadenoma > 75% villous 1) Villous – 35 to 40% malignant transformation 2) TubuloVillous – 20 to 35% malignant transformation
- 103. 1. Architecturally, non- complexcrypts containing nuclei that are pseudostratified. 2. Cell nuclei reach only the lower half of the cell cytoplasm 3. Mitotic activity brisk,Atypical mitoses, significant loss of polarity, and pleomorphism minimal 4. Crypts are arranged in a parallel configuration Low grade dysplasia
- 104. High grade dysplasia 1)Marked pseudostratification /stratification, 2) Increased mitotic activity/atypical mitoses 3) Marked loss of polarity 4) Architectural changes – back to back gland configuration and cribriforming
- 105. Intramucosal adenocrcinoma Invasion ofmucosa or muscularis mucosae Differentiation of high grade dysplasia is based on presence of definite invasion of the lamina propria. Recommended that documentation of this entity should always include the statement regarding absence of invasive cancer in the polyp stalk and status of resection margin.
- 106. Composite adenoma -microcarcinoid 1) Adenomas associated with minute proliferation of well differentiated neuroendocrine cells underlying dysplastic crypts. 2) When these nests are confined to lamina propria – considered benign
- 107. 1. Average risk(no first-degree relative with colon cancer) Colonoscopy at age 50 yr: • If no adenoma or carcinoma, repeat in 10 yr • If 1-2 small (<1 cm) tubular adenomas with low-grade dysplasia, repeat in 5-10 yr. • If 3-10 adenomas, or any adenoma ≥1 cm, with villous features, or with high-grade dysplasia, repeat in 3 yr • If >10 adenomas, repeat in <3 yr; consider possibility of underlying familial syndrome • If carcinoma, colonoscopy 1 yr after resection, then repeat in 3 yr Guidelines for adenoma surveilance
- 108. 2. Moderate risk(first-degree relative with colon cancer at <60 yr or ≥2 first-degree relatives with colon cancer) Colonoscopy at age 40 yr, or 10 yr before age of occurrence in relative, whichever comes first: follow guidelines as above Guidelines for adenoma surveilance
- 109. Adenoma with epithelialmisplacement (pseudocarcinoma) 1. Foci of misplaced epithelium or extravasated mucin within the submucosa of an adenoma 2. Occurs in 2- 4% of adenomatous polyp 3. More common - left sided polyps and pedunculated polyps. Lobule of misplaced glands in submucosa
- 110.
- 111.
- 112. Flat adenomas definedas dysplastic, non-invasive lesions without a polypoidal component. Typically have a central depression. Constellation of molecular abnormalities different from conventional adenomas Gastrointest Endosc 2002 Nov;56(5):663-71. Molecular analysis of diminutive, flat, depressed colorectal lesions: are they precursors of polypoid adenoma or early stage carcinoma? Morita T, Tomita N, Ohue M
- 114. FAMILIAL ADENOMATOUS POLYPOSIS 1%of all large intestinal tumour diagnosIs Autosomal dominant condition caused by inheritance of a mutated APC gene (Chr 5q) Characterized by 100-1000s adenomatous polyps in large bowel
- 115. FAP symptoms occurearlier and generally start to appear in the 2nd and 3rd decade of life with most patients developing adenomas by age 35.
- 117. Signs and Symptoms Brightred blood in the stool Diarrhea and/or constipation Abdominal pain, cramping, or bloating Continued weight loss Anemia
- 118. Genetics - APCgene Tumor suppressor gene Location: 5q21 Dual function 1) Inhibition of signal transduction 2) Gatekeeper Gene – regulates levels of ß-catenin ( a member of cadherin based cell adhesive complex)
- 119. Regulates the WNT/ß-cateninsignaling pathway Loss of APC function: ß-catenin accumulates and activates the transcription of MYC and cyclin D1 - proliferation of cells Half of tumors without APC mutations have ß-catenin mutations
- 122. Pathological features MACRO Flexible endoscopyis the gold standard - screening Mild – 100-1000 Severe - >1000 Classic - small raised lesion with a rounded contour AFAP - flat in appearance, showing only minimal mucosal elevation (<1cm)
- 123. Resected specimen ofcolon showing diffuse polyposis
- 125. Extracolonic manifestations • Congenitalhypertrophy of retinal pigment epithelium (CHRPE) • Osteomas, desmoid tumours, epidermoidcysts (Gardner’s syndrome) • CNS malignancies including medulloblastoma and glioblastoma (Turcot’s syndrome) • Duodenal, hepatobiliary-pancreatic, thyroid tumours
- 127. Screening of FAP Geneticscreening of family members for APC mutations Annual flexible sigmoidoscopy beginning at age 10-12 until age 40,then every 3-5 years. If polyposis is present, colectomy should be considered UGIE every 1-3 years is also recommended to evaluate for upper GI adenomas
- 128. Attenuated FAP 8%of patients Fewer polyps ,<100 (median 25) Average age of onset of 41 years Lifetime risk of malignancy – 80%
- 129. Diagnostic criteria 1. 2patients in a family are diagnosed with 10-99 adenomas at age >30 years or 2. 1 patient diagnosed with 10-99 adenomas at age >30 and a first- degree relative is diagnosed with colorectal cancer
- 130. MUTYH - associatedpolyposis • Autosomal recessive syndrome - mutations of the mutY homolog (MUTYH) gene(Chr 1) • Penetrance for colon polyps is close to 100% and bi-allelic MUTYH mutation carriers generally develop 10-100 adenomatous polyps/ adenomas of the colon and rectum. • 60-70% of MAP CRC patients - first diagnosed at a mean age of 47 years.
- 131. Microsatellite instability accounts for6-15% of CRC and caused by inactivation of DNA mismatch repair (MMR) genes If a mismatch or small loop is found, endonuclease cuts the strand bearing the mutation and exonuclease (MLH1 and PMS2) then digests this strand. MMR corrects errors that spontaneously occur during DNA replication, such as single base mismatches or short insertions and deletions.
- 132. MSI refers toaltered lengths (“instability”) of short nucleotide repeat sequences (“microsatellites”) in tumor DNA compared with normal DNA Mutations of coding mononucleotide repeats in tumor suppressor genes Tansforming growth factor (TGF)- receptor type 2 (TGFBR2) BAX (proapoptotic gene) have been shown to be important in carcinogenesis
- 133. microsatellites areshort, sequences of 1 to 6 nucleotide base pairs which are repeated dozens to hundred times throughout the genome. are a ubiquitous component of the genome of higher organisms. The most common microsatellite in humans is a dinucleotide repeat of the nucleotides C and A, which occurs tens of thousands of times across the genome.
- 134. Frameshift mutationsoccur when the number of bases added or deleted is not a multiple of three. The reading frame is shifted so that completely different sets of codons are read beyond the point of mutation. frameshift mutations → affecting critical areas of cell growth regulation genes → promotion of tumorigenesis
- 135. • Mutation ofboth alleles of mismatch repair (MMR) system → DNA strand might be displaced, and realigns creating small loop of unpaired DNA → unable to remove the loops → microsatellite increases or decrease in size due to either insertion or deletion of repeating units when compared to the normal cell’s
- 136. Hereditary nonpolyposis coloncancer syndrome (HNPCC/Lynch syndrome) AD disorder characterised by familial CRCs Individuals inherit one abnormal copy of DNA mismatch repair gene. When loss of function mutation occurs in the 2nd allele their “proofreading” function is lost. Errors accumulate and these may activate proto-oncogenes or inactivate tumor suppressor genes.
- 137. One of thehallmarks of patients with mismatch repair defects is microsatellite instablitity Of various mismatch repair genes two most commonly involved are: ◦ MLH1 ◦ MSH2 Each of these account for 30% cases of HNPCC. Other mutated genes: TGF-receptor II, BAX and TCF component of beta-catenin pathway
- 138. Diagnosis Amsterdam criteria1 Due to lack of phenotypic markers like polyps,diagnosis is based on family history of CRC only 1. One member less than 50 years of age 2. Two involved generations 3. Three family members affected, one of whom is a first degree relative of the other two
- 139.
- 141. MSI testing MOLECULAR TESTING ◦Evaluation of certain loci within human genome that are known to harbour microsatellites ◦ DNA extracted from both normal tissue & tumor tissue ◦ After PCR amplification of selected microsatellites , size of PCR products obtained from normal & tumor tissue are compared. MSI is defined as change of any length due to either insertion or deletion of repeating units in a microsatellite within a tumor.
- 142. Bethesda panel -MSI is typically assessed by analyzing five microsatellite markers: A) 2 mononucleotide repeat (BAT 25 & BAT 26) B) 3 dinucleotide repeats (D2S123, D5S346 & D17S250 ) • MSI-H : >2/5 • MSI-L : 1/5 • MSS : None (Genome does not have instability of its microsatellite DNA & so may have chromosomal instability instead)
- 145. MSI-H is presentas a distinct phenotype in approximately 15% of CRCs Tumors with microsatellite instability can also be recognized by the absence of immunohistochemical staining for mismatch repair proteins.
- 146. MMR protein IHC+ for all 4 proteins; does not rule out MSI: Missense mutation -5% Epigenetic changes at promoter site Mutation of lesser known MMR enzymes
- 147. Screening Colonoscopy every 2years starting at ages 20-25 or 5 years younger than the earliest diagnosis of CRCwhichever is earlier until 40yr , and then annually Flexible sigmoidoscopy is not acceptable, due to the proximal location of tumours Transvaginal US and endometrial aspiration annually starting at ages 25-35 years are also recommended
- 148. Treatment Total colectomy withileorectal anastomosis Restorative proctocolectomy with ileal pouch- anal anastomosis Segmental colectomy not recommended because of high rate of metachronous CRC TAHBSO for endometrial cancer
- 149. Adenoma and adenomalike dysplasia Dysplasia in IBD FLAT RAISED No endoscopic lesion Visible endoscopic lesion
- 151. Malignant epithelial polyps Defined as adenoma that contains invasive adenocarcinoma ( cancer extends beyond muscularis mucosa into the submucosal polyp stalk)
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- 157. Esophagus Epithelial Benign Inflammatory polyp Hyperplastic polyp Gastricheterotopia Adenoma Glycogenic acanthosis Malignant Polypoid dysplasia Spindle cell carcinoma Squamous cell carcinoma Adenocarcinoma Melanoma Mesenchymal Granular cell tumour Leimyoma Fibrovascular polyp GIST Leimyosarcoma
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- 162. Next activity 24/07/17Dr Seema (journal club)