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- 1. GIT - 7 Dr.CSBR.Prasad, M.D.,
- 2. What are the possibilities? A 59-year-old woman presented with: h/o 20-year history of papules on the dorsa of the hands and feet Benign tumor of the breast at age 16 Bone cyst of the femur at age 21 Breast cancer at age 45 At age 46, she developed hyperthyroidism Breast cancer in the contralateral breast at age 52 Five years later, bilateral partial nephrectomies were performed for renal cell carcinoma
- 3. What is the abnormality? What is your suspicion?
- 4. What is the abnormality? What is your diagnosis?
- 5. What is the abnormality? What is your diagnosis?
- 6. Some questions • What is the important criterion in the definition of adenoma in GIT? • What is a Hamartoma? • What do you understand by the term familial? • How do you define a polyp? • How a polyp is different from adenoma? • What do you understand by the terms: – Sessile – Pedunculated
- 7. Polyps ofPolyps of Small & Large intestinesSmall & Large intestines Dr.CSBR.Prasad, M.D.,
- 8. Polyps - terms • Sessile / Pedunculated
- 10. INFLAMMATORY POLYPS • Example: Solitary rectal ulcer syndrome • CF: Triad – Rectal bleeding – Mucus discharge and – Inflammatory lesion of the anterior rectal wall • Pathology: Impaired relaxation of the anorectal sphincter
- 13. Histologic features - SRU • Mucosal prolapse and include lamina propria • Fibromuscular hyperplasia • Mixed inflammatory infiltrates • Erosion and epithelial hyperplasia
- 14. HAMARTOMATOUS POLYPS What is hamartoma? •Jumbled mixture of tissue native to the site
- 15. HAMARTOMATOUS POLYPS • Occurrence: – Sporadically or – As components of Syndromes • Rare • Importance: – Intestinal and extra-intestinal manifestations – May be present in other family members
- 17. Juvenile Polyps • Focal malformations of the mucosal epithelium and lamina propria • Age: < 5 years • Types: – Sporadic – solitary – Juvenile polyposis syndrome (> 3 polyps)
- 18. Morphology • Gross: – <3 cm – Pedunculated – Surface ulceration – c/s cystic spaces • Microscopy: – Dilated glands – Neutrophilic debris in the lumen – Lamina propria – inflammatory cells – Muscularis mucosa - normal
- 19. Juvenile Polyps Pathogenesis: • Incompletely understood • In AD juvenile polyposis: – TGF-β signaling pathway (50% cases) • SMAD1 • BMPR1A – Other genes Importance: Increased risk of colonic carcinoma
- 20. Peutz-Jeghers Syndrome Dr. Johannes Peutz, 1951 Dr. Harold M Jeghers
- 21. Peutz-Jeghers Syndrome • AD • Age of presentation: ~11yrs • Multiple polyps and mucocutaneous hyperpigmentation • Increased risk for several malignancies – colon, pancreas, breast, lung, ovaries, uterus, and testicles, sex cord tumors
- 23. Peutz-Jeghers Syndrome Pathogenesis: • LOH of tumor suppressor gene LKB1/STK11 – LKB1/STK11 is a kinase that regulates cell polarization, growth, and metabolism • Polyps in PJ syndrome: – Are not premalignant – Adenocarcinomas arise independently
- 24. Peutz-Jeghers Syndrome • Barium enema radiograph showing multiple polyps (mostly pedunculated) and at least one large mass at the hepatic flexure coated with contrast in a patient with Peutz–Jeghers syndrome.
- 25. Polyps are large and pedunculated with a lobulated contour
- 26. Morphology • Hamartomatous polyp • Arborizing network of connective tissue, smooth muscle, lamina propria • Glands lined by normal-appearing intestinal epithelium
- 27. DD - Polyps of PJ syndrome from Juvenile polyps • The arborization and presence of smooth muscle intermixed with lamina propria are helpful in distinguishing polyps of Peutz- Jeghers syndrome from juvenile polyps
- 28. Peutz-Jeghers Syndrome Diagnosis: – Multiple polyps in the small intestine – Mucocutaneous hyperpigmentation & – Positive family history – Detection of LKB1/STK11 mutations Surveillance: – There is increased risk of cancer – Routine surveillance of the GI tract, pelvis, and gonads is recommended
- 29. Peutz-Jeghers Syndrome Because of the increased risk of cancer, routine surveillance of the GI tract, pelvis, and gonads is typically recommended
- 30. Cowden Syndrome • AD • Hamartomatous polyps • Loss-of-function mutations in PTEN • Characterized by: – Macrocephaly – Intestinal hamartomatous polyps – Benign skin tumors • Increased risk of GI malignancy • Other cancers: – Breast carcinoma – Follicular carcinoma of the thyroid and – Endometrial carcinoma
- 31. Cowden Syndrome
- 32. HYPERPLASTIC POLYPS • Sixth and seventh decades • Result from decreased epithelial cell turnover and delayed shedding of surface epithelial cells • No malignant potential • Importance: they must be distinguished from sessile serrated adenomas, histologically similar lesions that have malignant potential
- 33. HYPERPLASTIC POLYPS Morphology: •Commonly found in the left colon •< 5 mm in diameter •Smooth, nodular protrusions of the mucosa •Multiple (more frequently) •Serrated surface architecture
- 34. Hyperplastic polyp • A: Polyp surface with irregular tufting of epithelial cells • B: Tufting results from epithelial overcrowding • C: Epithelial crowding produces a serrated architecture when glands are cut in cross- section
- 36. NEOPLASTIC POLYPS Colonic adenomas: • Characterized by the presence of epithelial dysplasia • Importance: precursors to colorectal adenocarcinomas • Small, pedunculated polyps / large sessile lesions • Clinical Features: – Most adenomas are clinically silent – Large polyps may produce occult bleeding and anemia – Villous adenomas that cause hypoproteinemic hypokalemia
- 37. Adenoma - Morphology Gross: •Size: 0.3 to 10 cm in diameter •Pedunculated or Sessile •Velvetty surface Histology: •Dysplasia (Hyperchromatic nuclei, stratification, large nucleoli, reduced number of goblet cells)
- 38. • Adenomas can be classified as: (Architectural) – Tubular – Villous or – Tubulovillous
- 39. Tubular adenomas • Small • Pedunculated polyps • Histology: composed of small rounded, or tubular, glands
- 40. Tubular adenomas
- 42. Tubular adenoma
- 43. Tubular adenoma
- 44. Villous adenomas • Often larger • Sessile • Covered by slender villi
- 45. Villous adenomas
- 46. Surface of villous adenomaSurface of villous adenoma
- 47. Villous adenomas
- 48. Villous adenomas
- 49. Adenoma with intramucosal carcinoma
- 50. Tubulovillous adenomas • They have a mixture of tubular and villous elements
- 53. Villous adenomas with adenocarcinoma Note: Villous architecture alone does not increase cancer risk when polyp size is considered
- 54. Sessile serrated adenomas • Overlap histologically with hyperplastic polyps • More commonly found in the right colon • High malignant potential • They lack features of dysplasia • Histology: – Serrated architecture throughout the full length of the glands – Lateral growth and crypt dilation – DD: Hyperplastic polyp: Serrated architecture is typically confined to the surface
- 57. Tubular, Villous & Serrated adenomas
- 58. Adenomas - Risk of malignancy • Most colorectal adenomas are benign • Risk factors for malignancy: – Number of adenomas – Size is the most important characteristic that correlates with risk of malignancy • Adenomas <1 cm in diameter – BENIGN • Adenomas > 4 cm in diameter – May contain Malignancy – High-grade dysplasia increases the risk in that polyp
- 59. Familial Polyposis SyndromesFamilial Polyposis Syndromes
- 60. Familial Syndromes Several syndromes characterized by the presence of colonic polyps and increased rates of colon cancer
- 61. Familial Syndromes The genetic basis of these disorders has been established
- 62. FAMILIAL ADENOMATOUS POLYPOSISFAMILIAL ADENOMATOUS POLYPOSIS • AD • Manifests in teenage • Numerous colonic polyps – At least 100 polyps are necessary for a diagnosis of classic FAP • Polyps are morphologically similar to sporadic adenomas
- 64. Importance: if untreated – Colorectal adenocarcinoma - 100% – Often before age 30yrs Note: Prophylactic colectomy is the standard therapy for individuals carrying APC mutations
- 65. Colectomy and Malignancy • Colectomy prevents colorectal cancer • Risk for neoplasia at other sites remains unchanged – Eg: Adenomas may develop elsewhere in the GI tract, particularly adjacent to the ampulla of Vater and in the stomach
- 66. Variants of FAP • Specific APC mutations have been associated with the development of other manifestations of FAP – Gardner syndrome – Turcot syndrome
- 69. HEREDITARY NON-POLYPOSIS COLORECTAL CANCER - HNPCC • Synonym: Lynch syndrome • Familial clustering of cancers at several sites: – Colorectum (at younger ages) – Stomach – Small bowel – Hepatobiliary tract – Endometrium – Ovary – Ureters – Brain and – Skin
- 70. HEREDITARY NON-POLYPOSIS COLORECTAL CANCER - HNPCC Genetic defect: •Defective DNA mismatch repair genes •There are five such mismatch repair genes – Majority of HNPCC cases involve MSH2 and MLH1
- 71. Causes for Lower GI bleedingCauses for Lower GI bleeding
- 75. E N D
Editor's Notes
- Cowden&apos;s syndromeOlympia Kovich MD, and David Cohen MD MPH Dermatology Online Journal 10 (3): 3 From the Ronald O. Perelman Department of Dermatology, New York University Dermatology online Journal &lt;https://escholarship.org/uc/item/6bp1n1k3Cowden&gt;
- PJ syndrome.
- Gardner syndrome: Polyposis coli Osteomas
- People with Turcot syndrome have multiple adenomatous colon polyps (polyps in the colon made up of cells that form mucous), an increased risk of colorectal cancer, and an increased risk of brain cancer (Medulloblastoma). The two most common types of brain tumors in Turcot syndrome are: Glioblastoma. This type of brain tumor is a very aggressive form of astrocytoma that is commonly found in families who have features of HNPCC. Medulloblastoma. This type of brain tumor begins in granular cells in the cerebellum (back of the brain). Medulloblastoma most often occurs in children and is commonly found in families who have features of FAP.
- These are referred to as sessile, a term borrowed from botanists who use it to describe flowers and leaves that grow directly from the stem without a stalk. As sessile polyps enlarge, several processes, including proliferation of cells adjacent to the mass and the effects of traction on the luminal protrusion, may combine to create a stalk. Polyps with stalks are termed pedunculated. In general, intestinal polyps can be classified as non-neoplastic or neoplastic in nature.
- FIGURE 17-41 Solitary rectal ulcer syndrome. A, The dilated glands, proliferative epithelium, superficial erosions, and inflammatory infiltrate are typical of an inflamatory polyp. However, the smooth muscle hyperplasia within the lamina propria suggests that mucosal prolapse has also occurred. B, Epithelial hyperplasia. C, Granulation tissue-like capillary proliferation within the lamina propria caused by repeated erosion and re-epithelialization.
- Hamatoma: Hamartomas are tumor-like growths composed of mature tissues that are normally present at the site in which they develop.
- Although hamartomatous polyposis syndromes are rare, they are important to recognize because of associated intestinal and extra-intestinal manifestations and the possibility that other family members are affected.
- FIGURE 17-42 Juvenile polyposis. A, Juvenile polyp. Note the surface erosion and cystically dilated crypts. B, Inspissated mucous, neutrophils, and inflammatory debris can accumulate within dilated crypts.
- Although the morphogenesis of juvenile polyps is incompletely understood, some have suggested that mucosal hyperplasia is the initiating event. This hypothesis is consistent with the discovery that mutations in pathways that regulate cellular growth cause autosomal dominant juvenile polyposis. The most common mutation identified is of SMAD4, which encodes a cytoplasmic intermediate in the TGF-β signaling pathway. BMPR1A, a kinase that is a member of the TGF-β superfamily, may be mutated in other cases (see Table 17-9 ). However, these mutations account for fewer than half of patients, suggesting that changes in other genes can also cause juvenile polyposis. Dysplasia occurs in a small proportion of juvenile polyps, and the juvenile polyposis syndrome is associated with an increased risk of colonic adenocarcinoma.
- Peutz-Jeghers Syndrome, An Overview Introduction In the 1920s and 1930s two physicians on opposite sides of the Atlantic ocean published and reviewed case reports about individuals with distinctive mucosal and skin pigment lesions and concurrently had intestinal polyps.[1] Often these individuals were members of the same family. The complex of skin and mucosal pigment abnormalities and associated intestinal polyps would later bare their names, the Peutz-Jeghers Syndrome. Dr. Harold Jeghers of the United States and Dr. Johannes Peutz of Holland [2] and subsequent investigators of the Peutz-Jeghers Syndrome recognized that these mucocutaneous pigment lesions and concurrent gastrointestinal polyps &quot;must be due to the presence of a single pleiotropic gene, responsible for both characteristics, the polyps and the spots.&quot;[3] With the passage of time and continued observations, medical investigators realized that individuals with these clinical findings were at increased risk for neoplasias and a life shortened by cancer. Discovery The syndrome now characterized at the molecular level; had its beginnings in case reports as early as the 1890s.[4,5] One early report by Dr. Peutz dating back to the winter of 1920 described a 15 year old boy with anorexia, nausea, abdominal pain, weight loss and distinctive pigmentation on his face. Dr. Peutz recalled treating this patient&apos;s brother the previous summer. Other family members were found to have abnormalities associated with the syndrome. Four siblings had pigment lesions of the mucosa and three members had intestinal polyposis, while two had nasal polyposis.[3] Dr. Jeghers&apos; contribution to the understanding of this syndrome came through his studies of prior published cases and his subsequent publication of followup evaluations. His use of a personal medical library, served him in retrieving prior case reports which he used in his review and analysis. Although Dr. Jeghers&apos; studies in the 1940s lacked the statistical rigor of current analyses of the medical literature, his use of the literature in tracking prior cases was unusual for its time. He identified a case report from a 1895 publication, describing 12 year old identical twin sisters having dark pigmented lips, gums and hard palate.[4] He subsequently obtained followup history of these two individuals. His use of a personal library demonstrated the value of researching medical literature. Clinical Findings The early case reports of the 1920s and 1930s described intussusceptions, a form of intestinal blockage, and gastrointestinal bleeding as complications of this syndrome. As case reports and case studies accumulated throughout the 1950s and 1970s, the association of malignancies as part of the Peutz-Jeghers Syndrome evolved. The intestinal polyps associated with the Peutz-Jeghers Syndrome, described as hamartomatous in nature and their occurrence in unusual sites such as the jejunum, mark the individual as being at increased risk for developing a cancer. Although initially characterized as a syndrome associated with gastrointestinal polyps and other gastrointestinal neoplasms, clinicians have come to realize that tumors of the extra-intestinal organ systems could also develop. Conclusion Much has been learned over the past decades about the Peutz-Jeghers Syndrome. The benign nature of the skin and mucosal findings belie the more sinister nature of the syndrome&apos;s malignant predisposition. In recent times the Peutz-Jeghers Syndrome has become the focus of molecular genetic studies. The ease with which international collaboration regarding medical matters occurs today is a far cry from that existing in the era of Drs. Jeghers and Peutz. The understanding of the Peutz-Jeghers Syndrome which evolved over decades would today most probably occur in months. Peutz-Jeghers Syndrome is thoroughly described in medical publications and is recognized as occurring in the world&apos;s population. 1. Keller JJ, Offerhaus GJ, Giardiello FM, Menko FH. Jan Peutz, Harold Jeghers and a remarkable combination of polyposis and pigmentation of the skin and mucous membranes. Fam. Cancer 2002 1:181-185. 2. Peutz, JL. Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. (Dutch). Nederl. Maandschr. Geneesk. 1921 10:134-146. 3. Jeghers H, McKusick VA, Katz, KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits. N Engl J Med. 1949 Dec 22;241(25):993, illust; passim. Large file (4 MB) 4. Connor JT.Aesculapian Society of London.Lancet 1895 2:1169. 5. Hutchinson, J. : Pigmentation of lips and mouth. Arch. Surg. 1896 7:290-1.
- PJ-Syndrome: This rare autosomal dominant syndrome presents at a median age of 11 years with multiple GI hamartomatous polyps and mucocutaneous hyperpigmentation. The latter takes the form of dark blue to brown macules around the mouth, eyes, nostrils, buccal mucosa, palmar surfaces of the hands, genitalia, and perianal region. These lesions are similar to freckles but are distinguished by their presence in the buccal mucosa. Peutz-Jeghers polyps can initiate intussusception, which is occasionally fatal. Of greater importance, Peutz-Jeghers syndrome is associated with an increased risk of several malignancies, including cancers of the colon, pancreas, breast, lung, ovaries, uterus, and testicles, as well as other unusual neoplasms, such as sex cord tumors.
- Pathogenesis. Germline heterozygous loss-of-function mutations in the gene LKB1/STK11 are present in approximately half of individuals with familial Peutz-Jeghers syndrome as well as a subset of patients with sporadic PeutzJeghers syndrome. LKB1/STK11 is a kinase that regulates cell polarization, growth, and metabolism. The function of the second “normal” copy of LKB1/STK11 is often lost through somatic mutation in cancers occurring in Peutz-Jeghers syndrome, consistent with the view that LKB1/STK11 is a tumor suppressor gene and providing an explanation for the high risk of neoplasia in affected patients. The GI adenocarcinomas arise independently of the hamartomatous polyps, indicating that the hamartomas are not preneoplastic precursor lesions.
- Pathogenesis. Germline heterozygous loss-of-function mutations in the gene LKB1/STK11 are present in approximately half of individuals with familial Peutz-Jeghers syndrome as well as a subset of patients with sporadic PeutzJeghers syndrome. LKB1/STK11 is a kinase that regulates cell polarization, growth, and metabolism. The function of the second “normal” copy of LKB1/STK11 is often lost through somatic mutation in cancers occurring in Peutz-Jeghers syndrome, consistent with the view that LKB1/STK11 is a tumor suppressor gene and providing an explanation for the high risk of neoplasia in affected patients. The GI adenocarcinomas arise independently of the hamartomatous polyps, indicating that the hamartomas are not preneoplastic precursor lesions.
- Morphology. The polyps of Peutz-Jeghers syndrome are most common in the small intestine, although they may occur in the stomach and colon, and, with much lower frequency, in the bladder and lungs. Grossly, the polyps are large and pedunculated with a lobulated contour. Histologic examination demonstrates a characteristic arborizing network of connective tissue, smooth muscle, lamina propria, and glands lined by normal-appearing intestinal epithelium ( Fig. 17-43 ). The arborization and presence of smooth muscle intermixed with lamina propria are helpful in distinguishing polyps of Peutz-Jeghers syndrome from juvenile polyps. FIGURE 17-43 Peutz-Jeghers polyp. A, Polyp surface (top) overlies stroma composed of smooth muscle bundles cutting through the lamina propria. B, Complex glandular architecture and the presence of smooth muscle are features that distinguish Peutz-Jeghers polyps from juvenile polyps. Compare to Figure 17-42 .
- Papules on the nose Filiform papule on the right nasolabial fold
- FIGURE 17-45 Colonic adenomas. A, Pedunculated adenoma (endoscopic view). B, Adenoma with a velvety surface. C, Low-magnification photomicrograph of a pedunculated tubular adenoma
- FIGURE 17-47 Adenoma with intramucosal carcinoma. A, Cribriform glands interface directly with the lamina propria without an intervening basement membrane. B, Invasive adenocarcinoma (left) beneath a villous adenoma (right). Note the desmoplastic response to the invasive components.
- Sessile serrated adenomas overlap histologically with hyperplastic polyps, but are more commonly found in the right colon.[110] Despite their malignant potential, sessile serrated adenomas lack typical cytologic features of dysplasia that are present in other adenomas ( Fig. 17-46C ). Histologic criteria include serrated architecture throughout the full length of the glands, including the crypt base, associated with lateral growth and crypt dilation ( Fig. 17-46D ). In contrast, serrated architecture is typically confined to the surface of hyperplastic polyps.
- FIGURE 17-46 Histologic appearance of colonic adenomas. A, Tubular adenoma with a smooth surface and rounded glands. Active inflammation is occasionally present in adenomas, in this case, crypt dilation and rupture can be seen at the bottom of the field. B, Villous adenoma with long, slender projections that are reminiscent of small intestinal villi. C, Dysplastic epithelial cells (top) with an increased nuclear-to-cytoplasmic ratio, hyperchromatic and elongated nuclei, and nuclear pseudostratification. Compare to the nondysplastic epithelium below. D, Sessile serrated adenoma lined by goblet cells without typical cytologic features of dysplasia. This lesion is distinguished from a hyperplastic polyp by extension of the neoplastic process to the crypts, resulting in lateral growth. Compare to the hyperplastic polyp in Figure 17-44A
- Although most colorectal adenomas are benign lesions, a small proportion may harbor invasive cancer at the time of detection. Size is the most important characteristic that correlates with risk of malignancy. For example, while cancer is extremely rare in adenomas less than 1 cm in diameter, some studies suggest that nearly 40% of lesions larger than 4 cm in diameter contain foci of cancer. In addition to size, high-grade dysplasia is a risk factor for cancer in an individual polyp (but not other polyps in the same patient).
- FIGURE 17-48 Familial adenomatous polyposis. A, Hundreds of small polyps are present throughout this colon with a dominant polyp (right). B, Three tubular adenomas are present in this single microscopic field.
- FAP is associated with a variety of extra-intestinal manifestations including congenital hypertrophy of the retinal pigment epithelium, which can generally be detected at birth and can be an adjunct to early screening. Specific APC mutations have been associated with the development of other manifestations of FAP and explain variants such as Gardner syndrome and Turcot syndrome. In addition to intestinal polyps, Gardner syndrome families have osteomas of mandible, skull, and long bones, epidermal cysts, desmoid tumors, thyroid tumors, and dental abnormalities, including unerupted and supernumerary teeth. Turcot syndrome is rarer and characterized by intestinal adenomas and tumors of the central nervous system. Two thirds of patients with Turcot syndrome have APC gene mutations and develop medulloblastomas. The remaining one third have mutations in one of several genes involved in DNA repair and develop glioblastomas. Some FAP patients without APC loss have mutations of the base-excision repair gene MUTYH.[112] The role of these genes in tumor development is discussed below. In addition, certain APC and MUTYH mutations are associated with attenuated forms of FAP, which are characterized by delayed polyp development, the presence of fewer than 100 adenomas, and the delayed appearance of colon cancer, often to ages of 50 or above.[113]
- Polyposis coli Osteomas
- People with Turcot syndrome have multiple adenomatous colon polyps (polyps in the colon made up of cells that form mucous), an increased risk of colorectal cancer, and an increased risk of brain cancer (Medulloblastoma). The two most common types of brain tumors in Turcot syndrome are: Glioblastoma. This type of brain tumor is a very aggressive form of astrocytoma that is commonly found in families who have features of HNPCC. Medulloblastoma. This type of brain tumor begins in granular cells in the cerebellum (back of the brain). Medulloblastoma most often occurs in children and is commonly found in families who have features of FAP.