Polyposis Jodie Ouahed, MD Victor Fox, MD Boston Children’s Hospital Reviewed by Diana Riera, MD of the Professional Education Committee

Common presentations of polyposis syndromes: Rectal Bleeding (often painless) Abdominal Pain Altered bowel habit Prolapse of polyp/rectum Intussusception Asymptomatic

Classification and diagnostic considerations: 1) Hamartomas 2) Adenomas 3) Inflammatory 4) Mixed polyposis syndromes 5) Hyperplastic Most commonly seen: -Solitary: Solitary Juvenile Polyp (hamartoma) -Familial: Familial Adenomatous Polyposis Diagnosis of pediatric Polyposis Syndromes: Requires clinical presentation with thorough physical exam including Macrocephaly Penile freckling Unusual lentigines (pigmented macules on lips, mouth, face, extremities, café au lait macules ) Histologic findings Once detected  careful Family History (FHx) must be obtained including history of cancer, and age of onset

2 Main Histopathological Classification 1) Hamartomas -Solitary Juvenile Polyp -Juvenile Polyposis Syndrome -Peutz-Jeghers Syndrome -PTEN- Hamartoma tumor syndromes (Cowden’s, Bannayan-Riley-Ruvalcaba Syndrome ) 2) Adenomas -Familial Adenomatous Polyposis (FAP) -MYH-associated polyposis -Lynch Syndrome

Pathologic features: Grossly Size (cm) Microscopically Juvenile Polyp - Either small sessile or large pedunculated – Ulcerated friable surface 1-3 - Dilated cysts filled with mucin - Abundant lamina propria - Prominent inflammatory infiltrate - Not well organized Peutz-Jeghers - Sessile or Pedunculated - Lobulated surface 0.5-5 -Frondlike structure -Long branching arborizing strands of smooth muscle Tubular and villous Adenoma Pedunculated - Smooth red lobulated surface - Possible to have flat spreading sessile lesions - Glands and tubules +/- inflammatory infiltrate. *Dysplasia always present*

Familial Adenomatous Polyposis: Hundreds-thousands of adenomas in the colon, rectum as well as stomach and small intestines Most of the gastric polyps are non-neoplastic fundic gland type polyps, but can develop foci of dysplasia or adenoma The duodenum is frequently involved while more distal portions of the small bowel are rarely involved Begin in childhood/adolescence Increase in number with age Clinical dx of classic FAP: if >100 colorectal adenomatous polyps identified Attenuated FAP (8%): Milder form with fewer adenomas and later presentation; less likely to present in childhood

Epidemiology & Presentation FAP: Epidemiology: 1/100 000 births 20-30% are spontaneous mutation Pre-symptomatic presentation: for genetic testing (affected family member) Symptomatic: with multiple colonic adenomas Typically identified in teenage years, at the time of screening (not usually following symptoms) Most have easily detectable colorectal adenomas by late childhood-early adolescence Age of presentation is debatable (depends on when scope is performed) Some found as young as 4-5 y/o

Signs and Symptoms of FAP: GI manifestations: Often asymptomatic, until advanced neoplasia occurs Increased frequency of bowel movements Looser stools Mucous discharge Rectal bleeding Abdominal or back pain. Extra-intestinal manifestations: Hepatoblastoma Thyroid and adrenal carcinoma Teeth: impacted, supernumerary, uninterrupted teeth Connective tissue: desmoid tumors, subcutaneous cysts, fibromas, excessive adhesions Eyes: Benign asymptomatic retinal lesions called congenital hypertrophy of retinal pigment epithelium (CHRPE)

Pathophysiology: Genetics Autosomal Dominant Mutated APC (Adenomatous Polyposis Coli) gene on chromosome 5q21, usually results in truncated protein APC is a tumor suppressor gene; thus inactivation of one APC allele predisposes to adenoma formation Phenotypic variability with: Location of mutation: Most severe between codons 1250-1464, especially codon 1309. Environmental factors Other modifier genes Autosomal recessive form exists (mutated MUTYH gene) This does not present in childhood

Screening and Diagnosis of FAP: Genetic testing for APC in at risk relatives is recommended just before 10-12 y/o Controversy on whether to test for APC earlier, given rare risk of hepatoblastoma (~1%) , which usually presents within first 5 years of life Diagnosis is confirmed by finding polyps on flex sig/colonoscopy, histologically confirmed as adenomas Assure detailed counseling prior to screening Anticipate psychological, family, insurance, and employment implications Have clear plan in place for post-test management

Screening and Diagnosis of FAP: Mutations may only be detected in 70-90% of cases! A) If mutation not found: Can’t offer predictive testing Require endoscopic surveillance Protocols vary, but annual sigmoidoscopy on all first degree relatives until adenomas are found Starting at 20 y/o colonoscopy with dye spray q5 years B) If mutation identified: directed testing is used to predict risk of FAP in relatives: Absence of this gene mutation – excludes FAP; relatives are at average population risk for adenomas/cancer Presence of gene mutation confirms diagnosis of FAP - requires endoscopic assessment

Management of FAP: At risk children need a screening flexible sigmoidoscopy q1-2yrs by 10-12 yrs old Earlier if early aggressive disease in family If colonic adenomas found If no colonic adenomas found Annual colonoscopy until colectomy - Full colonoscopy is required by 14-16 yo to determine polyp density, location, degree of dysplasia EGD surveillance should commence - EGD by 20-25 yo, with end and side-viewing scopes (to visualize periampullary tumors). - Screen q5 yrs with biopsies to assess for dysplasia, earlier if symptomatic.

Management of FAP continued: Colectomy indicated if large # of adenomas, or adenomas with high degree of dysplasia Colectomy is only means to eliminate inevitable risk of colorectal cancer Severe dysplasia and carcinoma reported in < 12 y/o Surgical options: IPAA preferable if large # of rectal adenomas (>15-20), >1000 colonic adenomas, high risk genotypes, or if severe dysplasia Subtotal colectomy with Ileo-Rectal Anastomosis (IRA): Restorative proctocolectomy with Ileo Pouch Anal Anastomosis (IPAA): Less morbidity Higher morbidities, increased stool frequency Rectum remains at risk of cancer lower risk of cancer Requires surveillance q6months post-op Risk of cancer still exists at/below anastomosis, and pouches need to be examined regularly.

FAP prognosis: Almost all will develop colorectal cancer by 5th decade, if not detected and treated at an early age Average age of colorectal cancer is 39 y/o In pediatric population, polyps in stomach and small intestine don’t usually require intervention Adults at higher risk of cancer of duodenum, Ampulla of Vater. Risk of Hepatoblastomas in children < 5y/o Higher risk of other cancers: thyroid (in adolescence) brain, pancreas Higher risk of death from extra-colonic manifestations (desmoid tumor, duodenal cancer)

FAP Variants Gardner Syndrome Turcot Syndrome Familial colorectal polyposis Extracolonic tumors include osteomas of the skull, thyroid cancer, epidermoid cysts, fibromas, sebaceous cysts, and desmoid tumors Turcot Syndrome Brain tumor-polyposis syndrome Association of familial polyposis of the colon with brain tumors including medulloblastoma and malignant glioma Celiac Disease

Juvenile Polyp: Typical presentation Solitary hamartoma at diagnosis Mean age of presentation: 4 y/o Painless rectal bleeding Perianal polyp protrusion Up to 40% children have multiple polyps; 60% proximal to rectosigmoid

Juvenile Polyp: Management: Requires full colonoscopy, because if multiple polyps, 60% are proximal to rectosigmoid Polyps should be removed, even if incidental finding If solitary polyp after full colonoscopy, and no relevant family history, polypectomy is sufficient

Juvenile Polyp: Prognosis: A) If solitary- no increased risk of colorectal cancer, though polyp can recur in patients who present with a solitary polyp B) If recurrence of symptoms- it may represent a first presentation of hamartamotous polyposis syndrome; so always re-investigate! C) If multiple juvenile polyps or a +FHx of colonic polyps or colorectal cancer, must consider juvenile polyposis syndrome

Juvenile Polyposis Syndrome (JPS): Epidemiology and Presentation 1/100 000 individuals Multiple juvenile-type hamartomatous polyps Increased risk of GI malignancies Consider JPS if: >5 juvenile polyps in colon Juvenile polyps in other parts of GI tract Any # of juvenile polyps in a patient with a positive family history

Juvenile Polyposis Syndrome: Form of JPS Features Presentation Course Prognosis Juvenile Polyposis of Infancy Onset at infancy - Anemia - Hemorrhage - Diarrhea - Protein-Losing-Enteropathy - Intussusception - Rectal bleeding - Fulminant - In severe cases, can result in death at <2 y/o despite colectomy - Premalignant - 15% incidence of colorectal cancer by 35 y/o - 50% lifetime risk of colorectal cancer, but very rare to develop in childhood - Higher risk of malignancy with generalized JP than in juvenile polyposis coli Juvenile Polyposis Syndrome - 3-5 polyps to make diagnosis (sometimes termed Juvenile Polyposis Coli-if only affects colon) - Chronic GI bleed - Acute GI bleed - Prolapsed rectal polyps - Abdominal pain - 50-200 polyps in lifetime

JPS: Pathophysology Autosomal Dominant Fully penetrant; Variable expression 60% familial; the rest are sporadic Germline mutations in SMAD4 (20%), BMPR1A (20%), and possibly ENG1. Some include PTEN mutations in this description too. SMAD4 mutation is a tumor suppressor gene, and predisposes to gastric polyps and hereditary hemorrhagic telangiectasia

JPS management: Once a gene mutation is identified, test at risk family members If gene mutation known: - Genetic testing, after appropriate counseling. - If SMAD4 mutation, should also screen for HHT (Hereditary hemorrhagic telangiectasia) If gene mutation unknown: -Screen first degree children with colonoscopy by 12 y/o -Colonoscopic surveillance q2years for children JPS patients  surveillance EGD and full colonoscopy q2-3 years starting at 15 y/o; earlier if polyps are clinically apparent Colectomy is warranted if cancer, high-grade dysplasia, or high polyp burden can’t be controlled endoscopically

Peutz-Jerghers Syndrome (PJS): 1/50 000-1/200 000 live births Muco-cutaneous pigmentation and hamartomatous polyps throughout GI tract Polyps are mostly in SI (especially jejunum), less in stomach and colon Presumptive dx if positive family history and typical freckling Patients may have polyps in kidneys, bladder, lungs, and nares

PJS presentation: Polyps can cause bleeding, anemia, SI intussusception with intestinal obstruction at young age Pigmentation occurs in infancy Sites of pigmentation: on lips and inside mouth, nostrils, perineum, hands and feet- including fingers and toes Pigmentation may fade after puberty, but persists in buccal mucosa

Clinical diagnosis and pathophysiology of PJS: Any child/adolescent with any one of: 2 or more histologically confirmed PJ polyps Any # of PJ polyps and positive family history in close relative(s) Characteristic mucocutaneous pigmentation and positive family history in close relative(s) Any # of PJ polyps in an individual with characteristic mucocutaneous pigmentation Autosomal Dominant Mutated STK11 gene (tumor suppressor) is found in 90% patients Marked phenotypic variability between and within families.

Management of PJS: If mutation identified, test at risk relatives after genetic counseling Midgut complications require polypectomy, either by deep enteroscopy (eg. double or single balloon technique), or laparotomy/laparoscopy and intra-operative enteroscopy (IOE) Management of asymptomatic polyps: Polyps < 1.0 cm, no symptoms → counsel about risk of intususception Polyps >1.5cm → consider removal with deep enteroscopy or IOE and screen q2-3 years with endoscopy, colonoscopy and wireless capsule endoscopy or MRE Polypectomy should be only performed by experienced experts!

Screening for polyps and malignancies in patients with PJS Baseline EGD and colonoscopy by 8 y/o If polyps present: q3yrs till 50 y/o If no polyps: repeat at 18 y/o, then q3 yrs till 50 y/o Small bowel should be assessed by wireless capsule endoscopy or MRI enterography q3yrs from 8 y/o Annual clinical exam, Hgb, liver function tests Annual exam of genital tract (testicular U/S q2yrs from birth till 12 y/o; cervical smear q3 yrs from 25 y/o) Monthly self breast exam from 18 y/o; annual breast MRI from 25-50, then yearly mammography

Prognosis of PJS: 60% affected will require laparotomy in childhood High re-operation rate after first laparotomy for SI obstruction presenting at young age Relative risk of cancer is 15.2 compared to rest of population, majority are in GIT and occur in adulthood Tumors in GI tract: colon, pancreas, stomach Extraintestinal tumors: lung, testes, ovary, breast, uterus, cervix

PTEN Hamartoma Tumor Syndrome Group of genetic syndromes each associated with mutated PTEN tumor suppressor gene. Rare 1/200 000; 50% de novo mutations Phenotypic variants include: Cowden syndrome: Autosomal dominant 90% have small hamartomatous colonic polyps distal to hepatic flexure. Rarely presents in children. associated with macrocephaly, acral keratosis, Bannayan-Riley-Ruvalcaba Syndrome: Autosomal Dominant Presents before adolescence Associated with Macrocephaly, developmental delay, lipomatosis, hemangiomatosis, increased risk of cancer (renal, thyroid, breast) Proteus Syndrome: Hemi-hypertrophy, but few GI issues

References: Barnard J. Screening and Surveillance Recommendations for Pediatric Gastrointestinal Polyposis Syndromes. Journal of Pediatric Gastroenterology and Nutrition. 2009. 48 (Suppl 2) S75-S78 Fox V. Juvenile polyps: recurrence in patients with multiple and solitary polyps. Clinical gastroenterology and hepatology 2010 8(9):795-799 Beggs et al. PeutzeJeghers syndrome: a systematic review and recommendations for management. Gut. 2010 Jul;59(7):975-86. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Van hattem et al. Gut. 2008 May;57(5):623-7. Wyllie, Hyams and Kay. Pediatric Gastrointestinal and Liver Disease. Fourth ed, Ch. 43: p462-471.