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

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

3. 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

4. 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

5. 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*

6. 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

7. Epidemiology & Presentation FAP:
Epidemiology: 1/ 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

8. 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)

9. 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 , especially codon 1309.
Environmental factors
Other modifier genes
Autosomal recessive form exists (mutated MUTYH gene)
This does not present in childhood

10. Screening and Diagnosis of FAP:
Genetic testing for APC in at risk relatives is recommended just before 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

11. 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

12. Management of FAP:
At risk children need a screening flexible sigmoidoscopy q1-2yrs by 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 yo to determine polyp density, location, degree of dysplasia
EGD surveillance should commence
- EGD by yo, with end and side-viewing scopes (to visualize periampullary tumors).
- Screen q5 yrs with biopsies to assess for dysplasia, earlier if symptomatic.

13. 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.

14. 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)

15. 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

16. 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

17. 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

18. 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

19. Juvenile Polyposis Syndrome (JPS): Epidemiology and Presentation
1/ 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

20. 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
polyps in lifetime

21. 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

22. 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

23. Peutz-Jerghers Syndrome (PJS):
1/ / 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

24. 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

25. 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.

26. 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!

27. 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

28. 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

29. PTEN Hamartoma Tumor Syndrome
Group of genetic syndromes each associated with mutated PTEN tumor suppressor gene.
Rare 1/ ; 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

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