Peutz-Jeghers Syndrome and Other Polyposis Syndromes

AUTHOR: Fred F. Ferri, MD

Definition

A hamartomatous polyp is a benign intestinal growth that may contain all components of the intestinal mucosa. In Peutz-Jeghers syndrome (PJS), hamartomas are found primarily in the small bowel but can also be present in the colon and stomach. In GI polyposis, multiple such polyps coexist within the intestinal tract, and associated manifestations are usually also present.
Juvenile polyps are benign polyps composed of cystic dilations of glandular structures within the fibroblastic stroma of the lamina propria. They may cause bleeding or intussusception.
Commonly recognized syndromes are Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden disease, Bannayan-Ruvalcaba-Riley syndrome, and Cronkhite-Canada syndrome. Other, lesser-known inherited hamartomatous polyposis syndromes are hereditary mixed polyposis syndrome, intestinal ganglioneuromatosis and neurofibromatosis (variant of von Recklinghausen syndrome), Devon family syndrome, basal cell nevus syndrome, and tuberous sclerosis (may involve GI tract). Table E1 describes general features of some inherited colorectal cancer syndromes.

ICD-10CM CODE
D12.6		Colon, unspecified (adenomatosis of colon, hereditary polyposis)

Epidemiology & Demographics

The incidence of PJS is 1 in 200,000.
Colonic adenomas, the precursors of nearly all colorectal cancers, are found in nearly 40% of patients by age 60 yr.
25% of men and 15% of women who undergo colonoscopy are found to have one or more adenomas.
Detection of any adenoma in patients <60 yr confers an increased risk of colorectal cancer (by a factor of 2.6) in their first-degree relatives.

Physical Findings & Clinical Presentation

Peutz-Jeghers Syndrome

Transmission: Autosomal dominant with incomplete penetrance. The syndrome is caused in the majority of patients by a germline mutation of the STK11/LKB1tumor suppression gene on chromosome 19P13.
Disease expression:
1. Stomach, small and large intestinal hamartomas with bands of smooth muscle in the lamina propria
2. Pigmented lesions around mouth (lips and buccal mucosa [Fig. E2]), nose, hands, feet, genitals, and perineal areas
3. Ovarian tumors
4. Sertoli cell testicular tumors
5. Airway polyps
6. Pancreatic cancer
7. Breast cancer
8. Urinary tract polyps
Cumulative lifetime cancer risk:
1. Colon cancer: 39%
2. Stomach cancer: 29%
3. Small intestine cancer: 13%
4. Pancreatic cancer: 36%
5. Breast cancer: 54%
6. Ovarian cancer: 10%
7. Sertoli cell tumor: 9%
8. Overall cancer risk: 93%
Clinical manifestation:
1. GI, small-bowel obstruction, intussusception, GI bleeding
2. See chapters on relevant malignancies for their signs and symptoms

Diagnosis

The diagnosis of PJS is made with any of four major criteria:

Two or more histologically confirmed PJS polyps
Any number of PJS polyps and a family history of PJS
Characteristic mucocutaneous pigmentation and a family history of PJS, or
Any number of PJS polyps and characteristic mucocutaneous pigmentation

Juvenile Polyposis Syndrome

Transmission: Autosomal dominant
Disease expression:
1. Solitary juvenile polyps numbering 10 or more in the rectum or throughout the GI tract; the polyps are smooth and covered with normal epithelium.
2. Various congenital abnormalities coexist in 20%.
Cumulative cancer risk is increased (may be as high as 50%)
Clinical manifestation:
1. Intestinal obstruction
2. Intussusception
3. GI bleeding

TABLE E1 General Features of Some Inherited Colorectal Cancer Syndromes

Syndrome	Polyp Histology	Polyp Distribution	Age of Onset	Risk of Colon Cancer	Genetic Lesion	Clinical Manifestations	Associated Lesions
Familial adenomatous polyposis (Fig. E1)	Adenoma	Large intestine, duodenum	16 yr (range, 8-34 yr)	100%	5q (APC gene)	Rectal bleeding, abdominal pain, bowel obstruction	Desmoids, CHRPE
Peutz-Jeghers syndrome	Hamartoma	Large and small intestine	First decade	Slightly above average	19p (STK11 gene)	Possible rectal bleeding, abdominal pain, intussusception	Orocutaneous melanin pigment spots, other tumors
MUTYH-associated polyposis	Adenoma	Large intestine, duodenum	45-50 yr (range, 13-60 yr)	75% (range, 50%-100%)	1p (MYH gene)	Rectal bleeding, abdominal pain, bowel obstruction	CHRPE, osteomas
Juvenile polyposis	Hamartoma (rarely adenoma)	Large and small intestine	First decade	∼9%	PTEN, SMAD4, BMPR1	Possible rectal bleeding, abdominal pain, intussusception	Pulmonary AVMs
Hereditary nonpolyposis colon cancer	Adenoma	Large intestine	40 yr (range, 18-65 yr)	30%	Mismatch repair genes+∗	Rectal bleeding, abdominal pain, bowel obstruction	Other tumors (e.g., ovary, uterus, pancreas, stomach)

AVM, Arteriovenous malformation; CHRPE, congenital hypertrophy of the retinal pigment epithelium; MUTYH, mutY homolog (Escherichia coli).

^∗Including hMSH2, hMSH3, hMSH6, hMLH1, hPMS1, and hPMS2.

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Cowden Disease

Transmission: Autosomal dominant, rare
Disease expression:
1. Juvenile intestinal polyposis
2. Orocutaneous hamartomas
3. Fibrocystic breast disease and breast cancer
4. Goiter and thyroid cancer
5. Facial tricholemmomas (papules) in 83%
Cumulative cancer risk:
1. GI: Same as general population
2. Thyroid: 3% to 10%
3. Breast: 25% to 50%

Figure E1 Familial adenomatous polyposis.

The disorder is marked by the development of hundreds of large bowel adenomas, as seen in this segment of large bowel covered with adenomas of various sizes. It usually arises in the second and third decades.

(From Skarin AT: Atlas of diagnostic oncology, ed 4, St Louis, 2010, Mosby.)

Figure E2 Peutz-Jeghers syndrome, macular pigmentation of lower lip.

(From James WD et al: Andrews’ diseases of the skin, ed 12, Philadelphia, 2016, Saunders.)

Bannayan-Ruvalcaba-Riley Syndrome

Transmission: Autosomal dominant, rare
Disease expression:
1. Juvenile intestinal polyposis
2. Macrocephaly
3. Developmental delay
4. Penile pigmented spots
5. Cumulative cancer risk unknown

Cronkhite-Canada Syndrome

Transmission: Acquired
Age of onset: Midlife
Disease expression:
1. Diffuse GI juvenile polyposis (50% to 95% of cases)
2. Chronic diarrhea and protein-losing enteropathy (the entire intestinal mucosa may be inflamed), which leads to abdominal pain, weight loss, and various complications of malnutrition
3. Dystrophic nails
4. Alopecia
5. Hyperpigmentation
Cumulative cancer risk: Same as the average population

General Rx/Surveillance

Peutz-Jeghers syndrome:

Colonoscopies with polypectomies and upper endoscopy every 2 to 3 yr beginning in teen years
MRI or endoscopic ultrasound of the pancreas every 1 to 2 yr beginning at age 30
Screening for breast cancer, testicular cancer, possibly ovarian cancer
Surveillance of small bowel with capsule endoscopy or CT or magnetic resonance enterography every 2 to 3 yr starting at age 8 to 10 yr

Juvenile polyposis syndrome:

Colonoscopies with polypectomies and upper endoscopy every 2 to 3 yr beginning at age 15
Total colectomy if numerous polyps
Esophagogastroscopies and polypectomies

Cowden disease:

Rigorous breast cancer screening or prophylactic simple bilateral mastectomy with reconstruction

Cronkhite-Canada syndrome:

Progressive malabsorption syndrome is the hallmark of this syndrome, and no specific treatment exists. Enteral or parenteral feeding is the cornerstone of management and can result in remission
Other syndromes:
1. Serrated polyposis syndrome: Colonoscopy yearly
2. PTEN hamartoma tumor syndrome: Colonoscopy every 5 yr beginning at age 35

Disposition

The screening of first-degree relatives of patients with colonic adenomas detected before 60 yr of age is controversial. Some recommend beginning colonoscopic screening at age 40 yr, or 10 yr younger than the age at diagnosis of the youngest person in the family with an adenoma.
Recommended intervals between colonoscopies from the U.S. Consensus Guidelines for Colonoscopic Surveillance after Polypectomy are as follows:
1. 10 yr for small, rectal hyperplastic polyps
2. 5 to 10 yr for one to two low-risk adenomas (tubular adenomas <1 cm)
3. 3 yr for low-risk adenomas or any high-risk adenoma (large [≥1 cm] or histologically advanced adenomas [tubulovillous or villous adenomas or villous adenomas and those with high-grade dysplasia])
4. <3 yr for presence of >10 adenomas
5. 2 to 6 mo for inadequately removed adenomas

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆