OVERVIEW: What every practitioner needs to know
Are you sure your patient has Peutz-Jeghers syndrome? What are the typical findings for this disease?
Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by hamartomatous polyps in the gastrointestinal tract and mucocutaneous hyperpigmentation. Polyps predominate in the small bowel but also can develop in the stomach and large bowel.
For the pediatric patient, small bowel intussusception secondary to small bowel polyps is the most common complication. Emergent laparotomy for intussusception has been reported to occur in 30% of patients by 10 years of age.
Patients with PJS are at high risk of gastrointestinal and nongastrointestinal malignancies.
Case reports of malignancies have been reported in the pediatric age group. The lifetime risk for all cancers in PJS is 93% with a relative risk of 15.2 (95% CL 2.0,19.0).
Typical clinical findings for Peutz-Jeghers Syndrome in children are:
Mucocutaneous pigmentation (See Figure 1).
Hamartomatous polyps in the GI tract
Intussusception with intestinal obstruction due to polyps is the most common presentation of Peutz-Jeghers Syndrome in children
The mucocutaneous pigmentation occurs in infancy and diminishes in later adolescence. Pigmentation is seen in 95% of PJS patients. The majority of pigmentation is found on the lips but can also be seen on the buccal mucosa, hands and feet. In contrast to the pigmentation in PJS, normal freckles are not found on the buccal mucosa. The histology consists of pigment-laden macrophages. The pigmanted lesions may fade throughout life so examining photographs of the patient from early childhood may be helpful as many patients will not remember having pigmented lesions.
Occasionally a patient may be referred for evaluation for possible PJS because a physician has noted the characteristic pigmentation when evaluating a child for another issue.
The PJ polyp is a true hamartoma. Histopathologic features include the characteristic frond-like structure, epithelium for the location of the polyp in the gastrointestinal tract, and smooth muscle proliferation.
Beyond the early childhood period when intussusception is seen, the majority of patients present in the second and third decade of life with symptoms related to bowel obstruction due to a polyp. Other presentations include abdominal pain, rectal bleeding and rectal prolapse of a polyp. The characteristic mucocutaneous pigmentation may be absent since this finding is most prominent during infancy and diminishes in later adolecence.
Making the diagnosis
A careful family history is important. Clues to raise the index of suspicion for an inherited polyposis syndrome include early onset of gastrointestinal cancers and a family history of polyps. In PJS, in addition to gastrointestinal cancers, there may be a family history of pancreatic and breast malignancies. It is also important to ask for a history of mucocutaneous pigmentation in relatives.
An upper endoscopy and colonoscopy may identify polyps which can be removed by polypectomy and reviewed by the pathologist. Polyps are most frequently found in the small bowel but also in the stomach and large bowel. Polyps may range in size from 0.1 to 5 cm.
Polyps from the small bowel in PJS typically have very specific histologic characteristics with smooth muscle proliferation. A well developed PJS polyp complete with a good “tree” of smooth muscle is fairly characteristic. Previously a small bowel series was recommended to evaluate the small bowel for polyps. Currently most gastroenterologists suggest either capsule endoscopy and/or MR enterography as more sensitive tests. Capsule endoscopy and MR enterography also have the benefit of avoiding radiation in these young patients already at increased risk of malignancy longterm.
Referral to a genetic counselor with the option of genetic testing should be offered. Polyposis registries can also help make the diagnosis by contacting treating hospitals and obtaining polyp or cancer slides from relatives’ tumors for pathological review.
What other disease/condition shares some of these symptoms?
When the histologic changes in a polyp are subtle, it can be difficult to differentiate the hamartomatous polyps of PJS from filiform polyps seen in inflammatory colitis.
Occasionally juvenile polyps can also be difficult to differentiate from the hamartomatous polyps of PJS, and therefore the diagnosis of juvenile polyposis syndrome may be difficult to differentiate from PJS. The histology of gastric or colonic polyps in PJS can be distinguished due to minimal smooth muscle bundles and are sometimes mistaken for reactive hyperplastic polyps or juvenile polyps. Consultation by a pathologist experienced in polyposis syndromes is important in making the correct diagnosis.
Polyps found in other polyposis syndromes may share features found in the polyps of PJS. Cowden’s syndrome can have a variety of hamartomatous polyps such as juvenile and hyerplastic polyps. Clinical features such as macrocephaly, papillomatous lesions and developmental delay are typically associated with Cowden’s syndrome and help differentiate the syndromes. Cronkite-Canada syndrome polyps can be differentiated from PJS as they are more inflammatory or hyperplastic.
Other syndromes associated with melanotic pigmented macules can be difficult to differentiate from the hyperpigmentation seen in PJS. For example, a benign condition, Laugier-Hunziker is associated with macules in a similar location and with a very similar appearance to JPS. In contrast to PJS the macules seen in Laugier-Hunziker develop throughout adulthood. Consultation with a dermatologist can be helpful in differentiating hyperpigmentation syndromes.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
An upper endoscopy and colonoscopy may identify polyps which can be removed by polypectomy and reviewed by the pathologist. Previously a small bowel series was recommended to evaluate the small bowel for polyps. Currently most would advocate capsule endoscopy and/or MR enterography as more sensitive tests. Capsule endoscopy and MR enterography also have the benefit of avoiding radiation in these young patients already at increased risk of malignancy long-term.
Genetic testing for mutations in the STK11 gene is available for identification of the proband mutation. This autosomal dominant disorder has incomplete penetrance. At-risk members of the kindred can also be evaluated for a known mutation. Mutations are found in 30 to 70% of patients with sporadic PJS. The rate of spontaneous mutation is not clear. Ongoing research is evaluating genotype-phenotype correlation in PJS.
If you are able to confirm that the patient has Peutz-Jeghers syndrome, what treatment should be initiated?
Endoscopic polypectomy is recommended for symptomatic polyps. Double balloon enteroscopy is used for small bowel polyps but open surgery may be required for polyps not amenable to polypectomy.
Preliminary results using therapy with cyclooxygenase-2 inhibitors for suppression of polyp growth in PJS shows some promise. Long-term chemoprevention in PJS requires further study.
Many gastroenterologists recommend the following approach to screening in patients who are 18 years of age and older:
GI tract screening: colonoscopy, upper endoscopy and evaluation of small bowel with small bowel series (or capsule endoscopy) every 2-3 years.
Non-GI screening: Routine primary care screening for breast and gynecological cancer are recommended. More invasive or aggressive screening for these cancers and for pancreatic cancer are currently being evaluated in ongoing prospective trials.
What are the adverse effects associated with each treatment option?
Endoscopic evaluation will require anesthesia in young children with known potential complications of sedation. Laparotomy increases the risk of adhesions. The surveillance protocol is time consuming with potential for stress and anxiety. We recommend that families entering any clinical surveillance protocols be offered psychosocial support.
What are the possible outcomes of Peutz-Jeghers syndrome?
Genetic counseling is important as patients require education about increased risk of malignancy.
Prenatal counseling should be offered.
What is the cancer risk in PJS?
Patients with PJS are at a significant risk of gastrointestinal and nongastrointestinal cancers (Table I). Genetic counseling and education regarding specific cancers is important. The lifetime risk of any cancer is 93%, relative risk of all cancers 15.2 (95% CL 2, 19).
|Site||Cumulative risk (15-64 years)|
above adapted with permission from Giardiello FM.
Pediatric cancer risks
There are no controlled studies on the effectiveness of cancer surveillance strategies in PJS and controversy exists regarding screening recommendations, particularly in the pediatric population. Although stomach, small bowel and colon cancer has been reported in the first two decades of life in patients with PJS, the majority are diagnosed in adulthood. Testicular cancer is fairly rare and the practitioner can consider annual physical examination and optional testicular ultrasound.
What causes this disease and how frequent is it?
PJS is a genetic disorder found in all ethnic groups
Incidence data 1/50 0009 to 1/200 000
STK11/LKB1 gene extends over 23 kb and encodes a STK protein
Majority of STK11 mutations affect protein structure
What complications might you expect from the disease or treatment of the disease?
Overall rates of intussusception in patients with PJS are reported to occur in 40% to 69% of patients in various studies. An intussusception rate of 50% rate by 20 years of age is also reported.
The majority (95%) of intussusception lead points are in small bowel.
Malignancy is the other major complication of PJS.
How can Peutz-Jeghers syndrome be prevented?
Genetic counseling and consideration of prenatal testing.
What is the evidence?
Management and treatment based on expert opinion. Prospective trials to look at outcome with surveillance protocols have been proposed.
van Lier, MG, Westerman, AM, Wagner, A. “High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome”. Gut. vol. 60. 2011. pp. 141-147.
Giardiello, FM, Trimbath, JD. “Peutz-Jeghers syndrome and management recommendations”. Clin Gastroenterol Hepatol. vol. 4. 2006. pp. 408-415.
van Lier, MG, Mathus-Viegen, EM, Wagner, A. “High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines”. Am J Gastroenterol. vol. 106. 2011. pp. 940-945.
Ongoing controversies regarding etiology, diagnosis, treatment
The major debate in management is whether to attempt to clear the small intestine of polyps in childhood.
Specific cancer surveillance recommendations are also controversal. The use of periodic capsule endoscopy and MR endoscopy for small bowel surveillance is under investigation.
There are no controlled studies on the effectiveness of cancer surveillance in PJS and prospective cancer surveillance studies are needed.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has Peutz-Jeghers syndrome? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- If you are able to confirm that the patient has Peutz-Jeghers syndrome, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of Peutz-Jeghers syndrome?
- What causes this disease and how frequent is it?
- What complications might you expect from the disease or treatment of the disease?
- How can Peutz-Jeghers syndrome be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment