Description

• Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant (AD), inherited condition characterized by the development of unique benign hamartomatous polyps throughout the gastrointestinal (GI) tract in association with mucocutaneous hyperpigmentation, most notably of the lips.
• Although malignancy most commonly occurs in the small bowel, PJS also carries an increased risk for developing extraintestinal malignancies—mainly breast, gynecologic, and pancreatic.

Epidemiology

Incidence

• PJS appears equally in males and females, without any ethnic predominance.
• Median age of diagnosis is 15 years but with wide variability (range 3.7 to 45.4 years of age).
• The incidence of PJS in the United States has been estimated to be approximately 1:8,300 and 1:200,000 per year.

Prevalence
PJS occurs at a prevalence of approximately 1/100,000 population.

Etiology and Pathophysiology

• Mucocutaneous lesions
  • Secondary to increased melanin in basal cells, which is possibly due to an inflammatory block on melanin migration from melanocytes to keratinocytes
• Polyps (hamartomas)
  • Found throughout the GI tract, but most are located in the small bowel (60–90%) and colon (50–64%)
  • May be located in extraintestinal sites, including gallbladder, respiratory tract, and bladder
  • Proposed theories of polyps suggest they may result from a mechanical process/stromal neoplasia.
• Proposed pathways:
  • Role of the PJS polyp in cancer development can be supported by a unique “hamartoma-adenoma-carcinoma pathway” due to the findings of adenomatous foci and malignant foci within PJS polyps.
  • Some suggest no malignant potential within PJS polyps and that cancer arises from mucosal instability via conventional neoplastic pathways involving proliferation of mutant cell lines.

Genetics

• AD with high degree of penetrance for polyposis, skin pigmentation, and cancer
• Germline mutations
  • Can be found in STK11 gene (19p13.3)—a tumor suppressor gene—encoding a serine-threonine kinase; occurs in up to 94% of patients who fulfill the diagnostic criteria
  • K-RAS in a mutated form may increase risk of PJS-associated cancers.

General Prevention

• Smoking cessation should be encouraged in all patients with PJS to avoid the added risk for malignancy development.
• Clinical awareness and early diagnosis are important. Affected patients and at-risk family members should be offered genetic counseling and surveillance.

Commonly Associated Conditions

• Common
  • Characteristic hyperpigmentation can be seen in up to 90% of PJS patients.
  • Polyp-related symptoms usually arise in childhood, with 33% of patients by age 10 years requiring laparotomy.
  • GI polyps are at risk of acute bleeding, intussusception, and bowel obstruction.
  • Anemia due to occult blood loss, hematochezia (intestinal polyps), or hematemesis (gastric/duodenal polyps, less common) may be seen.
  • Recurrent abdominal pain due to intussusception in 50% of patients by age 20 years
• Rare
  • Bowel ischemia secondary to bowel infarction
• Cancers: The overall cumulative risk for cancer has been estimated at >76% in PJS patients.
  • The relative risk of developing malignancy is highest in the small bowel, with a median age of 41 years and significant increase after age 50 years.
  • Studies have shown that the risks of cancers are similar in those patients with identified mutations in STK11 as well as those without.
  • Risk of cancer is higher in females than males.
  • The associated cancers commonly include (frequency, %) breast (54%), colorectal (39%), pancreatic (36%), gastric (29%), and small bowel (13%).
  • The increased risk of extraintestinal malignancy is largely due to breast and gynecologic cancers in women along with pancreatic cancer, particularly in men.
  • The risk for breast cancer among PJS patients is similar to that of women with BRCA1/BRCA2 mutations.
  • K-RAS mutation can lead to lobular endocervical glandular hyperplasia, which increases the risk of developing cervical cancer.