BASICS
DESCRIPTION
- Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant (AD), inherited condition characterized by the development of unique benign hamartomatous polyps throughout the 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/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 (1)
- Polyps (hamartomas)
- Found throughout the GI tract, but most are located in the small bowel (60 " “90%) and colon (50 " “64%) (1)
- 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 (1).
- 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 (1).
- 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 (2).
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 (2)
- K-RAS in a mutated form may increase risk of PJS-associated cancers (3).
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 is 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. 33% of PJS patient are affected by age 10 years and 50% of PJS patients by 20 years of age (1).
- GI polyps are at risk of acute bleeding, intussusception in 47% to 69 %, and bowel obstruction (4).
- 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 or polyp obstruction of bowel lumen
- Rare
- Bowel ischemia secondary to bowel infarction is rarely seen.
- Gynecomastia is rarely reported in PJS (5).
- Cancers: The overall cumulative risk for cancer has been estimated at over >76% in PJS patients (2).
- 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 (1).
- 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%) (1).
- The increased risk of extraintestinal malignancy is largely due to breast and gynecologic cancers in women along with pancreatic cancer, particularly in men (2).
- The risk for breast cancer among PJS patients is similar to that of women with BRCA1/BRCA2 mutations (2).
- K-RAS mutation can lead to lobular endocervical glandular hyperplasia, which increases the risk of developing cervical cancer (3).
DIAGNOSIS
HISTORY
- PJS may be discovered incidentally by suggestive mucosal hyperpigmentation or by family history.
- Clinical presentation most commonly appears in 2nd and 3rd decades of life manifested by recurrent abdominal pain due to transient intussusception, anemia, GI bleeding, or rectal prolapse (6).
- Mucocutaneous pigmented lesions may be the initial presentation.
- A clinical diagnosis of PJS may be made when any ONE of the following is present:
- ≥2 histologically confirmed hamartomatous polyps
- Any number of hamartomatous polyps detected in an individual who has a family history of PJS in a close relative
- Characteristic mucocutaneous hyperpigmentation in an individual who has a family history of PJS in a close relative
- Any number of hamartomatous polyps in an individual who also has characteristic mucocutaneous hyperpigmentation (7)
- Clinical diagnosis may be supported by genetic testing (2).
PHYSICAL EXAM
- Hyperpigmented mucocutaneous lesions
- Appearance: macular, 1 to 5 mm, blue-gray to brown, hairless, resembling freckles
- Distribution: Lips and perioral region are the most common; also hands, buccal mucosa, feet, and genitals may be affected.
- Umbilical pigmentation may be an early marker of PJS which can appears before lip pigmentation (8).
- Timing: more common in infancy and tend to fade after puberty, leaving only buccal lesions; often first clue of PJS diagnosis (6)
- Hamartomatous polyps
- Appearance: Polyps are often observed in groups and in up to 20 per segment of the intestinal tract, varying in size from 1 mm to >5 cm.
- Distribution: most frequent locations in order of prevalence: jejunum, ileum, duodenum, colon, and stomach (6)
- Timing: Polyps arise in 1st and 2nd decades of life, but symptoms often begin between ages 10 and 30 years; mean age of 24 years (1)
DIFFERENTIAL DIAGNOSIS
- Hyperpigmented mucocutaneous lesions
- Common freckles: spare buccal mucosa; present around lips and nose
- Carney complex: spotty skin pigmentation and lentigines
- Cowden disease: facial and oral papillomas, fibromas, and skin tumors
- LEOPARD syndrome
- Laugier-Hunziker syndrome
- Polyposis
- Juvenile polyposis syndrome: no mucocutaneous hyperpigmentation
- Cronkhite-Canada syndrome: macular facial pigmentation, as well as pigmentation changes of hair, nail, and skin; no mucosal involvement; and not familial
- Mucosal prolapse/cloacogenic polyp: solitary polyp, rare in small intestine; no oral pigmentation
- Gastric hyperplastic polyp: no polyps in small intestine, not familial, and no associated mutations
- Adenocarcinoma (vs. PJS polyp with misplaced glands)
- Gardner syndrome
- Familial adenomatous polyposis syndrome
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
CBC, fecal occult blood testing (FOBT), liver enzymes, and blood chemistries should routinely be done in all PJS patients. ‚
- In the setting of acute abdominal pain, CT imaging should be performed to further evaluate the underlying etiology; in PJS, suspect bowel obstruction secondary to intussusception.
- Polyps outside the GI system may require imaging modalities based on presenting symptoms and organ system involved.
Follow-Up Tests & Special Considerations
Genetic testing ‚
- Available at specialized laboratories, which can be found through https://www.genetests.org/.
- Molecular genetic testing of STK11 (LKB1) reveals disease-causing mutations in 80 " “94% of affected individuals.
- In addition to STK11, another genetic locus may predispose to the clinical features of PJS; therefore, a negative test result does not necessarily exclude a diagnosis of PJS (1).
Diagnostic Procedures/Other
- The relative inaccessibility of the small bowel complicates surveillance and diagnosis.
- Endoscopic surveillance by colonoscopy is the mainstay of evaluation of colonic polyposis (2).
- Other procedures with proven use for the surveillance of the small bowel in PJS patients include the following:
- Video capsule endoscopy (VCE)
- Double-balloon enteroscopy (DBE)
- Multidetector CT (MDCT) enterography or enteroclysis
- MRI enterography or enteroclysis
- Peroral VCE has suboptimal sensitivity. Double-balloon small bowel enteroscopy is useful to resect polyps. MRI and MDCT with enterography or enteroclysis allow for the detection of majority of polyps in PJS, with the advantage of providing accurate information with respect to lesion size and tumor location (2).
Test Interpretation
- Characteristic histologic features of hamartomas include frond-like elongated epithelial components and cystic gland dilatations extending into the submucosa or muscularis propria as well as arborizing smooth muscle extending into polyp frond (2).
- Polyps may be mistaken for invasive carcinoma if there is pseudoinvasion, which can be distinguished from true invasion by the lack of atypia (2).
TREATMENT
There are a few therapeutic options for PJS. ‚
- Management primarily involves minimizing symptoms by screening for long-term complications (surveillance).
- Surgical strategies are common for managing sequelae of PJS such as small bowel intussusception or obstruction due to polyps or resection of neoplastic lesions (1).
- Endoscopic polypectomy have reduced the need for future operative polypectomy from the small bowel (1).
MEDICATION
- Polyp burden
- No established chemoprophylactic regimens for reduction of polyp burden (1)[A]
- Potential roles for COX-2 inhibitors or rapamycin in prevention of hamartomas, but adverse effects may undermine long-term use (1)[A]
- Metformin has been identified as a potential agent that may slow the development of neoplasia (1).
- Mucocutaneous pigmentation
- Reports of successful intense pulsed light or laser therapy. However, use is not supported in routine clinical practice unless there is psychological morbidity related to lesions (1)[A].
ADDITIONAL THERAPIES
- Summary of recommendations for surveillance and follow-up (1)[C]:
- General
- Annual CBC, FOBT, liver function tests (LFTs)
- Annual clinical examination starting at age 10 years
- Genitourinary cancers
- No evidence to support routine screenings
- Recommended cervical smears per guidelines for unaffected women
- Testicular exam annually, US evaluation of any abnormality
- No recommendations for routine screenings for endometrial/ovarian cancers
- GI cancers
- Baseline endoscopy, GI VCE or colonoscopy beginning at age 10 years
- Polyps detected: Resect polyps and continue screening every 3 years until age 50 years.
- No polyps detected: Repeat every 3 years until age 50 years.
- Colonoscopy every 1 to 2 years after age 50 years
- Barium follow-through (BaFT), less accurate for polyps <1 cm and exposes patient to radiation, used less frequently
- Balloon-assisted enteroscopy can remove small bowel polyps detected by other modalities.
- Breast cancer
- No screening specific to PJS. Because breast cancer risk approaches that of patients with BRCA mutations, close surveillance is warranted.
- Monthly self-exam from age 18 years
- Annual breast MRI from age 25 years; switch to annual mammogram at age 50 years.
- Pancreatic cancer
- Screening is not recommended due to lack of proven benefit (1)[A].
- Other cancers
- No evidence for screening for other malignancies in PJS
- Limitations of screening guidelines:
- Lack of sensitive and specific tumor markers for early neoplasia, except for colorectal cancer (FOBT, fecal kRAS).
SURGERY/OTHER PROCEDURES
- Endoscopic polypectomy reduces polyp-related complications and risk of future surgical laparotomy with polypectomy.
- Urgent laparotomy on patients with obstruction or intussusception
- Elective laparotomy with or without intraoperative enteroscopy is performed for removal of large symptomatic polyps (1)[A].
ONGOING CARE
PATIENT EDUCATION
Given the familial nature and increased lifetime risk of cancer in PJS, patients benefit from education on genetic testing, disease course, associated complications, and risk of malignancies. Patients should be made aware of potential symptoms that warrant further evaluation and should be encouraged to adhere to recommended screening procedures and maintain long-term follow-up with a multidisciplinary team. Psychological counseling may be indicated at times. ‚
PROGNOSIS
Patients have nearly a 10-fold higher cancer risk compared with the general population; mortality increases accordingly. Acute bowel intussusception is an important cause of morbidity. Surveillance may prolong life expectancy and improve outcomes via early carcinoma detection and timely hamartoma removal to prevent intussusception and reduce bleeding risk (9). ‚
COMPLICATIONS
Complications in PJS result from the disease itself (i.e., GI polyposis and cancers) but also from treatment of PJS-associated problems. Endoscopic and laparoscopic techniques are encouraged to decrease complications associated with repeat laparotomies (i.e., bowel adhesions, incisional hernias, perioperative infections). ‚
REFERENCES
11 Beggs ‚ AD, Latchford ‚ AR, Vasen ‚ HF, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010;59(7):975 " “986.22 Tomas ‚ C, Soyer ‚ P, Dohan ‚ A, et al. Update on imaging in Puetz-Jeghers syndrome. World J Gastroenterol. 2014;20(31):10864 " “10875.33 Ito ‚ S, Tase ‚ T, Satoh ‚ K, et al. Gastric-type endocervical glandular neoplasms associated with aberrant p16 expression and K-RAS gene mutation in Peutz-Jeghers syndrome. Pathol Int. 2014;64(6):283 " “288.44 Ozer ‚ A, Sarkut ‚ P, Ozturk ‚ E, et al. Jejunoduodenal intussusception caused by a solitary polyp in a woman with Peutz-Jeghers syndrome: a case report. J Med Case Rep. 2014;8:13.55 Di Grezia ‚ G, Romano ‚ T, De Francesco ‚ F, et al. Breast ultrasound in the management of gynecomastia in Peutz-Jeghers syndrome in monozygotic twins: two case reports. J Med Case Rep. 2014;8:440.66 Jelsig ‚ AM, Qvist ‚ N, Brusgaard ‚ K, et al. Hamartomatous polyposis syndromes: a review. Orphanet J Rare Dis. 2014;9:101.77 Islam ‚ RS, Patel ‚ NC, Lam-Himlin ‚ D, et al. Gastric polyps: a review of clinical, endoscopic, and histopathologic features and management decisions. Gastroenterol Hepatol (N Y). 2013;9(10):640 " “651.88 Morrison ‚ PT, Donnelly ‚ DE, Morrison ‚ PJ. Umbilical pigmentation in Peutz-Jeghers syndrome. Clin Dysmorphol. 2014;23(3):114 " “115.99 Giardiello ‚ FM, Trimbath ‚ JD. Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol. 2006;4(4):408 " “415.
ADDITIONAL READING
- Korsse ‚ SE, Dewint ‚ P, Kuipers ‚ EJ, et al. Small bowel endoscopy and Peutz-Jeghers syndrome. Best Pract Res Clin Gastroenterol. 2012;26(3):263 " “278.
- Lynch ‚ HT, Lynch ‚ JF, Lynch ‚ PM, et al. Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management. Fam Cancer. 2008;7(1):27 " “39.
- Patel ‚ SG, Ahnen ‚ DJ. Familial colon cancer syndromes: an update of a rapidly evolving field. Curr Gastroenterol Rep. 2012;14(5):428 " “438.
- van Lier ‚ MG, Westerman ‚ AM, Wagner ‚ A, et al. High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome. Gut. 2011;60(2):141 " “147.
CODES
ICD10
- Q85.8 Other phakomatoses, not elsewhere classified
- K31.7 Polyp of stomach and duodenum
- K63.5 Polyp of colon
ICD9
- 759.6 Other hamartoses, not elsewhere classified
- 211.2 Benign neoplasm of duodenum, jejunum, and ileum
- 211.3 Benign neoplasm of colon
SNOMED
- Peutz-Jeghers syndrome (disorder)
- Peutz-Jeghers polyps of small bowel (disorder)
CLINICAL PEARLS
- Consider hereditary polyposis syndromes in the following:
- Cancer at very young age compared with usual presentation
- Presence of multiple tumors, especially hamartomas
- Family history of similar tumors
- Mucocutaneous pigmentation: seen in 95% of PJS patients and sometimes first clue, especially arising in infancy (usually perioral)
- Patients require strict surveillance due to increased risk of GI, pancreatic, and breast cancers.