Clinical Description
Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal (GI) polyposis and mucocutaneous pigmentation. The risk for GI and extraintestinal malignancies is significantly increased. Distinct benign and malignant gonadal and gynecologic tumors can also be seen. Variable expressivity is common; for example, some affected individuals in families with PJS may have only polyps or perioral pigmentation.
GI polyposis. PJS-type hamartomatous polyps can occur anywhere in the GI tract but occur most commonly in the small intestine. The density of polyps is greatest in the jejunum, followed by the ileum, then the duodenum. Polyps also occur in the stomach and large bowel. Polyps have also been reported in the renal pelvis, urinary bladder, ureters, lungs, nares, and gallbladder.
Adenomas also appear with increased prevalence throughout the GI tract.
The malignant potential of PJS-type hamartomatous polyps is unknown; however, the polyps can cause significant complications including bowel obstruction, rectal prolapse, and/or severe GI bleeding with secondary anemia requiring multiple emergency laparotomies and bowel resections. The age of onset of symptoms from polyps is variable, with some children developing symptoms within the first few years of life. The risk of intussusception was estimated to be 44% by age ten years and 50% by age 20 years [van Lier et al 2011a]. Intussusception risk increases with polyp size ≥15 mm [Latchford et al 2019]. One small single-center retrospective study concluded that endoscopic management of small-bowel polyps in PJS using balloon assisted endoscopy (BAE) – or when needed, laparoscopically assisted double-balloon endoscopy – decreased the occurrence of urgent laparotomy [Belsha et al 2017].
Significant interfamilial variability in the age at which polyps first appear is observed, suggesting that the natural history of polyps in a family may be a predictor of severity for offspring. Increasingly, case series have demonstrated a younger onset of GI pathology either through diagnostic testing or evaluation based on a positive family history. These data have prompted recommendations to begin surveillance at a younger age to detect and remove GI polyps, decrease risk of malignancy, and reduce complications of bowel obstruction [Wagner et al 2021, NCCN 2021]. Increasingly, the literature demonstrates the efficacy and safety of BAE and polypectomy in children with PJS.
Mucocutaneous pigmentation. Melanocytic macules (MM) are rarely present at birth; they become pronounced in most children before the fifth year, but then may fade in puberty and adulthood. Children often present with dark blue to dark brown mucocutaneous MM around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa. Hyperpigmented MM on the fingers are also common. In one series, 94% of individuals with PJS had perianal MM, 73% had MM that affected the digits, 65% had MM on the buccal mucosa, and 21% had MM at other sites [Utsunomiya et al 1975].
Histologically, increased melanocytes are observed at the epidermal-dermal junction, with increased melanin in the basal cells. No malignancy risk is associated with MM. In sporadic cases, MM is often the first diagnostic clue to PJS. STK11 molecular analysis has been recommended in children with characteristic PJS freckling even in the absence of additional clinical criteria [Latchford et al 2019].
Gonadal tumors. Females with PJS are at risk for ovarian sex cord tumors with annular tubules (SCTATs) and mucinous tumors of the ovaries and fallopian tubes. Symptoms include irregular or heavy menstrual periods and, occasionally, precocious puberty due to hyperestrogenism. PJS-related SCTATs are bilateral multifocal small tumors with focal calcification and a typically benign course [Wagner et al 2021]. In contrast, sporadic SCTATs are large, unilateral, and associated with a 20% risk of malignancy.
Males occasionally develop large cell calcifying Sertoli cell tumors of the testes derived from sperm cord cells. These tumors may secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated. Multifocal calcifications are typically seen on testicular ultrasound. Aromatase inhibitors help reverse the hormonal effects of Sertoli cell tumors including reduction of gynecomastia and slowing of linear bone growth and bone age [Crocker et al 2014].
Malignancy. Individuals with PJS are at increased risk for intestinal and extraintestinal malignancies. A meta analysis of 583 individuals with PJS found an overall cancer risk of 83% by age 70 years [Ishida et al 2016]. A cohort study of 336 individuals with PJS reported an overall cancer diagnosis of 55% by age 60 years [Chen et al 2017].
Table 2.
Cumulative Risk of Cancers in Peutz-Jeghers Syndrome
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Cancer Site | General Population Risk | Peutz-Jeghers Syndrome |
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Risk | Mean Age at Diagnosis |
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Colorectal | 5% | 39% | 42-46 yrs |
Stomach | <1% | 29% | 30-40 yrs |
Small bowel | <1% | 13% | 37-42 yrs |
Breast | 12.4% | 32%-54% | 37-59 yrs |
Ovarian (mostly SCTAT) | 1.6% | 21% | 28 yrs |
Cervix (adenoma malignum) | <1% | 10% | 34-40 yrs |
Uterine | 2.7% | 9% | 43 yrs |
Pancreas | 1.5% | 11%-36% | 41-52 yrs |
Testicular (Sertoli cell tumor) | <1% | 9% | 6-9 yrs |
Lung | 6.9% | 7%-17% | 47 yrs |
SCTAT = sex cord tumor with annular tubules
Colorectal and gastric cancers can arise from adenomas that are commonly found in individuals with PJS. The incidence of cancer increases markedly after age 50 years. Colorectal cancer (28% by age 60) was the most common cancer reported by Chen et al [2017] in individuals with PJS.
Breast cancer can occur at early ages in women with PJS. The breast cancer risk in women with PJS may approach that of women who have a pathogenic variant in BRCA1 or BRCA2. Early-onset breast cancer has been reported in multiple families with PJS.
Ovarian cancer. In an Italian series of 61 females with PJS, three had ovarian cancer, one of which was a malignant SCTAT [Resta et al 2013]. In a Dutch series of 69 females with PJS, two females had malignant Sertoli cell ovarian tumors and one had ovarian small cell cancer [van Lier et al 2011b].
Cervical cancer. Minimal deviation adenocarcinoma (adenoma malignum) is a rare well-differentiated adenocarcinoma of the uterine cervix. Presenting symptoms include bleeding or a mucoid, watery vaginal discharge. Histologic diagnosis can be difficult on small pathologic samples and a core biopsy or endo-cervical curettage is often necessary.
The current risk for gynecologic cancer in females with PJS is estimated to range from 18% to 50% by age 50 years [Wagner et al 2021].
Testicular cancer. Malignant transformation of Sertoli cell tumors is unusual. In a series including 64 males with PJS, one testicular seminoma was reported [van Lier et al 2011b].
Pancreatic cancer is among the top causes of cancer death in the US and Europe with a dismal five-year survival after diagnosis. Recent advances in the detection of early pancreatic adenocarcinoma amenable to curative surgical resection and identification of premalignant lesions by endoscopic ultrasound and MRI/MRCP have supported surveillance in high-risk individuals including individuals with PJS [Korsse et al 2013, Goggins et al 2020].