PEUTZ–JEGHERS SYNDROME (PJS)
PJS is a rare autosomal dominant inherited hamartoma cancer syndrome characterized by tiny pigmented mucocutaneous macules on the skin and GI hamartomatous polyps and a high risk of GI, breast, and pancreatic carcinomas (Hemminki et al. 1997; Eng et al. 2001). Germline mutations in STK11 on chromosome 19p13 are found in most classical cases of PJS, but a very small proportion of cases do not have detectable mutations in this gene (de Leng et al. 2007; Volikos et al. 2006).
The presence of melanin spots on the lips, perioral region, and buccal mucosa is pathognomonic for PJS and probably occurs in 95 % of such individuals (Peutz 1921; Jeghers et al. 1949). These tiny macules can also occur as black or bluish spots on the hands (especially the palms), arms, feet (especially plantar areas), legs, genitalia, and anus. The skin pigmentation is present from early childhood and may fade after the age of 25 years. The absence of the pigmented spots therefore does not exclude the diagnosis of PJS (Lampe et al. 2003). Most patients present because of symptomatology related to their GI hamartomatous polyps, although polyps can occur in the nasal mucosa, bladder, uterus, and gallbladder as well. They can present with episodes of colicky abdominal pain from childhood (usually the second decade).
Intussusception and obstruction are not uncommon complications, and rectal bleeding, severe enough to present with anemia, may occur. The distribution of polyps is most commonly in the small intestine (60–90 %), but also in the colon (50–64 %), stomach (49 %), and rectum (32 %) (Jeghers et al. 1949). The polyps are broad-based hamartomas of the smooth muscle that extend into the lamina propria. Many show histological features of “pseudoinvasion.” Nevertheless, adenomatous change may develop within the polyps, and there is an increased risk of malignancy (relative risk 13), and mortality from cancer as high as 40 % by 50 years of age has been quoted for this condition (Boardman et al. 1998; Giardiello et al. 1987; Lim et al. 2004). In the absence of the characteristic melanin spots, the histopathology of the polyps is critical in making the diagnosis of PJS, as the PJS polyp has a diagnostically useful central core of smooth muscle that extends in a tree-like manner (“arborization”) into the superficial epithelial layer. There is frond- like elongated epithelium and cystic gland dilatation extending to the muscularis propria with arborizing smooth muscle. Thus invagination of the epithelial layer occurs, essentially trapping these cells within the smooth muscle component, and causing “pseudoinvasion” of the bowel wall that can be misdiagnosed as cancer, but has no evidence of cytological atypia. This involvement of the three tissue layers predisposes to intussusception and the formation of the distinctive lobulated PJS polyp. Nonetheless, the operational clinical diagnostic criteria for PJS are as follows:
- Two or more histologically confirmed PJS polyps
Any number of PJS polyps or characteristic mucocutaneous pigmentation, with a positive family history of PJS
Any number of PJS polyps with characteristic mucocutaneous pigmentation
(Aretz et al. 2005; Aaltonen et al. 1998)
In addition to an increased risk of GI cancer, extraintestinal cancers are overrepresented in PJS as well (Giardiello et al. 1987). Invasive ductal carcinomas of the breast and pancreatic adenocarcinomas are significantly associated with PJS (Boardman et al. 1998). Nonmalignant Tumours associated with this syndrome include ovarian sex cord Tumours and testicular (Sertoli cell) Tumours. The histology of these Tumours is intermediate between granulosa cell Tumours and Sertoli cell Tumours. They are common in this syndrome, and rarely malignant, although at least one such malignancy has been described.
The clinical effects are mainly due to the hyperestrogenization in females and can give rise to adenoma malignum of the cervix, which can be very malignant. Many of these Tumours occur in young adults, and the Sertoli and sex cord Tumours may occur in prepubertal boys, causing sexual precocity and gynecomastia. Sertoli cell Tumours of the ovary may occur, and ovarian sex cord Tumours are common, bilateral and multifocal.
The relative risks of all cancers in PJS are high, assessed as 3 % by age of 30 years, 19 % by 40 years, 32 % by 50 years, 63 % by 60 years, and 81 % by age of 70 years. The respective risks of GI cancer (esophagus, stomach, small bowel, colorectum, and pancreas) are 1, 10, 18, 42, and 66 % and of gynecological cancer 3, 6, 13, and 13 % overall, and the breast cancer risks are 8 % by 40 years of age, 11 % by 50 years, and 32 % by 50 years of age. The risk of pancreatic cancer may reach 5 % by age 40 years and 8 % by 60 years (Lim et al. 2003, 2004).
Germline loss-of-function mutations in STK11, on19p13.3, encoding a multifunctional nuclear serine-threonine kinase, were found in a proportion of PJS individuals and kindreds (Hemminki et al. 1997, 1998; Jenne et al.
1998). STK11 mutations have been found in 80–96 % of cases, leading to the suggestion of either locus heterogeneity or the presence of large deletions and promoter mutations, which have not been systematically analyzed. There is
no clear genotype-phenotype association; current evidence suggests that it is unlikely that there is another major PJS locus.
STK11 has nine exons, and the normal protein product acts as a Tumours suppressor, a notable role for a protein kinase. Studies show that biallelic inactivation of STK11 in the Tumours, either through germline mutation plus somatic mutation or more commonly promoter hypermethylation of the wild-type allele, causes hamartomatous polyps to develop. The gene product is a serine-threonine kinase which regulates cell proliferation, partly via G1 cell- cycle arrest. It also plays a role in cell polarity and WNT signaling and is a negative regulator of mTOR in the TSC pathway.
Genetic and Medical Management
As with other inherited cancer syndromes, patients with or suspected to have PJS should be referred to clinical cancer genetic consultation. The presence of a germline STK11 mutation is diagnostic of PJS. However, failure to find a mutation in an individual who meets the clinical diagnostic criteria for PJS does not exclude the diagnosis, and such individuals should be managed like anyone with PJS and/or germline STK11 mutation.
Initial follow-up and management in PJS is aimed at detecting polyps in the bowel to prevent complications arising such as intussusception and intestinal obstruction. Later in adult life, screening is done to detect precancerous lesions and early cancer. Suggested protocols are baseline colonoscopy and upper GI endoscopy at 8 years and if no polyps are detected, initiating further small bowel video capsule endoscopies and colonoscopies at 18 years, 3 yearly. If polyps are detected at 8 years of age, 3-yearly screening is recommended from that age. It is also recommended that after the age of 50 years, the frequency is increased to every 12 months due to the rapid increase in cancer risk after this age. If video capsule endoscopies are not available, barium meal and follow-through in adults or MRI can be alternatives. If a laparotomy is being performed, endoscopic polypectomy (“on table enteroscopy and polypectomy”) should be considered. Screening for breast cancer by MRI annually from 25 years should be performed if possible, and cervical smears with liquid-based cytology are advised in adult women. However, screening for pancreatic or other cancers is not of proven benefit and is not recommended (Beggs et al. 2010). Treatment with MTOR inhibitors such as Rapamycin is under development with some initial indications of success.
Laparotomy may be required for suspicious symptoms. Polypectomy should be as complete as possible and can be performed at endoscopy.
Surveillance for extraintestinal malignancy includes mammography, yearly gynecological evaluation and pelvic ultrasound, and 3-yearly cervical smears. Testicular ultrasound is suggested for males with feminizing features because of the risk of feminizing Sertoli cell Tumours of the testis.