Hyperpigmentation is present as mucocutaneous macules on the lips (Figure ) and around the mouth, eyes, nostrils, and on the buccal mucosa; and sparsely on the fingers, soles of the feet, palms, anal area and intestinal mucosa. Characteristic pigmentations are present in 95% of the patients and are caused by pigment-laden macrophages in the dermis. They are typically flat, blue-gray to brown spots 1-5 mm in size. Malignant degeneration of these lesions is extremely rare. These macules can be distinguished from common freckles as the latter never appear in the oral cavity, are sparse near the lips and nostrils, and absent at birth. Hyperpigmentations can even disappear during adolescence. Diagnosis is defined by the presence of histopathologically confirmed hamartomatous polyps (Figure ) and at least two of the following clinical criteria: family history, hyperpigmentation and polyps in the small bowel[11,13-17,21,22,29
] (Figure ).
Pigmentations of the lips and oral mucosa.
The median time to first presentation with polyps is about 11-13 years of age, and approximately 50% will have experienced symptoms by the age of 20 years[13,14
]. During the first three decades of life, anemia, rectal bleeding, abdominal pain, obstruction and/or intussusception are common complications in patients with PJS[13,15
]. Nearly half of the patients experience an intussusception during their lifetime, most often in the small intestine[30
The setting of 222 patients with PJS was presented by Utsunomiya et al[31
] in 1975. They presented patients with PJS in Japan ascertained between 1961 and 1974. The average age at diagnosis was 23 years in men and 26 years in women, with a male to female ratio of 1:1.13. Obstruction was observed in 42.8%, intussusception in 46.9%, most often in the small intestine, and rectal bleeding in 13.5% of the patients. The polyps occurred in the stomach in 48.6% (Figure and ), small intestine 64%, colon 53.2%, and rectum 32%[31
]. This study demonstrated the natural history of the disease despite this being based on surveys, and the study suffering some imperfections (e.g. cancer was found only in 28 of 222 patients).
Hamartomas of the stomach. A: Multiple; B: Voluminous.
Hearle et al[32
] have published a study of STK11 status and intussusception risk in PJS. According to this study, 135 (60%) of the probands possessed a germline STK11 mutation, and 109 (48%) probands had a history of intussusception at a median age of 15.0 years but with wide variability (range: 3.7-45.4 years). Median time to onset of intussusception was not significantly different between those with identified mutations and those with no mutation detected, at 14.7 and 16.4 years, respectively. Similarly, no differences were observed between patient groups on the basis of the type or site of STK11 mutation[32
A quite rare but possible complication is gastric outlet obstruction caused by a giant gastric polyp[33-35
] (Figure and Figure ). Children with PJS have a risk of numerous laparotomies due to the complications. Gastrointestinal screening of the small bowel should be started from childhood and when polyps develop they should be managed if possible by endoscopic resection[29,36
]. PJS-related polyps occur most frequently in the small intestine. Over 90% of affected individuals will develop polyps in the small intestine during their lifetime. The incidence within the small intestine is greatest in the jejunum and progressively decreases in the ileum and duodenum[13,37,38
]. Involvement of the colon (53% of patients), stomach (49%), and rectum (32%) is also seen[15,33-35
]. Well-timed polypectomy may obviate the need for repeated urgent operations and extensive small bowel resections leading to short bowel syndrome[39,40
Gastric outlet obstruction (same patient as seen in Figure ). A: Endoscopic view; B: fluoroscopy, mass of polyps marked by arrows.
Extraintestinal polyps are also reported. Nasal polyposis is thought to be a rare complication. de Leng et al[41
] have observed nasal polyposis in eight (15%) of 52 Dutch patients with PJS. The loss of heterozygosity, and the absence of eosinophilia suggest a distinct pathogenesis compared with sporadic nasal polyposis. In the same study, 11 of 12 PJS-associated nasal polyps were found to express cyclooxygenase-2 (COX-2) compared with 19 of 28 sporadic nasal polyps[41
]. Six of 22 members of the original Peutz pedigree have been diagnosed with nasal polyposis[6
]. Three PJS patients have been reported with nasopharyngeal carcinoma[6,42
In a series of 72 PJS patients, three (4.1%) had gallbladder polyps[43
]. Also reported are one PJS patient who required cholecystectomy for gallbladder obstruction by polyps, and one with common bile duct obstruction caused by polyps[44
]. Two PJS patients have been reported with gallbladder cancer; one of whom had gallbladder cancer arising near but not in hamartomatous gallbladder polyps[31,45
]. Several PJS patients have been reported with bile duct cancer (cholangiocarcinoma)[46,47
]. Hamartomatous polyps in PJS patients have also been reported in the ureter[48
], respiratory tract[49,50
] and on the tonsils[51
PJS is associated with specific genetic mutations and an increased lifetime risk of both gastrointestinal and extraintestinal malignancies[22
]; i.e. pancreatic, lung, breast, uterine, ovarian and testicular malignancies (Sertoli cell tumors secrete estrogen and can lead to gynecomastia). Inherited forms of gastrointestinal cancer have attracted the attention of scientists over the past two decades, putting the accent on prevention. The possibility of developing any cancer by age 65 years was 37% in accordance with data from the St. Mark’s Polyposis Registry[52
]. Hearle et al[53
] have analyzed the incidence of cancer in 419 PJS patients, and 297 of them had documented STK11/LKB1 mutations. Ninety-six cancers were found among these patients. The risk for developing cancer at ages 20, 30, 40, 50, 60 and 70 years was 2%, 5%, 17%, 31%, 60% and 85%, respectively. The most common cancers represented in this analysis were of gastrointestinal origin. In non-gastrointestinal tumors, breast cancer was the most common, with the risk being 8% and 31% at ages 40 and 60 years, respectively. The cancer risk was similar in the STK11/LKB1 mutation positive and negative group[53
Mehenni et al[42
] have followed the cumulative incidence of cancer in 149 PJS patients with germline mutation(s) in LKB1, this being estimated using Kaplan-Meier analysis of time to cancer onset, and compared between relevant subgroups with log rank tests. Thirty-two cancers were found in LKB1 mutation carriers. Overall cancer risks at ages 30, 40, 50, 60 and 70 years were 6%, 18%, 31%, 41% and 67%, respectively. There were similar overall cancer risks between male and female carriers. However, there were overall cancer risk differences for exon 6 mutation carriers vs
non-exon 6 mutation carriers. Most (22/32) of the cancers occurred in the gastrointestinal tract, and the overall gastrointestinal cancer risks at ages 40, 50, 60 and 70 years were 12%, 24%, 34% and 63%, respectively. In female patients, the risk of developing gynecological cancer at age 40 and 50 years was 13% and 18%, respectively. Mutations in exon 6 of LKB1 were associated with a higher cancer risk than mutations within other regions of the gene[42
In a meta-analysis of Giardiello et al[54
], the cumulative risk of developing any cancer in PJS was 93%. Of all tumors associated with PJS, breast cancer poses the greatest risk, affecting 32%-54% of patients[54
]. In their systematic study, Boardman et al[55
] have determined that the relative risk for all cancers in PJS patients significantly increased (RR = 9.9). The relative risk for gynecological and breast cancers in women was 20.3, and for gastrointestinal cancers, 50.3[55
]. Screening recommendations for PJS patients includes not only gastrointestinal multiple polyp resolution, but also regular cancer screening.