N-methylnitrosourea aggravates gastrointestinal polyposis in Lkb1+/- mice.

Peutz-Jeghers patients develop hamartomatous polyps and carcinomas of the gastrointestinal tract. Cyclooxygenase-2 accelerates polyp growth in Lkb1 (+/-) mice modelling Peutz-Jeghers polyposis. In this study, we aimed to evaluate the effect of the mutagenic carcinogen N-methylnitrosourea (MNU) on gastrointestinal tumourigenesis in Lkb1 (+/-) mice and to investigate the role of cyclooxygenase-2 on the tumourigenesis. We treated 40 Lkb1 (+/-) and 51 wild-type mice with MNU, 10 mice from both groups received the cyclooxygenase-2 inhibitor celecoxib. Carcinogen-treated Lkb1 (+/-) mice displayed worse survival (60%) than treated wild-type (100%, P = 0.028) or untreated Lkb1 (+/-) mice (92%, P = 0.045). Also, the gastrointestinal tumour burden was almost 10-fold higher in carcinogen-treated (2181 mm(3)) than in untreated (237 mm(3), P = 0.00045) Lkb1 (+/-) mice. Celecoxib was much less efficient in reducing tumourigenesis in MNU-treated mice (by 23%; 1686 mm(3)) than in untreated mice (76%; 58 mm(3)). Surprisingly, the increase in tumour burden in MNU-treated mice was not accompanied by consistent histological changes, with only a single focus of epithelial dysplasia noted. This study suggests that MNU promotes Peutz-Jeghers polyposis independently from the acceleration by cyclooxygenase-2.

Peutz-Jeghers syndrome: a study of long-term surgical morbidity and causes of mortality.

Patients with Peutz-Jeghers syndrome (PJS) require lifelong multidisciplinary care for gastrointestinal polyposis and increased risk of cancer. Their long-term morbidities and causes of mortality are unknown. Patients with a definitive diagnosis of PJS (n = 54) were retrospectively reviewed for disease course and outcome. Operative details, pathology and complications were noted for those treated surgically (n = 33). Median follow-up was 7.0 years (interquartile range: 2-20). Two malignancies were found intra-operatively (duodenal and rectal adenocarcinoma). In the long-term, 42% underwent additional operations; 1 patient developed short bowel syndrome, while another, chronic partial bowel obstruction and pain. Twenty-one additional cancers were treated in 19 patients: gynecologic (11), lung (3), and prostate (2) being the most common. 16 patients (30%) were deceased, at a median age of 51 years. The cause of death was unknown in 4 patients, but was due exclusively to malignancies in all other patients, most commonly due to metastatic gynecologic cancer (5). The overall survival of PJS patients was significantly shorter than the expected survival of an age-and gender-matched reference population (P < 0.001). Given the morbidities associated with repeated operations and the risk for cancer-related mortality in the long-term, efforts should focus on minimizing the need for surgical intervention and optimizing cancer detection, treatment and prevention.

Cancer and the Peutz-Jeghers syndrome.

Among 72 patients with the Peutz-Jeghers syndrome malignant tumours have developed in 16 (22%) of whom all but one have died. There were nine gastrointestinal and seven nongastrointestinal tumours. The relative risks of death from gastrointestinal cancer and all cancers were 13 (95% CI 2.7-38.1) and 9 (95% CI 4.2-17.3) respectively. The chance of dying of cancer by the age of 57 was 48%. There is evidence for a hamartoma/carcinoma sequence in the Peutz-Jeghers syndrome, suggesting that the gene locus involved is relevant to the development of malignancy in general.

Peutz-Jeghers syndrome: 78-year follow-up of the original family.

BACKGROUND: The association between heredity, gastrointestinal polyposis, and mucocutaneous pigmentation in Peutz-Jeghers syndrome (PJS) was first recognised in 1921 by Peutz in a Dutch family. This original family has now been followed-up for more than 78 years. We did mutation analysis in this family to test whether the recently identified LKB1 gene is indeed the PJS gene in this family. METHODS: The original family was retraced and the natural history of PJS was studied in six generations of this kindred by interview, physical examination, chart view, and histological review of tissue specimens. DNA-mutation analysis was done in all available descendants. FINDINGS: Clinical features in this family included gastrointestinal polyposis, mucocutaneous pigmentation, nasal polyposis, and rectal extrusion of polyps. Survival of affected family members was reduced by intestinal obstruction and by the development of malignant disease. A novel germline mutation in the LKB1 gene was found to cosegregate with the disease phenotype in the original family. The mutant LKB1 allele carried a T insertion at codon 66 in exon 1 resulting in frameshift and stop at codon 162 in exon 4. INTERPRETATION: The morbidity and mortality in this family suggest that PJS is not a benign disease. An inactivating germline mutation in the LKB1 gene is involved in the PJS phenotype in the original and oldest kindred known to be affected by PJS.

Course and follow-up of solitary Peutz-Jeghers polyps: a case series.

BACKGROUND AND AIMS: Peutz-Jeghers syndrome (PJS) is a rare, autosomal-dominant disease characterized by hamartomatous polyps of the alimentary tract, hyperpigmentation of the skin, and family history of PJS. Rarely, solitary Peutz-Jeghers polyps (PJP) arise in patients without other features of PJS. PATIENTS AND METHODS: We reviewed eight patients since 1979 with solitary PJP, six men and two women. RESULTS: The average age at diagnosis was higher (56+/-13 years) than that of PJS patients in the literature. Polyps were found in the sigmoid colon ( n=4), cecum ( n=1), stomach ( n=1), and duodenum ( n=2). The colonic polyps were diagnosed and removed endoscopically. Indications for colonoscopy included routine screening ( n=4) or rectal bleeding ( n=1). The duodenal and gastric polyps were diagnosed and removed during gastroduodenoscopic examinations, which were performed for nonspecific dyspepsia ( n=2) or gastrointestinal bleeding ( n=1). The median size was 20 mm (range 2 mm-25 mm). Patients were followed for a median of 11.5 years (range 3-22) without another PJP or cancer. Three patients died of causes unrelated to PJP. Five patients are alive and polyp free. CONCLUSION: Solitary PJP do not carry a risk of gastrointestinal cancer and are not an indication for specific high-risk screening.