14800-DvRappard

154 Chapter 9 asymptomatic and as such an incidental finding, with about 75% are benign. 23, 24 They are, however, associated with an increased risk of evolving into carcinoma. This risk is substantially higher for hyperplastic than for cholesterol polyps, for polyps larger than 10 mm and for those associated with a thickened gallbladder wall. 23, 25 The evolution to gallbladder carcinoma, which takes approximately 10 to 15 years, progresses from metaplasia to dysplasia, carcinoma in situ and eventually invasive tumor. 26 The average age for dysplastic changes in the general population is 51.9 years, for localized gallbladder carcinoma 56.8 years and for advanced carcinoma 62.9 years. 14 Because gallbladder carcinoma remains asymptomatic for a prolonged period, 14 it is usually diagnosed in an advanced stage with a high risk for metastases and dismal prognosis, reflected by the overall mean survival rate of only 6 months and a 5-year survival of 5%. 24 Current guidelines therefore recommend cholecystectomy for polyps larger than 10mm in otherwise healthy persons, and for polyps exceeding 5 mm in patients with conditions associated with increased risk of gallbladder carcinoma. 27-29 Findings in our patient cohort confirm earlier single case reports of gallbladder abnormalities in MLD. Our results suggest a causal relationship between MLD and the development of gallbladder polyps and eventually carcinoma, because of the high incidence of abnormalities found, in contrast to the situation in otherwise healthy children and young adults in whom polyps are very rare and carcinoma virtually nonexistent. 14 It has been hypothesized that gallbladder polyposis in MLD is caused by the prolonged contact of gallbladder epithelium with sulfatides accumulating in bile. 5 The putative role of sulfatides in this process is uncertain. Of note , sulfatide expression is elevated in many human cancer cell lines and tissues, although their role in carcinogenesis is not yet understood. 30 After HSCT, the number of sulfatide-laden macrophages in the gallbladder wall was decreased, but not normal, consistent with a limited effect of HSCT on sulfatide accumulation in visceral organs. Presence and aspect of polyps were, however, grossly unchanged. With improved symptomatic treatment, the life expectancy of neurodegenerative disorders has increased over the last few decades. As treatments for MLD as HSCT and gene therapy are emerging, life expectancy of successfully treated patients will increase further and hopefully normalize. This implies that late or unusual disease complications will become more frequent. An additional risk factor for developing malignancies may be the exposure to the myelo-ablative and intensive immunosuppressive therapy that patients receive around HSCT although we did not find a higher incidence of premalignant abnormalities in HSCT-treated compared to untreated patients, with the limitation of short follow-up time, not reflecting potential long-term effects of immunosuppression.