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Familial syndromes
Two rare familial syndromes are associated with a high prevalence of papillary thyroid cancers. Table 2: Familial syndromes associated with thyroid tumors of follicular cells
*PTC: Papillary thyroid carcinoma; FA: Follicular adenoma; FC: Follicular carcinoma Papillary thyroid cancer (PTC) affects about 1–2% of patients with familial adenomatous polyposis coli or with its subtypes, Gardner’s syndrome and Turcot’s syndrome 32. These thyroid cancers are mainly found in females (female : male, 10 : 1) less than 35 years old, and show peculiar pathological features: frequent multicentricity and association of classical papillary structures with a cribriform pattern and solid areas with elongated cells 33. In these familial forms, patients with PTC have mutations in the APC gene that usually cluster in exon 15, in the genomic area usually associated with congenital hypertrophy of the retinal pigment epithelium 34. In these papillary thyroid carcinomas, no bi-allelic inactivation of the APC gene was found, but RET/PTC1 rearrangements were frequent. Patients with Cowden’s disease, a very rare autosomal dominant disorder, with multiple hamartomas and a high risk of benign and malignant breast tumors, have a significant risk of developing papillary thyroid carcinoma 35. Predisposition is conferred by germinal mutations in the PTEN gene which is a tumor suppressor gene. Other rare syndromes associated with an increased risk of papillary and follicular thyroid carcinoma include Carney complex 36, Peutz-Jeghers syndrome and Multiple Endocrine Neoplasia type I. These rare syndromes account for only very few cases of thyroid cancer, and the discovery of one of these syndromes in a patient presenting with a thyroid cancer is exceptional. Furthermore, APC has been excluded as a susceptiblity locus in some familial PTC families; PTEN accounts for less than 5 % of families with breast and papillary thyroid carcinomas without other features of Cowden’s syndrome. Familial clustering of papillary and follicular thyroid cancers Familial clustering of papillary or follicular thyroid cancers account for 3–7 % of all these cancers. These kindreds usually show 2–4 affected members, but up to 8 cases have been described in the same family; other family members may report benign thyroid diseases 37–46. AFrench family with cell oxyphilia in multiple cases of both benign and malignant tumors 47 and a family with PTC and papillary renal neoplasia 48 were recently reported. Also, among 28 types of cancer studied in the Utah cancer registry, the risk in familial differentiated thyroid cancer to develop thyroid carcinoma is the highest amongst all cancers, being equal to 8.6 as compared to controls 49 . These results were confirmed by another populationbased study, suggesting an increased thyroid cancer risk in the offspring when one parent has been affected by a thyroid carcinoma; this risk is higher when both parents were affected, and was 2.8 times higher among males 50 . An earlier age of onset, a more aggressive pattern with a higher recurrence rate have been reported in some families with papillary thyroid carcinomas 38. In our experience, clinical presentation and outcome of these familial papillary thyroid carcinomas were similar to those of their sporadic counterparts. We thus advice similar work-up and initial treatment as for sporadic cases. Due to the low number of patients with clinical papillary or follicular thyroid carcinoma in each family, a coincidence or common environmental factors cannot be excluded. Also, extensive screening in family members may account for a number of familial cases. In fact, most papillary and follicular thyroid carcinomas are clinically latent, and may remain unknown for years or even decades, if they are not sought for by neck palpation or neck ultrasonography. Most published pedigrees of familial papillary carcinomas are compatible with inheritance of one autosomal dominant gene with reduced penetrance. In fact, there is probably a complex situation of genetic heterogeneity, polygenic inheritance, and gene-environment interactions. The localization of putative predisposing genes in thyroid cancer families is presently ongoing. Some preliminary findings have been recently reported, such as the mapping of the gene responsible for thyroid tumors with cell oxyphilia to chromosome 19p13.2 47, and the mapping of a putative multinodular goiter susceptibility gene (MNG1) to chromosome 14q31 in a Canadian family. However, the majority of kindreds with familial PTC do not link with these two loci 41. Finally, in the family with PTC and papillary renal carcinoma , the gene was mapped to 1q21 48. Up to now, there is no general consensus on the extent of screening in families with one affected subject. The risk of occurrence of other cases of thyroid cancers or of benign thyroid diseases may be either similar or higher in family members than in the general population. Indeed, a genealogical tree should be drawn. In the absence of other known thyroid diseases in the family, the costeffectiveness of familial screening is low, and is usually not justified. For reassuring family members, neck palpation and in doubtful cases neck ultrasonography every 5 years may be advised, starting at the age of 10–15 years. The discovery of a thyroid nodule in such family members should dictate the same work-up as in the general population, starting with a fine needle biopsy. Familial predisposition for papillary thyroid carcinoma after neck irradiation Studies in subjects exposed to ionizing radiation during childhood suggest the existence of genetic predisposition to develop radiation-induced thyroid cancer. Patients with one radiation-related tumor (thyroid, salivary, parathyroid, benign neural, or depending on the radiation fields, brain or breast tumors) are more likely to develop another radiation-related tumor 51. In sibling pairs who were both exposed to ionizing radiation during childhood, either external irradiation or after the Chernobyl radioactive fallout 43,51,52, the development of a thyroid tumor was concurrent more often than would have been expected by chance. Preliminary data suggest that familial predispositions of developing a thyroid tumor after irradiation may be related to a defect in DNA repair mechanisms 53. The risk of developing a thyroid tumor for subjects undergoing radiotherapy during childhood for a cancer was 3 to 10 times higher than in children treated with ionizing radiation for benign conditions; among them, children treated for a neuroblastoma had a 5-fold higher risk compared to those treated with radiotherapy for another cancer 54. These epidemiological data suggest that some subjects are at high risk of developing a thyroid tumor after irradiation during childhood. |
