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Institute of Surgical Clinics University of Siena 53100 Siena, Italy
Some papers and an Editorial recently published in JCEM have dealt with familial nonmedullary thyroid carcinoma (1, 2, 3, 4). In particular, the paper by Stratakis et al. (1) described two patients with thyroid carcinoma (one papillary, one follicular) as a candidate component of the Carney syndrome, an autosomal dominant genetic disease, characterized by spotty skin pigmentation, mixomas, primary pigmented nodular adrenocortical disease, and endocrine overactivity of other glands (pituitary, testis, ovary, breast). Thyroid tumours have also been reported in other familial syndromes. In particular, an increased predisposition to papillary thyroid carcinoma (PTC) is well established in certain families with familial adenomatous polyposis (FAP). Thyroid cancers in FAP exhibit a marked female preponderance (female:male rate 10:1) and are more common under the age 30. In addition, thyroid tumors are the most frequent extracutaneous manifestations of Cowden’s disease (multiple hamartoma syndrome), being observed in two thirds of patients. They include benign thyroid lesions (adenomas, goiter) and follicular thyroid carcinoma. There are case reports describing the association of thyroid carcinoma in patients with Peutz-Jeghers syndrome and ataxia-telangectasia (1, 2, 3). In patients with multiple endocrine neoplasia type 1 (MEN1), thyroid disease is observed mostly as benign lesions and far more rarely as malignancy (3). Recently, expression of papillary thyroid carcinoma has also been observed in two patients from a single kindred with MEN 2A (5). In addition to the occurrence of PTC in kindreds with well-defined multitumoral genetic disease, the familial occurrence of PTC as a unique pathologic event has also been reported (2, 4). One paper described two large kindreds from Tasmania (2), while another (4) reported six pairs of siblings with familial PTC in children exposed to radiation after Chernobyl (4). In these reports it cannot be stated whether genetic susceptibility played a substantial role in the occurrence of PTC or if PTC simply resulted from the simultaneous exposure to common environmental agents.
Some recent observations suggest that phenotypic expression of thyroid carcinoma in patients with inherited multitumoral disease is a multifactoral phenomenon, more related to epigenetic or environmental factors than the development of tumors in other districts in the same subject. Among environmental determinants, sex related factors and radiation seem to be particularly involved (3, 4, 6).
All thyroid carcinomas included in multitumoral genetic syndromes tend to share some common characteristics (early age of onset, multicentricity, high frequency of papillary histotype, etc.). PTC with familial aggregation, even if with no documented genetic predisposition also shows frequent multicentricity. A similarly aggressive surgical approach has been invoked for all "familial nonmedullary thyroid cancers" (7, 8). Our group has recently observed two kindreds with FAP-associated thyroid carcinoma (one kindred had three siblings with PTC, the other had just one affected member) (9) and one with Cowden’s disease, having follicular carcinoma (F. Cetta, unpublished data). Three of the four patients, all females, with FAP associated PTC, had ret-PTC activation (ret-PTC1 in 2 cases). Ret-PTC is activated in 20–40% of all papillary thyroid tumors. Despite frequent involvement of local lymph nodes, most of 200 patients with PTC and ret-PTC activation screened up to now, had long-term disease-free survival and "benign" biological behaviour. Analogously, most patients with FAP-associated PTC, regardless of ret-PTC activation, had a mean survival without recurrence greater than 10–15 yr. Therefore, we suggest a word of caution, before stating that all familial nonmedullary thyroid carcinomas show "unusual aggressiveness" (1) or warrant "aggressive or hyperradical treatment" (7, 8). It is likely that, despite common features, thyroid carcinomas included in multitumoral genetic syndromes are heterogeneous diseases that show different "natural histories" and require better characterizations to distinguish one from the other. In particular, histotypes associated with FAP are greatly different from those associated with Cowden’s disease. Whereas an aggressive approach is justified when thyroid is the only site of the cancerous disease, it is less justified in other subjects, such as FAP patients. In fact, thyroid carcinomas in FAP patients are just one of the numerous tumors (from 4 to 7) (colon, stomach, duodenum and ampulla of Vater, hepatoblastoma, desmoids) (9), that are going to occur in each patient. Therefore, ethical questions must also be addressed concerning these young patients, who decide to preserve as long as possible at least partial function of their affected organs, namely endocrine glands, and who usually also want to have children, even if they are aware that 50% of their offspring will inherit the germ-line mutation.
Footnotes
Received August 19, 1997. Address correspondence to: Francesco Cetta, M.D., Professor of Surgery, Center for Research in Hepatobilliary Disease, Institute of Surgical Clinics, University of Siena, Nuovo Policlinio, viale Bracci, 53100 Siena, Italy.
The study has been supported in part by: CNR (Grants No. 93.00239.CT04; No. 94.02376.CT04; No. 95.00897.CT04); Regione Toscana (Grant No. 358/C, 1995), Murst 40%–Murst 60% and by Telethon (Grant No. E611).
References
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