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Differentiated Thyroid Carcinoma and Intestinal Polyposis Syndromes

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Differentiated Thyroid Carcinoma and Intestinal Polyposis Syndromes Send Orders of Reprints at [email protected] Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, 12, 377-381 377 Differentiated Thyroid Carcinoma and Intestinal Polyposis Syndromes Vincenzo Triggiani1,*, Vito Angelo Giagulli1, Angela Tafaro1, Francesco Resta2, Carlo Sabbà2, Brunella Licchelli1 and Edoardo Guastamacchia1 1Endocrinology and Metabolic Diseases, 2Rare Diseases Center, University of Bari, Bari, Italy Abstract: Familial Adenomatous Polyposis, Cowden’s Syndrome, and Peutz-Jeghers Syndrome are well known as Intestinal Polyposis Syndromes, inherited conditions characterized by the development of polyps of the gastro-intestinal tract in association with extra-intestinal manifestations, in particular malignant tumors at different sites. Thyroid carcinoma is sometimes a part of the clinical picture of these syndromes. The aim of this paper is to review the literature dealing with the association between differentiated thyroid carcinomas and Intestinal Polyposis Syndromes in order to point out peculiar aspects, providing suggestions for the screening and the management of thyroid tumors in these patients. Keywords: Cowden’s syndrome, differentiated thyroid carcinoma, familial adenomatous polyposis, follicular thyroid carcinoma, intestinal polyposis syndromes, papillary thyroid carcinoma, peutz-jeghers syndrome. INTRODUCTION The syndrome is due to an autosomal dominant mutation of the Adenomatous Polyposis Coli gene (APC), located on Intestinal Polyposis Syndromes are clinical conditions chromosome 5, with near 100% penetrance. More than 300 characterized by the development of polyps of the different types of mutations have been recognized as the gastro-intestinal tract associated with extra-intestinal cause of FAP. Most of these mutations (insertions, deletions, manifestations, in particular malignant tumors at different nonsense mutations, etc.), result in a truncated protein. Some sites, even at thyroid level. correlations exist between the site of specific genetic So far, three forms of Intestinal Polyposis Syndromes mutation and the clinical manifestations of the disease [3, 4]. have been well known in their clinical aspects as well as on The incidence is about 1/10,000 with no gender their specific genetic basis: Familial Adenomatous Polyposis differences. In 20- 30% of patients without a family history (FAP), Cowden’s Syndrome, and Peutz-Jeghers Syndrome. of FAP, the mutation can often begin with a “de novo” and Among the possible extraintestinal manifestations, thyroid spontaneous mutation [5, 6]. The diagnosis of classic FAP is cancer, especially the differentiated ones (i.e. papillary and based on the presence of either a suggestive family history, follicular thyroid carcinomas), can develop, and at times, or on clinical findings. However, the clinical diagnosis even be the first manifestation of the syndrome. In fact, should be confirmed by genetic testing which consists in the about 1- 2% of patients with FAP have a Papillary Thyroid sequencing of the APC gene. Carcinoma (PTC), and up to 10% of patients with Cowden’s Although colorectal polyps are often asymptomatic, Syndrome can develop Follicular Thyroid Carcinoma when the adenomas are large and numerous, they can cause (FTC), while the association between differentiated thyroid rectal bleeding and even anemia. Change in bowel habits carcinomas and Peutz-Jeghers Syndrome is rare, given that with constipation or diarrhea, abdominal pain or palpable only few cases have been described in literature so far. abdominal masses or weight loss can lead to recto-sigmoid examination, and the identification of polyps is indicative of FAMILIAL ADENOMATOUS POLYPOSIS FAP. Patients suffering from FAP could also develop a variety of extracolonic gastrointestinal manifestations: fundic Familial Adenomatous Polyposis is characterized by the development of hundreds or even thousands of adenomatous gland polyps of the stomach, adenomatous polyps of the duodenum and periampullary region and small bowel polyps in the colon at a young age (median age of 16 within adenomas. However, these lesions rarely progress into the age range of 5 to 38 years) [1] which can shortly develop cancer [7-9]. FAP patients (in particular those affected by into colorectal cancer. Therefore, an early detection of such particular variants of FAP, such as Gardner’s and Turcot’s syndrome is essential to prevent cancer progression. In fact, syndromes), moreover, can present also brain tumors, colorectal cancer develops at a mean age of 39 years, with a life expectancy of 42 years [2], and, therefore, prophylactic pancreatic carcinoma, hepatoblastomas, desmoid tumors, osteomas, fibromas of the scalp, shoulders, arms, and back, colectomy should be performed in any case. lipomas, sebaceous and epidermoid cysts, nasopharyngeal angiofibromas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary *Address correspondence to this author at the via Repubblica Napoletana n. teeth, cysts and odontomas), congenital hypertrophy of the 7, 70123-Bari, Italy; Tel/Fax: 0039805478814; E-mail: [email protected] retinal pigment epithelium, etc. [10-13]. Desmoid tumors are 2212-3873/12 $58.00+.00 © 2012 Bentham Science Publishers 378 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4 Triggiani et al. soft-tissue benign tumors that can develop in the mesentery, are skin changes [34-43]: small, multiple and colored facial abdominal wall or areas of scars, characterized by the papules and papillomas, acral keratoses of the dorsal side of progressive enlargement and compression on gastrointestinal forearms, hands and feet, palmo-plantar keratotic papules, or urinary tracts, nerves and vessels. In some cases the first "cafe au lait spots", vitiligo, angiomas, dermal fibromas, manifestation of FAP is represented by colorectal cancer or lipomas, neurinomas, neurofibromas, naevocytic naevi, other manifestations, even differentiated thyroid carcinomas. xanthomas and xanthelasmas, melanomas, basal cell and squamous cell carcinomas and carcinomas of Merkel. Differentiated thyroid carcinomas occur in 0.7-2% of patients with FAP, being the most common extraintestinal Mucosal manifestations [30, 34, 35, 38-40, 43, 44] malignancy in these subjects [10, 14-17]. The estimated risk consist of papillomatoses, involving the palate, the gums, of PTC in women affected by FAP is 23 to 160 -folds higher labial and nasal mucosa and ano-genital region, scrotal than in women without FAP [14-16, 18]. Several specific tongue, gingival hypertrophy, gingivitis, macrocheilitis, clinical characteristics as well as pathological differences polyps of hypopharynx, larynx and vocal fold, uvula between FAP-associated and sporadic PTC may help the hypoplasia, dental caries, periodontitis, and squamous cell clinicians to diagnose a previously unsuspected case of FAP. carcinomas of tongue and lips. In fact, PTC associated with FAP, at variance with the Associated non-cutaneous malignancies may especially sporadic form, typically occurs before the age of 30 [11, 15, 19-21], it has a 20:1 female: male ratio [12], it is more involve the breast and the thyroid [2]. In particular, FTC is often multicentric [10, 12, 19, 22, 23] and frequently shows a the second most frequent carcinoma after breast cancer that peculiar histological pattern known as cribriform-morular can occur in these patients [32]. It is less frequent (7-10% of variant of PTC, characterized by a mixture of the cribriform, patients) [45, 46] than benign thyroid conditions, such as the squamoid-morular, the trabecular, the follicular, and the multinodular goiter and adenomas, that are the most common papillary architecture [19, 23-26]. The histological diagnosis non-cutaneous manifestations of Cowden’s Syndrome, being of this rare variant of PTC should lead to screening for FAP, encountered in 50% to 67% of patients [12, 33]. Although no especially in young women. guidelines have been published regarding the screening for FTC in patients with Cowden’s Syndrome so far, physical In FAP-associated PTC the most common Ret-PTC examination of the thyroid, coupled with thyroid ultrasono- rearrangements involve Ret-PTC1 and Ret-PTC3 [12, 27], graphy every 1 to 2 years, should be recommended in whereas BRAF mutations, which are frequently encountered consideration of the relatively high risk for FTC in these in sporadic PTC, have not been studied. The prognosis of patients [47]. Prophylactic thyroidectomy is hardly justifiable PTC in the context of FAP is good [12, 14, 25], although a given the excellent prognosis of FTC. Nevertheless, lower than expected, 5- to 20- year disease-specific survival when thyroid nodules have been found at clinical and rate has been reported [19]. ultrasonographic assessments, fine needle aspiration should PTC may precede the diagnosis and may be even the first be performed in order to distinguish hyperplasic or colloid manifestation of FAP [16, 17]; therefore, in young patients, nodules from follicular neoplasms or PTC. When the especially young women, presenting PTC, FAP should be cytological diagnosis is that of intermediate cytology or considered as a possible diagnosis. However, given the rarity follicular neoplasm, thyroidectomy should be performed of PTC in patients with FAP and FAP in patients with PTC, in order to eventually diagnose FTC at histological recommending screening by means of colonoscopy to all examination. Clinicians encountering FTC in a young young female patients
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