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. , 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 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 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 with PTC, is probably not justified. patient, particularly if it is multifocal or associated with Colonoscopy, however, is mandatory in young patients with multiple follicular adenomas, should consider Cowden’s both PTC and a family history of colorectal carcinoma Syndrome and look for the presence of the classical or polyps. Some authors have recommended thyroid cutaneous and mucosal manifestations of this syndrome. The ultrasonographic screening for all patients with FAP [23, identification of patients affected by Cowden’s Syndrome is 28], while others do not have the same opinion [14, 20]. really important especially because of the high risk of breast Given the relatively low incidence of PTC in patients with cancer. FAP, the potential complications of thyroidectomy, and the excellent prognosis of PTC in young women, prophylactic PEUTZ-JEGHERS SYNDROME thyroidectomy is not recommended. Peutz-Jeghers Syndrome is a rare condition inherited in an autosomal dominant pattern, with incomplete penetrance, COWDEN’S SYNDROME characterized by the presence of mucocutaneous Cowden’s Syndrome or multiple syndrome hyperpigmentation of the lips and the buccal mucosa in is a rare form of Intestinal Polyposis Syndrome, with less association with hamartomatous polyposis of the than 200 cases on record [29, 30], characterized by the gastrointestinal tract and increased cancer risk at different development of benign hamartomatous polyps. This sites [48, 49]. The Serine Threonine-Protein Kinase 11/Liver syndrome is due to autosomal dominant mutations in the Kinase B1 (STK11/LKB1) is the gene responsible for this and tensin homolog gene (PTEN), located on syndrome [50, 51]. LKB1 is located on chromosome 19p13.3 chromosome 10 [2, 31, 32], with variable penetrance and and encodes for a serine threonine kinase [52] acting as a incomplete expressivity. Cowden’s Syndrome is more . Germline mutations of LKB1 are common in women (60% of cases) and has a mean age at identified in nearly 90% of the patients presenting clinical diagnosis of 39 years [33]. The most characteristic findings manifestations of the disease [53]. The incidence of the Thyroid Carcinoma and Intestinal Polyposis Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4 379 syndrome ranges from 1 in 8300 to 1 in 280,000 live births prognosis for PTC. In any case, clinicians should be aware [54, 55]. It is commonly diagnosed in the third decade of that the wide spectrum of cancer diseases possibly occurring life, although one-third of the cases are identified in children in Peutz-Jeghers Syndrome patients could also include before the age of 10 [56]. The polyps are usually confined to Differentiated Thryoid Cancer, although this association is the small bowel, often in the jejunum, and less frequently in rare. the ileum and duodenum [57], but they can also involve the stomach, the colon, the nose, the bladder, the gallbladder, CONCLUSIONS the bronchi, and the ureter [58]. Polyps are responsible for clinical manifestations including acute intestinal Differentiated could be associated with intussusception, bleeding anemia due to ulceration, Intestinal Polyposis Syndromes, even if this association is chronic abdominal pain, or anal prolapse of rectal polyps not very frequent. As described above, in fact, approximately [56]. Furthermore, in Peutz-Jeghers Syndrome patients have 1-2% of patients with FAP will develop PTC, and between increased risk for malignancies in the gastro-intestinal 7% and 10% of patients with Cowden’s Syndrome could tract as well as in several extraintestinal sites including the develop FTC, while the presence of Differentiated Thyroid pancreas, breast, uterus, ovary, and testes [59, 60]. The Cancer in Peutz-Jeghers Syndrome patients is quite rare and association between Differentiate Thyroid Carcinoma and probably only coincidental. In any case, ultrasonographic Peutz-Jeghers Syndrome is rare and may be coincidental. In evaluation of the thyroid should be a part of the surveillance fact, at the best of our knowledge, only seven cases program in all patients affected by Intestinal Polyposis have been reported in the literature [61-67]. Recently, we Syndromes, given the fact that this exam is non-invasive, described a case of PTC observed in a Peutz-Jeghers reproducible, easy to perform, it has a low cost and can guide Syndrome patient (Triggiani et al. Thyroid 2011) [67]. A 22- the fine needle aspiration when nodules are present. year-old woman presenting with hyperpigmented lesions When the diagnosis of Differentiated Thyroid Cancer is of the lips and hamartomatous polyps in the stomach, performed in a patient already affected by Intestinal duodenum, jejunum, and ileum, with the truncating Polyposis Syndromes, its management does not differ from mutation E265X, had a 6 mm hypoechoic nodule with one of the sporadic forms of Differentiated Thyroid Cancer. microcalcifications and a perinodular vascular pattern in the Total thyroidectomy, associated to radioiodine ablation right thyroid lobe. The Ultrasound-guided fine-needle (when indicated) and TSH-suppressive treatment by means aspiration biopsy of the nodule demonstrated the presence of of levothyroxine is the treatment of choice. The follow-up is PTC, confirmed at histological examination as a follicular the same as for sporadic Differentiated Thyroid Cancers, variant of the papillary microcarcinoma. We tried to assess according to the published guidelines [69]. whether PTC and Peutz-Jeghers Syndrome were genetically correlated. We performed both the sequencing and the PTC, however, may precede the diagnosis of FAP. In this multiplex ligation–dependent probe amplification analysis case, the diagnosis of PTC in a young female patient, which failed to identify any LKB1 mutation in the tumor particularly if the PTC is multifocal or of the cribriform- specimen, while the methylation-specific polymerase chain morular variant, should lead to the suspicion of FAP which reaction assay excluded the hypermethylation of the LKB1 must be ruled out in consideration of the risk for colorectal promoter as the mechanism of inactivation for the remaining carcinoma. On the other hand, an FTC diagnosed in a young normal allele in the tumor. Although other mechanisms of patient, particularly if it is multifocal or associated with LKB1 silencing could be responsible for its inactivation in multiple follicular adenomas, should raise the suspicion of a the thyroid cancer, we concluded that the occurrence of PTC possibly undiagnosed Cowden’s Syndrome. was probably a coincidental finding in this patient. Further studies, however, are needed since an in vitro study by Kim CONFLICT OF INTEREST et al. [68] provided a possible molecular explanation for the association between Peutz-Jeghers Syndrome and The author(s) confirm that this article content has no differentiated thyroid cancer, suggesting that LKB1 conflict of interest. suppresses tumor growth by inhibiting RET/PTC-dependent activation of oncogenic STAT-3, which is the mechanism ACKNOWLEDGEMENTS involved in the tumorigenesis of PTC. Declared none. In any case, the ultrasound evaluation of the thyroid could possibly become an integral part of the evaluation and REFERENCES the follow-up program adopted for Peutz-Jeghers Syndrome patients. The management of Differentiated Thyroid Cancer [1] Bülow, S. (1987) Familial polyposis coli. Dan. Med. Bull., 34(1), in a patient with Peutz-Jeghers Syndrome does not differ 1-15. from the standard guidelines for Differentiated Thyroid [2] Strate, L.L. and Syngal, S. 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Received: 18 March, 2012 Accepted: 22 March, 2012