Differentiated Thyroid Carcinoma and Intestinal ... - Ingenta Connect

7 downloads 56 Views 135KB Size Report
Keywords: Cowden's syndrome, differentiated thyroid carcinoma, familial adenomatous polyposis, follicular thyroid carcinoma, 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 1

Endocrinology 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 Intestinal Polyposis Syndromes are clinical conditions characterized by the development of polyps of the gastro-intestinal tract associated with extra-intestinal manifestations, in particular malignant tumors at different sites, even at thyroid level. So far, three forms of Intestinal Polyposis Syndromes have been well known in their clinical aspects as well as on their specific genetic basis: Familial Adenomatous Polyposis (FAP), Cowden’s Syndrome, and Peutz-Jeghers Syndrome. Among the possible extraintestinal manifestations, thyroid cancer, especially the differentiated ones (i.e. papillary and follicular thyroid carcinomas), can develop, and at times, even be the first manifestation of the syndrome. In fact, about 1- 2% of patients with FAP have a Papillary Thyroid Carcinoma (PTC), and up to 10% of patients with Cowden’s Syndrome can develop Follicular Thyroid Carcinoma (FTC), while the association between differentiated thyroid carcinomas and Peutz-Jeghers Syndrome is rare, given that only few cases have been described in literature so far. FAMILIAL ADENOMATOUS POLYPOSIS Familial Adenomatous Polyposis is characterized by the development of hundreds or even thousands of adenomatous polyps in the colon at a young age (median age of 16 within the age range of 5 to 38 years) [1] which can shortly develop into colorectal cancer. Therefore, an early detection of such syndrome is essential to prevent cancer progression. In fact, colorectal cancer develops at a mean age of 39 years, with a life expectancy of 42 years [2], and, therefore, prophylactic colectomy should be performed in any case.

*Address correspondence to this author at the via Repubblica Napoletana n. 7, 70123-Bari, Italy; Tel/Fax: 0039805478814; E-mail: [email protected] 2212-3873/12 $58.00+.00

The syndrome is due to an autosomal dominant mutation of the Adenomatous Polyposis Coli gene (APC), located on chromosome 5, with near 100% penetrance. More than 300 different types of mutations have been recognized as the cause of FAP. Most of these mutations (insertions, deletions, nonsense mutations, etc.), result in a truncated protein. Some correlations exist between the site of specific genetic mutation and the clinical manifestations of the disease [3, 4]. The incidence is about 1/10,000 with no gender differences. In 20- 30% of patients without a family history of FAP, the mutation can often begin with a “de novo” and spontaneous mutation [5, 6]. The diagnosis of classic FAP is based on the presence of either a suggestive family history, or on clinical findings. However, the clinical diagnosis should be confirmed by genetic testing which consists in the sequencing of the APC gene. Although colorectal polyps are often asymptomatic, when the adenomas are large and numerous, they can cause rectal bleeding and even anemia. Change in bowel habits with constipation or diarrhea, abdominal pain or palpable abdominal masses or weight loss can lead to recto-sigmoid examination, and the identification of polyps is indicative of FAP. Patients suffering from FAP could also develop a variety of extracolonic gastrointestinal manifestations: fundic gland polyps of the stomach, adenomatous polyps of the duodenum and periampullary region and small bowel adenomas. However, these lesions rarely progress into cancer [7-9]. FAP patients (in particular those affected by particular variants of FAP, such as Gardner’s and Turcot’s syndromes), moreover, can present also brain tumors, pancreatic carcinoma, hepatoblastomas, desmoid tumors, osteomas, fibromas of the scalp, shoulders, arms, and back, lipomas, sebaceous and epidermoid cysts, nasopharyngeal angiofibromas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium, etc. [10-13]. Desmoid tumors are © 2012 Bentham Science Publishers

378 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4

soft-tissue benign tumors that can develop in the mesentery, abdominal wall or areas of scars, characterized by the progressive enlargement and compression on gastrointestinal or urinary tracts, nerves and vessels. In some cases the first manifestation of FAP is represented by colorectal cancer or other manifestations, even differentiated thyroid carcinomas. Differentiated thyroid carcinomas occur in 0.7-2% of patients with FAP, being the most common extraintestinal malignancy in these subjects [10, 14-17]. The estimated risk of PTC in women affected by FAP is 23 to 160 -folds higher than in women without FAP [14-16, 18]. Several specific clinical characteristics as well as pathological differences between FAP-associated and sporadic PTC may help the clinicians to diagnose a previously unsuspected case of FAP. In fact, PTC associated with FAP, at variance with the 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 often multicentric [10, 12, 19, 22, 23] and frequently shows a peculiar histological pattern known as cribriform-morular variant of PTC, characterized by a mixture of the cribriform, the squamoid-morular, the trabecular, the follicular, and the papillary architecture [19, 23-26]. The histological diagnosis of this rare variant of PTC should lead to screening for FAP, especially in young women. In FAP-associated PTC the most common Ret-PTC rearrangements involve Ret-PTC1 and Ret-PTC3 [12, 27], whereas BRAF mutations, which are frequently encountered in sporadic PTC, have not been studied. The prognosis of PTC in the context of FAP is good [12, 14, 25], although a lower than expected, 5- to 20- year disease-specific survival rate has been reported [19]. PTC may precede the diagnosis and may be even the first manifestation of FAP [16, 17]; therefore, in young patients, especially young women, presenting PTC, FAP should be considered as a possible diagnosis. However, given the rarity of PTC in patients with FAP and FAP in patients with PTC, recommending screening by means of colonoscopy to all young female patients with PTC, is probably not justified. Colonoscopy, however, is mandatory in young patients with both PTC and a family history of colorectal carcinoma or polyps. Some authors have recommended thyroid ultrasonographic screening for all patients with FAP [23, 28], while others do not have the same opinion [14, 20]. Given the relatively low incidence of PTC in patients with FAP, the potential complications of thyroidectomy, and the excellent prognosis of PTC in young women, prophylactic thyroidectomy is not recommended. COWDEN’S SYNDROME Cowden’s Syndrome or multiple hamartoma syndrome is a rare form of Intestinal Polyposis Syndrome, with less than 200 cases on record [29, 30], characterized by the development of benign hamartomatous polyps. This syndrome is due to autosomal dominant mutations in the phosphatase and tensin homolog gene (PTEN), located on chromosome 10 [2, 31, 32], with variable penetrance and incomplete expressivity. Cowden’s Syndrome is more common in women (60% of cases) and has a mean age at diagnosis of 39 years [33]. The most characteristic findings

Triggiani et al.

are skin changes [34-43]: small, multiple and colored facial papules and papillomas, acral keratoses of the dorsal side of forearms, hands and feet, palmo-plantar keratotic papules, "cafe au lait spots", vitiligo, angiomas, dermal fibromas, lipomas, neurinomas, neurofibromas, naevocytic naevi, xanthomas and xanthelasmas, melanomas, basal cell and squamous cell carcinomas and carcinomas of Merkel. Mucosal manifestations [30, 34, 35, 38-40, 43, 44] consist of papillomatoses, involving the palate, the gums, labial and nasal mucosa and ano-genital region, scrotal tongue, gingival hypertrophy, gingivitis, macrocheilitis, polyps of hypopharynx, larynx and vocal fold, uvula hypoplasia, dental caries, periodontitis, and squamous cell carcinomas of tongue and lips. Associated non-cutaneous malignancies may especially involve the breast and the thyroid [2]. In particular, FTC is the second most frequent carcinoma after breast cancer that can occur in these patients [32]. It is less frequent (7-10% of patients) [45, 46] than benign thyroid conditions, such as multinodular goiter and adenomas, that are the most common non-cutaneous manifestations of Cowden’s Syndrome, being encountered in 50% to 67% of patients [12, 33]. Although no guidelines have been published regarding the screening for FTC in patients with Cowden’s Syndrome so far, physical examination of the thyroid, coupled with thyroid ultrasonography every 1 to 2 years, should be recommended in consideration of the relatively high risk for FTC in these patients [47]. Prophylactic thyroidectomy is hardly justifiable given the excellent prognosis of FTC. Nevertheless, when thyroid nodules have been found at clinical and ultrasonographic assessments, fine needle aspiration should be performed in order to distinguish hyperplasic or colloid nodules from follicular neoplasms or PTC. When the cytological diagnosis is that of intermediate cytology or follicular neoplasm, thyroidectomy should be performed in order to eventually diagnose FTC at histological examination. Clinicians encountering FTC in a young patient, particularly if it is multifocal or associated with multiple follicular adenomas, should consider Cowden’s Syndrome and look for the presence of the classical cutaneous and mucosal manifestations of this syndrome. The identification of patients affected by Cowden’s Syndrome is really important especially because of the high risk of breast cancer. PEUTZ-JEGHERS SYNDROME Peutz-Jeghers Syndrome is a rare condition inherited in an autosomal dominant pattern, with incomplete penetrance, characterized by the presence of mucocutaneous hyperpigmentation of the lips and the buccal mucosa in association with hamartomatous polyposis of the gastrointestinal tract and increased cancer risk at different sites [48, 49]. The Serine Threonine-Protein Kinase 11/Liver Kinase B1 (STK11/LKB1) is the gene responsible for this syndrome [50, 51]. LKB1 is located on chromosome 19p13.3 and encodes for a serine threonine kinase [52] acting as a tumor suppressor gene. Germline mutations of LKB1 are identified in nearly 90% of the patients presenting clinical 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

syndrome ranges from 1 in 8300 to 1 in 280,000 live births [54, 55]. It is commonly diagnosed in the third decade of life, although one-third of the cases are identified in children before the age of 10 [56]. The polyps are usually confined to the small bowel, often in the jejunum, and less frequently in the ileum and duodenum [57], but they can also involve the stomach, the colon, the nose, the bladder, the gallbladder, the bronchi, and the ureter [58]. Polyps are responsible for clinical manifestations including acute intestinal intussusception, bleeding anemia due to polyp ulceration, chronic abdominal pain, or anal prolapse of rectal polyps [56]. Furthermore, in Peutz-Jeghers Syndrome patients have increased risk for malignancies in the gastro-intestinal tract as well as in several extraintestinal sites including the pancreas, breast, uterus, ovary, and testes [59, 60]. The association between Differentiate Thyroid Carcinoma and Peutz-Jeghers Syndrome is rare and may be coincidental. In fact, at the best of our knowledge, only seven cases have been reported in the literature [61-67]. Recently, we described a case of PTC observed in a Peutz-Jeghers Syndrome patient (Triggiani et al. Thyroid 2011) [67]. A 22year-old woman presenting with hyperpigmented lesions of the lips and hamartomatous polyps in the stomach, duodenum, jejunum, and ileum, with the truncating mutation E265X, had a 6 mm hypoechoic nodule with microcalcifications and a perinodular vascular pattern in the right thyroid lobe. The Ultrasound-guided fine-needle aspiration biopsy of the nodule demonstrated the presence of PTC, confirmed at histological examination as a follicular variant of the papillary microcarcinoma. We tried to assess whether PTC and Peutz-Jeghers Syndrome were genetically correlated. We performed both the sequencing and the multiplex ligation–dependent probe amplification analysis which failed to identify any LKB1 mutation in the tumor specimen, while the methylation-specific polymerase chain reaction assay excluded the hypermethylation of the LKB1 promoter as the mechanism of inactivation for the remaining normal allele in the tumor. Although other mechanisms of LKB1 silencing could be responsible for its inactivation in the thyroid cancer, we concluded that the occurrence of PTC was probably a coincidental finding in this patient. Further studies, however, are needed since an in vitro study by Kim et al. [68] provided a possible molecular explanation for the association between Peutz-Jeghers Syndrome and differentiated thyroid cancer, suggesting that LKB1 suppresses tumor growth by inhibiting RET/PTC-dependent activation of oncogenic STAT-3, which is the mechanism involved in the tumorigenesis of PTC. In any case, the ultrasound evaluation of the thyroid could possibly become an integral part of the evaluation and the follow-up program adopted for Peutz-Jeghers Syndrome patients. The management of Differentiated Thyroid Cancer in a patient with Peutz-Jeghers Syndrome does not differ from the standard guidelines for Differentiated Thyroid Cancer. Total thyroidectomy as well as radioiodine ablation therapy are recommended, although some concerns could be raised about the possible tumorigenic effects of radioiodine therapy in these cancer-prone individuals. Prophylactic thyroidectomy is not indicated in Peutz-Jeghers Syndrome patients, given the relatively low incidence of PTC, the potential complications of thyroidectomy, and the excellent

379

prognosis for PTC. In any case, clinicians should be aware that the wide spectrum of cancer diseases possibly occurring in Peutz-Jeghers Syndrome patients could also include Differentiated Thryoid Cancer, although this association is rare. CONCLUSIONS Differentiated Thyroid Cancer could be associated with Intestinal Polyposis Syndromes, even if this association is not very frequent. As described above, in fact, approximately 1-2% of patients with FAP will develop PTC, and between 7% and 10% of patients with Cowden’s Syndrome could develop FTC, while the presence of Differentiated Thyroid Cancer in Peutz-Jeghers Syndrome patients is quite rare and probably only coincidental. In any case, ultrasonographic evaluation of the thyroid should be a part of the surveillance program in all patients affected by Intestinal Polyposis Syndromes, given the fact that this exam is non-invasive, reproducible, easy to perform, it has a low cost and can guide the fine needle aspiration when nodules are present. When the diagnosis of Differentiated Thyroid Cancer is performed in a patient already affected by Intestinal Polyposis Syndromes, its management does not differ from one of the sporadic forms of Differentiated Thyroid Cancer. Total thyroidectomy, associated to radioiodine ablation (when indicated) and TSH-suppressive treatment by means of levothyroxine is the treatment of choice. The follow-up is the same as for sporadic Differentiated Thyroid Cancers, according to the published guidelines [69]. PTC, however, may precede the diagnosis of FAP. In this case, the diagnosis of PTC in a young female patient, particularly if the PTC is multifocal or of the cribriformmorular variant, should lead to the suspicion of FAP which must be ruled out in consideration of the risk for colorectal carcinoma. On the other hand, an FTC diagnosed in a young patient, particularly if it is multifocal or associated with multiple follicular adenomas, should raise the suspicion of a possibly undiagnosed Cowden’s Syndrome. CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2] [3] [4]

[5]

Bülow, S. (1987) Familial polyposis coli. Dan. Med. Bull., 34(1), 1-15. Strate, L.L. and Syngal, S. (2005) Hereditary colorectal syndromes. Can. Causes Con., 16(3), 201-213. Grady, W.M. (2003) Genetic testing for high-risk colon cancer patients. Gastroenterol., 124(6), 1574-1594. Nishisho, I.; Nakamura, Y.; Miyoshi, Y.; Miki, Y.; Ando, H.; Horii, A.; Koyama, K.; Utsunomiya, J.; Baba, S. and Hedge, P. (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science, 253(5020), 665-669. Rowley, P.T. (2005) Inherited susceptibility to colorectal cancer. Annu. Rev. Med., 56, 539-554.

380 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4 [6]

[7]

[8] [9]

[10]

[11]

[12]

[13]

[14]

[15]

[16] [17]

[18] [19]

[20]

[21]

[22]

[23]

[24]

[25]

Rustin, R.B.; Jagelman, D.G.; McGannon, E.; Fazio, V.W. and Lavery Weakley, F.L. (1990) Spontaneous mutation in familial adenomatous polyposis. Dis. Colon. Rectum., 33(1), 52-55. Bianch, K.L.; Buerke, C.A.; Bennett, A.E.; Lopez, R.; Hasson, H. and Church, J.M. (2008) Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin. Gastroenterol. Heptatol., 6(2), 180-185. Spigelman, A.D.; Williams, C.B.; Talbot, I.C.; Domizio, P. and Phillips, R.K. (1989) Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet, 2(8666), 783-785. Groves, C.J.; Saunders, B.P.; Spigelman, A.D. and Phillips, R.K. (2002) Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study. Gut., 50(5), 636-641. Truta, B.; Allen, B.A.; Conrad, P.G.; Kim, Y.S.; Berk, T.; Gallinger, S.; Bapat, B.; Terdiman, J.P. and Sleisenger, M.H. (2003) Genotype and phenotype of patients with both familial adenomatous polyposis and thyroid carcinoma. Fam. Can., 2(2), 95-99. Cetta, F.; Montalto, G.; Gori, M.; Curia, M.C.; Cama, A. and Olschwang, S. (2000) Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study. J. Clin. Endocrinol. Metab., 85(1), 286-292. Cetta, F.; Olschwang, S.; Petracci, M.; Montalto, G.; Baldi, C.; Zuckermann, M.; Mariani Costantini, R. and Fusco, A. (1998) Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection. World. J. Surg., 22(12), 1231-1236. Groen, E.J.; Roos, A.; Muntinghe, F.L.; Enting, R.H.; de Vries, J.; Kleibeuker, J.H.; Witjes, M.J.; Links, T.P. and van Beek, A.P. (2008) Extra-intestinal manifestations of familial adenomatous polyposis. Ann. Surg. Oncol., 15(9), 2439-2450. Iwama, T.; Mishima, Y. and Utsunomiya, J. (1993) The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs: its rational treatment. Ann. Surg., 217(2), 101-108. Giardiello, F.M.; Offerhaus, G.J.; Lee, D.H.; Krush, A.J.; Tersmette, A.C.; Booker, S.V.; Kelley, N.C. and Hamilton, S.R. (1993) Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut., 34(10), 1394-1396. Plail, R.O.; Bussey, H.J.R.; Glazer, G. and Thomson, J.P.S. (1987) Adenomatous polyposis: an association with carcinoma of the thyroid. Br. J. Surg., 74(5), 377-380. Bülow, C. and Bülow, S. (1997) Is screening for thyroid carcinoma indicated in familial adenomatous polyposis? The Leeds Castle Polyposis Group. Int. J. Colorectal. Dis., 12(4), 240-242. Bülow, S.; Holm, N.V. and Mellemgaard, A. (1988) Papillary thyroid carcinoma in Danish patients with familial adenomatous polyposis. Int. J. Colorectal. Dis., 3(1), 29-31. Perrier, N.D.; van Heerden, J.A.; Goellner, J.R.; Williams, E.D.; Gharib, H.; Marchesa, P.; Church, J.M.; Fazio, V.W. and Larson, D.R. (1998) Thyroid cancer in patients with familial adenomatous polyposis. World. J. Surg., 22(7), 738-743. van der Linde, K.; Vasen, H.F.A. and van Vliet, A.C.M. (1998) Occurrence of thyroid carcinoma in Dutch patients with familial adenomatous polyposis: an epidemiological study and report of new cases. Eur. J. Gastroenterol. Hepatol., 10(9), 777-781. Kelly, M.D.; Hugh, T.B.; Field, A.S. and Fitzsimons, R. (1993) Carcinoma of the thyroid gland and Gardner’s syndrome. Aust. N. Z. J. Surg., 63(6), 505-509. Coletta, G.; Schiacchitano, S.; Palmirotta, R.; Ranieri, A.; Zanella, E.; Cama, A.; Mariani Costantini, R.; Battista, P. and Pontecorvi, A. (1994) Analysis of adenomatous polyposis coli gene in thyroid tumours. Br. J. Cancer., 70(6), 1085-1088. Herraiz, M.; Barbesino, G.; Faquin, W.; Chan-Smutko, G.; Patel, D.; Shannon, K.M.; Daniels, G.H. and Chung, D.C. (2007) Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations. Clin. Gastroenterol. Hepatol., 5(3), 367-373. Harach, H.R.; Williams, G.T. and Williams, E.D. (1994) Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm. Histopathology, 25(6), 549-561. Tomoda, C.; Miyauchi, A.; Uruno, T.; Takamura, Y.; Ito, Y.; Miya, A.; Kobayashi, K.; Matsuzuka, F.; Kuma, S.; Kuma, K. and Kakudo, K. (2004) Cribriform-morular variant of papillary thyroid

[26]

[27]

[28] [29]

[30]

[31]

[32] [33] [34]

[35] [36]

[37] [38]

[39] [40] [41]

[42]

[43] [44]

[45]

[46]

[47]

Triggiani et al. carcinoma: clue to early detection of familial adenomatous polyposis-associated colon cancer. World J. Surg., 28(9), 886-889. Cameselle-Teijeiro, J. and Chan, J.K. (1999) Cribriform-morular variant of papillary carcinoma: a distinctive variant representing the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma? Mod. Pathol., 12(4), 400-411. Soravia, C.; Sugg, S.L.; Berk, T.; Mitri, A.; Cheng, H.; Gallinger, S.; Cohen, Z.; Asa, S.L. and Bapat, B.V. (1999) Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study. Am. J. Pathol., 154(1), 127-135. Hizawa, K.; Iida, M.; Aoyagi, K.; Yao, T. and Fujishima, M. (1997) Thyroid neoplasia and familial adenomatous polyposis/ Gardner’s syndrome. J. Gastroenterol., 32(2), 196-199. Lloyd, K.M. and Dennis, M. (1963) Cowden’s disease: a possible new symptom complex with multiple system involvement. Ann. Intern. Med., 58, 136-142. Campos, F.G.; Habr-Gama, A.; Kiss, D.R.; Atuí, F.C.; Rawet, V.; Goldstein, P.J. and Gama-Rodrigues, J. (2006) Cowden syndrome: report of two cases and review of clinical presentation and management of a rare colorectal polyposis. Curr. Surg., 63(1), 15-19. Orloff, M.S. and Eng, C. (2008) Genetic and phenotypic heterogeneity in the PTEN hamartoma tumor syndrome. Oncogene, 27(41), 5387-5397. Zbuk, K.M. and Eng, C. (2007) Hamartomatous polyposis syndromes. Nat. Clin. Pract. Gastroenterol. Hepatol., 4(9), 492-502. Williard, W.; Borgen, P.; Bol, R.; Tiwari, R. and Osborne, M. (1992) Cowden’s disease: a case report with analyses at the molecular level. Cancer, 69(12), 2969-2974. Botma, M.; Russell, D.I. and Kell, R.A. (2002) Cowden's disease: a rare cause of oral papillomatosis. J. Laryngol. Otol., 116(3), 221-223. Longy, M. and Lacombe, D. (1996) Cowden disease. Report of a family and review. Ann. Genet., 39(1), 35-42. Kacem, M.; Zili, J.; Zakhama, A.; Hadj Youssef, F.; Mahjoub, S.; Boubakri, C. and El May, M. (2000) Multinodular goiter and parotid carcinoma: a new case of Cowden's disease. Ann. Endocrinol. (Paris), 61(2), 159-163. Hildenbrand, C.; Burgdorf, W.H. and Lautenschlager, S. (2001) Cowden syndrome-diagnostic skin signs. Dermatology, 202(4), 362-366. Boutet, G. and Boisserie-Lacroix, M. (1995) Cowden's disease in a young girl: mammographic problems. J. Gynecol. Obstet. Biol. Reprod. (Paris), 24(7), 686-690. Ravi Prakash, S.M.; Suma, G.N. and Goel, S. (2010) Cowden syndrome. Indian. J. Dent. Res., 21(3), 439-442. Cnudde, F.; Boulard, F.; Muller, P.; Chevallier, J. and Teron-Abou, B. (1996) Cowden disease: treatment with acitretine. Ann. Dermatol. Venereol., 123(111), 739-741. Schrager, C.A.; Schneider, D.; Gruener, A.C.; Tsou, H.C. and Peacocke, M. (1998) Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer. Hum. Pathol., 29(1), 47-53. Haibach, H.; Burns, T.W.; Carlson, H.E.; Burman, K.D. and Deftos, L.J. (1992) Multiple hamartoma syndrome (Cowden's disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Am. J. Clin. Pathol., 97(5), 705-712. Fistarol, S.K.; Anliker, M.D. and Itin, P.H. (2002) Cowden disease or multiple hamartoma syndrome - cutaneous clue to internal malignancy. Eur. J. Dermatol., 12(5), 411-421. Stanich, P.P.; Francis, D.L. and Sweetser, S. (2011) The spectrum of findings in Cowden syndrome. Clin. Gastronterol. Hepatol., 9(1), e2-3. Starink, T.M.; van der Veen, J.P.W.; Arwert, F.; de Waal, L.P.; de Lange, G.G.; Gille, J.J. and Eriksson, A.W. (1986) The Cowden syndrome: a clinical and genetic study in 21 patients. Clin. Genet., 29(3), 222-233. Hanssen, A.M.N.; Werquin, H.; Suys, E. and Fryns. J.P. (1993) Cowden syndrome. Report of a large family with macrocephaly and increased severity of signs in subsequent generations. Clin. Genet., 44(6), 281-286. Wirtzfeld, D.A.; Petrelli, N.J. and Rodriguez-Bigas, M.A. (2001) Hamartomatous polyposis syndromes: molecular genetics,

Thyroid Carcinoma and Intestinal Polyposis

[48]

[49]

[50]

[51]

[52] [53]

[54]

[55] [56]

[57] [58] [59]

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4

neoplastic risk, and surveillance recommendations. Ann. Surg. Oncol., 8(4), 319-327. Peutz, J.L.A. (1921) Very remarkable case of familial polyposis of the membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentations of the skin and mucous membrane. Ned. Maandschr. GeneeKd., 10, 134-146. Jeghers, H.; McCusick, V.A. and Katz, K.H. (1949) Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance. N. Engl. J. Med., 241(25), 993-1012. Jenne, D.E.; Reimann, H.; Nezu, J.; Friedel, W.; Loff, S.; Jeschke, R.; Muller, O.; Back, W. and Zimmer, M. (1998) Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat. Genet., 18(1), 38-43. Hemminki, A.; Markie, D.; Tomlinson, I.; Avizienyte, E.; Roth, S.; Loukola, A.; Bignell, G.; Warren, W.; Aminoff, M.; Höglund, P.; Järvinen, H.; Kristo, P.; Pelin, K.; Ridanpä, M.; Salovaara, R.; Toro, T.; Bodmer, W.; Olschwang, S.; Olsen, A.S.; Stratton, M.R.; de la Chapelle, A. and Aaltonen, L.A. (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature, 391(6663), 184-187. Ballhausen, W.G. and Gunther, K. (2003) Genetic screening for Peutz-Jeghers syndrome. Expert. Rev. Mol. Diagn., 3(4), 471-479. Aretz, S.; Stienen, D.; Uhlhaas, S.; Loff, S.; Back, W.; Pagenstecher, C.; McLeod, D.R.; Graham, G.E.; Mangold, E.; Santer, R.; Propping, P. and Friedl, W. (2005) High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum. Mutat., 26(6), 513-519. Lindor, N.M.; McMaster, M.L.; Lindor, C.J.; Greene, M.H. and National Cancer Institute, Division of Cancer Prevention, Community Oncology and Prevention Trials Research Group (2008) Concise handbook of familial cancer susceptibility syndromes– second edition. J. Natl. Can. Inst. Monogr., 38, 1-93. Gammon, A.; Jasperson, K.; Kohlmann, W. and Burt, R.W. (2009) Hamartomatous polyposis syndromes. Best. Pract. Res. Clin. Gastroenterol., 23(2), 219-231. Boseto, F.; Shi, E.; Mitchell, J.; Preddy, J. and Adams, S. (2002) Gastroduodenal intussusceptions due to Peutz-Jeghers syndrome in infancy. Pediatr. Surg. Int., 18(2-3), 178-180. McGarrity, T.J.; Kulin, H.E. and Zaino, R.J. (2000) Peutz-Jeghers syndrome. Am. J. Gastroenterol., 95(3), 596-604. Schreibman, I.R.; Baker, M.; Amos, C. and McGarrity, T.J. (2005) The hamartomatous polyposis syndromes: a clinical and molecular review. Am. J. Gastroenterol., 100(2), 476-490. Ayadi-Kaddour, A.; Bouraoui, S.; Bellil, K.; Bellil, S.; Kchir, N.; Zitouna, M.M.; Haouet, S. (2004) Colonic adenocarcinoma and

Received: 18 March, 2012

Accepted: 22 March, 2012

[60]

[61] [62] [63]

[64]

[65]

[66]

[67]

[68]

[69]

381

bilateral malignant ovarian sex cord tumor with annular tubules in Peutz-Jeghers syndrome. Pathologica., 96(3), 117-120. Brichard, B.; Chantrain, C.; Wese, F.; Gosseye, S. and Vermylen, C. (2005) Peutz-Jeghers syndrome and bilateral ovarian tumors in a 14-year-old girl. J. Pediatr. Hematol. Oncol., 27(11), 621-623. Spigelman, A.D.; Murday, V. and Phillips, R.K.S. (1989) Cancer and the Peutz-Jeghers syndrome. Gut., 30(11), 1588-1590. Reed, M.W.R.; Quayle, A.R.; Harris, S.C. and Talbot, C.H. (1990) The association between thyroid neoplasia and intestinal polyps. Ann. R. Coll. Surg. Engl., 72(6), 357-359. Yamamoto, M.; Hoshino, H.; Onizuka, T.; Ichikawa, M.; Kawakurbo, A. and Hayakawa, S. (1992) Thyroid papillary adenocarcinoma in a woman with Peutz-Jeghers syndrome. Int. Med., 31(9), 1117-1119. Boardman, L.A.; Thibodeau, S.N.; Schaid, D.J.; Lindor, N.M.; McDonnell, S.K.; Burgart, L.J.; Ahlquist, D.A.; Podratz, K.C.; Pittelkow, M. and Hartmann, L.C. (1998) Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann. Intern. Med., 128(11), 896-899. Zirilli, L.; Benatti, P.; Romano, S.; Roncucci, L.; Rossi, G.; Diazzi, C.; Carani, C.; Ponz De Leon, M. and Rochira, V. (2009) Differentiated thyroid carcinoma (DTC) in a young woman with Peutz- Jeghers syndrome: are these two conditions associated? Exp. Clin. Endocrinol. Diab., 117(5), 234-239. Yalçin, .; Kirli, E.; Ciftci, A.O.; Karnak, .; Resta, N.; Bagnulo, R.; Akçören, Z.; Orhan, D. and enocak, M.E. (2011) The association of adrenocortical carcinoma and thyroid cancer in a child with Peutz-Jeghers syndrome. J. Pediatr. Surg., 46(3), 570-573. Triggiani, V.; Guastamacchia, E.; Renzulli, G.; Giagulli, V.A.; Tafaro, E.; Licchelli, B.; Resta, F.; Sabbà, C.; Bagnulo, R.; Lastella, P.; Stella, A. and Resta, N. (2011) Papillary Thyroid Carcinoma in Peutz-Jeghers Syndrome. Thyroid, 21(11), 1273-1277. Kim, D.; Chung, H.; Park, K.; Hwang, J.H.; Jo, Y.S.; Chung, J.; Kalvakolanu, D.V.; Resta, N.; Shong, M. (2007) Tumor suppressor LKB1 inhibits activation of signal transducer and activator of transcription 3 (STAT3) by thyroid oncogenic tyrosine kinase rearranged in transformation (RET)/papillary thyroid carcinoma (PTC). Mol. Endocrinol., 21, 3039-3049. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer; Cooper, D.S.; Doherty, G.M.; Haugen, B.R.; Kloos, R.T.; Lee, S.L.; Mandel, S.J.; Mazzaferri, E.L.; McIver, B.; Pacini, F.; Schlumberger, M.; Sherman, S.I.; Steward, D.L. and Tuttle, R.M. (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19(11), 1167-1214.