Accepted 20 March 2009 Published online 17 June 2009 in Wiley InterScience ( DOI: /hed.21156

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1 CLINICAL REVIEW David W. Eisele, MD, Section Editor DIFFERENTIATED THYROID CANCER ASSOCIATED WITH INTESTINAL POLYPOSIS SYNDROMES: A REVIEW William J. Harb, MD, 1 Erich M. Sturgis, MD, MPH 2,3 1 Department of Surgery, Baptist Hospital, 2011 Church Street, Suite 703, Nashville, Tennessee billharb@yahoo.com 2 Department of Head and Neck Surgery, Unit 1445, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030; esturgis@mdanderson.org 3 Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas Accepted 20 March 2009 Published online 17 June 2009 in Wiley InterScience ( DOI: /hed Abstract: Intestinal polyposis syndromes, such as familial adenomatous polyposis (FAP) and Cowden s syndrome, are often associated with extraintestinal manifestations, and while many of these manifestations are benign, malignant extraintestinal manifestations, such as differentiated thyroid cancers, do occur. Although differentiated thyroid cancers (ie, papillary and follicular thyroid carcinomas) are associated with multiple syndromes, they are most commonly associated with intestinal polyposis syndromes. In the general population, the probability of developing thyroid cancer by age 65 years is only.5%. However, 1% to 2% of patients with FAP develop papillary thyroid carcinoma, the most common extraintestinal malignancy in patients with FAP. Also, up to 10% of patients with Cowden s syndrome will develop follicular thyroid carcinoma. The purpose of this review was to provide an overview of FAP, Cowden s syndrome, and Peutz-Jeghers syndrome, to discuss in detail the associations between intestinal polyposis syndromes and differentiated thyroid cancers, and to provide suggestions for screening and managing these diseases. VC 2009 Wiley Periodicals, Inc. Head Neck 31: , 2009 Correspondence to: W. J. Harb. or E. M. Sturgis VC 2009 Wiley Periodicals, Inc. Keywords: Cowden s syndrome; cribriform-morular variant papillary thyroid cancer; familial adenomatous polyposis; Peutz- Jeghers syndrome; thyroid cancer Intestinal polyposis syndromes, such as familial adenomatous polyposis (FAP), Cowden s syndrome, and Peutz-Jeghers syndrome, are often associated with extraintestinal manifestations, which include differentiated thyroid cancers (ie, papillary and follicular thyroid carcinomas). About 1% to 2% of patients with FAP develop papillary thyroid carcinoma (PTC), and up to 10% of patients with Cowden s syndrome will develop follicular thyroid carcinoma (FTC). The purpose of this review was to provide an overview of FAP, Cowden s syndrome, and Peutz-Jeghers syndrome, to discuss in detail the associations between intestinal polyposis syndromes and differentiated thyroid cancers, and to provide suggestions for screening and managing these diseases. Thyroid Cancer in Intestinal Polyposis Syndromes HEAD & NECK DOI /hed November

2 FAMILIAL ADENOMATOUS POLYPOSIS FAP, formerly known as familial polyposis coli or adenomatous polyposis coli, is the prototypical intestinal polyposis syndrome. It is one of the most well-known inherited colorectal cancer syndromes; it was first described in 1882 by Cripps. 1 Of the 154,000 cases of colorectal cancer diagnosed in the United States annually, approximately 1% is due to FAP. 2 FAP is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and has an incidence of approximately 1/10,000. FAP is caused by a mutation of the adenomatous polyposis coli gene (APC), located on chromosome 5, which is inherited in an autosomal dominant manner. Men and women are equally affected, and a child of a parent with FAP has a 50% chance of inheriting the mutation. However, in the 20% to 30% of patients with FAP who do not have a family history of FAP, the mutation in the APC gene has arisen de novo. 3 In fact, a review of the FAP registry at the Cleveland Clinic revealed that 22% of cases were due to a spontaneous mutation. 4 Because colorectal polyps are not always symptomatic, the first manifestation of FAP or clue to its diagnosis may be colorectal cancer or an extraintestinal manifestation such as thyroid cancer. In patients with FAP, colonic polyps develop early in life, at a median age of 16 years with a range of 5 to 38 years. 5 The penetrance of the mutated APC is almost 100%; in other words, essentially every patient with the mutation will develop polyps and, without prophylactic colectomy, colorectal cancer. In patients who do not undergo prophylactic colectomy, the mean age at diagnosis of colorectal cancer is 39 years, and the mean life expectancy is 42 years. 6 Screening in patients with FAP should therefore begin at puberty with flexible sigmoidoscopy, and colonoscopy should be done when adenomatous polyps are identified. Colectomy is indicated by the development of endoscopically unmanageable or dysplastic polyps. Surgical options for patients with FAP include total abdominal colectomy, total proctocolectomy with end-ileostomy, total proctocolectomy with Kock pouch, and total proctocolectomy with ileal pouch anal anastomosis. Although the choice of procedure is beyond the scope of this review, these options are reviewed in detail elsewhere. 2 Prevalence of PTC in Patients with FAP. In 1949, Crail 7 first described the association of FAP and PTC; thereafter, multiple reports of PTC associated with FAP were published. 5,8 11 Estimates using data from several series suggest that differentiated thyroid cancer occurs in 1% to 2% of patients with FAP, making it the most common extraintestinal malignancy in these patients 8,9 (Table 1). In their summary of 62 registries of 3727 patients with FAP worldwide, Bülow et al 12 found the prevalence of PTC to be 1.2% (44 women and 1 man), and these authors had previously estimated the risk of PTC in women with FAP to be approximately 100-fold that of women without FAP. 15 In a review of almost 1200 patients in the hereditary cancer registries from the University of California, San Francisco, and the Familial Gastrointestinal Cancer Registry, Toronto, Truta et al 10 found that only 16 had both PTC and FAP, yielding a 1.3% prevalence of PTC among patients with FAP. Germline DNA analysis later identified APC Table 1. Crude thyroid cancer prevalence in large series of patients with familial adenomatous polyposis. No. of patients, % DTC subtype Mean age, First author Year Location Total DTC PTC Mixed FTC Multifocal y F:M ratio Plail United Kingdom (0.7) (28.6) :0 Iwama Japan (1.1) NR NR NR NR :2 Giardiello United States (0.4) NR :1 Bülow 12 * 1997 Worldwide (1.2) 37 NR 3 20 (44.4) :1 Perrier United States (0.4) (66.7) :1 van der Linde Holland (0.7) NR :0 Truta United States/Canada (1.3) (68.8) :0 Abbreviations: DTC, differentiated thyroid cancer; PTC, papillary thyroid cancer; FTC, follicular thyroid cancer; F:M, female-to-male; NR, not reported. *Bülow series includes patients from numerous registries around the world and thus likely has some overlap with the other series listed here. Also, the age reported for this series is the median age Thyroid Cancer in Intestinal Polyposis Syndromes HEAD & NECK DOI /hed November 2009

3 mutations in 12 of 13 of these patients. In a St. Mark s series of almost 1000 patients with FAP, only 7 (.7%) developed PTC; however, the authors estimated that female patients with FAP younger than 35 years had a 160-fold increased risk of PTC when compared with those without FAP. 11 In a series of 1050 patients with FAP from Japan, Iwama et al 8 identified 11 (1.1%) patients with PTC, estimated the increased risk of PTC in women with FAP to be only 23-fold that of women without FAP, and suggested that, for unknown reasons, PTC occurs less frequently in Japanese patients with FAP than in non-japanese patients with FAP. However, others have reported similar relative risks in Western populations for PTC among patients with FAP. 9 Differences Between FAP-Associated and Sporadic PTC. Several clinical differences between FAPassociated and sporadic PTC may help the clinician diagnose a previously unsuspected case of FAP. PTC associated with FAP typically occurs before the age of 30. 9,13,14,16,17 Additionally, PTC associated with FAP has a 20:1 female:male ratio. 18 In fact, some have commented that PTC associated with FAP occurs almost exclusively in women. However, women are only 2 to 3 times more likely than men to develop sporadic PTC, a much smaller sex-related disparity than in patients with PTC associated with FAP. Another characteristic of FAP-associated PTC is its propensity for multicentricity, similar to other inherited thyroid carcinomas. Truta et al 10 reported that 11 (69%) of 16 PTCs in patients with FAP were multicentric, and Coletta et al 19 found a 2-fold higher than expected incidence of multifocality in PTC in patients with FAP. In Perrier et al s 13 series of 12 patients with FAP associated with PTC, 8 had multicentric tumors (66%), and 5 (42%) had bilateral tumors. Also, Herraiz et al 20 reported that all 6 patients with FAP associated with PTC in their series had multifocal disease, and 4 of them had bilateral disease. For the surgeon treating PTC in a patient with FAP, these findings would suggest that a total thyroidectomy is needed. 21 Additionally, a pathologic finding of multifocal PTC in patients without a diagnosis of FAP should raise the suspicion of a genetically associated thyroid carcinoma, particularly for young women. 18 Cribriform-morular PTC, a specific pathologic variant of PTC, occurs much more commonly in patients with FAP than in the general population and may be a clue to the diagnosis of FAP. Histologically, the cribriform-morular variant is characterized by the blending of cribriform, morular, trabecular, follicular, and papillary architecture. This unusual histologic appearance can lead to the variant s being pathologically misdiagnosed as a more aggressive, poorly differentiated thyroid carcinoma 22 (Figure 1). Harach et al 21 described cribriformmorular PTC in multiple patients with FAP but, it occurs in fewer than 1 in 1000 sporadic PTC cases. 23 In fact, it was not until 1999 that Cameselle-Teijeiro and Chan 24 described an apparently sporadic case of cribriform-morular PTC. When Tomoda et al 23 reviewed all of the 4194 patients diagnosed with PTC for more than 11 years from a single institution, they found only 7 patients (.16%) had the cribriformmorular variant of PTC and of whom all were women aged 16 to 32 years old. Of these 7 women, 2 were diagnosed with FAP, 1 refused testing for FAP but had a family member with FAP, and 4 had neither a clinical history of FAP nor an APC mutation. In the Herraiz et al 20 series, all 6 patients with FAP associated with PTC were women with the cribriform-morular variant; the mean age at diagnosis was 33 years. In the series reported by Perrier et al, 13 a pathologic re-review of 12 tumors identified 11 tumors histologically consistent with the cribriform-morular variant. Because of the rarity of the cribriform-morular variant and its strong association with FAP, the finding of this variant of PTC should lead to screening for FAP, especially in a young female patient. Survival in Patients with PTC and FAP. Although disease-specific and recurrence-free survival of patients with FAP with PTC were traditionally thought to be very good, only small case series exist on which to be these conclusions. In Iwama et al s 8 series, no thyroid cancer deaths were reported in 11 patients with FAP-associated PTC. With a median follow-up of 60 months, Tomoda et al 23 reported no recurrent thyroid cancer in a series of 7 patients with cribriform-morular variant PTC of whom 3 were associated with FAP. Cetta et al 18 noted that patients with FAP-associated PTC have excellent survival, although neither mean nor median survival was reported, and the survival data for 6 of 15 patients were not available. In Thyroid Cancer in Intestinal Polyposis Syndromes HEAD & NECK DOI /hed November

4 FIGURE 1. The histologic features of the cribriform-morular variant of PTC as published by Dalal et al. 22 The features are as follows: upper left: cribriform; upper right: papillary; lower left: hyalinized areas; lower right: islands of squamoid and spindle cells (morules as delineated by the arrows). Reprinted with permission of John Wiley & Sons, Inc. contrast to these reports suggesting excellent survival, Perrier et al 13 reported that 5- and 20- year disease-specific survival rates were lower than expected after adjustment for age and sex in a log-rank analysis. Although all 12 patients had disease stages associated with low risks for recurrence and an expected 99% 20-year disease-specific survival rate, their 20-year diseasespecific survival rate was only 77%. Screening for FAP in Patients with PTC. PTC may precede the diagnosis and be the first manifestation of FAP 11,12 ; therefore, in young patients (especially young women) presenting with PTC, FAP should be considered as a possible diagnosis. Of patients who have both FAP and PTC, approximately one-third are diagnosed with FAP first, about one-third are diagnosed with both simultaneously, and the remaining are FIGURE 2. Genotype phenotype correlations of extraintestinal FAP manifestations as depicted by Groen et al 26 for the APC gene which consists of 15 exons. CHRPE-congenital hypertrophy of retinal pigment epithelium. With kind permission from Springer Science and Business Media Thyroid Cancer in Intestinal Polyposis Syndromes HEAD & NECK DOI /hed November 2009

5 diagnosed with PTC first. 12,16 However, given the rarity of PTC in patients with FAP and FAP in patients with PTC, whether all female patients with PTC diagnosed before age 35 should be referred for colonoscopy is unclear. Certainly, a young patient with both PTC and a family history of colorectal carcinoma or polyps should undergo a colonoscopy for screening. Screening for PTC in Patients with FAP. No formal prospective studies that we are aware of have evaluated whether all patients with FAP should undergo ultrasonographic screening for thyroid cancer; however, the clinician should always at least palpate the thyroid in patients with FAP and maintain a low threshold for using screening ultrasonography, which is both safe and relatively inexpensive. In a retrospective study, Herraiz et al 20 explored the feasibility of screening for PTC in 51 patients with FAP at the Massachusetts General Hospital. Six women were identified with PTC (prevalence, 19% of women), and the mean age at PTC diagnosis was 33 years (median, 29.5 years). One 19-year-old patient diagnosed with FAP after pathologic review revealed that she had the cribriform-morular variant of PTC. Moreover, 3 of 6 patients were diagnosed because they were symptomatic with a mass of the thyroid; however, the other 3 were identified by screening, 1 by physical examination, and 2 by thyroid ultrasonography. Because of these findings and the relatively high incidence of PTC in patients with FAP, Herraiz et al 20 have recommended thyroid ultrasonography for all patients with FAP over age 16. Hizawa et al 25 detected thyroid tumors ultrasonographically in 2 of 8 patients (25%); these authors also advocate the liberal use of thyroid ultrasonography in patients with FAP. However, others have not shared this view. Because of the good prognosis of PTC and low incidence of PTC in 1050 patients with FAP, Iwama et al 8 did not believe that the benefits of screening for occult PTC outweighed the costs. Similarly, van der Linde et al 14 found only 4 patients (all females) with differentiated thyroid cancer in a series of 601 patients with FAP, and thus only recommended periodic physical examination of the thyroid in patients with FAP. To help clarify this issue, inherited colorectal cancer registries are considering PTC screening programs for patients with FAP. No authors whom we are aware of have recommended prophylactic thyroidectomy, 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. Genetics of FAP-Associated PTC. Patients with variants of FAP, such as Gardner s and Turcot s syndromes, have intestinal polyposis and numerous different extraintestinal manifestations, such as dental abnormalities, brain tumors, hepatoblastomas, gastric polyps, duodenal adenomas and carcinomas, desmoid tumors, osteomas, congenital hypertrophy of the retinal pigment epithelium, and PTC. It was suggested that the phenotypic pattern of these extraintestinal manifestations is predicted by the site of the mutation within the APC gene 10,16,18,26 (Figure 2). Cetta et al 18 retrospectively studied 15 patients with FAPassociated thyroid carcinoma; 13 of 15 patients had mutations in the APC gene between codons 778 and 1309 in 5 0 end of exon 15. Truta et al 10 similarly screened 16 patients with both FAP and PTC and found germline APC mutations in 12 of 13 patients tested with 10 of these within exon 15 (8 in the 5 0 end). The majority of these APC mutations associated PTC appear to be proximal to the mutation cluster region (codons ) of most patients with FAP but with significant overlap with the APC gene region (codons ) associated with hypertrophy of the retinal pigment epithelium For instance, in Cetta et al s 18 study, 14 of 15 patients had mutations in this region of the APC gene, and fundoscopic examination revealed that 12 of these 14 patients had retinal pigment hypertrophy. In Truta et al s 10 study, 9 of the 12 APC mutations were within this region, yet only 3 had documented retinal pigment hypertrophy. Thus, it may be possible to use fundoscopy to screen patients with FAP for retinal pigment hypertrophy to identify those at elevated risk for PTC. However, as germline testing with DNA sequencing is now available on those with an established diagnosis of FAP, it could also be argued that mutation site (5 0 end of exon 15) should direct PTC screening. 16 Others argue for multi-institutional studies to confirm these associations before targeted PTC screening among patients with FAP can be recommended. 10 Alternatively, it may be possible to augment efforts Thyroid Cancer in Intestinal Polyposis Syndromes HEAD & NECK DOI /hed November

6 to identify undiagnosed patients with FAP by subjecting young women with PTC to fundoscopic screening for retinal pigment hypertrophy rather than colonoscopy. The overwhelming majority of PTC tumors have somatic BRAF mutations or Ret-PTC rearrangements with Ret-PTC rearrangements being particularly common among radiationassociated PTC. 29 The Ret-PTC rearrangement oncogene was studied in the FAP-associated PTC tumors. In the 4 tumors Cetta et al 18 evaluated from 4 patients with FAP-associated PTC, Ret-PTC 1, the most common of the 3 isoforms of the oncogene, was activated in 3. Soravia et al 30 screened tumors from 3 patients with FAP-associated PTC for Ret-PTC gene rearrangements; all 3 patients were positive for Ret-PTC 1,1was also positive for Ret-PTC 3, and none were positive for Ret-PTC 2. Whether FAP-associated PTC tumors have BRAF mutations, which are common to many sporadic PTC tumors, has not been studied. COWDEN S SYNDROME Cowden s syndrome is an intestinal polyposis syndrome characterized by the development of hamartomatous polyps and is inherited in an autosomal dominant manner. Cowden s, Bannayan-Riley-Ruvalcaba, and Proteus syndromes involve mutations in the phosphatase and tensin homolog gene (PTEN), located on chromosome 10, and these 3 syndromes are collectively known as PTEN hamartoma tumor syndrome. 6,31,32 Cowden s syndrome was first described in 1963 by Lloyd and Dennis 33 and named for the first patient described with the disease. Fewer than 200 cases were reported over the 4 decades since the initial report. 33,34 Cowden s syndrome is more common in women (60% of cases) and has a mean age at diagnosis of 39 years. 35 In contrast to the adenomatous polyps associated with FAP, the hamartomatous polyps of Cowden s syndrome are not thought to be premalignant. The most characteristic findings in Cowden s syndrome are skin changes, which include trichilemmomas, palmoplantar keratoses, and oral mucosal papillomatoses. Additionally, small papules may be found on the face and distal extremities. 34 Malignancies associated with Cowden s syndrome most commonly include breast, skin, and differentiated thyroid cancer. 6 Differentiated thyroid cancer, predominantly follicular, is the second most frequent carcinoma after breast cancer to occur in patients with Cowden s syndrome. 32 Benign thyroid conditions, including multinodular goiter and adenomas, are the most common noncutaneous manifestations of Cowden s syndrome in 50% to 67% of patients and are much more common than differentiated thyroid cancer. 18,35 The association between differentiated thyroid cancer and Cowden s syndrome was evaluated by multiple authors, and differentiated thyroid cancer is thought to occur in approximately 10% of patients. Starink et al 36 noted a 10% incidence of differentiated thyroid cancer in 21 patients with Cowden s syndrome, and in a review of 98 patients with Cowden s syndrome, Hanssen et al 37 identified 7 patients (7%) with differentiated thyroid cancer. Harach et al 38 described the pathologic findings in 11 patients with Cowden s syndrome who underwent thyroidectomy for a goiter. The series of patients consisted of 6 women and 5 men with a mean age of 26 years, and the most common pathologic finding was multifocal follicular adenomas. Of the 5 patients who underwent partial thyroidectomy, FTC subsequently developed in the residual lobe in 2 patients, prompting the recommendation for total thyroidectomy in all patients with Cowden s syndrome undergoing thyroidectomy. 38 No guidelines have been published regarding the screening for FTC in patients with Cowden s syndrome. However, some authors believe that yearly physical examination of the thyroid, coupled with thyroid ultrasonography every 1 to 2 years, is a reasonable precaution given the relatively high risk for FTC in these patients. 39 Although the incidence of FTC is likely 5- to 10- fold higher in Cowden s syndrome patients than that of PTC in patients with FAP, prophylactic thyroidectomy is unlikely to be justifiable given the typically excellent prognosis of FTC and the low morbidity and cost of serial FTC screening. The prognosis of FTC associated with Cowden s syndrome is not known because of the uncommon entity. Clinicians encountering FTC in a young patient (particularly multifocal FTC or FTC associated with multiple follicular adenomas) should consider Cowden s syndrome and look for the classic cutaneous and mucosal findings. Because breast cancer risk is higher in 1516 Thyroid Cancer in Intestinal Polyposis Syndromes HEAD & NECK DOI /hed November 2009

7 these patients and such breast cancers are commonly diagnosed at an earlier age, are bilateral and have nodal metastases, enhanced breast cancer screening is recommended in patients with Cowden s syndrome. 36,37 PEUTZ-JEGHERS SYNDROME Peutz 40 first described the findings of mucosal hyperpigmentation and gastrointestinal polyps, and 23 years later, Jeghers 41 reported more patients with the same disease characteristics. Peutz-Jeghers syndrome is known as an intestinal polyposis syndrome characterized by the development of hamartomatous polyps throughout the gastrointestinal tract along with mucocutaneous hyperpigmentation. Similar to the other intestinal polyposis syndromes, Peutz-Jeghers syndrome is inherited in an autosomal dominant fashion. A germline point mutation in the serine-threonine kinase 11 gene (STK11) located on chromosome 19 (19p13.3) is the genetic basis of the syndrome. 42 Approximately 70% of patients with a family history of Peutz-Jeghers syndrome will have an STK11 mutation; however, only 20% to 30% of patients with Peutz-Jeghers syndrome lacking a family history will have an STK11 mutation. 43 The most easily recognizable aspect of Peutz- Jeghers syndrome is hyperpigmentation, which develops most commonly on the lips (95%) but may also be found on the buccal mucosa (83%). Interestingly, lip pigmentation fades with age, but buccal hyperpigmentation does not. 44 As with other intestinal polyposis syndromes, patients with Peutz-Jeghers syndrome are at an increased cumulative risk for both intestinal and extraintestinal malignancies, including breast (54%), colon (39%), pancreatic (36%), gastric (29%), and ovarian (21%) cancer, but apparently not thyroid cancer. 45,46 Peutz-Jeghers syndrome is most commonly diagnosed in the third decade of life, and there is no sex disparity. 43 Peutz-Jeghers syndrome is very uncommon, with a wide range of incidence reported (from 1/25,000 to 1/300,000). 47 Three cases of thyroid cancer in patients with Peutz-Jeghers syndrome have been reported. In the first, a 22-year-old Japanese woman was diagnosed with Peutz-Jeghers syndrome after having a laparotomy with small bowel resection for an intussusception, though the characteristic mucocutaneous pigmentation changes were noted at age 4. More than 20 hamartomatous polyps were identified in the surgical specimen. At age 29, a thyroid mass was found, and the patient underwent a subtotal thyroidectomy, which revealed PTC. 48 In a report by Spigelman et al, 49 malignant tumors were diagnosed in 16 of 72 patients with Peutz- Jeghers syndrome, and 1 of these was unspecified thyroid cancer. Boardman et al 50 briefly mentioned a single thyroid cancer in a report of 26 noncutaneous cancers arising in 34 patients with Peutz-Jeghers syndrome. Thyroid cancer is not part of the known spectrum of Peutz-Jeghers syndrome, and these 3 thyroid cancers may be coincidental. Although some may find the similarities to other intestinal polyposis syndromes and a potential link to thyroid cancer intriguing, to our knowledge, no formal studies of the association have been conducted. CONCLUSIONS Although differentiated thyroid cancer associated with intestinal polyposis syndromes is uncommon, the association should not be overlooked. Approximately 1% to 2% of patients with FAP will develop PTC, and between 7% and 10% of patients with Cowden s syndrome will develop FTC. PTC may precede the development of FAP; therefore, the diagnosis of PTC in a young female patient (particularly if the PTC is multifocal or of the cribriform-morular variant) should arouse a suspicion of FAP and an awareness of the possibly increased risk for colorectal carcinoma. Similarly, FTC in a young patient (particularly if it is multifocal or associated with multiple follicular adenomas) should raise a suspicion of possibly undiagnosed Cowden s syndrome and a possibly elevated risk for breast cancers. Careful serial examination of the thyroid with ultrasonography should be considered for all patients with a known diagnosis of FAP (especially young women, those with hypertrophy retinal pigment epithelium, or those with an APC mutation in the 5 0 end of exon 15) or Cowden s syndrome. Total thyroidectomy is the treatment of choice for differentiated thyroid cancer occurring in patients with intestinal polyposis syndrome. Acknowledgments. The authors thank Angelique Geehan for the assistance in editing the manuscript, and Dr. James Church and Thyroid Cancer in Intestinal Polyposis Syndromes HEAD & NECK DOI /hed November

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