LETTER TO THE EDITOR Screening for Thyroid Cancer in Patients With Familial Adenomatous Polyposis To the Editor: arrar et al,1 in an attempt to clarify the incidence of thyroid cancer in patients with familial adenomatous polyposis (FAP), offered thyroid ultrasonography to every FAP patient in their registry. Actually, of 487 FAP patients undergoing annual gastrointestinal surveillance, 192 FAP patients participated in the thyroid ultrasonographic screening. They included 88 men with a mean age of 40 (range = 11–70) years and 104 women with a mean age of 41 (range = 12–76) years. Of the 192 screened patients, 72 (38%) had thyroid nodules and 5 (2.6%) had thyroid cancer. There were 3 women (aged 35, 55, and 60 years) and 2 men (aged 27 and 45 years). One patient had the cribriform-morular variant (C-MV), whereas the other had the conventional variant. In these patients, papillary thyroid carcinoma (PTC) would remain undetected in the absence of intensive screening. In addition, in a retrospective review of thyroid cancer cases reported in their FAP registry, 14 of 664 (2.1%) were found to have thyroid cancer. Eleven of 14 (89%) were female patients. The study is interesting because it is the first prospective study attempting to detect previously undetected thyroid cancer in FAP subjects. We would like to make some comments on the basis of our extensive experience on this subject.2–8 We were the first to show, as Jarrar et al recognize, a significant genotype-phenotype correlation, suggesting that most of APC germline mutations in patients with FAPassociated PTC are located in a well-defined genomic area.2–4 During the last decade, we have continued (1) to recruit FAP-associated PTC, (2) to follow up those previously collected, and (3) to collect all available data from the literature. In our review of the various series (often including just 1 or 2 cases), we could document that, whereas in our first report on FAPassociated PTCs,2 the prevalence for females was 17:1, after year 2000, there was a striking increase (female to male ratio = 80:1 vs 2.5–3:1 in sporadic tumors). More than 80%
J
Disclosure: No conflicts and no funding received for this letter. C 2014 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/14/26101-e0013 DOI: 10.1097/SLA.0000000000000442
of PTCs were diagnosed between 18 and 35 years of age; in an overall series of 200 cases reported in the literature (112 before 2000 and about 90 after this year), there were very few recurrences and only one death, possibly related to FAP-associated PTC.2–8 In particular, there was no recurrence in 9 of our patients, with a follow-up longer than 15 years (180 months) in every subject. In fact, whereas tumors in the colon rectum occur invariably in almost 100% of subjects with APC germline mutations, with no prevalence for any sex with the same incidence in males and females (and in most colorectal polyps or cancer, there is a complete loss of the APC germline function documented by the high rate of loss of hetherozigosity (LOH) for APC in the tumoral tissue), thyroid papillary carcinoma occurs in a minority of affected subjects, in the absence of LOH for APC6 and almost invariably in the female sex.8 This is a very unusual finding in an inherited multitumoral syndrome. There is no doubt that PTC is part of the multitumoral syndrome due to germline mutations of a tumor suppressor gene as APC. In fact, there is a frequent association of PTC in siblings with the same germline mutation. Interestingly, all the 23 siblings reported up to now were females. There is a statistically significant association between PTC and the site of the germline mutation.2 However, the absence of complete inactivation of the gene5,6 suggests that the germline mutation of the APC gene confers only a generic susceptibility to thyroid cancer, but perhaps other factors, namely, modifier genes, sex-related factors (hormonal, but also dietary, metabolic, immunological), or environmental factors,8 are also required for the phenotypic expression. It is likely that FAP-associated PTC represents a veritable example of cooperation between purely inherited factors (APC germline mutation) and epigenetic or environmental factors, namely, those strictly connected with the female sex, as the striking female to male ratio of 80:1 strongly suggests. It must be outlined that PTC in patients with FAP may have distinct histological features, namely, the C-MV, which are different from features of conventional PTC. C-MV represents 0.1% to 0.2% of all PTCs, but it has been reported with an impressive prevalence in FAP patients (>60%). As Jarrar et al suggest, this may raise the question as to whether the non–C-MV thyroid cancers are truly associated with FAP or just sporadic. In our personal series of 18 FAP-associated PTCs, a clear C-MV was detected in 9 cases, whereas conventional PTC was present in 7 (the last 2 had other variants). These data are only partly in accordance with
Annals of Surgery r Volume 261, Number 1, January 2015
the finding of the Jarrar group of only one patient (out of 4 or 5) showing the typical feature of C-MV PTC. The last comment concerns the mean age of patients. In our first report, it was 24.8 years in a series of 15 female patients, but it also was 24.8 years in a series of 97 patients collected from the literature.2 The mean age has been similar in the 81 patients reported in the literature after 2000. Therefore, in addition to histological variants, demographic features reported by Jarrar et al (3 women aged 35–45 and 60 years and 2 men, aged 27 and 45, respectively) are also different from data in the literature. The main criticism that can be raised in the interpretation of the findings of Jarrar et al concerns the significance of these data. In fact, even if a thyroid nodule with positive diagnosis after fine needle aspiration biopsy (FNAB) can be first detected at 60 years of age in a FAP patient with APC germline mutations, we think that this is an exception, because the great majority (>80%) of FAP PTCs occur between 18 and 35 years of age, quite exclusively in females, namely, those with congenital hypertrophy of the retinal pigment epithelium (CHRPE), or with an APC germline mutation in the 5 portion of the gene.2 We suspect that demographic differences between the data of Jarrar et al and those from the literature could be due, at least partly, to a different (and maybe opposite) approach to data collection. In fact, on one hand, it could be that the literature has a “publication bias,” which facilitates the selection of single case reports, mainly concerning the so-called C-MV (which in some cases was the clue for the diagnosis of a previously undetected FAP kindred).9 Therefore, demographic and pathological features of literature cases are usually typical of this variant. On the other hand, there is the approach of Jarrar et al, an intensive screening for thyroid nodules in completely asymptomatic subjects, excluding “a priori” patients who are easy to diagnose, who are representative of the average presentation of the disease. Does the latter approach facilitate the detection of a population with different characteristics. Is it the same disease? That is the question. We could suggest caution before stating that malignant nodules detected by Jarrar et al belong to the same disease and have the same biological behavior as FAP PTCs reported in the literature. On the contrary, it could be a different disease, occurring because of different factors, acting in FAP subjects in different age periods, namely, after the occurrence of colonic polyps and even colorectal cancer. Only a detailed pathological and genetic analysis of these nodules (LOH for APC,
www.annalsofsurgery.com | e13
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 1, January 2015
Cetta et al
RET/PTC activation, immunostaining for β-catenin, search for BRAF mutations, the precise detection of the histological variant), and demographic data including patient history, and the description of the exact germline mutation could help unravel “which is which” and could answer the question as to whether these tumors are exactly the same as those reported in the literature as “typical FAP-associated PTCs.” This information will greatly contribute to a deeper insight into this intriguing extracolonic manifestation of FAP. Concerning the actual prevalence of PTC in FAP patients, Jarrar et al suggest a possible incidence of 2.6% (intensive screening) or 2.1%. This is an increased value in comparison with the previously reported data (1.2% or even 1.1%),2,9 which were an underestimation of the actual rate, even if recent data from other studies using intensive screening in superselected populations reported very high values (up to 12%).10 We deem that a 2% to 5% prevalence of PTC in FAP patients could be a more realistic value in the present era of improved early diagnosis.
e14 | www.annalsofsurgery.com
Francesco Cetta, MD IRCCS MultiMedica Milan, Italy [email protected] Gabriele Ugolini, MD Jacopo Martellucci, MD Giuseppe Gotti, MD Department of Surgery University of Siena Siena, Italy [email protected]
REFERENCES 1. Jarrar AM, Milas M, Mitchell J, et al. Screening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg. 2011;253:515–521. 2. Cetta F, Montalto G, Gori M, et al. 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. 2000;85:286–282. 3. Cetta F, Pelizzo MR, Curia MC, et al. Genetics and clinicopathological findings in thyroid carcinoma associated with familial adenomatous polyposis. Am J Pathol. 1999;155:7–9. 4. Cetta F, Dhamo A. Inherited multitumoral syndromes including colorectal carcinoma. Surg Oncol. 2007;16:S17–S23.
5. Cetta F, Dhamo A, Malagnino G, et al. Germline and somatic mutations of the APC gene and/ or beta-catenin gene in the occurrence of FAP associated thyroid carcinoma. World J Surg. 2007;31:1366–1367. 6. Cetta F, Curia MC, Montalto G, et al. Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene. J Clin Endocrinol Metab. 2001;86:427– 432. 7. Cetta F, Chiappetta G, Melillo RM, et al. The ret/ptc1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas. J Clin Endocrinol Metab. 1998;83:1003– 1006. 8. Cetta F, Dhamo A, Civitelli S, et al. Comment on “Extra-intestinal manifestations of familial adenomatous polyposis” Ann Surg Oncol. 2009;16:1446–1448. 9. Tomoda C, Miyauchi A, Uruno T, et al. Cribriform-morular variant of papillary thyroid carcinoma: clue to early detection of familial adenomatous polyposis-associated colon cancer. World J Surg. 2004;28:886– 889. 10. Herraiz M, Barbesino G, Faquin W, et al. Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations. Clin Gastroenterol Hepatol. 2007;5:367–373.
C 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J
Disclosure: No conflicts and no funding received for this letter. C 2014 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/14/26101-e0013 DOI: 10.1097/SLA.0000000000000442
of PTCs were diagnosed between 18 and 35 years of age; in an overall series of 200 cases reported in the literature (112 before 2000 and about 90 after this year), there were very few recurrences and only one death, possibly related to FAP-associated PTC.2–8 In particular, there was no recurrence in 9 of our patients, with a follow-up longer than 15 years (180 months) in every subject. In fact, whereas tumors in the colon rectum occur invariably in almost 100% of subjects with APC germline mutations, with no prevalence for any sex with the same incidence in males and females (and in most colorectal polyps or cancer, there is a complete loss of the APC germline function documented by the high rate of loss of hetherozigosity (LOH) for APC in the tumoral tissue), thyroid papillary carcinoma occurs in a minority of affected subjects, in the absence of LOH for APC6 and almost invariably in the female sex.8 This is a very unusual finding in an inherited multitumoral syndrome. There is no doubt that PTC is part of the multitumoral syndrome due to germline mutations of a tumor suppressor gene as APC. In fact, there is a frequent association of PTC in siblings with the same germline mutation. Interestingly, all the 23 siblings reported up to now were females. There is a statistically significant association between PTC and the site of the germline mutation.2 However, the absence of complete inactivation of the gene5,6 suggests that the germline mutation of the APC gene confers only a generic susceptibility to thyroid cancer, but perhaps other factors, namely, modifier genes, sex-related factors (hormonal, but also dietary, metabolic, immunological), or environmental factors,8 are also required for the phenotypic expression. It is likely that FAP-associated PTC represents a veritable example of cooperation between purely inherited factors (APC germline mutation) and epigenetic or environmental factors, namely, those strictly connected with the female sex, as the striking female to male ratio of 80:1 strongly suggests. It must be outlined that PTC in patients with FAP may have distinct histological features, namely, the C-MV, which are different from features of conventional PTC. C-MV represents 0.1% to 0.2% of all PTCs, but it has been reported with an impressive prevalence in FAP patients (>60%). As Jarrar et al suggest, this may raise the question as to whether the non–C-MV thyroid cancers are truly associated with FAP or just sporadic. In our personal series of 18 FAP-associated PTCs, a clear C-MV was detected in 9 cases, whereas conventional PTC was present in 7 (the last 2 had other variants). These data are only partly in accordance with
Annals of Surgery r Volume 261, Number 1, January 2015
the finding of the Jarrar group of only one patient (out of 4 or 5) showing the typical feature of C-MV PTC. The last comment concerns the mean age of patients. In our first report, it was 24.8 years in a series of 15 female patients, but it also was 24.8 years in a series of 97 patients collected from the literature.2 The mean age has been similar in the 81 patients reported in the literature after 2000. Therefore, in addition to histological variants, demographic features reported by Jarrar et al (3 women aged 35–45 and 60 years and 2 men, aged 27 and 45, respectively) are also different from data in the literature. The main criticism that can be raised in the interpretation of the findings of Jarrar et al concerns the significance of these data. In fact, even if a thyroid nodule with positive diagnosis after fine needle aspiration biopsy (FNAB) can be first detected at 60 years of age in a FAP patient with APC germline mutations, we think that this is an exception, because the great majority (>80%) of FAP PTCs occur between 18 and 35 years of age, quite exclusively in females, namely, those with congenital hypertrophy of the retinal pigment epithelium (CHRPE), or with an APC germline mutation in the 5 portion of the gene.2 We suspect that demographic differences between the data of Jarrar et al and those from the literature could be due, at least partly, to a different (and maybe opposite) approach to data collection. In fact, on one hand, it could be that the literature has a “publication bias,” which facilitates the selection of single case reports, mainly concerning the so-called C-MV (which in some cases was the clue for the diagnosis of a previously undetected FAP kindred).9 Therefore, demographic and pathological features of literature cases are usually typical of this variant. On the other hand, there is the approach of Jarrar et al, an intensive screening for thyroid nodules in completely asymptomatic subjects, excluding “a priori” patients who are easy to diagnose, who are representative of the average presentation of the disease. Does the latter approach facilitate the detection of a population with different characteristics. Is it the same disease? That is the question. We could suggest caution before stating that malignant nodules detected by Jarrar et al belong to the same disease and have the same biological behavior as FAP PTCs reported in the literature. On the contrary, it could be a different disease, occurring because of different factors, acting in FAP subjects in different age periods, namely, after the occurrence of colonic polyps and even colorectal cancer. Only a detailed pathological and genetic analysis of these nodules (LOH for APC,
www.annalsofsurgery.com | e13
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 1, January 2015
Cetta et al
RET/PTC activation, immunostaining for β-catenin, search for BRAF mutations, the precise detection of the histological variant), and demographic data including patient history, and the description of the exact germline mutation could help unravel “which is which” and could answer the question as to whether these tumors are exactly the same as those reported in the literature as “typical FAP-associated PTCs.” This information will greatly contribute to a deeper insight into this intriguing extracolonic manifestation of FAP. Concerning the actual prevalence of PTC in FAP patients, Jarrar et al suggest a possible incidence of 2.6% (intensive screening) or 2.1%. This is an increased value in comparison with the previously reported data (1.2% or even 1.1%),2,9 which were an underestimation of the actual rate, even if recent data from other studies using intensive screening in superselected populations reported very high values (up to 12%).10 We deem that a 2% to 5% prevalence of PTC in FAP patients could be a more realistic value in the present era of improved early diagnosis.
e14 | www.annalsofsurgery.com
Francesco Cetta, MD IRCCS MultiMedica Milan, Italy [email protected] Gabriele Ugolini, MD Jacopo Martellucci, MD Giuseppe Gotti, MD Department of Surgery University of Siena Siena, Italy [email protected]
REFERENCES 1. Jarrar AM, Milas M, Mitchell J, et al. Screening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg. 2011;253:515–521. 2. Cetta F, Montalto G, Gori M, et al. 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. 2000;85:286–282. 3. Cetta F, Pelizzo MR, Curia MC, et al. Genetics and clinicopathological findings in thyroid carcinoma associated with familial adenomatous polyposis. Am J Pathol. 1999;155:7–9. 4. Cetta F, Dhamo A. Inherited multitumoral syndromes including colorectal carcinoma. Surg Oncol. 2007;16:S17–S23.
5. Cetta F, Dhamo A, Malagnino G, et al. Germline and somatic mutations of the APC gene and/ or beta-catenin gene in the occurrence of FAP associated thyroid carcinoma. World J Surg. 2007;31:1366–1367. 6. Cetta F, Curia MC, Montalto G, et al. Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene. J Clin Endocrinol Metab. 2001;86:427– 432. 7. Cetta F, Chiappetta G, Melillo RM, et al. The ret/ptc1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas. J Clin Endocrinol Metab. 1998;83:1003– 1006. 8. Cetta F, Dhamo A, Civitelli S, et al. Comment on “Extra-intestinal manifestations of familial adenomatous polyposis” Ann Surg Oncol. 2009;16:1446–1448. 9. Tomoda C, Miyauchi A, Uruno T, et al. Cribriform-morular variant of papillary thyroid carcinoma: clue to early detection of familial adenomatous polyposis-associated colon cancer. World J Surg. 2004;28:886– 889. 10. Herraiz M, Barbesino G, Faquin W, et al. Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations. Clin Gastroenterol Hepatol. 2007;5:367–373.
C 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
