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Endocrine-Related Cancer 15 (4) 1075 -1081     DOI: 10.1677/ERC-08-0080
Copyright © 2008 by the Society for Endocrinology
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Familial non-medullary thyroid carcinoma displays the features of clinical anticipation suggestive of a distinct biological entity

 M Capezzone, S Marchisotta, S Cantara, G Busonero, L Brilli, K Pazaitou-Panayiotou1, A F Carli 2, G Caruso3, P Toti 4, S Capitani 5, A Pammolli5 and F Pacini

Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, Policlinico Santa Maria alle Scotte, Viale Bracci 1, 53100 Siena, Italy1 Department of Endocrinology-Endocrine Oncology, Theageniu Cancer Hospital, Thessaloniki, Greece2 Section of Endocrine Surgery, Department of Surgical Science, University of Siena, Siena, Italy3 Unit of Otorinolaringoiatry, University of Siena, Siena, Italy4 Department of Human Pathology and Oncology, University of Siena, Siena, Italy5 Biology Section, Department of Surgery, University of Siena, Siena, Italy

(Correspondence should be addressed to F Pacini; Email: pacini8{at}unisi.it)


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Declaration of interest
 References
 
Non-medullary thyroid carcinoma (NMTC) is mostly sporadic, but familial clustering is described. We aimed to compare the features of patients with sporadic and familial NMTC (FNMTC) patients and to assess whether FNMTC patients with parent–child relationship exhibit the ‘anticipation’ phenomenon (earlier age at disease onset and increased severity in successive generations). Among 300 NMTCs followed in the Section of Endocrinology (University of Siena, Italy), 34 (11.3%) patients, all with the papillary histotype, (16 kindred), met the criteria of FNMTC. Twenty-seven of them (79.4%) exhibited a parent–child relationship and seven (20.6%) a sibling relationship. These patients were compared with 235 patients with sporadic papillary thyroid cancer (PTCs). To analyze the features of FNMTC of the first and second generations, we cumulated the series of Siena with 32 additional FNMTC patients (15 kindred) from the Department of Endocrinology-Endocrine Oncology, Thessaloniki, Greece. Significant difference between sporadic PTC and FNMTC patients included more frequent tumor multifocality (P=0.001) and worse final outcome in FNMTC patients (P=0.001). Among 47 FNMTC with parent–child relationship, we found an earlier age at disease presentation (P<0.0001), diagnosis (P<0.0001), and disease onset (P=0.04) in the second generation when compared with the first generation. Patients in the second generation were more frequently males (P=0.02); their tumors were more frequently multifocal (P=0.003) and bilateral (P=0.01), had higher rate of lymph node metastases at surgery (P=0.02) and worse outcome (P=0.04) when compared with the first generation. In conclusion, FNMTC displays the features of clinical ‘anticipation’ with the second generation acquiring the disease at an earlier age and having more advanced disease at presentation.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Declaration of interest
 References
 
Non-medullary thyroid cancer (NMTC) of the follicular thyroid epithelium accounts for nearly 80% of all thyroid cancers and it is mainly represented by the papillary histotype (papillary thyroid cancer; PTC), mostly sporadic in nature (Hay et al. 2002). Nevertheless, the recurrence of NMTC, in more than one subject of the same family has been described (Stoffer et al. 1986, Loh 1997, Hemminki & Li 2003). Cohort-based studies (Goldgar et al. 1994, Frich et al. 2001, Pal et al. 2001) have shown that the risk of developing NMTC is significantly greater (between 3 and 9 fold) in first-degree relatives of subjects with NMTC. While some studies reported no difference regarding outcome and survival of familial NMTC (FNMTC) patients and their sporadic counterpart (Loh 1997, Maxwell et al. 2004), recent studies (Grossman et al. 1995, Alsanea et al. 2000, Uchino et al. 2002, Triponez et al. 2006) have demonstrated that with respect to sporadic NMTCs, FNMTCs are more frequently multifocal, have higher rate of relapse, and are diagnosed at younger ages.

In this study, we demonstrate that in a series of NMTC including patients with FNMTC, the latter exhibit more aggressive tumor phenotype. In addition, when comparing the first and the second generation of FNMTC patients (47 cases), we observed that offsprings show an earlier age at disease onset and have more aggressive disease when compared with their parents. These features might recall the presence of ‘genetic anticipation’, the phenomenon defined as the occurrence of a genetic disorder at progressively earlier ages and with increased severity in successive generations (McInnis 1996), and suggest that FNMTC is a true familial disease rather than the fortuitous association of the same disease in a family.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Declaration of interest
 References
 
Our study analyzed two different issues: i) the comparison of clinical and pathological features of sporadic and familial NMTC and ii) the comparison of the first and the second generation of FNMTC with parent–child relationship.

For the first part, we retrospectively reviewed, after informed consent obtained in accordance with the local ethical committee guidelines, the clinical records of all NMTC patients (n=300) followed in the Section of Endocrinology of University of Siena (Italy) from 1978 to 2007. There were 230 females and 70 males, ratio F/M is 3/1, ranging 8–84 years. Final histology was PTC in 269 (89.7%) and follicular thyroid cancer (FTC) or Hürthle cell cancer in 31 (10.3%). Initial treatment (near-total thyroidectomy and 131I remnant ablation) and follow-up strategy were the same in all of them. Mean follow-up was 57.7±48.8 months (range 12–368 months). FNMTC was found in 34/300 (11.3%) patients belonging to 16 kindred. In the agreement with other authors (Musholt et al. 2000, Alsanea et al. 2000, Uchino et al. 2002, Sturgeon & Clark 2005), we defined as FNMTC the presence of two or more first-degree relatives with thyroid cancer of follicular cell origin after excluding clinical or pathological evidence of hereditary syndromes associated with NMTC, such as familial adenomatous polyposis, Gardner syndrome, Peutz–Jegher syndrome, Cowden disease. We analyzed the clinical–pathological features of familial and sporadic NMTC patients, including gender, age at diagnosis, tumor diameter, extension of the disease at diagnosis, histology, intrathyroidal dissemination of the tumor (multicentricity and bilaterality), rate of lymph node metastases, presence of other cancers, and recurrence and final status at the end of follow-up. Since all FNMTC patients had PTC, their comparison was limited to the 235 sporadic PTCs excluding patients with FTC and Hürthle cell tumors. According to standard criteria and recent guidelines (Cooper et al. 2006, Pacini et al. 2006), we define ‘cured or free of disease’ patients with undetectable stimulated serum Tg levels (<1.0 ng/ml), negative TgAb, and no evidence of disease (at clinical examination, neck ultrasound, negative diagnostic 131-I whole body scan, and/or other imaging techniques), whereas patients with detectable basal or stimulated serum Tg and/or evidence of disease were classified as having persistent/recurrent disease.

For the second part of the study, we pooled the 34 FNMTC patients of the Italian series (16 kindred) and 32 additional FNMTC patients (15 kindred) derived from the series of the Department of Endocrinology of the University of Thessaloniky (Greece). In total, we had 66 FNMTC patients belonging to 31 kindred.

Statistical analysis

Statistical analysis was conducted with StatView for Windows, ver.5.00.1 (SAS Institute, Cary, NC, USA). All data are presented as mean±S.D. and medians when appropriate. To compare the statistical differences between the variables of two independent groups where the condition of normality is not satisfied, the Mann–Whitney U test was used. To assess the association among qualitative variables, the Fisher's exact test was used if the expected frequencies were less than 5, otherwise the {chi}2 test was performed. The age-dependent cumulative hazard of FNMTC diagnosis in the first and the second generation was calculated by Nelson–Aalen estimate and statistical comparison was made by log-rank test. Two-sides P<0.05 was considered significant.

To evaluate the presence of anticipation and avoid the ‘insufficient follow-up time bias,’ a specific procedure was created using the program Matlab (ver.6.5). In order to take this potential bias into account, we analyzed differences in age at disease manifestation, age at diagnosis, year of disease manifestation, year at diagnosis of parents, and offsprings with adjustment for a possible inadequate follow-up time (Age at Onset, AOA test) as described in details by Vieland & Huang (1998). The concept of ‘age at disease onset anticipation (AOA)’ is the tendency for children to develop clinical disease at an earlier age than the affected parents. The AOA test is based on the correct, bivariate right-truncated, age-at-onset distribution and has been validated as the one able to avoid the above-mentioned bias. After the age correction at the diagnosis, for the different risk period, we applied the ZAO test not to evaluate random effects but to determine the real difference between the age at onset of parents and offsprings.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Declaration of interest
 References
 
Comparison of FNMTC and sporadic PTC patients of the Italian series

The clinical–pathological features of FNMTC (n=34) and sporadic PTC patients (n=235) are shown in Table 1. Tumors of FNMTC patients were more frequently multifocal (P=0.001), tended to have higher recurrence rate (P=0.05), and had worse outcome (P=0.001) when compared with sporadic PTC patients. No difference was found regarding gender, age, primary tumor diameter, bilaterality, tumor extension, lymph node metastases, and length of follow-up and history of other malignancy. Only 2 of 34 patients affected by FNMTC showed another type of cancer: one had breast cancer with age at onset of 64 years and another had lymphoma with age at onset of 6 years, (1 and 8 years of age before the diagnosis of PTC respectively). No other known thyroid cancer-associated syndromes was present clinically in FNMTC patients.


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  		Table 1 Demographic and disease characteristics of sporadic PTC and FNMTC patients (Italian cohort)

 
Comparison of FNMTC patients in the first and second generation

Cumulating the Italian and the Greek series (31 pedigrees, 66 FNMTC patients, and all PTC), FNMTC recurred in two family members in 28 pedigrees, in three family members in 2 pedigrees, and in four members in 1 pedigree. A parent–child relationship was found in 22 kindred (47 family members) and a sibling relationship was found in 9 kindred (19 members). The two pedigrees with three affected family members had both parent–child and sibling relationships: one family had one parent and two offsprings affected, the other had two sisters and one of theirs offspring affected. The single pedigree with four family members had one parent and three offsprings affected. To compare the clinical–pathological features of FNMTC patients with parent–child relationship, we excluded the nine kindred with a sibling relationship.

The diagnosis of PTC was made firstly in the first generation in 17/22 (77.3%) kindred. The time interval between the diagnosis in the propositus and in the second familial member ranged between 1 and 20 years with a mean of 4.5 years. As shown in Fig. 1, age at diagnosis was always younger in the second generation when compared with the first generation with a mean negative difference of –29.3±7.9 years and a range of –12/–43 years.


Figure 1
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  		Figure 1 Intrapair difference in age at diagnosis in parent–offspring pairs (22 kindred) of FNMTC (age at diagnosis of the offspring minus age at diagnosis of the corresponding parent). Each bar represents a parent–offspring pair (*same kindred and **same kindred).

 
As shown in Table 2, mean age at presentation and at diagnosis were significantly (P<0.0001) younger in the second generation. To rule out that this phenomenon may be due to a screening effect (members of the second generation may be screened for thyroid cancer after a member of the first generation has been diagnosed with thyroid cancer), we applied the AOA test. Using this test and assuming different variances Formula , the estimated mean age at onset of the disease in the first generation was 71.7±12.7 years, significantly older (ZAO test=1.8159, P=0.0347) than the estimated mean age at onset of the offsprings (44.4±8.3 years). Applying the Nelson–Aalen method (Fig. 2), the age-dependent cumulative hazard of FNMTC diagnosis in patients of the second generation was significantly higher than in those of the first generation (P<0.001). In addition, as shown in Table 3, patients of the second generation had a higher rate of local or distant metastases (P=0.02), tumor multicentricity (P=0.003), and bilaterality (P=0.01) at the time of diagnosis and a worse outcome (P=0.04) at final follow-up when compared with their parents. These findings and that of younger age at disease onset in the second generation confirm that ‘anticipation’ is present in these pedigrees and that the recurrence of thyroid cancer in the family is not due to a screening bias.


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  		Table 2 Age at presentation, at diagnosis and at disease onset in FNMTC (both Italian and Greek cohorts) of the first and second generations, respectively

 

Figure 2
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  		Figure 2 Age-dependent hazard of FNMTC diagnosis in the second (open circles) and the first (close circles) generations (by Nelson–Aalen plot. P<0.0001 by log-rank test).

 

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  		Table 3 Demographic and disease characteristics of FNMTC patients (both Italian and Greek cohorts) with parent–child relationship

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Declaration of interest
 References
 
A minority of human cancers is recognized as inherited with an autosomal-dominant form of transmission, and the gene responsible for the disease has been characterized (Turnbull & Hodgson 2005). Nevertheless, clustering of a given cancer in the same family is also frequent in those cancers, the majority, that are usually considered sporadic and where a predisposing gene is not discovered. This is also the case of FNMTC, whose prevalence has been reported in up to 10% in different series (Stoffer et al. 1986, Loh 1997), and is one of the human cancers with higher risk in close relatives (Hemminki et al. 2005). In a large population-based analysis (Goldgar et al. 1994), among 399,786 first-degree relatives of index cancer patients, the authors found a ninefold increase in risk of non-medullary thyroid cancer, the highest among all cancer types. Similarly, Hemminki et al. (2005) in their population-based study of the Sweden cancer registry found that for an individual, the risk of PTC was 3.21 and 6.24 respectively, when his/her parent and his/her sibling were diagnosed with thyroid cancers.

Several studies (Alsanea et al. 2000, Uchino et al. 2002, Triponez et al. 2006) reported that compared with sporadic PTCs, FNMTCs are usually more aggressive. At variance with these studies, other authors (Loh 1997, Maxwell et al. 2004) have reported no differences in the clinical behavior of sporadic and familial PTCs. In our series, there was a marginal trend to higher aggressiveness of FNMTC which were more frequently multifocal at presentation and exhibited more frequent recurrences and worse outcome during follow-up.

The demonstration of the real existence of inherited FNMTC is particularly difficult when compared with other human cancers, due to some peculiar features of the thyroid gland. Firstly, thyroid cancer is frequently found within uni- or multinodular goiter that per se is recognized as a familial disease (Krohn et al. 2005). In this setting, thyroid cancer may arise from somatic mutations in the background of a long-standing familial goiter. Second, the diagnosis of thyroid cancer is particularly frequent after the introduction of neck ultrasound in clinical practice, as demonstrated by the finding that thyroid cancer is the human cancer at the largest increase in the last 10 years in USA, Australia, and Europe (Burgess 2002, Leenhardt et al. 2004, AIRT Working group 2006, Davies & Welch 2006, Capezzone et al. 2007). In some malignancies, as in medullary thyroid cancer without germline RET (rearranged during transfectron) proto-oncogene mutations, the definition of familial disease is based on the presence of four or more affected family members (Mulligan et al. 1995). At variance with this definition, several authors define FNMTC as the presence of two or more first-degree relatives affected by differentiated thyroid cancer. However, the presence of only two affected members in kindred may represent a fortuitous association of the disease, as suggested by Charkes (2006), who applied an exact probability measure to a series of first-degree family members with FNMTC. According to his mathematical simulation, 62–69% of 2-hit families are sporadic occurrences and thus, only families with more than three affected first-degree relatives should be considered for clinical and genetic investigations of FNMTC. Deliberately, we considered in this study all pedigrees of our center, including those with only two affected members (the large majority), just to ascertain whether, even in them it was possible to detect peculiar clinical features that might, at least indirectly, suggest a true familial background rather than a fortuitous association of sporadic cases. Indeed, compared with their parents, patients in the second generation were significantly younger at diagnosis and, after ruling out the bias of screening effect, had younger age at disease onset. In addition, tumors of the second generation were more advanced at presentation, including multicentricity, bilaterality, and lymph node metastases and had worst outcome at follow-up. Interestingly, the mean diameter of the primary tumors in family members diagnosed with thyroid cancer after the diagnosis in the proband was not different from the mean diameter of the proband tumors. If the tumors were discovered by screening, one would expect to find mainly microcarcinomas, as in case of autoptic studies or ultrasound series (Harach et al. 1985, Mazzaferri & Massoll 2002). The above features are consistent with the so-called phenomenon of ‘genetic anticipation’ (McInnis 1996). This concept was developed in the 19th century by Morel (1857) in his Traitè des Degenèrescences and indicates the occurrence of a disease at earlier age and increased aggressiveness in successive generations. The concept of genetic anticipation has gained new attention in the last decades and has been fully demonstrated for several inherited benign and malignant disorders (Ashizawa et al. 1992, Ranen et al. 1995, Horwitz et al. 1996, Polito et al. 1996, Golden et al. 1999, Dagan & Gershoni-Baruch 2002, Vulliamy et al. 2004, Westphalen et al. 2005, Yaturu et al. 2005, Auer et al. 2007). In some of them, such as Huntington disease (Ranen et al. 1995) or dyskeratosis congenita (Vulliamy et al. 2004), a molecular mechanism possibly underlying ‘anticipation’ has been recognized (unstable trinucleotide repeat expansion in Huntington's disease and TERC (telomerase RNA component) mutation in congenital dyscheratosis). As far as FNMTC is concerned, no candidate genetic alterations has been discovered, apart from susceptibility loci found in a few pedigrees with FNMTC: the locus TCO (thyroid tumors with cell oxyphilia) on 19p13.2, the locus PRN1 on 1q21, the locus NMTC1 on 2q21 (Canzian et al. 1998, Malchoff et al. 2000, McKay et al. 2001) and, although not confirmed, the locus MNG1 on 14q32 (Bignell et al. 1997). In addition, we have recently demonstrated in a series of patients with familial papillary thyroid cancer (including also some patients of the present study), an imbalance of the telomere–telomerase complex at the germline level, consisting of short telomeres, increased telomerase copy number, and expression when compared with sporadic papillary thyroid cancer (Capezzone et al. 2008). This alteration may contribute (among other as yet unknown abnormalities) to confer genetic predisposition to develop FNMTC and might be involved in the anticipation phenomenon.

In conclusion, this study provides clinical evidence of ‘anticipation’ in FNMTC, possibly suggesting the inheritance of this familial form of thyroid cancer even when only two members of a family are affected. In view of some features of aggressiveness (particularly in the second generation) at diagnosis and during follow-up, patients with FNMTC should probably be offered radical initial treatment, including total thyroidectomy with central neck dissection, and post-surgical radioiodine ablation as a routine procedure regardless of the primary tumor size.


   Declaration of interest
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Declaration of interest
References
 
There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.


   Funding
 
This research did not received any specific grant from any funding agency in the public, commercial or not-for-profit sector.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Declaration of interest
 References
 
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