Abstract
Background:
Epidemiological studies have shown a higher risk of thyroid cancer among individuals who have a relative with papillary thyroid cancer (PTC) compared to those without a family history. This study evaluated the prevalence of thyroid cancer among subjects with only one first-degree relative (sibling) with PTC who had no palpable nodules, factors predictive of this malignancy, and the characteristics of tumors discovered during ultrasonographic screening.
Methods:
A total of 757 siblings of 447 patients with apparently sporadic PTC were examined. Nodules were palpable in 34 subjects (excluded). The 723 individuals without palpable abnormalities were submitted to thyroid ultrasonography and comprised the study group. The control group, consisting of 241 volunteers without a family history of thyroid cancer matched for gender and age to the study group, was also submitted to thyroid ultrasonography. All nodules ≥5 mm were examined by fine-needle aspiration cytology. Subjects with benign cytology were not submitted to surgery, whereas the subjects having malignant, suspicious for a malignancy, indeterminate, or inadequate cytology were referred for thyroidectomy.
Results:
Ultrasonography detected nodules in 303 (41.9%) study subjects. PTC was observed in 5.94% of the 723 subjects studied (8% women and 3.75% men, p=0.017) and in 14.2% of the 303 subjects with nonpalpable nodular disease. In the control group, 80 (33.2%) of the volunteers had nodules. PTC was observed in 1.2% of them and in 3.8% of those with nodular disease. In addition, 7.17% of the 447 patients had siblings with PTC detected only by ultrasonography. Multicentricity of the tumor was the main predictor of the presence of malignancy in siblings of patients with PTC. Twenty-two subjects (3% of those screened) had tumors that were not intrathyroid microcarcinomas (whereas all three tumors detected in controls were intrathyroid microcarcinomas). Screening permitted an earlier diagnosis of the disease when compared to siblings with a spontaneous diagnosis.
Conclusions:
The present results favor ultrasonographic screening of first-degree relatives of patients with apparently sporadic multicentric PTC, especially among women.
Introduction
It is possible that the risk reported in these epidemiological studies (1 –4) is underestimated, since the subjects were not screened for the disease. Obviously, the recommendation of routine investigation (with ultrasonography) requires that the frequency of malignancy is high among relatives without palpable thyroid nodules. In addition, it is important to know the potential aggressiveness of tumors detected by this strategy, that is, ultrasonographic screening of asymptomatic subjects (6).
This study evaluated, the prevalence of thyroid cancer among subjects with only one first-degree relative (sibling) with PTC who had no palpable nodules, factors predictive of the presence of this malignancy, and the characteristics of tumors discovered during ultrasonographic screening.
Subjects and Methods
Patients who had living siblings and were seen at Santa Casa de Belo Horizonte (Brazil) with apparently sporadic PTC (i.e., no history of exposure to radiation or family history of thyroid carcinoma as reported by the patient and obtained from the medical record), were selected for the study. The characteristics of these patients are shown in Table 1.
The siblings of these patients were invited to participate in the study. The study was limited to siblings because it has been suggested that the risk of cancer is different (apparently higher) when compared to parents or children of patients with PTC (1,9). Of these, 150 subjects were not studied because they could not attend the evaluation or they refused to participate. A total of 757 subjects were examined and interviewed, and the initial information that no other relative had a known diagnosis of thyroid cancer was confirmed. Nodules were palpable in 34 subjects and these patients were excluded from the study. It should be noted that PTC was diagnosed in three of these subjects. Ultrasonography was performed in 723 individuals without palpable thyroid abnormalities and they comprised the study group (377 women and 346 men ranging in age from 12 to 70 years; mean: 39 years).
A control group consisting of 241 volunteers without a family history of thyroid cancer or a history of radiation exposure, who had no abnormalities upon thyroid palpation, was matched for gender (126 women and 115 men) and age (13 to 68 years; mean: 40 years) to the study group. Ultrasonography was also obtained in these subjects.
All nodules ≥5 mm, or those associated with lymphadenopathy, that had characteristics suspicious of metastasis (10) as identified by ultrasonography, were submitted to fine-needle aspiration cytology (FNAC) (11). Subjects with benign cytology were not submitted to additional investigation or surgery, whereas the remaining subjects were referred for total or near-total thyroidectomy. The study was approved by the local Research Ethics Committee (Santa Casa de Belo Horizonte), and the subjects gave a written informed consent.
Sonography was performed with a linear multifrequency 10–12-MHz transducer for a morphological analysis and with a 4.5–7-MHz transducer for a color-Doppler evaluation. FNAC was performed with a 22-gauge needle and a 5- or 10-mL syringe was guided by ultrasonography. The cytological diagnosis was classified as benign, suspicious for a malignancy, malignant, indeterminate, or inadequate.
Means were compared between groups by the Student t-test or the nonparametric Mann-Whitney U test. The Fisher exact test or the ( 2 test was used to detect differences in the proportion of cases. A p-value of <0.05 was considered to be significant.
Results
Ultrasonographic screening
Among the 723 subjects studied, 303 (41.9%) [56.6% women and 26% men, p<0.001] had nodule(s) on thyroid ultrasonography readings. They ranged in size from 3 to 17 mm. Twenty-seven subjects with nodules <5 mm did not have a FNAC. After 6–20 months of follow-up these nodules had not increased in size and no other indication for FNAC had developed. Among the 276 subjects with nodules ≥5 mm who had a FNAC, benign cytology was observed in 180. Malignant cytology (PTC) was observed in 18 subjects, a suspicion of PTC in 14, an indeterminate result in 35, and cytology was inadequate (on two occasions) in 29. Ninety-two of the 96 subjects with non-benign cytology were submitted to thyroidectomy and histology revealed papillary thyroid carcinomas in 43. In these 43 patients, there were 18 whose cytology readings were malignant, 10 whose cytology readings were suspicion of PTC, 10 whose cytology readings were indeterminate, and 5 whose cytology readings were inadequate. Therefore, PTC was observed in 5.9% of the 723 subjects studied (8% of the women and 3.75% of the men, p=0.017) and in 14.2% of the 303 subjects with nonpalpable nodular disease (14.1% of the women and 14.4% of the men). In addition, 7.2% of the 447 patients with spontaneously diagnosed cancer had siblings with PTC detected only by ultrasonography (2.46% had two affected siblings and 4.7% had only one affected sibling).
Characteristics of the tumors detected by ultrasonographic screening
The pathological stage of the tumors detected only by ultrasonography is shown in Table 2. Twenty-two subjects (3% of those screened) had tumors that were not intrathyroid microcarcinomas and 16 (2.2% of those screened) had tumors not restricted to the thyroid (i.e., tumors with extrathyroid extension and/or metastases). The comparison between patients with PTC (spontaneous diagnosis) and their respective siblings with a diagnosis made by ultrasonographic screening is shown in Table 3 and Figure 1. The results confirm that screening resulted in an earlier diagnosis of the disease.
Comparison of age at diagnosis between patients with spontaneously diagnosed papillary thyroid carcinoma (continuous line) and their siblings diagnosed by ultrasonographic screening (dashed line).
Lymph node dissection was only performed in the case of a pre- or perioperative suspicion of metastasis, not prophylactically.
Largest tumor when multicentric.
NS, not significant.
Factors predictive of the presence of malignancy in siblings
With respect to patient characteristics, gender or age at diagnosis were not associated with the increased or decreased presence of PTC in siblings. Thirteen of 294 (4.4%) patients with unifocal tumors compared to 19 of the 152 (12.5%) with multicentric tumors had siblings with PTC detected by ultrasonography (p<0.001). Twenty-one of 294 (9.5%) patients with lymph node metastases compared to 11 of the 225 (4.9%) without metastases had siblings with PTC detected by ultrasonography (p=0.043). Distant metastases or extrathyroid invasion were not associated with the increased or decreased prevalence of thyroid cancer in siblings. The comparison between patients with and without siblings with PTC diagnosed by ultrasonographic screening is shown in Table 4.
Comparison of those with and without siblings with papillary thyroid carcinoma whose diagnosis was initiated by ultrasonographic screening.
Largest tumor when multicentric.
PTC, papillary thyroid cancer.
Control group
Eighty (33.2%) of the 241 controls studied (42.8% women and 22.6% men) had a thyroid nodule or thyroid nodules noted by thyroid ultrasonography. Seven subjects with nodules <5 mm did not require FNAC. Among the 73 subjects with nodules ≥5 mm that had FNAC, benign cytology was observed in 56. Malignant cytology (PTC) was observed in one subject, a suspicion of PTC in one subject, an indeterminate result in 5 subjects, and inadequate cytology in 10 subjects. Twelve subjects with malignant cytology reading (n=1), or suspicious cytology reading (n=1), or indeterminate cytology readings (n=10) had thyroidectomy. Of these 12 individuals who had thyroidectomy, PTC was observed in 3. Of those with PTC the cytology reading was malignant in 1, suspicious in 1, and indeterminate in 1. Therefore, PTC was observed in 1.2% of the 241 controls studied (1.6% women and 0.8% men) and in 3.8% of the 80 subjects with nodular disease (3.6% women and 4.1% men). All three tumors were intrathyroid microcarcinomas.
The prevalence of malignancy was lower in the control group than among siblings of patients with PTC (1.2% vs. 5.9%, p<0.05). Considering only subjects with nodules detected by ultrasonography, the rate of malignancy was also higher among those who had a sibling with PTC when compared to control (14.2% vs. 3.8%, p<0.01).
Discussion
Thyroid cancer was observed in 6% of subjects without palpable nodular disease and with only one first-degree relative (sibling) with PTC. This rate was higher when the first diagnosed sibling had a multicentric tumor or when the subject screened was a woman. This prevalence was higher than that observed by us during ultrasonographic screening of subjects without a family history of PTC matched for gender and age (controls). Among subjects with nodules, the rate of malignancy was also higher among those who had a sibling with PTC when compared to control. The percentage observed was also similar to that reported by Uchino et al. (6), who evaluated subjects with two or more first-degree relatives with differentiated thyroid carcinoma, and ultrasonographic screening is already recommended in this situation (5 –8). Concordantly, the American Thyroid Association (ATA) also defined individuals with nodular thyroid disease and with only one relative with PTC to be at high risk for thyroid malignancy (11). A cross-sectional design was used in the present investigation, and it is possible that these rates are even higher.
The three cases of malignancy detected by ultrasonographic screening of subjects without a family history of PTC were <1 cm and intrathyroid. In contrast, 51% of the tumors diagnosed among siblings of patients with PTC were not microcarcinomas restricted to the thyroid, a fact weakening the hypothesis that tumors diagnosed by screening in these patients are not clinically relevant. In addition, comparison of siblings with PTC diagnosed spontaneously, versus malignancy detected by screening (tumor size, frequency of lymph node metastases, and extrathyroid invasion) clearly shows that this screening permitted an earlier diagnoses of the disease.
Finally, comparison of patients with and without siblings with PTC diagnosed by screening showed a higher frequency of tumor multicentricity in the former, as well as a trend toward extrathyroid invasion and lymph node metastases, although these patients were similar in terms of gender, age, and tumor size. Mazeh et al. demonstred that patients with PTC having a family history of thyroid cancer have more aggressive disease, regardless of whether they meet the current definition of familial nonmedullary thyroid cancer regarding number of affected family members (12). Further studies are needed to determine whether the prognosis of familial PTC is worse than that of sporadic carcinoma after adjusting for tumor stage, requiring more aggressive treatment and more extensive follow-up, although these tumors are apparently of low risk as proposed by some authors (6).
In conclusion, the present results favor ultrasonographic screening of first-degree relatives (siblings) of patients with apparently sporadic multicentric PTC, but the age for first ultrasound and the follow-up of subjects with an initially negative examination remain undefined. In addition, the criteria for indication of FNAC and surgery (in cases of nondiagnostic cytology) need to be better defined.
Footnotes
Disclosure Statement
The authors declare that no competing financial interests exist.