Abstract
Purpose
The natural history of papillary thyroid carcinoma (PTC) is characterized by a slow growth rate and an excellent prognosis at 20 and 30 years. However, there is a small subset of patients with poorer outcome.
Methods
Twenty patients who died of PTC within 10 years of diagnosis were studied to identify prognostic indicators and biological markers of early death. Findings were statistically compared with a previous review of all patients with PTC treated in the same institute and studies in the literature.
Results
The study group included 6 men and 14 women with a mean age of 65 years at diagnosis. Average tumor size was 3.6 cm; 16 patients had extracapsular extension. All tumor samples studied histologically stained poorly for p53, Ki67, and CD34. Regional metastases were present in half the patients, and distal metastases in all. All patients had an advanced disease stage (Tumor, Node, Metastases classification), and only 4 had a low score on the Metastases, Age, Completeness of resection, local Invasion, tumor Size risk stratification. Analysis of the findings against data in the literature for the whole population of patients with PTC, who had a considerably better survival (<8% mortality within 8-15 years vs 100% within 10 years in our sample), yielded significant differences for rates of extrathyroidal extension ( P = .0001), regional metastases ( P = .016), and distant metastases ( P = .0001).
Conclusion
Extrathyroid extension, late regional metastases, and distant metastases may be risk factors for early death from PTC.
1
Introduction
Thyroid cancer is a relatively uncommon malignancy, accounting for approximately 2% of all new malignancies in the United States . The female-male ratio is about 3:1, and the median age at diagnosis is about 45 years . The great majority of tumors are well differentiated and of follicular cell origin; most (80%) are histologically defined as papillary thyroid carcinoma (PTC) . Surgical resection is the treatment of choice in most cases, followed by radioactive iodine treatment of residual tumor and metastases. External beam radiation is sometimes administered in patients with aggressive, recurrent disease, although its survival benefit is uncertain .
The known significant poor prognostic indicators in PTC are age more than 41 years for men and 51 years for women, male sex, large tumor size, extrathyroid extension, and metastases. Although the effect of regional metastases on recurrence and survival is still controversial, the presence of distant metastases is clearly associated with a worse outcome .
To more accurately establish the prognosis in patients with PTC, researchers have developed scoring systems, such as Tumor, Node, Metastases (TNM) and Metastases, Age, Completeness of resection, local Invasion, tumor Size (MACIS) . In addition, attention has been focused on potential molecular and cytological markers of biological behavior. Mutations in the p53 tumor-suppressor gene and expression of Ki67, a marker of cell proliferation, which have been linked to the behavior of tumors of the lung, breast, colon, and oral mucosa , were found to correlate with tumor aggression in differentiated thyroid carcinoma. However, their prognostic value has not been statistically evaluated in this context . CD34 serves as a marker of endothelial neovascularization and, thereby, tumor ability to metastasize. It has been associated with prognosis in colon, lung, and liver carcinoma; but there are no clear data on its role in thyroid cancer .
The natural history of PTC is characterized by a slow growth rate and an excellent prognosis. Whereas survival in other head and neck cancers is calculated for 5 and 10 years, in PTC, it is calculated for 20 and 30 years, with death usually occurring in the second or third decade of the illness . Nevertheless, there is a small but important subgroup of patients in whom outcome is poor. The aim of the present study was to identify specific clinical and biological factors affecting unusual tumor aggressiveness in patients with PTC and to validate the commonly used prognostic indicators.
2
Patients and methods
A search of the computerized database of the Department of Otolaryngology–Head and Neck Surgery of a major tertiary medical center identified 1134 patients with thyroid cancer who were diagnosed and treated between 1995 and 2008. The diagnosis of thyroid carcinoma was based on fine needle aspiration and histologic study of formalin-fixed paraffin blocks. Cases were managed according to standard European guidelines . Of the 106 patients who died during follow-up, we had complete data for 99: 79 died of intercurrent disease; the remaining 20 patients died of PTC within 7 months to 10 years from diagnosis. These 20 patients formed the basis for the present study.
The following data were collected from the medical charts: patient age and sex; tumor size, histological subtype, extrathyroid extension, and molecular markers; regional nodes and distant metastases at presentation or during the course of the disease; treatment; and prognostic indexes (cause of death and length of survival).
Prognostic scores based on the data at the time of diagnosis were calculated using 2 established scoring systems: TNM and MACIS. The TNM system classifies patients by disease stage (I-IV); the prognosis for stages I and II is excellent . The MACIS system divides patients by 20-year mortality risk, as follows; group 1, 1% risk; group 2, 11%; group 3, 44%; and group 4, 76% .
Late distant metastases were defined by clinical, radiologic, or pathologic evidence of systemic disease spread outside the primary tumor or regional nodal basins 6 months or more after thyroidectomy.
The results were compared with our previous review of all patients with PTC from our center and other studies in the literature .
2.1
Statistical analysis
Differences in variables between groups were analyzed by χ 2 test or Fisher exact test, as appropriate. Survival rate was calculated from the date of diagnosis to the date of death by the Kaplan-Meier method. P < .05 was considered statistically significant. For statistical analyses, we used SPSS 15.0.1 software (SPSS Inc, Chicago, IL).
2
Patients and methods
A search of the computerized database of the Department of Otolaryngology–Head and Neck Surgery of a major tertiary medical center identified 1134 patients with thyroid cancer who were diagnosed and treated between 1995 and 2008. The diagnosis of thyroid carcinoma was based on fine needle aspiration and histologic study of formalin-fixed paraffin blocks. Cases were managed according to standard European guidelines . Of the 106 patients who died during follow-up, we had complete data for 99: 79 died of intercurrent disease; the remaining 20 patients died of PTC within 7 months to 10 years from diagnosis. These 20 patients formed the basis for the present study.
The following data were collected from the medical charts: patient age and sex; tumor size, histological subtype, extrathyroid extension, and molecular markers; regional nodes and distant metastases at presentation or during the course of the disease; treatment; and prognostic indexes (cause of death and length of survival).
Prognostic scores based on the data at the time of diagnosis were calculated using 2 established scoring systems: TNM and MACIS. The TNM system classifies patients by disease stage (I-IV); the prognosis for stages I and II is excellent . The MACIS system divides patients by 20-year mortality risk, as follows; group 1, 1% risk; group 2, 11%; group 3, 44%; and group 4, 76% .
Late distant metastases were defined by clinical, radiologic, or pathologic evidence of systemic disease spread outside the primary tumor or regional nodal basins 6 months or more after thyroidectomy.
The results were compared with our previous review of all patients with PTC from our center and other studies in the literature .
2.1
Statistical analysis
Differences in variables between groups were analyzed by χ 2 test or Fisher exact test, as appropriate. Survival rate was calculated from the date of diagnosis to the date of death by the Kaplan-Meier method. P < .05 was considered statistically significant. For statistical analyses, we used SPSS 15.0.1 software (SPSS Inc, Chicago, IL).
3
Results
Table 1 shows the clinical and pathological characteristics of the 20 patients with PTC who died of their disease within 10 years of diagnosis compared with data from our previous study of 503 patients with PTC and other series from the literature .
| Segal et al | Kjellman et al | Chow et al | Hamzany et al (present study) | |
|---|---|---|---|---|
| Patient number | 503 | 220 | 842 | 20 |
| Mean age (y) | 45 | 49 | No data | 65 |
| Sex F/M (ratio) | 376/127 (2.9) | 166/54 (3) | 689/153 (4.5) | 14/6 (2.3) |
| Size | ||||
| Mean (cm) | No data | 2.5 | 2 | 3.6 |
| ≥4 cm | 443 (88%) | No data | No data | 13 (76%) |
| <4 cm | 60 (12%) | No data | No data | 4 (24%) |
| Extrathyroid extension | 20 (4%) | 78 (35%) | 332 (39%) | 16 (80%) |
| Regional metastasis | ||||
| At diagnosis | 264 (52%) | 95 (43%) | 280 (33%) | 10 (50%) |
| Late presentation | 39 (8%) | No data | No data | 5 (25%) |
| Distant metastasis | ||||
| At diagnosis | <20 (4%) | 4 (2%) | 27 (3%) | 3 (15%) |
| Late presentation | 15 (3%) | 12 (5%) | 48 (6%) | 17 (85%) |
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