Long-term results in elderly patients with differentiated thyroid carcinoma

Abstract

BACKGROUND

The authors assessed the biologic behavior of differentiated thyroid carcinoma in patients age 70 years or older and evaluated factors that influenced long-term survival.

METHODS

Among 1448 patients with differentiated thyroid carcinoma who were treated at the authors' institution over the past 60 years, 111 patients were identified who were age 70 years or older at the time of their initial diagnosis (range, 70–93 years). The authors conducted a retrospective analysis of the outcome of these 111 patients, who had a median follow-up of 9 years (range, 2–9 years).

RESULTS

There were 83 female patients and 28 male patients (female to male ratio, 3:1). Fifty-eight tumors were papillary, 46 tumors were follicular, and 7 tumors were Hürthle cell carcinoma. Eighty percent of patients presented with a thyroid mass, and 70% of tumors were pathologic stage T3 (pT3) or pT4. Lymph node disease was evident at presentation in 44% of patients, and distant metastases were documented at diagnosis in 23% of patients. Forty-six patients underwent total thyroidectomy, and the remaining patients underwent subtotal thyroidectomy or biopsy only. Radioiodine was administered to 80 patients, and external beam radiotherapy was administered to 19 patients. The cause specific survival rates were 75%, 50%, and 50% at 5 years, 10 years, and 15 years, respectively. Multivariate analysis showed that the presence of metastases was the most important independent prognostic factor for survival. External beam radiotherapy was associated with a poorer prognosis, in that it was reserved for patients with either inoperable disease or residual disease after surgery and patients with no uptake of radioiodine.

CONCLUSIONS

A large proportion of thyroid tumors showed extrathyroid spread and distant metastases, which frequently were not iodine-avid. The prevalent histologic type was papillary, often with features of poor differentiation. Thyroid carcinoma in the elderly appears to behave more aggressively, and they have a less favorable prognosis compared with younger adults. Cancer 2003;97:2736–42. © 2003 American Cancer Society.

DOI 10.1002/cncr.11410

Carcinoma of the thyroid gland represents < 0.5% of all malignancies in England and Wales.1 Annually, there are approximately 1000 new diagnoses and about 250 deaths from thyroid carcinoma. The highest incidence of thyroid carcinoma in the United Kingdom is seen in North and Mid-Wales, where the levels of fallout radiation are highest.1

Differentiated thyroid carcinoma predominately affects young adults, with the highest incidence occurring between ages 25–54 years.2 The median age at diagnosis for patients with papillary carcinoma is 40 years for females and 44 years for males, whereas the median age at diagnosis for patients with follicular carcinoma is 48 years for females and 53 years for males.3 However, thyroid carcinoma affects all age groups, including the very young and the elderly. Between 2.5% and 12% of differentiated carcinomas occur in individuals older than 65 years, and the incidence in this age group appears to be rising in recent series.4, 5

Although the overall survival of young adults with differentiated thyroid carcinoma is excellent, there is little published information on the outcome of treatment in the elderly. The objective of this study was to investigate the clinical and pathologic characteristics of differentiated thyroid carcinoma in elderly patients, to assess the biologic behavior of their tumors, and to evaluate the results of their treatment.

MATERIALS AND METHODS

The Royal Marsden Hospital serves as a tertiary referral unit for patients with thyroid disease and maintains a tumor registry of all patients with thyroid carcinoma based on a confirmed report of thyroid malignancy. All clinical information at the time of presentation and at follow-up is entered at the time of the consultation. The database holds 54 parameters for each patient, including demographic information, details of initial presentation, staging, and treatment. Patients are followed until death, and the cause of death is recorded.

Patients

Over the past 60 years, 1448 patients with differentiated thyroid carcinoma were treated in our unit. Histologic typing of thyroid carcinoma was in accordance with the most recent World Health Organization (WHO) classification system.6 We analyzed the results of 1390 of these patients, who had a minimum follow-up of 2 years after the completion of treatment. Among these, we identified 111 patients who were age 70 years or older at diagnosis. Their records were reviewed with respect to clinical presentation, pathologic features, treatment, patterns of recurrence, and survival.

Statistical Analysis

Actuarial survival was calculated from the date of diagnosis to the date of last follow-up or the date of death by the Kaplan–Meier method.7 Comparisons between subgroups of patients defined by various prognostic factors were performed with the log-rank test. Because many prognostic factors were identified as significant for survival in a univariate analysis, variables that were identified as significant at P < 0.01 were entered into a stepwise Cox proportional hazards model. Then, a multivariate analysis was performed to select a small set of independent predictors of survival.

Overall survival was defined as the number of patients who remained alive at the last follow-up. Cause specific survival was defined in patients who had a known cause of death relating to thyroid carcinoma. Patients were censured at the time of death or last follow-up. Patients who died of other diseases were censored from the calculation.

RESULTS

Since 1949, 111 patients age 70 years or older with differentiated thyroid carcinoma have been treated in our unit. This equates to a mean of 1.8 patients per year in the early years of the study and 3.8 patients per year since 1990. There were 83 female patients and 28 male patients, with a female-to-male ratio of 3:1. The median follow-up was 9 years (range, 2–19 years). The oldest patient was age 93 years, and the median age was 75 years. Eighty-nine patients presented with a thyroid mass, although associated symptoms (such as dysphagia, pain, hoarse voice, or breathing difficulties) were uncommon. Cervical lymph node enlargement was the presenting symptom in 17 patients, and bone pain was the presenting symptom in 6 patients, including 2 patients with pathologic fractures.

A family history of differentiated thyroid carcinoma was documented in only one patient. Two patients had a history of radioiodine treatment for thyrotoxicosis 10 years previously, and 1 patient had received external beam radiotherapy to the neck for non-Hodgkin lymphoma 8 years previously.

Table 1 summarizes the clinical stage and histologic grade for all patients in this study. Tumor histology was designated according to the WHO classification system as papillary carcinoma in 58 patients, follicular carcinoma in 46 patients, and Hürthle cell carcinoma in 7 patients. Fifty-five tumors were well-differentiated (Grade 1), 22 tumors were Grade 2, and 34 tumors were Grade 3. The majority of tumors were locally advanced, with 78 tumors (70%) that measured > 4 cm in greatest dimension or that infiltrated beyond the thyroid capsule (pT3 or T4). At the time of diagnosis, lymph nodes were involved in 49 patients (44%), and distant metastases were documented in 26 patients (23%).

Table 1. Classification and Histologic Grade of Tumors from 111 Patients with Differentiated Thyroid Carcinoma

Characteristic	No. of patients (%)
Histology
Papillary	58 (52)
Follicular	46 (42)
Hürthle cell	7 (6)
Differentiation
Grade 1	55 (49)
Grade 2	22 (20)
Grade 3	34 (31)
TNM classification
T1	7 (6)
T2	26 (23)
T3	22 (20)
T4	56 (51)
N0	62 (56)
N1a	23 (21)
N1b	2 (23)
M0	85 (77)
M1	26 (23)

Sites of distant spread included the skeleton in 12 patients, the lung in 7 patients, lung and bone in 6 patients, and soft tissue in 1 patient. Asymptomatic metastatic disease was discovered on the postablation radioiodine (I-131) scan in 7 patients.

Treatment is shown in Table 2. Surgery consisted of total thyroidectomy in 46 patients (41%), subtotal thyroidectomy in 36 patients (33%), and biopsy only in 29 patients (26%). Postoperative radioiodine was administered to 80 patients (72%); 22 patients received a single ablation dose of 3 GBq, and 58 patients required repeated doses (cumulative activity, 6.6–29 GBq). External radiotherapy to the neck was delivered to 19 patients with either inoperable or residual disease after surgery and with no uptake of radioiodine. In addition, five patients received palliative radiotherapy for bone pain.

Table 2. Treatment of 111 Patients with Differentiated Thyroid Carcinoma

Treatment	No. of patients (%)
GBq: gigabecquerel.
Surgery
Total thyroidectomy	46 (41)
Subtotal thyroidectomy	36 (33)
Biopsy only	29 (26)
Radioiodine
Ablation (3 GBq) only	22 (20)
Further doses (6.6–29.0 GBq)	58 (52)
External beam radiotherapy
Neck	19 (17)
Bone disease	5 (4)

With a median follow-up of 9 years (range, 2–19 years), 23 patients (21%) developed a local recurrence in the thyroid bed or neck, and 17 patients (15%) developed distant metastases. Local recurrent disease preceded the appearance of distant metastases in 13 of 17 patients who developed metastases. The median time to recurrence was 9 months (range, 2–32 months). Five patients underwent excision of recurrent disease, five patients received external beam radiotherapy, and seven patients received radioiodine. The management of patients with recurrent disease was mainly palliative because of patients' poor general condition and advanced tumor extent.

Overall survival is shown in Figure 1. The cause specific survival rates at 5 years, 10 years, and 15 years were 75%, 50%, and 50%, respectively. Survival according to the presence of metastases is shown in Figure 2, cause specific survival according to treatment by external beam radiotherapy is shown in Figure 3, and cause specific survival according to extent of surgery is shown in Figure 4. Figure 5 shows changes in cause specific survival according to decade of treatment.

Figure 1. Overall survival of elderly patients with differentiated thyroid carcinoma age ≥ 70 years at the time of diagnosis.

Figure 2. Cause specific survival of elderly patients with differentiated thyroid carcinoma comparing patients who developed metastases (Mets) with patients who did not develop metastases (No Mets).

Figure 3. The survival of elderly patients with differentiated thyroid carcinoma comparing patients who received radiotherapy (RT) with patients who did not receive RT (No RT).

Figure 4. Cause specific survival of elderly patients with differentiated thyroid carcinoma according to patients who underwent thyroidectomy, patients who underwent subtotal thyroidectomy, and patients who underwent biopsy only.

Figure 5. Cause specific survival by decade in elderly patients with thyroid carcinoma. Lines show 95% confidence intervals for survival at 3 years.

Results of the Cox regression analysis of various prognostic factors is shown in Table 3. In the univariate analysis, histologic type, lymph node status, extent of surgery, presence of metastases, and treatment with external beam radiotherapy all were independent prognostic factors for cause specific survival. Tumor size had borderline significance as an independent risk factor for local recurrence in univariate analysis (P = 0.052). It is noteworthy that follicular histology was associated with a better prognosis and a lower risk of metastatic spread compared with other histologic types.

Table 3. Cox Regression Analysis of Cause-Specific Survival in 111 Patients with Differentiated Thyroid Carcinoma

Prognostic factor	No. of patients	Univariate analysis		Multivariate analysis
		Crude HR (95% CI)	P value	Adjusted HR (95% CI)	P value
HR: hazard ratio; 95% CI: 95% confidence interval; N/A: not applicable.
Age group
70–74 yrs	50	1.00	—	N/A	—
75–79 yrs	37	1.38 (0.91–2.1)	—	N/A	—
≥ 80 yrs	24	1.91 (1.26–2.91)	0.13	N/A	—
Follicular histology
No	65	1.00	—	1.00	—
Yes	46	0.48 (0.25–0.91)	0.02	0.6 (0.31–1.2)	0.148
Lymph node status
N0	62	1.00	—	1.00	—
N1a	23	1.89 (1.3–2.77)	—	0.76 (0.28–2.05)	—
N1b	26	3.59 (2.45–5.25)	0.001	1.75 (0.78–3.91)	0.19
Surgery
Total	46	1.00	—	1.00	—
Subtotal	36	2.5 (0.92–6.6)	—	1.94 (0.71–5.32)	—
Biopsy	29	5.5 (1.7–17.8)	0.002	3.73 (1.29–10.78)	0.07

In the multivariate analysis (Table 4), the only two factors that emerged with statistical significance for cause specific survival were metastatic spread and external beam radiotherapy. The outcome for patients who underwent total thyroidectomy was much improved compared with patients who underwent biopsy alone; however, in the multivariate analysis, the independent effect of surgery did not quite achieve statistical significance (P = 0.07). Patients who received external radiotherapy had 3 times the risk of an adverse outcome compared with patients who did not receive radiotherapy (95% confidence interval [95%CI], 1.8–5.3), and the risk persisted when patients were subdivided into patients who received radical radiotherapy to the neck and patients who received palliative treatment for bone metastases. The former group was comprised of patients who had either inoperable or residual disease and had no uptake of radioiodine.

Table 4. Multivariate Analysis of Treatment Outcomes in Patients with Differentiated Thyroid Carcinoma

Outcome	HR	95% CI	P value
HR: hazard ratio; 95% CI: 95% confidence interval; RT: external beam radiotherapy.
Cause-specific survival
Metastases (present vs. absent)	4.72	2.4–9.3	< 0.001
RT (treated vs. no treatment)	2.95	1.5–5.8	0.001
Distant recurrence
Metastases (present vs. absent)	4.8	1.67–13.8	0.004
Overall survival
Age (< 75 yrs vs. > 75 yrs)	2.95	2.1–4.2	0.002
Metastases (present vs. absent)	3.11	1.7–5.6	0.001
RT (treated vs. no treatment)	3.11	1.8–5.3	0.001

No significant benefit of ablative radioiodine treatment on cause specific survival was evident in this study (treatment vs. no treatment: hazard ratio, 0.98; 95%CI, 0.53–1.81). Older age emerged as an important risk factor for overall survival in both univariate and multivariate analyses, with patients older than 80 years showing a 3-fold increased adverse risk (95%CI, 2.16–4.12) compared with patients younger than 75 years.

The probability of survival improved significantly according to the decade of treatment (P = 0.03; chi-square test) (Fig. 5). The most marked improvement was seen in patients treated since 1990, when total thyroidectomy followed by ablative radioiodine became routine for suitable patients. The median survival improved from 4.7 years before 1970, to 6.0 years before 1980, to 8.8 years before 1990 and is now > 10 years.

DISCUSSION

Overall survival rates for adult patients with differentiated thyroid carcinoma range from 80% to 95%.8–11 Age at diagnosis was identified as a major independent prognostic factor in several large retrospective series.8, 9, 11, 12 In a previous study of patients with differentiated thyroid carcinoma of all ages treated in our unit, we found that age was the single most important independent prognostic factor determining outcome.13 For any 10-year difference in age, there was a near doubling of risk. The risk of recurrence and death increased linearly with age, particularly after age 50 years. The reason for the better prognosis in younger adults is unknown but partly may reflect greater iodine avidity.

The current results confirm that thyroid carcinoma in the elderly has an aggressive biologic behavior. At presentation, 70% of patients had locally advanced disease, 44% of patients had associated lymph node disease, and 23% of patients had evidence of distant metastases. In addition, histologic differentiation was > Grade 1 in 50% of patients. By comparison, of all 1390 patients with differentiated thyroid carcinoma on our data base, only 18% of patients had locally advanced disease, 35% of patients had associated lymph node disease, and 10% had distant metastases at presentation.13 Furthermore, 80% of patients had well-differentiated tumors (Grade 1). Girelli and colleagues reported similar observations in the only other large series of elderly patients.4 In children and adolescents, extensive disease, including distant metastases at presentation, still may be associated with an excellent long-term prognosis.14–16 Children younger than 10 years have a higher risk of death, although only 5–14% die of the disease.15, 17 These observations imply that extremes of age have an adverse effect on prognosis independent of the extent of disease at presentation.

In the current series, 21% of patients developed locoregional recurrent disease, and 15% of patients developed distant metastases. Recurrent disease occurred relatively soon after initial treatment. The median time from the end of therapy to clinical recurrence was only 9 months, compared with 34 months in the whole series of 1390 adults with differentiated thyroid carcinoma. The interval between the detection of recurrent disease and death also was short, with a median of 9 months. This may indicate that tumors in older patients have a shorter doubling time. Other authors also have reported that age influences the probability of developing recurrent disease, the interval from initial treatment to recurrence, and the duration of survival after recurrence.8, 18–19

Only 41% of patients in the current series underwent total thyroidectomy due mainly to the poor condition of the patient or to the advanced tumor stage, precluding definitive surgery. In the majority of these patients, disease progressed rapidly despite radioiodine treatment or external beam radiotherapy. The extent of surgery was identified as an independent risk factor for survival in the univariate analysis but failed to achieve statistical significance in the multivariate analysis, probably because of small numbers. Other series have shown a significant survival advantage after total thyroidectomy compared with lobectomy.8, 20 In a recent prospective study of patients with high-risk papillary carcinoma, total thyroidectomy enhanced survival considerably compared with lesser procedures.21

Not only are these tumors more extensive in the elderly, but uptake of radioiodine also is much lower. Schlumberger and colleagues noted I-131 uptake at metastatic sites in only 53% of patients older than 40 years compared with 90% of patients younger than 40 years.22

In the current series, only three patients with diffuse lung metastases demonstrated good radioiodine uptake and remained disease free 3–5 years posttreatment. Previous dosimetry studies have shown that the radiation dose absorbed in tumor must exceed 100 grays (Gy) to achieve complete remission.23 We observed very low radioiodine uptake in 4 of 21 patients with bone metastases, none of whom showed evidence of a response. We also noted poor response of the primary tumors to radioiodine in patients with large-volume disease despite persistent uptake in the neck. These findings, taken together with the results of other studies, suggest a biologic difference in thyroid tumor cells in older patients, resulting in a reduced capacity to take up radioactive iodine.5, 8, 22, 24

We noted a poorer outcome in patients who received external radiotherapy to the neck or to bone. Because this treatment was reserved for patients with inoperable, recurrent, or metastatic disease, the poorer outcome reflects more advanced disease in these patients. External radiotherapy is effective in local disease control and prevention of locoregional recurrence for patients with papillary carcinoma.25–27 We have previously shown that external radiotherapy achieves local control in 81% of patients when residual microscopic disease is present and achieves complete regression in 37% of patients with macroscopic disease.27 Radiotherapy also is effective in the palliation of patients with distressing local symptoms. Doses of 40–50 Gy to the thyroid bed are recommended when local invasion of vital structures, such as the trachea, carotid sheath or cervical esophagus, precludes complete surgical removal.28

To improve outcome in this older population, we recommend total thyroidectomy and selective lymph node dissection (when lymph nodes are involved) followed by radioiodine. Since these measures became routine in our unit, we have noted a significantly improved outcome in our older patients. This has occurred at a time when we have been treating greater numbers of older patients, and it reinforces our view that patients should be offered total thyroidectomy and ablative radioiodine provided they are fit enough to undergo this treatment. Management by a multidisciplinary team in a specialized unit is considered essential.29 Complication and mortality rates of surgery may be reduced to the same rates that are acceptable in younger patients, provided that surgery is undertaken by experienced surgeons.30 Coexisting cardiovascular and respiratory disease must be recognized and managed effectively prior to surgery.

In summary, differentiated carcinoma of the thyroid generally is more aggressive in elderly patients, and the prognosis for the elderly is less favorable compared with younger adults. Tumors in elderly patients frequently show extrathyroid spread, with a higher incidence of distant metastases in bones and lungs, and often are not iodine-avid. These tumors frequently exhibit features of poor differentiation.

Clinicians who see older patients with thyroid carcinoma need to be aware of their poorer prognosis. Consideration should be given to more radical treatment, avoiding suboptimal therapy if the patient is fit enough. In the United Kingdom, national guidelines for the management of patients with thyroid carcinoma have been published recently that recognize the more aggressive nature of these tumors in the elderly.28