Recurrence of follicular cancers

The ‘recurrence’ rate was positively correlated with the extent of the disease, (7.1%, 20.0%

and 26.0% in intra-thyroidal, regional and distal disease, respectively) indicating that the metastatic disease already present (in the cervical nodes or in distant regions) tends to recur more often as compared to that without metastasis (Fig. 16.6).

Time to recurr after initial treatment (yrs) 20

FIG. 16.6. Shows recurrence rate in follicular cancer when presented with thyroid nodule, nodal and distal metastases.

The mean time to recur in patients with intra-thyroidal disease was 5.9 years which was significantly longer than those which occurred in patients with metastatic regional (2.9 years) and distal disease (3.4 years) at initial presentation. Of the total 104 ‘recurrence’, 34.6% were DFR suggesting that a higher percentage (65%) of recurrences occurred in an already existing disease. A larger proportion of recurrences were DFR in patients with intra-thyroidal disease (82.6%) as compared to 43.5% and 12% seen in those with regional and distal disease, respectively. In other words, patients with DM have a lesser chance to be cured and have progressive disease while those with intra-thyroidal disease tend to experience a longer disease-free interval. The predominant sites of recurrence were 36.5% in nodes, 21.2% in the skeletal system, 15.4% in the lungs and mediastinum, 15.4% in the multiple sites, 6.7% in the thyroid bed and 4.8% at other rare sites such as brain and liver.

The DR also significantly (p <0.00001) differed with the extent of the disease (4.1%, 3.5%

and 18.8% in intra-thyroidal, regional and distal disease, respectively) at initial presentation These findings suggest that the regional disease at initial presentation tends to recur loco-regionally, distal disease tend to recur more distally, and intra-thyroidal disease could metastasize with equal frequency to the cervical nodes or to distant sites. The overall mortality in the recurrent disease was 54.8%. The death due to recurrence may vary between 0.0-100%. In fact in one study, it has been shown as an independent predictor for adverse outcome [16.26]. The rather high mortality resulting from recurrence of disease indicates that

treatment should aim at reducing the recurrence to a low level so that eventually the mortality due to cancer can be reduced and controlled.

16.2.1. Survival

An overall 30-year mortality rate of 21.0% (139/663) seen in this series is well within the published range of 3.3-64%.The average age at death was 52.3 years (median, 52 years) and average age at initial presentation was 43.3 years. The mean time for cancer specific death for 139 patients was 4.6 years (median 3.9). About 96.4% of the deaths occurred within 15 years indicating that death at a later period is rare. In a series of 49 patients, DeGroot, et al. [16.26]

did not observe any death or recurrence after 13 years. In another study, no recurrence or death was recorded 10 years after treatment.

There was a direct relationship between mortality and extent of disease (3.1%, 15.7% and 49.8% in intra-thyroidal, nodal and distal disease at initial presentation, respectively. The mean time to die was significantly longer (p= 0.003) for intra-thyroidal disease (7.6 years) as compared to 4.2 years in distal disease at initial presentation. An improved survival rate in recent years has been reported by others also [16.27,16.28].This has been perhaps because of early diagnosis and availability of sophisticated techniques for management of the disease. An individual with nodal disease is therefore at a high risk for mortality if the (a) nodal disease does not concentrate ¹³¹I, (b) disease recurs and (c) ¹³¹I treatment has not been received.

Years after initial treatment

FIG. 16.7. Survival rate of follicular cancers when presenting with thyroid nodules, nodal or distal metastases.

The recurrence and the mortality rate were 26.0% and 49.8%, respectively for patients with distal metastases (Fig. 16.7). The presence of DM has a poor outcome and is the prime predictor both for mortality and recurrence in univariate analysis as observed by us, and reported by others. The 10 and 15 year survival for patients with pulmonary metastasis in this series was 74.8% and 68.6%, which is much higher than the corresponding values of 28.9%

and 11.4% reported by Nemec, et al. [16.31]. The outcome of the disease depends upon the site to recur, with a better outcome for pulmonary metastasis, which concentrate ¹³¹I [16.13, 16.32] and are micronodular in nature [16.33]. In this study, the 5-year survival rate (63.5%) for patients with DM concentrating ¹³¹I (FM) was higher than 43.8% seen with NFM. Similar findings of better survival in metastatic disease concentrating ¹³¹I as compared to those, which

the disease tends to recur regardless of host factors, tumour features or treatment modality.

However, a patient with DM is at a ‘high-risk’ for mortality if he (a) is above 34 years and (b) has not received ¹³¹I treatment. The reported factors in univariate analysis in 85 cases of DM have been age at diagnosis, extent of disease, lung pattern, ¹³¹I uptake and treatment [16.35].

Follicular carcinoma is believed to have a more aggressive course of disease as compared to PTC, because it is a disease predominant in the elderly age group, where tumours are believed to be large, more invasive, less differentiated and have a propensity to metastasize to distal sites. When matched for age and sex, the mortality in follicular and papillary types of the tumour has been comparable. With a comparable stage of the disease and similar age the survival does not differ significantly between the PTC and FTC. The outcome of a minimally invasive FTC confined to the thyroid bed and intra-thyroidal PTC is reported to be excellent.

In one [16.36] series, the 6.3% mortality in FTC was not significantly different from 5.4% in PTC in patients without the presence of DM. When the age was matched decade wise for 663 patients of FTC and 739 patients for PTC, except for the extreme ages; below 19 years and above 60 years, there was a significantly higher death rate of 3.1%, 12.1%, 27.3% and 33.6%

for age groups in 3rd, 4th, 5th and 6th decade in FTC as compared to 0.0%, 1.5%, 10.1% and 17.8% for the respective age groups in PTC. There was no significant difference in the mortality rate when the intra-thyroidal disease was matched for both types of histology. There was a significant difference (p= 0.024) in mortality rate between FTC (14.8%) as compared to PTC (7.8%) for nodal disease as well as distal disease (p= 0.0002). Nodal disease in FTC has a poorer prognosis than that in PTC. Distal metastases also had a poorer prognosis in FTC.

This is because skeletal metastasis was a predominant site in FTC while incidence of the pulmonary metastasis is higher in PTC. The lung metastasis had a better prognosis as compared to skeletal metastases as observed by us and reported by others (Table 16.2). In contrast, some studies have reported comparable results between the two types of tumours when matched for the extent of the disease.

TABLE 16.2. COEFFICIENT AND HAZARD RATIO FOR MORTALITY

Factors Coefficient Hazard ratio

Age 35 years 1.08 0.34

+ Local invasion 0.25 0.77

+ Distant metastases 1.13 0.32

+ Less well-differentiated

tumour 0.24 0.78

No radioiodine treatment 0.34 1.4

Hence the above data indicates that frequent follow-up of patients for clinical evaluation and investigations such as whole body scans with radioiodine,^99mTc MIBI or Tetrofosmin ,or ²⁰¹Tl chloride or ¹⁸F FDG if available should be considered. Wherever noniodine concentrating disease is suspected other investigations such as CT scans, MRI or ultrasound studies should be done to localize disease in the presence of high levels of serum Tg. Early detection is essential for instituting therapy with Radioiodine when concentration is observed or surgery where possible and external radiotherapy if disease is extensive and surgery is not possible or disease removal is partial.

The other strategy employed in the follow–up of patients is to look for the effects of the treatment given to the patient. Radioiodine therapy is known to produce chronic side effects and these have to be carefully assessed at the time of the follow–up.