Difference between papillary and follicular thyroid carcinoma outcomes: an experience from Egyptian institution

Introduction

Differentiated thyroid carcinoma (DTC) originates from epithelial follicular cell and considered as a major form of thyroid carcinoma. DTC includes two histological types, namely, papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC)¹.

DTC is mostly indolent and a clinically nonsignificant disease that is found incidentally with good prognosis in most cases and a high 10-year survival rate (90%-95%)².

A thyroid nodule is the first symptom of thyroid cancer and of particular concern when found in patients younger than 20 years old, with greater potential for malignant presentation in such cases. Pain in the anterior region of the neck and changes in voice may occur as late symptoms because of the involvement of the recurrent laryngeal nerve³.

Approximately 80%-85% of all thyroid malignancies are PTCs. In addition to the classic form of PTCs, several morphological variants, usually classified as biologically aggressive, have been identified: diffuse sclerosing, tall cell, columnar cell, solid/trabecular, and insular variants⁴. The aggressive behavior of PTC is attributed to its invasion into extrathyroidal tissues and extensive vascular invasion⁵. However, recent studies have shown that some of these variants (sclerosing and tall cell) are not related to poor outcome per se, but rather tumor prognosis is dependent on the presence of aggressive features, such as extracapsular and vascular invasion, larger tumor size, and the presence of distant metastasis (DM)^6,7. FTC is the second most frequent subtype and accounts for approximately 10%-15% of all thyroid cancers. Hürthle cell thyroid carcinoma is a variant of FTC that accounts for 3% of thyroid malignancies and is characterized by less sensitivity to iodine therapy^8,9.

DTCs are analyzed as a single group in clinical studies that investigate the prognostic factors and prognosis of patients. However, the biological behaviors of the two types of DTC significantly vary. PTC metastasizes frequently to the regional lymph nodes and may show a high incidence of significant extrathyroid extension to adjacent organs. By contrast, FTC more frequently metastasizes to more distant organs, such as the lung, bone, and brain, than PTC¹⁰.

PTC and FTC are often treated similarly despite their numerous biological differences. The most effective management of thyroid cancers is the surgical removal of the thyroid gland (thyroidectomy), followed by radioactive iodine (RAI) ablation and thyroid replacement therapy for TSH suppression. Chemotherapy or radiotherapy has a limited role only in cases with DM or advanced cancer stage¹¹.

Unlike most cancers, recurrence of DTC does not necessarily correlate with increased risk of mortality. This phenomenon is particularly demonstrated in young patients who have higher rates of local recurrence, but have low mortality risk. Several clinical features enable initial risk stratification, including patient age, size of the primary tumor, histology, gross extra-thyroidal extension, completeness of resection, involvement of the cervical lymph nodes, or DM¹².

In the present study, we aimed to distinguish the outcomes of prognosis between PTC and FTC in a single institution (Mansoura University Hospital in Egypt).

Patients and methods

Results

In the present retrospective study, 558 patients were enrolled, and their data were analyzed with median follow-up period of 52 months (range: 12-120 months). A total of 477 patients (85.5%) were diagnosed with PTC, whereas FTC was found in 81 (14.5%) patients.

Other patients’ characteristics are shown in Table 1.

Survival

The 10-year OS rates were 97% and 89% for PTC and FTC, respectively, with a statistically significant difference (P=0.003) (Figure 1). The 10-year DFS rates were 77.2% in PTC vs. 65% in FTC, without statistically significant difference (P=0.179).

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Figure 1

Kaplan-Meier plot of OS for PTC and FTC. OS, overall survival; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma.

Discussion

PTC and FTC are generally indolent diseases and show good prognosis if treated appropriately. These DTCs are studied as a single group in investigative studies on the prognosis of thyroid carcinoma, in spite of their distinct biological behavior. Therefore, prognostic factors and prognosis of PTC and FTC patients should be analyzed independently¹⁴. In the present study, we evaluated the factors that affected the prognosis of PTC and FTC in Egypt and compared them with other reports. Our results showed that the significant prognostic factors differed between the two types of DTC. However, some studies could not distinguish the PTC and FTC outcomes^10–15, and other reports have considered a significantly poorer prognosis for FTC^16,17, which is consistent with our report.

The age of PTC patients in our study ranged from 8 to 71 years old, with a median of 43 years old for PTC. By contrast, the age of FTC patients, ranged from 21 to 72 years old with a median of 43 years old. Other studies have reported an age range from 25 to 65 years old with the median age at diagnosis of 49 years old¹⁵. These results agree with previous studies demonstrating that PTC and FTC can occur in children (accounting for 80% and 10%-20%, respectively)¹⁶.

Female patients were more common than males in our study with a ratio of 2.28:1 in PTC and 2.5:1 for FTC, which agrees with the results of another report¹⁵.

Ages older than 45 years old affected the OS and DFS of PTC patients on the univariate analysis. However, this factor was not an independent prognostic factor, contrary to previous results¹⁸. Other studies have reported that its prognostic effect on DFS was weak¹⁹. However, some studies have stated that ages 45 years old or older are a significant prognostic factor for FTC on univariate analysis (which is not consistent with our results), but are not an independent prognostic factor²⁰.

A previous study has demonstrated that gender only has a weak prognostic significance in DTC, with women showing better survival advantage than men. This result was attributed to a younger age distribution among women, and if age was also considered, gender would not exhibit prognostic significance²¹. However, other studies have reported that male gender was an independent prognostic factor for PTC and FTC^18,22. By contrast, our study showed the sex of a patient had no effect on DFS and OS for both PTC and FTC. The difference in the results can be attributed to the difference in the numbers of cases.

In our study, multifocality had no effect on the OS of PTC and FTC patients. However, multifocality significantly influenced the DFS of PTC on the univariate analysis, but not on the multivariate analysis, which agrees with previous results¹⁹. Passler et al. stated that multifocality significantly affects the outcome of both PTC and FTC patients¹⁸. One study has reported that PTC with lymph node metastasis is more frequently detected in multiple than in solitary microcarcinomas and suggested that multiplicity reflects the aggressive behavior of PTC to some extent²³.

Tumor size of larger than 4 cm significantly affected OS and DFS of PTC patients, which is consistent with other studies^18,22. Therefore, careful and extensive surgery, as well as postoperative follow-up, is recommended for PTC tumor sizes larger than 4 cm even in the absence of other high-risk features. In FTC, the size of larger than 4 cm had marginal significance for DFS in FTC, but not for cause-specific survival (CSS) on multivariate analysis²⁰.

Lymph node metastasis was not an independent prognostic factor in our series, contrary to previous reports, which determined that this is an independent prognostic factor in PTC^18,19. Other studies have found that pathological node metastasis increases the rate of carcinoma recurrence²³.

We found that lymph node metastasis did not affect the outcome of FTC, which could be explained by the low possibility of FTC to metastasize to the regional lymph node, and lymph-node dissection is rarely performed during surgery for patients suspected of FTC. Thus, evaluating the prognostic value of this factor is important. Previous studies have found that FTC with pathological node metastasis show an aggressive pathology, e.g., widely invasive carcinoma, and extensive lymph-node dissection is recommended for these FTC cases²⁰. Passler et al.¹⁸ found that involvement of cervical lymph nodes is statistically significant in univariate analysis only in patients >45 years of age.

In our result and in those of other studies, the variant of PTC did not significantly affect survival²⁴. The tall cell variant has been reported to be typical with aggressive behavior and independently affects DFS and CSS of PTC patients, as shown by multivariate analysis²⁵. The difference in the results could be attributed to the very small number of this variant in our study.

The survival in Hürthle cell carcinoma was lower than the classic variant in the present study, but no statistical significance was found. Previous studies have found that most cases of oxyphilic cell variant were RAI refractory with worse prognosis than conventional FTC¹⁸. Moreover, the prognosis of oxyphilic cell variant is reportedly similar to or even better than that of conventional FTC²⁰.

Similar to the reported results, the extrathyroid extension in our study was an independent prognostic factor for OS and DFS in PTC and DFS in FTC^18,19. A rare event of extrathyroid extension in FTC had been reported and accounted for only 2% of patients and predicted an adverse prognosis²⁰.

The widely invasive FTC is more likely to recur and exhibit poorer prognosis than the minimally invasive FTC. Therefore, whether an FTC is widely or minimally invasive should be diagnosed during pathological examination to predict patient prognosis and select a subsequent therapy²⁰. In the present series, OS and DFS in widely invasive FTC were significantly lower than those of patients with minimally invasive FTC, which agrees with other studies. Thus, completion of total thyroidectomy followed by RAI ablation for widely invasive FTC patients is advised¹⁸.

Although the incidence of DM in PTC is lower than that in FTC, PTC can metastasize not only to regional lymph nodes, but also to distant organs, such as the lung, bone, and brain. This study showed that the development of DM was an independent prognostic factor of PTC and FTC, as stated in previous reports¹⁸. DM at surgery is one of the most important prognostic factors for CSS of patients¹⁹.

Total or near-total thyroidectomy is primarily recommended to reduce the risk of recurrence, thereby improving survival²⁶. Bilimoria et al.²⁷ demonstrated that total thyroidectomy results in lower recurrence rates and improves survival for PTC compared with lobectomy. However, less radical surgery for all low-risk patients is preferred in some studies²⁸.

Postoperative treatment consisted of radioactive ¹³¹I (80-120 mCi) in patients who underwent at least a near-total thyroidectomy and thyroxin suppression therapy. This treatment was used to ablate residual normal thyroid tissue and adjuvant therapy of subclinically or clinically apparent residual disease. Several studies have suggested a 50% 10-year reduction in recurrence risk and decrease in mortality rate and risk of metastasis^29,30. Chemotherapy was used in some cases of metastatic, non-resectable, or iodine non-responder-differentiated thyroid cancer. However, this modality may result in rare complete remission and uncommon long-term responses³⁰. Several single chemotherapeutic agents are used in thyroid cancer. Additionally, this treatment has no benefit when used in combination therapy to improve the overall response, but may instead increase toxicity³⁰.

In conclusion, the significant prognostic factors differ between the two types of DTC. Therefore, PTC and FTC patients should be analyzed and reported independently.

PTC prognosis is widely and significantly affected by the age and extrathyroid extension compared with FTC. Additionally, survival of FTC patients is significantly poorer than that of PTC patients.