Clinical Significance of Multinodularity in Patients with Papillary Thyroid Carcinoma

Discussion

The study was undertaken to investigate characteristics and clinical significance of nodules in multinodular thyroid if one nodule is diagnosed as PC. Thyroid cancer is a relatively rare tumor but it represents the most frequent form of malignant tumor found in the endocrine glands, with PC being its most common variety. Co-existence of PC and other abnormalities of the thyroid is known to be present in a significant proportion of patients, and was investigated in several former studies. However, the clinical significance of other nodules in patients with multinodular thyroid and confirmed PC in one of the nodules is not yet fully understood. In our study, additional diagnoses that were confirmed in other nodules were NG (66%), ID (29%), HT (27%), and adenoma (7%).

HT is a frequent inflammatory thyroid disease and the main cause of hypothyroidism, characterized by the infiltration of the thyroid gland by inflammatory cells (6). The clinical importance of co-existing HT in patients with PC was investigated in several former studies, especially since it is known that the prevalence of HT is significantly higher in patients with PC (7-9). Our results show that in these patients the risk of RLN metastasis is significantly lower than in those without HT (p<0.05). Kim and colleagues separately analyzed different regions of affected lymph nodes, and concluded that only central lymph node metastases were found at lower frequency in patients without HT, while the difference in involvement of lateral lymph nodes was not statistically significant between study and control groups (10). These results are in accordance with the results of Singh and associates, which confirmed positive correlation between HT and disease-free (DFS) and overall (OS) survival of patients with PC, since metastasis in lymph nodes place a patient in higher disease stage than in cases without lymph node involvement, and the presence of coexistent HT does not affect the diagnostic evaluation or management of PC (9). Pisanu et al. also investigated the frequency of co-existence of HT and differentiated thyroid cancer, and the impact of HT on the management of differentiated thyroid cancer in 44 patients with HT, and concluded that an adequate follow-up of patients with HT may permit an early diagnosis of differentiated thyroid cancer and its appropriate management (11). Thus, regular follow-up of patients with confirmed HT may be one of the reasons for prolonged DFS and OS in these patients. Another study reviewed the medical records of 195 consecutive patients with PC who underwent total thyroidectomy and bilateral central lymph node dissection (12). In this study, a large proportion of patients with PC were found to have coexisting HT (28.7%), and these patients had smaller tumor size, lower incidence of capsular invasion and central lymph node metastases than patients without HT. Compared to patients without HT, patients with HT were younger, with a female predominance, which are the most important and well-known prognostic variables for thyroid cancer mortality. This is in accordance with our results, which confirmed smaller average PC nodule size in patients with PC and co-existing HT or NG than in patients without these diseases (although the difference did not reach statistical significance), as well as positive correlation of PC nodule size and the presence of RLN metastases. Although the role of the inflammatory-immune cells is not yet fully understood, more favorable course of PC in the presence of lymphocytic infiltration may also be due to immune reaction which controls tumor growth and proliferation (13, 14).

NG is a very common thyroid disorder. In our patients with PC and additional diagnosis of NG, a smaller average PC nodule size was observed than in patients without NG (13.2 mm vs. 15.2 mm), probably due to regular routine follow-up of patients with diagnosed NG. Again, PC nodule size was positively correlated with the presence of RLN metastases, consequently making RLN metastases less common in patients with additional diagnosis of NG (p<0.05). These results are in correlation with a former study by Cheng et al., who also reported smaller tumor size in patients with PC and additional diagnosis of NG (15). In that study, the difference in tumor size between the two groups was even larger (14.2 mm vs. 22 mm). When comparing HT and NG, the former results indicate that the frequency of PC is significantly higher in combination with HT than with NG, and is associated with increased levels of serum TSH (16). Similar results were obtained in our cohort of patients, since 66% of them had NG, and only 27% HT. However, although NG may harbor cancer, it cannot be considered as a condition predisposing to cancer, and there is no reason to consider the surgical treatment of NG as prophylaxis of PC (17, 18). Association of NG and PC is variable, and surprisingly a high occurrence of malignancy in patients with NG has been reported in several studies (19-21), while other studies did not confirm such a strong association (22). One teaching hospital reported a high prevalence of malignancy in patients with NG (1/7), although follicular carcinoma was found to be the prevalent histological type (19). The results were consistent with the findings elsewhere in endemic goitrous regions. Considering these results, although many of these cases appear to remain clinically silent, and factors predisposing micro PCs to evolving from a sub-clinical to a clinically apparent form are still not recognized (20), it is recommended to value the dominant nodule in patients with NG as if it were a solitary nodule in an otherwise normal gland (21, 22). Our results also show the necessity of closely following-up not only the dominant nodule, but also other nodules, since the number of dominant and non-dominant PC nodules in patients with co-existing NG was approximately the same. By evaluation of only the dominant nodule, the true occurrence of PC in these patients might be under-estimated. One study reported that the cancer risk is similar for patients with one or two nodules larger than 1 cm, and decreases with more than two thyroid nodules (23). In contrast, one Center reported a markedly low frequency of carcinoma in NG (only 0.25%), while it was found in 42% of patients with solitary thyroid nodules, with PC being the most common variety (24). Problems arising in patients with co-existence of PC and NG were also studied in several former studies, since a significant discrepancy between the clinical impression and the FNA biopsy diagnosis may occur, leading to the suspicion that a false-positive FNA diagnosis was obtained (25).

In conclusion, patients with PC and additional NG or HT less often had RLN metastases, probably due to smaller PC nodule size found during routine follow-up of these benign diseases, and patients with NG also had lower rates of ID, while patients with ID had more often RLN metastases. In our cohort of patients, results show that PC was more commonly confirmed in the dominant nodule. Nevertheless, in a significant proportion of patients, PC was confirmed in the non-dominant nodule. Thus, careful follow-up of all registered nodes in patients with multinodular thyroid is mandatory. Our study group suggests US for follow-up, and in the case of newly detected suspicious nodes, or nodes that become suspicious over time (and were not assessed by FNA before), FNA is indicated.