Thyroid nodules in Graves' disease: implications in an endemically iodine deficient area.A Mishra, S Mishra
Department of Endocrine Surgery, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow - 226 014, India., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 11832639
Source of Support: None, Conflict of Interest: None
BACKGROUND AND AIM: The presence of thyroid nodules with Graves' disease raises concern about co-existent thyroid malignancy. The objective of this study is to evaluate the risk of thyroid carcinoma and the need for surgical intervention in, patients with Graves' disease with co-existent nodules in an endemically iodine deficient area (IDA). SUBJECTS AND METHODS: Retrospective study of 130 surgically managed patients of Graves' disease (1990-1999). Out of these 35 (26.9%) cases had palpable nodules. No patient had history of previous head and neck irradiation or radioiodine therapy. The clinico-pathological findings and follow-up of these cases were noted. RESULTS: Mean age of patients with nodules was 40.2 +/- 9.5 years and male to female ratio was 1:2.2. The overall incidence of thyroid carcinoma in Graves' disease was 6.2% (8/130 cases), while the incidence, in cases having nodule with Graves' disease was 17.1% (6/35 cases). The median age of patients with carcinoma was 45 years (5 women and 1 man). Besides laboratory investigations for hyperthyroidism, preoperative investigations included fine needle aspiration cytology (FNAC) and thyroid scintigraphy in 29 and 25 cases respectively. Incidence of malignancy in palpable cold nodules was 20%. FNAC could not predict malignancy with certainty in any of these cases. Five patients had papillary thyroid carcinoma while one had follicular carcinoma. Median tumour diameter was 10 mm. Tumour was multi-centric in two cases while one case had metastases to cervical lymph node. In follow-up (median =5.5 years) one patient died of unrelated cause, while rest are alive with no evidence of disease. CONCLUSIONS: Nodules are frequently associated with Graves' disease in IDA. Incidence of carcinoma is high in palpable cold nodule. We recommend early thyroidectomy in these cases.
Keywords: Adult, Aged, Endemic Diseases, Female, Graves′ Disease, complications,epidemiology,surgery,Human, India, epidemiology,Iodine, deficiency,Male, Middle Age, Risk Factors, Thyroid Nodule, epidemiology,etiology,surgery,
Thyroid nodules are frequently found in patients with Graves’ disease. Presence of these nodules raise concern about co-existent thyroid carcinoma., The reported incidence of nodules in Graves’ disease varies from to 10-33.6%.,,,, The incidence of malignancy in these nodules ranged from 3.8-15%.,, The incidence varies in different series and seems to increase in recent reports mainly due to employment of ultrasonography in diagnostic work-up and increasing popularity of total thyroidectomy for surgical treatment. Pathogenic relationship between Graves’ disease and thyroid carcinoma is still obscure. While some authors have reported that carcinoma in the background of Graves’ disease behaves more aggressively,, others have not found so., There is yet no consensus on pre-operative work-up and need for surgery in these cases.,, Though, carcinoma is the major concern, there are other causes of nodules in Graves’ disease. In an endemically iodine deficient region thyroid nodule is a frequent finding and we wonder if the implication of this finding differs in our country. At our institution, we cater to patients mainly hailing from the sub-Himalayan iodine deficient region. The objective of this study is to evaluate the risk of thyroid carcinoma and need for surgical intervention in patients with Graves’ disease with co-existent nodules in an endemically iodine deficient area.
This was a retrospective study of 130 surgically managed patients with Graves’ disease at our centre (1990-1999). No patient had history of previous head and neck irradiation or radioiodine therapy. The clinico-pathological findings and follow-up of these cases were noted. The diagnostic evaluation in these cases included, serum T4, TSH, TMA estimation, thyroid scan (I131/Tc99) and fine needle aspiration cytology (FNAC). Follow up investigations included serum TSH estimation in all and serum thyroglobin (Tg) estimation and I131 scan, in cases with thyroid carcinoma.
Out of 130 cases of surgically treated Graves’ disease 35 (26.9%) had palpable nodules. The nodules were palpable pre-operatively in 30 (85.7%) and intra-operatively in five (14.3%) cases. Mean age of these patients was 40.2 + 9.5 years (30-67 years), and females outnumbered males (M: F =1:2.2). Thyroid scintigraphy was performed in 25 cases. Scintigraphy showed cold nodule in 15, warm nodule in one, and diffuse uptake in nine cases. All the cases showing cold nodules had palpable lesions. Three out of these 15 (20%) turned out to be malignant. FNAC was performed in 29 cases and the findings were, colloid nodule (N=8), cellular colloid nodule (N=8), hyperplastic nodule (N=4), follicular or oncocytic neoplasm (N=3), and adenomatous nodule (N=3), lymphocytic thyroiditis (N=1), inconclusive (N=2). Thirty cases were referred for surgery because of failed medical treatment, while five of these cases were referred primarily because of the presence of nodule. Type of surgery performed in these cases included total thyroidectomy (n=29), near-total thyroidectomy (n=1), and subtotal thyroidectomy (n=5). One patient (case 6) of thyroid carcinoma required modified radical neck dissection (MRND) in addition to total thyroidectomy as jugular lymph nodes were involved. The main post-operative complications were, permanent hypoparathyroidism in one case, temporary hypoparathyroidism in 8 cases (22.8%), and temporary recurrent laryngeal nerve palsy in 5 cases (14.3%). There was no case of permanent recurrent laryngeal nerve palsy.
The incidence of thyroid carcinoma, in cases having nodule with Graves’ disease was 17.1% (6/35 cases), while the overall incidence of malignancy in Graves’ disease in our series was 6.2% (8/130 cases). The median age of these patients was 45 years (5 women and 1 man). Five had papillary thyroid carcinoma while one had follicular carcinoma. Clinico-pathological details of these cases are summarised in [Table - 1].
Two out of three patients who had had subtotal thyroidectomy operation refused to undergo completion of thyroidectomy. These two and case six received post-operative radioiodine ablation. All received post-operative thyroxin suppression. At the median follow up of 5.5 years (2-7.5 years), five patients were alive with no evidence of disease. One case died of cardiovascular disease.
The most common histopathological finding in other cases (31.4%) was adenomatous nodule. Histopathology findings of other cases are given in [Table - 2].
The coexistence of hyperthyroidism and thyroid carcinoma is no longer considered a rare finding, though there is no consensus yet on many aspects of this clinical condition., In Graves’ disease concern for malignancy is more in the presence of thyroid nodules.,, The incidence of these nodules reported in literature varies from 12.8%-33.6%. The main factor influencing the difference in reported prevalence of these nodules is the method used to detect these (e.g. clinical, thyroid scan, ultrasound or combination of these). When only clinical examination and scan are employed the prevalence can be much lower as compared to when ultrasonography is used. Kraimps et al in their multicentric study of 557 cases reported that out of 140 cases having nodules only 40 (28.6%) were palpable and scintigraphy showed cold nodule in 54 (38.6%) cases only. However ultrasonography could detect 116 (82.9%) of these cases (prevalence of 25.1%). Similarly Cantalmessa et al employed ultrasonography and the prevalence in their series was 33.6% (106/315 cases). Since we did not employ ultrasonography to look for these nodules and 86% of nodules in this study were palpable pre-operatively, the prevalence of 26.9% can be regarded as grossly underestimated.
At present there is no consensus regarding the appropriate work-up of these patients. Ultrasonography may be the most sensitive method to detect thyroid nodules. But the clinical significance of most of these nodules remains controversial, since thyroid nodules are frequently found in ultrasonographic studies of thyroid. However, it could be helpful to guide FNAC of non-palpable nodules. FNAC is an excellent tool in the work-up of thyroid nodule. But it is difficult to perform in small nodules. Because of this and the problem of haemorrhage, the interpretation of results may not be easy in the presence of hyperplastic tissue in Graves’ disease. This is particularly relevant in cases that developed the nodule after treatment with radioactive iodine. However some workers believe, if it is done before radioiodine ablation, the utility of FNAC is comparable to results seen in standard thyroid nodules. If a definitely benign diagnosis on FNAC is obtained then it is reasonable to use non-surgical therapy., In our series three out of six cases of carcinoma had FNAC. One case had haemorrhagic aspirate while in one case it was reported as cellular colloid, which we consider as suspicious for malignancy. However in the remaining one, hyperplastic lesion was reported; the reason could be that the needle might have failed to hit the small lesion. Pathogenic role of Graves’ disease in influencing biological behaviour of thyroid carcinoma in such clinical setting is controversial. While some workers believe that thyroid carcinomas occurring in this clinical setting are aggressive, others did not find any difference.,,, The suggested reason for increased aggressiveness is attributed to thyroid stimulating antibodies (TSAb), resulting in continuous proliferation stimulus.,,
Though most of the incidentally discovered nodules may not be of any clinical significance, many believe that in the presence of a palpable cold nodule in the background of Graves’ disease the incidence of malignancy is high, and can range from 19% to 45.8%., In our series it was 20%. In our earlier study, we found that presence of thyroid nodules in Graves’ disease is a predictor of high incidence of carcinoma. As there are no pre-operative investigation that can exclude malignancy with certainty, now we perform total thyroidectomy in these cases. Completion total thyroidectomy after subtotal thyroidectomy is fraught with danger. The reported incidence of recurrent nerve paralysis and hypothyroidism are many times higher for re-operation as compared to primary operation. It can be argued that sub-total thyroidectomy suffices in these cases, as most of these are micro-carcinoma. However, with conflicting reports in the literature about aggressiveness of these tumours, we believe if total thyroidectomy can be performed with acceptable morbidity, this should be the procedure of choice in this clinical setting. This not only avoids second surgery, but also helps in rapid and permanent cure of hyperthyroidism and makes follow-up of these cases easy with serum Tg estimation or radioiodine scan. Others have also advocated early surgery and favored total thyroidectomy in such situation. We have previously reported our results of total thyroidectomy for benign thyroid disorders and have shown that complication rate in our series were comparable to other reported international series.
Nodules are frequently associated with Graves’ disease in IDA and incidence of carcinoma seems comparable to that in iodine sufficient region. We recommend early thyroidectomy in these cases.
[Table - 1], [Table - 2]