The role of estimation of the ratio of preoperative serum thyroglobulin to the thyroid mass in predicting the behaviour of well differentiated thyroid cancers.AK Sharma, AK Sarda, TK Chattopadhyay, MM Kapur
Department of Surgery, All India Institute of Medical Sciences, New Delhi, India., India
Although serum thyroglobulin (STg) is a useful tumour marker to detect the recurrence of tumour in well differentiated thyroid carcinoma, it has as yet not been reported to be of value in predicting the behaviour of thyroid cancer. In the present study of 20 patients, the measurement of preoperative Stg/thyroid mass has been utilised to find out Tg synthesizing capacity of the tumour. This ratio was significantly higher in the patients with follicular variety than in papillary thyroid carcinoma. It was significantly higher in the metastasis group than in the group of patients without metastasis. The patients with functioning metastasis had a higher than average value of this 'ratio' than those with non functioning metastasis, though the difference was not statistically significant. Despite the limitation of a small number of patients included in this study, it is possible to highlight the possible utility of preoperative Stg estimation as a tumour marker in categorization of the patients of carcinoma of the thyroid gland.
Keywords: Adenocarcinoma, Follicular, blood,surgery,Carcinoma, Papillary, blood,surgery,Follow-Up Studies, Human, Preoperative Care, Reproducibility of Results, Thyroglobulin, blood,Thyroid Neoplasms, blood,surgery,Tumor Markers, Biological, blood,
Following the initial reports of Van Herle & Uller a number of studies have impressed upon the utility of serum thyroglobulin (STg) as a tumour marker in the follow-up of patients of well-differentiated carcinoma of thyroid. The value of STg in the detection of recurrence or persistence of disease in the thyroid has more or less been accepted especially when the results are supplemented with other modalities like whole body scan (WBS). However, the classification and categorisation of the patients of well-differentiated thyroid carcinoma, based on thyroglobulin (Tg) has not yet been established.
Immunohistomorphological and immunocytochemical studies have been performed in order to evaluate Tg synthesising capacity of different well-differentiated thyroid tumours in order to predict their biological behaviour.
In the present study, the measurement of the ratio of STg to tumour mass has been utilised as a measure of Tg synthesising capacity of tumour which in turn is dependent on various factors such as:
- Total mass of thyroid tissue (normal/neoplastic)
- Histopathology of tumour 2 reportedly higher in follicular than in papillary cancers; and almost zero in medullary and anaplastic cancers.
- Differentiation of function.
Between 1982 and 1988, 46 patients of well-differentiated thyroid carcinoma were followed up on the basis of serum thyro-globulin (STg) values and radio-nuclide whole body scanning (WBS). Pre operation value of STg and the measure of the thyroid mass were available in only 20 patients (operated between 1986 and 1988) in a single surgical unit of the All India Institute of Medical Sciences, New Delhi.
Preoperative STg was measured, at the time of admission, using radio immunoassay from already prepared kits based on the method described by Roit et al These patients were subjected to total/near total thyroidectomy with or without lymph node dissection. The patients who were subjected to hemithyroidectomy or subtotal thyroidectomy were excluded from the study, because thyroidectomy specimen in such patients did not represent the whole of thyroid tumour mass. Similarly, the patients with metastasis demonstrable on preoperative work up, were excluded because of the same reason. Preoperative X-ray chest & skeletal system, bone scan, liver scan, liver ultra sound scan, and biochemical investigations were performed as and when indicated and needed. The weight of thyroidectomy specimen was measured after making it dry with a gauze piece. Henning Dralle et al quantified the thyroid (tumour) tissue by X-ray, ultrasound scan and by131 I scintigraphy also. In our study, we have taken into account the weight of total (or near total) thyroidectomy specimen as a direct and simple measure of tumour mass.
During the follow-up of these patients, the WBS was done three days after injecting 2 MCI of131 I, using a scintiscanner to pick up the functioning metastatic/ residual thyroid tumour. With the aim of finding out non-functioning metastasis, chest x-ray, x-ray skeletal system, bone scan, liver scan, ultrasound scan were performed whenever there was suspicion of non-functioning metastasis. As mentioned earlier, we utilised the ratio of STg (in ng/ml) to the thyroid mass (in gm) as a parameter of the thyroglobulin producing capacity of tumour.
The results were tabulated and graphically represented in two groups divided on the basis of histopathological report. Each of these groups was further divided into smaller subgroups of absent metastasis, functioning metastasis and non-functioning metastasis. For the tests of significance, Student's t-test and Mann Whitney U Test were utilised. These 20 patients were followed up for a period ranging from 14 to 39 months (median 27 months). The follow-up was scheduled every 3 months for the first year and then on a yearly basis. During the follow-up, 4 patients developed functioning metastasis, and in 7 other patients non-functioning metastasis was detected. Nine patients did not develop metastasis.
In the follicular carcinoma group (n=9), mean preoperative STg was 160 mg/ml (rang e-49.5- 255) and the mean weight of the thyroidectomy specimen was 92 gm (range 41-135) [Table - 1].
Patients who did not develop metastasis had significantly higher pre-op STg/thyroid mass ratio of 1.8 - 2.1 (n = 4) than the patients who developed metastasis (with a ratio value of 1.2-1.9; n = 5). The level of significance was just at 5% level and the p value was <0.05.
In papillary carcinoma group (n = 11), mean preoperative STg was 76 ng/ml (range 34.6-133) and the mean weight of thyroid mass was 83 gm (range 45115). Although the preoperative STg thyroid mass ratio was not significantly different in patients without metastasis (n = 5) when compared to those who developed metastasis (n = 6), yet the mean values were 1.2 (range 03-1.5) and 0.8 (range 0.3-1.2) respectively. On excluding the patients of functioning metastasis ie, when the comparison was made between no metastasis sub-group (n = 5), and the patients who developed non-functioning metastasis (n = 4), the value were higher in the former than in the latter subgroup p value <0.05); [Table - 1] and [Table - 2].
Comparison of Metastasis vs absent Metastasis Sub group.
Overall comparison of patients (combined group of follicular and papillary carcinoma) who did not develop metastasis (n = g) with the patients who developed metastasis (n = 11), showed a significantly higher preoperative STg/thyroid mass ratio in the former subgroup with the level of significance at 5% [Figure:1].
Comparison of Follicular vs Papillary Group:
Preop STg/thyroid mass ratio was higher in follicular carcinoma patients (n = g) than in papillary carcinoma patients (n = 11), the level of significance at 5% level and p value <0.001. When the corresponding subgroup also as compared, follicular carcinoma patients had significantly higher values than papillary carcinoma patients [Figure:1] & [Figure:2].
Comparison of functioning with Non-functioning Metastasis subgroups:
Overall comparison of all patients with functioning metastasis with that of patients with non-functioning metastasis (combined follicuiar and papillary) did not show any significant difference in preoperative STg/thyroid mass ratio, nevertheless, the mean value of 1.3 was higher in the former group of patients [Figure:3].
In a study of 323 patients of carcinoma thyroid by Arnika Ryff de Leche et al immunocytochemical studies showed positive findings of Tg in 100% patients of follicular carcinoma and 95% of papillary carcinoma T9 could not be identified in anaplastic, clear cell carcinoma and epidermoid metaplasia. Henning Dralle et al showed higher STg levels in follicular carcinoma than papillary carcinoma. In contrast, immunohistochemical studies did not demonstrate statistically different Tg synthesising capacity of follicular and papillary carcinoma.
As is evident from results in the present study, the patients with follicular carcinoma had higher Tg production capacity than those with papillary carcinoma. The less aggressive tumours (tumours which did not metastasise) had higher thyroglobulin (Tg) synthesising capacity (pre of STg/ thyroid mass ratio) than the tumours with more aggressive (which metastasised) tumours and the difference was significantly different in the follicular but not in the papillary group. In patients with papillary carcinoma there was significant difference when the comparison was made between the absent metastasis and non-functioning metastasis subgroups.
A dissociation in Tg synthesis and radio iodine uptake has been observed. It has been observed that the reduction in radio iodine uptake usually precedes the decrement in Tg concentration. Botsch et al reported that in many cases, the growth of nodules or the development of new metastatic nodules occurs concomitantly with the disappearance of radio ioidine uptake in spite of persistently high STg values suggesting a step wise de-differentiation of thyroid carcinoma. In other words, the patients with non-functioning metastasis represent a further state of de-differentiation than those with functioning metastasis. In contrast to this observation, a few studies, show that mean STg in patients with functioning metastasis did not differ from that in the patients with non-functioning metastasis. In our study, although the trend was favouring higher Tg production capacity in functioning metastasis than in non-functioning metastasis, yet the difference was not statistically significant. This finding of lesser mean value of pre operative STg/thyroid mass ratio suggests that the patients who developed non-functioning metastasis (ie whose metastasis did not pick up radio iodine) had a certain degree of de-differentiation of cell line/s with lesser Tg production capacity.
In conclusion, follicular carcinoma has a higher capacity of Tg production than papillary carcinoma. The patients in whom the tumour did not metastasise had a higher Tg production capacity than those in whom it metastasised. Further, the patients who developed functioning metastasis had a higher Tg production capacity than in those who developed non-functioning metastasis (although this particular observation is statistically not significant). Thus the estimation of T9 production capacity by preoperative STg/thyroid tumour mass ratio can be used in predicting the behaviours of the well-differentiated thyroid tumour in a particular patient. However, the main limitation of the study is the small number of patients in each subgroup and therefore, further studies and a longer follow-up are necessary to elucidate these conclusions.
[Table - 1], [Table - 2]