Postoperative calcitonin study in medullary thyroid carcinoma

Transcription

1 Postoperative calcitonin study in medullary thyroid carcinoma S I Ismailov and N R Pulatova Scientific-Research Institute of Endocrinology, Public Health Ministry, Republic of Uzbekistan, Tashkent (Requests for offprints should be addressed to N R Pulatova; nargiza_pulatova@rambler.ru) Abstract Calcitonin (CT) is a sensitive marker for medullary thyroid carcinoma. Normalization of early postoperative CT level is a favorable prognostic factor. The aim of this study was to establish the prognostic value of CT-level kinetics by preoperative tumor stage and postoperative elimination rate. Blood serum from 22 medullary thyroid carcinoma (MTC) patients without remote metastases was assayed. A commercial RIA DSL-1200 test was used to assay CT levels. Basal CT42 pg/ml and stimulated CT120 pg/ml were considered normal. The patients were divided into three groups according to the intensity of the postoperative CT level reduction in blood serum. Group 1 comprised patients who showed basal CT normalization within the first 2 3 days after surgery. Group 2 included those patients with slow (from 2 to 4 weeks) CT-level normalization. Group 3 included patients with CT levels that reduced within 14 days, but subsequently increased. Preoperative basal CT varies from 216 to 1654 pg/ml and depends on tumor node metastasis (TNM) stage. In seven patients, no basal CT decrease to normal values was observed; in five of these patients, disease recurrence was detected 2 6 months after surgery. In the group with slowly decreasing CT levels, no strong correlation between preoperative CT level and the postoperative time to normalization of basal and peak CT could be established; this may be due to the small number of patients. Our study showed that preoperative CT level depended on the disease stage. Postoperative CT elimination rate is independent of preoperative CT level. Postoperative increase in the basal or stimulated CT level is an unfavorable prognostic factor, implying disease recurrence. Endocrine-Related Cancer (2004) Introduction Calcitonin (CT) is today the most sensitive and specific marker for medullary thyroid carcinoma (MTC). CT is encoded by the CT1 gene located on the tenth chromosome (Zaidi et al. 1991). In addition, three other genes with similar structure have been described, but in C-cells only CT1 gene is found to be active. Highly sensitive methods can detect CT in 50% of the normal population (Guilloteau et al. 1990, Perdrizot et al. 1990). In patients with MTC, the adequacy of surgery is assessed by CTlevel reduction to normal or undetectable values (Wells et al. 1975), postoperative normalization of serum CT taking place within several weeks (Stepanas et al. 1979, Tisell et al. 1996). Fugazzola et al. (1994) examined six patients, establishing CT normalization in two patients 2 weeks postoperatively, in one subject 12 weeks after surgery and in one patient in 24 weeks. Girelli et al. (1994) studied CT prognostic value early after surgery in 33 patients. They found CT normalization in 15 patients within 3 postoperative days. In 18 patients no CT normalization took place and in 16 of them the disease recurred. CT elimination has two short (4.5 and 22.5 h) and one long (up to 26 h) half-lives (Ardoillou et al. 1970). In patients with renal, pancreatic or hepatic dysfunction, an increase in CT half-lives can be observed (Ardoillou et al. 1970, Henriksen et al. 2000). Increased postoperative CT levels are evidence of a persistent disorder, mainly associated with metastases to regional lymph nodes. In connection with the above, this study aimed to establish the prognostic value of CT-level kinetics by tumor preoperative stage and postoperative elimination rate. Materials and methods Blood serum from 22 patients (mean age years) was examined. Patients had histologically established MTC and had been operated on between 1999 and Endocrine-Related Cancer (2004) /04/ # 2004 Society for Endocrinology Printed in Great Britain Online version via

2 Ismailov and Pulatova: Calcitonin and medullary thyroid carcinoma Table 1 Patient profiles Clinical characteristics of patients Group 1 Group 2 Group 3 Number of patients Mean age (years) Heredity TNM classification Node negative (pn0) pt1a 3a pt4a pt1b 3b pt4b Node positive (pn1) T1a 3a T4a T1b 3b T4b Number of lymph nodes with metastases in node-positive patients (total number of nodes excised) 3, 4 (34) 2 4 (46) 3 (41) UICC stage I II III IV MTC, medullary thyroid carcinoma; TNM, tumour node metastasis; UICC, Union Internationale Contre le Cancer Upon examination, the following diseases associated with possible CT elevation were excluded: pernicious anemia, small-cell carcinoma of the lung, acute and chronic renal insufficiency, hepatic disorders, breast cancer and acute pancreatitis. The study included patients without remote metastases; these patients gave their consent to have their blood assayed within several days after surgery. All patients underwent total thyroidectomy and lymph node dissection in the central neck department at least. Follow-up showed recurrences in five (22.7%) patients. The control group included ten donors (mean age years). The stimulation test with intravenous administration of calcium gluconate (15 mg/kg) was performed in all patients. The serum was assayed before the administration of the calcium preparation and 5 10 min after. Biochemical screening was used to establish three groups of patients, i.e. those with postoperative CT normalization within 2 3 days (group 1) or within 7 14 days (group 2), and those with basal CT levels normalizing at 7 14 days, but increasing again later (group 3). Highly sensitive RIA by means of a commercial test, Calcitonin RIA DSL-1200, was used to assay serum CT level. Normal basal CT values were 40 pg/ml; for the stimulated CT, levels three times higher than basal were considered normal (Guilloteau et al. 1990, Perdrizot et al. 1990, Barbot et al. 1994, Nicoli et al. 1997). Measurements of CT levels in healthy people and in 90% of patients with various thyroid pathologies, MTC excluded, showed that basal CT was 42 pg/ml. Basal CT levels higher than 100 pg/ml and stimulated CT levels higher than 300 pg/ml are regarded as the pathological and MTC normal respectively. CT stimulation was performed postoperatively in 2 3 and 7 14 days, in 2 4 weeks and every 6 months. The statistical significance of any differences was assessed using Student s t-test; P < 0:05 was considered significant. Results The patients were divided into three groups according to the intensity of the postoperative CT reduction in blood serum. Six patients with basal CT normalization within the first 2 3 days after surgery (27.3%) comprised group 1. Nine patients (40.95%) with slow postoperative CT reduction (from 2 to 4 weeks) were included group 2. Group 3 included seven patients with CT levels reducing within 7 14 days, but subsequently increasing (31.8%). Preoperative CT level, tumor stage, classification of metastases, number of metastases in lymph nodes, sporadic or hereditary nature of the disease, as well as concomitant disorders and medical history were identified for all patients. Characteristics of patients by TNM stage and their distribution by the vassal CT elimination rate can be seen in Table 1. There were no age, sex or 358

3 Figure 1 Mean preoperative basal calcitonin (CT) levels. inheritance differences between the groups. No difference in tumor size and number of metastases was observed either. However, the three groups differed in the number of lymph nodes dissected (34, 46 and 41 in groups 1, 2 and 3 respectively). Basal calcitonin levels Upon studying preoperative basal CT levels, CT mean value was shown to significantly vary and to be dependent on TNM stage and classification (Fig. 1). The preoperative CT level in group 1 varied from 216 to 754 pg/ml, in group 2 it was pg/ml and in group 3, pg/ ml. The highest CT values were observed on the III tumor stage (Fig. 1). There was no significant difference in mean preoperative CT between the groups: , and pg/ml in groups 1, 2 and 3 respectively. These findings provide evidence for the dependence of preoperative CT level on tumor size and the presence of metastases. Due to the small number of patients in groups 1 and 2, we failed to establish any correlation between preoperative CT level and basal CT normalization time after surgery (Table 2). In two patients in group 1 (patients 3 and 6), with preoperative CT levels of 216 and 754 pg/ml, basal CT levels normalized on the second day. In two patients in group 2 (patients 1 and 7), with preoperative CT levels of 541 and 1362 pg/ml, basal CT values normalized in 21 and 28 days respectively. In a patient in the third group, with a basal CT of 1654 pg/ml, normalization took place on the eighth day. Data on preoperative basal CT normalization can be seen in Fig. 2. In patients 1 and 2 of group 1, with preoperative CT levels of 367 and 748 pg/ml respectively, basal CT normalization Table 2 Preoperative basal CT level, CT normalization time and postoperative stimulated CT level Patients Preoperative basal CT Normalization time (days) Postoperative stimulated CT Group Group n n Group I3 1* * * * * y y *Patients with metastases to neck lymph nodes detected 2 6 months after surgery. y Patients without metastases, with the simulated CT pathological values 6 months after surgery. n Patients without metastases, with the stimulated CT pathological values 3 4 weeks after surgery 359

4 Ismailov and Pulatova: Calcitonin and medullary thyroid carcinoma Figure 2 Postoperative course of basal calcitonin (CT) levels and follow-up basal CT levels in five patients. Preoperative CT values are shown on each line. occurred on the second and third day after surgery. In two patients in group 2, with preoperative basal CT levels of 1260 and 945 pg/ml respectively, basal CT reduced to and pg/ml, respectively, in 7 days after surgery. By the third and fourth weeks basal CT normalized and remained stable for the next 6 months. In a female patient (P, patient 1 in group 3, Table 2) with a high preoperative basal CT level (765 pg/ml), the postoperative value reduced within 2 weeks, but began increasing 1.5 months later to a level of pg/ml at 2 months. Despite total thyroidectomy and lymph-node dissection in the central neck department, early preoperative metastazing to the regional neck lymph nodes occurred in this patient; this was clinically detected 2 months after surgery. Stimulated calcitonin levels Next we studied C-cell stimulation by loading tests. According to literature, C-cell stimulation can be performed by -adrenergetics, calcium, pentagastrin and glucagon (Girelli et al. 1994). The surgery adequacy was determined by calcium gluconate stimulation of CT in all patients. Early CT normalization occurred in group 1 within first 2 3 days with no pathologically high CT levels observed (Table 2). Mean stimulated CT level in group 1 was 7812 pg/ml. In group 2, slow (from 2 to 4 weeks) CT normalization was observed; mean stimulated CT level was pg/ml. Testing showed pathologically stimulated CT varying from 318 to 385 pg/ml in two patients (patients 2 and 6) 3 and 4 weeks after surgery. We failed to establish any correlation between preoperative basal CT levels and postoperative stimulated peak values. This is, probably, due to the small number of patients in the group. Groups 1 and 2 differed in postoperative mean peak CT values only (78 and 143 pg/ml respectively). In group 3, patients basal and stimulated peak CT values occurred within 14 days in one patient and in 7 10 days in six patients. Mean peak CT in group 3 was 717 pg/ml. It was interesting to observe in a female patient (P, patient

5 Table 3 Basal and stimulated CT before secondary surgery and CT normalization time after secondary surgery in patients with recurrences (group 3) Patients Time of CT measurement after first operation (months) Basal CT before second operation Stimulated CT before second operation CT normalization time (months) Stimulated CT after second operation Group in group 3, Fig. 2), that 2 weeks after surgery the stimulated value was lower than the basal one (78 and 90 pg/ml respectively) (Table 2). However in patients with lower basal CT values, normal peak CT levels were 2 3 times higher than the basal ones 7 10 days after surgery (Table 3). The repeated stimulation tests were supposed to be performed in 6 months. However in five (71.4%) of seven patients, the disease recurred 2 6 months after surgery. Palpation revealed metastases to the lateral cervical lymph nodes. Diagnostic ultrasound showed the enlarged lymph nodes with diameters from 7 mm to 1.5 cm. The number of lymph nodes varied from two to four. Unfortunately there were no data on much earlier postoperative CT values in these patients, CT levels were measured at admission. The test results showed that in patients with recurrences, peaks of pathologically stimulated CT were in the range pg/ml, basal CT levels being similarly high, from 846 to 1760 pg/ml (Table 3). Mean basal CT level before the repeated surgery was pg/ml, 1.5 times higher than mean basal CT before the first surgery (921 pg/ml). After the lateral cervical lymph node dissections, basal and stimulated CT normalized within months. Mean stimulated CT levels after the first and repeated surgery differed insignificantly, 73.2 and 89 pg/ml respectively. However, the difference in normalization time was significant, 7 14 days after the first surgery and months after the second one (Tables 2 and 3). In another two patients from group 3, recurrences were unobserved. At 6 months after surgery, basal CT levels were 128 and 147 pg/ml, while stimulated levels were 374 and 439 pg/ml respectively. It should be noted that mean stimulated CT value in these two patients (406.5 pg/ml) differed significantly from mean stimulated CT level in patients with metastases ( pg/ml). Follow-up No recurrences were observed in patients in groups 1 and 2 during the 24-month follow-up. In addition, no differences were found between CT levels measured at the moment of normalization from 2 days to 4 weeks and the long-term CT levels. In two patients (group 3), aged 38 and 45 years, with high CT levels detected 6 months after surgery, pathologically high CT was detected at 18 months. Basal CT level increased up to 264 and 312 pg/ml, the stimulated CT values being higher than those measured previously, 342 and 387 pg/ml respectively Table 4 Follow-up results and CT levels Patients Basal CT Stimulated CT (days) Follow-up (months) Group Group n n Group 3 1* * * * * y y *Patients with metastases to neck lymph nodes detected 2 6 months after surgery. y Patients without metastases, with the simulated CT pathological values 6 months after surgery. n Patients without metastases, with the stimulated CT pathological values 3 4 weeks after surgery

6 Ismailov and Pulatova: Calcitonin and medullary thyroid carcinoma (Table 4). In these two females with inherited MTC neither basal nor stimulated CT normalization occurred during the whole follow-up, but neither local nor systemic recurrence was found. In five reoperated patients (group 3) with CT normalization taking place months later, CT values were in the normal ranges during the whole follow-up. By the end of follow-up (22 months) mean stimulated CT values reduced to 46.5 pg/ml. In addition to the females above, two other patients (group 2, Table 2) with pathologically high postoperative stimulated CT levels, were tested repeatedly during the follow-up (Table 4). No pathologically stimulated CT values were observed in these patients. Discussion The study showed that postoperative CT level normalization in MTC patients could take place within various periods. Our study failed to establish the interrelation between basal CT normalization and preoperative CT values, but evident correlation between preoperative CT level and tumor stage was observed. There were no significant differences in preoperative CT level between patients with rapid basal CT normalization within 2 3 days (group 1) and those with slow CT normalization within 2 4 weeks (group 2). We observed no differences in tumor size and number of metastatic lymph nodes, but the patients differed in the number of lymph nodes dissected. In five patients (group 3) the delayed CT normalization occurred months after the repeated surgery. In two patients, no CT normalization had taken place 18 months after surgery. In contrast to many other tumor markers, CT is released by the thyroid C-cells and is extremely sensitive and specific in MTC diagnosis. Rarely, CT can be secreted by other neuroendocrine tissues. Recently several authors have reported on the prognostic value of preoperative CT concentration (Hinse et al. 1998, Machens et al. 2000), but a precise threshold was not determined. In addition, other authors have reported that a short period of postoperative CT increase after tumor resection is a significant prognostic indicator of unfavorable outcome and practically always means disease recurrence (Wells et al. 1975, Gimm et al. 1998, Machens et al. 2000). Postoperative basal CT kinetics, its correlation with preoperative level and tumor stage is regarded as a highly significant prognostic factor. Early basal CT normalization after surgery is a favorable prognostic factor. Wells et al. (1975) emphasize the significance of normal postoperative CT values as a parameter of biochemical cure. The prognostic value of early postoperative CT levels was studied by Girelli et al. (1994) who analyzed CT in 33 patients. These investigators reported on the high prognostic value of CT normalization within the first 72 h. During the next 12 months, no recurrences were observed in 15 patients, as confirmed by pentagastrin test. In 18 patients with no normalization within the period that the elevated CT levels were detected, 88% had tumor recurrence within 12 months of the first surgery. In contrast, Stepanas et al. (1979) and Tisell et al. (1996) observed isolated cases of CT normalization several months later. The findings were confirmed in a small series of experiments performed by Fugazzola et al. (1994) who managed to detect basal CT normalization 2 24 weeks after surgery. Fugazzola et al. concluded that CT normalization did not imply cure. However, the best prognosis was observed in patients with undetectable basal CT levels. We have revealed the delayed normalization in 16 patients of groups 2 and 3. In all patients of group 3, basal CT reduction to normal values was registered within 7 14 days, but in five (71.4%) the disease recurred 2 6 months after surgery, mean basal CT level before the second surgery being higher than mean basal CT level before the first one. It was established that these patients had regional metastases and radiotherapy was recommended, following lateral cervical lymph node dissection. In four of these patients sporadic MTC form was found, female patient P. having the familial one. Our study on the stimulated postoperative CT values failed to establish any interrelation between preoperative CT levels, postoperative CT normalization time and postoperative stimulated CT levels. But, as other authors report and our findings show, pathologically high values of postoperative stimulated CT are a poor prognostic indicator (Miyauchi et al. 1984). However, cases of detectable and even elevated postoperative CT levels after total tumor excision without apparent recurrence or metastases are documented abundantly (van Heerden et al. 1990). Brauckhoff et al. (2001) studied a 14-patient group and found pathological basal CT levels in only one of them 12 months later (Brauckhoff). They supposed that the delayed postoperative CT normalization and possibly CT stimulation, observed in some patients, could be an indicator for pre- or perioperative dissemination of tumor cells. These cells can lose their hormone-producing potential, become inactive or perish. However, tumorcell dissemination upon MTC has not been reported yet. Our study supports the idea, since in two patients (group 3), CT normalization did not occur and despite the adequacy of surgery, in 18 months we observed two-fold elevation in postoperative CT, registered 6 months after the surgery. Due to the small sample size and the relatively short follow-up we failed to establish the prognostic value of the delayed basal CT normalization. However, the findings confirm that delayed normalization of basal CT levels could be of high prognostic value, as 362

7 observed here in the five patients with the highest basal CT levels and the association with disease recurrence. Conclusions CT normalization terms after tumor excision do not depend on preoperative CT level, tumor size or number of metastatic lymph nodes. However, preoperative CT level depends on the disease stage. CT normalization within the first week after surgery serves as a favorable prognostic factor, but elevation of postoperative basal and stimulated CT levels is an unfavorable indicator, implying disease recurrence. As to therapy of MTC, the findings showed that total thyroidectomy and central cervical lymph node dissection should not be the only ways out. Even in the apparent absence of lympadenopathy, central, lateral modified and suprahyoid dissection of neck lymph nodes should be performed. Due to the small sample and the short follow-up, the prognostic value of delayed CT normalization remains unclear. It is necessary to measure CT levels starting from the first postoperative day and to consider the possibility of pre- or perioperative dissemination of tumor cells. A lengthier follow-up and larger samples would assist in the determination of the prognostic value of delayed CT normalization and the elucidation of the nature of this phenomenon. References Ardaillou R, Sironenko P, Meyrier A, Vallee G & Beaugas C 1970 Metabolic clearance rate of radioiodinated human calcitonin in man. Journal of Clinical Investigation Barbot N, Calmettes C, Schuffenecker I et al Pentagastrin stimulation test and early diagnosis of medullary thyroid carcinoma using an immunoradiometric assay of calcitonin comparison with genetic screening in hereditary medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism Brauckhoff M, Gimm O, Dralle H et al Calcitonin kinetics in early postoperative period of medullary thyroid carcinoma. Langenbeck s Archives of Surgery Fugazzola L, Pinchera A, Luchetti F, Lacconi P, Miccoli P, Romei C et al Disappearance rate of serum calcitonin after total thyroidectomy for medullary thyroid carcinoma. International Journal of Biological Markers Gimm O, Ukkat J & Dralle H 1998 Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma. World Journal of Surgery Girelli ME, Dotto S, Nacamulli D, Piccolo M, De Vido D, Russo T et al Prognostic value of early postoperative calcitonin level in medullary thyroid carcinoma. Tumori Guilloteau D, Perdrizot R, Calmettes C, Baulieu JL, Lecomte P, Kaphan G et al Diagnosis of medullary carcinoma of the thyroid (MTC) by calcitonin assay using monoclonal antibodies criteria for the pentagastrin stimulation test in hereditary MTC. Journal of Clinical Endocrinology and Metabolism Henriksen JH, Schifter S, Moller S & Bendtsen F 2000 Increased circulating calcitonin in cirrhosis. Relation to severity of disease and calcitonin gene-related peptide. Metabolism Hinze R, Holzhausen HJ, Gimm O, Dralle H & Rath FW 1998 Primary hereditary medullary thyroid carcinoma C-cell morphology and correlation with preoperative calcitonin levels. Virchows Archives Machens A, Gimm O, Ukkat J, Hinze R, Schneyer U, Dralle H 2000 Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis. Cancer Miyauchi A, Onichi T, Morimoto S, Takai S, Matsuzuka F, Kuma K et al Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma. Annals of Surgery Nicoli P, Wion-Barbot N, Caron P et al Interest of routine measurement of serum calcitonin study in a large series of thyroidectomized patients. Journal of Clinical Endocrinology and Metabolism Pedrizot R, Bigorgne JC, Guilloteau D & Jallet P 1990 Monoclonal immunoradiometric assay of calcitonin improves investigation of familial medullary thyroid carcinoma Clinical Chemistry Stepanas AV, Samaan NA, Hill CS Jr & Hickey RC 1979 Medullary thyroid carcinoma, importance of serial serum calcitonin measurement. Cancer Tisell LE, Dilley WG & Wells SA Jr 1996 Progression of postoperative residual medullary thyroid carcinoma as monitored by plasma calcitonin levels. Surgery van Heerden JA, Grant CS, Gharib H, Hay ID & Ilstrup DM 1990 Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Annals of Surgery Wells SA Jr, Ontjes DA, Cooper CW, Hennessy JF, Ellis GJ, McPherson HT et al The early diagnosis of medullary carcinoma of the thyroid gland in patients with multiple endocrine neoplasma type II. Annals of Surgery Zaidi M, Moonga BS, Bevis PJR, Towhidul Alam ASM, Legon S,Wimalawansa S et al Expression and function of the calcitonin gene products. Vitamins and Hormones