Medullary Thyroid Cancer 101: Hard To Diagnose Without Screening Calcitonin.
1.The survival rate of patients with medullary thyroid carcinoma (MTC) is significantly better in patients diagnosed and treated when the tumor is limited to the thyroid.
2.Routine measurement of serum calcitonin (CT) in nodular thyroid disease allowed the preoperative diagnosis of unsuspected sporadic MTC with better accuracy than routine fine needle aspiration cytology (FNAC).
3. 10,864 patients studied. The prevalence of MTC found by CT screening in group 1 was 0.40% (44/10,874 patients).
4. A positive CT test had a higher diagnostic sensitivity and specificity compared with FNAC.
5.Treatment of MTC at an earlier stage, resulting in a better outcome compared with MTC not detected by serum CT measurement.
6. Routine measurement of serum CT in thyroid nodules is, at the moment, the most informative test for the early diagnosis and treatment of sporadic MTC.
Impact of Routine Measurement of Serum Calcitonin on the Diagnosis and Outcome of Medullary Thyroid Cancer: Experience in 10,864 Patients with Nodular Thyroid Disorders
MEDULLARY THYROID CARCINOMA (MTC) is a malignant tumor originating from the parafollicular C cells of the thyroid (1). Among well differentiated thyroid carcinomas (papillary, follicular, and medullary), it is the most aggressive, with survival rates of 40–50% at 10 yr (2). The survival rate of MTC patients is significantly better in subjects diagnosed and treated when the tumor is limited to the thyroid. The definitive cure of the tumor is dependent on early detection and the completeness of the first surgical treatment (3). Unfortunately, most patients with MTC do not achieve normalization of postsurgical serum calcitonin (CT) levels (4) or definitive cure (5).
A better outcome is observed in hereditary MTC cases (nearly 20% of all MTCs) detected by genetic screening of the RET protooncogene and treated in a preclinical phase, when the tumor is microscopic and confined to the thyroid (6–9).
Serum CT is the most specific and sensitive marker of MTC for both the primary diagnosis and the postsurgical follow-up (10); it is produced in abnormally high concentrations by almost 100% of primary and metastatic MTCs (11). Only a few other human diseases can be associated with detectable levels of CT (12) that may be suspected on clinical grounds. Positive pentagastrin (Pg) stimulation tests can be also found in patients with C cell hyperplasia, which is indeed considered, although not proven, by many researchers to be a preneoplastic lesion (13).
In a previous study spanning 1 yr (1991), we demonstrated that routine measurement of CT in nodular thyroid disease allowed the preoperative diagnosis of unsuspected sporadic MTC with better accuracy than routine fine needle aspiration cytology (FNAC) (14). Similar studies were performed in the following years by other researchers, confirming our results and strongly supporting the use of CT measurement in the diagnostic evaluation of nodular thyroid diseases (15–20). Whether this strategy has an impact on the patient’s outcome remains to be established.
In this study we report the results of screening nodular thyroid disease by serum CT measurement in more than 10,000 patients during 1991–1998. The aim of the study was to assess whether we could confirm the results of our preliminary study of 1991 and to compare the outcome of patients diagnosed by serum CT measurement with that of a historical group of MTC patients diagnosed and treated before the introduction of serum CT screening.
Patients and Methods
The study included 10,864 patients seen in our Department between 1991–1998 for nodular thyroid disease, who were screened for MTC by serum CT measurement. The clinical diagnosis, as assessed by clinical examination, thyroid ultrasound, 99Tc thyroid scan (when indicated), and thyroid function tests, included single nodules, nontoxic multinodular goiter, autonomous functioning thyroid nodules, and autoimmune thyroid disease associated with distinct cold nodules. There were 8692 females and 2172 males (female/male ratio, 4:1), ranging in age from 12–82 yr (mean, 49 yr). A blood sample for measurement of free thyroid hormones, TSH, thyroid antibodies, and calcitonin was obtained from all patients. Fine needle aspiration was performed as a routine procedure. Patients with detectable levels of basal CT always underwent a Pg stimulation test to exclude the possibility of CT secretion related to pathological conditions other than MTC. Surgery was recommended in patients with elevated basal CT levels (confirmed by abnormal Pg-stimulated CT levels) regardless of the results of FNAC and in those with FNAC suspicious of malignancy independently from the results of serum CT.
Patients found to harbor MTC by CT screening (group 1) were followed for a mean period of 6.2 ± 2.5 yr (range, 3–10), and their outcomes were compared with those of a historical group of 45 MTC patients (group 2) diagnosed from 1970–1990 when CT screening was not performed. The diagnosis of MTC in these patients had been obtained by presurgical FNAC in 2 patients and by postsurgical histological examination in 43 patients. As shown in Table 1, mean age and sex distribution were similar in the two groups. Median age was significantly younger in group 2 (P < 0.0001, by Mann Whitney).
|Group 1||Group 2||P|
|No. of patients||44||45|
|Mean± sd||52.1± 14.9||46.3± 14.3||NS|
|Hereditary,aMTC||8/40 (20)b||2/14 (14.2)||NS|
|Sporadic MTC||32/40 (80)||12/14 (85.8)||NS|
|C cells hyperplasia||2/44||0/45||NS|
All presented as apparently sporadic.
Percentages are given in parentheses.
Serum CT was measured using a solid phase, 2-site, immunoradiometric assay (ELSA-hCT, CIS, Gif-Sur-Yvette, France) with a functional sensitivity of 14 pg/ml. The upper limit of normal range in our laboratory is 20 pg/ml, with most normal controls (86%) having undetectable serum CT levels (<14 pg/ml). For the Pg stimulation test, blood was collected before and 2, 5, 15, and 30 min after Pg injection (0.5 μg/kg, iv). To define our positive CT peak after Pg stimulation, we based our conclusions on the evidence that in our laboratory none of 30 normal volunteers showed increased levels of serum CT (peak CT, >14 pg/ml) after a Pg stimulation test. On the contrary, patients treated with total thyroidectomy on the basis of genetic screening were found to harbor at least a microfoci of MTC when the CT peak was at least 40 pg/ml after a stimulation test. However, this is a particular group of patients in whom the Pg response is also influenced by the presence of C cell hyperplasia. Based on these observations in our laboratory, a Pg test is considered abnormal when the CT peak is at least 3 times the upper limit of the basal normal range (i.e. >60 pg/ml). However, with the exception of the multiple endocrine neoplasm mutation gene carriers who are always submitted to the Pg test (even if the basal level is undetectable and no nodules are visible at neck ultrasound), the routine CT measurement is performed only in subjects with well documented thyroid nodules (any size, even <1 cm in diameter), and if levels are elevated and twice confirmed, the patients are submitted to a Pg stimulation test.
FNAC was performed according to standard methodologies in nodules bigger than 1 cm or in smaller nodules only if suspicious aspects were found at neck ultrasound (21). Smears were examined by the same cytologist, who was unaware of the results of serum CT.
MTC histological diagnosis was addressed by typical histological (i.e. tumoral cells arranged in trabecular, insular, or sheet-like growth patterns) and immunohistochemical (cells positive for CT and chromogranin and negative for thyroglobulin) findings. As additional criteria for MTC diagnosis, dense collagenous and/or hyalinized material containing amyloid deposits and an invasive pattern of thyroid tissue were analyzed. C cell hyperplasia was diagnosed when two to five C cells with more than 50 cells per low power field were found (22).
MTC in CT-screened patients (group 1)
Of 10,864 patients, 47 had elevated basal serum CT levels, ranging from 20–6200 pg/ml. In 2 cases increased serum CT was attributable to chronic renal failure; basal serum CT was 205 pg/ml with no response to Pg stimulation in 1 case, and basal serum CT was 68 pg/ml in the other patient who was not submitted to Pg stimulation. These 2 patients had FNAC suggestive of benign thyroid nodules and did not undergo surgery. One patient with a serum CT of 30 pg/ml and benign FNAC refused a Pg test and surgery and was lost to follow-up. The remaining 44 patients, 4 of whom arrived at our first observation with a known elevated basal serum CT (CT measurements performed in other laboratories not more than 3 months previously), were all submitted to a Pg test, and peak CT levels were abnormal in all of them, with values ranging from 118–72,000 pg/ml (Fig. 1). As shown in Table 2 the clinical diagnosis in these patients was multinodular goiter in 26, uninodular goiter in 15, toxic multinodular goiter in 1, autonomously functioning thyroid nodule in 1, and autoimmune thyroid disease with nodule in 1. FNAC was suspicious for MTC in 20 of 44 cases (45.5%), suspicious for undefined malignancy in 9 (20.4%), suggestive of benign lesion in 11 (25%), and inadequate in 4 (9.1%). These 44 patients were submitted to total thyroidectomy and dissection of the central neck compartment. Histology revealed the presence of MTC in all cases, including the 1 with autonomous functioning thyroid nodule, who at surgery was found to have a 0.9-cm additional nodule harboring the MTC. With the exception of the autonomous functioning thyroid nodule case, in all 23 other cases in which the cytology (cancer/benign/inadequate) and the histology (MTC) were discordant (Table 2), FNA was performed exactly in the tumoral nodule. In 2 cases, 1 sporadic and 1 familial isolated MTC, C cell hyperplasia was also described at histology (Table 1). In summary, the incidence of MTC was 0.40% (44 of 10,864 patients). No case of MTC was detected among patients with normal serum CT levels who underwent surgery for other reasons. According to the TNM (23) classification, 8 patients (18.2%) had stage I disease (T1N0M0), 22 (50%) had stage II (T2–4N0M0), 13 (29.5%) had stage III (T1–4N1M0), and 1 (2.3%) had stage IV (T4N1M1; Fig. 2).
|Multinodular goiter||26 (59)a||12||5||7||2|
|Uninodular goiter||15 (34.1)||7||4||3||1|
|Toxic multinodular goiter||1 (2.3)||1|
|Autonomously functioning thyroid noduleb||1 (2.3)||1|
|Autoimmune thyroid disease with nodule||1 (2.3)||1|
|Total||44 (100)||20 (45.5)||9 (20.4)||11 (25)||4 (9.1)|
Percentages are given in parentheses.
MTC found in a second nodule in the same lobe of the adenoma.
Staging of historical MTC patients diagnosed and treated before 1991 (group 2)
FNAC in this group was performed in 13 of 45 patients. It was suggestive of MTC in 2 (15.3%) and suspicious for unspecified malignancy in the remaining 11. In the other 32 patients the diagnosis was obtained at final histology. According to the TNM system (Fig. 2), no patient had stage I, 20 patients (44.5%) had stage II disease, 18 (40%) had stage III, and 7 (15.5%) had stage IV. A significantly more advanced staging was found in this group compared with that of screened patients (P = 0.0004, by χ2 analysis).
Outcome of MTC patients of group 1 and group 2
After surgery (2–3 months), basal serum CT levels in group 1 became undetectable in 29 of 44 patients (66%), with no response to Pg stimulation in 26 and a mild increase in 3 (range, 122–273 pg/ml). In 15 cases (34%) basal serum CT was still detectable (range, 18–920 pg/ml), although reduced with respect to presurgical levels. In group 2, serum CT measurements postsurgery were available for 36 of 45 patients, and it was detectable in all but 1 (35 of 36, 97.2%). The difference between the 2 groups was statistically significant (P < 0.0001, by Fisher’s exact test; Fig. 3).
The mean follow-up was 6.2 ± 2.5 yr (range, 3–10 yr) in group 1 and 18.7 ± 5.4 yr (range, 10–39 yr) in group 2. In the last group, 9 patients were lost to follow-up. The final outcome is reported in Table 3. Deaths occurred in 2 of 44 (4.5%) patients in group 1 and in 25 of 36 (69.6%) in group 2. Forty-two of 44 patients were still alive (95.5%) in group 1, 26 (59%) of whom were free of disease (including undetectable basal and Pg-stimulated serum CT), 6 (13.7%) had evidence of local or distant disease and elevated serum CT levels, and 10 (22.8%) had no evidence of disease, but detectable basal and/or Pg-stimulated serum CT levels. In group 2, 11 of 36 patients were still alive (30.5%), 1 (2.7%) of whom was free of disease, 6 (16.6%) had evidence of local or distant disease and elevated serum CT levels, and 4 (11.1%) had no evidence of disease, but detectable basal and/or Pg-stimulated serum CT levels. The difference between the 2 groups was statistically significant (P < 0.0001, by χ2 analysis). To correct for the longer period of follow-up in group 2, this analysis was also performed considering the first 6 yr of follow-up of this group, corresponding to the mean period of follow-up for group 1. As shown in Table 3, in this case, patients in group 1 had a significantly better outcome (P < 0.0001, by χ2 analysis).
|Free of disease||Persistent disease|
|Group 1||6.2 ± 2.5 (3–10)a||26 (59)b||16 (36.5)||2 (4.5)c|
|Group 2||18.7 ± 5.4 (10–39)||1 (2.7)||10 (27.7)||25 (69.6)|
|Group 2||6||1 (2.3)||27 (64.2)||14 (33.3)|
Mean ± sd (range).
P < 0.0001 vs. groups 1 and 2.
The survival curve (by Kaplan-Mayer analysis) of the two groups (Fig. 4) showed a significantly better survival (P = 0.0005, by log-rank test) of group 1 patients (5-yr survival, 97.7%; 10-yr survival, 86.8%) compared with group 2 patients (5-yr survival, 81.5%; 10-yr survival, 43.7%).
The results of this study confirm, in a larger series, previous reports indicating that screening nodular thyroid disease by CT measurement is a specific and sensitive method for the diagnosis of unsuspected MTC (14, 15–20), even more sensitive than FNAC. We found an incidence of MTC of 0.40%, nearly 1 in 250 patients, similar to that (0.51%) reported in our previous study, which was limited to 1 yr (14). Other series reported similar or higher incidence rates, ranging from 0.52–2.85% (15–20). This difference may be due to patient selection, technical aspects related to different kits for CT measurement, or differences in the definition of the normal range of serum CT. A false positive elevation of serum CT (i.e. elevated CT without histological evidence of MTC or C cell hyperplasia) was not encountered in our series. However, a few cases have been reported in the series reported by Niccoli et al. (16) and Vierhapper et al. (17). The reason for this discrepancy may be attributable to methodological problems or to interference causing false CT elevation, as reported by Bieglmayer et al. (24) and Tommasi et al. (25). However, in the study reported by Niccoli et al. (16), patients were not submitted to a Pg stimulation test before they underwent thyroidectomy.
Another important aspect of our work is the confirmation that serum CT was more sensitive than FNAC in the preoperative diagnosis of MTC. In group 2 we found 13 of 13 patients with FNAC suspicious for malignancy, but only 2 of 13 were suspected to have MTC. In group 1, 66% of CT-positive patients required surgery based on FNAC, which means that, based in FNAC results, 34% would have escaped the diagnosis of malignancy and the execution of thyroidectomy. Moreover, FNAC correctly detected only 45.5% of the MTCs suspected by elevated serum CT and confirmed at histology. The discrepancy of FNAC results in these 2 groups might be due to the small size of the samples in group 2 and to the more advanced stage of the disease at diagnosis. Similar disappointing results of FNAC have been reported in other series (15, 16, 19, 20). Typical features of MTC may escape recognition in cytological smears processed by standard techniques (May-Grunwald-Giemsa) (26–28). Amyloid deposits that could help in the diagnosis of MTC are indeed quite rare [33% in the study by Kaur and Jayaram (29)]. Immunohistochemistry with anti-CT antibody improves the diagnostic sensitivity of FNAC, but this procedure is only performed when there is a strong suspicion of MTC and not on routine basis. Furthermore, in multinodular goiter, usually only big nodules (>1 cm) and smaller nodules with suspicious echogenicity (21), but not small unsuspected nodules, are aspirated. In these cases CT measurement is even more important because it can reveal MTC in small nodules that would not undergo FNA. Together, our study and the above-mentioned series demonstrate that MTC is probably more frequent than commonly believed and that routine measurement of serum CT is the most sensitive test for its detection. The next relevant question is whether this procedure will result in some clinical benefit for the patient.
To answer this question we introduced the comparison of MTC patients detected by CT screening with a historical group of similar patients diagnosed by conventional methods (mainly definitive histology) in previous years. This comparison shows that CT-screened patients had a less advanced stage of MTC and that both the postsurgical normalization of serum CT and the long-term outcome were significantly improved compared with unscreened patients. In our opinion, one of the reasons for this finding is that increasing the preoperative diagnostic accuracy of MTC allows the diagnosis of otherwise not suspected MTC (at an early stage) and alerts the surgeon to perform a more radical initial treatment, which is fundamental for definitive cure. Another possible explanation is that the CT test overcame the frequent false negative result of FNAC, which might delay the diagnosis and treatment of MTC.
The comparison of two groups diagnosed and treated in different decades may raise some concern for possible bias. In the 1970s and 1980s thyroid ultrasound was rarely performed, and small nodules were probably not detected. Indeed, in group 1, 8 of 44 patients had nodules smaller than 1 cm as opposed to 0 of 45 in group 2. However, it is worth noting that FNAC in these 8 nodules was suggestive of MTC or cancer in only 1. All of the others were inadequate or falsely benign. These cases were treated only on the basis of elevated basal serum CT. Although nodules smaller than 1 cm were discovered by ultrasound, without the CT measurement they would have escaped diagnosis and treatment and probably would have been discovered in later years at a more advanced stage, similar to that in the unscreened group, when definitive cure is difficult to be achieved.
Another possible bias is that the worst outcome of group 2 compared with group 1 may be due to the longest period of follow-up. This is probably not the case in our series, because significantly more patients in group 1 had normalization of serum CT after surgery, which is the most favorable prognostic factor in MTC. In addition, when the period of follow-up was normalized in the two groups, CT-screened patients still had a more favorable outcome.
It might be supposed that the group of screened MTC found between 1991 and 1998 represents a group of MTC with a better prognosis, and if this is the case, we cannot completely exclude that a group of less aggressive MTC have been missed in the 1970–1990 period when the CT screening was not performed. On this basis, it is conceivable to think that a high number of less aggressive MTC would not show any clinical manifestation during the patient’s life, and death will occur for other reasons. However, as the autopsy studies reported to date show a quite low incidence of MTC (0.01–3.3%) (30–34), in our opinion it is unlikely that the reason for the different clinical behaviors of these two groups of MTC is the missing of less aggressive MTC in the 1970–1990 period.
A final important consideration is the problem of cost-benefit. Currently, the cost of serum CT assays ranges between $35–100 (U.S. dollars), depending on the country. Considering the incidence of 1 MTC of 250 thyroid nodules found in the present series, the cost for detecting 1 MTC by CT measurement (at an Italian cost of $50 U.S. dollars) will be o$12,500 U.S. dollars. The same patient diagnosed and treated at a later stage, not achieving normalization of postsurgical serum CT will undergo for his/her entire life, at least annually, a complex and expensive diagnostic work-up in search of residual disease and one or more additional surgical procedures (usually palliative) if, eventually, the site of the disease is localized. The cost of these additional tests and reoperations could be considerably higher than that for the detection of a single case at an early stage. Similar considerations have been made by other researchers when analyzing the cost-benefit of serum CT screening in other countries (35, 36).
In conclusion, routine measurement of serum CT in thyroid nodules is, at the moment, the most informative test for the early diagnosis and treatment of sporadic MTC. As demonstrated by the better outcome of MTC patients diagnosed by serum CT measurement, screening for serum CT represents the most determinative factor for biochemical cure together with the skill of the surgeon in performing a radical initial surgery. On these bases, we recommend serum CT measurement routinely in the clinical work-up of thyroid nodules, followed by a Pg stimulation test in all cases of detectable basal CT levels to be performed preferably in a referred center. The fact that the lowest peak CT in our screened MTC was 118 pg/ml suggests that within a CT peak between 60–120 pg/ml there is a gray zone. Although we favor surgical treatment, the therapeutic decision in such patients should probably depend on the clinical situation and FNAC results. In this regard it is important to stress that the cut-off value of basal CT and peak CT after Pg should be accurately defined in each center.