Relevance of Calcitonin Cut-off in the Follow-up of Medullary Thyroid Carcinoma for Conventional Imaging and 18-Fluorine-Fluorodihydroxyphenylalanine PET

Discussion

It could be assumed that local MTC recurrences and/or its metastases are present as soon as the basal calcitonin is detectable (>2 pg/ml). The prevalence of locoregional recurrence varies widely from 4.8% at 5 years to 50% at 7.3 years (12, 13, 14). However, it must be emphasized that the management of patients with metastatic disease outside the neck remains very controversial (15) and that only local recurrences can be more easily cured with a chance of complete remission. Due to the recent promising results with systemic therapy, (2, 3, 4) it is of out most importance to implement an accurate imaging modality to correctly identify the anatomical correlate for the biochemical relapse (local recurrence/metastases).

The PET scintigraphy with the tracer 18F-DOPA is currently used for the detection of neuroendocrine tumors, such as MTC. To our knowledge, our study group included the most numerous 18F-DOPA cases (n= 68) of MTC patients (39 patients in total) in the follow-up after thyroidectomy with biochemical evidence of disease. We found, on the one hand, an overall low sensitivity (52%) taking the detectable calcitonin level of >2 pg/ml in MTC patients in the follow-up after thyroidectomy. On the other hand, 18F-DOPA showed a high sensitivity and specificity (79%, 82%) given the calcitonin cut-off proposed by ATA of 150 pg/ml. Luster et al. (8) found the same sensitivity in their study with 26 patients in the follow-up of MTC, considering the detectable basal calcitonin levels. Koopmans et al. (9) found a sensitivity of 71% in their study with 31 patients. Hoegerle et al. (16) in their study with 11 patients (primaries and relapses) found a sensitivity of 63%. The higher sensitivity of Hoegerle et al. and Koopmans et al. in comparison to Luster et al. and our study might be explained by the fact that these two latter studies included patients with very high calcitonin levels. Koopmans et al. (9) in fact state that MTC lesions are best detectable when serum calcitonin was >500 pg/ml. Also in our study the increase in calcitonin levels paralleled with the increase in positivity of PET and US, whereas CT shows an equal distribution.

Kauhanen et al. (11) confirmed the results of Hoegerle et al. (16). Moreover, they found that the best discriminative value for detecting metastasis with any of the imaging methods they analyzed (including 18F-DOPA PET/CT) was a cut-off of 54 pmol/l (=192 pg/ml).

The above-mentioned studies, with regard to sensitivity and specificity of 18F-DOPA PET and other imaging modalities, were not calculated with the same gold-standards, as some studies used biochemical measurements, others a radiologist-consensus and only rarely the decision was taken on a basis of histological results. The most accurate work was performed by Kauhanen (11) as his group either used histology or scan findings by at least 2 imaging methods, as performed in our study. In general, the main problem in studies of MTC is the lack of histological confirmation and the relative small number of patients, given the rarity of MTC.

Finally, Luster et al., as well as Hoegerle et al., Marzola et al. (17), Koopmans et al., Kauhanen et al. (11) and Behesti et al. (18) are all unanimous in declaring that 18F-DOPA PET/CT might be the best non-invasive diagnostic method, as it combines morphological and functional imaging.

As we have stated before, ATA strongly recommends additional imaging procedures from a basal calcitonin level of 150 pg/ml. In our patient population this recommendation is only partially followed as 18F-DOPA PET and other procedures were commissioned at levels which were widely below this value; however, true positive findings (confirmed by histology or by various other imaging procedures) were found also at levels <150 pg/ml.

At a basal calcitonin level below 150 pg/ml, 18F-DOPA PET correctly identified 25 true negative scans in the neck region, 3 in the thorax and 7 in the abdomen; PET, moreover, spotted 2 true positive scans of the thorax. Nonetheless, we could also uncover 4 false negative scans of the thoracic region. At a basal calcitonin level above 150 pg/ml, 18F-DOPA PET correctly identified 9 true negative scans in the neck region, 5 in the thorax and 17 in the abdominal region, as well as 20 true positive scans in the neck, 11 in the thorax and 6 in the abdomen. Even so, also at these levels, we could definitely spot-out false negatives (4 in the neck, 3 in the thorax and 1 in the abdomen), which is not surprising, given the high basal calcitonin levels. In this context it has to be underlined once more that our gold-standard were histological findings and/or imaging follow-ups.

In addition we also examined a relative high number of patients and an even more important number of 18F-DOPA PET scans (64 in total). Such a high number might even compensate our insecurity –the lack of additional imaging procedures- in some cases. We also operate a case-based analysis as well as a lesion-based analysis.

The biggest discrepancies were found between 18F-DOPA PET and CT: in most of the cases CT discovered more lesions than PET (in total 62 lesions of CT versus 41 of PET) however only in 7 out of 28 scans did CT detect more positive regions than PET, of these cases, 2 CT positive regions turned out to be false positive. In the 5 other cases, none are surely false negatives of 18F-DOPA, as we did not possess any further diagnostic tool to be able to surely assess the negativity or positivity of the region. In one case neither 18F-DOPA PET nor CT successfully detected a liver metastasis. In this context we want to mention the sensitivity of stand-alone CT found by Luster et al. on a per-patient basis, namely 68%; the specificity was 78% (8). The sensitivity of morphologic imaging (CT/MRI) on a region-based analysis found by Koopmans et al. was 64%.

The neck US did perform quite similarly to 18F-DOPA PET; however, 18F-DOPA PET was false negative in 4 cases (6.25%), US in one case only (3.6%). In addition, we cannot omit to underline the better practicability and absence of radiation in the case of US.

The bone MRI was more sensitive than 18F-DOPA PET in detecting bone metastases: it detected more lesions per region and also bone metastases, not identified at all by 18F-DOPA PET. Also Kauhanen et al. (11) state that MRI is indeed very sensitive, even though in his study it had the highest rate of false positive results, especially in the neck region.

It is important to underline that up to now, the best –and often only- curative options are reserved for patients with local recurrences and/or local metastases, as these only need reoperation. In this respect, it is crucial to detect metastatic disease at the early locoregional stage, where reoperation with curative purpose can be planned (17). With these patients, as with virtually any other patients too, imaging modalities cannot yet offer a gold standard; we still have to rely more on the biochemical relapse.

Yet, Modigliani et al. (5) found out that survival rate of MTC patients appears better than expected even in non-cured patients. Also van Heerden et al. (19) only advocate actively non-invasive pursuing of MTC localizations to identify resectable disease; they also state that truly occult disease does exist, even if it is very rare. In fact, not in every patient, hypercalcitoninemia is resolved by re-operation. However, even with persistent elevated calcitonin levels, these patients have a rather good 10-year survival rate (15). Finally, van Heerden and his group also confirmed the good overall course of patients who are treated conservatively. Thus, the question remains whether 18F-DOPA PET or any other full body scan is indeed relevant in the management of patients. The definite proof of metastases might frighten more than assure a patient if there is still no curative option. In fact, up to now, patients with distant metastases may be offered systemic therapy with possible surgery mostly for palliative intent (17); in most of these cases, operations are still experimental. Chemotherapy does not play an important role so far. Indeed, in our patient population only one underwent chemotherapy.

In our patient population (39 patients, 64 scans) we found a sensitivity of 79% and a specificity of 80% for 18F-DOPA PET according to the calcitonin cut-off of 150 pg/ml proposed by the ATA. Of all the PET scans that were performed at a basal calcitonin level below 150 pg/ml, 7% were true positive. Astonishingly, 24% of all PET scans performed at a calcitonin level above 150 pg/ml were false negative. Focusing on the neck region, 18F-DOPA PET has an important number of false negatives (4 cases), which is relatively high given the fact that local recurrences can be easily reoperated; US did perform quite good, with only one false negative result. CT found more positive lesions per patient and in 7 cases per region: 2 out of these were false positives and the remaining 5 could not be confirmed. MRI showed to have a higher sensitivity in detecting bone metastases in comparison to 18F-DOPA PET.

Our study contains several limitations due to its retrospective character. Regarding the laboratory work up, we lack CEA levels, calcitonin doubling times and pentagastrin stimulation tests. Moreover, we do not possess the complete history of the patients. For this rare tumor entity a large patient population should be analyzed for statistical analysis; nonetheless, it is relatively large in comparison with the other studies. Assuming that local MTC recurrences and/or their metastases are present as soon as the basal calcitonin is detectable (>2 pg/ml), the definition itself of “true negative” is controversial, but necessary for a subsequent morphological evaluation. Our gold-standard were histological findings and/or imaging follow-ups. Naturally, histological proof is the most precise tool, however it is not always practicable.

In conclusion, we cannot confirm the calcitonin cut-off proposed by the ATA (150 pg/ml) for detecting MTC recurrences, as true positive imaging results are found beneath this value, but contemporaneously we cannot state that 18F-DOPA PET has a very good sensitivity in the detection of MTC recurrences. For the neck region 18F-DOPA PET and US have similar results. 18F-DOPA PET in combination with CT (18F-DOPA PET/CT) is the best imaging modality for whole-body tumor detection. Bone metastases are best detected by MRI.