Journal of Clinical Chemistry and Laboratory Medicine
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Medullary Thyroid Carcinoma with Normal Calcitonin: Case Report with a Typical Presentation and Poor Prognosis

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Case Presentation

A 56-year-old man was referred for investigation of interscapular pain and lower limb paresis for 2 months, with a previous history of type 2 diabetes mellitus and smoking. Computed tomography of the chest and spine showed multiple osteolytic lesions in costal arches, diffuse vertebral bodies and the left iliac, in addition to infiltration and major obliteration of the vertebral canal. Biopsy of the thoracic spine injury was compatible with undifferentiated malignancy with characteristics of carcinoma with a possible primary thyroid site. Thyroid ultrasound was requested, which showed a heterogeneous nodule with defined margins, with cystic areas and hyperechogenic foci, measuring 1.7 × 1.1 × 1.1 cm. The fine needle puncture cytology revealed thyroid carcinoma and immune histochemistry compatible with medullary thyroid carcinoma (CMT). The serum CT level was less than 2 pg/ml and the CEA was 3.23 ng/ml, both within normal limits. The CT was evaluated in two collections with sample dilution in order to detect possible hook effect; all results showed normal CT. The genetic screening for mutations in exons 10, 11, 13, 14, 15 and 16 of the RET proto-oncogene was negative. After a discussion among endocrinologists, a team of head and neck surgeons and a patient, the decision was not to undergo thyroidectomy due to the extremely advanced disease, and we opted for clinical management with vandetanib. The patient underwent thoracic spine arthrodesis due to spinal compression and was discharged for outpatient follow-up, not returning to follow up.

Discussion

CMT is a neuroendocrine tumor originating from parafolicular thyroid C cells with an incidence ranging from 1 to 10% [1]. It can occur sporadically or in a hereditary form, which is associated with mutation of the germline of the RET protooncogene. It may present as a family form, as part of multiple endocrine neoplasia type 2A (MEN2A), combination of pheochromocytoma and hyperparathyroidism and type 2B (MEN2B), more common in childhood and associated with pheochromocytoma, mucosal neuromas, gastrointestinal neurogangliomatosis, megacolon and with worse prognosis. There is also the sporadic form whose tumor is well differentiated, with a slow growth rate and local aggressiveness [1,2]. CMT is associated with the production of calcitonin (CT) and carcinoembryonic antigen (CEA), which are generally related to mass size and prognosis, are part of the diagnosis and are useful in monitoring [3].

Due to the aggressiveness of this tumor, early identification, surgical resection and careful postoperative surveillance are extremely important. The serum TC level has important sensitivity and specificity when at baseline levels above 100 pg/ml. However, elevated levels may also be present in patients with autoimmune thyroid diseases, in heavy smokers, in advanced stages of kidney disease and in patients with pancreatic lung cancer [4]. It is possible to perform a differential diagnosis of a pentagastrin stimulating test, which shows an increase in TC above 1000 pg/ml, in addition to the serum CEA measurement [5]. Currently, new tests are proposed for diagnosis, such as the determination of calcitonin levels in fine needle aspiration fluid (FNAP), serum proCT measurement; peptide related to the calcitonin gene (CgA) and stimulated CT [6].

Few reports in the literature are associated with normal or negative levels of TC, being the first description of the 1980s [7,8]. A recent literature review on the topic found 49 described cases of CMT with atypical calcitonin values [9]. The pathophysiology of reduced or absent secretion in CMT differs from the literature, some of the hypotheses deal with a possible hook effect in the sample analyzed, another argues that there may be a differentiation process in parafolicular cells, compromising CT secretion [2]. The most widely accepted hypothesis currently supported by the American Thyroid Association suggests that the aggressiveness and differentiation of certain CMT subtypes causes a loss of the ability to produce CT [10]. Our case had a worse prognosis than the other previously reported cases, presenting itself on arrival at the hospital with distant metastases, which significantly impaired functionality. The patient did not return to the clinic for followup in 2 months due to possible death.

Treatment is similar to that of CMT with increased CT, total thyroidectomy and lymphadenectomy, in accordance with current guidelines [3]. In very advanced cases like the one described here, it is accepted not to perform the cervical surgical approach [11]. Chemotherapy and radiation therapy can be used in cases of advanced disease. The follow-up of these patients is a challenge, due to the absence of serum biomarkers such as CT. Thus, post-operative surveillance with imaging tests, including ultrasound and computed tomography of the neck, magnetic resonance imaging of the liver and chest, is necessary due to the difficult identification of distant metastases in these cases [12].

Conclusion

Non-calcitonin producing CMT is a rare and challenging entity, associated with a poor prognosis. It requires a high degree of suspicion on the part of physicians in order to avoid a late diagnosis in advanced stages of the disease and presenting, in the great majority, a reserved prognosis.

Acknowledgements

We authors thank our friends in the department of medical laboratory sciences for their unreserved assistance.

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