Serum calcitonin negative Medullary thyroid carcinoma
© Sand et al; licensee BioMed Central Ltd. 2006
Received: 21 November 2006
Accepted: 21 December 2006
Published: 21 December 2006
Medullary thyroid carcinomas (MTC) constitute about 5 to 7 % of thyroid neoplasms. They originate from parafollicular C cells which produce Calcitonin, a hormone which has an impact on calcium metabolism and represents the biochemical activity of MTC. In rare cases pre-operative serum calcitonin can be negative.
We report on a 73-year-old female patient with a rare case of a serum calcitonin negative medullary thyroid carcinoma who suffered fulminant post-operative course and died of multiple metastasis.
This case shows that in very rare cases MTCs do not secrete calcitonin making diagnosis and tumour follow-up difficult. To this date, only few reports describing this combination of circumstances were found in the English literature.
Medullary thyroid carcinomas (MTC) constitute about 5 to 7 % of thyroid neoplasms. They originate from parafollicular C cells which are derived from the ultimobranchial body and neural crest . C cells produce Calcitonin, a hormone which has an impact on calcium metabolism. Microscopically the tumor is characterized by small nests of small, round cells, production of amyloid and dense irregular areas of calcification . Cervical lymph node metastases occur early in the disease in about 50 % of cases with distant metastases occurring later. Cervical metastases most commonly involve the central, paratracheal and jugular regions. Distant metastases favor the mediastinum, liver, lung and bone . The incidence in male/female ratio is roughly equal over a wide age range. Most of MTC are sporadic and usually unilateral. Familial medullary carcinoma occurs in the multiple endocrine neoplasia syndromes (MEN) of the type 2 variety. When occurring in association with MEN syndromes it is usually bilateral and typically the first abnormality observed in both MEN 2A and 2B syndromes.
The biochemical activity of medullary thyroid carcinoma includes production of calcitonin and cacinoembryogenic antigen (CEA). In rare cases pre-operative serum calcitonin can be negative. To this date, only few reports describing this combination of circumstances were found in the English literature [3–5].
Medullary thyroid carcinoma is a rare calcitonin-secreting neoplasm that occurs in both a familial and sporadic form . It is the most aggressive well differentiated thyroid carcinoma, with survival rates of 40–50 % at 10 years . Routine measurements of serum calcitonin levels are considered to be an integral part of the diagnostic evaluation of thyroid nodules and the diagnosis of medullary thyroid carcinoma. It has been suggested that calcitonin testing, both with and without pentagastrin stimulation, may facilitate early diagnosis of this disease and ultimately decrease morbidity and mortality [8–12]. Serum CT is the most specific and sensitive marker of MTC for both the primary diagnosis and the postsurgical follow-up ; it is produced in abnormally high concentrations by almost 100 % of primary and metastatic MTCs. However in rare cases, as described here, serum calcitonin can be negative. Although our patient had a voluminous, rapidly growing medullary thyroid carcinoma with multiple metastases pre-operative serum calcitonin was within normal range. An calcitonin assay-specific problem is unlikely because different assays were used postoperatively (Nicols Advantage Chemiluminescence Assay, Nichols Institute Diagnostics Inc., San Clemente, CA, USA and Immulite Calcitonin Assay, DPC-Bühlmann GmbH, Salzburg, Austria). Before referral to our department the patient's thyroid nodules were monitored by annual checks of thyroid hormone and serum calcitonin. One would expect that the expression of an antigen in the neoplastic cells would be associated with the hypersecretion of the corresponding antigen in the circulation, as in the case of Calcitonin and CEA. The levels of these antigens are described to be elevated in patients with metastastatic medullary thyroid carcinoma and as accurate reflections of new metastases [12–15]. Regrettably this was not the case in our patient. It is possible that rare forms of MTC go along with mutations in the calcitonin/CGRP gene which might be responsible for the normal or relatively reduced calcitonin levels. It would be interesting to examine the calcitonin/CGRP gene structure in these patients. Analysis of white blood cell DNA by Southern blot hybridizations could show deletions or rearrangements in the calcitonin/CGRP gene locus. Additionally defects in the cellular machinery needed for calcitonin synthesis and/or secretion could be responsible. The tumour showed positivity for calcitonin in the immunhistochemistry which is in line with the latter hypothesis that calcitonin production is active but secretion mechanisms might be altered. Bockhorn et al. also reported a similar case of a 50 year old woman with a serum calcitonin negative MTC. Comparing the histologies we have observed some (uncharacteristic) similarities: the cells described were also relatively large with an increased caryoplasmic ratio, indistinct cell borders and partly spindled cytoplasm. It would be interesting to compare the histologies of other serum calcitonin negative MTC's which might show histomorphologic similarities.
This report illustrates that in rare cases the diagnosis of medullary thyroid carcinoma cannot be excluded by means of laboratory values such as serum calcitonin. When serum calcitonin is negative a cytomorphologic analysis of fine needle aspiration and a determination of RET proto-oncogene mutations are two diagnostic tools which are available for detection and accurate management of patients in whom medullary thyroid carcinoma is expected .
This case shows that in very rare cases MTCs do not secrete calcitonin making diagnosis and tumour follow-up difficult.
The written consent was obtained from the patient for publication of this case report.
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