Diagnosis and treatment aspects of medullary thyroid carcinoma

Introduction
Medullary thyroid carcinoma (MTC) is a rare malignancy. It accounts for 5-10% of all thyroid carcinomas, but it is responsible for up to 13.4% of all deaths related to this disease (2-4). MTC arises from the parafollicular cells or C cells of the thyroid gland. Like normal C cells, medullary carcinomas secrete calcitonin, the measurement of which plays an important role in the diagnosis and postoperative follow- up of patients. Plasma calcitonin (CT) levels correlate closely with medullary carcinoma size, especially in familial cases (5).
It occurs in three clinically different situations: 1. as a sporadic neoplasm; 2. in combination with pheochromocytoma or parathyroid hyperplasia or both [multiple endocrine neoplasia, type 2A (MEN 2A)]; and 3. associated with pheo-chromocytoma, ganglioneuromatosis, and skeletal abnormalities [multiple endocrine neoplasia, type 2B (MEN 2B)]. MTC occurs in 1 sporadic and 3 hereditary autosomal-dominant forms (familial MTC, multiple endocrine neoplasia types 2A and 2B). Sporadic MTC usually occurs as a clonal popullation of tumour cells which originate from a uniq C cell, whereas the heritable forms of MTC are typically multifocal (6). Since the detection of the inherited mutation of the RET proto-oncogene on chromosome 10, encoding a tyrosine-kinase receptor, the number of diagnosed hereditary carcinomas has increased constantly (7-9). RET germ-line mutations in humans affect essentially four types of tissues that originate from neural crest cells: thyroid C cells, parathyroid cells, chromaffin cells of adrenal medulla, and enteric autonomic plexus. The mutation sites differ in MEN 2A and MEN 2B and MTC develops more aggressively in MEN2B (10, 11). Medullary thyroid carcinoma which arises from thyroid C cells, mainly is found in the upper third of thyroid lobes. As described by Wolfe and associates C- cell hyperplasia is precursor of familial medullary carcinoma that progresses to medullary thyroid carcinoma (12, 13). Several studies indicated a significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma (14). In the literature, sporadic carcinomas were described in 48% to 86% of patients, and hereditary carcinomas in 14%, to 52% (5, 9, 15). In the familial forms of medullary thyroid carcinoma multicentric carcinomas were found in 56% to 85% of patients (9, 16). Both sporadic and familial medullary thyroid carcinoma were metastasizing to cervical lymph nodes in 68% to 80% of patients (17, 18). The 5- and 10-year-survival for medullary carcinomas were 65% to 89% and 71% to 87% respectively (15, 16, 19). Finally, medullary tumors of the thyroid gland are associated occasionally with papillary thyroid carcinoma (PTC), but the outcome of the MTC is probably not influenced by the presence of the PTC (20).

Diagnosis
Clinical
Clinically patients who have sporadic medullary thyroid carcinoma most often present with a “neck lump“, a painless nodular thyroid enlargement or neck nodes. When a thyroid nodule is palpable, cervical lymph node metastases are present in at least 50% of patients (21). Patients with palpable MTC may also present with advanced local disease (cough, hoarseness, dysphagia) or with signs of metastatic disease in lung, liver or bone. Occasionally patients develop diarrhoea owing to high levels of calcitonin stimulating intestinal secretion of water and electrolytes. Other symptoms of ectopic hormone production are facial flushing and rarely Cushing's syndrome (6).
Familial syndromes are associated with different situations (MEN 2A, 2B). Pheochromocytomas are seen in 10% to 50% of patients with MEN 2A, who are often totally asymptomatic (22). MEN 2B is characterized by its unique phenotypic features. The index case of familial medullary thyroid carcinoma may present with a thyroid nodule or neck mass or, more commonly, medullary thyroid carcinoma is diagnosed as a result of screening family members suspected to have hereditary MTC (23, 24).
Biochemical
The diagnosis of MTC owes its progress to the development of reliable calcitonin radioimmunoassays in the '70s and the demonstration that calcitonin is produced by thyroid C cells. The measurement of the basal CT levels in the serum, as well as the levels of CT after stimulation of the C cell population, is performed for diagnostic purposes (6). Pentagastrin is generally regarded as the most effective CT secretory discriminator in patients with MTC and currently is the most widely used test. Positive 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, 25).
Serum calcitonin 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 (26). Although calcitonin is increased in all cases of clinically palpable MTC, there is a small percentage of patients with smaller tumours or C cell hyperplasia who have normal basal CT levels. In these cases, the positive stimulation test will confirm the diagnosis (6). Only a few other human diseases can be associated with detectable levels of CT that may be suspected on clinical grounds. (27).
Plasma calcitonin also can be used for diagnosis of sporadic medullary thyroid carcinoma before surgery. Measuring serum calcitonin in patients with thyroid diseases allows also preoparative diagnosis of C-cell hyperplasia. Several studies measured the basal CT and Pentagastrin-stimulated CT in patients with sporadic MTC and patients with C-cell hyperplasia. The results of these studies indicated that under several circumstances a basal CT value of > or = 30 pg/ml or stimulated CT > or =200pg/ml is highly predictive of MTC (28). Recently, several studies have evaluated routine plasma medullary thyroid carcinoma measurement in patients presenting with nodular thyroid disease, and may be the only clue to a diagnosis of MTC in a multinodular goiter, although normal calcitonin levels do not rule out medullary carcinoma (29, 30).
Several studies have also suggested that pro-gastrin-releasing peptide, a precursor of gastin-releasing peptide which is produced by C-cells, can be an additional marker for the diagnosis and monitoring the response to therapy in patients with MTC (31).
Genetic
In the past years, it has been established that germline mutations in the RET proto-oncogene located in the proximal region of the long arm of chromosome 10, band q11.2, are responsible for familial MTC syndromes (32, 33). Genetic testing can be done with either direct mutation analysis or linkage analysis (34). Accumulated data on direct DNA analysis have identified germline mutations in the RET proto-oncogene in 95% to 97% of MEN 2A and 75% to 85% of familial non MEN MTC kindreds. In MEN 2B, 95% of patients have the same mutation at codon 918 in exon 16.
In sporadic MTC, no germline RET mutations have been identified; however, somatic mutations have been found in approximately 30% of these patients in exon 16 of the RET proto-oncogene at codon 918 (34,35).
FNA
The diagnosis is sometimes made by fine needle aspiration (FNA) biopsy preoperatively or, when unsuspected, at the time of thyroid operation. In some situations, accurate FNA diagnosis requires a more objective method than cytological examination alone.
Radiology
Ultrasonography detects tumors as small as 4 mm and has limited application in recurrent disease (36). Primary tumors and metastases may be localized using radioisotope techniques where available. Plasma CT immunoassay can be employed for the diagnosis and detection of the tumour. CT radioimmuno-assays vary considerably in their sensitivity and specificity. Recent immunoradiometric assays (IRMA) measure mono-meric CT and are presumed to be more sensitive / specific than currently used RIAs.
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 MTC followed by a Pg stimulation test in all cases of detectable basal CT levels. In addition, the correct diagnosis of MTC is usually obtained by means of fine needle aspiration biopsy or by plasma CT immunoassay.

Prognosis
Prognosis of MTC is closely related with the tumour stage. Patients with sporadic carcinoma are commonly diagnosed later than patients with hereditary MTC (who are usually diagnosed with MTC as a result of screening) and therefore have developed, when diagnosed, a more advanced disease. Nevertheless, no differences in survival were seen when patients with MEN 2A and sporadic MTC were matched for age and extend of disease. In addition, the survival rate in heritable MTC differs between patients with MEN 2A, who have better survival, and patients with MEN 2B,who develop more aggressive types of MTC (6).

Treatment
Successful treatment of MTC depends on early diagnosis. Often, this is not possible for sporadic MTC; however, genetic testing for hereditary MTC makes this possible if genetic carriers have surgery before C cells undergo malignant transformation. Routine pre-operative measurement of calcitonin should be performed because it is often the only indicator of MTC at an early stage. This could lead to an improved cure rate in sporadic MTC (37).
Screening
The preferred current method of screening is genetic screening. Every patient with MTC should undergo direct DNA analysis to identify the RET proto-oncogene (32).
If a RET mutation is identified, then all family members should be tested for the same mutation. Once gene carriers are identified, prophylactic thyroidectomy is offered (10). Total thyroidectomy to the gene carriers should be performed before the development of clinical disease and preferably in the first decade of life. Histopathological examination of such removed thyroid glands shows abnormalities of the parafollicular C-cells in almost all cases (10).
Surgical
Surgery is the most effective form of initial management of sporadic MTC. Aggressive surgery is required, so the minimum surgical procedure should be total thyroidectomy with central neck dissection (38, 39). This surgical approach is widely accepted in patients with non palpable tumour but there are controvertial perspectives about the sufficiency of this surgical prosedure in patients with palpable MTC (6). When occult disease is detected preoperative staging and the extent of previous surgery dictate the need for further neck dissection; if metastases are identified in the lateral neck, compartment-oriented lymphadenectomy is advised (4, 11, 39-41). Modified radical neck dissection provides the best outcomes in patients who have lateral nodes metastases (38,39,42). Lymph node metastases occurs early in the course of MTC and the pattern of lymph node metastasic distribution in neck areas is not related with the tumor size (41).
The goal of management of MEN type 2 is to prevent or cure MTC in all MEN2A carriers by performing genetic testing and thyroidectomy during early childhood (43). Total thyroidectomy with removal of the posterior capsule usually removes all normal and malignant C cells and prevents the development of persistened MTC or metastases (44). MEN2B carriers have more advanced tumor than those who have MEN2A, despite presenting at a younger age (10, 45). and should have a total thyroidectomy within the first 6 months of life, preferably within the first month of life. Accurate clinical staging and exclusion of concomitant pheochromocytoma are necessary before surgery; if concomitant pheochromocytoma exists, adrenalectomy should be performed before the removal of the thyroid gland. The most common surgical complications of central and lateral neck dissection are hypoparathyroidism, laryngeal palsy and hypocalcemia (15). Complication rates after further surgery of residual MTC are higher, ranging from 5-14% (41, 46).
Postoperatively (follow-up)
Patients are dismissed on lifelong levo-thyroxine replacement and should have repeat calcitonin determination within 3 months of initial thyroidectomy. Patients with normal stimulated CT and/or CEA levels are considered surgically cured and followed by annual neck palpation as well as plasma CT determination (47). An increased basal or stimulated plasma CT level suggests persistent MTC. Such a patient is followed carefully with repeat measurement of CT and CEA, neck palpation, and imaging studies (48). Increased CEA levels are noted occasionally in MTC patients with recurrent or metastatic disease. Therefore, CEA determination is used as a tumor marker in addition to CT measurements.
Reoperation
In patients with increased CT levels after initial operation, careful follow-up may reveal clinically significant, often palpable, recurrent MTC in the neck. In most wards, these recurrences are treated by a second operation; meticulous ultra-radical dissection has been proposed in order to improve the cure rates (49).
Adjuvant therapy
External irradiation has been used as palliative therapy for locally recurrent MTC, but it is not clear if it is beneficial. Although no improvement in overall survival rates from the combination of surgery and radiation therapy was observed in several studies, recent studies confirm that external radio therapy can induce the long-term stabilisation in patients with inoperable or incompletely excised tumours. Radio-nuclide therapy was an other therapeutic aproach, but has not been found to be of significant value (6). Furthermore,limited data are available on chemotherapy protocols for progressive MTC. Several studies indicate that regiments containing doxorubicin and combination of doxorubicin and cisplatinum or 5FU and DTIC have good responce rates in patients with rapidly progressive MTC. Moreover,biological response modifiers have been excluded by several studies as first line treatment of MTC. Otcreotide, a biological response modifier, may be considered for refractory diarrhea that commonly is associated with metastatic disease with high levels of CT (50). The perspective of gene therapy, as well as new drugs that lock the action of tyrosine kinase offer some hope (10, 51).

Conclusion
MTC is an aggressive thyroid tumour which requires early diagnosis and aggressive surgical excition. The past years our knowledge regarding the clinical, patholoanatomical and genetic base of this malignance has increased. Although surgical management of early prognosed MTC is though to be the primary treatment, controversial estimations/propositions still remain about the management of recurrent or metastatic MTC.

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