As early as the beginning of the 20th century studies reported thyroid tumors with amyloid deposition (Jaquet 1906). However, it was not until 1959 that Hazard et al. reported these tumors represent a clinicopathologic entity and proposed the term medullary (solid) carcinoma of the thyroid. Shortly thereafter, a hereditary form was described (Williams 1965). Surgery has always been the treatment of choice for both primary and recurrent tumor. The early diagnosis of both sporadic and hereditary medullary thyroid carcinoma is the prerequisite for curing patients harboring one or the other form (Wells 1994).
Definition, epidemiology and pathogenesis
Medullary thyroid carcinoma (MTC) derives from the parafollicular C-cells. Histologically, a variety of patterns such as classic, papillary, amyloid-rich, insular, trabecular, smallcell variant etc. have been described. Almost all tumors express to a greater or lesser extent calcitonin which can be used for both clinical and histological diagnosis.
The incidence of MTC is not well known. Only a few epidemiological studies exist, but most of them were published shortly after MTC was identified as a separate entity. In these studies, the incidence of MTC was quite low (3.6–3.8%), probably due to the misdiagnosis of MTC as undifferentiated carcinoma, dedifferentiated carcinoma or lymphoma. In recent studies that emphasized the necessity of measuring preoperative calcitonin in any patient with potentially malignant thyroid nodules, the incidence of MTC was as high as 16–40%. Generally, it is believed that MTC comprises about 5–10% of all thyroid malignancies.
Two forms of MTC exist: a sporadic and a hereditary or familial form.
About 25% of patients with MTC belong to one of three clinically distinct syndromes: familial MTC (FMTC), multiple endocrine neoplasia type 2A (MEN 2A) or type 2B (MEN 2B). About 50% of patients with MEN 2A or MEN 2B develop phaeochromocytomas. These tumors are almost always benign, however 50–80% are bilateral (synchronously or metachronously). In addition, up to 25% of patients with MEN 2A may develop primary hyperparathyroidism. Patients with MEN 2B present with a marfanoid habitus and ganglioneuromatosis. Patients with FMTC only develop medullary thyroid carcinoma. The remaining 75% of all MTCs are sporadic, i.e. from the clinical point of view these patients neither have a family history of MTC nor do they have any other MEN 2-specific disease.
Mutations of the proto-oncogene RET have been shown to play a role in the pathogenesis of hereditary MTC. In contrast, the etiology of sporadic MTC is not known.
Germline mutations of the proto-oncogene RET are found in about 95% of patients clinically diagnosed as having hereditary MTC (either FMTC, MEN 2A, or MEN 2B). Thus, all three hereditary syndromes share the same disease-causing gene. In mice, these mutations are clearly able to induce medullary thyroid carcinoma. Whether a clear genotype-phenotype correlation exists in humans is not yet clear. While all mutations found in MEN 2A patients have also been found in families with only FMTC, some mutations have been found exclusively in FMTC patients (e.g. E768D, L790F, S891A). Future large scale analysis is necessary to determine whether patients with these mutations can forego phaeochromocytoma and hyperparathyroidism surveillance. The current available data do not justify such an approach. Also, the term MEN 2-specific RET mutation generally includes those mutations which so far have only been associated with FMTC.
The etiology of sporadic MTC, however, is unknown. Somatic RET mutations are found in up to 70% of DNA from sporadic tumors. These somatic mutations are often heterogeneously present in tumor DNA, indicating that rather than initiating carcinogenesis, they more likely occur during clonal evolution. The deletions of several chromosome arms (ip, 3p, 3q, 11p, 13q, and 22q) have been reported in up to 40% of sporadic MTCs, however, the identification of a tumor suppressor gene is still awaited.
Factors which affect the prognosis of MTC include tumor stage, early postoperative calcitonin levels, DNA euploidy, calcitonin and CEA expression of the tumor, microvessel count, and somatic RET mutation.
The value of many of the MTC prognosis factors is not uniform in all studies. Tumor stage, however, is among those factors generally correlated with outcome. Besides tumor stage, the early pentagastrin-stimulated calcitonin levels have been repeatedly shown to be a powerful prognostic factor. Some studies reported a better prognosis for patients with hereditary MTC as opposed to patients with sporadic MTC. However, in hereditary cases, these patients are generally diagnosed at an earlier stage, thus resulting in a better prognosis. As of today, there has been no study analyzing only index cases of hereditary MTC versus sporadic cases.
The 5-year-survival-rate of sporadic MTC is 80–90%, the 10-year survival rate is about 60–70%. Most likely, more than 50% of patients with sporadic MTC will die of their disease.
MTC should be diagnosed as early as possible (preferably preoperatively) since a cure is limited if the disease is diagnosed at an advanced stage (i.e. tumor extension beyond the thyroid gland) or if primary surgery is inadequate.
Regarding hereditary MTC, the discovery of RET as the disease-causing gene enables the identification of patients at risk immediately after birth. These patients should undergo mutation analysis as soon as possible. Once a MEN 2-specific RET mutation is diagnosed, further monitoring of the extent of MTC can generally be limited (calcitonin measurement, ultrasound of the thyroid gland). Anyhow, the search for accompanying disease (phaeochromocytoma, hyperparathyroidism) needs to be undertaken. Germline mutation analysis of RET cannot be used in making the diagnosis of sporadic MTC. However, RET mutation analysis should be performed in every patient with MTC to exclude hereditary MTC, even in patients 70 years or older with apparently sporadic MTC. Their own risk might be low but it is mandatory to determine whether their descendants are at risk. If no RET mutation is found and there are no other signs or symptoms suggestive of hereditary MTC, these patients and their family members can forego further screening for MTC or other MEN 2-specific diseases. The diagnosis of sporadic MTC should only be made in the absence of MEN 2-specific RET mutations.
Fine-needle aspiration cytology (FNAC) and calcitonin measurements are helpful in making the diagnosis of sporadic MT. Generally, if thyroid nodules are suspected to be malignant, calcitonin should be measured (basally, if necessary after stimulation). Either calcium (2 mg/kg KG of 10% Ca2+ injected IV over 1 min) or, preferably, pentagastrin (0.5 μg/kg KG, diluted in 5–10 ml sterile saline, injected IV over 5–15 s) or a combination of both can be used as a provocative agent. Calcitonin should be measured immediately before, 1, 2, 5, and 10 min after injection. An increase of calcitonin levels more than 3 × compared to basal levels is considered pathologic.
In a primary operation, extensive imaging techniques are often not required unless invasion of the trachea or oesophagus or distant metastases are suspected. Ultrasound, however, should be performed to identify thyroid nodules and to diagnose enlarged locoregional lymph nodes. Before performing an extensive operation, distant macrometastases (most often found in liver, lung and bones) should be ruled out. In advanced cases, their presence can already be shown by ultrasound of the liver and a chest x-ray. If these techniques fail to detect distant metastases but their presence is suspected (e.g. excessive calcitonin levels) more complex methods (e.g. MRI, CT, octreoscan, MIBG, FDG-PET, selective venous catheterization sampling, laparoscopy, thoracoscopy) might be required. A more intensive search for metastases is also generally required in patients with recurrent disease. The different techniques have their distinct advantages in detecting metastases in different organs. Their overall sensitivity to detect the more common micrometastases is low.
Non-surgical treatment modalities
Generally, radioiodine therapy has no utility since C-cells do not uptake iodine. However, radioimmunotherapy with iodine-131-labeled anti-CEA antibodies might prove useful in the treatment of non-resectable locoregional tumor or the therapy of distant metastases.
Routine use of external radiation must be avoided. In a high percentage of cases, it is accompanied by unpleasant side effects. Furthermore, its use is limited and subsequent evaluation of images and reoperation may be more difficult. However, in no n-re sec table cases and in the treatment of bone metastases, external radiation can very well be indicated.
The usefulness of chemotherapy is also limited since remission has only been achieved in a few patients.
Octreotide though sometimes useful in imaging lymph node or lung metastases does not improve the outcome of patients with MTC. However, octreotide can be used to alleviated symptoms due to extensive calcitonin production.
Surgery is the treatment of choice for both primary and recurrent MTC. The indication to operate on a patient with proved MTC is almost always given.
The goal of surgery is to eliminate the locoregional tumor burden. Surgical success is monitored by measuring postoperative calcitonin levels. In several situations, e.g. the presence of distant metastases, lymph node metastases in all four locoregional lymph node compartments, or if the primary tumor is not limited to the thyroid gland, no normalization of calcitonin can be expected. However, in these cases surgery may still be indicated because MTC is generally a slowly progressing tumor and local complications (e.g. infiltration of the trachea or of the oesophagus) must be avoided.
The classification of four locoregional lymph node compartments according to anatomical structures has been proved to be useful for both defining the extent of lymphadenectomy and comparing patterns of metastasis.
Definition of the four cervicomediastinal lymph node compartments
Compartment 1, cervicocentral (C1): in between the two carotid sheaths, extending cranially up to the hyoid bone, caudally down to the brachiocephalic vein, including the cervical paratracheoesophageal lymph nodes.
Compartment 2 and 3, cervicolateral right (C2) and left (C3): extending laterally from the carotid sheath to the trapezoid muscle, caudally from the subclavian vein up to the hypoglossal nerve.
Compartment 4, mediastinal (C4): including the lymph nodes between the brachiocephalic vein and the tracheal bifurcation in the upper anterior and posterior mediastinum.
Lymph node metastases of MTC can be very small in size and diagnosable neither prenor intraoperatively. Thus, if a lymphadenectomy is performed it should include not only the obviously enlarged lymph nodes, but also the whole adipose and connective tissue of a compartment since the very small, single lymph nodes within may be involved, too.
Magnifying glasses, bipolar coagulation forceps and neuromonitoring of the recurrent laryngeal nerve are technically helpful. These tools facilitate the identification and preparation of important structures (e.g. recurrent laryngeal nerve, parathyroid glands) and enable complete dissection of each compartment while preserving these structures. It has been an unresolved issue whether the parathyroid glands should routinely be autotransplanted or remain in situ. The incidence of hypoparathyroidism seems to be similar in either case (grade C). The preservation of the upper glands is almost always feasible. In contrast, preservation of the lower glands is rarely manageable as a consequence of the cervicocentral lymph node dissection. Any clearly tumor-free parathyroid gland with insufficient vascularization should be cut into many little pieces and autotransplanted either into the sternocleidoid muscle or the forearm. The location of the autotransplant should be marked with a non-resorbable suture in case reoperation is required.
Total thyroidectomy and lymph node dissection of the cervicocentral compartment is regarded as the minimal treatment in all medullary thyroid carcinomas (grade C).
The general recommendation to perform total thyroidectomy seems to be justified since MTC is often multifocal (hereditary MTC 80–90%, sporadic MTC 10–20%) and not susceptible to radioiodine ablation. The prognostic significance of lymph node metastases is also widely accepted (grade C). Since 50–80% of non-screening patients harbor lymph node metastases, the routine inclusion of the cervicocentral compartment should be mandatory. It is also generally accepted practice to dissect compartments obviously involved with lymph node metastases. Different algorithms have been reported to determine extent of lymphadenectomy if no obvious involvement is present.
Extension of lymphadenectomy cervicolateral:
Lymph node dissection ipsilateral (regarding the site of the primary tumor) and/or bilateral cervicolateral in the presence of cervicocentral lymph node metastases.
Inclusion of the ipsilateral cervicolateral compartment if primary tumor > 2 cm in diameter.
General inclusion of the ipsilateral cervicolateral compartment.
Bilateral cervicolateral lymphadenectomy in any patient with clinical evidence of disease.
Extension of lymphadenectomy mediastinal:
More than 3 lymph node metastases in the cervicocentral compartment (C1).
Lymph node metastases in one of the cervicolateral compartments (C2 or C3).
Proved lymph node metastases within the upper mediastinum or cervicomediastinal transition.
Special considerations in hereditary MTC
The rationale for operating on patients harboring MEN 2-specific germline mutations derives from a study which showed that by the age of 70, there is up to a 70% incidence rate of clinically symptomatic cases in these patients. It is important to rule out the coexistence of a phaeochromocytoma in these patients which had to be treated first. Despite some obvious differences between sporadic and hereditary MTC, recommendations regarding surgical treatment in particular do not differ significantly. Interestingly, calcitonin levels are not unlikely to be within normal limits in young children identified as having MEN 2 by RET mutation analysis.
Total thyroidectomy and cervicocentral lymphadenectomy are generally accepted to be the minimal treatment for hereditary MTC (grade C). In some recent studies, correlation's could be shown between the presence of lymph node metastases and the patient's age, the preoperative calcitonin level or the presence of a specific RET mutation. In general, lymph node involvement seems to be extremely rare if stimulated calcitonin is within normal limits or if patients are younger than 10 years. In addition, patients harboring some RET mutations (e.g. E768D, L790F, Y791F, V804L, V804M) seem to develop lymph node metastases at a later age. Therefore, in these patients routine inclusion of the cervicocentral compartment might not be necessary. Further analysis of larger series of patients will be necessary to provide general recommendations. Ipsilateral (regarding the primary tumor) cervicolateral lymph node metastases are common (50–70%) in MTC. Since hereditary MTC is often bilateral, a routine bilateral cervicolateral extension of the lymphadenectomy seems to be justified. In patients younger than 15 years, however, cervicolateral lymph node metastases are extremely rare. In these instances, a routine extension of the lymph node dissection cervicolaterally might not be indicated. The recommendation to dissect the mediastinum follows the indications listed above.
All of these recommendations are based on the analysis of a relatively small number of patients and need to be validated in larger series.
After exposure of the thyroid gland, both lobes should be mobilized to enable identification of the recurrent laryngeal nerve. Thereafter follows the preparation of the cervicocentral compartment anterior and posterior of the recurrent laryngeal nerve. This lymph node compartment is removed en bloc with the thyroid gland. Lymphadenectomy of the cervicolateral compartments should be performed in a centripetal manner. The dissection of inter- and retrofascicular lymph nodes is important. Lymph node dissection of the mediastinal compartment is performed by a transsternal approach and should extend caudally to the azygous vein and laterally to the pleura.
The chance of biochemical cure after reoperation is much lower (up to 35%) as opposed to the primary therapy (45–70%), however it is feasible.
Reoperation is indicated if:
Calcitonin levels are elevated after a lessthan-total thyroidectomy (sporadic MTC).
Thyroid remnant is present even in the absence of elevated calcitonin levels (hereditary MTC).
There is proven locoregional recurrence or lymph node metastases.
The necessity of removing the entire thyroid gland in patients with hereditary MTC is due to the fact that every single C-cell harbors a malignant potentiality. Seemingly all patients with elevated calcitonin levels after primary surgery still have lymph node metastases at least within the cervicocentral and ipsilateral cervicolateral compartment. Therefore in these instances, reoperation seems to be justified even in the absence of positive imaging results. The extent of surgery at reoperation should be identical to the primary procedures if systematic lymphadenectomy was not performed previously.
Generally, the surgical approach during reoperation does not differ from the primary operation. Scar tissue and previous external radiation, however, can make a meticulous preparation more difficult. Remaining thyroid tissue should be resected; this is mandatory in hereditary MTC cases.
Surgery is the treatment of choice for primary and recurrent MTC and for both sporadic and hereditary MTC. While total thyroidectomy and dissection of the cervicocentral lymph node compartment are standard practice, no uniform approach exists beyond this point. Prospective studies are difficult to establish.
However, the following conclusions can be drawn based on recent studies in very specialized centers (grade C):
A compartment-oriented technique of lymph node dissection is superior to regional lymph node dissection or selective lymph node dissection regarding recurrence and survival.
If lymph node metastases are present, they are almost as common in the ipsilateral cervicolateral compartment as in the cervicocentral compartment. Therefore, these compartments should be part of the primary minimal therapy.
It is still an unresolved decision whether or not to dissect the contralateral cervicolateral and mediastinal compartment if not clearly nodal positive. The routine inclusion of the contralateral cervicolateral compartment seems justified since lymph node metastases were found in 10–40% when routinely dissected. Dissecting the mediastinum seems to be indicated if lymph node metastases are proved preoperatively by imaging techniques or intraoperatively by exploration, if more than 3 lymph node metastases are found in the cervicocentral compartment (C1) or if lymph node metastases are found in one of the cervicolateral compartments (C2 or C3).
The current available studies do not justify distinct approaches to sporadic and hereditary medullary carcinoma. An exception is the treatment of young patients with MEN 2-specific RET mutation where a less extensive approach might be justified.
Finally, the treatment of MTC beyond local disease is non-existent. Chemotherapy and/ or radioiodine therapy per se is not likely to be the answer. Instead, novel compounds against molecular targets must be sought.
Editorial help of Wendy M. Smith is gratefully acknowledged.
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