Medullary Thyroid Cancer
Medullary thyroid cancer has unique clinical implications.[18] Since MTC may be familial, a comprehensive approach to the patient and the family is required. Even if there is no family history of MTC, it is impossible to rule out the possibility that the patient represents the index case of a kindred with MTC. Therefore, if there is a preoperative diagnosis of MTC, usually after a biopsy of the thyroid nodule or enlarged lymph node is performed, it is important to perform appropriate preoperative biochemical testing for pheochromocytomas (usually bilateral) and, if detected, to resect them prior to thyroid surgery. A total thyroidectomy and central neck dissection must be performed for treatment of MTC, with every effort to remove all possible disease by sufficient systematic node dissection. Postoperative basal calcitonin levels provide evidence for the adequacy of resection and are used to test for residual disease or recurrence. In addition, carcinoembryonic antigen is another tumor marker that is often elevated in patients with MTC.
The best available treatment of persistent or recurrent disease is surgical resection, when possible. Progressive unresectable disease may be treated with external beam radiotherapy; however, this has not been shown to improve the survival rate. Chemotherapy is usually ineffective. Fortunately, some patients may survive for many years with minimal symptoms despite significant tumor burdens. Patients with considerable unresectable disease may have chronic diarrhea, which should be treated symptomatically.
Nutmeg oil, a combination of atropine sulfate and diphenoxylate hydrochloride (Lomotil), or subcutaneously administered somatostatin analogue have been effective in such cases. Approximately 25% of MTCs are familial, usually in the context of MEN IIa or IIb or familial (non- MEN) MTC. It is therefore essential to obtain a detailed family history. Individuals with MEN IIb (MTC, pheochromocytoma) have a phenotype that is also characterized by mucosal neuromas, so they should be distinguishable from patients with MEN IIa (MTC, pheochromocytoma, and hyperparathyroidism). Most patients with MEN IIb and MTC are curable only if a thyroidectomy is performed before clinical disease is apparent. Genetic testing to identify mutations in the RET proto-oncogene of patients with familial MTC has become clinically available, and this type of testing is very useful in identifying affected individuals. In addition, since familial MTC is expressed as an autosomal dominant trait, all first-degree relatives of patients with familial MTC must be screened. Traditionally, it has been standard practice to obtain basal and pentagastrin-stimulated serum calcitonin levels for this purpose, but genetic testing for the presence of RET proto-oncogene mutations may well replace the cumbersome, repetitive, and expensive stimulation tests with multiple calcitonin determinations. The role of surgery based on abnormal results of DNA tests in family members is currently being investigated. Patients who are identified with familial MTC by using DNA testing or serum calcitonin elevations should undergo a prophylactic total thyroidectomy. Recent trends are to perform a total thyroidectomy on children with positive RET mutations between 5 and 7 years of age.[19] Periodic biochemical screening for pheochromocytomas must be done indefinitely. Likewise, patients with MEN IIa must undergo screening for hyperparathyroidism.
Undifferentiated (anaplastic) Thyroid Cancer
Anaplastic thyroid cancer is the most aggressive and lethal solid tumor that occurs in humans; fortunately, it is the least common form of thyroid cancer.[20] With rare exception, it is rapidly fatal, usually within months of the diagnosis. Anaplastic cancer usually does not concentrate iodine or express Tg, so radioiodine scanning or therapy is of no utility and serum Tg measurements cannot be used as reliable tumor markers. It is essential to verify the diagnosis histologically since insular cancer, lymphomas, and MTCs that require different therapeutic approaches are occasionally confused with undifferentiated cancers.
Surgical treatment is of very limited usefulness and is indicated primarily for relief of airway obstruction. External-beam radiotherapy has been helpful in delaying local recurrence and preventing thoracic outlet obstruction, especially after surgery has been performed. However, this treatment has not been shown to alter the mortality rate. Chemotherapy has not been found to be effective for this tumor despite a variety of approaches that utilize single agents or various combinations of doxorubicin hydrochloride, etoposide (VP-16), cisplatin, and bleomycin sulfate. Rarely, partial responses to chemotherapy can prolong survival by several months. The role of chemotherapy, followed by external radiation and surgery, while also rarely if ever curative, has been reported to extend survival, in some patients; such an approach may need to be evaluated further. The most practical patient care requires close attention to pain control, maintenance of the airway, and other quality-of-life issues.
Occasionally, previously well-differentiated papillary or follicular thyroid cancer undergoes anaplastic dedifferentiation, and patients with such conditions should be managed as just described. On the other hand, some tumors are in intermediate states of dedifferentiation, in which tumor growth may be slower. When this occurs, resectable tumor should be removed, and external radiotherapy, and perhaps chemotherapy, should be used for unresectable or incompletely resectable metastases. Suppression of thyrotropin with levothyroxine therapy has not been proved to be beneficial, but replacement therapy is indicated.
Lymphoma of the Thyroid Gland
Primary non-Hodgkin lymphoma of the thyroid gland, an uncommon thyroid tumor, must be considered in the context of a rapidly growing goiter, particularly in older women with hypothyroidism because of autoimmune (Hashimoto) thyroiditis.[21] The FNAB is the initial diagnostic procedure of choice that is sometimes aided by B-cell immunotyping with flow cytometry, but open biopsy for pathologic confirmation is often required for a definitive diagnosis. Since this tumor requires a unique therapeutic approach, it must be distinguished from anaplastic and MTC, since there appears to be little benefit of surgical therapy for lymphomas. After diagnosis, patients can be clinically staged (without surgery) through use of appropriate computed tomography scans and magnetic resonance imaging. They are designated stage IE with disease confined to the thyroid gland (with possible local invasion), stage IIE with local lymph node metastases, stage IIIE with distant nodal metastases, or stage IV with diffuse involvement of multiple organs and sites.
Since distant metastases may develop in almost one third of patients with stage IE and IIE disease, and many patients present with micrometastatic disease, recent studies have demonstrated the best success with combined therapy, by using systemic chemotherapy and external radiotherapy to the neck and mediastinum. Although a variety of chemotherapeutic regimens have been used, most successful treatments have included an anthracycline agent.
