Medullary Carcinoma
Hazard et al. (286) first described a unique tumor in the thyroid characterized by sheets of cells with large nuclei, amyloid deposits, fibrosis, multicentricity, and an unexpectedly benign course in view of the solid tumor appearance. Over 50% may have local or distant metastases at diagnosis. The tumors may metastasize locally, or to bones and soft tissues. The thyroid primary tumor and the metastases may show dense calcification on x-ray film. The course tends to be progressive, and 10-year survivorship varies from 50 to 70%. These tumors, which constitute 2-8% of all thyroid cancers, are derived from the "light," or "C," or "parafollicular" cells. These are calcitonin (CT)-secreting cells, distinct from thyroid acinar cells, and are of ultimobranchial origin. The tumors may occur sporadically (about 70% of the total), in families, or as part of the MENII syndromes, which constitute about 10-20% of the cases, and are transmitted in families as dominant traits. In contrast with thyroid epithelial cell tumors, the female to male ratio is near unity. MEN-II (or IIA) includes patients with medullary thyroid cancers, pheochromocytomas, and parathyroid hyperplasia or adenomas. MEN- III (or MEN-IIB) includes medullary thyroid carcinoma, mucosal neuromas, pheochromocytomas, which are usually bilateral and often malignant, occasionally cafe-au-lait spots, and possibly Gardner's syndrome (mucocutaneous pigmented nevi and small intestinal polyps) (287-291, 293, 294). An occasional variant of medullary thyroid cancer appears to contain both CT and TG, suggesting the cells, surprisingly, have features of both medullary thyroid cancer and follicular cancer (295) The origin of these tumors through mutation of the ret proto-oncogene is described below (296, 297). Gastrointestinal symptoms including diarrhea, constipation, and rarely megacolon occur in these patients and may occur before the thyroid tumor is detected. Hyperplasia of C cells often precedes the development of familial cancers (298). Medullary tumors derived from the C cells not only secrete CT, which may cause diarrhea (299), but in addition may produce serotonin (with a carcinoid syndrome), prostaglandins, corticotropin releasing factor, and adrenocorticotropic hormone (causing Cushing's syndrome), histaminase, and somatostatin. Interestingly, expression of somatostatin appears to correlate with improved prognosis (300). Medullary thyroid carcinoma cells in tissue culture have been found to produce Ghrelin, which is an endogenous ligand for the GH secretagogue receptor. MTC is known to produce several gastrointestinal hormones and neuroendocrine peptides, in addition to calcitonin, and including CGRP, ACTH, serotonin, chromogranin A, and vasoactive intestinal peptide, and to this we now add Ghrelin (301). Alcohol ingestion is reported to induce attacks of flushing and diarrhea, and to stimulate CT secretion by the tumors (302). The CT secreted by these tumors rarely causes hypocalcemia (303), but may possibly induce parathyroid hyperplasia. Most evidence suggests that the parathyroid hyperplasia is actually a separate part of a pleomorphic genetic syndrome.
Medullary tumors have an ominous histologic pattern, with solid masses of cells with large vesicular nuclei (304). There may be considerable associated fibrosis, and deposits of amyloid are a helpful diagnostic point. At the time of initial histologic examination the pathologist should recognize these tumors as entities distinct from the undifferentiated cancers, for the medullary carcinomas have a much better prognosis.
Ret oncogene and Medullary Thyroid Cancer
Studies on patients with MEN I and MEN II indicated linkage to chromosomes 11 (305) and 10, respectively. Subsequent studies demonstrated that the ret oncogene is present at 10q11.2. Germline mutations have been detected in this oncogene in all patients with MEN II and MEN III (or IIB), and familial MTC (306). RET is a cell-membrane receptor of the growth factor family, with tyrosine kinase function. In up to 97% of patients with MENIIA, mutations are found in codons 609, 611, 618, 620, and 630 in exons 10 and 11. These all involve substitutions of other aminoacids for cysteine, and are thought to cause activation of the gene by aberrant disulphide bonding causing dimerization. Similar changes are seen in Familial MTC. In patients with the MENIIB syndrome, almost all, if not all, mutations involve an amino acid substitution of threonine for methionine at codon (918) in exon 16, and are thought to induce a change in substrate phosphorylation. Somatic mutations in ret are present in up to half of patients with sporadic MTC and are almost always in codon 918 (307, 308). Mutations in this codon are thought to imply a poor prognosis
Calcitonin and CEA in Medullary Tumors
The calcitonin assay provides a convenient screening procedure in families with this genetic trait (309). Every member of one of these families with either a thyroid mass or elevated calcitonin levels should have a thyroidectomy. In MEN-IIA, the tumors follow a rather benign course somewhat akin to that of follicular cancer, and usually can be controlled by surgery. MEN-IIB tumors are much more aggressive and often cause death in the second or third decade. One patient has been reported with a medullary cancer that was suppressed by thyroid hormone (310), but usually this treatment is not efficacious and has no logical basis. Secretion of calcitonin by medullary cancer is remarkably increased by calcium or pentagastrin infusion (311). This procedure can be helpful in establishing a diagnosis. At present the infusion of pentagastrin (0.5 µg/kg over 5 seconds), with determination of calcitonin levels at 0, 1, 2, 5, 10, and 15 minutes, appears to be the best test. Basal CT values are normally under (depending on the laboratory) 30 pg/ml (312). Values of 30-100 after pentagastrin indicate hyperplasia, and values over 100 typically indicate the presence of cancer. Calcitonin should drop to levels of < 30 pg/ml if the tumor is completely removed surgically. It should be noted that excess production of CT is not unique for medullary cancer, but can occur with granulomatous diseases and other cancers. Patients with the syndrome should also be studied with parathyroid hormone and catecholamine assays in order to determine the presence of other components of the syndrome.
The C cells also produce carcinoembryonic antigen (CEA) in large amounts. Serum CEA levels are elevated in medullary cancer with the same frequency as are CT levels (313). Although CEA determination provides another parameter to follow, it does not offer any obvious advantage, and lacks the specificity of CT determinations. Tumor dedifferentiation is associated with a fall of CT and increasing CEA. This is an ominous sign.
Several specialized scanning procedures have been used in MTC. Total body imaging with Tl-201 chloride and Tc-99m(V)DMSA have been successful in localizing metastases. 131I MIBG and 131I anti-CEA have been used both for localization and in attempts at therapy (314). Most recently, radiolabelled somatostatin has been used as a whole body scanning agent.
Since patients with MENIIA and IIB, and familial MTC, probably all have a germline mutation of the ret oncogene near the centromere of chromosome 10, and many patients with sporadic MTC have somatic ret mutations, molecular techniques can be used to detect at-risk subjects in recognized families (315). PCR amplification of exons 10, 11, and 16, followed by single strand conformational electrophoretic analysis, or use of specifically designed restriction enzyme sites, allows recognition of most mutations (316). This information is crucial in defining potential risk in young children and identifying need (317) for operation or frequent pentagastrin testing, and presumably will also screen out members of families who will not need to be repetitively screened by pentagastrin stimulation tests. Unlike occasional false positives with CT assays, the results of genetic screening are unambiguous (318).
For readers with an interest in a somewhat broader view of oncogenesis, it may be noted that a syndrome entirely analogous to metastatic medullary thyroid carcinoma appears frequently in aged bulls (319). Histologically similar adenomas are also frequently found. The lesion may be due to excessive dietary calcium; whether a similar stimulus could operate in human disease is unknown.
MTC is unique since it can be detected in MEN-II or MEN-III families by genetic analysis and screening tests measuring pentagastrin-stimulated CT secretion before the disease reaches clinical detectability. In families with familial MTC, MENIIa, and IIB, repeatedly observed elevations to well above the normal range (e.g., peak values of 30-100 pg/ml) constitute a basis for operation. In these patients focal tumors or C-cell hyperplasia may be found after near-total or total thyroidectomy is performed. Since C-cell hyperplasia precedes the development of malignancy, it is currently believed logical to operate at this stage of the disease even in young children with MENIIB. Patients with MENIIA or familial MTC are similarly followed, tend to develop tumor later, and 20-40% may never develop cancer (320). International Workshops on MTC have recommended prophylactic thyroidectomy before the age of 5 years in persons harboring mutations of codons 611, 618, 620, and 634 because of their high efficiency in transformation. Consensus on best treatment for patients with other mutations (codons 609, ,630,768, 790,791, 804, 891) is not clear, with thyroidectomy recommended from ages 5 to 10(319a).
Patients with clinical tumor of any size, sporadic or familial, are also treated by near-total or total thyroidectomy. Invasive disease is resected if possible. Since cervical nodal metastasis occur in up to 90% of patients with palpable tumors, a careful modified radical neck dissection is performed with removal of nodes in the central and ipsilateral compartment. The exploration for nodes should include the upper mediastinum. Bilateral neck dissection may be appropriate in patients with hereditary tumors.
After these stages are reached, unanimity in approach is lost. After operation, patients can be scanned and residual functioning thyroid can be ablated with 131I, as in papillary or follicular tumors, since this procedure may ablate tiny foci of residual cancer (321, 322). However the value of this procedure is not proven, and most groups do not routinely use 131I. However it does remove residual thyroid tissue, which is often visualized on MRI or CAT scans and may suggest the presence of local recurrence. In patients with invasive disease, who are above age 45-50, radiotherapy (5,500-6,000 rads) may be useful, although there also is disagreement on this point. (v.i.). In all other patients, baseline CT levels should be followed. Pentagastrin stimulation may be done if the baseline CT level is normal. Occasionally CT levels fall gradually over a year. It is also possible to follow the serum level of CEA as a tumor marker, or CT-related peptide (323). A discordant elevation of CEA in relation to CT may be an indicator of an aggressive tumor. However, in general, CT is the most informative marker.
What to do about the frequently-found elevated CT level without an obvious tumor source is less certain. A thorough workup including cervical ultrasound, bone scan, neck, chest and abdominal CAT scans, is in order. Thallium201 chloride, 99mTc DMSA, somatostatin scanning, and FDG-PET may be informative. Residual or recurrent resectable disease should be approached surgically. Neck dissection, if not done previously with a unilateral tumor, should be considered. In the absence of identifiable source of the CT, careful, extensive, microdissection of the neck and upper mediastinum may eliminate the source of CT in 30% of patients (324). Catheterization of the superior vena cava and internal jugulars, with an attempt to localize the tumor by means of multiple venous sampling for CT (268) during pentagastrin stimulation, is possible. The technical success of this approach has been demonstrated, but often the CT level is not reduced to normal, even if operation is subsequently performed on the identified area (325). This complicated proceedur4e has fallen out of favor. Radiotherapy may be given to identified non-resectable lesions.
In many cases, no source for the CT is found. Watchful waiting is the approach preferred by many experienced clinicians. Alternatively, mantle irradiation can be recommended. We prefer to give mantle irradiation, especially if there is progressive elevation of the CT value. As shown by Simpson (326), medullary tumors are radiosensitive, although a full response may not be seen for many months. This irradiation has been shown to prolong local relapse-free time, but not to clearly improve ultimate prognosis (327). The effectiveness of radiotherapy was evaluated in 24 of 139 patients with medullary thyroid cancer who were given radiotherapy because of advanced local disease at presentation. Only one had normalization of calcitonin, but ten remained free of clinical recurrence. Local relapse was significantly reduced after radiotherapy, but there was no difference in ten year survival between those with and without treatment. These authors believe that radiotherapy does reduce the incidence of loco-regional relapse, but do not advise routine use of radiotherapy because of the relatively favorable long term survival of patients even with elevated calcitonin levels after operation (328). Other investigators question the value of X-ray therapy, contending that patients with MEN-II have multicentric foci from the start, and that radiotherapy may actually worsen prognosis (329). Chemotherapy is reserved for patients with proven symptomatic metastases, and the program is described below. New and semi-experimental therapies include treatment with [131I]-MIBG or [131I]-anti-CEA antibodies (330), and potentially gene therapy.
MTC is associated in MEN-II with parathyroid adenomas and hyperplasia, and in both MEN-IIA and MEN-IIB with pheochromocytomas that are often bilateral and malignant. Parathyroid hormone, VMA, and catecholamine assays should be done to evaluate these problems, and pheochromocytoma, if present, should be treated before the thyroid cancer. Occasionally neuromas cause problems requiring surgery of the intestine or other organs, including the larynx.
