Clinical and Pathologic Characteristics

Although it may arise sporadically, MEN 2B more frequently occurs as a familial disorder inherited in an autosomal dominant fashion. MEN 2B is less common than MEN 2A.

Extracellular--Intracellular-

LB TM TK CT

Extracellular--Intracellular-

LB TM TK CT

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FIGURE 83-2. A diagram of the ret protooncogene demonstrating both highly conserved elements and sites of mutation known to be responsible for sporadic and familial medullary thyroid carcinoma (MTC) as well as the multiple endocrine neoplasia (MEN) 2 syndromes. Vertical bars within the diagram indicate sites of cysteine codons. Cysteine codon mutations in the juxtamembrane extracellular domain (609, 611, 618, 620, 634) are responsible for familial MTC as well as the MEN 2A syndrome. Mutation at 630 (underlined) gives rise to sporadic MTC. Segments 1 to 4 in the tyrosine kinase domain represent highly conserved elements, whereas asterisks denote possible sites for tyrosine autophosphorylation. The substitution of threonine for methionine in position 918 produces the MEN 2B phenotype. LB = ligand-binding segment; TM = transmembrane domain; TK = tyrosine kinase; CT = carboxyterminus; ATP = site of adenosine triphosphate binding. (From Carlson K, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the ret proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Sci USA 1994;91:1580.)

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FIGURE 83-2. A diagram of the ret protooncogene demonstrating both highly conserved elements and sites of mutation known to be responsible for sporadic and familial medullary thyroid carcinoma (MTC) as well as the multiple endocrine neoplasia (MEN) 2 syndromes. Vertical bars within the diagram indicate sites of cysteine codons. Cysteine codon mutations in the juxtamembrane extracellular domain (609, 611, 618, 620, 634) are responsible for familial MTC as well as the MEN 2A syndrome. Mutation at 630 (underlined) gives rise to sporadic MTC. Segments 1 to 4 in the tyrosine kinase domain represent highly conserved elements, whereas asterisks denote possible sites for tyrosine autophosphorylation. The substitution of threonine for methionine in position 918 produces the MEN 2B phenotype. LB = ligand-binding segment; TM = transmembrane domain; TK = tyrosine kinase; CT = carboxyterminus; ATP = site of adenosine triphosphate binding. (From Carlson K, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the ret proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Sci USA 1994;91:1580.)

For example, a multicenter study by Modigliani and associates identified 300 MEN 2 patients with pheochromocytoma. There were only 26 (<10%) with MEN 2B.17 Significantly, disease that arises de novo is also subsequently transmitted to descendant generations in an autosomal dominant fashion.18 Penetrance is believed to be nearly 100%, but expressivity is variable. As a result, all the manifestations of the syndrome may not be present in a given afflicted patient. Whereas medullary thyroid cancer, mucosal neuromas, and a marfanoid habitus are essentially universal among MEN 2B patients, pheochromocytoma is found in only about one half.19 The sexes are apparently affected equally.20 Families in which the diagnosis of MEN 2B has been made seldom persist beyond a few generations, owing to the aggressive nature of the neoplasia involved.

Neuromas and Habitus

The outstanding clinical features of MEN 2B comprise the near-pathognomonic physical appearance (Figs. 83-3 and 83-4). Patients afflicted with this syndrome possess a tall, slender, "marfanoid" habitus with varying degrees of muscle wasting. The face is generally elongated; neuromas cause enlarged and nodular lips as well as thickened eyelids. Slit-lamp examination may reveal thickening of corneal nerves. Skeletal abnormalities are also characteristic and may include genu valgum, pes cavus, and kyphoscoliosis. Significantly, these characteristic physical features are often recognizable in infancy or even at birth, affording the careful clinician the opportunity to diagnose the disorder before the thyroid and adrenal neoplasia have become clinically manifest.

Although found most frequently in the gastrointestinal tract, the neuromas of MEN 2B may be present in any organ possessing a submucosa, including the bronchi and urinary bladder. These neuromas have been described as hamar-tomatous proliferations of Schwann cells, nerve fibers, and, less frequently, ganglion cells.21 When present in the gut, they predispose the patient to significant gastrointestinal symptoms, especially constipation or diarrhea, which may constitute the presenting complaint.

FIGURE 83-3. Ganglioneuromatosis of the lips and tongue in a patient afflicted with multiple endocrine neoplasm 2B. Note the thickened lips as well as multiple submucosal nodules. (From Dodd G. The radiologic features of multiple endocrine neoplasia types 2A and 2B. Semin Roentgenol 1985;20:79.)
FIGURE 83-4. Marfanoid habitus of a patient with multiple endocrine neoplasia 2B. Note the disproportionately long limbs, muscle wasting, and joint deformities. (From Dodd G. The radiologic features of multiple endocrine neoplasia types 2A and 2B. Semin Roentgenol 1985;20:81.)

Medullary Thyroid Carcinoma

Medullary carcinoma of the thyroid, a tumor of the calcitonin-producing parafollicular C cells, is an invariable feature of MEN 2B. If early diagnosis based on phenotype is not made, this tumor is generally the first abnormality discovered. Classically, the clinical course of this tumor in the context of MEN 2B has been characterized as being more virulent than when it appears in MEN 2A or in an isolated form, with a more ominous metastatic potential. This perception, however, is evolving. Studies have suggested that the natural histories of these tumors in MEN 2A and 2B may, in fact, be comparable. The major difference appears to be that medullary thyroid cancer develops in MEN 2B at a significantly earlier age (in one study, diagnosis of medullary thyroid carcinoma in MEN 2B occurred at a mean age of 22 years vs. a mean age of 38 years in MEN 2A).22 However, a review of the German Medullary Thyroid Carcinoma Registry demonstrated a significantly decreased survival rate in patients with this disease in the context of MEN 2B in comparison to those with the tumor in MEN 2A (survival rates in patients with sporadic medullary thyroid cancer were similar to those in MEN 2B patients) (see Fig. 83-6).23 A measure of the aggressive nature of this neoplasm in MEN 2B may be derived from a review of the syndrome in which 100% of symptomatic patients had metastases at the time of surgery.24 Medullary thyroid carcinoma in MEN 2A and 2B is almost invariably bilateral and multicentric and is preceded by a focal or diffuse proliferation of parafollicular calcitonin-producing cells termed C-cell hyperplasia. By contrast, sporadically arising medullary thyroid cancer is typically unilateral and, classically, is not preceded by a premalignant proliferation. Therefore, bilateral disease, multicentricity, and presence of C-cell hyperplasia have all been considered to be evidence for familial rather than de novo disease. However, several authors have described the presence of C-cell hyperplasia in nonhereditary medullary thyroid cancer as well as benign thyroid disease and, moreover, its absence in medullary cancer in the setting of known MEN 2A, suggesting that the identification of this pathologic entity may be of less value than previously thought.25'26 In fact, aside from the suggestive evidence of multicentricity and bilaterality, there are no microscopic differences between sporadically arising and hereditary medullary thyroid cancer that can be detected by histopathologic means at this time.

Medullary thyroid cancer is typically found in the superior portion of the gland, where the greatest concentration of C cells exists. The tumor presents clinically as a thyroid mass or nodule, most often noted incidentally on physical examination, which may appear unilateral or bilateral to palpation. Fine-needle aspiration biopsy may provide cytologic evidence of the disease, which is subject to confirmation by immunocytochemical staining for calcitonin. The gross pathologic appearance is of whitish brown, well-circumscribed nodules. Microscopically, the lesion appears as nests of polygonal or round, uniform cells surrounded by a fibrous and vascular stroma in which material with the staining properties of amyloid frequently resides (Fig. 83-5). This material consists of a calcitonin prohormone secreted by the tumor cells.

The tumor cells of medullary thyroid carcinoma actively secrete a number of peptide hormone products. Foremost is calcitonin, the serum level of which is markedly increased in the presence of the tumor. Levels of calcitonin greater than 1000 pg/mL in the presence of elevated carcinoembryonic antigen are said to be diagnostic of the disease, and persistently elevated calcitonin after surgical resection suggests residual or recurrent tumor.27 Provocative tests in which

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FIGURE 83-5. The microscopic appearance of medullary thyroid carcinoma. Compressed nests of small round and polygonal tumor C cells amid stromal amyloid. Normal follicles are seen peripherally. (From Dodd G. The radiologic features of multiple endocrine neoplasia types 2A and 2B. Semin Roentgenol 1985;20:81.)

FIGURE 83-5. The microscopic appearance of medullary thyroid carcinoma. Compressed nests of small round and polygonal tumor C cells amid stromal amyloid. Normal follicles are seen peripherally. (From Dodd G. The radiologic features of multiple endocrine neoplasia types 2A and 2B. Semin Roentgenol 1985;20:81.)

pentagastrin (either alone or in combination with calcium) is injected to stimulate calcitonin release (analogous to the secretin stimulation test in gastrinoma diagnosis) have also been advocated. Elevations of calcitonin higher than 300 pg/mL on provocation are considered diagnostic of C-cell hyperplasia or medullary thyroid cancer.28 Other peptides elaborated by the medullary thyroid cancer cells include calcitonin gene-related peptide, somatostatin, corticotropin, and chromogranin A.29 Paraneoplastic syndromes (particularly Cushing's syndrome from excessive corticotropin) occur but are unusual. Diarrhea, presumably from an unidentified humoral source, arises in approximately 30% of patients with this tumor and is amenable to conservative therapy.

The most distinctive feature of medullary carcinoma of the thyroid in the setting of MEN 2B is the ominous potential for early metastases. These appear first in the regional cervical or mediastinal lymph nodes, with distant metastases arising later in the lung, liver, and bone. Patients presenting with advanced local disease may manifest hoarseness or dysphagia, whereas distant metastases may be suggested by symptoms referable to the systems involved.

Relatively little controversy attends the question of the preferred method of treating medullary thyroid cancer. Because this tumor is not responsive to present conventional chemotherapeutic or radiologic treatment regimens, surgical therapy is the only option. Most authorities recommend total thyroidectomy once the diagnosis has been made, whether this diagnosis is based on clinical evidence or biochemical screening tests. Imaging studies are of little use because localization of the tumor within the thyroid is of academic interest only. Advocacy of total thyroidectomy is particularly sensible in the case of MEN 2B in light of the understanding that medullary thyroid cancer is frequently bilateral as well as unusually aggressive in the setting of this syndrome. Central neck compartment lymph nodes should be dissected in all patients in an effort to achieve local control of disease. Thyroid replacement therapy must, of course, be initiated in the postoperative period.

Data from the German Medullary Thyroid Carcinoma Registry indicate a 5-year (after diagnosis) survival rate of 82.5% in MEN 2B patients (Fig. 83-6). By 10 years after diagnosis, the survival rate decreased to 66.0%.23 The major prognostic factor in this study appeared to be tumor stage at diagnosis. Previous reports have noted improved survival in patients whose thyroid tumors were detected by biochemical means over those first diagnosed on the basis of clinical grounds.30

Pheochromocytoma

Pheochromocytoma arises in approximately 50% of individuals with MEN 2B. The predisposition of pheochromocytoma in MEN 2 may be related to mutations in glial cell line-derived neurotrophic factor (GDNF). Some studies suggest that allelic variation at the GDNF locus may modify the susceptibility to pheochromocytoma.31 Although its histologic appearance in this familial setting is indistinguishable from that of the sporadically occurring tumor, bilateral involvement (which is unusual in de novo disease) occurs in more than half of MEN 2B patients.32 These tumors are rarely the initial presenting feature of MEN 2B; their presence is

0 12 24 36 48 60 72 84 96 108 120 months

FIGURE 83-6. Comparison of survival rates between medullary thyroid carcinoma (MTC) patients in whom the disease arose in the absence of other endocrine neoplasias, as part of the multiple endocrine neoplasia (MEN) 2A syndrome, and as part of the MEN 2B syndrome. Data from 741 cases are entered in the German Medullary Thyroid Carcinoma Registry. (From Raue F, FrankRaue K, Grauer A. Multiple endocrine neoplasia type 2: Clinical features and screening. Endocrinol Metab Clin North Am 1994;23:137.)

most often detected either after the existence of medullary thyroid carcinoma has been established or concurrently with the diagnosis of thyroid involvement, when suspicion of MEN 2B has been aroused. A multicenter center by Modigliani and colleagues showed pheochromocytoma presented first in 25% of 300 cases (274 MEN 2A and 26 MEN 2B) after medullary thyroid cancer diagnosis in 40% and in a synchronous manner in 35%.

Hyperplasia of the adrenal medulla precedes pheochromocytoma in MEN 2A and 2B. This hyperplasia is analogous to the C-cell hyperplasia that precedes medullary thyroid cancer in these patients. As in the thyroid disease in MEN 2, a spectrum of adrenal involvement may be encountered, including nodular or diffuse hyperplasia, multiple small pheochromocytomas, and thickening of the entire adrenal medulla. Most pheochromocytomas in this syndrome are benign.

As with the sporadic form, pheochromocytoma in MEN 2B may be either asymptomatic or associated with varying degrees of symptomatology referable to the catecholamines produced by these tumors. Symptoms include episodic diaphoresis, headaches, anxiety, and palpitations. Hypertension may be present and may be minimal or marked. The definitive diagnosis of pheochromocytoma may be made via biochemical means (e.g., elevated amounts of urinary catecholamines), abdominal computed tomographic (CT) or magnetic resonance imaging (MRI) scans, or metaiodobenzylguanidine (MIBG) scintigraphy.

In MEN 2B, diagnosis of pheochromocytoma should be followed by exploration and excision of the affected tissue. Bilateral disease requires bilateral adrenalectomy. Controversy has arisen, however, over the proper surgical treatment of unilateral pheochromocytoma in this setting. Some authorities maintain that bilateral adrenalectomy is indicated owing to the likelihood of eventual contralateral involvement. Others, however, have proposed that unilateral

■ MTC only MEN 2a -MEN 2b -all excision with close follow-up is sufficient. Proponents of the latter view note that this approach avoids both lifelong glucocorticoid-mineralocorticoid replacement therapy and the persistent risk of addisonian crisis.

If both medullary thyroid cancer and pheochromocytoma exist concurrently, adrenalectomy must be performed first followed by thyroidectomy. This order must be observed to avoid the potential of intraoperative hypertensive crisis during thyroid resection, and it underscores the importance of screening for pheochromocytoma when MEN is suspected.

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