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Multiple endocrine neoplasia type 2B: More than an endocrine disorder
Multiple endocrine neoplasia type 2B: More than an endocrine disorder Diarmuid S. O'Riordain, MD, FRCSI, Timothy O'Brien, MD, MRCPI, Thomas B. Crotty, MD, Hossein Gharib, MD, Clive S. Grant, MD, FACS, and Jon A. van Heerden, MB, FRCS(C), FACS, Rochester, Minn.
Background. Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disorder differentiated from MEN 2A primarily by its extraendocrine features. This report describes the clinical spectrum and outcome of MEN 2B. Methods. Twenty-one patients underwent operation for manifestations of MEN 2B between 1 970 and 1993. Median follow-up was 16. 9 years. Diagnosis was made through family screening in nine, the development of medullary thyroid carcinoma (MTC) in seven, phenotypic features in four, and constipation in one. Median age at presentation of colonic dysfunction, MTC, and pheochromocytoma was 0.1, 16, and 28years, respectively. Results. Every patient had MTC. Fifteen (94 %) of 16 patients undergoing primary thyroidectomies had multicentric disease, and seven (44 %) had nodal metastases. Seven patients (33 %) had pheochromocytoma, six bilateral and one malignant. Adrenalectomy was curative in every patient. Nineteen patients (90 %) had colonic disturbances, typically chronic constipation from birth. Megacolon developed in 14 patients, and eight required colonic surgery. Every patient had the characteristic phenotype. Dominant features included nenromas of the tongue, buccal mucosa, lips, conjunctivae, and eyelids and a marfanoid habitus. Other features included high arched palate, corneal nerve thickening, and dental and skeletal abnormalities. Four patients died, two of metastatic MTC, one after operation for metastatic MTC, and one as a consequence of colonic perforation. Of 1 7 survivors, three have hepatic metastases from MTC, eight have nodal metastases, and six are well with normal or mildly elevated calcitonin levels. Conclusions. MEN 2B is characterized by a relatively aggressive form of MTC, bilateral pheochromocytoma, severe colonic dysfunction, and a multitude of other extraendocrine abnormalities. Early recognition of MEN 2B and early prophylactic thyroidectomy are essential. Colonic dysfunction has previously received little attention, and further investigation of the pathogenesis and treatment of this disorder is warranted. (SuRCERY 1995;118:936-42.) From the Departments of Surgery and Pathology and Division of Endocrinology, Mayo Clinic and Mayo Foundation, Rochester, Minn.
MULTIPLE ENDOCRINENEOPLASIAT~E 2B (MEN 2B) is a rare a n d serious inherited disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, disorders of gastrointestinal function, a n d a typical phenotype. Sipple 1 first highlighted the relationship between thyroid carcinoma a n d pheochromocytoma in 1961, a n d later reports by Williams2 a n d Steiner et al. 3 led to the characterization of multiple e n d o c r i n e neoplasia type 2 (MEN 2), a syndrome comprising MTC, bilateral pheochromocytoma, a n d hyperparathyroidism. During the 1970s recognition of a diversity of extraendocrine Presented at the SixteenthAnnual Meetingof the AmericanAssociation of Endocrine Surgeons,Philadelphia,Pa., April 23-25, 1995. Reprint requests:Jon A. van Heerden, MB, Department of Surgery, Mayo Clinic,200 First St. SW, Rochester, MN 55905. Copyright 9 1995 by Mosby-YearBook, Inc. 0039-6060/95/$5.00 + 0 11/6/66989 936
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features a m o n g a subgroup of patients with MEN 2 led to the distinction between MEN 2A a n d MEN 2B. 4' 5 Subsequent reports confirmed that MEN 2B was a separate entity, a n d more recently investigators have concentrated o n identification of the MEN 2B gene. This gene has now b e e n localized to the region of chromosome 10 that contains the ret proto-oncogene, 6' 7 the same region as the genes for MEN 2A a n d familial MTC. Further progress in this area should lead to the clinical availabilityof genetic testing for MEN 2B, as has recently b e e n available for MEN 2A. This report describes the e n d o c r i n e a n d extraendocrine manifestations a n d outcome of a series of patients with MEN 2B.
PATIENTS AND METHODS Patient population. A consecutive series of patients with MEN 2B who u n d e r w e n t operation at the Mayo Clinic between 1970 a n d 1993 is reported. Diagnosis of
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Fig. 1. Facial features of patient with MEN 2B. Typical characteristics include neuromas on anterior one third of tongue, thick bumpy lips, and long narrow facial features.
MEN 2B was on clinical grounds on the basis of t h e occurrence of a typical mucosal n e u r o m a phenotype associated with MTC or pheochromocytoma. Twenty-one patients fulfilled the selection criteria; 20 underwent operation for MTC and six for pheochromocytoma, and two underwent cotectomy for megacolon. There were 11 male and 10 female patients. Median age (range) at diagnosis of MEN 2B was 15.8 (0.1 to 53 ) years. Thirteen patients had a family history of MEN 2B, seven of whom spanned three generations of one kindred, s Every patient had the typical mucosal n e u r o m a phenotype, and every patient had MTC. Nineteen patients (90%) had clinically apparent gastrointestinal dysfunction, seven (33%) had pheochromocytoma, and none had hyperparathyroidism. Serum calcitonin level was measured by radioimmunoassay. Basal and pentagastrin stimulated serum calcitonin levels were used for screening and postoperative management. Follow-up. Medical records of all patients were abstracted. Four patients had died during the follow-up period. Additional follow-up was obtained by direct contact with the surviving patients, and median (25th, 75th percentile) follow-up was 16.9 (8.4 to 19.4) years. RESULTS Presentation o f MEN 2B. Clinical diagnosis was made by screening affected kindreds in nine patients, recognition of the phenotypic features of MEN 2B in four, and the presence of thyroid disease in seven (thyroid nodules in five and cervical lymphadenopathy in two). The diagnosis was made in the remaining child after the development of severe constipation d u r i n g early infancy. Colonic disorders tended to present earliest, followed by MTC and, lastly, pheochromocytoma. Median ages (range) at presentation of colonic dysfunction, MTC, and pheochromocytoma, respectively, were 0.5 (0 to 19), 16 (0.6 to 53), and 28 (17 to 33) years. Of 18 patients with colonic symptoms, 12 had symptoms during
the first months of life and 16 had symptoms for a median (range) period of 13 (1 to 31) years before the diagnosis of MTC. In contrast, pheochromocytoma, which occurred in seven pauents, was diagnosed 8 (1 to 17) years subsequent to the diagnosis of MTC in six patients and simultaneously in one. Phenotypic features. The MEN 2B ganglioneuroma phenotype (Fig. 1) was evident in every patient; neuromas on the anterior one third of the tongue were the most characteristic feature. Neuromas and thickening of the lips and neuromas of the buccal mucosa, conjunctiva, and eyelids were also present in most patients. All adult patients displayed the classic marfanoid habitus (Fig. 2), typically consisting of a tall slender body build, high arched palate, and long extremities. Less frequently noted features included arachnodactyly,joint laxity, and skeletal abnormalities including pes cavus, dorsal scoliosis, and pectus excavatum. The principal ophthalmologic finding was corneal nerve thickening, which was documented in 13 patients. Among the other features noted in a minority of patients were peripheral neuropathy in four, xerophthalmia in three, xerostomia in one, facial hyperhidrosis in two. and testicular atrophy in two cases. Dental abnormalities were noted in 10 patients: four had extensive dental caries, two required extenswe orthodontic treatment, and the remaining four were noted to have abnormally widely spaced teeth. Gastrointestinal dysfunction. Nineteen patients (90%) had intestinal and especially colonic motility disturbances as a result of diffuse intestinal ganglioneuromatosis. Fourteen patients had evidence of megacolon (Fig. 3), commonly affecting the ascending, right, and proximal descending colon and associated with an area of narrowing in the rectosigmoid region. Three patients had severe colonic diverticulosis. In 10 patients pathologic specimens from the gastrointestinal tract were available for examination. Each of these patients had intestinal ganglioneuromatosis with marked hypertrophy of nerve fibers and increased numbers of ganglion
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Fig. 4. Ganglioneuromatosis of colon. Transverse section of colon shows hypertrophy of Auerbach's plexus between two layers of rnuscularis propria. Hypertrophy of submucosal nerves and prominence of ganglion cells (not evident at this power) are also present. (Hematoxylin-eosin stain; original magnification x20.)
Fig. 2. Characteristic marfanoid habitus in patientwith MEN 2B.
Fig. 3. Operative photograph from patient with MEN 2B with megacolon. Colon is greatly dilated and hypertrophied and grossly very similar to colonic appearances in Hirschsprung's disease. cells (Fig. 4). At autopsy two patients had ganglioneuromatosis affecting the entire gastrointestinal tract. In addition, resected specimens or biopsy specimens revealed ganglioneuromatosis of the colon in six cases, ileum in three, and appendix in three. Twelve patients had colonic dysfunction noted as early as the first year of life; the usual symptom at that
age was constipation. In only one of these patients did infantile constipation lead to the diagnosis of MEN 2B. Although symptoms persisted well into adult life in most cases, three patients had well-documented spontaneous regression of symptoms with time. The typical adult features of colonic disturbance were severe chronic constipation associated with abdominal distention, diarrhea, and borborygmi. Of 14 patients with well-documented symptoms, 10 (71%) had constipation, 2 (14%) diarrhea, and 2 (14%) alternating constipation and diarrhea. Eight patients underwent colonic operation, five of which were performed at other institutions before the diagnosis of MEN 2B. Three patients presented with colonic perforation, two of which resulted from perforated diverticula. Perforation resulted in the death of one patient at 70 years of age. Two infants required emergency surgery at 3 days and 6 weeks o f age; one underwent colectomy and the other a defunctioning ileostomy. Three patients underwent elective subtotal colectomy for chronic constipation. Three patients had esophageal motility disorders causing dysphagia. Two had esophageal dilatation not unlike that seen in achalasia of the esophagus. In each case esophageal pressure studies were abnormal but not consistent with achalasia. Medullary thyroid carcinoma. Sixteen patients had primary surgery for MTC performed at the Mayo Clinic. The youngest patient undergoing thyroidectomy for MTC was 7 months of age. Each patient underwent total thyroidectomy, and five underwent concomitant modified radical neck dissection, unilateral in three and bilateral in two. Neck dissection was performed on the
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basis of gross lymphadenopathy at the time of thyroidectomy. Four patients underwent reoperative procedures for MTC, after they had u n d e r g o n e initial thyroidectomy elsewhere. Two underwent completion thyroidectomywith lymphadenectomy, and two underwent lymph node dissection alone because they had undergone prior total thyroidectomy. The remaining patient had a total thyroidectomy performed at another institution and has not undergone thyroid surgery at the Mayo Clinic. Of the 16 patients undergoing primary thyroidectomy 15 (94%) had multicentric disease; one patient had a solitary tumor. Eleven patients had a solitary focus of tumor in each lobe, and four each had a total of between four and eight foci of tumor. At the time of primary thyroidectomy seven (44%) patients had metastatic nodal disease, five (31%) with involvement of central lymph nodes and five (31%) with lateral nodal involvement, of which two were bilateral. An additional three patients had subsequent lateral nodal metastases, bilateral in two and unilateral in one. O f 20 patients undergoing thyroid surgery at the Mayo Clinic, two have died of the direct effects of metastatic MTC at 34 and 48 years of age. One of these patients survived 17 years after the diagnosis of liver metastases. Another patient died after operation at 32 years of age after bilateral radical neck dissection for extensive metastatic nodal disease early in the series. One of the three patients who died had undergone primary thyroidectomy at this institution, and the other two had undergone reoperative surgery for metastatic nodal disease. Three patients are alive at 4, 13, and 17 years after the diagnosis of liver metastases from MTC. Eight patients had nodal metastases or markedly raised serum calcitonin levels (greater than 1000 p g / m l ) at the time of most recent follow-up (one has died of other causes). The remaining six patients are alive and well with either normal or mildly elevated calcitonin levels (less than 1000 p g / m l ) . A close correlation was noted between age at the time of surgery and outcome. The median (range) age of the six patients with normal or mildly elevated postoperative calcitonin levels was 4.2 (0.6 to 14.2) years compared with 18.1 (12.0 to 52.8) years for the 14 patients (p = 0.0011) with more extensive residual disease. Pheochromocytoma. Seven patients (33%) had pheochromocytoma. This figure, however, may be an underestimate because the incidence appears to increase with increasing follow-up. O f 13 patients monitored beyond 25 years of age, pheochromocytomas developed in seven (54%). O f the six patients undergoing surgery at the Mayo Clinic, four were diagnosed because of classic paroxysmal symptoms and two asymptomatic patients were diagnosed by means of screening. Each of these six patients had bilateral pheochromocytomas, and eight of
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12 resected adrenal glands contained multiple tumors. Three patients had pathologic evidence of adrenal medullary hyperplasia. Median (range) size of the largest tumor in each patient was 4.3 (1.2 to 6.4) cm. The patient with the largest tumor (6.4 cm) had microscopic vascular invasion. One patient has undergone a curative resection of multiple paraaortic extraadrenal catecholamine-secreting tumors 16 years after bilateral adrenalectomy. Patients in whom p h e o c h r o m o c y t o m a developed had more advanced thyroid disease than those in whom it did not, a factor that was independent of the age at the time of thyroidectomy. Of the seven patients in whom p h e o c h r o m o c y t o m a developed, each had nodal metastases from MTC at the time of thyroid operation. In contrast, only four instances (31%) of nodal metastases were noted a m o n g 13 patients in whom pheochromocytoma had not developed (p= 0.0047, Fisher's exact test). O f the seven patients with pheochromocytoma, two have died of MTC, two are alive with liver metastases (MTC), and the remaining three are alive with markedly elevated calcitonin levels. The median (range) age at the time of thyroidectomy was not significantly older in those in whom p h e o c h r o m o c y t o m a developed, 17.1 (12 of 33) years, compared with those in whom it did not, 14.2 (0.6 to 53) years, (p = 0.27). One patient had unilateral adrenalectomy performed at another institution. O f six patients undergoing operation at this institution, five underwent bilateral adrenalectomy via an anterior transperitoneal approach and one initially underwent unilateral surgery but required contralateral adrenalectomy 2 months later for persistent disease. This latter patient underwent a left adrenalectomy for a radiographically localized 6 cm tumor but remained symptomatic after operation and required right adrenalectomy, which revealed two microscopic foci of tumor in a background of adrenal medullary hyperplasia. Surgery was curative in every case; no recurrence occurred during a median (range) postoperative follow-up of 12.6 (0.9 to 20) years. O f the seven cases five are alive with no evidence of pheochromocytoma, and two have died without evidence of recurrent adrenal disease. Overall outcome. Four patients died on follow-up, two of metastatic MTC. one after operation for metastatic MTC. and one of colonic perforation. O f 17 survivors three have hepatic metastases from MTC, eight have nodal metastases from MTC a n d / o r markedly elevated calcitonin levels (greater than 1000 p g / m l ) , and the remaining six patients are well.
DISCUSSION Although MTC and p h e o c h r o m o c y t o m a dominate most descriptions of MEN 2B, extraendocrine features are many and varied and may also have a p r o f o u n d detrimental impact on the lives of affected patients. A m o n g the extraendocrine manifestations those affecting the
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gastrointestinal tract, especially the colon, predominate. The discipline of embryology helps us understand the diversity of the features of MEN 2B. The neural crest is the c o m m o n link between pheochromocytoma, MTC, and neuronal abnormalities of the gastrointestinal tract. It is known that C ceils of the thyroid, adrenal medullary cells, and ceils of the autonomic plexus and ganglia in the alimentary tract all arise from the neural crest. 9 A molecular abnormality affecting cells of this lineage could therefore readily account for all the dominant features of MEN 2B. The occurrence of gastrointestinal symptoms in 90% of our patients with MEN 2B highlights alimentary tract disorders as a major c o m p o n e n t of this syndrome. It has previously been shown that patients with MEN 2B have diffuse ganglioneuromatosis affecting the entire alimentary tract from the m o u t h to the anus. l~ Diffuse proliferation of the intestinal autonomic nerves and ganglia is present on histologic examination. The bowel is easily distended, and the usual clinical and radiologic finding is of a greatly dilated colon, giving rise to the term megacolon. 11 It is of considerable importance that colonic symptoms in most patients were present from birth and preceded the presentation of MTC in 16 of our patients. The significance of severe chronic constipation from birth as a marker for MEN 2B is generally not appreciated, and in only one patient in this series did this symptom lead to an accurate diagnosis. Although the association is rare, MEN 2B should always be considered in the differential diagnosis of chronic constipation in this age group. 12" 13 The clinical and radiologic colonic findings in MEN 2B often closely resemble and are often confused with Hirschsprung's disease. Although the colonic manifestations of MEN 2B differ from those of Hirschsprung's disease in that ganglioneuromatosis occurs rather than aganglionosis, it is of great interest that the genetic determinants of each condition are similar. The genes for MEN 2B and Hirschsprung's disease have each been localized to that region of chromosome 10 that contains the ret proto-oncogene, and in each case mutations affect the intracellular tyrosine kinase domain of that protein.7, 14 A similar defect has been shown in some patients with sporadic MTC. 7 Although the genes for MEN 2A and familial MTC are also located in the ret proto-oncogene, the locations of these mutations differ in that they affect the cysteine-rich extracellular domain of Ret. TM 16 Experimentally, a targeted mutation in the tyrosine kinase domain of the Ret protein in homozygous transgenic mice produces intestinal aganglionosis. 17 Further notable clinical observations are possibly explained by Ret mutations. Khan et al. 12 report true Hirschsprung's disease in nine patients a m o n g 92 members of a MEN 2A kindred. Ganglioneuromatosis of the small intestine together with aganglionosis of the colon has been reported in the same patient. 18although
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not in the setting of MEN. Collectively this evidence suggests that Ret plays an important role in the develo p m e n t and function of cells of neural crest origin. Mutations affecting Ret may explain tumorigenesis in thyroid C cells and adrenal medullary cells and may also explain abnormal development of the enteric nervous system, possibly by affecting the migration of neural crest cells. 17 Variations in the mutations that affect the Ret protein presumably determine the precise clinical syndrome produced. These c o m m o n embryologic and genetic links may explain both the wide clinical spectrum of MEN 2B and also the similarities and overlap between MEN 2A, MEN 2B, familial MTC, and Hirschsprung's disease. Clearly, however, more experimental work is required to explain the relationship between Ret mutations and associated clinical syndromes. The most characteristic feature of MEN 2B is the classic phenotype that resulted in recognition of MEN 2B in four of our patients. In c o m m o n with other reportsa9, 2o every patient in this series had typical neuromas. These developed chiefly on the anterior portion of the tongue and also on the lips, buccal mucosa, eyelids, and conjunctivae in many patients. These neuromas are the external manifestations of generalized ganglioneuromatosis of the alimentary tract. Most patients are marfanoid, exhibiting the typical tall slender body build. Peripheral nerve thickening is usually evident clinically through examination of the corneal nerves, and at thyroidectomy recurrent laryngeal nerve thickening is frequently noted. A variety of other facial, ophthalmic, and skeletal abnormalities complete the phenotype. These phenotypic features may be the only means of early diagnosis of the condition especially in sporadic cases. Recognition of this phenotype and appreciation of its relationship with thyroid malignancy are of the utmost importance. 21 MTC is the most c o m m o n cause of death in MEN 2B, accounting for two direct deaths and one indirect death in the current series. Although MTC can develop as early as the first year of life. survival can be very prolonged. The two patients who died of MTC in this series were 34 and 48 years of age. Prolonged survival is exemplified by four patients who survived 4, 13, 17. and 17 years after the diagnosis of liver metastases from MTC. MTC in MEN 2B is almost universally bilateral and multifocal and is associated with lymph node metastases at the time of primary surgery in 50% of patients. The bilateral nature of this disease mandates total thyroidectomy in every patient. Because of the high incidence of lymph node metastases, routine dissection of the central compartment of the neck is advised, and a modified radical neck dissection is indicated in the presence of gross or microscopic lateral nodal disease. 22 In a previous report we have compared MTC in MEN 2B with that in MEN 2A and have shown that MEN 2B-related disease is considerably more aggressive than that in MEN
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2A. 22 M E N 2 B - r e l a t e d M T C p r e s e n t s at a y o u n g e r age,
CONCLUSION
is a s s o c i a t e d w i t h m o r e e x t e n s i v e disease w i t h i n t h e thyr o i d g l a n d a n d a h i g h e r i n c i d e n c e o f m e t a s t a t i c disease, a n d is m u c h less a m e n a b l e to surgical c u r e . 22 I n c o n t r a s t
M E N 2B is a severe disease d o m i n a t e d b y a relatively aggressive f o r m o f M T C , b i l a t e r a l p h e o c h r o m o c y t o m a s i n u p to 5 0 % o f p a t i e n t s , severe c o l o n i c d y s f u n c t i o n i n m o s t p a t i e n t s , a n d a wide variety o f o t h e r e x t r a e n d o c r i n e f e a t u r e s . T h y r o i d disease a c c o u n t s f o r m o s t d e a t h s , a n d early r e c o g n i t i o n o f M E N 2B w i t h early p r o p h y l a c tic t h y r o i d e c t o m y is o f p a r a m o u n t i m p o r t a n c e . It is t h e multitude of extraendocrine abnormalities, however, t h a t h a v e t h e m o s t s i g n i f i c a n t effect o n t h e day-to-day lives o f m a n y p a t i e n t s w i t h M E N 2B. C o l o n i c dysfunct i o n h a s p r e v i o u s l y r e c e i v e d little a t t e n t i o n , a n d f u r t h e r i n v e s t i g a t i o n o f t h e p a t h o g e n e s i s a n d t r e a t m e n t o f this d i s o r d e r is w a r r a n t e d .
to M E N 2A, t h y r o i d disease i n M E N 2B is n e v e r d i a g n o s e d at t h e p r e i n v a s i v e stage. S u r g e r y a t a n early a g e is a s s o c i a t e d w i t h a b e t t e r o u t c o m e , a n d w i t h t h e occurrence of MTC in an infant of 7 months of age in this series, a s t r o n g case c a n b e m a d e f o r p r o p h y l a c t i c t h y r o i d e c t o m y d u r i n g t h e first y e a r o f life. I t is likely i n t h e very n e a r f u t u r e t h a t g e n e t i c t e s t i n g f o r M E N 2B will have a marked influence on the timing of diagnosis and thyroidectomy. Pheochromocytoma occurs later than the other mang e s t a t i o n s o f M E N 2B: m e d i a n a g e at d i a g n o s i s was 28 years. T h e p r e c i s e i n c i d e n c e o f p h e o c h r o m o c y t o m a is d e p e n d e n t o n t h e d u r a t i o n o f follow-up: this t u m o r developed in more than 50% of patients who were moni t o r e d b e v o n d 25 years o f age. T h e o u t c o m e a f t e r treatm e n t o f p h e o c h r o m o c y t o m a was e x c e l l e n t . O n e p a t i e n t had evidence of malignant pheochromocytoma with m i c r o s c o p i c v a s c u l a r i n v a s i o n , b u t every p a t i e n t was c u r e d by s u r g e r y a n d n o n e h a s h a d a r e c u r r e n c e o n l o n g - t e r m follow-up. T h e six p a t i e n t s w h o u n d e r w e n t a d r e n a l e c t o m y at t h e Mayo Clinic e a c h h a d b i l a t e r a l p h e o c h r o m o c y t o m a . It r e m a i n s o u r p r e f e r e n c e to perf o r m r o u t i n e b i l a t e r a l a d r e n a l e c t o m y i n M E N 2B bec a u s e o f t h e u n i v e r s a l o c c u r r e n c e o f b i l a t e r a l disease, a n d we h a v e p r e v i o u s l y r e p o r t e d t h e safety a n d efficacy o f this a p p r o a c h . 23 I n d e e d this p r a c t i c e is s u p p o r t e d by the outcome in the one patient who underwent unilate r a l s u r g e r y i n t h e p r e s e n t series a n d w h o r e q u i r e d c o n tralateral adrenalectomy 2 months later because of pers i s t e n t s y m p t o m s . T h e r e l a t i o n s h i p b e t w e e n t h e development of pheochromocytoma and the presence of m o r e a d v a n c e d t h y r o i d disease is a c u r i o u s o n e . T h i s ass o c i a t i o n d o e s n o t a p p e a r to r e l a t e to t h e a g e at d i a g n o sis a n d m a y r e f l e c t a v a r i a b l e o f t h e d e g r e e o f e x p r e s s i o n o f t h e R e t m u t a t i o n , a f a c t o r t h a t is c o m m o n to t h e p a t h o g e n e s i s o f b o t h p h e o c h r o m o c y t o m a a n d MTC. A l t h o u g h m o r e aggressive t h a n M E N 2A, t h e overall o u t l o o k i n M E N 2B is n o t as b a d as h a s b e e n s u g g e s t e d . i n spite o f a d i a g n o s i s o f M T C a t a m e d i a n o f 16 years o f a g e a n d t h e l i k e l i h o o d t h a t t u m o r is p r e s e n t m u c h earlier in most patients, no deaths occurred at younger t h a n 30 years o f age. O v e r a l l o n l y f o u r p a t i e n t s d i e d , three of the consequences of metastatic MTC and one a f t e r c o l o n i c p e r f o r a t i o n at 70 years o f age. T h e p r o t e a n m a n i f e s t a t i o n s o f M E N 2B do, h o w e v e r , h a v e a d i s r u p tive i m p a c t o n t h e quality o f life o f a f f e c t e d patients. T h e t h r e a t o f c a n c e r at a y o u n g age, t h e t r a u m a o f m u l t i p l e surgical p r o c e d u r e s , t h e p e r s i s t e n t g a s t r o i n t e s t i n a l sympt o m s , a n d t h e m u l t i t u d e o f skeletal a n d o t h e r p h e n o typic a b n o r m a l i t i e s c o n t r i v e to p r o d u c e a p r o f o u n d d e t r i m e n t a l effect o n t h e p s y c h o l o g i c a l well-being a n d everyday e x i s t e n c e o f m a n y o f t h e s e p a t i e n t s .
REFERENCES
1. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961:31:163-6. 2. Williams ED. A review of 17 cases of carcinoma of the thyroid and phaeochromocytoma. J Clin Pathol 1965:18:288-92. 3. Steiner AL. Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasaa. type 2. Medicine 1968;47:371408. 4. Chong GC, Beahrs OH, Sizemore GW, et al. Medullary carcinoma of the thyroid gland. Cancer 1975;35:695-704. 5. Rashid M, Khiari A. Dexter RN, et al. Mucosal neuroma, pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3. Medicine 1975:54:89-112. 6. Lairmore TC. Howe JR, Korte JA, et al. Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same regaon of chromosome 10 as multiple endocrine neoplasia type 2A. Genomics 1991:9:181-92. 7. Hofstra RM. Landsvater RM. Ceccherini I. et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367:375-6. 8. Sizemore GW. CarneyJA, Gharib H. Capen CC. Multiple endocrine neoplasia type 2B: eighteen year follow-up of a four generation family. Henry Ford Hosp Med J 1992:40:236-44. 9. Williams PL. Warwick R. Dyson M. Bannister LH. eds. Gray's anatomy. 37th ed. Edinburgh: Churchill Livingstone,1989:200, 1467. 10. Carney JA, Go VL. Sizemore GW. Hayles AB. Alimentary tracl ganglioneuromatosis: a major component of the syndrome of multiple endocrine neoplasia, type 2b. N EnglJ Med 1976;295: 1287-91. 11. Demos TC. Blonder J, Schey WL. Braithwaite SS. Goldstein PL. Multiple endocrine neoplasia (MEN) syndrome type IIB: gastrointestinal manifestations. AJR 1983:140:73-8. 12. Khan AH. DesjardinsJG, Youssef S. Gregoire H. Seidman E. Gastrointestinal manifestations of Sipple syndrome in children.J Pediatr Surg 1987:22:719-23. 13. Griffiths AM. Mack DR. Byard RW. Stringer DA. Shandling B. Multiple endocrine neoplasia IIb: an unusual cause of chronic constipation. J Pediatr 1990:116:285-8. 14. Romeo G, Ronchetto P. Luo Y. et al. Mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature 1994:367:377-8. 15. Mulligan LM. KwokJB, Healey CS. et al. Germ-line mutations of the RET proto-oncogene in nmltiple endocrine neoplasia type 2A. Nature 1993;363:458-60. 16. Donis-Keller H. Dou S, Chi D, et al. Mutations in the RET protooncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993:2:851-6.
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17. Schuchkardt A, D'Agati V, Larsson-Blomberg L, Constantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 1994; 367:380-3. 18. Schm'liAF, Meier-Ruge W. Localized mad disseminated forms of neuronal intestinal dysplasia mimicking Hirschsprung's disease. J Pediatr Surg 1981;16:164-70. 19. Vasen HF, van der Feltz M, Raue F, et al. The natural course of multiple endocrine neoplasia type IIb: a study of 18 cases. Arch Intern Med 1992;152:1250-2. 20. NortonJA, Froome LC, Farrell RE, Wells SA. Multiple endocrine neoplasia type 2B: the most aggressiveform of medullary thyroid carcinoma. Surg Clin North Am 1979;59:109-18. 21. White MP, Goel KM, ConnorJM, Coutts NA. Mucosal neuroma syndrome--a phenotype for malignancy. Arch Dis Child 1985; 60:876-7. 22. O'Riordain DS, O'Brien T, Hay ID, Grant CS, van HeerdenJA. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. SURGERY1994;116:1017-23. 23. van Heerden JA, Sizemore GW, Carney JA, Grant CS, ReMine WH, Sheps SG. Surgical management of the adrenal glands in the mnltiple endocrine neoplasia type II syndrome. World J Surg 1984;8:612-21.
DISCUSSION Dr. Mafia Allo (San Jose, Calif.). Given the early presentation of phenotypic abnormalities such as the mucosal neuromas in these patients to the point where people have actually advocated prophylactic thyroidectomies in children, are there any diagnostic or marker measurements that you might take to predict the extent of colonic disease in some of these young patients? How far do you feel comfortable in making recommendations about management of the colonic disease in these patients because you are reporting a fairly high incidence? Dr. O'Riordain. What we are trying to highlight is that colonic disease is certainly a major c o m p o n e n t of the syndrome and one that perhaps has not been given the attention it deserves. To date there really is no scientific evidence to answer some of your questions with regard to management of the colonic disease. A 10t of these patients present with the presumptive diagnosis of Hirschsprnng's disease and undergo rectal biopsies that show ganglia. A n m n b e r of patients underwent some sort of colectomy. I d o n ' t think that we can really make solid recommendations at the present time as to the m a n a g e m e n t of the colonic manifestations in these patients. It does n e e d to be looked at. Dr. Edwin Kaplan (Chicago, Ill.). I want to emphasize one part of the syndrome that you passed over briefly, testicular atrophy. We have three patients in our series with MEN 2 syndromes who have atrophic testicles. One patient, shared with Dr. Eberhard Mack, has MEN 2B with Klinefelter's Syndrome. Two other patients, one with MEN 2A and one with MEN 2B, have testicular atrophy, gynecomastia, and high pituitary levels of follicle-stimulating h o r m o n e and luteinizing hormone. Do any of your patients with MEN 2A have testicular atrophy as well? Dr. O'Riordain. Not that I am aware of. Dr. Jeffrey Norton (St. Louis, Mo.). This is like Back to the Future because Dr. Carney from your institution first described
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this in 1976. The hypothesis about the neural crest abnormality explaining the syndrome of MEN 2B is interesting, but how do you explain the bony abnormalities and the dental abnormalities as part of the neural crest? Dr. O'Riordain. I d o n ' t know what the exact answer is. Whether these skeletal and dental abnormalities mentioned result from some abnormalities of the neural crest function in the developmental stage, embryologically, I don't really know, and I don't think anybody can clearly answer that question for you. I suspect that ultimately it will be seen to tie in in some fashion. Dr. Colin Russell (Belfast, Northern Ireland). Just one question of detail regarding the colonic surgery. Can I assume that the three patients who underwent a colectomy in adult life had an abdominal colectomy with an ileorectal anastomosis? The question relates to the large bowel function in those patients after the operation. Was their motility problem alleviated or did they continue to have motility difficulties after the operation? Dr. O'Riordain. The three patients who underwent subtotal colectomies were evaluated, and all did much better symptomatically after operation. I would have to emphasize, however, that most of the colonic surgery that we are quoting here was not done at our institution. It was done elsewhere and in most cases before the diagnosis of MEN 2B. So our follow-up in terms of the exact preoperative and postoperative symptoms is a little bit vague, Dr. J e f f Moley (St. Louis, Mo.). You indicated that only 67% of the patients with MEN 2B had megacolons. I have never seen a patient with MEN 2B who didn't have a megacolon. What was the situation in the other 33% of patients? Dr. O'Riordain. Only 67% of our patients had a clear diagnosis, and this is a retrospective study. There were one third of our patients where that clear diagnosis of megacolon had not been made. I can't say that they didn't have it. Dr. Michael Roe (Chattanooga, Tenn.). I cared for a 3-year-old a couple of years ago who was diagnosed in a very similar fashion. She had undergone a rectal biopsy that showed ganglioneuromatosis, and eventually she was diagnosed with MEN 2. We performed a total thyroidectomy and found a 3 m m medullary carcinoma. She now is disease free about 2 or 2~ years later. At what age do you begin to see either regional or distant metastatic disease from the MTC in these younger pediatric patients? Once diagnosed, at what age in these younger patients would you r e c o m m e n d thyroidectomy? Dr. O'Riordain. In our series we have one patient who had invasive MTC without metastatic disease at the age of about 6 months. There are a n u m b e r of reports in the literature of patients with no gross disease and metastatic disease as young as 3 years of age. This is an aggressive disease in young children, and we would advocate early thyroidectomy after the diagnosis of MEN 2B, perhaps in the first year of life. It really is a balance between what your perception is of the severity of the disease, the age group versus the morbidity of thyroidectomy. Perhaps we d o n ' t have sufficient data on the morbidity of thyroidectomy in that age group. Our inclination would be toward surgery in the first year of life in those patients.
Background. Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disorder differentiated from MEN 2A primarily by its extraendocrine features. This report describes the clinical spectrum and outcome of MEN 2B. Methods. Twenty-one patients underwent operation for manifestations of MEN 2B between 1 970 and 1993. Median follow-up was 16. 9 years. Diagnosis was made through family screening in nine, the development of medullary thyroid carcinoma (MTC) in seven, phenotypic features in four, and constipation in one. Median age at presentation of colonic dysfunction, MTC, and pheochromocytoma was 0.1, 16, and 28years, respectively. Results. Every patient had MTC. Fifteen (94 %) of 16 patients undergoing primary thyroidectomies had multicentric disease, and seven (44 %) had nodal metastases. Seven patients (33 %) had pheochromocytoma, six bilateral and one malignant. Adrenalectomy was curative in every patient. Nineteen patients (90 %) had colonic disturbances, typically chronic constipation from birth. Megacolon developed in 14 patients, and eight required colonic surgery. Every patient had the characteristic phenotype. Dominant features included nenromas of the tongue, buccal mucosa, lips, conjunctivae, and eyelids and a marfanoid habitus. Other features included high arched palate, corneal nerve thickening, and dental and skeletal abnormalities. Four patients died, two of metastatic MTC, one after operation for metastatic MTC, and one as a consequence of colonic perforation. Of 1 7 survivors, three have hepatic metastases from MTC, eight have nodal metastases, and six are well with normal or mildly elevated calcitonin levels. Conclusions. MEN 2B is characterized by a relatively aggressive form of MTC, bilateral pheochromocytoma, severe colonic dysfunction, and a multitude of other extraendocrine abnormalities. Early recognition of MEN 2B and early prophylactic thyroidectomy are essential. Colonic dysfunction has previously received little attention, and further investigation of the pathogenesis and treatment of this disorder is warranted. (SuRCERY 1995;118:936-42.) From the Departments of Surgery and Pathology and Division of Endocrinology, Mayo Clinic and Mayo Foundation, Rochester, Minn.
MULTIPLE ENDOCRINENEOPLASIAT~E 2B (MEN 2B) is a rare a n d serious inherited disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, disorders of gastrointestinal function, a n d a typical phenotype. Sipple 1 first highlighted the relationship between thyroid carcinoma a n d pheochromocytoma in 1961, a n d later reports by Williams2 a n d Steiner et al. 3 led to the characterization of multiple e n d o c r i n e neoplasia type 2 (MEN 2), a syndrome comprising MTC, bilateral pheochromocytoma, a n d hyperparathyroidism. During the 1970s recognition of a diversity of extraendocrine Presented at the SixteenthAnnual Meetingof the AmericanAssociation of Endocrine Surgeons,Philadelphia,Pa., April 23-25, 1995. Reprint requests:Jon A. van Heerden, MB, Department of Surgery, Mayo Clinic,200 First St. SW, Rochester, MN 55905. Copyright 9 1995 by Mosby-YearBook, Inc. 0039-6060/95/$5.00 + 0 11/6/66989 936
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features a m o n g a subgroup of patients with MEN 2 led to the distinction between MEN 2A a n d MEN 2B. 4' 5 Subsequent reports confirmed that MEN 2B was a separate entity, a n d more recently investigators have concentrated o n identification of the MEN 2B gene. This gene has now b e e n localized to the region of chromosome 10 that contains the ret proto-oncogene, 6' 7 the same region as the genes for MEN 2A a n d familial MTC. Further progress in this area should lead to the clinical availabilityof genetic testing for MEN 2B, as has recently b e e n available for MEN 2A. This report describes the e n d o c r i n e a n d extraendocrine manifestations a n d outcome of a series of patients with MEN 2B.
PATIENTS AND METHODS Patient population. A consecutive series of patients with MEN 2B who u n d e r w e n t operation at the Mayo Clinic between 1970 a n d 1993 is reported. Diagnosis of
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Fig. 1. Facial features of patient with MEN 2B. Typical characteristics include neuromas on anterior one third of tongue, thick bumpy lips, and long narrow facial features.
MEN 2B was on clinical grounds on the basis of t h e occurrence of a typical mucosal n e u r o m a phenotype associated with MTC or pheochromocytoma. Twenty-one patients fulfilled the selection criteria; 20 underwent operation for MTC and six for pheochromocytoma, and two underwent cotectomy for megacolon. There were 11 male and 10 female patients. Median age (range) at diagnosis of MEN 2B was 15.8 (0.1 to 53 ) years. Thirteen patients had a family history of MEN 2B, seven of whom spanned three generations of one kindred, s Every patient had the typical mucosal n e u r o m a phenotype, and every patient had MTC. Nineteen patients (90%) had clinically apparent gastrointestinal dysfunction, seven (33%) had pheochromocytoma, and none had hyperparathyroidism. Serum calcitonin level was measured by radioimmunoassay. Basal and pentagastrin stimulated serum calcitonin levels were used for screening and postoperative management. Follow-up. Medical records of all patients were abstracted. Four patients had died during the follow-up period. Additional follow-up was obtained by direct contact with the surviving patients, and median (25th, 75th percentile) follow-up was 16.9 (8.4 to 19.4) years. RESULTS Presentation o f MEN 2B. Clinical diagnosis was made by screening affected kindreds in nine patients, recognition of the phenotypic features of MEN 2B in four, and the presence of thyroid disease in seven (thyroid nodules in five and cervical lymphadenopathy in two). The diagnosis was made in the remaining child after the development of severe constipation d u r i n g early infancy. Colonic disorders tended to present earliest, followed by MTC and, lastly, pheochromocytoma. Median ages (range) at presentation of colonic dysfunction, MTC, and pheochromocytoma, respectively, were 0.5 (0 to 19), 16 (0.6 to 53), and 28 (17 to 33) years. Of 18 patients with colonic symptoms, 12 had symptoms during
the first months of life and 16 had symptoms for a median (range) period of 13 (1 to 31) years before the diagnosis of MTC. In contrast, pheochromocytoma, which occurred in seven pauents, was diagnosed 8 (1 to 17) years subsequent to the diagnosis of MTC in six patients and simultaneously in one. Phenotypic features. The MEN 2B ganglioneuroma phenotype (Fig. 1) was evident in every patient; neuromas on the anterior one third of the tongue were the most characteristic feature. Neuromas and thickening of the lips and neuromas of the buccal mucosa, conjunctiva, and eyelids were also present in most patients. All adult patients displayed the classic marfanoid habitus (Fig. 2), typically consisting of a tall slender body build, high arched palate, and long extremities. Less frequently noted features included arachnodactyly,joint laxity, and skeletal abnormalities including pes cavus, dorsal scoliosis, and pectus excavatum. The principal ophthalmologic finding was corneal nerve thickening, which was documented in 13 patients. Among the other features noted in a minority of patients were peripheral neuropathy in four, xerophthalmia in three, xerostomia in one, facial hyperhidrosis in two. and testicular atrophy in two cases. Dental abnormalities were noted in 10 patients: four had extensive dental caries, two required extenswe orthodontic treatment, and the remaining four were noted to have abnormally widely spaced teeth. Gastrointestinal dysfunction. Nineteen patients (90%) had intestinal and especially colonic motility disturbances as a result of diffuse intestinal ganglioneuromatosis. Fourteen patients had evidence of megacolon (Fig. 3), commonly affecting the ascending, right, and proximal descending colon and associated with an area of narrowing in the rectosigmoid region. Three patients had severe colonic diverticulosis. In 10 patients pathologic specimens from the gastrointestinal tract were available for examination. Each of these patients had intestinal ganglioneuromatosis with marked hypertrophy of nerve fibers and increased numbers of ganglion
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Fig. 4. Ganglioneuromatosis of colon. Transverse section of colon shows hypertrophy of Auerbach's plexus between two layers of rnuscularis propria. Hypertrophy of submucosal nerves and prominence of ganglion cells (not evident at this power) are also present. (Hematoxylin-eosin stain; original magnification x20.)
Fig. 2. Characteristic marfanoid habitus in patientwith MEN 2B.
Fig. 3. Operative photograph from patient with MEN 2B with megacolon. Colon is greatly dilated and hypertrophied and grossly very similar to colonic appearances in Hirschsprung's disease. cells (Fig. 4). At autopsy two patients had ganglioneuromatosis affecting the entire gastrointestinal tract. In addition, resected specimens or biopsy specimens revealed ganglioneuromatosis of the colon in six cases, ileum in three, and appendix in three. Twelve patients had colonic dysfunction noted as early as the first year of life; the usual symptom at that
age was constipation. In only one of these patients did infantile constipation lead to the diagnosis of MEN 2B. Although symptoms persisted well into adult life in most cases, three patients had well-documented spontaneous regression of symptoms with time. The typical adult features of colonic disturbance were severe chronic constipation associated with abdominal distention, diarrhea, and borborygmi. Of 14 patients with well-documented symptoms, 10 (71%) had constipation, 2 (14%) diarrhea, and 2 (14%) alternating constipation and diarrhea. Eight patients underwent colonic operation, five of which were performed at other institutions before the diagnosis of MEN 2B. Three patients presented with colonic perforation, two of which resulted from perforated diverticula. Perforation resulted in the death of one patient at 70 years of age. Two infants required emergency surgery at 3 days and 6 weeks o f age; one underwent colectomy and the other a defunctioning ileostomy. Three patients underwent elective subtotal colectomy for chronic constipation. Three patients had esophageal motility disorders causing dysphagia. Two had esophageal dilatation not unlike that seen in achalasia of the esophagus. In each case esophageal pressure studies were abnormal but not consistent with achalasia. Medullary thyroid carcinoma. Sixteen patients had primary surgery for MTC performed at the Mayo Clinic. The youngest patient undergoing thyroidectomy for MTC was 7 months of age. Each patient underwent total thyroidectomy, and five underwent concomitant modified radical neck dissection, unilateral in three and bilateral in two. Neck dissection was performed on the
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basis of gross lymphadenopathy at the time of thyroidectomy. Four patients underwent reoperative procedures for MTC, after they had u n d e r g o n e initial thyroidectomy elsewhere. Two underwent completion thyroidectomywith lymphadenectomy, and two underwent lymph node dissection alone because they had undergone prior total thyroidectomy. The remaining patient had a total thyroidectomy performed at another institution and has not undergone thyroid surgery at the Mayo Clinic. Of the 16 patients undergoing primary thyroidectomy 15 (94%) had multicentric disease; one patient had a solitary tumor. Eleven patients had a solitary focus of tumor in each lobe, and four each had a total of between four and eight foci of tumor. At the time of primary thyroidectomy seven (44%) patients had metastatic nodal disease, five (31%) with involvement of central lymph nodes and five (31%) with lateral nodal involvement, of which two were bilateral. An additional three patients had subsequent lateral nodal metastases, bilateral in two and unilateral in one. O f 20 patients undergoing thyroid surgery at the Mayo Clinic, two have died of the direct effects of metastatic MTC at 34 and 48 years of age. One of these patients survived 17 years after the diagnosis of liver metastases. Another patient died after operation at 32 years of age after bilateral radical neck dissection for extensive metastatic nodal disease early in the series. One of the three patients who died had undergone primary thyroidectomy at this institution, and the other two had undergone reoperative surgery for metastatic nodal disease. Three patients are alive at 4, 13, and 17 years after the diagnosis of liver metastases from MTC. Eight patients had nodal metastases or markedly raised serum calcitonin levels (greater than 1000 p g / m l ) at the time of most recent follow-up (one has died of other causes). The remaining six patients are alive and well with either normal or mildly elevated calcitonin levels (less than 1000 p g / m l ) . A close correlation was noted between age at the time of surgery and outcome. The median (range) age of the six patients with normal or mildly elevated postoperative calcitonin levels was 4.2 (0.6 to 14.2) years compared with 18.1 (12.0 to 52.8) years for the 14 patients (p = 0.0011) with more extensive residual disease. Pheochromocytoma. Seven patients (33%) had pheochromocytoma. This figure, however, may be an underestimate because the incidence appears to increase with increasing follow-up. O f 13 patients monitored beyond 25 years of age, pheochromocytomas developed in seven (54%). O f the six patients undergoing surgery at the Mayo Clinic, four were diagnosed because of classic paroxysmal symptoms and two asymptomatic patients were diagnosed by means of screening. Each of these six patients had bilateral pheochromocytomas, and eight of
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12 resected adrenal glands contained multiple tumors. Three patients had pathologic evidence of adrenal medullary hyperplasia. Median (range) size of the largest tumor in each patient was 4.3 (1.2 to 6.4) cm. The patient with the largest tumor (6.4 cm) had microscopic vascular invasion. One patient has undergone a curative resection of multiple paraaortic extraadrenal catecholamine-secreting tumors 16 years after bilateral adrenalectomy. Patients in whom p h e o c h r o m o c y t o m a developed had more advanced thyroid disease than those in whom it did not, a factor that was independent of the age at the time of thyroidectomy. Of the seven patients in whom p h e o c h r o m o c y t o m a developed, each had nodal metastases from MTC at the time of thyroid operation. In contrast, only four instances (31%) of nodal metastases were noted a m o n g 13 patients in whom pheochromocytoma had not developed (p= 0.0047, Fisher's exact test). O f the seven patients with pheochromocytoma, two have died of MTC, two are alive with liver metastases (MTC), and the remaining three are alive with markedly elevated calcitonin levels. The median (range) age at the time of thyroidectomy was not significantly older in those in whom p h e o c h r o m o c y t o m a developed, 17.1 (12 of 33) years, compared with those in whom it did not, 14.2 (0.6 to 53) years, (p = 0.27). One patient had unilateral adrenalectomy performed at another institution. O f six patients undergoing operation at this institution, five underwent bilateral adrenalectomy via an anterior transperitoneal approach and one initially underwent unilateral surgery but required contralateral adrenalectomy 2 months later for persistent disease. This latter patient underwent a left adrenalectomy for a radiographically localized 6 cm tumor but remained symptomatic after operation and required right adrenalectomy, which revealed two microscopic foci of tumor in a background of adrenal medullary hyperplasia. Surgery was curative in every case; no recurrence occurred during a median (range) postoperative follow-up of 12.6 (0.9 to 20) years. O f the seven cases five are alive with no evidence of pheochromocytoma, and two have died without evidence of recurrent adrenal disease. Overall outcome. Four patients died on follow-up, two of metastatic MTC. one after operation for metastatic MTC. and one of colonic perforation. O f 17 survivors three have hepatic metastases from MTC, eight have nodal metastases from MTC a n d / o r markedly elevated calcitonin levels (greater than 1000 p g / m l ) , and the remaining six patients are well.
DISCUSSION Although MTC and p h e o c h r o m o c y t o m a dominate most descriptions of MEN 2B, extraendocrine features are many and varied and may also have a p r o f o u n d detrimental impact on the lives of affected patients. A m o n g the extraendocrine manifestations those affecting the
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gastrointestinal tract, especially the colon, predominate. The discipline of embryology helps us understand the diversity of the features of MEN 2B. The neural crest is the c o m m o n link between pheochromocytoma, MTC, and neuronal abnormalities of the gastrointestinal tract. It is known that C ceils of the thyroid, adrenal medullary cells, and ceils of the autonomic plexus and ganglia in the alimentary tract all arise from the neural crest. 9 A molecular abnormality affecting cells of this lineage could therefore readily account for all the dominant features of MEN 2B. The occurrence of gastrointestinal symptoms in 90% of our patients with MEN 2B highlights alimentary tract disorders as a major c o m p o n e n t of this syndrome. It has previously been shown that patients with MEN 2B have diffuse ganglioneuromatosis affecting the entire alimentary tract from the m o u t h to the anus. l~ Diffuse proliferation of the intestinal autonomic nerves and ganglia is present on histologic examination. The bowel is easily distended, and the usual clinical and radiologic finding is of a greatly dilated colon, giving rise to the term megacolon. 11 It is of considerable importance that colonic symptoms in most patients were present from birth and preceded the presentation of MTC in 16 of our patients. The significance of severe chronic constipation from birth as a marker for MEN 2B is generally not appreciated, and in only one patient in this series did this symptom lead to an accurate diagnosis. Although the association is rare, MEN 2B should always be considered in the differential diagnosis of chronic constipation in this age group. 12" 13 The clinical and radiologic colonic findings in MEN 2B often closely resemble and are often confused with Hirschsprung's disease. Although the colonic manifestations of MEN 2B differ from those of Hirschsprung's disease in that ganglioneuromatosis occurs rather than aganglionosis, it is of great interest that the genetic determinants of each condition are similar. The genes for MEN 2B and Hirschsprung's disease have each been localized to that region of chromosome 10 that contains the ret proto-oncogene, and in each case mutations affect the intracellular tyrosine kinase domain of that protein.7, 14 A similar defect has been shown in some patients with sporadic MTC. 7 Although the genes for MEN 2A and familial MTC are also located in the ret proto-oncogene, the locations of these mutations differ in that they affect the cysteine-rich extracellular domain of Ret. TM 16 Experimentally, a targeted mutation in the tyrosine kinase domain of the Ret protein in homozygous transgenic mice produces intestinal aganglionosis. 17 Further notable clinical observations are possibly explained by Ret mutations. Khan et al. 12 report true Hirschsprung's disease in nine patients a m o n g 92 members of a MEN 2A kindred. Ganglioneuromatosis of the small intestine together with aganglionosis of the colon has been reported in the same patient. 18although
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not in the setting of MEN. Collectively this evidence suggests that Ret plays an important role in the develo p m e n t and function of cells of neural crest origin. Mutations affecting Ret may explain tumorigenesis in thyroid C cells and adrenal medullary cells and may also explain abnormal development of the enteric nervous system, possibly by affecting the migration of neural crest cells. 17 Variations in the mutations that affect the Ret protein presumably determine the precise clinical syndrome produced. These c o m m o n embryologic and genetic links may explain both the wide clinical spectrum of MEN 2B and also the similarities and overlap between MEN 2A, MEN 2B, familial MTC, and Hirschsprung's disease. Clearly, however, more experimental work is required to explain the relationship between Ret mutations and associated clinical syndromes. The most characteristic feature of MEN 2B is the classic phenotype that resulted in recognition of MEN 2B in four of our patients. In c o m m o n with other reportsa9, 2o every patient in this series had typical neuromas. These developed chiefly on the anterior portion of the tongue and also on the lips, buccal mucosa, eyelids, and conjunctivae in many patients. These neuromas are the external manifestations of generalized ganglioneuromatosis of the alimentary tract. Most patients are marfanoid, exhibiting the typical tall slender body build. Peripheral nerve thickening is usually evident clinically through examination of the corneal nerves, and at thyroidectomy recurrent laryngeal nerve thickening is frequently noted. A variety of other facial, ophthalmic, and skeletal abnormalities complete the phenotype. These phenotypic features may be the only means of early diagnosis of the condition especially in sporadic cases. Recognition of this phenotype and appreciation of its relationship with thyroid malignancy are of the utmost importance. 21 MTC is the most c o m m o n cause of death in MEN 2B, accounting for two direct deaths and one indirect death in the current series. Although MTC can develop as early as the first year of life. survival can be very prolonged. The two patients who died of MTC in this series were 34 and 48 years of age. Prolonged survival is exemplified by four patients who survived 4, 13, 17. and 17 years after the diagnosis of liver metastases from MTC. MTC in MEN 2B is almost universally bilateral and multifocal and is associated with lymph node metastases at the time of primary surgery in 50% of patients. The bilateral nature of this disease mandates total thyroidectomy in every patient. Because of the high incidence of lymph node metastases, routine dissection of the central compartment of the neck is advised, and a modified radical neck dissection is indicated in the presence of gross or microscopic lateral nodal disease. 22 In a previous report we have compared MTC in MEN 2B with that in MEN 2A and have shown that MEN 2B-related disease is considerably more aggressive than that in MEN
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2A. 22 M E N 2 B - r e l a t e d M T C p r e s e n t s at a y o u n g e r age,
CONCLUSION
is a s s o c i a t e d w i t h m o r e e x t e n s i v e disease w i t h i n t h e thyr o i d g l a n d a n d a h i g h e r i n c i d e n c e o f m e t a s t a t i c disease, a n d is m u c h less a m e n a b l e to surgical c u r e . 22 I n c o n t r a s t
M E N 2B is a severe disease d o m i n a t e d b y a relatively aggressive f o r m o f M T C , b i l a t e r a l p h e o c h r o m o c y t o m a s i n u p to 5 0 % o f p a t i e n t s , severe c o l o n i c d y s f u n c t i o n i n m o s t p a t i e n t s , a n d a wide variety o f o t h e r e x t r a e n d o c r i n e f e a t u r e s . T h y r o i d disease a c c o u n t s f o r m o s t d e a t h s , a n d early r e c o g n i t i o n o f M E N 2B w i t h early p r o p h y l a c tic t h y r o i d e c t o m y is o f p a r a m o u n t i m p o r t a n c e . It is t h e multitude of extraendocrine abnormalities, however, t h a t h a v e t h e m o s t s i g n i f i c a n t effect o n t h e day-to-day lives o f m a n y p a t i e n t s w i t h M E N 2B. C o l o n i c dysfunct i o n h a s p r e v i o u s l y r e c e i v e d little a t t e n t i o n , a n d f u r t h e r i n v e s t i g a t i o n o f t h e p a t h o g e n e s i s a n d t r e a t m e n t o f this d i s o r d e r is w a r r a n t e d .
to M E N 2A, t h y r o i d disease i n M E N 2B is n e v e r d i a g n o s e d at t h e p r e i n v a s i v e stage. S u r g e r y a t a n early a g e is a s s o c i a t e d w i t h a b e t t e r o u t c o m e , a n d w i t h t h e occurrence of MTC in an infant of 7 months of age in this series, a s t r o n g case c a n b e m a d e f o r p r o p h y l a c t i c t h y r o i d e c t o m y d u r i n g t h e first y e a r o f life. I t is likely i n t h e very n e a r f u t u r e t h a t g e n e t i c t e s t i n g f o r M E N 2B will have a marked influence on the timing of diagnosis and thyroidectomy. Pheochromocytoma occurs later than the other mang e s t a t i o n s o f M E N 2B: m e d i a n a g e at d i a g n o s i s was 28 years. T h e p r e c i s e i n c i d e n c e o f p h e o c h r o m o c y t o m a is d e p e n d e n t o n t h e d u r a t i o n o f follow-up: this t u m o r developed in more than 50% of patients who were moni t o r e d b e v o n d 25 years o f age. T h e o u t c o m e a f t e r treatm e n t o f p h e o c h r o m o c y t o m a was e x c e l l e n t . O n e p a t i e n t had evidence of malignant pheochromocytoma with m i c r o s c o p i c v a s c u l a r i n v a s i o n , b u t every p a t i e n t was c u r e d by s u r g e r y a n d n o n e h a s h a d a r e c u r r e n c e o n l o n g - t e r m follow-up. T h e six p a t i e n t s w h o u n d e r w e n t a d r e n a l e c t o m y at t h e Mayo Clinic e a c h h a d b i l a t e r a l p h e o c h r o m o c y t o m a . It r e m a i n s o u r p r e f e r e n c e to perf o r m r o u t i n e b i l a t e r a l a d r e n a l e c t o m y i n M E N 2B bec a u s e o f t h e u n i v e r s a l o c c u r r e n c e o f b i l a t e r a l disease, a n d we h a v e p r e v i o u s l y r e p o r t e d t h e safety a n d efficacy o f this a p p r o a c h . 23 I n d e e d this p r a c t i c e is s u p p o r t e d by the outcome in the one patient who underwent unilate r a l s u r g e r y i n t h e p r e s e n t series a n d w h o r e q u i r e d c o n tralateral adrenalectomy 2 months later because of pers i s t e n t s y m p t o m s . T h e r e l a t i o n s h i p b e t w e e n t h e development of pheochromocytoma and the presence of m o r e a d v a n c e d t h y r o i d disease is a c u r i o u s o n e . T h i s ass o c i a t i o n d o e s n o t a p p e a r to r e l a t e to t h e a g e at d i a g n o sis a n d m a y r e f l e c t a v a r i a b l e o f t h e d e g r e e o f e x p r e s s i o n o f t h e R e t m u t a t i o n , a f a c t o r t h a t is c o m m o n to t h e p a t h o g e n e s i s o f b o t h p h e o c h r o m o c y t o m a a n d MTC. A l t h o u g h m o r e aggressive t h a n M E N 2A, t h e overall o u t l o o k i n M E N 2B is n o t as b a d as h a s b e e n s u g g e s t e d . i n spite o f a d i a g n o s i s o f M T C a t a m e d i a n o f 16 years o f a g e a n d t h e l i k e l i h o o d t h a t t u m o r is p r e s e n t m u c h earlier in most patients, no deaths occurred at younger t h a n 30 years o f age. O v e r a l l o n l y f o u r p a t i e n t s d i e d , three of the consequences of metastatic MTC and one a f t e r c o l o n i c p e r f o r a t i o n at 70 years o f age. T h e p r o t e a n m a n i f e s t a t i o n s o f M E N 2B do, h o w e v e r , h a v e a d i s r u p tive i m p a c t o n t h e quality o f life o f a f f e c t e d patients. T h e t h r e a t o f c a n c e r at a y o u n g age, t h e t r a u m a o f m u l t i p l e surgical p r o c e d u r e s , t h e p e r s i s t e n t g a s t r o i n t e s t i n a l sympt o m s , a n d t h e m u l t i t u d e o f skeletal a n d o t h e r p h e n o typic a b n o r m a l i t i e s c o n t r i v e to p r o d u c e a p r o f o u n d d e t r i m e n t a l effect o n t h e p s y c h o l o g i c a l well-being a n d everyday e x i s t e n c e o f m a n y o f t h e s e p a t i e n t s .
REFERENCES
1. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961:31:163-6. 2. Williams ED. A review of 17 cases of carcinoma of the thyroid and phaeochromocytoma. J Clin Pathol 1965:18:288-92. 3. Steiner AL. Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasaa. type 2. Medicine 1968;47:371408. 4. Chong GC, Beahrs OH, Sizemore GW, et al. Medullary carcinoma of the thyroid gland. Cancer 1975;35:695-704. 5. Rashid M, Khiari A. Dexter RN, et al. Mucosal neuroma, pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3. Medicine 1975:54:89-112. 6. Lairmore TC. Howe JR, Korte JA, et al. Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same regaon of chromosome 10 as multiple endocrine neoplasia type 2A. Genomics 1991:9:181-92. 7. Hofstra RM. Landsvater RM. Ceccherini I. et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367:375-6. 8. Sizemore GW. CarneyJA, Gharib H. Capen CC. Multiple endocrine neoplasia type 2B: eighteen year follow-up of a four generation family. Henry Ford Hosp Med J 1992:40:236-44. 9. Williams PL. Warwick R. Dyson M. Bannister LH. eds. Gray's anatomy. 37th ed. Edinburgh: Churchill Livingstone,1989:200, 1467. 10. Carney JA, Go VL. Sizemore GW. Hayles AB. Alimentary tracl ganglioneuromatosis: a major component of the syndrome of multiple endocrine neoplasia, type 2b. N EnglJ Med 1976;295: 1287-91. 11. Demos TC. Blonder J, Schey WL. Braithwaite SS. Goldstein PL. Multiple endocrine neoplasia (MEN) syndrome type IIB: gastrointestinal manifestations. AJR 1983:140:73-8. 12. Khan AH. DesjardinsJG, Youssef S. Gregoire H. Seidman E. Gastrointestinal manifestations of Sipple syndrome in children.J Pediatr Surg 1987:22:719-23. 13. Griffiths AM. Mack DR. Byard RW. Stringer DA. Shandling B. Multiple endocrine neoplasia IIb: an unusual cause of chronic constipation. J Pediatr 1990:116:285-8. 14. Romeo G, Ronchetto P. Luo Y. et al. Mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature 1994:367:377-8. 15. Mulligan LM. KwokJB, Healey CS. et al. Germ-line mutations of the RET proto-oncogene in nmltiple endocrine neoplasia type 2A. Nature 1993;363:458-60. 16. Donis-Keller H. Dou S, Chi D, et al. Mutations in the RET protooncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993:2:851-6.
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17. Schuchkardt A, D'Agati V, Larsson-Blomberg L, Constantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 1994; 367:380-3. 18. Schm'liAF, Meier-Ruge W. Localized mad disseminated forms of neuronal intestinal dysplasia mimicking Hirschsprung's disease. J Pediatr Surg 1981;16:164-70. 19. Vasen HF, van der Feltz M, Raue F, et al. The natural course of multiple endocrine neoplasia type IIb: a study of 18 cases. Arch Intern Med 1992;152:1250-2. 20. NortonJA, Froome LC, Farrell RE, Wells SA. Multiple endocrine neoplasia type 2B: the most aggressiveform of medullary thyroid carcinoma. Surg Clin North Am 1979;59:109-18. 21. White MP, Goel KM, ConnorJM, Coutts NA. Mucosal neuroma syndrome--a phenotype for malignancy. Arch Dis Child 1985; 60:876-7. 22. O'Riordain DS, O'Brien T, Hay ID, Grant CS, van HeerdenJA. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. SURGERY1994;116:1017-23. 23. van Heerden JA, Sizemore GW, Carney JA, Grant CS, ReMine WH, Sheps SG. Surgical management of the adrenal glands in the mnltiple endocrine neoplasia type II syndrome. World J Surg 1984;8:612-21.
DISCUSSION Dr. Mafia Allo (San Jose, Calif.). Given the early presentation of phenotypic abnormalities such as the mucosal neuromas in these patients to the point where people have actually advocated prophylactic thyroidectomies in children, are there any diagnostic or marker measurements that you might take to predict the extent of colonic disease in some of these young patients? How far do you feel comfortable in making recommendations about management of the colonic disease in these patients because you are reporting a fairly high incidence? Dr. O'Riordain. What we are trying to highlight is that colonic disease is certainly a major c o m p o n e n t of the syndrome and one that perhaps has not been given the attention it deserves. To date there really is no scientific evidence to answer some of your questions with regard to management of the colonic disease. A 10t of these patients present with the presumptive diagnosis of Hirschsprnng's disease and undergo rectal biopsies that show ganglia. A n m n b e r of patients underwent some sort of colectomy. I d o n ' t think that we can really make solid recommendations at the present time as to the m a n a g e m e n t of the colonic manifestations in these patients. It does n e e d to be looked at. Dr. Edwin Kaplan (Chicago, Ill.). I want to emphasize one part of the syndrome that you passed over briefly, testicular atrophy. We have three patients in our series with MEN 2 syndromes who have atrophic testicles. One patient, shared with Dr. Eberhard Mack, has MEN 2B with Klinefelter's Syndrome. Two other patients, one with MEN 2A and one with MEN 2B, have testicular atrophy, gynecomastia, and high pituitary levels of follicle-stimulating h o r m o n e and luteinizing hormone. Do any of your patients with MEN 2A have testicular atrophy as well? Dr. O'Riordain. Not that I am aware of. Dr. Jeffrey Norton (St. Louis, Mo.). This is like Back to the Future because Dr. Carney from your institution first described
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this in 1976. The hypothesis about the neural crest abnormality explaining the syndrome of MEN 2B is interesting, but how do you explain the bony abnormalities and the dental abnormalities as part of the neural crest? Dr. O'Riordain. I d o n ' t know what the exact answer is. Whether these skeletal and dental abnormalities mentioned result from some abnormalities of the neural crest function in the developmental stage, embryologically, I don't really know, and I don't think anybody can clearly answer that question for you. I suspect that ultimately it will be seen to tie in in some fashion. Dr. Colin Russell (Belfast, Northern Ireland). Just one question of detail regarding the colonic surgery. Can I assume that the three patients who underwent a colectomy in adult life had an abdominal colectomy with an ileorectal anastomosis? The question relates to the large bowel function in those patients after the operation. Was their motility problem alleviated or did they continue to have motility difficulties after the operation? Dr. O'Riordain. The three patients who underwent subtotal colectomies were evaluated, and all did much better symptomatically after operation. I would have to emphasize, however, that most of the colonic surgery that we are quoting here was not done at our institution. It was done elsewhere and in most cases before the diagnosis of MEN 2B. So our follow-up in terms of the exact preoperative and postoperative symptoms is a little bit vague, Dr. J e f f Moley (St. Louis, Mo.). You indicated that only 67% of the patients with MEN 2B had megacolons. I have never seen a patient with MEN 2B who didn't have a megacolon. What was the situation in the other 33% of patients? Dr. O'Riordain. Only 67% of our patients had a clear diagnosis, and this is a retrospective study. There were one third of our patients where that clear diagnosis of megacolon had not been made. I can't say that they didn't have it. Dr. Michael Roe (Chattanooga, Tenn.). I cared for a 3-year-old a couple of years ago who was diagnosed in a very similar fashion. She had undergone a rectal biopsy that showed ganglioneuromatosis, and eventually she was diagnosed with MEN 2. We performed a total thyroidectomy and found a 3 m m medullary carcinoma. She now is disease free about 2 or 2~ years later. At what age do you begin to see either regional or distant metastatic disease from the MTC in these younger pediatric patients? Once diagnosed, at what age in these younger patients would you r e c o m m e n d thyroidectomy? Dr. O'Riordain. In our series we have one patient who had invasive MTC without metastatic disease at the age of about 6 months. There are a n u m b e r of reports in the literature of patients with no gross disease and metastatic disease as young as 3 years of age. This is an aggressive disease in young children, and we would advocate early thyroidectomy after the diagnosis of MEN 2B, perhaps in the first year of life. It really is a balance between what your perception is of the severity of the disease, the age group versus the morbidity of thyroidectomy. Perhaps we d o n ' t have sufficient data on the morbidity of thyroidectomy in that age group. Our inclination would be toward surgery in the first year of life in those patients.