Nonfamilial medullary thyroid carcinoma

Nonfamilial medullary thyroid carcinoma

Nonfamilial Medullary Thyroid Carcinoma Ricardo L. Rossi, MD, Boston, Massachusetts Blake Cady, MD, Boston, Massachusetts William A. Meissner, MD, Bo...

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Nonfamilial Medullary Thyroid Carcinoma

Ricardo L. Rossi, MD, Boston, Massachusetts Blake Cady, MD, Boston, Massachusetts William A. Meissner, MD, Boston, Massachusetts Marvin S. Wool, MD, Boston, Massachusetts Cornelius

E. Sedgwick, MD, Boston, Massachusetts

Joan Werber, AB, Boston, Massachusetts

Hazard et al [1] in 1959 used the term medullary carcinoma of the thyroid to describe a type of thyroid carcinoma with distinctive characteristics, a tumor composed of a solid mass of cells that did not show a follicular pattern and that had amyloid [2] in the stroma. Other criteria in establishing the correct diagnosis in difficult cases have been reviewed recently [3]. It is currently accepted that medullary thyroid carcinoma originates from the calcitonin-producing parafollicular C-cell [4] within the thyroid gland and that such tumors may be of sporadic or familial occurrence [5-71. Because the familial type already has an extensive recent literature, we review our experience with patients treated surgically for nonfamilial medullary thyroid carcinoma to study the prognostic factors and natural history of this variety of tumor. Material and Methods Of 964 patients with thyroid carcinoma treated at the

Lahey Clinic between 1931and 1970 and whose records and pathologic reports were reviewed in 1975 [8], 25 patients were originally classified as having medullary carcinoma and 147 patients as having undifferentiated forms of cancer. In a further intensive review [9] by one of us (WAM), 10 of these 147 patients with undifferentiated carcinomas were reclassified as having medullary tumors, making a total of 35 thoroughly documented cases that form the From the Departments of Surgery and Internal Medicine, Lahey Clinic Foundation, and Laboratory of Pathology, New England Deaconess Hospital, Boston, Massachusetts. Reprint requests should be addressed to Ricardo L. Rossi, MD. Department of Surgery, Lahey Clinic Foundation, 605 Commonwealth Avenue, Boston, Massachusetts 02215. Presented at the 60th Annual Meeting of the New England Surgical Society, Whitefield. New Hampshire, September 26-30, 1979.

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basis of this report. These 35 patients represent 3.6 percent of all patients with thyroid malignancy seen in 40 years at this institution. One of the patients with medullary carcinoma had had a solitary parathyroid adenoma removed and was excluded from our study to obviate any suggestion of the familial variety. Therefore, 34 cases were considered for our study. Accurate follow-up study was achieved in all patients. Patients were considered dead of disease if they died or were last seen with disease present. All other patients were documented as living free of disease or as dead of other causes if they were alive free of disease or died free of disease more than 5 years after therapy. At operation, disease was classified as occult if the thyroid carcinoma was not suspected, intrathyroid if carcinoma was confined within the thyroid gland or extrathyroid if gross extension of carcinoma was observed to tissues outside the confines of the thyroid gland. Surgical therapy consisted of biopsy alone when thyroid carcinoma was unresectable, unilateral thyroid resection when excision of a nodule or subtotal or total thyroid lobectomy was performed, and thyroidectomy when bilateral removal of the thyroid gland was accomplished. Patients treated for cure included those in whom all macroscopic tumor was removed at operation and in whom no known metastatic disease existed. Questionnaires to family members, hospital records, physician reports and pathology slides, when available, were used to study the family members.

Results

The with a history ponent family

follow-up period ranged from 5 to 44 years median of 26 years. No patient had a family of medullary thyroid carcinoma or any comof multiple endocrine neoplasia. However, members were not screened by calcitonin as-

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TABLE I -----____

Extent of Tumor Involvement at Operation (34 Patients) -. No. Percent

Extent of primary cancerous lntraglandular Occult Clinically apparent Extraglandular

lesion

Lymph node metastasis lntraglandular fxtraglandular

TABLE II __~__

68 7 16

21 47

11

32

6/23 8111

26 73

Surgical Therapy (34 Patients) _

Therapy

Treatment

23

No.

-__

Percent

of primary cancer

I3iopsy only IJnilateral thyroidectomy Bilateral thyroidectomy Surgery of lymph node metastasis Neck dissections Surgical classification Curative (all gross disease excised) Palliative (gross residual disease at operation)

3 6 25

9 18 73

11

32

24

71

10

29

says. No clinical evidence of endocrinopathy developed in any patient during his follow-up period. The ratio of women to men was 1.8to 1.0. The median age for women was 52 years (range 21 to 75) and for men 61 years (range 33 to 76). The clinical findings at presentation consisted of a thyroid mass only in 20 patients (59 percent), thyroid mass and neck nodes in 5 (15 percent), distant, metastasis in 3 (9 percent) and enlarged cervical nodes only in 2 (6 percent). Disease was clinically occult in four patients (12 percent) because findings were not even suspected to indicate carcinoma by the examiner. Of the patients who presented with distant

TABLE Ill ---~~

Medullary

Thyroid

Carcinoma

metastasis, the most common site was the lung followed in frequency by the liver, bone and brain. The extent of disease at operation is shown in Table 1. Recurrent nerve invasion was noted in four patients (12 percent). Positive lymph nodes were found in 14 patients (41 percent), 10 had positive nodes only in the neck and 4 had them in both neck and the mediastinum. At pathologic examination, 71 percent had blood vessel invasion and 97 percent had capsular invasion. The extent of operation is shown in Table II. All visible tumor was removed in 24 (71 percent) of the patients. Tracheostomy was required in 3 patients (9 percent). Surgical complications, including serum collections, transient hypoparathyroidism, tracheocutaneous fistula and infection, were encountered in five patients and were not life-threatening. External radiation therapy was given to 29 patients (85 percent), to 19 (56 percent) as prophylaxis and to 10 (29 percent.) t.herapeutically for residual gross disease after operation. Fifty-nine percent of the patients died of disease. The prognosis was better in patients with surgically occult lesions and in those in whom all tumor was removed (Table III). The proportion of patients who died of disease in the group with extraglandular involvement was similar to that in the group with clinically apparent intraglandular lesions, although the latter patients had a better median survival. Of the seven patients with occult carcinoma at operation, only one (14 percent) died of disease :35 months after operation. When all tumor could be removed, only 46 percent of the patients died of disease. When gross residual tumor existed, all patients died of disease before 7 years, except for one who died without disease at 6.5 years from myocardial infarction. This difference was statistically significant (p = 0.039) by the Fisher exact test. For the patients who died of disease, the median survival was better when all tumor could be

Tumor Extent, Surgical Therapy and Survival (34 Patients) MedianSurvival of Patients Who Died of Disease (mo) -~__

No. of Patients

No.

Occult Clinically apparent Extraglandular Surgical therapy

7 16 11

1 11 8

14 69 73

35 48 14

(8-253) (3-122)

All cancer removed Gross residual tumor

24 10

11 9

46 90

48 15

(8-227) (3-83)

-

Died of Disease -

Percent

Tumor extent lntraglandular

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Figure 1. Medullary thyroid carcinoma determinate survival of 24 patients treated for cure and 70 patients wfth gross residual tumor at operation.

excised (48 versus 15 months). Figure 1 represents the determinate survival curve in our patients. For the patients treated for cure, the 5,10,15 and 20 year survival was 71,52,48 and 33 percent. Of 14 patients with positive nodes, 10 (71 percent) died of disease, but of 20 patients with negative nodes, only 8 (40 percent) died of disease. Although the Fisher exact test indicated no statistically significant difference (p = 0.14), the calculated 95 percent confidence limits of the 31 percent difference in survival between the two groups suggested the possibility of a significant difference that was not detectable by the small sample. Figure 1 illustrates the effect of lymph node metastasis on the survival curve in the patients treated for cure. Patients cured of disease were younger than those who eventually died of disease, a difference that was significant (p = 0.039) according to the Wilcoxon rank sum test. Cured patients had a median age of 47 years (range 26 to 76) versus a median age of 57 years (range 21 to 70) for those dead of disease. Seventeen percent of the men treated for cure died of disease, whereas 59 percent of the women treated for cure died of disease, a difference that was not statistically significant. The technique used for external radiotherapy was that of Smedal et al [IO] and consisted of a rotatory technique protecting the spinal cord and giving a total dose of 4,800 to 6,000 rads to the neck, supraclavicular areas and upper mediastinum. Radiotherapy was given to all 10 patients with gross residual tumor in the neck after the original operation. These patients had transient responses but eventu556

ally died of disease, except for one who had a myocardial infarction 6.5 years after operation. Three of these 10 patients (30 percent) lived longer than 4 years. No conclusions can be drawn about the effect of radiation therapy when used prophylactically because of the lack of a control group. Of the 24 patients treated for cure, and excluding the 3 patients who died without disease before 5 years of follow-up study, disease recurred in 9 (43 percent). The first recurrence occurred at the median time of 17 months (range 7 to 163). Disease recurred in the neck in five patients and in distant sites in four others. The median survival time after the first recurrence was 31 months (range 3 to 363). Eight of the nine patients died of disease, one of them as late as 9 years after treatment of a local recurrence with operation and radiation therapy. The ninth patient had a local recurrence treated with operation and radiation therapy and died without disease 30 years later. Four of the nine patients (44 percent) lived more than 5 years from the time of the first recurrence. Calcitonin stimulation studies using glucagon were performed in three of our eight patients who are alive and without evidence of disease. All had normal basal serum calcitonin levels that failed to increase after glucagon was administered. Case Report A 45 year old man consulted us in 1974 because his identical twin brother had undergone surgery for medullary thyroid carcinoma. Studies in our patient revealed a high normal basal calcitonin level (0.27 ng, normal up to 0.3 ng) and an abnormal calcium stimulation study with an increase in the calcitonin level to 0.65 ng. Physical examination, radiography of the sella turcica and thyroid scan were within normal limits. The calcium was 9.6 and the phosphorus 3.1. At operation no discrete thyroid nodule was found. Total thyroidectomy was performed; three parathyroid glands seen at operation appeared normal and were preserved. Pathologic examination grossly revealed no discrete thyroid nodule. The fluorescent antibody, light microscopy and electron microscopy showed C-cell hyperplasia. The follow-up basal calcitonin levels have been undetectable. The patient remains well. Our patient and his twin brother have eight siblings, none of them twins, four brothers and four sisters who range in age from 45 to 65 years. Although they have refused to be evaluated, they have had no clinical evidence of thyroid tumor or multiple endocrine neoplasia (MEN) type II syndrome. The parents died without evidence of pertinent disease. We have studied the four oldest of the five children of our patients (10 to 20 years of age), and all have normal calcitonin levels.

With the available family information, it appears that this case probably represents the previously The American Journal of Surgery

Nonfamilial Medullary Thyroid Carcinoma

unreported and distinctly unusual occurrence of a sporadic, nonfamilial medullary carcinoma in identical twins.

Comments

As demonstrated by Pearse and Carvalheira [II], the C-cells are of ectodermal origin. The cells can’ secrete calcitonin [12,13] and less commonly serotonin [ 14,151, prostaglandin [ 161, histaminase [ 171 a,nd melanocyte-stimulating hormone and ACTHlike substances [1.5,18]. Medullary tumors may occur sporadically or in familial groups [5-7,19,20]. The la.tt.er is of autosomal dominant inheritance, and when it is associated with pheochromocytoma and parathyroid hyperplasia or adenoma or both. forms the MEN type II syndrome [2f]. These last features make it necessary in every case of medullary carcinl)ma of the thyroid to investigate the possiblity of concomitant adrenal and parathyroid disease and to examine and study other members of the family. The origin of the C-cell in the neural crest explains the association of medullary carcinomas with other neural ectodermal disorders such as multiple neurcmas [ 7.22-241. A Marfan-like habitus also has been reported [2Z]. The int.roduction of calcitonin radioimmunoassay [25], eit,her basally or in response to calcium [26,27], glucagon [191, whiskey [21,28] or pentagastrin [27,29] administration, has increased the efficacy of early diagnosis of this malignancy in the patients at risk and of det,ermining its persistence or recurrence after primary treatment. Venous catheterization [30] has also been used to detect the site of metastasis or recurrent disease. Multicentricity and bilaterality are common in familial cases but occur only occasionally in sporadic cases [5-7,311. It has been suggested that survival is somewhat better in familial compared with sporadic cases [7]. Earlier diagnosis and perhaps a less aggressive form of neoplasia have been suggested as explanations of this difference. The prognosis of medullary carcinoma differs in different families with MEN [24]. In patients with multiple mucosal neuromas, for example, with or without a family history, the medullary carcinoma has an aggressive course. Wells et al [20], when comparing patients with MEN type II syndrome who had the diagnosis of medullary thyroid carcinoma established biochemically rather than clinically, encountered a more favorable pathologic stage of disease at the time of thyroidectomy. Graze et al [32], when administering provocative calcitonin tests yearly to a group of patients at high risk, documented a high incidence of C-cell hyperplasia and a microscopic foci of carcinoma with no detectable metasVolume

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tasis occurring in younger patients who had exploratory operation when the secretory responses converted from normal to abnormal. The immune response to tumor antigen has been studied [33]. Preliminary results indicate that patients with proved medullary carcinoma do have cellular response to tumor antigen. In addition, some family members without disease exhibit similar cellular responses. The clinical significance of this finding remains to be seen. The majority of our patients were diagnosed and treated before the clinical use of radioimmunoassay for human calcitonin; therefore, no such evaluation of the family members was performed. In our patients, the family history was not remarkable for medullary carcinoma. The median follow-up period for all of our patients was 26 years; the majority of the patients had died from disease or other causes by the time of this review. In none did clinical evidence suggest the MEN syndrome except in a single patient with a previous parathyroid adenoma. For these reasons, we believe our patients represent the sporadic form of the disease. Throughout the decades of the study, the incidence of sporadic medullary carcinoma remained essentially unchanged, representing 3.6 percent of all the thyroid malignancies seen at the Lahey Clinic. Recent series [7,20,32] have shown that the overall annual incidence has increased in t.he later years because of screening procedures based on calcitonin measurements to identify family members at high risk for the development of this tumor, but the incidence of the sporadic form probably has not increased. It should be kept in mind that about 90 percent of all medullary carcinomas are of the sporadic or nonfamilial type, The median age of Fj4 years at presentation of the disease contrasts with the much lower age of presentation of familial cases [ 7,20,31,32,34]. The clinical features and course of the disease are similar to those previously reported before the era of early diagnosis by radioimmunoassay [6,7]. Of our patients, 41 percent had positive lymph nodes at operation. In some series reporting early diagnosis of medullary carcinoma using calcitonin assay, and with tumors of less than 2 cm in diameter [26,35], a 50 percent incidence of metastatic disease to the central nodes of the neck was encountered on routine sampling, which suggests the early occurrence of metastatic nodal disease. Survival was negatively influenced by the extent of disease, the presence of lymph node metast,asis, elderly age and inability to completely remove all tumor at operation. The prolonged course of the disease is demonstrated by the finding that of the 557

Rossi et al

patients who died of disease and had been treated originally for cure, 45 percent died after 5 years and as late as 21 years after initial thyroidectomy. Even among the patients with gross residual tumor left at operation, in whom the median survival was 16 months, some survived longer than 5 years. Generally, the response of medullary carcinoma to radiation therapy is estimated to be poor [7]. Recently Steinfeld [36] reported beneficial effects of radiation therapy. In our patients in whom radiotherapy was used as the treatment of residual tumor or recurrent disease, only transient local regressions were produced except in two patients who died free of disease at 6.5 and 30 years. Although all but one of the patients with recurrence died of disease, our figures suggest that aggressive therapy combining operation and radiation should be attempted, as over half of the patients survived over 2 years after the first recurrence. The effect of chemotherapy was not analyzed in our patients. Gottlieb and Hill [37,38] have documented objective regressions of some medullary thyroid carcinomas treated with [email protected] Because the disease is sometimes multicentric and bilateral, the surgical procedure of choice in pat.ients with medullary carcinomas of the thyroid is total thyroidectomy [6,7,31]. Sampling or clearance of the nodes on the central part of the neck should be performed in view of the high incidence of lymph node metastasis, even in cases of occult or small tumors. When soft tissues are invaded locally, excision should be performed. There is no proof that extended radical procedures, including laryngectomy or esophagectomy, improve prognosis. Although the incidence of hypercalcemia after thyroidectomy for medullary carcinoma is low, the high incidence of parathyroid abnormalities in patients with familial medullary thyroid carcinoma makes it mandatory to identify the parathyroid glands during operation [31,39]. Current evidence does not support routine subtotal parathyroidectomy for patients with medullary thyroid carcinoma. The operative procedure should be individualized on the basis of preoperative and operative findings. Serum calcium and phosphorus studies should be part of the follow-up evaluation of patients with medullary thyroid carcinoma of the familial type. In general, an increased calcitonin level after operation reflects persistent disease [32,40], and if no evidence of distant metastasis is found, reoperation is indicated if adequate neck dissection has not been performed [40]. If serum calcitonin levels remain elevated in an otherwise asymptomatic patient with no gross evidence of disease, observation is advised as some of these cases remain dormant for years [40]. 558

Gradual decrease of calcitonin levels can occur after operation, a phenomenon that has no clear explanation [32]. A few instances of persistent elevated calcitonin levels have been documented after total thyroidectomy for C-cell hyperplasia in patients in whom metastatic disease seems an unlikely cause

[321.

On the basis of this report and the current literature, we conclude that the familial type of medullary thyroid carcinoma can be diagnosed early using basal and poststimulation levels of calcitonin. However, most of the patients with sporadic disease present with a neck mass later in life. The tumor has a tendency to invade locally and metastasize to lymph nodes early in its course. Prognosis is negatively influenced by the extent of disease, lymph node involvement and elderly age. The surgical procedures of choice should be total thyroidectomy with clearance of central nodes of the neck as well as neck dissection when indicated. All parathyroid glands should be inspected. For patients treated for cure, the determinant 10 year survival is 48 percent, and 20 year survival is 33 percent. Recurrence of local disease should be treated aggressively, as important palliation and prolongation of life can be achieved. Radiotherapy may be helpful in the management of residual tumor or recurrent disease. Basal calcitonin assays and poststimulation studies are useful in diagnosing residual or recurrent disease. In the familial cases, the existence of other endocrinopathies has to be considered in the management of the patients. References 1. Hazard JB, Hawk WA, Crile G Jr. Medullary (solid) carcinoma of the thyroid: a clinicopathologic entity. J Clin Endocrinol Metab 1959;19:152-61. 2. Huang S-H, Goltzman D. Electron and immunoelectron microscopic study of thyroidal medullary carcinoma. Cancer 1978;41:2226-35. 3. Normann T, Johannessen JV, Gautvik KM, Olsen BR. Brennhovd IO. Mdullary carcinoma of the thyroid: diagnostic problems. Cancer 1976;38:366-77. 4. Williams CR, Brewer DB. Medullary carcinoma of the thyroid. Br J Surg 1969;56:437-43. 5. Keynes WM. Till AS. Medullary carcinoma of the thyroid gland. Cl J Med 1971;40:443-56. 6. Gordon PR, Huvos AG, Strong EW. Medullary carcinoma of the thyroid oland: a clinicopathologic study of 40 cases. Cancer i973;31:9i5-24. 7. Chong GC, Beahrs OH, Sizemore GW, Woolner LH. Medullary carcinoma of the thyroid gland. Cancer 1975;35:695704. 8. Cady B, Sedgwick CE, Meissner WA, Bookwalter JR, Romagosa V, Werber J. Changing clinical, pathologic, therapeutic, and survival patterns in differentiated thyroid carcinoma. Ann Surg 1976;184:541-53. 9. Rossi R, Cady B, Meissner WA, Sedgwick CE, Werber J.

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Prognosis of undifferentiated carcinoma and lymphoma of the thyroid. Am J Surg 1978;135:589-95. Smedal MI. Salzman FA, Meissner WA. The value of 2 mv roentgen-ray therapy in differentiated thyroid carcinoma. Am J Radio1 1967;99:352-64. Pearse AG, Carvalheira AF. Cytochemical evidence for an ultimobranchial origin of rodent thyroid C cells. Nature 1967;214:929-30. Cunliffe WJ, Black MM, Hall R, et al. A calcitonin-secreting thyroid carcinoma. Lancet 1968;2:63-6. Melvin KE, Tashian AH Jr. The syndrome of excessive thyrocalcitonin produced by medullary carcinoma of the thyroid. Proc Nat1 Acad Sci USA 1968;59:1216-22. Moertel CG, Beahrs OH, Woolner LB, Tyce GM. “Malignant carcinoid syndrome” associated with noncarcinoid tumors. N Engi J Med 1965;273:244-8. lwanaga T, Koyama H, Uchiyama S, et al. Production of several substances by medullary carcinoma of the thyroid. Cancer 1978;41:1106-12. Williams ED, Karim SMM, Sandler M. Prostaglandin secretion by medullary carcinoma of the thyroid. Lancet 1968;l: 22.-3. Jackson CE, Tashjian AH Jr, Block MA. Detection of medullary thyroid carcinoma by calcitonin assay in families. Ann Intern Med 1973;78:845-52. Donahower GF, Schumacher OP, Hazard JB. Medullary carcinoma of the thyroid-a cause of Cushing’s syndrome: report of two cases. J Clin Endocrinol Metab 1968;28:11991204 Melvin KE, Tashjian AH Jr, Miller HH. Studies in familial (medullary) thyroid carcinoma. Recent Prog Horm Res 1972; 28:399--470.

20.

Wells SA Jr, Baylin SB, Gann DS, et al. Medullary thyroid carcinema: relationship of method of diagnosis to pathologic staging. Ann Surg 1978;188:377-83. 21. Taylor S. Thyroid medullary carcinoma. Ann R Coll Surg Engl 1977:59:374-81. 22. Williams ED, Pollock DJ. Multiple mucosal neuromata with endocrine tumours: a syndrome allied to von Recklinghausen’s disease. J Pathol 1966;91:-71-80. 23. Gorlin RJ. Sedan0 HO, Vickers RA, Cervenka J. Multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid-a syndrome. Cancer 1968;22:2939. 24. Williams ED. Thyroidectomy for genetically determined medullary carcinoma (letter). Lancet 1977;2:1309-10. 25. Tashjian AH Jr, Howland BG, Melvin KEW, Hill CS Jr. Immunoassay of human calcitonin: clinical measurement. relation to serum calcium and studies in patients with medullary carcinoma. N Engl J Med 1970;283:890-5. 26. Melvin KEW, Miller HH, Tashjian AH Jr. Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N Engl J Med 1971;285:1115-20. 27. Wells SA Jr, Baylin SB. Linehan WM, Farrell RE, Cox EB, Cooper CW. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 1978; 188:139-41. 28. Coombes RC, Hillyard C, Greenberg PB, Maclntyre I. Plasmaimmunoreactive-calcitonin in patients with nonthyroid tumours. Lancet 1974;1:1080-3. 29. Hennessy JF, Gray TK, Cooper CW, Ontjes DA. Simulation of thyrocalcitonin secretion by pentagastrin and calcium in two patients with medullary carcinoma of the thyroid. J Clin Endocrinol Metab 1973;36:200-3. 30. Argemi B, Hours MC, Kasbarian M, Grisoli J, Codaccioni JL, Simonim R. Localization of metastatic medullarv thvroid carcinoma by immunoreactive calcitonin assay. Ho;m f&tab

Res 1977;9:248-9. 31.

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Miller HH, Melvin KEW, Gibson JM, Tashjian AH Jr. Surgical approach to early familial medullary carcinoma of the thyroid gland. Am J Surg 1972; 123:438-43. Graze K, Spiler IJ. Tashjian AH Jr, et al. Natural history of familial medullary thyroid carcinoma: effect of a program for early

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Rocklin RE, Gage1 R, Feldman Z, Tashjian AH Jr. Cellular immune response in familial medullary thyroid carcinoma. N Engl J Med 1977;296:835-8. Fletcher JR. Medullary (solid) carcinoma of the thyroid gland: a review of 249 cases. Arch Surg 1970;100:257-62. Wells SA Jr, Ontjes DA, Cooper CW, et al. The early diagnosis of medullary carcinoma of the thyroid gland in patients with multiple endocrine neoplasia type Il. Ann Surg 1975;182: 362-70. Steinfeld AD. The role of radiation therapy in medullary carcinoma of the thyroid. Radiology 1977;123:745-6. Gottlieb JA, Hill CS Jr. Chemotherapy of thyroid cancer with adriamycin: experience with 30 patients. N Engl J Med 1974;290:193-7. Gottlieb JA, Hill CS Jr. Adriamycin (NSC-123127) therapy in thyroid carcinoma. Cancer Chemother Rep (part 3) 1975; 6:283-96. Block MA, Jackson CE, Tashjian AH Jr. Management of parathyroid glands in surgery for medullary thyroid carcinoma. Arch Surg 1975;110:617-24. Block MA, Jackson CE, Tashjian AH Jr. Management of occult medullary thyroid carcinoma: evidence only by serum calcitonin level elevations after apparently adequate neck operations. Arch Surg 1978;113:368-72.

Discussion Chiu-an Wang (Boston, MA): This is a very important paper because it deals with a disease that is curable if diagnosed and treated early enough. How do we make the diagnosis early? In the last 15 patients in our series, we made it by needle biopsy of the thyroid nodule and confirmed it by plasma radioimmunoassay of the calcitonin. It is advantageous to make the diagnosis before exploration in order to better plan the surgical approach. Moreover, having determined the calcitonin level ireoperatively, we can then evaluate the operation by follow-up calcitonin studies. Have the investigators performed preoperative needle biopsy or carried out calcitonin studies in their patients? My second point concerns long-term survival. If the tumor has spread beyond the thyroid or has metastasized to the central nodes, the prognosis is excellent. not nearly as gloomy as we had feared. In 50 percent or more of Dr. Rossi’s patients, the prognosis was poor. Would Dr. Rossi like to comment on whether, in comparing the survival rates, he grouped all of these patients together or placed them in groups according to different stages of the disease? I would also like to ask if Dr. Rossi has undertaken anv -i calcitonin studies in these patients. Menelaos A. Aliapoulios (Worcester, MA): This superb report is a fitting tribute on the 20th anniversary of the first reported cases of medullary cancer of the thyroid by Hazard, Hawk and Crile of the Cleveland Clinic in 1959. Since then, the association of medullary cancer with C-cells of the thyroid, the relation with other apudomas, calcitonin and the radioimmunoassay, have been elaborated by ourselves and others and represent a tremendous credit to modern-day scientists and technology. It required twice that period of time to achieve the same progress in the adjacent endocrine organs, the parathyroid glands, which are related endocrinologically and physiologically by way of calcium homostasis.

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The availability of radioimmunoassay makes thyroid cancer ideal for clinical follow-up study of the individual and epidemiologically from the point of view of other family members. If you have been following up your patients with calcitonin radioimmunoassay, how do you manage those patients with persistently elevated calcitonin levels who have no evidence of clinical disease? Harry Miller, (Boston, MA): Dr. Rossi’s paper has defined the fact that the prognosis in patients with medullary carcinoma is worse than that of patients with other types of thyroid cancer, and that patients with extraglandular disease have an even darker future. In a recent epidemiologic study performed in conjunction with the Henry Ford Hospital, the Harvard Medical School and the Pathology Department at Tufts New England Medical Center, patients with known medullary thyroid carcinoma, their families and others were studied by measuring calcitonin levels, including provocative calcitonin tests. Thus, 63 patients with familial thyroid carcinoma were identified together with an additional 26 sporadic cases. When histologic sections of the thyroid from sporadic and familial cases were presented as unknowns to a group of pathologists, the pathologists were able to separate familial versus sporadic disease in every case. In a family we have been following up, 106 members have been evaluated. Seven cases of medullary thyroid carcinoma were already identified, and we found a significant number of others with abnormal calcitonin levels. Twelve with no clinical evidence of disease were operated on and all are alive 6 to 7 years later. In an additional group screened subsequently, 20 patients were identified and operated on. Two had C-cell hyperplasia; eight had medullary thyroid carcinoma and none has died of the disease. There was no recurrent disease in &is group. The implications are clear that with early identification, prognosis, even with frank carcinoma, can be markedly improved. Radioimmunoassay provides an excellent tool for testing all family members on a continuing basis.

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Francis D. Moore (Boston, MA): How can the essayists be sure these are sporadic nonfamilial cases if they have not yet studied the entire family connection of each patient by the evocative calcitonin test? Moreover, would they tell us their experience? with tetany in recurrent cases. Ricardo L. Rossi (closing): No patient had a preoperative diagnosis of medullary carcinoma. All patients were operated on before the advent of calcitonin immunoassay. Eight patients were alive at the time of this review. We obtained follow-up studies in three patients with basal and poststimulation thyrocalcitonin assays, and all gave normal results. For patients who have a persistent positive calcitonin assay and have not had total thyroidectomy or ipsilateral node dissectiol;, reoperation with completion of thyroidectomy and ipsilateral node dissection is indicated. If adequate surgery was performed initially, a conservative and expectant approach is justified. Venous catheterization has been helpful at other institutions under similar circumstances to localize residual or recurrent disease. No beneficial effect could be demonstrated in patients who received prophylactic radiation therapy. Responses could be documented in patients who received radiation therapy for residual or recurrent disease. Two patients treated were free of disease when they died 6.5 and 30 years later, with possible evidence of disease control by radiotherapy. Whether our patients had familial or nonfamilial carcinoma is a key question. Thyrocalcitonin assay in family members can assess this problem. Our series antedates the use of thyrocalcitonin assay. We had a median follow-up period of 26 years, a minimal follow-up period of 15 years and the majority of patients were dead at the time of this review. We studied clinically the siblings and children of these patients by means of questionnaires. Our medical records, records of local physicians and autopsy reports and pathology slides, when available, were reviewed. No patient or any family member had any sign or symptom to suggest multiple endocrine neoplasia type II syndrome. No family member had a medullary thyroid carcinoma.

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