Total thyroidectomy for occult familial medullary carcinoma of the thyroid in children

Total Thyroidectomy for Occult Familial Medullary Carcinoma of the Thyroid in Children By Lucian L. Leape, Harry

H. Miller,

Kathleen Graze,

Robert F. Gagel, Hubert J. Wolfe, Armen H. Tashjian,

Zoila Torres

Feldman,

Ronald A. Delellis,

Jr., and Seymour

Reichlin

T

HE RELUCTANCE of physicians to refer patients for thyroid surgery is due in large part to the risk of complications, particularly injury to the recurrent laryngeal nerve and hypoparathyroidism. Total thyroidectomy increases the risk of these complications significantly. The rate of inadvertent section (as opposed to deliberate sacrifice in an attempted curative cancer operation) of the recurrent nerve varies from 5% to 10% in previously reported series of total thyroidectomies in adults and children.i-9 Permanent hypoparathyroidism is more disabling, and unfortunately more common, averaging 20% in reported series of total thyroidectomies.‘-‘O Lack of evidence that total thyroidectomy significantly improves the cure rate in papillary and follicular carcinoma has led various surgeons to advise strongly against total thyroidectomy in children.5~7~” Familial medullary carcinoma of the thyroid (MTC) appears to be an exception to this prohibition. The tumor is multicentric in origin, arising from C cells which are diffusely spread throughout the thyroid gland.‘* Only total thyroidectomy will reliably remove al1 of the C cells. The development of a sensitive means of detection of MTC in the high risk patients and its regular application by periodic screening tests has resulted in diagnosis at an early age so that most patients now undergoing thyroidectomy are children. We hereby report our experience with total thyroidectomy in 17 children with early disease. A complete summary of the clinical studies and of the methods used will be published separately.13 MEDULLARY

CARCINOMA

OF

THE

THYROID

GLAND

Medullary carcinoma of the thyroid was first recognized as a distinct entity in 1959.14 It accounts for approximately 10% of thyroid malignancies in adults and has a number of unusual characteristics. It occurs sporadically and in families where it is associated with pheochromocytoma and hyperparathyroidism (multiple endocrine neoplasia, type II). ‘5~‘6Both sporadic and familial forms of MTC secrete calcitonin (CT) as measured by radioimmunoassay.15 The tumor is bilateral in familial cases and tends to occur at the junction of the upper and middle thirds of each lobe. Tumors may be multifocal, and miFrom the Departments of Surgery, Medicine, and Pathology, New England Medical Center Hospital and Tufts University School of Medicine, the Laboratory of Pharmacology, Harvard School of Dental Medicine. and the Department of Pharmacolog_v, Harvard Medical School, Boston. Mass. Presented before the 7th Annual Meeting of the American Pediatric Surgical Association. Boca Raton, Fla.. April29-Ma-v 1, 1976. Supported in part by the following grants: USPHS, NIH RROOS4-14 (NEMCH), American Cancer Society PDT-24B (NEMCH). NIH AM10206 (Harvard School of Dental Medicine). Address for reprini requests: Lucian L. Leape, M.D., 171 Harrison Avenue, Boston, Mass. 021 Il. ‘EI976 by Grune &iStratton, Inc. Journal of Pediatric Surgery, Vol. 11, No. 5 (October), 1976

831

832

LEAPE ET Al.

croscopic foci of the tumor or hyperplastic C cells may occur throughout the thyroid gland. The tumor is not responsive to suppression with exogenous thyroid hormone. MTC arises from C cells normally present within the thyroid gland. Both MTC and normal C cells synthesize, store, and secrete the polypeptide hormone, calcitonin (CT). These cells are derived embryologically from the primitive neural crest. The tumors sometimes also secrete other substances: ACTH, histaminase, prostaglandins, and serotonin.‘5 CLINICAL

DETECTION

The secretion of CT, a consistent feature of MTC, makes possible the preclinical diagnosis of MTC by assay of increased levels of CT in the plasma and urine. Radioimmunoassays have been developed for this purpose. Elevated plasma levels of CT may be the only indication of disease and are detectable even when the tumor is otherwise clinically occult.” In normal individuals, basal plasma CT levels are less than 0.38 ng/ml. Patients with clinically apparent MTC have basal plasma CT levels of 1.O ng/ml or greater. The secretion of CT is markedly increased by calcium and pentagastrin which are used for provocative testing by intravenous administration. Use of provocative testing greatly enhances the sensitivity of detection of abnormal CT production. Maximum plasma levels of CT after stimulation do not exceed 0.55 ng/ml in normal persons. In patients with MTC, poststimulation CT values are over 0.55 ng/ml and values as high as 2200 ng/ml have been obtained.15 Patients with early MTC or C-cell hyperplasia (CCH), the premalignant precursor basal levels of CT but show excessive release with provocative tests.”

of MTC,

may have

normal

The ’ ‘J” Kindred The patients in this series belong to the “J” kindred which has been followed in this study since 1969. The first member of the family to enter the study was a 29-yr-old man who sought advice because of the occurrence of thyroid cancer in his sister, first cousin, uncle, and aunt. Although he was found to be free of disease, review of surgical and autopsy records and tissue sections of the tumors from these relatives as well as several others who had died established the diagnosis of medullary carcinoma of the thyroid in all of these individuals. Subsequently, other members of the family were studied by means of provocative testing and CT assay. Twelve patients were initially found to have elevated CT levels by provocative tests. Only one had an enlarged thyroid gland. In the remainder the gland was entirely normal to palpation and radioisotope scanning. The diagnosis of MTC was confirmed microscopically at the time of total thyroidectomy in all 12 of these individuals. Subsequently, annual screening of all members of the kindred has been carried out with repeated testing at 6-mo intervals in any individual in whom values were borderline.

Medullary Carcinoma of the Thyroid Gland in Children Since 1970, annual screening has been carried out on all members of generation IV of the “J” kindred over the age of 4 yr. A standard calcium infusion test with calcium gluconate (15 mg In recent years injection of pentagastrin (0.5 rg/kg i.v. calcium/kg in 4 hr) has been used.” over 30-60 set) has also been used as a provocative secretagogue.*’ Pentagastrin has been reported to be a more effective stimulant of CT secretion than calcium,2’ but we have noted several false negative responses to pentagastrin injection when calcium infusion in the same case clearly identified an abnormal response.22 Accordingly, both are used routinely, and elevated CT levels after either are accepted as a positive test. A series of typical responses of CT to provocative testing is shown in Fig. 1. All patients in whom CT values were elevated above 0.55 ng/ml after two separate provocative tests at least 6 mo apart have undergone total thyroidectomy. Meticulous dissections have been carried out to preserve the recurrent laryngeal nerves and at least two parathyroid glands. The recurrent nerves must be dissected out in their entirely early in the procedure, before the thy-

833

THYROIDECTOMY

E p

2.0

r

z z

Thyroidectomy J

? 3 s

LO#i; / o‘Norma, .................................................................................. ..._....._...................................... after / Calcium e-Y-4

H 1 % O

1970

1971

1972

1973

311974

111975

UN1974

Fig. 1. Serum calcitonin values before and after stimulation by calcium infusion in a typical case of CCH. Normal responses are noted in 1970-1973. In 1974, provocative testing resulted in the first abnormal elevation of calcitonin in this patient. After confkmation by repeat testing 7 mo later, total thyroidectomy was performed. Postoperative stimulation testing in 1975 revealed normal calcitonin values. (Reprinted with permission of the publisher, William J. Dornan, Inc., from The Transactions of the Association of American Physicians, Volume 88, 1975.)

roid is mobilized.

The “no

touch”

into the pharyngeal constrictors. Similarly. meticulous, atraumatic

technique

is used,

identification

freeing

the nerves

of the parathyroid

to their

glands

point

is essential.

of entry Unrec-

ognized removal of the parathyroids and operative trauma with loss of the blood supply to the glands are the most common causes of hypoparathyroidism following thyroidectomy. Since the blood supply enters posteriorly from branches of the inferior thyroid artery, the superior parathyroid glands may usually be safely mobilized by taking them with the local portion of the thyroid capsule, preserving the blood supply and capsule as a “mesentery.” Identification of at least two parathyroid glands must be verified by frozen section biopsy. Removal of the entire thyroid gland and dissection of the central lymph nodes between the carotid sheaths down to the superior mediastinum that can be reached from the neck above the innominate artery has been carried out. The excised thyroid glands have been studied in detail with mapping of C-cell populations by immunocytochemical and ultrastructural localization of calcitonin.”

RESULTS On initial survey all patients in generation IV had normal CT levels. The first patient in this generation to develop an abnormal elevation of CT did so in 1973 at the age of 18. As of April 1, 1976, a total of 17 patients in this generation have developed abnormal CT values after provocative testing, confirmed by repeat tests. All have undergone total thyroidectomy. Ages at the time of operation ranged from 8 to 18 yr (Table 1). No patient had any symptoms attributable to MTC and none had palpable thyroid nodules. At operation the thyroid glands were normal to examination in most patients although in several, small nodules could be palpated. None had tumor metastasis in regional lymph nodes grossly or microscopically by pathologic examination. In only one patient (C.G.) has a pheochrocytoma been diagnosed. This was symptomatic, causing headaches and nervousness, and was accompanied by a rise in urinary epinephrine and norepinephrine levels at the time of screening. She underwent unilateral adrenalectomy 3 mo prior to thyroidectomy and has since remained free of symptoms. (All patients undergo annual screening for elevated urinary catecholomines in addition to the CT-provocative testing.) It remains to be determined whether any patient will develop pheochromocytoma after total thyroidectomy.

LEAPE

834

Table 1. Medullary

Carcinoma of the

Patient

in Children

Date of

1st

1st. Pos.

Age at

Pathologic

CT Test

CT Test

ODeration

Findinas

SD

7/70

l/73

18

122

MJ

3/70

3/73

8

CCH

732

KJ

4170

4/74

11

MTC

111

CG

5/70

6/74

12

MTC

433

CF

4/70

7174

17

CCH

722

LR

7/73

7/74

8

CCH

721

BR

8/70

1 o/74

11

CCH

152

EJ

2170

12/74

16

MTC

151

KJ

2170

12/74

17

CCH

153

CJ

2/70

12/74

15

MTC

ccl-l

331

JS

7/70

l/75

13

MTC

332

ES

7/70

l/75

9

CCH

521

RH

4170

l/75

13

MTC

551

DJ

6/70

l/75

14

Normal

713

DP

8170

3/75

17

CCH

131

DT

2/70

6/75

12

MTC

611

PJ

6/70

7/75

14

MTC

Pathologic

calcitonin

findings of the thyroid

values

ranged

in the thyroid

tration

Thyroid

412

carcinoma

ings

of the

(maximbm

have undergone

had value

in

17 with

0.60

undergoing

evidence

of

intrathyroidal

1.4

ng/ml

ng/ml

modest, 0.76

children

but

ng/ml).

to

definite She

total

thyroidectomy. disease

preoperatively.

elevations is the sole

Al.

Kindred

Date of Kindred Number

“J”

ET

of false

CT

after

positive

only. The

MTC: CCH:

asymptomatic

medullary

hyperplasia.

Stimulated

C-cell

one patient

both

calcium

in 32

patients,

with and

no

pathologic

pentagastrin

adults

and

Rnd-

adminis-

children,

who

thyroidectomy.

Pathology

Examination of the resected glands showed early MTC in eight and CCH in eight. One patient had no pathologic findings in the thyroid gland. Neither the absolute levels of CT after calcium infusion or pentagastrin injection, nor the time course of its development distinguished completely the cases of very early MTC from CCH. Postoperative Course

Most patients had transient postoperative mild hypocalcemia which required supplemental oral calcium for several weeks. One patient had prolonged mild hypoparathyroidism which temporarily required vitamin D administration. All patients have received thyroid replacement therapy. In no patient was there injury to the recurrent laryngeal nerve. Six patients have had low but measurable levels of CT in the plasma postoperatively. These patients are being followed carefully for other signs of occult or recurrent MTC. All patients are retested at least annually. DISCUSSION

The development of radioimmunoassay methods for calcitonin and recognition of increased calcitonin secretion in early C-cell disease are of clinical significance for it is now possible to diagnose familial MTC in the preclinical stage

835

THYROIDECTOMY

(before there are any signs or symptoms). Furthermore, patients may be identified in whom the disease is preinvasive, i.e., CCH. Clearly, the hope is that all of these young patients have been cured by resection of early tumor and hyperplastic cells before metastatic spread. Only careful, long-term follow-up will tell if that hope is justified. The discovery of bilateral medullary carcinoma of the thyroid in any patient should lead to careful screening of all members of the family by means of CTprovocative testing to determine whether the disease is of the familial type. Since the familial form of MTC follows a Mendelian-dominant genetic pattern, the risk of development of thyroid cancer in family members is high. We believe that patients with confirmed elevation of calcitonin after provocative tests should undergo total thyroidectomy in order to remove all tumor or premalignant tissue before it has become clinically apparent or has metastasized. With careful attention to technical details, the incidence of recurrent laryngeal nerve or parathyroid injury should be very low. In this series, transient, treatable hypoparathyroidism was the only complication encountered. Calcitonin provocative testing should also be carried out in all patients in whom the diagnosis of pheochromocytoma is made because of the frequent association of this tumor with MTC. In some patients it is the pheochromocytoma which is symptomatic first, although the patient may have a well-developed unrecognized MTC that is readily detectable on provocative testing. SUMMARY

Experience with 17 children in one kindred with familial medullary carcinoma of the thyroid and pheochromocytoma has demonstrated the utility and validity of periodic provocative testing by calcium infusion or pentagastrin injection in the identification of children with early medullary carcinoma of the thyroid or its premalignant precursor, C-cell hyperplasia. In these 17 patients with two consecutive elevations of calcitonin levels greater than 0.55 ng/ml after stimulation all but one have had MTC or CCH at operation. Total thyroidectomy has been well tolerated and can be performed with an acceptably low incidence of complications in this group of patients. REFERENCES

I. Buckwalter JA, Thomas CC, Freeman

JB: Is childhood thyroid cancer a lethal disease? Ann Surg 181:632. 1975 2. Crile G Jr: Carcinoma of the thyroid in children. Ann Surg 150:959, 1959 3. Harness JK, Thompson NW, Nishiyama RH: Childhood thyroid carcinoma. Arch Surg 102:278, 1971 4. Hayles AB, Kennedy RLJ. Beahrs OH, et al: Management of the child with thyroidal carcinoma JAMA 173: 105, 1960 5. Liechty RD, Safaie-Shirazi S, Soper RT: Carcinoma of the thyroid in children. Surg Gynecol Obstet 134:595. 1972 6. Perzik SL, Catz 9: The place of total

thyroidectomy in the management disease. Surgery 62:436. 1967 7. Pollock in children.

WF, Juler G: Thyroid Am J Dis Child

of thyroid carcinoma

105:243, 1963

8. Rustad WH, Lundsay S, Dailey ME: Comparison of the incidence of complications following total and subtotal thyroidectomy for thyroid carcinoma. Surg Gynecol Obstet 116: 109. 1963 9. Thompson NW, Harness JK: Complications of total thyroidectomy for carcinoma. Surg Gynecol Obstet 131:861, 1970 IO. Block MA, Miller JM. Horn RC: Minimiring hypoparathyroidism after extended thy-

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836

ET Al.

roid operations. Surg Gynecol Obstet 123:501, 1966 1I. Tawes RL, DeLorimier AA: Thyroid carcinoma during youth. J Pediatr Surg 3:210,

18. Wolfe HJ, Melvin KEW, Cervi-Skinner SJ, et al: C-cell hyperplasia preceding medullary thyroid carcinoma. N Engl J Med 289: 437, 1973

1968 12. Wolfe HJ, Voelkel EF, Tashjian AH Jr: Distribution of calcitonin containing cells in normal adult human thyroid gland. J Clin Endocrinol Metab 38:688, 1974 13. Graze K, Gage1 RF, Tashjian AH Jr,

19. Melvin KEW, Voelkel EF, Tashjian AH Jr: Medullary carcinoma of the thyroid: Stimulation by calcium and glucagon of calcitonin secretion, in Taylor S (ed): Calcitonin, 1969. London, Heinemann, 1970, pp 487-496

for publication) 14. Hazard JB, Hawk WA, Crile G Jr: Med-

et al: (submitted

ullary (solid) carcinoma of the thyroid-a copathologic entity. J Clin Endocrinol

20. Hennessey JF, Gray TK, Cooper CW, et al: Stimulation of thyrocalcitonin secretion by

cliniMetab

19:152, 1959 15. Melvin KEW, Tashjian AH Jr, Miller HH: Studies in familial (medullary) thyroid carcinoma. Ret Progr Horm Res 28:399, 1972 16. Melvin KEW, Tashjian AH Jr: The syndrome of excessive thyrocalcitonin produced by medullary carcinoma of the thyroid. Proc Natl Acad Sci USA 59:1216, 1968 17. 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 285:1115, 1971

pentagastrin and calcium in 2 patients with medullary carcinoma of the thyroid. J Clin Endocrinol Metab 36:200, 1973 21. 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 II. Ann Surg 182:362, 1975 22. Gage1 RF, Tashjian AH Jr, Melvin KEW, et al: Pentagastrin stimulation of calcitonin secretion in familial medullary thyroid carcinoma. Presented at the meeting of the Am Thyroid

Assoc, St. Louis,

1974

Discussion P. Exelby

(New

York);

Dr.

Leape’s

study

represents

another

landmark

in early

detection

of

cancer by biochemical markers. In an earlier paper your group reported that 60% of adults with familial MTC had metastatic disease in neck nodes. In this group of children all the cancers were small localized lesions. Was this due to early diagnosis? What is known of the natural histoty of C-cell hyperplasia? Total thyroidectomy seems at first to be radical treatment for C-cell’ &perplasia, but if it is a real premalignant condition, then we should all be doing radical excision. Did any of these children show a raised calcitonin response that returned to lower or normal levels without surgery? I also wondered if you had any information on what percentage of MTC patients we can expect to be familial, At Memorial Hospital, where 7 or 8 adults are treated yearly for MTC, it is extremely rare to find this disease in children. Our incidence of 2 in 20 yr is much less than we would expect from the volume of adult thyroid cancers. Should we be screening more family members and finding more occult lesions in our younger patients? K. Ashcraft (Kansas City): The genealogic tables showed almost all of the children with the disease had a parent who had a tumor. You mentioned one child whose parent had not had a tumor. Has this parent had a total thyroidectomy, and if so, have you resectioned the thyroid looking for a tumor? It would certainly simplify the screening of families if you could eliminate those generations whose parents had not had tumors. L. Leupe (closing): None of these children had positive lymph nodes. We do a central lymph node dissection and not an extended lateral dissection. Although 60% of the adults have had positive nodes, and some of them have metastatic disease, in the children in all cases the disease was intrathyroidal. The natural history of C-cell hyperplasia is one that has bothered us a great deal. Our conclusions about C-cell hyperplasia and its significance are based entirely on the type of material I’ve of tumor location with C-cell location and the fact that shown you . , . that is, the correlation there is increased calcitonin secretion in C-cell hyperplasia. One of the annoying things about this study is that there is no correlation at all between the degree of elevation of calcitonin af-

THYROIDECTOMY

837

ter provocative testing and whether the patient has C-cell hyperplasia or medullary carcinoma of the thyroid. In these children there is also no correlation with the time period from the first positive test to the operation. which wasn’t always just a few months. I don’t know what happens if you leave C-cell hyperplasia alone, and I expect we will never know, because it would be very difficult to make the diagnosis at the present time by anything short of total thyroidectomy. Sometimes the C-cell hyperplasia is localized to a very small area. and it is only discovered by serial sectioning of these glands. We have had no patients who had elevation of the calcitonin level on two separate testings We think probably

6 mo apart that later went down to normal. about 20% are familial, but a few kindreds

great deal. Apparently the familial ones are always always unilateral; so I think we can cut the screening

like ours are going

to skew this a

bilateral and the sporadic ones are almost down if we restrict it to the patients who

have bilateral disease. I would certainly measure their norepinephrine/epinephrine levels as well, however, because they might have a pheochromocytoma. With regard to the patients who had parents who did not have disease, all we know is that they have normal calcitonin, and therefore they have not been explored. The disturbing thing is that our one negative in this series came from a child whose parents did not have disease, and yet the child had an elevated calcitonin. At the present time we cannot say whether, if your parent does not have disease,

you are safe. I think you probably

are not.