World J. Surg. 18, 577-582, 1994
0
WORLD Journal of
SURGERY 9 1994 by the Soci~t~ Internationale de Chirurgie
Presymptomatic Screening for Medullary Thyroid Carcinoma in Patients with Multiple Endocrine Neoplasia Type 2A Andrea Frilling, M.D., 1 Hans-Dietrich R6her, M.D., 2 Bruce A n t h o n y John Ponder, Ph.D. 3 1Department of Surgery, University of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany 2Department of Surgery, Heinrich-Heine-Universit~it, Moorenstrasse 5, 40225 Diisseldorf, Germany 3CRC Human Cancer Genetics Research Group, Department of Pathology, University of Cambridge, Cambridge, U.K. Abstract: Presymptomatic screening of medullary thyroid carcinoma in MEN IIA families enables the early diagnosis of this tumor with its significant morbidity. Biochemical screening consists of basal and stimulated serum calcitonin evaluation. Genetic screening is based on DNA analysis using linked DNA markers. Thyroidectomy at an occult tumor stage may be curative. Calcitonin measurement was carried out in 58 apparently unaffected family members at risk and 11 MEN IIA patients. Calcitonin elevation was detected in nine individuals. All nine underwent thyroidectomy. Histologic examination confirmed medullary thyroid carcinoma in eight patients and in one case C cell hyperplasia. Postoperatively, eight patients (89%) are clinically and biochemically tumor-free (mean follow-up 30 months). DNA screening results in one affected family are presented. DNA analysis allowed recognition of one apparently unaffected individual at risk as a MEN IIA gene carrier. One family member at risk was found not to carry the gene and may be excluded from further screening.
Medullary thyroid carcinoma (MTC) may occur either as a sporadic tumor or as a disease inherited in an autosomal dominant pattern with incomplete penetrance. The hereditary tumor is a component of three familial syndromes: multiple endocrine neoplasia type IIA (MEN IIA), MEN liB, and familial medullary thyroid carcinoma (MTC only). MEN II consists of an inconstant association of MTC, pheochromocytoma, and hyperplasia of the parathyroid glands. Additional phenotypic signs of MEN liB are mucosal neuromas, ganglioneuromatosis, and marfanoid habitus. Morbidity and mortality for patients suffering from MTC depends mainly on lymph node metastases. Sporadic MTC is usually diagnosed at an advanced stage and is characterized by cervical and mediastinal lymph node metastases in more than 50% of patients [1]. With familial disease screening enables the diagnosis of a occult tumor stage and enables potentially curative surgical treatment [2]. Evaluation of basal and stimulated serum calcitonin has gained widespread acceptance as a screening method in affected families. In 1987 Mathew et al. [3] and Simpson et al. [4] mapped the MEN IIA gene to the pericentromeric region of chromosome 10 by linkage to the retinol-binding protein gene (RBP3). Since Correspondence to: H-D. R6her, M.D.
then, numerous closely linked DNA markers for MEN IIA gene have been found, and genetic screening of MEN IIA families has shown promise. In comparison to calcitonin screening, which must be carried out yearly in all family members at risk, genetic screening offers an obvious advantage, as DNA testing need be performed only once. A negative result may allow biochemical screening to be abandoned. This study reports the experience of presymptomatic screening in patients with hereditary medullary thyroid carcinoma. Materials and Methods
From April 1986 to December 1991, 50 patients were operated on for MTC in the Department of Surgery, University Dtissseldoff. A sporadic tumor was found in 30 patients (60%) and in 20 patients (40%) the tumor was found to be familial and was still in an occult stage in 9 patients. The MEN IIA syndrome was present in 17 patients from 11 families and MEN IIB in 2. One further patient belonged to a family with an unusual MEN syndrome consisting of MTC, pheochromocytoma, and Hirschsprung's disease. Four persons were index cases of unrecognized MEN families. In the 11 families studied, calcitonin screening was performed in 58 relatives. In addition, DNA linkage analysis to predict gene carrier status was carried out in five kindreds. Biochemical Screening Serum calcitonin assays were performed using the commercially available radioimmunoassay Testkit RIA-mat Calcitonin (Byk-Sangtec Diagnostika, Dietzenbach). Calcitonin was measured before and 2, 5, 7, 10, and 15 minutes after an intravenous bolus injection of pentagastrin (0.5 /xg/kg body weight). The normal range for basal calcitonin was below 100 pg/ml and after stimulation below 300 pg/ml. Screening for pheochromocytoma and hyperparathyroidism included evaluation of serum calcium; parathyroid hormone; urinary catecholamine excretion; and specific imaging tech-
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World J. Surg. Vol. 18, No. 4, July/Aug. 1994
Table 1. Preoperative and postoperative basal and pentagastrin-stimulated calcitonin and CEA values.
Preoperative Age (years) 29 38 13 27 28 21 50 25 16
Postoperative
Calcitonin (pg/ml) Basal
Stim.
CEA (ng/ml)
171 304 120 76 154 181 706 136 186
817 1024 1320 865 518 8022 -1000 934
2.2 12.1 19.0 7.3 1.2 10.6 20.6 26.5 13.5
Calcitonin (pg/ml) Basal
Stim.
CEA (ng/ml)
TNM tumor stage
68 73 90 45 55 38 80 25 21
90 101 100 62 154 64 -86 29
2.4 2.4 0.7 0.8 3.2 1.1 2.8 4.0 1.0
TlbNOM0 TlbNOM0 TlbNOM0 C cell hyperplasia TlbNOM0 TlbNOM0 TlbN1M0 TlbNOM0 TlbNOM0
Stim.: pentagastrin-stimulated. Measurements were carried out 4 to 6 weeks postoperatively.
niques (ultrasonography, computed tomography, metaiodobenzyl-guanidine scintigraphy) and complemented the calcitonin studies. Thyroidectomy, including central lymph node dissection, was carried out when elevated calcitonin levels were found twice over a 4- to 6-week interval. Tumor diagnosis was confirmed by histology and immunohistochemistry. Basal and stimulated calcitonin testing was performed 4 weeks after the operation, and the patients were examined every 6 months for 2 years and annually thereafter. The follow-up program included carcinoembryonic antigen (CEA) measurement.
Genetic Screening The technique of genetic linkage in MEN IIA families is based on segregation of a D N A marker closely linked to the MEN II region on chromosome 10 with the disease in several members of a family. Highly polymorphic D N A markers are able to distinguish between each of the two no. 10 chromosomes of the affected person (restriction fragment length polymorphism). In informative families typing with D N A markers enables the prediction of gene carrier status of unaffected individuals. D N A must be available from at least two relatives proved to be affected. In short, after extraction from 10 ml EDTA blood, 5 /xg samples of genomic D N A were digested with appropriate restriction endonuclease. The D N A fragments were separated by agarose gel electrophoresis, transferred onto a nylon membrane, and hybridized overnight with 32p-labeled probes. After washing, the filters were exposed on x-ray film at -70~ for autoradiography in order to visualize the D N A bands [3-6]. Results
Biochemical Screening In 9 of 58 (16%) tested family members at risk calcitonin was elevated, and in 7 of the 9 (78%) the CEA levels were also abnormally high. Normal basal and elevated stimulated calcitonin levels were found in seven cases (Table 1). There were three men and six women aged 13 to 50 years (mean age 27 years) in the group.
Table 2. Results of preoperative scintigraphy with 99mTc(V)DMSA and of sonography.
MEN manifestation MTC MTC Bilateral pheochromocytoma MTC C cell hyperplasia MTC HPT Bilateral pheochromocytoma MTC MTC Bilateral pheochromocytoma MTC MTC
Preop. thyroid scintigraphy
MTC diameter~ Sonography
-Normal
Normal Pathology
4.0 1.5
----
Pathology Normal Normal
4.0 -6.0
-Normal
Pathology Pathology
5.0 8.0
Normal --
Pathology Normal
15.0 4.0
(mm)
aThe tumor diameter is related to the largest nodule.
None of the patients had palpable thyroid nodules. Ultrasonography showed normal thyroid glands in four patients. The three patients in whom 99mTc(V)DMSA scintigraphy was performed had no abnormality (Table 2). Adrenal and parathyroid screening revealed pathologic results in three persons at risk, all of whom also had calcitonin elevations. In one patient bilateral adrenalectomy and parathyroid surgery had been performed several years prior to the calcitonin screening (Table 2). All nine patients were subjected to a thyroidectomy and central lymph node dissection. One patient required lymphadenectomy in both lateral cervical compartments due to five proved lymph node metastases within the central compartment. In the three patients with adrenal and parathyroid abnormalities, adrenalectomy and subtotal parathyroidectomy were performed in addition to thyroid surgery. Histologic examination and immunohistochemical staining for calcitonin and C E A revealed bilateral multicentric medullary carcinoma in eight patients, and in one patient C cell hyperplasia was found. Cervical lymph node metastases were detected in one patient. Comparison of preoperative calcitonin
Frilling et al.: Medullary Thyroid Cancer Screening
579
Table 3. Follow-up of 41 of 50 patients with MTC operated on from April 1986 to December 1991.
Tumor-free MTC form
No. of patients
Sporadic One operation Two operations Familial One operation
23 11 12 18 9" 1b 8
Two operations
Occult MTC
MTC
No.
%
No.
%
5 2
45 17
5 4
45 33
8 0 0
89 ---
0 1 4
-100 50
Died
No.
%
No.
% 9 42
8
11 25
25
aTumor was diagnosed by screening. blndex case of a new MEN IIA family. MTC was detected in this patient at age 77.
1
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2
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10. 1
3
4
5
6
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1
o~
O-,OO.o,oo
-- _ ~176
1 Oo "Ool o o o . , o , o o , , o o
III 2-2
2"2
2"2
1-2
1- 1
ool
, 10
Fig. 1. DNA analysis in family S, showing transmission of alleles 1 and 2 distinguished by probe pret9.1T3-1 with restriction endonuclease TaqI [5, 20]. White symbols indicate clinically unaffected family members; black symbols indicate the affected ones.
values with the tumor stage showed the lowest calcitonin levels in the patient with C cell hyperplasia, and highest calcitonin levels appeared in the patient with lymph node metastases (Table 1). Two patients had transient recurrent laryngeal nerve paralysis, and in one patient hypocalcemia occurred postoperatively. Later all three patients were free of symptoms. After the operation all patients had normal calcitonin test results (Table 1). In one patient only the basal calcitonin level was measured. During the follow-up, calcitonin values remained normal in 8 patients (89%). In one patient after 2 years reoperation was necessary because of elevated calcitonin and calcium levels. Jugular lymph node metastases and parathyroid hyperplasia were found at operation.
Genetic Screening As an example of genetic screening the results are shown for family S (Fig. 1). This family consists of three generations. The grandmother died of medullary thyroid carcinoma. The grandfather and one of the grandchildren refused to be screened. The alleles recognized by the D N A marker used are 1 and 2. Siblings II-1, II-3, and 1I-5 are 1-2 heterozygous. II-1 and 11-3 are proved to be affected. The affected children III-1 and 111-4 are 2-2 homozygous. One of their two alleles, which must be linked to the M E N I I A gene, was inherited by their affected fathers, who are both heterozygous. The still unaffected 2-2 homozygous child (1II-2) is at high risk of being a gene carrier. His calcitonin testing at age 23 was negative. The unaffected child (III-6), whose genotype is 1-1 homozygous, has a minimal risk (< 1%).
! 20
oo,..o,
o, o.ooo.eloo~176
i
i
i
i
I
30
40
50
60
?D
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Fig. 2. Probability (%) that the offspring of an affected individual is a gene carrier, according to age and clinical history, pentagastrin-stimulated calcitonin, or DNA screening being negative. From top to bottom: Line 1, clinical history; line 2, pentagastrin-stimulated calcitonin; line 3, DNA test (single DNA marker) and calcitonin screening; line 4, DNA test (two DNA markers) and calcitonin screening.
No prediction of gene carrier status can be made in his 1-2 heterozygous brother (III-5) because their unaffected father is 1-2 heterozygous, and it is not known whether he inherited his allele 2 from his unaffected father or his affected mother. This problem can probably be solved by using further D N A markers. Discussion
The proved value of prospective screening for medullary thyroid carcinoma has been established in several M E N families [2, 7-9]. In their fundamental study on J kindred, Melvin et al. [10] detected 12 family members at risk with pathologic calcitonin values after stimulation with calcium infusion. Thyroidectomy proved C cell carcinoma in all 12 individuals, of whom 10 had occult tumors. Follow-up results of the family emphasized the importance of surgical treatment during the preclinical tumor stage [7]. Six patients remained tumor-free 14.5 years after operation. Two patients were thought to have micrometastases because of elevated calcitonin levels after stimulation; and in one patient liver metastases were diagnosed. Three patients died of unrelated diseases (Table 3). Telenius-Berg et al. [11] tested 105 family members of 12 MEN IIA families and recognized 48 occult medullary thyroid carcinomas and three borderline cases that were classified as C cell hyperplasia. Of the patients with occult carcinoma, 68% were cured by thyroidectomy, whereas curative treatment was possible in only 19% of the patients with manifest disease.
580
In the series of Brunt and Wells [12], lymph node metastases were found in only 9% of the patients with normal basal and elevated stimulated calcitonin levels. If there was elevation of basal calcitonin or a palpable tumor, the incidence of lymph node metastases rose to 50% and 71%, respectively. The results of our study confirm the importance of prospective screening to the early diagnosis of MTC. We were able to diagnose 9 of 58 (16%) family members at risk as being affected. In 89%, early thyroidectomy was curative (mean follow-up 30 months), whereas in our experience curative treatment was possible in only 45% of patients with sporadic medullary thyroid carcinoma who presented clinically at the time of surgery and in none of eight MEN IIA patients. Calcitonin provides an excellent highly specific tumor marker superior to all imaging techniques. In three of our eight patients (38%) ultrasonography of the thyroid revealed no pathologic abnormalities despite tumor nodules 4 to 6 mm in diameter. None of the patients had scintigraphic evidence of disease (Table 2). These results indicate that thyroidectomy should be performed when calcitonin levels are elevated despite normal sonographic and scintigraphic findings. Calcitonin screening should be considered for every patient diagnosed to have apparently sporadic MTC. In 10% to 15% these patients are index cases of unrecognized MEN families [13]. In their series of 39 MTC patients presenting without a family history, Ponder et al. [14] detected four MEN families with seven more affected individuals by screening 134 family members. Criteria indicating heredity are age below 45 years and histologic proof of tumor multicentricity or C cell hyperplasia [13]. There has been considerable controversy concerning the age at which to start calcitonin screening. The evidence suggests that screening should begin by the age of 3 to 5 years or even earlier in high risk families [15]. The screening should then proceed on an annual basis until age 35 or until a positive test result can be confirmed. The likelihood of conversion to a positive test after 35 years is less than 5%. Despite sensitive two-site immunoradiometric assays for intact calcitonin, it may be difficult to interpret screening results correctly [16]. Thyroidectomy should be carried out when the stimulated calcitonin level exceeds the normal range of the assay and is reproducible on two independent tests. In borderline cases evaluation of PDN-21 (katacalcin), which is cosecreted with calcitonin, may be helpful for confirming the diagnosis [17, 18]. A cause of "false positive" thyroidectomy can also be C cell hyperplasia, which occurs as a normal variation in children or in the elderly population [9, 19]. A consensus view is that for the occult tumor stage meticulous thyroidectomy and lymphadenectomy in the central cervical compartment are adequate surgical procedures. In cases of proved central lymph node metastases, anatomic microdissection with removal of fat and lymphatic tissue in the lateral cervical and mediastinal compartments must be performed to restore the plasma calcitonin to normal [1]. Because M E N IIA is an autosomal dominant trait each child of an affected parent has a 50% risk of inheriting the disease. Genetic screening allows recognition of gene carriers by D N A analysis of a single blood sample from individuals at risk. Biochemical screening can then be focused on apparently unaffected gene carriers and reduced or even omitted in those
World J. Surg. Vol. 18, No. 4, July/Aug. 1994
who have not inherited the gene [3, 6]. With an ideal family structure the accuracy of the prediction is better than 95%. No prediction can be made as to when the disease will present clinically and how aggressive it will be. Factors that influence the accuracy of prediction are family structure, the possibility of recombination between the D N A marker and the gene, nonpaternity, accuracy of carcinoma diagnosis, and mixing up of blood samples [20]. At the present time genetic and biochemical screening should be used in combination so as to achieve the greatest accuracy [13, 18]. A negative calcitonin test in a family member who was typed as a gene carrier by D N A analysis raises the question of whether prophylactic thyroidectomy should be performed. Because of incomplete gene penetrance, the low but not negligible morbidity associated with thyroidectomy and the possibility of a false-positive D N A test, prophylactic thyroid removal may be indicated in families who display an aggressive course of the disease. In all others, a positive genetic screening result indicates the need for more frequent calcitonin tests and thyroidectomy as soon as a biochemical abnormality is detected (Figure 2). Further improvement of genetic screening has been achieved by identification of the MEN IIA gene as the RET protooncogene. In MEN IIA patients RET mutations involve one of the cysteines in the extracellular domain [21]. In future, D N A testing will not require samples from two or more affected individuals; and in the case of apparently sporadic tumor the diagnosis of heritable disease may be possible without having to perform family screening. R6sum6
Le d6pistage du cancer m6dullaire de la thyroide avant l'apparition des sympt6mes dans les familles M E N 2A facilite le diagnostic de cette maladie accompagnde d'une morbidit6 non n6gligeable. Le ddpistage biochimique consiste en une 6valuation de la calcitonine basale et stimul~e. Le d6pistage g6ndtique comporte une analyse de I ' A D N qui utilise des marqueurs sp6cifiques des liaisons d ' A D N . La thyroidectomie a des chances d'etre curative au stade de tumeur occulte. La calcitonine a pu ~tre mesur6e chez 58 membres d'une famille atteinte mais sans sympt6mes et chez 11 patients MEN 2A. La calcitonine 6tait 61ev6e chez 9. Tous ces patients ont eu une thyroideetomie et un cancer m6dullaire a 6t6 retrouv6 chez 8 et une hyperplasie des cellules C chez le neuvi6me. Postop~rativement, 8 patients (89%) sont sans tumeur clinique et biologique (suivi moyen: 30 mois). Les r6sultats du d6pistage par I ' A D N chez une famille atteinte sont pr~sent6s e t a permis d'identifier un seut membre apparemment non symptomatique qui 6talt risque de porter le gSne M E N 2A. On a d6termin6 6galement qu'un membre n'~tait pas porteur du g~ne: il peut ~tre exclu de tout examen de d~pistage ult6rieur. Resumen
E1 tamizaje presintom~itico del carcinoma medular de la gl~indula tiroides en familias con sindrome N E M 2A hace posible el diagn6stico precoz de este tumor, el cual en forma caracterfstica se asocia con significativa morbilidad. E1 tamizaje bioquimico eonsiste en la determinaci6n de los niveles calcitonina s6rica basal y estimulada. E1 tamizaje gen6tico se basa en el
Frilling et al.: Medullary Thyroid Cancer Screening
an~ilisis de ADN utilizando marcadores ligados al ADN. La tiroidectomia que se realiza cuando el tumor es todavfa clinicamente oculto puede ser curativa. La determinaci6n de calcitonina fue realizada en 58 familiares aparentemente no afectados pero de reconocido riesgo y e n 11 pacientes con sfndrome NEN 2A; se detect6 calcitonina elevada en 9 individuos, y todos los nueve fueron sometidos a tiroidectomia. E1 examen histol6gico confirm6 carcinoma medular en 8 e hiperplasia de c61ulas C en 1. Postoperatoriamente 8 pacientes (89%) se hallan clfnica y bioquimicamente libres de tumor (promedio del seguimiento, 30 meses). Se presentan los resultados del tamizaje de ADN en una familia afectada. E1 amilisis de ADN permiti6 el reconocimiento de un individuo aparentemente no afectado pero de riesgo como portador del gen NEM 2A. Un familiar con riesgo fue marcado como no portador del gen y puede ser exclufdo de tamizajes ulteriores.
References 1. Dralle, H., Scheumann, G.F.W., Hundeshagen, H., Massman, J., Pichlmayr, R.: Die transsternale zervikomediastinale Prim~irtumorresektion und Lymphadenektomie beim Schilddrtisenkarzinom. Langenbecks Arch. Chir. 377:34, 1992 2. Vasen, H.F.A., Nieuwenhuijzen, A.C., Berkel, H., et al.: Multiple endocrine neoplasia syndrome type 2: the value of screening and central registration; a study of 15 kindreds in The Netherlands. Am. J. Med. 83:847, 1987 3. Mathew, C.G.P., Chin, K.S., Easton, D.F., et al.: A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature 328:527, 1987 4. Simpson, N.E., Kidd, K.K., Goodfellow, P.J., et al.: Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 328:528, 1987 5. Mathew, C.G.P., Easton, D.F., Nakamura, Y., Ponder, B.A.J., and the MEN 2A International Collaborative Group: Presymptomatic screening for multiple endocrine neoplasia type 2A with linked DNA markers. Lancet 337:7, 1991 6. Sobol, H., Narod, S.A., Nakamura, Y., et al.: Screening for multiple endocrine neoplasia type 2A with DNA-polymorphism analysis. N. Engl. J. Med. 321:996, 1989 7. Gagel, R.F., Tashjian, A.H., Jr., Cummings, T., et al.: The clinical
Invited Commentary M a l c o l m H. W h e e l e r , M . D . Department of Surgery, University Hospital of Wales, Cardiff, U.K.
Because medullary thyroid carcinoma (MTC) is derived from the C-cell, it possesses the biochemical tumor marker calcitonin, the measurement of which can be employed to detect the earliest stages of the disease. This is particularly relevant in the multiple endocrine neoplasia (MEN IIA and IIb) syndromes which are inherited in autosomal dominant manner. Gene carriers are at high risk of developing MTC and it is incumbent upon the clinician to screen family members considered to be at risk. Biochemical screening employing basal and stimulated serum
581 outcome of prospective screening for multiple endocrine neoplasia type 2a: an 18-year experience. N. Engl. J. Med. 318:478, 1988 8. Graze, K., Spiler, I.J., Tashjian, A.H., Jr., et al.: Natural history of familial medullary thyroid carcinoma: effect of a program for early diagnosis. N. Engl. J. Med. 299:980, 1979 9. Simpson, W.J., Carruthers, J.S., Malkin, D.: Results of a screening program for C-cell disease (medullary thyroid cancer and C-cell hyperplasia). Cancer 65:1570, 1990 10. Melvin, K.E.W., Miller, H.H., Tashjian, A.H., Jr.: Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N. Engl. J. Med. 285:1115, 1971 11. Telenius-Berg, M., Berg, B., Hamberger, B., et al.: Impact of screening on prognosis in the multiple endocrine neoplasia type 2 syndromes: natural history and treatment results in 105 patients. Henry Ford Hosp. Med. J. 4:225, 1984 12. Brunt, L.M., Wells, S.A., Jr.: Advances in the diagnosis and treatment of medullary thyroid carcinoma. Surg. Clin. North Am. 67:263, 1987 13. Ponder, B.A.J., Coffey, C., Gagel, R.F., et al.: Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 1:397, 1988 14. Ponder, B.A.J., Finer, N., Coffey, R., et al.: Family screening in medullary thyroid carcinoma presenting without a family history. Q. J. Med. 252:299, 1988 15. Telander, R.T., Zimmerman, D., Sizemore, G.W., van Heerden, J.A., Grant, C.S.: Medullary carcinoma in children: results of early detection and surgery. Arch. Surg. 124:841, 1989 16. Weissel, M., Kainz, H., Tyl, E., Ogunyemi, E., Woloszczuk, W.: Clinical evaluation of new assay for determination of serum calcitonin concentrations. Acta Endocrinol. (Copenh.) 124:540, 1991 17. Raue, F., Boden, M., Girgis, S., Rix, E., Ziegler, R.: Katacalcin--a new tumor marker in C-cell cancer of the thyroid gland. Klin. Wochenschr. 65:82, 1987 18. Calmettes, C., Ponder, B.A.J., Fischer, J.A., Raue, F., members of the European Community Concerted Action: Medullary thyroid carcinoma. Eur. J. Clin. Invest. 22:755, 1992 19. Lips, C.J.M., Leo, L.R., Berends, M.J.H., et al.: Thyroid C-cell hyperplasia and micronodules in close relatives of MEN-2A patients: pitfalls in early diagnosis and reevaluation of criteria for surgery. Henry Ford Hosp. Med. J. 35:133, 1987 20. Telenius, H., Mathew, C.G.P., Nakamura, Y., et al.: Application of linked DNA markers to screening families with multiple endocrine neoplasia type 2A. Eur. J. Surg. Oncol. 16:134, 1990 21. Mulligan, L.M., Kwok, J.B.J., Healey, C.S., et al.: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458, 1993
calcitonin measurements has traditionally been based on the belief that: 1. C-cell hyperplasia will develop into clinical cancer 2. Screening will permit early diagnosis 3. Early diagnosis should improve the results of surgery and lead to a better prognosis [1] In the present, carefully conducted study of MEN IIA families, Frilling and colleagues have beautifully demonstrated the ability of calcitonin measurement in 58 apparently unaffected family members at risk to identify 9 patients requiring surgery. None of the patients had palpable thyroid nodules and, indeed, in one patient, the disease was at the extremely early C-cell hyperplasia stage. Eight patients were rendered clinically and biochemically free of disease at mean follow up of 30 months. One patient, after two years, underwent further surgery and excision of cervical lymph node metastases. These