Reoperation in metastasizing medullary thyroid carcinoma: Is a tumor stage-oriented approach justified?

Reoperation in metastasizing medullary thyroid carcinoma: Is a tumor stage-oriented approach justified? Oliver Gimm, MD, and Henning Dralle, MD, Hde/SaaZe, Germany

Background.

Lymph node metastases (LNM) are very often found in medullary thyroid carcinoma. After primary therapy, elevated levels of calcitonin are measurable in many patients. Because of the low sensitivity and specificity of diagnostic tools to detect micrometastases, the question remains whether an extended lymphadenectomy improves the chance of cure and whether this approach should be tumor stage oriented. Methods. We analyzed the results of 36 patients with medullary thyroid carcinoma consecutively reoperated from 1988 to 1996, performing microdissection of all four locoregional lymph node compartments. Results. Pathologic tumor stage (PT) category was classified as pT1, n = 3; PTZ, n = 22; pT3, n = 6; and pT4, n = 5. LNM were found in 34 patients (94 %). The cervicocentral compartment contained LNM in 85 %, the cervicolateral compartments in 41% to 54 %, and the upPer mediastinum in 36%. Patients with different pT category did not dijjf er in the rate of LNM. Ipsilateral cervicolateral LNM were found in 50% to 71% and contralateral cervicolateral LNM in 14 % to 40%. Nine (35%) of 26 patients without distant metastases were biochemically cured. In 10 patients (38 %) calcitonin level decreased more than 50 %. Conclusions. LNM were almost always (94 %) found in patients who have elevated calcitonin levels after primary therapy. In patients without distant metastases, four-compartment lymphadenectomy gives a chance of cure in 35%. A tumor stage-oriented approach does not seem to be justified. (Surgery 1997;122:1124-31.) From the Department of General Surgery, Martin-Luther-Univ~s~~

metastaMEDULLARY THYROID CARCINOMA (MTC) sizes very often (50% to 80%) to the locoregional influence of lymph nodes,lm3 and the prognostic lymph node metastases (LNM) in MTC is well accepted. 4a5 Because other therapeutic methods of are not very effective,68 surgery is the treatment choice. The recommended primary therapy consists of total thyroidectomy and at least lymphadenectomy of the cervicocentral compartment.2,3,g,10 However, the indication and extent of lymphadenectomy in a case of persistently elevated calcitonin levels after primary therapy are controversial.2J10,11 In MTC calcitonin serves as a sensitive tumor marker. Elevated calcitonin levels are an indicator Presented at the Eighteenth Annual Meeting of the American Association of Endocrine Surgeons, Baltimore, Md., April 6-8, 1997. Reprint requests: 0. C&mm, MD, Martin-Luther-University Halle-Wittenberg, Department of General Surgery, ErnstGrube-Str. 40, 06097 Halle/Saale, Germany. Copyright 0 1997 by Mosby-Year Book, Inc. 0039-6060/97/$5.00+0 11/6/85184 1124 SURGERY

Hale-Wittenberg

Halle/Saale, Germany

of remaining calcitonin-producing c-cells1 and levels of calcitonin approximate the remaining tumor mass,l’ although there are single reports that levels of calcitonin do not necessarily correlate with the tumor mass.13 As a result of early lymph node metastasis, one could assume that continously elevated calcitonin levels after primary surgery are mainly due to remaining locoregional LNM indicating inadequate primary therapy. Unfortunately, the sensitivity and specifity of diagnostic tools to detect LNM are low.14>15 Therefore the question remains as to whether these patients benefit from a systematic meticulous microdissection of all locoregional lymph nodes and, if so, whether the approach should be determined by tumor stage.

PATIENTS AND METHODS From 1988 to 1996, of 109 patients with MTC, we consecutively reoperated on 36 patients, performing microdissection of all four locoregional lymph node compartments (four-compartment lymphadenectomy, 4CLA). These patients had ele-

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vated levels of calcitonin. Patients with progressive distant metastases were excluded. As recently describedI we used the following compartment classification (Fig. 1). Compartment Cl consisted of cervicocentral lymph node system, right (Cla) and left (Clb) from the trachea, between trachea and carotid sheath, and from the hyoid bone down to the brachiocephalic vein including the submandibular lymph nodes. Compartment C2 and C3 consisted of right (C2) and left (C3) cervicolateral lymph node system between the carotid sheath and trapezoid muscle, from the subclavian vein up to the hypoglossic nerve, anterior, posterior, and between the fascicles of cervical plexus. Compartment C4 consisted of mediastinal lymph node system on both sides of the trachea (right [C4a] and left [C4b]), from the innominate artery and brachiocephalic vein down to the tracheal bifurcation within the anterior and posterior parts of the mediastinum. Number of lymph nodes dissected and of lymph nodes containing tumor was analyzed for each compartment separately. The TNM classification was done according to the recommendations of the UICC.‘T RESULTS Patients. Thirty-six patients (24 female and 12 male) with a mean age of 45.6 years (range, ‘7 to ‘13 years) underwent reoperation 0.2 to 9.6 years (mean, 2.5 years) after primary operation. Previous operations and pTNM classification. Sixteen patients (45%) underwent one operation before 4CLA, 17 patients (47%) underwent two prior operations, and three patients (8%) underwent more than two (three, four, and five) prior operations. The extent of the previous operations and the primary pTNM classification are shown in Table I. Thirty-two patients (89%) had undergone a total thyroidectomy. Eight patients (22%) did not undergo lymph node dissection. Indication for reoperation and findings before 4CLA. Before operation all 36 patients had elevated levels of calcitonin after limited primary procedure; 34 (94%) were basal levels and two were after stimulation with pentagastrin. Enlarged or suspicious lymph nodes were diagnosed in 27 (79%) of 34 patients by ultrasonography, computed tomography, magnetic resonance imaging, or octreotide scintigraphy. Nonproliferating distant metastases were diagnosed in three (30%) of 10 patients undergoing repeated computed tomography, magnetic resonance imaging, or octreotide scintigraphy. Histology. All but two patients (94%) had LNM.

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4a Fig. 1. Compartment classification of the locoregional lymph node system of the thyroid.16

Table I. Extent of operation mary pTNM classification

before

4CLA and pri-

n Total thyroidectomy Subtotal thyroidectomy No lymphadenectomy (LA) LA restricted to cervicocentral compartment LA includes cervicolateral compartments LA includes upper mediastinal compartment PT.1 PT2 PT3 PT4 PN1 PNO PNX Ml MO MX

32 4 8 10 16 2 3 22 6 5 24 4 8 2 27 7

In one patient without LNM, preoperative calcitonin level was elevated after pentagastrin stimulation, and ultrasonogram was interpreted to show cervical LNM. None of 101 lymph nodes contained tumor. Interestingly, although no tumor was proved histologically, calcitonin levels became normal after operation. The other patient without LNM had an elevated basal calcitonin level; LNM were suspected after use of ultrasonography and octreotide scintigraphy. Histologic findings showed a small thyroid remnant but no LNM (55 lymph nodes dissected). Postoperative calcitonin levels

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Table II. Postoperative calcitonin levels of n = 36 patients according to pT category, ment, and time (in months) after primary operation (M status at 4CLA) Calcitonin level PT1 MO Ml PT2 .MO Ml PT3 MO Ml PT4 MO Ml Right lobe MO Ml Left lobe MO Ml Both lobes MO Ml <6 mo MO Ml 6-12 mo MO Ml 12-60 mo MO Ml >60 mo MO Ml All MO Ml

thyroid

gland

involve-

Normalized n (To)

Decreased >50 %

Decreased ~50 %

n (%I

n (%I

1 (50) 0 (0)

1 (50) 0 (0)

0 (0) 1 (100)

7 (3% 0 (0)

7 (39) 2 (50)

4 (22) 2 (50)

1 (25) 0 (0)

1 (25) 2 (100)

2 (50) 0 (0)

0 (0) 0 (0)

1 (50) 0 (0)

1 (50) 3 (100)

4 (40) 0 (0)

3 (30) 3 (20)

2 (80)

4 (33) 0 (0)

5 (42) 0 (0)

3 (25) 3 (100)

1 (25) 0 (0)

2 (50) 1 (50)

1 (25) 1 (50)

2 (25) 0 (0)

4 (50) 1 (60)

2 (25) 4 (40)

2 (40) 0 (0)

2 (40) 0 (0)

1 cw 0 (0)

3 (42) 0 (0)

2 (2% 2 (100)

2 (29)

2 (34) 0 (0) 9 (25) 9 (35) 0 (0)

2 1 14 10 4

decreased more than 50% but did not normalize. Two years after 4CLA, liver metastases were diagnosed. Of 56.9 lymph nodes (average) dissected, 9.4 lymph nodes contained tumor. Incidence of LNM, number of tumors involved, and number of dissected lymph nodes were separately analyzed for each compartment and are shown in Fig. 2. Although 28 patients (78%) had previously undergone lymphadenectomy, we found LNM in the cervicocentral compartment in more than 80% (n = 29). Furthermore, the cervicolateral compartments were involved with tumor in 41% to 54%, and metastases in the upper mediastinum were found in 36% (Fig. 2, a). The distribution of

(33) (33) (39) (38) (40)

3 (30)

0 (0) 2 (33)

2 (67) 13 (36) 7 (27)

6 (60)

tumor-positive nodes did not correlate with the pT category (Fig. 3). Ipsilateral cervicolateral LNM were found in at least 50%; contralateral cervicolateral LNM were found in up to 40%. Side of thyroid gland involvement did not influence the incidence of mediastinal LNM (Fig. 4). Distant metastases histologically proven at time of 4CLA were found in 10 patients (28%). Six patients had lung metastases, one patient had liver metastases, two patients had lung and liver metastases, and one patient had lung and bone metastases. Postoperative calcitonin. Postoperative calcitonin levels are shown in Table II. Postoperative calcitonin levels normalized in 25% of patients. No

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Fig. 2. a, Incidence of LIVM in n = 36 patients reoperated for MTC and (b) number of tumors involved and dissected lymph nodes (involved/dissected lymph nodes) separately analyzed for all four compartments. patients with proven distant metastases became normocalcitoninemic. In those without distant metastases, 35% (9 of 26 patients) had a normal stimulated calcitonin level (biochemically cured). Rate of patients biochemically cured decreased with higher pT category but did not differ significantly for intrathyroidal tumors (pT1 to 3). No patient with pT4 tumor had normal calcitonin levels after operation. Biochemical cure rate was not influenced by the time interval between primary operation and 4CLA. Complications. Rate of complications observed after 4CLA is shown in Table III. Parathyroid glands were autotransplanted when they were not associated with tumor-containing lymph nodes. Follow-up. Follow-up ranged between 1 and 8 years (mean, 4.4 years). Three patients underwent reoperation, and three patients died. Indication for reoperation and causes of death are shown in Table IV. All patients who underwent reoperation after 4CLA could not be biochemically cured. DISCUSSION In MTC, calcitonin enables a very sensitive follow-up regarding detection of calcitonin-producing tumor cells. However, this tumor marker is so sensitive that it may be elevated at a time when other techniques (e.g. ultrasonography, computed tomography, magnetic resonance imaging, octreotide scintigraphy) fail to show remaining tumors. In this situation the surgeon is confronted with an almost unique situation: to operate or not, on what he cannot localize by subtle diagnostic procedures, and to what extent, including distant

Table III. Complications 4CLA in 36 patients

within

6 months

after

Complication Permanent unilateral paresis of recurrent Permanent hypoparathyroidism Transient Horner’s syndrome Transient paresis of brachial plexus Retrosternal abscess Wound infection

n nerve

3 9 2 1 1 1

metastases. Some investigators report that even after an extended reoperation, the cure rate is very lowlo and excellent survival rates (lo-year survival, 86%) could be achieved without postoperative normalization of calcitonin level.’ But this excellent survival has not been reported by all investigators.18 Furthermore, others could achieve a normalization of calcitonin level by performing a meticulous microdissection in 20% to 30% of patients.3,11,1g*20 Al t h ough normalization of calcitonin level does not exclude tumor recurrence,21 it has been shown that postoperative calcitonin level, besides tumor stage, is a powerful prognostic factor.18,22 Therefore we used this marker to assess the effect of 4CLA. Patients were admitted to our department as cases of proven or suspected tumor recurrence. In all but two patients basal calcitonin level was elevated. In most cases (79%) imaging techniques were able to detect enlarged and suspicious lymph nodes, but these lymph nodes were not always those that were involved with tumors. Actually, the sensitivity and specifity of imaging techniques to

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Fig. 3. Incidence of LNM according to pT category. a, pT1: n = 3; b, pT2: n = 22; c, pT3: n = 6; d, pT4: n = 5.

for 4CLA identify LNM are low. 14J5 The indication was primarily an elevated level of calcitonin after a limited primary procedure and exclusion of progressive distant metastases. The pathologist did not find LNM in only two patients. In one patient thyroid remnant was misdiagnosed as LNM by imaging studies. Calcitonin level decreased by more than 50% in this patient. The reason calcitonin level did not become completely normal was clear 2 years later when liver metastases were diagnosed. The other patient had a slight elevation of calcitonin level after pentagastrin stimulation, and ultrasonogram was suspicious for LNM. No tumor could be found on histologic examination despite dissection of 101 lymph nodes. However, calcitonin level became normal, indicating that some tumor cells must have been removed, but this could not be proved histologically. Although 28 patients (78%) had undergone lymphadenectomy during initial operation, we found LNM in the cervicocentral compartment in more than SO%, indicating that the initial lymphadenectomy was insufficient. The cervicolateral compartments had LNM in more than 40%, and even in the upper mediastinum LNM were found below the left brachiocephalic vein in 36%. Most investigators do not recommend a routine medi-

astinal dissection.g,10 The present classification” includes the upper mediastinum in the locoregional lymph node system of the thyroid. We routinely dissect the upper mediastinum by a transsternal approach. This approach is essential not only to adequately dissect the lymph node of the upper mediastinum but also to gain access to all lymph nodes of the cervicocentral compartment down to the brachiocephalic vein.23 The high incidence (36%) of LNM in the upper mediastinal compartment described by othersll seems to justify this approach. However, only one patient with mediastinal LNM (8% of 13 patients) was biochemically cured. This raises the question whether LNM of the upper mediastinal compartment should really be considered not locoregional but distant metastases. Nevertheless, to prevent complications from locoregional tumor recurrence (trachea obstruction, infiltration of esophagus), we advocate a mediastinal dissection, at least for reoperation. Neither incidence or pattern of LNM nor rate of normalization of postoperative calcitonin level differed significantly among patients with intrathyroidal tumors of pT1 to pT3. Because of the extraordinarily high incidence of LNM in patients with pT4 tumors, we and others20 recommend an extended lymphadenectomy to prevent local com-

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Fig. 4. Incidence of LNM according to thyroid gland involvement. c, both lobes: n = 6.

Table IV. Reoperations

Reoperations 2yrand8mo 3yrand2mo

LNM LNM Liver metastases

2yr Tumor-associated 2mo

and causes of death after 4CLA Indication

Time after 4CLA

a, Right lobe: n = 15; b, left lobe: n = 15;

Operation

Cause of death

Lymphadenectomy cervicocentral Lymphadenectomy mediastinal Resection of one liver segment

deaths Bleeding of carotid artery (tumor infiltrated), patient did have lung metastases in addition

2yr

Patient did have multiple, rapidly progressive lung and liver metastases

2 yr and 7 mo

Patient did have lung metastases

plications, although these patients with extrathyroidal tumor could not be biochemically cured. Even 5 years after primary operation, 34% of those patients without distant metastases were biochemically cured. The reason that only 15% (2 of 13) of those patients who underwent 4CLA within 6 months after primary operation had normalized

calcitonin levels was the high prevalence of extrathyroidal tumor (n = 3, 23% of 13) and proven distant metastases (n = 5, 38% of 13) in this group. Complication rate for 4CLA is certainly higher than surgery of a lesser extent, but these were reoperations. Although the rate of hypoparathyroidism

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was quite high (25%), these patients can be managed by daily oral intake of calcium or vitamin D. The two patients with a retrosternal abscess or wound infection had a prolonged hospital stay, but both recovered and had normalized calcitonin levels. During a follow-up of 1 to 8 years after 4CLA (mean, 4.4 years), two patients underwent reoperation as a result of LNM (Table IV). The first patient initially underwent total thyroidectomy and so-called cervicocentral lymphadenectomy in an outside hospital. As a result of extensive scar tissue in the cervicocentral compartment (Cl), lymphadenectomy in this region was restricted when we performed 4CLA. Thirty-two months after 4CLA, we reoperated in this compartment (Cl) to prevent local complications caused by LNM. The second patient had tumor involving a lymph node at the bifurcation of the trachea that was considered a distant metastasis. Three patients died of MTC. One patient died 2 months after 4CLA because of local complications (infiltration of the carotid artery with secondary bleeding). The other two patients died of distant metastases. In conclusion, lymph node metastases were almost always (94%) found at reoperation performing 4CLA. No significant difference in the rate of node metastasis was found according to pT category or thyroid gland involvement. In patients without distant metastases, calcitonin levels normalized after 4CLA in nine patients (35%)) and in another 10 patients (38%) calcitonin level decreased more than 50%. Although no patient with pT4 tumor or distant metastases could be biochemically cured, we recommend 4CLA in these patients to prevent local complications. 4CLA seems to be justified even years after primary operation. Our encouraging results, however, need to be confirmed by a long-term follow-up. REFERENCES 1. Wells SA, Baylin SB, Gann DS, Farrell RE, Dilley WG, Preissig SH. Medullary thyroid carcinoma: relationship of method of diagnosis to pathologic staging. Ann Surg 1978;188:377-83. 2. van Heerden JA, Grant CS, Gharib H, Hay ID, Ilstrup DM. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 1990;212:395-401. 3. Dralle H, Damm I, Scheumann GF, Kotzerke J, Kupsch E, Geerlings H, et al. Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma. Jpn J Surg 1994,24:112-21. 4. Saad MF, Ordonez NG, Rashid RK, Guido JJ, Hill CS, Hickey RC, et al. Medullary carcinoma of the thyroid: a study of clinical features and prognostic factors in 161 patients. Medicine 1984;63:319-42. 5. Schriider S, Becker W, Baisch H, Biirk CG, Arps H, Meiners I, et al. Prognostic factors in medullary thyroid carcinomas:

survival in relation to age, sex, histology, immunocytochemistry, and DNA content. Cancer 1988;61:806-16. 6. Saad MF, Guidog, Samaan NA. Radioactive iodine in the treatment of medullary thyroid carcinoma of the thyroid. J Clin Endocrinol Metab 1983;57:1248. 7. Schertibl H, Raue F, Ziegler R. Kombinationstherapie von Adriamycin, Cisplatin und Vindesin beim C-Zell-Carcinom der Schilddrtise. Onkologie 1990;13:198-202. 8. Frank-Raue K, Raue F, Ziegler R. Therapie des metastasierten medullben Schilddriisenkarzinoms mit dem Somatostatinanalogon Octreotide. Med Klin 1995;90:63-6. 9. Kallinowski F, Buhr HJ, Meybier H, Ehrhardt M, Herfarth C. Medullary carcinoma of the thyroid: therapeutic strategy derived from fifteen years of experience. Surgery 1993;114:491-6. 10. Marzano LA, Porcelli A, Biondi B, Lupoli G, Delrio P, Lombardi G, et al. Surgical management and follow-up of medullary thyroid carcinoma. J Surg Oncol 1995;59:162-8. 11. Buhr HJ, Kallinowski F, Raue F, Frank-Raue K, Herfarth C. Microsurgical neck dissection for occultly metastasizing medullary thyroid carcinoma: three-year results. Cancer 1993;72:3685-93. 12. Brunt LM, Wells SA. Advances in the diagnosis and treatment of medullary thyroid carcinoma. Surg Clin North Am 1987;67:263-79. 13. Trump DL, Mendelsohn G, Baylin SB. Discordance between plasma calcitonin and tumor-cell mass in medullary thyroid carcinoma. N Engl J Med 1979;301:2533. 14. Sandrock D, Blossey HC, Steinroeder M, Munz DL. Contribution of different scintigraphic techniques to the management of medullary thyroid carcinoma. Henry Ford Hosp Med J 1989;37: 173-4. 15. Frank-Raue K, Bihl H, Dijrr U, Buhr H, Ziegler R, Raue F. Somatostatin receptor imaging in persistent medullary thyroid carcinoma. Clin Endocrinol 1995;42:31-7. 16. Dralle H, Scheumann GF, Kotzerke J, Brabant G. Surgical management of MEN2. Recent Results Cancer Res 1992;125:167-95. 17. Spiessl B, Beahrs OH, Hermanek P, Hutter RV, Scheibe 0, Sobin LH, et al. TNM-Atlas. Berlin: Springer; 1993. 18. Dottorini ME, Assi A, Sironi M, Sangalli G, Spreafico G, Colombo. Multivariate analysis of patients with medullary thyroid carcinoma. Cancer 1996;77:1556-65. 19. Tisell LE, Hansson G, Jansson S, Salander H. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 1986;99:60-6. 20. Moley JF, Wells SA, Dilley WG, Tisell LE. Reoperation for recurrent or persistent medullary thyroid cancer. Surgery 1993;114:1090-6. 21. Jackson CE, Talpos GB, Kambouris A, YottJB, Tashjian AH, Block MA. The clinical course after definite operation for medullary thyroid carcinoma. Surgery 1983;94:995-1001. 22. Girelli MA, Dotto S, Nacamulli D, Piccolo M, De Vido D, Russo T, et al. Prognostic value of early postoperative calcitonin level in medullary thyroid carcinoma. Tumori 1994;80:113-7. 23. Dralle H, Gimm 0. Lymphadenektomie beim Schilddrtisencarcinom. Chirurg 1996;67:788-806.

DISCUSSION Dr. Blake Cady (Boston, Mass.). This very elegant study obviously represents an enormous amount of clinical work and clinical expertise. But the real question is that it depends on what your conceptual framework about LNM is. Are lymph nodes filters that prevent cells

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Surgery Volume 122, Number 6 from spreading to the rest of the body? Or do they perform an indicator function about what is going on, in which case whether you remove them doesn’t make a difference. At least in all the studies that I know, with the exception of gastric cancer in Japan, every study has indicated that wider and wider removal of LNM has shown over time to make no difference in survival but increases morbidity and mortality. So, have you been able to demonstrate a difference in outcome other that just return of calcitonin level to normal in these patients, because this is a disease with a very, very long natural history that lasts over 20 to 25 years? What is your conceptual framework of LNM? If you do this kind of operation, it must be based on the assumption that these are filters catching cells before they spread to the rest of the body. Dr. Gii. To my knowledge the prognostic influence of LNM in MTC is generally well accepted. In a previous study we could confirm this. Furthermore, in this study preliminary results showed an improved survival of patients undergoing microdissection instead of berry picking. Having found a high incidence of LNM in all locoregional compartments, we changed our strategy and performed a 4CLA in all reoperative patients after exclusion of progressive distant metastases. But you are right, so far in these patients we cannot say much concerning recurrence and survival because of a short mean follow-up time of 4.4 years. At present no studies exist that show an improved survival of patients with normalization of calcitonin level compared with those with elevated calcitonin level but without proven recurrence by imaging tests. But there are some studies from Italy that could show that postoperative calcitonin level, besides tumor stage, is the most powerful prognostic factor. We still need to wait some years to prove that patients benefit from undergoing 4CLA. Dr. Irvin B. Rosen (Toronto, Canada). Do you use sestamibi scan after operation as a marker and a correlate of calcitonin? Dr. Gimm. No, we don’t use it. Dr. Rosen. How frequently do you do a sternal split? Is this routine with every procedure? Dr. Gimm. In all these cases we performed a sternal split routinely. Dr. Rosen. When you do your lateral neck dissection, do you transect the sternal mastoid, retract it, resuture it?

Dr. Gii. If we don’t get a good access, we don’t hesitate to transect the sternomastoid muscle. We resuture it after lymphadenectomy. Dr. Rosen. You do that fairly frequently? Dr. Giim. Yes. Dr. Robert Udelsman (Baltimore, Md.). When you did these random lung biopsies, you found 30% of the patients to have pulmonary metastases? Dr. Gimm. Yes, of the patients we have reoperated on, almost 30% had pulmonary micrometastases. Dr. Udelsman. That is an important finding. Because as far as I know, you are the first ones to do random lung biopsies in reoperative patients with MTC. If it is true that 28% have lung metastases at the time of cervical lymphadenectomy, then I argue that we are probably all wasting our time, at least in these 28% of patients who already have systemic disease at the time of operation. Are these random lung biopsies? Do you perform frozen sections on the lung biopsy material, and if that is positive, do you abort the rest of the operation? Dr. Gimm. You need to know that these micrometastases found by random biopsies are often not visible or detectable by digital examination in many patients intraoperatively. We are not talking about macrometastases. But assuming that we were able to identify these micrometastases intraoperatively by frozen section, we would continue with our operation to prevent local complications. Dr. Gary B. TaIpos (Detroit, Mich.). We continue to support selective reoperation, although we have not routinely used the microdissection technique. I wish to caution the membership that we have seen return of an elevated calcitonin level 10 years after operation that had initially resulted in a normalization of the stimulated calcitonin level. As these patients are followed, it will be necessary to document whether the medullary cancer is of a sporadic or hereditary nature because the survival curves potentially could be different. Do you have that information on your patients? Dr. Gimm. In rare cases we also have observed an increase of calcitonin level after previous normalization. Five patients had multiple endocrine neoplasia type 2 syndrome. Because this number is so low, no significant differences compared to sporadic cases have been found so far.

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