J. Endocrinol. Invest. 16.297-302,1993

CONSENSUS STATEMENT

Clinical thyroidology 1992: "What do we really need?" G. Riccabona (Innsbruck, Austria, moderator), L.J. DeGroot (Chicago, USA), F. Delange (Brussels, Belgium), J.T. Dunn (Charlottesville, USA), G. Galvan (Salzburg, Austria), RD. Piyasena (IAEA, Vienna, Austria), D. Reinwein (Essen, Germany), H. Roher (Dusseldorf, Germany), H. Rosier (Berne, Switzerland), M. Schlumberger (Villejuif, France), J.B. Stanbury (Boston, USA), P. Vitti (Pisa, Italy), D. Williams (Cardiff, United Kingdom)

This document summarizes the presentations and discussions at the 4th International Thyroid Symposium in Innsbruck (1) on establishing guide­lines for clinical work in thyroidology in the next years. The Symposium included the topics shown in Table 1. The panelists were aware of the fact that in the program some important items were either not presented at all, or in an insufficient and some­times controversial manner. We tried therefore to include such topics in the final statement (Tables 2-7). The conclusions were as follows:

1. Survey programs

1 .1. Assessment and monitoring of iodine supply in relation to thyroid diseases and other iodine re­lated disorders is recommended, especially in ar­eas of iodine deficiency and countries with iodine prophylaxis programs, using urine samples (Ilgl/dl or Ildl/g creatinine). These surveys should estab­lish iodine deficiency in a given population and could lead to appropriate prophylaxis, which can in general easily be achieved.

1.2. Screening for neonatal hypothyroidism: As it is known that early and appropriate treatment of con­genital hypothyroidism can prevent many of the se­vere sequelae of this condition, neonatal screen­ing of all newborns (parameter: TSH) should be done wherever possible. Neonatal thyroid screen­ing is also recommended in detection of iodine de­ficiency at a population level and can be used as a monitoring tool in programs of prevention of iodine deficiency as an additional criterion. In developed countries, blood spots taken on the 5th day of life are proposed for analysis. In developing countries, cord blood (possibly also measured from paper spots) can be used also. Cut-off levels will vary with the techniques applied and should be set up ac­cordingly in each country. Thyroxine determinations

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should only be used when no adequate TSH-assay is available. Thyroglobulin screening is at present not a substitute for the methods mentioned above but shows promise as a survey instrument. Pilot studies in populations with high risk of congenital hypothyroidism (iodine deficiency, iodine excess) are encouraged.

1.3. Monitoring of irradiated populations: Previous data from Japan and the Marshall Islands were dis­cussed and special emphasis was put by D. Williams on recent data on the excessive rate of thyroid cancer in childhood from Belarus (CIS) af­ter the reactor accident in Chernobyl. Such an ir­radiated population needs studies of the level of exposure immediately after the accident. It needs later studies to screen the population for thyroid carcinoma, together - if possible - with screening of a control group. Early diagnosis can then be made and - if necessary - adequate treatment can be performed (Table 5). Open questions remain concerning the size of a population sample to be surveyed, the technique of survey (e.g. ultrasound or fine needle biopsy) and the duration of follow­up, as radiation-induced cancers can appear also 20 years or more after exposure. International co­ordination of such programs would be mandatory. Particular attention should be paid to suppress thy­roid uptake by iodine prophylaxis immediately after the accident in potentially exposed populations.

1.4. Survey programs in "risk groups" for thyroid disease: Several panelists (F. Delange, L.J. DeGroot) proposed such programs which should include patients admitted to hospitals (thyroid dis­ease? Euthyroid sick syndrome - non thyroidal ill­ness?), females above age 50 years and pregnant women. The consensus was that such programs should be carried out wherever possible but that they could probably not cover developing coun-

G. Riccabona, L.J. DeGroot, F Delange, et al.

Table 1 - Subjects of discussion.

1) Survey programs

2) Pathology

3) Pathophysiology and molecular biology

4) Clinical diagnosis

5) Clinical management

6) Prophylaxis of thyroid disease and follow-up

tries. Pilot studies of the cost-effectiveness of such survey programs were recommended.

2. Pathology

2.1. Histological classification of thyroid tumors: There was a consensus that the WHO-classifica­tion of thyroid tumors can be accepted for general clinical purposes. Some modifications might be necessary concerning oxyphil cell tumors (="Hurthle-cell-carcinomas"). An increa~ed use of immunohistochemical techniques to define the bi­ology of thyroid tumors is recommended. These studies should be carried out with molecular biolo­gy techniques for research to pro~id.e a better un­derstanding of thyroid oncogenesIs In the future.

2.2. Fine needle biopsy (FNB): The role of patholo­gists in evaluating FNB-specimens will be to. pro­vide guidelines for therapy and not to establls~ a final diagnosis. With further development of Im­munohistochemistry and techniques in molecular biology an improvement of cytology might become possible (definition of malignancy?), but molecular biology will not become a substitute for morpho-logical exams in pathology.' . Fine needle biopsy findings are crucial for the plan­ning of a surgical strategy before operation but the results should only be valid if there are adequate specimens for cytological evalu~tion. Po.ssibly, DNA-content in such specimens might provide fur­ther information concerning malignancy. Reports concerning a specific tumor-related enzyme in thy-

Table 2 - Survey programs.

1) Assessment and monitoring of iodine supply (iodine deficiency? Iodine excess? Sources of

iodine excess? Thyroid disease?)

2) Screening for neonatal hypothyroidism?

3) Monitoring of irradiated populations concerning thyroid disease?

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Table 3 - Pathology.

1) Improvement of accuracy of fine needle biopsy?

2) Histological classification of thyroid tumors: Increased use of immunohistochemistry also

concerning "growth factors" ecl.?

roid cancer (dipeptidyl-aminopeptidase) require further confirmation and do not seem to be of sig­nificant value at present.

3. Pathophysiology

3.1. Molecular biology of thyroid tumors: M. Schlumberger and the other panelists stressed that re­search in oncogenes related to thyroid cancer is cer­tain�y fascinating but that it has no clinical value as yet. Even RAS-mutations are not specific for thyroid ma­lignancy. Research in molecular biology in thyroid can­cer should therefore be carried out (e.g.: Why are pap­illary carcinomas in younger people more "b~ningn" than in elderly patients?), but does not yet proVide help in decision making in clinical thyroidology.

3.2. Nonthyroidal illness=euthyroid sick syndrome: D. Reinwein and W. Reinhardt stated that "non thy­roidal illness" with alterations of thyroid hormone se­cretion, thyroid regulation and metabolism of thyroid hormones in the periphery can occur in a variety of clinical syndromes (e.g. poly trauma, shock, severe burns etc.). Further studies of metabolites of thyroid hormone may help to understand the pathophysiolo­gy of such diseases. Whether thyroid therapy should be given in such cases remain~ questionabl~ at pre­sent. Familial hyperthyroxinemla and autoantibodies against thyroid hormone exist, but the incidence of these syndromes is extremely low and therefore the panel suggested that one should. just be "awar~" of such possibilities and no screening for such diSor­ders should be planned. Another important incentive came from L.J. DeGroot: the combination of hyper­emesis gravidarum and acute psychosis seems fre­quently to be joined by evidence of hyperthyroid func­tion ("thyroid stimulation"). The panel agreed to pro­pose a prospective study on this item.

Table 4 - Pathophysiology.

1) Improvement of methods?

2) Familial hyperthyroxinemia as non-thyroidal illness?

3) Congenital hereditary defects?

4) Clinical necessity: what? When? How?

Table 5a - Factor influencing high indicence of thyroid Ca.

Level of exposure

Type of exposure

external

internal

Iodine deficiency

Age

(Size of population)

4. Clinical diagnosis

4.1. General strategy: A clear diagnostic strategy was proposed by L.J. DeGroot (2) and was ac­cepted. This means that in general disorders of thyroid function and regulation disorders ~an well be defined by in vitro parameters, thyroid mor­phology (in correlation with function), by ultra­sound, isotope scan, fine needle biopsy and e~en­tually radiological exam. Everybody would desire a more precise measure about effects of thyroid hor­mone in tissue, because ECG, achilles tendon re­flex time, BMR etc. do not provide adequate infor­mation as yet. Ultrasound of the neck should be­come the "extended arm" of thyroidologists. A va­riety of immunological studies may be valuable in relevant cases to understand better the patho­physiology of thyroid disease, but their use will re­main optional.

4.2. Special considerations: Concerning thyroid ra­dionuclide scanning H. Rosier proposed double tracer scanning in nodular goiter (99mTc/1231+99mTcMIBIj201T1) for definition of function and "cellularity" together with ultrasound and fine needle biopsy. Uptake of 99mTcMIBI is not altered by iodine exposure and can be considered as an analogue of K+ and for Caesium-uptake (Tschernobyl!). It can be used at

Table 5b - Evidence confirming relation to Chernobyl and in­creased incidence of thyroid carcinoma in children in Belarus.

1) Pathology diagnosis confirmed by Egloff, Ruchti, Williams for majority of cases

2) Patients from Belarus

3a) No evidence that early or occult tumors were now being found, <40% show direct

extra-thyroid invasion

b) If rates were always at this level this would be extraordinarily high

4) Relationship to Chernobyl demonstrated by distribution within Belarus and by age distribution

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Clinical thyroidology 1992

Table 5c - What needs to be done.

1) Treatment

2) Early diagnosis

3) Prevention

4) Further study

- dosimetry

- epidemiology

- pathology

- molecular biology

low cost in Nuclear Medicine Depts. using the trac­er for cardiac studies and providing good images of viable thyroid tissue even when there is no en­docrine function! The proposal to use 99mTcMIBI, however, was not accepted from all panelists. There was consensus that not every diffuse goiter with Graves' Disease must be scanned for diag­nostic purposes. In nodular gOiters ~nd in ~as~s of thyroid cancer scanning remains a diagnostic pillar. At present 111In-Octreotide-scanning is proposed to assess the activity of endocrine ophthalmopa­thy. Whether this technique bec?mes routine will become evident in the future. In diagnosIs of nodu­lar thyroid disease in certain cases one should be aware of the possibility of magnetic resonance imaging, nuclear magnetic spec~rosc?py and Positron-Em iss ion-Tomography which might pro­vide additional scientific and clinical information, especially when 3-D image reconstruction is avail­able. On the other hand venous blood sampling by iv catheter for calcitonin-assays is not an "imaging" procedure but can provide important informati~n on the location of metastases of medullary thyroid carcinoma. The use of human recombinant TSH might provide the possibility to ~can t~yroids wi~h radioiodine in the near future With optimal thyroid stimulation and without withdrawal of thyroid hor­mone for weeks and probably without side effects.

Table 6 - Clinical diagnosis.

1) Double tracer scanning?

2) Problems of ultrasound?

3) Significance of immunological parameters?

4) Significance of non-hormonal peripheral parameters for assessment of thyroid function?

5) Diagnostic entities?

6) Other radiological techniques?

G. Riccabona, L.J DeGroot, F. Delange, et a/.

Table 7 - Clinical management.

1) Non-toxic goiter: I? Thyroid hormone? Surgery? 131 1?

2) T4+antithyroid therapy for hyperthyroidism?

3) Ophthalmopathy?

4) Dosimetry for 1311-therapy?

5) Surgical methods in Thyroid Cancer?

6) Teleradiotherapy?

7) Chemotherapy?

8) Therapy of complications after treatment?

5. Clinical management

This was certainly the most controversial item of the program of the Symposium. We therefore agreed to follow clinical entities in the following section and not methods.

5.1. Primary hypothyroidism: The therapy of the condition with adequate doses of thyroid hormone is well established, overdosage should be avoid­ed (osteoporosis?).

5.2. Nontoxic goiter: P. Vitti stressed the effects of medical therapy with thyroid hormone with which in approx. 50% of the patients goiter volume can be reduced in a one to two year treatment course. After such a course, however, no further shrinking of the goiter can be expected. Treatment with thy­roid hormone is also intended to prevent a further increase of goiter, thus avoiding the complications. Thyroid hormone should be given in suppressive doses initially. Iodine is indicated in the prophylax­is of goiter in iodine deficient areas but not in the treatment of a goiter which is already established. The panel agreed, that any suspicion of malignan­cy (clinical picture, ultrasound, thyroid scan, fine needle biopsy) should immediately activate surgi­cal treatment. Such a therapy is also recommend­ed in cases with tracheal compression of more than a third of the tracheal diameter and with respirato­ry problems. With 131 1 in adequate doses (approx. 120 Gy) goiter volume can be reduced by about 40% and therefore this kind of therapy should be considered in patients who should have surgery, but who refuse it or who are at "high-risk" for surgery (recurrent goiters!). In such cases one might also consider to combine surgical removal of "cold" nodules with a shrinking therapy with 1311. While 131 1 will not produce problems due to tra­cheomalacia or tracheal stenosis due to postoper­ative scarring, radiation thyroiditis might produce respiratory distress after therapy in patients with

300

severe tracheal stenosis. In general, this compli­cation can be avoided by administration of corti­costeroids.

5.3. Graves' disease: There was a consensus that Graves' disease can be treated efficiently with an­tithyroid drugs. The combination of antithyroid drugs and thyroxine to reduce the rate of relapses after antithyroid drug therapy as reported by Japanese groups is still controversial. On the other hand it was agreed that after a short term initial high dose an­tithyroid drug therapy maintenance doses should be as low as possible. Methimazole, carbimazole and propylthiouracil are all of value. The remission rate after Methimazole is about 50% as recently con­firmed by a European Survey on antithyroid drug treatment in Graves' disease. In patients, who have relapse of hyperthyroidism, radioiodine treatment (rarely surgery) has to be considered. Endocrine ophthalmopathy should be treated pri­marily by a normalization of thyroid function (surgery? 131 I-therapy?). Improvement of ophthalmopathy can be achieved by high dose corticoid therapy for several weeks. Therapy with human immunoglobuline (HIG) is still in an experimental stage, but shows promise. Therapy with more aggressive immunosuppressive agents (Cyclosporin-A, AZT) does not improve re­sults but increases complication rate. The effects of retrobulbar high voltage radiotherapy alone seems uncertain. In surgical therapy "near total thyroidec­tomy" should be carried out to avoid recurrences. Postoperative hypothyroidism can easily be cor­rected, persistent hyperthyroidism may be a prob­lem. In general ophthalmopathy is also improved after surgery. Surgery should be carried out in rel­atively large goiters with Graves' disease, while in smaller glands 1311-therapy can be used, if the pa­tients are not pregnant and have had no previous iodine exposure. With proper dosimetry radioiodine has the same success rates as thyroid surgery with­out the risk of surgical complications. Post-therapy hypothyroidism may occur after an interval of some years, but can easily be detected and treated.

5.4. Plummers' disease (toxic nodular goiter, toxic adenoma, multifocal autonomy). In general such dis­eases cannot be cured by medical antithyroid drug therapy. For a cure they need either surgery or 131 1_ therapy. Isotope scans are mandatory to define the thyroidal lesions. Initial, short-term antithyroid drug therapy may be necessary, but no consensus could be achieved concerning indications for surgery and/or 131 I-therapy. Essentially both methods can cure the disease if done appropriately.

a

b

Clinical thyroidology 1992

Strategy for 131 I-therapy of Thyroid Ca.

suspect nodule Distant meta of thyroid (clin., FNB, US, scan) Adeno Ca. proven by histol.

t t surgery surgery

(if possible radical) (if possible radical)

Histol.: Thyroid Adeno Ca. Histol.: Thyroid Adeno Ca.

• 4 weeks

131 I-thyroid scan

, 4 weeks

(7.4 MBq), u~take, 48 h PB 1 11/1,

TSH, US, TG

US, TSH, TG

• Ablation of thyroid remnants with 131 1 (500 Gy)

thyroid ... hormone ..-

Therapy of metastatic disease 5-8 GBq

Posttherapy scan RX Posttherapy scan

3 months , chech-up: clin., X-ray, 74-185 M

BC, ESR, TSH, TG after 1 month BqWBS, RT? without T4 CT?

r-I --.... 1311-T88 (1-5mCi)+Tg (off ~T4)

1 year 1311-T88 I I , ~I ----------~--------~I

1311-treatment ... o(~--- Positive r Negative

Tg level (off LT4) I

I Detectable: Neck echography

I Undetectable

I >5 ng/ml

chest X-ray I

I <5 ng/ml

I 2-5 years

~

yearly on LT4, T8H, Tg

1311-T88 (1-5mCi)

Fig. 1 - Proposals for management of thyroid cancer: a) Riccabona G. b) Schlumberger M

301

G. Riccabona, L.J DeGroot, F. Delange, et a/.

5.5. Thyroid cancer: Here again the consensus was obtained concerning surgery: after a diagnosis - as early as possible - usually radical thyroid surgery should be done with lymph node exploration of the afflicted side and perhaps Iymphnode resection (especially for medullary thyroid Ca). Surgery was proposed also for regional recurrences if techni­cally feasible without too high risk (especially for medullary thyroid Ca.). Resection or orthopedic surgery for distant metastases in selected cases can be considered. No consensus, however, was achieved concerning indication and methods for 1311-therapy (thyroid remnant ablation? Which dose?). In general, appropriate elimination of thy­roid remnants in differentiated thyroid carcinoma was accepted but no definite dose proposal could be defined. Other indications (e.g. rising thy­roglobulin without significant 1311-uptake in diag­nostic whole body scans, duration of therapy and criteria for stopping the therapy) remained open, even as the necessity for a large dose whole body scan in patients with rising thyroglobuline is ac­cepted. A similar situation exists concerning per­cutaneous radiotherapy of thyroid cancer. While ev­erybody agreed that bone metastases of thyroid cancer without 131 I-uptake can be treated with tele­curietherapy as well as patients with inoperable thy­roid cancer no consensus was obtained concern­ing "prophylactic" postoperative radiotherapy in the neck also in "high-risk"-groups and radiation ther­apy of medullary carcinoma. Overall, one might propose strategies as shown in Figure 1. Chemotherapy in thyroid cancer is still an approach without definite answers: Obviously there are "re­sponders" and "non responders", without any sig­nificant difference for different chemotherapeutic programs (including anthracyclins, doxorubicin, aclarubicin, CIS-platinum, bleomycin, interferon-A). The rate of responders varies between 20 and 40%. Responders can show a longer survival, a signifi­cant local response and an improvement of life quality. 'In anaplastic carcinoma a combination of surgery, HV-therapy and chemotherapy has been shown useful in both local control and life ex­pectancy. Suppressive thyroid hormone medica­tion is considered to be necessary in differentiated thyroid carcinoma. In patients with anaplastic car­cinoma the thyroid hormone dose can be kept low­er. The indication for chemotherapy should be for evolutive disease without 131 I-uptake.

5.6. Thyroiditis: No comments were made on this item, so that we can assume, that the actual thera­peutic programs are adequate. In subacute thy-

302

roiditis one should, however, reexamine the diag­nosis within a few months to avoid inappropriate therapy for thyroid cancer!

6. Prophylaxis and follow-up after therapy

G. Galvan (and many other of the panel) recom­mended routine thyroid hormone medication after thyroid surgery in nontoxic goiter (75-100 /lg lJday). Further procedure will be established according to results of a check-up after approx. 2 months. After hyperthyroidism no immediate postoperative medi­cation is required. It can be started after a check-up 6 weeks after surgery if there is evidence of hy­pothyroidism. A rigid follow-up and prophylaxis pro­gram after surgery is important, as in uncontrolled populations recurrence rate can be up to 70%! One might consider omitting thyroid medication after years of stable thyroid function and after the menopause, if an adequate iodine intake is avail­able. Programs for follow-up in thyroid cancer vary: "suppressive" thyroid hormone medication (see above) in differentiated thyroid carcinoma can be proposed, but should be carried out on an individu­al basis (thyroid function parameters). Osteoporosis due to a long-term overdose of thyroid hormone should be avoided by careful follow-up over a long term. In anaplastic thyroid cancer or medullary thy­roid carcinoma there should be only "substitution therapy" and no suppressive therapy! With or without suppressive therapy patients after treatment of thy­roid disease require long-term follow-up. As may be seen this document provides answers to many questions relevant for clinical thyroidology, even though no consensus could be achieved on a few items. Nevertheless there is a trend, which can be recog­nized in the papers of the Symposium and then in this final conclusion: a large number of possibilities exist, but their actual value for the management of patients will sometimes be established only in the future! With scientific engagement and medical conscience we should be able to provide appro­priate answers.

REFERENCES 1. Riccabona G.

Clinical thyroidology 1992: What do we really need? J. Endocrino!. Invest Suppl. 5 to no. 8, 1992.

2. DeGroot L.J. Current diagnostic strategy. J. Endocrino!. Invest Suppl. 5 to no. 8, Vol. 15, p. 47, 1992.