54

CARCINOMA OF THE THYROIDBy SELWYN TAYLOR, M.Ch., F.R.C.S.

Surgeon and Lecturer in Surgery, Postgraduate School of London

.......

FIGS. Iand 2.-Patient aged i8 years with a papillary type of thyroid carcinoma.

Carcinoma of the thyroid is not a commondisease. In recent years, however, there have beennumerous reports that its incidence is higher thanhas previously been believed, whilst, at the sametime, a number of advances have been made intreatment by surgery, goitrogens, X-rays andradioactive iodine. A review of the subject at thistime is therefore not inappropriate.

IncidenceA study of the Registrar-General's returns for

England and Wales for the five years I943-47 re-veals that I,48I deaths were attributed to cancer of

the thyroid. 'T'his was approximately 300 deathsper annum, the ratio of females to males being 2.8to i. This is presumably the minimum deathrate from this disease. ITf it is assumed that adiagnosis of malignant disease of the thyroid usuallycauses the death of the patient harbouring it,another way of assessing the frequency of thedisease is to analyse the post-mortem records of alarge hospital. Van der Laan (I947) carried outsuch a review at the Boston City Hospital, Massa-chusetts, and found that during the half centuryfrom I896 to 1945, of i8,668 autopsies only fiveshowed carcinoma of the thyroid gland. Asimilar review (Van der Laan, I947) of the post-mortem material at two other large hospitals inBoston showed an incidence of less than I in I,OOO.

* Hammersmith Hospital, Ducane Road, London,W.I2.

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February 1951 TAYLOR: Caircinoma of the Thyroid 55

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FIG. 3.-Undifferentiated carcinoma of thyroid.Patient aged 42; presenting with a swelling inthe neck which had been present for only threemonths.

Such figures are difficult to interpret. Possibly,owing to the duration of the disease, patients ofthis type commonly die in their own homes.When a fairly certain diagnosis of malignancy

in a goitre can be made clinically, the prognosis isusually hopeless, but many enlarged thyroid glandsare removed for a variety of reasons and the diag-nosis of carcinoma only arrived at after a micro-scopical examination. Can a certain diagnosis ofmalignancy be made on the histological appear-ances? The answer is no. There are few moredifficult problems which confront the pathologistthan that of deciding when a nodular goitre hasbecome malignant. Graham (I925) presentedwhat he consid-ered to be the criteria of malignancyin the thyroid; since he insisted on invasion ofblood vessels by tumour cells his standards wereperhaps too stringent.

Age IncidenceThree-quarters of all these tumours occur be-

tween the ages of 40 and 70, the average age in

AC

FIG. 4.-A case of solid alveolar adenocarcinoma ofthe thyroid gland arising in a goitre which hadbeen present for 17 years, the patient being 8oyears old when first seen. The incision showsthe site of removal of a large pre-tracheal masswhich caused urgent dyspnoea.

men being 53 and in women 48 (Pemberton, 1939).However, cancer of the thyroid is occasionallyseen in children and young adults when it is usuallyof the papillary type. Reports from areas wheregoitre is endemic suggest a younger age incidence,Warren Cole (1945) reports an overall average ageof 48 in patients treated in Chicago and pre-sumably drawn from the surrounding state ofIllinois.

Sex IncidenceIn general about three females to every male are

affected by this disease. The Registrar-General'sfigures quoted above give a ratio of 2.8 to I; inJoll's (I932) series for I9I8-30 it was 3 to I. Sinceenlargement of the thyroid gland is approximatelynine times as common in women as in men, thelatter show a greater proneness to malignantchange.

Incidence of Carcinoma in GoitresThis depends chiefly on two factors. First,

when the patient comes from a region in whichgoitre is endemic, the incidence is much higher(Crile, I949) (i) and carcinoma of the thyroid maybe described as a geographical disease. Second,

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56 POSTGRADUATE MEDICAL JOURNAL February I95 I

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FIG. s.-Patient aged 37 with an undifferentiatedcarcinoma of the thyroid. Goitre present forI8 years, rapidly increasing in size in the last i8months.

FIG. 6.-Same patient post-operatively and beforeradiotherapy. This lady was fit and well i8months later with no evidence of recurrenceand having had a normal pregnancy.

.... ... .........I.... '

FIG. 7. FIG. 8.FIGS. 7 and 8.-Patient with a goitre of recent origin, fixed to surrounding structures and causing both

dyspnoea and dvsphagia. At operation a lymphadenoid goitre (Hashimoto's disease) was discovered.

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Fe.5ruary I95I TAYLOR: Carcinoma Qf the 7Thyroid 57

xlx

DIAGRAM I.-Uptake distribution of radioactiveiodine by an apparently normal thyroid gland.The contours (isocuries) indicate the per cent.of dose per square centimetre.

the experience of the pathologist in this particularfield of histology and his criteria of malignancy areall important (Ward, I949). It is not uncommonfor a multinodular goitre to be classified as benignin one laboratory and malignant in another, more-over since some of the slower growing tumourshave been known to lie dormant as long as 20years (Crile, 1949) (i), the clinician may be lulledinto a sense of false security and believe the gland tobe innocent. If these facts are borne in mind thevery conflicting statistics appearing from differentclinics do not appear so remarkable. Below aregiven some of the figures which have been pub-lished by clinics in the last few years; these show

Per Cent.Per Cent. Multiple

Single Nodules NodularAuthor Excised, Goitres Ex-

Found to be cised, FoundMalignant to be Malignant

Warren Cole, et al.(I945) 24.0 17.1

Warren Cole, et al.(1949) 24.4 17.1

Crile, G., Jun.(I949) 24 5 10.9

Cope, 0., et al.(I949) 19.0 IO.0

that when a solitary nodule in a non-toxic goitreis excised there is approximately a 20 per cent.chance of its being malignant. In the case of a

V

NOTCH.

DIAGRAM 2.-Uptake distribution of radioactiveiodine by a thyroid gland which had been re-placed by carcinoma with the exception of theleft lower pole.

multinodular non-toxic goitre the cancer rate isabout io per cent.These figures by no means represent the true

incidence of malignancy in nodular goitres. Thepatients who eventually have their thyroids ex-cised are a highly selected group of people asCrile (I949) (ii) has so rightly stressed. In the firstplace they or their family have usually noticedsome change in the configuration of the neck, andthis has been serious enough to make them consulttheir own doctor. He, in turn, has referred themto a surgeon or hospital clinic, and only when allthese different opinions have recommended opera-tion. is the gland excised, since no one wishes toundergo a surgical operation if any alternativeexists.Thus it is quite misleading to say that io per

cent. of non-toxic multinodular goitres are malig-nant. What is true is that io per cent. of themultinodular goitres excised are malignant.Even if we stress the peculiar selection which

must go on to produce these figures they are stilldisquieting, and there need be no doubt that thosereported malignant in Cole's series were correctlydiagnosed, since of the i6 in the I944-48 series i iwere already dead and two of the five remaininghad metastases by 1948.At this point it is perhaps permissible to digress

in order to discuss the pros and cons of removingnodular goitres because of their potential malig-nancy, In this country Branson and Houston

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(I949) reviewved 530 cases of nodular goitre whichhad been operated upon by the late Cecil Joll.Among these there were 65 cases of carcinoma, ofwhich 33 were classified as malignant adenomas,i.e. 6 to I2 per cent. were malignant according tothe histological diagnosis. The operative mor-tality was low, and these authors claim that allnon-toxic nodular goitres should therefore be re-moved surgically. Since the patients from whommalignant adenomas had been removed all survivedfor more than five years, the diagnosis in some ofthese may well be suspect.A quite contrary point of view is taken by Crile,

from consideration of not dissimilar statistics. Hestates that about 4 per cent. of all patients arrivingat the Cleveland Clinic for non-thyroid reasons arefound to have nodules in their thyroids, and hededuces that 6,675 adenoma, would have to be re-moved to prevent one patient dying from thyroidcancer.The writer does not subscribe to the view that

all patients with non-toxic, nodular goitres shouldbe submitted to a surgical operation, althoughmany will require thyroidectomies because thegland causes pressure symptoms or for cosmeticreasons. Nor does he believe that all solitarynodules should be excised, except in the veryyoung. It is important, however, that all suchpatients should be examined clinically by one wellexperienced in goitre work and a careful casehistory taken; if a suspicion of malignancy is stillentertained under these circumstances, then athyroidectomy should be done. The most im-portant observations leading to such a step will bethe presence of a single nodule in the thyroid of ayoung patient, evidence of recent increase in sizein a long-standing goitre, the hardness of thenodule or nodules, the occurrence of dysphagiaand, not least, the patient's own impression that allis not well in the neck. Recurrent laryngeal nerveinvolvement is pathognomonic of malignancy, butlikewise a late sign.PathologyThe very fact that so many different classifica-

tions of cancer of the thyroid have been suggestedin the past is good evidence that none is whollysatisfactory. rt will be found useful to divide thesetumours in the first place into two main groups,papillary and non-papillary (Proc. Nat. CancerConf., 1949).

Papillary cancer of the thyroid may occur at anyage, but shows a decided tendency to occur in theyoung, possibly the youngest reported being in achild of four years. Typically it is a slow growingtumour and I know of a patient who had a cervicallymph node containing such a metastasis removedi6 years ago, who has had no further symptoms.

Crile reports a patient who harboured a similartumour with little increase in size over 27 years.

Papillary carcinoma of the thyroid has a pre-dilection for spreading by the lymphatics, especi-ally in younger patients. This accounts for theprevious concept that thyroid tissue could appea,laterally in the neck as a developmental abnormalityrthe so-called lateral aberrant thyroid. Such tissueis the result of spread of a highly differentiatedpapillary tumour into a cervical lymph node,(Lahey, I946; Crile, I947). The primary growthmay be so small that it is only discovered aftercutting serial sections of the thyroid lobe on theaffected side; the title of ' occult carcinoma of thethyroid' has been suggested for such tumours(Wozencraft, I948).

The non-papillary tumours can be subdividedinto groups according to their histological ap-pearance (Wegelin, I926) or according to theirclinical behaviour (Lahey, I940).

Histologically they appear as:(a) Adenocarcinomas with colloid formation;

tumours which reproduce fairly faithfully thestructure of the parent gland.

(b) Adenocarcinomas without colloid formation;less differentiated than the foregoing.

(c) Carcinoma simplex; solid tumours whosecells show varying degrees of differentiation. Intheir most anaplastic form the histological pictureof these tumours may be indistinguishable fromsarcoma, though whether sarcoma of the thyroidever occurs is of academic interest only.One further tumour requires mention because

of its distinctive appearance. This is the so-calledHiurthle cell type, which is comprised of eosino-philic cells surrounding small alveoli. Willis(I948) has pointed out that it is trebly unfortunatethat such tumours should be classified separatelyand dignified with the eponym Hiirthle. Hurthlewas not the first to describe- these cells, since Bakerdid so 17 years earlier. Hiirthle thought thatthese large pink-staining cells were interfollicular,but interfollicular cells probably do not exist asRienhoff's (1929) wax reconstructions show. Fin-ally these cells are probably only a variant of alveolarcells and can be found in many other conditions,though not in such large numbers (Lennox, 1948).

Clinically the non-papillary thyroid cancers canbe conveniently divided into those which are welldifferentiated and show some degree of thyroidfunction and those which are non-functioning.The last 28 consecutive cases of thyroid cancer

treated at Hammersmith Hospital have includedfive proved cases of papillary adenocarcinoma. Theremainder have shown every type of histologicalpicture from the alveolar type with colloid forma-tion to the most undifferentiated variety which, onoccasion, was labelled sarcoma.

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SurgeryThe most important form of treatment for

almost every case of carcinoma of the thyroid is asurgical operation, but the form which the opera-tion takes must be decided by the variety andextent of the tumour. Once again it is convenientto consider separately two main groups; thepapillary and the non-papillary carcinomas.

Papillary carcinoma of the thyroid is essentiallyslow growing and occurs in the younger age groups.The diagnosis may be made on the operating tablewhen an enlarged lymph node removed from theneck is found to contain metastatic thyroid tissue.When the disease is confined to one side of theneck the lobe of the thyroid gland on that sideshould be removed in its entirety, no matter hownormal it appears, since a primary growth may beonly a millimetre in diameter. If the isthmus isinvolved then the resection will haive to include agenerous portion of the contralateral thyroid lobe.A decision has then to be made on how radicalshould be the removal of the lymphatic drainage onthe affected side. Here it has to be rememberedthat the tnmour is usually a slow growing one, thepatient often young and very often a girl. Bearingthese facts in mind it is not justifiable to carry outa block dissection of the neck, involving as it doesremoval of the sternomastoid muscle and probablythe internal jugular vein, although many surgeonshave proposed it (Metzger, 1948). Crile's sug-gestion that the excision should be local, non-mutilating, and multiple ifnecessary, is a good one,but not in all patients. If there is involvement ofmany lymph nodes it is far better to proceed atonce to a formal block dissection than run the riskof further operations in the near future in an areadistorted by scar tissue. A history of extremelyslow progress might modify this view.

Non-papillary carcinomas may present in avariety of different ways. At one extreme thediagnosis of malignancy is not even suspected anda non-toxic, or very rarely a toxic, nodular goitre isexcised, the pathologist subsequently reporting anearly cancerous change. At the other extreme theunfortunate patient who has had a goitre for manyyears consults her doctor because her neck hasstarted to enlarge and pressure symptoms havearisen. Such a condition may require tracheo-tomy, and vet despite this the patient may die in afew weeks.The treatment of these malignant goitres should

follow certain clearly defined basic principles. Assoon as the diagnosis of malignancy has been con-firmed at operation an attempt is made to do atotal thyroidectomy. If successful this serves twopurposes; the removal of the primary growth andthe removal of all normal functioning thyroidtissue. The latter is of value in that in some

patients the anterior pituitary may then stimulatemetastases to take on the production of thyroxinand thus make them accessible to treatment byradioactive iodine. Total thyroidectomy in apatient whose thyroid is enlarged and distorted bycarcinoma can be a formidable undertaking, more-over it is essential to preserve the recurrentlaryngeal nerves or at least one of them, and alsothe parathyroid glands. If the tumour has spreadwidely the operator should be content to be radicalon one side of the neck only, in order that only onevocal cord is jeopardized. Pretracheal miusclesand one internal jugular vein may be sacrificedtogether with all the involved tissue that it is pos-sible to remove; often the tumour can be slicedoff the trachea. If necessary the operation is com-pleted by performing a tracheotomy. Attemptshave been made recently to resect part of thetrachea and replace its wall by tantalum gauzeand fascia (Robb, I949). Two weeks later a blockdissection of the lymphatic drainage is made onthe side of the neck primarily involved. It may benecessary to repeat this on the opposite side if thetumour was extensive and involving the isthmusor contralateral lobe.There are a, few patients who have slowly

growing cancers and who when first seen presentserious signs of obstruction to trachea and greatvessels. Often these people are only capable ofbreathing whilst sitting bolt upright and they showgreat enlargement of their neck veins; surgery forthese can only be a palliative, but it is well worthwhile. They are taken to the operating theatreand, if possible, anaesthesia is induced with thepatient sitting up, and a tracheal tube passed. Asmuch of the tumour as possible is then cut away,and if necessary a tracheotomy tube is inserted.The latter is by no means always required. Thesubsequent treatment of these patients is mainlybv radiotherapy.

Finally there is an anaplastic type of thyroidcarcinoma often occurring in middle aged males,which can only be described as fulminating. Forthese radiotherapy is ideal. Surgical treatment isonly indicated in so far as a tracheotomy may berequired to spare the patient the agony of death bystrangulation. Even after intensive radiotherapythese tumours may fungate through the tracheo-tomy opening within the space of a few days.Fortunately, however, this type of tumour isusually radiosensitive.

X-ray TherapyFor many years X-ray therapy has been used ex-

tensively for the treatment of carcinoma of thethyroid, and an outstanding contribution to thissubject was made by Graham and McWhirter(1947) in their address to the Royal Society of

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Medicine in 1947. They came to the followingconclusions after reviewing the treatment given to.i44 consecutive unselected cases in Edinburgh.

i. Localized nodules in the thyroid should beremoved radically by surgery. If the tumourproves to be an adenocarcinoma or a papillaryadenocarcinoma then the value of subsequenttherapy is doubtful. If the tumour is an un-differentiated carcinoma then post-operative X-raytreatment should be given.

2. If the whole thyroid is enlarging rapidly thediagnbsis is probably an undifferentiated carcinomaand X-ray treatment is indicated using wide fieldsand including the thorax.

3. A biopsy should be obtained whenever pos-sible to guide treatment, except when rapid growthis causing dyspnoea. Under the circumstancesX-ray therapy is started forthwith.

4. In advanced tumours of high malignancy,X-ray treatment should not be accompanied bysurgical removal of the accessible part of the-cancer.The three years which have elapsed since these

statements were- made have seen few advanceslikely to alter them except in minor details.Phillips (Proc. Nat. Ca"ncer Conf., 1949) at theMemorial Hospital, New York, treats highlymalignant tumours with 4,ooor in four weeks, andthough cures do not result the patients usually dieof metastases involving liver and lung. When asolitary lung deposit causes troublesome haemop-tysis it is treated palliatively with 2,ooor givenover ten days. Such a technique is useless whenmultiple secondaries are present. Pre-operativeirradiation of the neck with 2,ooor for ten days wasgiven to the so-called malignant adenoma andoperation carried out on the i ith day. Post-.operative X-rays -were not indicated since whensecondaries appeared they were rarely locally in-the neck. Patients with papillary adenocar-cinomas, howeve-, were given post-operative ir-radiation since their spread was usually to the locallymph nodes; if they recurred after some years,3,ooor was given over a period of three weeks bothto the lower two-thirds of the neck and themediastinum.

R,adioactive IodineThe opening of a chain-reacting pile at Harwell

has resulted in there now being available a plentifulsupply of radioactive isotopes for research andtherapy in medicine. The thyroid- is ideally suitedabove all other tissues in the body for treatmentby radioactive material, since it has the uniqueproperty of extracting from the blood stream cir-culating iodine. In addition this iodine is thenconcentrated in the gland and stored within thevesicles for gradual liberation as required, in theform of thyroxine.

Stable iodine is usually designated as 1127, andalready many radioactive isotopes of this elementhave been discovered. The one which has provedmost suitable for work with the thyroid is 1131,which has a half lifq of eight days; this means thathalf the molecules in any sample will have givenoff their radioactivity by the end of eight days.

I131 is prepared in the pile by the bombardmentof metallic tellurium with slow neutrons accordingto the following reactions:

5 2Te'30+on'-*r2Te131-+y* 2Te131-* 1313+

The Te131 has a half life of only 25 mins. andthus rapidly becomes 1131. It is necessary tostudy how I131 decays in order to know what kindsof radiation it gives out when taken up by thethyroid. In fact, physicists have not yet'solvedthis problem completely, but Metzger and Deutsch(I948) have recently proposed a rather complicatedexplanation. The net result is the' emission of y raysof varying intensity and moderately hard f rays.The y rays are extremely penetrating and can bemeasured by a Geiger-Muller counter placed somedistance away from the source, thus enabling one tocount radiations over the neck. The ,B rays, whichaccount for the greater part of the radioactivityof 1131, only penetrate about 2 mm. in the thyroidand cannot therefore be detected outside the neckeven if the thyroid is immediately under the skin.

In the body the radioactive element I131 behavesin precisely the same manner as the stable formI127 and is concentrated in the thyroid gland. It isof importance that radioiodine can be prepared inthe atomic pile free from stable iodine (i.e., carrier-free) because then, when a dose of radioiodine isgiven to a patient, it will be known that the iodinetaken up by the gland is the radioactive isotope.The value of radioiodine in cancer of the'thyroid

is twofold. It may be used as an aid in diagnosisand, on rare occasions, for the treatment of thyroidmetastases.

Radioiodine in DiagnosisA substantial number of patients with thyroid

cancer have now been investigated with radio-iodine and the number showing uptake of radio-iodine by the tumour cells is small. Fitzgerald(1949) gave ioo patients radioiodine and 46 showedsome concentration in the tumour cells, but innone was it equal to the concentration in the un-involved thyroid. Because of these two observa-tions it will be seen that if a patient is given atracer dose and a directional Geiger-Millercounter is used to scan the activity in the neck,should a nodule show markedly less activity thanthe surrounding thyroid tissue it raises the pos-

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February I951 TAYLOR: Carcinoma of the Thvroid

sibility that the nodule may be malignant (Dobyns,i949).. Such a finding is no more.than suggestive,but it is of real value since the surgeon who knowsof this before operation can be prepared to carryout a radical excision.

At. this hospital a method -of mapping...out -thefunction of the thyroid gland (Taylor, 1951) hasbeenevolved, using a collimated counter designedby Veall (I950) and a tracer dose of only ioomicrocuries. The appearance of a normal glandusing this technique is shown. in Diagram i, andthat of..a gland containing carcinoma in the rightlobe in Diagram, 2. It will be seen -that the onlyfunctioning tissue in the latter is that at the leftlower pole, which was found at operation to be theonly. part of the gland not replaced by tumour.The finding by such a method that part of a

thyroid does not take 'up .radioiodine. is .no morethan suggestive of malignancy, since it might occurin many other pathological 'states. It may be ofvalue, however, when considered in Ponju,nctionwith all the other signs, symptoms and investiga-tions.

Radioiodine TherapyIRadioiodine can only be used for the treatment

of thyroid cancer if the'tumour cells take .upenough of the, isotope .*to irradiate themselvesadequately. Since almost all such tumours takeup less iodine than the parent gland it'is necessaryto find some means of stimulating their activity.If we .assume that the diagram (Diag. 3) re-presents in simplifi:ed form the balance. main-tained in the body between the pituitary and

He POTHALAMUS HYPOTHALAMUS

AhITCRIO R+>

PITUTARY 5 .ANTERIOR PITUITARY

THYROID STt1LATINO HORMONE

I,',1 ..I| -.A * r-J t -

ID- %

THYROID EXCISED

1 ~I n t

)IAGRAM 3 (above).-Pituitary-thyroid axis showing Mdiagrammatically the interaction of these endo-crine glands.

4',[)IAGRAM 4 (right).-Pituitary-thyroid axis showndiagrammatically in a patient after excision of 0,the thyroid for carcinoma with the presence ofmetastases which are taking on thyroid * °/ *function.

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thyroid gland, then the best stimulus to thetumour cells to take on thyroid activity will becomplete removal of the gland, since by this meansthere will be lack of thyroxine in the blood stream.This wlIl lead to overactivity of the anteriorpituitary and the production of thyroid stimulatinghormone (TSH), the latter inducing the tumourcells to manufacture thyroxine if they are in factcapable of so doing. The importance of thismechanism was first pointed out by Rawson et al.(I948) and is illustrated in Diag. 4.The practice of giving patients with carcinoma

of the thyroid a tracer dose of radioiodine in orderto see if the tumour or its metastases take upsignificant amounts is therefore not of much value.It gives no indication of how the metastases willbehave after any normal thyroid tissue has beenremoved. In order to use radioiodine to irradiatemalignant thyroid tissue it is necessary first todestroy any normal thyroid cells. Clearly the bestway of removing thyroid tissue is by a surgicaloperation since this serves three purposes: Itreveals the extent of the primary growth, providesthe pathologist with adequate material for histo-logical examination and permits an attempt tobe made to eradicate the tumour. In frail patientswho are unlikely to stand the strain of such' anoperation it is justifiable to give a dose of radio-iodine calculated to destroy all the normal func-tioning thyroid tissue. This will usually be of theorder of 40 to 8o millicuries, and overdosage is per-missible under the circumstances.The proportion of patients who benefit under

this plan of treatment is small. During the last12 months at the Christie Hospital, Manchester(Warrington, 1950), 2I patients were seen withcancer of the thyroid and 8 took up a significantamount of radioiodine. It is possible that patients'lives are prolonged under such circumstances andit is a great advantage that the treatment consistsmerely of drinking a glass of water containing 1131with practically ro toxic effects.The treatment of these patients can be carried

yet a stage further by various methods for stimu-lating the metastases to take on increased thyroidfunction after total thyroidectomy. Two differentlines of attack have so far produced satisfactoryresults. The first, and perhaps most obvious, is-the injection of thyroid stimulating hormone.(TSH) for a number of days before giving theradioiodine, following which a significantly greateruptake has been reported (Seidlin, I948). Thesecond method consists of giving really large doses(up 'to 2 gm. per day), of methyl thiouracil for amonth or longer, this appears to produce changesin the metastases comparable-with those that occurin the nonnal thyroid gland, i.e. disappearance ofcolloid, increase of acinar cell height, increased

vascularity and overall size of tumour. Thethiouracil is then stopped for two days, the block tothyroxine formation is thus released and on ad-ministering the radioiodine a substantially in-creased uptake is recorded (Trunnel, et al., I949).Ever since Von Eiselsberg (I894) first described

a patient with hyperfunctioning thyroid metastases,such cases have always held a fascination for thethyroidologist. The introduction of radioactiveiodine has made them almost ideal patients forisotope therapy and the first example of a happyresult from such treatment is the patient reportedby Seidlin (1946). Unfortunately this type ofthyroid carcinoma is excessively rare.The value of radioiodine in the treatment of

thyroid cancer can be summarized as follows:i. The principal use of radioiodine is in the

treatment of metastases.2. Only those metastases which will take up, or

can be made to take up, radioiodine can be treated.3. Less than 50 per cent. of all thyroid tumours

take up radioiodine.4. No tumour concentrates radioiodine as effec-

tively as normal thyroid tissue.5. The most important preliminary to this form

of treatment is the removal by surgery or thedestruction by radioiodine of all normal function-ing thyroid cells, in order that the metastases canbe stimulated to take on thyroid function.

6. The radioiodine uptake of the metastases canbe further stimulated by the prolonged administra-tion of methyl thiouracil in large dosage, which isthen stopped at least 48 hours before giving theradioiodine.

7. A rare form of thyroid cancer producesmetastases with hyperfunction and these are ideallysuited to isotope treatment.

8. No patient with thyroid cancer treated bythis technique is known to have been cured, butmany have been relieved of all their symptoms forvarying periods.

9. Autoradiographs prepared from tumourtissue removed from treated patients show a veryuneven distribution of the isotope, demonstratingthat the irradiation which takes place is not at alluniform.

io. The use of radioiodine in treatment of thiskind requires the services of a physicist and fairlyelaborate apparatus for its measurement. It is notwithout dangers for the patient, the most importantof these being suppression of bone marrow ac-tivity. It is likewise not without dangers for thosewho handle it and requires a form of discipline inthe clinician using it which he may find difficultyin adopting.

Experimental Thyroid TumoiursThe administration of thiourea or thiouracil to

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TAYLOR: Carcinoma of the Thyroid

rats and mice over a long period leads to tumourformation (Money, 1946). The first changes inthe thyroid are those of increased cell height, dis-appearance of colloid and greater vascularity.Then the epithelium throws out papillary pro-cesses into the acini and hypertrophy of thesepapillae eventually progresses to adenoma forma-tion. Occasionally one of these experimentallyproduced nodular goitres develops a true car-cinoma (Purves and Griesbach, I947), but it mustbe remembered that the thiouracil has to be ad-ministered to the animal for a time which, whentranslated into terms of man, would represent aconsiderable part of his life's span.

Such spontaneous cancers in thiouracil goitresin animals are rare. If, however, a carcinogen isgiven to the animals in addition to the thiouracil,thyroid cancer may be produced more readily.Bielschowsky (1945) produced such tumours bygiving rats allyl-thiourea and 2-acetyl-amino-fluorene. It has also been shown that radioiodinewhen administered to mtce treated over a longperiod with thiouracil can produce malignanttumours (Doniach, 1950). This is a most disturb-ing observation since both these, thiouracil andradioiodine, are in everyday use for the treatmentof thyrotoxicosis. Fortunately it appears that thesesubstances have to be used in considerably largerdoses and for longer periods than is normally thecase in man, but clearly it will be necessary to havemuch more information on this subject. It is par-ticularly important to know what will be the longterm results of giving radioiodine in therapeuticdoses to patients with toxic goitres. Until statisticsare available covering a period of 20 years it maywell be inadvisable to give radioiodine for thetreatment of Graves' disease in young peopleunless there were very good reasons for it, e.g.severe heart disease or previous multiple operationson the neck.

SummaryProphylaxisThe prevention of nodular goitre will inevitably

decrease the incidence of cancer of the thyroid,since often this develops in a longstanding goitre.The introduction in Britain this year of a smallquantity of iodine into domestic salt as recom-mended by the Medical Research Council will bea help in this direction.

DiagnosisA careful case history and a thorough examina-

tion, especially of the neck, offer the best chance ofproviding the diagnosis. Solitary nodules in non-toxic goitres, especially in younger patients,should always raise the strongest suspicion ofmalignancy.

Radioiodine may be of some assistance, sincemalignant tissue will pick up little if any in con-trast to normal thyroid tissue. Thus if, after atracer dose, the neck is carefully scanned with adirectional Geiger-Muller counter and a thyroidnodule is found to have no activity, the possibilityof malignancy might be entertained.The histological examination of tissue removed

from the thyroid gland will always be necessary fora firm diagnosis. Even then the pathologicalpicture may still give rise to varying interpretationsand it may be many years before the behaviour ofthe tumour makes the correct diagnosis possible.

TreatmentThe first and foremost form of treatment in car-

cinoma of the thyroid, whether it be overt or onlvsuspected is, with rare exceptions, surgical ex-cisiqn. There are three good reasons for this.First, it may prove possible to excise the tumourcompletely and thus offer the patient the bestchance of a cure. Secondly, tissue is removedwhich can be examined by a pathologist so that anaccurate diagnosis is obtained. Thirdly, should thetumour be- a well-differentiated type of adeno-carcinoma with metastases, the removal of theparent gland may result in the metastases takingon thyroid function and thus make them capable oftreatment with radioiodine.The operation performed will depend on the

type of tumour encountered. A solitary nodule isbest removed with that lobe of the gland in whichit is found. A papillary carcinoma in a youngerpatient is best dealt with by hemi-thyroidectomyand multiple non-mutilFting incisions for excisingthe affected lymph nodes as and when they be-come involved. If the lymph nodes are widelvinvolved a block dissection of that side of the neckcompletes the operation. Adenocarcinoma istreated, where possible, by total thyroidectomy andsubsequent block dissections of the cervical lymphnodes when they are found clinically to be in-volved.

Finally there is a small group of patients whopresent with rapidly growing tumours. Surgeryfor such patients does not prolong life and makesthem no more comfortable. 'Even when a tracheo-tomy is performed, tumour cells may start fungat-ing out of the opening within a short time. Suchpatients are best treated with X-ray therapy fromthe start, since the tumour occasionally regressestemporarily and the development of mediastinalmetastases makes their demise less unpleasant thanif they are choked to death.

Radiotherapy can also be used with advantagein those patients who have surgical ablation of thetumour. Metastases to lymph nodes in the neckmay be particularly suitable for irradiation. In

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64 POSTGRADUATE MEDICAL JOURNAL February I95I

addition radiotherapy offers useful palliation, es-pecially 'where a solitary metastasis in a lung isproducing haemoptyses.

Radioiodine is used 'in those patients whosemetastases take on function'after total thyroidec--tomy. It may prolong life and greatly increasethe patient's sense of well be'ing. Probably notmore than 15 per cent. of all patients with car-cinoma of the thyroid gland seen at the presenttime are capable of being treaLed in this manner.

BIBLIOGRAPHY

A 'very large number of articles has appearedon the subject of thyroid carcinoma in the lastfew years, and the references given below are notintended in any way to be a comprehensive list.The aim has been to give some of-the more im-portant contributions to thyroid literature whichwill serve as a guide to anyone wishing to discpvermore about this subject. The most useful generalaccounts -will be found in 'The Thyroid Gland'by J. H. Means, 1948; 'Practical Aspects ofThyroid Disease' by G. Crile, I949; and thesection on the thyroid in the ' Proceedings of theNational Cancer Conference' held at Memphis in1949.

BIELSCHOWSKY, F. (1945), Brit. Y7. exper. Path., 26, 270.BRANSON, K. M., and HOUSTON, W. (I949), Lancet, ii, 979.CATTELL, R. B. (Is5o), . Clin. Endocrinol., I0, I099.COLE, W. H., SLAUGHTER, D. P., and ROSSITER, L. J.

(1945), J. Amer. med. Ass., 127, 883..COLE, W. H., MAJARAKIS, J. D., and SLAUGHTER, D. P.

(I949),J. Clin. Endocrinol., 9, I007.COPE, O., DOBYNS, B. M., HAMLIN, E., and HOPKIRK, J.

(I949), Ibid., 9, 1012.

CRILE, G., JNR. (x947), Surg. Gynec. Obstet.j 85, 757.CRILE, G., JNR. (1949), 'Practical Aspects of Thyroid Disease,,

Philadelphia, p. 226.CRILE, G., JNR. (I949), Ibid., Pp. 236-237.CRILE, G., JNR. (I949), Ibid., Chapter 24.CRILE, G., JNR. (I949), J. Amer. med. Ass., 139, 1247.CRILE, G., INR. (I950), 7. Clin. Endocrinol., IO, 1152.DOBYNS B. M., SKANSE, B., and MALOOF, F. (i949), .

clin. Endor.,9g,1I71.,DONIACH, I. (x9SO), Brit. Y. Cancer, 4, 223.FITZGERALD, P. J., and FOOTE, F. W. (1949), J7. Qlin.

Endocrinol., 9, 1153.GRAHAM A. (1925), Ann. Surg., 82, 30.GRAHAM, A. (I94), Radiology, 37, 521.GRAHAM, J. M., and McWHIRTER, R. (I947), Proc. Roy. Soc.

Med., 40, 669.JOLL, C. (1932), 'Diseases of the Thyroid Gland,' London.LAHEY, F. H., HARE, H. F., and WARREN, S. (1940), Ann.

Surg., 112, 977.LAHEY, F. H., and FICARRA, B. J. (1946), Surg. Gynec. Obstet,

82, 705.LENNOX, B. (I948), 7. Path. Bact., 60, 295.METZGER, F., and DEUTSCH, M. (1948), Pliysiol. Rev., 74,

I640.MONEY, W. L. (I946), Anat. Rec., 96, 48.PEMBERTON, J. DE J. (1939), Surg. Gynec. Obstet., 69, 417.'Proceedings of the National Cancer Conference, Cancer of the

Thyroid' ( 949), Memphis.PURVES, H. D., and GRIESBACH, W. E. (947), Brit. J. exper.

Path., 28, 46.RAWSON, R. W., MARINELLI, L. D., SKANSE, B. M.,

TRUNNEL, J., and FLUHARTY, R. G. (1948), J. clin.Endocr., 8 826.

RIENHOFF, W. F. (1929), drch. Surg., I9, 986.ROBB, C. G., and BATEMAM G. H. (1949), Brit. 3r. -Surg., 37,

202.SEIDLIN, S. M. MARINELLI, L. O., and OSHRY, E. (I946),

7. Amer. med. Ass., 132, 838.SEIDLIN, S. M., OSHRY, E., and YALLOW, A. A. (1948), J7

Clin. Endocrinol., 8, 423.TAYLOR, S., and STEWART, F. S. Unpublished data.TRUNNEL, J. B., MARINELLI, L. D., DUFFY, B. J., HILL,

R., PEACOCK, W., and RAWSON, R. W. (1949), J. clin.Endocr., 9, 1138.

VAN DER LAAN, W. P. (1947), New Eng. 3. Med., 237, 221.VEALL, N. (1o05o), In the press.VON EISELSBERG (I894), Arch. klin. Chir., 48, 489.WARD, R. (1949), J. Clin. Endocrinol., 9, 1031.WARRINGTON, H. C. (I950), Lancet, i, 212.WEGELIN, C. (1926), 'Handbuch der speziellen pathologischen

Anatomie und Histologie,' Vol. VIII, Berlin.WILLIS, R. A. (1948), 'Pathology of Tumours,' London, p. 607.WOZENCRAFT, P., FOOTE, F. W., and FRAZELL, E. I.

(1948), Cancer, I, 574.

ANNOTATION

The PhosphatasesAlkaline Phosphatase

In 1923 Dr. R. Robison, of the Lister Institute,London, began a series of experiments on thephosphatase enzyme of bone, which has led to aclearer conception of the process of bone formationand a better understanding of the mechanism ofcalcium and phosphate deposition. The enzyme,which is shown to be present in bone and ossifyingcartilage, can be extracted by breaking up the boneand treating with chloroform water. This extract,added to a solution of a primary ester of phosphoricacid, will liberate phosphorus from its organic

combination: and in the presence of inorganiccalcium the liberated phosphate is deposited ascalcium phosphate. Robison suggested that thebone enzyme in the hypertrophic cells of thetissue where calcification takes place liberates freephosphate from the organic esters of phosphoruscontained in the fluids bathing the bone andcartilage, thus giving a local increase of the amountof inorganic phosphate in solution. According tothe law of mass action any increase in the con-centration of phosphate ion will, in the presenceof the ionic calcium of the plasma, lead to adeposition of bone salt. This bone enzyme phos-phatase is invariably present in bone or ossifyingcartilage, while unossifying cartilage fails to showany phosphatase activity. Young, rapidly-growing

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