J. clin. Path. (1966), 19, 103

Pathological and clinical findings in a series of67 cases of medullary carcinoma of the thyroid

E. D. WILLIAMS1, C. L. BROWN, AND I. DONIACH

From the Institute ofPathology, The London Hospital

SYNOPSIS The pathological features of 67 cases of medullary carcinoma of the thyroid were studied,and when possible the case histories were reviewed.The typical tumour is sharply demarcated but not encapsulated, is composed of sheets of cells

having eosinophilic granular cytoplasm, with the deposition of amyloid in the stroma. We wouldstress the frequency of binucleate cells, the scarcity of mitoses, and the frequent occurrence ofcalcification.The clinical findings show a wide variation in age at presentation of this tumour, and a wide

variation in prognosis, with a mean survival from the time of presentation to hospital of 6-6 years,

the longest being 21 years. Two of this group of patients also had phaeochromocytomas; these twoand three others showed small papillary tumours of the eyelids, lips, and tongue.

Despite the variation in some of its characteristics, medullary carcinoma of the thyroid is con-

sidered to be a distinct and sharply defined entity. It appears to be the only type of thyroid carcinomaassociated with phaeochromocytoma, the only type associated with multiple mucosal neuromas andthe only type with a familial incidence. These findings emphasize the validity of its separation fromother types of thyroid carcinoma.

Thyroid carcinomas have for many years beengenerally classified into a differentiated group ofpapillary and follicular carcinomas and an ana-plastic group. Various authors have noted that thereis a small group of tumours which may appearhistologically undifferentiated but which have a muchbetter prognosis than the typical anaplastic thyroidcarcinoma.Horn described a small series of these cases in

1951, and Laskowski in 1957 proposed the name'carcinoma thyroideum hyalinicum' for this type oftumour. Hazard, Hawk, and Crile, in 1959, clearlydefined the major histological features of thistumour in a study of 21 cases and recognized thediagnostic importance of the regular occurrence ofamyloid in the stroma. They also commented on therelatively good prognosis and suggested the name'medullary carcinoma of the thyroid'. Since theirdescription, this type of tumour has been classifiedas a separate type in the major studies of thyroidcarcinoma, and Woolner, Beahrs, Black, McConahey,and Keating (1961) found 57 examples in a survey ofLPresent address: The Department of Pathology, PostgraduateMedical School, Hammersmith Hospital, London.

Received for publication 29 September 1965.

885 cases of thyroid carcinoma. These authorsreferred to the tumour as 'solid carcinoma withamyloid stroma' rather than medullary carcinoma.Because of the prognostic importance of recognizingthis type of tumour histologically and because anumber of cases with unusual associated diseasescame to our attention, we decided to analyse thehistological features of a large series of medullarycarcinoma of the thyroid and study the availableclinical records and follow-up.

Sixty-seven examples of medullary carcinoma ofthe thyroid were studied histologically. Twenty-twowere from the London Hospital; the rest were ob-tained from the files of four other London hospitalsand from a number of individual pathologists whokindly sent in material. A major criterion for theinclusion of a case within the series was the presenceof amyloid in the stroma of the tumour. In the greatmajority of cases amyloid was identified by at leasttwo of the three generally used histological tech-niques for this substance, methyl violet, congo red,and thioflavin T. In two cases thioflavin T alonegave a positive result. In four cases only sectionsstained with haemalum and eosin were available; inthese amyloid was identified by its amorphous

103

E. D. Williams, C. L. Brown, and I. Doniach

eosinophilic appearance and by the development ofanomalous colours when the sections were viewedbetween crossed polaroids (Brewer, 1964). Thistechnique was also used with the Congo-Red stainedsections (Ladewig, 1945).

PATHOLOGICAL FINDINGS

The typical medullary carcinoma of the thyroid is afirm, rounded tumour up to 8 cm. in diameter, lyingwithin the substance of the thyroid lobe. On crosssection the tumour is grey-white, often gritty, and isusually sharply demarcated from the adjacentnormal thyroid. A few cases were described as en-capsulated, and in some an ill-defined lobulation wasseen.

Microscopically the tumour is made up of sheetsand nests of regular eosinophilic granular cells,separated by a fibrous stroma containing irregularmasses of amyloid (Fig. 1). Some of the specificfeatures will now be considered in more detail.

CYTOLOGY

The typical cell has an ill-defined cytoplasmic mem-brane and plentiful finely granular eosinophiliccytoplasm (Fig. 2). The nucleus is central, averaging8,u in diameter, with a speckled chromatin pattern;the nucleoli are not prominent. Binucleate cells arealmost invariably present and cells with three or morenuclei are not infrequent. A moderate degree ofvariation in nuclear size is usual and may sometimesbe marked (Fig. 3). Mitoses are infrequent: theywere seen after careful search in 26 tumours, in onlysix were they found easily.

,G -.*-.

FIG. 1.

In well-fixed tissue the commonest appearancewas of closely packed polygonal cells. In poorly-fixedtissue, cell shrinkage occasionally led to separationwith a single layer of cells remaining attached to theconnective tissue trabeculae giving a pseudo-papillary appearance (Fig. 4). A second cell type wasseen in just over half the tumours; these cells wereelongated, with oval, often hyperchromatic nuclei(Fig. 5), sometimes showing a whorled pattern andsometimes the streaming pattern described in oat-cellcarcinomas (Fig. 6). Although intermediate cell typesbetween these spindle-shaped cells and the typicalpolygonal cell were not uncommon, the two typesusually occurred in distinct areas within any onetumour. In 14 cases the spindle cell pattern was thedominant one. Within the islands of spindle celltumour small clear vacuoles were frequently seen; insome cases these appeared to be the result ofvacuolation within the cytoplasm of macrophages(Fig. 7).While in most tumours the polygonal cells were

arranged in irregular sheets or broad trabeculae withno definite pattern, in some regular cellular arrange-ments were present. In four cases well-markedpalisading of the peripheral cells of the tumourclumps was seen (Fig. 8); in other instances atendency for the nuclei of the peripheral cells to lietowards the inner side of the cell was noted. Thetype of nuclear palisading seen in neurilemmomaswhich has previously been described in this tumour(Russell, Ibanez, Clark, and White, 1963) was seenonly to a minor degree. In some areas of a few casesthe sheets of polygonal cells were regular in size andseparated by a thin connective tissue network, pro-ducing a pattern reminiscent of a carcinoidtumour,

**

t <

FIG. 2.

FIG. 1. Typical field of a medullary carcinoma showing sheets of uniform tamour cells and eosinophilic nodulardeposits of amyloid. H.E. x 160.FIG. 2. High-power field of a typical medullary carcinoma showing amyloid deposits and tumour cells with plentifulfinely granular cytoplasm, some nuclear variation and occasional multinucleate forms. H.E. x 640.

104

carcinoma.

FIG. 4. H.E. x 50. An area of medullary carcinoma inwhich shrinkage has led to pseudo-papillary appearance.

FIG. 6. H.E. x 1

carcinoma.'Oat cell' pattern in medullary

FIG. 7. H.E. x 400. Appearance of macrophage-like cellsand vacuoles within spindle cell medullary carcinoma.

e* R R o~~~~~~~~~~S t I ..:VWt'

<;1* t * t * **; ~~~~~~~~~~~~~~~~~~~i

FIG.8.H.E.x 160. Palisading of peripheral cellsin~~~~~~~~Ov

44o.rcums

t. ..w.#t.: 4.

FIG. 9. H.E.carcinoma.

rVO x <*9

.D:: k- :

s,':tEa,,,e,l S

O&Z . {s

FIG. I 0. H.E. x 200. Rare variant of tumour cellscontaining intracytoplasmic basophilic mucin.

x 400. Tulbule formation in a medullary

Pathological and clinical findings in a series of 67 cases of medullary carcinoma of the thyroid 107

or if rather more trabecular, of islet cell tumours.Tubule formation was present in small amounts infive cases (Fig. 9); these tubules occasionally con-tained a little basophilic mucin. In some of thesecases a luminal brush border was seen. No colloidsecretion was noted and no true papillary structureswere present. In three cases tumour cells with intra-cytoplasmic basophilic mucin were seen, resemblinggoblet cells (Fig. 10). While true tubular structureswere uncommon, structures resembling rosettes wereoccasionally seen; these consisted of elongated cellsorientated around a small central area of amyloid.Areas of necrosis in the tumour were extremelyunusual, extensive necrosis being found in only onecase. Focal calcification, however, was quite com-mon, being found in more than half the cases (Fig.11); extensive calcification was present in seventumours. Many of the calcified deposits were smalland rounded and resembled psammoma bodiesexcept that they did not show the same regularity oflamination. Occasionally calcification definitely with-in amyloid was observed, and the rounded bodieswere thought to represent calcification in smalldeposits of amyloid. Cystic areas in the tumourwere extremely uncommon, being seen only twice.The stroma of the tumour was variable, in some

cases forming thin connective tissue bands betweentumour cell groups but in most cases consisting ofdense relatively acellular collagen.The properties of the tumour cells were investiga-

ted by a number of techniques other than haemalumand eosin. Periodic-acid-Schiff technique showedpositive material in small amounts in tumourcytoplasm, and plentiful small granules in the clearmacrophage-like cells. In part this was due to thepresence of glycogen as shown by Best's carminemethod. The tumour cells were weakly positive toAlcian blue. Well over half of the 34 cases testedcontained a few cells positive with the Glees Marslandand Bodian argyrophil techniques; a few cases werestrongly positive.

AMYLOID

In the majority of cases a considerable amount ofamyloid was present in the primary tumour and inthe metastases (Figs. 12 and 13), although sometimesunevenly distributed throughout the tumour. Thesmaller deposits of amyloid were present in betweenthe tumour cells, sometimes closely apposed to thecell membrane or even within the cytoplasm. Largeramounts formed interlacing trabeculae between thecells, and massive deposition was present as irregularmasses either within the sheets of tumour cells or inthe stroma. Sometimes tumour cells were arrangedaround amyloid deposits in a pseudo-follicular4*

FIG. 11. H. V.G. x 200. Calcareous deposits in amyloidare shown as darkly staining irregular masses.

FIG. 12. and 13. Medullary carcinoma showing Congo redstaining of amyloid, and same area (Fig. 13) viewed be-tween crossed polaroids showing characteristic green colourof the stained amyloid. Congo red and haemalum. x 160.

E. D. Williams, C. L. Brown, and L Doniach

pattern. Scattered small deposits were not uncommonin the stroma and were seen in the adventitia of smallvessels within and immediately adjacent to areas oftumour. Amyloid in small amounts, remote fromthe tumour, was found in two cases with long-standing widespread secondary carcinoma. Themajor site of deposition was the renal glomeruli.This will be the subject of a further report.A foreign body giant cell reaction to the amyloid

deposits was noted in a few tumours (Fig. 14); insome instances it was difficult to be certain whethermultinucleated giant cells associated with amyloidwere of macrophage or tumour origin. In three casesround concentrically laminated masses of amyloidwere present in the stroma. These showed a maltesecross pattern of birefringence when viewed betweencrossed polaroids.

SPREAD OF THE TUMOUR

In nine cases the tumour was sharply demarcatedfrom the surrounding thyroid tissue by a complete orpartial fibrous capsule (Fig. 15). In the majority oftumours the adjacent thyroid parenchyma wasirregularly engulfed by advancing tumour, andscattered colloid containing non-neoplastic thyroidfollicles was often seen completely surrounded bytumour cells in the outer third of the carcinoma(Fig. 16). Small interstitial groups of tumour cellsseparated from the main mass were uncommon;lymphatic permeation was seen in a few cases. Themajor early site of metastasis was undoubtedly thecervical lymph nodes. In many cases the initialcomplaint of a lump in the neck was due to lymphnode enlargement; in several cases the thyroidtumour was not resected until several years after theremoval of tumour-containing lymph nodes from theneck. Three at least of these tumours had originallybeen diagnosed as carotid body tumours on histo-logical grounds. Cervical lymph node involvementwas present at the time of diagnosis of thyroid

TABLE IDISTRIBUTION OF METASTASES IN 20 POST-MORTEM CASES OF

MEDULLARY CARCINOMA

Site of Tumour Deposit Number ofCases

1 Local lymph nodes(including mediastinum)

2 Lungs3 Liver4 Adrenals5 Bones6 Pleura7 Heart8 Ovary9 Pancreas10 No disseminated tumour

1395442

4

carcinoma in two-thirds of the cases. At necropsy thepattern of distant metastases is shown in Table I. Attimes the anterior mediastinal lymph nodes werematted together by tumour to form a large retro-sternal mass; the hila of the lungs were also occasion-ally involved. In one case there was direct bronchialinvasion, and a bronchoscopic biopsy showedsecondary medullary carcinoma. Apart from thislocal involvement of neck and mediastinum thecommonest sites of distant spread were the lungs,liver, adrenals, and bones.

OTHER THYROID FINDINGS

The carcinoma was present in the right lobe in 24 ofthe 35 instances in which the side was recorded. Thenon-neoplastic thyroid parenchyma was in nearly allcases normal. No case showed severe focal thyroiditis,and evidence suggesting thyrotrophic stimulation wasnot seen. Uncommonly follicular adenomas separatefrom the primary medullary carcinoma were noted.In three examples small areas resembling embryonaladenoma were found within the carcinoma. In one ofthe 67 cases there was also a papillary carcinoma ofthe thyroid. This patient had noted a goitre from theage of 8; subtotal thyroidectomy at the age of 16showed a gland almost entirely consisting of papillarycarcinoma. She had repeated operations for recur-rence of carcinoma, all showing only papillarycarcinoma, until at the age of 28 the residualthyroid tissue from one lobe was resected andcontained discrete nodules consisting entirely oftypical medullary carcinoma, and quite distinct fromany papillary tumour.

CLINICAL DETAILS

The sex incidence, female to male, was 1-3 to 10.The age of the patients at presentation to hospitalwith a symptom, usually swelling of the neck, refer-able to the thyroid carcinoma varied widely. Theyoungest was 10 when he was first seen and theoldest 79 with a fairly uniform incidence over theadult decades (Fig. 17). In four patients the thyroidenlargement was first noted before the age of 20, andsix patients gave a history of five or more years ofthyroid swelling before they attended hospital. Theusual course of treatment adopted was subtotalthyroidectomy with removal of affected nodes. Insome cases radiotherapy was used following opera-tion and sometimes following the diagnosis ofanaplastic carcinoma. It is difficult to assess theresults of radiotherapy but no case of dramaticshrinkage was observed and we doubt if the naturalhistory of the disease is significantly altered. Where

108

Pathological and clinical findings in a series of 67 cases of medullary carcinoma of the thyroid 109

A+~

~~~~tW~~~~~~~~~Y~W

FIG. 14.

FIG. 14. H.E. x 200. Multinucleate giant cells offoreignbody type related to deposits of amyloid.

FIG. 15. H.E. x 50. Low-power view of the edge of anencapsulated medullary tumour.

FIG. 16. H.E. x 40. Low-power view of advancing edgeof a medullary carcinoma showing engulfed non-neoplasticthyroid follicles. ,

1

FIG. 1 5.

E. D. Williams, C. L. Brown, and L Doniach

15 M/ attempts were made to study the radio-iodine uptake]EM LE of the tumour by external scanning or by auto-

14 radiography, to induce it to concentrate radio-iodine13 by thyroid ablation, or to treat the tumour with12 radio-iodine, the results were completely negative.

The only systemic symptom which occurred with11m unexpected frequency was diarrhoea. Severe, pro-10 longed, unexplained diarrhoea was found in 14 cases.

In view of the lack of evidence of radio-iodine9e ; 0 s m //// //concentration by the tumour it may be due to the

8- ////2 %/// ///// //// production of a humoral factor other than thyroxineand will be the subject of a separate report.A variety of other diseases was found in this series

6- ~~~~~~~~~~~ofthyroid carcinoma, but with two exceptions none

i5 ll lil ///% X ///// of them was considered to be of any significance.Two cases also had phaeochromocytomas, in one

4l patient bilateral. Both these patients also had small3i papillary tumours of the conjunctiva, lips and tongue

which on histological study were shown to be2 neuromas. Full reports of these patients are to be1 published (Williams and Pollock, 1966). Three othero//11L0- E cases were also described as having similar papillary

0-10 11-20 21-30 31-40 41- 51-6561-20 71-60 tumours, in one case of the buccal mucosa only. AAGE (years) man and his daughter were noted in our series both of

FIG. 17. Incidence of medullary carcinoma of thyroid by whom had a medullary thyroid carcinoma. Thesex and age, in decades, at presentation. daughter was the patient mentioned above, who, in

r34d-52d' /,7)'ZM~~~~~~~~~~~Died.from MledullaryV///////////// carcinmar f thyrdid.

,Died trn urrebted condition1 1 year or more after presentation.

I Z I AJive at follow-u 1 year or morel55 d i////////////A s after presentation132 9 l t FIG. 18. Survival of

patientsfrom presen-31-dL Itation with medullary6974 ! [ tcarcinoma to death55 9 or latest follow up

(including among the-52 d' survivors only those52 9 cases tracedfor at2-0I least one year).

110

Pathological and clinical findings in a series of 67 cases of medullary carcinoma of the thyroid 111

addition, had bilateral phaechromocytomas andfacial neuromas.The survival of these cases is often extremely long

(Fig. 18). Eleven patients were known to have diedof their disease, with a mean survival of 6-2 yearsfrom the first symptom (range nine months to 21years) and a mean of 4-1 years from the time ofpresentation to hospital (range three months to 17years). Twenty-two patients who died of unrelatedcauses or who were alive when last seen werefollowed up for periods of one year or more. Thisgroup showed a mean survival from onset ofsymptoms of 11-2 years (range one to 35 years) and amean of 7-5 years from time of presentation tohospital (range 1 to 21 years). A total of 15 patientssurvived for five or more years from presentationwhile there were eight deaths in less than four years.

DISCUSSION

In this study we have confirmed and extended thepathological description of medullary carcinoma ofthe thyroid given by Hazard et al. (1959). Theseauthors have stressed the major features of thistumour: the solid sheets and islands of cells withdeposition of amyloid. In addition to these points wehave laid emphasis on the cytological details, thefrequent occurrence of binucleate cells and thefrequent finding of focal calcification, which in mostinstances was probably calcification within amyloid.A comparison of our findings with those of the majorAmerican series is given in Table II.Both Hazard et al. (1959) and Woolner et al.

(1961) consider the presence of amyloid an essentialdiagnostic feature of this tumour. We used thiscriterion for the selection of our cases, and we wouldagree with Hazard et al. that the amount of amyloidpresent varied widely. In eight cases amyloiddominated the histological picture, with large areasof the section containing more amyloid thantumour. In almost half the cases amyloid was a con-spicuous but not dominant feature. In 27 casesamyloid was found easily on searching after thecytological features of the tumour suggested thediagnosis, while in three cases only a small amount of

amyloid was found after prolonged search. Threecases were excluded because no amyloid was found,although in other respects the diagnosis of medullarycarcinoma seemed suitable. In common with otherworkers (Hazard et al., 1959; Vassar and Culling,1961) we have not found amyloid in other thyroidtumours, although we have examined only a smallseries with special stains for amyloid. The presence ofamyloid in a thyroid carcinoma is therefore of greatvalue in establishing a diagnosis; its absence,particularly if only small amounts of tissue areavailable, should not exclude the diagnosis ofmedullary carcinoma.

Albores-Saavedra, Rose, Ibanez, Russell, Grey,and Dmochowski (1964) have investigated theamyloid in this type of tumour, and conclude that itis formed by the tumour cells themselves. We agreewith their observations that amyloid may occasion-ally be seen within tumour cell cytoplasm, but wewere unable to find the myeloma-like renal tubularcasts they described in any of our necropsied cases.It has been suggested by Vassar and Culling (1961)that the amyloid in these tumours is an alteredthyroglobulin secreted into the stroma. It is difficultto understand, if this were true, why amyloid is notseen commonly in association with colloid formingfollicular and papillary carcinomas. We do notbelieve that there is any convincing evidence that theamyloid is related to thyroglobulin; these tumoursin our experience do not make thyroglobulin andshow no evidence of the ability to bind radio-iodine.Other tumours are known on occasion to showamyloid deposition in their stroma, and there seemsno need to invoke an explanation involving thyro-globulin. It does seem, however, that the amyloid isin all probability manufactured by the tumour cells,or alternatively that the cells may secrete a factorleading to the formation of amyloid from a circulat-ing glyco-protein. It is likely that the amyloid oramyloid-precipitating factor diffuses outwards local-ly; certainly vessels within and immediately adjacentto tumour deposits commonly show amyloid in theiradventitia.While the basic pattern of a solid cellular tumour,

with the cells arranged in sheets or packets, and with

TABLE IICOMPARISON OF FINDINGS IN THIS SERIES WITH THE TWO MAJOR AMERICAN SERIES OF CASES OF MEDULLARY CARCINOMA

Series No. of Cases Age Range at Sex Ratio F to M Range of Survival No. of Patients % Patients withDiagnosis in Years from Available for Lymph-node Involve-

Diagnosis to Death Follow-up ment at Operationfrom Thyroid Surviving > FiveCarcinoma Years

Hazard et al. 21Woolner et al. 57Present 67

33 to 6614 to 7410 to 79

2 : 11 3 : 11-3: 1

0-3 to 270-5 to 2003 to 17

10 out of 2120 out of 3716 out of 33

5859 666-7

E. D. Williams, C. L. Brown, and L Doniach

amyloid in the stroma, was common to all thetumours we studied, a number of histologicalfeatures, beside the amyloid content, showed con-siderable variation. It is of practical importance todetermine whether any of the variables correlate withthe great variation in prognosis shown by thistumour. Unfortunately the follow up of many of theearlier cases was very poor, but it was possible tomake a comparison between seven patients who diedfrom carcinomatosis within four years of diagnosis,and eight patients who were known to have survivedat least 10 years from diagnosis. The conclusionsfrom this remain tentative until we can obtainfollow-up data on a considerably larger series. Thevarious histological patterns of these tumours werescored on a four-point scale without knowledge ofthe survival of the case. No good correlation wasfound between the amount of amyloid and survival,or between either the frequency of binucleate cells orthe degree of nuclear variation and survival. Theamount of collagenous stroma was also withoutsignificance. Mitotic activity was noted in six ofseven short-lived patients, and was absent in all butone of the long-survival patients. Calcification waspresent in only two of the seven short-term groupbut was found in all but one of the long-term group.Necrosis was noted in four of the seven short-termsurvivors, but was not found in any of the long-termsurvivors. Finally the spindle cell pattern wasassociated with a relatively poor prognosis, formingthe major component in four of the seven patientswho died in less than four years, while being found inonly one of the patients who lived for more than 10years and then as the less common cell type. Thesefindings are not surprising; multinucleate cells andnuclear variation seem to be of less prognostic signi-ficance in endocrine tumours as a group than in othertypes, while the presence or absence of mitoseswould be expected to be of importance in anytumour. The calcification in these tumours mostlyoccurred in amyloid; its presence or absence isprobably related to the age of the amyloid and thusto the general growth rate of the tumour, as is thepresence of necrosis. The composite picture wewould draw of one of these tumours with a poorprognosis is a tumour with a predominant spindlecell pattern, fairly frequent mitoses, small areas ofnecrosis, variable amounts of amyloid but nocalcification. In contrast the medullary carcinomawith a good prognosis is composed of polygonalcells with abundant granular cytoplasm, possiblyshowing moderate nuclear pleomorphism and fairlyfrequent binucleate cells but without mitoses, withvariable amounts of amyloid and focal calcification.One feature that we have not discussed in relation

to prognosis is the absence or presence of a capsule.

An intact capsule was seen in two cases, while inseven a fibrous capsule was present but was breachedby tumour trabeculae. One of the tumours with anintact capsule was an incidental finding at necropsy;no secondary deposits were found; the other wasremoved from a patient of 25; our efforts to obtaina follow-up of more than one year have been withoutsuccess.We have not given any figure for the incidence of

these tumours partly because a considerable propor-tion of our cases has been contributed from otherhospitals, and partly because a number of our owncases had been mis-diagnosed in the past. Three ofour cases were originally indexed as secondarycarcinoma of the thyroid, and three as solid benignadenomas of the thyroid. Before we are able to givean accurate figure for the incidence of this tumourwe feel we should review every example of tumourinvolvement of the thyroid in our files, whetherindexed as benign or malignant, primary or secon-dary, and probably every cervical tumour massreported as being a metastatic tumour from anunknown site, or as a carotid body tumour. If acervical lymph node contained follicular or papillarycarcinoma of the thyroid, then we feel confident thatthe great majority would be recognized, furthersurgery on the thyroid would follow, and the casewould be included in our statistics as one of thyroidcarcinoma. We know, however, that in a number ofinstances a mass of medullary carcinoma in the neckhas been diagnosed as a carotid body tumour, whileother examples have been called secondary car-cinoma, primary unknown. One poorly fixedexample in this series was originally diagnosed asplasmacytoma with massive amyloid deposition.These past difficulties underline the importance ofbeing aware of this type of thyroid tumour, but theymake it impossible for us to give an exact figure forthe incidence of medullary carcinoma of the thyroid.However, our initial figures, taken only from thosecases included in The London Hospital index ascarcinoma of the thyroid, include 15 examples ofmedullary carcinoma out of a total of 135 thyroidcarcinomas. Further study has revealed seven moreexamples of medullary carcinoma, but has alsoshown that a number of tumours we would nowundoubtedly call carcinomas were termed papillaryadenomas up to about 25 years ago. We think thatmedullary carcinoma may well form more than the3 5% (Hazard et al., 1959) or 6-5% (Woolner et al.,1961) of all thyroid carcinomas, and its incidence isprobably in the region of 10% or more.With regard to some of its features, medullary

carcinoma is a very variable tumour. The ages atpresentation of our cases were widely scattered, andthe survival rate following diagnosis varied between

112

Pathological and clinical findings in a series of 67 cases of medullary carcinoma of the thyroid 113

three months and 21 years. Some of the histologicalfeatures were also very variable. The broad spectrum,however, does not imply that medullary carcinoma ismerely a histological variant of other types ofthyroid carcinoma, in the sense that both papillaryand follicular carcinoma may have Hurthle cellvariants. In support of the distinctive nature ofmedullary carcinoma of the thyroid is the part itplays in various tumour syndromes. The reasons forits association with phaeochromocytoma, and for itsassociation with multiple mucosal neuromas, areprobably genetic. Only one of the cases of phaechro-mocytoma and thyroid carcinoma reviewed byWilliams (1965) was unequivocally diagnosed aspapillary carcinoma of the thyroid, while afterreview of the histological findings in five examples,13 of the 21 cases were described as medullarycarcinomas. It seems that the association of thyroidcarcinoma and phaochromocytoma is specificallywith medullary carcinoma. It is also likely that theassociation of thyroid carcinoma with multiplemucosal neuromas is again specifically with medul-lary carcinoma, as we have found evidence for thisassociation in five of our 67 cases, while we have notfound it with any other type of thyroid tumour.Both these associations may be familial; a father

and daughter with medullary carcinoma and mucosalneuromas are included in our series. The daughteralso had bilateral phaeochromocytomas. We havetraced four other families in the literature (Williams,1965) with more than one member proven to havethyroid carcinoma; in three of these multiple

examples of phaeochromocytoma were also foundEleven members of these five families have hadthyroid carcinoma which in eightwas consideredto bemedullary in type. We know of no evidence thatother types of thyroid carcinoma can be familial.These clinical findings support our contention that

medullary carcinoma of the thyroid is an importantand distinct entity, clearly separable from other typesof thyroid carcinoma.

We are particularly grateful to Drs. Sybil Robinson andA. G. Stansfield, Professors C. V. Harrison and M. Pricefor allowing us access to their files, and to Drs. RaymondGreene and A. Stuart Mason, and Messrs. J. E. Piercy,J. E. Richardson and Selwyn Taylor for permitting us tostudy the clinical records of their cases. We would alsolike to thank the numerous pathologists and clinicianswho helped in the study of individual cases. We are grate-ful to Miss R. Cresswell for secretarial help.

REFERENCES

Albores-Saavedra, J., Rose, G. G., Ibanez, M. L., Russell, W. O.,Grey, C. E., and Dmochowski, L. (1964). Lab. Invest., 13, 77.

Brewer, D. B. (1964). Renal Biopsy, p. 20. Arnold, London.Hazard, J. B., Hawk, W. A., and Crile, G. Jr. (1959). J. clin. Endocr.,

19, 152.Horn, R. C., Jr. (1951). Cancer (Philad.), 4, 697.Ladewig, P. (1945). Nature (Lond.), 156, 81.Laskowski, J. (1958). Nowotwory, 7, 23.Russell, W. O., Ibanez, M. L., Clark, R. L., and White, E. C. (1963).

Cancer (Philad.), 16, 1425.Vassar, P. S., and Culling, C. F. (1961). Amer. J. clin. Path., 36, 244.Williams, E. D. (1965). J. clin. Path., 18, 288.-, and Pollock, D. J. (1966). J. Path. Bact., in the press.Woolner, L. B., Beahrs, 0. H., Black, B. M., McConahey, W. M., and

Keating, F. R. Jr. (1961). Amer. J. Surg., 102, 354.