FROM T H E RESEARCH INSTITUTE O F NATIONAL DEFENCE, SUNDBYBERG, SWEDEN.

RADIOSTRONTIUM-INDUCED CARCINOMAS OF THE EXTERNAL EAR

AGNAR NILSSON

The frequencies of carcinomas induced in the mucous membranes of the nose and mouth in mice were investigated in a previous study (NILSSON 1968) in relation to the dose of '"'Sr administered. In the same material a significant number of carcinonias were also observed in or around the external ear. The present report deals with the origin, development and frequency of these carcinomas.

Material and Methods . Four groups of GEA micr, 75 days old, were treatcd intraperitoneally with ""Sr (NO:<) 2. In addition, a control group of 95 animals without ""Sr treatment was used for a study of [lie natural incidence of tuniours. At intervals of 7, 14, 21. and SO days after injection of '"'Sr, and then at iiianthly intervals, five mice froln each group were selected at random and sacrificed, until all mice in each series had been utilized. The experimental conditions and the '"'Sr dozes employed are recorded in Table 1.

After the mice had been sacrificed, their heads were divided along the median plane, fixed in Stieve's solution, decalcified in formic acid, dehydrated in alcohol and embedded in paraplast as earlier described (NIISSON 1968). The heads were serially sectioned in a sagittal plane through the cartilaginous and bony

Submitted for publication 16 June 1970.

21-713004. .irla Rndiologicn ?'lirrapy PItyiir.i Biolo.<y V o l . 10 (1971) 32 1

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322 AGNAR NILSSON

Table 1

Experimental conditions and doses employed

Dose of O"Sr in Total number Nuniber oftnicc Duration of Number of ani- pCi/g body of mice killed in groups experiment mals dead brforr weight of 5 every month in clays sacrifice

1.6 120* 65 3 00 50 0.8 121 75 360 46 0.4 1 2 2 95 480 27 0.2 120** 100 540 1 7 Control 95 94*** 570 1

* Out of these animals five were lost during the experiment. * * Out of these animals three were lost during the experiment. * * * Only four animals were sacrificed in the last test group.

Table 2

Frequency of goSr-kiduced carcinomas arid precarcinornatour changes in the mucous membraner and sebaceous glands OJ' left external ear

Dose of !'OSSr in /tCi/g body weight

Mice with meta- and hyper- plasia and slightly to inoderately atypical nuclei Number Latrncy time

Mice with carcinomas

Nuriibrr Latency time

1.6 25 209.4:t 12.0 18 257.7 +9.0 0.8 17 323.1*9.7 2 324.5 0.4 3 484.5 0 0.2 0 . 0

0 Control 0

-

-

.- -

part of the left external auditory meatus and part of the middle ear. The section thickness was 5 /( and the equidistance between the sections 150 /(. All sections were stained according to the van Gieson method.

Results

Tumour frequettcies a7zd iwduction time. Twenty overt carcinomas were found, of which 18 in the 1.6 {rCi and 2 in the 0.8 /rCi group. Early changes of precarcinoniatous type such as metaplasia and hyperplasia in combination with nuclear atypism were found in the 1.6, 0.8 and also 0.4 !r@i groups, but

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RADIOSTRONTIUM-INDUCED CARCINOMAS OF T H E EXTERNAL EAR 323

Fig. 1. l l p p c r virrv; Sebaceous gland on the anterior, external wall of the bony and cartilaginous part of the external auditory meatus from mouse 210 day-s after injection of 1.6 !tCi "'Sr/g body weight, showing a circiirnscript area with distended excretory ducts and heavy accumulation of cells. van Gieson x 50. Lozrwr L ~ P Z U ; Magnification of the inserted area. hfetaplasia and hyper- plasia of cells inside glandular alveoli and ducts. Moderate nuclear atypism. van Gieson x.500.

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324 AGNAR NILSSON

Fig. 2. 1Jppt.r vieit>: Carcinoiiia of schacroirs gland ( P I ) on the anterior. ex- ternal wall of the auditory meatus. The gland and its orifice ( R ) into the cvterrial ear ( C 1 is highly distcndcd hy accumulation of kcratin. hfousc 2.10 days after injection ol I .6 !tCi !"'Sr/g body weight. van Gieson x 50. Lorow r ~ i r , r c ~ ; Magnification of carcinoma tissue from t!ie inaerted arra. van Gicson x 500.

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RADIOSTRONTIUM-INDUCED CARCINOMAS OF T H E EXTERNAL EAR 325

Fig. 3. Upper v i e w ; Carcinoma of the sebaceous gland on the anterior wall of the auditory meatus. Mouse 270 days after injection of 1.6 !tCi !'%rig body weight. van Gieson x 50. Lozwer u ~ ~ z R ) ; Magnification of carcinoma tissue from the inserted area. van Gieson x 500.

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326 AGNAR NILSSON

not in the 0.2 {tCi series. The latency times for these changes were significantly shorter with increasing dose (Table 2 ) . The carcinomas were detected approximately 2 months earlier in the 1.6 than in the 0.8 “Ci group. No carcinomas were detected in the control groups.

Site of tumour origin. These carcinomas originated predominantly from a sebaceous gland situated on the anterior outside wall of the external auditory meatus in close vicinity to bone and cartilage structures. From this gland an excretory duct lined with squamous epithelium passes into the external ear just at the border between the bony and cartilaginous part of the meatus. Nineteen out of the 20 cases of carcinomas found were located in this sebaceous gland. In some cases there was also a spread of the primary process to the mucous membrane of the external ear by infiltration through the excretory duct. Only one carcinoma primarily originating from the mucous membrane of the external ear was detected.

Tumour development and type of tunzour. The earliest changes seem to start in this gland as a squamous cell metaplasia and hyperplasia of the epithelium of the smaller ductuli and glandular alveoli (Fig. l ) , which suc- cessively become filled and distended by squamous cells. Inside these ‘buds’ of proliferating squamous epithelium there was a successively increasing number of mitoses and of cells with atypical nuclei. In time these buds increased in size and acquired the characteristics of an overt squamous cell carcinoma invading most parts of the gland. Most of these carcinomas were highly differentiated keratin-producing squamous cell carcinomas. In many of these the central part of the gland was filled with an accumulated mass of keratin, leaving only a narrow peripheral zone of compressed carcinoma tissue (Fig. 2 ) , which, however, in time expanded into the gland in a protuberance-like manner (Fig. 3 ) .

In many cases, instead of these changes, there was a more or less intense diffuse fibrosis in the gland.

Discussion The results of this investigation have shown that squamous cell carcinomas can

be induced by ““Sr in or around the external ear in structures in close vicinity to bone. The overwhelming majority of these carcinomas originated from a sebaceous gland located on the anterior, bony wall of the external auditory meatus. On the average these carcinomas, like those of the mouth and nose earlier described

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RADIOSTRONTIUM-INDUCED CARCINOMAS OF T H E EXTERNAL EAR 32 7

Table 3

Total number of carcinomas found at different sites o f the head in relation to doAe

Site Dose of 9USr/g body weight Total

1.6 pCi 0.8 pCi 0.4 pCi 0.2 /iCi

Num- Induction Num- Induction Num- Induction NLIIII- her time ber time her time ber

Hard palate 34 Lower jaw 9 Upper jaw 4 Mucous membranes of the nose 6 Regio olfactoria of the nose 3 Sebaceous ear gland 1 7 Mucous membranes of the external ear 1

Total 34

235.1 &6.3

243.8 263.1 t 6 . 1

241.31 7.9

250.0 255.2 L9.5

300

248.5&4.0

13 338.0*7.5 2 352.5 2 355.0

4 321.8

0 - 2 324.5

0 -

23 336.1 +5.5

0 443.5 0 450 0

0

0 0

0

446.8 0

47 13

7

10

3 19

1

100

(NILSSON 1968), seem to be induced at a considerable rate only after doses exceeding those which are considered optimal (0.7-1.0 pCi ““Sr/g body weight; FINKEL et coll. 1958, NILSSON 1970, and others) for osteosarcomas. Thus the total number of tumours was approximately 3 times greater in the 1.6 /4Ci than in the 0.8 /iCi group and about 25 times greater than in the 0.4 LcCi group (Table 3 ) . The latency time was also considerably longer with decreasing dose. As indicated in Table 3, the sites most prone to carcinoma development seem to be the mucous membranes of the hard palate and the sebaceous ear gland, at least in the 1.6 “Ci group.

S U M M A R Y The effect of W r on the soft tissues of the external ear was studied at different interval5

after a n intraperitoneal injection of %r( NO,), to four group’ of mice. Highly dif- ferentiated squamous cell carcinomas were detected in about 20 % of the mice given thr highest dose of “OSr(1.G !(Ci/g body weight). The majority of the carcinomas were found to start their development in a sebaceous qland outside the external auditory meatus.

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32% AGNAR KILSSON

Z U S A M M E N F A S S U N G Es wurdc dir Wirkung von !roSr auf die weichcn Gewcbc dcs iiussercn Olires zu vcr-

srhiedenen Zeitpunkten iiach einer intraperitonealen Injektion von ""Sr( NO,), bei vier Gruppen von Mauwn untersiicht. Hoch diffmenzierte squamiise Zvll-Karzinomc wurdcn in etwa 20 % der Mause, denen die hochste Dosis von !"'Sr (1,6 I'Ci/g Korpergewicht ge- gebcn war, gpfundm. Der Haupttril dcr Karzinornr h(.gann scine Entwickl~ing von cincr Talg-Driise ausserhalb des ausseren Geharganges.

R E S U M E I,'autc%ur a 6tudiC I ' e f f r t d r !%r sur ies tissus mous dc I'orcillr cxtcrne 5 difftrents intcr-

vallcs aprPs unc injection intraptritontale de o(JSr (NO,), i quatrc grouprs de souris. 11 a trouvt' des 6pithClioma trks diffCrenci6s chez 20 % environ des souris qui avaient r e p la plus fortr dosr de !%r (1,6 IcCi/g de poids corporel). I1 a constate q u e la plnpart des Cpithtlioma prenaient leur origine dans une glande s6haci.e en dehors da conduit auditif ex terne.

R E F E R E N C E S FINKEL M. P., BISKIS B. 0. and SCRIBNER G. M. : The influence of strontuini-90 upon life span

and neoplasms of mice. Geneva Conference Paper (1958) P/911. NILSSON A. : Pathologic effects of different doses of "Sr in mice. Development of carcinomas

in the mucous membranes of the head. Acta radiol. Ther. Phys. Biol. 7 (1968), 27. - Pathologic rffects of different doses of 90Sr in mice. Dose effect relationship in '"Sr-induced

bone turnours. Acta radiol. Ther. Phys. Biol. 9 (1970), 155.

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