malignant epithelial tumours associated...

J Clin Pathol 1986;39:497-502

Malignant epithelial tumours associated withautoimmune sialadenitisPD JAMES, IO ELLIS

From the Department ofHistopathology, University Hospital, Nottinghan

SUMMARY Malignant epithelial tumours associated with autoimmune sialadenitis are rare in whiteraces but occur more often in those of Eskimo or oriental descent. Ultrastructurally these tumoursare squamous in origin, and they may arise from the epithelial component of autoimmune sial-adenitis. The two cases reported are the first described in natives of this country, and in one, a case

of parotid tumour, autoimmune sialadenitis preceded the development of undifferentiated car-

cinoma by 12 years; the other, a submandibular lesion, indicates some diagnostic difficulties thatwere found. This condition deserves wider recognition, as adequate primary treatment may result inlong term survival.

In 1952 Godwin' introduced the term "benign lym-phoepithelial lesion" to describe a lymphoid infiltrateof salivary tissue associated with glandular atrophyand proliferation of salivary duct elements to formislands ofepithelial cells. This process is now acceptedas an autoimmune disease2 and there is an increasedincidence in the subsequent development both of car-cinomas and malignant lymphomas.3 Malignant epi-thelial tumours associated with autoimmune sial-adenitis are less common than malignant lymphomasand show geographic and ethnic predispositions.Over 50 cases have been reported, most havingoccurred in Eskimos, with additional reports fromJapan and China.We report two cases of malignant epithelial

tumours associated with autoimmune sialadenitis,which we believe to be the first described in Britain. Inone case a salivary lesion diagnosed as autoimmunesialadenitis had been removed from the parotid 12years before the subsequent development of anundifferentiated carcinoma. The second case pin-points some of the diagnostic difficulties, and, webelieve, reflects a lack of awareness and possibleunderdiagnosis of this condition.

Case reports

CASE IA 60 year old man of Scottish descent presented witha five month history of a rapidly growing lump in the

Accepted for publication 16 January 1986

right parotid region with more recent pain in the ear.He had no other complaints and examination showeda right parotid swelling. A superficial parotidectomywas performed, and the surgical specimen receivedshowed a well circumscribed yellow tumour 3 5 cm indiameter with surrounding salivary tissue and adja-cent enlarged lymph nodes. He was alive and well twoyears postoperatively.Twelve years previously he had complained of

swelling in the right parotid region, and at operationa soft mass 2-Ocm in diameter was removed fromwithin the lower pole of the parotid gland. He had noother symptoms at that time. Histology showed asmall amount of atrophic salivary gland at the periph-ery, but the major part consisted of lymphoid tissuewith islands of epithelial cells diagnosed as auto-immune sialadenitis.The more recent lesion showed residual atrophic

salivary gland and foci of lymphoid tissue with epi-thelial elements typical of autoimmune sialadenitis atthe periphery (Fig. 1). In addition, hyperplastic andvariably atypical epithelial elements that were pro-ducing multilayered duct like structures containingdesquamated cellular debris were seen (Fig. 2). Thesemerged into islands of solid undifferentiated car-cinoma separated by fibrous trabeculae containing alymphocytic and plasma cell infiltrate (Fig. 3). Thetumour cells were round, oval, and spindle shapedwith large pleomorphic nuclei and numerous mitoses(Fig. 4). In places tumour cells had a clear vacuolatedcytoplasm and showed foci of keratinisation (Fig. 5).Metastatic tumour was present in adjacent lymphnodes attached to the main specimen.

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James, Ellis

Fig. 1 Case 1. Atrophic salivary tissue with epithelialislands within lymphoid stroma at periphery ofsurgicalspecimen. (Haematoxylin and eosin.) x 50.

Fig. 3 Undifferentiated carcinoma separated byfibroustrabeculae containing lymphocytic infiltrate. (Haematoxylinandeosin.) x 126.

Fig. 2 Multilayered duct like structure containing Fig. 4 Pleomorphic malignant cells with adjacentdesquamated cellular debris. (Haematoxylin and eosin.) lymphocytic infiltrate. (Haematoxylin and eosin.) x 720.x 126.

CASE 2A 69 year old English woman presented with a leftsided swelling below the angle of the jaw that hadgradually enlarged over the previous six months. Asmall persistent ulcer on the frenulum of the tonguerelated to her dentures was found, but this resolvedwith conservative treatment. She had a history of

arthritis requiring non-steroidal anti-inflammatorydrugs.A submandibular mass was excised and subsequent

investigations including endoscopy of thenasopharynx, trachea, oesophagus, and stomachshowed no other abnormality. The neck was re-explored one month later because of persistent swell-

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Malignant epithelial twnours associated with autoimnmune sialadenitis

Fig. 5 Focal keratinisation; adjacent tumour cells haveclear, vacuolated cytoplasm. (Haematoxylin and eosin.)x 720.

- f _ e~~.i .:'jF,_ ,,,,w I w =

Fig. 7 Focal keratinisation with "pearl"formation.(Haematoxylin and eosin.) x 680.

Fig. 6 Case 2. Pleomorphic undifferentiated tumour withconspicuous mitoses. (Haematoxylin and eosin.) x 290.

ing, but biopsy showed no evidence of residual dis-ease. She was alive and well with no recurrence of herdisease nine months after the biopsy.The surgical specimen was an encapsulated mass 3

x 2 x 2cm composed of solid sheets and anas-tomosing cords of cells, with an interveningfibrovascular stroma containing a focal lymphocyticinfiltrate. The tumour cells were rounded, oval, or

Fig. 8 Periphery oftumour showing island ofepitheliumsurrounded and infiltrated by lymphoid cells, features typicalofautoimmune sialadenitis. (Haematoxylin and eosin.)x 290.

spindle shaped with large pleomorphic nuclei andconspicuous mitoses (Fig. 6); focal keratinisationwith "pearl" formation was also present (Fig. 7).Cords and islands of less atypical epithelial cells wereseen at the periphery, separated and focally infiltratedby lymphocytes (Fig. 8), an appearance that is charac-teristic of autoimmune sialadenitis. Fresh tissueappropriately fixed and processed was available for

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Fig. 9 Squamous differentiation is shown by desmosomeformation andpresence ofprominent tonofilament bundles.Electron micrograph x 23 500.

ultrastructural examination, and tumour cells showedsquamous differentiation with well formeddesmosomes and prominent tonofilament bundles(Fig. 9).

Discussion

The benign lymphoepithelial lesion described byGodwin' is an autoimmune disease2 affecting salivarytissue; and it may occur with or without the clinicalpicture of Sjogren's syndrome. The term benign ismisleading because of the association with malignantlymphoma, and this risk in patients with Sjogren'ssyndrome is estimated to be 43-8 times greater thanthat of a comparable normal population.4 Variousterms have been introduced to describe this conditionincluding immunosialadenitis,2 myoepithelial sial-adenitis,3 and autoimmune sialadenitis.5 Recentwork has shown that the "myoepithelial" islands con-

tain metaplastic epithelial cells but no demonstrablemyoepithelial cells.6 We do not propose to review thisentity, its terminology, or the incidence of malignantlymphomas but will draw attention to malignant epi-thelial tumours arising in association with "auto-immune sialadenitis".Hilderman et al7 reported an undifferentiated car-

cinoma of the parotid salivary gland with a lymphoidstroma that resembled the benign lymphoepitheliallesion described by Godwin.' This was considered tobe the malignant counterpart of Godwin's benignlesion and was termed malignant lymphoepithelial

James, Ellis

lesion with carcinomatous component. Over 50 simi-lar cases have now been reported worldwide.8-22Most have occurred in Eskimos and orientals, withthe parotid the most common site of origin, althoughsome cases arise in the submandibular gland.

Patients are commonly middle aged, but the rangevaries, with occasional cases occurring in the seconddecade of life.8 19 The tumours are undifferentiatedcarcinomas, often with a nodular gross appearanceand cells arranged in cords, sheets, or nests separatedby a fibrous stroma with a lymphocytic infiltration,which sometimes spills over into the tumour. The cellsusually show no differentiating features, but ultra-structural studies indicate that they are of squamousorigin.17 20 22 23 In some casesl' 11 19 a benignlymphoepithelial lesion had been removed severalyears before the subsequent development ofthe undifferentiated carcinoma while inothers13 15 17 19-22 residual areas of benign lympho-epithelial lesion have been described.On purely morphological grounds there is evidence

to indicate that these undifferentiated carcinomasarise within salivary tissue affected by autoimmunesialadenitis. It seems that they may arise from the epi-thelial component of autoimmune sialadenitis by aprogression of metaplasia, to dysplasia, to frankinvasive malignancy. Severe epithelial dysplasia inparallel with benign ductal elements has beendescribed in association with these tumours,17 21 andatypia within the epithelial islands was present in ourcases. Interestingly, only one of the patients describedin the published reports had symptoms of Sjogren'ssyndrome, and this case is the only adenocarcinomathat has been described.9Our two cases are typical of this condition but illus-

trate additional points of interest. One case presentedwith autoimmune sialadenitis, and although this hasbeen previously reported,'0 11 19 the 12 year intervalbefore the development of malignancy is the longestlatent period described. Even on reviewing the origi-nal histology there was no way in which the malig-nant transformation might have been predicted. Inboth cases areas of residual autoimmune sialadenitiswere present at the periphery of the tumour, and inone case transition of the epithelial elements throughsquamous metaplasia and dysplasia could be seen.The tumours were unusual as both showed kera-tinisation. A malignant epithelial tumour associatedwith autoimmune sialadenitis was confidently diag-nosed in one patient (case 1), based on the history ofautoimmune sialadenitis, the histological features ofthe presenting tumour, and the presence of residualautoimmune sialadenitis with adjacent atrophic sali-vary tissue. The diagnosis was more difficult in case 2and was made only after wide consultation. No sali-vary tissue was present in the specimen received,



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which was interpreted as being a lymph node. It wasreplaced by sheets and islands of undifferentiated car-cinoma, which showed focal squamous differentiationwith an intervening fibrovascular stroma containing alymphocytic infiltrate. At the periphery of thetumour, islands of hyperplastic epithelium with alymphoid stroma were identified with appearancestypical of autoimmune sialadenitis. Ultrastructuralstudies in case 2 showed desmosomes andtonofilament bundles indicating squamousdifferentiation, findings in keeping with previouslypublished data.17 20 22 23

These problems in diagnosis led us to consider thatthis may be a poorly recognised and underdiagnosedentity. We have identified only eight reported cases inthe world that have occurred in cau-casians, 7 10 13 15 17 21 and no cases of malignant epi-thelial tumours associated with autoimmune sial-adenitis were reported in a recent review of 2410salivary gland tumours from Britain.2' The absenceof salivary tissue and paucity of autoimmune sial-adenitis elements may obscure the lesion's true originand lead to a misdiagnosis-metastatic carcinoma ina lymph node. Metastasic invasions of the parotidgland or parotid associated lymphoid tissue do occur,but submandibular metastases are exceptionallyrare.25 These tumours bear a striking resemblance tonasopharyngeal carcinomas 20 and further clinicalinvestigation may be necessary to exclude the pres-ence ofan underlying carcinoma in the upper oral andnasal pharynx. The finding of sheets and islands ofundifferentiated carcinoma separated by lymphoidstroma should alert the pathologist to the possibilityof a malignant epithelial tumour associated withautoimmune sialadenitis. Subsequent search of tissuesections for residual autoimmune sialadenitis or sali-vary tissue may be fruitful and help in the diagnosis.The geographical distribution of this otherwise rare

salivary gland tumour is of great interest. Most caseshave been reported in north American8 11 14 22 andGreenland Eskimos16 with case reports from China'9and Japan.20 There is no satisfactory explanation forthe high incidence in Eskimos, although the possi-bility of vitamin A deficiency has been suggested.16 Ahigh incidence of nasopharyngeal carcinoma has beendescribed from China19 and Greenland"6 and it issuggested that Epstein-Barr virus infection may be afactor in the development of these salivary neo-plasms.'6 23Most patients have been treated with surgery alone,

although a minority have received radiotherapy andalso chemotherapy.20 Prognosis is difficult to assesswith these different regimens from various centres.The outlook for an undifferentiated neoplasm mightseem poor, and the natural history is one of localnodal metastases and ultimately widespread meta-

static disease. With radical local treatment, however,long term survival is possible. Two thirds of thereported patients were alive from eight months to10-5 years after initial treatment, only one third dyingfrom metastatic disease. Only one7 of the eight cau-casian patients described8 13 15 17 21 died from the dis-ease; survival varied from 20 months to 12 years.

We are grateful to Professor RE Cotton for his com-ments on the paper. We thank Mr Bill Brackenburyfor the photomicrographs and Mrs Margaret E Nor-ris for preparation of the manuscript.

References

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2 Siefert G, Donath K. Die Morphologie der Speicheldrusener-krankungen. Arch Otorhinolaryngol 1976;213:111-208.

3 Schmid U, Helbron D, Lennert K. Development of malignantlymphoma in myoepithelial sialadenitis (Sjogren's syndrome).Virchows Arch (Pathol Anat) 1982;395: 11-43.

4Kassan SS, Thomas TL, Moutsopoulos HM, et al. Increased riskof lymphoma in sicca syndrome. Ann Intern Med1978;89.888-92.

Ostberg Y. The clinical picture of benign lympho-epithelial lesion.Clin Otolaryngol 1983;8:381-90.

6 Kjorell U, Ostberg Y. Distribution of intermediate filaments andactin microfilaments in parotid autoimmune sialadenitis of Sjo-gren syndrome. Histopathology 1984;8:991-101 1.

Hilderman WC, Gordon JS, Large HL, Carroll CF. Malignantlymphoepithelial lesion with carcinomatous component appar-ently arising in parotid gland. A malignant counterpart ofbenign lymphoepithelial lesion? Cancer 1962;15:606-10.

Wallace AC, MacDougall JT, Hildes JA, Lederman JM. Salivarygland tumours in Canadian Eskimos. Cancer 1963;16:1338-53.

9 Delaney WE, Balogh K Jr. Carcinoma of the parotid gland associ-ated with benign lymphoepithelial lesion (Mikulicz's disease) inSjogren's syndrome. Cancer 1966;19:853-60.

0 Gravanis MB, Giansanti JS. Malignant histological counterpartof the benign lymphoepithelial lesion. Cancer 1970;26:1332-42.

l Arthaud JB. Anaplastic parotid carcinoma ("malignant lympho-epitheial lesion") in seven Alaskan natives. Am J Clin Pathol1972;57:275-86.

2 Schnitzer B, Weaver DK. In: Batsakis JG, ed. Tumours ofthe headand neck: clinical and pathological considerations. Baltimore:Williams and Wilkins, 1974:376.

13 Batsakis JG, Bernacki EG, Rice DH, Stebber ME. Malignancyand the benign lymphoepithelial lesion. Laryngoscope1975;85:389-99.

14 Sinha BK, Buntine DW. Parotid gland tumours. Clinico-pathologic study. Am J Surg 1975;129:675-81.

s Ferlito A, Fiore Donati L. Malignant lymphoepithelial lesions(undifferentiated ductal carcinoma of the parotid gland). Threecase reports and review of the literature. J Laryngol Otol1977;91:869-85.

6 Nielson NH, Mikkelsen F, Hansen JPH. Incidence of salivarygland neoplasms in Greenland with special reference to an ana-plastic carcinoma. Acta Pathol Microbiol Scand (A)1978;86:185-93.

17 Redondo C, Garcia A, Varquez F. Malignant lymphoepitheliallesion of the parotid gland: poorly differentiated squamous cellcarcinoma with lymphoid stroma. Cancer 1981;48:289-92.

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50218 Roncevic R, Tatic V. Malignant lymphoepithelial lesion: report of

a case. J Oral Surg 1981;39:449-50.19 Hanji D, Gohao L. Malignant lymphoepithelial lesions of the sali-

vary glands with anaplastic carcinomatous change. Report ofnine cases and review of literature. Cancer 1983;52:2245-52.

20 Nagao K, Matsuzaki 0, Saiga H, et al. A histopathologic study ofbenign and malignant lymphoepithelial lesions of the parotidgland. Cancer 1983;52:1044-52.

21 Amaral ALMP, Nascimento AG. Malignant lymphoepitheliallesion of the submandibular gland. Oral Surg 1984;58:184-90.

22 Yazdi HM, Hogg GR. Malignant lymphoepithelial lesion of thesubmandibular salivary gland. Am J Clin Pathol 1984;82:344-8.

23 Sehested M, Hainau B, Albeck H, Nielsen NH, Hansen JPH.

James, EllisUltrastructural investigation of anaplastic salivary gland car-cinomas in Eskimos. Cancer 1985;55:2732-6.

24 Eveson JW, Cawson RA. Salivary gland tumours. A review of2410 cases with particular reference to histological types, site,age and sex distribution. J Pathol 1985;146:51-8.

21 Evans RW, Cruickshank AH. Epithelial tumours of the salivaryglands. In: Bennington JL, ed. Major problems in pathology. Vol.1. Philadelphia: WB Saunders 1970.

Requests for reprints to: Dr PD James, Department ofPathology, University Hospital, Queen's Medical Centre,Nottingham NG7 2UH, England.



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