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Clinicalfeaturesofcystadenolymphoma(Warthin'stumor)oftheparotidgland:Aretrospectivecomparativestudyof96casesARTICLEinORALONCOLOGYJULY2006ImpactFactor:3.03DOI:10.1016/j.oraloncology.2005.10.017Source:PubMed

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AfshinTeymoortashPhilippsUniversityofMarburg122PUBLICATIONS762CITATIONS

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Clinical features of cystadenolymphoma

tively with those of 91 patients with pleomorphic adenoma. The medical history and clinical

and preoperative laboratory findings. However, a significant male predominace of patients withWarthins tumor could be noted (P < 0.05). The male to female ratio was 3.3:1 in patients with

rent smokers compared with never smokers was 8.3 (P < 0.0001). Compared with never smok-

Risk factors;

Multifocality;Smoking

The average incidence rate of all salivary gland tumors is 5per 100,000.1 According to the Hamburg Salivary Gland Reg-istry, about 65% of those tumors are benign. Cystadenolym-phoma (Warthins tumor) is ranked second in frequencyafter pleomorphic adenoma of the parotid gland. Warthinstumor accounts for about 15% of all epithelial tumors of theparotid gland.2

1368-8375/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.oraloncology.2005.10.017

* Corresponding author. Tel.: +49 6421 2866478; fax: +49 64212866367.

E-mail address: teymoort@med.uni-marburg.de (A. Teymoor-tash).

URL: www.ent-marburg.de (A. Teymoortash).

Oral Oncology (2006) 42, 569573

ava i lab le a t www.sc iencedi rec t . com

journal homepage: ht tp : / / in t l .e lseers, clearly higher odds of Warthins tumor was observed in heavy smokers (more than 30pack-years) (odds ratio = 24.1, P < 0.0001) than patients who smoked less than 30 pack-years(odds ratio = 4.9, P < 0.0001).c 2005 Elsevier Ltd. All rights reserved.

IntroductionWarthins tumor. Multifocal Warthins tumor were detected in five cases (6.2%), and 10 patients(12.3%) had bilateral lesions. The odds ratio for the incidence of Warthins tumor among cur-tumor characteristics of all patients were similar. There were no significant differencesbetween these two patient groups with respect to concomitant diseases, regular medications,

Gender;Bilaterality;Summary The details of the etiopathogenesis of cystadenolymphoma (Warthins tumor) arestill unclear. To explore the possible risk factors for the development of this tumor, medicalrecords of 81 patients with 96 Warthins tumors of the parotid glands were compared retrospec-

KEYWORDSWarthins tumor;Pleomorphic adenoma;(Warthins tumor) of the parotid gland:A retrospective comparative study of 96 cases

A. Teymoortash *, Y. Krasnewicz, J.A. Werner

Department of Otolaryngology, Head and Neck Surgery, Philipps University, Deutschhaus Str. 3,35037 Marburg, Germany

Received 13 August 2005; accepted 14 October 2005vierheal th .com/ journals /oron/

phocytic infiltrations,9 are polyclonal. If, however, neopla-

570 A. Teymoortash et al.sia is defined as a monoclonal process, this kind of tumorcannot be considered to be a true neoplasm. The almost to-tal lack of recurrence and malignant transformation of thistumor further supports this view.10 Multicentricity at firstexcision and growth from a new focus seem to be responsi-ble for the cases of recurrence reported in the literature.Malignant transformation of this tumor, if it ever occurs,is extremely rare.11

The details of the pathogenesis of Warthins tumor arestill unclear. However, because of the arguments against atrue neoplastic origin of this tumor, we favour a hypothesiscombining immunological interactions between tumor cellsand lymphocytic infiltrations with heterotopia and classifythis tumor in the group of tumor-like lesions.10 One impor-tant question still remains: Which triggers cause the tumor-ous changes and favour their development?

In the present study, we retrospectively analysed clinicaldata from patients with Warthins tumor to explore possiblerisk factors for development of this disease and for furthercharacterisation of this tumor.

Material and methods

A retrospective analysis of 81 patients with Warthins tumorof the parotid gland who were diagnosed and treated be-tween April 1998 to April 2005 was performed. For compar-ison, a second control population of 91 patients withpleomorphic adenoma of the parotid gland was selectedwho were treated within the same period of time. All pa-tients with Warthins tumor and pleomorphic adenoma weretreated by either superficial or subtotal parotidectomy. Thediagnosis of all tumors including bilateral and multifocal le-sions based on histopathological examinations of tumorspecimens after parotidectomy.

Tumor characteristics were reviewed and details of signsand symptoms at presentation and duration of illness untiladmission were noted and analysed. Staging of parotid glandtumors was defined by sonography and magnetic resonanceimaging (MRI) of the parotid glands in all cases. Tumor sub-localisations, tumor size, bilaterality and multifocality wereIn 1910 Albrecht and Arzt reported two tumors of theupper neck region which they interpreted as confused tis-sue in the entodermal pharyngeal anlage, particularly thatof salivary glands, in the lymph nodes.3 After these authorsa large number of studies drew the conclusion that this tu-mor develops due to salivary gland heterotopia in peri- andintraparotideal lymph nodes.4,5 Although various theorieshave been put forward to explain the development ofWarthins tumor,6 only two have ultimately remained. Thefirst is the mentioned hypothesis of heterotopia; the secondis the theory that this tumor is an adenoma with concomi-tant lymphocytic infiltration. According to the latter theory,when they are small and have a short history, Warthins tu-mors consist mainly of epithelial components, while whenthey are large they show, in addition to their epithelial com-ponent, a lymphoid stroma. Since they are observed first,the epithelial components are therefore thought to be thefundamental neoplastic elements.7 This theory was dis-proved by a recent study performed by Honda et al.,8 whoshowed that the epithelial tumor components, like the lym-Patient population and medical history

Warthins tumors had a significant higher incidence in themale than in the female population (P < 0.05). The maleto female ratio for Warthins tumor and pleomorphic ade-noma was 3.3:1 (62 versus 19) and 1:1.6 (35 versus 56),respectively. The mean age at diagnosis was 57.9 years(range, 1682) for Warthins tumor and 50.3 years (range,1582) for pleomorphic adenoma. The average duration ofcomplaints at diagnosis of Warthins tumor was 29.5 months(range, 0360 months) compared to 31 months (range, 0360 months) for pleomorphic adenoma. The most commonlyreported symptoms at diagnosis were painless swelling inthe tumor area (92.6%) and tenderness (10.5%) for Warthinstumor. Thirteen Warthins tumors were detected acciden-tally by sonography and MRI of the parotid glands (13.5%).Similarly, the most commonly reported symptoms at diagno-sis were painless swelling in the tumor area (94.6%) and ten-derness (3.7%) for pleomorphic adenoma.

There were no significant differences between the War-thins tumor and the pleomorphic adenoma patients groupwith respect to concomitant diseases and malignancies, reg-ular medications, and complete preoperative laboratoryevaluations. Tables 13 depict these clinical data of bothgroups.

Evaluation of smoking habits showed that 79% of patientswith Warthins tumor had a history of tobacco use; for pleo-morphic adenoma, only 30.8 % of patients had a history oftobacco use. Duration of smoking in the great majority ofassessed according to radiological and histopathologicalfindings.

The medical records of all patients were reviewed withrespect to age, gender, concomitant diseases and malignan-cies and regular medications. The complete preoperativelaboratory findings, including hematological studies, hepa-tic profiles, renal function and general metabolic functionswere studied and abnormalities of laboratory tests wereanalysed. Each result was classified as normal, increased,or decreased, according to reference normal values. Life-time exposure to tobacco smoke was recorded and patientswere classified according to their smoking habit into current(130, orP30 pack-years), former, or never smokers. Indi-vidual periods of smoking were summed to calculate totalcumulative duration of smoking and pack-years of smoking(calculated as number of packs per day times the cumula-tive number of years smoked). Patients who had stoppedsmoking up to 5 years before the diagnosis of the parotidgland tumor were classified as former smokers and excludedfrom smoking analysis. Odds ratios and 95% confidenceintervals for all patients with Warthins tumor were calcu-lated with a logistic regression model adjusted for smokingand compared with those patients with pleomorphic ade-noma. Different categories of patients data were comparedby Chi-squared test and Fishers exact test to analyse thestatistical significance. Statistical analysis was performedcomputerized with the software package SPSS (version11.5, SPSS Inc., Chicago, USA). P-values 6 0.05 were consid-ered to indicate statistical significance.

Results

Table 4 Smoking characteristics in patients with Warthins tumor and pleomorphic adenoma

Number of patients with WT Number of patients with PA

Never smokers 17 (21) 63 (69.2)

Current smokersIntensity of smoking in pack-years30 22 (27.2) 5 (5.5)

Former smokers 10 (12.3) 4 (4.4)

PA = pleomorphic adenoma, WT = Warthins tumor.

Table 3 The most pathologic laboratory parameters in patients with Warthins tumor and pleomorphic adenoma

Pathologic parameters Number of patients with WT Pathologic parameters Number of patients with PA

No pathologic parameter 9 No pathologic parameter 16Glukose 24 Hematocrit 18MCV 16 Glucose 17MCH 15 MCH 10c-glutamyltransferase 14 Thrombocytes 10Hematokrit 14 MCV 9C-reactive protein 13 C-reactive protein 8Leukocytes 10 Chlorid 7Chlorid 9 Protein 6Uric acid 9 c-glutamyltransferase 6

PA = pleomorphic adenoma, WT = Warthins tumor, increased, decreased, MCV = mean corpuscular volume, MCH = mean corpusclarhemoglobin.

Table 2 The most regular medications in patients with Warthins tumor and pleomorphic adenoma

Regular medications Number ofpatients with WT

Regular medications Number of patientswith PA

No regular medication 27 No regular medication 34Antihypertensive/coronary drugs 37 Antihypertensive/coronary drugs 24Anticoagulants 10 Thyroid therapeutics 20Antidiabetics 10 Sex hormones and their inhibitors 11Diuretics 9Antiasthmatics/broncholytics 7 Anticoagulants 6

PA = pleomorphic adenoma, WT = Warthins tumor.

Table 1 The most concomitant diseases in patients with Warthins tumor and pleomorphic adenoma

Concomitant disease Number of patients with WT Concomitant disease Number of patients with PA

No concomitant disease 19 No concomitant disease 35Hypertension 26 Hypertension 22Diabetes mellitus type II 12 Thyroid dysfunction 20Coronary heart disease 8 Cardiac arrhythmia 8COPD 7 Coronary heart disease 4Cardiac arrhythmia 6 Osteoporosis 4Cardiac failure 6 Prostatic hypertrophy 4

PA = pleomorphic adenoma, WT = Warthins tumor.

Warthins tumor 571

572 A. Teymoortash et al.smokers with Warthins tumor (83.3%) were over 20 years(Table 4). Current smokers had an odds ratio of 8.3 (95%confidence intervall [CI], 3.8418.32; P < 0.0001) than ner-ver smokers for Warthins tumor compared with pleomor-phic adenoma. Compared with nerver smokers, clearlyhigher odds of Warthins tumor was observed in heavy smok-ers (more than 30 pack-years). The odds ratio for the inci-dence of Warthins tumor among patients who smoked lessthan and over 30 pack-years compared with nerver smokerswas 4.9 (95% CI 2.799.11; P < 0.0001) and 24.1 (95% CI7.8283.06; P < 0.0001), respectively.

Clinical tumor characteristics

Ninety-six Warthins tumors were found in 81 patients. Therate of bilateral Warthins tumor was 12.3% (10 out of 81patients). Eight of these tumors were detected synchro-nously and two were detected metachronously after 19and 52 months. One patient with bilateral Warthins tumorhad also synchronously a pleomorphic adenoma of theparotid gland. Multifocality could be shown in 5 out of 81patients with Warthins tumor (6.2%). These patients hadsynchronously two lesions in the same parotid gland. All syn-chronously found multifocal and bilateral Warthins tumors(13 out of 96) were detected accidentally by sonography andMRI of the parotid glands. One patient with pleomorphicadenoma developed a metachronous pleomorphic adenomaof the contralateral parotid gland after 108 months. Salivarygland malignancies in association with Warthins tumorcould not be detected. However, in one patient a pleomor-phic adenoma and an acinus cell carcinoma were found syn-chronously in the same parotid gland.

The average size of Warthins tumors at diagnosis, asdetermined at preoperative sonography, was 25.6 9.9 mm (range, 950 mm) in greatest diameter. Similarly,the average maximum diameter of pleomorphic adenomawas 21.9 8.2 (range, 1850 mm). All Warthins tumors ex-cept for two were located in the lower pole of the superfa-cial lobe of the parotid gland (96.8%). The great majority ofpleomorphic adenoma were also found in the same subloca-tion (83.7%).

Discussion

Warthins tumors most commonly present as an asymptom-atic, slowly growing mass usually affecting men in the 5thand 6th decade. The male to female ratio ranges from2.6:1 to 10:1.6 In the present study the male to female ratiowas 3.3:1. The comparatively significantly greater tumorincidence in men might indicate a hormone dependence ofthis disease. The salivary glands are not considered as theclassical target organs of steroid hormones. The significanceof sex hormones is not clear with regard to their impact onthe salivary glands and their diseases. Only very few studieshave dealt with this question. In some malignant salivarygland diseases and even in Warthins tumor progesteronereceptors have been found.12 The evidence of progesteronereceptor in Warthins tumor may implicate a potential roleof endocrine factors in the development of this tumor whichmight explain the particular predominance of the male sexregarding this disease.Warthins tumor is the most common bilateral and multi-focal parotid neoplasm. In about 410% of Warthins tu-mors, there is bilateral tumor development, which iscommonly metachronous. In about 4% of the cases multipleWarthins tumors may be observed in one parotid gland.2,13

In our study 12.3% of patients with Warthins tumor hadbilateral lesions and multifocal tumors were detected in6.2% of cases. The relatively high incidence of bilateralityand multifocality of Warthins tumor of the present studymight be based on the preoperative staging of both parotidglands by sonography and MRI in all cases as a matter of rou-tine in our department. Bilaterality and multicentric natureof Warthins tumors can be explained by the hypothesis ofheterotopia in the pathogenesis of these tumors. The mainsupport for this hypothesis is the detection of salivary ductinclusions in lymphoid tissue in foetuses and infants. Duringthe embryogenesis of the parotid gland, epithelial cellsfrom the oral mucosa happen to penetrate into lympho-cyte-rich tissue. The late encapsulation of the parotid glandexplains the occurrence of intraparotideal lymph nodes andheterotopic salivary gland remnants entrapped in the parot-ideal lymph nodes. According to this theory, Warthins tu-mors have their origin in these epithelial inclusions.

Warthins tumors may occur simultaneously with pleo-morphic adenomas, various types of carcinoma and malig-nant lymphomas.14 In the present study, other salivarygland tumors and malignancies in association with Warthinstumour could not be detected. Some studies discussed theimportance of immunological reactions during the forma-tion of Warthins tumor. Due to the morphological similari-ties between Warthins tumor and Hashimoto thyroiditis,Allegra15 first established the hypothesis that Warthins tu-mor originates on the basis of an immune reaction of de-layed hypersensitivity type. A retrospective study ofpossible association of Warthins tumor with autoimmunepathologies revealed a higher incidence of autoimmune dis-orders in Warthins tumor patients.16 In the present study nosignificant difference between the Warthins tumor and thepleomorphic adenoma patients group with respect to con-comitant diseases could be found.

To explore possible risk factors for development ofWarthins tumor we analysed for the first time the clinicalrecords of these patients with respect to regular medica-tions and abnormalities of preoperative laboratory tests.There were no significant differences in pathologic bloodparameters and patients regular medications comparedwith patient with pleomorphic adenoma. However, thegreat majority of patients with Warthins tumor had a his-tory of over 20 years of smoking. The odds ratio of Warthinstumor for current smokers compared with never smokers inthis study was 8.3. Compared with nerver smokers, clearlyhigher odds of Warthins tumor was observed in heavy smok-ers (more than 30 pack-years) (odds ratio = 24.1) thanpatients who smoked less than 30 pack-years (odds ratio =4.9). Several studies showed that a significant number ofpatients suffering from Warthins tumor are smokers, incontrast to patients with other salivary gland tumors.17,18

Smoking was discussed as an important etiological factor.Warthins tumor consists of oncocytic cells containingnumerous mitochondria frequently showing structuralabnormalities and reduced metabolic function. The onco-cytic transformation of single striated epithelial cells

represents a process within the salivary glands that is fre-quently observed in advanced age. This fact seems to corre-late with age-related metabolic deficiencies. Smoking canlead to damage to mitochondrial DNA due to the develop-ment of numerous reactive oxygen species.19 In this contexta high rate of deleted mitochondrial DNA has been detectedin the oncocytic cells of Warthins tumor.20

In conclusion, comparing the clinical data of Warthinstumor with pleomorphic adenoma as the most common sal-ivary gland tumors, there were differences in the gender ofpatients, tumor bilaterality and multifocality as wells assmoking habits of these patients ascertainable. Other ana-lysed clinical characteristics of these tumors were similarwithout significant differences.

References

1. Pinkston JA, Cole P. Incidence rates of salivary gland tumors:results from a population-based study. Otolaryngol Head NeckSurg 1999;120:83440.

2. Seifert G. Warthin Tumoren (Adenolymphome). In: Doerr W,Seifert G, Uehlinger E, editors. Oralpathologie I, Pathologieder Speicheldrusen. Berlin: Springer; 1996. p. 44063.

1910;4:4769.4. Rauch S. Papillare Zystadenolymphome. Die Speicheldrusen

8. Honda K, Kashima K, Daa T, Yokoyama S, Nakayama I. Clonalanalysis of the epithelial component of Warthins tumor. HumPathol 2000;31:137780.

9. Takezawa K, Jackson C, Gnepp DR, King TC. Molecularcharacterization of Warthin tumor. Oral Surg Oral Med OralPathol Oral Radiol Endod 1989;85:56975.

10. Teymoortash A, Werner JA. Tissue that has lost its track:Warthins tumour. Virchows Arch 2005;446:5858.

11. Foschini MP, Malvi D, Betts CM. Oncocytic carcinoma arising inWarthin tumour. Virchows Arch 2005;446:8890.

12. Teymoortash A, Lippert BM, Werner JA. Steroid hormonereceptors in parotid gland cystadenolymphoma (Warthinstumour). Clin Otolaryngol 2001;26:4116.

13. Maiorano E, Lo Muzio L, Favia G, Piattelli A. Warthins tumour:a study of 78 cases with emphasis on bilaterality, multifocalityand association with other malignancies. Oral Oncol 2002;38:3540.

14. Seifert G, Bull HG, Donath K. Histologic subclassification of thecystadenolymphoma of the parotid gland. Analysis of 275 cases.Virchows Arch A Pathol Anat 1980;388:1338.

15. Allegra SR. Warthins tumor: a hypersensitivity disease? Ultra-structural, light, and immunofluorescent study. Hum Pathol1971;2:40320.

16. Gallo O, Bocciolini C. Warthins tumour associated withautoimmune diseases and tobacco use. Acta Otolaryngol

Warthins tumour of the parotid gland. Br J Oral Maxillofac

Warthins tumor 573des Menschen. Stuttgart: Thieme; 1959., p. 36873.5. Thompson AS, Bryant HC. Histogenesis of papillary cystade-

noma lymphomatosum (Warthins tumor) of the parotid salivarygland. Am J Pathol 1950;26:80729.

6. Chapnik JS. The controversy of Warthins tumor. Laryngoscope1983;93:695716.

7. Aguirre JM, Echebarria MA, Martinez-Conde R, Rodriguez C,Burgos JJ, Rivera JM. Warthin tumor. A new hypothesisconcerning its development. Oral Surg Oral Med Oral PatholOral Radiol Endod 1989;85:603.Surg 1998;36:1835.18. Yoo GH, Eisele DW, Askin FB, Driben JS, Johns ME. Warthins

tumor: a 40 years experience at The John Hopkins Hospital.Laryngoscope 1994;104:799803.

19. Allen JA, Coombs MM. Covalent binding of polycyclic aromaticcompounds to mitochondrial and nuclear DNA. Nature 1980;287:2445.

20. Lewis PD, Baxter P, Paul Griffiths A, Parry JM, Skibinski DO.Detection of damage to the mitochondrial genome in theoncocytic cells of Warthins tumour. J Pathol 2000;191:27481.3. Albrecht H, Arzt L. Beitrage zur Frage der Gewebsverirrung. I.Papillare Cystadenome in Lymphdrusen. Frankfurt Z Pathol

1997;117:6237.17. Yu GY, Liu XB, Li ZL, Peng X. Smoking and the development of