Pathology International

2004;

54

: 850–853

et al.

Correspondence: Tarou Irié, DDS, PhD, Department of Oral Pathol-ogy, Showa University School of Dentistry, 1-5-8 Hatanodai, Shina-gawa-ku, Tokyo 142-8555, Japan. Email: tarou@dent.showa-u.ac.jp

Received 25 June 2004. Accepted for publication 21 July 2004.

Case Report

Multiple granulomatous inflammation in the minor salivary glands: A proposed new entity, allergic granulomatous sialadenitis

Tarou Irié,

1

Yukiko Maeda,

1

Tadateru Aida,

1

Kaname Sumitani,

2

Masao Nagumo

2

and Tetsuhiko Tachikawa

1

1

Department of Oral Pathology and

2

Oral Surgery, Showa University School of Dentistry, Tokyo, Japan

We report a patient who presented with multiple small sub-mucosal nodules with granulomatous inflammation in theminor salivary glands of the oral cavity. A 43-year-oldwoman presented with a 1-week history of multiple smallsubmucosal nodules in her oral cavity after having takenmedicine for abdominal pain. The patient did not have ahistory of fever, rectal bleeding, skin lesions or arthritis, butdid have a history of drug allergy and bronchial asthma.Histopathological examination of the submucosal nodulesshowed sialadenitis with marked infiltration of lympho-cytes, eosinophilic cells, macrophages and Langhans-typeor foreign-body-type multinucleate giant cells. The mac-rophages tended to be aggregated and appeared to havecaused immature granuloma formation without caseousnecrosis. Degranulated eosinophilic cells were numerous.Sarcoidosis, Crohn’s disease, tuberculosis and atypicalmycobacterial infection were not identified by medicalexamination. Three weeks after discontinuing the medica-tion the patient was seen again at a follow-up visit. Multiplesubmucosal small nodules and other symptoms were notevident at that time. This case report may represent a newentity of salivary gland disease that we tentatively refer toas ‘allergic granulomatous sialadenitis’.

Key words:

allergic reaction, chemical induced, granuloma,sialadenitis

Local factors and systemic generalized factors play an im-portant role in the etiology of sialadenitis. Seifert

1

dividedsialadenitis into nine etiologic categories: acute bacterialsialadenitis, chronic recurrent parotitis, chronic scleros-ing sialadenitis of the submandibular gland, obstructivesialadenitis, radiation sialadenitis, viral sialadenitis, immunesialadenitis, other granulomatous sialadenitis and sialadenitisof the minor salivary gland. He proposed that three differentimmunopathological mechanisms could be distinguished in

immune sialadenitis: (i) hyperactivity of the immune systemproduces acute allergic sialadenitis; (ii) inflammation with cell-mediated antibodies of tuberculine type produce the chronictype of allergic sialadenitis; and (iii) an autoimmune reactioncaused by autoantigens produces autoimmune sialadenitis.Acute allergic sialadenitis is a rare type of sialadenitis that isbased on the effects of allergens on the salivary glands. Asubstratum of the morphological features of acute allergicsialadenitis includes periductal and perivascular inflamma-tory infiltration by leukocytes, lymphocytes and histiocytes inconnection with partial destruction of acinar cells.

1

Analogouschanges characterize experimental immune-complex sialad-enitis in rats.

2

Chronic allergic sialadenitis is a manifestationof generalized sarcoidosis, Crohn’s disease, Cheilitis granu-lomatosa and Wegener’s granulomatosis. A synonymousterm for autoimmune sialadenitis is benign lymphoepitheliallesion, including Sjögren’s syndrome

.

In a review by Batsakis

3

it was noted that granulomatous sialadenitis can result fromobstructive sialadenopathy, specific infection, sarcoidosis,Wegener’s granulomatosis or Crohn’s disease; it can occurin association with salivary tumor or foreign body granuloma;and it is in some cases iatrogenic (e.g. sialography). To date,there are no reports about acute allergic granulomatoussialadenitis in the minor salivary glands.

We report a case of a patient who presented with multiplesmall submucosal nodules with granulomatous inflammationin the minor salivary glands of the oral cavity, and we spec-ulate that her condition had a drug-induced allergic etiology.

CLINICAL SUMMARY

In June 2002, a 43-year-old woman presented with a 1 weekhistory of multiple small submucosal nodules in the oral cav-ity (Fig. 1). The patient was referred to a physician for abdom-inal pain 1 week previously and had been taking medicine(ranitidine hydrochloride, troxipide, timepidium bromide anddigestive enzyme) to treat the condition. A few days later she

Allergic granulomatous sialadenitis 851

Figure 1

Intraoral macroscopic findings. Multiple small submucosalnodules (arrows) were observed in the oral cavity. (

a

) Right side ofthe cheek. (

b

) Left side of the cheek. (

c

) Oral floor.

Figure 2

Low-power view of the biopsy sample. Inflammatorychanges were localized in the minor salivary glands (HE).

Figure 3

Microscopic findings in the minor salivary gland. (

a

)Marked infiltration of lymphocytes, eosinophilic cells, macrophagesand multinucleated giant cells with diffuse atrophic and degenerativechange of acini and mild fibrosis are shown using hematoxylin–eosin(HE) staining. (

b

) Degranulated eosinophilic cells were common (HE).

Figure 4

Microscopic findings in the minor salivary gland. (

a

) Mac-rophages tended to be aggregated and appeared to cause immaturegranuloma formation without caseous necrosis (hematoxylin–eosin(HE)). (

b

) Examples of the destructive changes in the duct by multi-nucleated giant cells are shown (HE).

852 T. Irié

et al.

noticed swelling of the oral mucosa and was admitted to theDental Hospital of Showa University. On examination it wasnoticed that the patient had multiple, firm, small, yellowishsubmucosal nodules in the bilateral upper and lower lip,bilateral buccal mucosa and oral floor. These nodules tendedto be aggregated on the oral floor and caused no spontane-ous pain or tenderness. There was no swelling of the parotidglands, submandibular glands or the regional lymph nodes.The patient did not have a history of fever, rectal bleeding,skin lesion or arthritis prior to this episode, but the patient didhave a history of drug allergy (pethidine hydrochloride) andbronchial asthma. Laboratory findings included an increasein the white blood cell count to 12 200/

m

L, increases inalkaline phosphatase (ALPase),

g

-glutamic transpeptidase(

g

-GTP), glutamic pyruvic transaminase (GPT) and leucineaminopeptidase (LAP), a slight decrease in direct reactivebilirubin and albumin, and no increase in angiotensin-converting enzyme (ACE) or lysozyme. A differential periph-eral white blood cell count showed an eosinophilia of 10%.Epstein–Barr virus, HIV, hepatitis B and hepatitis C viralantibodies were negative. Tuberculin test reaction was alsonegative. All other laboratory data examined were withinnormal ranges. Computed tomography (CT) of the breastshowed no swelling of the mediastinal and pulmonary hilarlymph nodes, and magnetic resonance imaging (MRI)showed no defined masses or lesions in the oral cavity. Abiopsy was taken from the one of the submucosal nodulesin the lower lip.

To exclude the possibility of other reported causes of sar-coidosis, such as Crohn’s disease, tuberculosis and atypicalmycobacterial infection, the patient was examined at theDepartment of Internal Medicine, Medical Hospital of ShowaUniversity. None of these diseases were identified after amedical examination.

The patient was seen for follow up 3 weeks after ceasingthe medication. At this time the multiple submucosal smallnodules and other symptoms were not evident. All laboratorydata were within normal range 4 weeks after the biopsy. Thepatient had no evidence of any disease at a follow-up visit2.8 years after the biopsy.

PATHOLOGICAL FINDINGS

Histologically the lesions were localized in the minor salivaryglands and were associated with marked infiltration of lym-phocytes and eosinophilic cells, diffuse atrophic and degen-erative changes of the acini and mild fibrosis (Figs 2,3a).Degranulated eosinophilic cells were often observed(Fig. 3b). The presence of Langhans-type or foreign-body-type multinucleate giant cells and macrophage infiltrationwas also remarkable (Fig. 3a). Langhans-type multinucleategiant cells had neither asteroid bodies nor Schaumann

bodies. These macrophages tended to be aggregated andappeared to have resulted in immature granuloma formationwithout caseous necrosis (Fig. 4a). Acid-fast bacillus was notidentified by Ziel–Neelsen stain. Some of the destructivechanges of the duct caused by Langhans-type or foreign-body-type multinucleate giant cells are shown (Fig. 4b).Definite virus inclusion bodies and fungi were not detected.No definite vasculitis was present.

DISCUSSION

There are several previous reports of sarcoidosis

4

andCrohn’s disease

5

causing multiple submucosal nodules in theoral cavity. However, these conditions did not appear to beinvolved in the present case because we did not observe anyof the typical clinical findings (i.e. swelling of pulmonary hilarlymph nodes, increase of ACE and lysozyme, and gas-trointestinal symptoms) or definitive pathological findings (i.e.asteroid bodies and Schaumann bodies in multinucleatecells) of these conditions. However, the possibility of tuber-culosis and atypical mycobacterial infection need to be con-sidered in this case. Atypical mycobacterial infection of thesalivary glands was shown to be identical microscopically totypical tuberculous infection.

6

However, tuberculosis andmycobacterial infection are not suggested in the present casebecause caseous necrosis and acid-fast bacillus were notdetectable in the immature granulomas.

The drugs that this patient used might have been an impor-tant factor contributing to this episode because multiple sub-mucosal nodules arose in the oral cavity after the patientbegan taking medication for abdominal pain (ranitidinehydrochloride, troxipide, timepidium bromide and digestiveenzyme) and regressed spontaneously after discontinuationof the medication. In a previous report patients with bronchialasthma exhibited airway-like inflammation of the minor sali-vary glands.

7

Moreover, allergy has been implicated as acause of parotid and submandibular gland swelling.

8

In onecase of submandibular gland swelling, which was believed tohave an allergic etiology, the patient had eosinophilia andsevere acute and chronic sialadenitis with dense eosinophilinfiltrates.

8

Waldbott

et al

.

9

reported three patients who expe-rienced recurrent parotid swelling after the ingestion of cer-tain foods. All three patients were asthmatic. David

et al

.

10

studied 23 children with recurrent suppurative parotitis andnoted systemic eosinophilia in nine of the patients. Tenpatients had a history of bronchial asthma, urticaria or hayfever, and eight patients reported these conditions in theirparents or siblings. Four patients had a family history ofparotitis. From these findings it was concluded that there wasa group of patients in whom allergic factors appeared to playa role. Therefore, sialadenitis, which is speculated to have anallergic etiology, is often accompanied by eosinophilia and

Allergic granulomatous sialadenitis 853

bronchial asthma. In our case, the patient had a history ofdrug allergy, bronchial asthma (asthmatic symptoms re-emerged 1 year prior to this episode) and had peripheralblood eosinophilia.

The possibility of other causes, such as viral sialadenitis,should also be considered in our case. Several viruses asidefrom mumps have been reported to be causally associatedwith acute sialadenitis, including coxsackie virus A and B3,

11

influenza

12

and parainfluenza viruses,

13

HIV

14

and Epstein–Barr virus.

15

These reports did not observe sialadenitis in theminor salivary glands as a result of these viruses, nor didthey describe abnormal findings such as multiple submu-cosal nodule formation in the oral cavity, as was observed inour case. Our patient did not have a history of fever, respira-tory symptoms, lymphocytosis or swelling of the parotidglands, submandibular glands or regional lymph nodes, andwas negative for HIV and Epstein–Barr virus antibodies. Wecannot completely exclude the possibility of viral sialadenitis,but the clinical course and clinicopathological findings did notmatch those previously reported for viral sialadenitis.

11–15

In this case, the sialodochitis fibrinosa should be consid-ered for differential diagnosis as allergic sialadenitis. How-ever, multiple granulomatous inflammation in minor salivaryglands and marked infiltration of Langhans-type or foreign-body-type multinucleate giant cells are not usually found incases of sialodochitis fibrinosa.

16

Thus, it is possible that the granulomatous inflammation inthe present case had an allergic etiology because the patienthad a history of bronchial asthma and drug allergy, eosino-philia, the presence of degranulated eosinophils, transienthepatic disorder and multiple submucosal nodules aftertaking medication, and the multiple submucosal nodulesregressed spontaneously after the medication was discontin-ued. Based on this case report we postulate a new entity ofsalivary gland disease tentatively referred to as ‘allergic gran-ulomatous sialadenitis’.

REFERENCES

1 Seifert G. Aetiological and histological classification of sialad-enitis.

Pathologica

1997;

89

: 7–17.2 Sela J, Ulmansky M, Dishon T, Rosenmann E, Boss JH. Exper-

imental allergic sialoadenitis. I. Acute sialoadenitis induced bya local immune reaction.

Virchows Arch A Pathol Pathol Anat

1972;

355

: 213–19.3 Batsakis JG. Granulomatous sialadenitis.

Ann Otol RhinolLaryngol

1991;

100

: 166–9.4 Nessan VJ, Jacoway JR. Biopsy of minor salivary glands in the

diagnosis of sarcoidosis.

N Engl J Med

1979;

301

: 922–4.5 Schnitt SJ, Antonioli DA, Jaffe B, Peppercorn MA. Granuloma-

tous inflammation of minor salivary gland ducts: a new oralmanifestation of Crohn’s disease.

Hum Pathol

1987;

18

: 405–7.6 Van der Walt JD, Leake J. Granulomatous sialoadenitis of the

major salivary glands. A clinicopathological study of 57 cases.

Histopathology

1987;

11

: 131–44.7 Tonnel AB, Janin A, Copin MC, Gosset P, Gosselin B, Wallaert

B. Airway-like inflammation of minor salivary glands in bronchialasthma.

Int Arch Allergy Immunol

1995;

107

: 387–8.8 Harkness P. Submandibular salivary disease: a proposed aller-

gic aetiology.

J Laryngol Otol

1995;

109

: 66–7.9 Waldbott GL, Shea JJ. Allergic parotitis.

J Allergy

1947;

18

: 51–7.

10 David RB, O’Connel EJ. Suppurative parotitis in children.

AmJ Dis Child

1970;

119

: 332–8.11 Howlett JG, Somlo F, Kalz F. A new syndrome of parotitis with

herpangina caused by the coxsackie virus.

Can Med Assoc J

1957;

77

: 5–7.12 Krilov LR, Swenson P. Acute parotitis associated with influenza

A infection.

J Infect Dis

1983;

15

: 145–8.13 Cullen SJ, Banblis JV. Parainfluenza type 3 parotitis in two

immunodeficient children.

J Pediatr

1980;

96

: 437–8.14 Rubinstein A, Sicklick M, Gupta A

et al.

Acquired immunodefi-ciency with reversed T4/T8 ratios in infants born to promiscuousand drug-addicted mothers.

JAMA

1983;

249

: 2350–56.15 Whittingham S, McNeilage J, Mackay IR. Primary Sjogren’s

syndrome after infectious mononucleosis.

Ann Intern Med

1985;

102

: 490–93.16 Darling MR, Phillips VM, Erasmus JH. Bilateral submandibular

salivary gland swelling-a report of chronic sialodochitis witheosinophilia.

SADJ

2002;

57

: 104–6.