Minor salivary gland involvement in sarcoidosis

Minor salivary gland involvement in sarcoidosis Report

of 3 cases

with

positive

lip

biopsies

Thomas M. Tarpley, Jr., D.D.X., Larry Anderson, M.D., Philip Lightbody, D.D.X., and John N. Xheagren, M.D.,* Bethesda, Md. NATIONAL PATHOLOGY,

INSTITUTE NATIONAL

OF DENTAL INSTITUTES

RESEARCH,

EXPERIMENTAL

ORAL

OF HEALTH

In view of the data obtained in three cases, biopsy of minor labial mucosa of the lower lip is proposed as an alternative the diagnosis of sarcoidosis.

salivary means

glands in the of establishing

S

Jrcoidosis is a disease of unknown etiology, characterized pathologically by formation of epithelioid tubercles with inconspicuous necrosis or absence thereof, occurring in many organs and tissues. The diagnosis is not confirmed unless clinical and radiologic features are supported by a positive biopsy or positive Nickerson-Kveim test and negative stains and cultures for infectious agents. Selection of a biopsy site poses little problem if there is either lymphadenopathy or visible or palpable nodules present on the skin or mucosal surfaces. In approximately 40 per cent of patients with sarcoidosis, however, either no such apparent abnormalities are present or biopsy of such abnormalities fails to demonstrate lesions diagnostic of sarcoidosis. l About three out of four patients with active sarcoid of recent onset are responsive to the Kveim test,2 but this test requires a waiting period of approximately 4 to 6 weeks before the reactivity becomes grossly visible for biopsy. Also, as the disease recedes or becomes more chronic, the level of the Kveim reactivity falls appreciably.3 In the absence of obvious clinical involvement of certain tissues as potential biopsy sites, the clinician must at times rely upon random biopsy of apparently uninvolved tissue in an attempt to establish a histologic diagnosis. Some of the currently used biopsy sites are the lung, mediastinal lymph nodes, liver, scalene fat pad, gastrocnemius muscle, and bone marrow. The yield of positive findings *Laboratory ease, National

of Clinical Investigation, National Institute Institutes of Health, Bethesda, Md. 20014.

of Allergy

and

Infectious

Dis-

755

from these sites variesA .1 Some biopsy sites involve significant risk, as well as discomfort to the patient, and are not always readily accessible. Involvement of the salivary glands with sarcoidosis as part of the Heerfordt’s syndrome, or uveoparotid fever, is well known. Oral and paraoral sites wit,h evidence of sarcoid, other than the major salivary glands, are reviewed in Table I, with attention focused on involvement of minor salivary glands. Only recently has it been appreciated that the minor salivary glands of clinically normal-appearing oral mucosa can be involved histologically in patients with sarcoidosis. Biopsies of normal-appearing palates in twenty-three patients with known sarcoidosis supported the diagnosis in 38 per cent4 of the cases. Recently, in a patient undergoing evaluation for possible SjGgren’s syndrome at the Clinical Center of the National Institutes of Health, biopsy of the lower lip demonstrated granulomas consistent with sarcoidosis in &+-minor salivary glands. Subsequently, two additional patients suspected of having sarcoidosis showed evidence of sarcoid granulomas in biopsies of the lip. All of these patients had normal-appearing oral mucosa. This report proposes the value of a safe and relatively nontraumatic biopsy technique as an important adjunct in establishing the diagnosis of sarcoidosis. The technique uses tissue t,hat is readily accessible from the mucosal surface of the lower lip, in which healing occurs rapidly (approximately 1 week). This procedure could prove to be most useful in supplementing or complementing currently established diagnostic techniques. METHODS lip biopsy

Biopsies of the lip were performed in a standard manner by one oral surgeon (P.L.) , After nerve-block anesthesia of the inferior alveolar nerve with 2 per cent Xylocaine with l/100,000 epinephrine, an elliptical segment of tissue, 1 cm. long, was removed with a scalpel. All tissue above the orbicularis oris was included in the specimen. Bleeding was easily controlled with the use of a chalazion forcep. The wounds were closed primarily with 4-O black silk suture. Patients generally experienced mild discomfort for the next 1 or 2 days. The tissue was placed in formalin, sent to the laboratory for routine processing, and stained with hematoxylin and eosin. CASE CASE

REPORTS 1. M.F.

(08-28-671

A 32.year-old Negro woman had a B-year history of irritated eyes, with recurrent redness and pain in both eyes. Six months prior to admission she noted the onset of photophobia. The diagnosis of keratoconjunctivitis~ sieca was made on the basis of cornea1 fluorescein staining and a positive Schirmer’s test. She was referred to the National Institutes of Health Eye Clinic, where this diagnosis was confirmed. Screening laboratory examinations revealed an elevated erythrocyte sedimentation rate of 66 and abnormal liver function tests, with alkaline phosphatase 437 I.U. and SGOT 50. A chest film was normal. Physical examination was normal except for dryness and injection of the conjunctivae. There were no oral mucosal lesions. During the course of evaluation for possible SjSgren’s syndrome in view of the keratoconjunctivitis sieea, the patient underwent a biopsy of the lower lip for histopathologie

1

et al.23

Tillman

Cahn

Tillman

Orlean and O’Brien16

and

Kolas

Roche

Cernha

Watt@

Usmanova20

Hobkirkzl

Hoggins Allan

Chisholm

1960

1964

1964

1966

1966

1967

1968

1968

1968

1969

1969

1971

c/w *It salivary

1

Kalman and Mallettiz

1954

= Consistent with. should be noted that, glands.

et al.18

et al.17

et al.15

et al.**

and Roehera

1

Cove111

1954

66

45

of the ten

1

1

30

1

42

1

27

37

1

24

1

33

1

1

37

positive

palatal

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Negro

Negro

Negro

-

1

Caucasian

18

-

1

Caucasian

Caucasian

Negro

Negro

Caucasian

Race

Sarcoidosis

10

15

54

26

41

1

Poe10

1943

Age

48

s

Schroff

1942

No. of cases

1

Author

of the literature.

Year

Table I. Review

biopsies

M

F

M

M

F

F

M

M

M

F

M

Sex

mucous

lumps

anterior or oral

lip

cheek

floor

palatine

by

Cahn

adenopathy

associates,

not

glands

salivary areas

salivary

antrum

minor molar

and

minor

and minor

gland-

glands

of mouth

cervical

floor

and

including and

and labial

cheek-maxilla

reported

Parotid

Left

tissue

right

tonsil

area

lip-scar

propia

cavity

region-mixed

membrane

of mouth

tongue

Buccal mucosa gland-premolar

Left

Gingivae

Lower

Sublingual

Right

Anterior

salivary

involvement or paraoral)

in oral

of

Palate, both of lamina salivary glands

Gingivae

Multiple

Maxillary nasal

Lower

Mandible

Right

(oral

Site

in sites other than major

all

tissue,

of histology

c/w

showed

Sarcoidosis involvement

Sarcoidosis Sarcoidosis

e/w

c/w

of

Boeck’s

the

minor

disease

sarcoid

sarcoidosis

of sarcoidosis

Besnier-Boeck-Schaumann

Sarcoid

Sarcoid

Sarcoid

Fibrous c/w

sarcoid

Sarcoid

Sarcoidosis c/w

form

Report

granuloma,

Sarcoidosis

Boeck’s

Focal

Sarcoidosis

Sarcoidosis

Unusual

Fig. 2. Case 1. S&ion demonstrates discrcltcl and roal~cing granulomas separated by bands of round cells and cont.aining residual glandular tissu,. (Hemat.oxylin and (losin stain. Magnification, x100.) Fig, 8. Case 1. Same section as in Fig. 1, at higher magnification. (ILematoxylin and eosin stain. Magnification, xl HO.) examination of the minor salivary ulomas, suggestive of sarcoidosis. showed noncaseating granulomas. Microscopic

glands. 5, s This biopsy demonstrated Concomitant biopsy of the liver and The Kveim test was negative.

noncaseating granlacrimal glands also

findings

Sections revealed lobules of salivary glands with increased intralobular and interlobular fibrosis and round cell infiltrates. One peripheral lobule contained several discrete and coalescing granulomas (Figs. 1 and 2), immersed in a meshwork of lymphocytes and plasma cells and residual glandular components. The granulomas were consistent with those seen in sarcoidosis. Special stains for microorganisms were negative. CASE

2.

I.P.

(07-75-36)

A 23-year-old Negro woman, raised the lacrimal glands 1 month prior to

in North admission,

Carolina, followed

noted the onset of swelling of by dryness of the eyes and a

Volume 33 Number

5

Minor

salivary

gland involvement

in sarcoidosis

Fig. 3. Case 2. Section of minor salivary gland with a focal granulomatous ing giant cells. (Hematoxylin and eosin stain. Magnification, x100.) Fig. 4. Case 2. Same section as in Fig. 3, at higher magnification reveals no inclusion bodies visible. (Hematoxylin and eosin stain. Magnification, x160.)

reaction giant

759

cont.aincells

with

rash on the legs. Biopsy of the lacrimal glands demonstrated noncaseating granulomas consistent with sareoidosis. Three weeks prior to admission she awakened with paralysis of the right side of her face. At that time she noted bilateral swelling of the parotid glands and dryness of the mouth. Her Sense of taste and smell seemed to be diminished. On admission to the Clinical Center in February, 1968, the patient had bilateral swelling of the lacrimal and parotid glands. There were no visible lesions of the oropharyngeal mucous membrane. One 2-by-2-em. nontender, anterior cervical node was palpable. There was no hepatosplenomegaly. There were isolated and confluent, 8caly, infiltrated, brownishred plaque8 over the lower extremities. There was no residual facial paralysis. The hematocrit was 42, the white blood count was 2,600 with 33 per cent neutrophils, 41 per cent lymphocytes, 7 per cent monocytes, 16 per cent eosinophils, and 3 per cent basophils. Erythrocyte sedimentation rate was 22 mm. per hour (Westergren). Alkaline phosphatase was 19 King-Armstrong units, SCOT 69, SGPT 87, with a normal bilirubin. Total serum protein was 6.7 Gm. per cent, with 1.8 Gm. per cent gamma globulin. Serum calcium wa8

760

l’arpley

normal. Chest radiograph function tests demonstrated A biopsy of the lower matous lesions, consistent Microscopic

Oral surg.

et ctl.

May,

demonstrated lower perjtracheal mild diflusion and restrictive lip and of the skin of the left with sarcoidosis.

1972

and hilar adenopathy. Pulmonar> defects. leg demonstrated nodular granrrlo-

findings

Sections of oral mucosa revealed a parakeratinized, stratified squamous epithelium overlying connective tissue containing lobules of minor salivary glands. Some lobules showed distention of acini and interstitial fibrosis. One area contained a focal granuloma (Fig. 3) with several giant cells, consistent with those found in sarcoidosis. No inclusion bodies were present in the giant cells (Fig. 4), and special stains for other pathogens were negative. CASE

3. P.S.

(08-62-08)

A 4%year-old white woman had noted, 1 month prior to admission, the onset of tender, violaceous nodules, diagnosed as erythema nodosum on her legs. Evaluation included a chest radiograph, which demonstrated bilateral hilar adenopathy. A fortuitous, routine chest film 3 months earlier had been interpreted as normal. At the time that the patient was admitted to the Clinical Center, the physical examination findings were normal, except for scattered, raised, indurated, violaceous skin lesions on the lower extremities. Blood counts were normal, except for an elevated erythrocyte sedimentation rate to 60 mm. per hour. The results of liver function tests were normal. Biopsy of the lower lip and the liver showed noneaseating granulomas consistent with sarcoidosis. The Kveim test was negative. Microscopic

findings

Sections revealed multiple lobules of minor salivary glands in a scant connective tissue stroma partially covered by stratified squamous epithelium. The lobules contained a few dilated acini and lumens filled with mucin. Minimal adipose tissue was noted within a few lobules. Deeper sections revealed a focal granulomatous area suggestive of that found in sarcoidosis, and similar to that found in the previous patient.

PATIENTS WITH NEGATIVE

LIP BIOPSIES

We have had the opportunity to examine biopsy specimens of the lower lip from four other patients with suspected sarcoidosis. None of these specimens showed evidence of sarcoid, even on serial sectioning. It is noteworthy that histologic diagnosis could not be established in two of the patients even by biopsies of the liver and scalene fat pad or by the Kveim test. Of the other two patients who had negative biopsies of the lip, one had positive biopsies of the liver and skin, and the other had positive biopsy of the scalene fat pad. DISCUSSION Histologically, sarcoid is recognized by the formation of epithelioid granulomas (Fig. 5). However, there are other disorders or agents capable of producing such granulomas. Most notable among these are tuberculosis and certain atypical mycobacterial infections, leprosy, syphilis, mycoses, beryllium, zirconium, silicosis, and, finally, neoplasms and viruses7 Special stains, use of polarized light, and careful history ruled out any of the foregoing as causes of the epithelioid granulomas. These granulomatous areas were found without the benefit of serial sectioning in two cases; however, deeper sections were necessary in one biopsy specimen.

Minor

salivary

gland involvement

Fig. 5. Section of a typical epithelioid or sarcoid granuloma of histiocytes surrounded by bands and aggregates of (Hematoxylin and eosin stain. Magnification, x250.)

in sarcoidosis

containing lymphocytes

focal and

761

accumulations plasma cells.

Sarcoid granulomas have a monomorphous character, as contrasted to the pleomorphy of tuberculosis. The sarcoid granuloma frequently contains a variety of inclusion bodies, which may at times be a prominent feature ; however, no special etiologic significance is attached to their presence. The inclusion bodies are of three types: the Schaumann or conchoid body, the asteroid body, and the microcentrosomes.8 None of these inclusions was observed in our cases. In the quest for histologic confirmation of the diagnosis of sarcoidosis, biopsy of lung, liver, and other sites often imposes serious risks and considerable discomfort to patients. This paper emphasizes a readily accessible alternative site, the mucosal surface of the lower lip, with a minimum discomfort to the patient, and an absence of risk. At the Clinical Center, more than eighty biopsies of the lower labial mucosa have been performed in a series of patients evaluated for Sjiigren’s synclrome.6 No complications have been encountered in these patients. Although the number of patients in the present study is small, we think that biopsy of the mucosal surface of the lower lip should be considered as an aid in establishing a diagnosis in patients suspected of having sarcoidosis. SUMMARY Granulomas consistent with sarcoidosis in minor salivary glands were found in biopsy specimens of the lower lip in three patients. This simple, nontraumatic, and safe technique of lower-lip biopsy should be used and evaluated as a diagnostic procedure in establishing the diagnosis of sarcoidosis in patients who have no visible or palpable nodules or who have nodes suggestive of the disease. Miss typing

We wish to thank the National June Dobos and Royd Ellis the manuscript.

Institutes of Health MAP for laboratory procedures,

Branch and

for Mrs.

photomicrographs, Hilda Stofko

for

762

l’aqdey

et al.

Oral May,

surg. 1972

REFERENCES

of Biopsy Procedures for Sarcoidosis Diagnosis, 1. Israel, L., and Sones, M.: Selection Arch. Intern. Med. 113: 255.260, 1964. 2. Kiltzbach, L. E.: Current Status of the Nickerson-Kveim R,eaction, Am. Rev. Reap. Dis. 84: 89-93, 1961. 3. Siltzbach, L. E.: Significance and Specificity of the Kveim Reaction, iicta Med. Stand., Suppl. 425, 176: 74-78, 1964. 4. Cahn, L. R., Eizenbud, L., Blake, M. N., and Stern, D.: Biopsies of Normal Appearing Palates of Patients With Known Sarcoidosis, ORAL SURG. 18: 342-345, 1964. 5. Chisholm, 33. M., and Mason, D. K.: Labial Salivary Gland Biopsy in Sjiigren’s disease, 5. Clin. Pathol. 21: 656-660, 1968. 6. Talal, N., Asofsky, R., and Lightbody, P.: Immunoglobulin Synthesis by Salivary Gland Lymphoid Cells in Sjogren’s syndrome, J. Clin. Invest. 49: 49-54, 1970. 7. Jaroszewicz, W.: Editorial: Sarcoidosis, Pol. Arch. Med. Wewn. 43: 1549-1554, 1969 (NIH Library Translation). 8. Uehlinger, E.: The Sarcoid Tissue Reaction, Beta Med. &and., Suppl. 425, 176: 7-13, 1964. 9. Schroff, J.: Sarcoid of the Face (Besnier-Boeck-Sehaumann) Disease. Report of a Case? J. Am. Dent. Assoc. 29: 22082211, 1942. 10. Poe, 0. L.: Sarcoidosis of the Jaw. Am. J. Orthod. 29: 52-56. 1943. 11. Covel, E.: Boeck’s Sareoid of Mucous Membrane, ORAL &RG. 7: 1242-1244,. 1954. 12. Kalman, 5. I., and Mallett, 8. P.: Aberrant Gland and Sarcoidosis in the Maxillae: Report of a Case, J. Oral Surg. 12: 63-66, 1954. 13. Kolas, S., and Roche, W. C.: Sareoidosis Lesions Primary in the Oral Cavity: Report of a Case, J. Oral Surg. 18: 169-172, 1960. 14. Tillman, H. H.: Sarcoidosis with Unsuspected Oral Manifestations. Report of a Case,

ORAL SURG. 18: 130-135. 1964. 15. Tillman, H. H., Taylor,‘R. CT., and Carchidi, J. E.: Snrcoidosis of the Tongue. R,eport of a Case, ORAL SURG. 21: 190-195, 1966. 16. Orlean, S. L., and O’Brien, J. J.: Sarcoidosis Manifesting a Soft Lesion in the Floor of the Mouth. Report of a Case, ORAL SURG. 21: 819.823,1966. 17. Roche, W. C., Morris, R., and Nemickas, R. das: Sarcoidosis of Sublingual Glands: Report of a Case, J. Oral Surg. 25: 77-79, 1967. S. : Besnicr-Boeek-Schumann 18. Cernea, P. C., Crepy, C., Ruffer, R., Pnyen, IJ ., and Mountain, Disease on Old Scars on the Face and Oral Mucosa, Rev. Stomatol. (Paris) 69: 197-214, 1968. (Translated from French by the Translation Unit, Library Division of Research Services, N.I.H.) 19. Watts. K. D.: Snrcoidosis. Br. J. Oral Surg. 6: 1~08-113. 1968. 20. Usmanova, N. F. : Observation of Pharyngial Sarcoidosis. Besnier-Boeck-Schumann Disease, Vestn. Otorinolaringol. 30: 105-106, 1968. (Translated from Russian by the N.I.H. Library Translation Unit.) 21. Hobkirk, J. A.: Sareoidosis With Oral Lesions. Report of a Case, J. Oral Surg. 27: 891894, 1969. 22. Hoggins, G. S., and Allan D.: Sarcoidosis of the Maxillary Region, ORAL SURG. 28: 623627, 1969. 23. Chmholm, D. M., Lyell, A., Hnroon, T. S., Mason, D. K., and Beely, J. A.: Salivary Gland Function in Sarcoidosis, ORAL SVRG. 31: '766-771, 1971. Repint

yequests

to :

Dr. Thomas M. Tarpley, Jr. National Institutes of Health National Inst,itute of Dental Research Bldg. 10, Rm. 2B-11 Bethesda, Md. 20014