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Oral involvement in sarcoidosis
Int. J. Oral Surg, 1982: 11: 21-29 (Key words: sarcoidosis: granuloma, epithelioid)
Oral involvement in sarcoidosis A. C. M. TH. VAN MAARSSEVEEN, I. VAN DER WAAL, J. STAM, R. W. VELDHUIZEN AND W. A. M. VAN DER KWAST Departments of Pathology, Pulmonology and Oral Surgery, Free University, Amsterdam, The Netherlands
ABSTRACT - The general aspects of sarcoidosis are presented, as well as some concepts derived from experimental work. Thereafter, a review of the literature on oral involvement insarcoidosis isgiven, including thepossible value of an oral biopsy in the case of suspected sarcoidosis. Finally, 3 patients - 2 with known sarcoidosis and I with unsuspected sarcoidosis - are presented as a brief illustration.
(Received for publication 3 March, accepted 21 August 1981)
Sarcoidosis is more common in the third and fourth decades oflife than in other decades and has no predilection for sex or races. Figures of the exact incidence are not available. The diagnosis is in many cases made as an incidental finding on the chest film. Sarcoidosis is a multisystem granulomatous disorder of unknown etiology. The disease may actually affect any organ or part of the body. In the past a relation with tuberculosis was often suggested, but that hypothesis is nowadays abandoned. Sarcoidosis is one of the diseases which are characterized by an abnormal immune response, mostly expressed by an impaired cellmediated delayed-type hypersensitivity, the humoral immunity being normal or even increased. It is most likely that different factors evoke the response, which is expressed in a sarcoid granuloma. However, a variety of other diseases and conditions can cause more or less similar histopathological findings. A sarcoid granuloma in the absence of generalized disease is commonly due to some local condition. 0300-9785/82/010021-09$02.50/0
General aspects of sarcoidosis Organs affected in sarcoidosis Cutaneous manifestations of sarcoidosis, originally named "lupus pernio", were first described by Besnier in 1889.The first histological description of the disease was given by Boeck in 1899. In 1914 Schaumann expressed the view that "lupus pernio" and Boeck's cutaneous sarcoids were part of the same disease and that nasal mucosa, tonsils, lymph nodes, conjunctiva, the lungs and the bones of the hands could also be affected. Ever since, the disease sarcoidosis is also known as Besnier-BoeckSchaumann disease. Mainly through the work of LOfgren has bilateral involvement of the pulmonary hilar lymph nodes been proven to be an early manifestation of the disease, sometimes accompanied by erythema nodosum, subfebrile and general malaise". temperature Uveoparotitis, as described by HEERFoRDT in 1909, is at present known as a rare manifestation of sarcoidosis". The complete
© 1982 Munksgaard, Copenhagen
22 VAN MAARSSEVEEN, VAN DER WAAL, STAM, VELDHUIZEN AND VAN DER KWAST Heerfordt's syndrome consists of uveitis, parotitis, fever and facial palsy. In a review of about 3,700 patients from different parts of the world suffering from sarcoidosis, it was observed that the most frequently affected organs were the lungs and their lymph nodes, the figure being 80%. The extra-thoracic lymph nodes were involved in about 22%, the eyesin 15%,the spleen in 6%, the central nerve system, the bones and the parotid glands in about 4% (JAMES et af.2S ) . During the 7th and 8th International Conferences on Sarcoidosis and Other Granulomatous Diseases, held in 1976 and 1978 respectively, no reports of oral involvement in sarcoidosis were presented, although quite a number of publications on that subject had been written, mainly in the literature on oral surgery and oral pathology. Histopathologic findings in sarcoidosis As mentioned before, the sarcoid granuloma is the histopathologic entity of sarcoidosis. The sarcoid granuloma consists of a focal collection of monocyte-derived epithelioid cells (giant cells) admixed with T-lymphocytes, occasional plasmacells and fibroblasts (JONES WILLIAMS'7 ) . At the early stage, the picture cannot always be distinguished from other local and generalized chronic granulomatous conditions such as tuberculosis. Occasionally, central areas with fibrinoid necrosis and a tendency to hyalinosis are found. In some cases concentrically or eccentrically laminated bodies, known as Schaumann bodies, are found. Also delicate, spidery radiating structures, known as "asteroid bodies", may be encountered in sarcoid lesions. These kinds of structures may also occur in other types of granulomas and are, therefore, not pathognomonic", The first indication of the development of sarcoidosis may be the appearance of a sarcoid granuloma in a site where irritatant material has lain donnant in the tissues. This type of sarcoid granuloma is not always associated with or
followed by sarcoidosis, but is sufficiently common to require that every patient with such a sarcoid reaction be kept under observation for signs of incipient sarcoidosis. Sarcoidosis in experimental pathology The macrophage is part of the mononuclear phagocytic system. This cell originates as a bone marrow precursor cell, circulates for a short time as monocyte, and becomes macrophage when it enters the tissue, either in a regular way or by inflammatory stimulation. The suggestion is made that in sarcoidosis, the mononuclear cells have an ineffective capacity to react to a stimulus in a normal way!"!". There are two categories of granulomas, one with a high turnover and one with a low turnover. High turnover granulomas are characterized by an impressive inflow of monocytes together with an extensive proliferation rate. The monocytes may disappear quickly by cell death or by drainage to a lymph node or may transform ultimately in epithelioid cells, which may become immobilized in the granuloma for months, without proliferation or cell death. The epithelioid cells orginate from macrophages, whose capacity for phagocytosis seems "frustated" 1l.43. There is evidence that maturation of macrophages into epithelioid cells is accompanied by a shift from phagocytosis and intracellular digestion to extracellular secretion of enzymes and mucoproteins. The multinucleated giant cell, often observed in the granuloma, has been formed by fusion of macrophages'":". The suggestion has been made that young and active macrophages ingest old and exhausted macrophages, thereby developing the aspect of giant cells". Subcutaneous implants in mice showed that these giant cells are short-lived and disappear within weeks". In the low turnover lesions, the macrophage population is relatively stable and the phenomena just described are much less evident. The presence of giant cells are scanty in low turnover and numerous in high turnover granuloma"•.
ORAL SARCOIDOSIS
To study the pathogenesis of sarcoidosis, many investigators produced sarcoid-like epithelioid cell granulomas in animals with "Freund complete adjuvant" with bacteria, isolated purified cell wall fractions':" or metals":": Their results suggest that some components may persist within macrophages due to ineffective handling, which seems to play a role in the pathogenesis of the epithelioid cell granuloma. Diagnosis and staging For a long time, biopsy of the subclavicular lymph node was considered most useful in cases of suspected sarcoidosis. Nowadays bronchoscopy is often preferred, since in about 90% of the patients suffering from sarcoidosis, intrathoracal involvement can be demonstrated':'. The histologic picture of the granuloma is by itself, as mentioned earlier, insufficient proof of the diagnosis of sarcoidosis-"; confirmatory support from the findings of the pulmonologist, dermatologist or ophthalmologist as well as from laboratory investigations such as calcium metabolism (hypercalcaemia) and SACE (serum angiotensin converting enzyme) is required", Other supporting evidence includes a depressed cellmediated immunity, resulting in a diminished DNCB or negative tuberculin skin test. An important diagnostic aid is the Kveim test, consisting of an intradermal injection of a reagent prepared from proven sarcoid lymphoid tissue. Histological verification for a positive reaction, consisting of a typical sarcoid granuloma at the site of inocculation, can be carried out after 5 or 6 weeks. The value of the test is dependent upon the quality of the Kveim antigen and the activity of the disease"-". A biopsy of apparently healthy oral mucosa may be of some significance in making a diagnosis of sarcoidosis, as will be discussed later. Based on the chest film, three stages of sarcoidosis can be distinguished: stage I: bilateral enlargement of the
stage II:
stage III:
23 hilar nodes without pathologic changes in the lung fields; bilateral enlargement of the hilar lymph nodes with pathologic changes in the lung fields around the hili; no enlargement of the lymph nodes, but extended, sometimes patchy or stripy, changes in both lung fields. The patches can join together and bullae may be formed.
Treatment In general, no treatment for sarcoidosis is necessary, since the natural tendency is towards healing I 3.24. In stage I a 65% complete, spontaneous remission will occur, while in stage II this happened in 49%. In about half of the patients of both stages I and II who did not have a spontaneous regression, cure was obtained with drug therapy. In general, the use of corticosteroids seems only to accelerate the disappearance of detectable signs of sarcoidosis. After a 3-5 year period, however, no remarkable difference could be demonstrated between patients who had been treated with corticosteroids and those who had not". In some instances sarcoid granulomas undergo fibrosis and hyalinosis. Particularly in the lungs, the tendency to fibrosis has serious consequences for the pulmonary function. Therefore, corticosteroids should be administered in cases of sarcoid lesions producing lung fibrosis. Steroid treatment is also indicated in cases of cardiac or neural involvement, in spite of the possible harmful side-effect of that kind of therapy.
Oral involvement in sarcoidosis; review of the literature and report of 3 cases In reviewing the literature on oral aspects of' sarcoidosis, some reports of extraoral involve-
24 VAN MAARSSEVEEN, VAN DER WAAL, STAM, VELDHUIZEN AND VAN DER KWAST ment, i.e, affected lymph nodes in the head and neck area, are included. Patients with already proven sarcoidosis, who also had lesions in the oral region In some of the patients with already proven sarcoidosis, the oral involvement consisted of one or more nodules in the oral mucosa, without preference for any specific site 12 •22,40,45. A few cases have been reported of involvement ofthejaw bones 4. 2 1,42. Involvement of glandular structures in the oral cavity is mentioned by KALMAN 29 as well as by NARANG & DIXON 37. A decreased level of a-amylase and increased levels of albumine and lysozyme have been observed by BEELEY & CHISHOLM2 in parotid saliva from a patient suffering from sarcoidosis with salivary gland involvement. These observations were interpreted as the result of damage to the gland. Some years earlier the value of salivary gland function tests in diagnosing sarcoidosis and in monitoring the response to possible therapy was described by CHISHOLM et al. to • Patients with already proven sarcoidosis in which an oral biopsy of apparently healthy tissue was taken CAHN et al,' have described a group of 23 patients with known sarcoidosis in which palatal biopsies of clinically normal areas were performed. They were able to demonstrate the presence of sarcoid granulomas in 38% of their cases, TILLMAN'3 described a 66-year-old man suffering from sarcoidosis. Oral examination showed a normal aspect of the gingiva. Nevertheless, a gingival biopsy was performed to rule out amyloidosis. More-or-less as a surprise, the microscopic findings were consistent with sarcoidosis. A biopsy of the labial glands of the lower lip has been reported positive in a number of patients suffering from sarcoidosis'v-":". NESSAN & JACOWAY even found 58% non-caseating granulomas in biopsies of the labial glands in a total number of75 patients with known sarcoidosis".
Apparently healthy patients with one or more sarcoid granulomas in the oral region, in which additional examination justified the diagnosis of sarcoidosis A number of patients have been described in which an oral lesion, microscopically diagnosed as a sarcoid granuloma, led to the detection of generalized sarcoidosisl.,33,44"7, KERR 30 described a 20-year-old man with multiple swollen lymph nodes in the parotid, submental, submandibular, superficial and deep cervical area. Roentgenographs of the chest showed enlargement of nodes in the upper mediastinum. A submental node was examined microscopically. The appearence was that of sarcoidosis. Apparently healthy patients with one or more sarcoid granulomas in the oral region, in which the diagnosis ofsarcoidosis could not be proven or remained somewhat debatable SCHROFF 46 has described a 48-year-old female with a swelling of the whole thickness of the cheek of 4 weeks duration. The lesion was biopsied and reported as being of tuberculous nature. All additional tests, chest films and other examinations were negative for tuberculosis, which led the author to suggest the diagnosis of sarcoid. Several of such cases have been reported thereafter J,9,2J,JI,54,56. NITZAN & AZAR 39 have described a 62-yearold woman with an indurated submandibular mass, measuring about 3 em. The radiograph revealed a sialolith in the submandibular gland. The clinical diagnosis was sialolithiasis. The submandibular gland was removed together with a surrounding lymph node. That lymph node showed the features of sarcoidosis. No Kveim test was performed. All other examinations were negative for sarcoidosis. The Mantoux intracutaneous test was negative. The patient was suffering from migrating arthritic pain and swellings, xerophthalmia, dyspnea and hypertension. Because ofthose symptoms it was felt that this patient, in spite ofnegative findings elsewhere in the body, suffered from systemic sarcoidosis. Nitzan and Azar mentioned that
ORAL SARCOIDOSIS
"specific treatment for sarcoidosis was of great benefit" and considered this another support for their diagnosis. ORLIAN & BIRNBAUM 4 ! described a 43-yearold woman with a lesion in the lower left anterior mucobuccal fold. There was no evidence of bony involvement. Lymphadenopathy was absent. The microscopic appearance was consistent with sarcoidosis. Additional examination for sarcoidosis was negative.
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Case reports Case 1. In May 1980, a 23-year-old man was referred because of multiple nodules on the hard and soft palate. The nodules were slightly elevated, measured a few mm and were of a firm elastic consistency. There was no ulceration (Fig. 1). The patient had his natural dentition. Possible irritating factors which could have played a role in the initiation of the palatal nodules could not be detected, although heavy smoking may have been of significance. The duration of the presence of the nodules was unknown to the patient. This man was known to suffer from sarcoidosis, the first clinical manifestations being multiple subcutaneous nodules on his legs and arms. The chest film had demonstrated bilateral enlargement of the hilar lymph nodes (Fig. 2). One of the palatal nodules was biopsied, The histopathology was compatible with a sarcoid granuloma (Fig. 3), Healing of the biopsy wound was uneventful. No treatment has been instituted so far.
Fig. 1. Multiple nodules on the palate in a 23-year-old man suffering from sarcoidosis.
Fig, 2. The chest film showing bilateral enlargement of the hilar lymph nodes without pathological changes in the lung fields.
The patient will be seen at 3-monthly intervals by the Department of Pulmonology, The nodules of the palate have not shown any change during a 6 months follow-up period.
Case 2. In June 1977, a 69-year-old woman was referred because of a small submucosal nodule on the tip of the tongue of some months duration. On palpation, a firm, submucosal, somewhat mobile nodule was felt. The overlying mucosa was intact. The
Fig, 3, Biopsy specimen of one of the palatal nodules showing rather well-circumscribed epithelioid cell granulomas compatible with sarcoidosis (H.E. x 200).
26 VAN MAARSSEVEEN, VAN DER WAAL, STAM, VELDHUIZEN AND VAN DER KWAST lesion of the tongue was excised and histopathologically reported as compatible with sarcoidosis. Additional examination by the Department of Pulmonology showed the presence of pulmonary sarcoidosis. The Kveim test proved to be positive (Fig. 4). So far, no treatment has been instituted. In the following 3 years, up to December 1980, no other lesions or manifestations appeared.
Case 3. In November 1978, a 25-year-old man was referred because of a rather well-circumscribed submandibular swelling on the left side. The patient had noticed this swelling for about 6 months. The medical history was essentially negative. A clinical diagnosis of salivary gland tumor, most likely pleomorphic adenoma, was made. It was not felt necessary at that time to carry out additional diagnostic work-up such as sialography, scintigraphy or aspiration cytology. Pre-operative physical examination did not reveal any abnormality. In January 1979, a suprahyoidal approach was chosen to remove the submandibular tumor. At operation, it was clear that the submandibular salivary gland was of normal size and consistency, but that a large lymph node, measuring about 3 em, was lying lateral to that gland. A fresh frozen section was performed, showing sarcoid granulomas in the lymph node (Fig. 5). Nevertheless, it was decided to complete the excision of the suprahyoidal triangle. In the surgical specimen,
b Fig. 5. Submandibular lymph node with homoge-
neous replacement of lymphoid tissue by many characteristic confluent epithelioid cell granulomas (H.E. x 200).
multiple enlarged nodes were found. Also in those nodes sarcoid granulomas were seen. The patient was then referred to the Department ofPulmonology. The diagnosis of sarcoidosis was confirmed by findings on the chest film and a positive Kveim test. No palpable lymph nodes elsewhere in the body could be detected. No treatment has so far been instituted. During the two-year follow-up period no other lesions or manifestations have developed. A very similar experience has been reported by MANDEL
& BAURMASH'4.
Discussion and conclusions
Fig. 4. Skin biopsy of the forearm 5 weeks after
injection of Kveim's reagent. Notice the many giant cells (H.E. x 80).
Sarcoidosis may affect any organ or part of the body .'Sarcoid lesions seem to be the result of an impaired mechanism of some of the macrophages, The histologic finding of a sarcoid granuloma is by itself insufficient proof of the diagnosis of sarcoidosis and may well be due to some local condition. In view of the numerous reports on sarcoidosis, the incidence of oral involvement, as extracted from the literature, is rather low. In a number of papers, evidence of the oral sarcoid being a manifestation of generalized sarcoidosis is either not presented or remains somewhat debatable. Some authors have suggested that oral sarcoid may not be rare, but probably remains undiagnosed or unreported. Two of the patients with oral sarcoid described in this report were already known to
ORAL SARCOIDOSIS suffer from sarcoidosis. The third patient, however, was apparently healthy. A submandibular, rather well-circumscribed swelling was clinically diagnosed as being most likely a salivary gland tumor. No sialography or cytologic puncture, nor any additional examination was felt necessary at that time. The true nature of the swelling, being an enlarged lymph node, first became evident at operation, thus illustrating the limitation of a provisional diagnosis by clinical judgement only. There are several reports mentioning the presence of sarcoid granulomas in biopsies of apparently normal oral tissue, especially from the palate and the lower lip, in patients with proven sarcoidosis. We hesitate, however, to advocate the use of such biopsies when gathering supporting evidence for the diagnosis of sarcoidosis only, since staging of the disease is usually based upon the radiographic findings on the chest films. On the other hand, one should know that an oral sarcoid granuloma can be an early manifestation of sarcoidosis and that such a patient should at least be seen by the pulmonologist for further evaluation. Acknowledgement - We thank Mrs. M. Mooijen for her help in preparing the manuscript and Mr. G. J. Oskam for photography of the histologic slides.
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granuloma: characterization of a model system for infectious and foreign body granulomatous inflammation using soluble mycobacterial, histoplasma and schistosoma antigens. Immunol. 1973: 24: 511-529. 7. CAHN, L. R., EISENBUD, L., BLAKE, M. N. & STERN, D.: Biopsies of normal-appearing palates of patients with known sarcoidosis; a preliminary report. Oral Surg, 1964: 18: 342-345. 8. CAIN, H. & KRAUS, B.: Mehrkcrnige Riesenzellen in Granulomen. Neu-ordnung der Binnenstructur nach Konfluenz von Zellen des Makrophagensystems. Virchows Arch. A. Path. Anat. und Histol. 1980: 385: 309-333. 9. CAMPBELL, 1.: Sarcoidosis or tuberculosis? Br, Dent. J. 1944: 77: 159-163. 10. CHISHOLM, D. M., LYELL, A., HARoON, T. S., MASON, D. K. & BEELEY, 1. A.: Salivary gland function in sarcoidosis: report of a case. Oral Surg, 1971: 31: 766-771. II. Corrmn, H., HESS, M. W., KELLER, H. D., RODS, B. & Tosr, P.: Macrophage kinetics and granuloma formation. In: Abstracts Int. Siena Sarcoidosis Symposium. Siena, Italy, 1979. 12. COVEL, E.: Boeck's sarcoid of mucous membrane; report ofa case. Oral Surg, 1954: 7: 12421244. 13. CRETIEN, J.: Course and treatment of sarcoidosis in 350 patients. 3rd European Conf. on Sarcoidosis and other granulomatous disorders. Novi Sad. Jugoslavia, May 1980. 14. DJURIC:, B., MANDl, L. & VEZENDI, S.: Sarcoidosis in six European cities. In: JONES WILLIAMS, W. & DAVIES, B. H. (eds.): 81h Int. Con]. on sarcoidosis and other granulomatous diseases. Alpha Omega Pub\. Ltd. 1980,527-531. 15. EULE, H., ROTH, 1. & WEIDE, W.: Clinical and functional results of a controlled clinical trial of the value of prednisolone therapy in sarcoidosis, stages I and II. In: JONES WILLIAMS, W. & DAVIES, B. H. (eds.): Bth Int. Conf. on sarcoidosis and other granulomatous diseases. Alpha Omega Publ. Ltd. 1980, 624-628. 16. FRITSCH, P.: Quantification et renouvellement des cellules des alveoles et bronchioles des poumon des rats. Thesis. Rapport CEA-R-4947, 1979. 17. GORDON, L. 1., DOUGLAS, S. D. & KAY, N. E.: Inhibition of neutrophil migration by sarcoid sera, with partial reversal by trissacharide of Nacetyl glucosamine, a lysozyme inhibitor. In: JONES WILLIAMS, W. & DAVIES, B. H. (eds.): 8th Int. Conf. on sarcoidosis and other granulomatous diseases. Alpha Omega Publ. Ltd. 1980, 84-88. 18. GREER, R. O. & SANGER, R. G.: Primary intraoral sarcoidosis. J. Oral Surg. 1977: 35: 507-509.
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19. GROSS, N. J. & VALDlMARSON, H.: Ability of a Iymphokin preparation to mediate delayed hypersensitivity in humans. CUn. Res. 1972: 20: 510. 20. BEERFORDT, C. F.: Ueber eine Febris uveoparotidea subchronica an der Glandula parotis und der Uvea des Auges lokalisiert und haufig mit Paresen cerebrospinaler Nerven kompliziert. Arch. Ophth. 1909: 70: 254-273. 21. HILLERUP, S.: Diagnosis of sarcoidosis from oral manifestation. Int. J. Oral Surg. 1976: 5: 95-99. 22. HOBKIRK, J. A.: Sarcoidosis with oral lesions; report of case. J. Oral Surg. 1969: 27: 891-894. 23. HOGGINS, G. S. & ALLAN, D.; Sarcoidosis of the maxillary region. Oral Surg, 1969: 28: 623-627. 24. JAMES, D. G.: Treatment of extra-thoracic sarcoidosis. 3rd European Conf. on sarcoidosis and other granulomatous disorders. Novi Sad. Jugoslavia, May, 1980. 25. JAMES, D. G., NEVILLE, E., SILTZBACH, L. E. & TURIAF, J.: A worldwide review of sarcoidosis. In: SILTZBACH, L. E. (ed.): 7th Int. Conf. on sarcoidosis and other granulomatous disorders. Ann. New York Acad. of Sci. 1976: 278: 321-334. 26. JONES WILLIAMS, W.: Sarcoidosis -1977. Beitr. Path. 1977: 160: 325-336. 27. JONES WILLIAMS, W. : The nature and significance of granulomas in sarcoidosis. In: Abstracts Int. Siena Sarcoidosis Symposium. Siena, Italy, 1979. 28. JONES WILLIAMS, W., JONES, D. L. & WHITTAKER, J. L.: Isolated sarcoid-like granulomas in Hodgkin disease. In: JONES WILLIAMS, W. & DAVIES, B. H. (eds.): 8th Int. Con! on sarcoidosis and other granulomatous diseases. Alpha Omega Pub!. Ltd. 1980,758-763. 29. KALMAN, S. E.: Aberrant gland and sarcoidosis in the maxillae: report of case. J. Oral Surg. 1954: 12: 63-66. 30. KERR, N. W.: Sarcoidosis. Oral Surg. 1965: 20: 166-173. 31. KOLAS, S. & ROCHE, W. C.: Sarcoidosis lesions primary in the oral cavity: report of a case. Oral Surg. 1960: 18: 169-172. 32. LOFGREN, S.: Primary pulmonary sarcoidosis; early signs and symptoms. Acta Med. Scand. 1953: 145: 424-431. 33. MACDONALD, D. G., ROWAND, R. M. & BLAIR, G. S.: Sarcoidosis involving the mandible. Br. Dent. J. 1969: 126: 168-171. 34. MANDEL, L. & BAURMASH, H.: Differentiation of submaxillary lymphadenopathy and submaxillary gland pathology. Oral Surg, 1962: 15: 3-14. 35. MARIANO, M. & SPECTOR, W. G.: The formation and properties of macrophage polykaryons (inflammatory giant cells). J. Path. 1974: 113: 1-19. 36. MEYER, S., STAM, J_, SIRKS, J. L. & Koov, R.: Reaction to Kveim-test material in sarcoidosis.
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Address: I. van der Waal, Pathoiogiscli Instituut Vrije Universiteit De Boelelaaen II17 Amsterdam Holland
29
Oral involvement in sarcoidosis A. C. M. TH. VAN MAARSSEVEEN, I. VAN DER WAAL, J. STAM, R. W. VELDHUIZEN AND W. A. M. VAN DER KWAST Departments of Pathology, Pulmonology and Oral Surgery, Free University, Amsterdam, The Netherlands
ABSTRACT - The general aspects of sarcoidosis are presented, as well as some concepts derived from experimental work. Thereafter, a review of the literature on oral involvement insarcoidosis isgiven, including thepossible value of an oral biopsy in the case of suspected sarcoidosis. Finally, 3 patients - 2 with known sarcoidosis and I with unsuspected sarcoidosis - are presented as a brief illustration.
(Received for publication 3 March, accepted 21 August 1981)
Sarcoidosis is more common in the third and fourth decades oflife than in other decades and has no predilection for sex or races. Figures of the exact incidence are not available. The diagnosis is in many cases made as an incidental finding on the chest film. Sarcoidosis is a multisystem granulomatous disorder of unknown etiology. The disease may actually affect any organ or part of the body. In the past a relation with tuberculosis was often suggested, but that hypothesis is nowadays abandoned. Sarcoidosis is one of the diseases which are characterized by an abnormal immune response, mostly expressed by an impaired cellmediated delayed-type hypersensitivity, the humoral immunity being normal or even increased. It is most likely that different factors evoke the response, which is expressed in a sarcoid granuloma. However, a variety of other diseases and conditions can cause more or less similar histopathological findings. A sarcoid granuloma in the absence of generalized disease is commonly due to some local condition. 0300-9785/82/010021-09$02.50/0
General aspects of sarcoidosis Organs affected in sarcoidosis Cutaneous manifestations of sarcoidosis, originally named "lupus pernio", were first described by Besnier in 1889.The first histological description of the disease was given by Boeck in 1899. In 1914 Schaumann expressed the view that "lupus pernio" and Boeck's cutaneous sarcoids were part of the same disease and that nasal mucosa, tonsils, lymph nodes, conjunctiva, the lungs and the bones of the hands could also be affected. Ever since, the disease sarcoidosis is also known as Besnier-BoeckSchaumann disease. Mainly through the work of LOfgren has bilateral involvement of the pulmonary hilar lymph nodes been proven to be an early manifestation of the disease, sometimes accompanied by erythema nodosum, subfebrile and general malaise". temperature Uveoparotitis, as described by HEERFoRDT in 1909, is at present known as a rare manifestation of sarcoidosis". The complete
© 1982 Munksgaard, Copenhagen
22 VAN MAARSSEVEEN, VAN DER WAAL, STAM, VELDHUIZEN AND VAN DER KWAST Heerfordt's syndrome consists of uveitis, parotitis, fever and facial palsy. In a review of about 3,700 patients from different parts of the world suffering from sarcoidosis, it was observed that the most frequently affected organs were the lungs and their lymph nodes, the figure being 80%. The extra-thoracic lymph nodes were involved in about 22%, the eyesin 15%,the spleen in 6%, the central nerve system, the bones and the parotid glands in about 4% (JAMES et af.2S ) . During the 7th and 8th International Conferences on Sarcoidosis and Other Granulomatous Diseases, held in 1976 and 1978 respectively, no reports of oral involvement in sarcoidosis were presented, although quite a number of publications on that subject had been written, mainly in the literature on oral surgery and oral pathology. Histopathologic findings in sarcoidosis As mentioned before, the sarcoid granuloma is the histopathologic entity of sarcoidosis. The sarcoid granuloma consists of a focal collection of monocyte-derived epithelioid cells (giant cells) admixed with T-lymphocytes, occasional plasmacells and fibroblasts (JONES WILLIAMS'7 ) . At the early stage, the picture cannot always be distinguished from other local and generalized chronic granulomatous conditions such as tuberculosis. Occasionally, central areas with fibrinoid necrosis and a tendency to hyalinosis are found. In some cases concentrically or eccentrically laminated bodies, known as Schaumann bodies, are found. Also delicate, spidery radiating structures, known as "asteroid bodies", may be encountered in sarcoid lesions. These kinds of structures may also occur in other types of granulomas and are, therefore, not pathognomonic", The first indication of the development of sarcoidosis may be the appearance of a sarcoid granuloma in a site where irritatant material has lain donnant in the tissues. This type of sarcoid granuloma is not always associated with or
followed by sarcoidosis, but is sufficiently common to require that every patient with such a sarcoid reaction be kept under observation for signs of incipient sarcoidosis. Sarcoidosis in experimental pathology The macrophage is part of the mononuclear phagocytic system. This cell originates as a bone marrow precursor cell, circulates for a short time as monocyte, and becomes macrophage when it enters the tissue, either in a regular way or by inflammatory stimulation. The suggestion is made that in sarcoidosis, the mononuclear cells have an ineffective capacity to react to a stimulus in a normal way!"!". There are two categories of granulomas, one with a high turnover and one with a low turnover. High turnover granulomas are characterized by an impressive inflow of monocytes together with an extensive proliferation rate. The monocytes may disappear quickly by cell death or by drainage to a lymph node or may transform ultimately in epithelioid cells, which may become immobilized in the granuloma for months, without proliferation or cell death. The epithelioid cells orginate from macrophages, whose capacity for phagocytosis seems "frustated" 1l.43. There is evidence that maturation of macrophages into epithelioid cells is accompanied by a shift from phagocytosis and intracellular digestion to extracellular secretion of enzymes and mucoproteins. The multinucleated giant cell, often observed in the granuloma, has been formed by fusion of macrophages'":". The suggestion has been made that young and active macrophages ingest old and exhausted macrophages, thereby developing the aspect of giant cells". Subcutaneous implants in mice showed that these giant cells are short-lived and disappear within weeks". In the low turnover lesions, the macrophage population is relatively stable and the phenomena just described are much less evident. The presence of giant cells are scanty in low turnover and numerous in high turnover granuloma"•.
ORAL SARCOIDOSIS
To study the pathogenesis of sarcoidosis, many investigators produced sarcoid-like epithelioid cell granulomas in animals with "Freund complete adjuvant" with bacteria, isolated purified cell wall fractions':" or metals":": Their results suggest that some components may persist within macrophages due to ineffective handling, which seems to play a role in the pathogenesis of the epithelioid cell granuloma. Diagnosis and staging For a long time, biopsy of the subclavicular lymph node was considered most useful in cases of suspected sarcoidosis. Nowadays bronchoscopy is often preferred, since in about 90% of the patients suffering from sarcoidosis, intrathoracal involvement can be demonstrated':'. The histologic picture of the granuloma is by itself, as mentioned earlier, insufficient proof of the diagnosis of sarcoidosis-"; confirmatory support from the findings of the pulmonologist, dermatologist or ophthalmologist as well as from laboratory investigations such as calcium metabolism (hypercalcaemia) and SACE (serum angiotensin converting enzyme) is required", Other supporting evidence includes a depressed cellmediated immunity, resulting in a diminished DNCB or negative tuberculin skin test. An important diagnostic aid is the Kveim test, consisting of an intradermal injection of a reagent prepared from proven sarcoid lymphoid tissue. Histological verification for a positive reaction, consisting of a typical sarcoid granuloma at the site of inocculation, can be carried out after 5 or 6 weeks. The value of the test is dependent upon the quality of the Kveim antigen and the activity of the disease"-". A biopsy of apparently healthy oral mucosa may be of some significance in making a diagnosis of sarcoidosis, as will be discussed later. Based on the chest film, three stages of sarcoidosis can be distinguished: stage I: bilateral enlargement of the
stage II:
stage III:
23 hilar nodes without pathologic changes in the lung fields; bilateral enlargement of the hilar lymph nodes with pathologic changes in the lung fields around the hili; no enlargement of the lymph nodes, but extended, sometimes patchy or stripy, changes in both lung fields. The patches can join together and bullae may be formed.
Treatment In general, no treatment for sarcoidosis is necessary, since the natural tendency is towards healing I 3.24. In stage I a 65% complete, spontaneous remission will occur, while in stage II this happened in 49%. In about half of the patients of both stages I and II who did not have a spontaneous regression, cure was obtained with drug therapy. In general, the use of corticosteroids seems only to accelerate the disappearance of detectable signs of sarcoidosis. After a 3-5 year period, however, no remarkable difference could be demonstrated between patients who had been treated with corticosteroids and those who had not". In some instances sarcoid granulomas undergo fibrosis and hyalinosis. Particularly in the lungs, the tendency to fibrosis has serious consequences for the pulmonary function. Therefore, corticosteroids should be administered in cases of sarcoid lesions producing lung fibrosis. Steroid treatment is also indicated in cases of cardiac or neural involvement, in spite of the possible harmful side-effect of that kind of therapy.
Oral involvement in sarcoidosis; review of the literature and report of 3 cases In reviewing the literature on oral aspects of' sarcoidosis, some reports of extraoral involve-
24 VAN MAARSSEVEEN, VAN DER WAAL, STAM, VELDHUIZEN AND VAN DER KWAST ment, i.e, affected lymph nodes in the head and neck area, are included. Patients with already proven sarcoidosis, who also had lesions in the oral region In some of the patients with already proven sarcoidosis, the oral involvement consisted of one or more nodules in the oral mucosa, without preference for any specific site 12 •22,40,45. A few cases have been reported of involvement ofthejaw bones 4. 2 1,42. Involvement of glandular structures in the oral cavity is mentioned by KALMAN 29 as well as by NARANG & DIXON 37. A decreased level of a-amylase and increased levels of albumine and lysozyme have been observed by BEELEY & CHISHOLM2 in parotid saliva from a patient suffering from sarcoidosis with salivary gland involvement. These observations were interpreted as the result of damage to the gland. Some years earlier the value of salivary gland function tests in diagnosing sarcoidosis and in monitoring the response to possible therapy was described by CHISHOLM et al. to • Patients with already proven sarcoidosis in which an oral biopsy of apparently healthy tissue was taken CAHN et al,' have described a group of 23 patients with known sarcoidosis in which palatal biopsies of clinically normal areas were performed. They were able to demonstrate the presence of sarcoid granulomas in 38% of their cases, TILLMAN'3 described a 66-year-old man suffering from sarcoidosis. Oral examination showed a normal aspect of the gingiva. Nevertheless, a gingival biopsy was performed to rule out amyloidosis. More-or-less as a surprise, the microscopic findings were consistent with sarcoidosis. A biopsy of the labial glands of the lower lip has been reported positive in a number of patients suffering from sarcoidosis'v-":". NESSAN & JACOWAY even found 58% non-caseating granulomas in biopsies of the labial glands in a total number of75 patients with known sarcoidosis".
Apparently healthy patients with one or more sarcoid granulomas in the oral region, in which additional examination justified the diagnosis of sarcoidosis A number of patients have been described in which an oral lesion, microscopically diagnosed as a sarcoid granuloma, led to the detection of generalized sarcoidosisl.,33,44"7, KERR 30 described a 20-year-old man with multiple swollen lymph nodes in the parotid, submental, submandibular, superficial and deep cervical area. Roentgenographs of the chest showed enlargement of nodes in the upper mediastinum. A submental node was examined microscopically. The appearence was that of sarcoidosis. Apparently healthy patients with one or more sarcoid granulomas in the oral region, in which the diagnosis ofsarcoidosis could not be proven or remained somewhat debatable SCHROFF 46 has described a 48-year-old female with a swelling of the whole thickness of the cheek of 4 weeks duration. The lesion was biopsied and reported as being of tuberculous nature. All additional tests, chest films and other examinations were negative for tuberculosis, which led the author to suggest the diagnosis of sarcoid. Several of such cases have been reported thereafter J,9,2J,JI,54,56. NITZAN & AZAR 39 have described a 62-yearold woman with an indurated submandibular mass, measuring about 3 em. The radiograph revealed a sialolith in the submandibular gland. The clinical diagnosis was sialolithiasis. The submandibular gland was removed together with a surrounding lymph node. That lymph node showed the features of sarcoidosis. No Kveim test was performed. All other examinations were negative for sarcoidosis. The Mantoux intracutaneous test was negative. The patient was suffering from migrating arthritic pain and swellings, xerophthalmia, dyspnea and hypertension. Because ofthose symptoms it was felt that this patient, in spite ofnegative findings elsewhere in the body, suffered from systemic sarcoidosis. Nitzan and Azar mentioned that
ORAL SARCOIDOSIS
"specific treatment for sarcoidosis was of great benefit" and considered this another support for their diagnosis. ORLIAN & BIRNBAUM 4 ! described a 43-yearold woman with a lesion in the lower left anterior mucobuccal fold. There was no evidence of bony involvement. Lymphadenopathy was absent. The microscopic appearance was consistent with sarcoidosis. Additional examination for sarcoidosis was negative.
25
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Case reports Case 1. In May 1980, a 23-year-old man was referred because of multiple nodules on the hard and soft palate. The nodules were slightly elevated, measured a few mm and were of a firm elastic consistency. There was no ulceration (Fig. 1). The patient had his natural dentition. Possible irritating factors which could have played a role in the initiation of the palatal nodules could not be detected, although heavy smoking may have been of significance. The duration of the presence of the nodules was unknown to the patient. This man was known to suffer from sarcoidosis, the first clinical manifestations being multiple subcutaneous nodules on his legs and arms. The chest film had demonstrated bilateral enlargement of the hilar lymph nodes (Fig. 2). One of the palatal nodules was biopsied, The histopathology was compatible with a sarcoid granuloma (Fig. 3), Healing of the biopsy wound was uneventful. No treatment has been instituted so far.
Fig. 1. Multiple nodules on the palate in a 23-year-old man suffering from sarcoidosis.
Fig, 2. The chest film showing bilateral enlargement of the hilar lymph nodes without pathological changes in the lung fields.
The patient will be seen at 3-monthly intervals by the Department of Pulmonology, The nodules of the palate have not shown any change during a 6 months follow-up period.
Case 2. In June 1977, a 69-year-old woman was referred because of a small submucosal nodule on the tip of the tongue of some months duration. On palpation, a firm, submucosal, somewhat mobile nodule was felt. The overlying mucosa was intact. The
Fig, 3, Biopsy specimen of one of the palatal nodules showing rather well-circumscribed epithelioid cell granulomas compatible with sarcoidosis (H.E. x 200).
26 VAN MAARSSEVEEN, VAN DER WAAL, STAM, VELDHUIZEN AND VAN DER KWAST lesion of the tongue was excised and histopathologically reported as compatible with sarcoidosis. Additional examination by the Department of Pulmonology showed the presence of pulmonary sarcoidosis. The Kveim test proved to be positive (Fig. 4). So far, no treatment has been instituted. In the following 3 years, up to December 1980, no other lesions or manifestations appeared.
Case 3. In November 1978, a 25-year-old man was referred because of a rather well-circumscribed submandibular swelling on the left side. The patient had noticed this swelling for about 6 months. The medical history was essentially negative. A clinical diagnosis of salivary gland tumor, most likely pleomorphic adenoma, was made. It was not felt necessary at that time to carry out additional diagnostic work-up such as sialography, scintigraphy or aspiration cytology. Pre-operative physical examination did not reveal any abnormality. In January 1979, a suprahyoidal approach was chosen to remove the submandibular tumor. At operation, it was clear that the submandibular salivary gland was of normal size and consistency, but that a large lymph node, measuring about 3 em, was lying lateral to that gland. A fresh frozen section was performed, showing sarcoid granulomas in the lymph node (Fig. 5). Nevertheless, it was decided to complete the excision of the suprahyoidal triangle. In the surgical specimen,
b Fig. 5. Submandibular lymph node with homoge-
neous replacement of lymphoid tissue by many characteristic confluent epithelioid cell granulomas (H.E. x 200).
multiple enlarged nodes were found. Also in those nodes sarcoid granulomas were seen. The patient was then referred to the Department ofPulmonology. The diagnosis of sarcoidosis was confirmed by findings on the chest film and a positive Kveim test. No palpable lymph nodes elsewhere in the body could be detected. No treatment has so far been instituted. During the two-year follow-up period no other lesions or manifestations have developed. A very similar experience has been reported by MANDEL
& BAURMASH'4.
Discussion and conclusions
Fig. 4. Skin biopsy of the forearm 5 weeks after
injection of Kveim's reagent. Notice the many giant cells (H.E. x 80).
Sarcoidosis may affect any organ or part of the body .'Sarcoid lesions seem to be the result of an impaired mechanism of some of the macrophages, The histologic finding of a sarcoid granuloma is by itself insufficient proof of the diagnosis of sarcoidosis and may well be due to some local condition. In view of the numerous reports on sarcoidosis, the incidence of oral involvement, as extracted from the literature, is rather low. In a number of papers, evidence of the oral sarcoid being a manifestation of generalized sarcoidosis is either not presented or remains somewhat debatable. Some authors have suggested that oral sarcoid may not be rare, but probably remains undiagnosed or unreported. Two of the patients with oral sarcoid described in this report were already known to
ORAL SARCOIDOSIS suffer from sarcoidosis. The third patient, however, was apparently healthy. A submandibular, rather well-circumscribed swelling was clinically diagnosed as being most likely a salivary gland tumor. No sialography or cytologic puncture, nor any additional examination was felt necessary at that time. The true nature of the swelling, being an enlarged lymph node, first became evident at operation, thus illustrating the limitation of a provisional diagnosis by clinical judgement only. There are several reports mentioning the presence of sarcoid granulomas in biopsies of apparently normal oral tissue, especially from the palate and the lower lip, in patients with proven sarcoidosis. We hesitate, however, to advocate the use of such biopsies when gathering supporting evidence for the diagnosis of sarcoidosis only, since staging of the disease is usually based upon the radiographic findings on the chest films. On the other hand, one should know that an oral sarcoid granuloma can be an early manifestation of sarcoidosis and that such a patient should at least be seen by the pulmonologist for further evaluation. Acknowledgement - We thank Mrs. M. Mooijen for her help in preparing the manuscript and Mr. G. J. Oskam for photography of the histologic slides.
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Address: I. van der Waal, Pathoiogiscli Instituut Vrije Universiteit De Boelelaaen II17 Amsterdam Holland
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