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Cervical lymphadenopathy and parotid gland swelling in sarcoidosis: a study of 31 cases
Cervical lymphadenopathy and parotid gland swelling in sarcoidosis: a study of 31 cases
James E. Hamner, III, DDS Henry H. Scofield, DDS, Bethesda, Md.
Although there is no unanimous opinion con cerning the nature and etiology of sarcoidosis, there are several reliable criteria for the diag nosis of this disease. The dentist should know these criteria since he is most likely to detect sarcoidosis initially— the major symptoms are cervical lymphadenopathy and parotid gland swelling.
Physicians and dentists are becoming more aware of the term “sarcoidosis,” since it occurs as the diagnosis with increasing frequency in medical histories, pathology reports, and the literature. Schroff,1 Poe,2 Campbell,3 Bernier,4 Covel,5 Kalmon,6 Kolas,7 Mandel,8 Kerr,9 Tillman,10' 11 and Orlean 12 have reported oral-related cases. The disease is accurately described by the statement issued in 1960 at the Second Interna tional Conference on Sarcoidosis: Sarcoidosis is a systemic granulomatous disease o f un determined etiology and pathogenesis. Mediastinal and peripheral lymph nodes, lungs, liver, spleen, skin, eyes, phalangeal bones, and parotid glands are most often involved, but other tissues may be affected. The Kveim reaction is often positive, and the tuberculin test often negative. Other important findings are hypercalciuria and increased serum globulins. The characteristic histo logical appearance o f epithelioid tubercles with little or n o necrosis is not pathognom onic; tuberculosis, fun gal infection, beryllium disease, and local sarcoid tissue reactions must be excluded. The diagnosis should be restricted to patients w ho have consistent clinical and radiologic features together with biopsy evidence o f epithelioid tubercles or a positive Kveim test.13
Eponyms in connection with this disease entity are numerous: Hutchinson’s papillary psoriasis or Mortimer’s malady (1869), Besnier’s lupus per 1224
nio (1889), Boeck’s multiple benign sarcoid (1899) and benign miliary lupoid (1905), Heerfordt’s uveoparotid fever (1909), Jungling’s os teitis tuberculosa multiplex cystica (1911), and Schaum ann’s benign lym phogranulom a (1917).13’14 Three international conferences have agreed that “sarcoidosis,” the term that Boeck originally coined, is best. In 1964, at the Third International Confer ence on Sarcoidosis, Scadding14 summarized the principal etiological hypotheses as follows: (a ) Sarcoidosis is due to an unidentified specific agent, and the interaction between this agent and the host is the cause o f the im m unological peculiarities; (b ) Sar coidosis is related to the collagenoses or to the reticu loses, in which im m unological changes are prominent; or ( c ) Sarcoidosis occurs only in individuals w h o have a pre-existing im m unological peculiarity, and in them develops a reaction to an agent, or one o f several pos sible agents, which may or may not be known already as causing some well-known disease [tuberculosis].
This increased emphasis on the prevalence of sarcoidosis requires the dentist in general prac tice to know the clinical signs and symptoms of this disease to consider it in his differential diag nosis and to channel patients in whom it is sus pected for additional medical examination and treatment.
M a terials and methods One autopsy and 21 surgical cases from the Na tional Institutes of Health and nine surgical cases from the Dental and Oral Division of the Armed Forces Institute of Pathology, which met the cri teria of systemic sarcoidosis, furnished the ma terial for this study. Clinical data, including fam ily histories, physical symptoms, blood chemistry values, pulmonary radiographs, tuberculin reac tion, and Kveim tests were reviewed in conjunc tion with microscopic sections. All tissue sections were stained with hematoxylin and eosin; 71 per cent of the specimens were stained by the ZiehlNeelsen acid-fast method, and 42 percent of the specimens were stained by the periodic acidSchiff method or the Gomori’s methenamine silver nitrate method. Careful attention was given to discovering oral-related findings in each instance of systemic sarcoidosis. Follow-up information from the patients and clinicians was used to study the progress of the disease and to evaluate the therapy.
Table 1 ■ Site of involvement Positive involvement/ total no. of patients*
Tissue site Lymph nodes (generalized) Cervical lymph nodes Lungs Spleen Liver Bone Skin Parotid glands Sublingual glands Eye (uveal tract! Joints
29/31 24/31 26/31 3/31 8/31 2/31 7/31 11/31 1/31 9/31 8/31
* N o t every region was specified in every patient.
Results The age of the patients at the time of diagnosis of sarcoidosis ranged from 16 to 58 years; the mean age was 30.13 years, which is slightly high er than that reported in other surveys in which the peak incidence has occurred in persons 25 to 30 years of age.1415 Thirteen of the 31 patients were Caucasian, and 18 were Negro. The sex ratio was 12 males to 19 females. Table 1 lists the sites involved. Lymph nodes and pulmonary sites were most frequently in volved, although the parotid glands, uveal tracts, joints, and liver were often involved. Sokoloff16 described the joint pain as a polyarthritis in his report of 5 cases and said that joint disease is an intrinsic manifestation of sarcoidosis. These fig ures should not be miconstrued because the sites listed were the ones proved positive by micro scopic, radiographic, or clinical examination. Many of the regions were not tested in every patient since the other clinical and laboratory evidence was considered sufficient by the attend ing physician to support the diagnosis of sarcoi dosis, that is, hepatic, splenic, and joint biopsies were not performed on every patient. Also, the clinical signs of this disease (parotid swelling,
Table 2 ■ Physical and laboratory findings Symptom or test Hilar lymphadenopathy Generalized lymphadenopathy Cervical lymphadenopathy Parotid swelling Erythema nodosa Fatigue Weight loss Dyspnea family history of tuberculosis Positive tuberculin test Positive Kveim test Hypercalciuria Increased serum globulins
Positive involvement/ total no. of patients 27/31 25/31 24/31 11/31 3/31 24/31 15/31 23/31 5/31 3/31 6/31 10/31 11/31
Not specified 1 0 0 0 0 6 6 6 1 1 25 2 2
Hamner— Scofield: CERVICAL LY M P H A D E N O P A T H Y A N D PAROTID SW ELLING IN SARCOIDOSIS ■ 1 225
F ig . 1 ■ M u l t i p l e , n o n c a s e a t ing granulom as in splenic sarcoid section
dyspnea, fatigue, and so forth) may vary in degree. Table 2 shows 12 symptoms or clinical labo ratory tests significant in the diagnosis of sarcoi dosis. Hilar lymphadenopathy seen in a pulmo nary radiograph is an important finding; it appears early in the course of the disease and may persist, increase, or disappear spontaneously or with treat ment. This finding was noted in 27 of the 29 patients in whom this examination was performed. Generalized lymphadenopathy was also a com mon finding. Biopsies were performed on cervical, submandibular, supraclavicular, axillary, scalene,
Fig. 2 ■ S ublingual g la n d : mucous and serous a c in i, S; noncaseating g ra nulom ata composed o f e p ith e lio id histiocytes, lym pho cytes, and m u ltin u cle a te d g ia n t cells (a r row s), G, and saliva ry d u ct, D
1 226 ■ JA D A , V o l. 74, M ay 1967
inguinal, and femoral lymph nodes, which were most frequently enlarged. Cervical lymphadeno pathy was prominent and occurred in 78 percent of the patients. Parotid gland swelling, unilateral or bilateral, with subsequent biopsy confirmation of sarcoi dosis occurred in 11 of the 31 patients. The sub lingual glands were involved in one instance. No lesions were seen in the submaxillary glands. In sidious swelling of the salivary glands could easily be overlooked since this finding has not been emphasized in the literature. Erythema nodosum, which is much more com
Fig. 3 ■ G ia n t cell w ith ch a ra c te ris tic a c id o p h ilic asteroid body of sarcoidosis
were classified in this study as positive sarcoid. Three other patients in this study had a positive tuberculin reaction at one time. The Kveim test, which is considered a definite indication of true systemic sarcoidosis,14 was per formed on only six of the 31 patients. It was po sitive in all six patients. This test consists of an intracutaneous injection of a suspension of posi tive sarcoid lymph node or splenic tissue; 4 to 6 weeks later a biopsy of the induced papule re veals epithelioid cell tubercles identical to those in naturally occurring sarcoid lesions. Siltzbach17 has found that three out of four patients with
mon in Scandinavians with sarcoidosis than in Americans with sarcoidosis,13 was noted in only three patients in this study. Almost all of the pa tients suffered from fatigue, malaise, and dyspnea, and about half reported a recent weight loss vary ing from 9 to 40 lb. Five of the 31 patients recalled that one or more of their parents or siblings or both had a positive diagnosis of tuberculosis, and three of the five patients reported family members suffer ing from sarcoidosis and tuberculosis. None of the patients who gave a familial history of tuber culosis had a positive tuberculin reaction, but all
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active sarcoidosis have a positive Kveim response when proper testing preparations are used. Hypercalciuria was found in ten of the 31 pa tients, and the serum globulins were elevated in 11 patients in the study. Microscopically, the sarcoid lesions appeared as multiple sharply defined granulomatous tu bercles composed of epithelioid histiocytes and multinucleated giant cells of the Langhan’s or foreign body type. Caseation necrosis, which is rare, was not seen. The lymphocytic infiltrate at the periphery of the granulomas tended to be less dense than that in tuberculosis. Figure 1 shows these findings in a splenic sarcoid section. Re placement of normal tissue may be slight or ex tensive. The granulomas may have a tendency toward fibrous induration with age. Sarcoidosis affecting the parotid glands may cause a severe loss of normal acini with a con comitant reduction in salivary flow, thus mimick ing Mikulicz’s disease, parotiditis (mumps), or other salivary gland disorders. Figure 2 shows the microscopic appearance of an inconspicuous nodule in the floor of a young adult’s mouth. Closer scrutiny revealed the presence of an aste roid body, a small, acidophilic, star-shaped con figuration in a giant cell (Fig. 3). Figure 4 shows several of these asteroid bodies in a scalene lymph node biopsy specimen of another sarcoid patient. Minute, basophilic oval bodies with concentric laminations, called Schaumann bodies, are some times found in giant cells of sarcoid granulomas. Figure 5 shows one of these bodies. When pres
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ent, these inclusions are highly suggestive of sarcoidosis, although they must be evaluated with respect to the total findings. In this study, asteroid bodies were seen in 13 biopsy specimens; Schau mann bodies were seen in only three biopsy spe cimens and, in each instance, they were in con junction with asteroid bodies. Refvem18 says that these inclusions result from phagocytosis of de generated fragments of collagen fibers and pos sibly other material.18 The acid-fast and other special stains failed to reveal causative microorganisms in these 31 pa tients.
Discussion There is no unanimity of opinion concerning the nature and etiology of sarcoidosis. Some investi gators believe it represents an atypical, slowly progressive form of tuberculosis, whereas others maintain it is a nonspecific granulomatous dis ease. Zettergren15 thinks it is a particular form of tuberculosis in persons who are resistant to this disease. He postulated that a strong reaction by the reticuloendothelial system causes rapid and complete destruction of the tubercle bacillus cre ating a condition that he termed “lymphogranulomatous benigna.” He based his belief on the apparent similarity between the clinical pattern and tissue involvement in the two diseases, the histologic findings, the relatively high incidence of positive tuberculin reactions in patients with
sarcoidosis, and the fact that patients with sar coidosis frequently die of tuberculosis. Features that suggest a nontuberculous origin for sarcoidosis are as follow: the majority of sarcoid patients do not come from familial tuber culous environment; the incidence of tuberculin sensitivity is low during the disease; parenchymal sarcoid lesions may show spontaneous regression, which is seldom seen in tuberculosis; the histo logic findings, although similar, are distinct, and acid-fast organisms are absent in sarcoidosis; a positive reaction to the Kveim test, which is spe cific for sarcoidosis and previously, patients who were thought to have died from sarcoidosis prob ably contacted tuberculosis and died from it be cause of misdiagnosis and misplacement in tuber culosis wards.14 The findings in this study of 31 cases indicate a nontuberculous origin for sarcoi dosis. Siltzbach,14 who has had much experience in clinical sarcoidosis research, especially Kveim testing, thinks that sarcoidosis is a hypersensi tivity disease that affects a genetically susceptible portion of the population. Such persons are sen sitized early in childhood by infection with some bacterium, fungus, pine pollen, or other agent. Later, at 20 to 30 years of age, when challenged by some internal or external precipitating agent, these persons manifest the typical clinical picture and granulomatous response that is called sar coidosis. The absence of acid-fast bacilli and fungi in the tissue sections and fluid cultures in this study does not support hypersensitivity etiology. Of the 31 patients in this study, three had a familial history of sarcoidosis involving one or more family members. None of the family mem bers of the other 38 patients were specifically tested. Merchant and Utz19 found 75 cases of sarcoidosis involving more than one member of 32 families, which suggested that a complex hered itary trait could be operative in the pathogenesis of sarcoidosis. Sarcoidosis rarely leads directly to death; in patients who die, death is usually caused by cor pulmonale or acute respiratory failure:20 Nitter21 found that 1,000 R of X-radiation per field did not influence the course of the disease. Corti costeroid hormones have proved to be the best medication for treating patients with severe sar coidosis. Criteria for their use are progressive pulmonary disease with impaired alveolar func tion; active ocular disease; persistent hypercal cemia or hypercalciuria; central nervous system
involvement; myocardial lesions, and disfiguring cutaneous lesions.14 Treatment with steroids removes the lympho cytic infiltrate, and the granulomas heal with scarring. Radiographic clearing of pulmonary le sions is often seen after therapy, but functional improvement is less pronounced since it has no effect on the scar tissue already present. If a patient with progressive pulmonary involvement does not receive steroid treatment, however, in creasing granulomatous lesions may cause severe pulmonary insufficiency. Sum m ary and conclusions A brief review of the current concepts of the etiology of sarcoidosis is presented. This disease entity is of interest and importance to the dentist because two of the chief symptoms, cervical lymphadenopathy and parotid gland swelling, are most likely to be initially detected by him. Thirty-one cases of systemic sarcoidosis were reviewed with respect to the clinicopathologic findings. The most frequent sites of involvement were lymph nodes, lungs, parotid glands, uveal tract, joints, and liver. Hilar lymphadenopathy, parotid swelling, fatigue, dyspnea, weight loss, polyarthritis, and uveitis were the most common clinical symptoms. Asteroid bodies were found in 11 of the 31 patients, and Schaumann bodies were found in three of the 31 patients. Corticosteroid hormones have proved to be the best treatment for patients with severe sarcoidosis and are indicated for patients with progressive pulmonary disease, active ocular disease, persist ent hypercalcemia or hypercalciuria, central nerv ous system involvement, myocardial lesions, and disfiguring cutaneous lesions. Although this study does not clarify the nature or etiology of sarcoidosis, it calls attention to the most reliable criteria for the diagnosis of the disease: a compatible clinical picture; hilar lym phadenopathy on a pulmonary radiograph; his tologic sections showing epithelioid granulomas with the absence of necrosis and microorganisms in specific stains; negative cultures for bacteria and fungi in body fluid and biopsy tissues, and a positive Kveim test.
Doctor Ham ner is from th e U.S. D epa rtm e n t o f H ealth, Education, and W e lfa re , Public H e a lth Service, N a tio n a l Institu te s of H ealth, N a tio n a l In s titu te o f Dental Re search, oral m edicine and surgery branch, a nd Doctor
H am ner— Scofield: CERVICAL LY M P H A D E N O P A T H Y A N D PARO TID SW ELLING
IN SARCOIDOSIS ■ 1229
Scofield is head of the oral pathology division, U.S. Naval Dental School, Bethesda, M d. 2 0 0 1 4 . The authors thank the department of anatomic pathol ogy of the National Institutes of Health and the Armed Forces Institutes of Health and the Armed Forces Insti tute of Pathology for the case material used in this study. Acknowledgment is made to John McGuire of the medical illustrations branch of the National Institutes of Health for the photomicrography. 1. Schroff, Joseph. Sarcoid of the face (BesnierBoeck Schaumann disease) : report of a case. JADA 2 9 :2 2 0 8 Dec., 1942. 2. Poe, D. L. Sarcoidosis of jaw. A new disease of the mandible. Am er J Orthodont 2 9 :5 2 Jan., 1943. . 3. Campbell, J. Sarcoidosis or tuberculosis. Brit Dent J 7 7 :1 5 9 Sept. 15, 1944. 4. Bernier, J. L., and Tiecke, R. W . Sarcoidosis. J Oral Surg 9 :2 5 6 July, 1951. 5. Covel, E. Boeck's sarcoid of mucous membrane. Report of a case. Oral Surg 7 :1 2 4 2 Nov., 1954. 6. Kalman, S. I., and M alle tt, S. P. Aberrant gland and sarcoidosis in the m axillae: report of case. J Oral Surg 12:63 Jan., 1954. 7. Kolas, Steve, and Roche, W . C. Sarcoidosis lesions primary in the oral cavity: report of a case. J Oral Surg 1 8 :1 6 9 M arch, 1960. 8. M andel, Louis, and Baurmash, Harold. Differen tiation of submaxillary lymphadenopathy and submaxillary salivary gland pathology. Oral Surg 15:3 Jan., 1962. 9. Kerr, N. W . Sarcoidosis. Oral Surg 2 0 :1 6 6 Aug., 1965. 10. Tillm an, H. H. Sarcoidosis with unsuspected oral
12 3 0 ■ JADA, Vol. 7 4 , M ay 1967
manifestations. Report of a case. Oral Surg 1 8 :1 3 0 Jyly, 1964. 1 1. Tillm an, H. H.; Taylor, R. G., and Carchidi, J. E. Sarcoidosis of the tongue. Report of a case. Oral Surg 21 :190 Feb., 1966. 12. Orlean, S. L., and O'Brien, J. J. Sarcoidosis m ani festing a soft lesion in the floor of the mouth. Report of a case. Oral Surg 21 : 8 19 June, 1966. 13. Proceedings of the International Conference on Sarcoidosis. Am er Rev Resp Dis 84:1 Nov., 1961. 14. Lofgren, S. L. (ed itor), Proceedings of the Third International Conference on Sarcoidosis. Acta Med Scand (suppl.) 4 2 5 :1 , 1964. 15. Zettergren, L. Lymphogranulomatosis benigna; a clinical and histopathological study of its relation to tuberculosis. Acta Soc Upsal (suppl. 5 ) 5 9 :1 , 1954. 16. Sokoloff, L., and Bunim, J. J. Clinical and patho logical studies of joint involvement in sarcoidosis. New Eng J Med 260 :8 4 1 April 23, 1959. 17. Siltzbach, L. E. The Kveim test in sarcoidosis. Amer J Med 3 0 :4 9 5 April, 1961. 1 8. Refvem, O. Pathogenesis of Boeck's disease ( sar coidosis); investigation on significance of foreign bodies, phospholipides and hypersensitivity in formation of sar coid tissue. Acta Med Scand (suppl. 2 9 4 ) 1 49:1, 1954. 19. Merchant, R. K., and U tz, J. P. Familial sarcoido sis. A report of two cases. Arch Intern M ed (Chicago) 1 0 6 :6 4 July, 1960. 20. Raben, A. S. Sarcoidosis and so-called sarcoid reaction. Postgrad M ed 3 1 :2 3 2 M arch, 1 962 21. N itter, L. Changes in the chest roentgenogram in Boeck's sarcoid of the lungs. Acta Radial (suppl.) 1 05 :1 , 1953.
James E. Hamner, III, DDS Henry H. Scofield, DDS, Bethesda, Md.
Although there is no unanimous opinion con cerning the nature and etiology of sarcoidosis, there are several reliable criteria for the diag nosis of this disease. The dentist should know these criteria since he is most likely to detect sarcoidosis initially— the major symptoms are cervical lymphadenopathy and parotid gland swelling.
Physicians and dentists are becoming more aware of the term “sarcoidosis,” since it occurs as the diagnosis with increasing frequency in medical histories, pathology reports, and the literature. Schroff,1 Poe,2 Campbell,3 Bernier,4 Covel,5 Kalmon,6 Kolas,7 Mandel,8 Kerr,9 Tillman,10' 11 and Orlean 12 have reported oral-related cases. The disease is accurately described by the statement issued in 1960 at the Second Interna tional Conference on Sarcoidosis: Sarcoidosis is a systemic granulomatous disease o f un determined etiology and pathogenesis. Mediastinal and peripheral lymph nodes, lungs, liver, spleen, skin, eyes, phalangeal bones, and parotid glands are most often involved, but other tissues may be affected. The Kveim reaction is often positive, and the tuberculin test often negative. Other important findings are hypercalciuria and increased serum globulins. The characteristic histo logical appearance o f epithelioid tubercles with little or n o necrosis is not pathognom onic; tuberculosis, fun gal infection, beryllium disease, and local sarcoid tissue reactions must be excluded. The diagnosis should be restricted to patients w ho have consistent clinical and radiologic features together with biopsy evidence o f epithelioid tubercles or a positive Kveim test.13
Eponyms in connection with this disease entity are numerous: Hutchinson’s papillary psoriasis or Mortimer’s malady (1869), Besnier’s lupus per 1224
nio (1889), Boeck’s multiple benign sarcoid (1899) and benign miliary lupoid (1905), Heerfordt’s uveoparotid fever (1909), Jungling’s os teitis tuberculosa multiplex cystica (1911), and Schaum ann’s benign lym phogranulom a (1917).13’14 Three international conferences have agreed that “sarcoidosis,” the term that Boeck originally coined, is best. In 1964, at the Third International Confer ence on Sarcoidosis, Scadding14 summarized the principal etiological hypotheses as follows: (a ) Sarcoidosis is due to an unidentified specific agent, and the interaction between this agent and the host is the cause o f the im m unological peculiarities; (b ) Sar coidosis is related to the collagenoses or to the reticu loses, in which im m unological changes are prominent; or ( c ) Sarcoidosis occurs only in individuals w h o have a pre-existing im m unological peculiarity, and in them develops a reaction to an agent, or one o f several pos sible agents, which may or may not be known already as causing some well-known disease [tuberculosis].
This increased emphasis on the prevalence of sarcoidosis requires the dentist in general prac tice to know the clinical signs and symptoms of this disease to consider it in his differential diag nosis and to channel patients in whom it is sus pected for additional medical examination and treatment.
M a terials and methods One autopsy and 21 surgical cases from the Na tional Institutes of Health and nine surgical cases from the Dental and Oral Division of the Armed Forces Institute of Pathology, which met the cri teria of systemic sarcoidosis, furnished the ma terial for this study. Clinical data, including fam ily histories, physical symptoms, blood chemistry values, pulmonary radiographs, tuberculin reac tion, and Kveim tests were reviewed in conjunc tion with microscopic sections. All tissue sections were stained with hematoxylin and eosin; 71 per cent of the specimens were stained by the ZiehlNeelsen acid-fast method, and 42 percent of the specimens were stained by the periodic acidSchiff method or the Gomori’s methenamine silver nitrate method. Careful attention was given to discovering oral-related findings in each instance of systemic sarcoidosis. Follow-up information from the patients and clinicians was used to study the progress of the disease and to evaluate the therapy.
Table 1 ■ Site of involvement Positive involvement/ total no. of patients*
Tissue site Lymph nodes (generalized) Cervical lymph nodes Lungs Spleen Liver Bone Skin Parotid glands Sublingual glands Eye (uveal tract! Joints
29/31 24/31 26/31 3/31 8/31 2/31 7/31 11/31 1/31 9/31 8/31
* N o t every region was specified in every patient.
Results The age of the patients at the time of diagnosis of sarcoidosis ranged from 16 to 58 years; the mean age was 30.13 years, which is slightly high er than that reported in other surveys in which the peak incidence has occurred in persons 25 to 30 years of age.1415 Thirteen of the 31 patients were Caucasian, and 18 were Negro. The sex ratio was 12 males to 19 females. Table 1 lists the sites involved. Lymph nodes and pulmonary sites were most frequently in volved, although the parotid glands, uveal tracts, joints, and liver were often involved. Sokoloff16 described the joint pain as a polyarthritis in his report of 5 cases and said that joint disease is an intrinsic manifestation of sarcoidosis. These fig ures should not be miconstrued because the sites listed were the ones proved positive by micro scopic, radiographic, or clinical examination. Many of the regions were not tested in every patient since the other clinical and laboratory evidence was considered sufficient by the attend ing physician to support the diagnosis of sarcoi dosis, that is, hepatic, splenic, and joint biopsies were not performed on every patient. Also, the clinical signs of this disease (parotid swelling,
Table 2 ■ Physical and laboratory findings Symptom or test Hilar lymphadenopathy Generalized lymphadenopathy Cervical lymphadenopathy Parotid swelling Erythema nodosa Fatigue Weight loss Dyspnea family history of tuberculosis Positive tuberculin test Positive Kveim test Hypercalciuria Increased serum globulins
Positive involvement/ total no. of patients 27/31 25/31 24/31 11/31 3/31 24/31 15/31 23/31 5/31 3/31 6/31 10/31 11/31
Not specified 1 0 0 0 0 6 6 6 1 1 25 2 2
Hamner— Scofield: CERVICAL LY M P H A D E N O P A T H Y A N D PAROTID SW ELLING IN SARCOIDOSIS ■ 1 225
F ig . 1 ■ M u l t i p l e , n o n c a s e a t ing granulom as in splenic sarcoid section
dyspnea, fatigue, and so forth) may vary in degree. Table 2 shows 12 symptoms or clinical labo ratory tests significant in the diagnosis of sarcoi dosis. Hilar lymphadenopathy seen in a pulmo nary radiograph is an important finding; it appears early in the course of the disease and may persist, increase, or disappear spontaneously or with treat ment. This finding was noted in 27 of the 29 patients in whom this examination was performed. Generalized lymphadenopathy was also a com mon finding. Biopsies were performed on cervical, submandibular, supraclavicular, axillary, scalene,
Fig. 2 ■ S ublingual g la n d : mucous and serous a c in i, S; noncaseating g ra nulom ata composed o f e p ith e lio id histiocytes, lym pho cytes, and m u ltin u cle a te d g ia n t cells (a r row s), G, and saliva ry d u ct, D
1 226 ■ JA D A , V o l. 74, M ay 1967
inguinal, and femoral lymph nodes, which were most frequently enlarged. Cervical lymphadeno pathy was prominent and occurred in 78 percent of the patients. Parotid gland swelling, unilateral or bilateral, with subsequent biopsy confirmation of sarcoi dosis occurred in 11 of the 31 patients. The sub lingual glands were involved in one instance. No lesions were seen in the submaxillary glands. In sidious swelling of the salivary glands could easily be overlooked since this finding has not been emphasized in the literature. Erythema nodosum, which is much more com
Fig. 3 ■ G ia n t cell w ith ch a ra c te ris tic a c id o p h ilic asteroid body of sarcoidosis
were classified in this study as positive sarcoid. Three other patients in this study had a positive tuberculin reaction at one time. The Kveim test, which is considered a definite indication of true systemic sarcoidosis,14 was per formed on only six of the 31 patients. It was po sitive in all six patients. This test consists of an intracutaneous injection of a suspension of posi tive sarcoid lymph node or splenic tissue; 4 to 6 weeks later a biopsy of the induced papule re veals epithelioid cell tubercles identical to those in naturally occurring sarcoid lesions. Siltzbach17 has found that three out of four patients with
mon in Scandinavians with sarcoidosis than in Americans with sarcoidosis,13 was noted in only three patients in this study. Almost all of the pa tients suffered from fatigue, malaise, and dyspnea, and about half reported a recent weight loss vary ing from 9 to 40 lb. Five of the 31 patients recalled that one or more of their parents or siblings or both had a positive diagnosis of tuberculosis, and three of the five patients reported family members suffer ing from sarcoidosis and tuberculosis. None of the patients who gave a familial history of tuber culosis had a positive tuberculin reaction, but all
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Fig. 4 ■ A ste ro id bodies (arrow s) in g ia n t cells o f scalene lym ph node biopsy specimen fro m p a tie n t w ith sarcoidosis
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H am ner— S cofield: C ER VIC AL L Y M P H A D E N O P A T H Y A N D PARO TID S W ELLIN G IN SARCOIDOSIS ■
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Fig. 5 ■ Small concentric, baso p h ilic Schaum ann body (a rro w ) in g ia n t cell o f ce rvical lym ph node sarcoid lesion
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active sarcoidosis have a positive Kveim response when proper testing preparations are used. Hypercalciuria was found in ten of the 31 pa tients, and the serum globulins were elevated in 11 patients in the study. Microscopically, the sarcoid lesions appeared as multiple sharply defined granulomatous tu bercles composed of epithelioid histiocytes and multinucleated giant cells of the Langhan’s or foreign body type. Caseation necrosis, which is rare, was not seen. The lymphocytic infiltrate at the periphery of the granulomas tended to be less dense than that in tuberculosis. Figure 1 shows these findings in a splenic sarcoid section. Re placement of normal tissue may be slight or ex tensive. The granulomas may have a tendency toward fibrous induration with age. Sarcoidosis affecting the parotid glands may cause a severe loss of normal acini with a con comitant reduction in salivary flow, thus mimick ing Mikulicz’s disease, parotiditis (mumps), or other salivary gland disorders. Figure 2 shows the microscopic appearance of an inconspicuous nodule in the floor of a young adult’s mouth. Closer scrutiny revealed the presence of an aste roid body, a small, acidophilic, star-shaped con figuration in a giant cell (Fig. 3). Figure 4 shows several of these asteroid bodies in a scalene lymph node biopsy specimen of another sarcoid patient. Minute, basophilic oval bodies with concentric laminations, called Schaumann bodies, are some times found in giant cells of sarcoid granulomas. Figure 5 shows one of these bodies. When pres
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ent, these inclusions are highly suggestive of sarcoidosis, although they must be evaluated with respect to the total findings. In this study, asteroid bodies were seen in 13 biopsy specimens; Schau mann bodies were seen in only three biopsy spe cimens and, in each instance, they were in con junction with asteroid bodies. Refvem18 says that these inclusions result from phagocytosis of de generated fragments of collagen fibers and pos sibly other material.18 The acid-fast and other special stains failed to reveal causative microorganisms in these 31 pa tients.
Discussion There is no unanimity of opinion concerning the nature and etiology of sarcoidosis. Some investi gators believe it represents an atypical, slowly progressive form of tuberculosis, whereas others maintain it is a nonspecific granulomatous dis ease. Zettergren15 thinks it is a particular form of tuberculosis in persons who are resistant to this disease. He postulated that a strong reaction by the reticuloendothelial system causes rapid and complete destruction of the tubercle bacillus cre ating a condition that he termed “lymphogranulomatous benigna.” He based his belief on the apparent similarity between the clinical pattern and tissue involvement in the two diseases, the histologic findings, the relatively high incidence of positive tuberculin reactions in patients with
sarcoidosis, and the fact that patients with sar coidosis frequently die of tuberculosis. Features that suggest a nontuberculous origin for sarcoidosis are as follow: the majority of sarcoid patients do not come from familial tuber culous environment; the incidence of tuberculin sensitivity is low during the disease; parenchymal sarcoid lesions may show spontaneous regression, which is seldom seen in tuberculosis; the histo logic findings, although similar, are distinct, and acid-fast organisms are absent in sarcoidosis; a positive reaction to the Kveim test, which is spe cific for sarcoidosis and previously, patients who were thought to have died from sarcoidosis prob ably contacted tuberculosis and died from it be cause of misdiagnosis and misplacement in tuber culosis wards.14 The findings in this study of 31 cases indicate a nontuberculous origin for sarcoi dosis. Siltzbach,14 who has had much experience in clinical sarcoidosis research, especially Kveim testing, thinks that sarcoidosis is a hypersensi tivity disease that affects a genetically susceptible portion of the population. Such persons are sen sitized early in childhood by infection with some bacterium, fungus, pine pollen, or other agent. Later, at 20 to 30 years of age, when challenged by some internal or external precipitating agent, these persons manifest the typical clinical picture and granulomatous response that is called sar coidosis. The absence of acid-fast bacilli and fungi in the tissue sections and fluid cultures in this study does not support hypersensitivity etiology. Of the 31 patients in this study, three had a familial history of sarcoidosis involving one or more family members. None of the family mem bers of the other 38 patients were specifically tested. Merchant and Utz19 found 75 cases of sarcoidosis involving more than one member of 32 families, which suggested that a complex hered itary trait could be operative in the pathogenesis of sarcoidosis. Sarcoidosis rarely leads directly to death; in patients who die, death is usually caused by cor pulmonale or acute respiratory failure:20 Nitter21 found that 1,000 R of X-radiation per field did not influence the course of the disease. Corti costeroid hormones have proved to be the best medication for treating patients with severe sar coidosis. Criteria for their use are progressive pulmonary disease with impaired alveolar func tion; active ocular disease; persistent hypercal cemia or hypercalciuria; central nervous system
involvement; myocardial lesions, and disfiguring cutaneous lesions.14 Treatment with steroids removes the lympho cytic infiltrate, and the granulomas heal with scarring. Radiographic clearing of pulmonary le sions is often seen after therapy, but functional improvement is less pronounced since it has no effect on the scar tissue already present. If a patient with progressive pulmonary involvement does not receive steroid treatment, however, in creasing granulomatous lesions may cause severe pulmonary insufficiency. Sum m ary and conclusions A brief review of the current concepts of the etiology of sarcoidosis is presented. This disease entity is of interest and importance to the dentist because two of the chief symptoms, cervical lymphadenopathy and parotid gland swelling, are most likely to be initially detected by him. Thirty-one cases of systemic sarcoidosis were reviewed with respect to the clinicopathologic findings. The most frequent sites of involvement were lymph nodes, lungs, parotid glands, uveal tract, joints, and liver. Hilar lymphadenopathy, parotid swelling, fatigue, dyspnea, weight loss, polyarthritis, and uveitis were the most common clinical symptoms. Asteroid bodies were found in 11 of the 31 patients, and Schaumann bodies were found in three of the 31 patients. Corticosteroid hormones have proved to be the best treatment for patients with severe sarcoidosis and are indicated for patients with progressive pulmonary disease, active ocular disease, persist ent hypercalcemia or hypercalciuria, central nerv ous system involvement, myocardial lesions, and disfiguring cutaneous lesions. Although this study does not clarify the nature or etiology of sarcoidosis, it calls attention to the most reliable criteria for the diagnosis of the disease: a compatible clinical picture; hilar lym phadenopathy on a pulmonary radiograph; his tologic sections showing epithelioid granulomas with the absence of necrosis and microorganisms in specific stains; negative cultures for bacteria and fungi in body fluid and biopsy tissues, and a positive Kveim test.
Doctor Ham ner is from th e U.S. D epa rtm e n t o f H ealth, Education, and W e lfa re , Public H e a lth Service, N a tio n a l Institu te s of H ealth, N a tio n a l In s titu te o f Dental Re search, oral m edicine and surgery branch, a nd Doctor
H am ner— Scofield: CERVICAL LY M P H A D E N O P A T H Y A N D PARO TID SW ELLING
IN SARCOIDOSIS ■ 1229
Scofield is head of the oral pathology division, U.S. Naval Dental School, Bethesda, M d. 2 0 0 1 4 . The authors thank the department of anatomic pathol ogy of the National Institutes of Health and the Armed Forces Institutes of Health and the Armed Forces Insti tute of Pathology for the case material used in this study. Acknowledgment is made to John McGuire of the medical illustrations branch of the National Institutes of Health for the photomicrography. 1. Schroff, Joseph. Sarcoid of the face (BesnierBoeck Schaumann disease) : report of a case. JADA 2 9 :2 2 0 8 Dec., 1942. 2. Poe, D. L. Sarcoidosis of jaw. A new disease of the mandible. Am er J Orthodont 2 9 :5 2 Jan., 1943. . 3. Campbell, J. Sarcoidosis or tuberculosis. Brit Dent J 7 7 :1 5 9 Sept. 15, 1944. 4. Bernier, J. L., and Tiecke, R. W . Sarcoidosis. J Oral Surg 9 :2 5 6 July, 1951. 5. Covel, E. Boeck's sarcoid of mucous membrane. Report of a case. Oral Surg 7 :1 2 4 2 Nov., 1954. 6. Kalman, S. I., and M alle tt, S. P. Aberrant gland and sarcoidosis in the m axillae: report of case. J Oral Surg 12:63 Jan., 1954. 7. Kolas, Steve, and Roche, W . C. Sarcoidosis lesions primary in the oral cavity: report of a case. J Oral Surg 1 8 :1 6 9 M arch, 1960. 8. M andel, Louis, and Baurmash, Harold. Differen tiation of submaxillary lymphadenopathy and submaxillary salivary gland pathology. Oral Surg 15:3 Jan., 1962. 9. Kerr, N. W . Sarcoidosis. Oral Surg 2 0 :1 6 6 Aug., 1965. 10. Tillm an, H. H. Sarcoidosis with unsuspected oral
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manifestations. Report of a case. Oral Surg 1 8 :1 3 0 Jyly, 1964. 1 1. Tillm an, H. H.; Taylor, R. G., and Carchidi, J. E. Sarcoidosis of the tongue. Report of a case. Oral Surg 21 :190 Feb., 1966. 12. Orlean, S. L., and O'Brien, J. J. Sarcoidosis m ani festing a soft lesion in the floor of the mouth. Report of a case. Oral Surg 21 : 8 19 June, 1966. 13. Proceedings of the International Conference on Sarcoidosis. Am er Rev Resp Dis 84:1 Nov., 1961. 14. Lofgren, S. L. (ed itor), Proceedings of the Third International Conference on Sarcoidosis. Acta Med Scand (suppl.) 4 2 5 :1 , 1964. 15. Zettergren, L. Lymphogranulomatosis benigna; a clinical and histopathological study of its relation to tuberculosis. Acta Soc Upsal (suppl. 5 ) 5 9 :1 , 1954. 16. Sokoloff, L., and Bunim, J. J. Clinical and patho logical studies of joint involvement in sarcoidosis. New Eng J Med 260 :8 4 1 April 23, 1959. 17. Siltzbach, L. E. The Kveim test in sarcoidosis. Amer J Med 3 0 :4 9 5 April, 1961. 1 8. Refvem, O. Pathogenesis of Boeck's disease ( sar coidosis); investigation on significance of foreign bodies, phospholipides and hypersensitivity in formation of sar coid tissue. Acta Med Scand (suppl. 2 9 4 ) 1 49:1, 1954. 19. Merchant, R. K., and U tz, J. P. Familial sarcoido sis. A report of two cases. Arch Intern M ed (Chicago) 1 0 6 :6 4 July, 1960. 20. Raben, A. S. Sarcoidosis and so-called sarcoid reaction. Postgrad M ed 3 1 :2 3 2 M arch, 1 962 21. N itter, L. Changes in the chest roentgenogram in Boeck's sarcoid of the lungs. Acta Radial (suppl.) 1 05 :1 , 1953.