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Inflammation in the salivary glands
INFLAMMATION IN THE SALIVARY GLANDS*
J. P. WATERHOUSE,M.D., B.S., B.D.S., M.C.Path., Senior Lecturer, Department of Dental Pathology and Oral Medicine, London Hospital Medical College, Turner Street, London, E. I INTRODUCTION THE detailed nature of the pathological process underlying the syndrome now named after Sj6gren (I933), a symptom of which is commonly dryness of the mouth, has attracted much speculation, but remains unproven. In recent years, however, writers including Si6gren himself (Sj6gren, I961), Bunim (I96I), Anderson et al. (I96I) and Bloch and Bunim (I963) have drawn attention to the autoimmune aspects of the syndrome and have suggested that they play a part in its causation. The histopathological changes in the salivary and lacrimal glands, and in other organs in the syndrome, correspond to those found in many tissues and organs in a group of disease states in humans and in experimental animals in all of which autoantibodies are detectable. The diverse clinical and serological abnormalities in patients (Heaton, i959, I962) suffering from Sj6gren's syndrome and the widespread distribution of lesions in the body point to multiple causative factors and susceptible organs. The lack of detailed knowledge of the pathogenesis of the disease process is reflected, as might be expected, in the fact that no curative treatment is known. The first published account of what is now best termed Sj6gren's syndrome was that by Mikulicz (I888, I892) who described at a clinical meeting the condition of a 42-yeaW-Iod~-an suffering from multiple salivary gland swellings, and later reported his findings in detail, giving an illustration of the histology of a submandibular salivary gland excised from the patient. In his illustration marked replacement of functional acini of the gland by aggregates of lymphoid cells is seen. Among later papers are those of Gougerot (I926), whose name is given to the syndrome in the French literature, and Lutman and Favata (I946) who used the terms 'keratoconjunctivitis sicca' and 'buccoglossopharyngitis sicca'. The latter is an unwieldy though descriptive title. Morgan and Castleman (1953) and Morgan (I954) pointed out that the histological findings in the glands in S~gren's syndrome and Mikulicz's disease were identical. They suggested that Mikulicz's disease should be regarded as one aspect of a wider syndrome, Sj6gren's syndrome, and that the pathological process underlying this was of systemic origin as evidenced by the high prevalence in those patients of rheumatoid arthritis. Bunim (I96I) presented the results of the investigation, clinically and serologically, of 4o patients with Sj6gren's syndrome. He pointed out the overlap of the clinical and serological findings with those in rheumatoid arthritis and other diseases having autoimmune characteristics, including Hashimoto's thyroiditis, *Based upon a paper read to a meeting of the British Association of Oral Surgeons at the London Hospital on April 25th, 1964. This paper includes a part of the work approved by the University of London for the award of the M.D. degree.
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and suggested that a genetic relationship existed between the occurrence of thyroglobulin antibodies and the development of Hashimoto's thyroiditis and of Sj6gren's syndrome. The writer accepts the evidence adduced by Bunim at that time that the term 'Sj6gren's syndrome' should be used in a comprehensive sense and should include 'Mikulicz's disease'. It will therefore be defined as a disease involving in its full form the eyes (with changes termed keratoconjunctivitis sicca), the lacrimal glands, the salivary glands, the joints and other organs, and having the histological aspects described in the salivary and lacrimal glands by Morgan (1954). These are, in outline, replacement of functional gland acini by infiltrations of lymphocytes and hyperplasia of the epithelium lining ducts. Clinically it is manifested by some or all of the following main symptoms and signs: dryness and a pricking sensation of the eyes, dryness of the mouth sometimes with recurrent swelling of the salivary glands, and the joint lesions of rheumatoid arthritis. Serological abnormalities found commonly include hypergammaglobulinaemia, rheumatoid factor, antinuclear factor, and complement fixing antibodies to, e.g. thyroglobulin. Partial and mixed syndromes occur (Heaton, 1959; Bloch & Bunim, 1963). The patients are predominantly women and often present themselves when over 4 ° years of age. As to the degree of overlap with rheumatoid arthritis, roughly one half of patients with Sj6gren's syndrome have rheumatoid arthritis, and approximately one-eighth of patients with rheumatoid arthritis have keratoconjunctivitis (Bunim, 1961). Kellgren (1963) quotes figures for the prevalence of rheumatoid arthritis in the relatives of sufferers from that disease, and Bloch and Bunim (1963) present evidence of the levels of partial forms of Sj6gren's syndrome in the relatives of patients with that disease. In both the above papers, the finding that relatives of sufferers are themselves more commonly affected, to some degree, than are nonrelatives, leads to consideration of the predisposing role played by genetically determined factors in these disease states. Inquiry as to the past or present diseases of relatives may therefore be helpful clinically. In work reported in detail elsewhere (Waterhouse, 1963) a histopathological and experimental investigation of salivary and lacrimal glands was designed to examine the hypothesis that the histological changes of loss of functional secretory gland acini and replacement by aggregates of lymphocytes and histiocytes seen in salivary glands, termed focal lymphocytic adenifis, might represent a focal form of Sj6gren's syndrome. Two approaches to the problem were used: firstly, the examination of human postmortem material, which has allowed conclusions to be based on large numbers of glands free from infection or neoplasm, and secondly, experimental attempts to reproduce the lesions in two species of laboratory animals. The present paper is concerned only with the data from the first of the above sources, namely, the examination of the human autopsy subjects. Materials and methods.--Details of the methods used have been described (Waterhouse, 1963). The submandibular and parotid salivary glands, and the lacrimal glands of 248 subjects undergoing autopsy in the Bernhard Baron Institute of Pathology of the London Hospital were examined macroscopically and microscopically. The lacrimal glands are, of course, like the salivary glands, exocrine glands and produce a watery secretion containing one substance also present in
,
INFLAMMATION IN THE SALIVARY GLANDS
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saliva, i.e. lysozyme. The work has since been extended by the examination (Waterhouse & Doniach, 1964) of the submandibular glands from a further 277 subjects (making 525 in all), the submandibular lymph nodes from 20 of them, the thyroid glands from 219 of them. A large representative histological section was obtained from each by standard techniques. Before a gland was included in the series, criteria which were designed
)US ACINUS
iROUS ACINUS
DUCT
FIG. I Normal human submandibular gland. The connective tissue adjacent to blood vessels and ducts, and separating gland lobules, is free from inflammatory cells apart from occasional isolated lymphocytes. Haemalum and eosin. × 64.
Reproduced by courtesy of the honorary editors of the Proceedings of the Royal Society of Medicine.
to exclude infection and neoplasm as causes of pathological change were applied. Those glands in which the criteria were met were examined for loci of lymphocytes and histiocytes replacing gland acini. To enable detailed comparisons between individuals and of groups by age and sex, a numerical count of all loci containing fifty cells or more, per unit area of histological section was made. The glands were graded upon a scale ranging from Grade o (no focal lymphocytic adenitis, i.e. o-I focus per standard size section), to Grade 4 ('very severe adenitis', i.e. more than half the gland parenchyma replaced in a section).
Histopathological findings.--The arrangement of the cells in the secretory units or acini of a salivary gland is essentially radial. The representation of the salivary duct tree seen in a sialogram includes the main duct and the large and small branches of the system. The acini feed the duct system with a secretion which in all probability is modified as regards water and ionic concentrations as it
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passes along the branches of the duct tree (Burgen & Emmelin, I96I), and reaches the oral cavity as saliva. The normal histology of human submandibular salivary glands is illustrated in Figure I. The secretory acini, made up of serous and mucous cells, the duct epithelium, and connective tissue showing only a few isolated lymphocytes are shown. The histological appearances of normal parotid gland are similar but mucous cells are absent from the acini.
--
FOCUS
FIG. 2 A focus in the submandibular salivary gland of a female subject aged 53 years who died of ischaemic heart disease and hypertension. Haemalum and eosin. × 9o. Reproduced by courtesy of the honorary editors of the Proceedings
of the Royal Society of Medicine.
The appearances of a gland affected by focal lymphocytic adenitis are shown in the following figures. Figure 2 shows a focus in the submandibular salivary gland of a female subject age 53, who died of ischaemic heart disease. Replacement of acini by lymphocytes and histiocytes which individually are infiltrating ahead of the main body of these cells is seen. The focus is situated in relationship to a small vein or veins. Figure 3 illustrates a similar focus in the parotid salivary gland in the same subject: The lacrimal gland of the same subject was similarly affected. The histopathological changes are thus similar in the three glands. Figure 4 illustrates the parotid gland of a male aged 66 who died with rheumatoid arthritis and pancytopenia. Marked replacement of the acini by infiltrations of lymphocytes and histiocytes, through which the ducts course, is seen. His submandibular gland was similarly affected. This represents a severe degree of focal adenitis. Clinically the salivary glands of this man were normal. A postmortem diagnosis of Sj6gren's syndrome was made. The duct hyperplasia or thickening of the lining epithelium which takes place in Sj6gren's syndrome and which must provide the mechanical basis for clinical episodes of swelling and pain associated with blockage and infection, was quite commonly found to a mild degree in severe degrees of focal lymphocytic adenitis.
I N F L A M M A T I O N I N THE SALIVARY GLANDS
I6 5
FIG. 3 A focus in the parotid salivary gland of the same subject. Haemalttm and eosin. × 9 o.
Fla. 4
Marked focal lymphocytic adenitis in the parotid gland of a male subject aged 66 years who died with rheumatoid arthritis and pancytopenia. A postmortem diagnosis of SjOgren's syndrome was made. Haemalum and eosin. × 43.
Relationship with comparable conditions and age incidence.--A comparable condition affects the endocrine (ductless) thyroid gland--focal thyroidifis (Bastenie, 1937; Williams & Doniach, 1962). Associations have been shown to exist between focal thyroiditis and each of the following: Sj6gren's syndrome (Heaton, I959), Addison's disease (Wells, 193o; Sloper, I953), panhypopituitarism (Sheehan, 1939) and pernicious anaemia (Williams & Doniach, 1962). There is evidence that focal thyroiditis is associated with focal salivary and lacrimal adenitis in the present series although the association is not so strong as that between salivary and lacrimal glands (Waterhouse & Doniach, 1964). M
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Focal thyroiditis of severe degree was found in the thyroid gland of the subject whose parotid gland was illustrated in Figure 4. The early figures for the prevalence of focal adenitis which have been reported in detail elsewhere (Waterhouse, 1963) will be briefly summarized. The numbers of male subjects of different age groups in the series affected by focal lymphocytic adenitis, based upon findings in the most severely affected gland among the submandibular, parotid and lacrimal glands, are shown in Table I. TABLE I F O C A L A D E N I T I S OF SALIVARY AND L A C R I M A L G L A N D S P R E V A L E N C E IN AGE G R O U P S MALES Number and percentage of subjects in 'Summary ~ grades' 0 - 4
Age groups o 0-44 45-54 55-64 Over 64
8 7 I8 I4
2
3& 4
3
I
o
I
2
I
II
5 5
o I
o I
23 2I
4 (6%)
2
I
(75%) (64%) (78%) (67%)
47 (70%)
I4 (2I~o)
Total 12
(3%)
67
eThe 'summary grade' of an individual subject is the grading in the most severely affected gland of that subject. Thus, a subject in 'summary grade': o had: no focal adenitis in any gland. I had: 2-8 foci per representative section in at least one gland. 2 had: 9-4o foci per representative section in at least one gland. 3 had: over 4° foci per representative section in at least one gland. 4 had: more than half the parenchyma replaced in at least one gland.
In Table II (below) the numbers of female subjects of different age groups affected are presented. TABLE II FOCAL A D E N I T I S OF SALIVARY AND L A C R I M A L G L A N D S P R E V A L E N C E IN AGE G R O U P S FEMALES Number and percentage of subjects in 'Summary ~ grades' 0- 4
Age groups 0
o-44 45-54 55 64 Over 64
I
2
3&4
(Io%) 9 (26%) I4 (27%) I4 (27%)
7 II (3I%) 24 (46%) 27 (52%)
3 I2 (34%) I3 (25%) IO (I5%)
o
47 (3o%)
69 (43%)
38 (24%)
5 (3I%)
IO
*See Table I for key.
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A significantly higher proportion of women of 45 and over, than of younger women or of men, was affected (p < o.ooi) when the prevalence of focal adenitis in the most severely affected gland in each subject among the submandibular, parotid and lacrimal glands was analysed. It was seen, moreover, that the trend of prevalence with increasing age was similar in each gland for each sex separately, which indicated that the three glands are similarly affected through life. This was confirmed by detailed analysis of the figures. The prevalence of focal adenitis was not significantly different (p >0.3) in 21 coroner's autopsy subjects who had died 'sudden deaths' from that in the main group. There is thus no evidence to support a suggestion that a slow death in hospital affects focal adenitis. TABLE I I I PREVALENCE, OBSERVED AND EXPECTED OF FOCAL ADENITIS IN SUBJECTS OF THE HOSPITAL AUTOPSY SERIES SUFFERING FROM CERTAIN DISEASES Number
Number with:
of ,cases es . . . . . . .
.
.
A n y degree of adenitis
'Collagen disease' (see text)
More than 40 foci per section
.
] Observed Rheumatoid arthritis
Nine or more foci :per section
Expected
9
8
5"3
27
22
15 '8
Observed l Expected --
Observed
Expecte,
6
2"0
2
0"3
15
5"8
3
0.8
In Table III is seen some evidence for an association between focal adenitis and rheumatoid arthritis. The number of subjects who died with rheumatoid arthritis in whom focal lymphocytic adenitis was found was greater than that which would have been expected, both when all grades and when more severe grades only were considered. The expected figures were calculated from that percentage of the total series who suffered from the degree of focal adenitis given at the head of each column. The figures appear to indicate a consistent trend but are too small for statistical analysis and so the evidence must be regarded as tentative. This trend is confirmed in the larger series of 525 subjects (Waterhouse & Doniach, I964). The appearance of a consistent trend with evidence of a statistically significant (p < o.o2) difference is found for a group termed 'collagen disease' which included those in whom a diagnosis of scleroderma (3) rheumatoid arthritis (9) rheumatic carditis (I2), glomerulonephritis (5) or Wegener's granulomatosis (I) was made. The findings in this part of the work may be summarized by saying that focal lymphocytic adenitis (loci of lymphocytes and histiocytes associated with apparent loss of parenchyma) occurred quite commonly in human postmortem lacrimal, submandibular and parotid glands especially in women of over 45 years of age. It may be a focal form of Sj6gren's syndrome, which has features of an autoimmune disease, including the presence in the serum of patients suffering from it auto-antibodies to antigens present in certain of their tissues.
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Immunity and autoimmunity to tissue antigens.--The problems of immunity and autoimmunity to tissue antigens (that is, immunity to tissue constituents, as opposed to the antigens of, for example, bacteria or viruses) have recently attracted much attention. Autoantibodies may be defined concisely as antibodies formed by an animal to some constituent of its own body. By 1945, autoantibodies to a number of tissue elements had been reported in human sera: for instance, in syphilis and in rheumatic fever (Davies et al., 1945) (Cavelti, 1945). Burner (Burnet Co" Fenner, 1949) made a great conceptual advance by pointing out that for autoimmunization to occur, the body had to fail to recognize some of its own tissues for what they were, that is, part of itself, and to proceed to make antibodies to them as if they were foreign. That is to say, the mechanism for recognition must exist and must sometimes break down. Since the experimental production in rabbit of autoantibodies to thyroid by Witebsky and Rose in 1956, autoantibodies to, and histological lesions (comparable to those in salivary glands in Sj6gren's syndrome, and probably in the nature of delayed hypersensitivity reactions) have been produced experimentally, in many organs including thyroid and adrenal, testis and kidney. Of equal interest is the fact that autoantibodies have been demonstrated, in humans, to antigens present in all these organs, and others. Autoimmunization is thus a widespread phenomenon. However, it must be said that some of the human autoantibodies are transient and follow common types of tissue damage such as trauma, ischaemia and infection (Waksman, 1962) and that the simple presence of autoantibodies in serum does not in itself lead to progressive autoimmune disease (Doniach & Roitt, 1962). The underlying abnormality or propensity to develop these diseases is probably genetically determined, as evidenced by family studies. In some patients with Sj/Jgren's syndrome the presence of persistent autoantibodies to salivary gland (which are however not organ-specific), to constituents of cell nuclei (antinuclear factors) and to thyroid, the presence of rheumatoid arthritis, and a considerable overlap with systemic lupus erythematosus are grounds for including it ill what has been termed a 'broader spectrum of autoimmune disease' as was suggested by Bunim in 1961. The finding of partial syndromes in relatives of patients with the full syndrome by Bloch and Bunim in 1963 supports this. The associations of the above diseases with the clinical complaint of a swelling of a salivary gland or glands will now be considered. What has been termed Mikulicz's disease, the central finding of which is a swelling of one or more of the salivary and lacrimal glands not primarily due to infection or neoplasm, should I believe, as Morgan and Castleman have urged, be included in Sj~gren's syndrome because of histological and serological overlap. When a gland which is affected by Sj6gren's syndrome has owing to hyperplasia of the duct epithelium become infected, some of the typical histologlca-1 Attrloutes are lost and dlagnosls wllYdepend upon clinical and serological findings together with the histology of the gland itself. The development of an enlargement of a salivary gland in the p~rotid region in association with the histopathological changes of Sj6gren's syndrome has been termed benign lymphoepithelial lesion by Godwin (1952) and Foote and Frazell (1954). It seems likely that some aT least of these patients would be shown by further investigation to suffer from a partial form of Sj6gren's syndrome. The reported predilection of the benign lymphoepithelial lesion for females of
INFLAMMATION IN THE SALIVARY GLANDS
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middleage or olderand the undoubtedassociationof the fullydevelopedSjbgren's syndromewith this age and sex group, support the suggestion.
Implications of the relationship of salivary glands to lymph nodes. - - T h e close physical relationship of lymphoid tissue to salivary glands is of direct surgical interest. Either of these adjacent tissues may be the seat of surgical enlargement, making the interpretation of physical signs difficult. A parotid lymph node, with a salivary gland lobule partly, and with isolated acini completely, enclosed within it, is illustrated in Figures 5 and 6. In this series of autopsy salivary glands, lymph nodes conversely were a constant finding within the parotid gland. They were not however found in any subject within the submandibular gland capsule--always outside it. T h e constant presence of lymph nodes within the parotid, and their absence within the submandibular, gland is in keeping with the fact that the Warthin's tumour or adenolymphoma for practical purposes only occurs in or adjacent to the parotid7 As tor wlaer and more speculative ideas: Burner and Mackay (z962) noted the close relationship of epithelium to lymphocytes in thymus (from the lymphoid tissue of which all immunologicall~r competent ceUs-in the bodv probably steml,L and m salivary glands in Sj6gren's disease and adenolymphoma. They suggested the possibility that immunologically functioning cells might revert to cells of epithelial type and that the proliferative activity of abnormal epitheloid cells with immunological potentialities takes place much more readily in organs derived from branchial epithelium than from other sites. Lymphocytes and epithelium may, then, have a special mutual relationship in the head and neck and thorax. SUMMARY The great majority of patients with Sj6gren's syndrome suffer fr0m xerostomia and a specific salivary gland abnormality based upon a generalized disturbance of immunological reactivity. T h e aetiology of this is essentially unknown, and no curative treatment is available. Focal lymphocytic adenitis of salivary and lacrimal glands occurs commonly in human autopsy subjects in the absence of evidence of gland infection. By reason of its histological appearances, its tendency to affect most commonly middle-aged or older women, and its apparent association with rheumatoid arthritis it may be a focal form of Sj6gren's syndrome. This has attributes of an autoimmune disease, and partial forms and clinical and laboratory findings which overlap with those of other connective tissue diseases occur. Rheumatoid arthritis and Sj6gren's syndrome each occur more commonly in the relatives of pafienls with each disease than in non-relatives. This fact, together with the clinical finding of partial forms of Sj6gren's syndrome, points to the operation of a genetic predisposition and suggests that the family history of patients in whom the diagnosis is being considered will on occasions provide information of value. Some patients with swelling of salivary glands not due primarily to salivary calculus or neoplasm have, as the pathological basis for their salivary gland disease, ~eplacement of gland parenchyma by infiltrations of lymphocytes and histiocytes and duct obstruction due to duct hyperplasia (Mikulicz's disease). This is best regarded as a variant or partial form of Sj6gren's syndrome. Clinical infection of glands follows duct obstruction.
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AREA SHOWN IN FIG. 6 1 ~
FIG. 5 A lymph node in close relationship on two sides to a lobule of the parotid salivary gland 'within' an infolding of tile node. Haemalum and eosin. × 15.
FIG. 6 A higher power view of a part of Figure 6 shows that isolated gland acini and ducts lie deep within the node substance. Haemalum and eosin. × lO5.
INFLAMMATION
IN THE SALIVARY GLANDS
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The clinical consequence of the great infrequency with which lymph nodes occur actually within the submandibular salivary gland capsule by contrast with their practically constant presence within the parofid gland, is that the detection of clinical enlargement of parotid lymph nodes will be made difficult by the presence of parotid lymph gland tissue enclosing them, whereas the palpation of the submandibular nodes is not hindered in this way. ACKNOWLEDGEMENTS I should like to thank the Head of my department, Professor A . E. IV. Miles, for his support during this work, and Professor I. Doniach, in whose department the work was carried out. REFERENCES ANDERSON,J. R., GRAY, K. G., BECK, J. S. & KINNEAR,W. F. (1961). Lancet, 2, 456. BASTENIE, P. (1937). Arch. int. mdd. exp. 12, I. BLOCH, K. J. & BUNIM, J. J. (1963). J. chron, dis. I6, 915 . BUNIM, J. J. (I96I). Ann. rheum. Dis. 2o, I. BURGEN, A. S. V. & EMMELIN, N. G. (1961). Physiology of the salivary glands, P. 9. London: Arnold. BURNET, F. M. & FENNER,P. (1949). The production of antibodies, p. 76. Melbourne: Macmillan. BURNET, F. M . ~-~ MACKAY, I. R. (I962). Lancet, 2, lO3O. CAVELTI, P. A. (1945). Proc. Soc. exp. Biol. (N.Y.). 6o, 379. DAVIES, B. D., MOORE, D. H., KABAT, E. A. & HARRIS, A. D. (I945). ft. Immunol. 5 0 , I.
DONIACH, D. & ROITT, I. M. (1962). Ann. Rev. Med. 13, 213. FOOTE, F. W. 6 ' FRAZELL,E. L. (I954). Atlas of tumour pathology. Section IV. Fasc. 1I, p. 146. Washington: Armed Forces Institute of Pathology. GODWIN, J. T. (I952). Cancer, 5, IO89. GOUGEROT, H. (1926). Bull. todd. 40, 360. HEATON, J. M. (1959). Brit. med. ft. I, 466. HEATON, J. M. (1962). Proc. roy. Soc. reed. 55, 479KELLGREN, J. H. (1963). Ann. rheum. Dis. 23, lO9. LUTMAN, F. C. & FAVATA,B. V. (1946). Arch. Ophthal. 35, 227. MIKULICZ, J. (1888). Berl. Kl. W, 25, 759. MIKULICZ, J. (I892). Ueber eine eigenartige symmetrische Erkriinkung der Thrfinen und Mundspeicheldrfisen. (Concerning a remarkable symmetrical disease of the lacrimal and salivary glands.) Beitrfige zur Chirurgie, Festschrift Theodor Billroth, 61o. MORGAN, W. S. (1954)- New Engl. ft. Med. 251 , 5. MORGAN, W. S. ~9' CASTLEMAN,B, (I953). A clinicopathological study of Mikulicz's disease. Amer. ft. Path. 29, 471. SI-IEEHAN,H. L. (1939). Quart. ft. Med. 8, 277. SJOGREN, H. (1933). Acta ophthal. Suppl. 2, I. SJOGREN, H. (I96I). Acta ophthal. 39, 619SLOPER, J. C. (1953). ft. Path. Bact. 66, 53. WAKSMAN, B. (1962). Medicine. (Baltimore). 41, 93. WATERHOUSE,J. P. (1963). Proc. roy. Soc. Med. 56, 911. WATERHOUSE,J. P. fig' DONIACH, I. (1964). To be published. WELLS, H. G. (193o). Arch. Path. IO, 499. WITEBSKY, E. ~ ROSE, N. R. (I956). ft. Immunol. 76, 408. WILLIAMS, E. D. & DONIACH, I. (1962). ft. Path. Bact. 83, 255.
J. P. WATERHOUSE,M.D., B.S., B.D.S., M.C.Path., Senior Lecturer, Department of Dental Pathology and Oral Medicine, London Hospital Medical College, Turner Street, London, E. I INTRODUCTION THE detailed nature of the pathological process underlying the syndrome now named after Sj6gren (I933), a symptom of which is commonly dryness of the mouth, has attracted much speculation, but remains unproven. In recent years, however, writers including Si6gren himself (Sj6gren, I961), Bunim (I96I), Anderson et al. (I96I) and Bloch and Bunim (I963) have drawn attention to the autoimmune aspects of the syndrome and have suggested that they play a part in its causation. The histopathological changes in the salivary and lacrimal glands, and in other organs in the syndrome, correspond to those found in many tissues and organs in a group of disease states in humans and in experimental animals in all of which autoantibodies are detectable. The diverse clinical and serological abnormalities in patients (Heaton, i959, I962) suffering from Sj6gren's syndrome and the widespread distribution of lesions in the body point to multiple causative factors and susceptible organs. The lack of detailed knowledge of the pathogenesis of the disease process is reflected, as might be expected, in the fact that no curative treatment is known. The first published account of what is now best termed Sj6gren's syndrome was that by Mikulicz (I888, I892) who described at a clinical meeting the condition of a 42-yeaW-Iod~-an suffering from multiple salivary gland swellings, and later reported his findings in detail, giving an illustration of the histology of a submandibular salivary gland excised from the patient. In his illustration marked replacement of functional acini of the gland by aggregates of lymphoid cells is seen. Among later papers are those of Gougerot (I926), whose name is given to the syndrome in the French literature, and Lutman and Favata (I946) who used the terms 'keratoconjunctivitis sicca' and 'buccoglossopharyngitis sicca'. The latter is an unwieldy though descriptive title. Morgan and Castleman (1953) and Morgan (I954) pointed out that the histological findings in the glands in S~gren's syndrome and Mikulicz's disease were identical. They suggested that Mikulicz's disease should be regarded as one aspect of a wider syndrome, Sj6gren's syndrome, and that the pathological process underlying this was of systemic origin as evidenced by the high prevalence in those patients of rheumatoid arthritis. Bunim (I96I) presented the results of the investigation, clinically and serologically, of 4o patients with Sj6gren's syndrome. He pointed out the overlap of the clinical and serological findings with those in rheumatoid arthritis and other diseases having autoimmune characteristics, including Hashimoto's thyroiditis, *Based upon a paper read to a meeting of the British Association of Oral Surgeons at the London Hospital on April 25th, 1964. This paper includes a part of the work approved by the University of London for the award of the M.D. degree.
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and suggested that a genetic relationship existed between the occurrence of thyroglobulin antibodies and the development of Hashimoto's thyroiditis and of Sj6gren's syndrome. The writer accepts the evidence adduced by Bunim at that time that the term 'Sj6gren's syndrome' should be used in a comprehensive sense and should include 'Mikulicz's disease'. It will therefore be defined as a disease involving in its full form the eyes (with changes termed keratoconjunctivitis sicca), the lacrimal glands, the salivary glands, the joints and other organs, and having the histological aspects described in the salivary and lacrimal glands by Morgan (1954). These are, in outline, replacement of functional gland acini by infiltrations of lymphocytes and hyperplasia of the epithelium lining ducts. Clinically it is manifested by some or all of the following main symptoms and signs: dryness and a pricking sensation of the eyes, dryness of the mouth sometimes with recurrent swelling of the salivary glands, and the joint lesions of rheumatoid arthritis. Serological abnormalities found commonly include hypergammaglobulinaemia, rheumatoid factor, antinuclear factor, and complement fixing antibodies to, e.g. thyroglobulin. Partial and mixed syndromes occur (Heaton, 1959; Bloch & Bunim, 1963). The patients are predominantly women and often present themselves when over 4 ° years of age. As to the degree of overlap with rheumatoid arthritis, roughly one half of patients with Sj6gren's syndrome have rheumatoid arthritis, and approximately one-eighth of patients with rheumatoid arthritis have keratoconjunctivitis (Bunim, 1961). Kellgren (1963) quotes figures for the prevalence of rheumatoid arthritis in the relatives of sufferers from that disease, and Bloch and Bunim (1963) present evidence of the levels of partial forms of Sj6gren's syndrome in the relatives of patients with that disease. In both the above papers, the finding that relatives of sufferers are themselves more commonly affected, to some degree, than are nonrelatives, leads to consideration of the predisposing role played by genetically determined factors in these disease states. Inquiry as to the past or present diseases of relatives may therefore be helpful clinically. In work reported in detail elsewhere (Waterhouse, 1963) a histopathological and experimental investigation of salivary and lacrimal glands was designed to examine the hypothesis that the histological changes of loss of functional secretory gland acini and replacement by aggregates of lymphocytes and histiocytes seen in salivary glands, termed focal lymphocytic adenifis, might represent a focal form of Sj6gren's syndrome. Two approaches to the problem were used: firstly, the examination of human postmortem material, which has allowed conclusions to be based on large numbers of glands free from infection or neoplasm, and secondly, experimental attempts to reproduce the lesions in two species of laboratory animals. The present paper is concerned only with the data from the first of the above sources, namely, the examination of the human autopsy subjects. Materials and methods.--Details of the methods used have been described (Waterhouse, 1963). The submandibular and parotid salivary glands, and the lacrimal glands of 248 subjects undergoing autopsy in the Bernhard Baron Institute of Pathology of the London Hospital were examined macroscopically and microscopically. The lacrimal glands are, of course, like the salivary glands, exocrine glands and produce a watery secretion containing one substance also present in
,
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saliva, i.e. lysozyme. The work has since been extended by the examination (Waterhouse & Doniach, 1964) of the submandibular glands from a further 277 subjects (making 525 in all), the submandibular lymph nodes from 20 of them, the thyroid glands from 219 of them. A large representative histological section was obtained from each by standard techniques. Before a gland was included in the series, criteria which were designed
)US ACINUS
iROUS ACINUS
DUCT
FIG. I Normal human submandibular gland. The connective tissue adjacent to blood vessels and ducts, and separating gland lobules, is free from inflammatory cells apart from occasional isolated lymphocytes. Haemalum and eosin. × 64.
Reproduced by courtesy of the honorary editors of the Proceedings of the Royal Society of Medicine.
to exclude infection and neoplasm as causes of pathological change were applied. Those glands in which the criteria were met were examined for loci of lymphocytes and histiocytes replacing gland acini. To enable detailed comparisons between individuals and of groups by age and sex, a numerical count of all loci containing fifty cells or more, per unit area of histological section was made. The glands were graded upon a scale ranging from Grade o (no focal lymphocytic adenitis, i.e. o-I focus per standard size section), to Grade 4 ('very severe adenitis', i.e. more than half the gland parenchyma replaced in a section).
Histopathological findings.--The arrangement of the cells in the secretory units or acini of a salivary gland is essentially radial. The representation of the salivary duct tree seen in a sialogram includes the main duct and the large and small branches of the system. The acini feed the duct system with a secretion which in all probability is modified as regards water and ionic concentrations as it
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passes along the branches of the duct tree (Burgen & Emmelin, I96I), and reaches the oral cavity as saliva. The normal histology of human submandibular salivary glands is illustrated in Figure I. The secretory acini, made up of serous and mucous cells, the duct epithelium, and connective tissue showing only a few isolated lymphocytes are shown. The histological appearances of normal parotid gland are similar but mucous cells are absent from the acini.
--
FOCUS
FIG. 2 A focus in the submandibular salivary gland of a female subject aged 53 years who died of ischaemic heart disease and hypertension. Haemalum and eosin. × 9o. Reproduced by courtesy of the honorary editors of the Proceedings
of the Royal Society of Medicine.
The appearances of a gland affected by focal lymphocytic adenitis are shown in the following figures. Figure 2 shows a focus in the submandibular salivary gland of a female subject age 53, who died of ischaemic heart disease. Replacement of acini by lymphocytes and histiocytes which individually are infiltrating ahead of the main body of these cells is seen. The focus is situated in relationship to a small vein or veins. Figure 3 illustrates a similar focus in the parotid salivary gland in the same subject: The lacrimal gland of the same subject was similarly affected. The histopathological changes are thus similar in the three glands. Figure 4 illustrates the parotid gland of a male aged 66 who died with rheumatoid arthritis and pancytopenia. Marked replacement of the acini by infiltrations of lymphocytes and histiocytes, through which the ducts course, is seen. His submandibular gland was similarly affected. This represents a severe degree of focal adenitis. Clinically the salivary glands of this man were normal. A postmortem diagnosis of Sj6gren's syndrome was made. The duct hyperplasia or thickening of the lining epithelium which takes place in Sj6gren's syndrome and which must provide the mechanical basis for clinical episodes of swelling and pain associated with blockage and infection, was quite commonly found to a mild degree in severe degrees of focal lymphocytic adenitis.
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I6 5
FIG. 3 A focus in the parotid salivary gland of the same subject. Haemalttm and eosin. × 9 o.
Fla. 4
Marked focal lymphocytic adenitis in the parotid gland of a male subject aged 66 years who died with rheumatoid arthritis and pancytopenia. A postmortem diagnosis of SjOgren's syndrome was made. Haemalum and eosin. × 43.
Relationship with comparable conditions and age incidence.--A comparable condition affects the endocrine (ductless) thyroid gland--focal thyroidifis (Bastenie, 1937; Williams & Doniach, 1962). Associations have been shown to exist between focal thyroiditis and each of the following: Sj6gren's syndrome (Heaton, I959), Addison's disease (Wells, 193o; Sloper, I953), panhypopituitarism (Sheehan, 1939) and pernicious anaemia (Williams & Doniach, 1962). There is evidence that focal thyroiditis is associated with focal salivary and lacrimal adenitis in the present series although the association is not so strong as that between salivary and lacrimal glands (Waterhouse & Doniach, 1964). M
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Focal thyroiditis of severe degree was found in the thyroid gland of the subject whose parotid gland was illustrated in Figure 4. The early figures for the prevalence of focal adenitis which have been reported in detail elsewhere (Waterhouse, 1963) will be briefly summarized. The numbers of male subjects of different age groups in the series affected by focal lymphocytic adenitis, based upon findings in the most severely affected gland among the submandibular, parotid and lacrimal glands, are shown in Table I. TABLE I F O C A L A D E N I T I S OF SALIVARY AND L A C R I M A L G L A N D S P R E V A L E N C E IN AGE G R O U P S MALES Number and percentage of subjects in 'Summary ~ grades' 0 - 4
Age groups o 0-44 45-54 55-64 Over 64
8 7 I8 I4
2
3& 4
3
I
o
I
2
I
II
5 5
o I
o I
23 2I
4 (6%)
2
I
(75%) (64%) (78%) (67%)
47 (70%)
I4 (2I~o)
Total 12
(3%)
67
eThe 'summary grade' of an individual subject is the grading in the most severely affected gland of that subject. Thus, a subject in 'summary grade': o had: no focal adenitis in any gland. I had: 2-8 foci per representative section in at least one gland. 2 had: 9-4o foci per representative section in at least one gland. 3 had: over 4° foci per representative section in at least one gland. 4 had: more than half the parenchyma replaced in at least one gland.
In Table II (below) the numbers of female subjects of different age groups affected are presented. TABLE II FOCAL A D E N I T I S OF SALIVARY AND L A C R I M A L G L A N D S P R E V A L E N C E IN AGE G R O U P S FEMALES Number and percentage of subjects in 'Summary ~ grades' 0- 4
Age groups 0
o-44 45-54 55 64 Over 64
I
2
3&4
(Io%) 9 (26%) I4 (27%) I4 (27%)
7 II (3I%) 24 (46%) 27 (52%)
3 I2 (34%) I3 (25%) IO (I5%)
o
47 (3o%)
69 (43%)
38 (24%)
5 (3I%)
IO
*See Table I for key.
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A significantly higher proportion of women of 45 and over, than of younger women or of men, was affected (p < o.ooi) when the prevalence of focal adenitis in the most severely affected gland in each subject among the submandibular, parotid and lacrimal glands was analysed. It was seen, moreover, that the trend of prevalence with increasing age was similar in each gland for each sex separately, which indicated that the three glands are similarly affected through life. This was confirmed by detailed analysis of the figures. The prevalence of focal adenitis was not significantly different (p >0.3) in 21 coroner's autopsy subjects who had died 'sudden deaths' from that in the main group. There is thus no evidence to support a suggestion that a slow death in hospital affects focal adenitis. TABLE I I I PREVALENCE, OBSERVED AND EXPECTED OF FOCAL ADENITIS IN SUBJECTS OF THE HOSPITAL AUTOPSY SERIES SUFFERING FROM CERTAIN DISEASES Number
Number with:
of ,cases es . . . . . . .
.
.
A n y degree of adenitis
'Collagen disease' (see text)
More than 40 foci per section
.
] Observed Rheumatoid arthritis
Nine or more foci :per section
Expected
9
8
5"3
27
22
15 '8
Observed l Expected --
Observed
Expecte,
6
2"0
2
0"3
15
5"8
3
0.8
In Table III is seen some evidence for an association between focal adenitis and rheumatoid arthritis. The number of subjects who died with rheumatoid arthritis in whom focal lymphocytic adenitis was found was greater than that which would have been expected, both when all grades and when more severe grades only were considered. The expected figures were calculated from that percentage of the total series who suffered from the degree of focal adenitis given at the head of each column. The figures appear to indicate a consistent trend but are too small for statistical analysis and so the evidence must be regarded as tentative. This trend is confirmed in the larger series of 525 subjects (Waterhouse & Doniach, I964). The appearance of a consistent trend with evidence of a statistically significant (p < o.o2) difference is found for a group termed 'collagen disease' which included those in whom a diagnosis of scleroderma (3) rheumatoid arthritis (9) rheumatic carditis (I2), glomerulonephritis (5) or Wegener's granulomatosis (I) was made. The findings in this part of the work may be summarized by saying that focal lymphocytic adenitis (loci of lymphocytes and histiocytes associated with apparent loss of parenchyma) occurred quite commonly in human postmortem lacrimal, submandibular and parotid glands especially in women of over 45 years of age. It may be a focal form of Sj6gren's syndrome, which has features of an autoimmune disease, including the presence in the serum of patients suffering from it auto-antibodies to antigens present in certain of their tissues.
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Immunity and autoimmunity to tissue antigens.--The problems of immunity and autoimmunity to tissue antigens (that is, immunity to tissue constituents, as opposed to the antigens of, for example, bacteria or viruses) have recently attracted much attention. Autoantibodies may be defined concisely as antibodies formed by an animal to some constituent of its own body. By 1945, autoantibodies to a number of tissue elements had been reported in human sera: for instance, in syphilis and in rheumatic fever (Davies et al., 1945) (Cavelti, 1945). Burner (Burnet Co" Fenner, 1949) made a great conceptual advance by pointing out that for autoimmunization to occur, the body had to fail to recognize some of its own tissues for what they were, that is, part of itself, and to proceed to make antibodies to them as if they were foreign. That is to say, the mechanism for recognition must exist and must sometimes break down. Since the experimental production in rabbit of autoantibodies to thyroid by Witebsky and Rose in 1956, autoantibodies to, and histological lesions (comparable to those in salivary glands in Sj6gren's syndrome, and probably in the nature of delayed hypersensitivity reactions) have been produced experimentally, in many organs including thyroid and adrenal, testis and kidney. Of equal interest is the fact that autoantibodies have been demonstrated, in humans, to antigens present in all these organs, and others. Autoimmunization is thus a widespread phenomenon. However, it must be said that some of the human autoantibodies are transient and follow common types of tissue damage such as trauma, ischaemia and infection (Waksman, 1962) and that the simple presence of autoantibodies in serum does not in itself lead to progressive autoimmune disease (Doniach & Roitt, 1962). The underlying abnormality or propensity to develop these diseases is probably genetically determined, as evidenced by family studies. In some patients with Sj/Jgren's syndrome the presence of persistent autoantibodies to salivary gland (which are however not organ-specific), to constituents of cell nuclei (antinuclear factors) and to thyroid, the presence of rheumatoid arthritis, and a considerable overlap with systemic lupus erythematosus are grounds for including it ill what has been termed a 'broader spectrum of autoimmune disease' as was suggested by Bunim in 1961. The finding of partial syndromes in relatives of patients with the full syndrome by Bloch and Bunim in 1963 supports this. The associations of the above diseases with the clinical complaint of a swelling of a salivary gland or glands will now be considered. What has been termed Mikulicz's disease, the central finding of which is a swelling of one or more of the salivary and lacrimal glands not primarily due to infection or neoplasm, should I believe, as Morgan and Castleman have urged, be included in Sj~gren's syndrome because of histological and serological overlap. When a gland which is affected by Sj6gren's syndrome has owing to hyperplasia of the duct epithelium become infected, some of the typical histologlca-1 Attrloutes are lost and dlagnosls wllYdepend upon clinical and serological findings together with the histology of the gland itself. The development of an enlargement of a salivary gland in the p~rotid region in association with the histopathological changes of Sj6gren's syndrome has been termed benign lymphoepithelial lesion by Godwin (1952) and Foote and Frazell (1954). It seems likely that some aT least of these patients would be shown by further investigation to suffer from a partial form of Sj6gren's syndrome. The reported predilection of the benign lymphoepithelial lesion for females of
INFLAMMATION IN THE SALIVARY GLANDS
169
middleage or olderand the undoubtedassociationof the fullydevelopedSjbgren's syndromewith this age and sex group, support the suggestion.
Implications of the relationship of salivary glands to lymph nodes. - - T h e close physical relationship of lymphoid tissue to salivary glands is of direct surgical interest. Either of these adjacent tissues may be the seat of surgical enlargement, making the interpretation of physical signs difficult. A parotid lymph node, with a salivary gland lobule partly, and with isolated acini completely, enclosed within it, is illustrated in Figures 5 and 6. In this series of autopsy salivary glands, lymph nodes conversely were a constant finding within the parotid gland. They were not however found in any subject within the submandibular gland capsule--always outside it. T h e constant presence of lymph nodes within the parotid, and their absence within the submandibular, gland is in keeping with the fact that the Warthin's tumour or adenolymphoma for practical purposes only occurs in or adjacent to the parotid7 As tor wlaer and more speculative ideas: Burner and Mackay (z962) noted the close relationship of epithelium to lymphocytes in thymus (from the lymphoid tissue of which all immunologicall~r competent ceUs-in the bodv probably steml,L and m salivary glands in Sj6gren's disease and adenolymphoma. They suggested the possibility that immunologically functioning cells might revert to cells of epithelial type and that the proliferative activity of abnormal epitheloid cells with immunological potentialities takes place much more readily in organs derived from branchial epithelium than from other sites. Lymphocytes and epithelium may, then, have a special mutual relationship in the head and neck and thorax. SUMMARY The great majority of patients with Sj6gren's syndrome suffer fr0m xerostomia and a specific salivary gland abnormality based upon a generalized disturbance of immunological reactivity. T h e aetiology of this is essentially unknown, and no curative treatment is available. Focal lymphocytic adenitis of salivary and lacrimal glands occurs commonly in human autopsy subjects in the absence of evidence of gland infection. By reason of its histological appearances, its tendency to affect most commonly middle-aged or older women, and its apparent association with rheumatoid arthritis it may be a focal form of Sj6gren's syndrome. This has attributes of an autoimmune disease, and partial forms and clinical and laboratory findings which overlap with those of other connective tissue diseases occur. Rheumatoid arthritis and Sj6gren's syndrome each occur more commonly in the relatives of pafienls with each disease than in non-relatives. This fact, together with the clinical finding of partial forms of Sj6gren's syndrome, points to the operation of a genetic predisposition and suggests that the family history of patients in whom the diagnosis is being considered will on occasions provide information of value. Some patients with swelling of salivary glands not due primarily to salivary calculus or neoplasm have, as the pathological basis for their salivary gland disease, ~eplacement of gland parenchyma by infiltrations of lymphocytes and histiocytes and duct obstruction due to duct hyperplasia (Mikulicz's disease). This is best regarded as a variant or partial form of Sj6gren's syndrome. Clinical infection of glands follows duct obstruction.
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AREA SHOWN IN FIG. 6 1 ~
FIG. 5 A lymph node in close relationship on two sides to a lobule of the parotid salivary gland 'within' an infolding of tile node. Haemalum and eosin. × 15.
FIG. 6 A higher power view of a part of Figure 6 shows that isolated gland acini and ducts lie deep within the node substance. Haemalum and eosin. × lO5.
INFLAMMATION
IN THE SALIVARY GLANDS
171
The clinical consequence of the great infrequency with which lymph nodes occur actually within the submandibular salivary gland capsule by contrast with their practically constant presence within the parofid gland, is that the detection of clinical enlargement of parotid lymph nodes will be made difficult by the presence of parotid lymph gland tissue enclosing them, whereas the palpation of the submandibular nodes is not hindered in this way. ACKNOWLEDGEMENTS I should like to thank the Head of my department, Professor A . E. IV. Miles, for his support during this work, and Professor I. Doniach, in whose department the work was carried out. REFERENCES ANDERSON,J. R., GRAY, K. G., BECK, J. S. & KINNEAR,W. F. (1961). Lancet, 2, 456. BASTENIE, P. (1937). Arch. int. mdd. exp. 12, I. BLOCH, K. J. & BUNIM, J. J. (1963). J. chron, dis. I6, 915 . BUNIM, J. J. (I96I). Ann. rheum. Dis. 2o, I. BURGEN, A. S. V. & EMMELIN, N. G. (1961). Physiology of the salivary glands, P. 9. London: Arnold. BURNET, F. M. & FENNER,P. (1949). The production of antibodies, p. 76. Melbourne: Macmillan. BURNET, F. M . ~-~ MACKAY, I. R. (I962). Lancet, 2, lO3O. CAVELTI, P. A. (1945). Proc. Soc. exp. Biol. (N.Y.). 6o, 379. DAVIES, B. D., MOORE, D. H., KABAT, E. A. & HARRIS, A. D. (I945). ft. Immunol. 5 0 , I.
DONIACH, D. & ROITT, I. M. (1962). Ann. Rev. Med. 13, 213. FOOTE, F. W. 6 ' FRAZELL,E. L. (I954). Atlas of tumour pathology. Section IV. Fasc. 1I, p. 146. Washington: Armed Forces Institute of Pathology. GODWIN, J. T. (I952). Cancer, 5, IO89. GOUGEROT, H. (1926). Bull. todd. 40, 360. HEATON, J. M. (1959). Brit. med. ft. I, 466. HEATON, J. M. (1962). Proc. roy. Soc. reed. 55, 479KELLGREN, J. H. (1963). Ann. rheum. Dis. 23, lO9. LUTMAN, F. C. & FAVATA,B. V. (1946). Arch. Ophthal. 35, 227. MIKULICZ, J. (1888). Berl. Kl. W, 25, 759. MIKULICZ, J. (I892). Ueber eine eigenartige symmetrische Erkriinkung der Thrfinen und Mundspeicheldrfisen. (Concerning a remarkable symmetrical disease of the lacrimal and salivary glands.) Beitrfige zur Chirurgie, Festschrift Theodor Billroth, 61o. MORGAN, W. S. (1954)- New Engl. ft. Med. 251 , 5. MORGAN, W. S. ~9' CASTLEMAN,B, (I953). A clinicopathological study of Mikulicz's disease. Amer. ft. Path. 29, 471. SI-IEEHAN,H. L. (1939). Quart. ft. Med. 8, 277. SJOGREN, H. (1933). Acta ophthal. Suppl. 2, I. SJOGREN, H. (I96I). Acta ophthal. 39, 619SLOPER, J. C. (1953). ft. Path. Bact. 66, 53. WAKSMAN, B. (1962). Medicine. (Baltimore). 41, 93. WATERHOUSE,J. P. (1963). Proc. roy. Soc. Med. 56, 911. WATERHOUSE,J. P. fig' DONIACH, I. (1964). To be published. WELLS, H. G. (193o). Arch. Path. IO, 499. WITEBSKY, E. ~ ROSE, N. R. (I956). ft. Immunol. 76, 408. WILLIAMS, E. D. & DONIACH, I. (1962). ft. Path. Bact. 83, 255.