Brit. ]. Ophthal. (1973) 57, 852
`
`Histology of the lacrimal gland in
`keratoconjunctivitis sicca
`
`JOHN WILLIAMSON*, A. A. M. GIBSON**, T. WILSONT,
`J. V. FORRESTER*, K. WHALEY_’;, AND W. C. DICKI
`
`From the *Eye Department, Southern General Hospital, The **Department of Pathology, Tor/chill
`Hospital, The 'l'Tennent Institute of Ophthalmology, University Department of Ophthalmology,
`Western Infirmary, and The ,’_r_Centre for Rheumatic Diseases, University Department of Medicine,
`Royal Infirmary, Glasgow
`
`The histology of Sjogren’s syndrome, which is defined as keratoconjunctivitis sicca (KCS)
`with xerostomia and rheumatoid arthritis, for the purpose of this communication, has
`been studied post mortem either in single cases or in series of not more than three patients
`(Sjogren, I933; Holm, 1949; Allington, 1950; Bohm, 1950; Ellman, Weber, and Goodier,
`1951; Morgan and Raven, 1952; Cardell and Gurling, 1954; Szanto, Farkas, and Gyulai
`I957; Funatsu and Eguchi, I957; Bucher and Reid, 1959; Bain, 1960; Bloch, Buchanan,
`Mlohl, and Bunim, 1965).
`The lacrimal and salivary glands, and the mucous glands of the respiratory tract,
`mouth, and upper oesophagus are typically involved. However, most of the observa-
`tions on lacrimal gland structure were recorded in severe cases of KCS and in patients
`who had died as a result of the severe complications of arthritis or another connective
`tissue disease. The primary purpose of this study was to investigate the histology of the
`lacrimal gland in patients currently suffering from KCS.
`Patients with KCS and xerostomia, but no evidence of connective tissue disease, may
`be classified as suffering from the “sicca syndrome” (Bloch and others, 1965). Lacrimal
`gland tissue from such patients was studied to determine any features that may diHeren-
`tiate the “sicca syndrome” from Sjogren’s syndrome.
`Furthermore, reduced Schirmer II tear tests may be demonstrated in a number of
`rheumatoid arthritic patients who have no evidence of punctatc or filamentary keratitis.
`For study purposes, these patients may be regarded as cases of “possible” Sjé')gren’s syn-
`drome. Lacrimal gland biopsies were obtained from a sample of patients with “possible”
`Sj<'3'gren’s syndrome in an attempt to elucidate the validity of this classification.
`According to Manschot (1961), systemic corticosteroids or adrenocorticotrophic hormone
`therapy may be efleetive in controlling acute exacerbations of Sj6gren’s syndrome and,
`therefore, may be expected to modify the histological appearances of the lacrimal gland.
`Thus particular note was taken of any history of systemic steroid therapy.
`
`Materials and methods
`
`PATIENTS STUDIED
`
`Biopsies of the lacrimal gland were obtained from 29 female patients (eighteen Sj6gren’s syndrome,
`five sicca syndrome, and six “possible” Sjogren’s syndrome).
`In addition, the lacrimal glands of
`
`Received for publication December 23. [972
`Address for reprints: J. Williamson, F.R.C.S., Eye Department, Southern General Hospital. Govan Road, Glasgow
`
`1
`
`ALL 2020
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
`
`

`

`Keratoconjunctivitis sicca
`
`353
`
`ten age-matched patients, who had died from a variety of medical disorders not known to be related
`to rheumatoid arthritis or connective tissue disease and who had no history of ocular disease, were
`
`examined post mortem (Table I).
`
`Table I Ages ofpatients and controls and histology of lacrimal gland
`
`Clmical diagnosis
`
`Age (yrs)
`
`Histology (Stage)
`
`Number of patients mm mm
`Mean
`Range
`0
`I
`II
`III
`
`Sj6gren’s syndrome*
`Sicca syndrome'l‘**
`Possible Sj6gren’s syndrome
`
`18
`5
`6
`
`61 -4.
`61 -0
`60-2
`
`52-80
`55-81
`55—75
`
`8
`I — 9
`1
`— 2
`2
`6 — — —
`
`I 0
`
`64-0
`
`Controls
`Breast cancer (2)
`Coronary thrombosis (3)
`Cerebrovascular disease (5)
`
`
`32-76
`
`I 0 — ~ —
`
`* Two also had systemic lupus erythematosus
`‘I’ One had biliary cirrhosis
`** Three also had osteoarthritis
`
`The diagnosis of rheumatoid arthritis was based on the criteria of the American Rheumatism
`Association (Ropes, Bennett, Cobb, jacox, and Jessar, 1959).
`
`LACRIMAL GLAND BIOPSY TECHNIQUE
`
`Since removal of part of the palpebral portion of the lacrimal gland entails destruction of the excre-
`tory ducts, the orbital section was chosen for biopsy. Each patient understood the reason for the
`operation and that it was carried out on a voluntary basis. After infiltration with local anaesthesia,
`2 per cent. lignocaine without adrenaline, the skin was incised for a distance of I - 5 cm. from the lateral
`orbital tubercle towards the medical canthus, 0-5 cm. below and parallel to the superior orbital
`margin. Underlying fascia and muscle were separated by blunt dissection until the smoky-blue
`periorbital membrane was identified where it is closely attached to the rim of the orbit.
`Incision of
`the periorbital membrane resulted in protrusion of periorbital fat which was easily replaced with a
`probe. Toothed forceps were inserted into the superior lateral angle of the orbital roof and a piece
`of lacrimal gland tissue, no greater than I cu. mm., was abscised. The specimen was transported in
`formal saline. The skin wound was closed with three interrupted black silk sutures, no haemostatic
`
`or subcuticular stitches being necessary. Eyelid appearances returned to normal within 14 days
`and no complications were encountered. Histology was studied on paraffin sections 6 it thick
`stained by haematoxylin and eosin. Considerable care was taken to give the pathologist no infor-
`mation regarding the source of the lacrimal tissue.
`
`Results
`
`Table I shows the range of disorders from which the patients were suflering. Two of the
`24. rheumatoid arthritic patients also had systemic lupus erythematosus and three of the
`five “sicca syndrome” group also had osteoarthritis. There was no significant difference
`in the mean age and age range of the groups studied.
`
`Four distinct histological stages were recognized in this study (Table I):
`
`2
`
`

`

`854
`
`]o}zn Williamson, A. A. M. Gibson, T. Wilson, V. Forrester, K‘. Whale}, and W. C. Dick
`
`Stage 0 Normal lacrimal gland
`
`The lacrimal gland consists of tubulo-racemose tissue with short branched tubules and masses of
`lobules interspersed with fat (Fig. 1). Plasma cells are a normal feature of the interacinous and
`interlobular connective tissue; lymphocytes are less frequently detected.
`
`Stage 0.
`I
`FIG.
`Normal tissue.
`X 5
`
`Stage I
`
`.Mila' chronic inflammation
`
`The salient features in these cases are abnormal arrangement of the ducts, mild lymphocytic infil-
`tration, and slight intralobular fibrosis (Fig. 2).
`
`Stage I.
`FIG. 2
`Mild chronic in-
`
`flammation, showing
`abnormal duct
`
`arrangement.
`
`X 5
`
`3
`
`

`

`Keratoeonjunctivitis sicca
`
`855
`
`Stage II
`
`Severe chronic inflammation
`
`Total destruction of the normal lobular pattern, dense infiltration with lymphocytes, aggregating
`into lymph follicles and progressive acinar atrophy (Fig. 3) are the features of this grade.
`
`V
`
`n"'“:§.¢1¥*«:a'H...‘ 'u'»'.
`eff’ ‘fr ' or
`.
`.‘ 3*‘
`'
`W =.-:31"
`"
`'
`y
`3’
`
`4‘
`
`g:&,.’,.§.é',¢g
`
`Stage III Late fibrosis
`
`Fibrous tissue is increased. Few acinar cells remain (Fig. 4).
`
`Stage II.
`FIG. 3
`Severe chronic in-
`
`flammation.
`
`X 5
`
`Stage III.
`FIG. 4.
`Late fibrosix.
`X 5
`
`All of the ten post mortem control specimens and the six biopsies from patients suflering
`from “possible” Sj6gren’s syndrome showed normal lacrimal glands. Only one patient
`suffering from definite KCS had a normal tissue biopsy.
`Elk
`
`4
`
`

`

`856
`
`John Williamson, A. A. M. Gibson, T. I/Vilson, V. Forrester, K. IV/zaley, and I1’. C. Dick
`
`This patient was a 50-year-old woman with a 2-year history ofseropositive rheumatoid arthritis,
`xerostomia, and dry eyes. Her white blood count, serum globulin, and liver function tests were
`normal, the erythrocyte sedimentation rate being slightly raised to 25 mm. in the first hour. Tests
`for antinuclear factor and salivary duct antibody were negative and x-ray and functional grades were
`zero. All the evidence therefore indicated that the patient had mild chronic rheumatoid arthritis
`and KCS when the biopsy was taken.
`The remaining seventeen Sj(">gren’s syndrome and five sicca syndrome patients all
`showed abnormal lacrimal gland tissue (Table 1).
`Mild chronic inflammation (Stage I) was detected in one of the sicca syndrome patients
`who was also suffering from primary biliary cirrhosis.
`
`This was a 67-year-old wonnan with a 6-year history of liver disease without arthropathy and a
`6 months’ history of dry eyes. Salivary duct autoantibodies were present but there was no clinical,
`serological, or x-ray evidence of rheumatoid arthritis.
`
`The only other patient with mild chronic inflammation (Stage I) was a 75-year-old woman with
`a 6-year history of dry eyes and a dry mouth (sicca syndrome).
`
`Eleven patients, nine with Sjogren’s syndrome and two with the sicca syndrome, had
`severe chronic inflammatory changes (Stage II) and the late results of inflammation
`(Stage III) were recorded in the remaining nine patients, eight with Sjogren’s syndrome
`and one with sicca syndrome (Table II). No histological features distinguished the lacri-
`mal glands of patients with Sjo‘gren’s syndrome from those with the sicca syndrome.
`
`Table II Severity of lacrimal gland destruction
`related to duration of keratoconjunctivitix sicca
`
`N fl) t.
`t
`Duration of KCS
`Histology (Stages)
`a. o
`a zen s -
`9")
`0
`I
`11
`111
`
`4.
`4
`3
`4
`8
`
`0—I
`1-3
`3-5
`5-7
`7+
`
`Total 23
`
`3 —
`— 1
`I — 3 —
`— ~ — 3
`— I
`3 —
`— — 2
`6
`
`I
`
`2
`
`II
`
`9
`
`Severity of lacrimal gland destruction tended to be greater with increased duration of
`ocular disease (Table II). Thus none of the eight patients who had suffered from KCS
`for less than 3 years had Stage III changes. On the other hand, three patients with a
`3- to 5-year history showed only mild or severe chronic infiltration (Stages I and II).
`The groups are too small to compare with respect to severity of arthritis.
`Five of the patients with Sjogren’s syndrome had received steroid therapy for periods
`varying from 2 to 10 years in an average daily dose of 5 mg. prednisolone or its equivalent
`per day. Stage III (late) changes were described in four and Stage II (severe chronic) in one
`case. Steroid therapy had not prevented involvement of the lacrimal glands in these patients.
`All five patients had suffered from Sjogren’s syndrome for more than 5 years and had
`received systemic steroids during that
`time. Nevertheless, no difference in histology
`could be determined between these patients and the remaining group who had never
`received systemic steroids and who had also suffered from KCS for more than 5 years.
`
`5
`
`

`

`Keraloconjunctivitis sicca
`
`857
`
`Discussion
`
`Biopsy of the orbital portion of the lacrimal gland in patients suffering from KCS has not
`previously been recorded in a large series of patients. From our perusal of the literature,
`it appears that the lacrimal glands of no more than three patients have been examined
`post mortem in any one group, and in most instances only a single case has been reported.
`For these reasons, a series of 29 female patients depicting a range of involvement with
`KCS was selected for lacrimal gland biopsy. The specimens were classified into four stages:
`normal, mild chronic inflammation, severe chronic inflammation, and a late fibrotic
`phase.
`In general,
`the severity of destruction parallelled the duration of the ocular
`disease.
`
`Sjogren (1933), in discussing a patient who had suffered from KCS for 2 years, described
`chronic round cell infiltration around the excretory ducts and to a lesser extent in the inter-
`lobular and interacinous connective tissue. Secondary changes consisted of sclerosed
`connective tissue and degeneration in the epithelial cells near the infiltrated areas. Holm
`(1949), Ellman and others (1951), and Haas (1951) reported their findings in patients
`who had suffered from Sjogren’s syndrome for 6, 5, and 4 years respectively. Their des-
`criptions include destruction of the normal lobular pattern, infiltration with lymphocytes,
`and increase in fibrous tissue. Without examination of the sections, it is difficult to apply
`our classification to those specimens. However, the severity of lacrimal gland involvement
`in relation to the duration of the disease suggests that their findings are compatible with our
`Stages II and III.
`
`Furthermore, the investigation of two groups of three pateints was reported by Cardell
`and Gurling (1954) and Bloch and others (1965).
`The first authors described two female patients who had suffered from Sjogren’s syndrome for 4 and
`5 years respectively. Both had severe filamentary KCS and one also had polyarteritis nodosa.
`Both of those patients are relevant to this report in that they had been treated with ACTH and/or
`cortisone preparations. Nevertheless, the lacrimal glands contained areas densely infiltrated with
`chronic round cells, with some lymph follicle formation.
`Severe degeneration and atrophy of the
`parenchyma were widespread, as was replacement with fibro-adipose tissue. The specimens from
`these two patients could be classified as Stages II and III and, as in our series, the severity of the
`pathological changes seemed to have been unaffected by steroid therapy. Their third case was a
`
`man aged 73 years who had had KCS for 4 years without evidence of rheumatoid arthritis (sicca
`syndrome). Nevertheless, he had severe lacrimal gland destruction, obliterative endarteritis, and
`replacement of the normal glandular structure with fibro-adipose tissue. These findings substantiate
`our view that lacrimal gland changes are probably identical in both Sj6gren’s syndrome and KCS
`without evidence of connective tissue diseases.
`
`In our series the lacrimal glands of four patients with sicca syndrome were examined and
`no features were found to differentiate them from patients with Sj'o'gren’s syndrome.
`In the second group of three patients, Bloch and others (1965) described the pathology in the parotid
`gland of a 66-year-old woman who had suffered from Sj6gren’s syndrome for 11 years, and stated
`that the lacrimal gland changes were similar.
`They identified infiltration with small mononuclear cells and lymphocytes and noted that remnants
`of acinar components were sparse, located at the periphery of the lobules.
`Some of the ducts were
`distended with secretion, but the normal architecture of the lobules was preserved.
`It is interesting
`that they, like Cardell and Gurling, were able to identify occasional plasma cells.
`
`In our series plasma cells were not identified once lymphocytic infiltration had begun.
`
`The second case of Block and others (1965), a 49-year-old woman with progressive systemic
`sclerosis, had suffered from Sjogren’s syndrome for 14 years. The acinar atrophy was marked, and
`
`6
`
`

`

`858
`
`]ohn Williamson, A. A. M. Gibson, T. Wilson, ]. V. Forrester, K. Whaley, and W. C. Dick
`
`there was only slight lymphocytic infiltration. Replacement with fibro-adipose tissue was extensive.
`This description clearly falls into Stage III of the present series. Their third case was that of a
`68-year-old woman who had suffered from Sjogren’s syndrome for I year. The gland examined
`showed atrophy of acinar tissue and chronic inflammatory cell infiltration. Without more details,
`it is diflicult to identify the stage of involvement in this particular case.
`
`In our series, neither the ten age-matched patients examined post mortem, nor the six
`patients with “possible” Sjogren’s syndrome had abnormal lacrimal gland tissue. This
`would suggest that the definition of Sj6gren’s syndrome as a chronic inflammatory disease
`is valid, and it would appear from our biopsy findings that KCS without evidence of
`connective tissue disease is also a chronic inflammatory disorder. However, Radnot
`(1939) recorded over 30 years ago that patients over the age of 50 years undergo pro-
`gressive atrophy of the lacrimal glands and that infiltration with lymphocytes is a normal
`occurrence in this and older age groups. The mean age of the control group in this series
`was 64 years, yet no abnormalities of the lacrimal glands were detected.
`It would appear
`reasonable to suggest that more extensive examinations of “normal” lacrimal gland tissue,
`especially in older age groups, should be undertaken.
`
`Summary
`
`Histology of the lacrimal gland was studied in a series of 29 female patients, eighteen of
`whom had Sjogren’s syndrome, five the sicca syndrome, and six “possible” Sjogren’s
`syndrome. Furthermore, the lacrimal glands of ten patients with no history of ocular or
`connective tissue disease were examined post mortem.
`The appearances were classified into normal, mild chronic inflammation, severe chronic
`inflammation, and late fibrosis (Stages 0, I, II, and III). Both the controls and the
`“possible” cases of SJ'ogren’s syndrome had normal lacrimal glands. Those with Sjogren’s
`syndrome and the “sicca syndrome” showed abnormal
`lacrimal gland histology,
`the
`extent of which was related to the duration of the keratoconjunctivitis sicca. No specific
`features distinguished the lacrimal glands of Sj6gren’s syndrome from those of the sicca
`syndrome.
`In addition, long-term systemic steroid therapy did not seem to have reduced
`the extent of lacrimal gland pathology in the series examined.
`
`References
`
`ALLINGTON, H. v. (1950) Arch. Derm. Sy/2h., 62, 829
`BAIN, G. 0. (1960) Canad. mea'. Ass. j'., 82, 143
`
`BLOCH, K. J., BUCHANAN, w. w., WOHL, M. J., and BUNIM, J. J. (1965) Medicine (Baltimore), 44, 187
`BOHM, A. (1950) Miinch. med. Wschr., 92, 955
`BUCHER, U. G., and REID, L. (1959) Brit. ]. Dis. Chest, 53, 237
`CARDELL, B. s., and GURLING, K. J. (1954)
`j‘. Path. Bact., 68, 137
`ELLMAN, 12., WEBER, F. P., and GOODIER, T. E. w. (1951) Quart. ]. Med., 20, 33
`WUNATSU, H., and EGUCHI, F. J. (1957)
`clin. 0phthal., II (English Summary), 133
`HAAS, E. (1951)
`Virehows Arch. path. Anat., 320, 264
`HOLM, s. (1949) Acta ophlhal. (Kbh.), Suppl. 33, p. I
`MANSCHOT, w. A. (1961) Adv. 0phthal., n, I [Bibliotheca ophthalmologica Fasc. 58]
`MORGAN, A. D., and RAVEN, R. w. (1952) Brit. ]. Surg., 40, I54.
`RADNoT, M.
`(1939)
`“Die pathologische Histologie der Tranerdriise”, p. 64. Karger, Basel.
`Quoted by Holm (194.9)
`
`ROPES, M. w., BENNETT, G. A., coma, s., JAcox, R., and _]ESSAR, R. A. (1959) Ann. rheum. Dis., :8, 49
`sJ6GREN, H. (1933) Acta ophthal. (I{bh.), Suppl. 2.
`(Trans. J. B. Hamilton, 1943)
`SZANTO, L., FARKAS, K., and GYULAI, E. (1957) Rheumatism, I3, 60
`
`7
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`