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Diffuse Hyperplasia of Intratarsal Ectopic Lacrimal Gland Tissue
Arch Ophthalmol. 2002;120:1748-1752.
INTRODUCTION
Diffuse bilateral ectopia of lacrimal gland tissue in the tarsal plate has not been recorded previously, to our knowledge. This abnormality was studied in tissue removed from a middle-aged female patient who had bilateral nongranulomatous conjunctivitis and superficial punctate keratopathy. In addition, the patient had microcore myopathy, hypertension, and brittle diabetes mellitus. Clinical investigation revealed surface irregularities in the tarsal plate, and morphologic studies demonstrated large ectopic glands throughout the tarsal plate. Chronic inflammatory cell infiltration was present in the periacinal fibrous tissue, and this progressed to fibrofatty replacement of the glandular tissue. Dilatation of the ductules suggested that blockage of the acinar secretions led to, or was caused by, chronic inflammation in the overlying conjunctival stroma. The symptoms were relieved after excision of both tarsal plates.
Ectopic lacrimal glands on the bulbar conjunctiva within the uveal tract and on the surface of the cornea are a well-recognized source of choristomatous tumors, which are usually identified in early childhood.1 When ectopic lacrimal gland tissue gives rise to tumors in the orbit, the age of the patient may vary between childhood and middle age. Retention of secretions at this site has led to the formation of pseudotumors.2 In this report, we describe a diffuse bilateral hyperplasia of ectopic lacrimal gland tissue within the upper tarsal plates in association with chronic keratoconjunctivitis.
Report of a Case
A 58-year-old woman had poorly controlled diabetes for many years. She was referred by specialists in diabetes to the university eye department because she complained of a reduction in vision and severe photophobia. Twelve months prior to this, she had an allergic blepharitis when she received new spectacles. On examination, she was found to have superficial punctate keratopathy, although tear function was normal. Her visual acuity was 20/120 OD and 20/80 OS, and the intraocular pressure was normal in both eyes. Mild background diabetic retinopathy was noted on funduscopy. Extraocular movements and eyelid function were normal. On eversion, the upper tarsal conjunctiva on each side contained numerous concretions, and deeper in the tarsal plate there were multiple small mounds (Figure 1). The lower tarsus was normal on each side. A biopsy specimen was obtained from the tarsal plate on the left side, and following the initial pathologic analysis, the left tarsal plate was resected. The keratoconjunctivitis settled in the left eye. There was a similar clinical outcome after the right tarsal plate was resected.
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Figure 1. The appearances of the right (A) and left (B) upper tarsal plates. Note the pale nodular areas beneath the yellow concretions.
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The patient had severe insulin-dependent diabetes for 21 years. Since 1995, she had complained of progressive weakness in her limb muscles. When she attended the Tennent Institute (Glasgow, Scotland), she was unable to lift herself from her wheelchair; her shoulder muscles were extremely wasted. A muscle biopsy in 1995 revealed a microcore myopathy (David Doyle, MD, Institute of Neurological Sciences, Glasgow).
The patient is a carrier of cystic fibrosis and she has 1 daughter who is also a carrier and 1 grandson who is asthmatic and requires an inhaler but does not have cystic fibrosis. The daughter and the grandson do not have ocular disease.
The biopsy specimen measured 4 x 2 x 2 mm, and the left and right tarsal plate resections measured approximately 12 x 8 x 5 mm. Each specimen was fixed in 2% buffered glutaraldehyde, and samples were obtained for routine paraffin histologic analysis (hematoxylin-eosin and periodic acid–Schiff stains). For conventional transmission, electron microscopy using toluidine blue for semithin sections was performed. The morphologic features were essentially the same in each of the specimens.
In some areas, the conjunctival epithelium was hyperplastic and goblet cells were plentiful, while elsewhere the epithelium was atrophied or ulcerated. Surface stratification was not present, and the pattern was not that of keratoconjunctivitis sicca. The superficial stroma contained a dense nongranulomatous chronic inflammatory infiltrate and dilated lymphatics. Pseudoglands of Henle were prominent and many were enlarged by concretions. The tarsal plate contained large ectopic lacrimal gland elements, which retained identifiable architecture and almost extended to the surface epithelium (Figure 2). In most heterotopic glands, there was no evidence of a hilum, and the acinar tissue was distorted and infiltrated by fibrous tissue that contained a lymphocytic infiltrate. Fibrofatty tissue surrounded and penetrated some lobules. Dilated ductules were present within the glands and superficial stroma. The acinar cells possessed eosinophilic cytoplasm in some lobules, but in many atrophic lobules the cells were small and the cytoplasmic staining was weaker. In the well-preserved lobules, the acini appeared to be hyperplastic and the normal cuboidal architecture of the epithelial cells was lost (Figure 3). In some areas, the acini were surrounded by fibrous tissue and appeared shrunken and distorted. The presence or absence of secretory granules was easily determined in appropriately stained semithin sections; many acinar cells were devoid of these organelles. The ductules were of normal appearance. In fortuitous section planes it was possible to see a tubuloacinar architecture (Figure 3).
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Figure 2. A, A lobule of lacrimal gland tissue with a disorderly arrangement of the acini is located in the tarsal plate beneath the conjunctival stroma, which contains a nongranulomatous infiltrate. The acinar tissue is atrophic and surrounded by fibrous bands. Fibrofatty tissue surrounds the lobule (hematoxylin-eosin; original magnification x100). B, In some lobules, the acinar cells retain eosinophilic cytoplasm in contrast to those in a lobule that is almost entirely replaced by fibrous tissue. Note the dilated ductules in the lobules (hematoxylin-eosin; original magnification x100).
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Figure 3. A, While some acini possess a cuboidal monolayer, others are filled by cells that are irregularly arranged (hematoxylin-eosin; original magnification x350). B, Dense fibrous tissue distorts the surviving acini (toluidine blue/semithin section; original magnification x200). C, The tubuloacinar pattern in the lobules demonstrates the similarity of the tissue to accessory lacrimal gland tissue. Note the secretory granules in the acinar cells (toluidine blue/semithin section; original magnification x350). D, Cells with vacuolated cytoplasm are within the acini (toluidine blue /semithin section; original magnification x400).
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At the ultrastructural level, the cuboidal acinar cells contained lipid droplets and a variable number of secretory granules located in the apical part of the cell (Figure 4A). The intercellular attachment systems and the basal lamina were identifiable but the apical microvillar surface was flattened. The hyperplastic acini contained cells that were enlarged by swollen mitochondria, accompanied by irregular distribution of the secretory granules and the organelles throughout the cytoplasm (Figure 4B). In the latter acini, the normal intercellular attachments were disorganized, and in parts, the basement membrane was lost. Myoepithelial cells, nonmyelinated nerve fibers, and lymphocytes were in the interstitium. Viral particles and bacterial and fungal elements were not identified.
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Figure 4. A, At the ultrastructural level, many cells maintain normal architecture although isolated cells are distended by degenerate mitochondria and lipid inclusion bodies (original magnification x3200). B, The acinus is filled by disorganized cells with abnormally distributed organelles and distended mitochondria (original magnification x1900).
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Comment
The presence of numerous lacrimal gland elements within the tarsal plates in the specimens analyzed in this case of chronic keratoconjunctivitis was an unex pected finding. The glands were identified beneath the concretions overlying the center of the tarsal plate. This excluded the possibility that the lacrimal gland elements were the normal accessory lacrimal glands of Wolfring, which are located in the upper end of the tarsal plate and are usually small and inconspicuous. In the accessory lacrimal glands located in normal sites, the acini and tubules contain cells that form epithelial monolayers in a tubuloepithelial pattern (unlike the tubuloacinar pattern of the lacrimal gland).3 Thus, the intratarsal glands should be regarded as ectopic accessory lacrimal glands.
In some lobules, periacinal fibrosis was prominent and there was evidence that continuing inflammation had led to fibrofatty replacement of preexisting ectopic lacrimal glands. The presence of chronic inflammation and repair in the ectopic lacrimal tissue in the tarsal plate was similar to that found in the ectopia of lacrimal gland tissue in the orbit, where presumably there was obstruction to outflow secretion.2 In contrast, the lacrimal gland component of a choristoma in the upper eyelid possessed normal histologic characteristics,4 presumably because tear flow was not obstructed. In many of the case reports of intraocular lacrimal gland choristomas,5 the acinar architecture was described as being well preserved and inflammatory infiltration was minimal, although cyst formation was common. In our case, it was possible to demonstrate dilatation of the ducts and retention of secretion in the ductules so that inspissation could be an acceptable explanation for the periacinal inflammatory infiltrate. An alternative possibility is that there could have been an extension from the inflammatory process in the conjunctiva.
At the ultrastructural level, it was of interest to compare the features of ectopic glands with those of normal accessory glands3 and an intraocular lacrimal gland choristoma.6 There was much similarity among the 3 entities but the main differences were the presence of an inflammatory infiltrate in the ectopic tarsal glands and the changes that had occurred in the acinar cells. Within individual acini, there was cytoplasmic rarefaction and vacuole formation in degenerating cells, a feature that is absent from descriptions of accessory glands3 or a choristoma.6 One feature of normal accessory lacrimal glands is an irregular distribution of secretory granules3: this was a common feature in many of the cuboidal and hyperplastic acinar cells in the specimens in our case.
Hyperplasia in the acini of the ectopic lacrimal glands could be explained by the chronic nongranulomatous inflammation in the conjunctival stroma and eyelids, leading to the production of growth factors, eg, fibroblastic growth factor, which has been identified in the normal lacrimal gland after damage to the cornea.7 In transgenic mice that have been engineered to overexpress fibroblastic growth factor 7, ectopic glands will form in the cornea, and ectopic lacrimal buds will form in ocular explants that are exposed to fibroblastic growth factor 10.8-9 It is not unreasonable to suggest that growth factors could have entered the tarsal plate to stimulate proliferation in preexisting ectopic acinar cells in the 12-month period during which there was chronic inflammation in the tarsal conjunctiva.
The fact that the patient is a carrier for cystic fibrosis could be a contributory factor in the patient's keratitis. One study10 has shown that patients with full-blown cystic fibrosis have severe xerophthalmia, although a carrier status is not generally recognized as a risk factor for ocular surface problems. In cystic fibrosis, ocular surface disease may be the consequence of vitamin A deficiency due to malabsorption, or to changes in the production or stability of the tear film. In our case, some sectors of the conjunctival epithelium were hyperplastic with numerous goblet cells; this supports the clinical observation that the patient did not have keratoconjunctivitis sicca.
The association of ocular surface disease with a muscle wasting disease is intriguing but probably irrelevant. Microcore myopathy or multicore myopathy is manifest as central areas within enlarged muscle fiber in which there is negative staining for phosphorylation, adenosine triphosphatase, and glycogen. In these areas, mitochondria are absent and the Z-bands exhibit streaming on electron microscopy.11 A few case reports refer to ocular disease confined to weakness in the extraocular muscles but, as in the present case, the extraocular muscles were probably unaffected in most. There is no evidence in the literature of external eye disease in microcore myopathy, although in one report, a 15-year-old patient with myopathy was described as having features of ectodermal dysplasia, conical teeth, scaly skin, and sparse hair, without evidence of ocular surface disease.12
The most acceptable proposal for the pattern of disease in our case is that the ectopic lacrimal glands were present at birth and were innocuous, but the isolated attack of blepharoconjunctivitis initiated conjunctival stromal inflammation and fibrosis, which led to ductal compression, retention of secretions, and consequent chronic inflammation in the ectopic glands. This started a vicious circle of conjunctivitis and dacryoadenitis that was self-propagating. Resolution of the keratitis after resection of the tarsal plate (by removing inflamed tissue) supports this explanation.
AUTHOR INFORMATION
This report was presented at the combined European Ophthalmic Pathology Society/Verhoeff-Zimmerman Society Meeting, Zurich, Switzerland, June 10, 2001.
William R. Lee, MD;
Dorothy A. Aitken;
Colin M. Kirkness, FRCS
Glasgow, Scotland
Corresponding author: William R. Lee, MD, Tennent Institute of Ophthalmology, Gartnavel General Hospital, 1053 Great Western Rd, Glasgow G12 OYN Scotland (e-mail: wrl1v{at}clinmed.gla.ac.uk).
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