Original Investigation
Clinicopathological Features of Inflammatory Lesions of the Lateral Canthal Subconjunctival Area Min Joung Lee, M.D.*¶, Ji Eun Kim, M.D.†, Namju Kim, M.D.*‡, Ho-Kyung Choung, M.D.*§, and Sang In Khwarg, M.D.*║ * Department of Ophthalmology, Seoul National University College of Medicine; †Department of Pathology, Seoul National University Boramae Hospital, Seoul; ‡Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam; §Department of Ophthalmology, Seoul National University Boramae Hospital; ║Department of Ophthalmology, Seoul National University Hospital, Seoul; and ¶ Department of Ophthalmology, Hallym University Sacred Heart Hospital, Anyang, Korea
Purpose: To investigate the clinical and histopathological features of inflammatory lesions of the lateral canthal subconjunctival area. Methods: This is a retrospective case series of 12 patients with inflammatory subconjunctival masses in the lateral canthal area. All patients included in this study were treated at Seoul National University Hospital or Seoul National University Bundang Hospital between 2006 and 2012. Clinical data were obtained from the medical records. Histopathologic findings were thoroughly reviewed. Results: There was a woman predominance in the study group (10:2), and the median age at presentation was 39 years (range 33–70). Common symptoms included conjunctival injection, sticky discharge, and pain or discomfort. Histopathologically, all lesions originated from ductules of the lacrimal gland. Two cases showed cysts containing clear fluid with mild inflammation. One case showed lacrimal ductulitis without cyst formation. Nine cases showed lacrimal ductal cysts with varying periductal inflammation, and the contents were pinkish, amorphous materials in 7 cases. Embedded cilia were found in 8 cases. Conclusions: Inflammatory lesions of the lateral canthal subconjunctival area all originated from lacrimal gland ductules, showing a variable histopathologic spectrum of inflammation and cyst formation. Cilia impaction was a very frequently observed finding. (Ophthal Plast Reconstr Surg 2014;30:251–256)
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hronic, unilateral conjunctivitis often presents a difficult diagnostic dilemma, although it has many well-known causes, such as nasolacrimal duct obstruction, canaliculitis, floppy eyelid syndrome, and giant fornix syndrome.1–4 Sebaceous gland carcinoma, squamous cell carcinoma, or malignant lymphoma of the ocular adnexa may present with inflammatory signs and also can masquerade as conjunctivitis.5,6 When conjunctivitis is limited to the temporal area, inflammatory lesions originating from lacrimal gland ductules should be included in the differential diagnosis. Accepted for publication November 12, 2013. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Sang In Khwarg, M.D., Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110–744, Korea. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000087
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Lacrimal ductulitis is an uncommon disease and has not yet been well established. Lacrimal ductulitis has been rarely investigated, and a PubMed literature search by using the term “lacrimal ductulitis” revealed only 2 articles published in English.7,8 A pouting lacrimal ductule with viscous discharge is a typical sign. Lacrimal ductule stones (dacryoliths) can be simultaneously present and have been reported without definition of the originating disease.9–11 This condition has also been reported as a kind of infectious dacryoadenitis.12 The cause of lacrimal ductulitis is unclear; however, cilia have been reported as a nidus for dacryoliths in a few case reports.9,11,13 Recently, an association between lacrimal ductulitis and Actinomyces infection was proposed by some researchers.7 A lacrimal ductal cyst is a retention cyst of the lacrimal gland ductules and is most commonly located in the palpebral lobe.14 It is an uncommon condition, but an article from Denmark reported that it accounted for about 10% of pathologically verified lacrimal gland lesions.15 Insidious, painless swelling of the superotemporal conjunctival fornix is a classic presentation, and a bluish, well-transilluminated mass with a smooth surface is a characteristic ophthalmologic finding. However, inflammatory signs such as tenderness, irritation, or pain can accompany the lesion.16 When encountering a patient with an inflamed lesion of the lateral canthal subconjunctival area, the diagnosis might be confusing, and there has been no established, systematic analysis to date. In this study, the authors reported a series of patients with inflammatory lesions of the lateral canthal subconjunctival area and investigated the clinical and histopathological features.
PATIENTS AND METHODS Patients who underwent surgical excision of an inflammatory lesion from the lateral canthal subconjunctival area at Seoul National University Hospital or Seoul National University Bundang Hospital between 2006 and 2012 were included in this study. Clinical data, pathologic reports, and original slides were collected and reviewed to confirm the diagnosis. The main inclusion criteria were presentation with a lateral canthal area subconjunctival mass with inflammatory signs and the availability of a pathologic specimen. The necessary institutional review board approval was obtained for the study. The demographic data, symptom duration, presenting signs, treatment, and outcome were reviewed. Clinical photographs at presentation were also reviewed, and visible dacryoliths or cilia were checked with special attention. All histopathologic examinations were performed by an experienced pathologist (J.E.K.). The following features were assessed and documented: 1) presence of a cyst; 2) pathologic study of the cystic wall, such as specification of the epithelium and presence of
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TABLE 1. Demographics, clinical presentation, and treatment of 12 patients with inflammatory lesions in the lateral canthal subconjunctival area Case no.
Age (y) Gender
Duration of symptoms (mo)
Presenting symptoms
1 2 3
33 70 41
F F M
Red eye, upper eyelid swelling Eyelid mass on upper lateral area Discharge, red eye
24 2 2
4 5 6 7 8 9
49 53 37 20 39 36
M F F F F F
Pain, discomfort, upper eyelid swelling Pain, red eye, cilia production in mass Discharge, discomfort Pain, discharge Red eye, lateral canthal mass Discharge, red eye
0.5 36 4 22 0.5 36
10 11 12
40 37 35
F F F
Pain, upper eyelid swelling, discharge Red eye, lateral canthal mass Red eye, swelling
120 42 1
fibrosis or calcification; 3) the nature of the cystic contents; 4) the degree of inflammation and presence of a granulomatous reaction; 5) evidence of bacterial infection; and 6) evidence of cilia impaction. Hematoxylin and eosin-stained slides were reviewed, and periodic acid-Schiff (PAS) staining was added to observe the presence of Actinomyces colonies.
RESULTS The authors originally identified 34 cases involving surgical removal of a lateral canthal area subconjunctival mass through a search of electronic medical records. Among them, 12 cases presenting a lacrimal ductal cyst without inflammatory signs, 3 cases with simple conjunctival inclusion cysts without inflammatory signs, and 7 cases without available pathologic specimens were excluded. Thus, 12 cases were finally enrolled in this study. The demographics and clinical features of all patients are summarized in Table 1. Age at diagnosis ranged between 33 and 70 years (mean, 41.4 years; median 39 years), and there was a woman predominance (10 cases). All patients demonstrated unilateral lesions. The symptom duration varied between 2 weeks and 10 years (mean, 26.5 months; median 22 months), and 8 of the 12 patients underwent incision and drainage prior to referral, but symptoms recurred. No patient had a history of trauma or inflammatory diseases of the conjunctiva. All patients had conjunctival injection, 6 patients
Ocular examination Subconjunctival cystic mass with injection Subconjunctival cystic mass with injection Pouting mass with injection and mucous discharge Subconjunctival mass with yellowish precipitate, conjunctival injection, and chemosis Pouting mass with mucous discharge and visible cilia impaction Subconjunctival mass with yellowish dacryolith and cilia Small subconjunctival mass with viscous discharge on surface Pouting mass with severe injection Flat, yellowish subconjunctival mass with stringy discharge Large subconjunctival mass with yellowish precipitate, conjunctival injection, chemosis, mucous discharge Subconjunctival mass with yellowish dacryolith Subconjunctival cyst with yellowish precipitate
showed sticky discharge, and 5 patients reported pain or discomfort. A dacryolith or yellowish precipitate was visible in 5 patients. Cilia impaction was grossly visible in the lesions in 2 patients (Case 5, Case 6) (Fig. 1), and 1 patient (Case 5) complained that cilia had regrown repeatedly, even after removal. Eleven of 12 patients underwent surgical excision of the mass, and 1 patient underwent marsupialization and removal of the contents (Case 11). Follow-up periods after treatment ranged from 1 to 4 months (mean 2.00 ± 0.85 months). Resolution of symptoms and signs were noted in all patients at 1 month after surgery. The main histopathological features are summarized in Table 2. Microscopically, the lesions accompanied lacrimal gland tissues and lacrimal gland ductules in all cases. Based on the contents of the masses and degree of inflammation, all cases can be classified into 3 categories: 1) a cyst containing clear fluid with a mild inflammatory reaction (Case 1 and Case 2); 2) a dilated lacrimal gland ductule with a severe inflammatory reaction only (Case 3); and 3) cysts with varying degrees of inflammation, including 7 cases with pinkish, amorphous material, and 2 cases showing a moderate-to-severe periductal inflammatory reaction, although most contents were lost during the surgery (Case 4–Case 12). No case showed significant granulomatous changes. The inflammatory cells mainly included lymphoplasma cells, but Case 10, which had the longest symptom duration, showed focal eosinophil infiltration. Representative cases are described below. Case 1. A 33-year-old woman presented with a 2-year history of eye redness and eyelid swelling on the left side. She underwent multiple topical treatments and incision and drainage of a mass before referral. On examination, there was an oval subconjunctival mass with injection in the lateral canthal area. The mass was well transilluminated, and there was no visible discharge, precipitate, or dacryolith in the mass (Fig. 2A). Histologic examination after surgical excision of the mass revealed a cyst with clear fluid contents, and the cyst lining comprised a double layer of cuboidal epithelial cells with focal flattening (Fig. 2BC). There was mild inflammatory cell infiltration around the ductules and adjacent lacrimal gland (Fig. 2D).
FIG. 1. A case of inflammatory masses of a lacrimal gland ductule containing cilia. Cilia impaction in the masses was grossly observed (Case 5).
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Case 3. A 41-year-old man was referred with conjunctival swelling and discharge in the left canthal area for 2 months. He was managed by incision and drainage of a mass 2 weeks before referral; however, still there was a pouting, inflamed, subconjunctival mass with viscous discharge on the surface (Fig. 3A). On microscopic examination after surgical excision of the mass, a few lacrimal ductules showed luminal dilatation and squamous metaplasia of the ductular epithelium. Dense lymphocytic infiltration with focal stromal fibrosis was also seen (Fig. 3B).
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
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TABLE 2. Summary of histopathologic findings of 12 cases with inflammatory lesions of the lateral canthal subconjunctival area Case no.
Contents of cyst
1 2 3
Clear fluid Clear fluid No cyst formation
4 5
Mostly lost during operation Pinkish amorphous material
6 7
Pinkish amorphous material Pinkish amorphous material
8 9 10
Pinkish amorphous material Mostly lost during operation Pinkish amorphous material
11 12
Pinkish amorphous material Pinkish amorphous material
Epithelium Double layer with focal flattening Double layer with focal flattening Double layer with squamous metaplasia Denuded Double layer with squamous metaplasia Double layer Double layer with squamous metaplasia Double layer Double layer with squamous metaplasia Double layer with squamous metaplasia N/A Double layer
Periductular fibrosis
Periductular Presence of Calcification inflammation microorganism No. cilia
Mild N Moderate
N N N
Mild Minimal Severe
N N N
Absent Absent Absent
Moderate
Y
Moderate
N
1
N
Y
Moderate
N N
N Y
Mild N
N N
Mild
N
N/A N
N/A N
Bacterial colony Multiple present Mild N 1 Mild Bacterial colony 1 present Moderate N Multiple Moderate to N Absent severe Moderate to N 1 severe Moderate N* Multiple Moderate N 1
Y = yes; N = no; N/A = not accessible. *This case showed suspicious agglomeration of secretion on hematoxylin and eosin staining. However, following PAS staining failed to show Actinomyces species.
FIG. 2. A case showing a lacrimal ductal cyst with minimal inflammation (Case 1). A, A cystic mass with conjunctival injection is present in the lateral canthal area. B, Microscopic examination shows a unilocular cyst (×10). C, The cyst was lined with double cuboidal epithelial cells (×40). D, There is a mild inflammatory reaction in an adjacent lacrimal gland (×100). Case 10. A 40-year-old woman presented with a 10-year history of intermittent periocular pain and swelling over the lateral area of the left upper eyelid. She had a recent history of pain and swelling over the previous 2
weeks. A large lateral canthal subconjunctival mass with injection, chemosis, and purulent discharge was seen. After 2 weeks of systemic and topical antibiotic treatment, the mass slightly decreased, and the accom-
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FIG. 3. A case of lacrimal ductulitis without cyst formation (Case 3). A, Note the swollen, inflamed orifice of the lacrimal gland ductule with whitish discharge. B, The excised mass shows a dilated lacrimal ductule with double-layered cuboidal epithelial cells and marked infiltration of lymphoplasma cells (×100).
FIG. 4. A case of a lacrimal ductal cyst with chronic and severe inflammation (Case 10). A, The cystic mass contains yellowish debris, and accompanying inflammatory signs were much resolved by systemic and topical antibiotic treatment for 2 weeks. B, Microscopic examination showed the serpiginous cavity of the cyst and adjacent lacrimal gland (×40). C, Abundant lymphoplasma cells and focal eosinophils infiltrated the cyst wall (×200). D, Focal pseudoepitheliomatous hyperplasia is also seen (×100). panying inflammatory signs were greatly resolved, and there were visible, yellowish precipitates in the mass (Fig. 4A). Histopathological examination after surgical excision of the mass showed a large cyst lined with a double layer of epithelium with a focal, multilaminar appearance and squamous metaplasia, and the content was a pinkish, amorphous mate-
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rial. Moderate-to-severe inflammatory cell infiltration was noted around the cyst (Fig. 4B–D). One case (Case 11) showed suspicious agglomeration of secretions on histopathological examination. However, Actinomyces was not shown in subsequent PAS staining. Eight cases showed cilia in the
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FIG. 5. Multiple cilia in cystic contents. A, The cyst consists of double-layer epithelium and pinkish, amorphous material containing multiple short cilia (black arrows) (Case 8, ×50). B, The cystic mass content at a higher magnification demonstrates several long cilia (Case 11, ×100). mass contents (Fig. 5), and there were multiple cilia in 3 cases (Case 5, Case 8, and Case 11).
DISCUSSION In this study, the authors described the clinicopathologic characteristics of 12 cases of inflammatory masses of the lateral canthal subconjunctival area. All cases involved lacrimal ductular lesions showing varying histologic findings, such as a cyst of a large duct or lacrimal ductulitis with or without microscopic cysts. Inflammation was consistently found to varying degrees. The mass lining comprised a double layer of epithelium with fragmentary flattening. In some cases, multilaminar lining epithelium was partly observed, according to the section direction.17 Squamous metaplasia of the lining epithelia was a frequent finding, and fibrosis or calcification of the cystic wall, all of which suggest reactive changes resulting from chronic inflammation.18 Pseudoepitheliomatous hyperplasia, a benign condition characterized by hyperplasia of the epithelium and elongated, thick, downward projections with jagged borders, was observed in 1 case (Case 10). To the best knowledge, this is the first study describing pseudoepitheliomatous hyperplasia in a lacrimal ductal cyst or ductulitis. Pseudoepitheliomatous hyperplasia may be encountered in heterogeneous conditions, such as infection, neoplasia, and chronic inflammation or irritation; it has not been reported in a lacrimal ductal cyst or lacrimal ductulitis thus far.19 Apocrine metaplasia was suspected by the budding appearance of the secretions from the cells (Case 6). It is not well-recognized histologic finding in lacrimal gland ductal cyst, and there was only 1 case series that reported 6 cases of lacrimal gland ductal cysts, showing apocrine differentiation.20 However, Jakobiec et al.17 denied the presence of apocrine metaplasia in lacrimal ductal cysts based on the immunohistochemical results of GCDFP-15. In this study, they did not perform immunohistochemical staining, and further experiments will be needed to clarify this point. A noticeable finding was the presence of characteristic, pinkish, amorphous mass contents. Seven cases showed such contents, and among them, 2 cases presented corresponding visible dacryoliths. The composition of dacryoliths from lacrimal glands has been analyzed in a few studies.9–11 Previous studies reported the composition of dacryoliths as amorphous debris with or without polymorphonuclear cells adherent to the external surface, albumin, and carbonates/phosphates arranged
in concentric lamellae in a matrix of organic material with epithelial cells. An analysis by using Raman spectroscopy demonstrated that dacryoliths consisted of protein.10 Previously, some studies proposed that cilia may be agents initiating or contributing to dacryolith formation and ductular blockage.9,10,13,19 In this study, cilia were found in 8 (66.7%) cases. Moreover, 3 cases showed multiple cilia in a mass, and 1 patient reported repeated cilia production in the mass. Therefore, they were suspicious of the cilia-producing nature of masses but did not find any viable hair follicle cells. Accordingly, cilia may enter lacrimal gland ductules rather than being produced by the mass. In addition, cilia impacted in lacrimal ductules were normal in size, favoring the migration of cilia from normal eyelash roots. Cilia may be attached by thick discharge secreted from ductulitis and subsequently drawn from the conjunctival fornix in the lacrimal ductule by blinking. There is a possibility that cilia are the primary cause of inflammation, acting as a nidus. However, considering the direction of tear secretion, it is difficult to determine how cilia might move in a normal lacrimal ductule. In case of an inflamed duct, the sticky discharge and enlarged diameter of the ductule may help carry the cilia in the duct. In addition, it was recently found that normal lacrimal ducts and dacryops did not contain myoepithelial cells, and the contractility or pumping action of the duct was unclear.17 Thus, they suggest that cilia can be accompanied by preexisting lacrimal ductulitis and may secondarily aggravate the inflammation. Cilia also have been previously found in lacrimal sac stones.9,21 Jay and Lee21 reported an eyelash retained in the lacrimal sac as a possible initiating factor of dacryolith. Infection with certain microorganisms has been suggested as another important cause of lacrimal ductular lesions. Haemophilus influenzae and Pseudomonas aeruginosa have been isolated from lacrimal gland dacryoliths in previous studies.11,12 Recently, Hay-Smith and Rose7 proposed Actinomyces infection as a causative agent of lacrimal ductulitis. They reported Actinomyces or compatible pathologic changes in 5 of 7 cases at histopathological examination. Their perspective was reasonable, from a clinical point of view. The nature of discharge in lacrimal ductulitis is thick and viscous, similar to that of canaliculitis, and dacryoliths of lacrimal gland ductules resemble “sulfur granules” from Actinomyces. In this study, microbiologic infection was suspected in 3 cases based on histopathologic features. Among them, 2 cases showed cocci-form bacterial colonies, and another case showed agglomeration of
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filament-like materials indicating Actinomyces infection in hematoxylin-eosin staining; however, subsequent PAS staining failed to provide evidence of Actinomyces. Because of the retrospective nature of the study, they tried to investigate causative microorganisms through a histopathologic review instead of a culture study, and such a low rate of infection could be a false-negative result. A larger prospective study by using microbiologic cultures with special media will help to confirm whether inflammatory lacrimal ductular lesions are caused by microbiologic infection. The role of cosmetics was also suggested in a few reports based on the woman predominance and the makeup particles observed in dacryoliths.9,22 In this study, women patients represented the most cases (10 of 12). However, they did not find any evidence of foreign body materials or foreign body granulomas induced by makeup particles in the pathologic specimens. The mechanisms of lacrimal ductal cyst and lacrimal ductal dacryolith formation have been proposed by several authors and have some points of similarity. Loss of lacrimal ductule contractility combined with distention of the ductal wall has been thought to result in a lacrimal ductal cyst.23 A recent study analyzing the cytologic composition of dacryops suggested that a dysfunction of the neural plexus around lacrimal ductules may play an important role in the formation of dacryops, and the authors were skeptical of the presence of neuromuscular contractility of the lacrimal ductule because immunostaining of myoepithelial cells showed negative results.17 The pathogenesis of dacryolith formation in a lacrimal ductule includes a blockage of the lacrimal ductule, presence of a nidus, and infection.10 In this study, 2 cases (Case 1, Case 2) presented characteristic lacrimal ductal cysts with superimposed mild inflammation. One case (Case 3) presented with typical lacrimal ductulitis but did not show a definite cyst. Most cases (9 of 12 cases) showed cysts with modest inflammatory reactions and had dacryolith-like contents, and cilia were found in 8 cases. They presumed such conditions could be created following infection superimposed on a lacrimal ductal cyst or lacrimal ductal blockage combined with lacrimal ductulitis, and cilia may secondarily aggravate inflammation and obstruct the affected ductule. Excision of the mass through a conjunctival cul-de-sac approach is the procedure of choice for lacrimal ductal cysts.18 A lateral canthotomy is sometimes simultaneously performed to facilitate exposure.24 Cryoprobe-assisted removal was also reported.18 Complete removal of the mass and preservation of normal lacrimal gland tissues are the principal themes for successful treatment. Some authors have suggested marsupialization as an alternative treatment of choice.7,16,25 Marsupialization is a simple, less invasive technique, and can be a better choice for patients with tear deficiency. However, dacryoliths or cilia can be underestimated, and meticulous removal of mass contents is needed to prevent lesion persistence or recurrence. In summary, they demonstrated that lateral canthal subconjunctival inflammatory lesions were derived from lacrimal gland ductules. They showed a varying histopathologic spectrum of inflammation and cyst formation, and most cases had modest periductal inflammation and acellular eosinophilic contents. Cilia impaction was a common accompanying finding.
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REFERENCES 1. Tse BC, Shriver EM, Tse DT. Tarsoconjunctival crypts: unrecognized cause of chronic mucopurulent conjunctivitis. Am J Ophthalmol 2012;154:527–33. 2. Freedman JR, Markert MS, Cohen AJ. Primary and secondary lacrimal canaliculitis: a review of literature. Surv Ophthalmol 2011;56:336–47. 3. Rose GE. The giant fornix syndrome: an unrecognized cause of chronic, relapsing, grossly purulent conjunctivitis. Ophthalmology 2004;111:1539–45. 4. Mastrota KM. Impact of floppy eyelid syndrome in ocular surface and dry eye disease. Optom Vis Sci 2008;85:814–6. 5. Gloor P, Ansari I, Sinard J. Sebaceous carcinoma presenting as a unilateral papillary conjunctivitis. Am J Ophthalmol 1999;127:458–9. 6. Akpek EK, Polcharoen W, Chan R, et al. Ocular surface neoplasia masquerading as chronic blepharoconjunctivitis. Cornea 1999;18:282–8. 7. Hay-Smith G, Rose GE. Lacrimal gland ductulitis caused by probable Actinomyces infection. Ophthalmology 2012;119:193–6. 8. Chow K, Burt B, Rosser PR. Congenital anomalous lacrimal ductulitis. Clin Experiment Ophthalmol 2008;36:582–3. 9. Baratz KH, Bartley GB, Campbell RJ, et al. An eyelash nidus for dacryoliths of the lacrimal excretory and secretory systems. Am J Ophthalmol 1991;111:624–7. 10. Halborg J, Prause JU, Toft PB, et al. Stones in the lacrimal gland: a rare condition. Acta Ophthalmol 2009;87:672–5. 11. Baker RH, Bartley GB. Lacrimal gland ductule stones. Ophthalmology 1990;97:531–4. 12. Mawn LA, Sanon A, Conlon MR, et al. Pseudomonas dacryoadenitis secondary to a lacrimal gland ductule stone. Ophthal Plast Reconstr Surg 1997;13:135–8. 13. Zafar A, Jordan DR, Brownstein S, et al. Asymptomatic lacrimal ductule dacryolithiasis with embedded cilia. Ophthal Plast Reconstr Surg 2004;20:83–5. 14. Bullock JD, Fleishman JA, Rosset JS. Lacrimal ductal cysts. Ophthalmology 1986;93:1355–60. 15. von Holstein SL, Therkildsen MH, Prause JU, et al. Lacrimal gland lesions in Denmark between 1974 and 2007. Acta Ophthalmol 2013;91:349–54. 16. Smith S, Rootman J. Lacrimal ductal cysts. Presentation and management. Surv Ophthalmol 1986;30:245–50. 17. Jakobiec FA, Zakka FR, Perry LP. The cytologic composition of dacryops: an immunohistochemical investigation of 15 lesions compared to the normal lacrimal gland. Am J Ophthalmol 2013;155:380–396.e1. 18. Betharia SM, Pushker N, Sharma V, et al. Simple dacryops: a case series and review of the literature. Ophthalmologica 2002;216:372–6. 19. Zayour M, Lazova R. Pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol 2011;33:112–22; quiz 123–6. 20. Kacerovska D, Michal M, Ricarova R, et al. Apocrine secretion in lacrimal gland cysts (dacryops): a common but underrecognized phenomenon. J Cutan Pathol 2011;38:720–3. 21. Jay JL, Lee WR. Dacryolith formation around an eyelash retained in the lacrimal sac. Br J Ophthalmol 1976;60:722–5. 22. Herzig S, Hurwitz JJ. Lacrimal sac calculi. Can J Ophthalmol 1979;14:17–20. 23. Tsiouris AJ, Deshmukh M, Sanelli PC, et al. Bilateral dacryops: correlation of clinical, radiologic, and histopathologic features. AJR Am J Roentgenol 2005;184:321–3. 24. Brownstein S, Belin MW, Krohel GB, et al. Orbital dacryops. Ophthalmology 1984;91:1424–8. 25. Eifrig CW, Chaudhry NA, Tse DT, et al. Lacrimal gland ductal cyst abscess. Ophthal Plast Reconstr Surg 2001;17:131–3.
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Clinicopathological Features of Inflammatory Lesions of the Lateral Canthal Subconjunctival Area Min Joung Lee, M.D.*¶, Ji Eun Kim, M.D.†, Namju Kim, M.D.*‡, Ho-Kyung Choung, M.D.*§, and Sang In Khwarg, M.D.*║ * Department of Ophthalmology, Seoul National University College of Medicine; †Department of Pathology, Seoul National University Boramae Hospital, Seoul; ‡Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam; §Department of Ophthalmology, Seoul National University Boramae Hospital; ║Department of Ophthalmology, Seoul National University Hospital, Seoul; and ¶ Department of Ophthalmology, Hallym University Sacred Heart Hospital, Anyang, Korea
Purpose: To investigate the clinical and histopathological features of inflammatory lesions of the lateral canthal subconjunctival area. Methods: This is a retrospective case series of 12 patients with inflammatory subconjunctival masses in the lateral canthal area. All patients included in this study were treated at Seoul National University Hospital or Seoul National University Bundang Hospital between 2006 and 2012. Clinical data were obtained from the medical records. Histopathologic findings were thoroughly reviewed. Results: There was a woman predominance in the study group (10:2), and the median age at presentation was 39 years (range 33–70). Common symptoms included conjunctival injection, sticky discharge, and pain or discomfort. Histopathologically, all lesions originated from ductules of the lacrimal gland. Two cases showed cysts containing clear fluid with mild inflammation. One case showed lacrimal ductulitis without cyst formation. Nine cases showed lacrimal ductal cysts with varying periductal inflammation, and the contents were pinkish, amorphous materials in 7 cases. Embedded cilia were found in 8 cases. Conclusions: Inflammatory lesions of the lateral canthal subconjunctival area all originated from lacrimal gland ductules, showing a variable histopathologic spectrum of inflammation and cyst formation. Cilia impaction was a very frequently observed finding. (Ophthal Plast Reconstr Surg 2014;30:251–256)
C
hronic, unilateral conjunctivitis often presents a difficult diagnostic dilemma, although it has many well-known causes, such as nasolacrimal duct obstruction, canaliculitis, floppy eyelid syndrome, and giant fornix syndrome.1–4 Sebaceous gland carcinoma, squamous cell carcinoma, or malignant lymphoma of the ocular adnexa may present with inflammatory signs and also can masquerade as conjunctivitis.5,6 When conjunctivitis is limited to the temporal area, inflammatory lesions originating from lacrimal gland ductules should be included in the differential diagnosis. Accepted for publication November 12, 2013. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Sang In Khwarg, M.D., Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110–744, Korea. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000087
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Lacrimal ductulitis is an uncommon disease and has not yet been well established. Lacrimal ductulitis has been rarely investigated, and a PubMed literature search by using the term “lacrimal ductulitis” revealed only 2 articles published in English.7,8 A pouting lacrimal ductule with viscous discharge is a typical sign. Lacrimal ductule stones (dacryoliths) can be simultaneously present and have been reported without definition of the originating disease.9–11 This condition has also been reported as a kind of infectious dacryoadenitis.12 The cause of lacrimal ductulitis is unclear; however, cilia have been reported as a nidus for dacryoliths in a few case reports.9,11,13 Recently, an association between lacrimal ductulitis and Actinomyces infection was proposed by some researchers.7 A lacrimal ductal cyst is a retention cyst of the lacrimal gland ductules and is most commonly located in the palpebral lobe.14 It is an uncommon condition, but an article from Denmark reported that it accounted for about 10% of pathologically verified lacrimal gland lesions.15 Insidious, painless swelling of the superotemporal conjunctival fornix is a classic presentation, and a bluish, well-transilluminated mass with a smooth surface is a characteristic ophthalmologic finding. However, inflammatory signs such as tenderness, irritation, or pain can accompany the lesion.16 When encountering a patient with an inflamed lesion of the lateral canthal subconjunctival area, the diagnosis might be confusing, and there has been no established, systematic analysis to date. In this study, the authors reported a series of patients with inflammatory lesions of the lateral canthal subconjunctival area and investigated the clinical and histopathological features.
PATIENTS AND METHODS Patients who underwent surgical excision of an inflammatory lesion from the lateral canthal subconjunctival area at Seoul National University Hospital or Seoul National University Bundang Hospital between 2006 and 2012 were included in this study. Clinical data, pathologic reports, and original slides were collected and reviewed to confirm the diagnosis. The main inclusion criteria were presentation with a lateral canthal area subconjunctival mass with inflammatory signs and the availability of a pathologic specimen. The necessary institutional review board approval was obtained for the study. The demographic data, symptom duration, presenting signs, treatment, and outcome were reviewed. Clinical photographs at presentation were also reviewed, and visible dacryoliths or cilia were checked with special attention. All histopathologic examinations were performed by an experienced pathologist (J.E.K.). The following features were assessed and documented: 1) presence of a cyst; 2) pathologic study of the cystic wall, such as specification of the epithelium and presence of
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TABLE 1. Demographics, clinical presentation, and treatment of 12 patients with inflammatory lesions in the lateral canthal subconjunctival area Case no.
Age (y) Gender
Duration of symptoms (mo)
Presenting symptoms
1 2 3
33 70 41
F F M
Red eye, upper eyelid swelling Eyelid mass on upper lateral area Discharge, red eye
24 2 2
4 5 6 7 8 9
49 53 37 20 39 36
M F F F F F
Pain, discomfort, upper eyelid swelling Pain, red eye, cilia production in mass Discharge, discomfort Pain, discharge Red eye, lateral canthal mass Discharge, red eye
0.5 36 4 22 0.5 36
10 11 12
40 37 35
F F F
Pain, upper eyelid swelling, discharge Red eye, lateral canthal mass Red eye, swelling
120 42 1
fibrosis or calcification; 3) the nature of the cystic contents; 4) the degree of inflammation and presence of a granulomatous reaction; 5) evidence of bacterial infection; and 6) evidence of cilia impaction. Hematoxylin and eosin-stained slides were reviewed, and periodic acid-Schiff (PAS) staining was added to observe the presence of Actinomyces colonies.
RESULTS The authors originally identified 34 cases involving surgical removal of a lateral canthal area subconjunctival mass through a search of electronic medical records. Among them, 12 cases presenting a lacrimal ductal cyst without inflammatory signs, 3 cases with simple conjunctival inclusion cysts without inflammatory signs, and 7 cases without available pathologic specimens were excluded. Thus, 12 cases were finally enrolled in this study. The demographics and clinical features of all patients are summarized in Table 1. Age at diagnosis ranged between 33 and 70 years (mean, 41.4 years; median 39 years), and there was a woman predominance (10 cases). All patients demonstrated unilateral lesions. The symptom duration varied between 2 weeks and 10 years (mean, 26.5 months; median 22 months), and 8 of the 12 patients underwent incision and drainage prior to referral, but symptoms recurred. No patient had a history of trauma or inflammatory diseases of the conjunctiva. All patients had conjunctival injection, 6 patients
Ocular examination Subconjunctival cystic mass with injection Subconjunctival cystic mass with injection Pouting mass with injection and mucous discharge Subconjunctival mass with yellowish precipitate, conjunctival injection, and chemosis Pouting mass with mucous discharge and visible cilia impaction Subconjunctival mass with yellowish dacryolith and cilia Small subconjunctival mass with viscous discharge on surface Pouting mass with severe injection Flat, yellowish subconjunctival mass with stringy discharge Large subconjunctival mass with yellowish precipitate, conjunctival injection, chemosis, mucous discharge Subconjunctival mass with yellowish dacryolith Subconjunctival cyst with yellowish precipitate
showed sticky discharge, and 5 patients reported pain or discomfort. A dacryolith or yellowish precipitate was visible in 5 patients. Cilia impaction was grossly visible in the lesions in 2 patients (Case 5, Case 6) (Fig. 1), and 1 patient (Case 5) complained that cilia had regrown repeatedly, even after removal. Eleven of 12 patients underwent surgical excision of the mass, and 1 patient underwent marsupialization and removal of the contents (Case 11). Follow-up periods after treatment ranged from 1 to 4 months (mean 2.00 ± 0.85 months). Resolution of symptoms and signs were noted in all patients at 1 month after surgery. The main histopathological features are summarized in Table 2. Microscopically, the lesions accompanied lacrimal gland tissues and lacrimal gland ductules in all cases. Based on the contents of the masses and degree of inflammation, all cases can be classified into 3 categories: 1) a cyst containing clear fluid with a mild inflammatory reaction (Case 1 and Case 2); 2) a dilated lacrimal gland ductule with a severe inflammatory reaction only (Case 3); and 3) cysts with varying degrees of inflammation, including 7 cases with pinkish, amorphous material, and 2 cases showing a moderate-to-severe periductal inflammatory reaction, although most contents were lost during the surgery (Case 4–Case 12). No case showed significant granulomatous changes. The inflammatory cells mainly included lymphoplasma cells, but Case 10, which had the longest symptom duration, showed focal eosinophil infiltration. Representative cases are described below. Case 1. A 33-year-old woman presented with a 2-year history of eye redness and eyelid swelling on the left side. She underwent multiple topical treatments and incision and drainage of a mass before referral. On examination, there was an oval subconjunctival mass with injection in the lateral canthal area. The mass was well transilluminated, and there was no visible discharge, precipitate, or dacryolith in the mass (Fig. 2A). Histologic examination after surgical excision of the mass revealed a cyst with clear fluid contents, and the cyst lining comprised a double layer of cuboidal epithelial cells with focal flattening (Fig. 2BC). There was mild inflammatory cell infiltration around the ductules and adjacent lacrimal gland (Fig. 2D).
FIG. 1. A case of inflammatory masses of a lacrimal gland ductule containing cilia. Cilia impaction in the masses was grossly observed (Case 5).
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Case 3. A 41-year-old man was referred with conjunctival swelling and discharge in the left canthal area for 2 months. He was managed by incision and drainage of a mass 2 weeks before referral; however, still there was a pouting, inflamed, subconjunctival mass with viscous discharge on the surface (Fig. 3A). On microscopic examination after surgical excision of the mass, a few lacrimal ductules showed luminal dilatation and squamous metaplasia of the ductular epithelium. Dense lymphocytic infiltration with focal stromal fibrosis was also seen (Fig. 3B).
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TABLE 2. Summary of histopathologic findings of 12 cases with inflammatory lesions of the lateral canthal subconjunctival area Case no.
Contents of cyst
1 2 3
Clear fluid Clear fluid No cyst formation
4 5
Mostly lost during operation Pinkish amorphous material
6 7
Pinkish amorphous material Pinkish amorphous material
8 9 10
Pinkish amorphous material Mostly lost during operation Pinkish amorphous material
11 12
Pinkish amorphous material Pinkish amorphous material
Epithelium Double layer with focal flattening Double layer with focal flattening Double layer with squamous metaplasia Denuded Double layer with squamous metaplasia Double layer Double layer with squamous metaplasia Double layer Double layer with squamous metaplasia Double layer with squamous metaplasia N/A Double layer
Periductular fibrosis
Periductular Presence of Calcification inflammation microorganism No. cilia
Mild N Moderate
N N N
Mild Minimal Severe
N N N
Absent Absent Absent
Moderate
Y
Moderate
N
1
N
Y
Moderate
N N
N Y
Mild N
N N
Mild
N
N/A N
N/A N
Bacterial colony Multiple present Mild N 1 Mild Bacterial colony 1 present Moderate N Multiple Moderate to N Absent severe Moderate to N 1 severe Moderate N* Multiple Moderate N 1
Y = yes; N = no; N/A = not accessible. *This case showed suspicious agglomeration of secretion on hematoxylin and eosin staining. However, following PAS staining failed to show Actinomyces species.
FIG. 2. A case showing a lacrimal ductal cyst with minimal inflammation (Case 1). A, A cystic mass with conjunctival injection is present in the lateral canthal area. B, Microscopic examination shows a unilocular cyst (×10). C, The cyst was lined with double cuboidal epithelial cells (×40). D, There is a mild inflammatory reaction in an adjacent lacrimal gland (×100). Case 10. A 40-year-old woman presented with a 10-year history of intermittent periocular pain and swelling over the lateral area of the left upper eyelid. She had a recent history of pain and swelling over the previous 2
weeks. A large lateral canthal subconjunctival mass with injection, chemosis, and purulent discharge was seen. After 2 weeks of systemic and topical antibiotic treatment, the mass slightly decreased, and the accom-
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FIG. 3. A case of lacrimal ductulitis without cyst formation (Case 3). A, Note the swollen, inflamed orifice of the lacrimal gland ductule with whitish discharge. B, The excised mass shows a dilated lacrimal ductule with double-layered cuboidal epithelial cells and marked infiltration of lymphoplasma cells (×100).
FIG. 4. A case of a lacrimal ductal cyst with chronic and severe inflammation (Case 10). A, The cystic mass contains yellowish debris, and accompanying inflammatory signs were much resolved by systemic and topical antibiotic treatment for 2 weeks. B, Microscopic examination showed the serpiginous cavity of the cyst and adjacent lacrimal gland (×40). C, Abundant lymphoplasma cells and focal eosinophils infiltrated the cyst wall (×200). D, Focal pseudoepitheliomatous hyperplasia is also seen (×100). panying inflammatory signs were greatly resolved, and there were visible, yellowish precipitates in the mass (Fig. 4A). Histopathological examination after surgical excision of the mass showed a large cyst lined with a double layer of epithelium with a focal, multilaminar appearance and squamous metaplasia, and the content was a pinkish, amorphous mate-
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rial. Moderate-to-severe inflammatory cell infiltration was noted around the cyst (Fig. 4B–D). One case (Case 11) showed suspicious agglomeration of secretions on histopathological examination. However, Actinomyces was not shown in subsequent PAS staining. Eight cases showed cilia in the
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
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FIG. 5. Multiple cilia in cystic contents. A, The cyst consists of double-layer epithelium and pinkish, amorphous material containing multiple short cilia (black arrows) (Case 8, ×50). B, The cystic mass content at a higher magnification demonstrates several long cilia (Case 11, ×100). mass contents (Fig. 5), and there were multiple cilia in 3 cases (Case 5, Case 8, and Case 11).
DISCUSSION In this study, the authors described the clinicopathologic characteristics of 12 cases of inflammatory masses of the lateral canthal subconjunctival area. All cases involved lacrimal ductular lesions showing varying histologic findings, such as a cyst of a large duct or lacrimal ductulitis with or without microscopic cysts. Inflammation was consistently found to varying degrees. The mass lining comprised a double layer of epithelium with fragmentary flattening. In some cases, multilaminar lining epithelium was partly observed, according to the section direction.17 Squamous metaplasia of the lining epithelia was a frequent finding, and fibrosis or calcification of the cystic wall, all of which suggest reactive changes resulting from chronic inflammation.18 Pseudoepitheliomatous hyperplasia, a benign condition characterized by hyperplasia of the epithelium and elongated, thick, downward projections with jagged borders, was observed in 1 case (Case 10). To the best knowledge, this is the first study describing pseudoepitheliomatous hyperplasia in a lacrimal ductal cyst or ductulitis. Pseudoepitheliomatous hyperplasia may be encountered in heterogeneous conditions, such as infection, neoplasia, and chronic inflammation or irritation; it has not been reported in a lacrimal ductal cyst or lacrimal ductulitis thus far.19 Apocrine metaplasia was suspected by the budding appearance of the secretions from the cells (Case 6). It is not well-recognized histologic finding in lacrimal gland ductal cyst, and there was only 1 case series that reported 6 cases of lacrimal gland ductal cysts, showing apocrine differentiation.20 However, Jakobiec et al.17 denied the presence of apocrine metaplasia in lacrimal ductal cysts based on the immunohistochemical results of GCDFP-15. In this study, they did not perform immunohistochemical staining, and further experiments will be needed to clarify this point. A noticeable finding was the presence of characteristic, pinkish, amorphous mass contents. Seven cases showed such contents, and among them, 2 cases presented corresponding visible dacryoliths. The composition of dacryoliths from lacrimal glands has been analyzed in a few studies.9–11 Previous studies reported the composition of dacryoliths as amorphous debris with or without polymorphonuclear cells adherent to the external surface, albumin, and carbonates/phosphates arranged
in concentric lamellae in a matrix of organic material with epithelial cells. An analysis by using Raman spectroscopy demonstrated that dacryoliths consisted of protein.10 Previously, some studies proposed that cilia may be agents initiating or contributing to dacryolith formation and ductular blockage.9,10,13,19 In this study, cilia were found in 8 (66.7%) cases. Moreover, 3 cases showed multiple cilia in a mass, and 1 patient reported repeated cilia production in the mass. Therefore, they were suspicious of the cilia-producing nature of masses but did not find any viable hair follicle cells. Accordingly, cilia may enter lacrimal gland ductules rather than being produced by the mass. In addition, cilia impacted in lacrimal ductules were normal in size, favoring the migration of cilia from normal eyelash roots. Cilia may be attached by thick discharge secreted from ductulitis and subsequently drawn from the conjunctival fornix in the lacrimal ductule by blinking. There is a possibility that cilia are the primary cause of inflammation, acting as a nidus. However, considering the direction of tear secretion, it is difficult to determine how cilia might move in a normal lacrimal ductule. In case of an inflamed duct, the sticky discharge and enlarged diameter of the ductule may help carry the cilia in the duct. In addition, it was recently found that normal lacrimal ducts and dacryops did not contain myoepithelial cells, and the contractility or pumping action of the duct was unclear.17 Thus, they suggest that cilia can be accompanied by preexisting lacrimal ductulitis and may secondarily aggravate the inflammation. Cilia also have been previously found in lacrimal sac stones.9,21 Jay and Lee21 reported an eyelash retained in the lacrimal sac as a possible initiating factor of dacryolith. Infection with certain microorganisms has been suggested as another important cause of lacrimal ductular lesions. Haemophilus influenzae and Pseudomonas aeruginosa have been isolated from lacrimal gland dacryoliths in previous studies.11,12 Recently, Hay-Smith and Rose7 proposed Actinomyces infection as a causative agent of lacrimal ductulitis. They reported Actinomyces or compatible pathologic changes in 5 of 7 cases at histopathological examination. Their perspective was reasonable, from a clinical point of view. The nature of discharge in lacrimal ductulitis is thick and viscous, similar to that of canaliculitis, and dacryoliths of lacrimal gland ductules resemble “sulfur granules” from Actinomyces. In this study, microbiologic infection was suspected in 3 cases based on histopathologic features. Among them, 2 cases showed cocci-form bacterial colonies, and another case showed agglomeration of
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filament-like materials indicating Actinomyces infection in hematoxylin-eosin staining; however, subsequent PAS staining failed to provide evidence of Actinomyces. Because of the retrospective nature of the study, they tried to investigate causative microorganisms through a histopathologic review instead of a culture study, and such a low rate of infection could be a false-negative result. A larger prospective study by using microbiologic cultures with special media will help to confirm whether inflammatory lacrimal ductular lesions are caused by microbiologic infection. The role of cosmetics was also suggested in a few reports based on the woman predominance and the makeup particles observed in dacryoliths.9,22 In this study, women patients represented the most cases (10 of 12). However, they did not find any evidence of foreign body materials or foreign body granulomas induced by makeup particles in the pathologic specimens. The mechanisms of lacrimal ductal cyst and lacrimal ductal dacryolith formation have been proposed by several authors and have some points of similarity. Loss of lacrimal ductule contractility combined with distention of the ductal wall has been thought to result in a lacrimal ductal cyst.23 A recent study analyzing the cytologic composition of dacryops suggested that a dysfunction of the neural plexus around lacrimal ductules may play an important role in the formation of dacryops, and the authors were skeptical of the presence of neuromuscular contractility of the lacrimal ductule because immunostaining of myoepithelial cells showed negative results.17 The pathogenesis of dacryolith formation in a lacrimal ductule includes a blockage of the lacrimal ductule, presence of a nidus, and infection.10 In this study, 2 cases (Case 1, Case 2) presented characteristic lacrimal ductal cysts with superimposed mild inflammation. One case (Case 3) presented with typical lacrimal ductulitis but did not show a definite cyst. Most cases (9 of 12 cases) showed cysts with modest inflammatory reactions and had dacryolith-like contents, and cilia were found in 8 cases. They presumed such conditions could be created following infection superimposed on a lacrimal ductal cyst or lacrimal ductal blockage combined with lacrimal ductulitis, and cilia may secondarily aggravate inflammation and obstruct the affected ductule. Excision of the mass through a conjunctival cul-de-sac approach is the procedure of choice for lacrimal ductal cysts.18 A lateral canthotomy is sometimes simultaneously performed to facilitate exposure.24 Cryoprobe-assisted removal was also reported.18 Complete removal of the mass and preservation of normal lacrimal gland tissues are the principal themes for successful treatment. Some authors have suggested marsupialization as an alternative treatment of choice.7,16,25 Marsupialization is a simple, less invasive technique, and can be a better choice for patients with tear deficiency. However, dacryoliths or cilia can be underestimated, and meticulous removal of mass contents is needed to prevent lesion persistence or recurrence. In summary, they demonstrated that lateral canthal subconjunctival inflammatory lesions were derived from lacrimal gland ductules. They showed a varying histopathologic spectrum of inflammation and cyst formation, and most cases had modest periductal inflammation and acellular eosinophilic contents. Cilia impaction was a common accompanying finding.
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