Significance of Fuchs Flecks in Patients with Pterygium/ Pinguecula

CLINICAL SCIENCE

Signiﬁcance of Fuchs Flecks in Patients With Pterygium/ Pinguecula: Earliest Indicator of Ultraviolet Light Damage

Matthew H. Ip, BMed, MD,*† Jeanie J. Chui, MBBS, PhD,* Lien Tat, BAppSc, PhD,‡ and Minas T. Coroneo, MD, MS, MSc, FRACS*†‡

advancing head of a pterygium. These small cell aggregates Purpose: fl fi Fuchs ecks (FFs) have been previously identi ed at the possess a greater nuclear-to-cytoplasm ratio. Cells are leading edge of pterygia and may represent collections of epithelial anchored to the basement membrane and are associated stem-like cells that give rise to this condition. This study aims to with the corneal-like epithelium at the leading edge of evaluate the clinical significance of FFs in patients with ocular pterygia.1 surface disorders, such as pterygium and pinguecula, by in vivo We previously reported that FFs expressed stem cell- confocal microscopy (IVCM). like markers, such as p63-alpha and keratin 15, but these cells Methods: This study is a Single-center, retrospective, observational lacked immunoreactivity to proliferative marker Ki-67. case series of 40 eyes from 20 patients with clinical diagnoses of Despite not actively proliferating, FFs are believed to be activated through appropriate signaling pathways found in pinguecula or pterygium, or both. IVCM (Rostock Cornea Module; 2 Heidelberg Engineering, Heidelberg, Germany) was performed on developing pterygium. In vivo confocal microscopy (IVCM) is a noninvasive patients with pinguecula or pterygium, or both. The presence of FFs 3 on the ocular surface of patients with pterygium and pinguecula was method of evaluating the ocular surface. IVCM examination assessed by IVCM and subsequently documented. of pterygium previously showed increased Langerhans cell numbers, implicating an immune mechanism in its pathogen- Results: FFs were present in 24 of 30 eyes (80.0%) in paired esis.4 In addition to morphological assessment, IVCM has macroscopically normal nasal or limbal regions, 19 of 20 (95.0%) in been used to monitor corneal reepithelialization after ptery- pinguecula, 13 of 15 (86.7%) in primary pterygia, and 7 of 7 (100%) gium surgery.5 The diagnostic potential of IVCM may be in recurrent pterygia. improved if pterygia are evaluated with both impression cytology and confocal microscopy.6 Conclusions: fi High rates of FFs were identi ed at the head of Although the pathogenesis of pterygium is not com- pinguecula, primary pterygium, recurrent pterygium, and macroscop- pletely understood,7 the connection between pterygium and ically normal nasal and temporal limbus. We postulate that FFs may other UV-associated disorders (ophthalmohelioses), such as represent precursor lesions to UV-associated ocular surface pathology. pinguecula and cataract, has been established. Moreover, fi fl Identi cation of Fuchs eck by IVCM may permit clinicians to predict evidence for correlation between pterygium development the patients who may progress to develop more advanced pathology. and high UV exposure has strengthened.8,9 We present Key Words: Fuchs flecks, pterygium, pinguecula, in vivo confocal a study to investigate the presence of FFs in pinguecula, microscopy pterygium, and clinically normal temporal and nasal limbal regions. (Cornea 2015;34:1560–1563)

MATERIALS AND METHODS uchs flecks (FFs), also known as Fuchs islets, are defined Fas clusters of stem-like basal cells identified at the This study represents a retrospective, observational case interface between the healthy corneal epithelium and the series of 20 patients and 40 paired eyes that were selected from the private practice of Minas T. Coroneo associated with Received for publication June 23, 2015; revision received July 31, 2015; the Prince of Wales Hospital, Sydney, between 2009 and accepted July 30, 2015. Published online ahead of print September 21, 2012. Informed consent was obtained from patients for the 2015. use of IVCM and patient notes for this study. The study has From the *Department of Ophthalmology, Prince of Wales Hospital, Randwick, been approved by the South Eastern Sydney Area Health † New South Wales, Australia; University of New South Wales, Sydney, Service Human Research Ethics Committee (Eastern Section; Australia; and ‡Ophthalmic Surgeons, Randwick, Sydney, Australia. J. J. Chui received salary support from the Genetic Eye Foundation. The 15/062) and was performed in accordance with the tenets of sponsor had no role in the design or conduct of this research. The others the Declaration of Helsinki. authors have no funding or conflicts of interest to disclose. Inclusion criteria for patient selection were the clinical Presented as a poster at the Association for Research in Vision and diagnosis of either primary or recurrent pterygium, or Ophthalmology Annual Meeting, Denver, Colorado, 2015. Reprints: Matthew H. Ip, BMed, MD, 2 St Pauls St, Randwick, New South pinguecula in at least 1 eye. Subjects were excluded if they Wales 2031, Australia (e-mail: [email protected]). possessed 2 macroscopically healthy ocular surfaces or Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. a clinical diagnosis other than primary or recurrent pterygium

1560 | www.corneajrnl.com Cornea Volume 34, Number 12, December 2015

TABLE 1. subsequently organized into 4 groups according to the The Identiﬁcation of FFs With Slit-Lamp Examination clinical diagnosis at that region: normal, pinguecula, pri- and IVCM mary pterygium, and recurrent pterygium. The presence of Slit-Lamp Macroscopic Appearance (Nasal Examination IVCM FFs was evaluated independently by only 1 clinician who or Temporal Limbus) No. No. (%) No. (%) was masked to the diagnosis (J.J.C.), using IVCM for each eye. Normal limbus 37 0 (0.0) 24* (64.9) Pinguecula 21 0 (0.0) 19* (90.5) Primary pterygium 15 7 (46.7) 13 (86.7) Statistical Analysis Recurrent pterygium 7 4 (57.1) 7 (100.0) The patient history and investigation results were *30 of 37 in macroscopically normal limbus and 20 of 21 in pinguecula were reviewed, and data were analyzed using Microsoft Excel examined by IVCM. software (Microsoft Corp, Redmond, WA, 2007). Percentage and frequency statistics were used to highlight the presence of FFs in pingueculae, pterygia, and clinically normal temporal or pinguecula. Age, gender, and ocular histories were or nasal limbal regions. recorded, including any previous surgeries. Patients underwent routine slit-lamp examination and photography and IVCM (Rostock cornea module, Heidel- RESULTS berg Engineering, Heidelberg, Germany) to evaluate their Our cohort consisted of 40 eyes (80 nasal and temporal ocular surface. A paired evaluation of the patient’s other eye limbal regions) from 20 subjects (9 men and 11 women) with was also performed with both slit-lamp examination and a mean age 6 SD of 48.4 6 14.4 years, ranging from 27 to 79 confocal imaging. Each of the 40 eyes was divided into years. The patients’ background consisted of predominantly nasal or temporal limbal regions (n = 80) and were European continental descent. From slit-lamp examination,

FIGURE 1. Confocal appearance of macroscopically normal superior (A–C), temporal (D–E), and nasal limbus (F) from different subjects. Note the appearance of the superior limbal palisades with a central vascular core (A–C). In contrast, FFs from the temporal and nasal limbus have an irregular, ovoid morphology.

fl TABLE 2. could only be seen using IVCM. As re ected in our previous The Presence of FFs on Nasal and Temporal Limbal studies, FFs were identified in most eyes in the zone of the Regions With IVCM cornea-like epithelium just ahead of the advancing pterygium Macroscopic Appearance (Nasal or FFs Present FFs Absent 2,10 Temporal Limbus) No. No. (%) No. (%) head (n = 20; 90.9%). FFs were present in all recurrent pterygia despite complete surgical excision of the primary Normal limbus 30* 24 (80.0) 6 (20.0) lesion. Our findings suggest that these islands of cells Pinguecula 20* 19 (95.0) 1 (5.0) represent a pterygium “vanguard” and may signal activation, Primary pterygium 15 13 (86.7) 2 (13.3) proliferation, and further corneal invasion, perhaps when they Recurrent pterygium 7 7 (100.0) 0 (0.0) reach a “critical mass.” Their presence in clinically normal *30 of 37 in macroscopically normal limbus and 20 of 21 in pinguecula were fellow eyes in patients with pterygium or pinguecula may be examined by IVCM. evidence for early UV damage in these eyes that have yet to develop clinically obvious disease. IVCM is likely to be a more sensitive technique than UV fluorescence photogra- clinical diagnoses of limbal regions comprised 21 pinguecula, phy11 because 20% of patients with established pterygia 15 primary pterygia, and 7 recurrent pterygia with the showed no evidence of fluorescence in our earlier studies.12 remaining 37 being macroscopically normal. Two eyes The association between UV exposure and pinguecula possessed double pathology, with both eyes diagnosed with development has been previously demonstrated.8 Moreover, primary pterygia and pinguecula. despite being macroscopically distinct and with differing IVCM was performed on the nasal and temporal corneal involvement, it has been postulated that the histopa- limbus, and in most cases, the superior and inferior limbus thology of pinguecula and pterygium are identical, leading to were also examined. Initial slit-lamp examination identified the suggestion that pinguecula represents a precursor lesion the presence of FFs in 0 pinguecula, 7 primary pterygia, 4 for pterygium.13 In this case series, FFs were identified in recurrent pterygia, and 0 macroscopically normal nasal and most pinguecula (n = 19; 95.0%) (Fig. 2). This result supports temporal limbal regions, which subsequently increased with the notion that FFs represent UV-damaged cells, which may IVCM examination (Table 1). FFs, identified by their distinct herald progression to macroscopically visible pinguecula and appearance (Figs. 1, 2), were observed in 95.0% of pingue- subsequently pterygia. cula, 86.7% of primary pterygia, 100.0% of recurrent Despite observing high rates of FFs in both pterygia pterygia, and 80.0% of macroscopically normal nasal and and pinguecula, not all FFs progress to pinguecula and temporal limbus (Table 2). However, IVCM examination of subsequently pterygium. Although it is possible that a critical the superior (n = 30) and inferior (n = 12) limbal regions mass of cells is required over a period to permit trans- failed to identify any FFs. formation, we propose that continuous shedding of the corneal epithelium may clear the ocular surface of FFs, perhaps evidence of tissue repair if UV exposure is sub- DISCUSSION sequently limited. Ultimately, further longitudinal studies are Our study demonstrated the presence of FFs in lesions required to investigate the rate of FFs progression into either associated with UV damage, such as pterygium and pingue- pinguecula or pterygium. cula. Surprisingly, we also demonstrated, for the first time, From our case series, macroscopically normal nasal and similar changes in the temporal and nasal limbal areas in temporal limbal regions unexpectedly demonstrated high fellow eyes that were clinically normal. In these patients, FFs rates of FFs (n = 24; 80.0%) but were absent in superior

FIGURE 2. Confocal images of FFs from 1 subject. Macroscopically normal left temporal limbus (A), right nasal pinguecula (B), and left primary nasal pterygium (C).

and inferior limbus, zones that are largely protected from sun precursor lesions and may signal the development of more exposure. This is consistent with our previous studies, in advanced disease in patients with evidence of previous high which 81% of patients aged from 17 to 21 years demonstrated UV exposure. The noninterventional and in situ evaluation of limbal/conjunctival fluorescence in the horizontal ocular FFs with IVCM represents a modality that may assist in surface meridian.14 We propose that early detection of predicting the patients who may go on to develop more developing pinguecula and pterygium may be achieved using advanced pathology. IVCM by detecting the presence of FFs, despite the ocular surface possessing no macroscopically visible pathology. We believe that IVCM is a noninvasive, in situ, and quick REFERENCES imaging modality for monitoring pinguecula and primary and 1. Fuchs E. Ueber das Pterygium. Graefes Arch Ophthalmol. 1892;38:1–89. recurrent pterygium.5 2. Chui J, Coroneo MT, Tat LT, et al. Ophthalmic pterygium a stem cell disorder with premalignant features. Am J Pathol. 2011;178:817–827. We have hypothesized that the limbal barrier between 3. Guthoff RF, Zhivov A, Stachs O. In vivo confocal microscopy, an inner the corneal and conjunctival epithelium is damaged by vision of the cornea—a major review. Clin Experiment Ophthalmol. focusing of peripheral light at the limbus. Light, when 2009;37:100–117. focused by an order of magnitude, strikes the basal limbal 4. Papadia M, Barabino S, Rolando M. In vivo confocal microscopy in a case of pterygium. Ophthalmic Surg Lasers Imaging. 2008;39: stem cells, which subsequently transform, proliferate, and – 9,15 511 513. invade the cornea. Although the nasal limbus is pre- 5. Zhivov A, Beck R, Guthoff RF. Corneal and conjunctival findings after dominantly affected, the temporal limbus is also susceptible mitomycin C application in pterygium surgery: an in-vivo confocal in patients with a low nasal bridge in whom peripheral light microscopy study. Acta Ophthalmol. 2009;87:166–172. can be focused on the temporal limbus.9,16 In contrast, the 6. Labbé A, Gheck L, Iordanidou V, et al. An in vivo confocal microscopy and impression cytology evaluation of pterygium activity. Cornea. 2010; superior and inferior limbus remain anatomically protected 29:392–399. from the peripheral light-focusing effect, and therefore, 7. Chui J, Coroneo M. Pterygium pathogenesis, actinic damage, and extensive UV damage.9 Our findings are not only consistent recurrence. In: Hovanesian JA, ed. Pterygium: Techniques and Technol- with the peripheral light-focusing concept but also suggest ogies for Surgical Success. Thorofare, NJ: SLACK; 2011. 8. Lim R, Mitchell P, Cumming RG. Cataract associations with pinguecula that FFs represent precursor lesions for pinguecula and and pterygium: the Blue Mountains Eye Study. Am J Ophthalmol. 1998; pterygium in otherwise clinically normal eyes. 126:717–719. Although our “normal” eyes represented macroscopi- 9. Coroneo M. Ultraviolet radiation and the anterior eye. Eye Contact Lens. cally healthy temporal and nasal limbal surfaces, our paired 2011;37:214–224. fi data suggest that these eyes are abnormal. This is due to the 10. Chui J, Di Girolamo N, Wake eld D, et al. The pathogenesis of pterygium: current concepts and their therapeutic implications. Ocul Surf. increased risk of UV exposure in these supposedly normal 2008;6:24–43. eyes, as they were paired with eyes that possessed UV- 11. Sherwin JC, McKnight CM, Hewitt AW, et al. Reliability and validity of associated pathology, as according to our inclusion criteria. conjunctival ultraviolet autofluorescence measurement. Br J Ophthalmol. 2012;96:801–805. Interestingly, in very bright environments, the nondominant fl eye is closed in response to glare, and this could explain the 12. Ooi JL, Sharma NS, Sharma S, et al. Ultraviolet uorescence photog- 17 raphy: patterns in established pterygia. Am J Ophthalmol. 2007;143: asymmetry of the pathology observed. However, our study 97–101. did not intend to demonstrate the rates of FFs in clinically 13. Raizada IN, Bhatnagar NK. Pinguecula and pterygium (a histopatholog- normal fellow eyes, but rather determine the presence of FFs ical study). Indian J Ophthalmol. 1976;24:16–18. fl in patients with evidence of high UV exposure. The inherent 14. Ooi JL, Sharma NS, Papalkar D, et al. Ultraviolet uorescence photography to detect early sun damage in the eyes of school-aged bias from paired data may be addressed in future studies, children. Am J Ophthalmol. 2006;141:294–298. which include normal, age-matched control subjects, and by 15. Coroneo MT, Müller-Stolzenburg NW, Ho A. Peripheral light focusing analyzing 1 eye alone. by the anterior eye and the ophthalmohelioses. Ophthalmic Surg. 1991; In summary, our case series demonstrates high rates of 22:705–711. 16. Coroneo MT. Albedo concentration in the anterior eye: a phenomenon the presence of FFs in patients with pterygium and pingue- that locates some solar diseases. Ophthalmic Surg. 1990;21:60–66. cula, and macroscopically normal limbal regions of their 17. Jensen OL. Pterygium, the dominant eye and the habit of closing one eye fellow eyes. This finding suggests that FFs may represent in sunlight. Acta Ophthalmol (Copenh). 1982;60:568–574.