Corneal Changes in Xeroderma Pigmentosum: A Clinicopathologic Report SUNITA CHAURASIA, KAUSTUBH MULAY, MURALIDHAR RAMAPPA, VIRENDER SANGWAN, SOMASHEILA MURTHY, ROHINI NAIR, AND GEETA VEMUGANTI PURPOSE:
To report the clinicopathologic features of corneal involvement in patients with xeroderma pigmentosum. DESIGN: Retrospective review of corneal histopathology. METHODS: Thirteen corneal specimens of 11 patients with xeroderma pigmentosum who underwent keratoplasty (lamellar/full-thickness) for corneal involvement were studied. Five-micrometer-thick sections were made from all the samples and stained using hematoxylineosin and periodic acid–Schiff stains. A light microscopic examination was performed to study the histopathologic changes. RESULTS: The corneal findings on clinical examination were haze, scarring, vascularization, stromal edema, pigment clumps on endothelial surface, and corneal thinning. The histopathologic evaluation revealed changes in all layers of cornea. Epithelial changes seen were intraepithelial edema, fibrosis, epithelial downgrowths, and pannus formation. The Bowman membrane was fragmented or absent. Stroma was characterized by alteration in the lamellar pattern, scarring, edema, loss of keratocytic nuclei, and calcification. The Descemet membrane was thickened to a variable extent in most specimens and there was marked loss of endothelial cells in all. CONCLUSION: Most histologic features are consistent with the previous few reports. The remarkable finding in all corneal specimens was a moderate to severe degree of loss of the endothelial cells. This noteworthy finding supports the ultraviolet (UV) radiation–induced endothelial cell damage in these patients. This has an important clinical implication when planning for anterior lamellar keratoplasty, as endothelial cell density may be subnormal in these patients. (Am J Ophthalmol 2014;157:495–500. Ó 2014 by Elsevier Inc. All rights reserved.)
Accepted for publication Oct 24, 2013. From the Cornea and Anterior Segment Services (S.C., M.R., V.S., S.M.) and Ocular Pathology Services (K.M., G.V.), L.V. Prasad Eye Institute, Hyderabad, India; and School of Medical Sciences (R.N., G.V.), University of Hyderabad, Hyderabad, India. Geeta Vemuganti is currently Dean, School of Medical Sciences, University of Hyderabad, Hyderabad, India. Inquiries to Sunita Chaurasia, Cornea and Anterior Segment Services, L.V. Prasad Eye Institute, Kallam Anji Reddy Campus, L.V. Prasad Marg, Banjara Hills, Hyderabad - 500 034, India; e-mail:
[email protected]
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.10.016
Ó
2014 BY
X
ERODERMA PIGMENTOSUM IS AN AUTOSOMAL
recessive, rare genetic disorder characterized by solar injury to exposed skin and ocular tissues attributable to an enzymatic defect in the ability to repair DNA damage caused by ultraviolet (UV) light.1–3 Dermatologic changes are the most conspicuous findings and are mandatory for the diagnosis. Dermatologic involvement is characterized by extreme skin sensitivity to UV light, abnormal skin pigmentation, and high frequency of skin cancers, especially on sun-exposed skin. Ocular manifestations involve the eyelids, conjunctiva, sclera, and cornea. The eyelids are frequently involved. The eyelid skin may atrophy and ectropion may occur; the bulbar conjunctiva may become thin, pigmented, and atrophic, with inflamed patches; and eventually the lesions may become malignant. Cornea in xeroderma pigmentosum may show dryness, haze, edema, exposure keratitis, vascularization, pterygium-like growths, epithelial neoplasms, and opacification.1,3 Corneal opacification may result from epithelial/stromal changes or may be secondary to endothelial decompensation as a result of damage owing to chronic sun exposure.3,4 Corneal involvement often necessitates keratoplasty for visual rehabilitation. The decision about the type of keratoplasty (penetrating or selective) depends on the predominant corneal manifestation. Jalali and associates4 reported encouraging results following penetrating keratoplasty (PK) in 3 patients with xeroderma pigmentosum. We reported 2 cases with xeroderma pigmentosum, where Descemet stripping endothelial keratoplasty (DSEK) was performed for visual rehabilitation.5 In 1 patient, DSEK was performed for corneal edema attributable to endothelial failure as a result of chronic sun exposure. In the second patient, a deep anterior lamellar keratoplasty (DALK) was performed initially; although uneventful, it failed to maintain graft clarity, presumably owing to a poor endothelial reserve, and therefore a sequential endothelial keratoplasty was performed to restore graft clarity. Considering the fact that UV radiation can lead to endothelial damage,6,7 in eyes where anterior lamellar keratoplasty is performed, the surgical results are anticipated to depend on the preexisting endothelial status. There are few reports describing the histologic corneal changes in xeroderma pigmentosum patients. Pathologic corneal changes in these patients range from disorganized epithelium to Bowman membrane destruction, neovascularization, perivascular infiltration of inflammatory cells in the stroma, and loss of endothelial cells.8–10
ELSEVIER INC. ALL
RIGHTS RESERVED.
495
496
TABLE 1. Corneal Changes in Xeroderma Pigmentosum: Clinical and Histopathologic Details Case No. Age of Patient (y) Eye
Clinical Features
Specimen
AMERICAN JOURNAL OF OPHTHALMOLOGY
1
16
OD Vascularized corneal scar
Full-thickness CB
2
16
OS Vascularized corneal scar
Lamellar CB
3
27
OS Scar, corneal edema
Full-thickness CB
4
27
OD Corneal scar
Full-thickness CB
5
41
OD Corneal scar
Full-thickness CB
6
23
OS Vascularized corneal scar
Full-thickness CB
Epithelium
3-5 cell layered with intraepithelial edema, subepithelial fibrosis 3-5 cell layered thick, areas of hyperplasia, attenuation, downgrowths, subepithelial bullae, spheroidal degeneration 4-6 cell layered, subepithelial and intraepithelial bullae, basal cell edema, regenerative atypia 3-5 cell layered, basal cell edema, epithelial downgrowths, subepithelial fibrosis, pannus, subepithelial bullae 3-5 cell layered, irregular, subepithelial fibrosis 3-5 cell layered, irregular, subepithelial fibrosis
Bowman Membrane
Stroma
Descemet Membrane
Thickened
Endothelium
FEBRUARY 2014
Absent
Edema, scarring with irregular collagen pattern
Focally fragmented
Scarred with irregular lamella
-
Fragmented
Edematous, irregular arrangement of lamella
Endothelial cells absent
Thickened, fragmented
Edema, patchy loss of Markedly thickened, keratocytic nuclei posterior collagenous layer formation
Loss of endothelial cells
Absent
Thickened Thin, compact, scarring with loss of lamellar pattern
Very few endothelial cells
Replaced by fibrous tissue
Calcified mass in Minimal thickening stroma, scarred, blood vessels, perivascular lymphoplasmacytic infiltrates with few epithelioid cells and granulomas, elastotic degeneration
Absent endothelial cells
Mild thickening, posterior collagenous layer focally
Few endothelial cells
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VOL. 157, NO. 2
TABLE 1. Corneal Changes in Xeroderma Pigmentosum: Clinical and Histopathologic Details (Continued ) Case No. Age of Patient (y) Eye
Clinical Features
Specimen
Epithelium
CORNEAL CHANGES IN XERODERMA PIGMENTOSUM
7
29
OD PED, status/post TA application
Full-thickness CB
8
29
OS Corneal scar
Full-thickness CB
9
20
OS Corneal scar and edema
Full-thickness CB
10
16
OD Vascularized corneal scar, edema
Full-thickness CB
11
21
OS Vascularized corneal scar
Full-thickness CB
12
21
Descemet membrane -
13
22
OD Corneal edema with haze, pigments on endothelial surface OS Vascularized corneal scar, edema
Full-thickness CB
Bowman Membrane
Stroma
3-5 cell layered, Partly destroyed with separation from subepithelial Bowman at places, fibrosis subepithelial fibrosis
Edema, patchy loss of keratocytic nuclei, focal stromal defect, scarring, neovascularization, chronic infiltrates 2-5 cell layered, Intact; mild thickening Edema, loss of subepithelial fibrous lamellar pattern, membrane peripheral vascularization 1-3 cell layered, Fragmented Spheroidal irregular with degeneration, pigmented cells in irregular keratocytic basal cells, nuclei, peripheral regenerative atypia blood vessels Irregular, epithelial Fragmented, lost at Spheroidal downgrowths, the site of epithelial degeneration, pigmentation with downgrowths edema, basal cell edema vascularization, fibrosis 1-3 cell layered, Thickened, partly Scarring, focal focally denuded, destroyed by clustering of fibrosis, basal cell subepithelial keratocytic nuclei edema fibrosis, 1 edge shows subepithelial fibrovascular pannus -
2-4 layered, basal cell Replaced by fibrous edema, fibrosis tissue
CB ¼ corneal button; PED ¼ persistent epithelial defect; TA ¼ tissue adhesive.
-
Scarring, vascularization
Descemet Membrane
Endothelium
Markedly thickened with guttate changes
Loss of endothelial cells
Thickened
Loss of endothelial cells
Thickened
Very few endothelial cells
Thickened, breaks
Focal presence of few endothelial cells
Thickened, focally Loss of endothelial fragmented, partly cells buried in posterior stroma with retrocorneal fibrous membrane, adherent pigment cells Mild thickened, Very few endothelial adherent pigments cells Thickened - mild
Loss of endothelial cells
497
FIGURE. Histopathologic corneal changes in xeroderma pigmentosum. (Upper left) Section of cornea shows epithelial hyperplasia, downgrowths, stromal edema, and scarring (hematoxylin-eosin [HE], original magnification 3100). (Upper middle) One of the cases shows dysplastic epithelium with loss of polarity and surface maturation (arrows). Stroma shows foci of neovascularization (star). (Upper right) The corneal epithelium shows variable amount of pigmentation (white arrow) and hyperplasia (HE, original magnification 3400). (Lower left) Note the calcification and fragmentation of Bowman membrane with stromal calcification as well (HE, original magnification 3100). (Lower middle) Higher magnification of the cornea shows patchy lymphoplasmacytic infiltrates in the corneal stroma. (Lower right) The Descemet membrane with very few endothelial cells (HE, original magnification 3400).
The purpose of the report is to examine the histologic changes in the cornea of patients with xeroderma pigmentosum and correlate with the clinical findings.
Correlation of histologic endothelial cell counts with specular microscopic cell density was also performed using the equation: cell density ¼ (no. of endothelial cells per high-power field 3 145) þ 668.11
METHODS
RESULTS
THE STUDY INCLUDED 11 PATIENTS WHO WERE CLINICALLY
diagnosed to have xeroderma pigmentosum at L.V. Prasad Eye Institute, Hyderabad. Full-thickness corneal buttons were obtained in 9 patients during PK. In 2 of these, fullthickness corneal buttons were obtained from both eyes. In 1 case, a lamellar corneal button was obtained while in another case only a Descemet membrane was obtained. The corneal buttons were cut into 2 halves and both halves were submitted for histopathologic analysis. Five-micrometerthick sections were made from all the samples and stained using hematoxylin-eosin and periodic acid–Schiff stains. A light microscopic examination was performed by a trained pathologist to study the histopathologic changes. The number of endothelial cells per high-power field was counted in 12 specimens (the DALK specimen had no Descemet membrane or endothelium). Assessment of the endothelial cells per high-power field in the full-thickness corneal buttons of age-matched subjects of keratoconus who had undergone PK was done for a comparison. 498
ELEVEN
SPECIMENS
WERE
FULL-THICKNESS
CORNEAL
buttons obtained after PK, 1 was anterior lamellar corneal tissue following DALK, and 1 was a stripped Descemet membrane following DSEK. Table 1 and Figure shows the clinical and histopathologic features in the specimens studied. Table 2 shows a comparison of histopathologic features of this study with the existing reports. CLINICAL FINDINGS:
The corneal findings seen were varying degree of corneal scarring in all eyes, vascularization in 6 eyes, stromal edema in 5 eyes, pigment clumps on endothelium in 2 eyes, and epithelial defect with corneal thinning in 1 eye. In 1 patient (Case 12), the cause of corneal opacification was predominantly attributed to corneal edema, and therefore DSEK was performed for visual rehabilitation.
EPITHELIUM: The epithelium showed features such as intraepithelial edema, subepithelial bullae, areas of
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY 2014
TABLE 2. Corneal Changes in Xeroderma Pigmentosum: Histopathologic Findings and Prevalence in This Study Compared to Previously Published Reports Salient Histology Findings
Epithelial irregularities Intraepithelial edema Bowman membrane breaks/absence Subepithelial fibrosis Spheroidal degeneration Calcification Pigmentation Stromal scarring Intrastromal cholesterol clefts Neovascularization Stromal edema Descemet membrane thickening/guttata Reduced/absent endothelial cells
Rezaei Kanavi et al (n ¼ 1)9
Ramkumar et al (n ¼ 2)12
þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ
Present Study (n ¼ 13), Prevalence
þ (100%) þ (58.3%) þ (91.6%) þ (100%) þ (25%) þ (8.3%) þ (8.3%) þ (100%) þ (50%) þ (50%) þ (100%) þ (100%)
n ¼ Number of corneal specimens studied in each of the study; þ ¼ present; ¼ absent.
hyperplasia, attenuation, epithelial downgrowths, subepithelial fibrosis and pannus formation, regenerative atypia, and spheroidal degeneration. BOWMAN MEMBRANE:
The Bowman membrane was absent in 2 cases, was partly destroyed in 8 cases, was thickened in 2 cases, and showed subepithelial fibrosis in 2 other cases.
STROMA:
Stroma showed irregular arrangement of lamellar pattern in 8 cases and edema in 6 cases. Neovascularization was seen in 6 specimens. There was a patchy loss of keratocytic nuclei in 3 cases and focal clustering of nuclei was seen in 1 specimen. One case had calcified mass in stroma with an epithelioid cell granuloma around it. Spheroidal degeneration was seen in 3 cases.
DESCEMET MEMBRANE:
Descemet membrane was variably thickened in 13 cases, with noticeable thickening of the posterior collagenous layer in 2 cases and guttate changes in 1.
ENDOTHELIUM:
All specimens showed moderate to severe loss of endothelial cells. Pigment granules were seen adherent to the endothelial surface in 2 specimens. The mean endothelial cell numbers per high-power field were significantly lower in the xeroderma pigmentosum buttons compared to the keratoconus buttons (0.5 vs 15.25, P value
