Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency

Abstract

Purpose: Despite extensive knowledge gained over the last 3 decades regarding limbal stem cell deficiency (LSCD), the disease is not clearly defined, and there is lack of agreement on the diagnostic criteria, staging, and classification system among treating physicians and research scientists working on this field. There is therefore an unmet need to obtain global consensus on the definition, classification, diagnosis, and staging of LSCD.

Methods: A Limbal Stem Cell Working Group was first established by The Cornea Society in 2012. The Working Group was divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to obtain agreement on a strategic plan and methodology from all participants after a comprehensive literature search, and final agreement was reached on the definition, classification, diagnosis, and staging of LSCD. A writing group was formed to draft the current manuscript, which has been extensively revised to reflect the consensus of the Working Group.

Results: A consensus was reached on the definition, classification, diagnosis, and staging of LSCD. The clinical presentation and diagnostic criteria of LSCD were clarified, and a staging system of LSCD based on clinical presentation was established.

Conclusions: This global consensus provides a comprehensive framework for the definition, classification, diagnosis, and staging of LSCD. The newly established criteria will aid in the correct diagnosis and formulation of an appropriate treatment for different stages of LSCD, which will facilitate a better understanding of the condition and help with clinical management, research, and clinical trials in this area.

Figure 1.

Slit lamp photos (bright light and fluorescein staining). Slit lamp photos of normal eyes (A,B), sectoral limbal stem cell defciency (LSCD, C,D) and total LSCD eyes (E, F). The epithelium in the normal eye is transparent (A), which cannot be stained by fluorescein (B). In the eye with sectoral LSCD, the epithelium of affected area superiorly is greyish (C) under bright light. It can be better visualized with fluorescein staining under cobalt blue light, which often have a whorl-like pattern and fluorescein pooling in area where there is epithelial thinning (D). In eyes with total LSCD, corneal opacity and superficial neovascularization affecting the entire cornea sruface are visible under bright light (E). Fluorescein staining shows epithelial irregularity (F).

Figure 2.

Immunofluorescein and pathological staining of corneal impression cytology specimens. Figure 2A, 2B and 2C are specimens taken from central cornea, limbus and conjunctiva of a normal cadeveric eye, respectively. The expression of cytokeratin (CK) 12 is only found in corneal epithelial cells, and cannot be found in conjunctival epithelial cells. CK13 and CK7 are only expressed in conjunctival cells. At the limbal area, both CK12-positive cells and CK13-CK7-positive cells are visible. Figure 2 D-F are the samples taken from the eyes with limbal stem cell deficiency. CK13 positive cells are visible on the cornea (2D). The goblet cells can be found through periodic acid-Schiff staining (2E) or Papanicolaou staining (2F) in the samples taken in limbal stem cell deficiency eyes after immunostaining. The goblet cells have 2–3 times larger cell size compared with epithelial cells, and mucus blobs are visible within the cells. The mucus blobs are usually visualized as pink by PAS staining.

Figure 3.

In vivo confocal microscopy imaging. Confocal microscopic images of normal eyes and eyes with limbal stem cell deficiency (LSCD). Panels A-C are images of normal eyes. Panels D-F are images of eyes with LSCD. Normal corneal basal epithelial cells (A) have well-defined, bright cell borders and hypo-reflective cytoplasm, with a regular and uniform arrangement. The nuclei are not visible or are very faint. Sub-basal nerve plexus (B) and the palisades of Vogt (C) are clearly visible in normal eyes. In eyes with severe LSCD, corneal basal epithelial cells are absence and sub-basal nerves were fragmented and the nerve density decreases significantly (D). Goblet cells (arrow) are occasionally visible (E). The palisades of Vogt (F) are not present in eyes with LSCD, but inflammatory cell infiltrates are sometimes visible.

Figure 4.

AS-OCT assessment of normal eyes (A-E) and eyes with limbal stem cell deficiency (LSCD, F-J). In eyes with sectoral LSCD, the corneal epithelial thickness in the affected area is decreased (G) compared to normal eye (B) and unaffected area (G); this reduction is consistent with the slit-lamp finding (F). Cross-sections perpendicular to the limbus show a clear transition between the hyporeflective corneal epithelium and the hyperreflective conjunctival epithelium with limbal epithelial thickening in normal eyes (C) but not in eyes with LSCD (H). The limbal epithelium in the affected area becomes thinner (H). The palisades of Vogt (p in figure) and limbal crypts (c in figure) are clearly visualized in normal eyes on en face mode (D) and parallel section (E), whereas they are absent in LSCD eyes (I and J).

Figure 5.

Staging system of limbal stem cell deficiency (LSCD). The severity of LSCD is classified into 3 stages. Stage I disease only involves the periphery of the cornea and the degree of involvement is staged into A, B and C (top panel). Stage II disease involves both the periphery and the central 5 mm of the cornea (second panel). Stage III disease involves the entire corneal surface (bottom panel).