Pterygium is a benign, wing-shaped fibrovascular proliferation extending onto the cornea. As of today, there are many approaches to its treatment once it is decided that surgical intervention is required. The most common surgical techniques include excision of pterygium with bare sclera, using a conjunctival or conjunctival limbal autograft, coverage with amniotic membrane (AM), or the use of adjuncts such as mitomycin C. Recurrence rates among these techniques vary widely, with reports as high as 88% for the bare sclera technique 1,2,3 and more comparable results among the other mentioned techniques, with a recurrence rate between 0.003 and 40.9%. Conjunctival-limbal autograft offers a low recurrence rate and fewer complications. 4,5,6,7
The major environmental factor for pterygium generation is exposure to ultraviolet (UV) light. Therefore, pterygium has a worldwide distribution and common in peri-equatorial latitudes 37° north and south of the equator, forming a so-called pterygium belt.
Some advantages of using an AM are inhibition of angiogenesis and the possibility to cover a large area without the need of harvesting healthy conjunctiva. Nevertheless, the cosmetic results, postoperative inflammation, and recurrence rates are higher with AM transplantation than they are with conjunctival limbal autografts. 8,9,10
11.2 Pathophysiology
UV radiation (UVR) is damaging for the eye, resulting in a reduction or even loss of vision. The cornea is particularly susceptible to UVR due to its natural transparency and its shape, which contributes to a peripheral light focusing effect, affecting the nasal limbus where UV irradiation is 20-fold stronger. 11,12 This is the most frequent site for the onset of pterygium, a noncancerous growth of the cornea, usually bilateral, which occupies the corneal equator. The pterygium disrupts the limbal barrier, which separates the cornea from the conjunctiva and centripetally invades the cornea surface. It is characterized by squamous hyperplasia and goblet cell hyperplasia. In advanced cases, the visual axis may be covered by vascularized opaque tissue, thus leading to discomfort, deterioration of vision, or even blindness 13 As such dramatic phenotype changes occur in the limbus and its adjacent tissues, alterations in the limbal stem cell niche and its resident limbal epithelial stem cells (LESCs) must also occur. LESCs play a key role in the maintenance of cornea transparency and homeostasis by replenishing its outermost layer, the epithelium. 14 If these stem cells become depleted by injury or disease, the neighboring conjunctival epithelium infringes onto the corneal surface causing vascularization, persistent epithelial breakdown, severe pain, and blindness 15 Although an LESC specific marker remains elusive, the expression of certain proteins, including P63α, ABCG2, and cytokeratin 15 and more recently ABCB5, 16 has been recognized as putative stem cell markers for these cells. 15 High levels of putative stem cell marker expression combined with high colony-forming efficiency 17 are indicative of the stem cell phenotype.
11.2.1 Stem Cells
The major role of cell division in adult life is to maintain the number of differentiated cells at a constant level, that is, to replace cells that have died or been lost through injury. The rate at which new cells are produced is a measure of how rapidly the cell population is turning over. Tissues with a permanently renewing cell population, such as blood, testis, and stratified squamous epithelia (including corneal epithelium), are characterized by rapid and continuous cell turnover; the terminally differentiated cells have a short life span and are replaced through proliferation of a distinct subpopulation of cells, known as stem cells. 18,19 Stem cells are a small subpopulation of the total tissue. Potten and Loeffler 20,21,22 defined stem cells, by virtue of their functional attributes, as “undifferentiated cells capable of
Proliferation.
Self-maintenance.
Producing a large number of differentiated, functional progeny.
Regenerating the tissue after injury.
A flexibility in the use of these options.
11.2.2 Characteristics of Stem Cells
Stem cells are poorly differentiated; the cytoplasm of stem cells appears primitive and contains few, if any, differentiation products.
Stem cells have a high capacity for self-renewal, with an increased potential for error-free proliferation and cell division. Error-free proliferation is essential, as any genetic error at the level of stem cells will continuously and permanently pass on to the whole clone of cells, resulting in abnormal differentiation and cellular dysfunction.
Stem cells have a long life span, which might be equivalent to the life of the organism in which they reside.
Stem cells have a long cell cycle time or slow cycling (which indicates low mitotic activity). Although stem cells are endowed with high proliferative potential, under steady-state conditions they exhibit extremely low rates of proliferation.
Cell division within stem cells can be intrinsically asymmetric, asymmetric only with regard to daughter cell fate, or symmetric. When cell division is obligatorily asymmetric, one of the daughter cells remains as its parent and serves to replenish the stem cell pool, whereas the other daughter cell is destined to divide and differentiate with the acquisition of features that characterize the specific tissue. On the other hand, the asymmetry in division may be determined by the local environment, which induces otherwise similar daughter cells to behave differently.
Finally, all divisions of the stem cell may be symmetric, but are “self-renewing” only half the time.
Regardless of which mechanism is operative during or soon after cell division, one of the daughter cells may follow the path of differentiation. Such a cell is called a “transient amplifying cell” and is less primitive than its parent stem cell. Transient amplifying cells divide more frequently than stem cells, but have a limited proliferative potential and are considered the initial step of a pathway that results in terminal differentiation. They differentiate into “postmitotic cells” and, finally, to “terminally differentiated cells.” Both postmitotic and terminally differentiated cells are incapable of cell division.
Stem cells are usually under protection. In the hemopoietic system, stem cells are stored in bone marrow; in all epithelial tissues, stem cells are in the basal layer. In the corneal epithelium, the stem cells are located in the basal layer at the limbus. 23
11.2.3 Identification of Limbal Stem Cells
The concept that epithelial cells in the limbal region are involved in the renewal of corneal epithelium was first proposed by Davanger and Evensen in 1971. 24 In healed eccentric corneal epithelial defects in heavily pigmented eyes, they observed pigmented epithelial migration lines (cells) that migrated from the limbal region toward the central cornea. 24 They suggested that the limbal papillary structure (palisades of Vogt) serves as a generative organ for corneal epithelial cells. Later, experimental studies by Schermer et al 25 and Cotsarelis et al 26 confirmed that the source of cell proliferation and migration after a corneal epithelial defect is the sclerocorneal limbus.
The limbal basal epithelium contains the least differentiated cells of the corneal epithelium. Epithelial cells contain different types of keratins, some of which indicate a high level of differentiation, whereas others are found mostly in less differentiated cells. 25,27,28
The differential expression of keratins allows the separation of cell populations within the corneal epithelium according to their level of differentiation, though no markers have yet been identified to label LESCs. The 64 KD keratin K3 indicates a cornea-specific type of differentiation. It was observed that keratin K3 exists in the suprabasal epithelium of the limbus and the entire corneal epithelium, but is not expressed in either the limbal basal epithelium or the adjacent bulbar conjunctiva. 25 This observation led to the hypothesis that the limbal basal epithelium lacks a differentiated cornea-type phenotype, and therefore contains the least differentiated cells of the epithelium (i.e., stem cells). The limbal basal epithelium also lacks the expression of the corneal-specific keratin K12, which is expressed in both the suprabasal limbal epithelium and the entire corneal epithelium. 29
The limbal basal epithelium contains cells that exhibit the proliferative characteristics of stem cells. Limbal basal epithelial cells have a higher proliferative potential in culture than central and peripheral corneal epithelial cells. 30,31 Limbal basal cells respond to central corneal wounds and to tumor-promoting agents by undergoing higher proliferation than central corneal epithelial cells, which terminate proliferation-initiating differentiation. 26
Labeling studies have demonstrated that the mitotic index of the corneal epithelium tends to be higher toward the periphery, suggesting that the peripheral corneal basal cells are more active in DNA synthesis. 32
Further support for the limbal location of corneal epithelial stem cells is derived from experimental studies and clinical observations of abnormal corneal epithelial wound healing when the limbal epithelium is partially or completely removed. These studies produced a spectrum of corneal surface abnormalities characterized by conjunctival epithelial ingrowth (conjunctivalization), vascularization, and chronic inflammation, which indicated limbal stem cell deficiency. The conjunctival source of the epithelial ingrowth was proved by immunofluorescent staining with monoclonal antibodies and by the detection of goblet cells with impression cytology. 33,34,35,36
11.2.4 Different Surgical Techniques in Pterygium Excision
With time, different techniques have been employed for the excision of pterygium. One of the first techniques was simple excision with bare sclera. The reported rate of recurrence after simple excision without adjuvant treatment ranges from 24 to 89%. 37 Several techniques have been developed to reduce the recurrence rate, including limbal conjunctival autograft, 38 intraoperative or postoperative application of mitomycin C, 39 bulbar conjunctival autograft, 40 AM transplantation, 41 radiation, 42 photodynamic therapy, 43 antiangiogenic agents, 44 and the combination of two or more of these methods. 45
11.2.5 Role of Conjunctival Autograft in Surgical Management of Pterygium
The procedure involves obtaining an autograft, usually from the superotemporal bulbar conjunctiva, and suturing the graft over the exposed scleral bed after excision of the pterygium. The graft can be either sutured or secured with fibrin glue. Stark and coworkers 46 stress the importance of careful dissection of Tenon’s tissue from the conjunctival graft and recipient bed, minimal manipulation of tissue, and accurate orientation of the graft. Lawrence W. Hirst, MBBS, from Australia recommends using a large incision for pterygium excision and a large graft and has reported a very low recurrence rate with this technique. 47
Conjunctival or limbal conjunctival autografts are suggested to be the best treatment with a low recurrence rate ranging from 1.9 to 5.3%, and high safety according to some studies. 48,49,50,51 Furthermore, they have been demonstrated to be more effective at treating recurrent pterygium than other methods. 52
A meta-analysis to further explore the association between the application of fibrin glue in pterygium surgery and the recurrence rate, complication rate, and surgical duration was conducted. In total, 1,839 eyes from 24 studies were included in the meta-analysis. Based on the overall meta-analysis, it was found that, compared with sutures, fibrin glue was more effective at reducing the recurrence rate, but not the complication rate. Analysis indicated a significantly shorter surgical duration for fibrin glue compared with sutures. In the subgroup analysis, based on region, follow-up time, quality score, sample size, study type, and suture material, fibrin glue still had a lower recurrence rate. Moreover, there were no significant differences in complication rates between the two groups in terms of region, sample size, study type, and suture material. 53
11.2.6 Mini-SLET for Pterygium Treatment
Conjunctival-limbal autograft offers a low recurrence rate and fewer complications; however, it cannot be performed in cases where a large defect needs to be covered or in patients where the conjunctiva needs to be preserved for future glaucoma surgery to avoid conjunctival scarring at the harvesting site.
A novel technique has been described by Hernández-Bogantes et al, 54 taking advantage of the properties of AM and LESCs. This technique describes the use of an AM graft to cover the bare sclera area combined with a small autologous simple limbal epithelial transplant (mini-SLET) to provide stem cells at the limbal area.
A total of 10 eyes underwent pterygium excision with AM coverage of the bare sclera and placement of pieces of limbal epithelium in a linear fashion in the affected limbal area covered by a second AM using fibrin glue. After up to 8 months of follow-up, there were no signs of early recurrence or sight-threatening complications. The minor ipsilateral simple limbal epithelial transplantation technique for the treatment of pterygium requires less tissue than the conventional conjunctival autograft, leaving healthy conjunctiva if needed for another procedure in the future, and offers the advantages of epithelial stem cells, which in the long term may reduce the rate of recurrence significantly. 54
11.2.7 Surgical Technique and Steps of SLET in Pterygium Excision Surgery
Parts of the eye are painted with betadine and draped maintaining sterility (▶ Fig. 11.1).
Using a Lim’s forceps, the body of pterygium is grasped and subconjunctival dissection done with Vannas scissors from forniceal approach (▶ Fig. 11.2).
Once the plane is identified, the head of the pterygium is separated and peeled off using forceps and the conjunctiva falls back toward the fornix (▶ Fig. 11.3 and ▶ Fig. 11.4).
Snip biopsy of the limbus with stem cells is taken using Vannas and chopped into three to four pieces (▶ Fig. 11.5, ▶ Fig. 11.6, ▶ Fig. 11.7).
Pieces are placed over the limbus and the bare sclera, and secured using fibrin and thrombin glue (▶ Fig. 11.8).
After the glue settles (1–2 minutes), bandage contact lens is placed over the cornea.
Betadine eye drops are instilled and eye patched.
Postoperative management consists of removing the patch next day and using topical steroids in tapering fashion for 8 to 12 weeks and topical antibiotics for 1 to 2 weeks or until surface epithelium heals and no epithelial defect observed.
Fig. 11.1 Grade III pterygium: parts of the eye are painted with betadine and draped maintaining sterility.
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