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  5. FP397 : Limbal Stem Cell Transplantation in Extensive Ocular Surface Squamous Neoplasia: Muticentre Study

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Dr. Purvasha Narang, N12281, Dr. Bhaduri Anirban, Dr. Vikas Menon, Dr. Vikas Mittal

Abstract:

Introduction:

Ocular surface squamous neoplasia (OSSN) includes a spectrum of corneal and conjunctival dysplasia and squamous cell carcinoma and represents the most common tumour of the ocular surface.1 The surgical and medical management of OSSN includes wide mass excision with cryotherapy of the conjunctival margins, and chemotherapy (Mitomycin C, 5-Fluorouracil and Interferon alpha 2b) respectively.2 While the treatment for smaller lesions has excellent prognosis, that of larger tumours extensively involving limbus is far more challenging. The impact of the tumour and its treatment often results in significant loss of limbal stem cells leading to limbal stem cell deficiency (LSCD).3-5This may necessitatea repeat surgery in the form of limbal stem cell transplant (LSCT) using various techniques. We hereby report management of cases with extensive OSSN with simultaneous excisional biopsy of lesion and LSCT.

MATERIALS AND METHODS:

This was a multi- centre, comparative and interventional clinical study of cases and historical controls, performed at Cornea and Anterior Segment services of Sanjivni Eye Care (Now at LJ Eye Institute, Ambala, India), Ocular Oncology Services, CMRI Hospital (Kolkata, India) and Ocular oncology services of Centre for Sight (New Delhi, India) from January 2009 to June 2014. A written and informed consent was obtained from all patients for all the surgical procedures, photo documentation and investigations. Patients with a limbal mass suggestive of OSSN involving more than 3 quadrants of limbus (> 9 clock hours), who underwent primary surgical excision with or without adjuvant chemotherapy and had a minimum follow- up of 12 months were included in this study. The demographic and clinical data was collected in a pre-designed form that included the age and gender of the patient, history of  systemic disease, duration of the limbal mass prior to presentation, morphologic variant of tumor, quadrantic location and extent of encroachment over cornea, limbus or conjunctiva, and  number of clock hours of limbal involvement and any regional lymph node involvement, type of surgical intervention, clinical condition after surgery especially the signs of LSCD (absence of the limbal palisades of Vogt, dull and irregular corneal epithelium, superficial corneal vascularisation, persistent epithelial defects or PEDand conjunctival overgrowth on the corneal surface like pannus, symblepharon or pseudo-pterygium) and the time and extent of their occurrence, pre- and post-operative best corrected visual acuity (BCVA) and the  histopathological findings. All patients underwent extended tumour excision along with double freeze thaw cryotherapy and amniotic membrane grafting. The limbal tumours were excised along with a 4 mm zone of clinically clear conjunctiva around the tumour using the ‘No touch technique’. Free edges of the excised conjunctiva and the involved limbus were then treated with cryotherapy with two freeze-thaw cycles. Bare sclera was covered with preserved human amniotic membrane graft (AMG), secured with fibrin glue (Tisseel Kit, Baxter AG, Vienna, Austria). Patients 1 and 2 were treated with the above mentioned technique only. Three patients underwent simultaneous LSCT. Patients 3 and 4, in addition, also received a standard conjunctivo-limbal autograft (CLAG), from the contralateral healthy eye and were glued onto the entire bare tenons and limbus with proper orientation, prior to the AMT. Patient 5 underwent simple limbal epithelial stem cell transplant or SLET after excision of the tumour as described above. The surgical technique was similar to one described by Sangwan et al6 and Mittal et al7, 8. Topical prednisolone acetate 1%six times a day was started in the donor eye the same day after surgery and in the recipient eye from the following day. It was tapered over 4 weeks in the healthy donor eye (in cases 3, 4 and 5) and up to 3 months in the diseased eye depending upon the ocular surface inflammation. Topical moxifloxacin 0.5% was used 4 times a day until the ocular surface epithelialised in both eyes, usually for a week in the donor and 2 weeks in the diseased eye. Preservativefree lubricants were used in both eyes of all cases.

Primary outcome Measure: Presence or absence of LSCD after tumour control.

RESULTS:

Five eyes of 5 patients fulfilled the inclusion criteria. The patient details and results are summarised in Table 1. The median age was 62.8 years (Range 26-75 years). All patients were males. Mean follow up was 90 months (8 and 7 years respectively for the 2 eyes) for the non LSCT group and 50 months (62, 57 and 31 months respectively for the 3 eyes) for the LSCT group. Three out of five patients underwent limbal epithelial cell transplant (LSCT) along with primary tumour excision. The first two patients during the early period of thisstudy, underwent surgery for tumour control and amniotic membrane grafting only. The average time taken for surface re- epithelialisation in the first two cases was 26.5 days; whereas the rest of the eyes took an average of 18.67 days to re-epithelialise after either autografting or SLET. Histopathology revealed carcinoma-in-situ in one eye and invasive squamous cell carcinoma in the rest of the four cases. None of these patients developed any sign of local recurrence or loco-regional or systemic metastasis till the last follow up.

DISCUSSION:

We share our experience with 3 cases of extensive OSSN successfully managed with simultaneous limbal stem cell restoration. We were able to achieve a stable ocular surface even after excision of the entire tumour along with extensive limbal stem cell debridement. The aim of LSCT was to provide a smooth epithelial surface for maintenance of better optical clarity of cornea and to reduce patient morbidity postoperatively.

Asoklis et al, in their series of OSSN (with mean of 4 clock hours of limbal involvement) showed that AMT could suffice for primary surface reconstruction, but signs of LSCD developed in few of the cases.3 AMT alone may not be enough when dealing with more extensive disease. Advanced corneo-scleral limbal spread of OSSN can lead to destruction of the epithelial stem cells that reside in limbal palisades of Vogt. OSSN itself has been reported as a rare cause of LSCD.9Wide surgical excision is often undertaken in these cases, especially when chemotherapy fails to achieve remission. This has a deleterious impact on the survival of stem cells in the involved region, resulting in large conjunctival and often corneal epithelial defects. Many reports substantiate the prevalence of LSCD following wide tumour excision, leading to performance of secondary procedures to restore the limbal stem cells.5, 10Lyall et al have reported successful outcome of conjunctival autograft coupled with surgical tumour excision in one patient with extensive OSSN.9 A novel technique of restoring limbal stem cell niche, namely SLET, has proven to be very effective.10 Apart from avoidance of additional procedures, an autograft or SLET also have the added advantage of not requiring systemic immunosuppression. None of these cases showed any sign of LSCD at the end of follow up and all the patients were tumour free with no signs of recurrence locally or systemically. We observed that the LSCT procedures either in the form of CLAG orSLET, had been performed at different operative centres by various surgeons for comparable lesions but the results were similar and repeatable. Hence, as recommended, our study did not suffer any institutional bias.

Limitations of our study are its retrospective nature and a small sample size. OSSN being a rare disease and cases with more than three quadrants of limbus involvement being even rarer; a large sample size for the study was not possible. Also, we have not included treatment with interferons (immunotherapy) in this study as our experience i with them is limited due to financial and logistic constraints. Further studies on refinements in the techniques of LSCT might help in improving the post operative outcomes in these patients. However, caution needs to be exercised in cases of OSSN in xerodermapigmentosum as the tumours in such patients are usually bilateral , thereby rendering autograftinginadvisable.11 To summarise, our study describes the importance of LSCT, in any form (either a conjunctival limbal autograft or SLET) in extensive OSSN with more than three quadrants of limbal involvement, to prevent manifestations of stem cell deficiency, thus, suggesting extensive OSSN (involving the limbus) as an important indication for LSCT and more recently, SLET.

REFERENCES

  1. Grossniklaus HE, Green WR, Luckenbach M, et al. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 1987;6(2): 78-116.
  2. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol 1997;115(6): 808-815.
  3. Asoklis RS, Damijonaityte A, Butkiene L, et al. Ocular surface reconstruction using amniotic membrane following excision of conjunctival and limbal tumors. Eur J Ophthalmol 2011;21(5): 552-558.
  4. Meallet MA, Espana EM, Grueterich M, et al. Amniotic membrane transplantation with conjunctival limbal autograft for total limbal stem cell deficiency. Ophthalmology 2003;110(8): 1585-1592.
  5. Dua HS, Azuara-Blanco A. Autologous limbal transplantation in patients with unilateral corneal stem cell deficiency. Br J Ophthalmol 2000;84(3): 273-278.
  6. Sangwan VS, Basu S, MacNeil S, et al. Simple limbal epithelial transplantation (SLET): a novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol 2012;96(7): 931-934.
  7. Mittal V, Jain R, Mittal R, et al. Successful management of severe unilateral chemical burns in children using simple limbal epithelial transplantation (SLET). Br J Ophthalmol 2015 (issue and page number).
  8. Mittal V, Jain R, Mittal R. Ocular surface epithelialization pattern after simple limbal epithelial transplantation: an in-vivo observational study. Cornea 2015;34(10): 1227-1232.
  9. Lyall DA, Srinivasan S, Roberts F. Limbal stem cell failure secondary to advanced conjunctival squamous cell carcinoma: a clinicopathological case report. BMJ Case Rep 2009;2009.
  10. Mittal V, Narang P, Menon V, et al. Primary simple limbal epithelial transplantation along With excisional biopsy in the management of extensive Ocular Surface Squamous Neoplasia. Cornea 2016;35(12): 1650-1652.
  11. Gupta N, Sachdev R, Tandon R. Ocular surface squamous neoplasia in xeroderma pigmentosum: clinical spectrum and outcome. Graefes Arch Clin Exp Ophthalmol 2011;249(8): 1217-1221.

 

 

 

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