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Taiwan Journal of Ophthalmology 4 (2014) 97e99
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Case report
Post-chemotherapy bilateral limbal stem cell deficiency
Yen-Wen Hsieh a, Jiunn-Liang Chen a, b, c, *, Shwu-Jiuan Sheu a, c, Jyh-Seng Wang d
a
Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
Chung Hwa University of Medical Technology, Tainan, Taiwan
c
National Yang-Ming University School of Medicine, Taipei, Taiwan
d
Department of Pathology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2013
Received in revised form
14 August 2013
Accepted 29 August 2013
Available online 25 October 2013
We report an extremely rare case of bilateral total limbal stem cell deficiency (LSCD) induced by longterm systemic chemotherapy for squamous cell carcinoma of the lung, and the outcomes of bilateral
keratolimbal allograft transplantation (KLAT) in such a case. A 34-year-old male patient had underlying
disease of squamous cell carcinoma in the right upper lung with extensive mediastinum and lymph node
metastasis and received a series of systemic chemotherapy, including a combination of vinorelbine and
cisplatin and a combination of gemcitabine, cisplatin, and docetaxel. According to clinical manifestations
of ocular surface disorder, pathology findings, and immunostaining of cytokeratin 13 (CK13), LSCD
secondary to systemic chemotherapy was diagnosed. KLAT was performed in both eyes. Although graft
rejection developed in the right eye, complete re-epithelialization with favorable visual acuity occurred
in the left eye 3 years after limbal transplantation.
Copyright Ó 2013, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights
reserved.
Keywords:
keratolimbal allograft transplantation
limbal stem cell deficiency
systemic chemotherapy
1. Introduction
Corneal limbus is well known as an area containing stem cells
that are important as a regenerative source of corneal epithelial
cells. In addition, the limbus acts as a barrier between the cornea
and the conjunctival epithelium. Limbal stem cell deficiency (LSCD)
may lead to failure in the maintenance of the regenerative capacity
of corneal epithelial cells and lead to replacement of corneal
epithelial cells by the invading conjunctival epithelium. The clinical
features of corneal diseases with LSCD include conjunctivalization
of cornea, poor corneal epithelialization, persistent epithelial defects, corneal scarring, chronic inflammation, corneal vascularization, and fibrous ingrowth.1e3
LSCD may occur in two major clinical settings. It may be caused
by destruction of the limbal stem cell population [chemical or
thermal injuries, ocular cicatricial pemphigoid (OCP), StevenJohnson syndrome, contact lens-related trauma, severe microbial
infection, and iatrogenic causes such as repeated surgeries or
cryotherapies]; or dysfunction of the stromal microenvironment of
limbal stem cells (aniridia, ectodermal dysfunction, chronic
Conflicts of interest: The authors have no conflicts of interest relevant to this
article.
* Corresponding author. Department of Ophthalmology, Kaohsiung Veterans
General Hospital, 386, Ta-Chung First Road, Kaohsiung 813, Taiwan, ROC.
E-mail address: [email protected] (J.-L. Chen).
limbitis, peripheral ulcerative keratitis, and idiopathic keratopathy). Topical cytotoxic agents such as 5-fluorouracil and mitomycin C have been reported to delay corneal epithelialization and
induce LSCD when applied locally.4,5 Yet LSCD secondary to systemic chemotherapy has seldom been reported. To date, two cases
of LSCD related to hydroxycarbamide6,7 have been reported in the
literature. However, LSCD arising from combination systemic
chemotherapy has never been reported. Herein we report such an
extremely rare case.
2. Case report
A 34-year-old man visited our hospital in May 2009 due to
progressive blurred vision in both eyes for 1 year. The patient was a
victim of right upper lung squamous cell carcinoma with extensive
mediastinum and lymph node metastasis. He had received a series
of chemotherapy regimens of cisplatin combined with vinorelbine,
cisplatin combined with gemcitabine and docetaxel from
November 2007 to October 2008. He denied any history of ocular
trauma or surgery. Six months after chemotherapy, he complained
of decreased visual acuity with pain, severe photophobia, itching,
and redness in both eyes. He received treatment from his local
general practitioner, but in vain. At the initial visit, his best corrected visual acuity was 6/15 in the right eye and 6/60 in the left
eye. Slit lamp biomicroscopy revealed bilateral multiple irregular
whitish-gray opacifications on the corneal surface, and the lesions
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http://dx.doi.org/10.1016/j.tjo.2013.08.003
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Y.-W. Hsieh et al. / Taiwan Journal of Ophthalmology 4 (2014) 97e99
Fig. 1. Preoperative pictures showed an advanced ocular surface disorder in the chronic inflammation phase with raised whitish-gray opacifications (arrows) above the corneal
surface, marked 360-degree corneal vascularization (arrowheads) with vessel extending 4e5 mm from the limbus into the center of the cornea in the right eye (A) and 1e2 mm in
the left eye (B).
were localized between subepithelial and anterior stroma. In spite
of topical lubricants and anti-inflammatory medications, increasing
central corneal opacity with surrounding engorged hyperemic
vessels and 360-degree superficial and deep corneal vascularization towards the corneal center developed in both eyes 2 years later
(Fig. 1). He also experienced secondary glaucoma and recurrent
central corneal ulceration. His visual acuity had deteriorated to
counting fingers in the right eye and to 3/60 in the left eye.
Under the impression of LSCD, limbal stem cell transplantation was done to restore the ocular surface before lamellar
corneal transplantation. The procedure included keratolimbal
allograft transplantation (KLAT) from a cadaver donor following
superficial keratectomy and fine needle cauterization of stromal
neo-vascularization in both eyes (the left eye in June 2011 and
the right eye in November 2011). Systemic cyclosporine A (IVAX,
Opava, Czech) and Prednisolone VPP (Taiwan Veterans Pharmaceutical, Taoyuan County, Taiwan) were given for immunosuppression after the surgeries. The final visual acuity was 6/20 with
complete corneal re-epithelialization in the left eye but poor
corneal re-epithelialization in the right eye due to severe
rejection.
Corneal pathology disclosed marked thinning of the corneal
epithelium, focal absence of Bowman’s layer, moderate B-cell and
T-cell lymphocytes, and neutrophil infiltration in the left eye
(Fig. 2A). The pathologic picture of the limbus revealed few goblet
cells, T-lymphocyte infiltration with CD3 immunostaining (Fig. 2C),
B-lymphocyte infiltration with CD20 immunostaining (Fig. 2D),
fibrosis, and neovascularization in the subepithelial tissue of the
left eye (Fig. 2B). In addition, the presence of positive cytokeratin 13
(CK13) squamous epithelium overlying the corneal stroma of the
right eye supported the diagnosis of LSCD (Fig. 2E). OCP was less
favored because conjunctiva pathology revealed rare CD117positive mast cells (Fig. 3A), few CD68-positive macrophages
(Fig. 3B), and the negative finding of linear deposition of immunoglobulin G (IgG) along the epithelial basement membrane zone
by direct immunofluorescence (DIF) (Fig. 3C).
3. Discussion
The diagnosis of LSCD has long relied on clinical features such as
replacement of the corneal epithelium with conjunctiva, chronic
inflammation, poor corneal epithelial healing, and stromal corneal
Fig. 2. (A) The sections of the specimen showed a picture of corneal tissue with marked thinning epithelium and focal absence of Bowman’s layer (arrow) and aggregation of
lymphocytes composed of both B-cells and T-cells and neutrophils in the subepithelial tissue (arrowheads). (B) The sections of the limbal tissue specimen exhibited the presence of
moderate lymphocyte infiltration (arrow) composed of both T-cells and B-cells with CD3 immunostaining [in (C), arrow] and CD20 immunostaining [in (D), arrow], fibrosis, and
neovascularization (arrowhead) in the subepithelial tissue. (E) The immunohistochemistry stain of cornea reveals the presence of CK13-positive squamous epithelium (arrow)
overlying corneal stroma. (A: H&E 200; B: H&E 100; E: 100). CK13 ¼ cytokeratin 13; H&E ¼ hematoxylin and eosin.
Y.-W. Hsieh et al. / Taiwan Journal of Ophthalmology 4 (2014) 97e99
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Fig. 3. (A) A rare CD117-positive mast cell (400). (B) A few CD68-positive macrophages (400). (C) The negative finding of linear deposition of IgG (arrows) along the epithelial
basement membrane zone by DIF (400). DIF ¼ direct immunofluorescence; IgG ¼ immunoglobulin G.
scarring. The invasion of goblet cells in the cornea under impression cytology could also confirm the diagnosis.8 Identification of
surface marker would facilitate the diagnosis of LSCD. Poli et al
developed a validated and reliable technique by immunocytochemical detection of highly specific conjunctival and corneal
cytokeratins for diagnosis of LSCD,9 in which it was shown that
CK12 is specific for corneal differentiation whereas CK13 is specific
for conjunctival differentiation. In our case, the presence of positive
CK13 squamous epithelium overlying corneal stroma confirmed the
diagnosis of LSCD. OCP was ruled out by conjunctival biopsy plus a
DIF test of IgG.
Based on the history and clinical findings, we speculated that
chemotherapy is the cause of LSCD in our case. In Ellies’ report,
LSCD might be reversible after cessation of hydroxycarbamide.6
However, our case could not change the regimen of chemotherapy as the combination was the only responding one for him.
Although limbal graft failure occurred in his right eye, the worse
eye, a favorable outcome was obtained in his left eye. Compared to
the previous two case reports of LSCD following single chemotherapy, our case had been exposed to multiple chemotherapy
including vinorelbine, cisplatin, gemcitabine, and docetaxel.
Chemotherapy drugs can affect only dividing cells (cell cyclespecific) or cells at rest (cell cycle-nonspecific). Vinorelbine and
docetaxel inhibit the microtubule structures and ultimately result
in cell death. Gemcitabine is known as the family of drugs called
antimetabolites, which are very similar to normal substances and
are incorporated into cellular metabolism to make the cell cycle
cease. Cisplatin is classified as an alkylating agent, which is most
active in the resting phase. These cytotoxic agents with the
essential propensity of targeting rapidly dividing cells may
contribute to the induction of stem cell damage, including that of
the cornea. Even so, surgical treatment is still possible to offer
benefit.
The management of ocular surface disorders, particularly complete LSCD, has always been a challenging condition for ophthalmologists. Generally, the treatment depends on the extent of LSCD
whether it is partial, total, unilateral, or bilateral. In partial LSCD
with the visual axis involved and decreased vision, the conjunctivalized epithelium covering the cornea is removed to allow
the remaining intact limbal epithelium to reconstruct the corneal
surface. In total LSCD, limbal stem cell transplantation is the only
available treatment of LSCD, for instance autograft (from the
contralateral eye)10 in unilateral cases or allograft11 (from a living
related donor or a cadaver donor) transplantation can harvest
healthy limbal stem cells to the damaged eye. In allograft transplantation, systemic immunosuppression is required to diminish
the risk of graft rejection and maintain the survival of the limbal
transplant. Recently, with the increased knowledge on stem cell
biology, cultured limbal stem cells represent another source of cells
for subsequent transplantation to repair the LSCD disorder.12
Our case demonstrated a linkage between systemic chemotherapy and bilateral progressive LSCD, which was rarely reported.
The pathogenesis might be due to stem cell failure due to chemical
injury or a deficit in the stem cell niche.13 Chemotherapy can induce
systemic and local side effects, such as hematopoietic stem cell
impairment. Lucas et al demonstrated that cisplatin-induced neuropathy in the bone marrow may prevent hematopoietic regeneration in an animal study.14 However, the underlying mechanisms of
chemotherapy-induced stem cell suppression remain unresolved.
Clinically, we monitor blood cell count to evaluate the severity of
the hematopoietic stem cell impairment. After systemic administration of chemotherapy, we monitor the drug toxicity levels in the
aqueous and tear films, which reflect the LSCD. However, this
ocular drug level is hard to detect based on the current technique.
In our case, clinical manifestation and pathologic evidence
(including positive CK13) support the diagnosis of LSCD. With the
increasing number of people receiving systemic chemotherapy for
a variety of diseases, we recommend detailed history investigation
in all cases of idiopathic corneal epitheliopathy characterized by
progressive LSCD. Once drug toxicity is suspected, cessation or
modification of the toxic agent should be considered.
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