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 Table of Contents  
Year : 2017  |  Volume : 7  |  Issue : 2  |  Page : 75-77

Donor-transmitted melanoma after limbal stem cell transplantation

1 Department of Internal Medicine, Michigan State University College of Human Medicine, East Lansing, Michigan, USA
2 West Michigan Cancer Center, Kalamazoo, Michigan, USA

Date of Web Publication4-Apr-2017

Correspondence Address:
Anas Alsara
Michigan State University College of Human Medicine, East Lansing, Michigan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2231-0770.203609

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Limbal Stem Cells are a unique cell line located at the corneal limbus. They are responsible for regenerating and restoring corneal epithelial layers. Limbal stem cell transplantation is a promising technique that has been used to treat several hereditary and acquired corneal diseases. Cornea tissue lack vascularity. Hence, there were no special restrictions on collecting ocular tissues from donors with a diagnosis of metastatic melanoma. We are reporting a case of a patient who developed an ocular melanoma after she had limbal stem cell transplantation from a donor with history of melanoma. After this case, Eye Bank Association of America updated the donor criteria to exclude donors with any history of melanoma.

Keywords: Donor-transmitted melanoma, limbal stem cell transplant, transplant-related malignancy

How to cite this article:
Alsara A, Rafi M. Donor-transmitted melanoma after limbal stem cell transplantation. Avicenna J Med 2017;7:75-7

How to cite this URL:
Alsara A, Rafi M. Donor-transmitted melanoma after limbal stem cell transplantation. Avicenna J Med [serial online] 2017 [cited 2020 Sep 29];7:75-7. Available from: http://www.avicennajmed.com/text.asp?2017/7/2/75/203609

   Introduction Top

Limbal stem cell transplant (LSCT) represents a promising treatment for many ocular conditions. In general, posttransplant immunosuppression status predisposes to malignancy. We are reporting a case of donor-derived melanoma following LSCT. Before this case, Eye Bank Association of America accepted limbal stem cell donors with active malignancies except for leukemia, lymphoma, myeloma, retinoblastoma, and tumors of the anterior segment of the eye. To the best of our knowledge, there were no previous reports in the literature of LSCT with a similar complication.

   Case Report Top

Patient is a 56-year-old Caucasian female, with a history of corneal dystrophy that progressed to bilateral limbal stem cell deficiency (LSCD). The patient received a right eye LSCT from a cadaveric donor. The LSCT was initially complicated with keratoconjunctivitis, so she was treated with systemic and topical antibiotics. To prevent graft rejection, systemic immunosuppressive therapy (prednisone, tacrolimus, and mycophenolate mofetil), as well as topical ocular immunosuppressive therapy (prednisolone acetate, cyclosporine, and difluprednate), were initiated.

Ten weeks after the transplantation, she presented to her ophthalmologist with a complaint of a sudden decrease in vision acuity of the right eye. The eye exam revealed what appeared to be right eye subconjunctival hemorrhage. A following orbital computerized axial tomography scan revealed a right intraorbital soft tissue mass measuring 1.8 cm (horizontal) × 1.5 cm (vertical), with preseptal thickening [Figure 1]. There were no intraconal or intraocular masses. The management options were discussed with the patient, and she declined eye enucleation surgery and insisted on preserving her eyeball. The patient did agree to tumor resection, which was performed with partial tarsorrhaphy. Furthermore, the immunosuppression therapy was held.
Figure 1: Orbital computerized axial tomography scan illustrate intraorbital mass: Axial window (left) coronal window (right)

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The biopsy pathological evaluation was consistent with a malignant neoplasm. In addition, immunostaining was strongly positive for S100, melanoma antigen recognized by T cell (cytoplasm), and SOX-10 (nuclear). The tumor cells were negative for pankeratin, p40, and leukocyte common antigen (CD45). The histologic and immunohistochemical findings were characteristic of a malignant melanoma and ruled out both undifferentiated carcinoma and lymphoma.

At this point, the patient was referred to a medical oncologist for further management. A positron emission tomography scan ruled out any undifferentiated, occult primary neoplasm. A review of the donor medical records revealed that he died due to malignant melanoma. The histopathological evaluation of BRAF mutation in the melanoma cells was negative in both the patient and the deceased donor.

The patient was also treated with topical mitomycin C (MMC) chemotherapy and had a successful keratoprosthesis to improve her vision. She is now following up with an ocular oncologist for further management with possible radiation.

   Discussion Top

The cornea is an avascular tissue covered anteriorly by a multilayer stratified, nonkeratinized epithelium. This epithelium is constantly regenerated by limbal stem cells, a unique cell population located in the basal epithelial layer of the corneal limbus (the corneo-conjunctival junction).[1] The corneal stroma is an avascular collagenous layer with a very poor propensity for neoangiogenesis. Hence, before this case, there were no special restrictions on obtaining ocular tissues for transplantation from donors with metastatic melanoma. The Eye Bank Association of America accepted ocular tissue from donors with active malignant tumors except for active leukemia, lymphoma, myeloma, retinoblastoma, and tumors of the anterior segment of the eye.[2]

Corneal limbal stem cells may be destroyed or become dysfunctional as a result of several hereditary and acquired conditions. LSCD can lead to corneal opacity and vascularization, with consequent vision impairment or blindness. When limbal stem cells are completely depleted, then any successful treatment must include the introduction of new stem cells. This treatment is called LSCT. There are four LSCT procedures that have been developed: conjunctival-limbal autologous transplantation; living-related conjunctival-limbal allogeneic transplantation; keratolimbal allogeneic transplantation; and ex vivo expansion of LSCT.[3]

Reported long-term complications of LSCT include epithelial rejection; microbial keratitis; corneal necrosis; and corneal ulceration. These complications can usually be treated with antibiotics. However, failure of treatment may result in graft rejection.[3] In general, allograft transplantation has the risk of rejection even in human leukocyte antigen-matched recipients. Therefore, all allograft transplants require prolonged systemic immunosuppression to decrease eye inflammation and prevent allograft rejection.[4]

Topical (ophthalmic) immunosuppressants alone are usually insufficient in controlling allograft rejection. Treatment regimens combining both topical and systemic immunosuppressive are usually preferred.[1],[5]

However, one of the adverse effects of the long-term immunosuppressive status after organ transplantation is a malignancy, which represents a major contributor to morbidity and mortality in the organ-recipient population.[6] Malignancies might arise after different types of transplantation: solid organ transplantation, bone marrow transplantation, and hematopoietic stem cell transplantation.[7],[8]

These malignancies develop in one of three contexts:

  1. De novo malignancy in the immunosuppressed recipient is the predominant mechanism. Nonmelanoma skin cancer is the most common malignancy to develop following solid organ transplantation [9]
  2. Recurrence of treated pretransplant malignancy is less frequent. The highest recurrence rate was for breast cancer, symptomatic renal cell cancer, sarcoma, bladder cancer, and multiple myeloma.[10] There is no evidence of increased risk for melanoma in organ transplant population compared to the general population [7]
  3. Unintended transmission of malignant cells from a donor is relatively rare.[9] Birkeland and Storm estimated a 1.3% risk of having a donor with previously undetected malignancy and a risk of 0.2% for a recipient to develop a transmitted malignancy.[11] Renal cell carcinoma is the most commonly transmitted cancer originating in the donor organ, while malignant melanoma is the most common transmitted cancer with distant metastases.[6],[12]

To the best of our knowledge, this case of donor-transmitted malignant melanoma following LSCT is the first to be reported.

Donor transmission of melanoma can be explained by tumor cell dormancy. Melanoma cells are considered “dormant” when a balance is achieved between active proliferation and apoptosis in micrometastases. Dormancy also occurs in the absence of proliferation and apoptosis in solitary tumor cells. Melanoma cells, whether micrometastases or solitary tumor cells, can stay dormant for years, residing in the organ parenchyma or circulating within the vasculature. However, they may “escape” the state of dormancy in immunosuppression settings as with posttransplant conditions.[7]

Recommendations for management of donor-transmitted melanoma include withdrawal of immunosuppression therapy, which potentially prompts rejection of the tumor cells. Removal of the allograft may also be considered.[13],[14] Because the complete removal of malignant cells is not always possible, some authors suggest adding adjuvant chemotherapy to eliminate residual tumor cells.[15] In particular, topical chemotherapy with MMC has been established as a good adjuvant therapy option for various conjunctival tumors. MMC is an alkylating antibiotic that affects all phases of the cell cycle.[16] It has good tolerability with mild side effects, including transient keratoconjunctivitis and decreased conjunctival pigmentation.[17] Additional randomized trials are needed for the final evaluation of MMC therapy for ocular melanoma.[18]

   Conclusion Top

Posttransplant malignancy is a major limitation to successful transplantation and may increase transplant-related morbidity and mortality. Immunosuppression status following transplantation predisposes to malignancy. No previous case of donor-transmitted malignancy following LSCT has been reported yet. Management of donor-transmitted melanoma includes withdrawal of immunosuppression, tumor excision, and adjuvant therapy. Prevention is essential and emphasizes the importance of careful cancer screening for stem cell donors. After reporting this case to the Eye Bank Association of America, which previously accepted patients with an active or remote history of melanoma, the criteria for ocular tissue donors have been reviewed. New exclusionary criterion was added, stating that ocular tissue from donors with any history of melanoma may not be released for any surgical use.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Bakhtiari P, Djalilian A. Update on limbal stem cell transplantation. Middle East Afr J Ophthalmol 2010;17:9-14.   Back to cited text no. 1
[PUBMED]  [Full text]  
Campanelli M, Mistò R, Limongelli A, Valente MG, Cuttin MS, D'Amato Tóthová J. A donor cornea with metastatic cells from a cutaneous malignant melanoma. Cornea 2013;32:1613-6.   Back to cited text no. 2
Health Quality Ontario. Limbal stem cell transplantation: An evidence-based analysis. Ont Health Technol Assess Ser 2008;8:1-58.   Back to cited text no. 3
Liang L, Sheha H, Li J, Tseng SC. Limbal stem cell transplantation: New progresses and challenges. Eye (Lond) 2009;23:1946-53.   Back to cited text no. 4
Myron Kauffman H, McBride MA, Cherikh WS, Spain PC, Marks WH, Roza AM. Transplant tumor registry: Donor related malignancies. Transplantation 2002; 74:358-62.   Back to cited text no. 5
Morris-Stiff G, Steel A, Savage P, Devlin J, Griffiths D, Portman B, et al. Transmission of donor melanoma to multiple organ transplant recipients. Am J Transplant 2004;4:444-6.   Back to cited text no. 6
Strauss DC, Thomas JM. Transmission of donor melanoma by organ transplantation. Lancet Oncol 2010;11:790-6.   Back to cited text no. 7
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: Incidence and risk factors. J Clin Oncol 2003;21:1352-8.  Back to cited text no. 8
Zafar SY, Howell DN, Gockerman JP. Malignancy after solid organ transplantation: An overview. Oncologist 2008;13:769-78.   Back to cited text no. 9
Penn I. Evaluation of transplant candidates with pre-existing malignancies. Ann Transplant 1997;2:14-7.   Back to cited text no. 10
Birkeland SA, Storm HH. Risk for tumor and other disease transmission by transplantation: A population-based study of unrecognized malignancies and other diseases in organ donors. Transplantation 2002;74:1409-13.   Back to cited text no. 11
Džambová M, Secníková Z, Jiráková A, Juzlová K, Viklický O, Hošková L, et al. Malignant melanoma in organ transplant recipients: Incidence, outcomes, and management strategies: A review of literature. Dermatol Ther 2016;29:64-8.   Back to cited text no. 12
Penn I. Transmission of cancer from organ donors. Ann Transplant 1997;2:7-12.   Back to cited text no. 13
Kim JY, Djalilian AR, Schwartz GS, Holland EJ. Ocular surface reconstruction: Limbal stem cell transplantation. Ophthalmol Clin North Am 2003;16:67-77.   Back to cited text no. 14
Stephens JK, Everson GT, Elliott CL, Kam I, Wachs M, Haney J, et al. Fatal transfer of malignant melanoma from multiorgan donor to four allograft recipients. Transplantation 2000;70:232-6.  Back to cited text no. 15
Demirci H, McCormick SA, Finger PT. Topical mitomycin chemotherapy for conjunctival malignant melanoma and primary acquired melanosis with atypia: Clinical experience with histopathologic observations. Arch Ophthalmol 2000;118:885-91.   Back to cited text no. 16
Finger PT, Czechonska G, Liarikos S. Topical mitomycin C chemotherapy for conjunctival melanoma and PAM with atypia. Br J Ophthalmol 1998;82:476-9.   Back to cited text no. 17
Schallenberg M, Niederdräing N, Steuhl KP, Meller D. Topical mitomycin C as a therapy of conjunctival tumours. Ophthalmologe 2008; 105:777-84.  Back to cited text no. 18


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