Although post-transplant lymphoproliferative disorder (PTLD) is the most common malignancy complicating solid organ transplantation, it has rarely been associated with ocular manifestations. Review indicates that only 20 cases of ocular PTLD have been reported in the literature.
In 2018, a multidisciplinary team comprising four subspecialties — pediatric ophthalmology, ocular oncology, pediatric oncology and pediatric transplant — at Mayo Clinic's campus in Rochester, Minnesota, reported on its successful treatment of a case of bilateral ocular involvement by PTLD with histopathologic features of extranodal marginal zone (MALT) lymphoma in an 8-year-old boy after orthotopic heart transplantation. The anterior segment disease was treated successfully using a combination of intraocular and systemic injections of humanized anti-CD20 antibody (rituximab). Results were published in the Journal of AAPOS.
Ocular signs and symptoms, 5 years post-surgery
The patient, an 8-year-old boy, underwent orthotopic heart transplantation at 3 years of age for decompensated heart failure after presumed viral myocarditis.
His initial postoperative recovery was complicated by primary graft dysfunction, from which he recovered, and bilateral cerebrovascular accidents that resulted in bilateral hemiparesis and right visual field loss. Over the following year, he developed chronic low-grade Epstein-Barr virus (EBV) viremia that peaked at 19,800 copies/mL of whole blood, with concurrent elevation of liver enzymes, attributed to EBV hepatitis, which resolved after reduction of his immunosuppression.
Five years after transplant surgery, he presented at Mayo Clinic for persistent bilateral eye redness and rubbing. On examination, visual acuity in both eyes was 20/40. There was bilateral minimal conjunctival injection, small keratic precipitates in the right eye and larger mutton-fat keratic precipitates in the left eye, bilateral anterior chamber (AC) cellular reaction with flare, and multiple iris nodules in the left eye. Posterior segment examination was normal in each eye.
Biopsy of one of the left iris nodules revealed an infiltrate of small CD20-positive B cells with intermixed plasma cells that had restricted, monoclonal expression of kappa immunoglobulin light chains and absence of lambda light chains. The lesion was diffusely positive for EBV on immunohistochemical studies. The proliferating cells were small, with morphology resembling extranodal marginal zone lymphoma. A diagnosis of post-transplant lymphoproliferative disorder with marginal zone lymphoma-like features was made.
Intraocular and systemic rituximab injections
Lacking improvement after topical steroids and stopping mycophenolate mofetil, treatment with the anti-CD20 antibody, rituximab, was initiated. "Of the 20 previously reported cases, none received intraocular injections of rituximab and two received systemic injections," says Jose S. Pulido, M.D., an ocular oncologist at Mayo Clinic's campus in Rochester, Minnesota. "Rituximab has been increasingly used in treatment of CD20-positive PTLD in children, but there are very few reports on the use of intraocular rituximab."
"We elected to combine systemic rituximab with intraocular injections because of limited evidence on the effectiveness of systemic rituximab in penetrating the blood-aqueous barrier — and because one of the two previously reported cases developed ocular PTLD despite previously receiving systemic injections," says Shakila P. Khan, M.D., a pediatric oncologist at Mayo Clinic in Rochester, Minnesota. "We chose not to use intraocular injections as monotherapy, because there are no reports on exclusive use of this route to treat ocular PTLD."
The patient showed complete response initially to this combination but had a recurrence of keratic precipitates and AC cellular reaction several months later. "We cannot be certain whether that represented a true recurrence, but we elected to treat with further intraocular injections and no systemic injections," says Erick D. Bothun, M.D., a pediatric ophthalmologist at Mayo Clinic in Rochester, Minnesota. "We opted to inject methotrexate intraocularly as well, which may or may not have contributed to improvement." On final follow-up, eight months after the initial injection, the patient had not developed any signs of ocular toxicity.
One week after his last injections, both the AC cellular reaction and the iris masses had resolved. Improvement continued for three months, at which point AC reaction and keratic precipitates recurred bilaterally. An AC tap was negative for malignancy.
The patient was further treated with a single intravitreal injection of rituximab and a single injection of methotrexate in each eye. Within two weeks, keratic precipitates resolved completely, and he was left with trace AC cellular reaction, successfully controlled with topical corticosteroids. Four months later, the patient maintained this improvement. He had no keratic precipitates or AC reaction in either eye and visual acuity of 20/30 in both eyes.
"The success of this treatment regimen was a direct result of collaboration and coordination by our subspecialists in our multidisciplinary environment," says Sanjay V. Patel, M.D., chair of Ophthalmology at Mayo Clinic in Rochester, Minnesota. "Each contributed expertise that helped ensure the best possible course of treatment and outcome for this patient."
For more information
Bata BM, et al. Combined intraocular and systemic rituximab for ocular lymphoproliferative disorder with extranodal marginal zone lymphoma-type morphology after heart transplant. Journal of AAPOS. 2018;22:159.