Case report
An 80-year-old Italian born woman presented with floaters in both visual fields. An initial diagnosis of bilateral anterior uveitis was made and she was treated with multiple courses of topical steroids. Six months later she was referred to a subspecialist ophthalmologist due to suboptimal clinical response. At this time, she had 6/12+ visual acuity in her right eye and less than 6/15 in her left eye. Ocular pressures were normal. On slit lamp examination there were bilateral pigmented keratic precipitates, with many bilateral vitreous cells and extensive inflammatory debris. Recent investigations for the cause of the uveitis had been negative and the ophthalmologist at this time was suspicious of intraocular lymphoma. A diagnostic-therapeutic vitrectomy of the left eye was performed. Microscopy showed scattered small lymphocytes and there were inadequate cell numbers for flow cytometry, as commonly occurs in cases of intraocular lymphoma. The visual acuity of the left eye improved from less than 6/15 to 6/7.5 two weeks later.
Shortly after, tender erythematous left leg nodules, unintentional weight loss and night sweats emerged. She was treated with antibiotics without improvement. The rash progressed to involve the trunk and fresh skin biopsy of this lesion was performed (Fig 1).
Histology : Histological examination shows moderate dermal and subcutaneous infiltrate of abnormal intermediate sized lymphocytes with irregular, hyperchromic nuclei. Epidermotropism is negligible. The subcutaneous infiltrate is reminiscent of lobular panniculitis, however, there is no significant fat rimming or necrosis. In areas, the infiltrate is predominantly peri-adnexal and perivascular with focal angioinvasion and perineural spread but without associated fibrinoid necrosis of vessel walls (Fig. 2a-b)
Immunohistochemistry : The lymphoma cells express CD2, CD3 (cytoplasmic), CD4 (partial), CD56, GATA3, TIA1, granzyme B, perforin, EBER but not for CD7, CD8, CD2, CD5, CD30, LMP1, PD1, CD303, MPO, or CD68 (Fig. 2c-f).
The patient underwent 18F-flurodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT) scan, demonstrating mostly cutaneous disease in the legs with a single mildly FDG avid mildly prominent lymph node in the left inguinal region. There was no evidence of visceral or bone marrow involvement on PET/CT, although bone marrow biopsy was not performed as she was considered to be stage IVB on the basis of CNS (intraocular) involvement. Lumbar puncture was performed, and initial cerebrospinal fluid (CSF) cytology was reported as suspicious for leptomeningeal involvement although flow cytometry was negative. She was treated with three doses of intrathecal methotrexate, and subsequent CSF samples were negative for malignancy.
Apart from an elevated lactate dehydrogenase (2.2 x upper limit of normal) the remainder of the baseline blood tests were within normal limits and HIV and hepatitis B and C serology were negative.
The patient was treated with 2 cycles of SMILE chemotherapy, with 50% reduced doses of methotrexate, ifosfamide and etoposide complicated by fluid overload, atrioventricular nodal re-entry tachycardia requiring accessory pathway ablation, ifosfamide encephalopathy, and subsegmental pulmonary embolism in the context of L-asparaginase therapy despite anti-thrombin 3 replacement.
PET-CT post 2 cycles SMILE chemotherapy demonstrated resolution of lower leg cutaneous and left inguinal lymph node activity. Repeat lumbar puncture demonstrated no evidence of residual leptomeningeal lymphoma. There was clinical response of the cutaneous disease with residual skin pigmentation (Fig 1). Due to cumulative toxicity of therapy there was a substantial decline in performance status precluding further administration of reduced dose SMILE. As the chemotherapy administered to that point was considered insufficient to eradicate intraocular disease, binocular radiotherapy (20 Gray in 10 fractions) was administered. A highly conformal volumetric arc megavoltage external beam radiotherapy technique was utilised. Therapy was well tolerated with temporary eye dryness which responded to topical lubricant. A subjective improvement in vision was noted by the second week post therapy (she regained the ability to read).
Unfortunately, six weeks following completion of SMILE, new cutaneous lesions emerged on the back, biopsy confirmed as ENKL recurrence. Treatment with four cycles of 100mg of intravenous pembrolizumab at 3 weekly intervals failed to achieve a clinical response. Third line chemotherapy with P-GEMOX (peg-aspargase, gemcitabine, oxaliplatin) resulted in reduction in the skin lesions, however after three cycles the patient developed confusion, seizures and new focal neurological deficits. Lumbar puncture showed recurrent leptomeningeal ENKL; the patient was offered palliative care and died four days later.