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.