68‐Year Old Woman with Multiple Sclerosis, Cutaneous T‐Cell Lymphoma and Seizures.

Clinical History and Imaging

The patient was a 68‐year‐old female with a longstanding history of psoriasis and hypertension, as well as multiple sclerosis since 2013. In October of 2015, she was started on oral methotrexate for treatment of her psoriasis. Due to worsening symptoms, she was started on secukinumab, an interleukin‐17 antagonist. After taking secukinumab for 4–5 weeks, large masses developed on her right forearm and buttock. Her dermatologist discontinued the secukinumab and performed a skin biopsy of the lesions on May of 2016, which showed findings consistent with a cutaneous T‐cell lymphoma.

In June of 2016, patient presented with seizures. Brain MRI (Fig 1a) showed gyriform enhancement in the medial aspect of the right frontal lobe, including the right cingulate gyrus, as well as a smaller area of enhancement in the posterior right frontal lobe. PET scan showed high signal in the right medial frontal lobe (Fig 1b).The patient was started on anti‐seizure medications.

Figure 1.

In September of 2016, the patient started to have left‐sided weakness, difficulty finding words, and difficulty walking. Brain MRI scans (Fig 1c, 1d)showed increased T2/FLAIR hyperintensity and enhancing lesions in the right frontal and parietal lobes with further extension into the right parietal lobe, corpus callosum and the medial aspect of left frontal lobe, including the left cingulate gyrus. The increased surrounding edema and mass effect resulted in 5 mm right‐to‐left midline shift. A biopsy of the right frontal lobe lesion was performed in September of 2016.

Microscopic Pathology – Biopsy

Microscopic examination of the right frontal lobe biopsy demonstrated a proliferation of lymphoid cells with very little intact brain parenchyma, consistent with a mass‐like, destructive process (Fig 1e). These cells were frequently clustered around vessels, mostly small to moderate in size with an atypical appearance; the nuclei were round and chromatin frequently arranged in a “soccer‐ball” or clock face configuration with some perinuclear haloes (Fig 1f). Foamy macrophages and scattered, benign‐appearing plasma cells interspersed in variable densities. A subset of lymphoid cells showed slightly enlarged, irregular, grooved nuclei and hyperchromatism. Focally, there were increased mitotic figures and apoptotic cells. Tumor necrosis was identified. Ancillary work‐up showed tumor cells to be immunopositive for CD3 (Fig 1g), CD4 (Fig 1h), CD7 (Fig 1i), and CD8 (Fig 1j) but predominantly negative for CD5 (Fig 1k). All tumor cells were immunonegative for CD20, PAX‐5, in‐situ hybridization of Epstein‐Barr virus encoding RNA (EBER), and CD30. A Luxol fast blue‐periodic acid Schiff stain (LFB‐PAS) demonstrated no significant myelinated axons; neurofilament immunostains showed a few interspersed axons among the cellular infiltrate. What is your diagnosis?

Diagnosis

CD8+ cytotoxic t‐cell lymphoma

Discussion

Primary cutaneous aggressive intraepidermal cytotoxic T‐cell lymphoma is a rare (comprising <1%) subtype of cutaneous T‐cell lymphoma (CTCL) and follows a more rapid clinical course. In this particular patient, a right forearm biopsy taken approximately 4 months prior to the brain biopsy showed an intraepidermal as well as a dermal lymphoid infiltrate with marked adnexotropism, composed of medium‐sized lymphocytes with perinuclear haloes; less than 30% were enlarged. Among other markers, the tumor cells were positive for CD3, CD8, CD7, and CD4, with <50% of cells positive for CD5, and negative for CD30 and EBER. Given the similar morphology and immunophenotype in the brain biopsy material, we favored these tumors to represent the same lymphoma.

Rapid progression with extracutaneous dissemination to extranodal sites (lung, testis, central nervous system, and oral cavity) is typical. As described in one of the original studies, aggressive intraepidermal cytotoxic T‐cell lymphoma involved the central nervous system (CNS) in 2 of 8 patients with a distinct clinical course. The results of a recent task force workshop further distinguished this entity from other CD8+ lymphomas, including mycosis fungoides with CD8+ phenotype, lymphomatoid papulosis, and solitary pagetoid reticulosis. Aggressive intraepidermal cytotoxic T‐cell lymphoma occurred in 11 men and 7 women (18 cases total), ranging in age from 27–87 years (average, 54.5 years) 1, 3. The median survival in 13 fatal cases was 12 months. All cases were CD8 positive and expressed either or both TIA‐1 and granzyme B, while 14/18 cases lacked CD2 and/or CD5; 8/10 cases tested were positive for beta‐F1. All cases were negative for CD30, CD56, and EBER in‐situ hybridization.

CNS involvement by peripheral T‐cell lymphomas generally portends poor prognosis. A recent review from a single institution 2 documented 15 of 231 patients with CNS involvement by a peripheral T‐cell lymphoma over a 17‐year time period, of which 8 cases were pathologically confirmed. CNS disease typically presented early (median, 3.44 months from diagnosis of lymphoma to CNS involvement), and survival thereafter was a median of 2.63 months.