CD8+ mycosis fungoides: a wolf in sheep's clothing?

In this issue of the BJD, Doerschner and colleagues report on a case of mycosis fungoides (MF) with involvement of the central nervous system (CNS). Complete and ongoing remission of CNS lesions for 17 months was achieved with systemic chemotherapy and autologous stem‐cell transplantation (SCT). Interferon (IFN) alfa‐2a was used successfully to treat the subsequent relapse confined to the skin.1

Initially, the patient was timely diagnosed with advanced‐stage MF of 5 months’ duration restricted to the skin. Of note, the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study has demonstrated a median diagnostic delay of 36 months in early‐stage MF between first symptoms and initial diagnosis.2 However, in the face of currently lacking biomarkers for predictable disease progression it is debatable whether patients will benefit from early diagnosis. Moreover, accurate patient education on their prognosis is challenging with 5‐year survival rates ranging from 88% to 30% dependent on the clinical stage.3 The PROCLIPI study aims to fill these significant gaps in the management of patients with MF, highlighting the project's importance. The T‐cell phenotype of MF is usually CD4+/CD8–. The 2018 update of the World Health Organization–European Organization for Research and Treatment of Cancer classification for primary cutaneous lymphomas emphasizes that clinicopathological correlation is essential to differentiate among CD8+ cutaneous T‐cell lymphomas (CTCL).4 Indolent primary cutaneous acral CD8+ T‐cell lymphoma and aggressive epidermotropic CD8+ CTCL are distinct entities whereas CD8+ cases of MF are considered as disease variants. At present, it is unclear whether the atypical expression of CD8 in MF correlates with an unfavourable clinical course. Interestingly, CD4+ to CD8+ immunophenotype switching reported in a single case of MF was associated with intraocular and CNS involvement.5 A hypothesis implies that CNS disease spread of MF is caused by direct extension through nerves based on confirmed optical nerve involvement. However, CNS involvement in MF is a rare, fatal complication and has been observed in early‐ and advanced‐stage disease as well as in various subtypes of MF.6 Immediate neurological examination and imaging is needed when patients with MF present with either neurological or psychiatric symptoms. Diagnosis of CNS involvement can be suspected on the basis of cerebrospinal fluid analysis but for definitive diagnosis a brain biopsy is necessary. Fortunately, a complete remission of the CNS lesions was achieved in this patient due to high‐dose chemotherapy followed by autologous SCT. In line with this, high‐dose chemotherapy with autologous rescue has resulted in complete responses in the majority of reported patients.7 However, these responses were short‐lived in almost all cases in contrast to long‐term survival in selected patients after allogeneic SCT. Autologous SCT in CTCL is no longer regarded as a (curative) treatment option8 and therefore not included in the current treatment recommendations for MF.9 Of note, the limited cutaneous relapse together with the long‐term response to IFN alfa‐2a in this patient gives hope for a sustained benefit. This remarkable case provides a thought‐provoking impulse about the clinical relevance of CD8 positivity in MF. The question of whether CD8 expression plays a crucial role in MF will hopefully be answered by results from the PROCLIPI study in the future.