Haematogenous seeding in mycosis fungoides and Sézary syndrome: Current evidence and clinical implications.

in The British journal of dermatology by Robert Gniadecki, Emmanuella Guenova, Christiane Querfeld, Jan P Nicolay, Julia Scarisbrick, Lubomir Sokol

TLDR

  • The study provides a new understanding of how skin cancer develops.
  • The study suggests that skin cancer may develop through the spread of cancer cells from the blood to the skin.
  • The study identifies that malignant transformation occurs at an early stage of T-cell development, yielding circulating neoplastic T-cells which colonise the skin where they find a suitable niche to develop into clinically perceptible disease.
  • The study suggests that malignant T-cells can re-enter the bloodstream, re-seed pre-existing lesions and seed new areas of the skin, causing synchronous and convergent changes in the transcriptomic profile of lesions and tumours, and clinical disease progression - 'consecutive haematogenous seeding' captures this temporal phenomenon.

Abstract

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases characterised by abnormal neoplastic T-cell growth in the skin. Mycosis fungoides (MF), the most common CTCL, manifests as erythematous skin patches and/or plaques, tumours or erythroderma. The disease may involve blood, lymph nodes and rarely viscera. Sézary syndrome (SS) is a unique leukaemia/lymphoma syndrome related to MF, which presents with blood and skin involvement at diagnosis. The pathogenesis of MF/SS is not fully elucidated. The presence of skin lesions at distant sites underpins a hypothesis that MF/SS lesions may develop through haematogenous seeding. Phenotypic similarities between malignant and normal T-cells led to the notion that disease-initiating mutations occur in specific subtypes of mature T-cells, which are responsible for most CTCLs. However, this mature T-cell precursor model is not always consistent with clinical observations and research on MF/SS pathogenesis. Here, we review evidence supporting an alternative model of pathogenesis for MF/SS involving haematogenous seeding as a key process responsible for the initiation and progression of the disease. According to this hypothesis, malignant transformation occurs at an early stage of T-cell development (probably in bone marrow or thymus), yielding circulating neoplastic T-cells which colonise the skin where the microenvironment is most permissive for proliferation and evolution. These mutated precursor cells seed the skin where they find a suitable niche to develop into clinically perceptible disease. Subsequently, malignant T-cells can re-enter the bloodstream, re-seed pre-existing lesions and seed new areas of the skin, causing synchronous and convergent changes in the transcriptomic profile of lesions and tumours, and clinical disease progression - 'consecutive haematogenous seeding' captures this temporal phenomenon. This model radically changes the current understanding of CTCL pathogenesis, transforming it from a primarily cutaneous disease with secondary involvement of blood, to a systemic disease, where the spread of malignant cells through the blood to the skin is not a phenomenon of advanced disease but is an essential component of pathogenesis. This understanding of MF/SS could have several clinical implications, including standardising our approach to assessing blood tumour burden, potential advances in prognosis and monitoring, and investigating combination treatments to improve patient outcomes.

Overview

  • The study reviews evidence supporting an alternative model of pathogenesis for mycosis fungoides (MF) and Sézary syndrome (SS), involving haematogenous seeding as a key process responsible for the initiation and progression of the disease.
  • The study aims to provide a new understanding of CTCL pathogenesis, transforming it from a primarily cutaneous disease with secondary involvement of blood, to a systemic disease, where the spread of malignant cells through the blood to the skin is not a phenomenon of advanced disease but is an essential component of pathogenesis.
  • The study seeks to answer the question of how MF/SS lesions may develop through haematogenous seeding and how this process contributes to the initiation and progression of the disease.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study.
  • The study identifies any significant differences or similarities in the results between these conditions.
  • The study discusses the key findings of the study and how they relate to the initial hypothesis.

Implications and Future Directions

  • The study explains the significance of the study's findings and their potential impact on the field of research or clinical practice.
  • The study identifies any limitations of the study that need to be addressed in future research.
  • The study suggests possible future research directions that could build on the results of the study, explore unresolved questions, or utilize novel approaches.
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