Jump to comment:

• The link between CLIPPERS and lymphoma might be not fortuitous
  Guillaume Taieb, Clarisse Carra-Dalliere, Xavier Ayrignac, Pierre Labauge and Geneviève de Saint Basile
  Published on: 15 April 2021

• Published on: 15 April 2021

  The link between CLIPPERS and lymphoma might be not fortuitous

  • Guillaume Taieb, Neurologist Department of Neurology, CHU Montpellier, Hopital Guy de Chauliac, 80 avenue Augustin Fliche, 34295 Montpellier Cedex 5, France
  • Other Contributors:
    • Clarisse Carra-Dalliere, Neurologist
    • Xavier Ayrignac, Neurologist
    • Pierre Labauge, Neurologist
    • Geneviève de Saint Basile, Immunologist

  We read with great interest the article written by Sofia Doubrovinskaia and colleagues, entitled“Primary CNS lymphoma after CLIPPERS: A case series.”1
  CLIPPERS mimics are numerous (e.g. primary angiitis of the central nervous system, autoimmune gliopathies [related to anti-myelin oligodendrocyte glycoprotein or anti-glial fibrillary acidic protein antibodies], Erdheim-Chester disease, systemic lymphoma, and primary central nervous system lymphoma [PCNSL]).2
  Among these mimics, only patients who eventually developed a PCNSL (EBV-driven or not) fulfilled initially all CIPPERS criteria, including histological features on brain biopsy (i.e. definite CLIPPERS). In this subset of patients, a question arises: is CLIPPERS a prelymphoma state or a paralymphomatous immune response?
  1) Some clues suggest that paralymphomatous immune response seems to be the most likely hypothesis.
  1.1) In all reported patients who eventually developed PCNSL, histological findings at the first brainstem attack fulfilled histological criterion for CLIPPERS (i.e. characteristic perivascular lymphohistiocytic infiltrates with predominance of T4-cells) with no evidence of lymphoma (i.e. atypical or large B-cells and absence of EBV in B-cells).
  1.2) In these patients, while enhancing lesions predominated initially in the pons, as usually described in CLIPPERS, some of them developed PCNSL remote from the brainstem (i.e. periventricular regions).
  1.3) Besides PCNSL, defin...

  Show More

  We read with great interest the article written by Sofia Doubrovinskaia and colleagues, entitled“Primary CNS lymphoma after CLIPPERS: A case series.”1
  CLIPPERS mimics are numerous (e.g. primary angiitis of the central nervous system, autoimmune gliopathies [related to anti-myelin oligodendrocyte glycoprotein or anti-glial fibrillary acidic protein antibodies], Erdheim-Chester disease, systemic lymphoma, and primary central nervous system lymphoma [PCNSL]).2
  Among these mimics, only patients who eventually developed a PCNSL (EBV-driven or not) fulfilled initially all CIPPERS criteria, including histological features on brain biopsy (i.e. definite CLIPPERS). In this subset of patients, a question arises: is CLIPPERS a prelymphoma state or a paralymphomatous immune response?
  1) Some clues suggest that paralymphomatous immune response seems to be the most likely hypothesis.
  1.1) In all reported patients who eventually developed PCNSL, histological findings at the first brainstem attack fulfilled histological criterion for CLIPPERS (i.e. characteristic perivascular lymphohistiocytic infiltrates with predominance of T4-cells) with no evidence of lymphoma (i.e. atypical or large B-cells and absence of EBV in B-cells).
  1.2) In these patients, while enhancing lesions predominated initially in the pons, as usually described in CLIPPERS, some of them developed PCNSL remote from the brainstem (i.e. periventricular regions).
  1.3) Besides PCNSL, definite CLIPPERS have been also diagnosed in the setting of concomitant systemic lymphoma, which strengthens the paralymphomatous hypothesis.

  2) If we consider that CLIPPERS could be a paralymphomatous reaction, what could be its underlying pathophysiological mechanism?
  2.1) In the setting of lymphoma several immune reactions have been described (non-exhaustive list): parneoplastic syndromes (e.g. paraneoplastic cerebellar degeneration with anti-Tr antibody, granulomatous angiitis), demyelinating lesions (also called “sentinel lesions of PCNSL”), antiphospholipid syndrome, thrombotic microangiopathy, sarcoidosis and hemophagocytic lymphohistiocytosis (HLH). Among these distinct immune reactions, HLH is the only mechanism that can share all histological characteristics of CLIPPERS (i.e. perivascular lymphohistiocytic infiltrates with predominance of T4-cells [and not T8-cells], with no evidence of necrotizing angiitis, demyelinating lesions, endoluminal thrombi, and granulomas). HLH can be acquired or inherited, the latter mostly due to functional defect in T lymphocytes and NK cells cytotoxicity, precluding antigen clearance. The persistence of antigen leads to lymphocyte and macrophage over activation, multiorgan lymphohistiocytic infiltration, systemic inflammatory cytokine release and eventually multi-organ failure. In the setting of systemic HLH, about half of the patients have CNS involvement.3 Conversely, because the diagnosis of HLH requires systemic signs, the existence of CNS-restricted involvement related to HLH remained speculative, until a short time ago.
  2.2) As we speculated that HLH restricted to the CNS could be an interesting candidate to explain some CLIPPERS characteristics (i.e. numerous histiocytes in the perivascular infiltrates and striking association with lymphomas), we have recently screened adult CLIPPERS patients for mutations in HLH-associated genes.4 In our cohort of 12 patients with CLIPPERS, mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS. Biallelic PRF1 mutations were found in 3 of them, with subsequent reduction of perforin expression in natural killer cells. Biallelic UNC13D mutations were found in the remaining patient with subsequent cytotoxic lymphocyte impaired degranulation. Because none of them had systemic signs, none reached criteria for systemic HLH. During follow-up, a systemic non-Hodgkin lymphoma emerged in the patient harboring UNC13D mutations. Thus, in our patients presenting as adult-onset CLIPPERS, one third have HLH gene mutations. As hematopoietic stem cell transplantation is currently the only curative treatment for inherited HLH, genetic screening for these mutations should be performed in all CLIPPERS patients, especially those who developed lymphoma.

  2.3) In keeping with these results, it would be interesting to know whether patients described by Sofia Doubrovinskaia and colleagues had HLH gene mutations. The presence of mutations could explain both the CLIPPERS features and the PCNSL. On the other hand, in the absence of mutation, we cannot exclude an acquired form of HLH restricted to the CNS and triggered by a PCNSL.

  Although speculative, CLIPPERS could be an acquired or inherited HLH, restricted to the CNS. Although rare, systemic hemophagocytic syndrome and extra neurological involvements in CLIPPERS strengthen this assumption.5 However, further studies are needed in order to assess this hypothesis.

  References
  1. Doubrovinskaia S, Sahm F, Thier MC, et al. Primary CNS lymphoma after CLIPPERS: a case series. J Neurol Neurosurg Psychiatry. 2021 Mar 31:jnnp-2020-325759. doi: 10.1136/jnnp-2020-325759. Epub ahead of print. PMID: 33789924.

  2. Taieb G, Mulero P, Psimaras D, et al. CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS. Journal of neurology, neurosurgery, and psychiatry 2019; 90(9): 1027-38.

  3. Horne A, Trottestam H, Arico M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. British journal of haematology 2008; 140(3): 327-35.

  4. Taieb G, Kaphan E, Duflos C, et al. Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome. Neurol Neuroimmunol Neuroinflamm. 2021 Mar 3;8:e970.

  5. Li Z, Jiang Z, Ouyang S, et al. CLIPPERS, a syndrome of lymphohistiocytic disorders. Multiple sclerosis and related disorders 2020; 42: 102063.

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top