Leg‐type form of idiopathic multicentric Castleman disease associated with severe lower extremity chronic venous/lymphatic disease

Abstract Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disease of unknown etiology. Deciphering mechanisms involved in CD pathogenesis may help improving patients’ care. Six cases of stereotyped sub‐diaphragmatic iMCD affecting lower limb‐draining areas and associated with severe and often ulcerative lower extremity chronic dermatological condition were identified in our cohort. Pathological examination revealed mixed or plasma‐cell type MCD. In three patients, shotgun metagenomics failed to identify any pathogen in involved lymph nodes. Antibiotics had a suspensive effect while rituximab and tocilizumab failed to improve the condition. This novel entity requires a specific approach and exclusion of potentially harmful immunomodulation.


INTRODUCTION
Castleman disease (CD) is a rare lymphoproliferative disorder defined by peculiar pathological features ranging from the hyaline-vascular type with regressed germinal centres and hypervascularization to the plasma cell type with intense interfollicular plasma cell infiltration [1].
Three forms of the disease include the unicentric form with a usually asymptomatic single lymph node and two multicentric forms (multicentric Castleman disease [MCD]) often associated with inflammatory symptoms, hypergammaglobulinemia and fluid overload [2]. Some of these MCD cases are related to a polyclonal proliferation of human herpesvirus 8 (HHV8)-infected plasmablasts (HHV8+ MCD) [3], and the remaining cases are considered as 'idiopathic' (idiopathic MCD [iMCD]) [4][5][6]. Although an infectious origin of iMCD has been thoroughly sought, no causative infectious agent has been identified to date despite the use of high-throughput sequencing technologies [7]. We here describe six cases of iMCD associated with severe venous or lymphatic disease of the lower limbs. This novel subtype of MCD must be recognized as it requires specific treatment including prolonged antibiotics and specific care of the underlying venous/lymphatic disease.

Identification of the cases
Patients were identified in a cohort of 66 iMCD patients belonging to the French national reference centre for CD. All files were reviewed by a group of clinicians and pathologists with an expertise in the field of CD (DB, EO, RB, LG, VM, EP, AM). All patients fulfilled currently satisfying criteria for idiopathic MCD, including clinical, biological and histopathological criteria, as described in Fajgenbaum et al. [6] All patients gave informed consent for the research, and the project was reviewed and approved by local ethic committee.

Shotgun metagenomic analysis of three MCD samples
This aspect has been detailed in the Supplementary data section.

Detailed description of the first patient (P1)
A 67-year-old male, with a medical history of pulmonary tuberculosis and aspergilloma, was referred to our hospital for the management Lymph node biopsy was consistent with a diagnosis of mixed-type CD.
HHV8 latency associated nuclear antigen 1 (LANA-1) staining was negative. Biological evaluation showed high levels of CRP, elevated serum vascular endothelial growth factor (VEGF) and marked polyclonal hypergammaglobulinemia (

Patients' clinical and biological characteristics (P1 to P6)
Between      Table S1 and Figure S1. LANA staining was negative in all patients. Lymph node shotgun metagenomic analysis was performed on three samples and failed to identify any infectious agent.

Review of the literature
Review of the literature identified two additional patients with a similar presentation associating lymphedema, infected venous ulcers with repeated erysipelas and regional MCD. A surgical approach with extended removal of the lymphedema led to clinical improvement in the first patient but biological parameters and long-term follow-up were not available [8]. Remission was obtained in the second patient after skin resection and graft [9].

Disease course and treatment
Five patients were treated with antibiotics and local care, which led to transitory and partial clinical and biological improvement, but numer- an upstream hypothesis of this syndrome. It is noteworthy that some cases of iMCD present with fluid overload, edema and high levels of serum VEGF as in three patients from the present series [10,11]. We believe that this novel entity needs to be clearly identified by clinicians because conventional treatment of iMCD based on immunomodulatory drugs [11,12] failed to improve patients' condition and might even be harmful, as demonstrated by Pasteurella bacteriemia following tocilizumab therapy in patient 2. We therefore propose specific treatment guidelines for patients with leg-type MCD, such as prolonged treatment of infectious flares or long-term antibioprophylaxis, in association with treatment of the underlying venous or lymphatic condition when possible.

CONFLICT OF INTEREST
E. Oksenhendler is a consultant for Eusapharma. The other authors have no conflict of interest to disclose.