International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease

Abstract

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Trial registration: ClinicalTrials.gov NCT02817997 NCT03933904.

Graphical abstract

Figure 1.

Spectrum of histopathological changes seen in UCD. HV histopathological subtype is characterized by the presence of regressed germinal centers (GCs) and FDC prominence, whereas the plasmacytic subtype exhibits hyperplastic GCs and profuse plasmacytosis. Mixed subtype exhibits a combination of HV and plasmacytic features. Lymph node slides were obtained prestained with hematoxylin and eosin from clinical specimens for the ACCELERATE natural history registry, scanned, and captured using Aperio Imagescope. Bars represent 60 (A,E) and 200 mm (B-D). (A) Regressed GC. (B) FDC prominence in GC. (C) Blood vessels penetrating GC demonstrate prominent vascularity. (D) Hyperplastic GC. (E) Sheet-like plasmacytosis.

Figure 2.

Representative examples of UCD. HV subtype is characterized by the presence of regressed atretic germinal centers. There is increased vascularity with hyalinization, prominence of often dysplastic FDCs, and expanded mantle zones in an onion-skin appearance. There are radially penetrating blood vessels causing a lollipop appearance, multiple germinal centers within the same mantle zone referred to as twinning or budding, tight aggregates of plasmacytoid dendritic cells, and architectural disruption with obliterated sinuses. PC subtype exhibits hyperplastic germinal centers and profuse plasmacytosis. Mixed subtype exhibits a combination of HV and PC features.

Figure 3.

UCD treatment algorithm. UCD patients should be evaluated for lymph node resectability, with surgery being the preferred method of treatment. ¹Consider presurgical embolization in large vascular UCD lymph nodes to render surgery safer. Follow-up CT scans, physical examination, and laboratory testing can be done at 12-month intervals. In rare patients who continue to have symptoms after complete lymph node excision, other diagnoses and/or treatments should be considered. ²Watchful observation is an option in patients with unresectable asymptomatic disease or those with nonsevere compressive symptoms. UCD patients with compression-related symptoms may benefit from medical treatment (eg, rituximab ± steroids or anti–IL-6 monoclonal antibody therapy) if inflammatory symptoms (night sweats, fevers, anorexia, weight loss) and/or laboratory abnormalities (elevated ESR, elevated CRP, or anemia) are present. ³In selected cases, embolization as alternative or adjunctive therapy should be considered. ⁴Observation is an option in patients who have been rendered asymptomatic by medical therapy with rituximab/steroids or anti–IL-6 monoclonal antibody therapy. ⁵Patients who continue to be symptomatic are candidates for radiotherapy. Alternative options include treatment with immunomodulators/immunosuppressants, such as corticosteroids, cyclosporine A, and sirolimus.