International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease

Abstract

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

Trial registration: ClinicalTrials.gov NCT01024036.

Figures

Figure 1.

Significant clinical, histologic, and immunologic overlap between iMCD, malignancy, autoimmune, and infectious disorders. The exact location for iMCD on the spectrum from autoimmune, malignant, and infectious diseases is currently unknown and may vary from patient to patient. ALPS, autoimmune lymphoproliferative syndrome; AOSD, adult-onset Still disease; EBV, Epstein-Barr virus; FDC, follicular dendritic cell; HHV-8, human herpesvirus-8; HL, Hodgkin lymphoma; HLH-MAS, hemophagocytic lymphohistiocytosis- macrophage activation syndrome; IgG4, IgG4-related disease; JIA, juvenile idiopathic arthritis; M-HLH, malignancy-associated hemophagocytic lymphohistiocytosis; NHL, non-Hodgkin lymphoma; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, skin changes; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; V-HLH, viral hemophagocytic lymphohistiocytosis.

Figure 2.

Process of criteria development. An international working group with 34 leading physicians, pathologists, and clinicians was created to develop the diagnostic criteria for iMCD. A modified Delphi Method & Nominal Group Technique was selected to guide the criteria development process. A total of 244 patients’ clinical data were gathered along with lymph node slides from 88 cases. Two working group meetings were held to establish an agreed-upon diagnostic criteria. Postmeeting analyses were performed to reapply the agreed-upon diagnostic criteria to 79 cases from NCT01024036 and to use the newly defined histopathologic spectrum to subtype cases. The consensus criteria and results from analyses were compiled into a manuscript that was reviewed by the full expert working group.

Figure 3.

Grading of pathologic features seen in iMCD. The following images are examples of the respective grades for each histopathologic feature. Deidentified lymph node slides were obtained prestained with hematoxylin and eosin from Janssen Pharmaceuticals and scanned using an Aperio CS scanner (Leica Biosystems, Wetzlar, Germany) at 20×/0.75NA Plan Apochromat. Images were captured using Aperio Imagescope and enhanced to 300 dpi using Photoshop. Bars represent 500 μm (A,D), 80 μm (B), 200 μm (C), 60 μm (E). (A) Regressed/atrophic germinal centers. (B) Follicular dendritic cell prominence. (C) Vascularity. (D) Hyperplastic germinal centers. (E) Plasmacytosis.

Figure 4.

Algorithmic approach for assessment of lymph node with features of CD. Patients with lymph nodes with histologic features suggestive of CD should be evaluated for sites of involvement. If lymph node involvement is restricted to one site, the lesion most likely represents unicentric CD. If multiple sites are involved, patients should be evaluated for HHV-8, POEMS, and other infectious, malignant, and autoimmune disorders listed in Table 2 Exclusion Criteria. If these conditions are excluded, a diagnosis of iMCD should be considered. There are 3 major histopathologic subtypes of iMCD: hypervascular (formerly hyaline-vascular), mixed, and plasmacytic pathology. *iMCD patients with TAFRO syndrome frequently demonstrate hypervascular or mixed pathology.

Figure 5.

Histopathologic features of CD. Hypervascular subtype is characterized by the presence of regressed germinal centers and FDC prominence, whereas the plasmacytic subtype exhibits hyperplastic germinal centers and profuse plasmacytosis. Mixed subtype exhibits a combination of hypervascular and plasmacytic features. Vascularity is frequently observed in iMCD, but can be seen with either subtype. Deidentified lymph node slides were obtained prestained with hematoxylin and eosin from Janssen Pharmaceuticals and scanned using an Aperio CS scanner (Leica Biosystems, Wetzlar, Germany) at 20×/0.75NA Plan Apochromat. Images were captured using an Aperio Imagescope and enhanced to 300 dpi using Adobe Photoshop. Bars represent 60 μm (A,E), 200 μm (B-D). (A) Regressed germinal center. (B) FDC prominence in germinal center. (C) Blood vessels penetrating germinal center demonstrate prominent vascularity. (D) Hyperplastic germinal center. (E) Sheetlike plasmacytosis.

Figure 6.

Average grade for histopathologic features for each subtype of iMCD. Average grades for regressed germinal centers, FDC prominence, vascularity, plasmacytosis, and hyperplastic germinal centers in hypervascular, plasmacytic, and mixed subtypes of iMCD as well as cases determined to not be CD (not CD) as assessed by hematopathologic review. See Figure 3 for the grading scale for each feature. The bars depict average grades for histopathologic features for a given subtype with mean ± standard error.

Figure 7.

Percentage of patients meeting proposed Major Criteria who responded to therapy in the siltuximab study, based on number of proposed Minor Criteria. n represents total number of patients treated with at least that number of Minor Criteria and ≥1 laboratory abnormality. Using Fisher’s exact test, those who met ≥2 Minor Criteria were significantly more likely to respond to siltuximab than those who did not meet 2 Minor Criteria (P = .0003).