Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease

Abstract

Castleman disease (CD) comprises 3 poorly understood lymphoproliferative variants sharing several common histopathological features. Unicentric CD (UCD) is localized to a single region of lymph nodes. Multicentric CD (MCD) manifests with systemic inflammatory symptoms and organ dysfunction due to cytokine dysregulation and involves multiple lymph node regions. Human herpesvirus 8 (HHV-8) causes MCD (HHV-8-associated MCD) in immunocompromised individuals, such as HIV-infected patients. However, >50% of MCD cases are HIV and HHV-8 negative (defined as idiopathic [iMCD]). The clinical and biological behavior of CD remains poorly elucidated. Here, we analyzed the clinicopathologic features of 74 patients (43 with UCD and 31 with iMCD) and therapeutic response of 96 patients (43 with UCD and 53 with iMCD) with HIV-/HHV-8-negative CD compared with 51 HIV-/HHV-8-positive patients. Systemic inflammatory symptoms and elevated inflammatory factors were more common in iMCD patients than UCD patients. Abnormal bone marrow features were more frequent in iMCD (77.0%) than UCD (45%); the most frequent was plasmacytosis, which was seen in 3% to 30.4% of marrow cells. In the lymph nodes, higher numbers of CD3⁺ lymphocytes (median, 58.88 ± 20.57) and lower frequency of CD19⁺/CD5⁺ (median, 5.88 ± 6.52) were observed in iMCD patients compared with UCD patients (median CD3⁺ cells, 43.19 ± 17.37; median CD19⁺/CD5⁺ cells, 17.37 ± 15.80). Complete surgical resection is a better option for patients with UCD. Siltuximab had a greater proportion of complete responses and longer progression-free survival (PFS) for iMCD than rituximab. Centricity, histopathological type, and anemia significantly impacted PFS. This study reveals that CD represents a heterogeneous group of diseases with differential immunophenotypic profiling and treatment response.

Figure 1.

Lymph node involvement by location and immunophenotypic expression (CD3⁺ and CD5⁺/CD19⁺) in patients with UCD and iMCD subtypes of CD. (A) The distribution of lymphadenopathy among patients with HIV-negative UCD. (B) The locations of coexistent lymphadenopathies among patients with iMCD; (C,E) Flow cytometry images of CD3+ and CD5⁺/CD19⁺ in UCD; (D,F) flow cytometry images of CD3⁺ and CD5⁺/CD19⁺ in iMCD. FITC, fluorescein isothiocyanate; PE, phycoerythrin.

Figure 2.

Representative images showing immunohistochemical expression in patients with UCD and iMCD. (A-H) UCD case with B-cell–rich germinal centers and increased CD5⁺/CD19⁺ B cells, whereas CD3⁺ small T cells are relatively sparse. (I-P) iMCD case with dense T cells in the interfollicular regions and decreased CD20/PAX-5 B cells and CD5⁺/CD19⁺ B cells. Few polyclonal CD138⁺ PCs are present around the nodules in both UCD and iMCD. Original magnification ×100 for panels A-D,I-L and ×200 for panels E-H,M-P.

Figure 3.

PFS of patients with iMCD after treatment with different therapies. (A) Among all iMCD patients, siltuximab was not correlated with PFS when compared with rituximab or rituximab-based therapy significantly, although a trend toward better survival is suggested. (B) There was no significant difference in PFS between treatment with siltuximab and treatment with chemotherapy or corticosteroids. (C) There was no significant difference in PFS between treatment with rituximab or rituximab-based therapy and chemotherapy or corticosteroids. (D) Rituximab or rituximab-based therapy was correlated with better PFS in patients with HIV-positive and HHV-8–positive MCD compared with iMCD.^,, Chemo and Cor, chemotherapy or therapy with corticosteroids only; R and R-based, rituximab or rituximab-based therapy.

Figure 4.

PFS of patients with non-TAFRO iMCD and overall survival of patients with and without TAFRO. (A) Treatment with siltuximab led to better PFS than rituximab or rituximab-based therapy. (B) Rituximab or rituximab-based therapy and chemotherapy or corticosteroids had similar PFS. (C) Treatment with siltuximab was correlated with better PFS than treatment with chemotherapy or corticosteroids. (D) In all patients, TAFRO syndrome correlated with significantly poorer patient survival. Chemo and Cor, chemotherapy or therapy with corticosteroids only; OS, overall survival; R and R-based, rituximab or rituximab-based therapy.

Figure 5.

Prognostic significance of clinical characteristics in 74 HIV-negative patients with CD. Anemia (A), the pathologic subtypes of PC (B), and multicentricity (C) were correlated with significantly poorer PFS. (D) Sex did not correlate with PFS, although a trend toward better survival is suggested among males. MIX, mixed cellular variant.