American Society of Hematology

Case Study: 32-Year-Old Man with Adenopathy and Systemic Symptoms

A board-style question with an explanation and a link to a relevant article is a recurring feature of TraineE-News. The goal of the case study is to clarify specific and timely teaching points in the field of hematology. The following case study focuses on a 32-year-old man who is admitted to the hospital after the onset of fevers, fatigue, 10-pound weight loss, and diffuse lymphadenopathy. Examination reveals palpable splenomegaly and laboratory evaluation reveals a Cr of 2.5 mg/dL, hematocrit 22 percent, and C-reactive protein of 97 mg/L. HIV serology is negative. A right cervical lymph node biopsy is performed on the second hospital day and reveals atypical plasmablasts within the mantle zone of the lymph node follicle, which stain positive for human herpesvirus-8 (HHV-8).

Which of the following cytokines has been implicated in the pathogenesis of this disease?

  1. Interleukin-2
  2. Interleukin-6
  3. Interferon-gamma
  4. Interleukin-17

Answer

  1. Interleukin-6.

Explanation

This patient presents with constitutional symptoms, lymphadenopathy, splenomegaly, renal dysfunction, and elevation of CR-P-all of which support a diagnosis of multicentric Castleman disease (MCD). This diagnosis is confirmed by the findings on a lymph node biopsy of a plasmablastic infiltrate, and many cases are associated with HHV-8 (KSHV).1,2 The symptoms of MCD have been correlated with increased IL-6 production in the host3, as well as viral-IL-6 production in HHV-8 positive cases. Therapy directed at the IL-6 receptor4,5 as well as monoclonal antibodies directed against IL-6 itself have shown clinical activity5-7 in MCD.

None of the other listed cytokines are implicated in MCD. IL-2 is used as a therapeutic in melanoma and renal cell carcinoma, interferon-γ has been shown to correlate with severity of acute graft-versus-host disease,8 and IL-17 is implicated in the pathogenesis of autoimmune conditions such as aplastic anemia.9

References

1. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995;86:1276-1280.

2. Gessain A, Sudaka A, Briere J, et al. Kaposi sarcoma-associated herpes-like virus (human herpesvirus type 8) DNA sequences in multicentric Castleman's disease: is there any relevant association in non-human immunodeficiency virus-infected patients? Blood. 1996;87:414-416.

3. Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood. 1989;74:1360-1367.

4. Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005;106:2627-2632.

5. Song SJ, Tomosugi N, Kawabata H, et al., Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 2010;116:3627-3634.

6. van Rhee F, Fayad L, Voorhees P, et al., Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol. 2010;28:3701-3708.

7. Beck JT, Hsu SM, Wijdenes J, et al. Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med. 1994;330:602-605.

8. Xu J, Wei J, Zhu X, et al. Increased plasma indoleamine 2,3-dioxygenase activity and interferon-γ levels correlate with the severity of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:196-201.

9. de Latour RP, Visconte V, Takaku T, et al. Th17 immuneresponses contribute to the pathophysiology of aplastic anemia. Blood. 2010;116:4175-4184.

Question written by Matthew Ulrickson, MD, MD Anderson Cancer Center.

Case study submitted by Mark A. Walshauser, MD, Loyola University Medical Center.

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