Castleman's disease

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Microfoto of Castleman's disease, hyaline-vascular type, with the characteristic onion-skin-like shape. HE staining .

Castleman's disease ( Castleman's disease ) is a heterogeneous group of tumors of the lymph nodes , also known as angiofollikuläre lymph node hyperplasia or giant lymph node hyperplasia are referred to.

Classification

Even if all tumors share similar histological characteristics, there are different forms with different symptoms, therapy and prognosis. Clinically, different forms of Castleman disease can be distinguished. In addition to the localized ("unicentric") form with only one enlarged lymph node, there are multicentric forms.

The following classification is currently in use:

  • Unicentric Shapes (UCD)
  • HHV-8 ( Human Herpesvirus 8 ) associated multicenter form
  • Idiopathic multicenter form (iMCD)

The first case of such a peculiar form of lymph-node hyperplasia was presented in 1954 by the American pathologist Benjamin Castleman at a clinical-pathological case conference at Massachusetts General Hospital . The further description of the unicentric form followed in 1956 by Castleman, who then distinguished two histological forms in 1972:

  1. hyaline-vascular type in 91%: mostly a mediastinal tumor without any further systemic symptoms . This type is considered a benign clonal tumor of follicular dendritic cells . Cell dysplasia can also occur, and cytogenetic changes have occasionally been described. The hyaline-vascular form can rarely degenerate into a dendritic cell sarcoma .
  2. Plasma cell type in 9% that occurs more frequently outside the mediastinum and more often exhibits systemic symptoms such as anemia or hypergammaglobulinemia.

The multicentric form always consists of the plasma cell type. In the multicenter plasma cell type, an idiopathic form (iMCD) can be distinguished from a form associated with human herpesvirus 8 (HHV-8) infection (HHV-8-associated MCD). The TAFRO syndrome consisting of thrombocytopenia , anasarca , fever , reticular fibrosis and organomegaly is considered a variant of iMCD.

This form occurs particularly in HIV- positive patients and is considered a lymphoproliferative disease with a risk of progression to lymphoma . The HHV-8 viruses infect B cells and these proliferate as large plasmablasts .

The plasma cell form leads to an increased release of the proinflammatory cytokine interleukin-6 . In the HHV-8-associated form, this occurs through viral products; in the idiopathic form, the cause of the interleukin-6 release has not been clarified. Interleukin-6 is responsible for most systemic symptoms. Interleukin-6 also stimulates B-cell proliferation, has an angiogenic effect and induces an acute phase response .

Epidemiology

The disease occurs regardless of age and gender. It is estimated that fewer than 1 in 100,000 are affected by the disease, with the localized form being significantly more common. The mediastinum , but also the abdominal cavity, especially the retroperitoneal cavity , and the superficial lymph nodes are most frequently affected. The single lesion can grow to several centimeters in diameter.

Symptoms

The localized form does not cause any systemic symptoms in about half of the patients. The tumor is often discovered accidentally ("incidentally") or causes local symptoms of displacement due to pressure on vessels or nerves and thereby chest or abdominal pain. Otherwise " B symptoms " with fatigue, fever and weight loss can occur.

Multicentric forms usually cause symptoms that are caused by the increased interleukin-6 secretion: weight loss (69%), fever (67%), peripheral lymphadenopathy (81%), hepato and / or splenomegaly (74%), fatigue, Hypoalbuminemia and hypergammaglobulinaemia.

HHV-8 could be detected in more than 60% of all M. Castleman patients affected by HIV, while HIV-negative Castleman patients are only HHV-8 positive in 20 to 40% of cases.

Occasionally, Castleman's disease is associated with other conditions that should be considered:

  1. Kaposi's sarcoma , a form of skin cancer also caused by human herpes virus 8 in the HHV-8 positive form of the plasma cell type
  2. POEMS syndrome consisting of polyneuropathy , organomegaly , endocrinopathy , M-gradient in serum electrophoresis and skin changes , in up to 23%, in the plasma cell type
  3. osteosclerotic plasmacytoma in the plasma cell type
  4. Paraneoplastic pemphigus in the hyaline-vascular type
  5. Follicular dendritic cell sarcoma in the hyaline-vascular type

diagnosis

The diagnosis is made through a biopsy followed by a histological and immunohistochemical examination. In the case of unicentric forms, this can be done as a curative excisional biopsy.

histology

Histologically, the enlarged lymph node consists of a significantly increased number of lymph follicles, the sinuses are reduced or no longer recognizable due to the expansion of the follicles, and the capsule is thickened. The germinal centers in the follicles are atrophic or regressive. However, there are often several germinal centers in a follicle mantle zone, so-called twinning . Occasionally one can see hyalinized vessels entering the follicle vertically, so-called lollipop phenomenon. The coat zone is thickened and has an onion-skin- like appearance ( onion-skinning ). This is caused by an accumulation of mantle zone lymphocytes along the follicular dendritic cells around the atrophic germinal centers. In the interfollicular zone there is an increased number of endothelial venules as well as small lymphocytes and occasionally plasma cells.

While all the histological changes described can also occur individually in other reactive and neoplastic lymph node changes (such as lymphomas), their combination is typical and diagnostic of Castleman's disease.

treatment

Unicentric shapes

In the localized unicentric form, therapy consists of complete surgical removal. In a review with 278 cases, this was possible in 90% and showed a disease-free five-year survival rate of over 80% with an overall survival rate of over 90%. Less than 5% of patients died from unicentric Castleman's disease in the first ten years.

The systemic symptoms of the unicentric plasma cell type usually resolve after surgical resection.

If the unicentric lymph node hyperplasia is not surgically resectable, radiation therapy with or without partial resection is recommended. As a rule, the irradiation takes place with photons, 12 - 40 Gray are used. If progression or relapse occurs despite local therapy and possibly repeated surgical resection, systemic therapy must be used. Since interleukin-6, which is important in the multicentric form, does not play a role in the hyaline-vascular type, the use of the monoclonal antibody siltuximab directed against interleukin-6 is not indicated. In the event of a relapse or incomplete remission of the unicentric hyaline-vascular form, glucocorticoids , rituximab and, rarely, systemic chemotherapy remain the systemic therapy .

Multicentric shapes

In the multicenter form, systemic therapy is used. Since the interleukin-6 release is the basis of the pathogenesis and the symptoms, the monoclonal antibody siltuximab , which is directed against interleukin-6, was successfully used in a randomized controlled study and approved in 2014 by the US Food and Drug Administration (FDA) and the European Medicines Agency EMA approved for the treatment of the HHV-8-negative multicenter form as standard therapy.

In multicentric Castleman's disease with evidence of HHV-8 infection, the HHV-8 viruses themselves produce interleukin-6, which is why the use of the monoclonal antibody siltuximab does not make sense. Instead, the standard therapy consists of treatment with glucocorticoids and chemotherapy , which, however, lead to considerable toxic effects and only to a low rate of permanent remissions . More recent studies were carried out with the monoclonal antibody rituximab , which is directed against the B-lymphocyte antigen CD20 , and showed a considerably higher remission rate with longer-lasting remission and a relatively low rate of adverse effects .

Any underlying HIV disease is treated with antiretroviral drugs . The prognosis of the multicentre HHV-8 positive Castleman's disease is poor. In a study in HIV-infected patients, it was only 14 months on average.

literature

  • U.N. Riede: General and special pathology. Georg Thieme, 2004, ISBN 3-13-683305-8 , pp. 553ff.
  • Michael L. Blute, Jeremy S. Abramson, Kevin C. Cronin, Valentina Nardi: Case 5-2017: A 19-year-old man with hematuria and a retroperitoneal mass. New England Journal of Medicine 2017, Volume 376, Issue 7 February 16, 2017, pp. 684-692, doi: 10.1056 / NEJMcpc1610100 - Case description of a unicentric hyaline-vascular Castleman's tumor in the retroperitoneal space.

Individual evidence

  1. ↑ a b c d Castleman's disease. In: Orphanet (Rare Disease Database).
  2. ↑ DC Fajgenbaum, D. Shilling: Castleman Disease Pathogenesis. In: Hematology / oncology clinics of North America. Volume 32, number 1, 02 2018, pp. 11-21, doi: 10.1016 / j.hoc.2017.09.002 , PMID 29157613 (review).
  3. ↑ E. Oksenhendler, D. Boutboul, D. Fajgenbaum, A. Mirouse, C. Fieschi, M. Malphettes, L. Vercellino, V. Meignin, L. Gérard, L. Galicier: The full spectrum of Castleman disease: 273 patients studied over 20 years. In: British Journal of Hematology . Volume 180, number 2, 01 2018, pp. 206-216, doi: 10.1111 / bjh.15019 , PMID 29143319 .
  4. ^ B. Castleman, VW Towne: Case records of the Massachusetts General Hospital: Case No. 40231. In: N Engl J Med. 250 (23), Jun 10, 1954, pp. 1001-1005. PMID 13165944
  5. ↑ B. Castleman, L. Iverson, VP Menendez: Localized mediastinal lymphnode hyperplasia resembling thymoma. In: Cancer . tape 9 , 1956, pp. 822-830 .
  6. ↑ JM Hawkins, V. Pillai: TAFRO syndrome or Castleman-Kojima syndrome: a variant of multicentric Castleman disease. In: Blood. 126, 2015, p. 2163, doi : 10.1182 / blood-2015-07-662122
  7. ↑ N. Talat, AP Belgaumkar, KM Schulte: Surgery in Castleman's disease: a systematic review of 404 published cases. In: Annals of Surgery . Volume 255, 2012, pp. 677-684.
  8. ^ F. van Rhee, RS Wong, N. Munshi et al.: Siltuximab for multicentric Castleman's disease: a randomized, double-blind, placebo-controlled trial. In: The Lancet Oncology. Volume 15, 2014, pp. 966-977.
  9. ↑ EMA specialist information
  10. ↑ SYLVANT ™ (siltuximab) Receives FDA Approval to Treat Multi Centric Castleman's disease (MCD). , PM by J&J, Janssen on April 23, 2014, accessed April 29, 2014.
  11. ↑ E. Oksenhendler et al: Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients. In: AIDS. 10/1/1996, pp. 61-67. PMID 8924253

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