Castleman’s disease

A polyclonal lymphoproliferative disorder.

Involves the proliferation of B cells that produce cytokines.

Associated with hyper secretion of the cytokine IL-6.

Unicentric disease implies enlargement of lymph nodes at a single site.

In 90% of cases removal of a single node is curative.

Multicentric disease involves enlarged lymph nodes at multiple sites ad 50% of cases are caused by Kaposi[s sarcoma-associated Herpesvirus (KSHV).

Histopathological features are classified as hypervascular or hyaline vascular, plasmacytic, or mixed.

May be associated with POEMS.

Human herpesvirus (HHV)-8 and IL6 are etiologic factors and therapeutic targets.

More than half of patients with HIV associated Castleman disease also have concomitant Kaposi’s sarcoma (HHV-8).

Localized or unicentric disease affects a single lymph node and the chest and abdomen are affected most often.

In unicentric Castleman’s disease 80% of cases have chest lymphadenopathy.

Unicentric Castleman’s disease is almost hyaline vascular subtype and is usually HIV negative and HHV-8  negative and commonly presents in younger adults age 30 to 40 years, with a slight predominance in women.

Unicentric Castleman’s disease presentation includes the chest, neck, and abdomen and less commonly retroperitoneum.

Unicentric Castleman’s disease usually presents is localized, asymptomatic adenppathy and is commonly diagnosed through incidental imaging.

Idiopathic MCD affects 9.7 million per million individuals and a median age of 51 years and his classified into idiopathic MCD – TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis/kidney dysfunction, organomegaly).

The pathogenesis of idiopathic MCD is thought to involve excessive hypercytokinemia (IL-6), promoting inflammation that causes organ dysfunction.

Unicentric Castleman’s disease rarely present with peripheral adenopathy.

Unicentric Castleman’s disease is associated with a greater than  90% relapse free survival after surgical reception.

Unresectable disease can be treated with local Radiation, Rituximab, and/or steroids to reduce the mass to convert it to being socially surgically resectable.

50% of cases of multicentric Castleman’s disease (MCD) of unknown cause.

A nonclonal lymphoproliferative disorder that can affect single lymph node, or generalized involvement.

IL-6 plays role in pathogenesis of the disease.

Human herpesvirus 8, encodes for viral homolog of IL6 and is a driving force in HIV positive patients.

Outcome in HIV negative CD is excellent.

Responds to monoclonal antibody therapy directed at IL-6 receptor or IL-6 itself.

IL6 elaborated by B lymphocytes in germinal centers of CD lymph nodes

Multicentric disease (MCD) associated with Kaposi’s sarcoma Herpesvirus is the plasmacytic form of Castleman’s disease.

Affects roughly 1600 patients annually in the US.

Historical five year overall survival 55 to 77%, as it is a life-threatening disease.

Multicentric Castleman disease is associated with a range of signs and symptoms including multicentric lymphadenopathy, and an inflammatory syndrome with fluid accumulation.

Multi organ system dysfunction may develop as a consequence of a cytokine storm.

It has two pathologic sub types: a highly vascular tumor and the plasmacytic variant.

Approximately half of all cases of MCD are caused by uncontrolled infection with HHV8 or monoclonal plasma cell population associated with POEMS syndrome, and the remaining cases are idiopathic.

Polyclonal, hypergammaglobuinemia, lymphadenopathy, and elevated levels of inflammatory markers and IL-6 are characteristic of MCD.

Cases can be divided into clinical subtypes involving thrombocytopenia, anasarca, fever, bone marrow fibrosis, renal dysfunction, and organomegaly.

The hyaline vascular form of Castleman’s disease is negative for the KSHV.

Multicentric disease may be associated with fever, anemia, weight loss, anorexia and leukopenia, all of which may be associated with excess interleukin 6.

HHV8 positive MCD is generally associated with an IL-6 mediated inflammatory syndrome, is most commonly seen in the setting of HIV, but may be seen in other immunocompromised hosts.

MCD histology is mostly plasmacytic or mixed histology, with a male predominant.

Because of the nonspecific nature of the presentation diagnosis is difficult.

Diagnosis: diagnosis of idiopathic MCD’s based on the presence of two major criteria characteristic histopathology with regressed or hypoplastic germinal centers, follicular dendritic cell prominence, increased vascularity, and polytypic plasmacytosis on excisional lymph node biopsy and multicentric lymphadenopathy, and two or more minor criteria, including at least one laboratory abnormality such as an elevated C reactive, protein, or ESR, anemia, thrombocytopenia, or thrombocytosis, hypoalbuminemia, kidney dysfunction of proteinuria and polyclonal hypergammaglobulinemia, and clinical features, including constitutional symptoms of night sweats, fever, weight loss, hepatosplenomegaly, fluid accumulating– edema, anasarca,ascites, pulmonary involvement with lymphocytic interstitial pneumonitis and characteristic cutaneous findings of eruptive cherry hemangiomatosis, or violaceous plaques, which occur in 1/3 of patients with idiopathic MCD.

The differential diagnosis of idiopathic MCD includes: HHV – 8 and Epstein virus infections, clonal hematologic, malignancies-lymphoma, multiple myeloma, autoimmune or auto inflammatory disease diseases, such as SLE, rheumatoid arthritis, POEMS syndrome andig4-RD.

Prognosis for unicentric disease is excellent.

Severe idiopathic MCD is defined by presence of at least two severe features, including performance status, two or greater, estimated GFR of less than 30 milliliters per minute, fluid overload, hemoglobin level 8 g/dL or less, and pulmonary involvement.

Patients with severe idiopathic MCD require more intensive treatment and close monitoring

Treatment of multicentric disease has no standard approach as of this time.

AIDS related multicentric disease treated by management for HIV disease.

Multicentric form acts like lymphoma, and in fact, many patients develop lymphomas.

HHV-8 Associated MCD can be seen in patients with polyneuropathy, organomegaly, and organomegally, M proteins, and skin changes (POEMS).

HHV-8 associated MCD arises from replication of HHV-8 in plasmablasts resulting in constitutional symptoms and diffuse lymphadenopathy and is most commonly associated with chronic immunodeficient states such as HIV.

There is presently no standard treatment for multicentric CD.

Treatment with monoclonal antibody therapy targeting IL-6, approach that causes B cell proliferation, is recommended for patients with idiopathic MCD.

The prognosis for HHV positive MCD has improved with  the use of highly active antiretroviral therapy for HIV and biologic therapy for Castleman disease.

Bortezomib therapy may be efficacious.

Rituximab is efficacious in HHV associated MCD.

Siltuximab,  a monoclonal antibody that binds to interleukin-6 is utilized for the treatment of patients with multicentric Cattleman’s disease:it is first line therapy.

Other agents used for this disease include tocilizumab,, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and high-dose steroids.

Lifelong therapy may be necessary to prevent relapse.