Castleman's Disease is a benign disorder that was first described
by Dr. Benjamin Castleman, who was a pathologist at the
Massachusetts General Hospital in Boston, in 1956. Approximately
200 new cases are diagnosed each year in the U.S. Forty-five
patients with Castleman’s Disease have presented to the Myeloma
Institute. The Myeloma Institute has seen more Castleman’s Disease
patients than any other single institution in the world.
Also referred to as angiofollicular hyperplasia, Castleman’s
Disease is a non-clonal disease of the lymphnodes. It is
characterized by follicular hyperplasia of lymph nodes with
abnormally increased interfollicular vascularity. Castleman’s
Disease can be classified as:
1. unicentric versus multicentric, based on clinical and
radiological findings
2. hyaline vascular versus plasmacytic versus mixed cellularity
variety, based on histopathology
3. HIV negative versus HIV positive, based on the HIV status of
the patient.
Unicentric Castleman’s Disease
Unicentric Castleman’s Disease is usually marked by a slow growing
solitary mass typically located in the mediastinium or
mesenteries. There are no constitutional symptoms and no elevation
of acute phase reactants (Interleukin 6, ESR and CRP). Symptoms,
if present, are due to a mass effect of bulky lymphadenopathy. In
90-95% of cases, surgical resection is curative and usually there
is no progression to lymphoma. The prognosis is excellent.
Multicentric Castleman’s Disease
In multicentric Castleman’s Disease there is usually widespread
lymphadenopathy. In some cases there is also hepatosplenomegaly.
Symptoms can include severe fatigue, night sweats, fever, and
weight loss. These symptoms are typically driven by overproduction
of interleukin 6. Patients typically have peripheral edema, anemia
and hypoalbumenia, and respond poorly to loop diuretics.
Approximately 20% of patients have peripheral neuropathy.
Multicentric Castleman’s Disease runs a more aggressive course
than Unicentric Castleman’s, and can progress to non-Hodgkin’s
lymphoma. Multicentric Castleman’s Disease often requires systemic
therapy.
Histopathologic Classification of Castleman’s Disease
The histopathology of hyaline vascular Castleman’s Disease shows
that the lymphnode germinal centers are poorly formed with
dysplastic/atrophic CD21+ follicular dendritic cell networks
surrounded by an expanded mantle zone consisting of rims of small
CD20+ lymphocytes arranged in an onion skin manner. There is
increased interfollicular vascularity with capillary proliferation
and endothelial hyperplasia. The plasmacytic variety of
Castleman’s Disease is characterized by more numerous and larger
hyperplastic follicles, which have more expanded mantle zones
compared to hyaline vascular Castleman’s Disease. Sheets of plasma
cells are present in the interfollicular areas. The mixed
cellularity form of Castleman’s Disease has features of both
hyaline vascular and plasmacytic types of Castleman’s Disease.
Relationship between histological type and unicentric versus
multicentric disease
It has traditionally been thought that Unicentric Castleman’s
Disease is usually of the hyaline vascular variety and that
multicentric disease is of the plasmacytic type or mixed
cellularity variety. Based on review of 37 patients with
Castleman’s Disease treated at the Myeloma Institute, we have
found that patients with Unicentric Castleman’s disease indeed
exhibit pathology of the hyaline vascular variety. However, the
histopathology of multicentric disease can be evenly divided
between hyaline vascular variety, plasmacytic type, and mixed
cellularity variety. The mixed cellularity variety clinically
behaves more like plasmacytic type than like hyaline vascular
disease.
HIV status and Castleman’s Disease
HIV positive patients with Multicentric Castleman’s Disease
frequently have plasmacytic disease and the clinical course is
less favorable than that of HIV negative patients. HIV positive
patients more frequently have Kaposi’s sarcoma, and more
frequently progress to plasmablastic non-Hodgkin’s lymphoma.
Diagnosis
The diagnosis of CD is based upon a thorough clinical evaluation
that includes a detailed patient history, laboratory studies,
histopathology of affected lymphnode(s) and a variety of imaging
techniques, such as CT scan, MRI and PET-scan. Positron-emission
tomography (PET) is a non-invasive, functional imaging technology
that can be used for improved staging and detection of tumors. PET
scans can be used to determine biopsy location, stage disease,
diagnose cancer recurrence, and discern malignant from benign
conditions.
Therapy
Surgical excision is the preferred treatment in most cases of
unicentric Castleman’s Disease, and adjuvant therapy, such as
steroids and/or rituxan before surgery, is very useful to shrink
bulky or inoperable disease
A number of therapies have been used for multicentric disease:
intravenous immunoglobulin, anti-herpes drugs such as acyclovir,
ganciclovir in HIV positive disease, combination chemotherapy, and
even autologous transplantation. Other therapies include the
anti-angiogenesis agent thalidomide and anti- Interleukin 6 (IL6)
therapy. Surgery may also be useful in debulking multicentric
disease.
Anti-IL6 antibody therapy can induce disease regression with
durable remissions. Recently, a clinical trial with anti-IL6
receptor antibody has been used at the Myeloma Institute with
equal if not better responses than those observed with IL6
antibody.
Gene-array testing and Castleman’s Disease
With our large population of Castleman’s patients and the
expertise of Dr. John Shaugnessy and his Molecular Genetics
laboratory staff in gene expression profiling, we have a unique
opportunity to investigate the pathobiology of Castleman’s Disease
at the molecular level and gain new insights into the disease.
Goals Related to Castleman’s Disease at the Myeloma Institute
Our overall goals are to obtain long-term follow-up on all our
patients and conduct research to shed light on the pathogenesis of
this complex disease. A better understanding of Castleman’s
Disease will lead to new targeted therapies, which will improve
outcome and facilitate current therapies.
For more information about Castleman’s Disease, click
here.
Poems Syndrome is a rare multi-system disease that occurs in the setting of plasma cell dyscrasia. Five main features of the disease explain the acronym POEMS: (P) polyneuropathy, disease affecting many nerves; (O) organomegaly, abnormal enlargement of an organ; (E) endocrinopathy, disease affecting certain hormone-producing glands which help regulate growth rate, sexual development and certain metabolic functions; (M) monoclonal gammopathy; and (S) skin defects. Common symptoms include progressive weakness of the nerves in legs and arms, abnormal darkening of the skin, enlarged liver and/or spleen and excessive hair growth. In addition, endocrine abnormalities which may be present are failure of the ovaries and testes to function properly and type 1 diabetes. Treatment depends on the severity of the syndrome and may involve autologous stem cell transplantation
Waldenstrom's Macroglobulinemia
(WM) is a type of hematologic malignancy, or blood cancer, that
was identified in 1944 by Dr. Jan Waldenstrom, a Swedish
physician who died from this specific malignancy.
WM is a disorder of B-cell
lymphocytes, a type of white blood cell produced in the
lymphatic tissues and bone marrow. B-cell lymphocytes support
the body's immune system through the production of antibodies
that fight infection. These antibodies are also referred to as
immunoglobulins, which are proteins. Persons with WM have
elevated levels of immunoglobulin M (IgM). Elevated IgM levels
can result in clinical complications such as hyperviscosity
(thickening of the blood), bleeding, enlargement of the lymph
nodes and spleen, neuropathy (nerve degeneration).
WM is rare. At any given time
there are approximately 4,000 to 8,600 individuals who have been
diagnosed with WM. The mean age at diagnosis is 65 years. The
cause is unknown, although genetic predisposition and
environmental factors are possible suspected determinants. It is
chronic and is indolent, or slow-growing. It results when a
B-lymphocyte, during the course of its normal development into a
mature plasma cell, transforms into a cancer cell, which then
multiplies out of control. In the case of WM the transformation
takes place in the last stage just before the B-lymphocyte would
become a mature plasma cell.
Symptoms
It is possible for a
person to be asymptomatic and yet, based on high levels of IgM,
be diagnosed as having WM. There are also numerous symptoms that
may be present, including:
Fatigue
Bleeding Disorders
Neurologic manifestations
Bone pain
Lymph node enlargement
Spleen enlargement
Liver enlargement
Hearing Loss
Heart Problems
Weight Loss
Some cases have reported
eyelid thickening, gastric involvement, skin
problems/lesions, pulmonary complications, persistent
headaches.
Diagnosis
Diagnosis may be made
during the course of normal physical exam. Defining procedures
include bone marrow biopsy and x-rays.
Treatment
WM is considered
incurable but treatable, with palliative care being an important
component.
Treatment is based on one's symptoms and presenting
complications.
Hyperviscosity may be treated with
plasmapheresis. This is a
process whereby blood is taken from the body intravenously. The
blood travels through a machine that separates the cells,
platelets and plasma. The plasma is removed and is replaced with
a substitute that does not contain the IgM.
Chemotherapy
is indicated for those who are symptomatic. Typcially,
alkylating agents are used. Alkylating agents are drugs that
prevent division of cells through interaction with cell DNA,
such as cyclophosphamide and melphalan. Sometimes the alkylating
agent is paired with a glucocorticoid, such as prednisone, which
affects protein metabolism and the immune system. Drugs may be
combined according to investigative clinical protocols, which
are designed to examine the effectiveness of new treatments.
Many active protocols at the Myeloma Institute includes the use of thalidomide to
inhibit angiogenesis (development of new blood vessels that feed
cancerous cells).
Complications of the spleen may
be treated with radiation to remove the spleen's size, or the
spleen may be surgically removed (splenectomy).
Stem cell transplantation
may be indicated. This can be autologous (using one's own cells)
or allogeneic (using donor cells) [link here to the MM section
on transplantation]
Novel therapies
include biological therapies that focus on using
substances naturally produced in the body. Examples are the use
of interferons (proteins in the body that fight
viral infections), gene therapy (enhancement of
the immune system to defend against cancer).
Prognosis
While WM is considered
incurable, duration of survival has increased over the years,
with reported median survival of up to 20+ years.
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