Idiopathic Multicentric Castleman Disease - Causes, Symptoms, Diagnosis, and Treatment

Introduction

Idiopathic multicentric Castleman disease (iMCD) belongs to a subgroup of Castleman disease, also known by alternative names such as giant lymph node hyperplasia, lymphoid hamartoma, or angiofollicular lymph node hyperplasia. Castleman disease encompasses a spectrum of lymphoproliferative disorders characterized by the enlargement of lymph nodes, distinctive microscopic features in the affected lymph node tissue, and a wide range of clinical manifestations.

Individuals diagnosed with iMCD experience the enlargement of lymph nodes in multiple regions of the body and commonly exhibit flu-like symptoms, abnormal blood test results, and impaired functioning of essential organs like the liver, kidneys, and bone marrow.

What Is Castleman Disease?

Castleman disease (CD) is an uncommon disorder impacting the immune system, characterized by the enlargement of lymph nodes. The bone marrow, responsible for producing infection-fighting immune cells, experiences an abnormal proliferation of these cells in CD, resulting in swollen lymph nodes that may resemble tumors. These growths are noncancerous in nature. There are two primary classifications of Castleman disease:

• Unicentric Castleman disease involves a single group of lymph nodes and can be cured by removing swollen lymph nodes surgically.

• Multicentric Castleman disease, which involves multiple groups of lymph nodes and can be treated through targeted therapy

Idiopathic multicentric Castleman disease (iMCD) is a sub-type of multicentric Castleman disease.

What Is the Cause of Idiopathic Multicentric Castleman Disease?

The exact cause of idiopathic multicentric Castleman disease (iMCD) remains largely unknown. Researchers are still working to unravel the underlying mechanisms and triggers of this complex disorder. However, several factors have been identified that may contribute to the development of iMCD:

• Viral Infections: Some studies suggest that certain viral infections, such as human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), or Epstein-Barr virus (EBV), may play a role in the development of iMCD. These viruses may trigger abnormal immune responses and contribute to the lymph node enlargement and immune dysregulation seen in iMCD.

• Dysregulated Immune System: iMCD is characterized by dysregulation of the immune system, including abnormal production of cytokines and growth factors. Elevated levels of interleukin-6 (IL-6), a pro-inflammatory cytokine, have been observed in many iMCD patients. It is believed that these dysregulated immune responses contribute to the proliferation of lymphocytes and the characteristic enlargement of lymph nodes.

• Genetic Predisposition: While iMCD is not considered a hereditary disease, some studies suggest that certain genetic factors may predispose individuals to develop the condition. Further research is needed to understand the specific genetic variants or mutations associated with iMCD.

What Are the Symptoms of Idiopathic Multicentric Castleman Disease?

The symptoms of idiopathic multicentric Castleman disease (iMCD) can vary widely among individuals. The severity of symptoms may also fluctuate over time. Common symptoms experienced by individuals with iMCD include:

• Enlarged Lymph Nodes: The hallmark of iMCD is the presence of enlarged lymph nodes in multiple regions of the body. These swollen lymph nodes can be felt as lumps under the skin and are often painless.

• Flu-Like Symptoms: Many individuals with iMCD experience flu-like symptoms, such as fever, night sweats, fatigue, and generalized weakness.

• Abnormal Blood Test Results: Blood tests may reveal various abnormalities, including anemia (low red blood cell count), elevated levels of inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and abnormalities in liver function tests.

• Organ Dysfunction: iMCD can affect the functioning of vital organs, including the liver, spleen, kidneys, and bone marrow. This can cause symptoms such as abdominal pain, hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), abnormal kidney function, and decreased production of blood cells by the bone marrow.

• Skin Abnormalities: Some individuals may develop skin manifestations, including rashes, skin lesions, and generalized itching (pruritus).

• Neurological Symptoms: In rare cases, iMCD can affect the nervous system, leading to symptoms such as headache, cognitive impairment, dizziness, or peripheral neuropathy.

The presence of numerous enlarged lymph nodes is a distinctive characteristic of iMCD. In certain individuals, the enlarged lymph nodes might not be readily apparent and could necessitate the use of imaging examinations to verify their existence.

What Is the Diagnosis of Idiopathic Multicentric Castleman Disease?

Patients with idiopathic multicentric Castleman disease (iMCD) often experience delays in receiving a definitive diagnosis. Therefore, individuals must diligently monitor their symptoms and promptly report them to their healthcare provider.

If a patient suspects that he/she may have iMCD, the diagnostic journey may begin with a visit to a primary care physician. From there, the patient may be referred to specialists who have expertise in different areas relevant to the condition. These specialists will conduct various tests and examinations to aid in reaching an accurate diagnosis. The following tests can aid in diagnosing the iMCD:

• Physical Examination: A physical examination involves the palpation and evaluation of swollen lymph nodes, enlarged organs, and the presence of fluid accumulation in the body.

• Blood Tests: Blood tests are conducted to identify indicators of infection, autoimmune disorders, and kidney damage. These tests can help detect abnormalities in blood cell counts, assess kidney function, and evaluate inflammatory markers and autoantibodies.

• Imaging Studies: Imaging techniques such as X-rays, positron emission tomography (PET) scans, or computed tomography (CT) scans are used to visualize and identify multiple swollen lymph nodes and enlarged organs. These imaging studies provide a comprehensive view of the affected areas and help guide diagnosis and treatment decisions.

• Biopsies:

  • Fine Needle Aspiration (FNA) or Core Biopsy: FNA or core biopsy may be performed to obtain a tissue sample from a swollen lymph node for examination. However, it is important to note that the results of these biopsies may not always provide a definitive diagnosis of iMCD. In some cases, the findings may be inconclusive or insufficient for a conclusive determination.
  • Excisional Biopsy: An excisional biopsy is considered the gold standard and the only definitive method to diagnose iMCD. This procedure involves the complete removal of a swollen lymph node for detailed examination under a microscope. The excised tissue is then thoroughly analyzed to identify specific histopathological features that confirm the presence of iMCD.

What Is the Treatment of Idiopathic Multicentric Castleman Disease?

The treatment of idiopathic multicentric Castleman disease (iMCD) is complex and often requires a multidisciplinary approach involving hematologists, oncologists, and other specialists. The treatment goals are to manage symptoms, control disease progression, and improve the patient's quality of life. Treatment depends on several factors, including the severity of symptoms, the extent of organ involvement, and the individual patient's overall health.

• Medications: Various medications may be used in the treatment of iMCD. These include:

• Interleukin-6 (IL-6) Inhibitors: IL-6 plays a key role in the pathogenesis of iMCD. Drugs that target IL-6, such as Tocilizumab and Siltuximab, have shown efficacy in controlling disease symptoms and reducing inflammation.

• Chemotherapy: In more aggressive or refractory cases of iMCD, chemotherapy drugs such as corticosteroids, Etoposide, or combination regimens may be used to suppress the abnormal cell growth.

• Immunomodulatory Drugs: Medications like Rituximab, an anti-CD20 monoclonal antibody, or Thalidomide, an immunomodulatory agent, can be employed to modulate the immune system and help manage iMCD symptoms.

• Symptom Management: Supportive care plays a vital role in managing iMCD. This may include the use of pain relievers, antipyretics for fever control, and other supportive measures to address specific symptoms and complications, such as fluid accumulation, anemia, or kidney dysfunction.

• Clinical Trials: As iMCD is a rare disease with limited treatment options, participation in clinical trials may be considered. Clinical trials can provide access to novel therapies and contribute to the advancement of treatment options for iMCD.

Conclusion

In conclusion, idiopathic multicentric Castleman disease (iMCD) is a rare immune system disorder characterized by enlarged lymph nodes. Diagnosis may be challenging, requiring physical examinations, blood tests, imaging, and excisional biopsy. Treatment involves a multidisciplinary approach, including medication targeting interleukin-6, chemotherapy, immunomodulatory drugs, and supportive care.