Lymphoproliferative Disorders - Causes, Types, Diagnosis, and Treatment

Introduction

Lymphoproliferative disorders are a result of an abnormal increase in lymphocytes. Under healthy conditions, lymphocytes increase in number when there is an infection in the body in response to fighting the antigens. Sometimes, lymphocytes undergo vigorous proliferation irrespective of the presence of infection.

There are two types of lymphocytes: T and B lymphocytes which undergo uncontrolled regeneration to cause immunoproliferative disorders. These cells are prone to immunodeficiency characterized by dysfunctional immune systems and lymphocyte dysregulation. This must be due to the immunodeficiency of the body. This uncontrolled lymphocyte production leads to monoclonal lymphocytosis, lymphadenopathy, and bone marrow infiltration. The proliferation of lymphocytes can be attributed to iatrogenic or acquired genetic mutations.

Lymphocytes often increase in number inside the tiny organs called lymph nodes. Lymph nodes are present throughout the body and are interconnected. They carry lymph fluid that contains lymphocytes. When the body's defense system identifies an infection, lymphocytes increase in number and help fight the infection until it is eliminated. As a result of this increase in lymphocyte levels, lymph nodes enlarge and become palpable. Once the infection is eliminated, lymph nodes return to their normal size.

What Are Lymphoproliferative Disorders?

Lymphoproliferative disorders (LPD) are a heterogeneous group of diseases that result from abnormal increase and proliferation of lymphocytes in the blood. Whenever the body recognizes an infection, the immune system responds by producing more lymphocytes that help in fighting the infection. As a result, there shall be a transient increase in the number of lymphocytes. This is a normal, healthy immune response of the body. For some reason, when there is a defect in the body's immune system, lymphocytes proliferate in abnormal counts leading to lymphoproliferative disorders. These defects in the immune system are a complication of primary immunodeficiency (PID) and immunoregulatory syndrome. LPD has a high mortality rate with a poor prognosis.

What Are the Causes for Lymphoproliferative Disorders?

Many genetic mutations are responsible for lymphoproliferative disorders. These mutations may be acquired and iatrogenic.

• Childhood Immunodeficiency Syndromes: These syndromes cause lymphocyte proliferation, infiltrating lymphoid organs and undergoing metastasis. It carries a higher mortality rate, and most lymphoid neoplasms manifest by the age of ten years.

Inherited Causes of LPDs:

• X-Linked Lymphoproliferative (XLP) Disorders- Three phenotypes that are observed are fulminant infectious mononucleosis, B-cell lymphoma, and dysgammaglobulinemia. These disorders are further divided into XLP1 and XLP2. XLP1 is caused due to mutation of the SAP gene. XLP2 is caused due to mutation in XIAP (x-linked inhibitor of apoptosis).

• Autoimmune Lymphoproliferative Syndrome (ALPS) - This disorder is characterized by autoimmune cytopenia and susceptibility to malignant transformation.

Other Inherited Causes:

• Non-Hodgkin's Lymphoreticular B Cell Neoplasm- This lymphoreticular disorder is caused due to defects in the BTK gene. This defect causes abnormality in B-cell maturity, predisposing the individual to develop lymphoproliferative disorders.

• Common Variable Immune Deficiency (CVID)- This type of immune deficiency often leads to lymphoreticular malignancies along with B-cell lymphoproliferative disorders

• Chediak Higashi Syndrome (CHS)- Accelerated phase of this syndrome leads to lymphocytic infiltration.

• Wiskott-Aldrich Syndrome- Mutation in WASP (Wiskott-Aldrich syndrome protein) gene leads to abnormality in immune synapse formation.

• Ataxia Telangiectasia- This inherited autoimmune recessive disorder predisposes an individual to lymphoproliferation of the T-cell phenotype.

Acquired Causes:

HIV infection causes immunodeficiency that results in lymphoproliferative disorders.

Post Transplant Lymphoproliferative Disorder (PTLD):

These disorders are caused due to organ transplantation and immunosuppressive therapies.

What Are the Types of Lymphoproliferative Disorders?

Some of the lymphoproliferative disorders are as follows:

1. Follicular lymphoma.

2. Chronic lymphocytic leukemia.

3. Acute lymphoblastic leukemia.

4. Hairy cell leukemia.

5. B-cell lymphoma.

6. T-cell lymphoma.

7. Multiple myeloma.

8. Epstein-Barr virus-associated lymphoproliferative disorders.

9. X-linked lymphoproliferative disorders.

10. Post-transplant lymphoproliferative disorder.

How Are Lymphoproliferative Disorders Diagnosed?

Diagnosis of lymphoproliferative disorders includes clinical, histopathological, and imaging studies.

Clinical Findings: They include:

• Asthenia.

• Anemia.

• Loss of weight.

• Skin rash.

• Recurrent infections.

Laboratory Tests: These tests may reveal the presence of:

• Hepatomegaly.

• Splenomegaly.

• Thrombocytopenia.

• Granulocytopenia.

• Lymphadenopathy.

Biochemical Tests: These tests may evaluate:

• Serologic tests to detect cytomegalovirus and Epstein-Barr virus.

• Erythrocyte sedimentation rate.

• Levels of creatinine, calcium, and phosphate levels.

• Evaluation of lactic dehydrogenase levels.

Radiological Studies: Imaging studies are performed to assess the size and location of tumor mass:

• Computed Tomography (CT)- This scan uses contrast material to get detailed pictures of tumor masses. Contrast material can be given to the patient through an oral or intravenous route.

• Magnetic Resonance Imaging (MRI)- These studies help understand the involvement of the body's vital structures.

• Chest Radiography- This helps in assessing the pulmonary lesions.

• Bone scan: A bone nuclear imaging technique.

• Ultrasonography.

What Are the Treatment Modalities?

1. Chemotherapy: Patients with Epstein-Barr virus-associated lymphoproliferative diseases can be treated with steroids, Cyclosporine A and Etoposide. Some regimens include Cyclophosphamide, Prednisone, Vincristine, and Doxorubicin. Autoimmune disorders associated with lymphoproliferative diseases can be treated using intravenous immunoglobulins and Mycophenolate mofetil. In some cases, doctors use Sirolimus which provides a near-complete cure for autoimmune-associated lymphoproliferative disorders.

2. Surgical Therapy: Surgical resection or radiation helps locally control the lymphoproliferative disorder.

Is LPDs Serious?

Lymphoproliferative disorders are considered a complication of immunodeficiency, leading to life-threatening conditions.

What Is the Prognosis for Lymphoproliferative Disorders?

The prognosis depends on the prevalence of immunodeficiency. Most of the time, the prognosis is poor, with a median survival of seven years. Low-grade histological features of LPDs indicate that they remit when the immunodeficiency is cured. High-grade histological LPDs indicate aggressive therapy.

Conclusion

Lymphoproliferative disorders occur when the normal mechanism of the proliferation of lymphocytes breaks down, resulting in the proliferation of lymphoid cells. This leads to lymphocytosis and/or lymphadenopathy. Mainly, lymphoproliferative disorders occur due to primary immunodeficiency or immune dysregulation; the outcome depends on the specific underlying immune disorder and subtype of lymphoproliferation. Historically, lymphoproliferative disorders have a poor prognosis.