Lymphoma-Like Disorders - Causes and Types

Introduction

Lymphoma is a condition where the lymphatic system is affected. Usually, it refers to types of cancer. Lymphadenopathy (enlarged lymph node) is a common finding of lymphoma. However, enlarged lymph nodes occur in a few other conditions mimicking lymphoma. Lymphadenopathy is also seen in healthy individuals, and in some cases, it occurs due to underlying diseases. Some lymphoproliferative disorders, characterized by excessive white blood cell (lymphocyte) production, also clinically manifest lymphoma-like symptoms.

What Does Lymphadenopathy Signify?

• Individuals with lymph nodes less than 0.39 inches are less prone to malignancy.

• Single or localized lymph nodes indicate the presence of infection.

• Isolated enlarged supraclavicular, axillary, or epitrochlear lymph nodes have greater malignancy incidence.

• Metastatic solid tumors have localized lymphadenopathy. The lymph nodes may be firm, hard, and fixed to the tissues.

• Generalized lymphadenopathy with hepatosplenomegaly or abnormal CBC can represent severe lymphoma.

What Are the Causes of Lymphadenopathy?

The causes may be benign or malignant.

Benign Causes:

• Infections.

• Autoimmune disorders.

• Drug hypersensitivity.

• Other benign disorders.

Lymphoproliferative Causes:

• Benign lymphoproliferative disorders.

• Atypical lymphoproliferative disorders.

Malignant Disorders:

• Non-Hodgkin's lymphoma.

• Hodgkin’s lymphoma.

• Acute and chronic leukemia.

What Are the Benign Causes of Lymphadenopathy?

Infections:

Various bacterial, viral, and fungal infections can cause lymphadenopathy.

• Acute bacterial infections (Streptococcal, Staphylococcal) are commonly identified causes.

• Multifocal lymphadenopathy is seen in toxoplasmosis, tuberculosis, HIV (human immunodeficiency virus), EBV (Epstein-Barr virus), and cat-scratch disorders.

• EBV and HIV infections, though associated with benign lymphadenopathy, can also be seen with lymphoproliferative or malignant conditions.

• If HIV or EBV is diagnosed, a lymph node biopsy may be required to rule out malignancy in case lymph nodes are large and firm.

Autoimmune Disorders:

• Lymphadenopathy is seen in most patients with rheumatoid arthritis, systemic lupus erythematosus (SLE- autoimmune inflammatory disease), and Sjogren’s syndrome (immune disorder with dry mouth and eyes).

• In rheumatoid arthritis, lymphadenopathy is due to inflammation in joints. Generalized lymphadenopathy may also be seen during the disease due to reactive lymphoid hyperplasia (organ enlargement) with interfollicular plasmacytosis (increased plasma cells in tissues).

• Lymphadenopathy in SLE is due to diffuse hyperplasia with scarce follicles.

• Sjogren's syndrome develops lymphoproliferative disorder and shows enlarged salivary glands with increased lymphadenopathy. The cause is reactive adenitis or atypical lymphoid hyperplasia. In addition, individuals with Sjogren's syndrome show an increased tendency to develop marginal zone lymphoma in salivary glands. Therefore, a lymph node biopsy is recommended if the salivary gland is rapidly enlarged.

Drug Hypersensitivity:

Hypersensitivity to drugs causes fever, rash, eosinophilia (high eosinophil count), and diffuse lymphadenopathy. Anticonvulsants (Phenytoin) and Carbamazepine are common causes of drug hypersensitivity. Other drugs include antibiotics (Sulfa, Penicillin, and Erythromycin), Aspirin, and Allopurinol. The symptoms develop due to chronic triggers from drug reactions, and the lymphadenopathy resolves within a few days of drug stoppage. Biopsy of lymph nodes shows similar features to that of viral lymphadenopathy. The lymph node's architecture is partially or completely obliterated by infiltrates of eosinophils, plasma cells, and small lymphocytes. When the drug reaction induces cellular or humoral immunity, pathological changes in lymph nodes occur, causing lymphoma.

Other Benign Conditions:

• Sarcoidosis exhibits diffuse lymphadenopathy similar to lymphoma. Lymph node biopsy helps in diagnosis.

• Amyloidosis with nephrotic syndrome, cardiac issues, and neuropathy show lymphadenopathy. The clinical features help differentiate it from lymphoma.

• Regional lymphadenopathy may occur using silicone (breast implants, prosthetic replacements). Biopsy shows reactive lymphoid hyperplasia with multinucleated giant cells that contain silicone particles or cystic spaces caused by silicone liquid.

• Smallpox vaccines can cause lymphadenopathy similar to that caused by EBV, causing it to be confused with lymphoma. The enlargement occurs one to two weeks after vaccine administration and resolves independently.

What Are Benign Reactive Lymphoproliferative Disorders?

Benign reactive lymphoproliferative disorders are reactive conditions that may not show malignant changes. It comprises conditions such as:

• Kikuchi - Fujimoto Disease - The condition is also known as histiocytic necrotizing lymphadenitis and is self-limiting. Clinical symptoms are cervical lymphadenopathy, fever, and leukopenia (low white blood cell count) that resolve independently within three months. The lymphadenopathy is less than 0.78 to 1.57 inches in size. However, certain conditions show larger generalized lymphadenopathy. Histologically, the lymph nodes contain foci of necrotic debris, which is often confused with lymphoma.

• Rosai - Dorfman Disease - Also known as sinus histiocytosis. Incidence is common among healthy young adults with massive, matted cervical lymphadenopathy and other features. Most of the lymphadenopathy occurs in the head and neck region. In addition, there is lymph node capsule distention and histiocytic proliferation in the sinuses.

• Vascular Transformation of Sinuses - It is an uncommon condition in which the lymph nodes are transformed into complex endothelial-lined channels. Proliferated vessels of lymph nodes with obstructed and sclerosed sinuses, with parenchyma of lymph nodes showing atrophy, are pathological features. Therefore, vascular transformation warrants the search for cancer-causing lymph nodes.

• Inflammatory Pseudo-Motor of Lymph Nodes - In addition to the systemic complaint, young adults present with enlarged lymph nodes in single or multiple regions. The nodes are greater than 1.18 inches with the involvement of central and peripheral regions. Biopsy shows activated histiocytes, inflammatory cells, fibroblasts, and blood vessels.

• Progressive Transformation of Germinal Centers - Young adults present with asymptomatic lymphadenopathy. The nodal architecture is preserved. The lymph node enlargement may remain stable for years or regress. However, the condition can develop into lymphocyte-predominant type Hodgkin’s lymphoma.

What Are Atypical Lymphoproliferative Disorders?

There is an increased incidence of developing malignancy. The conditions associated are:

1. Unicentric Castleman’s Disease - There is solitary hyperplastic mediastinal lymph node enlargement with small atrophic (reduced size) germinal centers. Lymphadenopathy is most common in the hilar or mediastinal region with gradual involvement of the abdomen. The condition is asymptomatic, and peripheral lymphadenopathy is absent.

2. Multicentric Castleman's Disease - Peripheral lymphadenopathy with systemic complaints of hepatosplenomegaly (enlargement of liver and spleen), fever, night sweats, fatigue, and weight loss are present. The condition is often associated with HIV or Kaposci’s sarcoma and non-Hodgkin’s lymphoma. The prognosis is poor for patients with this condition.

3. Angioimmunoblastic Lymphadenopathy With Dysproteinemia - The symptoms are similar to malignant lymphoma with benign histological features. Therefore, the condition is re-classified as T-cell lymphoma. General lymphadenopathy with systemic complaints is present. Biopsy shows obliteration of nodal architecture with infiltration of small and medium-sized lymphocytes, plasma cells, eosinophils, and histiocytes. The clinical course is aggressive, as seen in lymphoma. Histologic evidence of T-cell or B-cell lymphoma is present in a few cases.

4. Lymphamatoid Granulomatosis - Studies suggest the condition is caused by EBV-related B-cell lymphoproliferative disorder. Skin, lung, and CNS (central nervous system) involvement and lymphadenopathy are seen. The condition can be fatal due to the development of lymphoma, infections, or pulmonary complications.

• Grade I - EBV-positive cells occur rarely.

• Grade II- Scattered EBV-positive cells are seen in lesions.

• Grade III - Large and atypical EBV-positive cells diagnostic for malignant lymphoma. Grade II and III lymphomas are treated with chemotherapy.

5. Lymphomatoid Papulosis - A cutaneous T-cell lymphoproliferative condition with histological features of malignancy. The clinical symptoms are benign with the development of papules, but histologically activated malignant appearing CD4+ and CD30+ helper T-cells are seen. Therefore, there is a high risk of developing T-cell lymphoma or anaplastic large-cell lymphoma.

Conclusion

Since various conditions comprise enlargement of lymph nodes, the diagnosis becomes difficult. If the enlargement of lymph nodes persists or increases, a biopsy is essential. Lymphoproliferative conditions caused by T-cells are often diagnosed with lymphoma and do not resolve with treatment. Misdiagnosis can cause failure in treating the condition and lead to adverse effects. Therefore, adequate training is essential for the identification of the conditions.