Angioimmunoblastic T-cell lymphoma

by Jason Wasserman MD PhD FRCPC and Aleksandra Paliga MD FRCPC
December 16, 2024

This article is designed to help you understand your pathology report for angioimmunoblastic T-cell lymphoma. Each section explains an important aspect of the diagnosis and what it means for you.

What is angioimmunoblastic T-cell lymphoma?

Angioimmunoblastic T-cell lymphoma is a rare immune system cancer that develops from T cells (a type of white blood cell) that arise from germinal centers. This disease typically affects the lymph nodes but can also affect other body parts, including the liver, spleen, bone marrow, and skin. It is considered an aggressive cancer, which means it can grow and spread quickly if not treated.

What are the symptoms of angioimmunoblastic T-cell lymphoma?

The symptoms of angioimmunoblastic T-cell lymphoma vary widely and are caused by both the cancer itself and changes in the immune system.

Common symptoms include:

• Fever, night sweats, and unexplained weight loss (B symptoms).
• Borderline enlarged lymph nodes, often in multiple areas of the body.
• Swelling of the liver or spleen may cause discomfort or a feeling of fullness in the abdomen.
• Skin rashes, including itchy or raised red spots.
• Fluid buildup in the chest (pleural effusion) or abdomen (ascites), leading to shortness of breath or swelling.
• Joint pain or arthritis.

Blood tests may show signs of hematologic and immune system problems, such as anemia (low red blood cell count), low platelets, or abnormal antibodies. These findings suggest immune dysregulation, a hallmark of this disease.

What genetic changes are associated with angioimmunoblastic T-cell lymphoma?

Angioimmunoblastic T-cell lymphoma develops due to mutations in the genetic material of follicular T cells. These mutations disrupt normal cell function, causing the cells to grow uncontrollably.

Key genetic changes include:

• TET2 and DNMT3A mutations: These mutations interfere with DNA regulation, allowing cells to behave abnormally. These changes occur early in the development of the disease.
• RHOA mutation: Found in most cases, this mutation alters a protein involved in cell signaling, promoting the transformation of T cells into cancer cells.
• IDH2 mutation: This specific mutation is sometimes seen and is associated with additional DNA changes that make the disease more aggressive.
• Other mutations: Changes in genes like VAV1, PLCG1, and CD28 enhance signals that drive cancer growth. These mutations are less common but may occur alongside the mutations mentioned above.

These genetic changes provide important clues about disease development and may influence treatment decisions. However, at this time, these genetic changes do not affect treatment decisions at most institutions.

What causes angioimmunoblastic T-cell lymphoma?

The exact cause of angioimmunoblastic T-cell lymphoma is unknown, but genetic mutations in the T cells appear to play a key role. These mutations allow the cells to grow uncontrollably. Some people with this lymphoma also show evidence of an immune system imbalance, possibly triggered by infections or other factors. Research is ongoing to understand the causes of this complex disease better.

How is this diagnosis made?

The diagnosis of angioimmunoblastic T-cell lymphoma involves several steps:

1. Medical history and physical exam: Your doctor will evaluate symptoms, including swollen lymph nodes or skin changes.
2. Biopsy: A sample of an affected lymph node or other tissue is examined under a microscope to identify cancer cells.
3. Blood tests: These may show abnormal immune activity or evidence of anemia and low platelet levels. Sometimes, cancer cells can be identified in the blood by flow cytometry.
4. Immunohistochemistry and genetic tests: Special tests confirm the diagnosis and identify genetic mutations in the cancer cells.

Microscopic features

Under a microscope, angioimmunoblastic T-cell lymphoma often shows a mixture of cancerous T cells and other types of immune cells. The cancerous T cells often represent a minority of total T cells, which makes the diagnosis challenging and can lead to false negative T cell clonality results.

Clusters of abnormal T cells replace the normal structure of the lymph node. These cancerous cells are usually small to medium in size, with pale, clear cytoplasm and mildly irregular nuclei. Reactive immune cells, including small lymphocytes, plasma cells, and histiocytes, surround these cells.

Overall, the appearance of angioimmunoblastic T-cell lymphoma is highly variable and easily mistaken for a reactive lymph node. Occasionally, it can mimic other lymphomas such as EBV-positive diffuse large B cell lymphoma, EBV-positive Hodgkin lymphoma, and rarely marginal zone lymphoma because the cancerous T cells promote clonal proliferations of EBV-positive B cells and plasma cells.

In the latter stages of the lymphoma, blood vessels in the lymph node may increase in number, become enlarged and prominent, and have thickened walls. Pathologists also use immunohistochemistry to identify the unique markers that confirm the diagnosis.

Immunohistochemistry

Immunohistochemistry is a laboratory test that helps pathologists identify cancer cells based on the proteins they produce. The cancer cells always express CD4, a marker of helper T cells. Other markers of follicular helper T cells, including CD10, BCL6, PD1, ICOS, BCL6, and CXCL13, are also typically expressed.  The cancer cells usually express various pan T cell markers such as CD2, CD3, and CD5, but may lose some markers like CD7. These tests confirm the diagnosis and help differentiate this lymphoma from other types.

Clonality assays

DNA-based T cell clonality assays show that the cancerous T cells in angioblastic T-cell lymphoma express the same TCR receptor. However, because the cancer T cells are often a minority of the cells in the tissue sample, false negatives are possible, and proof of T cell clonality is unnecessary for diagnosis.

Prognosis

The prognosis for angioimmunoblastic T-cell lymphoma varies widely. The disease is known to wax and wane over many years with seemingly spontaneous regressions followed by sudden recurrences. On average, about half of patients survive three years after diagnosis, but some achieve long-term remission.

A scoring system called the Prognostic Index for Angioimmunoblastic T-cell Lymphoma (PIAI) helps identify low-, intermediate-, and high-risk groups based on factors like age, inflammation markers, and overall health.