How Lymphoma Is Diagnosed

Diagnosing lymphoma can often be challenging. It not only involves surgery to check for cancer in the lymph nodes but also requires additional tests to determine which type and stage of cancer you have.

The road to a definitive diagnosis may involve a variety of specialists, including a surgical oncologist, a hematologist-oncologist (a specialist in blood cancers), and a hematopathologist (a specialist in the diagnosis of blood diseases).

Self-Checks

Lymphoma is a form of cancer that starts in the type of white blood cell called a lymphocyte. The disease affects the lymphatic system, a closed system is comprised of lymphatic vessels, lymph nodes, lymph fluid as well as the spleen, tonsils, adenoids, thymus gland, and bone marrow. When you have lymphoma, lymphocytes will change (mutate) and grow out of control.

Most people with lymphoma will see their healthcare provider because of one or more swollen lymph nodes that won't go away. The condition, known as lymphadenopathy, may also be accompanied by other symptoms such as fever, fatigue, night sweats, and weight loss.

Physical Exam

Because the symptoms of lymphoma can be caused by any number of illnesses, the diagnosis will typically start with a review of your medical history along with a physical examination.

A medical history may reveal certain risk factors that increase your likelihood of lymphoma, including advanced HIV infection, previous chemotherapy or radiation therapy, or a family history of the disease. The physical exam will focus on the lymph nodes as well as parts of the lymphatic system that can be physically felt (palpated).

An enlarged spleen or liver may also be suggestive of lymphoma. Certain types of lymphoma, known as cutaneous lymphoma, will manifest with dry, discolored patches of skin or reddish nodules or tumors.

Labs and Tests

Your healthcare provider will perform tests to either support the diagnosis or exclude other causes. These include such standard blood tests as:

• Complete blood count (CBC) to look for increases or decreases in red or white blood cells characteristic of lymphoma
• Beta-2 microglobulin (B2M), a protein shed by cells that increases in concentration with the development of blood cancers
• Lactate dehydrogenase (LDH), an enzyme commonly elevated in lymphoma
• Erythrocyte sedimentation rate (ESR), a generalized marker of inflammation suggestive of infection or malignancy
• Liver functions tests (LFTs) to check for liver inflammation and abnormalities in liver enzymes
• Human immunodeficiency virus (HIV) test, since HIV increases the risk of certain lymphomas and HIV therapy improve outcomes in people with AIDS-associated lymphoma
• Hepatitis B and hepatitis C tests, since both types of viral hepatitis are known to increase the risk of lymphoma

Imaging

If lymphoma is suspected but there are no signs of lymphadenopathy in the armpit, groin, or neck, your healthcare provider may order a CT scan of the chest to look for swollen lymph nodes in the chest or an abdominal ultrasound or magnetic resonance imaging (MRI) to look for swollen lymph nodes in the abdomen.

Excisional Biopsy

The lymph node biopsy is the gold standard for the diagnosis of lymphoma. It not only provides definitive proof of the malignancy but also begins the process of classifying and staging the disease should cancer cells be found.

The biopsy will target the lymph nodes which act as filters in the lymphatic system. If cancerous lymphocytes are present, they will accumulate in the lymph nodes and cause cellular changes that can be detected under the microscope.

There are two types of biopsies commonly used to diagnose lymphoma, both of which can be performed on an outpatient basis:

• Excisional lymph node biopsy, in which the entire lymph node is removed
• Incisional lymph node biopsy, in which part of the lymph node or lymph node tumor is removed

The surgery is performed under local anesthesia in a hospital operating room or outpatient surgical center. It usually takes around 30 to 45 minutes to perform.

Imaging studies—such as X-ray, ultrasound, MRI, and computed tomography (CT)—may be used to guide the surgeon into the correct position. Real-time positron emission tomography (PET) scans, viewed in a digital monitor, are especially useful when performing chest node biopsies.

An excisional biopsy is generally preferred because the architecture of the lymph node is as important to the classification of the disease as the presence of cancer cells. It also avoids the need for a second biopsy should lymphoma be found.

Once obtained, the biopsied tissue will be examined by a pathologist who will use special stains and procedures to confirm or exclude lymphoma as the cause. If lymphoma is diagnosed, additional tests will be used to classify and stage the disease.

Classification

The classification of lymphoma is rarely a straightforward process since there are so many types and subtypes of lymphoma, each with different outcomes and treatment protocols. The process involves a series of tests that differentiate the various types of lymphoma based on their physical and genetic characteristics as well as their location.

Among the tests commonly used to classify lymphoma:

• Histopathology involves the microscopic examination of tissues to look for specific, identifiable abnormalities.
• Immunophenotyping involves the detection of proteins (called antigens) on the surface of lymphocytes, variations of which serve as unique identifiers for each type of lymphoma.
• Cytogenetics is used to establish the position of chromosomes in cancer cells. The translocation (abnormal arrangement) of chromosomes can help identify the type of lymphoma involved.
• Molecular analysis is a genetic test that can identify the type of lymphocyte involved in lymphoma. Doing so predict the severity of the disease.

Together, these characteristics can accurately classify lymphoma so that the appropriate treatment is delivered.

Hodgkin vs. Non-Hodgkin Lymphoma

The first step in classification involves the differentiation of the two main categories of lymphoma, namely:

• Hodgkin lymphoma (HL) originates in the lymphocytes and the lymph nodes contain abnormal cells called Reed-Sternberg cells.
• Non-Hodgkin lymphoma (NHL), a group of blood cancers that include everything but Hodgkin lymphoma

The lack of Reed-Sternberg cells generally excludes HL as the cause.

B-Cell vs. T-Cell Lymphoma

If NHL is diagnosed, hematopathologists will want to establish the type of lymphocyte involved in the disease. This may either involve B-cells derived from bone marrow (whose role it is to target disease-causing microorganisms) and T-cells derived from the thymus gland (which directly kills the microorganism).

The differences are important for several reasons:

• Disease severity: B-cell lymphomas can range from indolent (slow-growing) to aggressive. T-cell lymphomas tend to be more aggressive form and require a specific type of treatment.
• Treatment: Indolent lymphomas are generally incurable but can often be kept in remission for decades. Aggressive lymphomas, by contrast, require aggressive treatment but stand a good chance of a cure in many instances.

Areas of Involvement

The organs and tissues affected can further aid in the classification of lymphoma. For example, lymphoma in the lining of the stomach is more likely to be mucosa-associated lymphoid tissue (MALT) lymphoma, while skin lesions are far more likely to occur with NHL than HL (at least in the early stages).

Based on the area of involvement, the mutation type, and other differentiating factors, lymphoma will be classified as one of 33 types or subtypes under the Revised European American Lymphoma Classification (REAL) system or one of over 70 types and subtypes under the expanded World Health Organization (WHO) Classification of Lymphoid Neoplasms.

Staging

After the initial diagnosis and classification, lymphoma staging will be performed to determine the appropriate course of the treatment as well as the likely outcome (referred to as the prognosis).

The staging is based on a number of factors, including the number of lymph nodes affected, their location above or below the diaphragm, and whether organs outside of the lymphatic system are involved.

According to the Lugano classification system for lymphoma revised in 2015, the stages of lymphoma are broken down as follows:

• Stage 1: Cancer is confined to one lymph node region or one organ of the lymphatic system.
• Stage 2: Cancer is confined to two or more lymph node regions on the same side of the diaphragm or one lymphatic organ in addition to nearby lymph nodes.
• Stage 3: Cancerous lymph nodes are found above and below the diaphragm.
• Stage 4: Cancer has spread to other organs outside of the lymphatic system, such as the liver, lungs, or bone marrow.

Differential Diagnosis

Because the signs and symptoms of lymphoma are subtle in the early stages, they are easily mistaken for other diseases. Even with advanced-stage extranodal lymphoma (lymphoma occurring outside of the lymphatic system), the symptoms can vary dramatically based on which organ is affected. Oftentimes, the disease will only be diagnosed when multiple extranodal sites are involved.

When diagnosing lymphoma, your healthcare provider will want to rule out any other possible cause, particularly if the results of your biopsy are inconclusive. These may include:

• Bacteria infections like syphilis and tuberculosis
• Viral infections like HIV, cytomegalovirus, hepatitis B, hepatitis C, and Epstein-Barr virus (infectious mononucleosis)
• Parasitic infections like toxoplasmosis and leishmaniasis
• Autoimmune disorders like lupus and Sjogren's syndrome
• Cancers such as renal cell carcinoma (kidney cancer), squamous cell carcinoma of the lungs, melanoma (skin cancer), and hepatocellular carcinoma (liver cancer)
• Granulomatous disorders like sarcoidosis and lymphomatoid granulomatosis
• Rare disorders like Castleman's disease (giant lymph node hyperplasia)

A Word From Verywell

Lymphoma can be a difficult disease to diagnose, particularly in the early stages. Symptoms are frequently missed or misdiagnosed with few tell-tale clues to rely on.

In the end, if you have persistently swollen lymph nodes or any other systemic symptom that fails to resolve despite treatment, see a healthcare provider as soon a possible. Even if lymphoma is not the cause, persistent symptoms of any sort warrant thorough investigation.

This is especially true if you have risk factors for lymphoma, including a compromised immune system, previous exposure to radiation or chemotherapy, long-term exposure to industrial chemicals, and a first-degree relative (parent, brother, or sister) with lymphoma.