How Non-Hodgkin Lymphoma Is Diagnosed

Non-Hodgkin lymphoma (NHL) is a group of blood cancers that develops in the lymphatic system, the networks of vessels and organs that help the body fight disease-causing organisms. With NHL, a type of white blood cell called a lymphocyte will turn malignant (cancerous), causing them to multiply out of control and accumulate in lymph nodes.

As the disease progresses and spreads to other organs, it can affect how they function and lead to respiratory failure, the inability to fight infection, and other serious complications.

The diagnosis of NHL can be challenging. Not only do doctors have to differentiate NHL from Hodgkin lymphoma (HL), a less common form of the disease, but there are many different types of NHL, some of which are indolent (slow-growing) and other of which are aggressive (fast-growing)

Once the NHL type is identified, the disease needs to be staged to determine how advanced the disease is and direct the appropriate course of treatment.

Doctor feeling patient's lymph nodes
Arthur Tilley/Getty Images

Self-Checks/At-Home Testing

There are no self-checks or at-home tests able to diagnose non-Hodgkin lymphoma. With that said, the early recognition of symptoms can help doctors diagnose the disease in the early stages when it is most treatable.

As a disease characterized by the accumulation of tumor cells in lymph nodes, NHL is most commonly recognized by the onset of lymphadenopathy (swollen lymph glands). The pattern of development can differentiate it, as least in part, from HL.

Unlike Hodgkin lymphoma, in which swollen lymph nodes tend to develop in the upper body, non-Hodgkin lymphoma can cause lymphadenopathy in any part of the body.

Lymphadenopathy in people with NHL is almost invariably painless and persistent, unlike those caused by viral infections. Around two-thirds will occur under the arms, near the inner elbow, behind the knee, or in the groin. Most will feel rubbery and gradually coalesce into larger masses.

But that's not always the case. Some indolent forms of NHL can cause recurrent lymphadenopathy in which the swelling of lymph nodes wax and wane.

The variability and non-specificity of lymphadenopathy in people with NHL can make the diseases difficult to differentiate from the plethora of other possible causes, including autoimmune diseases, systemic infections, and drug reactions.

Common Signs and Symptoms

NHL should be suspected when lymphadenopathy occurs with other signs and symptoms of the disease, including:

  • Persistent fatigue
  • Abdominal pain or swelling
  • Chest pain
  • Coughing
  • Trouble breathing

These can be accompanied by so-called "B symptoms" that occur with most forms of cancer, namely:

  • Fever
  • Night sweats
  • Unexplained weight loss

With that being said, by the time these symptoms develop, NHL will almost invariably be in the more advanced stages. Unlike HL—which progresses in an orderly fashion, moving from one group of lymph nodes to the next—NHL is more scattershot in its presentation.

According to a 2015 study in the British Journal of Cancer, around half of people with overt symptoms of NHL avoided seeing a doctor because they did not realize their symptoms a being serious.

At-Risk Groups

It is important to note that certain groups of people are more likely to get NHL than others. Knowing that you are at increased risk may help you recognize signs and symptoms of the disease earlier. These include:

Regular medical check-ups are important for people with known risk factors for NHL. Having these risk factors does not mean that you will get NHL, but it does provide an opportunity for early diagnosis.

Physical Examination

The diagnosis of NHL typically starts with a physical exam and a review of your medical history. Painless lymphadenopathy is often the first clue that NHL is involved. Lymphadenopathy is evaluated by palpation (touch) to establish the size, consistency, texture, location, and tenderness of swollen lymph nodes.

Although you cannot diagnose cancer based on the size or location of swollen lymph nodes, lymphadenopathy occurring in the supraclavicular region (above the collarbone) is more often associated with cancer.

Your doctor will also take into account any risk factors you may have for NHL, such as your age, HIV status, or the chronic use of immunosuppressive drugs.

Unlike some forms of cancer, a family history of NHL does not appear to increase the risk of the disease. Any genetic mutations associated with NHL appear to be acquired rather than inherited.

Labs and Tests

There are no blood tests that can diagnose NHL. They can, however, detect abnormalities suggestive of the disease, particularly if the cancer has spread to the liver or bones.

Some of the more common tests include:

The combination of anemia, high LDH, high ESR, low albumin, and "B symptoms" are highly suggestive of NHL as a possible cause.

Even though there are specific genetic mutations linked to NHL, there are no genetic tests used to diagnose the disease—in part because the presence of the mutation doesn't mean that you have (or will ever have) the disease.

Imaging

Imaging tests may be ordered during the initial diagnosis to detect areas of lymphadenopathy that may not be identified with palpation.

Although NHL usually presents in the peripheral nodes of the limbs, it can develop[ elsewhere and eventually spread to other groups of lymph nodes, including mediastinal lymph nodes of the chest and mesenteric lymph nodes of the abdomen.

Options for imaging during the initial diagnosis include:

  • Chest X-rays, which use ionizing radiation, are relatively reliable in detecting mediastinal lymphadenopathy.
  • Ultrasound, which uses high-frequency sound waves, is especially useful in evaluating cervical lymphadenopathy in the neck.
  • Computed tomography (CT), which uses multiple X-ray images to create three-dimensional "slices" of internal organs, is better able to detect internal than standard X-rays.
  • Magnetic resonance imaging (MRI), which uses powerful magnetic and radio waves, is generally superior to CT in detecting and characterizing lymphadenopathy.

Lymph Node Biopsy

A lymph node biopsy is considered the gold standard for the diagnosis of NHL and the only test able to definitively confirm the diagnosis.

If the initial tests are suggestive of NHL, the doctor will use one of several techniques to perform the biopsy:

  • Excisional biopsy, the preferred procedure, is performed under local anesthesia to remove the entire lymph node.
  • Incisional biopsy is similar to an excisional biopsy but only involves the extraction of a portion of the lymph node.
  • Core needle biopsy (CNB) is a less invasive technique in which a hollow needle is inserted through the skin and into a lymph node to obtain a narrow column of tissue.
  • Fine needle aspiration (FNA) involves a smaller needle, and, while occasionally used, doesn't always provide enough cells to return a reliable result.

Evaluation of a Lymph Node Biopsy

Once the biopsied sample is sent to the lab, it will undergo multiple tests to determine whether NHL is involved and, if so, what type of NHL it is.

Types of Non-Hodgkin Lymphoma

NHL can be broadly categorized into three groups:

  • B-cell lymphoma is the more common form of the disease that affects B-cell lymphocytes produced by the bone marrow. They include indolent types such as marginal zone lymphoma as well as aggressive types such as Burkitt lymphoma and mantle cell lymphoma.
  • T-cell lymphoma causes cancer in T-cell lymphocytes produced by the thymus gland. They include indolent types such as follicular lymphoma and small lymphocytic lymphoma and aggressive types like peripheral T-cell lymphoma and T-cell lymphoblastic lymphoma.
  • NK-cell lymphoma is a rare and aggressive form of the disease that causes cancer in natural killer (NK) T-cell lymphocytes.

The evaluation, overseen by a medical pathologist, typically involves the following tests:

  • Flow cytometry is a technique in which the tissues are treated with antibodies that attach to receptors on NHL cells. The treated sample is then placed in a machine called a flow cytometer that is able to detect whether attachment has occurred. A positive result confirms NHL as the cause.
  • Immunohistochemistry (IHC) is a similar technique in which the sample is treated with antibodies but, rather than using a machine, can identify NHL based on the sample's response to specialized stains (called immunostains).
  • Immunophenotyping, performed with either flow cytometry or immunohistochemistry, identifies the physical characteristics of NHL based on how different antibodies attach to the surface, nucleus, or cytoplasm of the cell. Immunophenotyping can quickly differentiate B-cell lymphomas from T-cell or NK-cell lymphomas.
  • Fluorescent in situ hybridization (FISH) can identify the genetic type of NHL based on how specialized fluorescent dyes attach to genes or chromosomes in the cell's DNA. It is a highly accurate test and often used alongside flow cytometry to identify the specific type and subtype of NHL.

Cancer Staging

Once NHL has been diagnosed, the results of the pathology report will provide the foundation by which the disease is staged. Staging is performed to characterize the severity of the disease, to direct the appropriate course of treatment, and to predict the likely outcome (prognosis).

To accurately stage NHL, the doctor will need to determine the extent of the malignancy, if it occurs above or below the diaphragm, and whether the cancer has become extranodal (spread beyond the lymph nodes).

To determine this, additional tests may be performed, including:

  • Positron emission tomography (PET): This is an imaging study that uses radioactive sugar molecules to detect areas of increases metabolic activity (such as occurs with cancer). It is an accurate tool able to detect if a cancer has metastasized (spread to distant organs).
  • Bone scan: Also known as bone scintigraphy, this imaging study uses radioactive tracers to detect if cancer has spread to bones.
  • Bone marrow aspiration: This type of biopsy involves the insertion of a hollow-core needle into a bone, usually the hip, to obtain a sample of marrow. This can confirm whether bone metastasis has occurred.
  • Lumbar puncture: Also known as a spinal tap, this involves the insertion of a needle into the spinal cord to obtain cerebrospinal fluid. This is performed is lymphoma is believed to have spread to the brain.

Based on these and other findings, the cancer specialist (known as an oncologist) can stage the disease. The most common system used in clinical practice today is called the Lugano Classification System.

The Lugano System is broken down into four stages—Stage I, Stage II, Stage III, and Stage IV—with the first two stages regarded as limited-stage disease and the latter two stages referred to as advanced-stage disease.

  Stage Definition
Limited I One node or group of affected nodes
  IE Same as Stage I but with a single extranodal lesion 
  II Two or more groups of affected nodes on the same side of the diaphragm
  IIE Same as Stage I or Stage II but with several contiguous extranodal lesions
Advanced III Affected nodes are around found on both sides of the diaphragm
  III(1) Same as Stage III but with involvement of the spleen or hilar lymph nodes of the lungs, splenic lymph nodes of the spleen, celia lymph nodes of the celiac artery, or portal lymph nodes of the liver
  III(2) Same as Stage III but with involvement of para-aortic lymph nodes of the aorta, iliac lymph nodes of the iliac artery, inguinal lymph nodes of the groin, or mesenteric lymph nodes of the chest
  IV Widespread disease affecting one or more organ other than the spleen, with or without nodal involvement

The stage of lymphoma is important when determining a person’s treatment options, but it is more important for some types of lymphoma than others. In some cases, the treatment is based on whether there is "bulky disease," meaning the presence of large tumors in the chest.

Even with early-stage NHL, the presence of bulky disease almost invariably indicates the need for more aggressive therapy.

Differential Diagnoses

As part of the diagnostic work-up, doctors will consider other conditions with symptoms and characteristics similar to that of non-Hodgkin lymphoma. This not only includes Hodgkin lymphoma but other benign or malignant conditions affecting the lymphatic system.

Among the possible conditions explored in the differential diagnosis are:

  • Castleman disease (a rare disease affecting lymph nodes)
  • Collagen vascular diseases (the autoimmune inflammatory condition targeting connective tissues in vessels)
  • Follicular hyperplasia (the benign swelling of lymphatic tissues)
  • Infections (including mononucleosis and tuberculosis)
  • Lymphoproliferative disorders (a group of diseases causing the overproduction of lymphocytes)
  • Metastatic cancers (the spread of cancer from other organs to the lymph nodes)
  • Sarcoidosis (a disease characterized by the formation of granular lumps in organs)

A Word From Verywell

Like all other forms of cancer, non-Hodgkin lymphoma is most readily treated in the early stages. However, because the symptoms can be so non-specific, it may be difficult to recognize the signs until the disease is already advanced.

In the end, the one sign you should never ignore is swollen lymph nodes. Lymphadenopathy should never be considered "normal," particularly when it persists or recurs for no apparent reason. Even if there are no other symptoms, have them checked out.

In most cases, cancer will not be the cause. But, even if it is, there are treatments today that can cure in NHL in many people or offer disease-free survival even in the advanced stages.

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