How Lymphoma Is Diagnosed

A lymph node biopsy is only the start of the process

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).

warning signs of lymphoma
Illustration by Brianna Gilmartin, Verywell


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).

Unlike other types of chronic lymphadenopathy, the swollen lymph nodes in lymphoma will usually be painless. On palpation, the nodes will also appear firm, rubbery, and movable in the surrounding tissues.

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:


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.

Neither blood nor imaging tests can diagnose lymphoma. They can, however, provide ample evidence to move you to the next stage in the diagnosis: the excisional biopsy.

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.

Needle biopsies, such as fine-needle aspiration (FNA), are less commonly used because they can often fail to obtain enough tissue to render an accurate diagnosis. Core biopsy, a less invasive procedure, is being used more frequently, though accuracy may not be as high as surgical biopsy.

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.


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 is differentiated from non-Hodgkin lymphoma by the presence of Reed-Sternberg cells, a type of deformed lymphocyte with two nuclei instead of one.

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.

Both B-cell and T-cell lymphomas can occur with non-Hodgkin lymphoma. Hodgkin lymphoma involves B-cells only.

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.


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.

The staging criteria for Hodgkin and non-Hodgkin lymphoma are the same, wherein "low-grade" lymphomas are known to grow slowly (but are generally incurable) while "high-grade" lymphomas spread quickly (but respond better to treatment).

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.

Stage 3 and stage 4 lymphomas are still highly treatable and often curable depending on their type and location.

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:

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.

Frequently Asked Questions

  • What do cancerous lymph nodes feel like?

    It is impossible to tell whether a lymph node is cancerous simply by touch, but when a lymph node does become cancerous, it may become swollen and more easily felt beneath the skin. However, there are other reasons that lymph nodes swell that do not include cancer, such as a viral infection like a cold.

  • How common is lymphoma?

    Non-Hodgkin lymphoma is one of the most common forms of cancer in the U.S., whereas Hodgkin lymphoma is less common. The American Cancer Society estimates that there will be over 81,000 new cases of non-Hodgkin lymphoma and only 8,800 new cases of Hodgkin lymphoma in 2021.

  • Is a lymph node biopsy painful?

    No, you should not feel pain. Depending on the type and location of the biopsy, you will be numbed or put under general anesthesia.

11 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Mohseni S, Shojaiefard A, Khorgami Z, et al. Peripheral Lymphadenopathy: Approach and Diagnostic Tools. Iran J Med Sci. 2014 Mar;39(2 Suppl):158-70.

  2. Bagherania N, Smoller BR. An overview of cutaneous T cell lymphomas. F1000Res. 2016;5:F1000 Faculty Rev-1882. doi:10.12688/f1000research.8829.1

  3. Fei B, Schuster DM. PET Molecular Imaging–Directed Biopsy: A Review. AJR Am J Roentgenol. 2017 Aug;209(2):255-69. doi:10.2214/AJR.17.18047

  4. Baron BW, Baron JM. The diagnostic value of biopsy of small peripheral lymph nodes in patients with suspected lymphoma. Am J Hematol. 2012 Feb;87(2):228-30. doi:10.1002/ajh.22240

  5. Pileri SA, Leoncini L, Falini B. Revised European-American Lymphoma Classification. Curr Opin Oncol. 1995 Sep;7(5):401-7.

  6. Quintanilla‐Martinez L. The 2016 updated WHO classification of lymphoid neoplasias. Hematol Oncol. 2017 Jun;35(Suppl 1):37-45. doi:10.1002/hon.2399

  7. Cheson BD. Staging and response assessment in lymphomas: the new Lugano classification. Chin Clin Oncol. 2015 Mar;4(1):5. doi:10.3978/j.issn.2304-3865.2014.11.03

  8. American Cancer Society. Lymph nodes and cancer.

  9. American Cancer Society. Key statistics for non-Hodgkin lymphoma.

  10. American Cancer Society. Key statistics for Hodgkin lymphoma.

  11. MedlinePlus. Lymph node biopsy.

Additional Reading

By James Myhre & Dennis Sifris, MD
Dennis Sifris, MD, is an HIV specialist and Medical Director of LifeSense Disease Management. James Myhre is an American journalist and HIV educator.