Cancer Lymphoma Non-Hodgkin Lymphoma Non-hodgkin Lymphoma Guide Non-hodgkin Lymphoma Guide Overview Symptoms Causes Diagnosis Treatment How Non-Hodgkin Lymphoma Is Diagnosed By James Myhre & Dennis Sifris, MD 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. Learn about our editorial process Updated on January 24, 2023 Medically reviewed by Archana Sharma, DO, FAAP Medically reviewed by Archana Sharma, DO, FAAP Archana Sharma, DO, is board certified in General Pediatrics and Pediatric Hematology/Oncology. Learn about our Medical Expert Board Print Table of Contents View All Table of Contents Self-Checks/At-Home Testing Physical Examination Labs and Tests Imaging Lymph Node Biopsy Cancer Staging Differential Diagnoses Next in Non-hodgkin Lymphoma Guide How Non-Hodgkin Lymphoma Is Treated The diagnosis of Non-Hodgkin lymphoma (NHL) can be challenging. Not only do healthcare providers have to differentiate NHL from Hodgkin lymphoma (HL), there are different types of NHL—some of which are indolent (slow-growing) and others of which are aggressive (fast-growing). Healthcare providers can use a multitude of tactics to diagnose NHL. Specifically, they can look for common signs and symptoms (e.g., chest pain, unexplained weight loss, night sweats) to determine if a person falls into an at-risk category (e.g., previous cancer survivors, immunocompromised people), or utilize medical technology, such as a lymph node biopsy, to procure a diagnosis. Once the NHL type is identified, the disease needs to be staged to determine how advanced it is and direct the subsequent course of treatment. Causes and Risk Factors for Lymphoma Arthur Tilley/Getty Images Self-Checks/At-Home Testing There are no self-checks or at-home tests able to diagnose NHL. With that said, the early recognition of symptoms can help healthcare providers 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, NHL 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. The Link Between Lupus and Lymphoma Common Signs and Symptoms NHL should be suspected when lymphadenopathy occurs with other signs and symptoms of the disease, including: Persistent fatigueAbdominal pain or swellingChest painCoughingTrouble breathing These can be accompanied by so-called "B symptoms" that occur with most forms of cancer, namely: FeverNight sweatsUnexplained 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 healthcare provider because they did not realize their symptoms were serious. Lymphoma Symptoms: What to Look Out For At-Risk Groups It is important to note that certain groups of people are more likely to get NHL than others. Knowing that you're at increased risk may help you recognize signs and symptoms of the disease earlier. These include: Older adults, who are typically diagnosed at age 69 (compare to 41 in people with HL) Immunocompromised people, such as organ transplant recipients and people with HL People with autoimmune diseases, such as rheumatoid arthritis, lupus, and Sjögren syndrome People on immunosuppressive therapies, such as Azasan (azathioprine) used to treat Crohn's disease, ulcerative colitis, and granulomatosis with polyangiitis People previously treated for cancer, wherein radiation therapy can increase in certain circumstances the risk of secondary NHL by as much as 50% . 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 healthcare provider 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: Complete blood count: This panel of tests measures the amount and proportion of red blood cells, white blood cells, and platelets in a sample of blood. With NHL, the disease will often manifest with anemia (low red blood count) as well as abnormally low white blood cell and platelet counts. Lactate dehydrogenase (LDH): This test measures the level of an enzyme called lactate dehydrogenase that rises in the presence of tissue damage or disease. LDH elevations are common with NHL, as they are with testicular cancer, ovarian cancer, leukemia, melanoma, and other noncancerous diseases. Erythrocyte sedimentation rate (ESR): This test, along with another called C-reactive protein, is used to detect generalized inflammation that occurs with many diseases, including NHL. Liver function tests: This panel of tests measures various enzymes and proteins to diagnose liver inflammation or disease. With NHL, there will often be significant reductions of a liver protein known as albumin. 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. Common Markers for Lyphoma in Blood Tests 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, your healthcare provider 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 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 involves a smaller needle, and, while occasionally used, doesn't always provide enough cells to return a reliable result. What to Expect When Undergoing a Biopsy 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 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 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, or FISH testing, 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 healthcare provider 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 the following. 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 when lymphoma is believed to have spread to the brain. What Is Primary Bone Lymphoma? 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 organs 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 a diagnostic work-up, healthcare providers will consider other conditions with symptoms and characteristics similar to that of NHL. 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 (an 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) How Lymphoma Is Treated A Word From Verywell Like all other forms of cancer, NHL 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 NHL in many people or offer disease-free survival even in the advanced stages. Coping With Lymphoma 22 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. American Cancer Society. Non-Hodgkin lymphoma risk factors. National Institute of Health and Care Excellence (UK). Non-Hodgkin's lymphoma: diagnosis and management. In: NICE Guideline, No. 52. Laurent C, Do C, Gourraud PA, De Paiva GR, Valmary S, Brousset P. Prevalence of common non-Hodgkin lymphomas and subtypes of Hodgkin lymphoma by nodal site of involvement: A systematic retrospective review of 938 cases. Medicine (Baltimore). 2015;94(25):e987. doi:10.1097/MD.0000000000000987 Sapkota S, Shaikh H. Non-Hodgkin lymphoma. StatPearls. Ciobanu A, Stanca O, Triantafyllidis I, Lupu A. Indolent lymphoma: Diagnosis and prognosis in medical practice. Maedica (Buchar). 2013;8(4):338-42. Howell DA, Warburton F, Ramirez AJ, Roman E, Smith AG, Forbes LJ. Risk factors and time to symptomatic presentation in leukaemia, lymphoma and myeloma. Br J Cancer. 2015;113(7):1114-20. doi:10.1038/bjc.2015.311 Smith A, Crouch S, Lax S, et al. Lymphoma incidence, survival and prevalence 2004-2014: sub-type analyses from the UK's Haematological Malignancy Research Network. Br J Cancer. 2015;112(9):1575-84. doi:10.1038/bjc.2015.94 Na R, Laaksonen MA, Grulich AE, et al. Iatrogenic immunosuppression and risk of non-Hodgkin lymphoma in solid organ transplantation: A population-based cohort study in Australia. Br J Haematol. 2016;174(4):550-62. doi:10.1111/bjh.14083 Kim CJ, Freedman DM, Curtis RE, Berrington de Gonzalez A, Morton LM. Risk of non-Hodgkin lymphoma after radiotherapy for solid cancers. Leuk Lymphoma. 2013;54(8):1691-7. doi:10.3109/10428194.2012.753543 Mohseni S, Shojaiefard A, Khorgami Z, Alinejad S, Ghorbani A, Ghafouri A. Peripheral lymphadenopathy: Approach and diagnostic tools. Iran J Med Sci. 2014;39(2 Suppl):158-70. American Cancer Society. What causes non-Hodgkin lymphoma?. Stanca O, Ciobanu AM, Lupu AR, et al. Onset risk factors and treatment response features of refractory Hodgkin lymphoma. Maedica (Buchar). 2013;8(4):343-6. Mehrian P, Ebrahimzadeh SA. Differentiation between sarcoidosis and Hodgkin's lymphoma based on mediastinal lymph node involvement pattern: Evaluation using spiral CT scan. Pol J Radiol. 2013;78(3):15-20. doi:10.12659/PJR.889056 Pattanayak S, Chatterjee S, Ravikumar R, Nijhawan VS, Vivek Sharma, Debnath J. Ultrasound evaluation of cervical lymphadenopathy: Can it reduce the need of histopathology/cytopathology?. Med J Armed Forces India. 2018;74(3):227-34. doi:10.1016/j.mjafi.2017.04.005 Manzella A, Borba-Filho P, D'Ippolito G, Farias M. Abdominal manifestations of lymphoma: Spectrum of imaging features. ISRN Radiol. 2013;2013:483069. doi:10.5402/2013/483069 American Society of Clinical Oncologists. Lymphoma - non-Hodgkin: Diagnosis. In: Cancer.Net. Giuliani M, Rinaldi P, Rella R, et al. Effect of needle size in ultrasound-guided core needle breast biopsy: Comparison of 14-, 16-, and 18-gauge needles. Clin Breast Cancer. 2017;17(7):536-43. doi:10.1016/j.clbc.2017.02.008 Al-Hmadani M, Habermann TM, Cerhan JR, Macon WR, Maurer MJ, Go RS. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol. 2015;90(9):790-5. doi:10.1002/ajh.24086 Algahtani FS, Farhat KH, Alshebly MM. Comparison of flow cytometric and immunohistochemical immunophenotyping data for diagnosis of B-cell neoplasms and classic hodgkin's lymphoma. J Nat Sci Med. 2019;2(1):35-40. doi:10.4103/JNSM.JNSM_22_18 Wang Y, Li Q, Zhu L, et al. Cytogenetics with flow cytometry in lymph node/extranodal tissue biopsies is sensitive to assist the early diagnosis of suspected lymphomas. Ann Hematol. 2017;96(10):1673-80. doi:10.1007/s00277-017-3066-y Van HGeertum RL, Scarimbolo R, Wolodzko JG, et al. Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma: an operational approach for clinical trials. Drug Des Devel Ther. 2017;11:1719-28. doi:10.2147/DDDT.S136988 Kumar A, Burger IA, Zhang Z, et al. Definition of bulky disease in early stage Hodgkin lymphoma in computed tomography era: prognostic significance of measurements in the coronal and transverse planes. Haematologica. 2016;101(10):1237-43. doi:10.3324/haematol.2016.141846 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. See Our Editorial Process Meet Our Medical Expert Board Share Feedback Was this page helpful? Thanks for your feedback! What is your feedback? Other Helpful Report an Error Submit By clicking “Accept All Cookies”, you agree to the storing of cookies on your device to enhance site navigation, analyze site usage, and assist in our marketing efforts. Cookies Settings Accept All Cookies