clinical presentation of lymphomas

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Non-hodgkin lymphoma.

Sumina Sapkota ; Hira Shaikh .

Affiliations

Last Update: February 24, 2023 .

• Continuing Education Activity

Non-Hodgkin lymphoma is a group of malignant neoplasms originating from lymphoid tissues, mainly the lymph nodes. These tumors may result from chromosomal translocation, various toxins, infections, and chronic inflammation. This activity describes the evaluation and management of non-Hodgkin Lymphoma and explains the interprofessional team's role in evaluating and treating patients with this condition.

• Identify the etiology of non-Hodgkin lymphoma.
• Assess the evaluation of non-Hodgkin lymphoma.
• Evaluate the management options available for non-Hodgkin lymphoma.
• Introduction

Non-Hodgkin lymphoma (NHL) is a neoplasm of the lymphoid tissues originating from B cell precursors, mature B cells, T cell precursors, and mature T cells. NHL comprises various subtypes, each with different epidemiologies, etiologies, immunophenotypic, genetic, clinical features, and response to therapy. It can be divided into 2 groups, 'indolent' and 'aggressive,' based on the disease's prognosis. The most common mature B cell neoplasms are Follicular lymphoma, Burkitt lymphoma, diffuse large B cell lymphoma, Mantle cell lymphoma, marginal zone lymphoma, and primary CNS lymphoma (see Image. Mantle Cell Lymphoma). Adult T cell lymphoma and mycosis fungoides are the most common mature T cell lymphomas. [1]  The treatment of NHL varies greatly, depending on tumor stage, grade, type of lymphoma, and various patient factors (eg, symptoms, age, performance status). 

The natural history of these tumors shows significant variation. Indolent lymphomas present with waxing and waning lymphadenopathy for many years, whereas aggressive lymphomas have specific B symptoms such as weight loss, night sweats, and fever and can result in deaths within a few weeks if untreated. Lymphomas usually have indolent presentations, including follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and splenic marginal zone lymphoma. Aggressive lymphomas include diffuse large B cell lymphoma, Burkitt lymphoma, precursor B and T cell lymphoblastic leukemia/lymphoma, adult T cell leukemia/lymphoma, and other peripheral T cell lymphomas. 

Up to two-thirds of patients present with peripheral lymphadenopathy. Rashes on the skin, increased hypersensitivity reactions to insect bites, generalized fatigue, pruritus, malaise, fever of unknown origin, ascites, and effusions are less common presenting features. Approximately half of the patients develop extranodal disease (secondary extranodal disease) during their disease, while between 10 and 35 percent of patients have primary extranodal lymphoma at diagnosis. Primary gastrointestinal tract lymphoma may present with nausea and vomiting, aversion to food, weight loss, fullness of the abdomen, early satiety, and visceral obstruction-related symptoms. Patients may even present with features of acute perforation and gastrointestinal bleeding and, at times, with features of malabsorption syndrome. Primary central nervous system (CNS) lymphoma may present with headaches, spinal cord compression features, lethargy, focal neurologic deficits, seizures, and paralysis (see Image. Central Nervous System Lymphoma, MRI).

NHL may be associated with various factors, including infections, environmental factors, immunodeficiency states, and chronic inflammation. Various infectious agents have been attributed to different types of NHL.

• Epstein-Barr virus, a DNA virus, is associated with the causation of certain types of NHL, including an endemic variant of Burkitt lymphoma.
• Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell lymphoma. It induces chronic antigenic stimulation and cytokine dysregulation, resulting in uncontrolled B- or T-cell stimulation and proliferation.
• Hepatitis C virus (HCV) results in clonal B-cell expansions. Splenic marginal zone lymphoma and diffuse large B-cell lymphoma are some subtypes of NHL caused by HCV.
• Human herpesvirus 8 is associated with primary effusion lymphoma (PEL) and is a rare high-grade B-cell NHL associated with Kaposi sarcoma.
• Helicobacter pylori infection is associated with an increased risk of gastric mucosa-associated lymphoid tissue lymphomas, a primary gastrointestinal lymphoma.

Drugs like phenytoin, digoxin, and TNF antagonists are also associated with NHL. Moreover, organic chemicals, pesticides, phenoxy-herbicides, wood preservatives, dust, hair dye, solvents, chemotherapy, and radiation exposure are also associated with the development of NHL. [2] [3]  

Congenital immunodeficiency states associated with increased risk of NHL are Wiskott-Aldrich syndrome, severe combined immunodeficiency disease, and induced immunodeficiency states like immunosuppressant medications. Patients with AIDS (Acquired immunodeficiency syndrome) can have primary CNS lymphoma.

Autoimmune disorders like Sjögren syndrome, rheumatoid arthritis, and Hashimoto thyroiditis are associated with an increased risk of NHL. Hashimoto's thyroiditis is associated with primary thyroid lymphomas. [4]  Celiac disease is also associated with an increased risk of NHL.

• Epidemiology

There are geographical variations in the incidence of individual subtypes, with follicular lymphoma being more common in Western countries and T cell lymphoma more common in Asia. Overall, NHL is common in ages 65 to 74, with the median age being 67 years. Epstein-Barr virus-related (endemic) Burkitt lymphoma is more common in Africa. The endemic variant of Burkitt lymphoma is found in equatorial Africa and New Guinea. The incidence of Burkitt Lymphoma in Africa is approximately 50 times higher than in the United States. [5]  The peak incidence in children is between the ages of 4 and 7 years, and the male-to-female ratio is approximately 2 to 1. The sporadic variant of Burkitt lymphoma is seen in the United States and Western Europe. Burkitt lymphoma comprises 30 percent of pediatric lymphomas and <1 percent of adult NHLs in the United States. Sporadic Burkitt lymphoma is more common among White race individuals than in African or Asian Americans, and the majority of patients are male with a 3 or 4 to 1 male: female ratio. 

Mantle Cell Lymphoma consists of about 7 percent of adult NHLs in the United States and Europe, with an incidence of approximately 4 to 8 cases per million persons per year. Incidence increases with age and appears to increase overall in the United States. Approximately three-quarters of patients are male, and people of the White race are affected almost twice as frequently as African Americans. The median age at diagnosis is 68 years. [6] [7]

NHL is the fifth most common diagnosis of pediatric cancer in children under the age of 15 years, and it accounts for approximately 7 percent of childhood cancers in the developed world. In the United States, approximately 800 new pediatric NHL cases are diagnosed annually, with an incidence of 10 to 20 cases per million people per year. High-grade lymphomas, such as lymphoblastic and small noncleaved lymphomas, are the most common types of NHL observed in children and young adults. Lymphomas are rare in infants (≤1 percent) and account for approximately 4, 14, 22, and 25 percent of neoplasms in children aged 1 to 4, 5 to 9, 10 to 14, and 15 to 19 years, respectively. There is a male predominance, and whites are more commonly affected than African Americans.

• Pathophysiology

NHL arises from B, T, or natural killer cells due to chromosomal translocation or mutation/deletion. Proto-oncogenes are activated by chromosomal translocation and tumor suppressor genes are inactivated by chromosomal deletion or mutation. The t (14;18) translocation is NHL's most common chromosomal abnormality. This translocation is most common in follicular lymphoma. The t (11;14) translocation is associated with mantle cell lymphoma. This results in the overexpression of cyclin D1, a cell cycle regulator. The t (8;14) translocation of c-myc (8) and heavy chain Ig (14) is associated with Burkitt lymphoma. Alteration in BCL-2 and BCL-6 is associated with diffuse large B-cell lymphoma. Primary CNS lymphoma is mostly associated with HIV/AIDS. [8]

• Histopathology

The common histological finding of NHL includes follicular pattern and diffuse pattern. Follicular lymphoma shows a follicular pattern where uniform nodularity is seen throughout the lymph node and little variation in the size and shape of the follicle. The diffuse pattern shows the normal lymph node architecture effaced by the infiltration of small lymphocytes. In Burkitt lymphoma, the lymph node is completely effaced with a monomorphic infiltrate of lymphocytes. There are clear spaces interspersed with reactive histiocytes containing phagocytic debris. Mantle Cell lymphoma can have a histologic pattern of diffuse, nodular, mantle zone, or a combination. Most cases are composed exclusively of small to medium-sized lymphoid cells with slightly irregular or "notched" nuclei. On histologic review, tumor cells are usually monomorphous small to medium-sized B lymphocytes with irregular nuclei. The degree of irregularity is usually, but not always, less than that of the centrocytes found in germinal centers and follicular lymphoma. [9]

• History and Physical

Patients present with complaints of fever, weight loss, or night sweats, also known as B symptoms. Systemic B symptoms are more common in patients with a high-grade variant of NHL. More than two-thirds of the patients present with painless peripheral lymphadenopathy. Waxing and waning episodes of lymphadenopathy, along with other symptoms, can be seen in low-grade lymphoma. Patients have different presentations and vary according to the site involved. Clinical features of the patients, according to the subtypes, are:

Burkitt Lymphoma: Patients often have rapidly increasing tumor masses. This type of lymphoma may present with tumor lysis syndrome.

Endemic (African) forms may have jaw or facial bone tumors in 50 to 60 percent of cases. The primary involvement of the abdomen is less common. The primary tumor can spread to extranodal sites like the mesentery, ovary, testis, kidney, breast, and meninges.

The non-endemic (sporadic) form involves the abdomen and presents most often with massive ascites involving the distal ileum, stomach cecum, mesentery, and bone marrow. Symptoms related to bowel obstruction or gastrointestinal bleeding, often having features of acute appendicitis or intussusception, can be seen. Approximately 25 percent of cases involve the jaw or facial bones. If Lymphadenopathy is present, it is usually localized. Bone marrow and CNS involvement are seen in 30 and 15 percent of cases at the time of initial presentation but are more common in recurrent or treatment-resistant diseases. [10]  The kidney, testis, ovary, and breast can also be involved.

Patients with  immunodeficiency-related  Burkitt Lymphoma present according to the signs or symptoms related to the underlying immunodeficiency (eg, AIDS, congenital immunodeficiency, acquired immunodeficiency due to hematopoietic or solid organ transplantation). Immunodeficiency-related cases most often involve lymph nodes, bone marrow, and CNS.

Mantle cell Lymphoma:  Most patients with mantle cell lymphoma have advanced-stage disease at diagnosis (70 percent). Approximately 75 percent of patients initially present with lymphadenopathy; the extranodal disease is the primary presentation in the remaining 25 percent. [11] Common sites of involvement include the lymph nodes, spleen (45 to 60 percent), Waldeyer's ring, bone marrow (>60 percent), blood (13 to 77 percent), and extranodal sites, such as the gastrointestinal tract, breast, pleura, and orbit. At presentation, up to one-third of patients have systemic B symptoms, such as fever, night sweats, and unintentional weight loss. 

Gastrointestinal Lymphoma:  Usually presents with nonspecific symptoms such as epigastric pain or discomfort, anorexia, weight loss, nausea or vomiting, occult gastrointestinal bleeding, or early satiety.

Primary central nervous system (CNS) lymphoma: Patients with primary central nervous system (CNS) lymphoma may present with headache, lethargy, focal neurologic deficits, seizures, paralysis, spinal cord compression, or lymphomatous meningitis.

Involved lymphoid sites should be carefully examined. These include Waldeyer's ring (tonsils, the base of the tongue, nasopharynx), cervical, supraclavicular, axillary, inguinal, femoral, mesenteric, and retroperitoneal nodal sites should be examined. The liver and spleen should be examined. A head and neck examination should be done. Enlargement of preauricular nodes and tonsillar asymmetry suggests nodal and extranodal involvement of the head and neck, including Waldeyer's ring. Orbital structures like the eyelid, extraocular muscles, lacrimal apparatus, and conjunctivae can be involved in the marginal zone, mantle cell lymphoma, and primary central nervous lymphoma (primary CNS lymphoma). Therefore, these structures should be examined.

Mediastinal involvement can be seen in primary mediastinal large B cell lymphoma or due to secondary spread. Patients with mediastinal involvement can present with a persistent cough, chest discomfort, or without any clinical symptoms, but patients usually have an abnormal chest X-ray. Superior vena cava syndrome can be part of the clinical presentation. The involvement of retroperitoneal, mesenteric, and pelvic nodes is common in most histologic subtypes of NHL. Ascites may be present due to lymphatic obstruction, which is usually chylous. About 50 percent of patients may develop extranodal disease (secondary extranodal disease), while 10 and 35 percent of patients have primary extranodal lymphoma at diagnosis. [12]  The most common site of primary extranodal disease is the gastrointestinal tract, followed by the skin. Other sites involved with aggressive NHLs at presentation include the testis, bone, and kidney. Rare sites include the ovary, bladder, heart, adrenal glands, salivary glands, prostate, and thyroid. Extra lymphatic disease symptoms are usually associated with aggressive NHL and are uncommon in indolent lymphomas.

Testicular NHL is the most common malignancy involving the testis in men over age 60. It usually presents as a mass and comprises 1 percent of all NHL and 2 percent of all extranodal lymphomas. [13]  Epidural spinal cord compression (ESCC) can cause irreversible loss of motor, sensory, or autonomic function. NHL is thought first to involve the paraspinal soft tissues and then invade the cord via the vertebral foramen without causing bony destruction. [14]

Workup in NHL should include the following:

• Complete blood count: May show anemia, thrombocytopenia, leukopenia, pancytopenia, lymphocytosis, and thrombocytosis. These changes in peripheral blood counts can be due to extensive bone marrow infiltration, hypersplenism from splenic involvement, or blood loss from gastrointestinal tract involvement.
• Serum chemistry tests  Can help rule out tumor lysis syndrome, commonly found in rapidly proliferative NHL such as Burkitt or lymphoblastic lymphoma (see  Image.  Burkitt Lymphoma, Lymphoblasts). Lactate dehydrogenase levels can also be elevated due to a high tumor burden or extensive liver infiltration.
• Imaging: usually a CT scan of the neck, chest, abdomen, and pelvis or a PET scan. Dedicated imaging might be needed, such as an MRI of the brain and spinal cord or testicular ultrasound. 
• Lymph node or tissue biopsy: A lymph node should be considered for a biopsy if 1 or more of the following characteristics are present: significant enlargement, persistence for more than 4 to 6 weeks, and progressive increase in size. Generally, lymph nodes greater than 2.25 cm (ie, a node with biperpendicular diameters of 1.5 x 1.5 cm) or 2 cm in a single diameter provide the best diagnostic yields. Excisional lymph node biopsy is the gold standard for diagnosis. Fine needle aspiration of the lymph node is avoided. An excisional biopsy of an intact node allows sufficient tissue for histologic, immunologic, and molecular biologic assessment and classification by hematopathologists. [15] [16]  Specific yields of peripheral lymph nodes in patients who are subsequently proven to have NHL are as follows: supraclavicular nodes are 75 to 90 percent, cervical and axillary nodes are 60 to 70 percent, and inguinal nodes are 30 to 40 percent. 
• Lumbar puncture:  usually reserved in those with a high risk of CNS involvement, ie, highly aggressive NHL (Burkitt lymphoma, diffuse large B cell lymphoma, peripheral T cell lymphoma, grade 3b FL, mantle cell lymphoma, precursor T or B lymphoblastic leukemia/lymphoma, human immunodeficiency virus (HIV)-positive NHL), who have epidural, bone marrow, testicular, or paranasal sinus involvement, or at least 2 extranodal disease sites. CSF should be sent for both cytology and flow cytometry.
• Immunophenotypic analysis of lymph node: peripheral blood, and bone marrow. The tumor cells in Burkitt lymphoma express surface immunoglobulin (Ig) of the IgM type and immunoglobulin light chains (kappa more often than lambda), B cell-associated antigens (CD19, CD20, CD22, CD79a), germinal center-associated markers (CD10 and BCL6), as well as HLA-DR and CD43Expression of CD21, the Epstein-Barr virus (EBV)/C3d receptor, is dependent on EBV status of the tumors. All endemic Burkitt lymphoma cases are EBV positive and express CD21, whereas most non-endemic Burkitt lymphoma in non-immunosuppressed patients are EBV negative and lack CD21 expression. Mantle cell tumor cells express high levels of surface membrane immunoglobulin M (IgM) and IgD (sIgM±IgD), more often of lambda light chain type. They also demonstrate pan-B cell antigens (eg, CD19, CD20), CD5, and FMC7. Nuclear staining for cyclin D1 (BCL1) is present in >90 percent of cases, including those that are CD5 negative.
• Bone marrow aspiration and biopsy  are  sometimes needed to stage the NHL. However, their utility is decreasing with the widespread use of PET scans.
• Treatment / Management

Treatment of NHL is based on the type, stage, histopathological features, and symptoms. The most common treatments include chemotherapy, radiotherapy, immunotherapy, stem cell transplant, and, in rare cases, surgery. Chemoimmunotherapy, i.e., rituximab, is most commonly used in combination with chemotherapy. Radiation is the main treatment for early-stage (I, II). Stage II with bulky disease, stage III, and IV are treated with chemotherapy along with immunotherapy, targeted therapy, and, in some cases, radiation therapy. Treatments, according to the type of lymphoma, are listed below:

B Cell Lymphoma

Diffuse Large B cell lymphoma: In Stage I or II, the R-CHOP regimen is often given for 3 to 6 cycles, with/without radiation therapy to the lymph node that is affected. In stage III or IV, 6 cycles of R-CHOP is the preferred treatment. Imaging tests such as PET/CT scans are done to evaluate treatment response after 2-4 cycles. Intrathecal chemotherapy or high doses of methotrexate intravenously is given to patients in the presence or at high risk of central nervous system involvement. For "Double-hit" lymphomas, that is, with translocations of MYC and BCL2 or BCL6 as detected by FISH or standard cytogenetics, DA-EPOCH-R is preferred. Refractory or relapsed diffuse large B cell lymphoma can be treated with a salvage regimen followed by bone marrow transplant for eligible patients or Chimeric antigen receptor T cell (CAR-T) cell therapy. [17] CAR-T therapy is a form of immunotherapy in which the patient's T lymphocytes are genetically modified with a gene that encodes a CAR that targets the patient's cancer. CAR-T therapy has shown effectiveness against refractory CD19-expressing B lymphoid malignancies. [18]

Follicular lymphoma:  This type of lymphoma has an indolent nature, and it shows a good response to treatment but is quite difficult to cure. Relapse is usually common after several years. Patients with low-burden disease can be observed, and treatment deferred unless symptomatic. The preferred treatment in stage I and stage II in the early stage is radiotherapy. Chemotherapy, along with a monoclonal antibody, is another option. Treatment in stage III, IV, and bulky stage II lymphoma includes a monoclonal antibody (rituximab or obinutuzumab) and chemotherapy. Among the chemotherapy options, bendamustine or a combination regimen such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone) are commonly used. After the response to initial treatment, the role of maintenance therapy is conflicting.

Mantle cell lymphoma:  Mantle cell lymphoma with multiple areas of involvement is commonly treated with aggressive chemotherapy plus rituximab in eligible patients. Intense chemotherapy regimens such as R-Hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone, alternately given with high-dose methotrexate plus cytarabine) + rituximab, alternating RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone, cytarabine, cisplatin), NORDIC regimen (dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP]) alternating with rituximab + high-dose cytarabine, or RDHAP (Rituximab, dexamethasone, cytarabine, cisplatin). After the response to initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation is undertaken in eligible patients. This is typically followed by maintenance of rituximab for 3 years. 

Burkitt lymphoma:  This is a very fast-growing lymphoma. Some examples of chemo regimens used for this lymphoma include Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) alternating with high dose methotrexate and cytarabine (ara-C) + rituximab, CODOX-M (cyclophosphamide, vincristine [Oncovin], doxorubicin, and high-dose methotrexate) alternating with IVAC (ifosfamide, etoposide [VP-16], and cytarabine [ara-C]) + rituximab, or Dose adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, and doxorubicin) + rituximab. [19] Intrathecal methotrexate is given when there is evidence of brain and spinal cord involvement. Tumor lysis syndrome is common in Burkitt lymphoma. Therefore, tumor lysis syndrome prophylaxis and monitoring are required. 

Primary CNS lymphoma:  The most effective treatment is a high-dose methotrexate-based chemotherapy regimen. If the patient achieves a complete response to initial chemotherapy, high-dose therapy followed by autologous stem cell transplantation should be considered for eligible patients.

T Cell Lymphoma

Anaplastic large cell lymphoma:  This rapidly growing lymphoma mainly affects the lymph nodes. Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone) is preferred. Other regimens include CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone).

Adult T cell leukemia/lymphoma: It is linked to infection with the HTLV-1 virus. There are 4 subtypes, and treatment varies depending on the subtype. Smoldering and chronic subtypes grow slowly. These often do not require treatment. If treatment is needed, interferon and the antiviral drug zidovudine to treat HTLV-1 infection, or skin-directed therapy if the skin is involved. The acute subtype is treated with either antiviral treatment or chemotherapy (typically the CHOP regimen). If it responds to chemotherapy, consider an allogeneic stem cell transplant. This lymphoma subtype is often treated with chemotherapy; antiviral therapy is not helpful for this subtype. It may involve the brain and spinal cord; therefore, intrathecal chemotherapy is given.

Enteropathy-associated T cell lymphoma: This is highly associated with celiac disease. Combination chemotherapy is preferred. Patients should be evaluated for surgery at the diagnosis, before chemotherapy or radiation, because they are at high risk of perforation or intestinal blockage (obstruction). A stem cell transplant may be an option if the lymphoma responds to chemotherapy.

HIV-associated lymphoma: Patients with HIV tend to have more aggressive forms of lymphoma, such as diffuse large B-cell lymphoma, primary CNS lymphoma, or Burkitt lymphoma. The use of highly active antiretroviral therapy (HAART) to treat HIV in addition to chemotherapy±immunotherapy is usually employed. 

Some exceptions in the treatment of lymphomas can be found here:

Mucosa-associated lymphoid tissue lymphoma of the stomach:  If infection with  Helicobacter pylori  is present and the lymphoma is confined to the stomach and peri-gastric lymph nodes, treatment with antibiotics and Histaminic (H2) blockers can eliminate the organism-related antigenic stimulus, and the lymphoma may regress permanently.

Mycosis fungoides: This type of T-cell lymphoma of the skin usually has a very indolent course and is best treated with skin-directed treatments, including topical steroids, topical retinoids, skin irradiation, psoralen-associated ultraviolet exposure, topical chemotherapy. If the patient experiences failure with skin-directed therapies, they can use systemic biologic therapies.

• Differential Diagnosis

Medical conditions mimicking symptoms similar to NHL are:

• Hodgkin lymphoma
• Epstein Barr virus infection
• Systemic lupus erythematosus
• Intussusception
• Appendicitis
• Toxoplasmosis
• Metastasis from the primary tumor (eg, nasopharyngeal carcinoma, soft tissue sarcoma)
• Malignancies or lymphoproliferative disorders like granulocytic sarcoma and multicentric Castleman disease.
• Mycobacterial and other bacterial infections cause benign lymph node infiltration and reactive follicular hyperplasia.

Diseases mentioned above may have localized or generalized lymphadenopathy and should be differentiated from NHL. Whenever the diagnosis is confusing and unclear, a second opinion from expert hematopathologists should be considered before treatment. Flow cytometry and cytogenetics can help differentiate various conditions.

• Radiation Oncology

Radiation therapy is recommended in the following situations: 

• Early-stage (stage I or II): Radiation therapy is given alone or in combination with chemotherapy. 
• Advanced and aggressive lymphomas: Usually, chemotherapy is the mainstay of treatment. However, radiation can be employed for palliation purposes, eg, pain and lymphadenopathy causing urinary/gastrointestinal tract obstruction.

Radiation therapies are given for several weeks and are mostly given 5 days a week if given for treatment. Palliative radiation is usually shorter.

• Toxicity and Adverse Effect Management

Complications following treatment vary depending on the type of chemotherapy used and if radiation or surgery were used as adjunctive measures. Common adverse events of chemotherapy include myelosuppression, neutropenic fever, and immunosuppression. Myelosuppression is treated with transfusions (red cells and platelets) or colony-stimulating factors (eg, granulocyte colony-stimulating factor). Neutropenia increases the risk of infections from bacteria, viruses, and fungi. Management is dependent on the degree of neutropenia and whether it is febrile. Patients are also susceptible to infections like Varicella and herpes zoster. Post-exposure prophylaxis is given against varicella-zoster infection.

Multiple chemotherapeutic agents induce nausea and vomiting. Usually, anti-emetic serotonin receptor antagonists or benzodiazepines, among other agents, are used for treatment and prophylaxis. Anthracycline can cause cardiotoxicity, especially doxorubicin. Dexrazoxane has shown significant benefits in anthracycline-induced cardiotoxicity. Radiotherapy can also cause heart failure, but the mechanism is different from that of chemotherapy. It causes diffuse fibrosis in the interstitium of the myocardium and progressive fibrosis of pericardial layers, cells in the conduction system, and the cusps or leaflets of the valves. The left ventricular ejection fraction is usually preserved. Vincristine can cause neurotoxicity.

Long-term fatigue is a common symptom present in two-thirds of survivors of NHL. Fatigue usually improves the year after treatment completion, but many patients continue to experience fatigue for months or years after treatment. The risk of developing a second malignancy is increased in long-term survivors of NHL. The risk of developing a second malignancy differs depending upon the subtype of NHL and the treatment received. The risk of developing myelodysplastic syndrome and acute myeloid leukemia is high. The risk of developing lung cancer and cutaneous melanoma was increased among survivors of follicular lymphoma. Depending on the area of radiation, patients can develop squamous cell carcinoma of the head and neck and breast cancer. 

Radiation to the neck and mediastinum can result in hypothyroidism. Patients undergoing hematopoietic cell transplantation with total body irradiation conditioning were documented to suffer from growth hormone deficiency, hypogonadism, insulin resistance, and dyslipidemia. NHL survivors are at risk for developing endocrine abnormalities such as gonadal dysfunction and hypothyroidism. Cytotoxic agents and radiation therapy can produce gonadal dysfunction in both males and females. Fertility preservation should be offered to all. Options include freezing (cryopreservation) of embryos, oocytes, and spermatozoa.

Cranial irradiation, a history of intrathecal chemotherapy, older age at the time of treatment, and hematopoietic cell transplantation can lead to neurologic and psychiatric complications like post-traumatic stress disorder. Patients treated with an anti-CD20 monoclonal antibody (rituximab) risk developing progressive multifocal leukoencephalopathy (PML). All patients at increased risk should undergo screening for neurocognitive impairment so that appropriate occupational therapy and social services referrals may be made.

The Lugano classification is the current staging used for patients with NHL. It is based on the Ann Arbor staging system, originally developed for Hodgkin lymphoma in 1974 and modified in 1988. This staging system is based on the number of tumor sites (nodal and extranodal) and their location.

• Stage I refers to NHL involving a single lymph node region (stage I) or a single extra lymphatic organ or site (stage IE) without nodal involvement. A single lymph node region can involve 1 node or a group of adjacent nodes.
• Stage II refers to 2 or more involved lymph node regions on the same side of the diaphragm (stage II) or localized involvement of an extra lymphatic organ or site (stage IIE).
• Stage III refers to lymph node involvement on both sides of the diaphragm (stage III).
• Stage IV refers to the widespread involvement of 1 or more extra lymphatic organs, such as the liver, bone marrow, and lung, with or without associated lymph node involvement.

The subscript "E" is used if the limited extranodal extension is noted; the more extensive extranodal disease is categorized as stage IV. Spleen involvement is considered nodal rather than extranodal. 

The prognosis of NHL mainly depends on histopathology, the extent of involvement, and patient factors. The International Prognostic Index (IPI) and its variants are the main prognostic tools in patients with NHL. It helps to determine overall survival after standard-of-care treatment. IPI is assessed by age>60 years, Serum LDH above normal, Eastern Cooperative oncology group performance status more than or equal to 2, clinical stage III or IV, and >1 extranodal involvement. One point is given for each factor, a total score from (0 to 5), which determines the degree of risk. These are classified as low risk (0-1 adverse factor), Intermediate risk (2 adverse factors), and poor risk (3 or more adverse factors). Congenital or acquired immunodeficiency states are associated with an increased risk of lymphoma, and response to therapy is poor. [20]  IPI has been modified for most of the NHL for better assessment of prognosis, eg, FLIPI for follicular lymphoma, MIPI for mantle cell lymphoma, and so on. Patients with aggressive T- or NK cell lymphomas usually have a worse prognosis. Patients with low-grade lymphomas have increased survival, usually 6 to 10 years. However, they can have the transformation into high-grade lymphomas.

• Complications

Life-threatening emergent complications of NHL should be considered during the initial workup and evaluation. Early recognition and prompt therapy are critical for these situations, which may interfere with and delay treatment of the underlying NHL. These can include:

• Febrile neutropenia
• Hyperuricemia and tumor lysis syndrome - Presents with fatigue, nausea, vomiting, decreased urination, numbness, tingling of legs, and joint pain. Laboratory findings include increased uric acid, potassium, creatinine, and phosphate and decreased calcium levels. This can be prevented with vigorous hydration and allopurinol.
• Spinal cord or brain compression
• Focal compression depending on the location and type of NHL - airway obstruction (mediastinal lymphoma), intestinal obstruction and intussusception, ureteral obstruction
• Superior or inferior vena cava obstruction
• Hyperleukocytosis
• Adult T-cell leukemia-lymphoma can cause hypercalcemia.
• Pericardial tamponade
• Lymphoplasmacytic lymphoma with Waldenstrom macroglobulinemia can cause hyperviscosity syndrome.
• Hepatic dysfunction [21]
• Venous thromboembolic disease [22]
• Autoimmune hemolytic anemia and thrombocytopenia - can be observed with small lymphocytic lymphoma
• Deterrence and Patient Education

The patient should receive detailed information on all the available treatment options, adverse effects of chemotherapy, and their treatment options and prognosis. The patient should be informed about oncologic emergencies requiring an emergency department visit. Patients dealing with anxiety and depression should be referred for psychosocial counseling. Lifestyle modifications, including smoking cessation, healthy diet, exercise, and no more than moderate alcohol consumption, are important for cancer survivors. [23] [24]  They have been shown to improve patient quality of life, risk of recurrence, and possibly mortality. Therefore, patients should be encouraged to adopt healthy habits. Long-term survivors should be educated on secondary malignancies, cardiovascular complications, etc.

• Enhancing Healthcare Team Outcomes

During treatment, NHL patients adjust to working closely with a multidisciplinary team that often includes medical oncologists, radiation oncologists, mid-level practitioners, nurses, and others. Communication among the healthcare team is essential for providing excellent care to the patient. The involvement of the patient's primary care physician (PCP) continues during treatment and after the patient completes the treatment, as the PCP often has a longstanding and important relationship with the patient that predates the patient's lymphoma diagnosis. The follow-up of cancer survivors can be discussed among the PCP, medical oncologist, and other cancer specialists. The type of cancer and treatment exposures, comorbidities, and other factors determine decisions regarding the need for shared care, mostly oncology care or transitioning to primary care. For example, head and neck survivors would best benefit from multi-specialty and multidisciplinary follow-up care. Also, specialty care may be required for some patients. For example, rehabilitation providers may be important in preventing and managing symptoms and late effects while uplifting survivor health and well-being.

The roles and responsibilities for survivorship care should be well-described for patients and their providers, particularly during transitions. For the patients, the survivorship care plan can guide the transition from oncology to primary care settings. The oncology team establishes the survivorship care plan with the completion of treatment, which is meant to be shared with the patient and his or her providers, including the PCP. The survivorship care plans help the patient meet the patient's emotional, social, legal, and financial needs. It includes referrals to specialists and recommendations for a healthy lifestyle, such as changes in diet and exercises and quitting smoking. [25]

The medical oncologist usually follows the patient closely for several years after finishing therapy, and subsequently, the patient transitions back to the PCP. This transition period can be distressing, with miscommunication between even the most well-meaning providers. Establishing a survivorship care plan helps facilitate communication and allocation of responsibility during this period. The patient's attendance at a survivorship clinic can also aid in promoting well-coordinated care. Psychological effects of cancer are common and include depression, anxiety, fatigue, cognitive limitations, sleep problems, sexual dysfunction, pain, and opioid dependence or use disorder. Evaluation of symptoms and management is needed. Financial implications for care must be addressed.

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Burkitt Lymphoma, Lymphoblasts Ed Uthman (Public Domain) via Wikimedia Commons

Mantle Cell Lymphoma. High power H&E of mantle cell lymphoma showing monotonous mature lymphocytes with mildly irregular nuclei. A pink histocyte is highlighted by the black arrow. Contributed by D Lynch, MD

Central Nervous System Lymphoma, MRI. A magnetic resonance image of the brain with gadolinium contrast is the recommended first test in the diagnostic workup for patients with suspected primary central nervous lymphoma. Contributed by O Chaigasame, (more...)

Disclosure: Sumina Sapkota declares no relevant financial relationships with ineligible companies.

Disclosure: Hira Shaikh declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Sapkota S, Shaikh H. Non-Hodgkin Lymphoma. [Updated 2023 Feb 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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• Review Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. [Drugs. 2003] Review Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Plosker GL, Figgitt DP. Drugs. 2003; 63(8):803-43.
• Non-Hodgkin's lymphomas in Greece according to the WHO classification of lymphoid neoplasms. A retrospective analysis of 810 cases. [Acta Haematol. 2005] Non-Hodgkin's lymphomas in Greece according to the WHO classification of lymphoid neoplasms. A retrospective analysis of 810 cases. Economopoulos T, Papageorgiou S, Dimopoulos MA, Pavlidis N, Tsatalas C, Symeonidis A, Foudoulakis A, Pectasides D, Rontogianni D, Rizos E, et al. Acta Haematol. 2005; 113(2):97-103.
• Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma. [Mod Pathol. 2004] Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma. Admirand JH, Rassidakis GZ, Abruzzo LV, Valbuena JR, Jones D, Medeiros LJ. Mod Pathol. 2004 Aug; 17(8):954-61.
• Dermatopathology, Cutaneous Lymphomas. [StatPearls. 2024] Dermatopathology, Cutaneous Lymphomas. Schukow C, Ahmed A. StatPearls. 2024 Jan
• Review The World Health Organization classification of malignant lymphoma: incidence and clinical prognosis in HTLV-1-endemic area of Fukuoka. [Pathol Int. 2002] Review The World Health Organization classification of malignant lymphoma: incidence and clinical prognosis in HTLV-1-endemic area of Fukuoka. Ohshima K, Suzumiya J, Kikuchi M. Pathol Int. 2002 Jan; 52(1):1-12.

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• What is lymphoma? An expert explains

Learn more from hematologist Stephen Ansell, M.D.

Hi. I'm Dr. Stephen Ansell. I'm a hematologist at Mayo Clinic. In this video, we're going to cover the basics of lymphoma. What is it? Who gets it? The symptoms. Diagnosis and treatment. Whether you're looking for answers for yourself or someone you love, we're here to give you the best information available. Lymphoma is an overarching term for a kind of cancer that starts in the lymphatic system. Cancer diagnosis of any kind can be very difficult to deal with. But recent advances in how we treat lymphoma and ongoing research means there's a lot of hope. Treatment is highly successful for the majority of patients. First, what exactly is the lymphatic system? Well, it's actually a crucial part of the immune system. The lymphatic system produces lymphocytes, or white blood cells, which fight off pathogens, bacteria and the like. There are two types of lymphocytes, T cells and B cells. And lymphoma occurs when one of these types of lymphocytes grow and multiply uncontrollably. Often, these abnormal cells will build up and cause tumors in the lymph nodes, which are actually present throughout your body. And so lymphoma cells can collect anywhere.

There are different types of lymphoma, but really two main categories. Firstly, Hodgkin lymphoma. This is an uncommon form of lymphoma identified by the presence of rare large cells, which are called Reed- Sternberg cells. And it usually begins in lymph nodes of the neck, the chest, under the arms, and progresses in an orderly fashion and predictable fashion to other lymph node sites. This often means that it can be detected and treated early. And it's actually considered one of the most treatable forms of cancer. Non-Hodgkin lymphoma, while more common than Hodgkin lymphoma, is still very uncommon and a relatively rare disease overall. This category includes any cancer of lymphocytes that doesn't involve Reed- Sternberg cells.

Like all cancers, lymphoma is the result of mutations in DNA that instruct the cells on how to grow, and the cells often grow out of control and live longer than they should. These disease cells then continue to multiply at a rapid rate, producing more disease cells. These particular DNA mutations affect lymphocytes, which accumulate in the lymph nodes and other parts of the lymphatic system to form tumors, crowding out healthy tissue and limiting its ability to function. We don't always know exactly what caused that initial mutation, but we know the effects that it has downstream. There are, however, a variety of things that can increase your risk. Although both Hodgkin and non-Hodgkin lymphoma can occur at any age, they do have a pattern. For non-Hodgkin lymphoma, the risk increases as you get older, with about half the people diagnosed over the age of 65. In Hodgkin lymphoma, cases are predominantly seen in two peaks, often in young adults 20 to 40, and again in older people over 55. Whether because of an immune disease or immune suppressive drugs, lymphoma is more common in people with an impaired immune system. Certain infections can be connected with higher rates of lymphoma. These infections include Epstein-Barr virus infections and helicobacter pylori infections.

Common symptoms of having lymphoma include swelling of lymph nodes in your neck, in your armpits or your groin. This is often but not always painless and often could be associated with fevers, or unexplained weight loss, or drenching night sweats, sometimes chills, persistent fatigue. Shortness of breath can often be found. And patients with Hodgkin lymphoma may develop an itchy skin. Just because you're experiencing these types of things doesn't mean you have lymphoma, but it is important to see your doctor if you're experiencing recurring symptoms.

Firstly, they're likely to give you a physical exam to check for swollen lymph nodes and see whether your spleen or liver feel swollen. A lymph node may in fact be removed for a biopsy. This can show not only if lymphoma cells are present but will actually help to identify the type of lymphoma. The bone marrow is where the cells are made, and so a sample of the bone marrow may also be taken. This is usually performed both on the liquid of the bone marrow, the so-called aspirate, and then a biopsy is taken from the solid portion of the bone marrow. This is done using a needle, and the sample is usually extracted from the hipbone and sent for analysis. Additionally, your doctor may recommend other kinds of tests including imaging studies. This could include a PET scan, a CT scan, or an MRI scan. All of them are being done to look for signs of lymphoma in other areas of your body.

A specialized team of doctors can work with you to develop a strategy for treating your lymphoma. And the strategy is based on the type of lymphoma, the stage of the lymphoma, the aggressiveness of the cancer, as well as your overall health. Some lymphomas grow very slowly, and it may not be necessary to start treatment right away. Active surveillance is often your best option. You and your doctor may decide not to treat the lymphoma until it interferes with your lifestyle. We call this watchful waiting. However, until then, you would need to have periodic tests to monitor your disease. Now, you may be given chemotherapy. These are usually powerful drugs that will kill lymphoma. Additional treatments are coming out that allow for targeted therapy. Targeted drug treatment focuses just on specific abnormalities in cancer cells and is highly effective. A further strategy is immunotherapy. And immunotherapy drugs use your own immune system to fight your cancer.

Finding out you have lymphoma and going through treatment can be overwhelming, but there are things you can do to help you cope. Learn about your lymphoma. Don't be afraid to ask your doctor questions and have them recommend resources for more information. Knowing more about your particular case and the options you have will help you feel confident and empower you to make decisions regarding treatment. Keep your friends and family close, rely on them for practical and emotional support. It may also be important to find a support group to talk with people who are going through the same thing. Although cancer and going through treatment is never easy, with lymphoma, there is plenty of hope and long-term success. A lot of progress has been made in fighting lymphoma, getting patients into remission, getting them back to a normal life. And as the research continues, ever-improving and more effective ways to combat lymphoma are being developed. If you want to learn more about your lymphoma, please go ahead and watch the related videos or visit mayoclinic.org. We wish you well.

Parts of the immune system

The lymphatic system is part of the body's immune system, which protects against infection and disease. The lymphatic system includes the spleen, thymus, lymph nodes and lymph channels, as well as the tonsils and adenoids.

• Lymph node clusters

Lymph nodes are bean-sized collections of cells called lymphocytes. Hundreds of these nodes cluster throughout the lymphatic system, for example, near the knee, groin, neck and armpits. The nodes are connected by a network of lymphatic vessels.

Lymphoma is a cancer of the lymphatic system. The lymphatic system is part of the body's germ-fighting and disease-fighting immune system. Lymphoma begins when healthy cells in the lymphatic system change and grow out of control.

The lymphatic system includes lymph nodes. They are found throughout the body. Most lymph nodes are in the abdomen, groin, pelvis, chest, underarms and neck.

The lymphatic system also includes the spleen, thymus, tonsils and bone marrow. Lymphoma can affect all these areas and other organs in the body.

There are many types of lymphoma. The main subtypes are:

• Hodgkin lymphoma (formerly called Hodgkin disease).
• Non-Hodgkin lymphoma.

Many treatments for lymphoma exist. The treatment that's best for you will depend on the type of lymphoma you have. Treatments can control the disease and give many people with lymphoma the chance of a full recovery.

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Swollen lymph nodes

One of the most common places to find swollen lymph nodes is in the neck. The inset shows three swollen lymph nodes below the lower jaw.

Signs and symptoms of lymphoma may include:

• Night sweats.
• Itchy skin.
• Painless swelling of lymph nodes in the belly, neck, armpits or groin.
• Pain in chest, abdomen or bones.
• Losing weight without trying.

When to see a doctor

Make an appointment with a doctor or other healthcare professional if you have any ongoing symptoms that worry you. Lymphoma symptoms are like those of many more common conditions, such as infections. The healthcare professional may check for those causes first.

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Healthcare professionals aren't sure what causes lymphoma. Lymphoma begins with changes in the DNA of a disease-fighting blood cell called a lymphocyte.

A cell's DNA holds the instructions that tell the cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. Healthy cells die at a set time.

In cancer cells, the DNA changes give different instructions. The changes tell the cancer cells to make more cells quickly. The cancer cells can go on living when healthy cells would die.

In lymphoma, the DNA changes happen in the lymphocytes. The changes can:

• Lead diseased lymphocytes to grow out of control.
• Cause too many diseased lymphocytes in the lymph nodes.
• Cause the lymph nodes, spleen and liver to swell.

Risk factors

Some factors can increase the risk of lymphoma. They include:

• A weakened immune system. If the immune system is weakened by medicines or illness, there might be a higher risk of lymphoma. People with a weakened immune system include those taking medicines to control the immune system, such as after an organ transplant. Certain health conditions, such as infection with HIV, also can weaken the immune system.
• Family history. People who have a parent, sibling or child with lymphoma are at higher risk of the disease.
• Specific infections. Some infections increase the risk of developing lymphoma. Examples include Epstein-Barr virus, Helicobacter pylori and HIV.
• Your age. Some types of lymphoma are more common in teens and young adults. Others happen more often in people over 55.

There is no way to prevent lymphoma.

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• Lymphoma – Non-Hodgkin. Cancer.Net. https:www.cancer.net/cancer-types/41246/view-all. Accessed Dec. 18, 2023.
• Lymphoma – Patient version. National Cancer Institute. https://www.cancer.gov/types/lymphoma. Accessed Dec. 18, 2023.
• What causes non-Hodgkin lymphoma? American Cancer Society. https://www.cancer.org/cancer/types/non-hodgkin-lymphoma/causes-risks-prevention/what-causes.html. Accessed Dec. 21, 2023.
• Elsevier Point of Care. Clinical Overview: Hodgkin lymphoma. https://www.clinicalkey.com. Accessed Dec. 21, 2023.
• Freedman A, et al. Clinical presentation and initial evaluation of non-Hodgkin lymphoma. https://www.uptodate.com/contents/search. Accessed Jan. 30, 2024.
• Lymphoma – Non-Hodgkin: Diagnosis. https://www.cancer.net/cancer-types/lymphoma-non-hodgkin/diagnosis. Accessed Dec. 22, 2023.
• Non-Hodgkin lymphoma treatment (PDQ) – Patient version. National Cancer Institute. https://www.cancer.gov/types/lymphoma/patient/adult-nhl-treatment-pdq. Accessed Jan. 1, 2024.
• Brondfield S, et al. Developing a community for patients with cancer through longer-term art therapy. Oncology Practice. 2020; doi:10.1200/OP.20.00419.
• Distress management. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1431. Accessed Jan. 3, 2024.
• Coping with cancer. Cancer.Net. https://www.cancer.net/coping-with-cancer. Accessed Jan. 4, 2024.
• Robetorye R, et al. Incorporation of digital gene expression profiling for cell-of-origin determination (Lymph2Cx Testing) into the routine work-up of diffuse large B-Cell lymphoma. Journal of Hematopathology. 2019; doi:10.1007/s12308-019-00344-0.
• Laurent C, et al. Impact of expert pathologic review of lymphoma diagnosis: Study of patients from the French Lymphopath Network. Journal of Clinical Oncology. 2017; doi:10.1200/JCO.2016.71.2083.
• Member institutions. Alliance for Clinical Trials in Oncology. https://www.allianceforclinicaltrialsinoncology.org/main/public/standard.xhtml?path=%2FPublic%2FInstitutions. Accessed April 14, 2024.
• Membership institution lists. NRG Oncology. https://www.nrgoncology.org/About-Us/Membership/Member-Institution-Lists. Accessed April 14, 2024.
• Lymphoma FAQs

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