clinical presentation of hodgkin's lymphoma

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• Hodgkin's lymphoma (Hodgkin's disease)

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.

Hodgkin's lymphoma is a type of cancer that affects the lymphatic system, which is part of the body's germ-fighting immune system. In Hodgkin's lymphoma, white blood cells called lymphocytes grow out of control, causing swollen lymph nodes and growths throughout the body.

Hodgkin's lymphoma, which used to be called Hodgkin's disease, is one of two general categories of lymphoma. The other is non-Hodgkin's lymphoma.

Advances in diagnosis and treatment of Hodgkin's lymphoma have helped give people with this disease the chance for a full recovery. The prognosis continues to improve for people with Hodgkin's lymphoma.

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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 Hodgkin's lymphoma may include:

• Painless swelling of lymph nodes in your neck, armpits or groin
• Persistent fatigue
• Night sweats
• Losing weight without trying
• Severe itching
• Pain in your lymph nodes after drinking alcohol

When to see a doctor

Make an appointment with your health care provider if you have any persistent signs or symptoms that worry you.

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Doctors aren't sure what causes Hodgkin's lymphoma. They know that it begins when infection-fighting white blood cells called lymphocytes develop changes in their DNA. A cell's DNA contains the instructions that tell a cell what to do.

The DNA changes tell the cells to multiply rapidly and to continue living when other cells would naturally die. The lymphoma cells attract many healthy immune system cells to protect them and help them grow. The extra cells crowd into the lymph nodes and cause swelling and other Hodgkin's lymphoma signs and symptoms.

There are multiple types of Hodgkin's lymphoma. Your type is based on the characteristics of the cells involved in your disease and their behavior. The type of lymphoma you have helps determines your treatment options.

Classical Hodgkin's lymphoma

Classical Hodgkin's lymphoma is the more common type of this disease. People diagnosed with this type have large lymphoma cells called Reed-Sternberg cells in their lymph nodes.

Subtypes of classical Hodgkin's lymphoma include:

• Nodular sclerosis Hodgkin's lymphoma
• Mixed cellularity Hodgkin's lymphoma
• Lymphocyte-depleted Hodgkin's lymphoma
• Lymphocyte-rich Hodgkin's lymphoma

Nodular lymphocyte-predominant Hodgkin's lymphoma

This much rarer type of Hodgkin's lymphoma involves lymphoma cells that are sometimes called popcorn cells because of their appearance. Nodular lymphocyte-predominant Hodgkin's lymphoma is usually diagnosed at an early stage and may require less intensive treatments compared to the classical type of the disease.

Risk factors

Factors that can increase the risk of Hodgkin's lymphoma include:

• Your age. Hodgkin's lymphoma is most often diagnosed in people in their 20s and 30s and those over age 55.
• A family history of lymphoma. Having a blood relative with Hodgkin's lymphoma increases your risk of developing Hodgkin's lymphoma.
• Being male. People who are assigned male at birth are slightly more likely to develop Hodgkin's lymphoma than are those who are assigned female.
• Past Epstein-Barr infection. People who have had illnesses caused by the Epstein-Barr virus, such as infectious mononucleosis, are more likely to develop Hodgkin's lymphoma than are people who haven't had Epstein-Barr infections.
• HIV infection. People who are infected with HIV have an increased risk of Hodgkin's lymphoma.

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• Hodgkin lymphoma. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1439. Nov. 15, 2021.
• Adult Hodgkin lymphoma treatment (PDQ) — patient version. National Cancer Institute. https://www.cancer.gov/types/lymphoma/patient/adult-hodgkin-treatment-pdq. Accessed Nov. 15, 2021.
• AskMayoExpert. Classic Hodgkin lymphoma (cHL) (adult). Mayo Clinic; 2021.
• Aster JC, et al. Pathogenesis of Hodgkin lymphoma. https://www.uptodate.com/contents/search. Accessed Dec. 1, 2021.
• Hoffman R, et al. Hodgkin lymphoma: Clinical manifestations, staging and therapy. In: Hematology: Basic Principles and Practice. 7th ed. Elsevier; 2018. https://www.clinicalkey.com. Accessed Nov. 25, 2021.
• Ansell SM. Hodgkin lymphoma: A 2020 update on diagnosis, risk-stratification and management. American Journal of Hematology. 2020; doi:10.1002/ajh.25856.
• Side effects of chemotherapy. Cancer.Net. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/chemotherapy/side-effects-chemotherapy. Accessed Dec. 1, 2021.
• Side effects of radiation therapy. Cancer.Net. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/radiation-therapy/side-effects-radiation-therapy. Accessed Dec. 1, 2021.
• Side effects of a bone marrow transplant (stem cell transplant). Cancer.Net. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/bone-marrowstem-cell-transplantation/side-effects-bone-marrow-transplant-stem-cell-transplant. Accessed Dec. 1, 2021.
• Distress management. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1431. Nov. 15, 2021.
• Lymphoma SPOREs. National Cancer Institute. https://trp.cancer.gov/spores/lymphoma.htm. Accessed Nov. 15, 2021.
• 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 .
• Braswell-Pickering BA. Allscripts EPSi. Mayo Clinic. Nov. 3, 2021.
• Goyal G, et al. Association between facility volume and mortality of patients with classic Hodgkin lymphoma. Cancer. 2020; doi:10.1002/cncr.32584.
• Member institutions. Alliance for Clinical Trials in Oncology. https://www.allianceforclinicaltrialsinoncology.org/main/public/standard.xhtml?path=%2FPublic%2FInstitutions. Accessed Dec. 7, 2021.
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• Hodgkin's vs. non-Hodgkin's lymphoma: What's the difference?

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Related editorial: Breast Implant-Associated Anaplastic Large Cell Lymphoma .

Patient information: See related handout on lymphoma , written by the authors of this article.

Author disclosure: No relevant financial affiliations.

Lymphoma is a group of malignant neoplasms of lymphocytes with more than 90 subtypes. It is traditionally classified broadly as non-Hodgkin or Hodgkin lymphoma. Approximately 82,000 new U.S. patients are diagnosed with lymphoma annually. Any tobacco use and obesity are major modifiable risk factors, with genetic, infectious, and inflammatory etiologies also contributing. Lymphoma typically presents as painless adenopathy, with systemic symptoms of fever, unexplained weight loss, and night sweats occurring in more advanced stages of the disease. An open lymph node biopsy is preferred for diagnosis. The Lugano classification system incorporates symptoms and the extent of the disease as shown on positron emission tomography/computed tomography to stage lymphoma, which is then used to determine treatment. Chemotherapy treatment plans differ between the main subtypes of lymphoma. Non-Hodgkin lymphoma is treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab (R-CHOP), bendamustine, and lenalidomide. Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) with radiotherapy. Subsequent chemotherapy toxicities include neuropathy, cardiotoxicity, and secondary cancers such as lung and breast, and should be considered in the shared decision-making process to select a treatment regimen. Once remission is achieved, patients need routine surveillance to monitor for complications and relapse, in addition to age-appropriate screenings recommended by the U.S. Preventive Services Task Force. Patients should receive a 13-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide vaccine at least eight weeks later with additional age-appropriate vaccinations because lymphoma is an immunosuppressive condition. Household contacts should also be current with their immunizations.

Lymphoma represents a heterogeneous group of malignant neoplasms of lymphocytes, which can involve lymphatic tissue, bone marrow, or extranodal sites. The World Health Organization’s classification system identifies more than 90 different subtypes ( Table 1 ) . 1 , 2 The initial stratification is derived from B-cell, T-cell, or natural killer cell origin. Further classification of distinct lymphoma subtypes is beyond the scope of this article; however, they are ultimately each defined by morphology, immunopheno-type, genetic, molecular, and clinical features. 1 , 3 This article will focus on the types of lymphoma traditionally classified as non-Hodgkin or Hodgkin.

Epidemiology

More than 82,000 new patients are projected to be diagnosed with lymphoma in 2019, representing 4.7% of all new cancer cases in the United States. The current five-year survival rate for non-Hodgkin lymphoma is 72.0%, and for Hodgkin lymphoma it is 86.6%. Almost 21,000 people are projected to die from lymphoma in 2019, representing 3.5% of all cancer deaths. Incidence of non-Hodgkin lymphoma is higher in men and whites, and it increases with age. The median age of patients at diagnosis of non-Hodgkin lymphoma is 67 years, and the median age at death is 76. Hodgkin lymphoma is most commonly diagnosed at 20 to 34 years of age; however, the median age at death is 68 because of the higher survival rate among younger patients. 2 , 4

Risk Factors

Genetic, infectious, and inflammatory etiologies increase the risk of lymphoma. First-degree relatives of patients with non-Hodgkin lymphoma and Hodgkin lymphoma have a respective 1.7-fold and 3.1-fold increased risk of developing lymphoma. A family history of a specific subtype of lymphoma is associated with developing that same subtype. 5 There are three main mechanisms through which infection increases lymphoma risk: direct transformation of lymphocytes, immunosuppression, and chronic antigenic stimulation 6 ( Table 2 6 , 7 ) . Rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, dermatomyositis, and celiac disease are inflammatory conditions that increase the risk of lymphoma through disease-specific causes and the chronic use of immunosuppressive medications. 8

Modifiable risk factors include current or former tobacco use 9 and obesity (body mass index of 30 kg per m 2 or higher). 10 Breast implants and long-term pesticide exposure have also been associated with non-Hodgkin lymphoma. 11 – 13

Clinical Presentation

Lymphoma commonly presents as painless adenopathy. Adenopathy can wax and wane over years in indolent presentations or involve rapidly progressive adenopathy in more aggressive subtypes. Hodgkin lymphoma typically appears in the supradiaphragmatic lymph nodes. Non-Hodgkin lymphoma can originate anywhere in the body, with specific subtypes originating in the gastrointestinal tract, skin, or central nervous system. Systemic symptoms of fever, unexplained weight loss, and night sweats occur in a subset of patients with more advanced disease. Lymphoma spreads to extranodal sites by direct invasion or by hematogenous spread to the spleen, liver, lungs, or bone marrow. 14 , 15 High-grade lymphomas can present as oncologic emergencies because of the structural compression from the enlarging tumor, including superior vena cava syndrome, malignant epidural spinal cord compression, or malignant pericardial effusion. 16 Paraneoplastic syndromes are rare with lymphoma, occurring as paraneoplastic cerebellar degeneration in Hodgkin lymphoma and as dermatomyositis and polymyositis in Hodgkin and non-Hodgkin lymphomas. 17

The diagnosis of lymphoma is made using an open lymph node biopsy, based off morphology, immunohistochemistry, and flow cytometry. 3 Although fine-needle aspiration and core needle biopsy are often part of the initial evaluation of any adenopathy, neither will provide adequate tissue for the diagnosis of lymphoma because of the need to verify Hodgkin lymphoma via the presence of Reed-Sternberg cells. 15 , 18

The Ann Arbor staging system was initially developed in 1971 for Hodgkin lymphoma, and was later adapted for non-Hodgkin lymphoma. The Lugano classification system further modified staging by incorporating positron emission tomography/computed tomography (PET-CT) results to determine the staging of the lymphoma  ( Table 3 19 ) . PET-CT is used for fluorodeoxyglucose-avid lymphoma subtypes, with symptoms alone being used for staging the remaining subtypes. The new staging system incorporates two symptom-based classifications: A (absence of symptoms) and B (presence of fever, weight loss, and night sweats) for Hodgkin lymphoma. A bone marrow biopsy is now recommended only for diffuse large B-cell lymphoma with a negative PET-CT result. 19

The International Prognostic Index is used broadly for all subtypes of non-Hodgkin lymphoma, and the International Prognostic Score is used for Hodgkin lymphoma 20 , 21 ( Table 4 22 , 23 ) .

Treatment of lymphoma consists of chemotherapy alone or in combination with radiotherapy. 24 Radiotherapy alone is not recommended. 25 Toxicity from radiotherapy can lead to serious long-term complications such as secondary cancers in the irradiated area, including breast or lung cancers. 25 Additionally, patients receiving chemotherapy can subsequently develop breast or lung cancers, melanoma, or acute myeloid leukemia. 26 , 27 Patients who are older than 60 years at diagnosis have worse outcomes, regardless of the staging. The National Comprehensive Cancer Network (NCCN) recommends avoiding certain chemotherapeutic agents in patients older than 60 years. The physician should focus on shared decision-making when discussing treatment options with all patients, but particularly for those older than 60 years, including whether the patient should pursue treatment. 25

The standard treatment for Hodgkin lymphoma is ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine [Velban], and dacarbazine), but other regimens such as the Stanford V (doxorubicin, vinblastine, mechlorethamine, etoposide [Toposar], vincristine, bleomycin, and prednisone) and escalated-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], and prednisone) can be used. 24 – 28 Treatment for non-Hodgkin lymphoma varies depending on the histology, but often uses treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab (Rituxan; R-CHOP), a monoclonal antibody specific for CD20-positive B lymphocytes. 29 Other medications such as bendamustine (Bendeka), an alkylating agent, and lenalidomide (Revlimid) are also used in many non-Hodgkin lymphoma treatments. 30 , 31 Common complications of these therapies are listed in Table 5 . 25 – 27 , 29 – 36

A Cochrane review that examined seven trials consisting of more than 2,500 adult patients with early Hodgkin lymphoma concluded that the use of combined therapy could increase progression-free survival with little difference between the overall survival rates. 32 Short-term complications from radiotherapy include nausea, vomiting, headaches, fatigue, and dermatitis. Radiotherapy can also lead to long-term complications, including cardiac and pulmonary toxicity, hypothyroidism, or breast or lung cancers. 24 – 32 Radiotherapy can be avoided in patients with stage IA or IIA lymphoma without bulky disease 25 ( Table 3 19 ) .

Interim Reassessment

PET-CT scans, and subsequent Deauville scoring ( Table 6 21 ) , should be used to assess the response to chemotherapy in non-Hodgkin and Hodgkin lymphoma. 25 , 30 , 31 , 33 A score of 3 or less is considered complete remission in non-Hodgkin lymphoma and should conclude the current treatment course. A score of 4 or 5 is an indicator to consider escalating therapy. 25 Patients with Hodgkin lymphoma with a Deauville score of 1 or 2 have been shown to have similar progression and mortality outcomes between radiotherapy and no further treatment. 32 Patients who receive a score of 3 or 4 should receive additional chemotherapy and/or radiotherapy, and a score of 5 indicates the need for a biopsy (excisional or core needle) in addition to chemotherapy and radiotherapy. 25 A positive biopsy should be considered refractory disease. 25

Relapse rates for non-Hodgkin lymphoma are variable and based on the specific subtype. The most common subtype, diffuse large B-cell lymphoma, has a 40% lifetime relapse rate. 37 Lifetime relapse in Hodgkin lymphoma occurs in 10% to 15% of patients with early stage disease and 40% of patients with advanced stage disease. 38

Surveillance

Patients who have achieved remission need routine surveillance to monitor for complications and relapse, as well as age-appropriate screenings recommended by the U.S. Preventive Services Task Force. 39 Complications of lymphoma treatment include secondary malignancies (e.g., breast, lung, skin, colon), cardiac disease, infertility, and endocrine, neurologic, and psychiatric dysfunctions. Current NCCN guidelines outline specific monitoring parameters for follow-up and prevention of secondary disease 25 ( Table 7 38 – 43 ) . The extent and frequency of follow-up specifically depend on the histologic subtype of lymphoma. Patients should follow up with an oncologist every three to six months for the first two years , every six to 12 months until year 3, then annually thereafter. After five years of being cancer free, the patient can be transitioned to a primary care physician. 40

If a patient is asymptomatic, routine surveillance imaging does not improve outcomes or provide a clinical benefit. 40 , 41 Surveillance imaging should be used in patients who have reported symptoms or who are at high risk of relapse in a place that would not be easily examined, and who would be candidates for treatment. However, NCCN imaging guidelines for lymphoma surveillance state that it is acceptable to perform chest radiography or CT of the chest every six to 12 months for the first two years and then yearly for the next three to five years posttreatment. 41 Surveillance imaging with PET-CT scans following complete remission is not recommended. 40 , 41 Disease marker research is ongoing, examining minimal residual disease measurements, a polymerase chain reaction–based method that looks at identifying tumor-specific DNA sequences. 41

Immunizations

All patients with lymphoma should receive pneumococcal vaccination initially with a 13-valent pneumococcal conjugate vaccine (Prevnar 13), followed at least eight weeks later by a 23-valent pneumococcal polysaccharide vaccine (PPSV23; Pneumovax 23) and then another PPSV23 at least five years later. 44 Patients receiving anti–B-cell antibodies should not receive annual influenza vaccination, and administration of live vaccines is contraindicated during chemotherapy. Routine vaccinations recommended by the Centers for Disease Control and Prevention (CDC) should resume, including any recommended inactivated or live vaccines three months after chemotherapy or six months after anti–B-cell antibody therapy. 43 , 45 Patients receiving a hematopoietic stem cell transplant should receive a series of three doses of Haemophilus influenzae type b vaccine starting six to 12 months after a successful transplant. Household contacts should receive appropriate CDC-recommended immunizations. 43

This article updates a previous article on this topic by Glass . 46

Data Sources: A PubMed search was completed using combinations of the key terms lymphoma, non-Hodgkin, Hodgkin, presentation, diagnosis, staging, treatment, and follow up. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Search dates: April 18, May 17, and May 31, 2018, and August 30, 2019. We also searched the Agency for Healthcare Research and Quality evidence reports, UpToDate, the Cochrane database, Essential Evidence Plus, the National Comprehensive Cancer Network, and the Surveillance, Epidemiology, and End Results database. Search dates: April 18, 2018, and August 30, 2019.

Research reported in this article was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number 5U54GM104942-03. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Glass C. Role of the primary care physician in Hodgkin lymphoma. Am Fam Physician. 2008;78(5):615-622. https://www.aafp.org/afp/2008/0901/p615.html

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Patterns of Clinical Presentation in Patients with Classical Hodgkin Lymphoma and Impact on Prognosis

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Lauren E. Strelec , Sarah Jordan Nagle , Zachary DiAngelo , Sunita Dwivedy Nasta , Anthony R. Mato , Daniel J. Landsburg , Stephen J. Schuster , Jakub Svoboda; Patterns of Clinical Presentation in Patients with Classical Hodgkin Lymphoma and Impact on Prognosis. Blood 2016; 128 (22): 3002. doi: https://doi.org/10.1182/blood.V128.22.3002.3002

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Background: Patients with classical Hodgkin lymphoma (cHL) often present with asymptomatic lymphadenopathy or generalized symptoms including fevers, night sweats, or cough. The non-specific nature of cHL presentation may contribute to long time intervals between symptom onset and diagnosis. An adverse effect on overall survival due to delays between diagnostic biopsy and treatment initiation has been suggested (Connors, Blood 2014). However, the impact on prognosis due to time interval between initial onset of lymphoma-related symptoms/signs to diagnosis is unknown.

Methods: We conducted a retrospective study of cHL patients seen at a tertiary university center between 2006 and 2015. Eligible patients were age ≥18 with biopsy-proven diagnosis of cHL who completed frontline curative-intent chemotherapy. We reviewed medical records to obtain date of patient-reported onset of cHL related symptoms/signs prior initial diagnosis, nature of initial symptoms, date of diagnostic biopsy, and date of initiation of therapy. Time to diagnosis (TTD) was defined as the interval between onset of cHL related symptoms/signs to diagnostic biopsy. Patients were divided into 2 cohorts: short TTD (0-12 weeks) and long TTD (>12 weeks). We then evaluated the impact of TTD on progression free (PFS) and overall survival (OS) measured from date of treatment initiation. Univariate and multivariate analyses were used to determine the association of TTD with variables known to affect cHL prognosis: stage (limited vs. advanced), age (<45 vs. ≥45), and sex. Descriptive and survival analyses using Kaplan-Meier methodology were performed (STATA v. 14). A log-rank test was utilized to compare OS and PFS in the two cohorts. Data are reported through 7/2016.

Results: A total 114 cHL patients were eligible for the study of which 59 (52%) were male. Median age at diagnosis was 36 years (range 18-78), and 15 (13%) were non-white. Disease stage included 13 (11%) stage I, 47 (41%) II, 21 (18%) III, 32 (28%) IV, and 2 (2%) unknown. Histologic subtypes included 80 (70%) nodular sclerosing, 16 (14%) mixed cellularity, 4 (4%) lymphocyte-rich, and 14 (12%) indeterminate. Most common initial cHL related symptom or signs included 60 (53%) patients with asymptomatic lymphadenopathy, 16 (14%) fevers, 42 (37%) night sweats, 30 (26%) weight loss, 16 (14%) cough, and 7 (6%) pruritus. Fifty-five (48%) patients had short TTD and 59 (52%) had a long TTD. At median follow-up of 36 months, median PFS and OS of the total cohort were not reached. PFS by TTD is shown in Figure 1. 22 (40%) patients with short TTD relapsed or failed to respond to therapy vs. 13 (22%) patients with long TTD (p<0.05). The mean time from pathologic diagnosis to treatment was 28 days for short TTD and 26 days for long TTD (p=0.54). Of 28 patients who had significant diagnostic delay (defined as more than 6 months between onset of symptoms to diagnosis), only 1 (4%) patient died of their disease and 5 (18%) relapsed or failed to respond to therapy. Univariate and multivariate analyses revealed that age, stage, sex, and histologic subtype were not significantly associated with TTD.

Conclusions: To our knowledge, this is the first study to examine the impact of interval from initial onset of lymphoma related symptoms/sign to diagnosis in cHL patients. In our cohort, shorter interval from symptom onset to diagnosis was associated with inferior PFS which may reflect the aggressive nature of cHL in these patients. Planned correlation of time to diagnosis with known adverse prognostic indicators may validate this hypothesis. In the meantime, patients and physicians may be reassured by our findings that support excellent outcomes even in those with significant delays from symptom onset to diagnosis.

Nasta: Millennium Pharmaceuticals: Research Funding. Mato: Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Schuster: Hoffman-LaRoche: Research Funding; Merck: Research Funding; Janssen Research & Development: Research Funding; Pharmacyclics: Consultancy, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Research Funding. Svoboda: Seattle Genetics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding.

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Clinical presentation and staging of Hodgkin lymphoma

Affiliations.

• 1 Research, Innovation and Statistics Department, A. Lacassagne Cancer Center, Nice, France. Electronic address: [email protected].
• 2 Department of Haematology, Rigshospitalet, Copenhagen, Denmark.
• 3 Haematology Department, European Institute of Oncology, Milan, Italy; National Cancer Institute, Cairo University, Cairo, Egypt.
• PMID: 27496305
• DOI: 10.1053/j.seminhematol.2016.05.005

In the present chapter the authors present a brief overview of the diagnostic methods proposed over time for Hodgkin lymphoma (HL) spread detection, moving from surgical procedures, through standard radiological and functional imaging techniques to the present state of the art for HL staging. The main body of the review will be dedicated to the recently published guidelines for lymphoma staging (including HL) agreed by the experts during the 12th International Congress for Malignant Lymphoma in Lugano. The recommendations of the panel on how to integrate flurodeoxyglucose positron emission tomography (FDG-PET) scan in the armamentarium of staging procedures will be presented and commented, with a special emphasis on the utility of special procedures, such as bone marrow trephine biopsy, which is deemed no longer needed in the PET era. While the HL diagnosis is straightforward in most cases, sometimes HL is a subtle disease, difficult to diagnose for the paucity of symptoms, the absence of physical findings, or for concomitant immunologic disorders: a compete overview of the common and rare patterns of HL clinical presentation will be also offered. The future perspective of PET scan use will be based on a operator-independent, quantitative readings of the scan thanks to a plethora of sophisticated dedicated software, which are now available, able to quantify every voxel captured by the tumor to display the metabolically active tumor volume. Moreover, new tracers are now available able to track the new pathways of cellular metabolism beside glycolysis such as amino acids or purine-analogues or specific oncoproteins; the preliminary, promising results will be reported. Preliminary results from other imaging techniques, such as diffusion-weighted magnetic resonance (DW-MRI) will be also reported.

Keywords: Hodgkin lymphoma; PET; Presentation; Staging.

Copyright © 2016 Elsevier Inc. All rights reserved.

Publication types

• Hodgkin Disease / diagnosis*
• Hodgkin Disease / pathology
• Neoplasm Staging
• Positron-Emission Tomography
• Tomography, X-Ray Computed

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• Continuing Education Activity

Lymphoma comprises heterogeneous malignancies that arise from the clonal proliferation of lymphocytes. It represents approximately 5% of malignancies. Overall survival is estimated to be 72%. This activity outlines the evaluation and management of lymphoma and highlights the role of the interprofessional team in managing patients with this condition.

• Describe the etiology of the common types of lymphoma.
• Describe the clinical presentation of the common types of lymphoma.
• Outline the treatment plan of the common types of lymphoma.
• Introduction

Lymphomas are a heterogeneous group of malignancies that arise from the clonal proliferation of B- cell, T- cell and natural killer (NK) cell subsets of lymphocytes at different stages of maturation. [1] [2]  Lymphoma comprises heterogeneous malignancies that arise from the clonal proliferation of lymphocytes. It represents approximately 5% of malignancies. Overall survival is estimated to be 72%.

Different environmental, infectious, and genetic factors have been identified, which predispose to lymphoma.

Occupational exposure: herbicides, pesticides

Infectious organisms: These include Helicobacter pylori (MALT lymphoma), Borrelia burgdorferi , Chlamydia psittaci , Campylobacter jejuni , human T- cell lymphotropic virus (adult T- cell leukemia/lymphoma), hepatitis C ( lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma and marginal zone lymphoma), human herpesvirus 8 (primary effusion lymphoma and Castleman disease). Chronic stimulation of lymphoid tissue also increases the risk of lymphoma development. Persistent infection with viruses like Epstein Barr virus and cytomegalovirus also predisposes to the development of lymphoma. [3] [4]

Immunodeficiency: HIV infection, transplant recipients, and those with genetic immunodeficiency disorders (severe combined immunodeficiency and common variable immunodeficiency). [5]

Drugs: Tumour necrosis factor-alpha inhibitors are associated in particular with T- cell lymphoma. Chronic immunosuppression in post-transplant patients (both solid organ transplant and bone marrow transplant recipients) increases the risk of lymphoma.

Autoimmune diseases: Inflammatory bowel disease (enteropathy associated lymphoma), rheumatoid arthritis and, Sjögren’s syndrome (diffuse large B-cell lymphoma)

Geographic location: Extranodal NK/T- cell lymphoma incidence is high in Southern Asia and some parts of Latin America. [1] [2]

• Epidemiology

The incidence of lymphoma in the United States from 2009 to 2013 was 22/ 100,000, representing approximately 5% of malignancies, it doubled in the time period 1970-1990, and it has been stable since. The median age of diagnosis is 63. Overall survival is estimated to be 72% at five years, and it is improving. [1]

Lymphomas are broadly classified into Hodgkin lymphoma (HL), 10% and Non- Hodgkin lymphoma (NHL), 90%.

HL is further classified into classical and non-classical types and NHL into B- cell, T- cell and natural killer (NK) cell types.

For clinical purposes, lymphoma is termed as aggressive (high grade) and indolent (low grade). [6]

Below is the revised 2016 revised WHO classification of lymphomas. [7]

Mature B-cell neoplasms

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
•  Monoclonal B-cell lymphocytosis
•  B-cell prolymphocytic leukemia
•  Splenic marginal zone lymphoma
•  Hairy cell leukemia
• Splenic diffuse red pulp small B-cell lymphoma
• Hairy cell leukemia-variant
• Waldenström macroglobulinemia
•  Monoclonal gammopathy of undetermined significance (MGUS), IgM
•  μ heavy-chain disease
•  γ heavy-chain disease
•  α heavy-chain disease
•  Monoclonal gammopathy of undetermined significance (MGUS), IgG/A
•  Plasma cell myeloma
•  Solitary plasmacytoma of bone
•  Extraosseous plasmacytoma
•  Monoclonal immunoglobulin deposition diseases
•  Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
• Pediatric nodal marginal zone lymphoma
• In situ follicular neoplasia
•  Duodenal-type follicular lymphoma
•  Pediatric-type follicular lymphoma
•  Large B-cell lymphoma with IRF4 rearrangement
•  Primary cutaneous follicle center lymphoma
• In situ mantle cell neoplasia
• Germinal center B-cell type
• Activated B-cell type
•  T-cell/histiocyte-rich large B-cell lymphoma
•  Primary DLBCL of the central nervous system (CNS)
•  Primary cutaneous DLBCL, leg type
•  EBV+ DLBCL, NOS
•  EBV+mucocutaneous ulcer
•  DLBCL associated with chronic inflammation
•  Lymphomatoid granulomatosis
•  Primary mediastinal (thymic) large B-cell lymphoma
•  Intravascular large B-cell lymphoma
•  ALK+ large B-cell lymphoma
•  Plasmablastic lymphoma
•  Primary effusion lymphoma
•  HHV8+DLBCL, NOS
•  Burkitt lymphoma
•  Burkitt-like lymphoma with 11q aberration
•  High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
•  High-grade B-cell lymphoma, NOS
•  B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Mature T and NK neoplasms

•    T-cell prolymphocytic leukemia
•  T-cell large granular lymphocytic leukemia
•  Chronic lymphoproliferative disorder of NK cells
•  Aggressive NK-cell leukemia
•  Systemic EBV+ T-cell lymphoma of childhood
•  Hydroa vacciniforme–like lymphoproliferative disorder
•  Adult T-cell leukemia/lymphoma
•  Extranodal NK-/T-cell lymphoma, nasal type
•  Enteropathy-associated T-cell lymphoma
•  Monomorphic epitheliotropic intestinal T-cell lymphoma
•  Indolent T-cell lymphoproliferative disorder of the GI tract
•  Hepatosplenic T-cell lymphoma
•  Subcutaneous panniculitis-like T-cell lymphoma
•  Mycosis fungoides
•  Sézary syndrome
• Lymphomatoid papulosis
• Primary cutaneous anaplastic large cell lymphoma
•  Primary cutaneous γδ T-cell lymphoma
•  Primary cutaneous CD8+aggressive epidermotropic cytotoxic T-cell lymphoma
•  Primary cutaneous acral CD8+T-cell lymphoma
•  Primary cutaneous CD4+small/medium T-cell lymphoproliferative disorder
•  Peripheral T-cell lymphoma, NOS
•  Angioimmunoblastic T-cell lymphoma
•  Follicular T-cell lymphoma
•  Nodal peripheral T-cell lymphoma with TFH phenotype
•  Anaplastic large-cell lymphoma, ALK+
•  Anaplastic large-cell lymphoma, ALK−
•  Breast implant-associated anaplastic large-cell lymphoma

Hodgkin lymphoma

 Nodular lymphocyte-predominant Hodgkin lymphoma

 Classical Hodgkin lymphoma

•   Nodular sclerosis classical Hodgkin lymphoma
•   Lymphocyte-rich classical Hodgkin lymphoma
•   Mixed cellularity classical Hodgkin lymphoma
•   Lymphocyte-depleted classical Hodgkin lymphoma

Posttransplant lymphoproliferative disorders (PTLD)

•  Plasmacytic hyperplasia PTLD
•  Infectious mononucleosis PTLD
•  Florid follicular hyperplasia PTLD
•  Polymorphic PTLD
•  Monomorphic PTLD (B- and T-/NK-cell types)
•  Classical Hodgkin lymphoma PTLD
• Pathophysiology

Different stressors in the form of infectious, inflammatory, and toxic factors interact with the genetic makeup of the human host in a complex manner to result in lymphomagenesis. [1] [2]  One of the widely accepted principles of lymphomagenesis is being on long term immunosuppressive therapies, which makes the innate immune system less able to detect and destroy cancer cells or ward off infections that could result in cancers.

• Histopathology

A diagnosis of lymphoma is confirmed by tissue biopsy, and commonly used methods include fine-needle aspiration, core biopsy, incision/wedge biopsy, and excisional biopsy. Excisional biopsy is considered the "gold standard" as it allows for the assessment of whole lymph node architecture. The different pathologic characteristics and histologic patterns of common lymphomas are as below.

Hodgkin Lymphoma (HL)

HL is defined by the presence of pathological Hodgkin Reed-Sternberg (HRS) cells, which are of B-cell origin on the background of nodular sclerosis, lymphocyte-predominant, or depleted stroma. Classical HL is divided into four different types, which in decreasing order of frequency are: nodular sclerosing, mixed cellularity, lymphocyte rich, and lymphocyte depleted. Non -classical HL is of an only single type, nodular lymphocyte-predominant.

HL presentation is bimodal with one age peak in the early 20s and second in the mid-60s.  For most cases, no underlying cause is found, but for some subtypes of classical HL, a significant number of patients test positive for EBV. The causative relationship between EBV and HL been investigated extensively. Other risk factors are genetic predisposition (high incidence among patient's relatives), immunodeficiency states, and environmental factors (high incidence in farmers, woodworkers, and meat processors).

Histologic features of HL: are HRS cells, which are odd-looking large, bilobed cells with two nuclei, appearing within a background of non-malignant inflammatory cells. Immunohistochemical staining of HL shows positive markers for CD30, CD15, but negative for CD20, making it difficult to determine the B-cell lineage. [1] [2] [7]

Non-Hodgkin Lymphoma (NHL)

Diffuse large B Cell lymphoma (DLBCL)

It is the most common NHL, accounting for 25% to 30% of cases.  It is a clinically aggressive lymphoma. DLBCL often arises in the lymph nodes but can also present anywhere else in the body, and the gastrointestinal tract is the most common system outside the lymphatic system. Other common involvement sites are testes, eyes, and central nervous system.

When an extranodal disease is present with minimal or no lymph node involvement, the disease is considered primary extranodal DLBCL, whereas when both nodal and extranodal disease is present, the disease is considered nodal lymphoma.

It is classified based on gene expression into three categories according to the cell of origin: germinal center B cell-like, activated B cell-like, and type 3; the last two have unfavorable prognosis.

Low-grade lymphomas like follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma can develop into high-grade through a transformation of disease into DLBCL, which is triggered by accumulation of additional transforming mutations.

Histologic features: include areas of diffuse involvement by large lymphoid cells that stain positive for B-cell markers CD20 and CD19. The proliferation index, determined by staining with Ki67 antibody is moderate to high. [1] [2] [7]

Follicular Lymphoma (FL)

It is an indolent lymphoma and accounts for about 20% of lymphoma diagnoses, making it the second most common lymphoma. Overall survival ranges from 8-15 years. It originates from the follicular cells in the germinal center of the lymph node. The tumor cells have overexpression of the anti-apoptotic protein BCL-2, due to translocation of the BCL-2 gene on chromosome 14 to the immunoglobulin or B-cell receptor gene on chromosome 18, t(14:18). It can transform into more aggressive DLBCL in some cases. [1] [2]

Histologic features: histologic diagnosis requires areas of considerable follicular proliferation and expansion within the lymph node. Within the expanded lymph node follicles,  small and large cells proliferate (similar to reactive lymph node), but instead of a  combination of B cells (CD20+) and some T cells (CD3+), the follicles are composed mostly of B cells positive for BCL-2 in FL. However, in FL, as in a reactive node, there is a difference in the size of follicle B cells, small cells, which are called centrocytes and large cells called centroblasts. The proportion of large cells, centroblasts, is measured as being either greater than or less than 15 cells per high-power field (HPF). The larger the number of centroblasts, the higher the grade; in grades I and II, there are 0 to 15 centroblasts/HPF, whereas, in grade III, there are more than 15 centroblasts/HPF. The difference between grade IIIA and grade IIIB is the presence of a mixture of centrocytes and centroblasts in all follicles in grade IIIA, whereas, in grade IIIB, follicles consist exclusively of centroblasts, immunoblasts (activated lymphocytes), or both. Of note, FL grade IIIB is managed the same way as DLBCL. [1] [2] [7]

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue

Normal mucosal tissue contains non-continuously spread collections of lymphocytes called mucosa-associated lymphoid tissue (MALT). Lymphoma that originates from the marginal zone of such collection is called MALT lymphoma and constitutes 7% of all lymphomas. It is a slow-growing B-cell lymphoma. Repeated antigen stimulation in the setting of infection, autoimmune disease, or other inflammatory condition predisposes to the pathogenesis. Some well-known associations are H.pylori (gastric), C. psitacci (ocular), C. jejuni (small intestine),   B. burgdorferi (skin), Hashimoto thyroiditis (thyroid) and Sjögren syndrome (salivary gland). It originates from a marginal zone cell, a B-cell. [1] [2] [7] [2]

Histologic features: Aggregates of small lymphocytes with IHC staining positive for CD20 and negative CD5 and CD10. [1] [2] [7]

Mantle Cell Lymphoma

It comprises 6% of lymphomas. It has the worst prognosis among all lymphoma subtypes with a median overall survival of 5 years. Despite that, it has a wide range of presentations, and in some older patients, it has a very slowly progressive course where close surveillance without immediate treatment initiation has been used. It has a male predominance. It usually presents as a widespread disease; bone marrow and gastrointestinal tract are the most common sites of involvement. In the gastrointestinal tract, it can cause obstruction due to the formation of multiple polyps, a condition called lymphomatous polyposis.

Histologic features: lt arises from the mantle zone cell of the lymph node, which is a post–GC (germinal center) B-cell. Histologic diagnosis is made by visualizing areas of small lymphoid cells, arising from mantle zone directly in some cases, with characteristic IHC staining and being always positive for cyclin D1, a protein involved in cell cycle regulation. It results from a translocation of the gene encoding for cyclinD1 on chromosome 11 and the one encoding for Ig (immunoglobulin) on chromosome 14, t(11;14). [1] [2] [7]

Burkitt Lymphoma (BL)

It was first described by the Irish surgeon Denis Burkitt in 1958 and is a very aggressive B-cell lymphoma. It is divided into three types: endemic, spontaneous, and immunodeficiency associated. The endemic form of BL is a pediatric tumor in Africa, usually presenting as a mandibular mass and is strongly associated with chronic EBV infection. In the United States, spontaneous BL is the most common form and usually presents as an abdominal mass or lymphadenopathy. Immunodeficiency associated BL is seen in HIV infection, and its presence can be an AIDS-defining condition. The pathogenesis is caused by translocation of the cell proliferation proto-oncogene, C-Myc to one of the sites encoding Ig expression, either the heavy chain t(8;14) or one of the two light chains, t(2;8) or t( 8;22).

Histologic features: histologic diagnosis is made by recognizing medium to large B-cells with a very high proliferation rate (Ki67 of almost 100%), with the classic starry sky appearance due to tingible body macrophages with surrounding clearing. [1] [2] [7]

Peripheral T Cell lymphomas  

The peripheral T-cell lymphomas (PTCLs) are a diverse group of diseases that constitute approximately 5% to 10% of NHL.

The PTCLs are classified into three main categories with predominantly leukemic, nodal, or extranodal involvement. The first subset of the peripheral T-cell lymphomas frequently presents with a leukemic phase. It includes T-cell prolymphocytic leukemia, T-cell large granular lymphocytic (LGL) leukemia, natural killer/T (NK/T)-cell leukemia, and adult T cell leukemia/ lymphoma. The second set presents with adenopathy, and it includes angioimmunoblastic T- cell lymphoma (AITL), systemic anaplastic large cell lymphoma (ALCL), and peripheral T- cell lymphoma (PTCL).

The extranodal PTCLs include mycosis fungoides (MF) and cutaneous ALCL.  These have chronic and slow progression with long term remission. Sezary syndrome represents the leukemic transformation of MF, presenting with abnormal circulating lymphocytes (Sezary cells), adenopathy, and erythroderma and has a worse prognosis.

Extranodal NK/T-cell lymphoma, nasal type (nasal NK/T lymphoma) is an aggressive lymphoma that is the most common cause of the "lethal midline granuloma" syndrome. It is strongly associated with EBV infection and is frequently seen in East Asia and among the indigenous population in Peru. It affects both children and adults and presents as a locally invasive disease presenting with nasal obstruction and destruction of nasal passages, hard palate, and sinuses [1] [2] [7] [8]

• History and Physical

Hodgkin Lymphoma

Usually presents with painless, superficial enlarged lymphadenopathy, which involves contiguous lymph node chains in a predictable manner with the spread of the disease. Later in the disease course, hematogenous spread occurs with vascular invasion. The majority of patients present with supradiaphragmatic disease and isolated infra-diaphragmatic disease occurs in only 3-7% of patients. Approximately 60 to 70% of patients present with cervical and/or supraclavicular lymphadenopathy, 30% with the axillary disease, 50 to 60% with mediastinal involvement seen on radiology in the absence of symptoms. Infra diaphragmatic disease involves para-aortic lymph nodes, but the involvement of abdominal organs is uncommon. Only 10-15 % of patients with HL have extranodal disease, and the commonly affected organs are bone, bone marrow, lung, and liver. CNS involvement is very rare, but extension from para-aortic adenopathy into epidural space can result in neurological symptoms. [1] [2] [9]

Approximately 25% of patients with previously undiagnosed HL develop systemic symptoms before the development of lymphadenopathy called B symptoms (fevers, drenching night sweats, and unintentional weight loss). The presence of these symptoms carries a worse prognosis in both early and advanced-stage disease.  Other symptoms include severe pruritis and alcohol-induced pain occurring minutes after alcohol intake and localized to regions of lymphadenopathy. Some rare neurological syndromes, including cerebellar degeneration and stiff-person syndrome, also have been reported. [1] [2]

Non-Hodgkin Lymphoma

The most common complaint is symptomatic, enlarging lymph nodal mass either located centrally or peripherally. 20% of patients present with stage I disease, approximately 40% with disease limited to one side of the diaphragm (stage II), and another 20% with involvement above and below the diaphragm and 40% with the widespread disease with extranodal involvement. Common sites of extranodal spread are lung, liver, kidney, and bone marrow. This is in contrast to primary extranodal sites of origin of DLBCL, which are the gastrointestinal tract, thyroid, bone, brain, testis, kidney, liver, breast, and skin.

Approximately 30% of patients will report B symptoms as well as less specific symptoms of malaise and fatigue.

Follicular Lymphoma

The most common presentation is subacute, or chronic asymptomatic peripheral lymphadenopathy, which sometimes persists or waxes and wanes over a period of years. Abdominal, pelvic, or retroperitoneal lymphadenopathy can be bulky without causing gastrointestinal or genitourinary symptoms, and nodal masses are not locally invasive and destructive. The lymph node involvement is not in an orderly manner, and early hematogenous dissemination is common.  B-symptoms are seen in less than 20% of patients and should prompt consideration for transformation into DLBCL. [10]

Marginal Zone Lymphoma

Presenting symptoms related to the sites of involvement (stomach, lung, ocular adnexa, breast, thyroid, bowel, skin, and soft tissue) and B-symptoms are rare and should raise suspicion for transformed lymphoma.

70% to 90% of patients present with detectable stage 4 disease. Bone marrow involvement is common, and a leukemic phase is seen as frequently as 75% in some series. The gastrointestinal tract is frequently involved and can present from diffuse lymphomatous polyposis to a normal lumen with microscopic disease seen on biopsy. Other common sites of involvement are the spleen and Waldyer’s ring.

Burkitt Lymphoma

Endemic BL presents in children as a tumor of the jaw or facial bones and spreads hematogenously early in the course to extranodal sites, including kidney, testis or ovary, CNS, or meninges. Sporadic BL presents as a bulky abdominal disease involving stomach, caecum, or small intestine with associated ascites. The involvement of kidneys, ovarian or testicular organs, CNS, or meninges is common as well. Immunodeficiency related BL usually presents with lymph node involvement, but can also involve the bone marrow, CNS, or meninges and rarely may present with leukemic phase. [1] [2]

After confirming the diagnosis of lymphoma by tissue biopsy, further evaluation involves the determination of tissue where disease activity is the greatest. PET/CT scans by measuring uptake of radiolabeled fluorodeoxyglucose (FDG) are used to measure the biological activity of lymphoma. [11] [1] [2]  Staging is performed before the initiation of therapy for lymphoma.

The clinical staging of both HL and NHL is derived from the Ann Arbor staging system. The presence or absence of B symptoms (persistent fever, weight loss in excess of 10% of body weight over six months, or night sweats) is included in the staging for lymphoma. Blood work includes lactate dehydrogenase along with complete blood counts with differential, comprehensive metabolic panel, and uric acid.

Whole-body PET/CT imaging is preferred over CT of the chest, abdomen, and pelvis. Bone marrow biopsy is often performed for staging but may be omitted for stage III DLBCL and HL because detection of stage IV disease over stage III does not change the treatment. [12]  In some cases where the lymphoma is judged to be high risk, standard staging is supplemented by cerebrospinal fluid testing. For aggressive lymphomas like DLBCL, CNS-IPI (CNS Internal Prognostic Index) tool can be used to predict CNS relapse or progression. [13]

Antigen-specificity for B and T-cells is defined by the cell-surface receptor, B-cell receptor, or T-cell receptor, respectively. T-cells are programmed for antigen recognition in the thymus. B-cells mature in the marrow and encounter foreign antigen for the first time within the lymph node germinal center (GC). As such, B-cells may be divided into GC or post-GC. Post-GC, some B-cells develop eventually into plasma cells, which secrete the soluble form of B-cell receptor, that is, immunoglobulin (Ig) or antibody. The method used for determining malignancy or clonality in B-cell lymphomas is by immunohistochemical staining for light chains to show that the sample has lymphocytes expressing all kappa or lambda light chains. It is called light chain restriction and shows the presence of lymphocytic clone. [1] [2]

• Treatment / Management

Hodgkin Lymphoma [14]

Combined modality therapy, including chemotherapy with antibody-drug conjugates and radiotherapy, is the usual standard of care. Most cases of HL are chemosensitive and overall survival is 86%.

Standard treatment in the United States (US) consists of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). In Germany, the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) is more popular. A third regimen that is used is Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone). All these regimens have similar response rates with BEACOPP carrying slightly better cure rates than the other two but at the cost of greater toxicity, including the development of secondary acute myeloid leukemia/myelodysplastic syndrome and sterility. In 2018, the FDA approved brentuximab vedotin (CD30 targeted antibody-drug conjugate) in combination with AVD chemotherapy for first-line treatment of stage III or IV classical HL. [15]

Systemic chemotherapy is supplemented by local radiation either because of bulky disease or persistent PET/CT positivity after chemotherapy. [1] [2] [16]

Repeat imaging is done to assess the response to treatment, which consists of a PET/CT scan. PET/CT results are evaluated by Deavullie criteria whereby signal less than or equal to the physiologic signal from the liver is negative (1-3) and signal greater than the liver (4-5) is positive. A new strategy evolving in both the United States and Europe is to start the initial treatment with ABVD, monitor response to chemotherapy with repeat PET/CT after two cycles, then escalate the treatment to BEACOPP only for those patients with an incomplete response. [17]  Recent indications are that if PET/CT response to ABVD is good, then bleomycin may be omitted from later cycles without compromising response, and avoiding unnecessary pulmonary toxicity.

Upon completion of therapy, patients are evaluated as part of surveillance at regular intervals to exclude disease recurrence, with history & physical and basic laboratory tests, but without routine repeat imaging. Because many patients with HL are young and cured, they will live for a long time after treatment and must be monitored for the sequelae of the treatment especially the development of secondary cancers within previous radiation fields, such as lung, breast, or thyroid, as well as coronary artery disease.

For patients with resistant or relapsed HL, several salvage regimens are available. Brentuximab vedotin is also approved by the FDA as a second-line agent. Salvage therapy, if successful, is followed by consolidation with high dose chemotherapy and autologous stem cell rescue. In cases where the disease is fully resistant or relapses again after autologous stem cell rescue, experimental agents within the context of a clinical trial are indicated, or, in selected cases, allogeneic stem cell transplantation. [1] [2] [18]

Diffuse Large B- Cell Lymphoma

Many patients with DLBCL achieve a long term disease-free status with aggressive combination chemotherapy.

The gold standard for DLBCL treatment is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). [1] [2] [19]

For localized disease, combination chemoradiation therapy can be used, with three cycles of systemic chemotherapy supplemented by involved field radiation therapy (IFRT) with the purpose of limiting overall exposure to the chemotherapy. For patients with poor performance status, milder treatment options include R-mini CHOP (reduced doses of all drugs except rituximab), R-CHOP minus doxorubicin (R–CVP), or single-agent rituximab. [1] [2] [20] [21]

Special consideration should be given to cardiac comorbidities due to the cardiac toxicity of doxorubicin, an anthracycline. Baseline echocardiography or multi gated acquisition (MUGA) scan should be performed before initiation of chemotherapy.

For a subgroup of DLBCL, categorized as double hit or triple hit lymphomas (based on rearrangements of two or three genes: c-MYC, BCL-2, and BCL-6), the prognosis is poor, and they tend to carry morphologic, biologic and cytogenetic properties similar to both DLBCL and much aggressive BL. There is a lack of data regarding the optimal chemotherapy regimen for such lymphomas but are usually treated with more intense chemotherapy regimens, similar to those used in the management of BL.

Reimaging by PET/CT is recommended to assess for treatment response at the end of the treatment. Interval assessment is also done during treatment, after 2 to 4 cycles of chemotherapy, with the purpose of identifying those cases not responding to initial chemotherapy. Patients who complete successful therapy should be followed at regular intervals as part of surveillance. Follow-up consists of history and physical examination, with basic laboratory tests (complete blood counts, metabolic panel, liver function tests, and lactate dehydrogenase). Repeat imaging is not needed routinely, in the absence of specific concerns. Most disease relapse occurs within two years, such that the follow-up interval is spaced out if the disease remains in remission beyond five years.

Clinical trials are currently underway to assess the efficacy and safety of adding immunomodulatory agents (lenalidomide) or Bruton’s tyrosine kinase inhibitors (ibrutinib) to R-CHOP in previously untreated DLBCL. [22] [23]

For those cases which do not respond or relapse after first-line chemotherapy, several higher-intensity chemotherapy regimens are used as salvage therapy. Common second-line regimens include R-ICE (rituximab, ifosfamide, carboplatin, etoposide), R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin)  which are more intense than R- CHOP and require inpatient administration of chemotherapy drugs. Survival after successful salvage therapy for resistant/relapsed DLBCL is improved significantly if salvage therapy is followed by high dose chemotherapy with autologous stem cell rescue (HD-SCT) consolidation.

The benefit of HD-SCT lies in the use of high doses of chemotherapy. A harvest of autologous peripheral blood stem cells before administration of high-dose chemotherapy allows for the use of chemotherapy doses, which are so bone marrow toxic that they would otherwise kill the patient, were it not for rescue by stem cell reinfusion. In cases where second-line therapies fail, clinical trials or allogeneic stem cell transplantation may be considered. [24]

The latest advance in the management of relapsed/refractory DLBCL is the utilization of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. [25] [26]

As an indolent slow-growing lymphoma, the clinical behavior of FL is variable. While some cases of FL remain asymptomatic, even being untreated, or wax and wane on their own, others progress and cause significant symptoms. Asymptomatic FL can be managed by close observation, that is, monitoring for appearance of signs of progression or significant symptoms before any intervention is planned. Treatment is usually not considered to be curative, so it must be chosen judiciously, weighing benefits against toxicities and the fact that after multiple therapies, toxicity will be cumulative. [27]

For localized FL confined to 1 lymph node area, radiotherapy may be chosen as the single modality of therapy. More commonly, several areas within the body are involved in FL, and systemic therapy is needed. Usually, a less aggressive approach such as single-agent rituximab may be chosen as first-line therapy, even for patients with good performance status, thus reserving the option of escalation in therapy for future needs. For higher disease burden FL, systemic cytotoxic chemotherapy is used. In FL, a number of different regimens have been used over the years.

Since overall survival in FL is measured in decades, it is difficult to show the superiority of 1 regimen over another. Recently, rituximab-bendamustine (R- Benda) has emerged as the most popular treatment, being superior to R-CHOP in terms of progression-free survival. [28]

Maintenance rituximab after completion of frontline systemic chemotherapy, usually once every two months for two years, has been shown to prolong progression-free survival but not overall survival. [29]

As an incurable disease, relapse of FL is anticipated at some point in clinical course and can be treated with the other regimens at frontline treatment. Upon recurrence of all indolent lymphomas, the possibility of transformation to aggressive lymphoma should be excluded. In cases where FL relapses early or show aggressive features, HD-SCT or allogeneic transplantation can be considered.

In many circumstances, the treatment of marginal zone lymphomas (MZL) is similar to FL, but it differs in certain specific scenarios. For early-stage gastric MALT lymphoma, eradication of H.pylori in patients with favorable cytogenetics results in tumor regression or remission in 50-80% of patients.

Patients with limited disease in whom H.pylori eradication is ineffective, are also cured usually with definitive radiotherapy.

Another important divergence from routine management of FL exists for splenic MZL. For patients with symptomatic splenomegaly and associated cytopenias, surgical splenectomy results in normalization of cell counts and helps to achieve disease stabilization and systemic regression. Single-agent rituximab therapy is also an approved non-surgical treatment alternative. 

Treatment of the less aggressive disease is with either R- CHOP or R- Benda, followed by maintenance rituximab. Most patients also need more intensive treatment regimens. One agent cytarabine is included in most regimens due to its activity in mantle cell lymphoma. The front line chemotherapy is followed in the first remission by consolidation with high dose chemotherapy and autologous stem cell transplantation. One such approach is the Nordic protocol (a maxi R–CHOP regimen alternating with rituximab and high-dose cytarabine). Another regimen is alternating hyper CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with methotrexate/cytarabine. Lenalidomide and bortezomib have single-agent activity in relapsed MCL. The Bruton’s tyrosine kinase inhibitor, Ibrutinib, is approved by the FDA for use in relapsed MCL as it has good activity in MCL. [14]

BL should be approached as an oncologic emergency due to a high proliferation rate of the tumor. This high proliferation rate requires immediate treatment with aggressive chemotherapy regimens in which the intensity of delivery is meant to outpace the capacity for the cellular division to prevent the development of tumor resistance. Failure to do so can result in rapid tumor proliferation, end-organ damage, and death. If treatment is initiated in a timely manner, results are favorable. Treatment options for BL include R-hyper CVAD-methotrexate/cytarabine and R-CODOX-M/IVAC (rituximab, cyclophosphamide, vincristine, doxorubicin, methotrexate/ ifosfamide, etoposide, cytarabine). Recently, DA-R-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) a more intense and easier to tolerate regimen has shown good results. These intense regimens are associated with complete remission rates of approximately 80 to 90% and disease-free survival rates of 50-75%. [30]

With BL, obtaining a good response with the first attempt of treatment is of particular importance.

Peripheral T- Cell Lymphoma (PTCL)

For different types of PTCL, there is no consensus on the treatment. Indolent slow-growing cutaneous T-cell lymphomas, including early-stage MF and cutaneous ALCL, can usually be monitored or treated with skin-directed treatments (topical medications, prednisone, ultraviolet therapy, involved-field radiotherapy) or mild systemic treatments such as retinoids. 18-FDG PET scanning is utilized in selected cases, mainly in the evaluation of cutaneous T-cell lymphoma, to identify the extracutaneous disease as it can change both prognosis and therapeutic approach. For the aggressive PTCLs, chemotherapy with multiple agents is used, such as CHOP, although with the exception of ALK-1 positive ALCL, where it is commonly associated with brief progression-free durations.

For nasal NK/T-cell lymphoma, early incorporation of radiation therapy in a combined modality therapy results in better outcomes.

For CD30 positive lymphomas, the antibody-drug conjugate brentuximab vedotin is effective. Histone deacetylase inhibitors such as romidepsin and belinostat have moderate activity in T- cell lymphoma. [1] [2] [11] [31]

• Differential Diagnosis
• Tuberculosis
• Sarcoidosis
• Behçet disease [2] [32]
• Radiation Oncology

For classic HL, radiation therapy (RT) is often used after chemotherapy for a residual, limited area of lymphadenopathy that is FDG avid on restaging PET/CT. RT by itself can be used to treat some cases of nodular lymphocyte-predominant HL.

In NHL, RT can be used in various scenarios;

• For early-stage (Ann Arbor stage I or II) indolent NHL with a limited amount of disease burden, RT can be used as a single modality treatment. 
• For more advanced and/or aggressive NHL, RT is used after chemotherapy as consolidation.

Consensus recommendations/guidelines from the International Lymphoma Radiation Oncology Group (ILROG):

• Positron emission tomography (PET)/computed tomography (CT) is recommended as the standard modality for staging and response assessment in fluorodeoxyglucose (FDG)-avid lymphomas, in line with the international Lugano guidelines. An accurate definition of sites of involvement before any systemic therapy is important for radiation therapy (RT) planning. Baseline pretreatment PET/CT is recommended as best practice.
• Radiation oncologists should familiarize themselves with the limitations of FDG imaging and recognize conditions that mimic lymphoma, such as brown fat; physiologic uptake in tonsils, nasopharynx, or salivary glands; inflammatory uptake; benign tumors of parotids; sarcoidosis; thymic hyperplasia; and physiologic bone marrow uptake.
• Magnetic resonance imaging (MRI) is indicated in certain anatomic areas: central nervous system, head (orbits, nose/paranasal sinuses, and skull base), and skeletal sites.
• The use of a 5-point score (known as Deauville criteria) is recommended for response assessment, in line with the international Lugano guidelines.
• Deauville score 3 requires cautious interpretation, with consideration given to clinical context, histological type, disease stage, bulk, and estimated prognosis, as well as the results of clinical trials. In some clinical trials using a de-escalation strategy with the omission of RT, Deauville score three was not considered a complete metabolic response.
• When defining RT targets based on PET/CT, the clinician should carefully consider the anatomical information from the CT part of the scan because some small involved nodes with low FDG uptake may be below the PET detection limit.
• Smaller nodes that are not FDG-avid but seen on CT adjacent to (or between) FDG-avid nodes, and judged to be involved, should be included in the target volume. For CT masses with partial FDG uptake, the entire mass should be included in the target volume.
• Residual FDG-avid areas can be treated to higher doses using an integrated boost technique.
• Thin-slice CT should be performed in the chosen treatment position, using immobilization devices if required, and should include relevant organs at risk as a whole. Intravenous contrast is recommended to help identify blood vessels and enhance soft-tissue definition.
• Breathing-control techniques (e.g., deep inspiration breath-hold) are recommended as best practice for mediastinal treatment to help reduce organ-at-risk doses.
• PET/CT is highly recommended as best practice for planning modern radiation volumes, according to the involved node or involved site RT concepts.
• If RT is the sole modality of treatment, a dedicated planning PET/CT can be performed in the treatment position, with the use of immobilization devices if required.
• If chemotherapy is given before RT, it is recommended that the prechemotherapy PET/CT be performed in a position similar to RT position to enable accurate coregistration with the planning CT and outlining of involved node RT volumes.
• If the prechemotherapy PET/CT cannot be obtained in the treatment position and accurate coregistration is not possible, the concept of involved site RT as described in other International Lymphoma Radiation Oncology Group guidelines should be used to account for the lack of optimal prechemotherapy imaging.
• In sites where MRI is useful, both PET/CT and MRI scans should be coregistered with planning CT scans to guide target volume definition.
• Image-guided radiotherapy, particularly using cone-beam CT, is recommended with modern RT techniques, which use small target volumes and steep dose gradients, to ensure accuracy of treatment delivery.
• The frequency of imaging has not been studied carefully in the context of lymphoma, and individual departments should decide on the frequency of imaging based on local setup accuracy data, margins used to create the planning target volume, specific treatment site, and use of immobilization devices. [33]

The clinical staging of both HL and NHL derive from the Ann Arbor (AA) staging system, which was subsequently modified at the Cotswolds meeting in 1989. The modification kept the previous four-stage system, with the addition of the modifier ‘‘X’’ for bulk, defined as greater than 10 cm in long-axis or for a mediastinal mass as measuring greater than one-third of the internal transverse thoracic diameter of a standard PA chest X-ray at the level of the fifth or sixth thoracic vertebral body. It is based on the extent of involvement of lymph node groups. The ‘‘E’’ modifier presents a direct extension of the tumor to an extranodal site, or for stage IE disease, isolated involvement of a single extranodal site without evidence of lymph node disease (e.g., primary lymphoma of bone or thyroid). The ‘‘B’’ modifier refers to the presence of one or more of a set of symptoms that are associated with more aggressive disease and worse prognosis, and these include unexplained recurring or persistent fever, drenching night sweats, or unexplained weight loss of 10% of body weight (B symptoms).

Cotswolds modification of the Ann Arbor staging system:

Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer’s ring) or involvement of a single extra lymphatic site (IE)

Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized contiguous involvement of only one extranodal organ or side and its regional lymph-nodes with or without other lymph node regions on the same side of the diaphragm (IIE)Note: The number of anatomic regions involved may be indicated by a subscript (e.g., II3)

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of only one extranodal organ side (IIIE) or both (IIISE)

Disseminated (multifocal) involvement of one or more extranodal organs or tissues, with or without associated lymph-node involvement or isolated extra lymphatic organ involvement with distant (non-regional) nodal involvement

Designations Applicable to Any Disease Stage

A: No symptomsB: Fever (temperature > 38 C), drenching night sweats, unexplained loss of more than 10% of body weight during the previous six months.X: Bulky diseaseE: Involvement of an extranodal site that is contiguous or proximal to the known nodal site [1] [2]

Due to the limited predictive power of Ann Arbor staging for both HL and NHL, clinical prognostic models are developed to help clinicians in conveying prognostic information to patients. Several models have been developed, which include HL international prognostic score, international prognostic index (IPI) for DLBCL, and FL international prognostic index (FLIPI) for follicular lymphoma. Low IPI score predicts a better outcome and high IPI a worse outcome. [2] [34] [35]

• Complications

HL Complications

Paraneoplastic syndromes: Limbic encephalitis (anti-metabotropic glutamate receptor 5 (mGluR5) antibodies), primary CNS angiitis, cerebellar degeneration (anti-Tr antibodies), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) [1] [36] [37]

NHL Complications

Transformation of indolent lymphomas such as follicular lymphoma, marginal zone lymphoma into more aggressive NHL such as diffuse large B-cell lymphoma

Chemotherapy Complications

Pancytopenias, sterility, cardiomyopathy(doxorubicin), pneumonitis (bleomycin), neuropathy (vincristine, brentuximab vedotin), and second primary malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia).

Radiotherapy Complications

Accelerated atherosclerosis, pericardial fibrosis, second primary cancers (lung, thyroid, breast, soft tissue sarcomas), and hypothyroidism [1] [36]

• Deterrence and Patient Education

Lymphomas are one of the common cancers of our immune system. It makes up to almost 5% of all cancers. It can affect both young and older adults. The common symptoms of this disease are persistent fevers, drenching night sweats, unintentional weight loss, and generalized or localized swelling of the lymph nodes. If any of these symptoms are observed, the primary care provider seeks a hematology consultation or opinion as soon as possible for timely diagnosis and treatment, since timely identification and treatment of lymphomas result in better survival rates with the least number of complications.

• Enhancing Healthcare Team Outcomes

While a hematologist is almost always involved in the care of patients with lymphoma, it is important to consult with an interprofessional team of specialists that include a radiologist, radiation oncologist, pathologist, and a surgical oncologist. The nurses are also vital members of the interprofessional group as they monitor the patient vital signs and assist with patient and family education. Having oncology trained social workers and psychologists as part of an interdisciplinary team also plays a significant role in addressing psycho-social issues pertaining to the diagnosis and management of lymphomas, especially in young patients.

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Disclosure: Ayesha Jamil declares no relevant financial relationships with ineligible companies.

Disclosure: Shiva Kumar Mukkamalla 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 Jamil A, Mukkamalla SKR. Lymphoma. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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RELATED TOPICS

INTRODUCTION

This topic will review the clinical presentation and initial evaluation of a patient with suspected NHL.

Classification of NHL and the general pretreatment evaluation, staging, and response assessment in lymphomas are discussed separately. (See "Classification of hematopoietic neoplasms" and "Pretreatment evaluation and staging of non-Hodgkin lymphomas" .)

Treatment and prognosis of specific subtypes of NHL are discussed in those particular topics.

CLINICAL PRESENTATION

General  —  The clinical presentation of NHL varies with the histologic subtype and sites of involvement. Some subtypes of NHL manifest variable lymphadenopathy for years, while others are highly aggressive and can cause death within weeks, if untreated. Even within a specific NHL subtype, the clinical presentation varies widely between individual patients. (See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms' .)