Background

Hodgkin lymphoma (HL), originally named Hodgkin’s disease, is an uncommon monoclonal lymphoid tumor with high rates of recovery. Through multiple clinical and biological investigations, this disease has been classified into nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma.

The clinical presentation and pathology of these two diseases are distinctly different. Almost all (95%) cases of Hodgkin lymphoma are attributed to classical Hodgkin lymphoma.

This disease is further divided into the following four subgroups:

• Nodular Sclerosis Hodgkin lymphoma
• Lymphocyte depleted Hodgkin lymphoma
• Lymphocyte-rich Hodgkin lymphoma
• Mixed Cellularity Hodgkin lymphoma

Hodgkin lymphomas have 4 distinct features which can be used to identify the disease:

• Young adults are more prone to this disease
• They often grow in cervical lymph nodes
• Large mononuclear Hodgkin cells are scattered around with multinucleated cells in a mixture of non-neoplastic cells
• T-lymphocytes are regularly found around neoplastic cells

4 out of 5 patients recover from Hodgkin Lymphoma, and it has a generally favorable prognosis for most patients.

Epidemiology

Hodgkin lymphoma is an uncommon malignancy in the United States, with an estimated incidence rate of 2.6 occurrences per 100,000 individuals. The disease accounts for 11% of all lymphomas diagnosed in the United States.

It has a bimodal distribution, with most affected patients being between the ages of 20 and 40, and another peak occurring between the ages of 55 and older. It is more prevalent in males than females, particularly in children, where 85 percent of occurrences occur in boys.

Hodgkin lymphoma with nodular sclerosis is more prevalent in young persons, whereas mixed cellularity Hodgkin lymphoma is more prevalent in older adults.

Given below is the incidence rates of all the subtypes of Classical Hodgkin lymphoma:

• Nodular sclerosis classical HL (70%)
• Mixed cellularity classical HL (25%)
• Lymphocyte-rich classical HL (5%)
• Lymphocyte-depleted classical HL (>1%)

Nodular lymphocyte-predominant Hodgkin lymphoma, accounts for around 5% of all Hodgkin lymphomas.

Anatomy

Pathophysiology

Unique neoplastic cells are present in both the classical and NLP-HL types of Hodgkin lymphoma. The Reed-Sternberg (RS) cell is a giant multinucleated neoplastic cell with two mirror-image nuclei inside a reactive cellular background.

For classical HL, the RS cell is pathognomonic. RS cells are produced from B cells with mutations in the IgH-variable region portion of the germinal center. Cytokines such as IL-5 and transforming growth factor-beta are secreted by the RS in order to recruit reactive cells. RS cells are often aneuploid, with no discernible cytogenetic abnormalities.

In the majority of isolated RS cells, conformational changes have been identified in the clonal lg gene. Immunohistochemistry stains for RS cells are positive for CD30, CD15, but typically negative for CD20 and CD45 that are positive only in neoplastic NLP-HL cells. In addition to CD15 and CD30, RS cells are usually positive for PAX5, CD25, HLA-DR, ICAM-1, Fascin, CD95 (apo-1/fas), TRAF1, CD40, and CD86. There are RS cell variants that include the Hodgkin cell, mummified cells, and lacunar cells. Hodgkin cells are mononuclear RS-cell variants.

Mummified cells show condensed cytoplasm and pyknotic reddish nuclei with smudgy chromatin. Lacunar cells have multilobulated nuclei, small nucleoli, and abundant, pale cytoplasm that often retracts during tissue fixation and sectioning, leaving the nucleus in what appears to be empty space (lacune-like space).

On the other hand, NLP-HL lacks the typical RS cells but has lymphocytic and histiocytic cells, which are characterized by larger cells with folded multilobulated nuclei (also known as “popcorn cells” or LP cells). The LP cells show a nucleus with multiple nucleoli that are basophilic and smaller than those seen in RS cells.

LP cells show clonally rearranged immunoglobulin genes that are only detected in isolated single LP cells. The LP cells are usually positive for C020, CD45, EMA, CD79a, CD75, BCL6, BOB.1, OCT2, and J chain.

Etiology

Hodgkin lymphoma’s exact cause is uncertain. However, Epstein-Barr virus (EBV) infection, autoimmune disorders, and immunosuppression all raise the chance of Hodgkin lymphoma. In Hodgkin lymphoma, there is additional evidence of a hereditary tendency. EBV was shown to be more prevalent in Hodgkin lymphoma subtypes with mixed cellularity and Hodgkin lymphomas which present lower levels of lymphocytes.

Immune deficiency has been considered as a probable cause of EBV-positive illness. No other virus has been identified as having a significant influence in the pathogenesis of Hodgkin lymphoma.  Immunosuppression as a result of solid organ or hematopoietic cell transplantation, immunosuppressive medication therapy, or HIV infection all increase the chance of developing Hodgkin lymphoma.

HIV patients frequently present with an advanced stage of the infection, atypical lymph node locations, and a disappointing prognosis. Studies have discovered a tenfold increase in the risk of developing HL among same-sex siblings of Hodgkin lymphoma patients, implying that certain gene-environments are predisposed to developing Hodgkin lymphoma.

Genetics

Prognostic Factors

The prognoses of Hodgkin lymphoma cases are often decided based on 3 subgroups. The first stage, called the “Early-stage favorable”, in which the patient can be in the first or second stage of the disease without presenting any unfavorable risk factor.

The second sub-group also includes the first and second stage of Hodgkin lymphoma but with unfavorable risk factors. These include:

• The present of 3 or more lymph nodes
• A mass in the chest covering 1/3rd of the chest-width, or any lymph node that is larger than 10cm in length
• Presence of disease affecting an organ outside the lymphatic system
• Erythrocyte sedimentation rate above 50%
• Symptoms such as fever, night sweats, or over 10% weight loss within 6 months

The last stage is the advanced stage, with the disease being in stage III or IV. The risk factors associated with this stage are:

• Male Gender
• Age 45<
• Stage IV of the disease
• Hemoglobin level: <10.5g/dL
• Leukocytosis: condition in which the white blood count is over 15,000/mm³
• Lymphocytopenia: condition in which the white blood cell count is 8% or more higher than the lymphocyte count, and/or the lymphocyte count is under 600/mm³

Clinical History

Age Group: 

• Young Adults (15-35 years): Hodgkin lymphoma often peaks in this age range. Common presentations include painless, firm lymph node enlargement, often in the neck, armpit, or groin. Systemic symptoms like fever, night sweats, and weight loss (B symptoms) are frequently observed. 
• Middle-aged and Older Adults (36-60 years): While Hodgkin lymphoma can occur in this age group, it is less common. The presentation may be similar to that in young adults, with lymph node enlargement and B symptoms. 
• Elderly (>60 years): Hodgkin lymphoma is less common in the elderly, and when it occurs, it may present with atypical features. Because the symptoms might be confusing for other age-related illnesses, making the diagnosis can be difficult. 

Associated Comorbidities or Activities: 

• Immunocompromised Individuals: Individuals who have recently received an organ transplant or who have HIV/AIDS may be more susceptible to Hodgkin lymphoma due to compromised immune systems. 
• Prior History of Cancer: Individuals with a history of certain cancers may be at a slightly increased risk of developing Hodgkin lymphoma. 
• Autoimmune Diseases: There may be an association between Hodgkin lymphoma and certain autoimmune diseases, although the relationship is not fully understood. 

Acuity of Presentation: 

• Chronic/Insidious Onset: Hodgkin lymphoma often has an indolent or gradual onset. Patients may notice painless lymph node enlargement over weeks to months. B symptoms (fever, night sweats, weight loss) may develop gradually. 
• Acute Onset: In some cases, especially when there is compression or invasion of nearby structures, symptoms may have a more acute onset. Examples of symptoms that may arise from mediastinal involvement include cough, chest discomfort, and dyspnea. 
• Symptomatic Systemic Features: B symptoms (fever, night sweats, weight loss) are considered systemic symptoms and, when present, may indicate a more aggressive form of the disease. 

Physical Examination

Lymph Node Examination: 

• Palpation: Healthcare providers will carefully palpate lymph nodes in different regions of the body, including the neck, armpits, and groin. Enlarged lymph nodes in Hodgkin lymphoma are often firm, rubbery, and painless. 
• Location and Size: Noted are the size and location of swollen lymph nodes. Lymphadenopathy that is confined and painless is a common symptom of Hodgkin lymphoma. 

Examination of Other Organs: 

• Spleen: The spleen may be palpated to check for enlargement. Splenomegaly can occur in some cases of Hodgkin lymphoma. 
• Liver: The liver may be examined to assess for hepatomegaly (enlargement). Hepatomegaly can occur in advanced cases. 

Skin Examination: 

• Skin Changes: In some cases, Hodgkin lymphoma can cause specific skin changes, such as reddish or purplish patches or nodules. This is known as cutaneous involvement. 

Respiratory Examination: 

• Chest Examination: If there is suspicion of mediastinal involvement, a thorough chest examination may be performed. This could include assessing for signs of respiratory distress, dullness on percussion, or decreased breath sounds. 

Neurological Examination: 

• Neurological Signs: If there is involvement of the central nervous system or nerve roots, there might be neurological signs such as weakness, sensory changes, or reflex abnormalities. 

B Symptoms: 

• Assessment for B Symptoms: Evaluate B symptoms, such as inexplicable fever, intense night sweats, and inadvertent weight loss, since these may point to a more severe type of Hodgkin lymphoma. 

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

• Non-Hodgkin Lymphoma (NHL): Non-Hodgkin lymphomas are a group of lymphatic system cancers that share some similarities with Hodgkin lymphoma but have distinct characteristics. 
• Infectious Diseases: Some infectious diseases, such as infectious mononucleosis (caused by the Epstein-Barr virus) or cytomegalovirus infection, can cause lymph node enlargement and symptoms similar to Hodgkin lymphoma. 
• Granulomatous Diseases: Conditions like sarcoidosis or tuberculosis can cause granulomas, leading to swollen lymph nodes and sometimes mimicking the appearance of Hodgkin lymphoma. 
• Castleman Disease: This rare disorder involves the abnormal growth of lymphocytes and can cause lymph node enlargement. It may share some clinical features with Hodgkin lymphoma. 
• Metastatic Cancer: Lymphadenopathy can be a manifestation of metastatic cancer from other primary sites, and distinguishing primary Hodgkin lymphoma from secondary involvement is crucial. 
• HIV/AIDS: Individuals with HIV/AIDS may develop lymphomas, and the presentation can overlap with Hodgkin lymphoma. HIV-related lymphomas may require specific considerations in diagnosis and management. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Staging: Accurate staging is crucial to determine the extent of the disease. Staging often includes imaging studies such as CT scans and PET-CT scans, bone marrow biopsy, and other tests. 

Risk Stratification: Based on the stage of the disease and other factors, patients may be stratified into different risk groups, such as low-risk, intermediate-risk, or high-risk. This helps guide treatment decisions. 

Chemotherapy: The standard first-line chemotherapy for Hodgkin lymphoma is the ABVD regimen, which includes the drugs doxorubicin, bleomycin, vinblastine, and dacarbazine. This regimen is typically administered over several months. 

Radiation Therapy: In some cases, especially for early-stage disease, radiation therapy may be used after chemotherapy to target specific involved lymph node regions. 

Autologous Stem Cell Transplantation: This involves high-dose chemotherapy followed by the infusion of the patient’s own previously collected stem cells. 

Immunotherapy: 

• Brentuximab Vedotin: This combination of antibody and medication targets CD30, a protein found on the outermost layer of Reed-Sternberg and Hodgkin cells. It may be used in specific cases, including relapsed or refractory disease. 

Checkpoint Inhibitors: 

• Nivolumab or Pembrolizumab: Checkpoint inhibitors, such as nivolumab or pembrolizumab, may be used in certain cases, particularly for relapsed or refractory disease. These drugs target the PD-1 receptor on lymphoma cells. 

Novel Agents: 

• Brentuximab Vedotin and Nivolumab Combination: Some patients may receive combination therapies, such as brentuximab vedotin and nivolumab, in specific clinical situations. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

use-of-a-non-pharmacological-approach-for-treating-hodgkin-lymphoma

• Nutritional Support: Ensuring proper nutrition is crucial during cancer treatment.To cater to the unique requirements of patients receiving treatment, a licensed dietitian can assist in creating a tailored nutrition plan. 
• Exercise and Physical Activity: Regular exercise, as recommended by healthcare providers, can help manage fatigue, improve mood, and enhance overall well-being. It’s important to tailor the exercise routine to the individual’s capabilities and consult with healthcare professionals before starting any new exercise program. 
• Mind-Body Techniques: Mindfulness meditation, yoga, and relaxation techniques can help reduce stress, anxiety, and improve the overall mental well-being of individuals undergoing treatment. 
• Psychosocial Support: Psychosocial therapies such as counseling and support groups can offer emotional support and assist patients in managing the difficulties associated with receiving a cancer diagnosis and undergoing treatment. 
• Acupuncture and Massage: Some individuals find relief from symptoms such as nausea, pain, and fatigue through complementary therapies like acupuncture or massage. These should be discussed with healthcare providers to ensure they are safe and appropriate. 
• Fatigue Management: Strategies to manage cancer-related fatigue may include pacing activities, prioritizing tasks, and getting adequate rest. Occupational therapists can provide guidance on energy conservation techniques. 
• Sleep Hygiene:During and after treatment, maintaining healthy sleep hygiene can help with fatigue management and general well-being. 

• Social Support: Sustaining robust social ties with loved ones might offer psychological assistance and mitigate sentiments of seclusion. Support from loved ones is an essential component of the healing process. 

Role of Antineoplastics, Alkylating for treating Hodgkin lymphoma

Antineoplastic agents, particularly alkylating agents, play a significant role in the treatment of Hodgkin lymphoma. A family of chemotherapy medications known as alkylating agents tamper with cancer cells’ DNA to stop them from proliferating and dividing They are commonly used in combination with other chemotherapy drugs in various treatment regimens for Hodgkin lymphoma.  

• Mechlorethamine (Mustargen): It is an alkylating agent that forms cross-links within DNA strands, disrupting DNA replication and leading to cell death. It has been used historically in the treatment of Hodgkin lymphoma, but its use has decreased due to the development of newer agents with improved toxicity profiles. 
• Cyclophosphamide (Cytoxan): It is an alkylating agent that interferes with DNA synthesis and repair by forming cross-links. It is commonly used in combination chemotherapy regimens for Hodgkin lymphoma, such as the ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine). It contributes to the overall effectiveness of the treatment. 

Role of Antineoplastics, Antibiotic for treating Hodgkin lymphoma

In the treatment of Hodgkin lymphoma, antibiotics with antineoplastic properties are sometimes used as part of combination chemotherapy regimens. One such example is bleomycin. Bleomycin is an antibiotic that has antineoplastic effects and is commonly used in combination with other chemotherapy drugs for the treatment of Hodgkin lymphoma. 

Bleomycin: It functions by inducing DNA strand breaks, leading to inhibition of DNA synthesis and ultimately causing cell death. It has a specific affinity for the G-C base pairs in DNA. 

• Bleomycin is a key component of the ABVD regimen, which is a standard and widely used chemotherapy regimen for Hodgkin lymphoma. 
• ABVD stands for doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine. 
• It is particularly effective against Hodgkin and Reed-Sternberg cells, the characteristic cells found in Hodgkin lymphoma. 

Bleomycin is typically administered intravenously, and the dose and schedule are determined by the specific chemotherapy regimen being used. 

Role of Antineoplastics, Vinca Alkaloid for treating Hodgkin lymphoma 

Vinca alkaloids are a class of antineoplastic agents that are derived from the periwinkle plant (Vinca rosea). By preventing the development of microtubules, which are necessary for the segregation of chromosome during cell division, they obstruct cell division. Vinca alkaloids are often used in combination with other chemotherapy drugs to treat various cancers, including Hodgkin lymphoma.  

• Vincristine: It disrupts the mitotic spindle, preventing proper cell division and leading to cell death. It is considered a microtubule destabilizing agent.It is a component of several chemotherapy regimens used in the treatment of Hodgkin lymphoma. One of the common regimens is ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), where vincristine, along with other agents, contributes to the overall efficacy of the treatment. It is typically administered intravenously. 

Role of Antineoplastics, Podophyllotoxin Derivatives for treating Hodgkin lymphoma

Podophyllotoxin derivatives are a class of antineoplastic agents that are derived from the roots of the Mayapple plant (Podophyllum peltatum). These agents interfere with cell division by inhibiting the action of topoisomerase II, an enzyme involved in DNA replication. Podophyllotoxin derivatives are used in the treatment of various cancers, including Hodgkin lymphoma. The most notable podophyllotoxin derivative used in Hodgkin lymphoma treatment is etoposide.  

• Etoposide: It inhibits topoisomerase II, an enzyme essential for DNA replication and repair. By interfering with this process, etoposide induces breaks in the DNA strands and prevents cancer cells from dividing and proliferating. Etoposide is often incorporated into chemotherapy regimens for Hodgkin lymphoma, especially in combination with other agents. It is commonly used in regimens for both initial treatment and in salvage therapy for relapsed or refractory cases.It can be administered orally or intravenously, depending on the specific treatment protocol. 

Role of Antineoplastics, Alkylating, DMARDs, Immunomodulators for treating Hodgkin lymphoma 

The mainstays of treatment for Hodgkin lymphoma include radiation therapy, chemotherapy, and occasionally, stem cell transplantation. Among the various classes of drugs used in the treatment of Hodgkin lymphoma, alkylating agents, disease-modifying antirheumatic drugs (DMARDs), and immunomodulators play specific roles. 

• Cyclophosphamide (Cytoxan): It is often used in combination chemotherapy regimens for Hodgkin lymphoma, such as the ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine). 

Role of Immunosuppressants; Antineoplastics, Antimetabolite; DMARDs, Immunomodulators for treating Hodgkin lymphoma

Antimetabolite antineoplastic drugs disrupt cellular activities by competing for receptor or enzymes involved in DNA synthesis. The tissues most susceptible to the impacts are those with high rates of cellular metabolism. 

• Methotrexate: The antimetabolite methotrexate prevents the enzyme dihydrofolate reductase from working, which is required to transform folate into tetrahydrofolate, which is physiologically active. 

Role of Antineoplastics, Anthracyclines for treating Hodgkin lymphoma

Anthracyclines are a class of antineoplastic agents commonly used in the treatment of Hodgkin lymphoma. They are known for their ability to interfere with DNA replication and inhibit the growth of cancer cells. Anthracyclines are often included in combination chemotherapy regimens for Hodgkin lymphoma due to their effectiveness. Anthracyclines, such as doxorubicin and epirubicin, exert their anticancer effects by intercalating with DNA, inhibiting topoisomerase II, and generating free radicals that cause DNA damage. These actions ultimately lead to cell cycle arrest and apoptosis (programmed cell death). 

• Doxorubicin (Adriamycin): It is a widely used anthracycline in the treatment of Hodgkin lymphoma. Typically administered intravenously as part of combination chemotherapy regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or other variations. 

Role of PD-1/PD-L1 Inhibitors for treating Hodgkin lymphoma

PD-L1 is frequently overexpressed by malignant Reed-Sternberg cells, which aids in immune evasion. Inhibitors of PD-1/PD-L1 interfere with this relationship, making it easier for the immune system to find and eliminate cancer cells. PD-1/PD-L1 inhibitors block the PD-1 receptor on T cells or PD-L1 on cancer cells, preventing the suppression of the immune response. PD-1/PD-L1 inhibitors are primarily used in relapsed or refractory Hodgkin lymphoma, where traditional treatments have been less effective. 

• Nivolumab (Opdivo): Treatment for relapsed or resistant classical Hodgkin lymphoma involves the use of PD-1 inhibitors. 
• Pembrolizumab (Keytruda): It is another PD-1 inhibitor with activity against Hodgkin lymphoma. 

use-of-intervention-with-a-procedure-in-treating-hodgkin-lymphoma

• Biopsy: Often, a biopsy is done to confirm the Hodgkin lymphoma diagnosis. A little portion of tissues from an expanded lymphatic node or other afflicted region must be removed in order to be examined under a microscope. 
• Bone Marrow Biopsy: To determine when the lymphoma has progressed to the bone marrow, a biopsy of the bone marrow may be necessary. A little portion of bone marrow is taken out of the hip bone so that it may be examined. 
• Lymph Node Biopsy: A lymph nodes biopsy may be done to confirm the diagnosis as well as to assess the degree of cancer involvement and inform therapy choices. 
• PET-CT Scan: A PET-CT scan combines positron emission tomography (PET) and computed tomography (CT) imaging to assess the extent of disease involvement and to aid in staging and treatment planning. 
• Central Venous Catheter Placement:  In patients requiring chemotherapy, especially those with difficult venous access or anticipated long-term treatment, a central venous catheter (such as a port or PICC line) may be inserted to facilitate administration of chemotherapy drugs and other medications. 
• Stem Cell Collection:  For patients undergoing high-dose chemotherapy followed by autologous stem cell transplantation, stem cells may be collected from the patient’s blood or bone marrow using a procedure called apheresis. 
• Radiation Therapy: It is used to kill cancer cells. It may be used as part of the treatment regimen for Hodgkin lymphoma, particularly in cases where the disease is localized to specific areas. 
• Surgical Intervention: While surgery is not typically the primary treatment for Hodgkin lymphoma, it may be used in some instances for diagnostic purposes, to remove localized masses, or to address complications such as a blocked airway or bowel obstruction. 
• Thoracentesis or Paracentesis: In cases where Hodgkin lymphoma has caused fluid accumulation in the chest (pleural effusion) or abdomen (ascites), procedures such as thoracentesis or paracentesis may be performed to drain the fluid and relieve symptoms. 

use-of-phases-in-managing-hodgkin-lymphoma

Diagnostic Phase: The diagnostic phase involves obtaining a definitive diagnosis of Hodgkin lymphoma through various tests, including biopsies, imaging studies (such as CT scans and PET-CT scans), and laboratory tests. During this phase, healthcare providers perform a comprehensive evaluation to confirm the presence of Hodgkin lymphoma, determine the subtype, assess the extent of disease involvement (staging), and establish baseline parameters for treatment planning. 

Staging Phase: Staging involves determining the extent of Hodgkin lymphoma spread throughout the body. Accurate staging helps guide treatment decisions and prognosis. Staging typically involves the combination of imaging studies (such as CT scans, PET-CT scans, and sometimes MRI scans), bone marrow biopsy, and other tests to assess lymph node involvement and detect potential spread to other organs or tissues. 

Treatment Planning Phase: Healthcare professionals create a personalized treatment plan for each patient throughout the course of treatment planning phase, taking into account the patient’s general health, illness stage, treatment objectives, and other variables. Treatment planning may involve multidisciplinary discussions among oncologists, hematologists, radiation oncologists, and other specialists to determine the most appropriate treatment approach. Immunotherapy, radiation therapy, chemotherapy, or a mix of these treatments may be part of the selected course of care. 

Treatment Phases: 

• Induction Therapy: The initial phase of treatment, often referred to as induction therapy, aims to achieve remission by reducing the bulk of the tumor and eliminating cancer cells. 
• Consolidation Therapy: Following induction therapy, consolidation therapy may be administered to further eradicate residual cancer cells and reduce the risk of disease recurrence. 
• Maintenance Therapy: In some cases, maintenance therapy may be recommended to prolong remission and prevent relapse. 
• Salvage Therapy: For patients who experience disease relapse or do not achieve remission with initial treatment, salvage therapy may be administered to induce remission before considering additional treatment options, such as stem cell transplantation. 

Monitoring and Surveillance Phase: After completing active treatment, patients enter a phase of monitoring and surveillance to detect and manage any signs of disease recurrence or treatment-related complications. Regular follow-up visits, imaging studies, laboratory tests, and physical examinations are performed to monitor the patient’s response to treatment, assess for recurrence, and manage any long-term side effects or late effects of treatment. 

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References

Hodgkin Lymphoma:ncbi.nlm.nih