Lymphoma – Causes, Symptoms, Diagnosis, Treatment

Lymphoma – Causes, Symptoms, Diagnosis, Treatment

Lymphoma 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. 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%.

Lymphoma is a group of blood malignancies that develop from lymphocytes (a type of white blood cell).[rx] The name often refers to just the cancerous versions rather than all such tumours.[rx] Signs and symptoms may include enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired. The enlarged lymph nodes are usually painless.[rx] The sweats are most common at night.[rx][rx]

Types of Lymphoma

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).

Below is the revised 2016 revised WHO classification of lymphomas.

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 B-cell lymphoma/leukemia, unclassifiable

    • Splenic diffuse red pulp small B-cell lymphoma
    • Hairy cell leukemia-variant
  •  Lymphoplasmacytic lymphoma

    • 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)
  •  Nodal marginal zone lymphoma

    • Pediatric nodal marginal zone lymphoma
  •  Follicular 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
  •  Mantle cell lymphoma

    • In situ mantle cell neoplasia
  •  Diffuse large B-cell lymphoma (DLBCL), NOS

    • 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+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
  •  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
  •  Primary cutaneous CD30+ T-cell lymphoproliferative disorders

    • 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

WHO classification

The WHO classification, published in 2001 and updated in 2008,[rx][3rx] is based upon the foundations laid within the “revised European-American lymphoma classification” (REAL). This system groups lymphomas by cell type (i.e. the normal cell type that most resembles the tumor) and defining phenotypic, molecular, or cytogenetic characteristics. The five groups are shown in the table. Hodgkin lymphoma is considered separately within the WHO and preceding classifications, although it is recognized as being a tumor, albeit markedly abnormal, of lymphocytes of mature B cell lineage.

Of the many forms of lymphoma, some are categorized as indolent (e.g. small lymphocytic lymphoma), compatible with a long life even without treatment, whereas other forms are aggressive (e.g. Burkitt’s lymphoma), causing rapid deterioration and death. However, most of the aggressive lymphomas respond well to treatment and are curable. The prognosis, therefore, depends on the correct diagnosis and classification of the disease, which is established after examination of a biopsy by a pathologist (usually a hematopathologist).[rx]

Lymphoma subtypes (WHO 2008)

Mature B cell neoplasms

DNA-microarray analysis of Burkitt’s lymphoma and diffuse large B-cell lymphoma (DLBCL) showing differences in gene expression patterns. Colors indicate levels of expression; green indicates genes that are underexpressed in lymphoma cells (as compared to normal cells), whereas red indicates genes that are overexpressed in lymphoma cells.

  • B-cell chronic lymphocytic leukemia/small cell lymphoma
3 to 4% of lymphomas in adults
Small resting lymphocytes mixed with variable numbers of large activated cells, lymph nodes diffusely effaced
CD5, surface immunoglobulin
5-year survival rate 50%.[rx]
Occurs in older adults, usually involves lymph nodes, bone marrow and spleen, most patients have peripheral blood involvement, indolent
  • B-cell prolymphocytic leukemia
  • Lymphoplasmacytic lymphoma (such as Waldenström macroglobulinemia)
  • Splenic marginal zone lymphoma
  • Hairy cell leukemia
  • Plasma cell neoplasms:
    • Plasma cell myeloma (also known as multiple myeloma)
    • Plasmacytoma
    • Monoclonal immunoglobulin deposition diseases
    • Heavy chain diseases
  • Extranodal marginal zone B cell lymphoma, also called MALT lymphoma
About 5% of lymphomas in adults
Variable cell size and differentiation, 40% show plasma cell differentiation, homing of B cells to epithelium creates lymphoepithelial lesions.
CD5, CD10, surface Ig
Frequently occurs outside lymph nodes, very indolent, may be cured by local excision
  • Nodal marginal zone B cell lymphoma
  • Follicular lymphoma
About 40% of lymphomas in adults
Small “cleaved” [cleft] cells (centrocytes) mixed with large activated cells (centroblasts), usually nodular (“follicular”) growth pattern
CD10, surface Ig
About 72–77%
Occurs in older adults, usually involves lymph nodes, bone marrow and spleen, associated with t(14;18) translocation overexpressing Bcl-2, indolent
  • Primary cutaneous follicle center lymphoma
  • Mantle cell lymphoma
About 3 to 4% of lymphomas in adults
Lymphocytes of small to intermediate size growing in diffuse pattern
About 50[35] to 70%
Occurs mainly in adult males, usually involves lymph nodes, bone marrow, spleen and GI tract, associated with t(11;14) translocation overexpressing cyclin D1, moderately aggressive
  • Diffuse large B cell lymphoma, not otherwise specified
About 40 to 50% of lymphomas in adults
Variable, most resemble B cells of large germinal centers, diffuse growth pattern
Variable expression of CD10 and surface Ig
Five-year survival rate 60%[rx]
Occurs in all ages, but most commonly in older adults, may occur outside lymph nodes, aggressive
  • Diffuse large B-cell lymphoma associated with chronic inflammation
  • Epstein–Barr virus-positive DLBCL of the elderly
  • Lymphomatoid granulomatosis
  • Primary mediastinal (thymic) large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • ALK+ large B-cell lymphoma
  • Plasmablastic lymphoma
  • Primary effusion lymphoma
  • Large B-cell lymphoma arising in HHV8-associated multicentric Castleman’s disease
  • Burkitt lymphoma/leukemia < 1% of lymphomas in the United States Round lymphoid cells of intermediate size with several nucleoli, starry-sky appearance by diffuse spread with interspersed apoptosis CD10, surface Ig Five-year survival rate 50%[rx] . Endemic in Africa, sporadic elsewhere, more common in immunocompromised and children, often visceral involvement, highly aggressive
Mature T cell and natural killer (NK) cell neoplasms
  • T-cell prolymphocytic leukemia
  • T-cell large granular lymphocyte leukemia
  • Aggressive NK cell leukemia
  • Adult T-cell leukemia/lymphoma
  • Extranodal NK/T-cell lymphoma, nasal type
  • Enteropathy-associated T-cell lymphoma
  • Hepatosplenic T-cell lymphoma
  • Blastic NK cell lymphoma
  • Mycosis fungoides/Sezary syndrome – Most common cutaneous lymphoid malignancy Usually small lymphoid cells with convoluted nuclei that often infiltrate the epidermis, creating Pautrier microabscesseses CD4 5-year survival 75%. Localized or more generalized skin symptoms, generally indolent, in a more aggressive variant, Sézary’s disease, skin erythema and peripheral blood involvement
  • Primary cutaneous CD30-positive T cell lymphoproliferative disorders. Primary cutaneous anaplastic large cell lymphoma. Lymphomatoid papulosis
  • Peripheral T-cell lymphoma not otherwise specified. Most common T cell lymphoma Variable, usually a mix small to large lymphoid cells with irregular nuclear contours CD3. Probably consists of several rare tumor types, often disseminated and generally aggressive
  • Angioimmunoblastic T cell lymphoma
  • Anaplastic large cell lymphoma
Precursor lymphoid neoplasms
  • B-lymphoblastic leukemia/lymphoma not otherwise specified
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
  • T-lymphoblastic leukemia/lymphoma 15% of childhood acute lymphoblastic leukemia and 90% of lymphoblastic lymphoma. Lymphoblasts with irregular nuclear contours, condensed chromatin, small nucleoli and scant cytoplasm without granules TdT, CD2, CD7. It often presents as a mediastinal mass because of involvement of the thymus. It is highly associated with NOTCH1 mutations, and is most common in adolescent males.
Hodgkin lymphoma
  • Classical Hodgkin lymphomas:
    • Nodular sclerosis form of Hodgkin lymphoma
Most common type of Hodgkin lymphoma
Reed-Sternberg cell variants and inflammation, usually broad sclerotic bands that consist of collagen
CD15, CD30
Most common in young adults, often arises in the mediastinum or cervical lymph nodes
    • Mixed cellularity Hodgkin lymphoma
Second-most common form of Hodgkin lymphoma
Many classic Reed-Sternberg cells and inflammation
CD15, CD30
Most common in men, more likely to be diagnosed at advanced stages than the nodular sclerosis form Epstein-Barr virus involved in 70% of cases
    • Lymphocyte-rich
    • Lymphocyte depleted or not depleted
  • Nodular lymphocyte-predominant Hodgkin lymphoma

Immunodeficiency-associated lymphoproliferative disorders

  • Associated with a primary immune disorder
  • Associated with the human immunodeficiency virus (HIV)
  • Post-transplant
  • Associated with methotrexate therapy
  • Primary central nervous system lymphoma occurs most often in immunocompromised patients, in particular those with AIDS, but it can occur in the immunocompetent, as well. It has a poor prognosis, particularly in those with AIDS. Treatment can consist of corticosteroids, radiotherapy, and chemotherapy, often with methotrexate.
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Causes of Lymphoma

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 burgdorferiChlamydia psittaciCampylobacter 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.
  • Immunodeficiency – HIV infection, transplant recipients, and those with genetic immunodeficiency disorders (severe combined immunodeficiency and common variable immunodeficiency).
  • 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.

Symptoms of Lymphoma

The lymph nodes where lymphoma most commonly develops

Lymphoma and lymphatic system. Lymphoma may present with certain nonspecific symptoms; if the symptoms are persistent, an evaluation to determine their cause, including possible lymphoma, should be undertaken.

  • Lymphadenopathy[rx][rx] or swelling of lymph nodes, is the primary presentation in lymphoma. It is generally painless.
  • B symptoms (systemic symptoms) – can be associated with both Hodgkin lymphoma and non-Hodgkin lymphoma. They consist of:
    • Fever
    • Night sweats
    • Weight loss
  • Other symptoms:
    • Anemia, bleeding, increase susceptibility to infections
    • Loss of appetite or anorexia
    • Fatigue
    • Respiratory distress or dyspnea
    • Itching
    • Swollen glands (lymph nodes), often in the neck, armpit, or groin that are painless
    • Cough
    • Shortness of breath
    • Fever
    • Night sweats
    • Fatigue
    • Weight loss

Other symptoms of both types of lymphoma may include:

  • ongoing fever without infection
  • night sweats, fever, and chills
  • weight loss and reduced appetite
  • unusual itching
  • persistent fatigue or a lack of energy
  • pain in lymph nodes after drinking alcohol
  • Soaking night sweats
  • Coughing, trouble breathing or chest pain
  • Weakness and tiredness that don’t go away

Some additional symptoms of non-Hodgkin lymphoma include:

  • persistent coughing
  • shortness of breath
  • pain or swelling in the abdomen

Asymptomatic soft swelling, which may or may not be ulcerated, is primarily seen on the tonsils, buccal mucosa, palate, gums, salivary glands, tongue, floor of the mouth, and retromolar region.

Diagnosis of Lymphoma


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.

History and Physical

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.

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.

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.

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.

Mantle Cell 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.


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. 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. 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.

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.

Treatment of Lymphoma

  • Biologic therapy – This is a drug treatment that stimulates the immune system to attack the cancer. The drug achieves this by introducing living microorganisms into the body.
  • Antibody therapy – A medical professional inserts synthetic antibodies into the bloodstream. These respond to the cancer’s toxins.
  • Chemotherapy – A healthcare team administers aggressive drug treatment to target and kill cancer cells.
  • Radioimmunotherapy – This delivers high powered radioactive doses directly into cancerous B cells and T-cells to destroy them.
  • Radiation therapy – A doctor may recommend this type of therapy to target and destroy small areas of cancer. Radiation therapy uses concentrated doses of radiation to kill cancerous cells.
  • Stem cell transplantation – This can help restore damaged bone marrow following high dose chemotherapy or radiation therapy.
  • Steroids – A doctor may inject steroids to treat lymphoma.
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Hodgkin Lymphoma

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.

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

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. 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.

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).

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.

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.

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.

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

Follicular Lymphoma

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.

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.

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.

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.

Marginal Zone Lymphoma

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.

Mantle Cell Lymphoma

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.

Burkitt Lymphoma

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%.

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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.

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.


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:

Stage I

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)

Stage II

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)

Stage III

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)

Stage IV

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


  • 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)
  • 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 leukemiaacute lymphoblastic leukemia).
  • Radiotherapy Complications – Accelerated atherosclerosis, pericardial fibrosis, second primary cancers (lung, thyroid, breast, soft tissue sarcomas), and hypothyroidism


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