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. 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.
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)
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.
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
Mature T and NK neoplasms
Nodular lymphocyte-predominant Hodgkin lymphoma
Classical Hodgkin lymphoma
Posttransplant lymphoproliferative disorders (PTLD)
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. 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.
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.
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.
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.
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.
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.
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).
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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%.
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.
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;
Consensus recommendations/guidelines from the International Lymphoma Radiation Oncology Group (ILROG):
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 symptoms
B: Fever (temperature > 38 C), drenching night sweats, unexplained loss of more than 10% of body weight during the previous six months.
X: Bulky disease
E: Involvement of an extranodal site that is contiguous or proximal to the known nodal site
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.
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)
Transformation of indolent lymphomas such as follicular lymphoma, marginal zone lymphoma into more aggressive NHL such as diffuse large B-cell lymphoma
Pancytopenias, sterility, cardiomyopathy(doxorubicin), pneumonitis (bleomycin), neuropathy (vincristine, brentuximab vedotin), and second primary malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia).
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.
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.
|||Mugnaini EN,Ghosh N, Lymphoma. Primary care. 2016 Dec; [PubMed PMID: 27866584]|
|||Matasar MJ,Zelenetz AD, Overview of lymphoma diagnosis and management. Radiologic clinics of North America. 2008 Mar; [PubMed PMID: 18619375]|
|||Hjalgrim H,Askling J,Rostgaard K,Hamilton-Dutoit S,Frisch M,Zhang JS,Madsen M,Rosdahl N,Konradsen HB,Storm HH,Melbye M, Characteristics of Hodgkin's lymphoma after infectious mononucleosis. The New England journal of medicine. 2003 Oct 2 [PubMed PMID: 14523140]|
|||Said W,Chien K,Takeuchi S,Tasaka T,Asou H,Cho SK,de Vos S,Cesarman E,Knowles DM,Koeffler HP, Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) in primary effusion lymphoma: ultrastructural demonstration of herpesvirus in lymphoma cells. Blood. 1996 Jun 15 [PubMed PMID: 8652805]|
|||Biggar RJ,Jaffe ES,Goedert JJ,Chaturvedi A,Pfeiffer R,Engels EA, Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood. 2006 Dec 1 [PubMed PMID: 16917006]|
|||[PubMed PMID: 6896167]|
|||[PubMed PMID: 26980727]|
|||[PubMed PMID: 9704731]|
|||Mauch PM,Kalish LA,Kadin M,Coleman CN,Osteen R,Hellman S, Patterns of presentation of Hodgkin disease. Implications for etiology and pathogenesis. Cancer. 1993 Mar 15 [PubMed PMID: 8443755]|
|||Montoto S,Davies AJ,Matthews J,Calaminici M,Norton AJ,Amess J,Vinnicombe S,Waters R,Rohatiner AZ,Lister TA, Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007 Jun 10 [PubMed PMID: 17485708]|
|||Piekarz RL,Frye R,Prince HM,Kirschbaum MH,Zain J,Allen SL,Jaffe ES,Ling A,Turner M,Peer CJ,Figg WD,Steinberg SM,Smith S,Joske D,Lewis I,Hutchins L,Craig M,Fojo AT,Wright JJ,Bates SE, Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011 Jun 2 [PubMed PMID: 21355097]|
|||[PubMed PMID: 12531812]|
|||[PubMed PMID: 27382100]|
|||Rummel MJ,Niederle N,Maschmeyer G,Banat GA,von Grünhagen U,Losem C,Kofahl-Krause D,Heil G,Welslau M,Balser C,Kaiser U,Weidmann E,Dürk H,Ballo H,Stauch M,Roller F,Barth J,Hoelzer D,Hinke A,Brugger W, Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet (London, England). 2013 Apr 6 [PubMed PMID: 23433739]|
|||Connors JM,Jurczak W,Straus DJ,Ansell SM,Kim WS,Gallamini A,Younes A,Alekseev S,Illés Á,Picardi M,Lech-Maranda E,Oki Y,Feldman T,Smolewski P,Savage KJ,Bartlett NL,Walewski J,Chen R,Ramchandren R,Zinzani PL,Cunningham D,Rosta A,Josephson NC,Song E,Sachs J,Liu R,Jolin HA,Huebner D,Radford J, Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. The New England journal of medicine. 2018 Jan 25 [PubMed PMID: 29224502]|
|||[PubMed PMID: 25901426]|
|||Diehl V,Franklin J,Pfreundschuh M,Lathan B,Paulus U,Hasenclever D,Tesch H,Herrmann R,Dörken B,Müller-Hermelink HK,Dühmke E,Loeffler M, Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. The New England journal of medicine. 2003 Jun 12 [PubMed PMID: 12802024]|
|||[PubMed PMID: 8096958]|
|||Coiffier B,Thieblemont C,Van Den Neste E,Lepeu G,Plantier I,Castaigne S,Lefort S,Marit G,Macro M,Sebban C,Belhadj K,Bordessoule D,Fermé C,Tilly H, Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23 [PubMed PMID: 20548096]|
|||Persky DO,Unger JM,Spier CM,Stea B,LeBlanc M,McCarty MJ,Rimsza LM,Fisher RI,Miller TP, Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 May 10 [PubMed PMID: 18413640]|
|||[PubMed PMID: 11807147]|
|||Younes A,Thieblemont C,Morschhauser F,Flinn I,Friedberg JW,Amorim S,Hivert B,Westin J,Vermeulen J,Bandyopadhyay N,de Vries R,Balasubramanian S,Hellemans P,Smit JW,Fourneau N,Oki Y, Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. The Lancet. Oncology. 2014 Aug [PubMed PMID: 25042202]|
|||[PubMed PMID: 26193343]|
|||Philip T,Guglielmi C,Hagenbeek A,Somers R,Van der Lelie H,Bron D,Sonneveld P,Gisselbrecht C,Cahn JY,Harousseau JL, Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. The New England journal of medicine. 1995 Dec 7 [PubMed PMID: 7477169]|
|||Neelapu SS,Locke FL,Bartlett NL,Lekakis LJ,Miklos DB,Jacobson CA,Braunschweig I,Oluwole OO,Siddiqi T,Lin Y,Timmerman JM,Stiff PJ,Friedberg JW,Flinn IW,Goy A,Hill BT,Smith MR,Deol A,Farooq U,McSweeney P,Munoz J,Avivi I,Castro JE,Westin JR,Chavez JC,Ghobadi A,Komanduri KV,Levy R,Jacobsen ED,Witzig TE,Reagan P,Bot A,Rossi J,Navale L,Jiang Y,Aycock J,Elias M,Chang D,Wiezorek J,Go WY, Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. The New England journal of medicine. 2017 Dec 28 [PubMed PMID: 29226797]|
|||[PubMed PMID: 30501490]|
|||Horning SJ,Rosenberg SA, The natural history of initially untreated low-grade non-Hodgkin's lymphomas. The New England journal of medicine. 1984 Dec 6 [PubMed PMID: 6548796]|
|||[PubMed PMID: 30811293]|
|||[PubMed PMID: 31339826]|
|||Thomas DA,Faderl S,O'Brien S,Bueso-Ramos C,Cortes J,Garcia-Manero G,Giles FJ,Verstovsek S,Wierda WG,Pierce SA,Shan J,Brandt M,Hagemeister FB,Keating MJ,Cabanillas F,Kantarjian H, Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1 [PubMed PMID: 16502413]|
|||O'Connor OA,Horwitz S,Masszi T,Van Hoof A,Brown P,Doorduijn J,Hess G,Jurczak W,Knoblauch P,Chawla S,Bhat G,Choi MR,Walewski J,Savage K,Foss F,Allen LF,Shustov A, Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015 Aug 10 [PubMed PMID: 26101246]|
|||Göknar N,Çakır E,Çakır FB,Kasapcopur O,Yegen G,Gedik AH,Oktem F, A Difficult Case of Hodgkin Lymphoma with Differential Diagnosis of Tuberculosis and Sarcoidosis. Hematology reports. 2015 Jun 3; [PubMed PMID: 26330996]|
|||Mikhaeel NG,Milgrom SA,Terezakis S,Berthelsen AK,Hodgson D,Eich HT,Dieckmann K,Qi SN,Yahalom J,Specht L, The Optimal Use of Imaging in Radiation Therapy for Lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group (ILROG). International journal of radiation oncology, biology, physics. 2019 Jul 1; [PubMed PMID: 30763664]|
|||Ziepert M,Hasenclever D,Kuhnt E,Glass B,Schmitz N,Pfreundschuh M,Loeffler M, Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 May 10 [PubMed PMID: 20385988]|
|||[PubMed PMID: 8141877]|
|||Mauermann ML, Neurologic Complications of Lymphoma, Leukemia, and Paraproteinemias. Continuum (Minneapolis, Minn.). 2017 Jun; [PubMed PMID: 28570324]|
|||[PubMed PMID: 1407576]|