What are the Signs and Symptoms of Lymphoma?
- Painless swelling of lymph nodes especially those in the neck, under the arm, or in the groin. Often these lymph nodes appear as a lump under the skin which gets bigger over time. Note that some other cancers and infections may also cause swollen lymph nodes.
- Enlarged spleen and/or liver.
- B Symptoms: Unexplained weight loss, Fever (>38 degree Celsius), and night sweats occur in many patients with NHL.
- Fatigue and weakness attributable to anemia, other anemia-related symptoms may include shortness of breath and dizziness.
- Loss of appetite.
- Cough or chest pain mainly due to swollen lymph nodes in the chest pressing on the trachea.
- Swelling in abdomen.
- Headache, weakness, confusion, mood changes, and seizures may appear when lymphoma affects the brain.
- Itching and other skin involvement signs may be visible in some NHL types mainly involving skin.
Besides above listed common symptoms, other symptoms may appear depending upon the type of lymphoma and site of disease.
Symptoms of Hodgkin’s Lymphoma
Broadly, it may have any one or more of the symptoms discussed above. But there are some specific symptoms may vary with the type of Hodgkin’s Lymphoma as discussed below.
Nodular Lymphocyte Predominant HL (NLPHL)
- Accounts for 5% of HL.
- Median age is mid 30.
- M:F ratio is 3:1.
- NLPHL usually involves peripheral LN, with sparing of mediastinum.
- 80% of cases are stage I or II at diagnosis.
- > 90% of patients have a complete response to treatment.
- Cause of death is often transformation to NHL, other cancers, or complications of treatment rather than HL.
Nodular Sclerosis HL
- Most common type of HL (60-80%)
- Most common in adolescents & young adults,
- Males are affected less than females
- Medistinum and supradiaphragmatic sites are involved commonly
Mixed Cellularity HL
- MCHL comprises 15-30% of HL
- May seen at any age (lacks in early adult)
- Abdominal LN & splenic involvement is more common than mediastinum
Lymphocyte Depleted HL
- Least common variant of HL, less than 1%.
- MC in older people, HIV + & non-industrialized countries.
- Frequently presents as Abdomen LN, spleen, liver, BM involvement without peripheral LN.
- Usually advanced at diagnosis, however response to treatment is similar to other types.
Lymphocyte Rich HL
- At presentation clinical features are intermediate between LPHL & cHL.
- Mostly it presents as an early stage disease and lacks bulky disease and B symptoms.
- In contrast to NLPHL, there is lack of mediastinal disease & male predominance.
- Like MCHL they had older median age.
Symptoms of Non-Hodgkin’s Lymphoma (NHL)
Although NHLs broadly have similar symptoms as discussed above, but there may be some differences depending on the subtype, as discussed below-
- The distribution of lymphoma types shows a markedly different bias in different sites.
- Low-grade NHLs usually present with advanced stage of disease
- High grade NHLs usually present at an early stage.
- B-symptoms are more commonly seen in high grade NHLs.
- Extranodal involvement (of tissues-skin, GIT & spleen, etc) is more common in high grade NHLs.
- Some NHLs (like extranodal, cutaneous, marginal zone, etc) usually produce symptoms depending upon the site of involvement.
What are B symptoms in Lymphoma?
B symptoms are important for prognostic purpose and help in staging of lymphoma. In the absence of any B symptoms, suffix A is added. If one or more symptom is present, suffix B is added in front of stage.
The B symptoms are as follows-
- Unexplained weight loss of more than 10% in the past 6 months
- Drenching night sweats
- Unexplained fever >38°C
Where does Lymphoma usually start and How does it progress?
Lymphoma is an uncontrolled proliferation of lymphocytes in the lymphoid organs. It may involve extralymphoid organ also (suffix E should be added with stage in such cases). It usually starts from one or more lymph node region or extranodal site.
In Hodgkin’s Lymphoma, it usually start from one site and progresses in a contiguous fashion to involve nearby lymph node sites in a predictable manner. Whereas, in a Non-Hodgkin’s lymphoma (NHL) it may progress in a non-contiguous manner to involve distant sites. But the pattern of involvement may differ in low-grade and high-grade NHLs.
In some cases (mostly NHLs and T Cell lymphoma) lymphoma may arise from extranodal sites (primary extranodal lymphoma) like skin, CNS, gastrointestinal tract, eye, thyroid gland etc.
- Orbit – Follicular Lymphoma, MALT lymphoma
- Scalp – Follicular Lymphoma
- Submandibular Gland – Follicular Lymphoma, MALT lymphoma
- Maxilla – Extranodal NK/T Cell Lymphoma, Plasmablastic Lymphoma, DLBCL
- Nasal Cavity – Extranodal NK/T Cell Lymphoma, Follicular Lymphoma
- Parotid Gland – DLBCL
- Mandible – DLBCL
- Thyroid – DLBCL
- Lacrimal Gland – DLBCL
What are the first signs of Lymphoma?
The first signs and symptoms of lymphoma may be due to the local or systemic manifestations.
- Nodal swellings in neck, axilla and/or groin
- Abdominal distension or discomfort
- Back pain
- Cough, breathlessness, chest discomfort
- Enlargement of liver and/or spleen
- Headache, altered sensorium
- Symptoms due to extranodal site involvement
Systemic or Constitutional Symptoms/Signs
- Unexplained weight loss
- Drenching night sweats
- Unexplained fever >38°C
Causes for Non-Hodgkin’s Lymphoma
Age and Gender
Most NHL types are common among old-age individuals with an exception of a few types more common among youngsters. Most NHL types are common in males compared to females with an exception of a few types more common in females.
Race and ethnicity
NHLs are most commonly reported in Caucasians compared to African Americans and Asian Americans, in the US.
Exposure to Radiation
Individuals with a history of exposure to radiation, for example, survivors of atomic bomb explosions and nuclear reactor accidents remain at high risk of developing NHLs.
Exposure to certain chemicals
Chronic exposure to certain chemicals like benzene, arsenic, chlorophenols, lead, vinyl chloride, asbestos, insecticides, and herbicides have been reported to elevate the risk of developing certain types of NHL.
Some NHL types are restricted to certain geographical locations, for example, endemic Burkitt lymphoma (BL) that is usually observed in equatorial African children and Adult T-cell leukemia/lymphoma (ATLL) that is generally observed in southern Japan, the Caribbean basin, western Africa, the Southeastern United States and northeast Iran.
Risk of developing certain types of NHL is higher in individuals who have a history of infection with associated viruses or other pathogens. Following are some examples:
- Epstein-Barr virus (EBV) infection is generally associated with the incidence of Burkitt lymphoma (BL) in African children, Angioimmunoblastic T-cell lymphoma (AITL), Extranodal NK-/T-cell lymphoma (ENKL), and post-transplantation lymphoproliferative disorder (PTLD). In conjunction with HIV, EBV infection may lead to the development of Plasmablastic lymphoma (PBL) and primary effusion lymphoma (PEL).
- Human T-cell lymphotropic virus (HTLV-1) infection has been linked with the development of Adult T-cell leukemia/lymphoma (ATLL) commonly observed in Japan and Caribbean region.
- Human herpesvirus 8 (HHV-8) infection increases the risk of PEL.
- HIV infection is usually associated with the development of primary CNS lymphoma (PCNSL), BL, and diffuse large B-cell lymphoma (DLBCL).
- Hepatitis C virus is usually associated with Lymphoplasmacytic lymphoma (LPL)/ Waldenström’s macroglobulinemia (WM) and splenic marginal zone lymphoma (MZL).
- Helicobacter pylori infection has been reported to cause mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach.
- Chlamydophila psittaci infection may result into MALT lymphoma in the tissues around the eye.
- Campylobacter jejuni infection may cause MALT lymphoma of the small intestine.
- Borrelia burgdorferi infection has been reported to be associated with the development of extranodal MZLs.
Weakened immune system
Individuals with a weak immune system that may be due to HIV infection, auto-immune disease, or immunosuppressants in patients who have undergone an organ transplant are considered at higher risk of developing certain types of NHL, for example, PTLD, AIDS-Related NHLs, and DLBCL.
Certain inherited immunodeficiency syndromes such as Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, X-linked lymphoproliferative syndrome, ataxia telangiectasia, and common variable immunodeficiency syndrome have been linked to increased incidence of aggressive lymphomas.
Individual with a history of NHL, HL, or chronic lymphocytic leukemia (CLL) in close relatives are considered to be at increased risk of developing NHL. The risk is particularly very high in individuals who have an identical twin who got the disease at a younger age.
Patients who had have breast implants with the textured surface are considered at an increased risk of developing breast implant-associated anaplastic large cell lymphoma (BIA-ALCL).
Body weight and diet have also been reported to play a role in the development of a few types of NHL. Obese people and individuals who consume fat-rich diet are generally at higher risk of developing some types of NHL.
Causes for Hodgkin’s Lymphoma
Epstein-Barr virus (EBV) infection
Individuals who have a history of EBV infection are considered to be at an increased risk of developing HL. The exact mechanism of developing HL from EBV infection is not clear. Parts of EBV have been found in HL cells in some individuals.
Weak immune system
Individuals with a weak immune system may be due to HIV infection, auto-immune disease, or immunosuppressants in patients who have undergone an organ transplant are considered at higher risk of developing HL.
Individuals with a history of HL in close relatives are considered to be at an increased risk of developing HL. The risk is particularly very high in individuals who have an identical twin who got HL at a younger age.
Age and Gender
HL is more common among individuals aged from 20 to 34 and individuals older than 55 years. HL is more common in males than females.
What are the Investigations for Diagnosis and Staging of Lymphoma?
If an individual is suspected to have lymphoma based on signs and symptoms, detailed investigations are required to establish the diagnosis and stage the disease, which in turn helps in selecting an appropriate treatment option.
Lymph Node Biopsy
This is the test which confirms the diagnosis of lymphoma. Whole node excision biopsy is recommended.
Excisional biopsy: In this technique, the affected lymph node is removed surgically. The collected biopsy sample is then tested in a laboratory and can help in establishing the diagnosis of lymphoma based on the microscopy and immunohistochemistry.
Laboratory Test for Biopsy Samples
The collected biopsy sample is then tested in a laboratory that helps in establishing the diagnosis of lymphoma based on the presence of characteristic cells in the biopsy sample. The biopsy samples can also provide other useful information.
Following are various techniques used for collecting this information:
In this technique, a very thin portion of the biopsy sample is first attached to a microscope glass slide.
The sample is then treated with a specific antibody which gets attached to a protein specific to certain types of cancer cells. Some reagents are then added to the treated sample that causes the bound antibody to changes its color. The change in color of the antibody-protein complex can be observed under the microscope, which confirms the type of cancer cells.
In this technique, chromosomes are evaluated for certain defects which are common in lymphoma.
The sample cells are first grown in the culture medium and are observed under a microscope after adding certain reagents that bind only to a specific defective portion of a chromosome. This test enables detection of chromosomal abnormalities like translocation, amplification, or deletion.
Fluorescent in situ hybridization (FISH)
In this technique, a fluorescent RNA probe is used which binds to a specific portion of a chromosome in the sample cells. Then, the sample can be examined under a microscope to determine the presence of certain chromosomal abnormalities like translocation, addition, or deletion.
This technique is very sensitive, fast, and accurate. Thus, it is preferably used for detecting specific chromosomal abnormalities.
These tests help to detect the involvement of lymph nodes, liver, spleen, bones, etc by lymphoma and play an important role in defining the extent of disease. Alternatively, these tests are employed after treatment to evaluate the treatment efficacy and to detect any signs of disease progression/recurrence.
Positron emission tomography (PET) scan
- More sensitive in detecting unsuspected metastasis or in differentiating active versus uninvolved nodes with accuracy approaching 95%.
- Highly useful in Initial staging
- Early evaluation during chemotherapy
- Evaluation at completion of therapy to differentiate residual lymphoma from post-therapy changes
- Routine follow-up.
- PET has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage HD.
The Deauville criteria are used to assess response to treatment during the treatment and at the end of the treatment based on the PET/CT assessed FDG uptake in the involved sites in HL. The criteria use a 5-point scale to designate the FDG uptake in the involved sites relative to that of the mediastinum and the liver. Following table describe the different responses to treatment assessed according to the Deauville criteria based on PET/CT results:
|3||Uptake > mediastinum but </= liver|
|4||Uptake moderately higher than liver|
|5||Uptake markedly higher than liver and/or new lesions|
Computed tomography (CT) scan
It detects retroperitoneal, mesenteric, portal, and other lymph node sites. The CT scan also detects splenomegaly, space-occupying lesions in the liver, spleen, and kidneys.
Magnetic resonance imaging (MRI) scan
Bone Marrow Biopsy
It is usually done in lymphoma, except in some cases. It helps to detect the involvement of bone by lymphoma and hence, stage the disease.
What is Ann Arbor Staging System for Lymphoma?
Ann Arbor staging system is the most commonly used for Non-Hodgkin’s Lymphoma Staging. It helps to determine the disease prognosis and to select an appropriate treatment strategy.
It is determined on the basis of various investigations done for staging of lymphoma.
It assigns four stages (I, II, III, and IV) to NHL. Letter ‘E’ can be added, which indicate that HL affects an organ outside of the lymphatic system (extranodal site).
Each stage can also be subdivided into A and B categories. “A” indicates absence of B symptoms and “B” indicates presence of classic B-symptoms(unexplained weight loss, fever, and night sweats).
Sometimes, letter X is added to Stage I or II, which indicate bulky disease. A bulky disease can be assessed with the help of mediastinal mass ratio (MMR, a ratio of the maximum width of the tumor mass and the maximum intrathoracic diameter) as a tumor mass of >0.33 MMR. Alternatively, a bulky disease is defined as a single node or nodal mass that is 10 cm or greater in diameter.
NHL is limited to only one site in the lymphatic system (single lymph node or lymphoid organ) OR only one site outside the lymphatic system is involved (IE).
NHL has extended to 2 or more lymph nodes regions on the same side of the diaphragm OR involvement of an extralymphatic site adjacent to the involved nodal site (IIE).
For example, if there are two nodal regions involved on same side of diaphram, it is stage II. And if there is one nodal region and one extranodal site involved on same side of diaphragm, it will be stage IIE.
NHL has spread to lymph nodes regions on both sides of the diaphragm OR NHL has affected lymph nodes above the diaphragm and the spleen (IIIS).
If only lymph nodes are involved on both sides of diaphragm, it is stage III. If there is involvement of extranodal site, it will be stage IIIE. And if there is involvement of spleen, it is stage IIIS.
Involvement of liver and/or bone OR involvement of a nodal site with non-regional extranodal site involvement.
Liver or bone marrow involvement makes it stage 4. Involvement of extralymphatic site with non-regional lymph nodes also makes it stage 4.
What are B symptoms in Lymphoma?
B symptoms are systemic symptoms in lymphoma that are important for prognostic purpose and help in staging of lymphoma. When one or more of B symptoms is present, a suffix B is added in front of stage, and in the absence of any B symptoms, suffix A is added in front of the stage.
The B symptoms in lymphoma are as follows-
- Unexplained fever >38°C (Classically it is described as Pel Ebstein fever which is present intermittently, but it may follow any pattern)
- Drenching night sweats
- Unexplained weight loss of more than 10% in the past 6 months
What is an Extralymphatic organ?
The organs other than the lymphoid organs are classified in extralymphatic organs. Lymphoid organs of the body include-
- Lymph nodes
- Bone Marrow
- Lymphoid tissue (Mucosa Associated Lymphoid Tissue in the lining of respiratory, digestive and urogenital tract)
The Cotswolds Modifications of the Ann Arbor Staging Classification
Cotswolds classification is a modification of the An Arbor classification
- Adding criteria for clinical involvement of spleen & Liver, require evidence of focal defects with 2 imaging techniques
- E : localized extra nodal disease (lung, pleura, chest wall, bone), excludes multiple extra nodal deposits or b/l lung extension
- Clinical stage (CS) or Pathologic stage (PS) should be mentioned
- Suffix X is added in case of bulky disease (maximum nodal diameter of >10 cm or mediastinal mass ratio >1/3)
- Number of anatomical sites involved should be mentioned (e.g. III3)
- Stage III may be divided further into
III1 with or without splenic, hilar, celiac, or portal nodes
III2 with para-aortic, iliac, or mesenteric nodes
How does Ann Arbor Staging determine Survival in HL?
5 Year Survival Rates:
Stage I – >90%
Stage II – 80-90%
Stage III – 60-85%
Stage IV – 50-60%
10 Year Survival Rates:
Stage IA, IB, IIA – 85-95%
Stage IIAX, IIB – 80-85%
Stage IIIA – 75-90%
Stage IIIB – 60-65%
Stage IV – 55-60%
Prognostic factors for Non-Hodgkin’s Lymphoma
Besides the stages of NHL, many factors have been identified in clinical research studies for different NHL types, which can predict the prognosis of disease. These factors are generally taken into account before starting the treatment of NHL. Following are certain examples:
International Prognostic Index (IPI)
IPI is a tool that is used for risk stratification and overall disease prognosis in NHL patients based on-
- patient’s age,
- performance status (a score that assesses overall health and well-being of an individual),
- serum LDH level,
- assigned stage, and
- the number of extranodal sites involved.
In patients younger than 60 years, tumor stage, performance status, and serum LDH level are considered as the prognostic factors. The NHL patients can be divided into 4 different risk groups (low, low-intermediate, high-intermediate, and high). The assigned risk-group is used to assess the prognosis of patient. This system works best for DLBCL and other aggressive NHL types.
Follicular Lymphoma International Prognostic Index (FLIPI)
FLIPI is a tool that is used exclusively for risk stratification in FL patients based on-
- patient’s age,
- serum LDH levels,
- hemoglobin levels,
- assigned stage, and
- the number of nodal sites involved.
The FL patients are divided into 3 risk groups: Low, Intermediate, and High. Recently, another similar risk stratification system, FLIPI-2 was designed that can predict treatment outlook in patients treated with modern chemoimmunotherapy regimens.
Non-Hodgkin’s Lymphoma Treatment
The treatment for NHL depends on the type of NHL, as discussed below-
Follicular lymphoma (FL)
This B-cells lymphoma is the second most common NHL diagnosed in the US and comprises about 20% of all new NHL cases. Involvement of multiple lymph nodes throughout the body along with bone marrow is commonly observed. FL cells in most patients possess t(14;18) translocation causing deregulated of BCL-2 gene and certain characteristic cell surface proteins (CD20+, CD10+, CD3–, CD5–).
In patients with Stage I to II, Involved-site radiotherapy (ISRT) or Immunotherapy with or without chemotherapy are the preferred treatment options. In patients with Stage III to IV, chemoimmunotherapy is considered the standard, if there is an indication for treatment. Maintenance therapy for up to 2 years with an immunotherapeutic agent (e.g. rituximab) may be considered in patients who receive chemoimmunotherapy. Targeted therapy and CAR-T cell therapy has also been approved for Follicular lymphoma patients in selected cases.
Lymphoplasmacytic lymphoma (LPL)/ Waldenström’s macroglobulinemia (WM)
LPL is a rare, indolent, B-cell lymphoma that accounts for about 1% of all NHL cases. Clinically the disease resembles small lymphocytic lymphoma and multiple myeloma. Cells are usually small and mainly present in the lymph nodes, spleen, and bone marrow. LPL that is associated with a monoclonal serum paraprotein of IgM type it is known as WM. WM cells mainly build-up in bone marrow causing a decreased number of other blood cells. The LPL cells generally possess activating mutations in MYD88 gene and express IgM, CD19 and CD20 surface antigens and lack CD10 or CD23.
In patients with symptomatic LPL/WM, chemoimmunotherapy is considered the standard treatment. Maintenance therapy for up to 2 years with an appropriate immunotherapeutic agent (e.g. rituximab) should be considered for patients achieving good response to initial therapy.
Marginal zone lymphoma (MZL)
These B-cell lymphomas make-up about 5% to 10% of all cases of NHL in the US. Common subtypes include Extranodal MZL (or mucosa-associated lymphoid tissue [MALT] lymphoma, Nodal MZL, and Splenic MZL.
MALT lymphoma is the most common MZL subtype that generally affects gastrointestinal tract (especially the stomach), parotid, salivary glands, skin, eyes, breast, lung, ovary, prostate, and other head and neck regions. The MALT lymphoma affecting stomach are generally associated with infection by Helicobacter pylori and its treating generally resolve lymphoma. Many other pathogens such as Chlamydia psittaci, Campylobacter jejuni, Borrelia burgdorferi, and hepatitis C virus (HCV) have been linked to the development of MZLs.
Nodal MZL is a rare subtype commonly affecting older females and is generally associated with peripheral lymphadenopathy.
Splenic MZL is another rare type commonly affecting older males. Enlarged spleen, low blood cell count, and bone marrow involvement are observed in almost all cases of splenic MZL. MZL cells in most patients possess t(11;18) translocation causing the formation of API2-MALT1 (a chimeric fusion gene) and certain characteristic cell surface proteins (CD5–, CD10–, CD20+, and cyclin D1–).
Treatment for MZL is somewhat similar to that of FL except below cases: In patients with gastric MALT lymphoma positive for H. pylori infection, treatment options include an appropriate antibiotic in combination with proton pump inhibitors in some cases. In patients with non-gastric MALT lymphoma and splenic MZL, surgical excision of the involved site may be employed for confirmative diagnosis and primary treatment. Also, in splenic MZL, anti-HCV therapy may be used in HCV positive cases.
Mycosis Fungoides (MF) and Sézary Syndrome (SS)
MF and SS are types of cutaneous T-cell lymphomas (CTCLs) characterized by the presence of abnormal mature T-cells primarily invading skin which may spread to lymph nodes, blood, and other organs. MF is the most common, indolent lymphoma accounting for about 50% to 70% of all CTCLs and SS is rare, aggressive lymphoma accounting for about 1% to 3% of all CTCLs.
Clinical skin manifestation of MF includes patches, plaques, cutaneous tumors, ulcers, and erythroderma (diffuse erythema involving more than 80% of the skin surface with or without scaling) while SS causes erythroderma with extensive skin involvement and diffuse exfoliation.
Sezary Syndrome is characterized by the presence of >/=1,000 Sézary cells/mm^3 of blood. MF and SS cells generally possess a high CD4/CD8 ratio with CD2+, CD3+, CD5+, CCR4+, TCR-beta+, and CD45RO+ and absence of T-cell markers, CD7 and CD26. In patients with generalized skin involvement, total skin electron beam therapy (TSEBT), or systemic chemotherapy may be employed.
In patients with blood involvement, systemic therapy with or without skin-directed therapies may be employed.
In patients with solid organ involvement, systemic therapy with or without local radiotherapy is generally employed. Palliative treatment for pruritus and secondary infections is generally provided along with primary treatment.
Diffuse large B-cell lymphoma (DLBCL)
As the name indicates, it arises from the B-cells (that looks large immature cells under the microscope), and it is the most common type of NHL in the US constituting about 30% of all newly diagnosed NHLs. Cells generally possess BCL-6 and BCL-2 gene rearrangements and certain characteristic cell surface proteins (CD20+, CD45+, and CD3–).
Based on gene expression profiling (GEP), DLBCL can be divided into 2 subtypes, germinal center B-cell (GCB) subtype and non-GCB subtype. The GCB subtype generally has a better prognosis compared to non-GCB subtype. Some lymphomas have characteristics intermediate between DLBCL and classical Hodgkin lymphoma (cHL) and known as grey zone lymphomas.
In patients with Stage I to II, chemoimmunotherapy with or without radiotherapy is considered the standard treatment.
In patients with Stage III to IV, chemoimmunotherapy is considered the standard treatment. CAR-T cell therapy may also be used for DLBCL treatment in selected cases. Autologous SCT may be considered in some patients who achieve complete response to treatment. Grey zone lymphomas are very hard to treat as no standard treatment option is available. They are generally treated with multi-agent chemotherapy.
Burkitt lymphoma (BL)
These B-cell lymphomas make-up about 1% to 2% of all cases of NHL in the US. This is a common childhood lymphoma but a rare malignancy in adults. Medical literature describes three variants of BL:
- The endemic BL is observed in equatorial African children with most cases linked to Epstein-Barr virus (EBV) infection.
- Sporadic BL is generally observed in the US and other western countries with about 30% cases liked to EBV infection.
- Immunodeficiency-associated BL is generally observed in immunocompromised people and commonly linked to HIV infection. The BL cells generally possess translocation and deregulation of MYC gene on chromosome 8 with and certain characteristic cell surface proteins (CD10+, CD20+, CD19+, CD22+, CD3–, CD10–, CD5–, TdT–, and Ki67+).
Dose-intensive, multiagent chemotherapy with or without immunotherapy along with CNS prophylaxis with intrathecal or intravenous chemotherapy is the standard treatment for patients with BL.
Primary mediastinal large B-cell lymphoma (PMBL)
This is a subtype of DLBCL that generally affect young adults and starts in the mediastinum (the middle chest region behind the breastbone). It is usually associated with difficulty in breathing (as the growing tumor presses on trachea), swelling in face and arms (as the growing tumor presses on superior vena cava), pericardial and pleural effusions. PMBL cells usually possess cell surface antigens (CD19+, CD20+, CD22+, CD21–, IRF4/MUM1+ and CD23+). Chemoimmunotherapy with or without radiotherapy is employed as the first-line treatment.
Mantle cell lymphoma (MCL)
These B-cell lymphomas constitutes about 5% to 6% of all new cases of NHLs. MCLs are inherently aggressive, which are usually diagnosed at an advanced stage. Cells are small to medium-sized and consist of relatively less cytoplasm with an irregular nucleus. They are generally found in expanded mantle region of lymph nodes and show diffuse arrangement. It generally harbors t(11;14) translocation leading to cyclin D1 overexpression and possess certain characteristic cell surface proteins (CD20+, CD5+, CD10–, and CD3–).
In patients with Stage I to II, radiotherapy or chemoimmunotherapy is considered the standard treatment.
In patients with Stage III to IV, chemoimmunotherapy is considered the standard treatment. Consolidative treatment with autologous SCT may also be considered in some cases. Maintenance therapy with an immunotherapeutic agent (e.g. rituximab) may be considered in patients who receive chemoimmunotherapy.
Post-transplantation lymphoproliferative disorder (PTLD)
PTLDs are a group of heterogeneous lymphomas that occur after solid organ transplantation (SOT) or allogeneic stem cell transplantation. Most of them arise from B-cells and have been linked with EBV infection. Following are four major subtypes of PTLD: early lesions, monomorphic PTLD, polymorphic PTLD, and classical Hodgkin lymphoma (cHL) type PTLD. Early lesion PTLD generally develops within the first year of transplantation. Monomorphic PTLD is the most common subtype and corresponds to an aggressive B-cell lymphoma, e.g. DLBCL. Polymorphic PTLD generally affects children and can consist of either monoclonal or polyclonal lymphoma cells. The cHL type PTLD is rare subtype and mostly associated with EBV infection. NHL treatment generally depends upon the type of NHL.
Reduction in immunosuppression (RI) is generally employed in all cases and is the only treatment required for some early-stage NHLs.
In patients with polymorphic PTLD, RI with or without immunotherapy or chemoimmunotherapy should be employed.
In patients with monomorphic PTLD, RI with or without immunotherapy or chemoimmunotherapy should be employed.
These are a group of lymphomas that affect individuals with AIDS. These mainly include systemic lymphoma (accounting for about 70% to 90%) and primary CNS lymphoma (PCNSL). Systemic lymphoma occurs mainly as BL or DLBCL. Plasmablastic lymphoma (PBL) and primary effusion lymphoma (PEL) are other lymphoma types that commonly affect HIV-infected individuals who are concomitantly infected with EBV and/or human herpesvirus 8 (HHV8). PBL mostly involves the jaw and oral cavity while PEL mostly involves pleural, pericardial, and abdominal cavities.
In patients with AIDS-related NHLs, treatment for both AIDS and NHL go hand in hand. NHL treatment generally depends upon the type of NHL. In most cases, chemotherapy with or without immunotherapy is employed as the primary treatment for NHL. Treatment decision is taken depending upon CD4 cell count.
Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)
This is a group of aggressive subtypes of T-cell lymphomas that accounts for about 6% of all NHLs. They generally affect lymph nodes but may be present as an extranodal manifestation involving the liver, bone marrow, GI tract, and skin. PTCL-NOS cells are generally mature T-cells that harbor t(7;14), t(11;14), inv(14), and t(14;14) translocation leading to TCR gene rearrangement and a majority of cases possess certain characteristic cell surface proteins (CD4+ and CD8–).
In patients with Stage I to IV PTCL-NOS, chemotherapy is considered the standard treatment. Patients who achieve response should be followed-up closely after treatment. Consolidative treatment with autologous SCT may also be considered in some cases.
Angioimmunoblastic T-cell lymphoma (AITL)
It is the second most common peripheral T-cell lymphoma that accounts for about 4% of all NHLs. It is generally associated with generalized lymphadenopathy, hepatomegaly or splenomegaly, eosinophilia, hypergammaglobulinemia, B symptoms, skin rash, and autoimmune disorder like polyarthritis, thyroid dysfunction, and hemolytic anemia. AITL cells are generally surrounded by EBV-infected B-cells and may progress to secondary B-cell lymphoma such as DLBCL. They express common T-cell surface antigens and are usually CD4+ with about 50% of cases featuring ten-eleven translocation 2 (TET2).
In patients with Stage I to IV AITL, chemotherapy is considered the standard treatment. Consolidative treatment with autologous SCT may also be considered in some cases.
Anaplastic large cell lymphoma (ALCL)
It is the third most common peripheral T-cell lymphoma accounting for about 2% of all NHLs. Following 3 are main subtypes of ALCL: ALK-positive systemic ALCL, ALK-1 negative systemic ALCL, and primary cutaneous ALCL.
- ALK-positive subtype is most commonly reported and is usually associated with t(2;5) translocation leading to overexpression of the ALK-1 protein. It is mostly reported in children and young adults.
- ALK-negative ALCL is generally an aggressive lymphoma that affects lymph nodes or extranodal sites
- Primary cutaneous ALCL can be indolent with the disease in most cases restricted to the skin and cancer cells not showing the ALK rearrangement.
- Breast implant-associated ALCL (BIA-ALCL) has been reported in patients with the textured-surface implant. Most patients have localized disease with breast enlargement, periprosthetic effusion, rash, lymphadenopathy, tumor mass, and skin ulceration. Almost all ALCL cells possess CD30 surface antigen (CD30+).
In patients with Stage I to II ALK-positive ALCL, chemotherapy with or without ISRT is considered the standard treatment. In patients with Stage III to IV ALK-positive ALCL, chemotherapy is considered the standard treatment.
In ALK-negative ALCL, chemotherapy with or without ISRT is considered the standard treatment. Consolidative treatment with autologous SCT may also be considered in some cases. In patients with breast implant-associated ALCL (BIA-ALCL), surgical excision of involved breast tissue along with the removal of breast implant is generally recommended. Radiotherapy or systemic therapy may be employed if surgery could not remove all involved tissue, and in cases of extended disease.
Enteropathy-associated T-cell lymphoma (EATL)
It is a rare type of T-cell lymphoma accounting for less than 1% of NHLs. It usually affects small intestine’s intraepithelial T-cells and commonly associated with Celiac disease (an autoimmune disease related to gluten-diet in which immune cells start attacking intestinal lining). Children who have been diagnosed and appropriately treated for celiac disease do not develop EATL. This is common in old age individuals especially men. EATL cells usually possess CD3 and CD103 cell surface antigens with intestinal lymphocytes possessing integrin.
In patients with Stage I to IV EATL, chemotherapy is considered the standard treatment. Consolidative treatment with autologous SCT may also be considered in some cases.
Adult T-cell leukemia/lymphoma (ATLL)
ATLL is almost always associated with human T-cell lymphotropic virus type I (HTLV-1) infection and thus reported in geographical regions where this virus is endemic, for example, southern Japan, the Caribbean basin, western Africa, the Southeastern United States and northeast Iran. A long latency period is generally observed between the HTLV-1 infection and ATLL development. ATLL can affect the lymph nodes, spleen, liver, bone marrow, skin, and other organs. Following four subtypes of ATLL have been reported:
- Smoldering (indolent subtype with >/=5% abnormal T-cells in the blood);
- Chronic (indolent subtype with lymphocytosis and chances of disease progression to acute form);
- Acute (aggressive subtype with leukemic manifestations); and
- Lymphoma (less aggressive than acute with lymphoid manifestations). ATLL cells usually possess characteristic cell surface antigen (CD4+, CD2+, CD3+, CD5+, CD25+, CD7–).
In patients with chronic or smoldering ATLL, observation is generally recommended until the appearance of bothering symptoms. In the case of symptomatic disease, skin-directed therapies or chemotherapy may be employed, as appropriate. In patients with acute or lymphoma ATLL, chemotherapy is considered the standard treatment. Antiviral therapy may be considered for acute ATLL. Allogeneic SCT may be considered in eligible cases.
Extranodal NK-/T-cell lymphoma (ENKL)
It a rare type of NHL that generally affect the upper respiratory tract with the extranodal presentation. It mostly involves NK-cells and virtually all cases are associated with EBV-infection. Clinical features include nasal obstruction, nasal bleeding, mucosal ulceration of the site, vascular invasion, and tissue necrosis. Common extranasal sites include the skin, testis, intestine, lungs, and eyes, which are associated with poor prognosis. ENKL cells generally possess typical cell surface antigen (CD2+, surface CD3–/cytoplasmic CD3+, CD43+, CD56+, CD20–, CD4–, CD5–) with overexpression of p53 and/or TP53.
In patients with the limited nasal disease, radiotherapy with or without chemotherapy is considered the standard treatment. Patients achieving a response can be observed after treatment.
In patients with an advanced nasal or extranasal disease, multiagent chemotherapy (pegaspargase-based) with or without radiotherapy should be employed.
Hodgkin’s Lymphoma Treatment
Treatment for Hodgkin’s Lymphoma depending on stage and subtype is as follows-
Stages I and II
Chemotherapy is the standard treatment upfront. Type of chemotherapy and number of cycles are determined by the presence/absence of poor prognostic factors. Further decision to add chemotherapy and/or radiation therapy depends upon the response to initial therapy (as assessed by PET-CT scan) and presence/absence of poor prognostic factors and disease bulk.
Stage III and IV
In patients with Stage III to IV, chemotherapy is the standard treatment upfront. Type of chemotherapy is determined by the presence/absence of poor prognostic factors. Further decision to add chemotherapy and/or radiation therapy is taken depending upon the response to initial therapy (as assessed by PET-CT scan) and disease bulk.
Nodular Lymphocyte Predominant HL
Stage I and II
In the absence of poor prognostic factors, observation or radiotherapy alone may be sufficient. In the presence of poor prognostic factors, chemotherapy with targeted therapy (rituximab) with/without radiotherapy is preferred.
Stage III and IV
Chemotherapy with targeted therapy (rituximab) with/without radiotherapy is the preferred treatment.
Role of Chemotherapy
Chemotherapy is the mainstay of treatment for Lymphoma. Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly-growing cancer cells.
Certain standard combination regimen involving multiple drugs are used for the treatment of HL, for example, ABVD (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine), and Stanford V (Adriamycin, Mechlorethamine, Vincristine, Vinblastine, Bleomycin, Etoposide, Prednisone). Certain standard combination regimen involving multiple drugs are used for the treatment of NHL, for example, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
Role of Radiation Therapy
Radiation therapy (or radiotherapy) uses high-energy x-rays or other high-energy radiations which are directed to the affected area to kill cancer cells. It is generally employed for the treatment of Hodgkin’s Lymphoma, especially in case of bulky disease limited to a part of the body. Radiation therapy alone is recommended for the treatment of early-stage NLPHL. It is generally employed for the treatment of Non Hodgkin’s Lymphoma, especially in case of bulky disease limited to a part of the body. Radiation therapy alone is recommended for the treatment of some early-stage indolent lymphomas. Sometimes, it is used as palliative therapy to relieve pain, bleeding, and obstructive problems associated with the advanced-stage disease.
Role of Monoclonal Antibodies
Monoclonal antibody is a targeted therapy which can be directed to certain protein characteristic of cancer cells. For the treatment of Hodgkin’s Lymphoma, Brentuximab Vedotin (that targets CD30 protein on HL cells) and Rituximab (that targets CD20 protein on the HL/NLPHL cells) may be employed.
Brentuximab Vedotin is generally employed for the treatment of advanced-stage HL in combination with chemotherapy or to treat a refractory disease that is not responding to chemotherapy and radiation therapy.
Rituximab is employed in the treatment of NLPHL along with other chemotherapy drugs. For the treatment of Non Hodgkin’s Lymphoma, Rituximab (that targets CD20 protein) is generally employed. These drugs help immune cells to destroy the cancer cells. Rituximab is generally employed for the treatment of NHL in combination with chemotherapy.
Role of Immunotherapy
Cancer cells utilize certain mechanisms to escape from the immune system of the patient from attacking these cells. Immune checkpoint inhibitors deactivate the checkpoints on cancer cells and thus enable the immune system to recognize and kill cancer cells. Nivolumab and pembrolizumab target PD-1 protein on T-cells and activate the immune system to kill the PD-L1 expressing Hodgkin Lymphoma cells. Trials have shown immunotherapy to be beneficial for the treatment of advanced stage disease unresponsive to chemotherapy.
Role of Stem Cell Tranplant
Autologous Stem Cell Transplant
In this technique, patient’s own stem cells are first collected from the healthy bone marrow tissue or peripheral blood (preferred). Then, the patient receives high-dose chemotherapy to kill all the lymphoma cells.
The collected stem cells are re-administered to the patient to slowly replenish the blood cells in the patient body. SCT can be considered for some patients with Hodgkin’s and Non Hodgkin’s Lymphoma who are good candidate for the same (younger patients in good health) and are not responding to chemotherapy and/or radiotherapy. This is the most common type of SCT employed for the treatment of lymphoma.
Allogenic Stem Cell Transplant
In this technique, healthy stem cells to be administered to the patient after high dose chemotherapy are obtained from another person known as the donor. It is very important that donor is a close blood relative (preferably a sibling) so that donor cells (HLA type) closely match with the patient’s cell types. It is used for treatment of refractory lymphomas that relapse after Autologous Stem Cell Transplant.
Best Lymphoma Specialist in Delhi
Dr Sunny Garg is a renowned Medical Oncologist in New Delhi with an experience of around 10 years of treating lymphoma patients. He has treated lymphoma patients with Chemotherapy, Targeted Therapy and Immunotherapy. He is currently practicing at Manipal Hospital, Dwarka.
Diagnostic modalities available at our hospital include Excisional Lymph Node Biopsy, CT Guided Biopsy, Immunohistochemistry, Genetic and Molecular Testing, Whole Body PET CT, etc. Other treatment facilities for Lymphoma available are Radiation Therapy, Palliative Care etc.
Call +91 9686813020 for appointment.