The lymph system is a network of lymph nodes and arteries that transport lymph fluid throughout the body. Lymph fluids include infection-fighting white blood cells. Lymph nodes operate as filters, collecting and eliminating germs and viruses to prevent illness from spreading.

While the lymph system normally defends your body, lymphocytes, which are lymph cells, can become malignant. Lymphomas are the medical term for malignancies that affect the lymphatic system.

Lymphomas, or tumors of the lymphatic system, account for almost half of all blood cancers diagnosed each year. This system, which is made up of lymph nodes in your neck, armpits, groin, chest, and belly, eliminates waste from your body and creates immune cells. Lymphoma cells form when abnormal lymphocytes, a kind of white blood cell that fights infection, proliferate and accumulate in your lymph nodes. These malignant cells weaken your immune system over time.

Lymphoma is a category of malignant lymphocyte neoplasms with over 90 subtypes. Lymphoma is a malignancy that begins in immune system cells in the body.

Lymphoma 

Lymphomas are cancers that originate in the lymphatic system (the different lymph glands throughout the body) when aberrant white blood cells proliferate. Lymphomas are the sixth most frequent type of cancer in the world.

There are two kinds of lymphoma, each of which spreads and is treated differently:

• Non-Hodgkin lymphoma (which accounts for about 90% of lymphomas) 
• Hodgkin lymphoma (which has a characteristic appearance in biopsies). 

Knowing what form of lymphoma you have is critical since it influences your treatment options and outlook (prognosis). If you are unsure about which type you have, consult your doctor so that you can receive the correct information.

More than 70 cancer forms are classified as lymphomas by doctors. Lymphomas can affect any part of the lymphatic system, including the following:

• bone marrow
• thymus
• spleen
• tonsils
• lymph node

What are the different types of blood cancer?

Blood malignancies (sometimes known as ‘haematological' cancers) include lymphoma, leukemia, and myeloma. Although certain forms of lymphoma and leukaemia are identical, the majority of them grow differently. They behave and are treated differently as well.

• Lymphoma affects lymphocytes. The abnormal cells develop in the lymph nodes or organs of the lymphatic system.
• Leukemia is cancer that attacks white blood cells, particularly lymphocytes. The aberrant cells form in the bone marrow or circulation.
• Myeloma: affects a specific type of white blood cell known as a plasma cell .

Etiology

Different environmental, viral, and genetic variables that predispose to lymphoma have been found.

• Occupational exposure: herbicides, pesticides
• Infectious organisms: 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), and human herpesvirus 8 are (primary effusion lymphoma and Castleman disease). Chronic stimulation of lymphoid tissue raises the possibility of lymphoma development. Persistent infection with viruses such as Epstein Barr virus and CMV also predisposes to lymphoma development.
• Immunodeficiency: HIV infection, transplant patients, and individuals suffering from hereditary immunodeficiency diseases are also at risk (severe combined immunodeficiency and common variable immunodeficiency).
• Drugs: Tumor necrosis factor-alpha inhibitors have been linked to T-cell lymphoma in particular. Chronic immunosuppression raises the likelihood of lymphoma in post-transplant patients (both solid organ transplant and bone marrow transplant recipients).
• Autoimmune diseases: Inflammatory bowel disease (enteropathy related lymphoma), rheumatoid arthritis, and Sjögren's syndrome are all examples of autoimmune diseases (diffuse large B-cell lymphoma)
• Geographic location: The incidence of extranodal NK/T-cell lymphoma is high in Southern Asia and some regions of Latin America.

Epidemiology

From 2009 to 2013, the incidence of lymphoma in the United States was 22/ 100,000, accounting for roughly 5% of all malignancies; it doubled between 1970 and 1990 and has been constant thereafter. The average age upon diagnosis is 63. At five years, overall survival is projected to be 72 percent, and it is improving.

Lymphomas are divided into two types: Hodgkin lymphoma (HL), which accounts for 10% of cases, and non-Hodgkin lymphoma (NHL), which accounts for 90% of cases.

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

Lymphoma is classified clinically as aggressive (high grade) or indolent (low grade) (low grade). Overall, Non-Hodgkin lymphoma is common in age 65 to 74, the median age being 67 years. 

Pathophysiology Lymphoma Cancer

Different stresses, including infectious, inflammatory, and toxic stimuli, interact in a complicated way with the genetic composition of the human host to cause lymphomagenesis. One generally recognized the concept of lymphomagenesis is that long-term immunosuppressive treatments render the innate immune system less capable of detecting and destroying cancer cells or warding off infections that might lead to cancer.

Non-Hodgkin lymphoma develops from either B cells, T cells, or Natural Killer cells as a result of chromosomal translocation or mutation/deletion. Chromosomal translocation activates proto-oncogenes, while chromosomal deletion or mutation inactivates tumor suppressor genes.

Lymphoma symptoms

• Hodgkin Lymphoma

Typically manifests as painless, superficial enlarged lymphadenopathy, which includes adjacent lymph node chains in a predictable manner as the disease progresses. Hematogenous spread with vascular invasion happens later in the disease's course. Only 3-7 percent of individuals have isolated infra-diaphragmatic illness, while the majority of patients have a supradiaphragmatic disease.

In the absence of symptoms, 60 to 70 percent of patients have cervical and/or supraclavicular lymphadenopathy, 30 percent have an axillary illness, and 50 to 60 percent have mediastinal involvement detected on radiography. Although para-aortic lymph nodes are involved in infra diaphragmatic illness, involvement of abdominal organs is infrequent.

Only 10-15% of HL patients develop extranodal illness, with bone, bone marrow, lung, and liver being the most often afflicted organs. Although CNS involvement is uncommon, para-aortic adenopathy that extends into the epidural space might cause neurological symptoms.

Approximately 25% of previously undetected HL patients exhibit systemic symptoms before the onset of lymphadenopathy, known as B symptoms (fevers, drenching night sweats, and unintentional weight loss). In both early and advanced stages of illness, the presence of these symptoms is associated with a poorer prognosis.

Other symptoms include severe pruritis and alcohol-induced discomfort that occurs minutes after consuming alcohol and is localized to lymphadenopathy areas. Some uncommon neurological disorders, such as cerebellar degeneration and stiff-person syndrome, have also been documented.

Features of Hodgkin lymphoma include the following:

• Asymptomatic lymphadenopathy
• Unexplained weight loss, unexplained fever, night sweats
• Chest pain, cough, shortness of breath
• Pruritus
• Pain at sites of nodal disease
• Back or bone pain
• Nodular sclerosis is a kind of nodular sclerosis. Hodgkin lymphoma (NSHL) has a significant hereditary component and is frequently detected in family members.
• Palpable, painless lymphadenopathy in the cervical area, axilla, or inguinal area
• Involvement of the Waldeyer ring (back of the throat, including the tonsils), occipital (lower back of the skull), or epitrochlear (inside the upper arm at the elbow) region
• Splenomegaly and/or hepatomegaly
• Superior vena cava syndrome may develop in patients with massive mediastinal lymphadenopathy
• Paraneoplastic disorders, such as cerebellar degeneration, neuropathy, Guillain-Barre syndrome, or multifocal leukoencephalopathy, can cause symptoms or signs in the central nervous system.

• Non-Hodgkin Lymphoma

The most typical complaint is asymptomatic, growing lymph nodal mass, either centrally or peripherally situated. Twenty percent of patients have stage I illness, roughly 40% have disease restricted to one side of the diaphragm (stage II), another 20% have involvement above and below the diaphragm, and 40% have an extensive disease with extranodal involvement. The lung, liver, kidney, and bone marrow are common sites of extranodal spread.

Around 30% of patients will experience B symptoms, as well as less specific symptoms such as malaise and tiredness.

Lymphoma in children

Many of the same risk factors for lymphoma in children also exist in adults, however, some kinds of lymphoma are more frequent in children.

Hodgkin's lymphoma, for example, is more prevalent in children aged 15 and younger, although the form of NHL that occurs in youngsters is generally aggressive and fast-growing.

Children with immune system defects, such as HIV, or those who use immune-suppressing medications are more likely to develop lymphoma. Similarly, children who have received radiation therapy or chemotherapy are at an increased risk of getting this kind of cancer. 

Lymphoma vs. Leukemia

Leukemia and lymphoma are both forms of blood cancer that overlap certain symptoms. However, the two kinds of cancer are distinguished by their origins, therapies, and unique symptoms.

Diagnosis of Lymphoma 

Following the confirmation of a lymphoma diagnosis by tissue biopsy, subsequent assessment entails determining the tissue with the highest disease activity. PET/CT scans that detect the uptake of radiolabeled fluorodeoxyglucose (FDG) are used to assess lymphoma biological activity. Staging is done prior to the start of lymphoma treatment.

The Ann Arbor staging technique is used for the clinical staging of both HL and NHL. The presence or absence of B symptoms (chronic fever, weight loss of more than 10% of body weight over six months, or night sweats) is considered in lymphoma staging. Lactate dehydrogenase, complete blood counts with differential, a comprehensive metabolic panel, and uric acid are all included in the blood work.

Laboratory tests include the following:

• Complete blood cell count studies for anemia, lymphopenia, neutrophilia, or eosinophilia
• Erythrocyte sedimentation rate
• Lactate dehydrogenase
• Serum creatinine
• Alkaline phosphatase
• HIV test is necessary since antiviral treatments can enhance illness outcomes in HIV-positive individuals; hepatitis B and C screening should also be explored.
• Cytokines (interleukin [IL]-6, IL-10) and soluble CD25 (IL-2 receptor) levels in the blood correlate with tumor load, systemic symptoms, and prognosis.

Imaging studies include the following:

• Plain radiographs: The gold standard for measuring mediastinal mass in relation to thoracic diameter on posteroanterior and lateral chest radiographs remains the measurement of mediastinal mass in proportion to thoracic diameter.
• Computed tomography: CT scanning has largely supplanted chest radiography; potential abnormal findings on CT scans of the chest, abdomen, and pelvis include enlarged lymph nodes, hepatomegaly and/or splenomegaly, lung nodules or infiltrates, and pleural effusions.
• Positron emission tomography: essential to the initial staging of Hodgkin lymphoma

A histologic examination is always necessary to identify Hodgkin lymphoma, and an excisional lymph node biopsy is suggested for this reason. To stage the patient, several imaging investigations are utilized.

Lymphoma treatment

General treatment principles include the following:

• Radiation therapy
• Induction chemotherapy
• Salvage chemotherapy
• Hematopoietic stem cell transplantation
• Hodgkin Lymphoma

The conventional standard of care is combined modality therapy, which includes chemotherapy using antibody-drug conjugates and radiation. The majority of HL patients are chemosensitive, and the overall survival rate is 86%.

ABVD is the standard therapy in the United States (US) (doxorubicin, bleomycin, vinblastine, and dacarbazine). The BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) is also commonly used.

Stanford V is a third regimen that is employed (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone). All three regimens had comparable response rates, with BEACOPP having somewhat higher cure rates than the other two but at the expense of increased toxicity, including the development of secondary acute myeloid leukemia/myelodysplastic syndrome and sterility.

Brentuximab vedotin (CD30 targeted antibody-drug conjugate) was authorized by the FDA in 2018 for the first-line treatment of stage III or IV classical HL in conjunction with AVD chemotherapy.

Because of the bulkiness of the illness or the persistence of PET/CT positive following chemotherapy, systemic chemotherapy is augmented with local radiation.

Repeat imaging, consisting of a PET/CT scan, is used to assess therapy response. Deavullie criteria are used to assess PET/CT data, with signal less than or equal to the physiologic signal from the liver being negative (1-3) and signal larger than the liver being positive (4-5).

A new technique emerging in both the United States and Europe is to begin treatment with ABVD, evaluate response to chemotherapy with repeat PET/CT after two cycles, and then escalate to BEACOPP only for patients with an incomplete response.

Recent evidence suggests that if the PET/CT response to ABVD is satisfactory, bleomycin can be removed from subsequent cycles without affecting response or causing extrapulmonary damage.

Following completion of therapy, patients are examined as part of a surveillance program at regular intervals to rule out illness return, including a history and physical exam as well as basic laboratory testing, but no routine repeat imaging.

Because many HL patients are young and cured, they will live for a long time after treatment and must be monitored for treatment-related complications, particularly the development of secondary cancers within previous radiation fields, such as lung, breast, or thyroid cancer, as well as coronary artery disease.

There are various salvage treatments available for individuals with resistant or relapsed HL. The FDA has also authorized brentuximab vedotin as a second-line agent. If salvage therapy is effective, it is followed by high-dose chemotherapy and autologous stem cell rescue. In situations when the illness is totally resistant or relapses following autologous stem cell rescue, investigational medicines in the framework of a clinical trial are appropriate, as is allogeneic stem cell transplantation in selected cases.

Differential Diagnosis

• Cytomegalovirus (CMV)
• Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono)
• Physical Medicine and Rehabilitation for Systemic Lupus Erythematosus
• Sarcoidosis
• Serum Sickness
• Small Cell Lung Cancer (SCLC)
• Syphilis
• Toxoplasmosis
• Tuberculosis (TB)

Radiation Oncology

Radiation treatment (RT) is frequently utilized after chemotherapy for a residual, restricted region of lymphadenopathy that is FDG avid on restaging PET/CT in typical HL. Some instances of nodular lymphocyte-predominant HL can be treated with RT alone.

In NHL, RT can be used in various scenarios;

• RT can be utilized as a single modality therapy for early-stage (Ann Arbor stage I or II) indolent NHL with a low disease load.
• For more advanced and/or aggressive NHL, RT is utilized as a consolidation treatment following chemotherapy.

Is Lymphoma Preventable?

There is no clear technique to avoid lymphoma because the etiology is unknown. However, if you suspect you have lymphoma, being aware of the risk factors and symptoms, as well as speaking with your doctor, are important to early diagnosis and treatment. It is especially important to watch for symptoms and share your family medical history with your doctor if you have a family history of lymphoma.

If you believe you have lymphoma or are at risk for it, see your doctor about screening and treatment options. You may be sent to a hematologist, a specialist who specializes in blood disorders, based on your physical condition, genetics, and medical history.

Lymphoma Prognosis

Clinical prognostic models are created to assist physicians in communicating prognostic information to patients. Several models have been created, including the HL international prognostic score, the IPI for DLBCL, and the FL international prognostic index (FLIPI) for follicular lymphoma. A low IPI score indicates a better outcome, while a high IPI value predicts a poorer outcome.

Hodgkin's lymphoma, according to the Leukemia & Lymphoma Society, is a very curable disease. Survival rates for both NHL and Hodgkin's lymphoma are determined by the extent to which the malignant cells have spread and the kind of malignancy.

The American Cancer Society (ACS) reports that the overall five-year survival rate for NHL patients is 70%, with a 60% 10-year survival rate. The prognosis for Hodgkin's lymphoma is determined by its stage.

Stage 1 has a five-year survival rate of 90%, whereas stage 4 has a five-year survival rate of 65%.

The International Prognostic System (IPS) is the most widely used prognostic system, and it employs the following factors to make predictions. The International Prognostic System (IPS) is the most widely used prognostic system, and it employs the following factors to predict prognosis:

• Serum albumin less than 4 g/dL
• Hemoglobin less than 10.5 g/dL
• Male sex
• Age of 45 years or older
• Stage IV disease (Ann Arbor classification)
• White blood cell (WBC) count greater than 15,000/mm3
• Absolute lymphocyte count less than 600/mm3, less than 8% of the total WBC count, or both

Complications

• HL Complications

Limbic encephalitis (anti-metabotropic glutamate receptor 5 (mGluR5) antibodies), primary CNS angiitis, cerebellar degeneration (anti-Tr antibodies), POEMS syndrome are all examples of paraneoplastic disorders (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes)

• NHL Complications

Indolent lymphomas, such as follicular lymphoma and marginal zone lymphoma, can progress to more aggressive NHL, such as diffuse large B-cell lymphoma.

• Chemotherapy Complications

Toxicities associated with treatment regimens include the following:

1. Hematologic toxicity: Anemia, thrombocytopenia, increased risk of infection (febrile neutropenia); or acute leukemia
2. Pulmonary toxicity, Increased risk of lung cancer or fibrotic lung disease, especially in smokers, if bleomycin or thoracic radiation are used;
3. Cardiac toxicity from anthracycline therapy; congestive heart failure from treatment
4. Infectious: Long-term infection risk from splenectomy (rarely performed in contemporary practice), long-term immunodeficiency from treatment effects
5. Cancer: In young women treated with mediastinal radiation, there is an increased risk of secondary malignancies, notably breast cancer; there is also an increased chance of sarcomas in radiation fields.
6. Neurologic: Chemotherapy-induced neuropathy, muscular atrophy
7. Psychiatric: Depression and anxiety 

• Radiotherapy Complications

Accelerated atherosclerosis, pericardial fibrosis, second primary malignancies (lung, thyroid, breast, soft tissue sarcomas), and hypothyroidism are all risk factors.

Staging

A CT scan of the abdomen and a bone marrow sample is used to evaluate the extent of the malignancy. When available, a PET scan gives additional information regarding distant spread, especially to bones. CT scans reveal larger lymph glands, but PET scans show metabolically abnormally active lymph nodes (although may not yet be swollen) and maybe a more reliable staging test.

Palliative care

In some cases of lymphoma, your medical team may discuss palliative care with you. Palliative care seeks to enhance your quality of life by reducing cancer symptoms rather than curing them.

Palliative care can reduce pain and assist manage other symptoms in addition to delaying the development of cancer. Radiation therapy, chemotherapy, and other pharmacological treatments may be used in treatment.

To ensure that you get a comprehensive picture and understand everything regarding Lymphoma, we invited Doctor Eom who is a leading doctor at Catholic University of Korea, Seoul St. Mary’s Hospital to address any questions you may have from an experienced point of view.

Interview

1. What is lymphoma?

Lymphoma is a cancer of the lymphatic system, which is a part of our body’s germ fighting network. Lymphoma is broadly divided into Hodgkin’s and non-Hodgkin’s lymphoma. Non-Hodgkin’s lymphoma is then divided into around 50 or more subtypes and are simply separated by aggressive and indolent lymphoma depending on their biologic behavior. 

2. What is exactly Hodgkin’s lymphoma?

Hodgkin’s lymphoma is a type of lymphoma, which was described by and then named after British physician Thomas Hodgkin in the 19th century. This kind of lymphoma has a pathology resembling RS-like so-called Reed Sternberg cells. Generally, Hodgkin’s lymphoma has favorable prognosis. Lymphomas other than non-Hodgkin’s lymphoma, that is lymphoma without Sternberg cells are collectively called non-Hodgkin’s lymphoma.

3. What’s the difference between aggressive and indolent lymphoma?

Aggressive lymphoma, also known as high-grade lymphomas, are defined as a group of fast-growing lymphomas. Since these tumors tend to progress and spread quickly, immediate intervention is required after the diagnosis. Otherwise, the patient could survive only several months or a year or less at most. On the other hand, indolent lymphomas are a type of lymphomas that grows and spreads slowly and their clinical course is very slow, spending several years even without any treatment. 

4. Talk to us more about the extra nodal lymphomas.

Yeah, extra nodal lymphomas refer to lymphomas, involvement in other sites than lymph nodes. Almost any tissues or organs can be affected by lymphoma, with the most common extra anodal sites of involvement being stomach, central nervous system, lung, bones, and skin.

5. What is the etiology of lymphoma?

It’s unclear what causes lymphoma, but a few risk factors are known to be associated with these two, these cancers. These risk factors include immunodeficiency, autoimmune disease, age, some type of viral infection such as Epstein Barr infection, and chemical and radiation exposure. 

6. Can you now tells us more about the symptoms of lymphoma?

Lymphoma may not always cause symptoms, especially in its early stage. Sometimes in might not cause any symptoms, until it grows quite large. Some people may notice swelling of the lymph nodes. Since there are lymph nodes all around the body, the swelling can occur everywhere in our body but usually in the neck, groin, abdomen, and armpits. The swellings are often painless. Other symptoms may include ongoing fever without any evidence of infection, night sweat, fever and chills, weight loss, and reduced appetite, and producing fatigue or lack of energy, especially in the, in advanced cases.

7. What are the main methods to diagnose lymphoma?

The ultimate method for diagnosis of lymphoma is pathologic examination where sample of tissue may be taken and presence of cancer cells is confirmed under the microscope by a pathologist. Other methods such as computer tomography and positron emission tomography (PET) are auxiliary in diagnosing lymphoma. Such methods are useful in determining stage of the disease rather than definite diagnosis.

8. What are the different stages that lymphoma has and how each stage is characterized?

The stage of lymphoma describes the extent of spread of the tumors using Roman numerals one through four. Stage one is defined if the cancer is found on one lymph node region. And stage two is if the cancer is in two or more lymph node regions on the same side of the diaphragm. Stages three and four are more spread disease. If the disease involves lymph node areas on both sides of diaphragm, the disease is defined as stage three. Stage four disease differs if the cancer spread throughout the body behind the lymph node. In this instance, the disease often, most often spreads to the liver, bone marrow, or lungs.

9. Are there any therapeutic tactics for lymphoma?

The principal modality for treating lymphoma is chemotherapy, usually given in combination. Radiation and surgery are auxiliary methods for lymphoma treatment. Radiation therapy can be given with curative intent, especially in early stages of a certain type of lymphoma. High-dose chemotherapy, followed by autologous stem cell transplantation is used for relapsed or aggressive lymphomas with high-risk features for relapse.

10. What is the prognosis for patients with lymphoma?

The prognosis for lymphoma is highly variable, depending on the subtype of the disease. According to a recent report, around 80% of the patients with non-Hodgkin’s lymphoma survived their cancer for one year or more after the diagnosis. 65% and 55% of the patients survived for five and ten year or more respectively after they are diagnosed.

11. Can you tell us, one last question about lymphoma, what is the clinical practice guidelines and how can people prevent it?

Unfortunately, many of the risk factors for non-Hodgkin’s lymphoma are outside a person’s direct control. The following factors, however, can be controlled. This includes avoiding behaviors that increase the chance of getting AIDS and hepatitis C infections, since both can weaken the immune system. Avoiding unnecessary exposure to radiation, maintaining a normal weight, and eating healthy food are important. Rarely, some women develop lymphoma in the scar tissue around breast implants. Therefore, the decision to get breast implants should be well thought out.

Conclusion 

Lymphomas are a kind of cancer that affects our immune system. It accounts for about 5% of all malignancies. It can have an impact on both young and old people. Persistent fevers, drenching night sweats, unintended weight loss, and widespread or localized enlargement of the lymph nodes are frequent signs of this illness.

If any of these symptoms are seen, the primary care provider seeks a hematology consultation or opinion as soon as possible to ensure timely diagnosis and treatment, since early detection and treatment of lymphomas results in higher survival rates with the fewest consequences.