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Non-Hodgkin’s Lymphoma

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Syed Intisar Hussain

Overview

Non-Hodgkin&#39;s lymphoma is a type of malignant disease that starts developing in your lymphatic system, a crucial part of your body&#39;s immune system. In non-Hodgkin&#39;s lymphoma, white blood cells called lymphocytes, exclusively grow in a pathological fashion and form tumors (abnormal cell growth) in your entire body<a href="#accordion">[1]</a>. 
&nbsp;

Non-Hodgkin&#39;s lymphoma (NHL), is considered to be the most common hematological (blood-related) malignancy globally. The counter variant of NHL is termed Hodgkin&rsquo;s lymphoma and both the conditions are differentiated by exclusive clinical characteristics along with the absence of Reed&ndash;Sternberg cells, Cd15 and Cd30 stain on histological examination. Currently, there are over 40 subtypes of NHL. However, the most common types are indolent follicular lymphoma (FL) and aggressive diffuse large B-cell lymphoma (DLBCL).&nbsp;

According to the latest report put forward by GLOBOCAN, an estimated 509,600 new cases of NHL were reported around the globe in the year 2018, which comprised 2.8% of global cancer diagnoses<a href="#accordion">[2]</a>.

The worldwide risk of NHL is 6.7 in men and 4.7 in women. Furthermore, on the basis of the latest World Health Organization (WHO) classification, the most common NHL in Western countries is DLBCL, which accounted for 31% of adult cases. In 2018, 248,700 global deaths resulted due to NHL, which summed up 2.6% of all the oncological (cancer-related) mortalities. As per research, men have a 0.33% lifetime risk of mortality due to NHL, whereas, the risk for women is 0.21%<a href="#accordion">[2]</a>.

The Karachi cancer registry reported a gradual increase in the yearly incidence of NHL in 2002 i.e. 8.4/100,000 and 6.5/100,000 in males and females respectively, almost twice higher than the rates ascertained in 1995. Studies also prove that a great number of adults who develop NHL in Pakistan, directly fall into the category of intermediate to high grade, with DLBCL &amp; ALCL presenting as the most common B &amp; T-cell NHL diagnoses in Pakistani adults<a href="#accordion">[3]</a>.

Non-Hodgkin lymphoma can arise from either B cells, T cells, or Natural Killer cells because of chromosomal translocation, mutation, or deletion. Pathogenesis of NHL initiates when the proto-oncogenes are activated due to chromosomal translocation, and the tumor suppressor genes are inactivated due to chromosomal deletion or mutation. The t (14:8) translocation variant is the most common chromosomal abnormality found in non-Hodgkin lymphoma. 
&nbsp;

NHL essentially can be classified into more than 30 types, based on the type of lymphocyte involved i.e., B lymphocytes (B cells) or T lymphocytes (T cells). Non-Hodgkin lymphoma can be also classified based on other factors, including its aggressiveness (fast-growing) or indolence (slow-growing)<a href="#accordion">[4]</a>.

&nbsp;

<ul>
	<li>
	<h5>Aggressive Lymphomas</h5>
	</li>
</ul>

These lymphomas progress relatively more quickly than the indolent ones, and patients with aggressive lymphomas even develop symptoms much sooner, creating an urgency for treatment initiation. Symptoms of the disease can range from enlarged lymph nodes and unintentional weight loss to broader bones and skin issues, solely based on the subtype of lymphoma. However, aggressive lymphomas respond extremely well to cancer treatments.

&nbsp;

The variants of the NHL which are commonly considered to be aggressive include:

<ol>
	<li>&nbsp;Diffuse large B-cell lymphoma</li>
	<li>&nbsp;Anaplastic large-cell lymphoma</li>
	<li>&nbsp;Burkitt lymphoma</li>
	<li>&nbsp;Lymphoblastic lymphoma</li>
	<li>&nbsp;Mantle cell lymphoma</li>
	<li>&nbsp;Peripheral T-cell lymphoma</li>
</ol>

&nbsp;

<ul>
	<li>
	<h5>Indolent Lymphomas</h5>
	</li>
</ul>

Such lymphomas progress comparatively slower than the aggressive type they don&rsquo;t even cause apparent symptoms in the early stages. Even though indolent lymphomas are fairly responsive to treatment, it can be challenging to eliminate them from the body. Similar to the aggressive type, symptoms present based on the subtype of the disease.

&nbsp;

Indolent subtypes include:

<ol>
	<li>Follicular lymphoma</li>
	<li>Cutaneous T-cell lymphoma</li>
	<li>Lymphoplasmacytic lymphoma</li>
	<li>Marginal zone B-cell lymphoma&nbsp;</li>
	<li>MALT lymphoma</li>
	<li>Small-cell lymphocytic lymphoma</li>
</ol>

&nbsp;

<ul>
	<li>
	<h5>Burkitt Lymphoma</h5>
	</li>
</ul>

Burkitt Lymphoma deserves special mention because it is considered as the most aggressive type of lymphoma and grows the fastest of all cancers. However, it is rare, accounting for almost 2% of all lymphoma diagnoses<a href="#accordion">[4]</a>. Burkitt lymphoma is often diagnosed in the younger population, especially in males. However, it can be seen in older adults with a weakened immune system.

&nbsp;

&nbsp;

According to the cells involved, the lymphomas can be again classified based on the origin being B-Cell or T-Cell.

&nbsp;

<ul>
	<li>
	<h5>B-Cell Origin Lymphomas</h5>
	</li>
</ul>

Almost 90% of the non-Hodgkin lymphoma diagnosis develop in your B cells<a href="#accordion">[4]</a>. Following are the subtypes of B-cell non-Hodgkin lymphoma:

<ol>
	<li>Diffuse Large B-cell Lymphoma (DLBCL): It is considered to be the most common type of non-Hodgkin lymphoma in the United States, accounting for almost 30% of all diagnosed cases, and is mostly reported in older adults<a href="#accordion">[4]</a>. Moreover, DLBCL is aggressive and can progress fast.</li>
	<li>Follicular Lymphoma: It is the most common type of indolent lymphoma and accounts for almost 20% of lymphoma diagnoses in the United States<a href="#accordion">[4]</a>. Follicular lymphoma is seen in middle-aged or older adults and mostly occurs in the bone marrow or lymph nodes.</li>
	<li>Marginal Zone Lymphomas: It is a lymphoma that grows slowly and forms in the mature B cells that circulate in your spleen. Marginal zone lymphomas can be subdivided into three types, namely mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone B-Cell lymphoma.</li>
</ol>

&nbsp;

<ul>
	<li>
	<h5>T-Cell Non-Hodgkin Lymphoma</h5>
	</li>
</ul>

This specific type of lymphoma is responsible for almost 10% of all diagnosed cases<a href="#accordion">[4]</a>. It is further divided into cutaneous T-cell lymphomas, which include mycosis fungoides and other peripheral T-cell lymphomas.

<ol>
	<li>Cutaneous T-Cell Lymphomas: These lymphomas are found in mature T cells and the subtypes include:</li>
	<li>Mycosis Fungoides: It is also known as Alibert-Bazin syndrome, a low-grade variant of non-Hodgkin lymphoma in which your white blood cells become cancerous and exclusively affect your skin.</li>
	<li>Sezary Syndrome: It is a much more aggressive classification of non-Hodgkin lymphomas. It is diagnosed when the cancerous lymphoma cells are found in the blood, lymph nodes, and other areas of the body, and not only the skin.</li>
	<li>Primary Cutaneous Anaplastic Large-cell Lymphoma: It is relatively rare, yet aggressive. Found in the mature T cells and mostly affects the younger population.</li>
	<li>Peripheral T-Cell Lymphomas: These are often aggressive cancers that are seen in the mature T cells. These cancers account for 15% of all non-Hodgkin lymphoma cases<a href="#accordion">[4]</a>.</li>
</ol>

<div>&nbsp;</div>

Signs And Symptoms

Signs and symptoms of non-Hodgkin&#39;s lymphoma reported by patients may comprise of<a href="#accordion">[1]</a>:

<ul>
	<li>Swollen lymph nodes in the neck, armpits, or groin</li>
	<li>Abdominal pain</li>
	<li>Pain in the chest, coughing, or difficulty breathing</li>
	<li>Constant fatigue</li>
	<li>Fever</li>
	<li>Night sweats</li>
	<li>Unexplained weight loss</li>
</ul>

<div>&nbsp;</div>

Causes

Non-Hodgkin lymphoma is caused by an alteration (or mutation) in your DNA of a specialized type of white blood cells, known as the lymphocytes. The mutations in your DNA allow the cells to grow pathologically and they multiply out of control. The multiplication usually takes place in either one or more of the lymph nodes in a specific area of the body, which includes your neck, armpit, or groin.

However, as time passes by, the abnormally multiplying lymphocytes may make their way to other parts of your body as well, including the bone marrow, spleen, liver, skin, lungs, stomach, and brain.

&nbsp;

Currently, there is no recommended screening guideline for NHL. However, the most reasonable method to catch lymphoma early on is to closely monitor the possible signs and symptoms. You should look out for any enlargement of one or more lymph nodes, which may cause a painless lump under the skin. The most common sites of such lumps are the side of the neck, armpit, or groin. Moreover, symptoms can also include fever, chills, night sweats, weight loss, lethargy, and swelling in the abdomen. 
&nbsp;

Diagnosis

As mentioned above, some variants of the NHL require urgent initiation of treatment. Hence, it needs to be diagnosed as early and efficiently as possible. Following are the diagnostic modalities that can be used<a href="#accordion">[6]</a>:

&nbsp;

<ul>
	<li>
	<h5>Biopsies</h5>
	</li>
</ul>

There are several forms of biopsies that can be used and are chosen on the basis of the subtype. These include:

<ol>
	<li>Excisional Or Incisional Biopsy: This type of biopsy is usually preferred because it provides ample samples to diagnose the type of NHL. If your doctor decides to remove the whole lymph node, it will be called an excisional biopsy, whereas if the decision taken includes only resecting a larger part of the tumor, it is called an incisional biopsy.</li>
	<li>Needle Biopsy:&nbsp;Most doctors do not use needle biopsies to diagnose lymphoma. However, if there is a suspicion of the lymph node being enlarged because of an infection or by the spread of cancer from another organ (such as the breast, lungs, or thyroid), a needle biopsy is often the first type of biopsy performed. An excisional biopsy might still be needed even after a needle biopsy, to diagnose and classify lymphoma. The two types of needle biopsy used are fine needle aspiration (FNA) and core needle biopsy.</li>
</ol>

&nbsp;

<ul>
	<li>
	<h5>Lab Tests On Biopsy Samples</h5>
	</li>
</ul>

The biopsy sample is evaluated by a pathologist. These lab tests include:

<ol>
	<li>Flow Cytometry And Immunohistochemistry: In both tests, the biopsy sample is treated with antibodies, which stick with the proteins on cells. The tests are named on the basis of the devices used to visualize the cells in the lab (immunohistochemistry) or with a special machine (for flow cytometry).</li>
	<li>Chromosome Tests: Physiologically a human has 23 pairs of chromosomes (strands of DNA), whereas, in some types of lymphoma, the cells have alterations in their chromosomes, such as having too many, too few, or abnormal chromosomes. Identifying these alterations can help in identifying the type of lymphoma.</li>
	<li>Polymerase Chain Reaction (PCR): A PCR is again used for identifying any genetic changes or certain chromosome variations which are too small to be seen with a microscope.</li>
</ol>

&nbsp;

<h5>Stages</h5>

The Lugano classification is the staging guideline that is used to classify patients with NHL. The staging system is essentially based on the number of areas where the tumor is present (nodal and extranodal) and their location<a href="#accordion">[5]</a>:

<ul>
	<li>
	Stage I -&nbsp;The first stage refers to a tumor that involves a single lymph node region (I) or a single extra lymphatic site (stage IE) without nodal involvement. It can involve a single node or a group of nearby residing nodes.
	</li>
	<li>
	Stage II -&nbsp;The second stage is defined as the involvement of two or more lymph node regions on the same side of your diaphragm. These regions may include the neck and underarm area. Moreover, it can be a localized involvement of an extra lymphatic site as well (stage IIE).&nbsp;
	</li>
	<li>
	&nbsp;Stage III -&nbsp;Stage three is termed when the lymph node involvement is on both sides of the diaphragm, or above the diaphragm, including the spleen.
	</li>
	<li>
	Stage IV -&nbsp;Stage four is the widespread involvement of multiple extra lymphatic organs such as the liver, bone marrow, and lungs, which can be with or without the association lymph node involvement.
	</li>
</ul>

<div>&nbsp;</div>

Treatment

The following treatment modalities can be used to manage NHL<a href="#accordion">[7]</a>:

&nbsp;

<ul>
	<li>
	<h5>Chemotherapy</h5>
	</li>
</ul>

Chemotherapy is a globally accepted treatment for NHL. It involves the usage of medications to kill the cancerous cells, and can even be used in combination with biological therapy and radiotherapy. Chemotherapy is administered through a drip into your vein (intravenous chemotherapy), orally, or as a combination of both. Examples of these agents include cisplatin and oxaliplatin.

&nbsp;

<ul>
	<li>
	<h5>High-Dose Chemotherapy</h5>
	</li>
</ul>

If NHL is not responding to the initial treatment, it is termed refractory lymphoma, and you may be prescribed a much stronger dose of chemotherapy. However, it should be noted that this intensive chemotherapy essentially destroys your bone marrow.

&nbsp;

<ul>
	<li>
	<h5>Radiotherapy</h5>
	</li>
</ul>

Radiotherapy is the preferred treatment of early-stage NHL i.e. where the cancer is only found in one part of your body. The duration of the treatment depends on the type and stage of the non-Hodgkin lymphoma you have developed. Radiotherapy is administered in brief daily sessions for no more than 3 weeks.

&nbsp;

<ul>
	<li>
	<h5>Monoclonal Antibody Therapy</h5>
	</li>
</ul>

Some types of NHL warrant a specific type of medicine called a monoclonal antibody. These agents stick on to both the healthy and cancerous cells, calling your immune system to attack and eliminate them. Once the treatment has been completed, the healthy cell count is regulated naturally. It can be given individually or in combination with chemotherapy to make the entire treatment more efficient. One of the main monoclonal antibody medicines used to treat non-Hodgkin lymphoma is called rituximab which can be administered as an injection directly into your vein over the course of a few hours.

&nbsp;

<ul>
	<li>
	<h5>Steroid</h5>
	</li>
</ul>

Steroids are used in combination with chemotherapy to treat NHL. Research shows that using steroids in combination makes chemotherapy more effective. Steroids can be given in an oral or injection form.

<div>&nbsp;</div>

NHL not only develops complications on its own but can even be caused due to treatment options. Some of the complications include<a href="#accordion">[8]</a>:

&nbsp;

<ul>
	<li>
	<h5>Infertility</h5>
	</li>
</ul>

Chemotherapy and radiotherapy, which are used for treating NHL, may cause infertility. This can be temporary but also has the tendency to be permanent. Your healthcare provider can estimate the risk of infertility in your case and inform you of your options.

&nbsp;

<ul>
	<li>
	<h5>Second Cancers</h5>
	</li>
</ul>

The treatment for NHL can drastically increase your chances of developing other various forms of cancers namely, second cancer. The pathology behind this is that chemotherapy and radiotherapy affect both the healthy cells, as well as cancer cells. This damage can cause the cells to become cancerous in a matter of years.

&nbsp;

<ul>
	<li>
	<h5>Depression</h5>
	</li>
</ul>

A cancer diagnosis puts you at grave risk for depression.

<div>&nbsp;</div>

Following are the risk factors that put you at a higher risk for developing NHL<a href="#accordion">[1]</a>:

<ul>
	<li>Increasing age has a strong association with lymphoma overall, with the peak age being 60 years. However, some types are more prevalent in younger people.</li>
	<li>NHL has a predilection towards the female gender.</li>
	<li>Your chances of developing NHL increase if you have a first-degree relative (parent, child, and sibling) diagnosed with NHL.</li>
	<li>Studies suggest that chemicals like benzene, herbicides, and insecticides (weed- and insect-killing agents) cause an increased risk of NHL. Moreover, some chemotherapeutic agents which are used to treat cancers can increase your risk of developing NHL.</li>
	<li>Anyone with a weakened immune system is at great risk of developing NHL.</li>
</ul>

<div>&nbsp;</div>

Even though there are no such guidelines that might help you to prevent NHL, studies prove that there are infections that are strongly associated with the disease. Thus, prevention from those diseases might help you avoid NHL. Such infections include<a href="#accordion">[9]</a>:

&nbsp;

<ul>
	<li>HIV</li>
</ul>

It is the virus that can cause acquired immunodeficiency syndrome, also known as AIDS. Research proves that AIDS may increase the risk of NHL. Hence, avoiding activities such as intravenous drug use or unprotected sex with multiple partners can limit one&rsquo;s risk of infection and in turn NHL.

&nbsp;

<ul>
	<li>HTLV-1</li>
</ul>

Another infection to steer clear of is the human T-cell lymphotropic virus (HTLV-1). This virus is common in the Japanese and Caribbean populations.

<div>&nbsp;</div>

Researchers are currently testing several treatment combinations for non-Hodgkin lymphoma. Several immunotherapy drugs are undergoing clinical trials for various types of lymphoma. An early-phase clinical trial assessing mosunetuzumab (Mosun) demonstrated long-lasting remission in almost 50% of patients with indolent B-cell non-Hodgkin lymphoma whereas 20% of people with aggressive B-cell non-Hodgkin lymphoma went into remission after treatment<a href="#accordion">[10]</a>.&nbsp; 
&nbsp;

Key Points

<ul>
	<li>Non-Hodgkin&#39;s lymphoma is a type of malignant disease which develops in your lymphatic system, a crucial part of your body&#39;s immune system</li>
	<li>Non-Hodgkin&#39;s lymphoma (NHL), is considered to be the most common hematological (blood-related) malignancy globally</li>
	<li>The most common types are indolent follicular lymphoma (FL) and aggressive diffuse large B-cell lymphoma (DLBCL).&nbsp;</li>
	<li>According to the latest report put forward by GLOBOCAN, an estimated 509,600 new cases of NHL were reported around the globe in the year 2018, which comprised 2.8% of the global cancer diagnoses</li>
	<li>The worldwide risk of NHL is 6.7 in men and 4.7 in women</li>
	<li>Mortalities were recorded at 248,700 globally due to NHL in 2018, which summed up for 2.6% of all the oncological (cancer-related) mortalities</li>
	<li>Data suggests that men have a 0.33% lifetime risk of mortality due to NHL. Whereas, the risk for women is 0.21%</li>
	<li>The Karachi cancer registry reported a gradual increase in the yearly incidence of NHL in 2002 -8.4/100,000 and 6.5/100,000 in males and females respectively, almost twice as much as the 1995 rates</li>
	<li>DLBCL &amp; ALCL present as the most common B &amp; T-cell NHL diagnoses in Pakistani adults.</li>
	<li>NHL can essentially be classified into more than 30 types on the basis of the type of lymphocyte involved i.e. B lymphocytes (B cells) or T lymphocytes (T cells)</li>
	<li>Aggressive lymphomas progress relatively more quickly than indolent ones, and patients with aggressive lymphomas even develop symptoms much sooner, creating an urgency for treatment initiation.</li>
	<li>Indolent lymphomas progress comparatively slower than the aggressive type, in fact, they don&rsquo;t even cause apparent symptoms in the early stages.</li>
	<li>Burkitt lymphoma deserves a special mention because it is considered the most aggressive type of lymphoma and grows the fastest of all cancers</li>
	<li>According to the cells involved, the lymphomas can be again classified on the basis of the origin being B-cell or T-cell.</li>
	<li>Almost 90% of the non-Hodgkin lymphoma diagnosis develop in your B cells</li>
	<li>T-Cell lymphoma is responsible for almost 10% of all diagnosed cases. It is further divided into cutaneous T-cell lymphoma, which includes mycosis fungoides and other peripheral T-cell lymphomas.</li>
	<li>The first stage refers tumor involving a single lymph node region or a single extra lymphatic site (stage IE), without nodal involvement</li>
	<li>The second stage is defined as the involvement of two or more lymph node regions on the same side of your diaphragm</li>
	<li>Stage three is termed when the lymph node involvement is on both sides of the diaphragm</li>
	<li>Stage four is the widespread involvement of multiple extra lymphatic organs.</li>
	<li>Signs and symptoms may include abdominal pain, lethargy and night sweats.</li>
	<li>Non-Hodgkin lymphoma is caused by an alteration (or mutation) in your DNA of a specialized type of white blood cell, known as the lymphocytes</li>
	<li>Currently, there is no recommended screening guideline for NHL. However, the most reasonable method to catch lymphoma early on is to closely monitor the possible signs and symptoms</li>
	<li>Diagnostic modalities include biopsies and lab tests on the biopsies.</li>
	<li>Treatment modalities include chemotherapy, radiotherapy, steroids and monoclonal antibodies.</li>
	<li>Complications include infertility and the risk of getting second cancer.</li>
	<li>Even though there are no such guidelines that might help you to prevent NHL, studies prove that there are infections which are strongly associated with the disease. Thus, prevention from those diseases might help you avoid NHL 
	&nbsp;</li>
</ul>

[1] Non-Hodgkin's Lymphoma. Mayo Clinic.

[2] Thandra KC, Barsouk A, Saginala K, Padala SA, Barsouk A, Rawla P. Epidemiology of Non-Hodgkin's Lymphoma. Med Sci (Basel). 2021;9(1):5. Published 2021 Jan 30.