Non-Hodgkin lymphomas (NHLs) are malignancies that arise from white blood cells in the lymphatic system. More specifically, they develop from B-lymphocytic and T-lymphocytic cells, which are more commonly known as white blood cells. Unlike Hodgkin lymphomas, non-Hodgkin lymphomas do not have Reed-Sternberg cells present.  

The lymphatic system is a network of tissues and organs that help our bodies fight infection and disease. It is composed of lymph vessels (carries lymph fluid around the body), lymph fluid (carries nutrients around the body and removes unwanted bacteria/viruses) and lymph nodes/glands (filters lymph fluid and empties it into the bloodstream). Some of the most well-known lymph tissues include the bone marrow, the spleen, and the tonsils. 

This page will focus on indolent (or slow growing) NHLs that develop from B-lymphocytes. While B-cell lymphomas are the most common subtype of all lymphomas (including Hodgkin lymphomas), indolent lymphomas are less common.

In general, NHLs are more commonly found in men, and are generally diagnosed after the age of 60. However, anyone can develop this disease.

Types of Non-Hodgkin Lymphomas (Indolent B-Cell) 

There are several types of Indolent B-cell NHL, which are often categorised based on cellular appearance under the microscope, tumour behaviour, and/or location of disease.

Follicular Lymphoma

Follicular lymphoma is the most common subtype of indolent NHL, and is characterised by the circular or clump-like appearance of cancerous follicular B-cells under the microscope. There are four main subtypes of follicular lymphoma.

Duodenal-type Follicular Lymphoma 

Duodenal-type follicular lymphoma, or primary gastrointestinal follicular lymphoma (PGFL), develops in the duodenum, which is the first portion of the small intestine. It is a very-slow growing type of NHL, is usually diagnosed in early stages, and often has an excellent prognosis.

Predominantly Diffuse-appearing Follicular Lymphoma 

Predominantly diffuse-appearing follicular lymphoma is characterised by scattered (or diffuse) follicular lymphoma cells spread throughout an area in the body (most commonly in the groin or inguinal area). Despite its diffuse appearance, it often carries a good prognosis.

Paediatric-type Follicular Lymphoma

Paediatric-type follicular lymphoma is a very rare subtype that mostly affects children, but can affect adults up to 40 years of age. It often behaves differently to standard follicular lymphoma, as it behaves more like a benign tumour. This subtype rarely metastasises, has a very low recurrence rate, and often carries a good prognosis.

Extranodal Follicular Lymphoma

In rare cases, follicular lymphoma can develop outside of the lymph nodes. This is known as an extranodal follicular lymphoma, and is usually found on the skin.

Chronic Lymphocytic Leukemia (CLL) & Small Lymphocytic Lymphoma (SLL)

Chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) are often coupled together and expressed as CLL/SLL, as the two diseases are very similar. The main difference between CLL and SLL is the location of the cancer. CLL is mostly found in the blood (like a leukaemia), whereas SLL is mostly found in lymph nodes and lymphoid tissue (like a lymphoma). CLL is also slightly more common than SLL. CLL/SLL can metastasise, and can have a good prognosis. 

For more information on CLL/SLL, please refer to the Rare Cancers Australia Chronic Lymphocytic Leukaemia (CLL) page.

Waldenstorm’s Macroglobulinemia (WM)

Waldenstorm’s Macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a rare subtype of NHL that is generally found in the spleen, which is a blood-filtering organ in the immune system. It is known for causing an overproduction of immunoglobulin macroglobulin (IgM), which is an antibody in the immune system that acts as a primary barrier against pathogens (agents that can cause disease). WM can be confused with myeloma, however the two diseases are treated differently. WM often has a good prognosis.

Marginal Zone Lymphoma (MZL)

Marginal zone lymphoma (MZL) is a rare subtype of indolent NHL that mainly affects lymphocytes at the edges of lymph nodes and/or lymphoid tissue. Unlike most NHLs, MZL is slightly more common in women. There are three main subtypes of MZL.

Mucosa-associated Lymphoid Tissue (MALT) Marginal Zone Lymphoma 

Mucosa-associated lymphoid tissue (MALT) MZL is the most common subtype of MZL, and is classified as an extra-nodal lymphoma (lymphoma developing outside of lymph nodes). The lymphoma is found in the mucosa that lines lymphoid tissue, such as the tonsils, and scattered around the rest of the body.

MALT MZL is often divided into gastric and non-gastric categories, and are treated differently from each other. Gastric MALT MZL is the most common subtype, and develops in the stomach. Non-gastric MALT MZL develops outside of the stomach, and is usually found in the eyes (ocular adnexa), lungs, and salivary glands.

Nodal Marginal Zone Lymphoma 

Nodal MZL, also known as monocytoid B-cell lymphoma, is the rarest type of MZL, and is found in the marginal zones surrounding lymph nodes. Unlike most other NHLs, this subtype is slightly more common in women than in men. It is slow growing, unlikely to metastasise, but can recur. Nodal MZL can have a good prognosis.

Splenic Marginal Zone Lymphoma 

Splenic MZL is a rare subtype of MALT MZL that develops in the spleen, bone marrow, and blood. It has been linked to people who have autoimmune disorders and/or the hepatitis C virus. Unlike most NHLs, splenic MZL does not cause swollen lymph nodes. It is slow growing, unlikely to metastasise, but can recur. Splenic MZL can have a good prognosis.

Cutaneous B-cell Lymphoma (CBCL)

Cutaneous B-cell lymphoma (CBCL) is a rare subtype of NHL that usually begins in the skin. There are two types of indolent CBCL, and one aggressive type. 

Primary Cutaneous Follicle Centre Lymphoma (PCFCL)

Primary cutaneous follicle centre lymphoma (PCFCL) is the most common subtype of CBCL. They normally develop on the head, neck or torso of the body, often develop slowly, and usually carry a good prognosis.

Primary Cutaneous Marginal Zone Lymphoma

Primary cutaneous MZL (PCMZL) is the second most common type of CBCL that originates from mucosa-associated lymphoid tissue (MALT). It is normally found on the torso or the arms, and tends to affect men twice as much as women. It develops slowly, has a high recurrence rate, and often carries a good prognosis.

Primary Cutaneous Diffuse Large B-cell Lymphoma

Primary cutaneous diffuse large B-cell lymphoma is an aggressive subtype of CBCL. For more information on this disease, please refer to the Rare Cancers Australia Non-Hodgkin Lymphoma (Aggressive B-Cell) page.

Treatment

If an indolent B-cell NHL is detected, it will be staged and graded based on size, metastasis (whether the cancer has spread to other parts of the body) and how the cancer cells look under the microscope. Staging and grading helps your doctors determine the best treatment for you.

All NHLs are staged using the Lugano classification system, which may also be referred to as a modification of the Ann Arbor staging system. In this system, NHLs are assigned numerical values, from stage I-IV:

• Stage I: cancer cells are confined to a single lymph node area, either above or below the diaphragm (large muscle separating the abdomen from the chest). This stage is also known as early-stage cancer.
• Stage II: cancer cells have spread to two or more lymph node areas on the same side of the diaphragm. This is also known as localised cancer.
• Stage III: the cancer has become larger and affected lymph node areas on both sides of the diaphragm. This is also known as localised cancer.
• Stage IV: Lymphoma is in multiple lymph node areas and may be present in other parts of the body, such as bone marrow, liver, and/or lungs. This is also known as advanced or metastatic cancer.

In addition to the numerical system, your doctor may also stage your cancer with a letter, which gives more information about your symptoms and how your body is being affected by the disease. These letters include:

• A – You feel well and have no B-symptoms of lymphoma.
• B – You have some or all of the B-symptoms of lymphoma.
• E – You have NHL in an organ that is not a part of the lymphatic system (such as lungs, skin, bladder etc.).
• X – You have a tumour that is greater than 10cm in size. This is also called ‘bulky disease’. 
• S – You have a lymphoma in your spleen.

As all cancers discussed on this page are classified as ‘indolent’, these cancers are all low-grade. 

Once your tumour has been staged and graded, your doctor may recommend genetic testing, which analyses your tumour DNA and can help determine which treatment has the greatest chance of success. They will then discuss the most appropriate treatment option for you. 

Treatment is dependent on several factors, including location, age, stage of disease and overall health.

Treatment options for indolent B-cell NHLs may include:

• Watch and wait.
• Chemotherapy.
• Radiation therapy.
• Targeted therapy, potentially including monoclonal antibodies.
• Immunotherapy, potentially including:
  • CAR T-cell therapy.
  • Rituximab.
• Stem cell and/or bone marrow transplant.
• Phototherapy.
• Splenectomy (surgery to remove the spleen – only required for patients who have a lymphoma in their spleen, such as splenic MZL).
• Surgery to remove skin lesion (only in patients with a lymphoma of the skin). 
• Clinical trials.
• Palliative care.

For more information on the treatment options, please refer to the Rare Cancers Australia treatment options page. 

Risk factors 

While the cause of all NHLs remains unknown, the following factors may increase the likelihood of developing the disease:

• Previous infections with viruses, including:
  • Epstein-Barr virus (EBV).
  • Human immunodeficiency virus (HIV).
  • Human T-lymphotropic virus type 1 (HTLV-1).
  • Hepatitis C (Hep C).
  • Human herpesvirus-8 (HHV-8)
• Chemical exposure to pesticides, fertilisers, and/or solvents.
• Having an autoimmune disease, such as:
  • Rheumatoid arthritis.
  • Scleroderma.
  • Sjögren’s syndrome.
• Having had a previous organ transplant.
• Infections with certain bacteria, such as helicobacter pylori (H. pylori – known to cause stomach ulcers). 
• Having a family history of NHL.

Not everyone with these risk factors will develop the disease, and some people who have the disease may have none of these risk factors. See your general practitioner (GP) if you are concerned.

Early symptoms 

Most patients with an indolent B-cell NHL will appear asymptomatic in the early stages of disease. As symptoms progress, some of the following symptoms may appear. 

General Symptoms

General symptoms of an indolent B-cell NHL may include:

• B-symptoms, which include:
  • Drenching night sweats.
  • Unexplained weight loss.
  • Persistent fevers over 37.5°C.
• Fatigue.
• Itchy skin.
• Recurrent infections.
• Shortness of breath.
• Low blood counts, potentially including anaemia (deficiency of red blood cells in the body), thrombocytopenia (deficiency of platelets in the body), and/or neutropenia (deficiency of neutrophils (a type of white blood cell) in the body), which may cause the following symptoms:
  • Shortness of breath.
  • Fatigue.
  • Dizziness.
  • Confusion.
  • Difficulty concentrating.
  • Paleness.
• Abnormal protein levels, which may cause the following symptoms:
  • Poor circulation (causing blue fingers and/or toes, numbness and/or tingling in fingers and toes etc.).
  • Confusion.
  • Headaches.
  • Nosebleeds.
  • Blurred vision.

Symptoms of Follicular Lymphoma

In addition to the general symptoms listed above, patients with follicular lymphoma may experience the following symptoms:

• Nausea and/or vomiting.
• Diarrhea.
• Constipation.
• Blood in urine and/or urine.
• Feeling of fullness after little food.
• Confusion and/or memory changes.
• Personality changes.
• Seizures.
• Weakness, burning, pins and needles, and/or numbness in limbs.
• Chest pain.
• Dry cough.
• Red/purple looking rash.
• Skin lumps.
• Abdominal pain (more common in duodenal-type follicular lymphoma).
• Heartburn (more common in duodenal-type follicular lymphoma).
• Mass in groin (more common in predominantly diffuse-appearing follicular lymphoma). 
• Swollen lymph node/lump in neck and head (more common in paediatric-type follicular lymphoma).

Symptoms of CLL/SLL

In addition to the general symptoms listed above, patients with CLL/SLL may experience the following symptoms:

• Easy bruising and/or bleeding.
• Painless lump in the neck, under arms, groin, and/or other areas.

Symptoms of Waldenstorm’s Macroglobulinemia 

In addition to the general symptoms listed above, patients with WM may experience the following symptoms:

• Abnormal bleeding from nose, gums, and/or gastrointestinal tract.
• Headache.
• Peripheral neuropathy.
• Muscle cramps.
• Poor concentration.
• Confusion.
• Hyper-viscosity syndrome.

Symptoms of Marginal Zone Lymphoma 

In addition to the general symptoms listed above, patients with MZL may generally experience the following symptoms:

• Swollen lymph nodes.
• Easy bruising and/or bleeding.
• Loss of appetite.
• Abdominal pain.

Gastric MALT MZL

• Persistent indigestion.
• Nausea and/or vomiting.

Non-gastric MALT MZL

• Low iron and/or haemoglobin.
• Diarrhea.
• Constipation.
• Bloating.
• Feeling full after little food.
• Redness of eyes.
• Dark pink lumps on the inside of the eyelid.
• Double vision.
• Droopy eyelids.
• Bulging eye(s).
• Cough, which may contain blood.
• Chest pain.
• Lump in the front of the ear, in the mouth, or on the jaw.
• Difficulty swallowing.
• Skin patches (usually pink, red, or purple in colour).
• Skin lumps.
• Hoarse voice.
• Sensitivity to the cold.
• Weight gain.

Nodal MZL

• Pressure on the airway, which may cause difficulties with breathing and/or swallowing.
• Nerve pain.

Splenic MZL

• Enlarged spleen.
• Feeling full after little food.

Symptoms of Indolent Cutaneous B-Cell Lymphoma 

In addition to the general symptoms listed above, patients with indolent cutaneous B-cell lymphoma may experience the following symptoms:

• Small, raised, solid lumps on the skin called papules (look like pimples).
• Thickened, flat, larger lumps.
• Nodules that are red or pink in colour.
• Ulcerations, which may occur with an infection.

Not everyone with the symptoms above will have cancer but see your GP if you are concerned. 

Diagnosis/diagnosing 

If your doctor suspects you have an NHL, they may order the following tests to confirm the diagnosis and refer you to a specialist for treatment.

Physical examination 

Your doctor will collect your overall medical history, as well as your current symptoms. Following this, they may examine your body to check for any abnormalities.

Blood tests

Your doctor will recommend a blood test for check for signs of Hodgkin lymphoma and determine overall health. The most common test is a full blood count, which will analyse the levels of red blood cells, white blood cells and platelets in the blood. Low counts in any of these categories could be indicative of disease.

Imaging 

The doctor will take images of your body using magnetic resonance imaging (MRI), a computed tomography scan (CT scan), ultrasound, and/or positron emission tomography (PET scan), to check for signs of tumours and/or metastasis. 

Lumbar puncture 

A lumbar puncture, or spinal tap, involves inserting a needle between two vertebrae in the lower spine and extracting a sample of cerebrospinal fluid (CSF) for analysis. A local anaesthetic or sedative is given prior to the procedure. Your doctor will discuss any risks and possible complications with you prior to the procedure.

Endoscopy

An endoscopy is a surgical procedure that involves inserting a long, flexible tube with a light and small camera through the oesophagus and into the stomach to examine the gastrointestinal tract. This procedure is used if it is suspected you have a B-cell lymphoma in this area. You will be given a sedative or anaesthetic throughout the procedure. You will be asked to fast for several hours prior to the procedure. An endoscopy is often done as a day surgery. Your doctor will discuss the risks and any possible complications prior to the procedure.  

Throughout the procedure, your doctor may also perform an endoscopic ultrasound to guide the needle during a biopsy, or to check for signs of cancer metastasis. 

Biopsy

Once the location of the cancer has been identified, the doctor will perform a biopsy to remove a section of tissue using a needle. In most cases, this may be done by either an excision biopsy (where the lymph node is completely or partially removed), a fine needle biopsy (a fine needle is inserted into the lymph node to remove a sample), or a core needle biopsy (where a bigger needle is inserted into the lymph node to remove a sample). Both procedures are often performed as a day surgery. In rare cases, a bone marrow biopsy may be performed to see if it contains any cancerous cells. This process involves inserting the needle into the hipbone (or the breastbone in some cases) to remove samples of solid and liquid bone marrow. These samples will then be analysed for cancer cells. 

Prognosis (Certain factors affect the prognosis and treatment options) 

While it is not possible to predict the exact course of the disease, your doctor may be able to give you a general idea based on the rate and depth of tumour growth, susceptibility to treatment, age, overall fitness, and medical history. Generally, early-stage NHLs have a better prognosis and survival rates. However, if the cancer is advanced and has spread, the prognosis may not be as good and there may be a higher risk of cancer recurrence. It is very important to discuss your individual circumstances with your doctor to better understand your prognosis.

References 

• Cancer Council Australia
• Leukaemia Foundation
• Lymphoma Australia

^{Some references are to overseas websites. There may be references to drugs and clinical trials that are not available here in Australia.}