Lymphoma: Signs, Symptoms, and Complications

Lymphoma is a group of blood cancers that affect a type of white blood cell known as a lymphocyte. There are no less than 70 different types and subtypes of lymphoma, broadly classified under two categories:

• Hodgkin lymphoma (HL), of which there are six types, accounts for around 10% of all lymphoma cases in the United States.
• Non-Hodgkin lymphoma (NHL), involving over 60 types and subtypes, represents roughly 90% of all cases.

The distinction between HL and NHL is made by looking at a sample of biopsied tissue under the microscope. With HL, there will be abnormal cells with two nuclei, called Reed-Sternberg cells, that do not occur with NHL.

Despite the cellular differences, both HL and NHL have many of the same symptoms, particularly in the early stages of the disease.

However, the pathogenesis (the manner in which the disease develops) differs significantly from one lymphoma subtype to the next. Some lymphomas develop in an orderly fashion as this malignancy moves through the lymphatic system (comprised of the lymph nodes, spleen, tonsils, thymus gland, and bone marrow).

Others develop haphazardly, establishing tumors in specific parts of the lymphatic system or moving outside of the system to affect distant organs.

The warning signs of lymphoma can often be so subtle that it may take years before you realize that anything is wrong. Moreover, many of the symptoms will be non-specific and easily confused with other, less serious diseases. Even so, there are tell-tale clues to watch out for if you think you may have lymphoma or have a family history of the disease.

The lymphatic system is a closed network of vessels and organs whose role is it to isolate and kill germs in the body. Central to this system are lymphocytes and lymph nodes.

Like all white blood cells, lymphocytes are part of the body's first line of defense against infection. They are transported throughout the vascular network of the lymphatic system in a fluid known as lymph. Scattered along the route are dense clusters of lymph nodes whose role it is to filter bacteria, viruses, and other microorganisms from lymph.

Under normal circumstances, lymphocytes move in and out of the lymph nodes freely to carry on their immune functions. When lymphoma develops, they will start to accumulate in the lymph nodes in an attempt to isolate and neutralize the malignancy.

This accumulation, along with the destruction of other white blood cells known as macrophages and monocytes, can lead to a cascade of symptoms characteristic to both HL and NHL, including:

• Lymphadenopathy (swollen lymph nodes)
• Fever
• Night sweats
• Anorexia (loss of appetite)
• Pruritus (itching)
• Dyspnea (shortness of breath)
• Unintended weight loss
• Persistent fatigue

Of all of the symptoms, lymphadenopathy is the central defining feature. The swollen nodes will typically be described as being firm, rubbery, and movable in the surrounding tissues. Unlike the tender lymph nodes associated with viral infections like HIV, lymphadenopathy caused by lymphoma is rarely painful.

The location of lymphadenopathy can also provide clues as to the type of lymphoma involved:

• With HL, which moves in a sequential fashion through the lymphatic system, lymphadenopathy will almost invariably start in the upper body—typically the neck (cervical lymph nodes), chest (mediastinal lymph nodes), or armpits (axillary lymph nodes)—before progressing to the lower body.
• With NHL, the disease develops haphazardly and can affect lymph nodes in any part of the body, including the abdomen (peritoneal lymph nodes) and groin (inguinal lymph nodes).

The very fact that you have swollen lymph nodes that do not resolve should be the first clue that you need to see a doctor.

The symptoms of lymphoma are defined by the type and subtype of lymphoma involved as well as its stage, and grade (severity), and location in the body. This is especially true if the disease is extranodal, meaning that it occurs outside of the lymph nodes.

There are two main categories of extranodal lymphoma:

• Primary extranodal lymphoma occurs when the disease originates outside of the lymphatic system. The vast majority of primary extranodal cases occur with NHL; it is exceptionally rare with HL.
• Secondary extranodal lymphoma originates in the lymphatic system and then spreads to other organs. This can occur with both HL and NHL.

The definition of extranodal can vary slightly based on whether HL or NHL is involved. With HL, the spleen, tonsils, and thymus are considered nodal sites since the disease spreads within the confines of the lymphatic system. By contrast, these same organs are considered extranodal with NHL given that the disease develops spontaneously in any part of the body.

While nodal lymphoma is characterized by lymphadenopathy and other classic symptoms, the symptoms of extranodal lymphoma are dictated by the organs affected.

The stomach and small intestine are the first and second most common sites for extranodal lymphoma. Primary NHL is the usual culprit, with most stomach lymphomas linked to a type known as mucosa-associated lymphoid tissue (MALT) lymphoma. The types of NHL affecting the small intestine include MALT, mantle cell lymphoma, Burkitt lymphoma, and enteropathy-associated lymphoma.

Symptoms of gastrointestinal lymphoma may include:

• Abdominal tenderness and pain
• Cramps
• Indigestion
• Constipation
• Diarrhea
• Malaise (a general feeling of unwellness)
• Early satiation (a feeling of fullness after a few bites)
• Nausea and vomiting
• Rectal bleeding
• Black, tarry stools
• Unintended weight loss

Cutaneous (skin) lymphoma occurs with both HL and NHL. Around 25% of nodal lymphomas will manifest with skin symptoms, while 65% of all NHL cases will be attributed to a subtype known as cutaneous T-cell lymphoma. One of the most common subtypes is mycosis fungoides.

Symptoms of cutaneous lymphoma may include:

• Round skin patches that may be raised, scaly, or itchy
• Lightened patches of skin
• Skin tumors that can spontaneously break open
• Thickening of the palms or soles
• An itchy, rash-like redness covering much of the body
• Alopecia (hair loss)

The primary involvement of the bone in NHL is classified as Stage 1 lymphoma, while the secondary involvement with widespread (disseminated) disease is considered Stage 4.

When lymphoma affects the bone marrow, it can drastically impair the production of red and white blood cells, causing anemia (low red blood cells) and thrombocytopenia (low platelets). It also suppresses a specific white blood cell produced in the bone marrow called a leukocyte, leading to leukopenia. (Leukocytes are the same cells in involved in a related blood cancer known as leukemia.)

Symptoms of bone lymphoma include:

• Bone pain
• Limb swelling
• Loss of range of motion in a limb
• Fatigue
• Easy bruising and bleeding

Lymphomas of the central nervous system (CNS) represent between 7% and 15% of all brain cancers. They are usually classified as B-cell lymphoma and occur most commonly in immunocompromised people, such as those with advanced HIV infection.

Symptoms of primary or secondary CNS lymphoma include:

• Headaches
• Muscle weakness in a specific body part
• Loss of sensation in a specific body part
• Problems with balance, memory, cognition, and/or language
• Changes in vision or partial vision loss
• Nausea and vomiting
• Seizures

Pulmonary (lung) lymphoma is more common with HL than NHL. With HL, it is secondary to the mediastinal lymph nodes of the chest. If it occurs with NHL, it is most often primary and caused by MALT lymphoma.

Symptoms of pulmonary lymphoma are often non-specific in the early stages of the disease and may include:

• Coughing
• Chest pain
• Fever
• Shortness of breath
• Crepitus (audible lung crackles)
• Hemoptysis (coughing up blood)
• Unintended weight loss

Primary liver lymphoma is extremely rare and almost exclusively associated with NHL. With that said, there will be secondary liver involvement in 15% of people with NHL and 10% of those with NL. In most cases, the malignancy will have spread from the retroperitoneal lymph nodes situated to the back of the abdominal cavity to the liver.

Symptoms of liver lymphoma are often mild and non-specific and may include:

• Extreme fatigue
• Pain or swelling in the upper right abdomen
• Loss of appetite
• Nausea and vomiting
• Jaundice (yellowing of the skin and/or eyes)
• Dark urine
• Unintended weight loss

As with the liver, primary lymphoma of the kidneys and adrenal glands is rare. Primary or secondary kidney lymphoma often mimics renal cell carcinoma, a type of cancer that starts in the small tubes of the kidney and causes symptoms such as:

• Flank pain
• A lump or swelling in the side or abdomen
• Hematuria (blood in urine)
• Loss of appetite
• Fever
• Persistent fatigue
• Unintended weight loss

Testicular lymphoma accounts for around 5% of all abnormal growth in the testicles. It typically manifests with painless swelling, usually in one testicle only. What makes testicular lymphoma especially concerning is that it tends to involve aggressive B-cell lymphomas that move quickly into the central nervous system.

Genital involvement is women is rare, although cases involving the cervix and uterus have been reported. More often than not, women will experience lymphoma not in the genitals themselves but in tissues surrounding the genitals, known as the adnexa.

There are six different types of HL (including "classical" nodular sclerosing Hodgkin lymphoma) and over 60 types and subtypes of NHL (of which 85% are B-cell lymphomas).

The types and subtypes can be further differentiated by their grade, some of which will be low-grade (slow-growing) and others of which will be high-grade (aggressive). These characteristics can often predict how quickly and extensively symptoms will develop and progress.

Because lymphoma weakens the immune system, it can lead to serious long-term complications. This is especially true with low-grade lymphomas, many of which cannot be cured.

Secondary cancers, including leukemia and solid tumors, are among the leading causes of death in people with lymphoma. Leukemia can often develop years and even decades after exposure to alkylating chemotherapy drugs, while 70% to 80% of all secondary solid tumors occur in people with previous exposure to combined radiation and chemotherapy.

Breast cancer in women with HL often occurs 10 to 15 years after chest irradiation, particularly in those under 35. Similarly, lung cancer rates are higher in people with HL who are smokers and have previously undergone radiation and/or chemotherapy.

Heart disease is believed to be the leading, non-cancer cause of death in people with lymphoma. Among the chief concerns is coronary artery disease (CAD), which occurs at a rate three- and five-times greater than that of the general population. Most CAD cases develop 10 to 25 years after exposure to chest radiation therapy for lymphoma.

Similarly, radiation to the neck is associated with a two- to five-fold increase in the risk of stroke. As with CAD, pre-existing heart disease, smoking, diabetes, and high blood pressure only adds to the risk.

As a disease that often affects organs of the endocrine system, lymphoma may cause hormonal imbalances or insufficiencies that can persist for years following the successful treatment of the disease.

The most common complication is hypothyroidism (low thyroid function), affecting as many as 60% of people with HL. The risk is hypothyroidism is directly related to the amount of radiation used to treat the disease, particularly in advanced, late-stage lymphoma.

Infertility is a common concern in people with lymphoma. While testicular lymphoma can most certainly impact a man's fertility, the alkylating chemotherapy drugs used to treat lymphoma are the most common causes of infertility in both men and women.

People treated with the BEACOPP regimen of chemotherapy drugs (bleomycin, etoposide, doxorubicin, cyclophosphamide, procarbazine, and prednisone) were most severely affected.

Other chemotherapy regimens (such as AVBD) are less impactful. By and large, men and women with chemotherapy-induced infertility will experience restored fertility after the completion of therapy, although some may end up experiencing permanent sterility.

The most difficult thing about diagnosing lymphoma is the non-specificity of symptoms. In many cases, the early signs may be totally absent and will only manifest with overt symptoms when the disease is advanced.

The most telling clue—persistently lymphadenopathy with no known cause—should warrant immediate investigation by your doctor. But, in cases where the disease is confined to the chest or abdomen, there may be no visible signs of lymphadenopathy at all. Moreover, the so-called "B" symptoms (fever, night sweats, weight loss) are often mistaken for other conditions.

In such cases, you will need to be proactive if you believe that you are at risk for lymphoma. This may be because you have a first-degree relative (parent, brother, or sister) with lymphoma, which is known to increase your risk of NHL by 1.7 fold and HL by 3.1 fold.

The long-term exposure to industrial chemicals, older age, and a compromised immune system are also key contributing factors to HL and NHL.

While risk factors can often point you in the direction of lymphoma diagnosis, you can have none of the risk factors and still get the disease. To this end, the most important thing you can do is to never ignore symptoms that persist, however mild they may be.

For example, if non-specific gastrointestinal symptoms improve with antacids and other medications, let your doctor know if they don't go away completely. Don't live with them in silence just because they're a little better.

If the symptoms occur alongside a drop in your red blood cell or white blood cell count, don't be afraid to suggest lymphoma as a possible cause, especially if you are immunocompromised or over the age of 60.

A simple chest X-ray may be all that is needed to identify swollen lymph nodes in the chest or abdomen if none are found in the neck, armpit, or groin.

If your doctor dismisses your concerns without a satisfactory explanation, seek a second opinion from a doctor more willing to explore your concerns.