When Lymphoma Develops in People With Lupus

What do we know about the connection between lupus and lymphoma? Well, we know more than we did decades ago, but the answer may still be “not enough,” according to an article published in 2017 issue of Case Reports in Rheumatology.

Lupus, or Systemic Lupus Erythematosus (SLE)

Lupus, or systemic lupus erythematosus (SLE), is a very complex autoimmune disease that can come on with any number of very different symptoms and can involve multiple organ systems within the body.

Any two people with lupus can have totally different symptoms, but symptoms may include:

• Joint pain, stiffness, and swelling
• Fatigue
• Unexplained fevers
• A rash on the face on the cheeks and bridge of the nose, said to be butterfly-shaped, with the nose as the body and the cheeks as the wings of the butterfly. The rash may be thick, itchy, or hot.
• Other skin problems that seem to worsen with sun exposure
• Symptoms from different organ systems; shortness of breath, chest pain, dry eyes
• Headaches, confusion, and memory loss

Lymphoma, a Cancer of the White Blood Cells

Lymphoma is a cancer of the white blood cells, particularly the white blood cells known as lymphocytes. The two basic categories of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma, or NHL.

Lymphoma typically begins in the lymph nodes, but can also involve different organs, and it can arise within different tissues and structures of the body, not just the lymph nodes. As with lupus, the symptoms of lymphoma are varied and different people have differing lymphoma symptoms. Sometimes, the only symptom is a swollen lymph node:

• Painless swelling of lymph nodes in your neck, armpits, or groin
• Fatigue and fever
• Drenching night sweats
• Loss of appetite, unexplained weight loss—as much as 10% or more of your body weight
• Itchy skin
• Cough or chest pain, abdominal pain or fullness, rashes, and skin bumps

What These Two Conditions Have in Common

Well, sometimes the symptoms can overlap, for one. And both diseases involve the immune system: Lymphocytes are key cells in the immune system, and the immune system is what’s awry in SLE. Lymphocytes are also the problematic cells in lymphoma.

But there is also this: A number of studies have found that people with SLE have a higher incidence of lymphoma compared with the general public. One of the many theories is that, in an immune system that lacks proper regulation (as in someone with SLE), the use of immunosuppressive therapy to treat lupus may cause the increased incidence of lymphoma in SLE.

However, many studies have been done on this subject, with contradictory findings, and that doesn’t appear to be the whole story.

The researchers of the 2017 article in Case Reports in Rheumatology gleaned some trends from their review of the medical literature on people with SLE who develop lymphoma.

Risk factors for lymphoma development in people with SLE are not entirely clear. People with more active or flaring SLE disease seemed to be at greater risk for lymphoma, and some risk has been theorized to be linked to the use of a cyclophosphamide and high cumulative exposure to steroids.

Though at times there were few studies to draw on—and often the numbers of people with both SLE and lymphoma were small in these studies—researchers used what they could find to construct a starting platform for further study. Some rough observations from studies with SLE patients who developed lymphoma follow.

People with SLE who developed lymphoma:

• Majority were women
• Age range was typically between 57 and 61 years
• On average, they’d had SLE for 18 years prior to lymphoma
• Lymphoma risk in people with SLE was higher across all ethnicities
• Symptoms, findings and lab tests of early-stage lymphoma overlapped quite a bit with what is seen in SLE.
• Lymph node swelling, sometimes the only sign of lymphoma, is also very common in people with SLE, occurring in up to 67%.

Lymphomas that develop in people with SLE:

• The most common NHL type in people with SLE was diffuse large B-cell lymphoma (DLBCL), which is also the most common NHL type in the general population.
• The subtypes of DLBCL in those with SLE seemed more often be in a category that carries a worse prognosis—the non-germinal center B-cell-like DLBCLs.
• NHL in SLE, as with NHL in the general population, usually originates in the lymph nodes, however, lymphomas that begin outside the lymph nodes are also possible in the general population and in those with SLE.

People who have SLE are often treated with glucocorticoids, alone or combined with other immunosuppressive or cytotoxic drugs including methotrexate, cyclophosphamide, and azathioprine to treat organ involvement or symptoms that don’t respond to the therapy initially used.

Many studies have tried to determine if immunosuppressive agents increase the risk of lymphoma in people with SLE, but oftentimes results of one study contradict the next.

There are several theories about why people with SLE may be at greater risk for cancer in general, and also lymphoma in particular:

• One such theory involves chronic inflammation. DLBCL originating from activated lymphocytes is the most common NHL subtype arising in SLE, so the idea is that chronic inflammation might heighten lymphoma risk in autoimmune diseases like SLE.
• Another theory is similar but has more of a genetic basis. The thought is that the autoimmunity of SLE revs up the immune system to cause lymphocytes, the cells of lymphoma, to divide and proliferate.
• Still another theory involves the Epstein-Bar virus, or EBV. This is the same virus that causes infectious mononucleosis, or mono, the kissing disease. The idea is that maybe an EBV infection that is persistent, which lingers to aggravate the immune system in just the right ways, is part of a common pathway to disease for both SLE and B-cell lymphomas.

SLE, Lymphoma, and Other Cancers

There seems to be an increased risk of both Hodgkin and non-Hodgkin lymphoma in people with SLE.

According to data published in 2018, there is an association between SLE and malignancy, not only demonstrating NHL, Hodgkin lymphoma, leukemia, and some non-blood cancers, but also cancers of the following:

• Laryngeal
• Lung
• Liver, bile ducts, or gallbladder
• Oropharyngeal
• Esophageal
• Gastric (stomach)
• Cervical
• Vaginal or Vulval
• Kidney
• Bladder
• Non-melanoma skin
• Thyroid

There may also be a reduced risk for melanoma skin cancer and prostate cancer. Breast cancer, endometrial cancer, ovarian cancer, pancreatic cancer, colorectal cancer, and brain cancer did not seem to track with SLE in excess of what would be expected for the general population.

People with Sjögren’s syndrome, a relatively common condition in people with SLE, experience an even greater risk of lymphoma, so there may be something intrinsic to the SLE disease that is linked to malignancy and especially lymphoma.

While certain immunosuppressive agents seem to be safe for people with SLE based on many studies, there is a cautionary caveat in the literature—that of primary CNS lymphoma (PCNSL) is a rare type of NHL that occurs in the central nervous system involvement without evidence of lymphoma elsewhere in the body.

Almost all cases of PCSNL reported in people with SLE are associated with immunosuppressive agents and mycophenolate in particular.