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 About Lymphoma > Spontaneous Regressions

Last update: 04/16/2013

What is it? | Terminology | How Might it Happen? | Abstracts by type

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Spontaneous regressions

Spontaneous regressions are the observed decreases in tumor burden, which is relatively common in patients with indolent lymphomas.

Depending on the source, as many as 20% to 30% of patients will experience regressions at some time in the clinical course of their disease. This observed clinical tendency is also called waxing and waning. 

The reasons for spontaneous regressions have not been identified and there may be different reasons in each case. The biology of the lymphoma varies and the interactions between the tumor and bystander cells in the tumor microenvironment are very complex and can vary for each of us - even when we have the same diagnosis.

  1. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. 
    N Engl J Med. 1984 Dec 6; 311(23): 1471-5. PMID: 6548796

Some Terminology:

Spontaneous regressions and spontaneous remission are sometimes used interchangeably, but these terms can have different meanings to different people:  

Remission is most often defined as the absence of disease activity (stable disease), which is common in indolent lymphomas ... 

... but remission is sometimes  thought of and used to describe being free of observable disease -- or having no evidence of disease (NED).  

... Spontaneous regression is often used to describe decreases in tumor burden that appear to occur  spontaneously, without treatment. 

The term waxing and waning is also used to describe the uneven course of lymphomas, particularly of the indolent (slow growing) types.  Waxing means progressing, and waning means regressing.   

Waxing and waning might be used to describe transient or short-term fluctuations in the size of lymph nodes that could be accounted for by inflammation and other factors unrelated to the actual number of malignant cells.  Waxing and waning is similar to the daily fluctuations in the stock market that may or may not be related to longer trends.

Finally, how does one distinguish between waxing and waning and spontaneous regressions?  

It may be that with spontaneous regressions there will be other signals that suggest true improvements in the state of the disease, such as  improving blood counts, decreasing LDH, and observable improvements in how the patient feels and performs.  

also see Remission, Response and Survival terms

Regressions are always welcomed by the patient, but this variable characteristic of the disease also makes it more difficult for investigators to evaluate new treatments - requiring larger numbers of patient in clinical trials.  

How Might it Happen?

Here are some theories taken from the literature, with some layperson-speculation mixed in:

Immune recognition of the tumor cells may produce an immune response against the tumors, which could include the production of antibodies against antigen targets on the tumor, or NK cell direct killing.

Antigen in the body may influence the behavior of lymphoma cells which like normal lymphocytes may react to the presence or absence of stimulating antigens (pathogens, virus, allergens and so on)

Variation in the mutations within the tumor cells may cause some lymphomas to be more normal in their behavior - less likely to grow and persist; and more likely to regress.

Inflammation may account for waxing and waning of lymph nodes, which would mean that both the waxing and waning are not real indications of tumor progression or regression. If inflammation is caused by immune system activity against the tumor, real regression may happen as well for some people.

Hypoxic microenvironments (with low oxygen levels) may cause tumors to implode when necrotic (dead areas) form in the center. NOTE: It's also possible that low oxygen conditions can cause cells to adapt and become more aggressive or refractory.

Placebo Effect Stephen Barrett, M.D. - quackwatch.org 

"Recovery from illness, whether it follows self-medication, treatment by a scientific practitioner, or treatment by an unscientific practitioner, may lead individuals to conclude that the treatment received was the cause of the return to good health."

Viruses may infect lymphoma cells as they do other lymphocytes, and thus make them more recognizable to other immune cells. This could be the mechanism behind the measles vaccine which is being studied in clinical trials for lymphoma.

Stress might raise levels of natural steroids and cause temporary regressions. 


Related Abstracts

General | CLL | Hodgkins | Low grade lymphoma | High grade lymphoma
Interfering with coinhibitory molecules: BTLA/HVEM as new targets to enhance anti-tumor immunity  http://www.sciencedirect.com
Spontaneous regression of cancer: possible mechanisms. In Vivo. 1998 Nov-Dec;12(6):571-8. Review. PMID: 9891219 - PubMed abstract
Spontaneous regression in non-Hodgkin's lymphoma: clinical and pathogenetic considerations.
Am J Hematol. 1989 Jun;31(2):138-41. Review. PMID: 2660545 PubMed abstract
CLL (uncommon but not rare)
Spontaneous reduction of leukemic lymphoma cells possibly by anti-tumor antibody-mediated phagocytosis; a kappa lambda-dual-positive B cell lymphoma. Leukemia. 2000 Feb;14(2):278-84. PMID: 10673745 - PubMed abstract
Spontaneous clinical regression in chronic lymphocytic leukaemia.
Br J Haematol. 2002 Feb;116(2):341-5. PMID: 11841436

"Chronic lymphocytic leukaemia (CLL) is a B-cell disorder, which has a median survival of over 10 years from diagnosis for stage A disease. The natural history of stage A disease is generally indolent or only slowly progressive. 

It is less well known that CLL may undergo spontaneous regression. We report a series of 10 such cases (eight stage A and two stage B) followed at our institutions."   - 
Hodgkins Disease (exceedingly rare)
Spontaneous regression of Hodgkin's disease: two case reports and a review of the literature. Mangel J, Barth D, Berinstein NL, Imrie KR. Hematology. 2003 Jun;8(3):191-6. Review. PMID: 12745644 
Low grade lymphoma (most common - approximately 30%)
Spontaneous remission of low-grade B-cell non-Hodgkin's lymphoma following withdrawal of methotrexate in a patient with rheumatoid arthritis: case report and review of the literature.
Br J Haematol. 2002 Aug;118(2):567-8. PMID: 12139747  PubMed
Comparison of "host cell infiltrates" in patients with follicular lymphoma with and without spontaneous regression. Am J Clin Pathol. 1988 Sep;90(3):257-61. PMID: 2970792  PubMed
Follicular lymphomas--a review of treatment modalities. Crit Rev Oncol Hematol. 2000 Jul;35(1):13-32. Review. PMID: 10863149 PubMed abstract
Clinical significance of natural killing activity in patients with advanced lymphoma.
J Clin Immunol. 1998 Mar;18(2):132-41. PMID: 9533657 PubMed abstract
Expression of wild-type p53 and Bcl-2 family genes oscillates with recurrent remission and relapse in an unusual case of low-grade lymphoma. Acta Haematol. 2000;103(4):177-85.
PMID: 11014890 PubMed abstract
High grade lymphomas
Spontaneous complete regression of high grade non-Hodgkin's lymphoma. Morphologic, immunohistochemical, and gene amplification analyses. Cancer. 1994 Dec 1;74(11):3023-8.
PMID: 7954265 PubMed abstract 
Spontaneous regression of acquired immune deficiency syndrome-related, high-grade, extranodal non-Hodgkin's lymphoma. Cancer. 1992 Apr 1;69(7):1856-7. PMID: 1551068 PubMed abstract
Regression of primary high-grade gastric B-cell lymphoma following Helicobacter pylori eradication. Eur J Gastroenterol Hepatol. 2001 Nov;13(11):1375-8. PMID: 11692066 PubMed abstract My note: Not really a spontaneous cause for regression.
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