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An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists

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Year : 2007  |  Volume : 11  |  Issue : 1  |  Page : 2-4

Understanding the possible mechanisms of spontaneous regression of oral cancer

Dept. of Dentistry, BJ Medical College, Pune - 411 001, India

Correspondence Address:
Vivek K Pakhmode
Dept. of Dentistry, BJ Medical College, Pune - 411 001
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-029X.33954

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Spontaneous regression of malignant neoplasms is an extremely rare event. However, it is reported virtually in all types of human cancer, including oral cancer. The induction of spontaneous regression may involve multiple mechanisms which may be either differentiation or cell death. Better understanding of the process of spontaneous regression may offer the possibility of improved methods of treating and preventing cancer.

Keywords: Spontaneous regression, oral cancer

How to cite this article:
Pakhmode VK. Understanding the possible mechanisms of spontaneous regression of oral cancer. J Oral Maxillofac Pathol 2007;11:2-4

How to cite this URL:
Pakhmode VK. Understanding the possible mechanisms of spontaneous regression of oral cancer. J Oral Maxillofac Pathol [serial online] 2007 [cited 2022 Aug 11];11:2-4. Available from: https://www.jomfp.in/text.asp?2007/11/1/2/33954

   Introduction Top

Cancer is probably the deadliest human affiliation. In the year 2000, malignant tumours were responsible for 12% of the nearly 56 million deaths worldwide from all causes. In many countries, more than a quarter of deaths are attributable to cancer. In 2000, 5.3 million men and 4.7 million women were reported to have developed malignancy and 6.2 million succumbed to the disease. [1]

Oral cancer is one of the eight leading cancers in the world. In India, it is one of the most common cancers and is an important public health problem. About 56,000 new cases have been estimated to occur each year (1986 data). [2]

Very few cancers are curable. However, it is observed that many cancers disappear spontaneously; though very rarely. It is generally regarded as mysterious, although there are some laboratory studies on regressing tumours; as well as new theoretical possibilities about their mechanisms.

The spontaneous regression of cancer is a tantalizing, heart-warming phenomenon, which offers hope in the face of fearsome disease. William Osler once said, " Spontaneous regression of the cancer is one of the most fascinating phenomenon observed in medicine". [3]

Spontaneous tumour regression is reported to occur in approximately one in every 140,000 cases of cancer. [4] The mechanisms involved in tumour regression are complex and interrelated. Understanding these mechanisms may shed light on why some tumours regress completely, while others, such as melanoma, show evidence of regression in the primary tumour simultaneous with the occurrence of distant metastasis.

The phenomenon of spontaneous regression is also known as, " Saint Peregrine Tumour ". Near the end of 13 th Century, Saint Peregrine, a young priest, developed a large bone tumour requiring amputation. On the night preceding surgery, he prayed intensely and, it is alleged, awoke without any trace of tumour!. [5] Was it a miracle? Or is there anything, which may explain this incident scientifically?

Spontaneous regression of malignant neoplasms is an extremely rare event. However, it is reported in virtually all types of human cancer, although the greatest numbers of cases are reported in patients with neuroblastoma, renal cell carcinoma, [6] malignant melanoma and lymhomas/leukemias.

Savarrio et al.,[7] claimed to report the first ever case of spontaneous regression of a neoplasm in the oral cavity of a subset of non-Hodgkins lymphomas known as Ki-1 anaplastic large cell lymphomas (ALCL).

Koga et al.,[8] reported a case of extranodal malignant lymphoma occurring in the upper gingiva, which regressed spontaneously. A 78-year-old female had noticed a diffuse bucco-lingual swelling of the left maxillary gingiva in the incisor regions for a month. Intraoral examination revealed diffuse swelling and redness in the maxillary gingiva of the incisor regions. Cervical and underarm lymphadenopathy were not detected. Surgical biopsy of the swollen gingiva revealed a malignant lymphoma, with diffuse large cells, B cell type.

After biopsy, the tumour spontaneously decreased in size; finally, the mass completely disappeared after three weeks. After regression, the lesions were externally irradiated with 30 Gy total dose. The patient was followed-up and had been found free from disease for 36 months.

King et al.,[9] reported a case of complete spontaneous regression of metastatic cutaneous melanoma with parotid and neck lymph node metastases.

The induction of spontaneous regression may involve multiple mechanisms in some cases although the end result is likely to be either differentiation or cell death.

Although immune modulation has been stated to be the most likely process causing spontaneous regression, other mechanisms, such as genetic therapy, withdrawal of carcinogens, infection, apoptosis, antibody, antiangiogenesis, maturation, withdrawal of therapy, natural killer activity, endocrine, hormones, pregnancy and prayers or psychoneuro-religious participation were also mentioned.

   Possible Role of Cytotoxic Immune Response in Spontaneous Regression Top

As demonstrated by Bayer-Garner [10] and others, cytotoxic immune responses appear to play a role in the regression of some tumours. Interleukin (IL)-18 stimulates T cell and natural killer cell activity, and is associated with interferon (IFN)-γ production that can induce anti-tumour immune responses. [11] Tumour-associated antigens that may be targets for CD8+ T cells include viral antigens, melanocyte differentiation antigens and cancer-testis antigens. Expression of the cancer-testis antigen, NY-ESO-1, has been shown to induce both humoral and cellular immune responses and is associated with a high rate of regression. [12] The observation that autoimmune manifestations may occur concomitantly with spontaneous tumour regression also suggests that regression may be immune-mediated. [13]

   Tumour Regression may be due to a Genetic Crisis Top

Spontaneous regression may reflect a process of terminal differentiation or may be related to vascular compromise. Genomic instability is another mechanism for tumour regression. Telomerase is associated with cellular immortality and tumourigenesis. Inhibition of telomerase may result in genomic crisis and tumour regression. [14] In neuroblastoma, high levels of telomerase activity correlate with poor outcome, whereas telomere shortening correlates with tumour regression. [15] Regressing tumours demonstrate a reduction of telomeric repeats and abnormal telomeric multi-centric and ring configurations.

A complex interplay of mechanisms is involved in tumour growth and tumour regression. Neoplastic transformation is related to the expression of oncogenes, the production of growth factors and inactivation of tumour suppressor genes. Regression, on the other hand, may be mediated by the immune response, apoptosis, antiangiogenesis, terminal differentiation or genomic crisis resulting from telomere exhaustion. Better understanding of these mechanisms may give us a better ability to predict tumour behavior and to effect cures.

   Is Apoptosis is Responsible for Spontaneous Regression Top

Spontaneous regression of solitary cutaneous mastocytomas has been shown to be related to apoptosis. [16] Programmed cell death is also involved in spontaneous regression and differentiation of neuroblastomas and may be related to expression of a variety of cell death-related proteases. [17] Spontaneous regression of some neuroblastomas is associated with a form of ras-mediated programmed cell death that is caspase cascade-independent (non-apoptotic). [18] These data suggest that apoptosis is often associated with tumour regression but is not required for regression. Apoptosis is an important mechanism of regression but is neither necessary for nor sufficient for regression to occur. Other mechanisms are important.

   Role of Antiangiogenic Factors in Spontaneous Regression Top

Angiogenesis is critical for the development of many tumours and antiangiogenic factors are promising agents in the treatment of cancer. The humanized monoclonal antibody bevacizumab exerts an effect on vascular endothelial growth factor and improves survival in metastatic colorectal cancer, suggesting that antiangiogenic therapy can have a meaningful clinical effect. [19] Ornithine decarboxylase (ODC) overexpression is associated with the formation of spontaneous skin carcinomas in some transgenic mice. ODC stimulates dermal vascularization. Treatment with difluoromethylornithine, an inhibitor of ODC, causes a decrease in blood vessel count and regression of the tumours. [20] Other promising antiangiogenic agents include thalidomide, IFN-γ and matrix metalloproteinases. Pharmacologic antiangiogenic factors can produce tumour regression, but the role of endogenous antiangiogenic factors in spontaneous regression remains a fertile area for research.

   Other Possible Mechanisms for Spontaneous Regression Top

Regressions are always welcomed by the patient, but there is a hidden cost: this characteristic also makes it more difficult and expensive for investigators to prove that a new treatment has clinical benefit, which is essential to making progress against the disease.

Truth be told, scientists do not know the reason for waxing and waning. Some of the theories put forth are:

  1. Immune recognition of the tumour cells may produce an immune response against the tumours, which could include the production of antibodies against antigen targets on the tumour or natural killer cell direct killing.
  2. 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.
  3. Cytokine signals may induce lymphoma cells to differentiate or induce them to die naturally in a process called apoptosis.
  4. High stress may raise levels of natural steroids and cause temporary regressions.
  5. Inflammation may account for waxing and waning of lymph nodes, which would mean that both the waxing and waning are not real indications of tumour progression and regression. If inflammation is caused by immune system activity against the tumour, real regression may happen as well for some people.
  6. Hypoxia may cause them to implode when necrosis form in the center.

Note: It is also possible that low oxygen conditions can cause cells to adapt and become more aggressive or refractory. This could account for part of the difficulty associated with treating bulky disease.

   Conclusion Top

A complex interplay of mechanisms is involved in tumour growth and tumour regression. Neoplastic transformation is related to the expression of oncogenes, the production of growth factors and inactivation of tumour suppressor genes. Regression, on the other hand, may be mediated by the immune response, apoptosis, antiangiogenesis, terminal differentiation or genomic crisis resulting from telomere exhaustion. Better understanding of these mechanisms may give us a better ability to predict tumour behavior and to effect cures.

   References Top

1.http://www.who.int/mediacentre/news/releases/2003/pr27/en/.  Back to cited text no. 1    
2.Jussawalla DJ, Yeole BB, Natekar MV (1983): Cancer morbidity and mortality greater bombay, 1986-87. The Indian Cancer Society: Mumbai.  Back to cited text no. 2    
3.Osler W (1901): The medical aspects of carcinoma of the breast, with a note on the spontaneous disappearance of secondary growths, Am Med 17-19: 63-6.  Back to cited text no. 3    
4.Akasu R, From L, Kahn HJ (1994): Characterization of the mononuclear infiltrate involved in regression of halo nevi, J Cutan Pathol 21: 302-11.  Back to cited text no. 4    
5.Pack GT (1967): St Peregrine, OSM-the patron saint of cancer patients, CA Cancer J Clin 17: 83-4.  Back to cited text no. 5    
6.Papac RJ (1998): Spontaneous regression of cancer: Possible mechanisms, In Vivo 12(6): 571-8.  Back to cited text no. 6    
7.Savarrio L, Gibson J, Dunlop DJ, O'Rourke N, Fitzsimons EJ (1999): Spontaneous regression of an anaplastic large cell lymphoma in the oral cavity: First reported case and review of the literature, Oral Oncol 35(6): 609-13.  Back to cited text no. 7    
8.Koga M, Kusukawa J, Hayabuchi N (2003): Spontaneous regression of extranodal malignant lymphoma occurred in the gingiva, Oral Oncol 39(3): 323-4.  Back to cited text no. 8    
9.King M, Spooner D, Rowlands DC (2001): Spontaneous regression of metastatic malignant melanoma of the parotid gland and neck lymph nodes: A case report and a review of the literature, Clin Oncol (R Coll Radiol) 13(6): 466-9.  Back to cited text no. 9    
10.Bayer-Garner IB, Ivan D, Schwartz MR, Tschen JA (2004): The immunopathology of regression in benign lichenoid keratosis, keratoacanthoma and halo nevus, Clin Med Res 2: 89-97.  Back to cited text no. 10    
11.Chang WY (2000): Complete spontaneous regression of cancer: Four case reports, review of literature and discussion of possible mechanisms involved, Hawaii Med J 59: 379-87.  Back to cited text no. 11    
12.Jager D, Jager E, Knuth A (2001): Vaccination for malignant melanoma: Recent developments, Oncology 60: 1-7.   Back to cited text no. 12    
13.Renno T, Lebecque S, Renard N, Saeland S, Vicari A (2003): What's new in the field of cancer vaccines? Cell Mol Life Sci 60: 1296-310.  Back to cited text no. 13    
14.Kim NW (1997): Clinical implications of telomerase in cancer, Eur J Cancer 33: 781-6.   Back to cited text no. 14    
15.Hiyama E, Hiyama K, Nishiyama M, Reynolds CP, Shay JW, Yokoyama T (2003): Differential gene expression profiles between neuroblastomas with high telomerase activity and low telomerase activity, J Pediatr Surg 38: 1730-4.   Back to cited text no. 15    
16.Inoue T, Yoneda K, Kakurai M, Fujita S, Manabe M, Demitsu T (2002): Alteration of mast cell proliferation/apoptosis and expression of stem cell factor in the regression of mastocytoma-report of a case and a serial immunohistochemical study, J Cutan Pathol 29: 305-12.   Back to cited text no. 16    
17.Nakagawara A, Nakamura Y, Ikeda H, Hiwasa T, Kuida K, Su MS, et al . (1997): High levels of expression and nuclear localization of interleukin-1 beta converting enzyme (ICE) and CPP32 in favorable human neuroblastomas, Cancer Res 57: 4578-84.   Back to cited text no. 17    
18.Kitanaka C, Kato K, Ijiri R, Sakurada K, Tomiyama A, Noguchi K, et al. (2002): Increased Ras expression and caspase-independent neuroblastoma cell death: Possible mechanism of spontaneous neuroblastoma regression, J Natl Cancer Inst 94: 358-68.   Back to cited text no. 18    
19.Sparano JA, Gray R, Giantonio B, O'Dwyer P, Comis RL (2004): Eastern Cooperative Oncology Group Portfolio of Clinical Trials. Evaluating antiangiogenesis agents in the clinic: the Eastern Cooperative Oncology Group Portfolio of Clinical Trials, Clin Cancer Res 10: 1206-11.   Back to cited text no. 19    
20.Lan L, Trempus C, Gilmour SK (2000): Inhibition of ornithine decarboxylase (ODC) decreases tumour vascularization and reverses spontaneous tumours in ODC/Ras transgenic mice, Cancer Res 60: 5696-703.  Back to cited text no. 20    

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