Spontaneous Regression of Oral Cancer: A Review
Manjunath Badni, Anil Singh, Dharmashree, Akhilesh Chandra, Varsha Tiwari
Spontaneous regression of some tumors is flimsy and inconceivable process. Nonetheless, it is observed in virtually all types of human cancer, Neuroblastoma, renal carcinoma being remarkable in number and a few reported cases of oral cancer. The induction of spontaneous regression involves multiple mechanisms which may either be differentiation, apoptosis and genetic crisis. But surpassed understanding of the process of spontaneous regression may include the indulgence of the possible and improved methods of treating and preventing cancer. The article gives an overview of the mechanisms involved in spontaneous regression and various reported cases of oral cancer.
Keywords: Spontaneous Neoplasm Regression;Oral Cancer;Head and Neck Neoplasms; Apoptosis;Recessive Genetic;Differentiation.
Manjunath Badni, Anil Singh, Akhilesh Chandra, Varsha Tiwari. Spontaneous Regression of Oral Cancer: A Review. International Journal of Oral & Maxillofacial Pathology; 2011:2(4):34-38. ©International Journal of Oral and Maxillofacial Pathology. Published by Publishing Division, Celesta Software Private Limited. All Rights Reserved.
Received on: 10/04/2011 Accepted on: 10/10/2011
These days the world is heading towards various types of non-communicable diseases, which are known as modern epidemics. Among these modern epidemics cancer is the second commonest cause of mortality in developed countries. In the developing countries cancer in among the ten commonest cause of mortality.1 Cancer is one of the most common causes of morbidity and mortality today, with more than 10 million new cases and more than 6 million deaths each year worldwide.2
More than 20 million persons around the world live with a diagnosis of cancer, and more than half all cancer cases occur in the developing countries. Cancer is responsible for about 20% of all deaths in high income countries and 10% in low-income countries. It is projected that by 2020 there will be every year 15 million new cancer cases and 10 million cancer deaths.3 Oro-pharyngeal cancer is significant component of the global burden of the cancer. Incidence rates for oral cancer vary in men from 1 to 10 cases per 100,000 populations in many countries. In south-central Asia, cancer of the oral cavity ranks among the three most common types of cancer. In India, the age standardized incidence rate of oral cancer is reported at 12.6 per 100,000 population.4,5
Spontaneous regression of cancer is one of the most fascinating phenomena observed in medicine. It is generally regarded as inexplicable, although there are now some lab studies of regressed or regressing tumors, as well as new possibilities about their mechanisms.6 Spontaneous regression of malignant disease has been defined as “the complete or partial disappearance of a malignant tumor in the absence of any treatment, or in the presence of therapy that is considered inadequate to exert a significant influence on neoplastic disease”.7,8 It is not usually associated with cure of malignant disease as most of the cases ultimately relapse. Spontaneous tumor regression is reported to occur in approximately one in every 1,40,000 cases of cancer and is one of the most tantalizing, heartwarming phenomenon.9
Spontaneous regression has been documented for many types of human cancers with majority in neuroblastoma, renal cell carcinoma, malignant melanoma and leukemia, including oral cancer. It was postulated that an intriguing but extremely effective mechanism was engaged in eradicating cancer cells after the development of advanced malignancy.10,11
Spontaneous regression was better fraternized as “Saint Peregrine Tumor” on the name of young priest “Saint Peregrine” at the end of 13th century. He had a large bone tumor which required amputation. He prayed immensely a night before the surgery. He awoke with absence of any tumor remnants.12
The first case of spontaneous regression of a carcinoma of tongue was reported by Roxburgh D in 70 years old female patient in 1935.7,13 Spontaneous regression of recurrent SCC of the tongue was reported by Oya R and Ikemura K in a 73 years old male. Without any specific therapy, the tumor gradually and spontaneously regressed, 4 months after the recurrence was diagnosed, and it had completely disappeared.13
Kurita M et al reported a case of spontaneous regression of cervical lymph node metastasis in a patient with nasopharyngeal squamous cell carcinoma of the tongue. The authors claimed that this may be the first case of squamous cell carcinoma undergoing spontaneous regression in which enhanced apoptosis was demonstrated quantitatively.14
First ever case of spontaneous regression of a neoplasm in the oral cavity of a subset of Non-Hodgkin’s lymphoma known as ki-1 anaplastic large cell lymphoma was reported by Savarrio et al.15
Carcinoma of tongue
Oya R and Ikemura K13
Recurrent SCC of tongue
Kurita M et al14
Cervical lymph node metastasis in a patient with nasopharyngeal squamous cell carcinoma of tongue
Savarrio et al15
Non Hodgkins lymphoma of oral cavity
King et al17
Metastatic cutaneous melanoma with parotid and neck lymph node metastasis
Koga et al16
Extra nodal malignant lymphoma with a diffuse bucco-lingual swelling on the left maxillary gingiva in the incisor region
Heibel H et al18
Highly malignant B-cell Non-Hodgkin's lymphoma with primary manifestation in the oral cavity
Regression of extra nodal malignant lymphoma in 78 years old female with a diffuse bucco-lingual swelling on the left maxillary gingiva in an incisor region was claimed by Koga et al.16 A case of complete spontaneous regression in metastatic cutaneous melanoma with parotid and neck lymph node metastasis was reported by King et al.17
A case of complete spontaneous remission of a histopathologically supported highly malignant B-cell Non-Hodgkin's lymphoma with primary manifestation in the oral cavity was presented by Heibel H et al. This regression, which has showed no signs of recurrence for more than 18 months, occurred following a diagnostic biopsy and without any therapeutic intervention.18
Contingent Role of Cytotoxic Immune Response: As explained by Beyer-Garner19 and others cytotoxic immune response plays a key role in regression of some tumors. Interleukin (IL-18) stimulates T-cell and natural killer cell activities and is associated with interferon (IFN)-γ production that can induce anti-tumor immune responses.9 Tumor-associated antigens that may be targets for CD8+T cells include viral antigens, melanocyte differentiation antigens and cancer testis antigens. Expression for 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.20 The observation that autoimmune manifestations may occur concomitantly with spontaneous tumor regression also depicts that regression may be immune-mediated.21
Genetic crisis - A possible reason: Spontaneous regression may present a process of terminal differentiation or may be related to vascular compromise. Genomic instability is another mechanism for tumor regression.22 Telomerase is related with cellular immortality and tumorigenesis. Inhibition of telomerase may result in genomic crisis and tumor regression.23 In neuroblastoma, high levels of telomerase activity correlate with poor outcome, whereas telomere shortening correlates with tumor regression.24
Apoptosis: Spontaneous regression of solitary cutaneous mastocytomas has been shown to be related to apoptosis.25 Programmed cell death is involved in spontaneous regression and differentiation of neuroblastoma and may be related to expression of a variety of cell death-related proteases.26 Spontaneous regression of some neuroblastomas is associated with a form of ras-mediated programmed cell death
that is caspase cascade-independent (non-apoptotic).27
Spontaneous regression attributable to antiangiogenic factors: Angiogenesis is imperative for the development of many tumors 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.28 Ornithine decarboxylase (ODC) over expression 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 tumors.29
Cytokines: These are proteins produced by many cell type; principally activated lymphocytes and macrophages. Cytokines implicated in spontaneous regression of tumors include:
- a. Tissue inhibitors of matrix metalloproteinase (TIMPs): TIMPs block tumor metastasis by inhibiting invasion of the basement membrane or by restraining tumor angiogenesis.22
- b. Tumor necrosis factor (TNF): Stoelcker et al demonstrated that TNF reduces XVβ3 an integrin mediated endothelial cell adhesion in-vitro resulting in detachment and apoptotic cell death. The endothelial destruction is the effector mechanism, thus indicating the endothelium as the target for TNF induced tumour necrosis.30
- c. Transforming growth factor (TGF-β): Corallini A demonstrated that over expression of TGF1 inhibits angiogenesis and causes formation of a fibrotic wall around tumor thus inducing tumor necrosis.31
- d. Secreted Protein Acidic and Rich in Cysteine (SPARC) (also known as Osteonectin, BM40 and 43kd protein): This is an intracellular calcium binding glycoprotein. Its biologic function is variable in human cancers. Its suppression results in significant decrease in tumorigenesis of melanoma cells which is one of the tumor that regresses spontaneously.32
Tumor Suppressor Genes: These anti-oncogene protein products also play important role in tumorigenesis; they include p53 gene and Retinoblastoma (Rb) gene. They act by inhibiting and preventing mitosis such that tumor cells do not complete the cell cycle.33
Hypoxia: Low oxygen levels that occur in the core of tumors lead to necrosis of the tumor cells, which may cause the tumor to implode.33,34
Stress: High stress may raise levels of natural steroids and cause temporary regression of tumor. Mild to moderate stress increases the production of proteins that help repair body cells including those in the brain and enables them to work at peak capacity.35
Other contrivances for spontaneous regression: Patients pleasurably incur the regressions, but at the same time this feature also makes it more challenging and expensive for investigators to prove that a new treatment has clinical benefit, which is essential to boon the progress against the disease.35 Some of the theories accorded are:
- 1. Immune response against tumors may be produced by immune recognition of the tumor cells.
- 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. Transient or short-term fluctuations in the size of lymph nodes could be accounted for inflammation and not related to tumor progression or regression. If inflammation is caused by immune system activity against the tumor, real regression may happen as well for some people.35
Neoplastic transformation is related to the expression of oncogenes, production of growth factors and inactivation of tumour suppressor genes. Spontaneous regression may be mediated by the immune response, apoptosis, antiangiogenesis, terminal differentiation, or genomic crisis. It is generally recognized that growth rates of different types of cancers varies greatly and also the growth rate of specific type of
cancer varies widely in different patients. A complex interplay of mechanisms is involved in tumor growth and tumor regression. Better understanding of these mechanisms may give us a better ability to predict tumor behavior and for effective cures.
1. Dr. Manjunath Badni, Reader, 2. Dr. Anil Singh, Professor & Head, 3. Dr. Dharmashree RD, Department of Oral and Maxillofacial Pathology, Sardar Patel Postgraduate Institute of Dental and Medical Sciences, Lucknow, 4. Dr.Akhilesh Chandra, Sr Lecturer, Dental College, Azamgarh, 5. Dr.Varsha Tiwari, Post Graduate Student, Department of Oral and Maxillofacial Pathology, Sardar Patel Postgraduate Institute of Dental and Medical Sciences, Lucknow, Uttar Pradesh, India.
We would like to thank all the staff members of Department of Oral Pathology and Microbiology for their support.
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Department of Oral Pathology & Microbiology,
Sardar Patel Postgraduate Institute of Dental and Medical Sciences,
Lucknow, Uttar Pradesh, India.
Source of Support: Nil, Conflict of Interest: None Declared.
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