- Email: [email protected]
Spontaneous remission of a squamous cell carcinoma of the floor of the mouth
Accepted Manuscript Spontaneous remission of a squamous cell carcinoma of the floor of the mouth Alexandre de Andrade Sousa, MD Rafael Lopes Rena, MD Guilherme Souza Silva, MD João Marcos Arantes Soares, PhD José Maria Porcaro-Salles, MD, PhD Laiz Nunes, DDS Ricardo Alves Mesquita, DDS, MS, PhD Bruno Correia Jham, DDS, MS, PhD PII:
S1010-5182(14)00149-8
DOI:
10.1016/j.jcms.2014.04.026
Reference:
YJCMS 1802
To appear in:
Journal of Cranio-Maxillo-Facial Surgery
Received Date: 11 February 2014 Revised Date:
27 February 2014
Accepted Date: 22 April 2014
Please cite this article as: de Andrade Sousa A, Rena RL, Silva GS, Soares JMA, Porcaro-Salles JM, Nunes L, Mesquita RA, Jham BC, Spontaneous remission of a squamous cell carcinoma of the floor of the mouth, Journal of Cranio-Maxillofacial Surgery (2014), doi: 10.1016/j.jcms.2014.04.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Spontaneous remission of a squamous cell carcinoma of the floor of the mouth
Alexandre de Andrade Sousa, MD,1 Rafael Lopes Rena, MD,1 Guilherme Souza Silva, MD,1
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João Marcos Arantes Soares, PhD,1,2 José Maria Porcaro-Salles, MD, PhD,1 Laiz Nunes, DDS,3 Ricardo Alves Mesquita, DDS, MS, PhD,3 Bruno Correia Jham, DDS, MS, PhD4
Instituto Alfa de Gastroenterologia, Federal University of Minas Gerais
2
School of Medicine, Federal University of Sao Joao Del Rey
3
School of Dentistry, Federal University of Minas Gerais
4
College of Dental Medicine – Illinois, Midwestern University
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1
Institution to which work should be attributed:
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Instituto Alfa de Gastroenterologia. Avenida Professor Alfredo Balena, 110, Santa Efigênia,
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Belo Horizonte - MG, 30130-100, Brazil. Head: Prof. Jose Maria Porcaro-Salles , MD, PhD.
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Corresponding author: Bruno Jham, DDS, MS, PhD, Assistant Dean for Academic Affairs. College of Dental Medicine Illinois, Midwestern University,555 31st Street, Science Hall 211-II, Downers Grove IL, 60515. Phone: 630 515 7469; Fax: 630 515 7290. E-mail address: [email protected]
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Spontaneous remission of a squamous cell carcinoma of the floor of the mouth
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Abstract Spontaneous remission is a rare, but well recognized event in oncology. Certain tumors, such as melanomas, hypernephromas and neuroblastomas, are known for more
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commonly showing spontaneous regression. Similarly, spontaneous regression of oral
lymphomas, as well as oropharyngeal and recurrent tongue carcinomas, has been reported. Here, we present a novel case of a patient with a primary squamous cell
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carcinoma on the floor of the mouth whose tumor regressed spontaneously in three months, without any treatment. We also review of the literature on the spontaneous
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remission of oral cancer and discuss possible mechanisms for this phenomenon.
Key words: Oral cancer; spontaneous regression; spontaneous remission; squamous
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cell carcinoma; primary; floor of the mouth.
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1.
Introduction
Spontaneous regression is the partial or complete disappearance of a malignant
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tumor proven by microscopic examination in the absence of any substantial treatment.
The word spontaneous implies absence of any apparent cause, and regression/remission
means a decrease in the size of the tumor or in the extent of disease in the body
SC
(Thomas and Badini, 2011).
Spontaneous remission is a rare, but well recognized event in oncology. The
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most common clinical entities to regress are melanomas, hypernephromas and neuroblastomas (Savarrio et al., 1999). In addition, there are several reports in the literature describing the regression of a variety of cancers, including HPV-induced cervical intraepithelial neoplasia (Kadish et al., 2002), cholangiocarcinoma (Yoshimitsu et al., 1996), hepatocellular carcinoma (Misawa et al., 1999; Harada et al., 2010)
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metastatic renal cell carcinoma (Crisci et al., 2008), esophageal carcinoma (Kubota et al., 2003) and Merkel cell carcinoma (Brown et al., 1999; Torroni et al., 2007; Vesely et al., 2008; Karkos et al., 2010).
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In the oral cavity, spontaneous regression of lymphomas (Savarrio et al., 1999; Koga et al., 2003; Heibel et al., 2004), as well as oropharyngeal (Kurita et al,. 2007)
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and recurrent tongue (Oya and Ikemura, 2004) carcinomas has been reported. Here, we present a novel case of a patient with a primary squamous cell carcinoma on the floor of the mouth whose tumor regressed spontaneously in three months, without any treatment. In addition, we review of the literature on the spontaneous remission of oral cancer and discuss possible mechanisms for this phenomenon.
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2. Case report
A 62-year-old male sought care at the Baleia Hospital (Belo Horizonte, Minas
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Gerais, Brazil) for evaluation of an ulcerated lesion in the oral cavity, which had grown
progressively for seven months. The medical history was unremarkable. During interview, the patient reported a smoking habit for 50 years and heavy alcohol use for
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40 years. The patient had discontinued the use of alcohol seven years earlier, but had continued to smoke.
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Extra-oral examination showed no alterations and absence of palpable lymph nodes. Intra-oral examination revealed an ulcerative-infiltrative lesion with slightly raised borders, located on the floor of the mouth and measuring 3 cm in the largest diameter (Figure 1). The lesion extended to, but did not infiltrate, the gingival borders. Laterally, the lesion reached the first molars, on both sides. The remaining area of the
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oral cavity, the pharynx and the larynx presented no changes. The teeth were in poor condition.
Following local anesthesia, an incisional biopsy was performed using a rongeur
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forceps. The tissue submitted for histopathological analysis and microscopic examination revealed invasion of the overlying epithelium through the basement
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membrane and into the underlying connective tissue (Figure 2A). Sheets and islands of squamous cells demonstrating dysplastic features were observed (Figure 2B). Keratin pearls, individual cell keratinization and mitotic activity were noted (Figure 2C). Immunohistochemical studies were performed and showed CD-117 and p53 positivity (Figure 2D). Staining for ki67 showed a high proliferative index. Cytokeratin 7,
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cytokeratin 20 and p16 were negative. The case was reviewed by two independent pathologists, who both confirmed the final diagnosis of primary oral SCC. Subsequent to the diagnosis, laboratory and imaging exams were requested to
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complement the pre-operative and staging evaluation. While waiting for these, signs of
tumor regression were observed. Surprisingly, the tumor disappeared completely after
three months. After the tumor disappeared, multiple biopsies of the floor of the mouth
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were performed. The pathological examination revealed only a thick and keratinized mucosal lining, without any cellular atypia and a stromal lymphoid infiltration (Figure
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3). The patient was monitored quarterly for 70 months without any signs of tumor recurrence (Figure 4) and lost to follow-up thereafter.
3.
Discussion
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It has been suggested that spontaneous healing of malignant neoplasms occurs in 1:80,000 to 1:140,000 cases (Challis and Stam, 1990; Chang, 2000). However, estimates of the ‘true’ rate vary widely and it has been argued that many cases are
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probably not reported. Further, difficulties involved in establishing what criteria must be met in order for a specific case to constitute an instance of regression further complicate
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determining the true frequency of this phenomenon (Challis and Stam, 1990). Few studies have provided information on the incidence of spontaneous
regression of head and neck cancer. Kowalski and Carvalho (2000) reviewed the charts of 808 untreated head and neck cancer patients and found no cases of spontaneous regression. Similarly, studies comparing the median survival rates of untreated cancer failed to reveal cases of spontaneous regression of head and neck cancer (Shimkin,
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1951; Shimkin et al., 1984). Further, data from studies examining cases of spontaneous cancer remission confirm the rarity of this phenomenon in the head and neck. In this context, Challis and Stam (1990) reviewed the spontaneous of remission of cancer, by
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searching the literature between 1900 and 1987. Out of a total of 741 cases, only 14 (0.018%) were found in the head and neck. Of these, five were adenoid cystic
carcinomas and three cases were presented as squamous cell carcinomas, without
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location. For six cases, only the location was presented, without specification of the histopathological subtype.
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The first report of what may have represented spontaneous regression of a squamous cell carcinoma of the left tonsil, root of tongue, and left lateral wall of the pharynx was described in 1910 (Godfrey, 1910). Later, in 1935, an additional study of what appears to be spontaneous regression of a tongue cancer was published (Roxburgh, 1935). Better documented cases appeared only more recently. In 2004, a recurrent
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tongue carcinoma was reported to gradually and spontaneously regress, without further therapy. The lesion completely disappeared both clinically and by computed tomography imaging at 1 year and 4 months after recurrence. No evidence of recurrence
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was noted at 3 years and 7 months follow-up (Oya and Ikemura, 2004). In 2007, Kurita et al. reported a case of oropharyngeal squamous cell carcinoma with spontaneous
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regression of lymph node metastasis. To our knowledge, the case here in described is the first well-documented case of a primary oral squamous cell carcinoma showing spontaneous regression. The mechanisms of tumor regression are still largely unknown. Explanations for
this phenomenon include immune modulation, removal of carcinogenic substances, infection, induction of apoptosis, action of antibodies, anti-angiogenic mechanisms of
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maturation, natural killer activity, endocrine system activity, tumor inhibition by growth factors and/or cytokines, induction of cell differentiation, tumor necrosis, and/or inhibition of angiogenesis, apoptosis and other epigenetic mechanisms (Papac, 1998;
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Chang, 2000). In the case here in described, we believe that the incisional biopsy triggered an immune response, which in turn led to tumor regression. Indeed, many reports of spontaneous regression have implicated surgery or operative trauma as an
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element that can increase immunological resistance to tumor growth and the removal of
a portion of the tumor would presumably facilitate the destruction of the remaining part
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of the neoplasm by the host immune system (Challis and Stam, 1990).
Interestingly, several reported cases of spontaneous cancer regression note concomitant infections, including diphtheria, gonorrhea, hepatitis, influenza, malaria, measles, smallpox, syphilis and tuberculosis, as well as various other pyogenic and nonpyogenic infections (Hoption et al., 2002). These infections normally bring about a
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strong immunological response and therefore fever. A strong febrile reaction from a natural or induced acute infection was the most common symptom associated with tumour regression (Thomas and Badini, 2011). Further, prior fever was recorded in 25-
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80% of documented cases of spontaneous regression of cancer. In a study with 26 spontaneous remissions in a cohort of 300 cases of childhood leukemia, 80% was
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accompanied by infection (Doran et al., 1989). In pancreatic cancer, it has been argued that possible cases of spontaneous
regression could have actually represented misdiagnosis with non-malignant diseases (Herreros-Villanueva et al., 2012). In the context of oral SCC, the keratoacanthoma (KA) represents a diagnostic challenge for the clinician and pathologist, since both clinical and histopathologic features of KA may resemble those of a well differentiated
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SCC (Schwartz, 1999; Schwartz, 2004; Jones and Blanco-Guzman, 2013). However, nearly 95% of KAs are found on sun-exposed areas (Neville et al., 2008) and, microscopically, a sharp demarcation between tumor and stroma, cup-shaped
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appearance and a deep but distinct collar-like invasive front of the epithelium are seen
(Ramos et al., 2009). These features were absent in our case. Further, abundant and atypical mitosis, as well as pleomorphism, as seen in the current case, favors SCC
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(Griffiths, 2004). The traumatic ulcerative granuloma with stromal eosinophilia
(TUGSE) may also clinically mimic a malignant process. TUGSE presents as an
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indurated, ulcerative, non-tender lesion of the oral mucosa, most commonly seen on the tongue. Interestingly, TUGSE is known for regressing upon an incisional biopsy (Kumar et al., 2008). However, microscopic examination of TUGSE fails to reveal cellular atypia or significant mitotic activity, as seen in our case. Furthermore, TUGSE is characterized by a significant infiltration of eosinophils within connective tissue,
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which is absent in SCC (Gopalakrishman et al., 1996). Finally, pseudoepitheliomatous hyperplasia (PEH), a benign condition in which the epithelium becomes hyperplastic and extends into the underlying connective, can closely mimic SCC. In most cases,
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examining multiple histological sections and obtaining detailed clinical information are sufficient to render a correct diagnosis (Zayour and Lazova, 2011). In addition, studies
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have shown that immunohistochemical staining for p53 reveals full-thickness nuclear reactivity in SCC as opposed to only basilar reactivity in PEH (Zarovnaya and Black, 2005). Others observed that the p53 staining pattern in PEH and was less intense and extensive compared with that of squamous cell carcinoma (Lee and Teh, 1994).
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4. Conclusion In conclusion, we have presented a case of spontaneous regression of a SCC of the oral cavity. This is a rare and unexpected phenomenon, which does not reflect the
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disease’s natural progression. In the event a tumor appears to have regressed, multiple
biopsies of the tumor site should be conducted to confirm complete remission of the cancer. Biopsies should also be repeated whenever tumor recurrence is suspected.
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Because little is known about this phenomenon, patients should be monitored indefinitely. Elucidation of the mechanisms of spontaneous regression may offer the
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possibility of improved methods of treating and preventing cancer in the future;
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however at this time current treatment recommendations should remain unaltered.
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Conflict of interest statement
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The authors have no conflicts of interest.
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26. Ramos LM, Cardoso SV, Loyola AM, Rocha MA, Durighetto-Júnior AF: Keratoacanthoma of the inferior lip: review and report of case with spontaneous regression. J Appl Oral Sci 17(3):262-265, 2009.
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27. Roxburgh D: Spontaneous Regression of Cancer. British Medical Journal 1: 39, 1935.
28. Savarrio L, Gibson J, Dunlop DJ, O'Rourke N, Fitzsimons EJ: Spontaneous
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regression of an anaplastic large cell lymphoma in the oral cavity: first reported case and review of the literature. Oral Oncol. 35(6):609-613, 1999.
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29. Schwartz RA: Keratoacanthoma. J Am Acad Dermatol 30:1-19, 1999. 30. Schwartz RA: Keratoacanthoma: a clinico-pathologic enigma. Dermatol Surg 30:327-333, 2004.
31. Shimkin MB, Griswold MH, Cutler SJ: Survival in untreated and treated cancer. CA-A Cancer J Clin 34:282-290, 1984.
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32. Shimkin MB: Duration of life in untreated cancer. Cancer 4:1-8, 1951. 33. Thomas JA, Badini M: The role of innate immunity in spontaneous regression of cancer. Indian J Cancer 48(2):246-251, 2011.
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34. Torroni A, Lorão B, Iannetti G: The importance of the head and neck region in regression of advanced MCC: a clinical report. J Craniofac Surg 18: 1173-1176,
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35. Vesely MJ, Murray DJ, Neligan PC, Novak CB, Gullane PJ, Ghazarian D: Complete spontaneous regression in Merkel cell carcinoma. J Plast Reconstr Aesthet Surg 61: 165-171, 2008.
36. Yoshimitsu K, Honda H, Kaneko K, Fukuya T, Irie H, Aibe H, Takenaka K, Kajiyama K, Masuda K: Temporary Spontaneous Regression of Intrahepatic
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Cholangiocarcinoma. Computerized Medical Imaging and Graphics 20: 115118, 1996. 37. Zarovnaya E, Black C: Distinguishing pseudoepitheliomatous hyperplasia from
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squamous cell carcinoma in mucosal biopsy specimens from the head and neck. Arch Pathol Lab Med 129:1032–1036, 2005.
38. Zayour M, Lazova R: Pseudoepitheliomatous hyperplasia: a review. Am J
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Figure legends. Figure 1. Clinical aspect of the patient’s squamous cell carcinoma located on the floor of the mouth.
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Figure 2. (A) Microscopic examination revealed invasion of the overlying epithelium through the basement membrane and into the underlying connective tissue. (B) Sheets
and islands of squamous cells demonstrating dysplastic features were noted. (C) Keratin
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pearls, individual cell keratinization and mitotic activity. (D) CD-117 and p53 positivity.
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Figure 3. Histopathological examination failed to reveal dysplastic or malignant changes three months after the initial diagnosis.
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Figure 4. The mucosa appeared clinically normal 70 months after the initial diagnosis.
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S1010-5182(14)00149-8
DOI:
10.1016/j.jcms.2014.04.026
Reference:
YJCMS 1802
To appear in:
Journal of Cranio-Maxillo-Facial Surgery
Received Date: 11 February 2014 Revised Date:
27 February 2014
Accepted Date: 22 April 2014
Please cite this article as: de Andrade Sousa A, Rena RL, Silva GS, Soares JMA, Porcaro-Salles JM, Nunes L, Mesquita RA, Jham BC, Spontaneous remission of a squamous cell carcinoma of the floor of the mouth, Journal of Cranio-Maxillofacial Surgery (2014), doi: 10.1016/j.jcms.2014.04.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Spontaneous remission of a squamous cell carcinoma of the floor of the mouth
Alexandre de Andrade Sousa, MD,1 Rafael Lopes Rena, MD,1 Guilherme Souza Silva, MD,1
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João Marcos Arantes Soares, PhD,1,2 José Maria Porcaro-Salles, MD, PhD,1 Laiz Nunes, DDS,3 Ricardo Alves Mesquita, DDS, MS, PhD,3 Bruno Correia Jham, DDS, MS, PhD4
Instituto Alfa de Gastroenterologia, Federal University of Minas Gerais
2
School of Medicine, Federal University of Sao Joao Del Rey
3
School of Dentistry, Federal University of Minas Gerais
4
College of Dental Medicine – Illinois, Midwestern University
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1
Institution to which work should be attributed:
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Instituto Alfa de Gastroenterologia. Avenida Professor Alfredo Balena, 110, Santa Efigênia,
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Belo Horizonte - MG, 30130-100, Brazil. Head: Prof. Jose Maria Porcaro-Salles , MD, PhD.
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Corresponding author: Bruno Jham, DDS, MS, PhD, Assistant Dean for Academic Affairs. College of Dental Medicine Illinois, Midwestern University,555 31st Street, Science Hall 211-II, Downers Grove IL, 60515. Phone: 630 515 7469; Fax: 630 515 7290. E-mail address: [email protected]
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Spontaneous remission of a squamous cell carcinoma of the floor of the mouth
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Abstract Spontaneous remission is a rare, but well recognized event in oncology. Certain tumors, such as melanomas, hypernephromas and neuroblastomas, are known for more
RI PT
commonly showing spontaneous regression. Similarly, spontaneous regression of oral
lymphomas, as well as oropharyngeal and recurrent tongue carcinomas, has been reported. Here, we present a novel case of a patient with a primary squamous cell
SC
carcinoma on the floor of the mouth whose tumor regressed spontaneously in three months, without any treatment. We also review of the literature on the spontaneous
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remission of oral cancer and discuss possible mechanisms for this phenomenon.
Key words: Oral cancer; spontaneous regression; spontaneous remission; squamous
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cell carcinoma; primary; floor of the mouth.
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1.
Introduction
Spontaneous regression is the partial or complete disappearance of a malignant
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tumor proven by microscopic examination in the absence of any substantial treatment.
The word spontaneous implies absence of any apparent cause, and regression/remission
means a decrease in the size of the tumor or in the extent of disease in the body
SC
(Thomas and Badini, 2011).
Spontaneous remission is a rare, but well recognized event in oncology. The
M AN U
most common clinical entities to regress are melanomas, hypernephromas and neuroblastomas (Savarrio et al., 1999). In addition, there are several reports in the literature describing the regression of a variety of cancers, including HPV-induced cervical intraepithelial neoplasia (Kadish et al., 2002), cholangiocarcinoma (Yoshimitsu et al., 1996), hepatocellular carcinoma (Misawa et al., 1999; Harada et al., 2010)
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metastatic renal cell carcinoma (Crisci et al., 2008), esophageal carcinoma (Kubota et al., 2003) and Merkel cell carcinoma (Brown et al., 1999; Torroni et al., 2007; Vesely et al., 2008; Karkos et al., 2010).
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In the oral cavity, spontaneous regression of lymphomas (Savarrio et al., 1999; Koga et al., 2003; Heibel et al., 2004), as well as oropharyngeal (Kurita et al,. 2007)
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and recurrent tongue (Oya and Ikemura, 2004) carcinomas has been reported. Here, we present a novel case of a patient with a primary squamous cell carcinoma on the floor of the mouth whose tumor regressed spontaneously in three months, without any treatment. In addition, we review of the literature on the spontaneous remission of oral cancer and discuss possible mechanisms for this phenomenon.
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2. Case report
A 62-year-old male sought care at the Baleia Hospital (Belo Horizonte, Minas
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Gerais, Brazil) for evaluation of an ulcerated lesion in the oral cavity, which had grown
progressively for seven months. The medical history was unremarkable. During interview, the patient reported a smoking habit for 50 years and heavy alcohol use for
SC
40 years. The patient had discontinued the use of alcohol seven years earlier, but had continued to smoke.
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Extra-oral examination showed no alterations and absence of palpable lymph nodes. Intra-oral examination revealed an ulcerative-infiltrative lesion with slightly raised borders, located on the floor of the mouth and measuring 3 cm in the largest diameter (Figure 1). The lesion extended to, but did not infiltrate, the gingival borders. Laterally, the lesion reached the first molars, on both sides. The remaining area of the
TE D
oral cavity, the pharynx and the larynx presented no changes. The teeth were in poor condition.
Following local anesthesia, an incisional biopsy was performed using a rongeur
EP
forceps. The tissue submitted for histopathological analysis and microscopic examination revealed invasion of the overlying epithelium through the basement
AC C
membrane and into the underlying connective tissue (Figure 2A). Sheets and islands of squamous cells demonstrating dysplastic features were observed (Figure 2B). Keratin pearls, individual cell keratinization and mitotic activity were noted (Figure 2C). Immunohistochemical studies were performed and showed CD-117 and p53 positivity (Figure 2D). Staining for ki67 showed a high proliferative index. Cytokeratin 7,
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cytokeratin 20 and p16 were negative. The case was reviewed by two independent pathologists, who both confirmed the final diagnosis of primary oral SCC. Subsequent to the diagnosis, laboratory and imaging exams were requested to
RI PT
complement the pre-operative and staging evaluation. While waiting for these, signs of
tumor regression were observed. Surprisingly, the tumor disappeared completely after
three months. After the tumor disappeared, multiple biopsies of the floor of the mouth
SC
were performed. The pathological examination revealed only a thick and keratinized mucosal lining, without any cellular atypia and a stromal lymphoid infiltration (Figure
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3). The patient was monitored quarterly for 70 months without any signs of tumor recurrence (Figure 4) and lost to follow-up thereafter.
3.
Discussion
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It has been suggested that spontaneous healing of malignant neoplasms occurs in 1:80,000 to 1:140,000 cases (Challis and Stam, 1990; Chang, 2000). However, estimates of the ‘true’ rate vary widely and it has been argued that many cases are
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probably not reported. Further, difficulties involved in establishing what criteria must be met in order for a specific case to constitute an instance of regression further complicate
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determining the true frequency of this phenomenon (Challis and Stam, 1990). Few studies have provided information on the incidence of spontaneous
regression of head and neck cancer. Kowalski and Carvalho (2000) reviewed the charts of 808 untreated head and neck cancer patients and found no cases of spontaneous regression. Similarly, studies comparing the median survival rates of untreated cancer failed to reveal cases of spontaneous regression of head and neck cancer (Shimkin,
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1951; Shimkin et al., 1984). Further, data from studies examining cases of spontaneous cancer remission confirm the rarity of this phenomenon in the head and neck. In this context, Challis and Stam (1990) reviewed the spontaneous of remission of cancer, by
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searching the literature between 1900 and 1987. Out of a total of 741 cases, only 14 (0.018%) were found in the head and neck. Of these, five were adenoid cystic
carcinomas and three cases were presented as squamous cell carcinomas, without
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location. For six cases, only the location was presented, without specification of the histopathological subtype.
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The first report of what may have represented spontaneous regression of a squamous cell carcinoma of the left tonsil, root of tongue, and left lateral wall of the pharynx was described in 1910 (Godfrey, 1910). Later, in 1935, an additional study of what appears to be spontaneous regression of a tongue cancer was published (Roxburgh, 1935). Better documented cases appeared only more recently. In 2004, a recurrent
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tongue carcinoma was reported to gradually and spontaneously regress, without further therapy. The lesion completely disappeared both clinically and by computed tomography imaging at 1 year and 4 months after recurrence. No evidence of recurrence
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was noted at 3 years and 7 months follow-up (Oya and Ikemura, 2004). In 2007, Kurita et al. reported a case of oropharyngeal squamous cell carcinoma with spontaneous
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regression of lymph node metastasis. To our knowledge, the case here in described is the first well-documented case of a primary oral squamous cell carcinoma showing spontaneous regression. The mechanisms of tumor regression are still largely unknown. Explanations for
this phenomenon include immune modulation, removal of carcinogenic substances, infection, induction of apoptosis, action of antibodies, anti-angiogenic mechanisms of
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maturation, natural killer activity, endocrine system activity, tumor inhibition by growth factors and/or cytokines, induction of cell differentiation, tumor necrosis, and/or inhibition of angiogenesis, apoptosis and other epigenetic mechanisms (Papac, 1998;
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Chang, 2000). In the case here in described, we believe that the incisional biopsy triggered an immune response, which in turn led to tumor regression. Indeed, many reports of spontaneous regression have implicated surgery or operative trauma as an
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element that can increase immunological resistance to tumor growth and the removal of
a portion of the tumor would presumably facilitate the destruction of the remaining part
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of the neoplasm by the host immune system (Challis and Stam, 1990).
Interestingly, several reported cases of spontaneous cancer regression note concomitant infections, including diphtheria, gonorrhea, hepatitis, influenza, malaria, measles, smallpox, syphilis and tuberculosis, as well as various other pyogenic and nonpyogenic infections (Hoption et al., 2002). These infections normally bring about a
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strong immunological response and therefore fever. A strong febrile reaction from a natural or induced acute infection was the most common symptom associated with tumour regression (Thomas and Badini, 2011). Further, prior fever was recorded in 25-
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80% of documented cases of spontaneous regression of cancer. In a study with 26 spontaneous remissions in a cohort of 300 cases of childhood leukemia, 80% was
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accompanied by infection (Doran et al., 1989). In pancreatic cancer, it has been argued that possible cases of spontaneous
regression could have actually represented misdiagnosis with non-malignant diseases (Herreros-Villanueva et al., 2012). In the context of oral SCC, the keratoacanthoma (KA) represents a diagnostic challenge for the clinician and pathologist, since both clinical and histopathologic features of KA may resemble those of a well differentiated
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SCC (Schwartz, 1999; Schwartz, 2004; Jones and Blanco-Guzman, 2013). However, nearly 95% of KAs are found on sun-exposed areas (Neville et al., 2008) and, microscopically, a sharp demarcation between tumor and stroma, cup-shaped
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appearance and a deep but distinct collar-like invasive front of the epithelium are seen
(Ramos et al., 2009). These features were absent in our case. Further, abundant and atypical mitosis, as well as pleomorphism, as seen in the current case, favors SCC
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(Griffiths, 2004). The traumatic ulcerative granuloma with stromal eosinophilia
(TUGSE) may also clinically mimic a malignant process. TUGSE presents as an
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indurated, ulcerative, non-tender lesion of the oral mucosa, most commonly seen on the tongue. Interestingly, TUGSE is known for regressing upon an incisional biopsy (Kumar et al., 2008). However, microscopic examination of TUGSE fails to reveal cellular atypia or significant mitotic activity, as seen in our case. Furthermore, TUGSE is characterized by a significant infiltration of eosinophils within connective tissue,
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which is absent in SCC (Gopalakrishman et al., 1996). Finally, pseudoepitheliomatous hyperplasia (PEH), a benign condition in which the epithelium becomes hyperplastic and extends into the underlying connective, can closely mimic SCC. In most cases,
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examining multiple histological sections and obtaining detailed clinical information are sufficient to render a correct diagnosis (Zayour and Lazova, 2011). In addition, studies
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have shown that immunohistochemical staining for p53 reveals full-thickness nuclear reactivity in SCC as opposed to only basilar reactivity in PEH (Zarovnaya and Black, 2005). Others observed that the p53 staining pattern in PEH and was less intense and extensive compared with that of squamous cell carcinoma (Lee and Teh, 1994).
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4. Conclusion In conclusion, we have presented a case of spontaneous regression of a SCC of the oral cavity. This is a rare and unexpected phenomenon, which does not reflect the
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disease’s natural progression. In the event a tumor appears to have regressed, multiple
biopsies of the tumor site should be conducted to confirm complete remission of the cancer. Biopsies should also be repeated whenever tumor recurrence is suspected.
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Because little is known about this phenomenon, patients should be monitored indefinitely. Elucidation of the mechanisms of spontaneous regression may offer the
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possibility of improved methods of treating and preventing cancer in the future;
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however at this time current treatment recommendations should remain unaltered.
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Conflict of interest statement
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The authors have no conflicts of interest.
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Figure legends. Figure 1. Clinical aspect of the patient’s squamous cell carcinoma located on the floor of the mouth.
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Figure 2. (A) Microscopic examination revealed invasion of the overlying epithelium through the basement membrane and into the underlying connective tissue. (B) Sheets
and islands of squamous cells demonstrating dysplastic features were noted. (C) Keratin
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pearls, individual cell keratinization and mitotic activity. (D) CD-117 and p53 positivity.
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Figure 3. Histopathological examination failed to reveal dysplastic or malignant changes three months after the initial diagnosis.
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Figure 4. The mucosa appeared clinically normal 70 months after the initial diagnosis.
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