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Download PDF Evidence Based Demonstration of the Concept Of Rom J Morphol Embryol 2015, 56(3):1027–1033 R J M E RIGINAL APER Romanian Journal of O P Morphology & Embryology http://www.rjme.ro/ Evidence based demonstration of the concept of ‘field cancerization’ by p53 expression in mirror image biopsies of patients with oral squamous cell carcinoma – an immunohistochemical study ALKA H. HANDE1), DEEPALI P. MOHITE2), MINAL S. CHAUDHARY1), MIMANSHA PATEL1), PRIYANKA AGARWAL1), SHRUTI BOHRA1) 1)Department of Oral Pathology and Microbiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences (DU), Sawangi (Meghe), Wardha, Maharashtra, India 2)Department of Oral Pathology and Microbiology, Swargiya Dadasaheb Kalmegh Smruti Dental College and Hospital, Hingna, Nagpur, Maharashtra, India Abstract Objective: The main rationale for treatment failure and death of the patients with oral squamous cell carcinoma (OSCC) is loco-regional recurrence, development of second primary tumor (SPT) and metastasis, which could be well explained by concept of field cancerization. Identification of patients at high risk for development of SPT is an important part of research for cancer management. This study was designed keeping this aspect in mind and utilizing the increased expression of p53 as an indicator of existence of altered fields in mirror image biopsies of OSCC patients. Design: Forty clinically diagnosed oral cancer patients were included in the study. Biopsy tissue samples from clinically diagnosed oral cancer patients (Group A) and the mirror image, clinically normal looking mucosa at corresponding contralateral anatomical site (Group B) were studied for histopathological evaluation and p53 immunoexpression. Results: Tissue alterations were observed in Groups A and B. There was statistically significant (chi-square value – 126.6, p=0.0001) difference in grades of epithelial dysplasia and p53 immunoexpression in Group B. Spearman’s Rank Correlation Coefficient shows non-significant positive correlation between epithelial dysplasia and p53 (r=0.28, p=0.05) in Group B. Conclusions: Evidence of presence of field cancerization, evaluated by histopathological alterations and enhanced p53 expression was observed in mirror image biopsies of OSCC patients. This could predict the altered state of oral mucosa secondary to carcinogen exposure. The realization of a genetically altered field as a cancer risk factor provides a new paradigm. It would be prudent to keep these patients under close observation and to advice them chemotherapeutic regimes. Keywords: oral squamous cell carcinoma, mirror image biopsies, p53, field cancerization. Introduction primary tumor (SPT). The incidence rate of SPT is 10– 35%, depending on both the location of first primary Head and neck cancer includes cancers originating in and age of the patient [6]. The term SPT may be used in the oral cavity, the oropharynx, the hypopharynx, and connotation with ‘field cancerization’, the term and the larynx [1]. Oral squamous cell carcinoma (OSCC) is concept first put forth by Slaughter et al. in 1953 [7]. the sixth most common cancer for both sexes in the The principle of field cancerization encompasses the general population, and the third most common cancer carcinogen induced early genetic changes in the mucosa in developing nations with high incidence of mortality and of oral cavity, which leads to development of precancerous morbidity rate [2]. OSCC is a heterogeneous disease with lesions and further multifocal tumors. Further, it is complex molecular abnormalities. It may arise from a frequently used to explain the persistence of abnormal precancerous progenitor followed by outgrowth of clonal tissue after surgical removal of tumor, which may result populations associated with cumulative genetic alterations in local recurrence and or SPT. The concept of field and phenotypic progression to invasive malignancy. During cancerization in context to SPT is further elaborated by this process of carcinogenesis, principal etiological factors many researchers [8–12]. The phenotypic expression of like tobacco, in its various forms (chewing, snuff, smoking), field cancerization could be attributed to independent and alcohol are responsible for genetic alterations, which molecular events affecting multiple cells independently in result in inactivation of multiple tumor suppressor genes the whole tissue region subsequent to carcinogen exposure and activation of proto-oncogenes [3]. or to molecular events occurring in a single progenitor Survival of OSCC patients is related to the site and with widespread expansion or lateral spread across the pathological stage of the primary tumor as well as the mucosa. Two types of migration may be involved that is histological grade and pattern of invasion [4]. Despite migration of tumor cells via saliva – micrometastasis or advances in treatment, the five-year relative survival intraepithelial migration of the progeny of the initially rate remains less than 50% and has not improved much transformed cells throughout the mucosa. There is also a over the past three decades [5]. The prognosis of OSCC possibility that the tumor itself exercises a regional is adversely influenced by the development of second effect on the oral mucosa [13]. ISSN (print) 1220–0522 ISSN (on-line) 2066–8279 1028 Alka H. Hande et al. The realization of a genetically altered field as a cancer obtaining written informed consent, 40 patients were risk factor provides a new paradigm. The existence of enrolled in the study. Detailed intraoral examination was field with genetically altered cells is a distinct biological done including both the pathological lesion and the contra- stage with continued risk for SPT [5]. Identification lateral mirror image biopsy site from clinically normal of patients at high risk for development of SPT is an looking mucosa. The pathological lesions were designated important part of management of cancer. Advances in as Group A lesions, whereas contralateral mirror image molecular biology have made it possible to investigate biopsy site from clinically normal looking mucosa were tumor growth and field at molecular level with some designated as Group B lesions. Under all aseptic precautions degree of accuracy. The process of carcinogenesis might and surgical preparation, a clean and defined elliptical involve not only increased cell proliferation but also incision was given producing a “V”-shaped wedge that decreased cell apoptosis and failure to undergo apoptosis includes both the lesion and healthy margin and the soft is a major contributor to the uncontrolled growth of tumors tissue specimen was excised. Biopsy from mirror image [14]. The carcinogens might induce a “fingerprint”-like site was performed from clinically normal looking mucosa pattern of mutations at the p53 gene. The p53 gene at corresponding contralateral anatomical site. Biopsy inactivation by means of carcinogen induced mutations, samples were fixed in 10% formalin and forwarded for deletions, and binding to viral proteins has been demon- conventional tissue processing in the histopathology strated in oral cancers [15]. laboratory. Two sections of 4-μm thickness were obtained Although a visible lesion precedes the development of from both the groups (Groups A and B) tissue. One section majority of OSCC, sometimes it may disguise itself and of each was stained with routine Hematoxylin–Eosin precancerous or cancerous changes are not always be (HE) stain for evaluation of the histopathological changes. discernible clinically or histologically. However, several The other section from both the groups (Groups A and B) studies support the fact that clinically normal appearing tissue was subjected to immunohistochemistry (IHC), mucosa of OSCC patients may be genetically altered due which was carried out by using monoclonal mouse anti- to disordered epithelial maturation and differentiation human antibody against p53 antibody. resultant to carcinogen exposure [5, 16, 17]. The genetic Histopathological evaluation changes present in normal appearing cells can be used for identification and recruitment of individuals at increased Histopathological evaluation of the clinically diagnosed risk of developing SPT for primary chemoprevention. oral cancer and mirror image tissue sections (Groups A Keeping this in mind, this study was aimed at and B) was done after staining with HE, by two oral demonstration of the concept of field cancerization by pathologists in double-blinded manner. Cases with discor- expression of structural and molecular alterations in mirror dant results underwent a consensus review with a third oral image biopsies of patients with OSCC. pathologist. The inclusion criteria used for the clinically diagnosed oral cancer tissue sections was in accordance Materials and Methods with the histological typing of cancer and precancer of oral mucosa [18]. The cases, which fulfill the definition of Study subjects squamous cell carcinoma that is, “A malignant epithelial The present study was carried out at the Department of neoplasm exhibiting squamous differentiation characterized Oral Pathology and Microbiology, Sharad Pawar Dental by the formation of keratin and/the presence of intercellular College and Hospital, Datta Meghe Institute of Medical bridges”, were included in the study. The histopathological Sciences (DU), Sawangi (Meghe), Wardha, Maharashtra, grading of oral cancer is generally based on the subjective India. The duration of the study was six months, from assessment of the degree of keratinization,
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