|Year : 2017 | Volume
| Issue : 2 | Page : 148-153
An evaluation of field cancerization in patients with oral cancer by “Mirror Image” biopsy
Ravikant V Sune, Atul D Indurkar, Rahul R Bhowate, Shirish S Degwekar, Vidya K Lohe
Department of Oral Medicine and Radiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences (Deemed University), Sawangi, Wardha, Maharashtra, India
|Date of Web Publication||8-Sep-2017|
Ravikant V Sune
Department of Oral Medicine and Radiology, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences (Deemed University), Sawangi, Wardha, Maharashtra
Source of Support: None, Conflict of Interest: None
Aim: The present study was conducted with the aim to define the incidence and type of field change in clinically apparent normal mucosa of new patients with unilateral oral squamous cell carcinoma (OSCC). Materials and Methods: Biopsy was carried out from clinically apparent normal oral mucosa on the contralateral site (mirror image site) in 38 consecutive newly diagnosed patients with unilateral OSCC. The mirror image tissue was analyzed histologically for abnormal features of dysplasia by two oral pathologists. Results: According to observer 1, 22 (57.89%) mirror image biopsies showed dysplasia of which 19 (50%) mirror image biopsies showed mild dysplasia and 3 (7.89%) mirror image biopsies showed moderate dysplasia. According to observer 2, 17 (44.74%) mirror image biopsies showed dysplasia of which 16 (42.11%) mirror image biopsies showed mild dysplasia and 1 (2.63%) mirror image biopsy showed moderate dysplasia. Conclusions: Histological observation of dysplasia at mirror image site was noted in about half of a sample of cases. Results displayed vulnerability to field change of oral mucosa chronically exposed to carcinogens. It acknowledges the risk for development of second or multiple primary tumors.
Keywords: Field cancerization, field change, oral cancer, oral squamous cell carcinoma
|How to cite this article:|
Sune RV, Indurkar AD, Bhowate RR, Degwekar SS, Lohe VK. An evaluation of field cancerization in patients with oral cancer by “Mirror Image” biopsy. J Datta Meghe Inst Med Sci Univ 2017;12:148-53
|How to cite this URL:|
Sune RV, Indurkar AD, Bhowate RR, Degwekar SS, Lohe VK. An evaluation of field cancerization in patients with oral cancer by “Mirror Image” biopsy. J Datta Meghe Inst Med Sci Univ [serial online] 2017 [cited 2019 Oct 18];12:148-53. Available from: http://www.journaldmims.com/text.asp?2017/12/2/148/214200
| Introduction|| |
Although many diseases, considered being life-threatening in the past, can be either curing or controlling, cancer remains one of the major burdens to public health. According to the World Health Organization Report 2004, cancer has caused 7.1 million deaths in 2003. Furthermore, the new cases are increasing in number and will rise by 50% in next 20 years. Oral cancer is considered eighth most common cancer worldwide with an incidence rate of 1-10 cases per 100.000 populations in men. Oral cancer is most prevalent in developing than developed countries. Oral cancer is among three most common cancers in South-East Asia and India incidence rate is 12.6 per 100.000 populations.,
Oral squamous cell carcinoma (OSCC) is a multistep carcinogenic event. Initial genetic alterations at molecular level lead to clinical and morphologic cellular changes, resulting in the formation of invasive neoplasm. It is suggested that principal etiological factors such as tobacco and alcohol are responsible for DNA mutation activating oncogenes, interfering with tumor-suppressor genes and interacting with various epithelial growth factors.
Today, it is widely accepted that exposure to carcinogens may cause premalignant change at multiple sites of oral mucosa. Hence, patients with oral cancer are at risk of developing second or multiple primary tumors. This concept in the literature is known by field cancerization., The term field cancerization was used for the first time by Slaughter et al. in 1953. In their memorable review of 783 patients with oral cancer, they found abnormal and hyperplastic, often atypical, epithelium surrounding oral cancer for varying distances and also independent multiple tumors in 11.2% of patients.
Two competing hypothesis have been emerged to explain the development of multiple tumors in oral cancer patients. One group of researcher consider that each tumor arise as an independent genetic event and are clonally unrelated,, other prefer the hypothesis that multiple transforming events are rare and each tumor arise from the widespread migration of initially transformed clonal cells. Still another group also stated that the carcinogenic process itself is likely to exert a regional effect on the mucosa of head and neck cancer.
In patients with OSCC, the incidence rate of second primary tumor (SPT) was found to be 14%. In other study, 5-year incidence rate was 13% and 10-year incidence rate was 21%. Many studies worldwide have reported the occurrence of such second primary or multifocal tumors in patients with oral cancer. In view of this, treatment of the first tumor does not predicatively arrest the development of SPT. Management of patient can become complicated and prognosis even worse with the occurrence of SPT. The detection of multifocal cancerous process at an earlier stage with scrupulous diagnostic procedures for better treatment should improve survival in these patients.
The present study was conducted to define the incidence and type of field change in clinically apparent normal mucosa of new patients with unilateral OSCC by clinical and histopathological examination.
| Materials and Methods|| |
The present study was conducted in the Department of Oral Medicine and Radiology, after the approval from the Institutional Ethics committee. This cross sectional study was conducted on 38 new (untreated) patients with unilateral OSCC. The purpose of the study and procedures involved were explained to the patients and written informed consent was obtained from all the participants. Patients with extensive midline tumors, bilateral tumors, metastatic disease in the oral cavity, previously treated OSCC, long term review for dysplasia or clinical evidence of widespread premalignant lesions including contralateral site were not included in the study.
Details were recorded of each patient's age, sex, clinical history, and the precise anatomical site of the pathological lesion and “mirror image” biopsy. Pathological lesions were grouped according to the size into three categories as T1, lesions with size of < 2 cm; T2, lesions with size of more than 2 cm but < 4 cm and T3, lesions with size of more than 4 cm.
After a detailed examination of each patient, biopsy was carried out from the representative area of the lesion and also from the selected site of normal oral mucosa on the contralateral site (which is further called as “mirror image” site in this study). The specimens were fixed in 10% formalin solution. Then, the samples were sent to the Department of Oral Pathology for histopathological examination which was done by two experienced oral pathologists. The second observer was not aware of the histopathological findings noticed by the first observer.
OSCC was classified into well, moderately, and poorly differentiated tumors according to conventional histopathological grading (Broder's Classification, 1920). The mirror image tissue was analyzed histologically for abnormal features of mild, moderate, or severe dysplasia. Mild dysplasia was considered when dysplastic changes does not extend beyond the lower third of the epithelium, moderate when extending into middle third, and severe when extending into upper third. The dysplastic features assessed were nuclear hyperchromatism, increased nuclear-cytoplasmic ratio, cell and nuclear pleomorphism, increased and abnormal mitotic figures, loss of polarity of basal cells, dyskeratosis, loss of differentiation between basal and prickle cells, diminished intercellular adherence, drop-shaped, and abnormal rete ridges.
The SPSS for Windows, version 14.0 (SPSS Inc., Chicago, Illinois, USA) was used in the calculation of all statistics. Two-tailed P < 0.05 was considered statistically significant. Analyses of patients were done particularly for age, sex, anatomic location, severity of pathologic lesion, and degree of dysplasia in the mirror image tissue. The comparison of histopathological examination of pathological lesions, as well as mirror image tissues among observer 1 and observer 2, was done by Chi-square test. The analysis of covariance using one-way ANOVA for regression analysis was carried out to find correlation among pathological lesion, age, sex, anatomical site, and the likelihood of discovering abnormal histology in the mirror image biopsies.
| Results|| |
The sample consisted of 38 patients, of which 32 were male and 6 were female patients. The age range was 32 years to 65 years with mean age of 52.00 ± 10.21 years. All patients were having a habit of either betel quid chewing, tobacco chewing, smoking, or alcohol consumption. Of 38 patients, 18 (47.27%) patients presented clinically with T1 OSCC, 10 (26.32%) with T2 OSCC and 10 (26.32%) with T3 OSCC. Twenty-five (65.79) patients had lesions on left buccal mucosa, 11 (28.95%) on right buccal mucosa, and 2 (5.26%) on the right lateral border of tongue.
According to observer 1, 23 (60.53%) lesions were well-differentiated squamous cell carcinoma, 8 (21.05%) lesions were moderately differentiated squamous cell carcinoma, and 7 (18.42%) lesions were verrucous squamous cell carcinoma. None of the lesions were poorly differentiated squamous cell carcinoma on histopathological examination. According to observer 2, 25 (65.79%) lesions were well-differentiated squamous cell carcinoma, 6 (15.79%) lesions were moderately differentiated squamous cell carcinoma, and 7 (18.42%) lesions were verrucous squamous cell carcinoma. None of the lesions were poorly differentiated squamous cell carcinoma on histopathological examination [Table 1].
|Table 1: Distribution of pathological lesions according to histopathological examination by observer 1 and observer 2|
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According to observer 1, 16 (42.10%) mirror image biopsies were normal, 19 (50%) mirror image biopsies showed mild dysplasia, and 3 (7.89%) mirror image biopsies showed moderate dysplasia. None of the mirror image biopsies showed severe dysplasia on histopathological examination. According to observer 2, 21 (55.26%) mirror image biopsies were normal on histopathological examination, 16 (42.11%) mirror image biopsies showed mild dysplasia, and one (2.63%) mirror image biopsy showed moderate dysplasia. None of the mirror image biopsies showed severe dysplasia on histopathological examination [Table 2], [Figure 1] and [Figure 2].
|Figure 1: H and E stained section of mirror image tissue showing mild dysplasia|
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|Figure 2: H and E stained section of mirror image tissue showing moderate dysplasia|
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|Table 2: Distribution of mirror image biopsies according to histopathological examination by observer 1 and observer 2|
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The difference among the two observers for histopathological examination of pathological lesions as well as mirror image tissues was not statistically significant as the P > 0.05 [Table 3]. For observer 1 and observer 2, correlation among pathological lesion, age, sex, anatomical site, and the abnormal histology in the mirror image biopsies, was not statistically significant. Furthermore, correlation among pathological lesion, age, sex, anatomical site and the likelihood of discovering abnormal histology in the mirror image biopsies was not statistically significant as the P > 0.05 [Table 4].
|Table 3: Comparison of histopathological examination of pathological lesions and mirror image biopsies among observer 1 and 2|
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|Table 4: Analysis of covariance of mirror image biopsies for observer 1 and observer 2|
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| Discussion|| |
The presence of epithelial dysplasia is more likely to result in oral cancer. Widely accepted oral lesions with malignant potential are leukoplakia and erythroplakia, but it is also found that up to 50% of OSCCs begin in clinically apparent normal mucosa. Clinical progression of individual precursor lesion is difficult to determine. In addition, none of the available molecular marker can definitely predict the fate of lesions in terms of its progression to cancer and none are tested in large prospective studies. Therefore, one has to rely on histopathological examination of lesions for the degree of dysplasia as a guide to malignant potential of lesions.
Carcinogenesis is a multistep process involving initiation and then progression of diseases. Carcinogens such as tobacco and alcohol initiate the disease process, subsequently, there is a symptom-free period during which cellular changes progresses gradually from normal to premalignant which are potentially reversible and then frank malignant changes may occur. However, the specific nature and order of structural and genetic changes preceding the malignant transformation are not characterized till date.
In the present study, dysplastic features were analyzed by histopathological examination in clinically apparent normal mucosa of patients with oral cancer. According to observer 1, 22 (57.89%) mirror image biopsies showed dysplasia of which, 19 (50%) mirror image biopsies showed mild dysplasia and 3 (7.89%) mirror image biopsies showed moderate dysplasia. According to observer 2, 17 (44.74%) mirror image biopsies showed dysplasia of which, 16 (42.11%) mirror image biopsies showed mild dysplasia and 1 (2.63%) mirror image biopsy showed moderate dysplasia.
The finding of mild-to-moderate dysplasia in the clinically apparent normal mucosa of oral cancer patients in the present study confirms the findings of various other studies reported in the literature supportive of a field change. Incze et al., found evidence at an ultrastructural level for premalignancy in normal appearing epithelium in patients with squamous cell carcinoma of the upper aerodigestive tract who were having smoking habit. They noted an increase in nuclear area and altered nuclear to cytoplasmic area ratio. Ogden et al. noted inappropriate cytokeratin expression in 12 out of 32 biopsies from clinically normal oral mucosa in patients with OSCC. Other studies utilizing exfoliative cytology presented further evidence supportive of a field change.,,
Thomson, while conducting study on field change and oral carcinogenesis found histologically abnormal tissue at mirror image site in 58% of oral cancer patients and no statistically significant correlation was found among pathological lesion, age, sex, anatomical site, and the likelihood of discovering abnormal histology in the mirror image biopsies. Similar results were obtained in the present study. However, in the study by Thomson increased vulnerability for dysplastic change in the normal mucosa of ventral and lateral tongue and floor of the mouth was present. In the present study, no such correlation is found probably because most of the cases were of buccal mucosa for which normal tissue biopsies were obtained from corresponding mirror image site.
After excision of primary OSCC, the margins are generally studied for residual cancer or cancer cells. The presence of dysplasia at resected margins is a concern, especially severe dysplasia. Studies have shown that even mild-to-moderate dysplasia can turn into cancer., The observation of field change in the present study that about half of a sample of 38 patients presenting with new OSCC lesions showed histological evidence of dysplasia at other, clinically normal oral sites, may be clinically significant. Results displayed vulnerability to field change in oral mucosa chronically exposed to carcinogens. It acknowledges the risk for development of multiple primary tumors. Furthermore, it warrants a careful interpretation of dysplasia at tumor resection margins and intraoperative frozen section biopsies.
Liao et al., in a retrospective study of OSCC patients, found significantly higher incidence of 5-year SPTs in preoperative betel quid chewers than non-chewers regardless of the treatment modality with no significant association with postoperative betel chewing, or cigarette smoking. Their results suggest that field change occur even before treatment of primary tumor and is not significantly influenced by postoperative oral habits. Most of the OSCC patients in the present study were having a habit of betel quid chewing with finding of dysplastic features in normal mucosa in about half of a cohort which suggests field change. Due to the high risk of SPTs in chewers, policies intended at preventing betel quid chewing initiation should be executed on large scale.
Patient with OSCC is at risk of developing SPT for over 10 years. The development of SPTs adversely affects survival of patients with oral cancers. Hence, routine and careful long-term follow-up of these patients at regular intervals is necessary. It may not be possible to remove altered fields of mucosa surgically. Researchers have tried to come up with chemopreventive agents that can reverse or arrest the progression of premalignant lesion and can also prevent tumor recurrence or SPT.
The most widely studied chemopreventive agent is 13-cis retinoic acid. It has shown good clinical response in head and neck premalignant lesions,, and in the prevention of SPT. Despite its efficacy in clinical regression of premalignant lesion, another study observed that genetic changes in altered fields of mucosa remain unchanged. Consequently, the definitive therapy should consist of targeted treatment directed to eradication of molecularly altered cells or repair of genetic mutations involved in carcinogenesis. The toxicity (conjunctivitis, mucositis, dry skin, hypertriglyceridemia, and malaise) of retinoid-based compounds at higher doses may limit its utility. Other chemopreventive agents that have been evaluated include vitamin E, Bowman-Birk inhibitor concentrate derived from soybeans, curcumin, and green tea polyphenol epigallocatechin-3-gallate. Agents showing promise in targeted molecular treatment includes cyclooxygenase-2 inhibitors and epidermal growth factor receptor inhibitors.
As the size of the present study population was small, larger scale investigation and long-term follow-up studies are now needed to emphasize the significance of field change in present management of oral cancer patients. Studies utilizing molecular techniques such as karyotype analysis, microsatellite analysis, p53 mutation screening, X-chromosome inactivation studies, mitochondrial DNA mutation assays, and urokinase-type plasminogen activation assays have helped to understand the possible relationship between OSCC primary tumor, local recurrence, and SPTs.,, The identification of reliable biomarkers is needed which can determine high-risk population who are more likely to develop recurrence or SPTs after radical surgery. Expectantly, such prognostic determination will have a positive outcome on survival. With the discovery and validation of a wide variety of biomarkers in OSCC patients, it may become possible to individualize treatment through targeted molecular intervention to specific genetic abnormality.
| Conclusion|| |
The present study demonstrated histological evidence of dysplasia at other clinically normal oral mucosa in about half of the sample of oral cancer patients. It signifies field change and acknowledges the risk for the development of second or multiple primary tumors. Along with the treatment of primary oral cancer, intense chemoprevention with nutritional counseling and tobacco cessation is required to prevent the emergence of SPT in future. More advanced, reliable and noninvasive methods are needed to detect dysplastic changes occurring in normal mucosa of oral cancer patients. Further research is needed in the identification of biomarkers which can determine high-risk oral cancer patients and also in individualized targeted molecular intervention for the treatment of field change.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]