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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 3  |  Page : 550-555

Estimation of serum ferritin level in potentially malignant disorders, oral squamous cell carcinoma, and treated cases of oral squamous cell carcinoma


1 Department of Oral Medicine and Radiology, Faculty of Dental Sciences, KGMU, Lucknow, Uttar Pradesh, India
2 Department of Oral Medicine and Radiology, Nair Hospital Dental College, Mumbai, Maharashtra, India
3 Department of Radiotherapy, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra, India
4 Department of Pediatric and Preventive Dentistry, Manvik Dental Clinic, Lucknow, Uttar Pradesh, India
5 Department of Oral and Maxillofacial Surgery, H.P. Government Dental College and Hospital, Shimla, Himachal Pradesh, India

Date of Web Publication31-Aug-2017

Correspondence Address:
Vikram Khanna
Department of Oral Medicine and Radiology, Faculty of Dental Sciences, KGMU, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.181182

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 > Abstract 


Introduction: Serum ferritin is the best indicator of iron stores in the body. The level of serum ferritin was found to be elevated in number of malignancies. Serum ferritin is also been established as prognostic marker for malignant lymphoma, cervical cancer, breast cancer, etc.
Aims and Objective: The aim of this study is to evaluate the level of serum ferritin in patients with pretreatment and posttreatment of squamous cell carcinoma and to determine the significance of serum ferritin as prognostic marker for oral squamous cell carcinoma (OSCC).
Materials and Methods: Blood samples of 15 normal, thirty potentially malignant lesions, and thirty patients of squamous cell carcinoma were taken and analyzed for serum ferritin using ELISA. Of thirty patients, 15 patients were followed up till 6 months after their treatment and serum ferritin was again determined.
Results: The average serum ferritin of 30 potentially malignant disorders was 62.70 ng/ml, and thirty patients with squamous cell carcinoma were found to be 162.47 ng/dl. After 6 months of the treatment, the mean fall in serum ferritin with nonrecurrence patients was 84 ng/dl and increase in the serum ferritin in recurrence cases was 13.4 ng/dl.
Conclusion: Determining serum ferritin is a convenient and nonexpensive method to determine the outcome of the treatment of the cases with OSCC. Its potential as prognostic marker could not be overlooked.

Keywords: Oral squamous cell carcinoma, potentially malignant disorders, serum ferritin


How to cite this article:
Khanna V, Karjodkar F, Robbins S, Behl M, Arya S, Tripathi A. Estimation of serum ferritin level in potentially malignant disorders, oral squamous cell carcinoma, and treated cases of oral squamous cell carcinoma. J Can Res Ther 2017;13:550-5

How to cite this URL:
Khanna V, Karjodkar F, Robbins S, Behl M, Arya S, Tripathi A. Estimation of serum ferritin level in potentially malignant disorders, oral squamous cell carcinoma, and treated cases of oral squamous cell carcinoma. J Can Res Ther [serial online] 2017 [cited 2019 Nov 16];13:550-5. Available from: http://www.cancerjournal.net/text.asp?2017/13/3/550/181182




 > Introduction Top


Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy of the oral cavity. It accounts for 2–3% of all cancer. However, its incidence varies according to the region like in Pakistan, it is about 10% whereas in India, it is extraordinarily 45%.[1],[2] In addition, the incidence of OSCC is increasing among the younger population.[3]

The etiopathogenesis of oral cancer is now drifting more toward the genetic composition of an individual. Several genes have been implicated in the pathogenesis of the oral cancer, predisposing the conversion of potentially malignant disorders into oral carcinoma. Chronic predisposition of the carcinogens activates these genes and results in the DNA mutation which triggers the mechanism.[4] During carcinogenesis, the changes in DNA are evident and clear, however, serum chemistry of the body fluid also changes during this transformation.

In 1986, Maxim and Veltri[5] carried out a study to show the high concentration of the serum ferritin levels in head and neck squamous cell carcinoma. They concluded that the concentration was significantly higher in the advanced stage of oral carcinoma. According to the study,[6] low iron and, subsequently, serum ferritin have a role to play in etiology of potentially malignant disorders such as oral submucous fibrosis (OSMF), Plummer–Vinson syndrome.

The abnormal concentration of serum ferritin in malignancies may be due to reticuloendothelial disturbances and release of ferritin from damaged cells or synthesis of ferritin by neoplastic cells.[7]

Second, iron is stored in form of ferritin in body and the amount of ferritin in blood (serum ferritin level) is directly related to the amount of iron stored in your body.[8] According to Gutteridge,[9] iron and oxygen together constitute a biologically highly damaging mixture due to increased formation of free radicals. Free radical mediated damage is known to be the root cause of many inflammatory, degenerative, and neoplastic diseases. Carcinogens are considered to be activated not only by the more usually accepted enzymic pathways but by free-radical reactions, catalyzed by iron, in the vicinity of critical sites. There is another way that iron can contribute to cancer growth. The functions in which iron participate relate to the properties of unremitting proliferation and a more anaerobic metabolism.[10] The levels of serum ferritin are evaluated in various other malignancies.[11],[12],[13],[14]

The present study is aimed to estimate the level of serum ferritin in the patients with potentially malignant disorders such as leukoplakia, OSMF, squamous cell carcinoma patients (OSCC), and treated cases of squamous cell carcinoma. The objectives are to determine the correlation between the serum ferritin level and the potential malignant disorders and to evaluate the level of serum ferritin in pre- and post-treated cases of squamous cell carcinoma patients. Finally, it is to establish the importance of serum ferritin as prognostic marker in OSCC.


 > Materials and Methods Top


The sample size of first group, i.e., normal group was 15, potentially malignant disorders and squamous cell carcinoma patients were thirty each and for the last group, i.e., treated cases of oral cancer was 15 which has been followed for 6 months (15 patients lost in follow).

Patients for normal, potentially malignant disorders, and squamous cell carcinoma are selected randomly from the outpatient department (OPD) of oral medicine and for treated cases of squamous cell carcinoma, the patients were followed for radiotherapy and blood sample was taken after 6 months of their treatment completion. The above mentioned study was approved from the Institutional Review Committee.

Inclusion criteria

All those individuals who had positive histopathology report for potentially malignant disorders and for OSCC were included in the study group. Patients who were willing to participate in the study and signed the informed consent form were included in the study. For normal group, patients were randomly selected from the OPD devoid of any systemic condition or healthy patients were included in the control group.

Exclusion criteria

Patients who have acute infection, history of any other malignancy, history of blood transfusion, ear, nose, throat infection, anemic patients, on iron supplements and on drug therapy which might alter the readings are excluded from the study. Patients who were not willing to participate in the study were not included in the study.

Method

After explaining the procedure to the patient, blood sample was collected from the patient. The sample was centrifuged at 3800 rpm in machine supplied by REMI laboratories. The supernatant fluid was separated from the sediment and stored at 4°C. The sample was subjected to the serum ferritin estimation by enzyme immunoassays. Serum ferritin was quantitatively analyzed using the kit manufactured by Demeditec Diagnostics, Kiel, Germany.

Statistical analysis

The statistical study was performed using SPSS version 18 (PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc) on Windows Microsoft operating system. Mean values and standard deviation were calculated for all the groups. P < 0.05 was considered statistically significant. Paired t-test was applied for the cancer patients' pre- and post-serum ferritin levels. One-way ANOVA was used to compare the significance among the groups.


 > Results Top


After following the described procedure discussed in materials and methods strictly, we obtained the following readings and findings were subjected to the analysis accordingly.

For normal group

There were 15 patients (13 males and two females) with mean age of 33.36. Of 15, six were not having any history of the habits and all were subjected to the serum ferritin analysis. The mean of the findings was done to get baseline levels of serum ferritin in the local area. The mean value obtained is 75.40 ng/L with standard deviation of 39.28 [Figure 1].
Figure 1: Graph showing the serum ferritin values in normal patients, potentially malignant disorders patients, and oral squamous cell carcinoma patients

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For potentially malignant disorder group

In this group, there were thirty patients (24 males and six females) with mean age of 38.83. The average serum ferritin concentration found in their serum is 62.70 ng/ml with standard deviation of 59.01 [Figure 1].

For patients with squamous cell carcinoma group

In this group, there were thirty patients (26 males and four females) with mean age of 51.7. Site-wise distribution of the OSCC revealed most number of the carcinoma occurs in the buccal mucosa area, i.e., 15, four each in palate and tongue, three in lower labial mucosa, and two each in retromolar area and floor of the mouth [Figure 2].
Figure 2: Pie diagram showing site-wise distribution of the oral squamous cell carcinoma

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After deriving the tumor-node-metastasis (TNM) staging for individual patient, the results obtained were 22 patients with Stage IV, seven with Stage III, and one with Stage II [Figure 3]. Among thirty patients, on histopathological examination, nine were well-differentiated, 14 were moderately differentiated, and rests were poorly differentiated [Figure 4].
Figure 3: Bar diagram showing serum ferritin levels according to the tumor-node-metastasis staging

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Figure 4: Bar diagram showing the serum ferritin levels according to the histopathological categories

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The average serum ferritin levels in the squamous cell carcinoma patients were found to be 162.47 ng/L with standard deviation of 127.15 [Figure 1].

For treated cases of squamous cell carcinoma

Of thirty cases of squamous cell carcinoma, 15 cases were followed and their serum ferritin level was recorded after treatment got over. The serum sample was collected after completion of 6-month treatment and any history of iron supplements was ruled out. All were males except one with mean age of 55 years. Of 15 patients, five patients were positive for recurrence and remaining were free of recurrence. The mean serum ferritin level was found to be 162.7 ng/L with standard deviation of 84.13. In recurrent cases, the mean value increases by 13.40 points and in patients with nonrecurrence, the value decreases by 87 points [Figure 5].
Figure 5: Bar diagram showing the change in values of serum ferritin pre- and post-treatment

Click here to view



 > Discussion Top


OSCC is considered to be the result of a multistep process which involves a number of qualitative and quantitative changes throughout the body. Advances in the analysis of these alterations at cellular and serum level in undergoing malignant transformation have increasingly revealed the mechanisms that led to the occurrence, progression, and prognosis of malignancies. The identification of variations that are associated with malignant transformation has led to an ever-increasing number of tumor markers that have been shown to be related to tumor stage and grading or may be indicative for the prognosis and the clinical course of the disease. Examples include oncofetal proteins, alpha-fetoprotein, chorionic gonadotropin, prostatic acid phosphatase, beta-2 microglobulin, etc.

Serum ferritin in normal patients

The mean value obtained in the normal individuals residing in the local area was 75.40 ng/ml. These values are, however, very similar to the mean ferritin levels of 69.2 ng/ml (men) and 34.8 ng/ml (women) reported by Jacobs et al.,[15] but much lower than those reported by Cook et al.,[16] i.e., 112 ng/ml (men) and 43 ng/ml (women). Further categorization of our study as male and female was not done as the female subjects were very less as compared to male subjects.

Serum ferritin in patients with potentially malignant disorder

In this group, the mean age of the patients was recorded as 38.83 years. The age group as studied by Talole et al.[17] (2006) in the Naigaon, Maharashtra population was found to be 45–55 years which is slightly on the upper side as compared to our study statistics. This finding confirms the shifting of prevalence of potentially malignant disorder toward the younger population due to the increase usage of tobacco in earlier stage of life. We also observed that the patients who started using tobacco at earlier phase of life were from low socioeconomic group. The increasing consumption of tobacco-related products in the younger population might be due to stress and change in lifestyle.

The mean serum ferritin level in the patients with potentially malignant disorders was 62.70 ng/ml, which is slightly low when equated with the mean in the normal population. As already described and evident from the various studies, iron deficiency has a role to play in etiology of the potentially malignant disorder.

Serum ferritin in patients with squamous cell carcinoma

The high male: female ratio in this group coincides with given literature[18] of male predilection (3–4 times) in squamous cell carcinoma. According to Shafer et al.,[18] the age of occurrence of epidermoid carcinoma is in later decades of life, i.e., after 40 years. According to our study, the mean age group of the patients was 51.7 years.

Again, patient with habit of chewing tobacco dominated the list and two patients who did not have any history were subjected to viral study of which one lost in follow-up and second was negative for the viral nuclei acids. However, both patients had positive family history of other carcinomas (one with sibling's leukemia and other with father's prostatic cancer). Therefore, etiology of both patients might be presumed due to genetic factors as patient was reluctant for further investigations.

Literature is ambiguous about the most frequent site affected in OSCC. Abdo et al.[19] reported tongue to be most common site, Shafer et al.[18] (text book of oral pathology) suggested lower lip, and Kayembe and Kalengayi[20] in Congo described palate and tongue to be most common sites involved. In our study, buccal mucosa was found to be most common site of squamous cell mucosa as out of thirty patients, 15 had the lesion in this site. Buccal mucosa was most frequently involved as most of the patients were tobacco chewer and used to put quid in buccal vestibule. Variation in the anatomical site distribution of OSCC could be imputed to the prevalence of form of tobacco ingested by the population of that area and regional diet difference in their lifestyles.

TNM staging system was first reported by Denoix in the 1940s.[21] The International Union Against Cancer eventually adapted the system and compiled the first edition of TNM staging system in 1968 for 23 body sites. It is important to realize that TNM staging system is simply an anatomic staging system that describes the anatomic extent of the primary tumor as well as the involvement of regional lymph nodes and distant metastasis.[22] In the present study, only one patient was there in Stage II, seven in Stage III, and 22 in Stage IV. This reveals that most patients reported in late stages of the carcinoma as most of the cases have Stage IV at the time of presentation. Mean serum ferritin levels in Stages II, III, and IV were 72.00 ng/ml, 197.29 ng/ml, and 155.50 ng/ml, respectively. The levels are quite high in Stage III and Stage IV and that in Stage II is below normal. This result is same as obtained by Maxim and Veltri.[5] Therefore, serum ferritin could be used as marker to differentiate early and late stages of the OSCC but lesser number of subjects in our study might restrict its importance.

Treatment of oral cancer is largely based on histological grading thus the relationship between histological grading of oral cancer and serum ferritin was derived. Mean values of serum ferritin in well-differentiated, moderately differentiated and poorly differentiated were 147.33 ng/ml, 149.50 ng/ml, and 207.86 ng/ml, respectively. According to these study results, poorly differentiated carcinomas have very high serum ferritin value whereas well-differentiated and moderately differentiated carcinomas have values more or less same. However, no study could be found which related the histological grading with serum ferritin levels. Significance levels for well-differentiated, moderately differentiated, and poorly differentiated are 0.0018, 0.0011, and 0.0116 for two-sided tests, respectively. Although the values for poorly differentiated was profoundly high, level of significance is >0.005 (nonsignificant).

Patients with serum ferritin showed tremendously high level of average ferritin level as compared to normal group. The mean value of serum ferritin was 162.47. The following finding is in accordance with studies done by Maxim and Veltri,[5] Bhattathiri,[10] and Pilon et al.[23] After applying two-tailed t-test, the P = 0.000 and interpreted as statistically significant. Although serum ferritin levels were markedly elevated in patients with OSCC, patients with other types of solid tumors had equally high levels, indicating low specificity of the tumor marker. In similar manner, the potential for using this protein for early detection is limited because in initial stages of tumor, the levels were equal or slightly increased to the normal which might be due to other nonneoplastic diseases.

On applying ANOVA for multiple comparisons among the first three groups, it was found that normal group was significantly related to cancerous group (P = 0.013) and precancerous group was significantly related to cancerous group (P = 0.000).

Serum ferritin levels in the patients in Group 3 treated for the squamous cell carcinoma

Fifteen patients from Group 3 were followed after treatment for 6 months, and their blood samples were collected for the estimation of serum ferritin levels. Five patients had relapse in the 6 months interval time and ten were free of recurrence. History of any iron supplements or active infection was ruled out at the time of history taking and examination as it might affect the reading of serum ferritin.

The mean reading of serum ferritin found in both categories (recurrence and nonrecurrence) was 162.67 ng/ml which is again greater than the baseline limit found in local population. The mean reading for the same patients before treatment was 216.20 ng/ml. On comparing pre- and post-mean values, the serum ferritin value has gone down substantially. On analysis by paired t-test, the significance level was borderline (P = 0.057).

Of ten patients who were free from recurrence, only two patients has the serum ferritin level below the baseline level and rest eight has the values higher than normal established. It may be proposed that inability of rest eight patients to reach true normal could be attributed to several factors. First, there is a high rate of second primary tumors among relapsed patients (SPTs) and a large number of occult metastasis is found in recurrence patients. Second, patients returned to habit of tobacco and alcohol abuse. Finally, less time frame of study for follow up of post-treated patients.

It is noteworthy that all the two patients who have serum ferritin level normal after treatment had more or less normal serum ferritin level before treatment. In fact, all the patients who were recurrence-free did not have tremendous decrease in the pre- and post-values of serum ferritin except in one patient where reading was dropped down from 520 to 240 ng/ml. The finding of decreased serum ferritin levels goes with the studies reported by Maxim and Veltri but, in their study, the levels of serum ferritin decreased enormously as the period from the treatment increased.

Similarly, the change in the readings of pre- and post-treatment in recurrence patients was not very high. Contrastingly, in one patient, the serum level decreased after treatment and still the carcinoma relapsed. As already stated, serum ferritin levels are influenced by many other factors and nonspecificity or the serum ferritin could be inferred.

On finding the mean difference in pre- and post-serum ferritin values of recurrence cases, it was found that in recurrent cases, the mean value increases by 13.40 points and in patients with nonrecurrence, the value decreases by 87 points. Heavy decrease in the mean values could ascribe to the fact that only one patient has markedly difference in serum values pre- and post-treatment and that might have changed the mean value readings.

Weakness of the study

From the things discussed above following weaknesses of the study could be derived:

  1. Small sample size in normal group to establish a baseline for the serum ferritin values
  2. Inability to exclude the patients with SPTs and occult metastasis
  3. Large standard deviation in serum ferritin values in all the groups
  4. Lesser time frame for follow-up of treated patients.



 > Conclusion Top


In our study, it was alarming to note increasing number of individuals consuming tobacco-related product at an early stage of life and getting affected with the deadening lesions. Further, the present study disclosed elevated levels of serum ferritin in squamous cell carcinoma and it was found to be statistically significant also, but the nonspecific nature of this protein might restrict its implication in the field of head and neck oncology. Also, the level of serum ferritin varied significantly after treatment, but not substantially, to prove its worth in predicting the outcome of treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Williams HK. Molecular pathogenesis of oral squamous carcinoma. Mol Pathol 2000;53:165-72.  Back to cited text no. 1
    
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Patel SC, Carpenter WR, Tyree S, Couch ME, Weissler M, Hackman T, et al. Increasing incidence of oral tongue squamous cell carcinoma in young white women, age 18 to 44 years. J Clin Oncol 2011;29:1488-94.  Back to cited text no. 3
    
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Díez-Pérez R, Campo-Trapero J, Cano-Sánchez J, López-Durán M, Gonzalez-Moles MA, Bascones-Ilundain J, et al. Methylation in oral cancer and pre-cancerous lesions (Review). Oncol Rep 2011;25:1203-9.  Back to cited text no. 4
    
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Maxim PE, Veltri RW. Serum ferritin as a tumor marker in patients with squamous cell carcinoma of the head and neck. Cancer 1986;57:305-11.  Back to cited text no. 5
    
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Marley JJ, Linden GJ, Cowan CG, Lamey PJ, Johnson NW, Warnakulasuriya KA, et al. Acomparison of the management of potentially malignant oral mucosal lesions by oral medicine practitioners and oral & maxillofacial surgeons in the UK. J Oral Pathol Med 1998;27:489-95.  Back to cited text no. 6
    
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Finch CA, Bellotti V, Stray S, Lipschitz DA, Cook JD, Pippard MJ, et al. Plasma ferritin determination as a diagnostic tool. West J Med 1986;145:657-63.  Back to cited text no. 7
    
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Beutler E, Felitti V, Ho NJ, Gelbart T. Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease. Acta Haematol 2002;107:145-9.  Back to cited text no. 8
    
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Gutteridge JM. Iron and oxygen: A biologically damaging mixture. Acta Paediatr Scand Suppl 1989;361:78-85.  Back to cited text no. 9
    
10.
Bhattathiri VN. Paradoxes in iron indices in oral cancer patients vis-a-vis tobacco-alcohol habits. Health Adm 2005;16:76-82.  Back to cited text no. 10
    
11.
Kimura Y, Fujieda S, Takabayashi T, Tanaka T, Sugimoto C, Saito H. Conventional tumor markers are prognostic indicators in patients with head and neck squamous cell carcinoma. Cancer Lett 2000;155:163-8.  Back to cited text no. 11
    
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Bhattathiri VN. Relation of erythrocyte and iron indices to oral cancer growth. Radiother Oncol 2001;59:221-6.  Back to cited text no. 12
    
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Wu T, Sempos CT, Freudenheim JL, Muti P, Smit E. Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann Epidemiol 2004;14:195-201.  Back to cited text no. 13
    
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Le Page L, Leflon P, Mahévas M, Duhaut P, Smail A, Salle V, et al. Aetiological spectrum of hyperferritinemia. Rev Med Interne 2005;26:368-73.  Back to cited text no. 14
    
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Jacobs A, Miller F, Worwood M, Beamish MR, Wardrop CA. Ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. Br Med J 1972;4:206-8.  Back to cited text no. 15
    
16.
Cook JD, Lipschitz DA, Miles LE, Finch CA. Serum ferritin as a measure of iron stores in normal subjects. Am J Clin Nutr 1974;27:681-7.  Back to cited text no. 16
    
17.
Talole KS, Bansode SS, Patki MB. Prevalence of oral precancerous lesions in tobacco of Naigaon, Mumbai. Indian J Community Med 2006;31:286.  Back to cited text no. 17
    
18.
Shafer GW, Hine MK, Levy BM, editors. Benign & malignant tumors of oral Cavity. In: A Textbook of Oral Pathology. 4th ed. Philadelphia: WB Saunders Company; 1993. p. 113.  Back to cited text no. 18
    
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Abdo EN, Garrocho Ade A, Barbosa AA, Oliveira EL, Franca-Filho L, Negri SL, et al. Time elapsed between the first symptoms, diagnosis and treatment of oral cancer patients in Belo Horizonte, Brazil. Med Oral Patol Oral Cir Bucal 2007;12:E469-73.  Back to cited text no. 19
    
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Kayembe MK, Kalengayi MM. Histological and epidemiological profile of oral cancer in Congo (Zaire). Odontostomatol Trop 1999;22:29-32.  Back to cited text no. 20
    
21.
Denoix PF. Tumor, node and metastasis (TNM). Bull Inst Nat Hyg (Paris) 1944;1:1-69.  Back to cited text no. 21
    
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Sobin LH. TNM: Evolution and relation to other prognostic factors. Semin Surg Oncol 2003;21:3-7.  Back to cited text no. 22
    
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Pilon VA, Howanitz PJ, Howanitz JH, Domres N. Day-to-day variation in serum ferritin concentration in healthy subjects. Clin Chem 1981;27:78-82.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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