oral field cancerization - Dr Sanjana Ravindra

Meenakshi Mohan, Nithya Jagannathan Oncology Reviews 2014; 8:244

ORAL FIELD CANCERIZATION: AN UPDATE ON CURRENT

CONCEPTS

Introduction

Liviu Feller, Johan Lemmer. Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment. Journal of Cancer Therapy, 2015, 3, 263-268

Oral cancer holds the 9th position in the cancer incidence

ranking worldwide

3

Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Level of Economic Development, 2013. Source: GLOBOCAN 2013

Ahmedin Jemal et al, Global Cancer Statistics, CA CANCER J CLIN 2014;61:69–90

Estimated new cases Estimated deaths

1,30,90074,500

Introduction

4`Nair K et al, Cancer: Current scenario, intervention strategies and projections for 2015

In india,Fourh most common cancer in females90% occur in patients over 45 years of age

Introduction

COMMON SITES OF OCCURENCE

Introduction

OScc-most common oral cancer worldwide

Over the last decade its incidence has increased

by 50%

Mainly occur after fourth decade of life

Affects men than women (M:F = 1.5:1)

Percentage of 5-year survival for patients

with OSCC varies from 40-50%.

Liviu Feller, Johan Lemmer. Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment. Journal of Cancer Therapy, 2015, 3, 263-268

OSCC develops from exposure to different carcinogens resulting in genetic or epigenetic mutations.

This type of cancer is particularly devastating to patients because treatment entails excision of facial structures essential for esthetics and function.

Introduction

INTRODUCTION Squamous cell carcinoma- most common

Average survival rate: 5 years

Mortality rate

unchanged

Recurrence

Locally or remote site

Process of transformation of an existing

precancerous lesion into a malignancy.

FIELD CANCERIZATION FIELD DEFECT FIELD EFFECT

INTRODUCTION

Anaplasia (from ancient Greek: ana, "backward" + plasis, "formation") is a condition of cells in which they have poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to each other and to

endothelial cells.

Oral cancer does not arise- isolated cellular phenomenon

Anaplastic tendency - many cells - once

Multifocal development process - various rates -within the entire field -

response - carcinogenTOBACC

O

INTRODUCTION

Oral cancer developing in multifocal areas of a pre-

cancerous change

Abnormal tissues surrounding the tumor

Oral cancer often consisting of multiple independent

lesions that may coalesce

The persistence of abnormal tissue even after surgery may explain secondary primary tumor and

recurrences

INTRODUCTION

NON CARCINOGENENIC

TAR FOUND IN TOBACCO

COMBINE WITH OXYGEN ON SLOW COMBUSTION

CARCINOGENIC TAREPOXIDE FORMS A REACTIVE CARCINOGEN

COMBINES TO GUANINE IN DNA

HIGH CANCER RISK!

Criteria used to diagnose multiple carcinomas

the neoplasm must be distinct and anatomically separate. A multi-centric primary neoplasm is diagnosed when a dysplastic mucosa is present next to it

a potential second primary carcinoma which represents a metastasis or a local relapse should be excluded. It has to occur 3 years after the initial diagnosis or it should be separate from the first tumor by at least 2 cm from the normal epithelium

WARREN AND GATES

67- 96 MONTHS

PRE MALIGNANT FIELD

INVASIVE CARCINOM

A

History of field cancerization

Slaughter et al

Concept and definition

(1953)Lateral

cancerization

Carcinogen- induced mucosal

changesConcept was extended to

other organs

Analyzed the tissues

adjacent to squamous

cell carcinoma.Th

e

first examined in the aerodigestive tract

due to a progressive transformation of the tissue adjacent to the tumor rather than the

expansion of pre-existing cancer cells

into the adjacent tissue

Oropharynxesophaguslungs stomach, colon cervix anus skin and bladder

Concept of field cancerization

Triggers sequential

cellular transformations that ultimately

lead to the replacement of

the normal epithelium by a

proliferating field

Process of carcinogenes

is initiates from multiple genetic and epigenetic

alterations in the mucosa

Carcinogen

s - large area -

damage a large

proportion of cells -

premalignant states within - surface

exposed.

Synergy

Formation of multiple patches of premalign

ant disease

FIELD CANCERIZATIO

N

higher-than-expected rate of multiple local second primary tumors

the clonal expansion of premalignant

daughter cells in a particular field

Multiple squamous cell lesions occur independently of each other. This is due to the exposure of the oral cavity to carcinogens in at the same time leading to multiple genetic abnormalities in the entire area

1st

Multiple lesions arise due to the migration of dysplastic and altered cells with two different patterns as follows:(1) migration of malignant cells through the saliva (micro metastasis);

(2) intra-epithelial migration of the progeny of initially transformed malignant cells.

2nd

Theories of field cancerization

POLYCLONAL MONOCLONAL

HISTOLOGICALLY

In smokers and alcoholics: TAM- migrating tumor cells In healthy individuals: Absent

CLONALITY

Two separate lesions are said to develop from a single clone when they share common genetic alterations

This clonal relationship between several premalignant and malignant lesions suggests that the tumor cells or the progenitor cells drift and result in cancerization

in the absence of a clonal relationship between multiple lesions, it is more likely that they derive from an independent event

INVESTIGATIONS

The process of carcinogenesis begins with a stem cell which develops one or more genetic and epigenetic alterations. Subsequently a clone of genetically altered cells forms a patch or a cluster.

Field cancerization model

PATCH PHASE

EXPANDING FIELD PHASE

PRECURSOR LESION WITHIN FIELD

DEVELOPMENT OF CARCINOMA

CARCINOMA EXCISED

SECOND FIELD TUMOUR

PATCH FIELD CARCINOMA MODEL

SECOND PRIMARY TUMOR

Despite advances in therapy long term survival of head and neck cancer patients has not significantly improved in the last 20 years.

An important reason for this lack of progress is the development of secondary primary tumor in the upper aerodigestive tract.

Patients at highest risk are those with early-stage disease, when control of the first tumor, and therefore survival, is greatest.

Jayam R. Oral field cancerization-A review. Journal of Indian Academy of Oral Medicine and Radiology 2010;22:201-5.

For SPT, (a) Each of the tumors must present a definite picture of malignancy(b) Each must be distinct(c) The probability of one being a metastasis of the other must be excluded.

Histological sections: To exclude the possibility of a local recurrence - use a distance of at least 2 cm between the first tumor and the SPT.

Warren and Gates(1932)

SECOND PRIMARY TUMOR

Jayam R. Oral field cancerization-A review. Journal of Indian Academy of Oral Medicine and Radiology 2010;22:201-5.

DISTANT SECOND LESIONS

The distance between two malignancies does not necessarily predict clonality but distant, peripheral, solitary, squamous lung lesions in conjunction with HNSCC are thought to be metastases and concurrent esophageal tumors are thought to be separate primary tumors.

While the probability of synchronous aerodigestive tract tumors remains high with environmental exposure, the relationship between them is often predicted by the anatomic subset rather than distance.

Alok A, Singh ID, Panat SR, Singh S, Kishore M. Oral Field Cancerization: A Review. Int J Dent Med Res 2014;1(3):98-104

Markers in the determination of field cancerization.

THERAPEUTIC IMPLICATIONS FOR FIELD CANCERIZATION

It is a well-known clinical experience that even after surgical removal of a tumor, there is a high risk for another tumor to develop in the same anatomical area.

In some cases, the new tumor formation can be explained because of the growth of incompletely resected carcinoma.

However, for the cases where the tumor had been removed, a genetically altered field is the cause of new cancer.

The presence of altered fields of mucosa beyond the limits of resection has been shown both histologically and on a molecular basis.

Initial studies performed demonstrated that p53 mutations noted in histologically normal margins could be detected in those patients with known mutations in altered margins.

Conclusions

The journey of a thousand miles must begin with a single step

The process of formation of oral cancer results from

multiple sites of pre-malignant change in the

oral cavity (field cancerization).

The presence of a field with genetically altered cells is a risk

factor for cancer.

To prevent field cancerization, habitual ingestion of carcinogens

such as alcohol and cigarettes should be stopped, and longterm

follow-up may be needed for patients treated with radiotherapy,

chemotherapy, and teratogenic drugs such as retinoids.

A good research in this field has a strong potential to reveal new diagnostic markers for early

detection, modalities to prevent progression, and lastly ways to combat development of second primary tumor (or second field

tumors

1. Puig S, Puig-Butillé JA, Díaz MA, Trullas C, Malvehy J (2014) Field cancerisation Improvement with Topical Application of a Film-Forming Medical Device Containing Photolyase and UV Filters in Patients with Actinic Keratosis, a Pilot Study. J Clin Exp Dermatol Res 5: 220.

2. Kini R, Naik V, Singla S. Field cancerisation of oral cavity. A case report and clinical implication.

3. Alok A, Singh ID, Panat SR, Singh S, Kishore M. Oral Field Cancerization: A Review. Int J Dent Med Res 2014;1(3):98-104

4. Aparna M., Shenai P, Chatra L, Veena K. Field cancerization: A review. Archives of Medicine and Health Sciences / Jul-Dec 2013 / Vol 1 | Issue 2

5. Kishore KS, Shenai KP, Chatra LK. Field cancerization- A case report. Journal of Indian Academy of Oral Medicine and Radiology 2006;18:124-8.

6. Jayam R. Oral field cancerization-A review. Journal of Indian Academy of Oral Medicine and Radiology 2010;22:201-5.

7. Liviu Feller, Johan Lemmer. Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment. Journal of Cancer Therapy, 2015, 3, 263-268

References

8. Bascones-Martínez A, Rodríguez-Gutierrez C, Rodríguez-Gómez E,et al. Evaluation of p53, Caspase-3, Bcl-2, and Ki-67 markers in oral squamous cell carcinoma and premalignant epithelium in a sample from Alava Province (Spain). Med Oral Patol Oral Cir Bucal 2013;18:e846-50.

9. Bloching M, Soulsby H, Naumann A, et al Tumor risk assessment by means of immunocytochemical detection of premalignant chages in buccal smears. Oncol Rep 2008;19:1373-9.

10. Eisbruch A, Blick M, Lee JS, et al. Analysis of the epidermal growth factor receptor gene in fresh human head and neck tumors. Cancer Res 1987;47:3603-5.

11. . Christensen ME, Engbaek F, Therkildsen MH, et al. A sensitive enzyme-linked immunosorbent assay used for quantitation of epidermal growth factor receptor protein in head and neck carcinomas: evaluation, interpretations and limitations. Br J Cancer 1995;72:1487-93.

12. Shin DM, Ro JY, Hong WK, Hittelman WN. Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 1994;54:3153-9.

13. Bergle W, Bier H, Ganzer U. The expression of epidermal growth factor receptors in the oral mucosa of patients with oral cancer. Arch Otorhinolaryngol 1989;246:121-5.

14. Schwindt AE, Savino TM, Lanfranchi HE, et al. Nuclear organizer regions in lining epithelium adjacent to squamous cell carcinoma of human oral mucosa. Cancer 1994;73:2674-9.

15. Weinberg WC, Howard JC, Iannaconne PM. Histological demonstration of mosaicism in a series of chimeric rats produced between congenic strains. Science 1985;227:524-7.

16. Worsham MJ, Wolman SR, Carey TE, et al. Common clonal origin of synchronous primary head and neck squamous cell carcinomas: analysis by tumor karyotypes and fluorescence in situ hybridization. Human Pathol 1995;26:251-61.

17. Shin DM, Kim J, Ro JY, et al Activation of p53 expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 1994;54:321-6.

18. Lee N, Ye Y, Li X, et al. Allelic loss on chromosome 13 can precede histological changes in head and neck cancer. Int J Oncol 1994;5:205-10.

19. Welkoborsky HJ, Bernauer HS, Riazimand HS, et al. Patterns of chromosomal aberrations in metastasizing and nonmetastasizing squamous cell carcinomas of the oropharynx and hypopharynx. Ann Otol Rhinol Laryngol 2000;109:401-10.

20. Gandor DW, Meyer J. A simple two-dye basic stain facilitating recognition of mitosis in plastic embedded tissue sections. Stain Technol 1988;63:75-81.

References

21. Reibel J. Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 2003;14:47-62.

22. Dakubo G, Jakupciak J, Birch-Machin M. Clinical implications and utility of field cancerization. Cancer Cell Inter 2007;7:2.

23. Hong WK, Endicott J, Itri LM, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;315:1501-5.

24. Shen L, Kondo Y, Rosner GL, et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst 2005;97:1330-8.

25. Suzuki H, Watkins DN, Jair KW, et al Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 2004;36:417-22.

26. Yan PS, Venkataramu C, Ibrahim A, et al. Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue. Clin Cancer Res 2006;12:626-36.

27. Endoh M, Tamura G, Honda T, et al. ASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer. Br J Cancer 2005;93:1395-9.

28. Mehrotra J, Varde S, Wang H, et al. Quantitative, spatial resolution of the epigenetic field effect in prostate cancer. Prostate 2008;68:152-60.

29. Nonn L, Ananthanarayanan V, Gann PH. Evidence for field cancerization of the prostate. Prostate 2009;69:1470-9.

30. Takahashi T, Habuchi T, Kakehi Y, et al. Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. Cancer Res 1998;58:5835-41.

31. Punnya VA, Savitha JK, Sanjay S, et al. Oral field cancerization: current evidence and future perspectives. Oral Maxillofac Surg 2012;16:171-80.

32. Boudewijn JMB, Maarten PT, Alain KJ, et al. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Canc Res 2003;63:1727-30.

References

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