Home Print this page Email this page Users Online: 179
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
INVITED ARTICLE
Year : 2014  |  Volume : 2  |  Issue : 1  |  Page : 12-16

Prognostic and predictive markers for oral squamous cell carcinoma: The importance of clinical, pathological and molecular markers


Department of Oral Medicine and Experimental Oral Pathology, King's College, Bessemer Rd, London SE5 9RS, United Kingdom

Date of Web Publication7-Mar-2014

Correspondence Address:
Saman Warnakulasuriya
Professor of Oral Medicine and Experimental Oral Pathology, King's College, Bessemer Rd, London SE5 9RS
United Kingdom
Login to access the Email id

DOI: 10.4103/1658-631X.128400

Rights and Permissions
  Abstract 

The overall 5-year survival rate following treatment for oral squamous cell carcinoma is around 50% in most published series. The major prognostic factors are stage at the time of diagnosis, unexpected close margins at resection, depth and pattern of tissue invasion by carcinoma and extracapsular spread. Grading by gross histological differentiation does not influence prognosis, unless deeply invasive margins are evaluated by the pathologist. Because stage at diagnosis is the most important factor affecting outcome, early detection results in better prognosis in most cases.

  Abstract in Arabic 

ملخص البحث :
تشير هذه الدراسة بأن نسبة البقاء على الحياة بعد علاج سرطان الفم تصل إلى %05 حسب معظم الدراسات المنشورة حاليا. وتعتمد عوامل التوقعات على مرحلة المرض عند التشخيص، وتغلغل الورم وانتشاره وإزالته وجميع حوافه.

كما أن تصنيف الورم نسيجيا لا يؤثر على توقعات الورم، إلا حين يقيّم أخصائي علم الأمراض مدى تغلغل الورم وحوافه. تلعب مرحلة المرض عند التشخيص دوراً مهماً في نتيجة العلاج، لذا فإن اكتشاف الورم المبكر يؤدي إلى توقع أفضل في معظم الحالات.

Keywords: Oral carcinoma, prognosis, pathology, tumor markers


How to cite this article:
Warnakulasuriya S. Prognostic and predictive markers for oral squamous cell carcinoma: The importance of clinical, pathological and molecular markers. Saudi J Med Med Sci 2014;2:12-6

How to cite this URL:
Warnakulasuriya S. Prognostic and predictive markers for oral squamous cell carcinoma: The importance of clinical, pathological and molecular markers. Saudi J Med Med Sci [serial online] 2014 [cited 2017 Sep 21];2:12-6. Available from: http://www.sjmms.net/text.asp?2014/2/1/12/128400


  Introduction Top


Survival rates for oral cancer and tumors of the oropharynx, caused by tobacco and alcohol, have not improved for decades except in major treatment centers. Treatment failures remain frequent despite improvements in clinical and imaging investigations and advances in surgical and radiotherapeutic techniques.

Most of the prognostic factors listed below have a direct impact on the management of the patient. The role of the infiltrative margins, HPV infection, ploidy status and cell proliferation indices are still being assessed but may have a significant role in determining treatment in the future. In some published studies that are retrospective in nature, small sample sizes, using more than one standard protocol for the management and use of univariate analyses have contributed to difficulties in interpretation of data from these trials.


  Demographic Factors Top


Several demographic factors are known to affect prognosis and survival. Young people (under the age of 45 years) are known to have better survival. [1] While the role of gender is not clear, single and divorced persons have poor survival rates. The socioeconomic status also plays a role. People who lived in deprived areas had a relative risk of 1.25 (95% confidence interval [CI]: 1.15-1.35) of dying from their cancer. [2] Tobacco consumption had a significant influence on the prognosis of oral cancer patients (P = 0.046), [3] and continuing to smoke after treatment contributes to poor survival. In a recent study in London, UK, smoking cessation and reduction in drinking alcohol and drinking cessation led to a significant reduction in mortality at 3 and 5 years (P < 0.001). [4]


  Tumor Stage and Nodal Status Top


Union for International Cancer Control TNM (UICC TNM) staging, [5] used in the treatment planning, allows comparison of data. Higher T stage correlates with poorer prognosis. [6] The TNM classification of oral squamous cell carcinoma provides a reliable basis for patient prognosis and therapeutic planning.

Size and multiplicity of lymph nodes are taken into account when assessing prognosis from cancer. The incidence of occult metastases to the neck can range from 15% to 60% depending on the different diagnostic procedures adapted. Clinical palpation, imaging, ultrasonography-guided fine-needle aspiration cytology and sentinel node biopsy techniques allow assessment of cases prior to surgery. Clinically, lymph nodes are assessed for location, number, size, shape, consistency and fixation. Nodes are considered to be malignant if their size is greater than 1 cm, and particularly if they are hard and fixed. After surgery, the analysis of the specimen allows pathological staging. The presence of nodal metastasis is the most important prognostic factor for oral cancers. [7],[8] An approximately 50% reduction in 5-year survival rate is seen with the development of lymph node metastasis in patients with squamous cell carcinoma of the oral cavity. Contralateral neck metastasis may be associated with higher distant metastasis as spread of tumor across the midline confirms aggressive behavior.

Extracapsular spread (microscopic or macroscopic) is related mostly to prognosis. [9] These authors recommend that extracapsular (microscopic) spread should be incorporated into pathological staging systems. In particular, the capsular rupture has the most significant prognostic influence.


  Tumor Thickness Top


Tumor thickness, which is objectively measurable, might influence the prognosis of early oral cancer. In general, median tumor thickness varies between 1.5 and 8 mm for T1 and T2 cancers. Tumor thickness of greater than 4 mm imparts a worse prognosis. [10] In a recent study, tumor thickness was the only independent predictor of neck failure: Regional recurrence-free survival was 94% versus 72% (P = 0.02) for tumors <4 mm versus ≥4 mm, respectively. [11]


  Pathological Grade (Degree Of Differentiation) Top


There is consistent evidence of the value of tumor grade in determining prognosis: Higher grades equate to a poorer prognosis. [6],[12],[13] Grading is based on the degree of resemblance of the invading carcinoma to the normal epithelium and its ability to form keratinizing islands, and follows the descriptions in the World Health Organization classification. [14] The most aggressive area (at × 100 magnification field) is graded as well, moderately or poorly differentiated. Most oral carcinomas are moderately differentiated. Tumor differentiation may well relate to the presence of up- or downregulated genes/proteins, but this has not been comprehensively tested. However, this pathological grading system is widely used and is listed in the current AJCC staging form. The system suffers from interexaminer variability and sampling errors. Prognostically useful Bryne's malignancy grading system [15] has been used to prognosticate oral cancers. [16]


  Pattern of infiltration Top


An infiltrative margin, as opposed to a smooth pushing margin, has been shown to be an adverse prognostic feature in the tongue, the supraglottis and the floor of the mouth. [17] More cells at the invasive front are proliferating compared with the center, confirming that this part of the tumor is likely to be more informative in determining the prognosis. [18]


  Perineural Infiltration Top


Perineural invasion (PNI) of the small nerves is an important predictor of outcome of patients and is a sensitive indicator for regional recurrence and distant metastasis. [19] The 5-year disease-specific survival for patients with and without PNI was 56.6% and 94.6%, respectively (P < 0.0001).


  Excision Margins Top


With respect to the tongue, either dysplasia or tumor at the margins may predict local recurrence. [20],[21] From a surgical point of view, a margin >5 mm is clear, 1-5 mm is close and <1 mm is involved. Incomplete resection leading to an involved margin or the presence of dysplasia at the margin is associated with a significantly increased risk of local recurrence. For T1 and T2 oral cancers, histological completeness of excision margins therefore reduces the recurrence at the primary site, making other histopathologic variables somewhat irrelevant. [22] An unexpected close surgical margin has been claimed to represent a bioaggressive tumor. It appears that the use of frozen sections to assess margins has not been shown to be beneficial.


  HPV Infection Top


Several studies have addressed the role of HPV in head and neck cancer. Data indicate that in oropharyngeal tumors, HPV status was associated with younger age, absence of traditional risk factors (such as smoking and alcohol consumption), high proliferation indices, high grade, basaloid subtype and an inverse association with p53 nuclear immunoreactivity. HPV positivity contributed to a favorable outcome attributable to an increased sensitivity toward radiotherapy. [23] There is, however, insufficient evidence to modify treatment intensity in these patients based on HPV status.


  Genetic Mechanisms Top


Numerous molecular studies have been undertaken to find pathways that are altered in oral squamous cell carcinomas at gene-expression and protein levels, with a special emphasis on their prognostic significance.

These could be considered under several pathways, such as signaling pathways, markers associated with the cell cycle/apoptosis, cell adhesion, cell motility and invasion, angiogenesis, immortalization and inflammation. [24] Many gene-expression profiles are altered and under- or overexpression is reported [Table 1], and some of these alterations are correlated with prognosis.{Table 1}

The highest number of studies was conducted to evaluate the prognostic significance of p53. Among the nine included studies in a meta-analysis, the hazard ratio for p53 was 1.48 (95% CI: 1.03-2.11), suggesting a survival advantage for negative p53 status. [25] However, the authors concluded that the current evidence on p53 was inconclusive. In a recent study, phosphorylated (p) epithelial growth factor receptor (EGFR) expression was observed in ~40% of the cases and in the multivariable analysis, this contributed to cause-specific survival. [26]

The combined evaluation of two or more phenotypic alterations might provide more prognostic information on oral carcinoma. This has been demonstrated by examining the coexpression of p53/p-glycoprotein, [27] coexpression of combined cytoplasmic and membranous EGFR and p53, [26] coexpression of c-erbB-2,3 and 4, [28] p16/cyclin D1 amplification [29],[30] and RAR alfa/p21 expression. [31] Alterations in the Rb pathway have been shown to be of higher significance in Indian cancers. [32],[33] The prognostic effect of p-mTOR on the overall survival of oral squamous cell carcinoma (OSCC) suggests that this marker may serve as a reliable biological marker to identify high-risk subgroups (with poor prognosis) and as a guide to therapy. Furthermore, the high expression of p-mTOR suggests that this protein may be a promising therapeutic target in OSCC. [34] Metastatic gene markers have not been investigated in detail in oral cancer.

The presence of allelic imbalance at 3p22-26, 3p14.3-12.1 and 9p21 are reliable predictors of outcome. Loss of heterozygocity (LOH) at each of these regions have an approximately 36-times increased risk of mortality relative to a case with retention of heterozygocity at these loci. [35]

None of these markers or combinations has been incorporated into large prospective clinical trials. At present, the overall evidence is insufficient to alter clinical practice or to consider aggressive treatment for subsets of patients identified on the basis of the use of molecular markers alone. [35] These markers are not yet available in routine practice. In the future, with further advances, new therapeutic approaches may become available to provide individualized therapy to patients based on the molecular analysis of a primary tumor.


  Conclusions Top


Based on the current evidence, the Royal College of Pathologists, London, [36] has categorized prognostic factors by their levels of evidence (A-D), A being the best evidence and D being the least. Level B evidence exists for: Tumor size that is the major contributor to stage, depth of invasion, patterns of tissue invasion by carcinoma, PNI predicting more aggressive cancers, presence of bone involvement and extracapsular spread. Level B/C evidence exists for histological grade of differentiation and margin status. The College considers these factors as "Core Data Items" that are supported by robust published evidence and are required for cancer staging and optimal patient management and to determine prognosis.

 
  References Top

1.Warnakulasuriya S, Mak V, Moller H. Oral cancer survival in young people in South East England. Oral Oncol 2007;43:982-6.  Back to cited text no. 1
    
2.Edwards DM, Jones J. Incidence of and survival from upper aerodigestive tract cancers in the UK: The influence of deprivation. Eur J Cancer 1999:35:968-75.  Back to cited text no. 2
    
3.Bundgaard T. Bentzen SM, Wildt J. The prognostic effect of tobacco and alcohol consumption in intra-oral squamous cell carcinoma. Eur J Cancer (Oral Oncol) 1994;30;323-8.  Back to cited text no. 3
    
4.Jerjes W, Upile T, Radhi H, Petrie A, Abiola J, Adams A, et al. The effect of tobacco and alcohol and their reduction/cessation on mortality in oral cancer patients: Short communication. Head Neck Oncol 2012;4:6.  Back to cited text no. 4
    
5.Sobin L, Gospodarowicz M, Wittekind C, Editors. TNM Classification of Malignant Tumours. 8 th Ed, New Jersey, United States: Wiley; 2009.  Back to cited text no. 5
    
6.Kademani D, Bell RB, Bagheri S, Holmgren E, Dierks E, Potter B, et al. Prognostic factors in intra oral squamous cell carcinoma: The influence of histologic grade. J Oral Maxilofac Surg 2005;63:1599-605.  Back to cited text no. 6
    
7.Shah JP. Cervical lymph node metastasis, its diagnostic, therapeutic and prognostic implications. Oncology (Williston Park) 1990;4:61-9.  Back to cited text no. 7
    
8.Tankere F, Camproux A, Barry B, Guedon C, Depondt J, Gehanno P. Prognostic value of lymph node invovement in oral cancers: A study of 137 cases. Laryngoscope 2000;110:2061-5  Back to cited text no. 8
    
9.Woolgar JA, Rogers SN Lowe D, Brown JS, Vaughan ED. Cervical lymph node metastasis in oral cancer; the importance of even microscopic extra-capsular spread. Oral Oncol 2003;39:130-7.  Back to cited text no. 9
    
10.O'Brien CJ, Lauer CS, Fredricks S, Clifford AR, McNeil EB, Bagia JS, et al. Tumour thickness influences prognosis of T1 and T2 oral cavity cancer- but what thickness? Head Neck 2003;25:937-45.  Back to cited text no. 10
    
11.Ganly I, Goldstein D, Carlson DL, Patel SG, O'Sullivan B, Lee N, et al. Long-term regional control and survival in patients with "low-risk," early stage oral tongue cancer managed by partial glossectomy and neck dissection without postoperative radiation: The importance of tumour thickness. Cancer 2013;119:1168-76.  Back to cited text no. 11
    
12.Odell EW, Jani P, Sherriff M, Ahluwalia SM, Hibbert J, Levison DA, et al. The prognostic value of individual grading parameters in small lingual squamous cell carcinomas. Cancer 1994;74:789-94.  Back to cited text no. 12
    
13.Fortin A, Couture C, Doucet R, Albert M, Allard J, Tetu B. Does histologic grade have a role in the management of head and neck cancers? J Clin Oncol 2001;19:4107-16.  Back to cited text no. 13
    
14.World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. In: Barnes L, Eveson JW, Reichart P, Sidransky O, editors. Geneva: WHO. p. 168-75.  Back to cited text no. 14
    
15.Bryne M, Nielsen K, Koppang HS, Dabelsteen E. Reproducibility of two malignancy grading systems with reportedly prognostic value for oral cancer patients. J Oral Pathol Med 1991:20:369-72.  Back to cited text no. 15
    
16.Sawair FA, Irwin CR, Gordon DJ, Leonard AG, Stephenson M, Napier SS. Invasive front grading and usefulness in the management of oral squamous cell carcinoma. J Oral Pathol Med 2003;32:1-9.   Back to cited text no. 16
    
17.Spiro RH, Guillamondegui O Jr., Paulino AF, Huvos AG. Pattern of invasion and margin assessment in patients with oral tongue cancer. Head Neck 1999;21:408-13.  Back to cited text no. 17
    
18.Dissanayake U, Johnson NW, Warnakulasuriya KA. Comparison of cell proliferation in the centre and advancing fronts of oral squamous cell carcinomas using Ki-67 index. Cell Prolif 2003;36:255-64.  Back to cited text no. 18
    
19.Rahima B, Shingaki S, Nagata M, Saito C. Prognostic significance of perineural invasion in oral and orophayngeal carcinoma. Oral Surg 2004;97:423-31.  Back to cited text no. 19
    
20.Weijers M, Snow GB, Bezemer PD, van der Wal JE, van der Waal I. The clinical relevance of epithelial dysplasia in the surgical margins of tongue and floor of mouth squamous cell carcinoma: An analysis of 37 patients. J Oral Pathol Med 2002;31:11-5.  Back to cited text no. 20
    
21.Bailey JS, Blanchaert RH JR., Ord RA. Management of oral squamous cell carincoma treated with inadequate excisional biopsy. J Oral Maxillofac Surg 2001;59:1007-11.  Back to cited text no. 21
    
22.van Es RJ, van Nieuw Amerongen N, Slootweg PJ, Egyedi P. Resection margins as a predictor of recurrence at the primary site for T1 and T2 oral cancers. Evaluation of histopathologic variables. Arch Otolaryngol Head Neck Surg 1996;122:521-5.  Back to cited text no. 22
    
23.Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM. Human papillomavirus positive squamous cell carcinomas of the oropharynx. Cancer 2001;92:805-13.  Back to cited text no. 23
    
24.Hunter KD, Parkinson EK, Harrison PR. Profiling early head and neck cancer. Nat Rev Cancer 2005;5:127-35.  Back to cited text no. 24
    
25.Tandon S, Tudur-Smith C, Riley RD, Boyd M, Jones TM. A systematic review of p53 as a prognostic factor of survival in squamous cell carcinoma of four main anatomical subsites of head and neck. Cancer Epidemiol Biomarkers Prev 2010;19:574-87.  Back to cited text no. 25
    
26.Monteiro LS, Diniz-Freitas M, Garcia-Caballero T, Warnakulasuriya S, Forteza J, Fraga MJ. Combined cytoplasmic and membranous EGFR and p53 overexpression is a poor prognostic marker in early stage oral squamous cell carcinoma. Oral Pathol Med 2012;41:559-67.  Back to cited text no. 26
    
27.Warnakulasuriya S, Jia C, Johnson N, Houghton J. p53 and P-glycoprotein expression are significant prognostic markers in advanced head and neck cancer treated with chemo/radiotherapy. J Pathol 2000;191:33-8.  Back to cited text no. 27
    
28.Ibrahim SO, Vasstrand EN, Liavaag PG, Johannessen AC, Lillehaug JR. Expression of c-erb B protooncogene family members in squamous cell carcinoma of the head and neck. Anticancer Res 1997;17:4539-46.  Back to cited text no. 28
    
29.Namazie A, Alavi S, Olopade OI, Pauletti G, Aghamohammadi N, Aghamohammadi M, et al. Cyclin D1 amplification and p16 (MTSI/CDK4I) deletion correlates with poor prognosis in head and neck tumours. Laryngoscope 2002;112:472-81.   Back to cited text no. 29
    
30.Jayasurya R, Francis G, Kannan S, Lekshminarayanan K, Nalinakumari KR, Abraham T, et al. p53, p16 and cyclin D1: Molecular determinants of radiotherapy treatment response in oral carcinoma. Int J Cancer 2004;109:710-6.  Back to cited text no. 30
    
31.Ralhan R, Chakravarti N, Kaur J, Sharma C, Kumar A, Mathur M, et al. Clinical significance of altered expression of retinoid receptors in oral precancerous and cancerous lesions: Relationship with cell cycle regulators. Int J Cancer 2006;118:1077-89  Back to cited text no. 31
    
32.Jayasurya R, Sathyan KM, Lakshminarayanan K, Abraham T, Nalinakumari KR, Abraham EK, et al. Phenotypic alterations in Rb pathway have more prognostic influence than p53 pathway proteins in oral carcinoma. Mod Pathol 2005;18:1056-66.  Back to cited text no. 32
    
33.Soni S, Kaur J, Kumar A, Chakravarti N, Mathur M, Bahadur S, et al. Alterations of rb pathway components are frequent events in patients with oral epithelial dysplasia and predict clinical outcome in patients with squamous cell carcinoma. Oncology 2005;68:314-25.  Back to cited text no. 33
    
34.Monteiro L, Delgado ML, Ricardo S, Garcês F, Amaral B, Warnakulasuryia S, et al. Phosphorylated m-TOR is associated with an adverse outcome in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:638-45.  Back to cited text no. 34
    
35.Partridge M, Gaballah K, Huang X. Molecular markers for diagnosis and prognosis. Cancer Metastasis Rev 2005;24:71-85.   Back to cited text no. 35
    
36.The Royal College of Pathologists (London). Dataset for histopathology reporting of mucosal malignancies of the oral cavity. October 2011, London.  Back to cited text no. 36
    



 
 
    Tables

  [Table 1]SaudiJMedMedSci_2014_2_1_12_128400_t1.jpg


This article has been cited by
1 a-Mangostin Induces Apoptosis and Cell Cycle Arrest in Oral Squamous Cell Carcinoma Cell
Hyun-Ho Kwak,In-Ryoung Kim,Hye-Jin Kim,Bong-Soo Park,Su-Bin Yu
Evidence-Based Complementary and Alternative Medicine. 2016; 2016: 1
[Pubmed] | [DOI]
2 Impact of EGFR and p53 expressions on survival and quality of life in locally advanced oral squamous cell carcinoma patients treated with chemoradiation
Seema Gupta,Huma Khan,Vandana Singh Kushwaha,Nuzhat Husain,MPS Negi,Ashim Ghatak,MLB Bhatt
Cancer Biology & Therapy. 2015; 16(9): 1269
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
   Abstract
  Introduction
  Demographic Factors
   Tumor Stage and ...
  Tumor Thickness
   Pathological Gra...
   Pattern of infil...
   Perineural Infil...
  Excision Margins
  HPV Infection
  Genetic Mechanisms
  Conclusions
   References
   Article Tables

 Article Access Statistics
    Viewed4430    
    Printed77    
    Emailed2    
    PDF Downloaded1121    
    Comments [Add]    
    Cited by others 2    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]