|Year : 2018 | Volume
| Issue : 1 | Page : 3-6
Importance of depth of invasion in patients with oral squamous cell carcinoma: A review article
Narges Ghazi1, Ala Ghazi2, Shahrzad Shafiee3, Mahsa Fayyazi3
1 Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad, Iran
2 Oral and Maxillofacial Diseases Research Center, Mashhad, Iran
3 School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
|Date of Web Publication||9-Jul-2018|
Dr. Ala Ghazi
Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad
Source of Support: None, Conflict of Interest: None
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Despite several diagnostic and therapeutic advances over the last decades, the rate of mortality and 5-year survival of patients with OSCC has not been improved markedly. The unpredictable behavior of squamous cell carcinoma in digestive and respiratory system has led to search the reliable parameters as prognostic predictors. Histomorphological parameters including the depth of invasion (DOI) may be used as a prognosticate factor in patients with OSCC. It is determined microscopically by detecting the deepest invasive cells in the underlying tissues. Given that planned treatment after histological examination may be changed, measuring the DOI should be considered as a part of routine histological evaluation. In this study, we attempted to review the importance of DOI in the prognosis of cancers as well as its determination in the patients with OSCC lesions.
Keywords: Depth of invasion, prognosis, squamous cell carcinoma
|How to cite this article:|
Ghazi N, Ghazi A, Shafiee S, Fayyazi M. Importance of depth of invasion in patients with oral squamous cell carcinoma: A review article
. J Orofac Sci 2018;10:3-6
|How to cite this URL:|
Ghazi N, Ghazi A, Shafiee S, Fayyazi M. Importance of depth of invasion in patients with oral squamous cell carcinoma: A review article
. J Orofac Sci [serial online] 2018 [cited 2019 Mar 18];10:3-6. Available from: http://www.jofs.in/text.asp?2018/10/1/3/236203
| Introduction|| |
Oral squamous cell carcinoma (OSCC) is the most common oral malignancy accounting for 94% of all malignant neoplasms of the oral cavity. Despite several diagnostic and therapeutic advances over the last decades, the rate of mortality and 5-year survival of patients with OSCC has not been improved markedly. Head and neck squamous cell carcinoma (SCC) remains a major cause of morbidity and mortality worldwide. The incidence and mortality of OSCC are higher in developing countries.,,
OSCC occurs mainly between the sixth and the seventh decades of life with a male predominant tendency. The most frequently affected sites of OSCC are the tongue, lip, and floor of the mouth.
The unpredictable behavior of SCC in digestive and respiratory system has led to search the reliable parameters as prognostic predictors. These parameters can be divided into several categories: epidemiologic parameters including patient’s age, sex, race, alcohol and tobacco use; clinical parameters such as the tumor, node, metastasis (TNM) stage classification and tumor location; and histological parameters including grading, perineural and perivascular invasion, pattern, and the depth of invasion (DOI). These parameters which are significantly associated with hidden metastases and the subsequent development of tumor and its recurrence can be effective in the treatment management.
The staging of OSCC, which is based on the TNM system, has been used for several years to estimate both the clinical response to therapy and survival outcome. The histopathological grading of OSCC is based on the proportion of the neoplasm resembling normal squamous epithelium and the amount of keratin production. Lesions are classified into three distinct grades of well, moderately, and poorly differentiated.
However, the stage of the tumor has always been a major contributor to the prognosis of the disease but recently, according to research studies, tumor grade is also an important factor for prognosis and the type of treatment. Therefore, the treatment and prognosis of OSCC depend on stage and grade of the tumor which are determined by the oncologist and the pathologist, respectively.
Moreover, current studies hypothesizing that histomorphological parameters including the DOI may be used as a prognosticate factor in patients with OSCC. The depth of attack and the microvascular proliferation caused by neoplastic growth might determine proximity to the blood vessels and lymphatic channels, thus facilitating the metastatic process. It has been shown that DOI may be helpful to stratify patients into low-risk and high-risk categories. Tumor thickness (TT) is considered as an objective parameter of DOI in connective tissue.
Therefore, in the present study, we attempted to review the importance of DOI/TT in the prognosis of cancers as well as its determination in patients with OSCC lesions.
| Depth of Invasion and Tumor Thickness|| |
DOI indicates the spread of tumor growth to the tissues underlying the epithelium and in cases where the basement membrane has been damaged, a hypothetical line is reconstructed at the surface and the invasion is measured from this line. On the other hand, the TT is related to the thickness of the total tumor mass. However, it is better to consider the DOI below the membrane rather than considering the thickness of the mass (DOI priority on TT).,,
While many authors consider these two terms as synonyms, it has been suggested that DOI and TT are not similar and should be distinguished from one another., Differences in the results of various studies can be attributed to the different definitions of DOI and TT and different ways to define these parameters.,
For objective measurements of the TT (which can be measured by the micrometric eye), it is better to consider the tumor mass below the presumed regenerated line as the basement membrane rather than the total tumor mass as the thickness of the tumor. Pentenero et al. have summarized TT measurements in different ways as follows:
- From the surface of the wound to the deepest point of invasion.
- From the adjacent healthy and intact mucosa to the deepest point of invasion.
- From the base membrane to the deepest point of invasion.
In terms of subjective examination, DOI has been expressed as a microscopic depth structure rather than an objective measurement of a micrometer on a millimeter scale. It is determined microscopically by detecting the deepest invasive cells in the underlying tissues., For the evaluation of DOI, the agreement between the pathologists is not easily achieved, because a series of subjective evaluations is necessary to determine the level of invasion.
| Depth of Invasion and Cancer Prognosis|| |
The increasing DOI and the microvascular proliferation caused by neoplastic growth might determine proximity to blood vessels and lymphatic channels, thus facilitating the metastatic process., It has been shown that DOI and TT are strong and independent predictors of metastatic neck lymph nodes and this finding has also been confirmed by meta-analytic studies.,
In stage A of cervical carcinoma (if the first stage of the cancer is divided by the size of the tumor into A and B), cancer occurs only in the cervix and the depth of the tumor is <5 mm with the width of <7 mm. In stage B, the DOI is >5 mm with a width of more than 7 mm. In the higher stages, cancer extends beyond the cervix and penetrates the surrounding tissues of the pelvis and bladder.
Delgado et al. evaluated 732 patients with cervical carcinoma who were initially treated. Patients were histopathologically evaluated in the first stages of cervical carcinoma. They revealed that disease-free interval was significantly associated with the DOI. Patients with an invasion depth of 5 mm had a disease free interval (DFI) of 94.6%. It has been demonstrated that increasing the DOI from 3 to 10 mm can increase the risk of recurrence by 21 times.
According to these results, absolute and pure invasion size (mm) is an important factor in cancer prognosis.
In 1970, Breslow found a significant correlation between TT and survival rate and metastasis in melanoma., According to Breslow study, measuring DOI in invasive cutaneous melanoma was defined from the deepest point of invasion to the top of the layer of granular epidermis.,
Several studies reported that the depth of submucosal invasion in colorectal cancer is an important factor in predicting and preventing metastasis to lymph nodes which shows the critical role of DOI in regional metastasis.,,,,,
It has been reported that if the depth of submucosal invasion was <1000 μm, lymph node metastases were not observed, whereas positive lymph node metastasis was detected in cases with invasion depth 1000–1500 μm.
| Depth of Invasion and Oral Squamous Cell Carcinoma Prognosis|| |
Despite numerous studies on histology, immunohistochemistry, and bimolecular markers, the treatment of patients with OSCC is still largely based on TNM staging. According to the previous findings, TNM may be diagnosed and treated for more advanced disease stages. It has been revealed that DOI, the tumor sprout, and the worst pattern of invasion are the only parameters that are independent predictors of patients with SCC at an early stage.
Mohit-Tabatabai et al. for the first time applied the Breslow hypothesis in OSCC. They evaluated the clinical and histological findings of patients with stage I and II OSCC of the mouth floor. Lesions were classified into three groups: histological TT of 1.5 mm or less, between 1.6 and 3.5 mm, and >3.6 mm. Metastases were reported as 2, 35, and 60%, respectively for these groups.,
It has also been shown that DOI is related to the rate of lymph nodes involvement in OSCC. Ross et al. showed a higher incidence of lymph node involvement in tumors with TT of more than 5 mm.
One theory for the positive relationship between DOI and lymph node involvement is the formation of tumor mass in vessels, which is more difficult in small lymphatic vessels and superficial regions than those in deep tissues.
Moreover, an increase in DOI along with tumor volume is often associated with the increased risk of local recurrence.
TT and DOI are predictors for the relapse and survival rate of patients with tongue SCC. Therefore, the determination of TT/DOI in tongue squamous cell carcinoma (TSCC) and OSCC is an important factor for the evaluation of OSCC prognosis.
According to studies, cutoff point for DOI varies from 1.5 to 10 mm in OSCC.,,
Byers et al. suggested that patients with T1N0 cancer who have the depth of muscle invasion >4 mm should definitely undergo elective neck dissection.
Researchers examined the histomorphological parameters for predicting the mortality in the patients with early stages of SCC. In the study by Almangush et al., the DOI was measured from the tumor level to the deepest intrusion point and divided by 4 mm cutoff point. They concluded that the patient’s age and tumor germination and DOI were positive parameters that were strongly related to the mortality associated with SCC in early stages.
Therefore, evidence suggests that DOI is a reliable parameter for predicting the lymph node involvement as well as the survival of patients with OSCC.
| Depth of Invasion and Microinvasive Squamous Cell Carcinoma|| |
For the histopathological examination of DOI in OSCC lesions, it is important to consider the microinvasion. It has been shown that disturbance in the membrane is the first criterion for the diagnosis of microinvasion.
Microinvasive SCC (MISCC) is defined as a SCC that extends into the stroma from the adjacent non-neoplastic epithelial membrane <0.5 mm. The diagnosis of microinvasion is primarily based on histopathological evaluation.,,,
As previously mentioned, two of the most important features of any epithelial malignancy that determine local tumor involvement are TT and DOI which are measured from four different reference points.
Researchers found that the most reliable measurement is from the basement membrane to the deepest point of invasion., It is important to note that two factors that are necessary for assessing the DOI are: correct cut and proper sample. The determination of the depth of the tumor invasion in MISCC is difficult because of excessive vascular involvement and an increase in the regional metastasis of the lymph nodes.
According to studies, cutoff point for DOI has been reported in the range of 1.5–10 mm in MISCC.,,, The difference can be explained by the various methods adopted by the pathologists for DOI measurements. Nevertheless, exact depth cutoff point has not been defined, although it is an important parameter of the disease.
A depth of <5 mm for cervical carcinoma is considered as microinvasion. With extensive research and sample size, such results should be obtained for OSCC.,
In addition, several other authors have proposed a combination of the TT system with the TNM staging of a modified category. The same trend for OSCC should also be considered.
| Conclusion|| |
Given that planned treatment after histological examination may be changed, measuring the DOI should be performed as a part of routine histological evaluation. This may also be useful for classifying patients in the early stages of OSCC as well as for their treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Saghravanian N, Ghazi N, Meshkat Z, Mohtasham N. Human papillomavirus in oral leukoplakia, verrucous carcinoma, squamous cell carcinoma, and normal mucous membrane. Oman Med J 2015;30:455.
Mohtasham N, Anvari K, Memar B, Saghravanian N, Ghazi N, Bagherpour A et al.
Expression of E-cadherin and matrix metalloproteinase-9 in oral squamous cell carcinoma and histologically negative surgical margins and association with clinicopathological parameters. Rom J Morphol Embryol 2014;55:117-21.
Salehinejad J, Sharifi N, Amirchaghmaghi M, Ghazi N, Shakeri MT, Ghazi A. Immunohistochemical expression of p16 protein in oral squamous cell carcinoma and lichen planus. Diagn Pathol 2014;18:210-3.
Shenoi R, Devrukhkar V, Chaudhuri xx, Sharma BK, Sapre SB, Chikhale A. Demographic and clinical profile of oral squamous cell carcinoma patients: A retrospective study. Indian J Cancer 2012;49:21-6.
] [Full text]
Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: A review of the literature. Head Neck 2005;27:1080-91.
Neville BW, Damm DD, Allen CM, Bouquot JE. Oral & Maxillofacial Pathology. 4th
ed. China: Saunders Elsevier; 2016. p. 383-8.
Saghravanian N, Anvari K, Ghazi N, Memar B, Shahsavari M, Aghaee MA. Expression of p63 and CD44 in oral squamous cell carcinoma and correlation with clinicopathological parameters. Arch Oral Biol 2017;82:160-5.
Almangush A, Bello IO, Keski-Säntti H, Mäkinen LK, Kauppila JH, Pukkila M et al.
Depth of invasion, tumor budding, and worst pattern of invasion: Prognostic indicators in early-stage oral tongue cancer. Head Neck 2014;36:811-8.
Huang SH, Hwang D, Lockwood G, Goldstein DP, O’sullivan B. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity. Cancer 2009;115:1489-97.
Moore C, Kuhns JG, Greenberg RA. Thickness as prognostic aid in upper aerodigestive tract cancer. Arch Surg 1986;121:1410-4.
Okamoto M, Nishimine M, Kishi M, Kirita T, Sugimura M, Nakamura M et al.
Prediction of delayed neck metastasis in patients with stage I/II squamous cell carcinoma of the tongue. J Oral Pathol Med 2002;31:227-33.
Breslow A. Problems in the measurement of tumor thickness and level of invasion in cutaneous melanoma. Hum Pathol 1977;8:1-2.
Delgado G. Stage IB squamous cancer of the cervix: The choice of treatment. Obstet Gynecol Surv 1978;33:174-83.
Delgado G, Bundy B, Zaino R, Sevin B-U., Creasman WT, Major F. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 1990;38:352-7.
Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970;172:902.
Breslow A. Tumor thickness, level of invasion and node dissection in stage I cutaneous melanoma. Ann Surg 1975;182:572.
Breslow A. Prognostic factors in the treatment of cutaneous melanoma. J Cutan Pathol 1979;6:208-12.
Kitajima K, Fujimori T, Fujii S, Takeda J, Ohkura Y, Kawamata H et al.
Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: A Japanese collaborative study. J Gastroenterol 2004;39:534-43.
Kudo S. Endoscopic mucosal resection of flat and depressed types of early colorectal cancer. Endoscopy 1993;25:455-61.
Kikuchi R, Takano M, Takagi K, Fujimoto N, Nozaki R, Fujiyoshi T et al.
Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum 1995;38:1286-95.
Nascimbeni R, Burgart LJ, Nivatvongs S, Larson DR. Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 2002;45:200-6.
Okabe S, Arai T, Maruyama S, Murase N, Tsubaki M, Endo M. A clinicopathological investigation on superficial early invasive carcinomas of the colon and rectum. Surg Today 1998;28:687-95.
Tanaka S, Haruma K, Teixeira CR, Tatsuta S, Ohtsu N, Hiraga Y et al.
Endoscopic treatment of submucosal invasive colorectal carcinoma with special reference to risk factors for lymph node metastasis. J Gastroenterol 1995;30:710-7.
Mohit-Tabatabai MA, Sobel HJ, Rush BF, Mashberg A. Relation of thickness of floor of mouth stage I and II cancers to regional metastasis. Am J Surg 1986;152:351-3.
Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg 1986;152:345-50.
Ross G, Soutar D, MacDonald D, Shoaib T, Camilleri I, Robertson A. Improved staging of cervical metastases in clinically node-negative patients with head and neck squamous cell carcinoma. Ann Surg Oncol 2004;11:213-8.
DiTroia J. Nodal metastases and prognosis in carcinoma of the oral cavity. Otolaryngol Clin N Am 1972;5:333-42.
Keski-Säntti H, Atula T, Törnwall J, Koivunen P, Mäkitie A. Elective neck treatment versus observation in patients with T1/T2 N0 squamous cell carcinoma of oral tongue. Oral Oncol 2006;42:95-100.
Amit-Byatnal A, Natarajan J, Shenoy S, Kamath A, Hunter K, Radhakrishnan R. A 3 dimensional assessment of the depth of tumor invasion in microinvasive tongue squamous cell carcinoma − A case series analysis. Med Oral Patol Oral Cir Bucal 2015;20:e645.
Fakih AR, Rao RS, Borges AM, Patel AR. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Am J Surg 1989;158:309-13.
Byers RM, El-Naggar AK, Lee YY, Rao B, Fornage B, Terry NH et al.
Can we detect or predict the presence of occult nodal metastases in patients with squamous carcinoma of the oral tongue? Head Neck 1998;20:138-44.
Al-Rajhi N, Khafaga Y, El-Husseiny J, Saleem M, Mourad W, Al-Otieschan A et al.
Early stage carcinoma of oral tongue: Prognostic factors for local control and survival. Oral Oncol 2000;36:508-14.
Bean SM, Kurtycz DF, Colgan TJ. Recent developments in defining microinvasive and early invasive carcinoma of the uterine cervix. J Low Genit Tract Dis 2011;15:146-57.
Copeland LJ, Silva EG, Gershenson DM, Morris M, Young DC, Wharton JT. Superficially invasive squamous cell carcinoma of the cervix. Gynecol Oncol 1992;45:307-12.
Ambrosch P, Kron M, Fischer G, Brinck U. Micrometastases in carcinoma of the upper aerodigestive tract: Detection, risk of metastasizing, and prognostic value of depth of invasion. Head Neck 1995;17:473–9.