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Metastasis from Oral Cancer: an Overview

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Metastasis from Oral Cancer: an Overview CANCER GENOMICS & PROTEOMICS 9: 329-336 (2012) Review Metastasis from Oral Cancer: An Overview JULIANA NOGUTI1, CAROLINA FOOT GOMES DE MOURA1, GUSTAVO PROTASIO PACHECO DE JESUS1, VICTOR HUGO PEREIRA DA SILVA2, THAIS AYAKO HOSSAKA1, CELINA TIJUKO FUJIYAMA OSHIMA1 and DANIEL ARAKI RIBEIRO1,2 Departments of 1Pathology and 2Biosciences, Federal University of São Paulo, UNIFESP, Sao Paulo, Brazil Abstract. Oral cancer is a common neoplasm worldwide. Its surrounding tissues, with lymph node and distant metastasis, incidence and mortality have also increased over the past and a peculiarly high risk of second malignancy during the decades. It is characterized by poor prognosis and a low patient’s lifetime (1). Metastasis has been interpreted in a survival rate despite sophisticated surgical and radiotherapeutic Darwinistic perspective as being a process whereby genetic modalities. Metastasis of oral cancer is a complex process instability in the primary tumor fuels cell heterogeneity, involving detachment of cells from tumor tissue, regulation of allowing for a few metastatic clones to eventually emerge and cell motility and invasion, proliferation and evasion through the be positively selected to disseminate cancer at distance (7). It lymphatic system or blood vessels. In this review, we will focus represents the most devastating feared stage of malignancy on the current knowledge in metastasis from oral cancer and the leading cause of death from cancer. Metastasis regarding facts, such as incidence; stage, histopathology and consists of sequential and selective steps including grade of primary tumor; clinical manifestations; diagnosis; and proliferation, stimulation of angiogenesis, detachment, treatment. Certainly, such information will contribute to the motility, invasion into bloodstream and cross-talk with understanding of oral cancer pathogenesis. components of the new microenvironment, including parenchymal, stromal and inflammatory cells (8, 9). It is clear Head and neck cancer is a common neoplasm that that only a minority of malignant cells undertake the encompasses epithelial malignancies of the paranasal sinuses, metastatic route, due to an interplay between host factors and nasal cavity, pharynx and larynx, representing about 6% of intrinsic characteristics of cancer cells; thus metastasis may all cases and accounting for an estimated 650,000 new cancer represent an escape of these cells from the hostile cases and 350,000 cancer-related deaths worldwide every year environment they themselves created, such as shortage of (1, 2). Oral cancer is the most frequent type of cancer of the oxygen and nutrients, inflammation and immune system head and neck area, with squamous cell carcinoma being the attacks (10-12). This review aims to reveal recent findings, most common single entity. It may appear in any location, regarding especially oral cancer research thereby raising our although there are certain areas in which it is found more level of understanding of this crucial strategy by which cancer frequently, such as the tongue and floor of the mouth. These cells escape death, and in addition to provide new areas represent about 90% of all malignancies of the oral perspectives on oral cancer diagnosis and treatments. cavity (3, 4). However, despite significant advances in surgery and chemotherapy achieved over the past decades (5), oral Incidence cancer is still characterized by poor prognosis and a low survival rate (6). In patients diagnosed with tumors at an Oral cancer is one of the most common types of tumor in the advanced stage, there is a high occurrence of invasion to head and neck (38%) with an incidence of 75% in male patients over age 60 years old, while about 95% of cases are squamous cell carcinomas (13). Oral squamous cell carcinoma is an invasive lesion with the presence of Correspondence to: Daniel Araki Ribeiro, DDS, Ph.D., perineural growth. It has a significant recurrence rate and Departamento de Biociências, Av. Ana Costa, 95, Vila Mathias, Santos – SP, 11060-001, Brazil. Tel: +55 1332218058, Fax: +55 frequently metastasizes to cervical lymph nodes (14). Lymph 1332232592, e-mail: [email protected] node metastatic tumors occur in about 40% of patients with oral cancer. Clinically, their manifestations are hidden in rates Key Words: Oral cancer, metastasis, review. of 15% to 34% (15, 16). 1109-6535/2012 $2.00+.40 329 CANCER GENOMICS & PROTEOMICS 9: 329-336 (2012) Metastasis of oral cancer is a complex process involving The TNM classification of oral squamous cell carcinoma (33) detachment of cells from the tumor tissue, regulation of cell provides a reliable basis for patient prognosis and therapeutic motility and invasion, proliferation and evasion through the planning. There are a number of clinically detected or small lymphatic system or blood vessels. This process is due to undetectable primary tumors that display biological reduced intercellular adhesion of tumor cells as they progress aggressiveness, with early regional metastasis and death. to malignancy because of loss of E-cadherin; they thereby Typically, T1-T2 lesions are often associated with a risk of begin to express proteins such as mesenchymal vimentin and regional metastasis of 10% to 30% respectively, especially to N-cadherin, promoting cell elongation and interfering with cell lymph nodes, whereas several studies have shown a clear polarity. This morphological transition, called epithelial- correlation between increasing tumor thickness and an increased mesenchymal transition (EMT) leads to molecular alterations risk of cervical metastasis (34, 35); T3-T4 lesions have a interfering with the behavior of these cells (17). significantly higher risk of regional neck disease (13, 36). The major determinant of the prognosis of oral carcinoma is the risk of cervical metastasis. While it is widely accepted that Clinical Manifestations more advanced oral tumors be treated with elective neck dissection, management of stage I disease remains The basic procedure in checking cervical lymph nodes is controversial. In the absence of clinical neck disease, stage I physical examination (37). To facilitate treatment planning and oral cancer is often treated with primary tumor resection and to provide a sense of outcome, clinical staging is generally clinical follow-up of the neck. However, studies have shown used. The TNM clinical stage system has been adopted the incidence of occult neck metastases in stage I/II disease to worldwide. This system uses the size of the primary tumor (T), be as high as 42% (18). the extent of regional lymph node involvement (N), and the At least 50% of patients with locally-advanced head and presence of distant metastases (M) to predict prognosis (38). neck cancer develop locoregional or distant relapses, which Clinically, lymph nodes are assessed for location, number, are usually detected within the first two years of treatment size, shape, consistency, and fixation. Nodes are considered to (19). Investigators suggested that squamous cell carcinoma be malignant if their size is greater than 1 cm, and they are of the upper aerodisgetive tract with parotid metastasis most hard and fixed (39). Patients without clinical manifestations of often arises from the oral cavity or oropharynx (20, 21). It the disease are great candidates to be submitted to cervical has been postulated that unlike the parotid gland, the intervention and/or co-adjuvant therapy (40). submandibular gland is unlikely to be the host tissue for metastasis because of its lack of lymph nodes and vessels Diagnosis (22). In fact, hematogenous spread of cancer may rise from tissues outside the head and neck region (23). In addition, Auxiliary modern diagnostic modalities such as computed- unlike many other types of cancer, it characteristically tomography (CT), magnetic resonance imaging (MRI), metastasizes to the regional lymph nodes through the positron emission tomography (PET), lymphoscintigraphy draining lymphatics in the early stages (24). Lymph node (LS), ultrasonography (USG) and USG-guided fine-needle involvement is considered as the first indication for spread aspiration cytology are recommended to increase the and a strong prognostic factor (25). At present, only 25%- efficacy of the neck evaluation in patients with oral 40% of patients with lymph node metastasis will achieve 5- carcinoma, and some have become routine screening year survival, in contrast to approximately 90% of patients procedures in recent years, playing an important role in the without metastasis (26-28). According to published data, the detection of metastasis to cervical nodes (37, 41). The main incidence of occult metastases to the neck can range from advantage of CT and MRI is less inter-observer variation 15% to 60% depending on different prognostic factors (29). and these are relatively standardized techniques that can be Currently, new and highly sensitive detection methods such performed in most institutions and can be interpreted by as immunohistochemistry and molecular analysis have been radiologists without specific knowledge of images of the developed; these could be an explanation as to why the head and neck (42). Criteria such as size, laterality and rapid incidence of metastasis has even increased in the last few increase of diameter of lymph nodes are most important as years (13, 30). selection criteria for nodes to be punctured to detect occult metastasis (43). Stage, Histopathology and Grade of Primary Tumor Sentinel lymph node (SLN) status has been shown to
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