ONCOLOGY LETTERS 8: 7-11, 2014

Histological and molecular aspects of oral

squamous cell carcinoma (Review)
CÉSAR RIVERA1,2 and BERNARDO VENEGAS3

1
Unit of Histology and Embryology, Department of Basic Biomedical Sciences;
2
Biomedical Sciences Master Program, Oral Pathology Mention; 3Unit of Oral Pathology,
Department of Dentistry, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile

Received July 23, 2013; Accepted February 13, 2014

DOI: 10.3892/ol.2014.2103

Abstract. Oral squamous cell carcinoma (OSCC) represents 1. Introduction

95% of all forms of head and neck cancer, and over the last
decade its incidence has increased by 50%. Oral carcinogen- Head and neck cancer is one of the 10 most common types of
esis is a multistage process, which simultaneously involves cancer worldwide, afflicting >500,000 individuals each year.
precancerous lesions, invasion and metastasis. Degradation of Oral cancer is considered to be a preventable condition, due to
the cell cycle and the proliferation of malignant cells results in the possibility of early detection and treatment (1). Oral squa-
the loss of control mechanisms that ensure the normal function mous cell carcinoma (OSCC) represents 95% of all forms of
of tissues. The aim of the current review is to present the histo- head and neck cancer, and during the past decade its incidence
pathological features of OSCC, including potentially malignant has increased by 50% (2,3). Snuff and alcohol consumption
changes, the international classification of tumors, the tumor are associated with 90% of patients that exhibit oral cancer (1)
invasion front and tumor biomarkers (Ki‑67, p53, homeobox and the two factors appear to have a synergistic effect (4).
genes and collagen type IV), as well as the tumor microenvi- The majority of OSCC are diagnosed at a late phase (5), in
ronment and function of cancer‑associated fibroblasts in the stages III or IV (6,7), which markedly decreases the chances
most common type of oral cancer that is encountered by dental of survival and leads to a significant deterioration in patient
surgeons. In OSCC, associations have been identified between quality of life.
the proliferation, basal lamina degradation and connective Despite the currently available therapeutic strategies,
tissue modulation. Therefore, the comparison of these factors which include the excision of malignant tissue and combina-
with the survival time of OSCC patients from the histopatho- tion of radiotherapy and chemotherapy, the five‑year survival
logical diagnosis is of interest. rate is only 53% (3). In addition, a high percentage of patients
have a poor response to therapy and high recurrence rates (8).
The purpose of the current review was to present the histo-
Contents logical and molecular characteristics of the most common type
of oral cancer encountered by dental surgeons.
1. Introduction
2. Histology 2. Histology
3. Tumor biomarkers
4. Tumor microenvironment In general, cancers, including OSCC, emerge from the accu-
5. Conclusion mulation of genetic changes and epigenetic anomalies in the
signaling pathways that are associated with cancer, resulting
in phenotypes that facilitate OSCC development. This process
was summarized by Hanahan and Weinberg in ‘Hallmarks of
Cancer’ (9).
OSCC is a malignant neoplasm derived from the stratified
squamous epithelium of the oral mucosa (10). Its pathogenesis
Correspondence to: Dr César Rivera, Department of Basic
Biomedical Sciences, Faculty of Health Sciences, University of is multifactorial, associated with cigarette smoke, alcohol (11)
Talca, Avenida Lircay S/N, Maule Region, Talca 3460000, Chile and snuff, as well as the papilloma virus, among others (12).
E‑mail: [email protected] The malignant neoplasm occurs at various sites, the most
frequent being the lip, lateral edges of the tongue (Fig. 1A) (13)
Key words: mouth neoplasms, oral squamous cell carcinoma, and floor of the oral cavity. The incidence of OSCC increases
oral cancer, p53, Ki‑67, collagen type IV with age, with the majority of OSCC occuring in patients
>40 years (14).
OSCC is characterized by histopathological and clinical
manifestations. All carcinogenesis evolves from initial
8 RIVERA and VENEGAS: HISTOLOGICAL AND MOLECULAR ASPECTS OF OSCC

cell injury to the formation of a malignant neoplasm (9). 3. Tumor biomarkers

Histologically, the lesion passes through various phases
(preneoplastic damage) until the ultimate formation of a Transformed neoplastic cells determine the biological
cancer. This carcinogenesis may be associated with precan- behavior of the tumor. Aberrant cells, which posess common
cerous lesions (such as leukoplakia, erythroplakia and mixed). features, present a wide range of morphological and functional
However, it is necessary to consider that not all reactional disorders.
lestions or potentially malignant lesions result in the subse- Genetic and epigenetic alterations in OSCC lead to changes
quent development of malignant neoplasms (15). that include reduced expression or overexpression of proteins.
The accumulation of these changes in oncogenes and tumor
Potentially malignant changes. According to their histological suppressor genes may lead to the formation of OSCC. The
appearance, lesions that present in the epithelium during the genes that are critically altered in OSCC include cyclin D1, p53,
process of carcinogenesis may be classified according to their retinoblastoma, epidermal growth factor receptor, signal trans-
reactive epithelial changes (such as hyperkeratosis, hyper- ducer and activator of transcription 3, and vascular endothelial
plasia and acanthosis) or preneoplastic changes (including growth factor receiver, as well as other molecules (26,27).
mild, moderate and severe dysplasia; Fig. 1B) (16) prior to the
establishment of an invasive carcinoma (12,14,17). Oral cancer Ki‑67 and p53. Ki‑67 and p53 are the most commonly used
originates as an epithelial dysplasia and is characterized by tumor markers for studying cell proliferation. The p53 protein
the altered proliferation of dysplastic squamous cells on the is one of the transcription factors that is implicated in cell cycle
surface of the epithelial layer, which subsequently degrades control, apoptosis and preservation of genetic stability (28). In
the subepithelial basement membrane (BM). Degradation of addition, the p53 gene is one of the most commonly mutated
the BM results in local destruction and distant invasion via genes in OSCC with mutations detected in >50% of OSCC
metastasis. Local invasion to the underlying tissue occurs via cases (29). The activation of p53 has been reported in a number
the islets and cords of epithelial cells (18). of processes, such as DNA damage, hypoxia and oncogene
The ability to metastasize is directly associated with activation. In addition, p53 protects against tumor formation
the differential grade of tumor cells, similar to that of the by preventing the accumulation of cells with DNA damage,
neoplastic tissue architecture and normal epithelium (14). which subsequently induces a loss of function in the majority
of malignant neoplasms (30). Although not completely under-
International Classification of Tumors (World Health stood, Ki‑67 is considered to be an important protein in cell
Organization) and the tumor invasion front (TIF). Currently, division, as it has been observed that the antigen is expressed
two systems are used to histologically classify tumor lesions; primarily during the cell cycle stages of G1, S, G2 and M, with
the International Histological Classification of Tumors a marked emphasis on the M phase. However, Ki‑67 expression
(Fig. 1C‑E) and the pattern of the TIF (19). The initial is not observed during the G0 phase and has a low expression
classification of lesions is based on the degree of tumor in the G1 and S phases (31). Furthermore, Ki‑67 is considered
differentiation (well‑, moderately‑ and undifferentiated) (20), to be one of the best predictors of survival (Fig. 1J and K) (16)
which is essential to evaluate the tumor's growth rate and and recurrence (5).
ability to metastasize (14).
The TIF constitutes the area of the lesion with the greatest Homeobox (HOX) genes. Recently, novel markers have been
depth of invasion and progression into the surrounding used to assess morphogenesis and cell differentiation. Previous
tissues (21). In addition, the cells of the TIF have differing studies have demonstrated that the aberrant expression of genes
molecular characteristics when compared with the cells at the is associated with cancer embryogenesis, particularly the HOX
superficial areas of the tumor (10,22). The TIF is considered genes that may induce embryological development, as well
to be the most representative area of the tumor (23) and is as contribute to the onset and progression of tumors (32,33).
identified by four characteristics; the degree of keratinization, Furthermore, HOX gene overexpression has been associated
nuclear polymorphism, lymphocytic infiltration and pattern of with carcinogenesis, including head and neck neoplasms (34)
invasion (PI) (23,24). Of these, the PI is considered to be a and HOXB7, a member of the family of homeodomain
good prognostic factor in OSCC (1). To evaluate the severity transcription factors, is a critical regulator of development,
of the invasion, several morphological criteria exist, associated controlling the proliferation and survival of progenitor cells. In
with certain PIs, according to the following three catego- OSCC, HOXB7 is overexpressed (Fig. 1L and M) (32), which
ries (Fig. 1F‑I): i) Islet‑infiltrating cells with wide fronts of has been confirmed to be associated with a poor prognosis in
invasion; ii) thin infiltrating cords; and iii) individual infil- OSCC and other types of cancer (32,35).
trating cells (1).
In the clinical field, the majority of medical centers base Collagen type IV (ColIV). Infiltration is a key prerequisite for
their decisions upon the clinical and pathological informa- cancer metastasis, making it a significant factor in the prognosis
tion. The TNM stage (T, tumor size; N, regional lymph node of patients with OSCC (36). For the activation of the process,
compromise; and M, metastasis) (25) and the degree of tumor degradation of the BM must occur between the epithelium and
differentiation (20), combined with the patient's health status, lamina propria, which is located around the nest of cancer cells
are the predominant factors that determine the therapeutic and blood vessels. The BM has been identified as a crucial struc-
strategy. To advance the knowledge of OSCC, numerous ture in the regulation of tumor invasion. Its molecular assembly
pathological and molecular clinical markers have been identi- is a barrier for the invasion of the connective tissue, in particular
fied for the prediction of prognosis (1). of the epithelial cells, unless a molecular rupture occurs (37).
 ONCOLOGY LETTERS 8: 7-11, 2014 9

A B C

D E F

G H I

J K L

M N

Figure 1. (A) Oral squamous cell carcinoma (OSCC) of the lateral edge of the tongue (13). (B) Severe dysplasia of the surface epithelium associated with
chronic inflammatory infiltration at the stromal‑epithelial interface of the dysplastic epithelium (stain, H&E; magnification, x50) (13). Histological grades of
tumor differentiation of OSCC: (C) Well‑differentiated, hyperkeratosis and inflammation associated with the stromal‑epithelial interface; (D) moderately dif-
ferentiated; and (E) undifferentiated infiltrating and dispersed cells with no clear demarcation between the front and surrounding tissue invasion (stain, H&E;
magnification, x25) (13). Different patterns of invasion at the tumor invasion front according to the cell morphology: (F) Wide fronts of invasion (score 1); (G) islet
cell widths (score 1); (H) thin infiltrating cords (score 2); and (I) individual cells invading the interface (score 3) (1). OSCC patients (J) with recurrence and (K)
without recurrence. Antibody staining for Ki‑67 with a high degree of nuclear staining (magnification, x400) (16). Representative samples of homeobox protein,
HOXB7 immunohistochemical expression in OSCC with (L) high and (M) low expression (32). (N) Immunohistochemical expression of type IV collagen α2 chain
in undifferentiated OSCC (38).

Figure 2. In the tumoral microenvironment (TME), different stromal cells, as well as tumor cells were observed, including vascular and lymphatic endothelial
cells, and pericyte support fibroblast innate and adaptive immune cells. Furthermore, the TME contained no cellular components, including the extracellular
matrix, growth factors, proteases, protease inhibitors or other signaling molecules that are significant in the reactions of the stroma in the TME (4).
10 RIVERA and VENEGAS: HISTOLOGICAL AND MOLECULAR ASPECTS OF OSCC

ColIV is the most important protein component of the BM invasion and metastasis (47), and is associated with a poor
and its integrity is altered by the degradation of the BM via prognosis (48).
matrix metalloproteinases (MMP) 2 and 9 that are present
in OSCC (Fig. 1N) (38) and the surrounding tissues (36). 5. Conclusion
Furthermore, MMP 2 and 9 facilitate the development of
lymph node metastases (38,39). Therefore, monitoring the In conclusion, an association between cell proliferation markers
changes in the expression of ColIV may have prognostic value in the basal lamina and connective tissue has been identified
in OSCC patients (36,40). in OSCC. In addition, hyperproliferative neoplastic cells may
induce ColIV degradation and facilitate tumor invasion. Once
4. Tumor microenvironment (TME) installed in the connective tissue, the invading tumor cells may
stimulate fibroblasts, which results in an increase in the pres-
For a number of years, cancer has been considered a ence of CAFs. This scenario may be associated with clinical
cell‑autonomous process in which consecutive mutations in and histopathological characteristics, in terms of a more
the oncogenes and tumor suppressor genes lead to the infinite aggressive stage of disease and a poor differentiation grade
proliferation of neoplastic cells (41). Thus, cancer therapeutic of tumor invasion, as well as the decreased survival time of
strategies have been focused and limited on such mutations patients with increased rates of cell proliferation, loss of BM
within the tumor cells (4). However, increasing evidence integrity and CAF expression within the connective tissue.
indicates that the genesis and progression of the tumor is Therefore, the comparison of these factors with the
determined by tumor cells as well as by a low TME (42). survival time of OSCC patients, from the time of histopatho-
Recent findings have indicated that for the effective control logical diagnosis, is of interest. The results of the present
of cancer, the genesis and progression of the tumor must not review may be useful to clarify the tumor‑stromal interaction,
only be considered to be cell‑autonomous, but predominantly and its significance regarding the clinical and histological
as a disease that involves complex heterotypic multicellular characteristics of OSCC, in order to expand the quantity of
interactions within the newly formed tissue and the original specific prognostic factors available as alternatives to the
cancerous tissue. Furthermore, the disease must be considered classic TNM.
to be a a systemic, solid‑tumor tissue disease rather than a
single disease entity. Therefore, the concept of the TME has Acknowledgements
been proposed as an integral aspect and essential area of
cancerous tissues. Recent evidence from a study concerning The authors would like to thank the Investigations Directorate
the TME has emerged, forcing the scientific community to (DI) and the Master Program of Biomedical Sciences,
review the basics of cancer biology (43). University of Talca (Talca, Chile) for its cooperation.
The TME contains numerous types of cells, including
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