ReviewPerineural invasion in oral squamous cell carcinoma: A discussion of significance and review of the literature
Introduction
Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide and encompasses at least 90% of all oral malignancies. OSCC is associated with severe disease and treatment-related morbidity and is often reported as having high rates of recurrence and poor disease-free survival despite advances in cancer treatment.1 However, recent studies do show some improvement in outcomes following primary surgery, depending upon the site of the lesion and the use of more aggressive therapy such as elective neck dissection.[2], [3] When difficulties managing these patients do arise, it is often because of occurrence of regional or distant metastatic spread of their disease.4 Like other epithelial malignancies, OSCC is a heterogeneous group of tumors that arises from the accumulation of a series of genetic and epigenetic alterations, usually from exposure to tobacco-associated carcinogens, resulting in the activation of oncogenes and inactivation of tumor suppressors. These genetic changes confer proliferation and survival advantages to the altered cells, characterized by growth factor-independent cell division, resistance to apoptotic signaling and an enhanced capacity to degrade and move through the tissues of the extracellular matrix and invade adjacent structures. The ability of cells of a carcinoma to break through the basal lamina, liberate themselves from the primary lesion, avoid host defenses, gain access to lymphatics or the circulation, and establish a new growing lesion at a distant site is the basis for metastasis and represents one of the most difficult barriers to overcome in the treatment of oral cancer.5
Another quality possessed by certain tumors, referred to as ‘neurotropic malignancies,’ is perineural invasion (PNI). PNI is a tropism of tumor cells for nerve bundles in the surrounding tissues. PNI is a form of metastatic tumor spread similar to but distinct from vascular or lymphatic invasion that hinders the ability to establish local control of a malignancy because neoplastic cells can travel along nerve tracts far from the primary lesion and are often missed during surgery.6 As a result, these tumors can exhibit pain and persistent growth with a long clinical course and late onset of metastases, a pattern that has been observed in neurotropic tumor types such as melanoma, prostate and pancreatic cancer and the salivary gland malignancies adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma.[7], [8], [9] Among the various parameters used to predict the outcome of malignant disease, PNI is in wide use as an indicator of aggressive behavior.5 PNI is well known as an independent predictor of poor outcome in colorectal carcinoma and salivary gland malignancies.[9], [10], [11] The purpose of this review is to draw attention to OSCC as a neurotropic malignancy and review the findings in the literature that describe this phenomenon as it relates to mechanism, treatment and disease prognosis.
Section snippets
Mechanism and histopathological assessment of PNI
Cruveilheir was the first to recognize PNI in head and neck cancer in 1835.12 Despite the fact that it has been identified for more than 150 years, the mechanism of PNI is still poorly understood and, to date, no treatments have been developed to target this pathologic entity. Different theories have been proposed to explain the exact nature of PNI. Previously, it was considered to be a mechanical extension of cancer cells along planes of least resistance, for example by proliferation through
Relationship between PNI and recurrence, lymph node involvement, tumor stage and age of the patient in OSCC
Prognosis and therefore treatment decisions in OSCC are currently based on TNM staging, as determined by clinical examination, imaging studies, and histopathological features observed in the biopsy that are believed to be risk factors affecting patient outcomes.28 These factors, which include the pattern of invasion of the tumor, the presence of PNI, and the quality of the lymphocytic response, were shown to be statistically significant independent predictors of both local recurrence and
Nerve and cancer cell interactions
In the last few years many hypotheses have emphasized the importance of microenvironment for providing the biological and physical parameters necessary to promote PNI. Cancer cell migration towards nerves and then along the nerve trunk within the perineural space likely requires activation of numerous signaling pathways involving trophic factors, extracellular matrix adhesion proteins and regulators of chemotaxis. For example, tumor cell expression of CD74, a cell surface protein associated
Axonogenesis, neurogenesis, and cancer
Emerging models of PNI strongly suggest that interactions between tumor cells and nerves not only induce tumor cell migration but also stimulate axonogenesis, or the enlargement of nerves, axon extension or increased axon number, and neurogenesis, an increase in neuron body cell numbers, that can lead to increased nerve density in and around neurotropic malignancies. This process, important in many normal physiologic processes such as growth, development and wound healing, is a newly recognized
Conclusions
Treatment failures in patients with OSCC are primarily due to loco-regional recurrence and distant metastasis. Among different parameters, PNI is a widely accepted clinical and histopathological feature that is frequently associated with aggressive disease and a poor prognosis. However, we did detect variations in the prognostic significance of PNI throughout the literature, probably due to a lack of consistent methodology and study design, a limitation in the number of cases analyzed, and the
Conflict of interest statement
The authors do not have financial or personal relationships with persons or organizations that would influence or bias this work.
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