Oral Oncology 47 (2011) 1005–1010 Contents lists available at SciVerse ScienceDirect Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology Review Perineural invasion in oral squamous cell carcinoma: A discussion of significance and review of the literature ⇑ Nada O. Binmadi a,b, John R. Basile a,c, a Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, 7-North, Baltimore, MD 21201, USA b Department of Oral Basic & Clinical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia c Marlene and Stuart Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA article info summary Article history: Perineural invasion (PNI) is a tropism of tumor cells for nerve bundles in the surrounding stroma. It is a Received 20 May 2011 form of tumor spread exhibited by neurotropic malignancies that correlates with aggressive behavior, Received in revised form 27 July 2011 disease recurrence and increased morbidity and mortality. Oral squamous cell carcinoma (OSCC) is a neu- Accepted 1 August 2011 rotropic malignancy that traditionally has been difficult to treat and manage. Evidence suggests that Available online 23 August 2011 demonstration of PNI in OSCC should impact adjuvant treatment decisions and surgical management of this disease. Despite its importance as a prognostic indicator, experimental studies to explore the Keywords: molecular mechanisms responsible for PNI are limited. The aim of this review is to discuss the difficulties Oral squamous cell carcinoma in evaluating for PNI, review the literature regarding the relationship of PNI with patient outcomes in Perineural invasion Metastasis OSCC, and summarize the recent studies describing the molecular agents associated with this patholog- Neurotropic carcinoma ical phenomenon. Ó 2011 Elsevier Ltd. All rights reserved. Introduction of cells of a carcinoma to break through the basal lamina, liberate themselves from the primary lesion, avoid host defenses, gain ac- Oral squamous cell carcinoma (OSCC) is the sixth most common cess to lymphatics or the circulation, and establish a new growing malignancy worldwide and encompasses at least 90% of all oral lesion at a distant site is the basis for metastasis and represents malignancies. OSCC is associated with severe disease and treat- one of the most difficult barriers to overcome in the treatment of ment-related morbidity and is often reported as having high rates oral cancer.5 of recurrence and poor disease-free survival despite advances in Another quality possessed by certain tumors, referred to as cancer treatment.1 However, recent studies do show some improve- ‘neurotropic malignancies,’ is perineural invasion (PNI). PNI is a ment in outcomes following primary surgery, depending upon the tropism of tumor cells for nerve bundles in the surrounding tissues. site of the lesion and the use of more aggressive therapy such as PNI is a form of metastatic tumor spread similar to but distinct elective neck dissection.2,3 When difficulties managing these pa- from vascular or lymphatic invasion that hinders the ability to tients do arise, it is often because of occurrence of regional or distant establish local control of a malignancy because neoplastic cells metastatic spread of their disease.4 Like other epithelial malignan- can travel along nerve tracts far from the primary lesion and are of- cies, OSCC is a heterogeneous group of tumors that arises from ten missed during surgery.6 As a result, these tumors can exhibit the accumulation of a series of genetic and epigenetic alterations, pain and persistent growth with a long clinical course and late on- usually from exposure to tobacco-associated carcinogens, resulting set of metastases, a pattern that has been observed in neurotropic in the activation of oncogenes and inactivation of tumor suppres- tumor types such as melanoma, prostate and pancreatic cancer and sors. These genetic changes confer proliferation and survival the salivary gland malignancies adenoid cystic carcinoma and advantages to the altered cells, characterized by growth factor- polymorphous low-grade adenocarcinoma.7–9 Among the various independent cell division, resistance to apoptotic signaling and an parameters used to predict the outcome of malignant disease, enhanced capacity to degrade and move through the tissues of PNI is in wide use as an indicator of aggressive behavior.5 PNI is the extracellular matrix and invade adjacent structures. The ability well known as an independent predictor of poor outcome in colo- rectal carcinoma and salivary gland malignancies.9–11 The purpose of this review is to draw attention to OSCC as a neurotropic malig- ⇑ Corresponding author at: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, 7-North, nancy and review the findings in the literature that describe this Baltimore, MD 21201, USA. Tel.: +1 410 706 7936; fax: +1 410 706 0519. phenomenon as it relates to mechanism, treatment and disease E-mail address: [email protected] (J.R. Basile). prognosis. 1368-8375/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2011.08.002 1006 N.O. Binmadi, J.R. Basile / Oral Oncology 47 (2011) 1005–1010 Mechanism and histopathological assessment of PNI need to be considered when discussing PNI.17 The perineural space provides a suitable microenvironment for the growth of cells from Cruveilheir was the first to recognize PNI in head and neck can- neurotropic malignancies, probably due to cellular factors and cer in 1835.12 Despite the fact that it has been identified for more their respective receptors that attract the cancer cells and stimu- than 150 years, the mechanism of PNI is still poorly understood late their growth along the nerves. cDNA microarrays used to pro- and, to date, no treatments have been developed to target this file differential gene expression in adenoid cystic carcinomas with pathologic entity. Different theories have been proposed to explain and without PNI have identified dysregulation of genes associated the exact nature of PNI. Previously, it was considered to be a with cell cycle, the cytoskeleton and cell–extracellular matrix mechanical extension of cancer cells along planes of least resis- interaction that influence the production of neurotropic factors tance, for example by proliferation through the loose connective and adhesion molecules contributing to PNI.18 It is clear that a bet- tissue sheath of the perineurium or via the lymphatics of the epi- ter understanding of the molecular and biological mechanisms in- neurium.13 These theories were discarded with the emergence of volved will be necessary if we are to target PNI as part of advanced ultra-structural scans of the nerve sheath which revealed that therapies for cancer. the perineurium is actually a relatively tight and highly selective Neural extension of OSCC can be demonstrated not only by MRI barrier separating nerves from surrounding tissue.14 Tumor cells and CT, but also through a thorough histologic examination of biop- do not passively grow along nerves but instead penetrate the peri- sied tissue. While both the Royal College of Pathologists in the Uni- neurium in a direct and continuous manner, becoming intimately ted Kingdom (http://www.rcpath.org; see: Head and Neck Datasets, associated with Schwann cells and axons in the endoneurium.15 Section A) and the College of American Pathologists19 require Further studies also have shown that the perineurium and endo- recording of the presence or absence of invasion of the perineural neurium are devoid of lymphatic channels.16 Because it is known space by head and neck carcinomas, particularly when occurring that some specific tumor types exhibit characteristic neural ahead of the invasive front of the tumor, the accuracy of PNI analy- invasion, whereas other more aggressive tumors fail to do so even sis is controversial and open to subjectivity. There is a marked at advanced stages, it is instead likely that there are complex variation in the frequency of PNI reporting, ranging in OSCC from biological interactions between certain cancer cells and nerves that a low of anywhere between 2% and 30%20–23 to a high of 82%,23 with Figure 1 Perineural invasion in OSCC. (A) PNI as defined by Dunn et al.24 demonstrating malignant cells exhibiting total circumferential involvement of a nerve in a tangential histological section (hematoxylin and eosin stain, original magnification 20Â). (B) Based upon the definition of PNI by Liebig et al.12, tumor cells involving approximately one- third of nerve circumference (hematoxylin and eosin stain, original magnification 20Â). (C) The presence of tumor cells within the nerve sheath (hematoxylin and eosin stain; original magnification 20Â). (D) Tumor cells inside the nerve sheath, an example of intraneural invasion, as highlighted by pan-cytokeratin stain (black arrows; dotted line represents boundary of the nerve, original magnification 20Â). N.O. Binmadi, J.R. Basile / Oral Oncology 47 (2011) 1005–1010 1007 increasing rates of detection where biopsies are specifically re- 5-year survival rate.20,22,30–33 Variations in the prognostic impor- viewed to detect PNI or when certain neural stains are used. Other tance of a histological finding of PNI among these studies might concerns in detection of neural invasion in tissue examination are be due to the size of the nerves involved, with invasion of small biopsy technique, slide preparation, and the number of histological nerve branches having a lower correlation with patient outcomes sections examined. Taken together, these findings suggest that the compared to more major nerves. While a review by Woolgar cites accuracy and prognostic significance of PNI in many studies of OSCC evidence that OSCC exhibiting PNI in either major nerves or those could be compromised due to errors of underreporting. of a smaller diameter (61 mm) are all associated with reduced sur- A great difficulty exists in that there is no one accepted or stan- vival rates and an increased risk of loco-regional recurrence,31 it is dardized definition of PNI among pathologists.