Perineural growth in head and neck squamous cell carcinoma: a review

Abstract

Perineural growth is a unique route of tumor metastasis that is associated with poor prognosis in several solid malignancies. It is diagnosed by the presence of tumor cells inside the neural space seen on histological or imaging evaluations. Little is known about molecular mechanisms involved in the growth and spread of tumor cells in neural spaces. The poor prognosis associated with perineural growth and lack of targeted approaches necessitates the study of molecular factors involved in communication between tumor and neural cells. Perineural growth rates, shown to be as high as 63% in head and neck squamous cell carcinoma (HNSCC), correlate with increased local recurrence and decreased disease-free survival. Here we describe the literature on perineural growth in HNSCC. In addition, we discuss factors implicated in perineural growth of cancer. These factors include brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 and -4, glial cell-line derived neurotrophic factor (GDNF), the neural cell adhesion molecule (NCAM), substance P (SP), and chemokines. We also explore the literature on membrane receptors, including the Trk family and the low-affinity nerve growth factor receptor. This review highlights areas for further study of the mechanisms of perineural invasion which may facilitate the identification of therapeutic targets in HNSCC.

Keywords: Chemokines; Neurotrophic factors; Neurotrophin; Perineural growth; Perineural invasion; Squamous cell carcinoma.

Figure 1. Histological analyses of perineural invasion of HNSCC

Photomicrographs with representative examples of perineural (A), and intraneural invasion (B) by squamous cell carcinoma of the head and neck (Hematoxylin and Eosin, magnification 100 and 200x, respectively). White dotted lines indicate the nerve, black dotted lines indicate PNI, and black arrows indicated intraneural invasion.

Figure 2. Magnetic resonance images indicate perineural spread of head and neck cancer

MRI of carcinoma in a 67-year old female in the (A) cavernous sinus which houses several cranial nerves, and the foramen ovale where the V3 branch of the trigeminal nerve emerges from the brain, and (B) foramen rotundum where the V2 branch of the trigeminal nerve emerges from the brain. White dotted lines indicate perineural spread.

Figure 3. Critical signaling molecules with potential relevance in HNSCC neuron-tumor cell interaction

(A) HNSCC tumor cells can secrete molecules including NGF, BDNF and NT-3 which lead to neurite outgrowth toward the cancer cells. The nerves also secrete molecules which can cause complex signaling cascades in the cancer cells facilitating tumor invasion and migration. [39-43, 45](B) Major cytoplasmic signaling cascades activated downstream of neurotrophic receptors induce a variety of cellular responses including cell survival, differentiation or death.