Perineural invasion (PNI) is the process of neoplastic invasion of nerves and is an under-recognized route of metastatic spread. It is emerging as an important pathologic feature of many malignancies, including those of the pancreas, colon and rectum, prostate, head and neck, biliary tract, and stomach. For many of these malignancies, PNI is a marker of poor outcome and a harbinger of decreased survival. PNI is a distinct pathologic entity that can be observed in the absence of lymphatic or vascular invasion. It can be a source of distant tumor spread well beyond the extent of any local invasion; and, for some tumors, PNI may be the sole route of metastatic spread. Despite increasing recognition of this metastatic process, there has been little progress in the understanding of molecular mechanisms behind PNI and, to date, no targeted treatment modalities aimed at this pathologic entity. The objectives of this review were to lay out a clear definition of PNI to highlight its significance in those malignancies in which it has been studied best. The authors also summarized current theories on the molecular mediators and pathogenesis of PNI and introduced current research models that are leading to advancements in the understanding of this meta- A key feature of malignant cells is their ability to dissociate from the primary tumor and to establish metastatic deposits at distant sites. Vascular and lymphatic channels are well accepted routes of metastatic spread. They are well characterized in the literature and are the focus of much current research on tumor biology. However, another route of tumor spread that occurs in and along nerves has been described in the literature since the mid-1800s but has received relatively little research attention. Perineural invasion (PNI) is the process of neoplastic invasion of nerves. It also has been called neurotropic carcinomatous spread and perineural spread. PNI was reported first in the European literature by scientists who described head and neck cancers that exhibited a predilection for growth along nerves as they made their way toward the intracranial fossa.1,2 PNI has emerged since then as a key pathologic feature of many other malignancies, including those of the pancreas, colon and rectum, prostate, biliary tract, and stomach. For many of these malignancies, PNI is a marker of poor outcome and a harbinger of decreased survival.3-7

PNI is grossly underreported in CRC and could serve as an independent prognostic factor of outcomes in these patients. PNI should be considered when stratifying CRC patients for adjuvant treatment.

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