Perineural invasion in cancer

Abstract

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

Does perineural invasion in a radical prostatectomy specimen predict biochemical recurrence in men with prostate cancer?

“…Later, the nerve sheath was presumed to provide a low-resistance path for tumour spread. 4,5 Most recently it has been discovered that the process of PNI is not passive, but instead PNI occurs as a result of symbiotic interactions between nerves and malignant cells that result in co-stimulation of growth. The nerve microenvironment affords prostate cancer cells a survival advantage that is evident through reduced apoptotic activity and increased proliferation compared to prostate Predicting biochemical recurrence in prostate cancer cancer cells in non-PNI sites.…”

El papel pronóstico de la invasión perineural en la biopsia prostática

“…La vía vascular y linfática de diseminación tumoral son bien conocidas, pero la vía perineural ha recibido menos atención 1,2 . La invasión perineural (IPN) de los nervios se considera una ruta metastásica en algunos tumores 1 .…”

“…La invasión perineural (IPN) de los nervios se considera una ruta metastásica en algunos tumores 1 . Se considera que al entrar las células tumorales en las vainas nerviosas encuentran un plano facilitador de la migración, una zona de menor resistencia a la diseminación tumoral 2 , aunque las múltiples capas de colágeno y la membrana basal de la vaina nerviosa realmente no la confieren baja resistencia; por ello, se empieza a considerar que la IPN es más un efecto de invasión que de simple difusión 1 . Además, varias neurotrofinas y elementos estromales, como los fibroblastos, seguramente juegan un papel importante en las interacciones complejas que permiten la IPN 1 .…”

“…Se considera que al entrar las células tumorales en las vainas nerviosas encuentran un plano facilitador de la migración, una zona de menor resistencia a la diseminación tumoral 2 , aunque las múltiples capas de colágeno y la membrana basal de la vaina nerviosa realmente no la confieren baja resistencia; por ello, se empieza a considerar que la IPN es más un efecto de invasión que de simple difusión 1 . Además, varias neurotrofinas y elementos estromales, como los fibroblastos, seguramente juegan un papel importante en las interacciones complejas que permiten la IPN 1 . Existen varias revisiones amplias sobre IPN y su significación en el pronóstico del paciente 1,[3][4][5][6][7][8] , que alimentan el tema clave de discusión de si merece tener impacto en la decisión terapéutica por establecer un riesgo de diseminación tumoral antes de la cirugía 6,7,[9][10][11] .…”

“…Además, varias neurotrofinas y elementos estromales, como los fibroblastos, seguramente juegan un papel importante en las interacciones complejas que permiten la IPN 1 . Existen varias revisiones amplias sobre IPN y su significación en el pronóstico del paciente 1,[3][4][5][6][7][8] , que alimentan el tema clave de discusión de si merece tener impacto en la decisión terapéutica por establecer un riesgo de diseminación tumoral antes de la cirugía 6,7,[9][10][11] . Para muchos la presencia de IPN en la biopsia es un indicador de riesgo de extensión extraprostática (EEP), de afectación de márgenes y de recidiva bioquímica [5][6][7][8]12 .…”