Peak density of immature nerve cells occurs with high-grade dysplasia in intraductal papillary mucinous neoplasms of the pancreas.

The development of neural structures within tumors is now considered vital for carcinogenesis. However, the time course of this development in human pre-invasive neoplasia has been incompletely described. Therefore, we performed a detailed analysis of nerves across the neoplastic spectrum in resected intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Histology and multiplexed immunochemistry demonstrated that nerve density increased from low-grade (LG) to high-grade dysplasia (HG) but did not further increase once invasive IPMN (INV IPMN) was present. Higher nerve density correlated with increasing expression of nerve growth factor (NGF) by the tumor cells. Intra-tumoral nerves were immature and lacked markers of sympathetic, parasympathetic, and sensory lineages. Here, we show for the first time the presence of neural precursor cells (NPCs) within the stroma of pancreatic tumors. The density of these doublecortin (DCX)-positive NPCs increased from LG to HG, but not from HG to INV IPMN. We conclude that peak neural density of tumors is reached in high-grade dysplasia (often termed carcinoma in situ) rather than after invasion. These findings suggest that nerve-tumor interactions are important in IPMN progression and may serve as the basis for future mechanistic studies and novel therapeutic modalities. © 2022 The Pathological Society of Great Britain and Ireland.

The Biology of Chronic Pain and Its Implications for Pain Neuroscience Education: State of the Art.

Pain is an individualized experience for the person suffering from chronic pain. Significant strides have been made in the last few decades in understanding various biological changes that coincide with chronic pain. This state-of-the-art overview looks at the current evidence related to the biology of chronic pain and the implications these findings have on the delivery of pain neuroscience education (PNE). The paper summarizes the various (epi)genetic, neural, endocrine, and immune factors discovered and explored in the scientific literature concerning chronic pain. Each of these biological factors has various implications for the content and delivery of PNE. We discuss the future directions these biological factors have for the clinical implementation of PNE by linking the importance of behavior change, optimizing the learning environment, and using an individualized multimodal treatment approach with PNE. In addition, future directions for research of PNE based on these biological factors are provided with importance placed on individualized patient-centered care and how PNE can be used with traditional modes of care and growing trends with other care methods. PNE was originally and continues to be rooted in understanding chronic pain biology and how that understanding can improve patient care and outcomes.

Nerve Density and Neuronal Biomarkers in Cancer.

Certain histologic characteristics of neurons, novel neuronal biomarkers, and nerve density are emerging as important diagnostic and prognostic tools in several cancers. The tumor microenvironment has long been known to promote tumor development via promoting angiogenesis and cellular proliferation, but new evidence has shown that neural proliferation and invasion in the tumor microenvironment may also enable tumor growth. Specific neuronal components in peripheral nerves and their localization in certain tumor sites have been identified and associated with tumor aggressiveness. In addition, dense neural innervation has been shown to promote tumorigenesis. In this review, we will summarize the histological components of a nerve, explore the neuronal biomarkers found in tumor sites, and discuss clinical correlates between tumor neurobiology and patient prognosis.