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 metastatic process.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.24396

Perineural invasion in cancer: A review of the literature

Publisher Summary This chapter deals with the immunologically privileged sites. Genetically alien grafts of a wide variety of both normal and malignant tissues have repeatedly been transplanted to anatomically unnatural sites in the body—that is, transplanted heterotopically—for many different though frequently interrelated purposes. The chapter presents a critical account of the status of the known or suspected privileged sites in the body and evaluates their significance from both the immunologic and therapeutic viewpoints. The chapter focuses on following considerations of privileged sites: (1) privileged sites can be created artificially, (2) it is recognized that better understanding of the modus operandi of privileged sites may lead to improvement in the results obtainable with therapeutic allografts, and (3) naturally occurring privileged sites afford important “experiments of nature” pertinent to critical evaluation of the theory of immunologic surveillance against neoplastic disease. Finally, the chapter concludes by highlighting nude mice because their basic congenital athymic status renders them “immunologically privileged” hosts that sustain on an indefinite basis both allografts and xenografts from a wide spectrum of vertebrate donors.

Immunologically Privileged Sites

In a study of 208 total prostates removed surgically for early carcinoma of the prostate and studied by the step-section technique, we found that 97% were located either peripherally or both peripherally and centrally; 80% were bilateral, and 85% were multifocal. In most of the cases, the tumor was actually more extensive than detected by rectal examination, but there was reasonable agreement (74.5%) between the urologist and pathologist in assessing the presence of local extension of carcinoma. Evaluation of various factors affecting survival and mortality disclosed that an extension of the tumor to seminal vesicles or invasion of the capsule, whether detected clinically or pathologically, had an unfavorable prognosis while the side involved, the location of the tumor, and perineural invasion had no significant effect on the prognosis.

Carcinoma of the prostate: Prognostic evaluation of certain pathologic features in 208 radical prostatectomies

Detailed histologic study of 45 cancerous prostate glands in 134 autopsies provided new information on the natural history of prostatic carcinoma. Origin of carcinoma was limited to one of two histologically distinct regions, but with no apparent predilection for the “posterior lobe” or sub capsular area. Carcinoma selectively originated from active gland epithelium rather than a trophic glands, and distinctive premalignant changes accompanied its origin. Evidence from volume distribution data suggests that there are not two types of prostatic carcinoma with different biologic potential, but a single species having slow growth rate with a logarithmic growth curve. The development of carcinoma in the gland follows predictable patterns, including early involvement of the capsule and perineural spaces. The later course of tumor growth is characterized by loss of differentiation and the ability to penetrate the capsule and periurethral stroma. This suggests a gradual increase in biologic malignant potential which is closely linked to tumor size. Probably the capacity for distant metastasis is almost limited to large carcinomas, and penetration of the gland capsule may be the most important predisposing factor.

Origin and development of carcinoma in the prostate

Objective To determine if perineural invasion (PNI) of small nerves affects the outcome of patients with squamous cell carcinoma (SCC) of the upper aerodigestive tract. Design Retrospective clinicopathological study of patients with at least 2 years of follow-up and with negative margins and no prior, synchronous, or metachronous SCC. Setting Academic otolaryngology department. Patients One hundred forty-two patients who had SCC of the oral cavity, oropharynx and hypopharynx, or larynx resected between 1981 and 1991. Intervention Surgery with or without adjuvant therapy. Main Outcome Measures Local recurrence was examined with respect to PNI, nerve diameter, and microvascular or microlymphatic invasion. Perineural invasion was correlated with lymph node metastasis, extracapsular spread, and survival. Results Perineural invasion of nerves less than 1 mm in diameter was present in 74 patients, lymphatic invasion in 53, and vascular invasion in 9. Perineural invasion was significantly associated with local recurrence (23% for PNI vs 9% for no PNI; P =.02), and disease-specific mortality (54% mortality for PNI vs 25% for no PNI; P P =.03). Perineural invasion was not associated with extracapsular spread ( P =.47). Microvascular invasion, lymphatic invasion, and nerve diameter were not significantly related to local recurrence. Conclusions Perineural invasion of small nerves is associated with an increased risk of local recurrence and cervical metastasis and is, independent of extracapsular spread, a predictor of survival for patients with SCC of the upper aerodigestive tract.

https://jamanetwork.com/journals/jamaotolaryngology/articlepdf/219920/OOA7154.pdf

Perineural Invasion in Squamous Cell Carcinoma of the Head and Neck

A number of experiments designed to determine the mechanism of tumor extension along nerves are described together with clinical observations. The data presented indicate that perineural lymphatics are a myth and not a fact for the following reasons. (1) Lymphatics do not drain into nerves. (2) Perineurial spaces do not flow into lymphatics. (3) Intraneural injection of tumor cells in the rat and clinical observations concerning tumor extension along nerves show that tumor patterns are not compatible with lymphatic spread. (4) Special studies, including electron microscopy, indicate that there are no lymphatics within nerves.

Perineural lymphatics: Myth or fact

The concept of perineural lymphatics is widely accepted, particularly in reference to prostatic carcinoma. A study of serial sections of many tissue blocks from 12 prostatic carcinomas revealed involvement of perineurium in only five cases; however, the assumption that these tumor cells are in lymphatics is unlikely because of the absence of an endothelial lining and the involvement of the entire circumference of the nerve by tumor in some instances. Experimental studies were performed to further investigate the perineurium. When India ink was injected into the lymphatics of the prostatic capsule of dogs, none was found in perineural areas either grossly or microscopically. Inoculation of Walker 256 carcinoma directly into the perineurium of femoral nerves of rats resulted in variable spread within the nerve and along tissue spaces in the perineurium, with no evidence of invasion of lymphatics or regional lymph nodes. Electron microscopy of canine and human nerves did not reveal any evidence of lymphatics in the perineurium. Therefore, the authors conclude that spread of malignant tumors along nerves in the prostate and elsewhere is not within performed lymphatics but within tissue planes of least resistance.

Nature of the perineural space invaded by prostatic carcinoma.

Twenty-eight cases of papillary serous cystadenocarcinoma are evaluated by light and electron microscopy. Five cell types are commonly identified in these tumors. Cell types A and B are similar to those seen in the upper female genital tract (fallopian tube). Cell type C is similar to the responding cell of the endometrium. Cell type D is composed of two secretory types of cells, one resembling endocervical epithelium. Cell type E is of an unusual cell type not compatible with any cell previously seen in the female genital tract by the authors. These findings support the hypothesis that these tumors (and other cystomas) are derived from “germinal epithelium.” Findings common to other tumor cells are identified including annulate lamellae, unusual appearing mitochondria, numerous free polyribosomes, large irregular nuclei with macronucleoli, and nuclear inclusions.

https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/1097-0142%28197004%2925%3A4%3C947%3A%3AAID-CNCR2820250432%3E3.0.CO%3B2-O

Ultrastructure of ovarian tumors. I. Papillary serous cystadenocarcinoma

This article reports the light and electron microscopic study of normal human parathyroid and seven parathyroid adenomas. Six patients received selenium 75 methionine, a gamma emitter, in tracer doses to try to localize the adenoma. Ultrastructural differences between normal individuals, patients, not receiving the isotope and those receiving the isotope were noted. The changes were most marked in adenomas removed 10 to 40 days after isotope and absent in one removed 192 days after isotope. The authors suggest that the ultrastructure of the parathyroid cell might have been altered by isotope exposure or may be a characeristic of certain parathyroid adenomas related to their neoplastic nature.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%281967%2920%3A4%3C512%3A%3AAID-CNCR2820200408%3E3.0.CO%3B2-W

Daniel K. Roberts

Papers

Perineural lymphatics: Myth or fact

Nature of the perineural space invaded by prostatic carcinoma.

Ultrastructure of ovarian tumors. I. Papillary serous cystadenocarcinoma

Adenomas of the human parathyroid. Light and electron microscopic study following selenium 75 methionine scan