Perineural Invasion in Cancer A Review of the Literature Catherine Liebig, MD 1 ; Gustavo Ayala, MD 2 ; Jonathan A. Wilks, MD 1 ; David H. Berger, MD 1 ; and Daniel Albo, MD, PhD 1 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 dis- tinct 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 tar- geted 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- static process. Cancer 2009;115:3379–91. V C 2009 American Cancer Society. KEY WORDS: perineural invasion, perineural spread, neurotropic carcinoma, cancer, neurotrophins, axon guidance molecule. A key feature of malignant cells is their ability to dissociate from the primary tumor and to establish meta- static 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 malignan- cies, 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 Received: September 9, 2008; Revised: December 5, 2008; Accepted: January 7, 2009 Published online: May 29, 2009 V C 2009 American Cancer Society DOI: 10.1002/cncr.24396, www.interscience.wiley.com Corresponding author: Daniel Albo, MD, PhD, Michael E. DeBakey VA Medical Center, 2002 Holcombe Boulevard, OCL 112-A, Houston, TX 77030; Fax: (713) 794-7352; [email protected]1 Department of Surgery, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas; 2 Department of Pathology, Baylor College of Medicine, Houston, Texas Cancer August 1, 2009 3379 Review Article
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Perineural Invasion in Cancer
A Review of the Literature
Catherine Liebig, MD1; Gustavo Ayala, MD2; Jonathan A. Wilks, MD1; David H. Berger, MD1;
and Daniel Albo, MD, PhD1
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 dis-
tinct 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 tar-
geted 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-
static process. Cancer 2009;115:3379–91. VC 2009 American Cancer Society.
A key feature of malignant cells is their ability to dissociate from the primary tumor and to establish meta-static deposits at distant sites. Vascular and lymphatic channels are well accepted routes of metastaticspread. They are well characterized in the literature and are the focus of much current research on tumorbiology. However, another route of tumor spread that occurs in and along nerves has been described in theliterature 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 carcinomatousspread and perineural spread. PNI was reported first in the European literature by scientists who describedhead and neck cancers that exhibited a predilection for growth along nerves as they made their way towardthe intracranial fossa.1,2 PNI has emerged since then as a key pathologic feature of many other malignan-cies, including those of the pancreas, colon and rectum, prostate, biliary tract, and stomach. For many ofthese malignancies, PNI is a marker of poor outcome and a harbinger of decreased survival.3-7
Received: September 9, 2008; Revised: December 5, 2008; Accepted: January 7, 2009
Published online: May 29, 2009 VC 2009 American Cancer Society
rotrophins and axonal guidance molecules have implicated
a few of the molecular mediators involved in the process,
although we have only just begun to scratch the surface.
We have highlighted the clinical significance of PNI
in those malignancies in which it has been studied best.
These include cancers of the head and neck, pancreas, co-
lon and rectum, and prostate. Overall, PNI portends a sig-
nificantly lower 5-year survival rate and signifies more
advanced disease. There are many malignancies, however,
for which we have only begun to recognize the signifi-
cance of PNI. Breast cancer and hepatobiliary cancers are
among these malignancies; however, preliminary evidence
suggests that, 1 day, PNI also will be recognized as a sig-
nificant pathologic feature in these and other tumors.
With a better understanding of the pathogenesis and
through work using animal models, we can begin to target
PNI in our treatment strategies against those malignances
for which PNI is significant. Gene profiling already has
been used to identify an expression profile predictive
of PNI in biliary tract cancers.101 These expression
profiles are being evaluated for use in risk stratification
and in guiding the extent of surgical resection; however,
1 day, the candidate genes or their downstream molec-
ular pathways could serve as therapeutic targets. Sev-
eral neurotrophins, including NGF, BDNF, and NT-3,
have been implicated in promoting tumor cell invasion
and may be key mediators in the pathogenesis of
PNI.34,36,38 Researchers have begun searching for viable
therapeutic targets among these neurotrophins and their
Perineural Invasion in Cancer/Liebig et al
Cancer August 1, 2009 3387
receptors.36,102-104 Both anti-NGF antibodies and small
interfering RNA against NGF have demonstrated efficacy
against cell proliferation and angiogenesis in a breast can-
cer murine model.104 Intratumoral and peritumoral injec-
tion with antibodies against receptors for NGF and NT-3
have produced significant growth inhibition in both
human pancreatic cancer and prostate cancer xenografts
in a nude mouse model.105
Although much of our research has focused on tu-
mor cell invasion of nerves, the PNI story is beginning to
include axonal growth and possibly nerve ‘‘invasion’’ of tu-
mor. A study performed by Maru et al. indicated that PNI
diameter, measured with an ocular micrometer and
defined as the largest focus of PNI in a tumor, was a better
predictor of outcome in prostate cancer than PNI status
alone.55 There is no clear explanation why this is the case.
It is possible that tumors with larger foci of PNI are simply
more advanced cancers, which we would expect to have
worse outcomes; or perhaps there is nerve enlargement
within these foci of PNI as a result of a cancer cell-pro-
moted nerve growth phenomenon during PNI. Clearly,
this aspect of PNI needs to be explored further; however,
in vitro evidence certainly suggests that there is a reciprocal
growth interaction occurring between nerves and tumors.
It seems that progress in understanding PNI has
been stymied by the lack of a concise definition for this
pathologic process. We conclude that the definition
offered by Batsakis in 1985—tumor cell invasion in,
around, and through the nerves—leaves too much room for
interpretation and is not precise enough to promote uni-
formity among researchers. After a thorough review of the
literature, we have compiled criteria for the identification
of PNI in a histologic specimen. Finding tumor cells
within any of the 3 layers of the nerve sheath or tumor foci
outside of the nerve with involvement of �33% of the
nerve’s circumference are sufficient features for calling
PNI. It is likely that, as our understanding of the pathoge-
nesis of PNI evolves, so too will this definition.
Conflict of Interest Disclosures
The authors made no disclosures.
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