Clinical Investigation
Perineural Invasion and Perineural Tumor Spread in Head and Neck Cancer

https://doi.org/10.1016/j.ijrobp.2018.12.009Get rights and content

Perineural invasion (PNI), the neoplastic invasion of nerves, is a common pathologic finding in head and neck cancer that is associated with poor clinical outcomes. PNI is a histologic finding of tumor cell infiltration and is distinct from perineural tumor spread (PNTS), which is macroscopic tumor involvement along a nerve extending from the primary tumor that is by definition more advanced, being radiologically or clinically apparent. Despite widespread acknowledgment of the prognostic significance of PNI and PNTS, the mechanisms underlying its pathogenesis remain largely unknown, and specific therapies targeting nerve invasion are lacking. The use of radiation therapy for PNI and PNTS can improve local control and reduce devastating failures at the skull base. However, the optimal volumes to be delineated with respect to targeting cranial nerve pathways are not well defined, and radiation can carry risks of major toxicity secondary to the location of adjacent critical structures. Here we examine the pathogenesis of these phenomena, analyze the role of radiation in PNI and PNTS, and propose guidelines for radiation treatment design based on the best available evidence and the authors' collective experience to advance understanding and therapy of this ominous cancer phenotype.

Section snippets

Pathology and Pathogenesis

Perineural invasion (PNI) is a common pathologic finding in many head and neck cancers, including squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC; Table 1). Initial theories suggested that PNI was simply an extension of lymphatic metastasis, which was eventually disproven. Modern studies have demonstrated that PNI is a deliberate, molecularly mediated process that results from reciprocal interactions between cancer and nerve, challenging the historic notion that this is an event

Clinical Significance

PNI by head and neck cancers is a significant cause of morbidity and mortality, and it confers a poor prognosis.12, 13, 14 PNI has been reported across many case series at varying prevalence rates of 25% to 80% of head and neck mucosal SCCs,15, 16, 17, 18 and it constitutes a pervasive feature present in at least half of ACCs.19, 20, 21, 22 Although PNI is rare in most skin cancers, it is seen in 36% to 50% of desmoplastic melanoma,23, 24, 25 and the rare cutaneous SCCs (<5%) that manifest with

Imaging and Anatomy

Magnetic resonance imaging (MRI) is the most sensitive imaging method for the detection of extratumoral extension along a large nerve, which is referred to as perineural tumor spread (PNTS). PNTS can be subtle on imaging, and it usually requires careful evaluation over multiple sequences.42 It has been suggested that because of this and perhaps also because of inadequate training of radiologists to look for it, PNTS on MRI might be missed frequently.43

The T1-weighted sequence is often referred

Rationale and Consensus Indications for Radiation

Radiation therapy is usually indicated after discovery of PNI in head and neck mucosal SCC,13, 18, 28, 33, 34, 35, 36, 37, 40 cutaneous SCC,39 or salivary gland malignancies21 because of its association with local, regional, and nerve pathway recurrence. With the advent of highly conformal technologies, radiation given as definitive, adjuvant, or salvage treatment can simultaneously or selectively address all or some of these potential patterns of recurrence. The most common scenario in which

Radiation Therapy Design

When designing target volumes in cases of PNI, it is essential to weigh the risk–benefit level in the decision to cover the relevant CN pathways electively in addition to the primary tumor bed (Table 2). The optimal radiation treatment volume with respect to tracing the CN back to the skull is not well defined and can carry a significant risk of toxicity. The decision to include elective CN pathways in addition to the primary tumor region depends on the extent of PNI, histology, margin status,

Dose Selection

Dose selection for cases of PNI balances disease burden and aggressiveness, risk of subsequent inoperable disease failure, and probabilities of toxicity to adjacent normal tissues. Although there is limited and mostly empirically derived clinical data to guide dose determination in these cases, general principles can be applied (Table 2).16, 43 The following recommendations are based largely on such principles in combination with our collective experience. Dose-painting techniques are highly

Systemic Therapy

Platinum-based compounds and biologic therapies targeting the epidermal growth factor receptor have been established in landmark head and neck cancer trials as radiosensitizers.97, 98, 99 In the presence of PNI, the addition of systemic treatment combined with radiation is considered in selective situations depending on the extent of perineural disease (microscopic PNI versus PNTS), the tumor site (mucosal versus salivary gland versus primary skin cancer), and the histology (cutaneous versus

Treatment-Related Toxicities

Although radiation is effective and usually of only moderate localized risk in treating most cases of PNI, treatment of PNTS at the skull base and CN pathways may be exceptionally challenging and fraught with a risk of significant morbidity, including permanent blindness, hearing loss, temporal lobe necrosis, and cranial neuropathies. Radiation-induced cranial neuropathies can increase over time because of long latency, such as the incidence reported in 35% of nasopharyngeal cancer survivors at

Future Directions

A growing understanding of the molecular basis for PNI opens the possibility of many novel therapeutic strategies. Preclinical data suggest that targeting neurotrophic factors or their receptors can directly inhibit nerve invasion.2, 5 Importantly, the irradiation of nerve pathways might act not only by inducing cancer cell death, but by also directly suppressing neurotrophic factor secretion critical to PNI pathogenesis. In an in vivo model of PNI, low doses of radiation to the nerve alone

Conclusion

PNI is an ominous pathologic finding associated with poor clinical outcomes and morbidity. Appropriately targeted radiation therapy can improve local control and reduce the risk of unresectable failures in cases of PNI/PNTS. Designing target volumes requires careful attention to nerve-pathway anatomy and appropriate integration of clinical, radiographic, and pathologic information. Dose selection in cases of nerve invasion balances the issues of disease burden, risk of catastrophic failure, and

References (114)

  • C.J. Balamucki et al.

    Skin carcinoma of the head and neck with perineural invasion

    Am J Otolaryngol

    (2012)
  • C.J. Balamucki et al.

    Adenoid cystic carcinoma of the head and neck

    Am J Otolaryngol

    (2012)
  • J.G. Douglas et al.

    Treatment of locally advanced adenoid cystic carcinoma of the head and neck with neutron radiotherapy

    Int J Radiat Oncol Biol Phys

    (2000)
  • A.M. Chen et al.

    Local-regional recurrence after surgery without postoperative irradiation for carcinomas of the major salivary glands: Implications for adjuvant therapy

    Int J Radiat Oncol Biol Phys

    (2007)
  • M. Anwar et al.

    Delineation of radiation therapy target volumes for cutaneous malignancies involving the ophthalmic nerve (cranial nerve V-1) pathway

    Pract Radiat Oncol

    (2016)
  • I. Gluck et al.

    Skin cancer of the head and neck with perineural invasion: Defining the clinical target volumes based on the pattern of failure

    Int J Radiat Oncol Biol Phys

    (2009)
  • H.C. Ko et al.

    A contouring guide for head and neck cancers with perineural invasion

    Pract Radiat Oncol

    (2014)
  • W.F. Mourad et al.

    Clinical validation and applications for ct-based atlas for contouring the lower cranial nerves for head and neck cancer radiation therapy

    Oral Oncol

    (2013)
  • G. Moonis et al.

    Patterns of perineural tumor spread in head and neck cancer

    Magn Reson Imaging Clin N Am

    (2012)
  • L.E. Ginsberg

    MR imaging of perineural tumor spread

    Neuroimaging Clin N Am

    (2004)
  • E.B. Holliday et al.

    Proton therapy reduces treatment-related toxicities for patients with nasopharyngeal cancer: A case-match control study of intensity-modulated proton therapy and intensity-modulated photon therapy

    Int J Particle Ther

    (2015)
  • F.M. Singh et al.

    Patterns of spread of head and neck adenoid cystic carcinoma

    Clin Radiol

    (2015)
  • C. Lin et al.

    Perineural infiltration of cutaneous squamous cell carcinoma and basal cell carcinoma without clinical features

    Int J Radiat Oncol Biol Phys

    (2012)
  • I. Leibovitch et al.

    Cutaneous squamous cell carcinoma treated with mohs micrographic surgery in Australia II. Perineural invasion

    J Am Acad Dermatol

    (2005)
  • I. Leibovitch et al.

    Basal cell carcinoma treated with Mohs surgery in Australia III. Perineural invasion

    J Am Acad Dermatol

    (2005)
  • J.K. Salama et al.

    ACR appropriateness criteria adjuvant therapy for resected squamous cell carcinoma of the head and neck

    Oral Oncol

    (2011)
  • M.W. McCord et al.

    Skin cancer of the head and neck with clinical perineural invasion

    Int J Radiat Oncol Biol Phys

    (2000)
  • A. Stratigos et al.

    Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline

    Eur J Cancer

    (2015)
  • J.T. Chang et al.

    Nasopharyngeal carcinoma with cranial nerve palsy: The importance of MRI for radiotherapy

    Int J Radiat Oncol Biol Phys

    (2005)
  • A.W. Lee et al.

    International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma

    Radiother Oncol

    (2018)
  • L. Kong et al.

    Radiation-induced cranial nerve palsy: A cross-sectional study of nasopharyngeal cancer patients after definitive radiotherapy

    Int J Radiat Oncol Biol Phys

    (2011)
  • I. Chatzistefanou et al.

    The role of neck dissection and postoperative adjuvant radiotherapy in CN0 patients with PNI-positive squamous cell carcinoma of the oral cavity

    Oral Oncol

    (2014)
  • J.P. Pignon et al.

    Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients

    Radiother Oncol

    (2009)
  • R.L. Bakst et al.

    Mechanisms of perineural invasion

    J Neurol Surg B Skull Base

    (2016)
  • Z. Gil et al.

    Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves

    J Natl Cancer Inst

    (2010)
  • R.L. Bakst et al.

    Inflammatory monocytes promote perineural invasion via CCL2-mediated recruitment and cathepsin B expression

    Cancer Res

    (2017)
  • S. Deborde et al.

    Schwann cells induce cancer cell dispersion and invasion

    J Clin Invest

    (2016)
  • I.E. Demir et al.

    Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion

    J Natl Cancer Inst

    (2014)
  • K. Akert et al.

    The fine structure of the perineural endothelium

    Cell Tissue Res

    (1976)
  • C. Liebig et al.

    Perineural invasion in cancer: A review of the literature

    Cancer

    (2009)
  • J.G. Batsakis

    Nerves and neurotropic carcinomas

    Ann Otol Rhinol Laryngol

    (1985)
  • M. Dunn et al.

    Perineural invasion: Identification, significance, and a standardized definition

    Dermatol Surg

    (2009)
  • Z. Gil et al.

    Patterns and incidence of neural invasion in patients with cancers of the paranasal sinuses

    Arch Otolaryngol Head Neck Surg

    (2009)
  • S.B. Chinn et al.

    Impact of perineural invasion in the pathologically n0 neck in oral cavity squamous cell carcinoma

    Otolaryngol Head Neck Surg

    (2013)
  • J.J. Fagan et al.

    Perineural invasion in squamous cell carcinoma of the head and neck

    Arch Otolaryngol Head Neck Surg

    (1998)
  • K.C. Soo et al.

    Prognostic implications of perineural spread in squamous carcinomas of the head and neck

    Laryngoscope

    (1986)
  • P. Baumeister et al.

    Is perineural invasion of head and neck squamous cell carcinomas linked to tobacco consumption?

    Otolaryngol Head Neck Surg

    (2018)
  • R.W. Hinerman et al.

    Postoperative irradiation for squamous cell carcinoma of the oral cavity: 35-year experience

    Head Neck

    (2004)
  • K.A. Kurtz et al.

    Perineural and vascular invasion in oral cavity squamous carcinoma: Increased incidence on re-review of slides and by using immunohistochemical enhancement

    Arch Pathol Lab Med

    (2005)
  • G.D. Dodd et al.

    Radiographic findings in adenoid cystic carcinoma of the head and neck

    Ann Otol Rhinology Laryngol

    (1972)

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