Timothy A. Warren

Perineural Invasion of Head and Neck Skin Cancer: Diagnostic and Therapeutic Implications

Perineural invasion of head and neck skin cancer is a poorly understood and often misdiagnosed pathological entity. Incidental or microscopic perineural invasion is identified by the pathologist and often leads to confusion as to how the patient should be further treated. The less common but more aggressive clinical perineural spread presents with a clinical deficit, which is too commonly misinterpreted by the clinician. This review will try to clarify the terminology that exists in the literature and explore the mechanisms of invasion and spread. It will look at the recent advances in diagnosis and comment on the limitations inherent in current classification schemes. A review of outcomes will be included and current treatment strategies utilized discussed.

Outcomes after surgery and postoperative radiotherapy for perineural spread of head and neck cutaneous squamous cell carcinoma

Queensland, Australia, has the highest rates of cutaneous squamous cell carcinoma (SCC). Perineural invasion (PNI) is associated with reduced local control and survival.

Histopathological features of clinical perineural invasion of cutaneous squamous cell carcinoma of the head and neck and the potential implications for treatment.

Nonmelanoma skin cancer (NMSC) with perineural invasion (PNI) is most commonly seen in cutaneous squamous cell carcinoma of the head and neck (SCCHN). The cranial nerves are a conduit for skin cancer to reach the brainstem.

The natural history and treatment outcomes of perineural spread of malignancy within the head and neck

Understanding the natural history of diseases enables the clinician to better diagnose and treat their patients. Perineural spread of head and neck cancers are poorly understood and often diagnosis is delayed resulting in poorer outcomes and more debilitating treatments. This article reviews a large personal series of head and neck malignancy presenting with perineural spread along almost exclusively the trigeminal and/or facial nerves. A detailed analysis of squamous cell carcinoma of cutaneous origin is presented including an analysis of likely primaries, which most often have occurred months to years prior. The importance of early detection is reinforced by the highly significant (p < 0.0001) differences in disease specific survival, which occur, depending on how far along a cranial nerve the disease has been allowed to spread.

Defining incidental perineural invasion: the need for a national registry

This article by the Perineural Invasion (PNI) Registry Group aims to clarify clinical and histopathological ambiguities surrounding PNI in non‐melanoma skin cancer (NMSC). PNI is reportedly present in approximately 2–6% of cases of NMSC and is associated with greater rates of morbidity and mortality. The distinction between clinical PNI and incidental PNI is somewhat unclear, especially in regard to management and prognosis. One important objective of the PNI Registry is to develop a standardised method of classifying perineural invasion. Hence, in this article we propose a definition for PNI and for its sub‐classification. This article also provides a critical analysis of the current literature on the treatment of incidental PNI by evaluating the key cohort studies that have investigated the use of surgery or radiotherapy in the management of incidental PNI. At present, there are no universal clinical guidelines that specify the acceptable treatment of NMSC exhibiting incidental PNI. Consequently, patients often receive surgery with varying wider margins, or radiotherapy despite the limited evidence substantiating such management options. It is evident from the existing literature that current opinion is divided over the benefit of adjuvant radiotherapy. Certain prognostic factors have been proposed, such as the size and depth of tumour invasion, nerve diameter, the presence of multifocal PNI and the type of tumour. The PNI Registry is a web‐based registry that has been developed to assist in attaining further data pertaining to incidental PNI in NMSC. It is envisaged that this information will provide the foundation for identifying and defining best practice in managing incidental PNI.

Insight into the epidemiology of cutaneous squamous cell carcinoma with perineural spread

Background Perineural spread (PNS) of cutaneous squamous cell carcinoma of the head and neck (SCCHN) can be associated with poor outcomes. Disease understanding and awareness is limited leading to delayed diagnosis and treatment. The purpose of this study was to identify epidemiological features of patients with PNS of cutaneous SCCHN. Methods Tumor characteristics and demographics of patients with PNS of cutaneous SCCHN managed through a single institution were collected between 1998 and 2013. Results One hundred twenty patients were included in this study. The majority had a history of skin cancer (85.8%). The median time from primary tumor treatment to PNS symptom onset was 16 months (range, 1–86 months). A total of 34.2% had no perineural invasion (PNI) detected in the primary, and 22.5% had no known primary tumor. Only 5.8% of the patients had nodal involvement at presentation. Conclusion Patients can present with PNS from cutaneous SCCHN with no known primary tumor or with primary tumors without PNI. The majority of patients presented without regional nodal involvement.

Expression profiling of cutaneous squamous cell carcinoma with perineural invasion implicates the p53 pathway in the process

Squamous cell carcinoma (SCC) is the second most common cancer worldwide and accounts for approximately 30% of all keratinocyte cancers. The vast majority of cutaneous SCCs of the head and neck (cSCCHN) are readily curable with surgery and/or radiotherapy unless high-risk features are present. Perineural invasion (PNI) is recognized as one of these high-risk features. The molecular changes during clinical PNI in cSCCHN have not been previously investigated. In this study, we assessed the global gene expression differences between cSCCHN with or without incidental or clinical PNI. The results of the analysis showed signatures of gene expression representative of activation of p53 in tumors with PNI compared to tumors without, amongst other alterations. Immunohistochemical staining of p53 showed cSCCHN with clinical PNI to be more likely to exhibit a diffuse over-expression pattern, with no tumors showing normal p53 staining. DNA sequencing of cSCCHN samples with clinical PNI showed no difference in mutation number or position with samples without PNI, however a significant difference was observed in regulators of p53 degradation, stability and activity. Our results therefore suggest that cSCCHN with clinical PNI may be more likely to contain alterations in the p53 pathway, compared to cSCCHN without PNI.

The fallacy of skip lesions as an example of misinterpretations being propagated in the scientific literature

We read the recent article by Mendenhall et al. on ‘‘Cutaneous head and neck basal and squamous cell carcinoma with perineural invasion’’ and were disappointed to see once again a misconception on skip lesions continued to be propagated in the literature. The authors are reported to be ‘‘members of the International Head and Neck Scientific Group’’ and as such have a duty to ensure the references relied upon to write their summary article are based on fact and proper scientific interpretation. These summary articles on rare pathologies form the basis for practice and so the evidence needs to be thoroughly reviewed and reported. We have not detected skip lesions in any of our cases of clinical perineural invasion of cutaneous skin cancer treated with surgical resection (i.e. resectable disease extending up to and including ganglia) and so became curious as to the origins of skip lesions. We have performed a thorough literature search covering several electronic databases using a wide search pattern for all English articles discussing skip lesions in perineural invasion and spread of skin cancer. In 1967 Rodin et al. described the possibility of skip areas if perineural lymphatics were the source of perineural tumour, yet perineural lymphatics were then disproved. In 1982 Cottel, a Mohs surgeon also discussed the concept of ‘‘skip’’ areas: ‘‘areas in the nerve where no tumour is present’’. Cottel’s point was that these areas are apparent only and could be missed if Moh’s surgery was not utilised in analyzing excised specimens and used the inverted commas around the word skip to emphasis it was not real. He was comparing normal frozen section histological methods (vertical) with Moh’s methods (horizontal) stating ‘‘only by examining the entire undersurface of the surgical specimen by horizontal frozen section can small involved nerve fibres be detected’’. Hanke et al. the following year quoted Cottel’s ‘‘skip areas’’ and went on to define it as ‘‘areas in the nerve that are observed microscopically to be free of tumour when there is still tumour present in the more proximal portion of the nerve’’. Hanke et al also stated that ‘‘we have observed skip areas’’ and ‘‘whenever we observe perineural basal-cell carcinoma, we always remove at least one Mohs surgical stage beyond the point where sections are free of tumour’’. No evidence of skip lesions were given and one extra Moh’s stage suggests a further 1–1.5 mm would take care of any theoretical skip areas. Following this, more reports predominantly from Mohs chemosurgery case series attested to the presence of ‘‘skip’’ areas, including, Lawrence and Cottel, Dzubow, Birkby and Whitaker, and Ratner et al. One article cites a case from the well known series by Ballantyne et al. as evidence of skip lesions occurring up to 14 cm away from the primary tumour. However, the original paper only describes continuous perineural tumour growth and

Pictorial review: Vascular anomalies of the head and neck

Vascular anomalies encompass a broad spectrum of tumours and malformations as classified by the International Society for the Study of Vascular Anomalies. Despite being one of the most common congenital abnormalities, they are often misunderstood in clinical practice: use of the term ‘haemangioma’ to denote any vascular anomaly still occurs. They are found frequently in the head and neck, often as complex lesions that require multidisciplinary management which necessitates an accurate diagnosis. Precise radiological assessment is therefore crucial. This pictorial review will briefly discuss the current classification system of vascular anomalies and the optimal radiological tools for their evaluation.

Managing perineural and skull base involvement

Australia is recognized as the non-melanoma skin cancer (NMSC) capital of the world with approximately 300,000 cases diagnosed annually [1]. NMSC with perineural invasion (PNI) is an aggressive feature, which carries a worse prognosis through higher rates of locoregional recurrence and reduced survival [2–5]. NMSC with PNI has been shown to be associated with a disease-specific survival at 3 years of 64 %, compared to NMSC without PNI of 91 % [6].