Elsevier

Oral Oncology

Volume 98, November 2019, Pages 102-108
Oral Oncology

Setting the stage: Contemporary staging of non-melanomatous skin cancer and implementation of the new American Joint Committee on cancer eighth edition staging manual

https://doi.org/10.1016/j.oraloncology.2019.09.020Get rights and content

Highlights

  • High-quality CT and MR imaging should be performed for all cases of advanced NMSC.

  • PET/CT & SLNB are promising for high-risk cHNSCC but require further investigation.

  • The AJCC8 NMSC system has resulted in significant stage migration compared to AJCC7.

  • AJCC8 offers limited prognostic discrimination between nodal stages & TNM stages.

  • HPV status is more reliable than p16 to determine an occult OPC cancer in a CUP-SCC.

Abstract

Non-melanomatous skin cancer (NMSC) generally refers to basal cell and squamous cell carcinoma of the skin. The majority of patients are curatively treated with simple excision. Only few present with locally advanced disease or have evidence of high-risk features, placing them at an elevated risk of relapse. In such cases, further investigations may guide the multidisciplinary management plan. There are no universally agreed on indications for recommending additional staging investigations, due to a lack of prospective data reporting their impact on patient outcomes. Some generally agreed upon indications are discussed in this review article. Most commonly, computed tomography (CT) and magnetic resonance imaging (MR) are used in cases of locally advanced NMSC for staging purposes and surgical planning. While Positron Emission Tomography (PET)/CT and sentinel lymph node biopsy have shown utility, data is lacking to establish their roles in the staging algorithm. An updated NMSC system was included in The American Joint Committee for Cancer eighth edition staging manual (AJCC8). Under AJCC8 the majority of patients with regional disease are upstaged by the presence of extranodal extension, however, this updated system appears to provide limited prognostic discrimination between the nodal categories and the overall TNM stages. This review article will explore the contemporary role of staging investigations, including evolving technologies, and review the changes implemented in AJCC8. It will also discuss the implications of the AJCC8 decision to assign patients with p16-positive cervical nodal SCC with an unknown primary to the oropharyngeal staging system, with particular relevance to clinicians working in areas of high NMSC incidence.

Introduction

The term non-melanomatous skin cancer (NMSC) includes a range of skin neoplasias, but generally refers to the most common malignancies worldwide; cutaneous basal cell (BCC) and squamous cell carcinomas (cSCC) [1]. Worldwide, Australia has the highest incidence of NMSC as a consequence of high ultraviolet exposure to a predominantly fair-skinned population [2], [3]. BCC’s account for the vast majority, with approximate rates of 884/100,000 and 387/100,000 person years for BCC and cSCC in Australia, respectively [4]. There, the incidence and mortality rates from NMSC have increased over recent decades [5], [6], although this could possibly represent improved reporting in an aging population. The vast majority of NMSC’s occur in the sun-exposed areas of the head and neck region [7], [8]. The standard treatment of localized NMSC is simple surgical excision while obtaining clear surgical margins, which on its own is often curative. Approximately 5% of all cSCC of the head and neck (cHNSCC), will spread to regional lymph nodes, heralding a significant shift in prognosis and treatment-related morbidity [9], [10], [11], [12].

The work-up and staging of patients with NMSC is evolving, although strong evidence is generally lacking. Most NMSC are staged primarily by pathological means at curative excision, and only patients with a suspicion of local extension or nodal disease require further investigation with cross-sectional imaging, for example, where there is suspicion of deep soft tissue or bone involvement or where there are symptoms of perineural spread (PNS) detected [13]. While the term perineural invasion (PNI) typically refers to histopathological evidence of tumour cells within a nerve sheath, radiological evidence is more commonly referred to as PNS, and magnetic resonance imaging (MR) is considered the optimal imaging modality for assessment, while additionally providing the most accurate determination of soft tissue invasion. Computed-tomography (CT) is often utilised where there is suspicion of bone invasion or there is a clinically-positive neck. Emerging staging modalities in cSCC staging include positron-emission tomography/computed-tomography (PET/CT) and sentinel lymph node biopsy (SLNB), although their exact place in the staging schema requires further research [13], [14].

The eight edition of the American Joint Committee for Cancer (AJCC8) manual was released in 2016, with significant changes to the NMSC staging system (Table 1). The most significant changes were to the risk factors used to upstage the T-category of small skin lesions and, for the first time, extranodal extension (ENE) was included, resulting in the vast majority of node-positive cases being upstaged from the 7th edition [1]. A further recommendation was that where there is pathological confirmation of p16-positive SCC in cervical lymph nodes with an unknown primary (CUP-SCC), that patients be staged according to the HPV-associated oropharyngeal cancer (OPC) system. This particular directive poses challenges to clinicians working in areas with a high NMSC prevalence.

The objectives of this article are to review:

  • The indications and utility of contemporary staging investigations in NMSC

  • AJCC8 changes to NMSC staging and its effectiveness in prognostication

  • Challenges in the staging system to clinicians working in areas with a high prevalence of NMSC

Section snippets

Contemporary Work-up and investigation of NMSC

Any lesions suspicious for NMSC should be assessed with a full history and physical examination, including a comprehensive skin examination. A biopsy should be performed on all suspicious lesions to characterise the histological subtype and identify adverse features for risk-stratification. Further investigations can be used more judiciously in advanced cases of NMSC, based on history, examination and pathological findings. These investigations include ultrasound (US), CT, MR, PET/CT and SLNB.

Role and evidence for use of PET/CT

FDG PET/CT has a well-established role in mucosal head and neck SCC (mHNSCC), allowing for identification of occult primaries [30], nodal and systemic staging [31], therapy response [32] and detection of second primary malignancies. While cSCC is also highly FDG avid [33] (Fig. 1), the evidence base in the NMSC setting is sparse, and its application has largely been extrapolated from the mHNSCC experience [17], [34].

A Japanese group recently reported the utility of FDG PET/CT in 26 patients

Role of SLNB in the clinically N0 neck

SLNB an emerging modality in cSCC [40]. The sentinel lymph node (SLN) is theoretically the most likely location for occult metastases in the cN0 neck [41], and identification of subclinical metastases by SLNB may help to guide management. However, the anatomy of the head and neck region, with its unpredictable superficial lymphatic drainage, variable watershed lymphatics, multiple lymph node basins and complex neurovascular structures, creates challenges for the use of SLNB in this region [42],

Imaging to assess treatment response

There are no standardised imaging surveillance protocols following treatment. The NCCN for example suggest simply history and examination following definitive management of both cSCC and BCC [13], [14]. A baseline MRI three months after treatment may be useful for follow up in cases of PNI treated with curative intent. Depending on the level of concern for recurrence (surgical margins, zonal classification of disease at surgery), MRI scans can then be performed at six monthly intervals for

Changes in the American Joint Committee on cancer 8th edition staging system for cutaneous squamous cell carcinoma

Although there are a number of staging systems in use for cSCC, including the BWH system, the most commonly used is the AJCC TNM classification. The recently revised AJCC8 cSCC staging system, which applies to all NMSC lesions of the head and neck (only Merkel cell carcinoma has its own staging system), incorporated a number of changes to both the T- and N-categories (Table 1) [18]. The prognostic value of these changes has been questioned in a number of recent publications. A major drawback in

Implications of the new staging system for p16 + carcinoma unknown primary cancers in regions with a high prevalence of NMSC

With contemporary diagnostic protocols, patients with true squamous cell carcinoma of unknown primary in the head and neck (CUP-HNSCC) are an infrequent occurrence, accounting for approximately 1–3% of all new head and neck presentations [63]. Determination of the putative candidate sites may be aided by consideration of clinical (age, sun exposure, smoking history, other dermatologic history), radiological (nodal location) and pathological factors (basaloid histology) [64]. Although

Summary/conclusion

Although high quality data is lacking, staging investigations in high-risk NMSC may aid the multidisciplinary team in treatment planning. The introduction of the new AJCC8 staging system for NMSC has not improved prognostication, particularly where the nodal category is concerned. Further research to assess the utility of staging investigations and to improve risk stratification is needed. cHNSCC regional metastases are p16-positive in approximately one-third of cases, and in settings of high

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors declared that there is no conflict of interest.

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