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SANDRO V. PORCEDDU
A review by Alam and Ratner reported that the risk for local
recurrence and metastases for cSCC increases in the presence
of factors such as rapid growth, greater than 2 cm
diameter, primary site of lip or ear, immunosuppression,
previous RT, recurrence, greater than 4 mm thickness or
Clark level IV, poor differentiation, infıltrative or peripheral
margins, spindle or acantholytic features, and perineural invasion
(PNI). 2
Brantsch et al published the results of a prospective study
assessing the risk factors for recurrence and regional metastases
in cSCC. They reported that patients with a tumor
thickness of 2.0 mm or smaller did not develop metastases.
Metastases occurred at a rate of 4% among patients with tumors
between 2.1 to 6.0 mm and 16% for tumors larger than
6.0 mm. The risk for local recurrence depended on increasing
tumor thickness and desmoplasia. 5
The National Comprehensive Cancer Network (NCCN)
has produced a table detailing high- and low-risk factors for
recurrence of BCC and cSCC based on a combination of
available evidence and workshop group consensus. 6
Clayman et al identifıed several factors that reduce diseasespecifıc
survival (DSS) in patients with cSCC. These factors
include local recurrence at presentation, increasing tumor
size and depth, invasion beyond subcutaneous tissues, and
PNI. Patients with one or more risk factors, when compared
with patients with no risk factors, had a signifıcantly inferior
3-year DSS of 70% vs. 100%, respectively (p 0.001, log-rank
test). 7
PNI, immunosuppression, and regional nodal involvement
are well-recognized prognostic risk factors for LRC and
distant relapse, and are discussed in greater detail below.
Table 1 summarizes the commonly accepted prognostic
risk factors in NMSC of the head and neck.
KEY POINTS
Non-melanoma skin cancer (NMSC) is the most common
cancer worldwide. Approximately 75% to 80% of cases
are basal cell carcinoma and 20% to 25% of cases are
cutaneous squamous cell carcinoma.
Division into low- and high-risk NMSC is somewhat arbitrary
since disease type falls on a continuous spectrum, as data
from retrospective series have shown.
Approximately 5% of patients with NMSC (mainly
cutaneous squamous cell carcinoma) are considered to be
at high risk for relapse, either local, regional, or distant
(rarely), following surgery.
Because of the dearth of high-level evidence on the
benefits of adjuvant radiation therapy (RT), there is a lack
of universally adopted guidelines regarding its use. Use of
adjuvant RT is commonly based on individual institutional
policy.
Retrospective series support consideration of adjuvant RT
in the presence of advanced primary disease (stages T3-
T4), regional nodal involvement, clinical perineural invasion
(cPNI) and immunosuppression.
TABLE 1. Prognostic Risk Factors for Relapse of
NMSC of the Head and Neck
Risk Factors Low Risk High Risk
Tumor size and T-stage 2cm 2cm
(AJCC/UICC)
T1-2 Stages T3-T4
Tumor thickness (SCC) 2mm 2mm
Clark level 4
Sites
Lip, mask areas of face
Differentiation Well Poor
Subtype (SCC)
Basosquamous,
desmoplastic,
adenosquamous
Perineural invasion Absent or single
small nerve
Multifocal small nerve,
named nerve
Rapid growth Absent Present
Borders Well-defined Poorly defined, in-transit
Lymphovascular space Absent Present
invasion
Margin status Negative Positive
Immune status
Immunosuppressed
Chronic inflammation, Absent Present
scars (SCC)
Previous radiation therapy Absent Present
Nevoid basal cell carcinoma Present Absent
syndrome* (BCC)
Recurrent disease No Yes
Abbreviations: NMSC, non-melanoma skin cancer; AJCC, American Joint Committee on
Cancer; UICC, Union for International Cancer Control; SCC, squamous cell carcinoma; BCC,
basal cell carcinoma.
*Also known as Gorlin syndrome.
Perineural Invasion
PNI can be divided into two categories: (1) disease detected
incidentally on pathologic assessment (pPNI) and (2) involving
a named nerve (cPNI). For patients with cPNI, a prior
history of pPNI is not always present.
PNI is more frequently seen in patients with cSCC (5% to
10%) than in patients with BCC (2% to 5%). 8,9 In the case of
cPNI, the Trigeminal (V) and Facial (VII) cranial nerves
(CN) are commonly affected, typically involving retrograde
progression (progression of disease from the periphery
(skin) toward the brain/brainstem). Diagnosis may be delayed
with VII CN involvement because of an initial misdiagnosis
of Bell’s palsy. Diagnosis can be facilitated with the
use of targeted 3 Tesla MRI neurography, which provides superior
sensitivity and specifıcity compared with computed
tomography (CT). 10
There is some evidence that extratumoral disease (PNI
seen extending beyond the main tumor mass), large nerve
diameter involvement, and multifocal PNI are associated
with more aggressive disease behavior. 8,11
cPNI is more aggressive when seen in cSCC compared with
BCC. Jackson et al reported 5-year local control (LC) rates of
90% for pPNI compared with 57% for cPNI (p 0.0001). The
pPNI and cPNI groups also differed in relapse-free survival
(76% vs. 46%, p 0.003), DSS (90% vs. 76%, p 0.002), and
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