REVIEWS

High-risk cutaneous squamous cell carcinoma

and the emerging role of sentinel
lymph node biopsy: A literature review
Cristi
an Navarrete-Dechent, MD,a Michael J. Veness, MD,d,e Nicol
as Droppelmann, MD,b,c
and Pablo Uribe, MD, PhDa,c
Santiago, Chile, and Sydney, Australia

See related works on pages 120 and 165

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the world. A
minority of patients will be given a diagnosis of a high-risk cSCC (HRcSCC) and a proportion of these will
have a poor outcome. HRcSCC is characterized by an increase in aggressiveness manifested as locoregional
recurrence, and occasionally death. The utility of sentinel lymph node biopsy in this group of patients is
unclear without high-level evidence or clear-cut recommendations. If clinicians accept a cutoff threshold of
10% risk of harboring occult nodal metastasis, then a selected group of patients with HRcSCC may benefit
from sentinel lymph node biopsy. We performed a review of the currently available evidence, in the form
of systematic reviews, meta-analysis, trials, and case series and analyzed the features that define a HRcSCC
and the feasibility of performing sentinel lymph node biopsy in this group of patients. ( J Am Acad
Dermatol 2015;73:127-37.)

Key words: high risk; lymph node; metastasis; nonmelanoma skin cancer; review; sentinel lymph node
biopsy; squamous cell carcinoma.

C utaneous squamous cell carcinoma (cSCC)

originates from keratinizing cells of the
epidermis or its appendages.1 Lesions can
be locally invasive and have the potential to metas-
Abbreviations used:
AJCC:

AJCC-7:
American Joint Committee on
Cancer
American Joint Committee on
tasize to regional lymph nodes, or rarely to distant Cancer Cancer Staging Manual,
organs. cSCC represents approximately 20% of all 7th Edition
cSCC: cutaneous squamous cell carcinoma
nonmelanoma skin cancers, ranking second in GROINSS-V: Groningen International Study on
frequency after basal cell carcinoma, but is the Sentinal Nodes in Vulvar Cancer
leading cause of death.2 Mortality from cSCC is often HNCSCC: head and neck cutaneous squamous
cell carcinoma
as a result of uncontrolled regional disease.3 HRcSCC: high-risk cutaneous squamous cell
Incidence of cSCC varies and is influenced by carcinoma
geographic location, with higher rates at lower NCCN: National Comprehensive Cancer
latitudes4 and a lifetime risk of 9% to 14% among Network
OTR: organ transplant recipients
men and 4% to 9% among women.2 This lifetime risk is SCC: squamous cell carcinoma
increasing worldwide4-6 with an increasing incidence SLN: sentinel lymph node
of 50% to 300% in the last 3 decades7 and 250,000 SLNB: sentinel lymph node biopsy
cSCCs diagnosed annually in the United States.8

From the Department of Dermatology,a Department of Surgical Reprint requests: Pablo Uribe, MD, PhD, Department of
Oncology,b and Melanoma and Skin Cancer Unit,c Facultad de Dermatology, Facultad de Medicina, Pontificia Universidad
Medicina, Pontificia Universidad Cat

olica de Chile; Department Cat
olica de Chile, 4686 Vicu~na Mackenna Avenue, First Floor,
of Radiation Oncology, Westmead Hospital, Westmead, Syd- Macul, Santiago, Chile. E-mail: puribeg@med.puc.cl.
neyd; and Faculty of Medicine, Sydney University.e 0190-9622/$36.00
Funding sources: None. Ó 2015 by the American Academy of Dermatology, Inc.
Conflicts of interest: None declared. http://dx.doi.org/10.1016/j.jaad.2015.03.039
Accepted for publication March 20, 2015.

127
128 Navarrete-Dechent et al J AM ACAD DERMATOL
JULY 2015

HIGH-RISK cSCC patients with chronic lymphocytic leukemia, report-

The majority of patients with cSCC have a ing a 2-year local recurrence rate of 15.2% from
favorable prognosis and are cured by excision or diagnosis. These patients had an estimated 3-year
local destructive therapies.2,8-10 In the setting of cause-specific survival of 65% for the entire cohort,
nodal metastasis, 5-year survival decreases to which decreased to 53% with nodal metastases.23
approximately 50% to 70% after regional surgery These 2 clinical scenarios (OTR and chronic
and adjuvant radiotherapy.11,12 lymphocytic leukemia) highlight the poor outcome
High-risk cSCC (HRcSCC) of immunosuppressed pa-
is characterized by aggres- tients with HRcSCC.
sive biologic behavior and CAPSULE SUMMARY Moreover, when they
increased risk of developing develop nodal metastases
locoregional recurrence and
d Most patients with squamous cell
many often have unfavorable
occasionally distant metasta- carcinoma have a favorable prognosis;
features such as multiple
ses. In this subset of patients however, high-risk squamous cell
lymph nodes involved, extra-
local recurrence ranges from carcinoma is associated with aggressive
nodal spread, and close mar-
10% to 47.2%, with the rate of clinical behavior and higher morbidity/
gins, and have a mortality
mortality.
regional and distant metasta- risk of more than 50%.24
ses ranging from 11% to d The extent of regional nodal Another factor associated
47.3%,13 depending on the involvement is an important prognostic with an increased risk of
interplay of patient-, tumor-, factor for survival. nodal metastasis not
and treatment-related fac- d Sentinel lymph node biopsy may identify included in AJCC-7 is recur-
tors. One study identified a occult nodal metastases in patients at rence.25 Recurrent lesions
high-risk group of patients risk. are often larger, more likely
with lesions 4 cm or larger, to display high-risk features,
presence of perineural inva- and involve subcutaneous
sion, and deep invasion beyond subcutaneous tissues, in contrast to primary cSCC.14
structures. Three-year disease-specific survival was Finally, lymphovascular invasion is also a poten-
100% for patients without risk factors versus 70% for tial risk factor for developing nodal metastasis.
patients with any of these 3 risk factors.14 Brougham et al26 reported a hazard ratio of 8.03 on
Despite this, the definition of a HRcSCC is broad univariate analysis (not statistically significant on
and often not clearly defined.15-17 Numerous studies multivariate analysis).
have documented high-risk factors associated with It is noteworthy that the AJCC-7 does not include
poor outcomes (Table I).8-10,13,15,17-19 other factors often considered as high risk, especially
Based on a combination of consensus and low host-associated factors, in contrast to the National
level evidence, the American Joint Committee on Comprehensive Cancer Network Clinical Practice
Cancer (AJCC) Cancer Staging Manual, 7th Edition Guidelines in Oncology (NCCN Guidelines)
(AJCC-7), identified 5 high-risk features.20 Patients (Table II). In a study that included 269 cases of
with 2 or more high-risk features were categorized as cSCC, the authors classified 13.9% as T2 using the
a T2 primary irrespective of size. Patients with lesions AJCC-7 criteria; in contrast, using the National
larger than 2 cm were considered T2 independently Comprehensive Cancer Network (NCCN) criteria,
of other risk factors. The majority of patients who 87% of these lesions (231 tumors) were classified as
develop nodal metastasis belong within this T2 high risk: These data highlight the lack of consensus
subgroup. Immunosuppression was acknowledged in defining HRcSCC.27
as being associated with a worse outcome but does cSCC metastasize via lymphatic vessel spread28,29
not currently alter staging. with the extent of regional nodal involvement an
The risk of developing aggressive cSCC is important prognostic factor as survival decreases
increased in solid organ transplant recipients with increasing nodal size and number of involved
(OTR).7,19 In a study of 619 cardiac and/or lung nodes.3,14,30 Therefore, it is possible that early
OTR, 19 developed an ‘‘aggressive cutaneous malig- detection of subclinical (or occult) nodal disease
nancy’’; 8 died (42%) with a mean follow-up time of could lead to fewer deaths from cSCC31 as opposed
21
20 months. Eleven were alive but 5 had ‘‘disease to watching and waiting for clinicoradiologic nodal
present.’’21 In another study, the 3-year disease- involvement.32 In a study of patients with metastatic
specific survival was 26.5% in OTR cases that cSCC to the parotid and/or cervical lymph nodes
developed metastatic cSCC.22 Tomaszewski et al23 who underwent neck dissection, 35% of patients
evaluated the aggressive behavior of cSCC in 34 with a clinically negative neck dissection had
J AM ACAD DERMATOL Navarrete-Dechent et al 129
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Table I. Summary of high-risk features and clinical implications

Factors* Rate of local recurrencey; relative risk (RR) Rate of metastasisz; relative risk or hazard risk
Size: [2 cm 15.2%; RR = 2 30.3%-42.5%; RR = 3
Depth: Breslow [2-4 mmx or Clark IV, V 17.2%; RR = 2 4.0%-45.7%; RR = 5
Recurrent tumor 10%-27.5%; RR = 3k 16.3%-45%; RR = 4
Poorly differentiated in histology 28.6%; RR = 2 32.8%-57.9%; RR = 3
Perineural invasion{ 47.2%; RR = 5 15%-50%; RR = 5
Site:
Lip 10.5%; RR = 2 13.7%; RR = 4
External ear 18.7%-53%; RR = 2 11%; RR = 3
Lymphovascular invasion# — 40%; RR = 7
Histologic subtype (mainly desmoplastic) 24% Desmoplastic; RR = 16 21.4%-44.4% Desmoplastic; RR = 3
Incomplete excision 50%; — —
De novo cSCC** — 20%-38%; —
Immunosuppression:
Solid organ transplantationyy 13%-39%; — 8%-12.9%;—
CLL 15% 14%

Data collected and modified from Rowe et al,25 Alam and Ratner,2 Nun ~o-Gonz
alez et al,15 Brantsch et al,9 Martorell-Calatayud et al,17 Veness
16,32
et al, Ross and Schmults, Tomaszewski et al, and Brougham and Tan.7
31 23

CLL, Chronic lymphocytic leukemia; cSCC, cutaneous squamous cell carcinoma; RR, relative risk or hazard risk.
*These numbers are not comparable as they originate from different trials and populations and are not adjusted. They are just a reference.
**De novo cSCC are tumors that arise from chronic inflammatory processes: burn scars (Marjolin ulcer), cutaneous lupus erythematosus, and
erythema ab igne, among others.
y
Recurrence rate varies among series and with different treatments and they are not uniformly stated in case series and trials. Follow-up
time also influences the recurrence rate.
z
Metastasis is sometimes defined as distant metastasis and sometimes as lymphatic metastasis. There is not uniformity among trials.
Follow-up time also influences the recurrence rate.
x
Some authors consider the 2-mm cutoff (recent publications) and others the 4-mm cutoff (older publications).
k
Risk of developing a second recurrence is increased in recurrent tumors.
{
Approximately 5%-10% of cSCC spread with perineural invasion. Usually invasion affecting nerves [0.1 mm in diameter is associated with
metastasis.
#
Evidence is of low quality for this group.
yy
This is a heterogeneous group as the risk is not the same for heart, kidney, and liver transplantation. In general, aggressive cSCC occurs in
heart/lung, kidney, and liver transplant recipients, in descending order.19

pathologically involved nodes.3 Although identi- site (only cSCC) and included articles in English and
fying patients with a clinically N0 neck who may Spanish. We excluded single case reports and cases
have microscopic involvement would allow appro- located on the anogenital area and oral cavity. We
priate regional treatment and reduce the risk of nodal included the hair-bearing lip area.
relapse, current investigations (mainly radiologic)
add little to the clinical examination, having a THE LOGIC BEHIND SLNB FOR HRcSCC
relatively low sensitivity for identifying subclinically A meta-analysis (19 articles)38 documented micro-
involved lymph nodes.16,33 Sentinel lymph node scopic nodal metastases detected by SLNB in 12.3% of
(SLN) biopsy (SLNB) provides a minimally invasive patients with a false-negative rate of 2.6%. The
analysis of the nodal basin when there is not clinical authors highlighted the ambiguity of the term
or radiological suspicion of involved lymph nodes. ‘‘high-risk’’ and undertook a comparative analysis:
SLNB is routinely performed in cutaneous firstly, by using the AJCC-7 criteria and then an
melanoma34,35 and breast cancer.36,37 alternative TNM system (also known as Brigham
and Women’s Hospital system) proposed by
SEARCH STRATEGY Jambusaria-Pahlajani et al.39 The last one is based
We searched MEDLINE database for articles on risk factors found to predict more than 1 negative
published through November 25, 2014, using the outcome on multivariate analysis (Table III). Using
key words: ‘‘squamous’’ or ‘‘nonmelanoma’’ or the AJCC-7 criteria, 11.2% had positive SLN within T2
‘‘non-melanoma’’ or ‘‘squamous cell carcinoma’’ cSCC and 60% in patients within T4 tumors. All
AND ‘‘cutaneous’’ or ‘‘skin’’ AND ‘‘sentinel lymph patients with positive SLN had cSCC larger than 2
node.’’ References within retrieved articles were also cm in diameter. Using the alternative TNM system no
reviewed to identify potentially missed studies. We cases (0 of 9 patients) of a positive SLN were
included all studies published to date, irrespective of documented in T1 primary (0 risk factors), 7.1% in
130 Navarrete-Dechent et al J AM ACAD DERMATOL
JULY 2015

Table II. List of NCCN high-risk features regional metastasis in a previously negatively
NCCN high-risk factors, only 1 risk factor is needed to classify cSCC
mapped nodal basin.
as high risk Another systematic review reported a 21% rate for
Clinical a positive SLNB, in 85 nonanogenital cSCC with 1
Size by anatomic location false-negative result.31
Area medium risk (forehead, scalp, cheek, neck) $10 mm*
Area high risk (‘‘mask area’’; central aspect of face, SYSTEMATIC REVIEW RESULTS
ears, periauricular) $6 mm* The search yielded 156 articles that were manually
Area low risk $20 mm* reviewed. Sixteen met the inclusion criteria. One was
Poorly defined borders excluded (single case report). A review of all
Recurrent case series reporting SLNB in cSCC is detailed in
Immunosuppression
Table IV.13,18,28,41-52
Site of prior radiotherapy or chronic inflammatory
Our systematic review identified an overall
process
Rapidly growing tumor positive rate for SLNB of 13.9% (32 of 231 patients)
Neurologic symptoms and a false-negative rate of 4.6% (10 of 215 patients)
Pathology in cSCC. The authors usually stated that patients had
Moderately or poorly differentiatedy histology high-risk factors for lymph node involvement.
Acantholytic, adenosquamous, or desmoplastic subtypes However, these high-risk factors were not homoge-
Depth: $2 mmy or Clark levels IV, Vy neous and not always adequately detailed.
Perineuraly or vascular involvement Tumor characteristics of SLNB-positive cSCC were
available in 26 of 35 patients. Documented tumor
Adapted with permission from the NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines) for Squamous Cell
depth was available in 12 cases, with an average of
Carcinoma V.1.2015. Ó 2014 National Comprehensive Cancer 10.7 mm (range 2.2-19.0 mm). Tumor diameter was
Network, Inc. All rights reserved. The NCCN Guidelines and available in 18 patients, with an average size of 4.6
illustrations herein may not be reproduced in any form for any cm (range 2.3-11.0 cm). Other tumor and patient
purpose without the express written permission of the NCCN. To characteristics were poorly documented.
view the most recent and complete version of the NCCN
Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE
Of interest Fukushima et al47 performed positron
CANCER NETWORKÒ, NCCNÒ, NCCN GUIDELINESÒ, and all other emission tomography/computed tomography or
NCCN Content are trademarks owned by the National ultrasonography on 52 patients before SLNB. Most
Comprehensive Cancer Network, Inc. lesions were located on the head and neck (46.2%),
cSCC, Cutaneous squamous cell carcinoma; NCCN, National or upper (25%) and lower (23%) limbs. In all, 41
Comprehensive Cancer Network.
*Cutoff values for diameter of these lesions were defined from a
patients had negative positron emission tomogra-
cohort of 5755 basal cell carcinomas intended to establish phy/computed tomography-ultrasonography results
recurrence rates in 1991.68,69 with 3 (7.3%) harboring nodal micrometastasis on
y
American Joint Committee on Cancer Cancer Staging Manual, 7th SLNB. Not surprisingly, SLNB was more sensitive
Edition only recognizes these 4 high-risk features in addition to than positron emission tomography/computed
location on the ear or lip.
tomography in detecting occult nodal cSCC47 and,
as stated previously, imaging probably adds very
T2a lesions (1 risk factor), 29.4% in T2b lesions (2-3 little to the staging of a clinically N0 region.
risk factors), and 50% in T3 lesions (4 risk factors or
bone invasion). There was a statistically significant DOES SLNB IMPROVE SURVIVAL AND
difference between the proportion of positive SLN OTHER OUTCOMES IN cSCC?
within T2a and T2b cases (P = .02).38 The authors Takahashi et al46 documented survival in 26
concluded that it would be reasonable to consider patients with HRcSCC with 23.1% (6 of 26) having a
the 2-cm cutoff as an independent risk factor for positive SLNB. This study included patients with
considering SLNB and patients with 2 or more risk external genital squamous cell carcinoma (SCC). The
factors (definition of T2b for the alternative TNM authors reported a 3-year survival 100% for
system) may also warrant SLNB. SLN-negative SCC cases but only 20.8% for
In a systematic review of 11 studies 13.7% of SLN-positive cases. Four patients died during the
patients with a head and neck HRcSCC had a positive follow-up, all having a positive SLNB, 3 of 3 external
SLNB.40 Mean tumor diameter was 4.23 cm and all genital SCC, and 1 of 3 cSCC.46 To our knowledge,
positive SLNB cases were T2 or greater. The this is the only study evaluating long-term outcomes
sensitivity, specificity, and negative predictive and suggests a prognostic role of SLNB for predicting
value were 77%, 100%, and 95.2%, respectively. survival. In a case series, 17 patients underwent SLNB
Interestingly, 3 of 63 patients (4.76%) developed and had 2 or more years follow-up; 6 (35.2%)
J AM ACAD DERMATOL Navarrete-Dechent et al 131
VOLUME 73, NUMBER 1

Table III. Comparison of American Joint Committee on Cancer Cancer Staging Manual, 7th Edition70 staging
system with the alternative tumor-staging system
Alternative tumor staging system
AJCC-7* (Brigham and Women’s Hospital system)y
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor T0 In situ SCC
Tis Carcinoma in situ T1 0 Risk factors
T1 Tumor #2 cm in greatest dimension with \2 high-risk features T2a 1 Risk factor
T2 Tumor [2 cm in greatest dimension or any size with T2b 2-3 Risk factors
$2 high-risk features
T3 Tumor with involvement of maxilla, mandible, orbit, or temporal T3 4 Risk factors or bone invasion
bone
T4 Tumor with invasion of skeleton (axial or appendicular)
or perineural invasion of skull bone

AJCC-7, American Joint Committee on Cancer Cancer Staging Manual, 7th Edition; SCC, squamous cell carcinoma.
*Risk factors included in the AJCC-7: tumor thickness [2 mm, Clark level $IV, location on ear or nonhair-bearing (vermillion) lip, poorly
differentiated histologic finding for the first time, tumor diameter of $2 cm, perineural invasion.
y
Risk factors included in the alternative tumor-staging system: tumor diameter $2 cm, poorly differentiated histologic characteristics,
perineural invasion, tumor invasion beyond the subcutaneous fat (excluding bone invasion, which automatically upgrades tumor to
alternative T3).
Modified from Schmitt et al38 and Jambusaria-Pahlajani et al.39 All rights reserved.

developed either locoregional (n = 3) or distant (n = SLNB was positive for occult metastases in 32% of
3) metastases despite a negative SLNB.52 clinically N0 necks.57
As the available data are limited, extrapolating SLNB has also been proposed as an alternative to
from other malignancies where SLNB is performed the morbidity of bilateral lymphadenectomy in
routinely may aid us in addressing our question vulvar SCC.58 In these patients, the size of the
indirectly, ie, in melanoma, breast cancer, and head sentinel node metastasis was strongly associated
and neck SCC, among others. SLNB in these patients with survival: the Groningen International Study on
has an important staging role and identifies patients Sentinal Nodes in Vulvar Cancer (GROINSS-V) trial
who could benefit from regional treatment. showed that the 5-year disease-specific survival was
The final report evaluating SLNB in melanoma 97% with isolated tumor cells in SLN: 88% for those
reported that in the subgroup of intermediate- with SLN metastasis of 2 mm or less, 70% for those
thickness melanomas (1- to 4-mm thick) the with metastases from 2 to 5 mm, and 69% for those
10-year disease-free survival was improved in with SLN metastases larger than 5 mm.59
the SLNB group in comparison with the nodal The multiple clinical scenarios in which SLNB has
observation group, with 24% less recurrences or been tested demonstrate its usefulness, and although
metastasis. In addition, if the SLN was positive the diverse in biologic behavior, we believe these results
hazard ratio for death from melanoma was 3.09.34 can be partially extrapolated to patients with cSCC.
In breast cancer, a negative SLNB specimen All these patients share a more than 10% risk
is associated with a better overall crude 5-year of developing nodal metastases, a frequently
survival in comparison with survival after a negative encountered scenario in patients with HRcSCC, as
axillary lymph node dissection.53 Moreover, distant discussed below. Larger series and longer follow-up
metastases occurred at a lower rate in the SLNB are needed to demonstrate an improvement in
group in contrast with the lymph node dissection survival documented in only 1 study.46
group (1.1% vs 14.6%).54
SLNB has also has been evaluated in mucosal
head and neck SCC to avoid the morbidity of neck LIMITATIONS, DIFFICULTIES, AND
dissection.55 It improves staging of clinically N0 oral COMPLICATIONS
cavity SCC and the oropharynx by identifying Although SLNB may be prognostic and alter
micrometastasis,55 with a pooled sensitivity of 93% management and outcome, patients with HRcSCC
and negative predictive values from 88% to 100%.56 located on the head and neck (the most frequent
In a study including patients with oral cavity SCC, site of cSCC approximately 75%-90% cases)3,14
there was a trend towards a longer 5-year have some specific difficulties related to this
disease-specific survival (97% for SLNB-negative anatomic site in comparison with trunk and
cases and 85% for SLNB-positive cases; P = .059). extremities.29
Table IV. Summary of case reports and case series evaluating the utility of sentinel lymph node biopsy in high-risk cutaneous squamous cell carcinoma

132 Navarrete-Dechent et al
Characteristics No. of deaths
of positive SLN caused by SCC
False tumors (risk in patients with Type
Author Year Patients, n Inclusion criteria Location Positive SLN negative factors) Follow-up positive SLN of study
Altinyollar 2002 20 (17 male) cSCC of the Lower lip 3/18 (16.6%); 0/18 Not specified N/A N/A Prospective,
et al43 lower lip in 2 Patients, case series
SLN was not
found
Michl 2003 37 NMSC N/A Head and 2/11 (18.1%) 0/11 [2 cm Diameter Mean 30 mo 0/11 (1 Retrospective,
et al42 (11 SCC; neck, trunk, (2/2), poorly for the Patient with case series
7 male) extremities, differentiated (2/2) whole positive SLN
and 2 NMSC is alive with
tumors on group metastases)
genitalia
Reschly 2003 9 (6 male) One of the 9 Head and 4/9 (44.4%) 0/9 Breslow [2 mm Mean 12 mo 2/4 (2 Patients Prospective,
et al44 high-risk neck, (4/4), recurrent with positive case series
criteria (not extremities, (1/4), diameter SLN died of
specified as trunk [2.0 cm (4/4), metastatic
inclusion moderately- cSCC)
criteria) poorly
differentiated
(2/4)
Wagner 2004 24 (17 SCC) [40 mm, Head and 5/17 (29.4%); 1/17 [2 cm Diameter Median N/A Prospective,
et al41 Recurrent neck, 2/12 Excluding (2/12) 11 mo in SLN- case series
tumor, [20 mm extremities, vulvar (16.6%) negative
if immunosup- perineum, cases
pressed, [10 mm and 5 on
in genitalia vulva
Eastman 2004 4 (2 patients Marjolin ulcer Extremities 4/5 (80%; no 0/5 Marjolin ulcers (4/4) N/A 0/4 Prospective,
et al50 with 2 SCC; over burn scar SLN could be case series
total 6 SCC) identified in
1 case)

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J AM ACAD DERMATOL
Nouri 2004 8 (all male) [20 mm, Depth Head and neck 1/8 (12%) 0/8 Not specified 18 mo only 0/1 Prospective,
et al49 [5 mm, Clark for the case series
level $IV, patient with
moderate or positive SLN
poorly
differentiated,
lymphovascular
invasion,
location (lower
lip, ear, or over
burn scars),
recurrent tumor,
or immunosup-
pression
Hatta 2005 14 patients N/A Lower 0/4 0/4 — N/A N/A Prospective,
et al51 (4 cSCC, extremity case series
all male)
Cecchi 2006 10 (6 cSCC, Recurrent tumor Head, 1/6 (16.6%) 0/6 [2 cm (1/1), Median 25 mo 0/1 N/A, case
et al48 4 male) cSCC extremities Recurrent (1/1) in the SLN- series
negative
group
Res
endiz- 2007 20 (12 male) [20 mm and 1 Head and neck, 4/20 (20%) 0/20 [2 cm (4/4), Mean 23.5 1/4; 4 More Prospective,
Colosia of these: extremities, Breslow [2 mm mo (7-44) deaths, 3 case series
et al45 Moderate or and trunk (4/4), poorly unrelated, 1
poorly differentiated of them
differentiated, (2/4) from local
depth [5 mm, progression
Clark level [ of SCC (no
or = IV, nodal
lymphovas- involvement)
cular invasion

Navarrete-Dechent et al 133
Renzi 2007 22 (19 male) HRcSCC defined as Not detailed 1/22 (4.5%) — [2 cm (1/1), Median 17 mo 0/1; 4 Unrelated Prospective,
et al18 any risk criteria Breslow (6-64) deaths case series
reported in the [2 mm (1/1)
literature
Continued
Table IV. Cont’d

134 Navarrete-Dechent et al
Characteristics No. of deaths
of positive SLN caused by SCC
False tumors (risk in patients with Type
Author Year Patients, n Inclusion criteria Location Positive SLN negative factors) Follow-up positive SLN of study
Rastrelli 2010 20 (16 male) [20 mm, Depth Head and neck, 1/20 (5%) 2/20 [2 cm Diameter Median 24 mo 1/1; Another Retrospective,
et al28 [4 mm, extremities, (1/1), [2 mm (1-81) patient died case series
moderate and trunk Breslow (1/1) of gastric
or poorly cancer
differentiated,
perineural
invasion,
recurrent tumor,
aggressive
subtype (eg,
desmoplastic)
Kwon 2011 6 (5 male) All had at least 2 Head, 0/6 — — Median 10.1 mo 0/0; 2/6 Retrospective,
et al13 high-risk factors* extremities, (1.3-15.5) Patients case series
perineum had disease
progression
(not stated
if they died)
Takahashi 2014 26 (11 male) Invasive SCC and Head and neck, 6/26 (23.1%); 0/26 [2 cm Diameter Mean 35.5 mo 4/6; Survival Retrospective,
et al46 at least 1 risk extremities, Excluding (3/3), [2 mm (10-91) was 100% if case series
factor of NCCN trunk, and genitalia Breslow (3/3), the SLN was
Guidelines, external 3/19 (17.5%) poorly negative
V.1.2015 genitalia differentiated
(1/3)
Fukushima 2014 54 (37 male) N/A Head and neck, 4/54 (7.4%); If 1/54 Not specified Mean 33.2 mo N/A Prospective,
et al47 extremities, considering (1.8%) (3.2-97.1) case series
trunk, and only $T2 12.9%
genitalia positive rate

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Lymph nodes are numerous and the lymphatic

*Size $20 mm (trunk/extremities), size $10 mm (head), size $6 mm (face, genitalia, hands/feet); poorly defined borders; recurrent; immunosuppression; moderate or poorly differentiated; rapidly
cSCC, Cutaneous squamous cell carcinoma; HRcSCC, high-risk cutaneous squamous cell carcinoma; N/A, not available; NCCN, National Comprehensive Cancer Network; NMSC, nonmelanoma skin
Retrospective,
case series
drainage is complex, with more than 1 SLN in some

Systematic
review
circumstances. Bilateral or contralateral drainage is
reported in 7% to 10% of patients.60
Difficulties associated with lymphatic mapping of
the head and neck include61: (1) difficulty visualizing
lymphatic channels using lymphoscintigraphy
N/A

because of proximity to the injection site (‘‘shine-

through effect’’); (2) if more than 1 node is visible, it
can be difficult to distinguish first-echelon nodes
from second-echelon nodes (as they are in a very
comparable

small anatomic space); and (3) the SLN may be small

and not easily accessible (eg, in the parotid gland).
$2 cm diameter (1/2); [24 mo

Most metastatic lymph nodes from head and neck

cutaneous squamous cell carcinoma (HNCSCC)
Not

occur in the parotid gland (70%), which is consid-

(35.2%) moderately or poorly

ered the metastatic basin for cSCC of the head and

differentiated (2/2);
tumor site (ear, lip,

thickness $4 mm

neck32 with a theoretical possibility of damage to

non-sun exposed
area; 1/2); tumor

facial and accessory nerves.62 However, data from

or Clark level

the Sunbelt Melanoma Trial identified only 1 tempo-

$4 (1/2)

rary facial nerve injury in 95 SLNB in the parotid

region and no definitive damage.63 The use of
combined radioisotope and dye injection is the
standard for localization of SLNs, improving the
Some studies included only cSCC whereas other included other types of NMSC and SCC other than cutaneous.
(4.6%)

sensitivity of this technique. Immunohistochemistry

10/215

with cytokeratins AE1/AE3 has been proposed to

6/17

improve the detection rate with an unknown role.31

The surgeon’s experience is another potential
32/231 (13.9%)
2/17 (11.7%)

limitation to the accurate identification of SLN, with

data from oral cavity SCC suggesting that a surgeon
requires a case load of at least 10 patients to identify
SLN in more than 90% of cases.64 Morton et al65
estimated that a surgeon requires 30 consecutive
Head and neck,

cases to become skilled with the technique in

lower limbs,
and trunk

cutaneous melanoma and to obtain successful SLN

genitalia
Anywhere
except

identification irrespective of the center case volume

or experience.
cancer; SCC, squamous cell carcinoma; SLN, sentinel lymph node.

Complications of SLNB in melanoma and breast

cancer are generally uncommon, and include allergic
reactions to the blue dye used intraoperatively,28
High-risk factors*

lymphedema,66 wound infection, hematoma, se-

roma, cutaneous lymphatic fistula, and dehiscence.38
In a series of 80 patients undergoing SLNB only 3
Diverse

complications occurred: immediate postoperative

hematoma (2 patients) and seroma.67
growing; and perineural involvement.
2014 17 (13 male)

Conclusion
214 cSCC

Patients with cSCC are at risk of developing nodal

metastasis, death, or both, especially if risk factors are
present. SLNB may identify occult nodal metastases
in patients at risk. Its utility in cSCC is still to be
confirmed because it is considered to be more precise
Total cSCC
et al52

than imaging procedures and less invasive than

Krediet

lymph node dissection and may ultimately emerge

as the gold standard for HRcSCC staging.
136 Navarrete-Dechent et al J AM ACAD DERMATOL
JULY 2015

We encourage clinicians to enroll eligible patients 15. Nu~ no-Gonz
alez A, Vicente-Mart
ın FJ, Pinedo-Moraleda F,
onto clinical trials evaluating SLNB to develop L
opez-Estebaranz JL. High-risk cutaneous squamous cell
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of patient care. Meanwhile, there is some evidence mous cell carcinoma. Australas J Dermatol. 2006;47:28-33.
that supports considering SLNB in cSCC classified 17. Martorell-Calatayud A, Sanmart
ın Jimenez O, Cruz
as AJCC-7 T2 larger than 2 cm diameter or T2b in Mojarrieta J, Guill
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included in clinical trials evaluating the utility of carcinoma: case series and review of the literature. Eur J Surg
SLNB in cSCC. Oncol. 2007;33:364-369.
19. Zwald FO, Brown M. Skin cancer in solid organ transplant
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