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CLINICAL REVIEW

Mark K. Wax, MD, Section Editor

CUTANEOUS HEAD AND NECK SQUAMOUS CELL CARCINOMA


METASTATIC TO PAROTID AND CERVICAL LYMPH NODES
Michael J. Veness, MMed (Clin Epi), FRANZCR,1 Sandro Porceddu, FRANZCR,2
Carsten E. Palme, FRACS,1 Gary J. Morgan, FRACDS, FRACS1
1
Head and Neck Cancer Service, Westmead Hospital, University of Sydney, New South Wales, Australia.
E-mail: michael@radonc.wsahs.nsw.gov.au
2
Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia

Accepted 7 October 2006


Published online 17 January 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20576

gating the role of molecular factors such as the epidermal


Abstract: Nonmelanoma skin cancers occur at an epidemic rate
growth factor receptor. VC 2007 Wiley Periodicals, Inc. Head
in Australia and are increasing in incidence worldwide. In most
Neck 29: 621–631, 2007
patients, local treatment is curative. However, a subset of
patients will be diagnosed with a high-risk cutaneous squamous Keywords: cutaneous squamous cell carcinoma; nodal metas-
cell carcinoma (SCC) and are defined as patients at increased tases; radiotherapy; surgery
risk of developing metastases to regional lymph nodes. Patients
with high-risk SCC may be identified based on primary lesion
and patient factors. Most cutaneous SCC arises on the sun- Nonmelanoma skin cancer (NMSC) is the most
exposed head and neck. The parotid and upper cervical nodes common malignancy worldwide and a conse-
are common sites for the development of metastases arising
quence of chronic exposure to the mutagenic and
from ear, anterior scalp, temple/forehead, or scalp SCC. The
mortality and morbidity associated with high-risk cutaneous SCC immunosuppressive effects of solar ultraviolet
is usually a consequence of uncontrolled metastatic nodal dis- radiation.1 Men are overrepresented secondary to
ease and, to a lesser extent, distant metastases. Patients with occupational sun exposure. Most patients (75% to
operable nodal disease have traditionally been recommended 80%) diagnosed with NMSC will have a small
for surgery. The efficacy of adjuvant radiotherapy has previously
(<2 cm) basal cell carcinoma (BCC) that is easily
been questioned based on weak evidence in the early literature.
Recent evidence from larger studies has, however, strength- treatable, with a high probability of local control
ened the case for adjuvant radiotherapy as a means to improve (90% to 95%). Death from a BCC is rare, although
locoregional control and survival. Despite this, many patients still local morbidity can be significant in advanced cases.
experience relapse and die. Research aimed at improving out- The sun-exposed head and neck is the most common
come such as a randomized trial incorporating the addition of
site (70% to 80%) for the development of a NMSC,
chemotherapy to adjuvant radiotherapy is currently in progress
in Australia and New Zealand. Ongoing research also includes and populations of fair-skin individuals living in
the development of a proposed new staging system and investi- countries close to the equator and tropics (eg, Aus-
tralia and the southern United States) are particu-
larly afflicted.
Correspondence to: M. J. Veness Since the 1960s, the worldwide incidence of
V
C 2007 Wiley Periodicals, Inc. NMSC has markedly increased and continues to

Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007 621


rise.2 Possible reasons include depletion of the (þ/ cervical nodes). The parotid gland is consid-
ozone layer, an aging population, increasing use of ered the metastatic basin for cutaneous SCC of
immunosuppression, and changing social trends. the head and neck, with high-risk sites draining
Australia has the highest incidence of NMSC in via lymphatic vessels located on or around the ear,
the world, with an annual incidence of almost cheek, or temple/forehead.15 The current clinical
1200/100,000 population.3 TNM (tumor, nodes, metastases) staging system
A minority (20% to 25%) of patients with inadequately prognosticates for patients with cu-
NMSC are diagnosed with a cutaneous squamous taneous SCC because most patients developing
cell carcinoma (SCC). In regions of northern Aus- nodal metastases have a T1 (2 cm)/T2 (>2–5 cm)
tralia, the annual incidence of SCC in men primary. Size alone is currently the only criterion
exceeds 1300/100,000 population.4 All patients for assigning T stage in patients without invasion
with cutaneous SCC are at risk of developing me- of muscle or cartilage (T4).16 Important features
tastases, although outpatient-based studies sug- such as tumor thickness/depth of invasion, histo-
gest only a minority (2% to 3%)5,6 ever develop logical grade, or the presence of perineural inva-
metastases, most often nodal. Despite this, hospi- sion or lymphovascular invasion are not consid-
tal-referred patients with SCC often have a higher ered. Despite this, patients with high-risk SCC
incidence of nodal metastases. The development can be identified, and clinicians should be aware so
of metastases places patients at risk of significant that appropriate management can be considered.
morbidity and death.7,8
The majority of immunocompetent patients Tumor Size. Size alone is probably a weak pre-
with a nonrecurrent, small (<2 cm) and superfi- dictor for metastases, although many studies
cial (2–3 mm) SCC can be considered at low risk document a threshold size of approximately 2 cm
for developing nodal metastases. Conversely, (T1 primary lesion) beyond which patients have
many patients who develop nodal metastases will an increasing propensity to have nodal metastasis
have a high-risk SCC,9,10 although a minority develop. In a large review reporting outcome for
(20% to 30%) will not have an identifiable index patients with cutaneous SCC, the authors
lesion, and factors not well understood are reported a metastatic rate of 30% for lesions >2
involved in this subgroup of patients. cm versus 9% for lesions <2 cm.17 In a series of 97
The absolute number of patients diagnosed patients with lower lip SCC treated with local
with cutaneous SCC worldwide makes this a excision, 13% developed lymph node metastases
major public health issue. In the United States, at with tumor size (T1 vs T2/3), a significant predic-
least 2500 people die annually from the conse- tor of nodal metastases on multivariate analysis
quences of advanced SCC, usually as a result of (HR: 13.5; p ¼ .005).18 Moore et al19 reported me-
developing metastatic nodal disease.11 Many Aus- dian lesion size as highly significant (3 cm vs 2 cm;
tralians also die as a consequence of developing p ¼ .0002) in a study of 40 patients with meta-
metastatic SCC, although accurate epidemiologi- static SCC when compared with 153 control
cal data are lacking. In 1 study over a 5-year pe- patients without metastases. Veness et al20
riod, 120 NMSC deaths occurred in western Aus- reported a median lesion size of only 15 mm in a
tralia and accounted for approximately 1% of all large series of 266 patients with metastatic cuta-
cancer-related deaths.12 The morbidity of treating neous HNSCC, suggesting that even patients
patients with metastatic SCC is considerable, with small SCC have metastatic potential.
with most requiring hospitalization for major sur-
gery, followed by 6 to 7 weeks of daily outpatient Thickness/Depth of Invasion. Tumor thickness/
adjuvant radiotherapy. Although the early litera- depth of invasion beyond 4 to 5 mm is an impor-
ture suggested a very poor outcome with current tant predictor of nodal metastases. In a study of
best practice (surgery þ radiotherapy), 5-year dis- patients undergoing excision of a lower lip SCC,
ease-free survival is around 70% to 75%.13,14 there was a significant difference in mean depth
of invasion in node-negative patients when com-
PRIMARY CUTANEOUS SQUAMOUS CELL pared with those developing nodal metastases
CARCINOMA (4.2 mm vs 11.2 mm; p < .001).18 In another study
of patients with metastatic SCC of the head and
Most
High-risk Patients and the TNM Staging System. neck, only 17% with a lesion <4 mm deep meta-
metastatic (60% to 70%) nodes from head and stasized when compared with 83% with lesions
neck cutaneous SCC occur in the parotid gland >4 mm.21 A large study of 550 patients with 594

622 Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007


SCC (including 149 lip SCC) documented 4% of IV differentiation compared with only 11% with a
patients developing nodal metastases with only nondesmoplastic SCC.
7 patients (2.9%) with a tumor 5 mm thick
developing metastases when compared with 14 Perineural Invasion. Perineural invasion occurs
(17.5%) patients with a tumor >5 mm thick.22 Of in approximately 5% to 10% of patients, is usually
note, this study had a median follow-up of 5.3 years an incidental finding, and is reported to be associ-
(minimum 4 years), and importantly, no patient ated with a higher incidence of nodal metasta-
with a superficial SCC (<2 mm thick) developed me- ses.9,26 In 1 study, there was a significant increase
tastases. Clark levels have also been analyzed, with in both nodal (35% vs 15%; p < .0005) and distant
1 study identifying patients with metastatic SCC metastases (15% vs 3.3%; p < .0005) for patients
significantly (p ¼ .0001) more likely to have lesions with perineural invasion when compared with
beyond Clark level III when compared with those those without.27 In a study of 135 patients treated
without metastases.9 In a large review of prognostic with radiotherapy þ/ surgery, half of all failures
factors in patients with SCC, those with a tumor in patients with microscopic perineural invasion
<4 mm or Clark levels I–III had a metastatic rate of were nodal, prompting the authors to recommend
6.7% when compared with 45.7% in those with a elective nodal treatment.28 A study comparing
tumor >4 mm or Clark level IV–V.17 prognostic features of patients with metastatic
and nonmetastatic lip SCC also reported a highly
significant difference in the presence of perineural
Recurrent Squamous Cell Carcinoma. Recurrent invasion (41% vs 5%; p < .0001).26 Similarly, in
SCC is associated with a higher incidence of nodal another study of patients with HNSCC, the rate of
metastases. In a study of patients with lip SCC, perineural invasion differed between patients
those with recurrent lip SCC experienced a signif- with nodal metastases and those without (40% vs
icant difference in developing nodal metastases 18%; p ¼ .005).19
when compared with those not developing local re-
currence (15% vs 2%; p < .0001).23 In a large Lymphovascular Invasion. Recent evidence sug-
review of the literature, patients experienced a gests that the presence of lymphovascular inva-
32% and 45% incidence of nodal metastases in sion may increase the risk of developing nodal me-
the setting of recurrent lip SCC and ear SCC, tastases. Moore et al19 documented lymphovascu-
respectively.17 Clayman et al7 reported recurrent lar invasion as an independent predictor of nodal
SCC as larger (2.4 cm vs 1.5 cm; p < .0001) and sig- metastases on multivariate analysis (OR: 7.54;
nificantly more likely to exhibit perineural inva- p < .00001). In this study, 40% of patients with
sion (24% vs 10%) or lymphovascular invasion nodal metastases had lymphovascular invasion
(17% vs 8%), and invade beyond subcutaneous when compared with only 8% of node negative
tissues (30% vs 10%) when compared with nonre- patients. Other studies of high-risk SCC also
current lesions. These findings suggest recurrent report the presence of lymphovascular invasion
SCC as biologically more aggressive. although fail to find any significant impact on out-
come.7,9,12

Tumor Grade. Poorly differentiated SCCs are Tumor Location. Lesions located on or around
more likely to be associated with the development the ear are considered to have a higher incidence
of regional metastases. A study of 571 patients of nodal metastases as a result of the close proxim-
reported a significant difference in the rate of me- ity and consequential lymphatic drainage to the
tastases for high-grade SCC when compared with parotid gland.15,29,30 Researchers from The Uni-
other grades (17% vs 4%; p ¼ .004).24 The inci- versity of Texas M. D. Anderson Cancer Center
dence of poorly differentiated lesions in 1 series of documented in 40 node-positive patients that
patients with metastatic SCC was significantly most developed metastasis to the parotid þ/
increased in patients developing metastases (44% neck (70%) and that the majority (52%) had a pri-
vs 5%; p < .01).9 Similarly, there are also data mary located in the parotid drainage (periauric-
that desmoplastic SCC, an aggressive histological ular or frontotemporal scalp).19 Lower lip SCC, at
variant of SCC, possess a high propensity to re- least in Australia and in some other countries, can
gional metastases, especially with increasing tu- also be considered a cutaneous SCC secondary to
mor thickness.22,25 Using Broder’s classification, chronic sun exposure and usually seen in men
27% of patients in Breuninger et al’s22 study with a history of chronic outdoor occupational sun
with a desmoplastic SCC were assigned a grade exposure.31 Although most patients with a super-

Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007 623


ficial T1 lower lip SCC will not be at risk of devel- opsy (SNB) has evolved in malignancies such as
oping metastatic nodal disease, those with larger melanoma and breast cancer to identify patients
more deeply invasive lesions may develop nodal with subclinical spread to first echelon lymph
metastases similar to other patients with high- nodes. There are emerging data that SNB may
risk SCC.32 Metastases from lower lip SCC usu- also have a role in identifying patients with high-
ally involve level I nodes. risk SCC.39,40 In a series of 9 patients with high-
risk SCC, 4 of 9 (44%) were positive on SNB, with
Immunosuppression. Immunosuppression, par- 2 subsequently dying of metastatic disease. All
ticularly in the setting of an organ transplanta- node-positive patients had SCC >3 cm in diameter
tion recipient, often leads to significant morbidity and >8 mm in depth. The 5 with a negative SNB
from NMSC, usually SCC. Patients develop SCC remained disease free, although the median fol-
at a much younger age and experience recurrent low-up of 8 months was short.39 In another series
new SCC. Unlike immunocompetent patients, SCC of 24 patients with high-risk NMSC (n ¼ 17 SCC)
in organ transplant recipients occurs at a much undergoing SNB, 7 (29%) had a positive sentinel
higher incidence than BCC. One Australasian node, with only 1 false positive.40 This included
study reported a 66% probability of developing a 5 SCC positive on SNB, although only 2 involved
cutaneous malignancy by 24 years post–renal head and neck nodes. A recent study documented
transplant.33 A subset of SCC in immunosup- the lymphatic drainage pattern of the ear (high-
pressed patients is aggressive in nature, with risk site) in healthy patients utilizing lympho-
rapid growth and the development of regional and scintigraphy.41 The findings from this study sug-
distant metastases. In an Australian study of 619 gest a more predictable pattern of spread than
cardiothoracic transplant recipients, 26 developed previously thought. Despite this, and other stud-
an aggressive NMSC, with most diagnosed with a ies, the role of SNB in patients with high-risk
poorly differentiated SCC.34 Death occurred in 13 cutaneous HNSCC is evolving and still requires
of the 26, with 10 patients dying from systemic further validation. Similarly, the role and benefits
disease. Martinez et al35 reported the outcome of of positron emission tomography in highlighting
60 organ transplant recipients all with metastatic subclinical disease is unproven but with emerging
skin cancer (85% SCC), noting that 27% of data in the setting of mucosal HNSCC, and with
patients had an unknown index lesion. In this further research, this investigation may also be of
study, median primary lesion size was 12 mm and benefit in cutaneous HNSCC.
median depth of invasion was 3.2 mm. Three-year
disease-specific survival was only 56%. This Elective Nodal Treatment. The option of elec-
would suggest a smaller lesion size and depth of tively treating at-risk nodes to prevent regional
invasion threshold for the development of meta- relapse may be considered. Radiotherapy or sur-
static cutaneous SCC and a significantly worse gery is an option, and the recommendation of one
outcome when compared with immunocompetent over another is based on multiple factors. Yoon
patients. In another study comparing immuno- et al42 reported on 38 patients with external ear
competent and organ transplant recipient patients, SCC treated predominantly with surgery. The
a significant proportion of organ transplant recipi- authors reported a 53% recurrence rate with
ents had thick (>5 mm) tumors and exhibited almost half metastasizing to regional lymph nodes
early dermal invasion when compared with and recommended prophylactic parotidectomy
immunocompetent patients.36 Of note, patients and neck dissection þ/ radiotherapy in patients
immunosuppressed as a consequence of chronic with poor prognostic features such as cartilage
lymphocytic leukemia also have a similar in- invasion, deep invasion, or poor differentiation.
creased risk of cutaneous SCC and poor outcome Similarly, Afzelius et al29 recommended elective
from developing metastases.37 nodal dissection in patients with unfavorable ear
SCC: >4 cm, cartilage invasion, or deep invasion.
Sentinel Node Biopsy. Despite evidence docu- Vartanian et al32 suggest patients with T3/T4 lip
menting factors that place a patient at risk of deve- SCC are at >20% risk of having occult spread to
loping nodal metastases, accurately predicting an upper cervical lymph nodes and should undergo
individual’s risk is difficult.9,10,12,17,19,20,26,32,38 an elective supraomohyoid neck dissection. Zitsch
Routine investigations usually contribute little to et al43 recommended elective nodal dissection in
a thorough clinical examination in the setting of a the setting of lip SCC that are undifferentiated or
clinically N0 neck. The concept of sentinel node bi- locally recurrent (if initial lesion > 2 cm).

624 Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007


Electively irradiating nodes is also an option,
Table 1. Selected early studies reporting locoregional relapse
although high-level supportive evidence is lack- based on treatment.
ing. Kwan et al44 reported a higher locoregional
failure (30% vs 20%) in 37 patients with advanced Surgery/
radiotherapy, Surgery, Radiotherapy,
SCC who did not receive nodal irradiation when
Author/year % % %
compared with 5 patients undergoing elective
nodal treatment. Other proponents also recom- delCharco et al,47 1998 10 20 47
Khurana et al,48 1995 38 24 NR
mend elective nodal treatment (surgery or radio- Taylor et al,49 1991 11 37 54
therapy) in the presence of adverse or high-risk Shimm and Wilder50 1991 27 – 63
features.15,19,22,28,29 Shimm 198851 36 – 29
Accurately predicting patients who may de- Mendenhall et al,52 1985 12 85 50
velop nodal relapse is difficult; however, clinicians Cassisi et al,53 1978 20 75 50
should consider patients with recurrent SCC that Abbreviation: NR, not reported.
is >4 to 5 mm thick and in the vicinity of the pa-
rotid gland (ear, lateral scalp, forehead, temple,
cheek) at higher risk of developing parotid nodal incorporating adjuvant radiotherapy given the
metastases. It is these patients who should be con- extended treatment time (5–7 weeks) and the
sidered as candidates for the elective treatment of perceived side effects. Because of this uncertainty,
parotid nodes. Depending on the type of treatment many patients who may have benefited from
to the primary cutaneous lesion, elective nodal adjuvant radiotherapy were not offered further
treatment may entail either a superficial paroti- treatment.
dectomy or alternatively radiotherapy to the pa- In patients that have relapse develop, most
rotid gland. (70% to 80%)13,14 experience locoregional relapse
as the first site of relapse. This finding would
strongly suggest that any treatment to improve
METASTATIC NODAL SQUAMOUS CELL CARCINOMA disease control in the head and neck is likely to
also impact on survival. Patients suffering locore-
Background. In Australia, metastatic cutaneous gional relapse are often incurable either second-
SCC is overwhelmingly the most frequent parotid ary to untreatable regional disease or the subse-
malignancy.5,10,13 The lateral/anterior head and quent development of distant disease.
neck sites (ear, anterior scalp, forehead, temple,
cheek) are the most frequent sites for a primary Early Evidence. Early studies suggested that
index SCC. Most patients (70% to 80%) who have patients might achieve a better outcome (im-
an identifiable index lesion and subsequently de- proved locoregional control and survival) follow-
velop nodal metastases do so after treatment for ing surgery and adjuvant radiotherapy when com-
this lesion rather than present with a concomitant pared with either surgery or radiotherapy alone
primary and nodal disease. Median time for (Tables 1 and 2; refs. 21 and 47–54). Of note, the
the development of nodal metastases following University of Florida Group published updates of
treatment of an index SCC is approximately their series of patients, concluding that a better
12 months, although late relapse (2–3 years) is outcome was achieved with combined treat-
well documented and justifies ongoing regular fol- ment.47,49,52,53 In 1978, Cassisi et al53 reviewed
low-up of patients following treatment of a high- 20 patients with parotid lymph node metastases
risk SCC.45,46 The pattern of distribution of nodal from SCC. Following surgery and adjuvant radio-
metastases is approximately equally divided be- therapy, they reported a locoregional recurrence
tween the parotid alone, the parotid and neck, and rate of 10% and an absolute survival rate of
the neck alone (levels I–V). 80%. The outcomes of these patients with further
accrual were updated in 1985, 1991, and 1998,47,49,52
Evidence-Based Management. The optimal man- again demonstrating improved absolute and dis-
agement of a patient with cutaneous metastatic ease-free survival following combined-modality
nodal HNSCC has evolved. Early evidence usually treatment, when compared with patients treated
consisted of small case series often reflecting with a single modality.
selection and treatment bias. The paucity of evi- However, many early studies were small and
dence meant clinicians were often unclear of the heterogeneous with regard to the site and stage of
benefit of recommending combined treatment disease and treatment approach (extent of sur-

Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007 625


Table 2. Selected early studies reporting outcome after surgery and adjuvant radiotherapy.

Patients treated with surgery/ Locoregional relapse,


Author/year/number adjuvant radiotherapy, % % Survival*
Kraus et al,21 1998 (n ¼ 36) 80 NR 5 y 34% DFS
delCharco et al,47 1998 (n ¼ 48) 69 10 5 y 72% DSS
Khurana et al,48 1995 (n ¼ 75) 74 38 5 y 60% DSS
Taylor et al,49 1991 (n ¼ 60) 60 11 5 y 75% CSS
Shimm and Wilder,50 1991 (n ¼ 23) 65 27 NR
Shimm 198851 (n ¼ 18) 61 36 NR
Mendenhall et al,52 1985 (n ¼ 16) 42 12 5 y 45% AS
Jackson and Ballantyne 198154 (n ¼ 141){ 32 26 NR
Cassisi et al,53 1978 (n ¼ 20) 50 20 5 y 80% AS
Abbreviations: NR, not reported; AS, absolute survival; CSS, cause specific survival; DSS, disease-specific survival; DFS, disease free survival.
*In some studies, only results for patients treated with surgery and radiotherapy are presented in the table.
{Only 132 were SCC and some had direct extension into the parotid.

gery, radiotherapy technique/doses). The poten- tice in operable patients (see Tables 3 and 4; refs.
tially biased selection of patients for treatment 13, 14, 19, and 55–66). Taking into consideration
may have resulted in patients with unfavorable the heterogeneity of patient, tumor, and treat-
features being recommended combined treat- ment factors across multiple studies, a patient
ment, perhaps explaining the wide variation in treated with a combined approach can probably
reported locoregional relapse rates. The percent- expect a 20% to 25% chance of locoregional
age of patients receiving adjuvant radiotherapy relapse. Those treated with a single modality (sur-
varied markedly in most series almost certainly gery or radiotherapy) can expect a less than 50%
reflecting the uncertain benefit and the doubt of likelihood of achieving freedom from locoregional
many clinicians. No studies were controlled, and relapse. Many publications, particularly from
most were retrospective and descriptive in analy- Australia, present the results from large single
sis and lacked the number of patients and events institutional series. Publications from the West-
to perform multivariate analysis. Earlier studies mead Group,13,58,61,62,64 Sydney, have docu-
were often criticized as weak and inconclusive, mented the outcome of a large number of prospec-
with authors concluding the need for larger, tively analyzed patients treated with curative
multi-institutional, prospectively randomized tri- intent within the context of a tertiary referral
als to identify the best approach, or even discount- multidisciplinary head and neck cancer service. A
ing the role of adjuvant radiotherapy because of a consistent treatment approach since the 1980s
lack of a statistically significant proven benefit. has been followed, with operable patients under-
going surgery followed by adjuvant radiotherapy.
Recent Evidence. Recent publications support The most recent analysis from this group con-
surgery and adjuvant radiotherapy as best prac- firmed a marked decrease in locoregional relapse
(20% vs 43%) and improved disease-free survival
(73% vs 54%; p ¼ .004) with the addition of adju-
vant radiotherapy when compared with surgery
Table 3. Selected recent studies reporting locoregional
alone.13 Other authors have also reported results
relapse based on treatment.
for patients treated with metastatic cutaneous
Surgery/ nodal HNSCC, although many studies remain
radiotherapy, Surgery, small and heterogeneous.
Author/year % % Radiotherapy
Hong et al,56 2005 7 33 – Adjuvant Radiotherapy. Bron et al63 reported ad-
Barzilai et al,57 2005 0 50 – juvant radiotherapy as the only factor that signifi-
Veness et al,13 2005 20 43 –
cantly improved local control in the parotid and
Audet et al,14 2004 27 57 17
Martinez et al,35 2003* 33 24 45 recommended it as standard treatment. In con-
Veness et al,58 2003 15 77 44 cordance, O’Brien et al65 also reported adjuvant
Gooris et al,59 2002 13 0 – radiotherapy as significantly improving parotid
Jol et al,60 2002 17 44 25 control on multivariate analysis. Similarly, del-
*Organ transplant recipients. Charco et al47 documented treatment (surgery/

626 Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007


Table 4. Selected recent studies reporting outcome relapse after surgery and adjuvant radiotherapy.

Patients treated with surgery/ Locoregional relapse,


Author/year/number adjuvant radiotherapy, % % Survival*
Ying et al,55 2006 (n ¼ 41) 61 36 64% AS-cured
Moore et al,19 2005 (n ¼ 40) 93 18 NR
Hong et al,56 2005 (n ¼ 20) 70 7 NR
Barzilai et al,57 2005 (n ¼ 22) 55 0 5 y 73% OS
Veness et al,13 2005 (n ¼ 167) 87 20 5 y 73% DFS
Audet et al,14 2004 (n ¼ 56) 79 27 3 y 72% DSS
Veness et al,58 2003 (n ¼ 74) 70 15 5 y 61% DSS
Dona et al,61 2003 (n ¼ 74) 100 24 5 y 72% CSS
Martinez et al,35 2003 (n ¼ 68){ 37 29 3 y 56% DSS
Palme et al,62 2003 (n ¼ 126) 89 28 5 y 68% DSS
Bron et al,63 2003 (n ¼ 101) 85 25 5 y 65% DSS
Gooris et al,59 2002 (n ¼ 44) 73 13 NR
Jol et al,60 2002 (n ¼ 41) 59 17 5 y 46% OS
Chua et al,64 2002 (n ¼ 52) 100 31 5 y 65% CSS
O’Brien et al,65 2002 (n ¼ 87) 86 24 5 y 63% DSS
Baker et al,66 2001 (n ¼ 12) 100 50 NR
Abbreviations: AS, adjusted survival; NR, not reported; CSS, cause-specific survival; DSS, disease-specific survival; DFS, disease-free survival; OS,
overall survival.
*In some studies, only results for patients treated with surgery and radiotherapy are presented.
{Organ transplant recipients.

radiotherapy vs radiotherapy) as the only factor outcome was clinical stage of disease and that
to predict parotid disease control on multivariate patients with limited-stage metastases had a 53%
analysis (p ¼ .004). In another series, 5-year dis- 2-year disease-free survival when compared with
ease-free survival was significantly improved in 18% of those with more advanced-stage metasta-
patients undergoing surgery and adjuvant radio- ses (p < .009). In 1 small series, no patients sur-
therapy when compared with surgery alone (73% vived beyond 5 years with both parotid and neck
vs 18%; p ¼ .001), as was locoregional control metatsases.57 Khurana et al48 reported positive
improved (77% vs 15%).58 Barzilai et al57 docu- surgical margins associated with poor local disease
mented improved 5-year survival in patients control (p ¼ .02), as did O’Brien et al,65 who identi-
receiving adjuvant radiotherapy, although this fied margin positivity as an independent predictor
failed to reach statistical significance (73% vs for parotid relapse. Veness et al13 identified extra-
38%; p ¼ .26). Jol et al60 also reported decreased nodal spread as a predictor for survival on univari-
locoregional failure in patients undergoing sur- ate analysis, although on multivariate analysis,
gery and adjuvant radiotherapy when compared only number of nodes and treatment remained sig-
with surgery alone (17% vs 44%). Most recent nificant. Immunosuppression strongly predicts a
studies suggest 60 Gy in 2 Gy daily fractions as an very poor outcome.37,62,67 Southwell et al67 re-
acceptable dose of adjuvant radiotherapy to a dis- ported no immunosuppressed patients alive at
sected involved nodal region and 50 Gy to the 2 years when compared with 87% of immunocom-
undissected at-risk neck. petent patients alive in a study of 49 patients.
Palme et al62 also identified immunosuppression
Prognostic Variables. In 74 patients with SCC to as an independent predictor of survival on multi-
nonparotid head and neck nodes, increasing nodal variate analysis. In a recent consensus survey,
size (3 cm), multiple nodes, extranodal spread, leading transplant physicians recommended a
and single-modality treatment independently severe reduction in the level of immunosuppres-
predicted survival.58 Poor prognosis with increas- sion in patients with metastatic cutaneous SCC.68
ing nodal size (>3 cm) and multiple nodes were
also reported by O’Brien et al.65 Similarly, Palme Treatment of the Parotid. In the setting of a func-
et al62 in a study of 126 patients found increasing tioning facial nerve, there is a little convincing
metastatic parotid disease associated with evidence that more aggressive surgery in the form
decreasing local control and a trend (p ¼ .1) for of a total parotidectomy, as opposed to a facial
worsening survival with advanced neck disease. nerve-sparing superficial parotidectomy followed
Kraus et al21 reported that the only predictor of by adjuvant radiotherapy, will improve locore-

Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007 627


gional control.65 The incidence of facial nerve sac- Patients with nasal/cheek/lip SCC are more likely
rifice (partial or complete) varies across series to benefit from the addition of a level I dissection
(5% to 43%)14,19,56,61,66,67 and possibly reflects dif- when compared with lesions located on the fore-
ferences in disease location and stage in conjunc- head/scalp.
tion with clinician preference. Patients with Deleting a neck dissection in the setting of pa-
involvement of the facial nerve often have a worse rotid disease and a N0 neck is an option. However,
outcome.14,67 However, the facial nerve should this will commit all patients to receive elective
only be sacrificed if the patient has malignant fa- radiotherapy (50 Gy) directed to the hemineck.
cial nerve palsy or is found to have nerve involve- Although it is well accepted that neck control is
ment at the time of operation. Surgery rarely equivalent in a clinically N0 neck with either sur-
achieves oncological excision margins (>5 mm) gery or radiotherapy, the finding of pathologically
especially in the deep plane in proximity to the fa- negative upper level neck nodes may result in a
cial nerve. Studies have documented high rates of patient not requiring adjuvant radiotherapy to
close or incomplete excision (40% to 65%) follow- the lower neck.
ing parotidectomy.47,64,67 Extranodal spread is Patients with clinical involvement of cervical
also a common pathologic finding (30% to nodes should undergo an appropriate neck dissec-
75%)19,60,64,67 and in combination with a close or tion. Radiotherapy is delivered to the ipsilateral
positive margin adds weight to the importance of neck if disease is identified in multiple nodes (2)
adjuvant radiotherapy to improve locoregional or extranodal spread is present in a single node.
control and may explain the high recurrence rate An undissected neck should be irradiated in the
following surgery alone. presence of parotid nodal disease even if clinically
negative.
Neck Treatment. Treatment to clinically unin-
volved cervical nodes is important. One study Radiotherapy Alone. Disease in patients with
documented a 35% rate of subclinical metastases skull base or carotid vessel involvement can be
in dissected clinically negative neck nodes.13 Sim- considered inoperable. Skin involvement does not
ilarly, O’Brien et al69 reported a 35% incidence of preclude surgery but will necessitate excision of
subclinical spread in 37 patients with metastatic skin and soft tissue and appropriate reconstruc-
parotid nodes following elective neck dissection. tion. In patients with operable disease that are
This compares with a lower incidence (16%) of treated with high-dose (66–70 Gy) radiotherapy
occult spread in neck nodes in another Australian (medically unfit/patient refusal), there is a chance
series61 and a 16% occult rate in a Canadian study of cure although patients with advanced and inop-
by Audet et al.14 Researchers from The University erable disease are unlikely to obtain durable
of Texas M. D. Anderson Cancer Center docu- locoregional control. The addition of chemother-
mented a 42% incidence of occult cervical metas- apy to these patients is experimental but may be
tases in a study of patients with metastatic pa- considered in suitable good performance patients.
rotid SCC.19 Ying et al55 similarly documented
44% of patients with parotid metastases as hav-
ing pathologically positive cervical nodes. There- FUTURE RESEARCH
fore, all patients with parotid metastases and a
clinically negative neck should undergo a selec- Adjuvant Radiochemotherapy. There are emerg-
tive neck (levels I/II or levels I/II/III) dissection in ing data in postoperative mucosal HNSCC that
conjunction with a parotidectomy. In a recent arti- combination concurrent platinum chemotherapy
cle reporting the patterns of nodal metastases in and adjuvant radiotherapy may improve lo-
cutaneous SCC of the head and neck, 79% of coregional control and disease-free survival in
pathologically involved cervical nodes were high-risk patients (extranodal spread, multiple
located at level II.70 The authors recommended nodes).71,72 High-risk pathologic features, such as
that the external jugular node, which is not multiple nodes, extranodal spread, positive mar-
assigned to a specific level although often included gins, and perineural or vascular invasion, are of-
as a level node II, be excised in any dissection. ten present in metastatic cutaneous HNSCC
Involvement of this node can be considered patho- patients. Patients with these pathologic features
gnomonic for spread from a cutaneous malig- may benefit from means to improve locoregional
nancy. Level IV/V nodes were usually only control. Data from a Peter MacCallum Cancer
involved in the setting of extensive nodal disease. Institute, Melbourne, pilot study73 using weekly

628 Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007


concomitant platinum-based chemotherapy and
Table 5. Proposed staging system of O’Brien et al.65
adjuvant radiotherapy suggests a possible role for
combined treatment to improve locoregional con- Parotid
trol in high-risk cutaneous (extracapsular spread, P1 Node 3 cm
P2 Node >3 cm but 6 cm or multiple nodes
close/positive margins) SCC patients, although
P3 Node >6 cm or facial nerve involvement or
randomized data in this setting are needed to con- skull base invasion
firm any hypothesis. A trial testing this has been Neck
activated in Australian and New Zealand patients N0 Clinically negative neck
under the auspices of the Trans Tasman Radiation N1 Single node 3 cm (ipsilateral)
N2 Single node >3 cm, multiple or
Oncology Group (TROG), with the aim to accrue
contralateral nodes
265 patients randomized to receive adjuvant
radiotherapy (60 Gy) or adjuvant radiotherapy
and weekly carboplatin (Post-Operative Skin
Trial; POST 05.01). Carboplatin was chosen on
the basis that the patient cohorts in this study are system in identifying patients who have a worse
unlikely to tolerate cisplatin, as many are older outcome based on PN criteria. A recent large col-
with preexisting comorbidities. Patients with T3/ laborative retrospective series of 325 patients
T4 N0 SCC are also included in this study to test from 3 Australian institutions (Royal Prince
the improvement in local control and where possi- Alfred, Westmead, Queensland Radium Institute)
ble to also electively treat first echelon nodes. and 3 North American institutions (Memorial
Sloan-Kettering, Toronto General, University of
Florida) analyzed outcome for patients with meta-
Molecular Prognostic Factors. There are limited static cutaneous HNSCC using the proposed PN
data investigating prognostic molecular factors staging system of O’Brien et al65 (Table 5). The
that could provide valuable data to guide novel findings from this large study confirm the utility
treatment. Differences at a molecular level may, of separate parotid and neck stages in predicting
in part, also explain the metastatic potential of outcome.77 Patients with pathologic involvement
SCC lacking established high-risk features such of both the parotid and neck did worse when com-
as size and thickness and explain why patients pared with those having only parotid disease.
with relatively small, thin SCC have metastasis
develop. The overexpression of epidermal growth
factor receptor (EGFR) is postulated as 1 possible CONCLUSIONS
factor.74,75 The authors of 1 study suggest the
The rising worldwide incidence of cutaneous SCC
potential use of tyrosine kinase inhibitors in
implies that clinicians are increasingly likely to
patients with EGFR-positive tumors.74 The asso-
encounter patients with a high-risk primary
ciation of human papillomavirus (HPV) and
HNSCC or metastatic nodal HNSCC. Patients at
NMSC is also an area of potential research, with
risk of developing nodal metastases often have
some evidence to implicate oncogenic HPV sub-
features that may predict an increased risk
types and the development of NMSC.76 However,
beyond the often-quoted 2% to 3% in the litera-
further research is required in this area so that a
ture. However, accurately predicting a patient’s
clearer understanding of the biology of metastatic
risk is difficult. The parotid nodes represent a fre-
SCC can be elucidated.
quent site of metastatic nodes, and electively
treating first echelon nodes may prevent the con-
Proposed Staging System. The TNM staging sys- sequences of nodal disease, although high-level
tem currently assigns all patients with metastatic evidence to support this approach is lacking.
cutaneous SCC as stage N1. Collaborative re- Patients with operable metastatic nodal disease
search must be undertaken with a staging system should be offered surgery and adjuvant radiother-
that takes into account important and proven apy. Single-modality treatment is less likely to
prognostic variables such as nodal location and cure a patient. Patients with parotid metastases
size, number of metastatic nodes, and facial nerve should also have the neck treated. Using a pro-
involvement (perineural invasion). Using a modi- posed new staging system may allow the identifi-
fied P (Parotid; P0-3) and N (Nodes; N0-2) clinical cation of patients at higher risk of relapse and jus-
staging system, O’Brien et al,65 Palme et al,62 and tify more intensive treatment such as the addition
Audet et al14 have validated the benefit of such a of chemotherapy to adjuvant radiotherapy. Con-

Cutaneous HNSCC HEAD & NECK—DOI 10.1002/hed July 2007 629


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