Neck Surgery. Brendan C. Stack, Jr., Mauricio A. Moreno, MD

16. Neck Management in Skin Cancer

William Harris, Mauricio A. Moreno, and Brian Moore Abstract

This chapter examines the risk factors and clinical approach to regional management of aggressive skin cancer of the head and neck. Initially, the chapter touches on the epidemiology, patient evaluation, and role of imaging in head and neck cutaneous cancer. As the chapter progresses, the workup and management of aggressive cutaneous lesions is discussed, including the role of sentinel lymph node biopsy and the technique involved. Management of the N0 neck is also discussed as well as a comprehensive overview of posterolateral neck dissection technique and indications. Finally, the current recommendations on adjuvant therapy and the treatment of systemic disease are explored.

Keywords: neck dissection, sentinel lymph node biopsy, NMSC, posterolateral neck dissection, adjuvant therapy, cutaneous squamous cell cancer, Merkel cell carcinoma, lymphoscintigraphy

16.1 Introduction

Skin cancer of the head and neck is a heterogeneous and common malignancy. The vast majority of cases are nonmelanoma skin cancer (NMSC), especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), followed by melanoma and Merkel cell carcinoma (MCC). Melanoma, cutaneous squamous cell cancer (cSCC), and MCC may be aggressive diseases that frequently require a multidisciplinary approach. Such cutaneous malignancies are at increased risk of regional metastases, with increased morbidity and an increased risk of disease-specific death. This chapter discusses the risk factors for and clinical approach to regional management of aggressive skin cancer of the head and neck.

16.2 Epidemiology

Approximately 5.4 million NMSCs are diagnosed yearly in the United States.1 BCC and SCC account for about 99% of cases, while MCC, rare adnexal carcinomas, and sarcomas comprise about 1%. NMSC is not typically reported to cancer registries, such as the Surveillance, Epidemiology, and End Results (SEER) Program database, so the true incidence is difficult to assess—such data are extrapolated from procedural claims and longitudinal health cohorts. Health care expenditures related to NMSC in the United States were estimated at $4.8 billion between 2007 and 2011, with the majority attributed to office-based visits.2

Similarly, the incidence of cutaneous melanoma has been increasing over the past three to four decades and currently accounts for an estimated 65% of all deaths from skin cancer.While melanoma is historically acknowledged as an aggressive and potentially lethal diagnosis, with 9,730 U.S. deaths estimated for 2017, the mortality risk for aggressive NMSC, particularly cSCC, has been more difficult to quantify.4 At least 4,000 deaths annually in the United States were attributed to cSCC in 2012, with that number continuing to rise.5

Skin cancer is associated with prolonged exposure to ultraviolet (UV) radiation, with 75% of NMSC arising on the head and neck because of the increased sun exposure of these areas and nearly 65% of all melanomas attributed to prolonged exposure.6.7 NMSC and melanoma are increasing in frequency, with a trend toward younger patients.8.9 The risk factors associated with the various cutaneous malignancies are denoted in Table 16.1.

Table 16.1 Risk factors for developing skin cancer of the head and neck3.10.11

Risk factors

Melanoma

BCC and SCC

Merkel cell

Skin types

Fair skin, freckling, light hair

Fair skin, freckling, light hair

Fair skin, freckling, light hair

History

Family or personal history of

melanoma

Immunosuppression

Elderly

Male

Psoriasis treatment (PUVA and psoralen)

Smoking

HPV

Prior BCC or SCC lesions Male

Lymphoma

Albinism

Genodermatoses Xeroderma pigmentosum Bazex syndrome Epidermodysplasia verruciformis Chronic irritation

Psoriasis treatment (PUVA and psoralen)

HIV/AIDS; CLL (immunosuppression)

Elderly

Male

Merkel cell polyomavirus

Preexisting skin lesions

Atypical moles Congenital melanocytic nevi Dysplastic nevus syndrome

Basal cell nevus syndrome Actinic keratosis Bowenoid papulosis Epidermodysplasia verruciformis

 

Environmental exposures

UV light

UV light

Arsenic exposure Polycyclic hydrocarbons Coal tar

UV light

Abbreviations: AIDS, acquired immunodeficiency syndrome; BCC, basal cell carcinoma; CLL, chronic lymphocytic leukemia; HIV, human immunodeficiency virus; HPV, human papillomavirus; PUVA, psoralen and ultraviolet A therapy; SCC, squamous cell carcinoma; UV, ultraviolet.

16.3 Patient Evaluation

16.3.1 History

Cutaneous lesions of the head and neck must be addressed with a comprehensive and methodical approach, coupled with a high index of suspicion. A detailed history of potential recreational or occupational exposures, use of sun-protective behaviors (if any), past history of skin lesions and type, a family history of skin cancer, and comorbid conditions, especially transplant status and immunosuppression, must be obtained. The presence of formication (the sense that insects are crawling under the skin), facial pain, or cranial nerve paralysis should raise concern for perineural invasion (PNI), triggering anatomic imaging studies. PNI often presents as progressively worsening severe pain in one branch of the trigeminal nerve or as a slowly evolving paresis of one branch of the facial nerve that progresses over time to complete facial paralysis. This evolving paralysis is often misdiagnosed as Bell’s palsy.

Patients with a neck or parotid mass should be queried as to their history of benign or malignant skin lesions in the region, particularly the cheek, zygomatic-temporal region, or temporoparietal scalp, as the parotid serves as the primary nodal basin for these anatomic areas.12 This inquiry is essential, because skin cancer of the head and neck is often treated in the office setting, so patients (and providers) may underestimate the disease and its metastatic potential.13

16.3.2 Physical Examination

A patient’s propensity to develop skin cancer can be generalized by the skin phenotype, with a determination of the Fitzpatrick scale: types I and II skin (light skin, light eyes, and a propensity to burn rather than tan) have historically been associated with the development of skin cancer, although this disease can affect all skin types.14 Lesions found within the H-zone of the face, including the midface, upper lip, nose, medial canthus, eyelids, temples, lateral forehead, malar eminences, preauricular cheek, and periauricular tissues, are considered more difficult to treat due to a high risk of local recurrence and a tendency for deep invasion.15 Suspicious lesions should be measured and palpated to estimate depth of invasion. Intranasal and intraoral examinations, including nasal endoscopy, are imperative to identify full-thickness involvement of the nose, cheek, or lip. Dermoscopy can be also be used as an instrument to aid in noninvasive diagnosis of NMSC and pigmented lesions, and has been shown to be useful in the preoperative evaluation of tumor margins, monitoring outcomes of topical treatments, as well as in posttreatment follow-up.8

In order to initially assess for evidence of potential PNI, a detailed cranial nerve examination is imperative. This is especially crucial in SCC, where 5 to 10% of individuals present with this feature, and where PNI is frequently associated with regional lymph node metastases and has a significantly negative impact on local control and survival.16 The trigeminal nerve and the facial nerve are most commonly involved when PNI is present, and a thorough assessment of sensation and motor function in all branches, respectively, is required.17

Palpation of the parotid glands and cervical lymphatics, including those in the posterior triangle and suboccipital regions, is indicated as well. The lymphatic drainage system is notably complex, and not always reliable in regard to anatomical course.12 In patients presenting with a parotid or neck mass, a thorough inspection should be performed for a potential synchronous skin primary, with particular focus paid to the temporoparietal scalp and periauricular region. In addition, examination of the upper aerodigestive tract (UADT) should be performed to rule out an unknown mucosal primary—level II adenopathy and metastatic parotid-area adenopathy are often difficult to distinguish clinically.

16.3.3 Biopsy

Suspicious cutaneous lesions of the head and neck warrant incisional or narrow-margin excisional biopsy. Incisional biopsy with a 2-, 3-, or 4-mm punch may be performed for a full-thickness assessment. Adequate shave biopsy that allows depth measurement is an acceptable technique in NMSC, and fine-needle aspiration biopsy is indicated for evaluating neck and parotid masses. Ideally, the resulting report will provide not only a pathologic diagnosis, but also information about depth of invasion, differentiation, and vascular or PNI. Synoptic reporting (Table 16.2) of surgical specimens is more commonly used in melanoma evaluation, and has yet to be widely adopted in cSCC.18

Table 16.2 Synoptic report comparison for cutaneous squamous cell carcinoma (cSCC) and melanoma19.20

cSCC

Melanoma

Procedure

Procedure

Tumor site

Specimen laterality

Tumor size

Tumor site

Histologic type

Tumor size

Histologic grade

Macroscopic satellite nodules

Maximum tumor thickness

Histologic type

Anatomic level

Maximum tumor (Breslow) thickness

Margins (peripheral and deep)

Ulceration

Lymphovascular invasion

Mitotic rate

Perineural invasion

Lymphovascular invasion

Lymph nodes (number examined and number involved by metastatic carcinoma)

Neutropism

Pathologic staging (pTNM, AJCC, 8th ed.)

Tumor regression

Regional lymph nodes (number of sentinel nodes involved, lymph nodes involved, matted nodes, lymph nodes examined, and sentinel lymph nodes examined)

Pathologic stage classification (pTNM, AJCC 8th ed.)

Presence of S-100, MARTI, HMB-45

Abbreviations: AJCC, American Joint Committee on Cancer; pTNM, pathological tumor-node-metastasis.

16.3.4 Imaging

The role of imaging in skin cancer depends on patient symptoms as well as clinical findings and the biopsy report. The majority of cutaneous malignancies do not require imaging in their initial workup and management. Larger lesions, and clinically thick or fixed lesions of the cheek and preauricular region, have the potential to involve the parotid gland or Stensen’s duct, and a contrasted CT scan of the neck may identify parotid extension and facilitate adequate preoperative planning and comprehensive resection. CT imaging may also identify invasion into underlying bone, cartilage, muscle, and fascia, as well as bony remodeling, enlargement of neural foramina and canals, or widening of the pterygopalatine fossa in cases of suspected PNI. MRI remains the more sensitive modality as compared with CT in detecting early perineural spread, manifest as subtle nerve enhancement.16 MRI and CT often provide complementary information in patients with deep scalp lesions, as the CT scan may demonstrate bony destruction and the MRI may depict the extent of intracranial spread. Clinically suspicious parotid masses or cervical lymph nodes also benefit from anatomic imaging with MRI, CT scan, or comprehensive neck ultrasound to permit accurate nodal staging. Nodes larger than 1.5 cm in levels I and II and those larger than 1 cm in other neck levels may warrant additional evaluation with fine-needle aspiration biopsy.

Routine use of PET-CT in head and neck NMSC is currently not recommended, except in MCC, where PET scans have been shown to alter staging in up to 33% of cases and change disease management in 43% of cases.10 21 Alternatively, although it is integral to the clinical staging of stage III and IV melanoma, it is not recommended in stage I and II melanoma due to its low yield.22 Approximately 60% of patients with palpable or macroscopic melanoma nodal metastasis will develop distant meta- stases. In addition, PET-CT has been shown to be 83% sensitive and 85% specific when evaluating deep soft tissue, lymph node, and visceral metastasis in patients with stage III or IV melano- ma.23 24 PET-CT imaging is also valuable in assessing response to immunotherapy, and for detection of recurrence in the follow-up period in late-stage disease.23 The recent development of selective PET probes capable of detecting melanoma more specifically is being studied in small animal models with some promise as well.25

16.4 Patterns of Lymphatic Spread

Compared to other anatomic regions, lymphatic drainage from cutaneous sites in the head and neck exhibits marked complexity and variability. The lymphatic drainage patterns for the skin of the head and neck are depicted in Fig. 16.1.26 In general, lesions anterior to a vertical line extending toward the vertex from the auricle will drain to the ipsilateral parotid gland and upper cervical lymph nodes, including lymph nodes along the external jugular chain in the parotid region. More posteriorly located lesions will drain to the postauricular, occipital, and posterior cervical nodes.27 Lesions of the midface and lower lip may drain to the bilateral anterior cervical nodes, including the superficially located perifacial nodes, submental nodes, and submandibular nodes. Lesions on the neck will likely drain to the closest underlying lymph nodes and those along the external jugular vein, but they are unlikely to involve the parotid gland. Within this general framework, there is significant variability, as is evidenced by studies that reveal a discordance of up to 34% between the clinical prediction and lymphoscintigraphy, making this imaging modality invaluable in depicting bilateral drainage (Fig. 16.2).28

Fig.16.1 Patterns of head and neck lymphatic spread.26

16.5 Management of Aggressive Lesions

16.5.1 Identification of High-Risk Lesions

Although the vast majority of NMSCs are curable through multiple different treatment modalities, aggressive lesions are capable of nodal metastases. Although aggressive variants of BCC exist (infiltrative/morpheaform and micronodular subtypes), they are associated with local recurrence rather than regional metastases and will not be discussed here.29 There is a growing awareness of the clinical features of aggressive cSCC, which is leading to an appreciation of the need for a multidisciplinary, more proactive approach to the regional lymphatics.30 Characteristics of aggressive cSCC, as noted by the American Joint Committee on Cancer (AJCC) eighth edition, and risk factors for regional metastases in both cSCC and melanoma are depicted in Table 16.3 and Table 16.4, respectively.

Fig. 16.2 Lymphoscintigraphy depicting bilateral drainage from a scalp vertex lesion.

Table 16.3 Aggressive features for cutaneous squamous cell carcinoma31

High-risk histologic feature

Description

Affects T staging

Tumor size (cm)

> 2

Yes

Tumor thickness (mm)

>6

Yes

Level of invasion

Beyond dermis

Yes

Perineural invasion

Large caliber

(> 0.1 mm diameter)

Yes

Differentiation

Poor differentiation

No

Growth pattern

Desmoplastic and spindle cell

No

Lymphovascular invasion

Tumor cells within vascular spaces

No

Anatomical location

Hair-bearing (lip and ear)

No

Immunosuppression

Organ transplant recipients (heart and lung especially), CLL, CML, AIDS

No

Abbreviations: AIDS, acquired immunodeficiency syndrome; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia.

Table 16.4 Risk factors for regional metastases in skin cancer of the head and neck3.12.32.33

Nonmelanoma skin cancer

Melanoma

Recurrent lesion size >2.0 cm

Breslow thickness (continuous variable)

Depth>4.0mm

Clark level > III

Clark levels IV-V

Ulceration of primary

Invasion to subcutaneous tissues

Patient age <60 y

Poor histologic differentiation

Histologic type other than superficial spreading

Preexisting scar

Lymphovascular invasion

Ear or lip location

Vertical growth phase present

Perineural invasion

Infiltrative tumor strands

Lymphovascular invasion

Single cell infiltration

Inflammation

Acantholysis

16.5.2 Impact of Regional Metastases

The reported rate of metastatic cSCC ranges from 0.1 to 21% in the literature, and these metastases are often delayed by several months from diagnosis of the primary lesion.11.12 The range of variance in the literature is partly due to the aforementioned issue that NMSC is not routinely reported by cancer registries, or followed by SEER. Patients with nodal metastases of cSCC exhibit diminished overall survival (OS; 46.7 vs. 75.7%), disease-free survival (DFS; 40.9 vs. 65.2%), and disease-specific survival (DSS; 58.2 vs. 91.5%) at 5 years, compared with patients without nodal metastases.12 As a result, there is a growing appreciation that nodal metastases in cSCC demand aggressive treatment, predicated on the early identification of high-risk features in the primary lesion or, perhaps, early detection of regional metastases through sentinel lymph node biopsy (SLNB). Increasing depth of invasion and the histologic presence of lymphovascular invasion have exhibited the strongest correlation with nodal metastases.12

As in NMSC, the presence of nodal metastases in cutaneous melanoma portends a worse prognosis. Patients with subclinical lymphatic involvement detected on sentinel lymph node biopsy have a 3-year DFS of roughly 56%; in contrast, patients with comparable primary lesions but with negative sentinel nodes have a 3-year DFS of more than 88%. In fact, the presence of lymph node metastases has emerged as a stronger predictor of diminished DFS and DSS than Clark’s level, Breslow’s thickness, and ulceration status.34 Much of the recent data on high-risk features for nodal metastases in melanoma have been gleaned from prospective trials evaluating SLNB. Historically, the depth of the primary melanoma was the most significant determinant of regional metastases, as lesions less than 1.0 mm thick have less than a 5% rate of nodal metastases, and lesions greater than 4.0 mm thick have a 30 to 50% rate of nodal metastases.35 Erman et al found that a positive SLNB was the strongest factor for a decreased recurrence-free survival (RFS) and decreased OS. Other factors, such as an increased Breslow thickness of the primary lesion and presence of ulceration, were both found to decrease RFS and OS.36

16.5.3 Staging

Although the importance of clinical staging in melanoma has been well established, clinical staging, particularly of the regional lymph nodes, in cSCC continues to evolve. O’Brien et al helped describe that higher “P” and “N” stages correlate with larger or more numerous nodal metastases in either the parotid gland or cervical lymph nodes, and thus have adverse effects on locoregional control and survival, validating the parotid gland as a nodal basin for cutaneous malignancy of the head and neck. Further updates have been made to the eighth edition of the AJCC staging system for cSCC of the head and neck.37 High-risk features such as location, size, depth, and differentiation are highlighted in cSCC, as depicted in Table 16.5.

Table 16.5 Staging of skin cancer of the head and neck

Primary tumor (T)

Melanoma

 

cSCC

 

TX

Primary tumor cannot be assessed

Primary tumor cannot be assessed

 

T0

No evidence of primary tumor

No evidence of primary tumor

 

Tis

Melanoma in situ

Carcinoma in situ

 

T1

Tumor< 1.0 mm in thickness

Tumor<2 cm

 

a

<0.8 mm without ulceration

   

b

<0.8 mm with ulceration or 0.8-1.0mm with or without ulceration

   

T2

Tumor>1.0-2.0mm in thickness

Tumor>2cm but<4

 

a

1-2 mm without ulceration

   

b

1-2 mm with ulceration

   

T3

Tumor>2.0-4.0mm thick in thickness

Tumor >4 cm or minor bone erosion or PNI or deep invasion

a

2.0-4.0 mm without ulceration

   

b

2.0-4.0mm with ulceration

   

T4

Tumor>4.0mm in thickness

See below

 

a

>4.0 mm without ulceration

Tumor with gross cortical bone/marrow invasion

b

>4.0 mm with ulceration

Tumor with skull base invasion and/or skull base foramen involvement

Regional lymph nodes (N)

Melanoma

   

cSCC

   

Presence of in-transit, satellite, and/or microsatellite metastases

 

NX

Regional lymph nodes not assessed

No

Regional lymph nodes not assessed

N0

No regional lymph node metastases

No

No regional lymph node metastases

N1

One positive lymph node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes

Metastasis in a single ipsilateral lymph node < 3 cm and ENE (-)

a

One clinically occult (i.e., detected with SLNB)

No

 

b

One clinically detected

No

 

c

No regional lymph node disease

Yes

 

Continued

N2

Two or three positive lymph nodes or in-transit, satellite, and/or microsatellite metastases with one tumor-involved node

See below

a

Two or three clinically occult (i.e., detected No with SLNB)

Metastasis in single ipsi- or contralateral lymph node <3 cm and ENE (+) or a single ipsilateral node>3 cm but< 6cm and ENE (-)

b

Two or three, at least one that was clinically No detected

Metastasis in multiple ipsilateral lymph nodes < 6cm and ENE (-)

c

One clinically occult or clinically detected Yes

Metastasis in bilateral or contralateral lymph nodes < 6 cm and ENE (-)

N3

Four or more positive nodes, or in-transit, satellite, and/or microsatellite metastases with two or more positive nodes, or any number of matted nodes with/without in-transit, satellite, and/or microsatellite metastases

See below

a

Four or more clinically occult (i.e., detected No with SLNB)

Metastasis in a single lymph node>6 cm and ENE (-)

b

Four or more, at least one of which was No detected clinically, or presence of matted nodes

Metastasis in a single lymph node>3 cm and ENE (+) or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE (+)

c

Two or more clinically occult or clinically Yes detected and/or presence of matted nodes

N/A

Distant métastases (M)

Melanoma

 

cSCC

M0

No distant metastases

No distant metastases

Ml

Distant metastases

Distant metastases

a

Distant metastasis to skin, soft tissue (muscle and/or nonregional lymph node). M1a (0): LDH not elevated; M1a (1): LDH elevated

N/A

b

Lung metastasis. M1b (0): LDH not elevated; M1b (1): LDH elevated

N/A

c

Distant metastasis to non-CNS visceral sites with/without M1a or M1b sites of disease. M1c (0): LDH not elevated; M1c (1): LDH elevated

N/A

D

Distant metastasis to CNS with/without M1a, M1b, or M1c sites of disease. M1d (0): LDH normal; M1d (1): LDH elevated

N/A

Abbreviations: CNS, central nervous system; ENE, extranodal extension; LDH, lactate dehydrogenase; PNI, perineural invasion; SLNB, sentinel lymph node biopsy.

Source: Adapted from Amin et al.31

Given the challenges in identifying aggressive cSCC, alternative systems have recently been proposed that may offer increased prognostic accuracy by dividing T2 tumors based on the number of identified risk factors, incorporating other risk factors such as soft-tissue metastases, and modifying the nodal classification. Ideally, this evolution of staging systems and appreciation of high-risk features will drive changes in pathology reports to facilitate proactive treatment of at-risk nodal basins. One alternative staging system has demonstrated increased accuracy for predicting local recurrence, nodal metastases, and disease-specific death, compared to the AJCC or Union for International Cancer Control (UICC) systems.38

16.5.4 Management of the Primary Lesion

Because it is so common and enjoys a generally accepted favorable prognosis, cutaneous malignancy of the head and neck is treated by a variety of both practitioners and modalities. In general, treatments may be destructive or excisional in nature. For premalig- nant—or early low-risk lesions—destructive therapies may be appropriate, but multidisciplinary evaluation (including dermatologists, dermatologic surgeons, head and neck surgeons/surgical oncologists, radiation oncologists, and reconstructive surgeons) prior to excision, with comprehensive margin assessment, is the standard of care for aggressive lesions. Although traditional wide local excision is typically performed in advanced or aggressive lesions—at risk for, or associated with, nodal metasta- ses—it should be noted that evaluation and treatment of regional lymph nodes can be performed with both wide local excision and Mohs’ micrographic technique. Typical margins of excision are depicted in Table 16.6.

Table 16.6 Recommendations for surgical margins according to the histology of the primary

Lesion

Surgical margin

Malignant melanoma

5 mm: pTis melanoma (in situ)

1cm: pT1 melanoma (<1.0 mm)

1-2 cm: pT2 melanoma (1.0-2.0 mm) 1-2 cm: pT3 melanoma (2.0-4.0mm) 2 cm: pT4 melanoma (>4.0mm)

Squamous cell carcinoma

4 mm in low-risk lesions 6 mm in high-risk lesions

Basal cell carcinoma

3 mm in small lesions (<2cm)

5-15 mm in morpheaform type or >2 cm

16.6 Management of Regional Metastases

16.6.1 The N0 Neck

Traditionally, regional metastases of head and neck NMSC have been approached in a reactive fashion, after a period of observation has occurred following primary treatment; melanoma was approached more aggressively because of a higher rate of lymph node metastasis (roughly 20%). The reported rate of regional lymph node metastases in cSCC is generally accepted as 4 to 5%, but it may reach as high as 20% in select populations.39 40 Options for managing the N0 neck include watchful waiting, SLNB, and elective neck dissection (END) or radiation. Watchful waiting is recommended for patients with low-risk NMSC, and for patients with thin (<0.8 mm) melanoma.

Elective Neck Dissection

The current literature does not support routine END for cutaneous malignancy in the clinically and radiographically negative neck (cN0); however, recent studies have shown it may be beneficial in specific situations. END has been advocated in the presence of isolated parotid metastasis, since occult microscopic disease is identified in the cervical lymph nodes (levels II and III) in 42% of patients. As the understanding of the role of the parotid gland as the primary lymphatic basin for the majority of the head and neck has evolved, the concurrent neck dissection is less viewed as “elective” but rather “therapeutic,” since the first echelon nodes are already in- volved.41 This is a reciprocal relationship, as occult parotid disease was identified in a comparable number of patients with anterior cervical lymph node metastases from cSCC of anterior/lateral scalp and facial primaries.

There are certain clinical situations when END for skin cancer is justified. Patients with skull base invasion by cSCC who underwent END demonstrated a significant difference in 5-year DFS versus those whose lymphatics were observed (57 vs. 32%, respectively). This was an orphan benefit for another indication for END: the need to identify and isolate recipient vessels for free tissue transfer as part of managing the primary tumor.42 These findings all support the basis for including an END if the parotid gland is involved and an elective parotidectomy if the cervical nodal bundle is involved (site dependent) and, potentially, when there is skull base involvement by the primary lesion.

Sentinel Lymph Node Biopsy

SLNB has become increasingly important in the management of cutaneous malignancy. First introduced in 1992 by Morton et al, sentinel lymph node (SLN) mapping and biopsy is predicated on the premise that metastasizing tumor cells will spread first to the draining lymphatic basin, and an identifiable node within that basin accurately represents the status of the entire basin in both melanoma and cSCC.43 The identification of a positive SLN has emerged as the most important prognostic factor for recurrence and survival in cutaneous melanoma, and is increasingly performed for MCC.34 Increasing clinical primary tumor size (without a lower threshold of benefit), increasing tumor thickness, increasing mitotic rate, and an infiltrative growth pattern of primary MCC have been associated with positive SLNB, with reported positivity rates of 11 to 57%.44 Although SLNB for MCC has been accompanied by false-negative results in up to 20% of cases, a negative SLNB has been associated with improved 5-year DSS (84.5 vs. 64.6%).45,46

With the increased acceptance of high-risk features in cSCC, there is growing interest in SLNB for cSCC—the technique has been shown to be reliable and feasible, with a false omission (false negative/false negative + true negative) rate of 5% that mirrors melanoma.36,47 Unfortunately, specific risk factors have not been universally reported, and the low overall rate of regional metastases discourages routine SLNB in all cSCC patients. A recent meta-analysis identified positive sentinel nodes in 12.3% of reported patients with cSCC, noting the majority of positive results in AJCC stage T2 lesions and alternative stage T2a and T2b lesions, but additional prospective trials are re- quired.48 Schmitt et al have suggested that T2 tumors > 2 cm according to the AJCC-7 guidelines and T2b tumors in the alternative staging guideline proposed by Jambusaria-Pahlajani et al may warrant SLNB, as they were found to have 11.9 and 29.4% positive SLNB findings, respectively.48

Sentinel Lymph Node Biopsy Technique

According to current clinical practice, SLNB requires both preoperative lymphoscintigraphy and intraoperative lymphatic mapping. Preoperative lymphoscintigraphy involves the intradermal injection of 1.0 to 4.0 pCi of 99mTc sulfur colloid or 99mTc antimony trisulfide colloid in the four quadrants of the lesion periph- ery.49,50 Looking forward, a newly Food and Drug Administration (FDA) approved receptor-binding molecular imaging agent, 99mTc-tilmanocept, has shown unique advantages over the colloid versions in its ability to rapidly clear injection site, yield high sentinel node extraction, and propensity for low distal node ac- cumulation.51 Immediate and delayed images are then performed to identify the draining lymphatic basins. More recently, fused single-photon emission CT/CT (SPECT/CT) has shown promise for these imaging studies in large part due to the clarity achieved through increased three-dimensional detail and superior resolution. One large prospective study comparing the modality to planar lymphoscintigraphy found it to be not only superior but also instrumental in changing surgical planning in 22% of cases (Fig. 16.3).52 Intraoperatively, the radiolabeled dye may be augmented by the intradermal injection of isosulfan blue dye, or methylene blue to increase the accuracy of the procedure.34 Evidence supporting the use of one blue agent over another is limited in the head and neck literature, but a case-control study comparing the use of isosulfan blue to methylene blue showed no significant difference in the success rate of sentinel lymph node biopsy in those undergoing mapping for breast cancer.53

After obtaining baseline radioactivity levels with a gamma counter, the primary lesion is excised, and the previously identified basins are inspected with the gamma counter to locate areas of increased radioactivity. The frequent close proximity of the primary lesion to the primary nodal basin may create a phenomenon called “shine-through,” whereby the different sites are not discernible or the proximate location of the primary falsely elevates the counts in the basin. It is for this reason that the primary lesion is typically excised first, but the sentinel lymph node biopsy may be performed first when the locations are farther apart. The sentinel nodes are accessed through small incisions that can be incorporated into a definitive nodal basin dissection incision if needed. Each SLN is identified and removed based on increased radioactivity counts and bluish discoloration (Fig. 16.4). Some authors routinely monitor the facial nerve in the cases in which the SLNs map to the parotid basin, although this is not a universal practice.49 Identified SLNs are then analyzed with routine hematoxylin and eosin (H&E) staining, as well as immunohistochemical staining for proteins such as S-100, MARTI, Melan-A, and HMB-45 for melanoma, cy- tokeratin for cSCC, and CK-20 in MCC. Patients with positive sentinel nodes are often returned to the operating room within 2 to 3 weeks for comprehensive neck dissections (completion lymph node dissection [CLND]).55

Identification of the SLN allows the detection of occult regional metastases, promotes accurate staging, and facilitates appropriate delivery of adjuvant therapies. Meticulous serial sectioning of the lymph nodes, augmented by routine analysis and immunohistochemical staining, has identified more patients with positive nodes than END.56 Limiting formal neck dissections to those patients with positive sentinel nodes spares unnecessary surgical morbidity for the roughly 80% of patients with intermediate-thickness melanoma, and the roughly 95% of patients with cSCC who do not have regional metastases. Subsequently, systemic therapy may be targeted to those patients who are at the greatest risk of metastases.34

Increasing experience with sentinel lymph node biopsy in the head and neck, however, has led to widespread acceptance, after a prolonged period of equipoise.49 Because lymphatic drainage in the head and neck may be highly variable, discordant drainage basins should be anticipated and investigated. SLNB in the head and neck remains challenging, because of the variability in lymphatic drainage, the proximity of the basins to the primary (shine- through), and the higher number of sentinel nodes per basin.50

Complications are uncommon, and they include seroma, hematoma, sialocele formation, cranial nerve injury to the spinal accessory nerve or the facial nerve, and adverse reactions to the blue dye that range from erythema to anaphylaxis.57 Although there is an acknowledged learning curve for sentinel lymph node biopsy, false-negative results have been documented in up to 10% of cases, and have been attributed to surgical failure or insufficient histopathologic detection.49.50 By adhering to the “10% rule” proposed by McMasters et al, detection of occult metastases may be optimized by removing all blue lymph nodes, all clinically suspicious nodes, and all nodes that are > 10% of the ex vivo radioactive count of the most radioactive sentinel node.58 A falsenegative result may lead to delayed detection and treatment of regional metastases, which could negatively impact survival.59

Fig.16.4 Sentinel lymph node biopsy performed for a T1a melanoma of the left ear lobe. Preoperative lymphoscintigraphy mapped to the tail of parotid/level II region (a), and this was marked with an “X” in the nuclear medicine suite. Because the primary site and sentinel node basin were distinct, sentinel lymph node biopsy was performed prior to wide local excision of the melanoma through an incision that would accommodate a parotidectomy with neck dissection. Intraoperative use of blue dye augments the preoperative radionucleotide, yielding a “hot” blue sentinel node immediately adjacent to the external jugular vein in the tail of parotid (b).

16.6.2 The N +Neck

The parotid gland constitutes a lymphatic basin for metastatic skin cancer, and occult cervical lymph node metastases are likely in over 40% of patients with cSCC parotid metastases.12,60 Regional metastases of cSCC typically present within 6 to 12 months after the primary, and only 20 to 65% of lymphatic metastases present concurrently with the primary lesion.61 Once identified, regionally metastatic NMSC or melanoma often merits multimodality therapy, with an appropriate lymphade- nectomy, followed by adjuvant therapy.

In cSCC, disease-free intervals of< 9 months presage a twofold elevated risk of locoregional failure, and a threefold increased risk of disease-specific death, despite best current therapies.62 The type of lymphadenectomy performed depends on the location (if known) of the primary malignancy and the history (if any) of prior treatment, especially radiation therapy (RT). The surgical principles for clinical nodal metastases are common for both NMSC and melanoma. If the parotid is involved with a functioning facial nerve, a superficial parotidectomy with facial nerve preservation may be performed followed by RT without adversely impacting disease control and survival in cSCC, even in the setting of microscopic residual dis- ease.63 Because the presence of nodal metastases in melanoma indicates more aggressive disease and a greater likelihood of distant metastases, every effort should be made to save a functioning facial nerve in melanoma as well. There is no difference in OS or DFS in patients undergoing a selective neck dissection compared to a modified radical neck dissection, although a comprehensive neck dissection or modified radical neck dissection may be required in previously radiated patients.64 When the parotid is involved and the neck is clinically negative, a selective neck dissection of at least levels II and III is sufficient for many cases in cSCC, although dissection of levels I to III is indicated for facial primaries, and levels II to V for posterior scalp and neck primaries.12.62 The posterolateral neck dissection (PLND), described in the following section, is indicated for patients with posterior triangle metastases, or those with watershed or more posteriorly located primary lesions.

Posterolateral Neck Dissection: Technique

PLND has become the mainstay treatment for patients with metastatic lymphadenopathy from the posterior scalp and neck, which primarily includes two distinct groups of nodes (retro- auricular and suboccipital).65 Metastases from melanoma or NMSC originating posterior to a coronal plane made at the anterior border of the ears are thought to typically exclusively drain to the nodes in the parotid gland, postauricular nodes, or the suboccipital nodes.66 It has been demonstrated by Lengele et al that the posterior scalp and retroauricular cutaneous regions primarily follow the superficial lateral and posterior accessory pathways. More specifically, drainage is thought to travel via the suboccipital and retroauricular nodes, and then most reliably enters the jugulodigastric nodes of level IIB, superficial jugular nodes, and finally the deep nodes of levels VA and VB. Due to the extent of this pathway, PLND, including removal of levels II to V as well as the retroauricular and suboccipital nodes, is generally considered an accepted approach in the setting of metastasis from a primary in this region.67 Certain clinical situations may dictate that a parotidectomy be performed with the PLND, but routine, elective concurrent performance of parotidectomy with PLND is not required.

As with any patient, a thorough historical timeline, physical examination, and appropriate imaging as described earlier should be obtained prior to proceeding with PLND. Counseling should cover the risks of injury to the facial, spinal accessory, hypoglossal, and phrenic nerves, as well as the brachial and cervical plexuses, potential chyle leak, numbness (due to sacrifice of the supraclavicular plexus), and shoulder dysfunction (related to extensive dissection of and around cranial nerve [CN] XI and brachial plexus).

The surgical approach for a PLND is commonly performed through an S-shaped incision, or through a half-apron incision with a posterior limb (Fig. 16.5). The skin is marked and injected with 1% lidocaine with 1:100,000 epinephrine. Subpla- tysmal flaps can be elevated over the mandible superiorly and the clavicles inferiorly; care should be taken to expose to nearly the midline posteriorly in the subcutaneous plane, beyond the anterior edge of the trapezius (Fig. 16.6). Depending on the location of the primary lesion and the extent of adenopathy, levels IA and IB can be removed with the focus then turning to

dissection of levels II to IV, including the retroauricular and suboccipital nodes. In order to aid in the access to these nodes, the head of the trapezius can be reflected posteriorly, and the nodal packet delivered from the extreme posterior aspect of the dissection (Fig. 16.7). Alternatively, the superior aspect of the trapezius muscle may be removed en bloc with the suboccipital nodes, as these structures are dissected off the sple- nius muscle (Fig. 16.8). The spinal accessory nerve may first be identified entering the anterior border of the trapezius muscle, two fingerbreadths above the clavicle, or by using Erb’s point as a reference. This nerve is then dissected and skeletonized along its course in the posterior triangle (Fig. 16.9). The transverse cervical vessels may then be identified as the inferior limit of dissection. The fibrofatty tissue is then released from the posterior border of sternocleidomastoid muscle (SCM) for preparation, and to pass underneath this muscle as the external jugular vein is divided and included with the specimen due to the potential for adjacent nodal involvement.

Fig.16.5 Common surgical approaches for a posterolateral neck dissection. (a) S-shaped incision. (b) Apron or half-apron incision with posterior limb.

Fig. 16.6 Superficial anatomy of the posterior neck triangle following elevation of skin flaps. EJV, external jugular vein; GAN, greater auricular nerve; SCM, sternocleidomastoid muscle; TRP, trapezius muscle.

Fig. 16.7 Approach to the suboccipital nodes (*) by posterior retraction of the superior aspect of the trapezius muscle. SAN, spinal accessory nerve; SCM, sternocleidomastoid muscle; TRP, trapezius muscle.

Fig. 16.8 Diagram of the posterior neck illustrating en bloc resection of the superior trapezius muscle with suboccipital nodes (*). SCM, sternocleidomastoid muscle; SPL, splenius capitis muscle; TRP, trapezius muscle;

Subsequently, attention is turned to the SCM where the fascia was released, thus allowing for elevation along with the fibro- fatty contents of levels II to IV off the SCM moving from superior to inferior. With release of this fascia from the medial edge of the muscle, the segmental blood supply to the SCM can be divided. The proximal aspect of the spinal accessory nerve is then identified and dissected superiorly, to the point where it transitions lateral to the internal jugular vein, but deep to the posterior belly of digastric at the level of the transverse process of C1 (Fig. 16.10). Using C1 as a landmark at this point in the dissection has been shown helpful in identifying not only the spinal accessory nerve and internal jugular vein but also the internal carotid artery.68 The proximal spinal accessory nerve should then be skeletonized, and the contents exenterated off of the SCM in the floor of the neck. If performing an anterior approach, this allows for this to be passed underneath CN XI, and then brought forward with the remainder of the neck dissection specimen.

Fig.16.9 Identification and dissection of the spinal accessory nerve through the posterior neck triangle. EJV, external jugular vein; ERB’s, Erb’s point; SAN, spinal accessory nerve; SCM, sternocleidomastoid muscle; TRP, trapezius muscle.

Fig. 16.10 Exposure of the proximal trunk of the spinal accessory nerve though a posterior neck approach. The nerve can be seen as it enters the SCM on its medial aspect, while its distal branch emerges from its posterior aspect in direction to the trapezius. GAN, greater auricular nerve; SAN, spinal accessory nerve; SANt, trapezius branch of the spinal accessory nerve; SCM, sternocleidomastoid muscle; TCN, transverse cervical nerve.

In a similar fashion, the dissection can be continued medially along the SCM allowing for identification of the cervical rootlets, thereby preserving the cervical contribution to the spinal accessory nerve. In moving more inferiorly, the contents of levels II to IV are dissected off the internal jugular vein. The plane of dissection is superficial to the deep cervical fascia with visual identification and preservation of the phrenic nerve. The omohyoid muscle may then be divided to allow for easier access to the inferior aspect of level IV, with no appreciable functional deficit. The inferior limit of the internal jugular vein is exposed bluntly, allowing for the dissection to progress laterally to connect with the posterior limit of the dissection. Finally, the carotid sheath is opened and the fibrofatty contents of levels II to IV elevated off the carotid artery, vagus nerve, and internal jugular vein in sequence. The facial vein and superior thyroid vein are best identified and preserved if possible. Multiple branches of the external carotid system may be similarly identified and preserved. In this manner, the neck dissection specimen is then detached from the strap muscles and sectioned into levels ex vivo to be sent for permanent pathologic analysis.

Alternatively, the contents of levels II to IV may be approached through the posterior neck by retracting the SCM anteriorly. In this setting, once the proximal trunk of the spinal accessory nerve has been identified and dissected, the fibrofatty contents of the lateral neck are dissected off the lateral aspect of the internal jugular vein, maintaining the continuity of the specimen with the contents of the posterior triangle (Fig. 16.11). The specimen is subsequently dissected off the floor of the neck musculature, divided, and sent for permanent pathologic analysis (Fig. 16.12, Fig. 16.13, Fig. 16.14).

Completion Neck Dissection in SLN (+) Patients

The appropriate treatment pathway for head and neck melanoma patients with sentinel node positive (SN-positive) neck diagnoses remains undetermined. The combination of discordant drainage patterns, and the potential for bilateral drainage raise the specter of regional failure outside of the dissected beds. Recent findings noted in the Multicenter Selective Lymphadenectomy Trial II (MSLT-II) and DeCOG-SLT (complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma) trials have shown that neck CLND did not offer a melanoma-specific survival benefit compared with observation in SN- positive patients.6970 The MSLT-II trial did show, however, that CLND offered more comprehensive staging information by demonstrating additional lymph node metastases in 11.5% of the patients, potentially leading to the use of systemic therapy, and delivered improved regional control. A smaller study of 140 stage IIIa melanoma patients found a similar rate of 11.6% positive nonsentinel nodes on CLND, but the additional information led to a stage change in only 5.8% of cases.71 The decision to proceed with CLND depends on patient- and tumor-related factors, such as the number of sentinel nodes involved, the tumor burden within the nodes, and patient preference, but additional studies are certainly needed to answer this question.

Fig. 16.11 The jugular nodes (levels II—IV) are addressed throughout the posterior neck. The specimen is dissected off the internal jugular vein and kept in continuity with the posterior neck contents. IJV, internal jugular vein; M, mastoid; SCM, sternocleidomastoid muscle; SPL, splenius capitis muscle; TRP, trapezius muscle.

Fig.16.12 The superior aspect of the trapezius muscle is reflected inferiorly to reveal the presence of a pathological suboccipital lymph node (*). The specimen is in continuity with normal-appearing postauricular lymph nodes. IJV, internal jugular vein; LS, levator scapulae muscle; M, mastoid; SPL, splenius capitis muscle; TRP, trapezius muscle; VB, nodal group Vb.

Fig. 16.13 View of the surgical field upon completion of the posterolateral neck dissection. Note that the trapezius muscle was transected (arrows), and its superior portion removed en bloc with the suboccipital lymph nodes. The spinal accessory nerve expresses branching pattern distally and receives a contribution from the cervical rootlets (*). BP, brachial plexus; CR, transected cervical rootlets; IJV, internal jugular vein; LS, levator scapulae muscle; M, mastoid; Phr, phrenic nerve; SAN, spinal accessory nerve; SCM, sternocleidomastoid muscle; SPL, splenius capitis muscle; TC, transverse cervical vessels; TRP, trapezius muscle.

Fig. 16.14 Shoulder function of the same patient at 2 weeks postoperatively.

Management of the Unknown Primary with Neck Metastases

In NMSC, the development of regional metastases in the absence of a primary lesion presents a clinical challenge. Patients should be queried as to their history of skin cancer, or skin lesions that have been removed previously. Often, an index lesion can be identified, but an exhaustive search for potential lesions should be undertaken in the absence of a clear history. Importantly, patients with parotid or cervical involvement by SCC should be evaluated for UADT primary lesions. Patients with regional metastases and no identifiable primary should be treated aggressively with neck dissection followed by XRT for cSCC. Concurrent chemotherapy may be beneficial in SCC with adverse features.

16.6.3 Radiation Therapy in Regionally Metastatic Skin Cancer of the Head and Neck

When judiciously applied as a primary treatment modality in select patients who are poor surgical candidates, in anatomic regions that are difficult to reconstruct, or for those who refuse surgery, RT exhibits local control rates comparable to surgery for smaller lesions, BCC (vs. SCC), and for primary (vs. recurrent) tumors. RT has also been demonstrated to achieve local control in inoperable patients with MCC at a mean dose of 50 Gy, and there is also demonstrated efficacy in elective neck irradiation (without neck dissection or SLN biopsy) in MCC.72 As with surgery, the clinical treatment volume is determined by the clinical and histologic features of the tumor. Larger margins are required for SCC and lesions larger than 2 cm; fields can be extended to the skull base along the course of involved cranial nerves.73

Adjuvant Therapy

Postoperative RT is commonly recommended in patients with parotid or cervical metastases from cSCC after either comprehensive or therapeutic selective neck dissection. At-risk, undissected levels are included in the radiation portals, thereby minimizing potential surgical morbidity in levels with a low likelihood of involvement.12 Patients with lymphatic metastases from cSCC have demonstrated significant improvements in lo- coregional control (80 vs. 57%), and 5-year DFS (74 vs. 54%) with surgery and radiation compared with neck dissection alone.74 Adjuvant RT has been included in a prognostic scoring model (Immunosuppression, Treatment, Extranodal spread, and Margin status [ITEM] score) as a favorable variable, in contradistinction to other components (immunosuppression, extranodal spread, and margin status) that accurately stratify patients into low-, moderate-, and high-risk categories for disease-specific death.75 Adjuvant RT has demonstrated similar improvements in locoregional control and survival after SLN biopsy or regional lymphadenectomy in MCC.76 The role of RT after a positive SLB biopsy in cSCC has not been explored, but may be an option for patients who refuse CLND.77

Postoperative RT has gained favor in cutaneous melanoma because of improved locoregional control rates up to 85 to 90% in high-risk patients, without an attendant impact on survival. High-risk patients are those individuals who are unable or unwilling to undergo re-excision for recurrent primary disease, those with surgical margins that are close (< 1 cm) or frankly positive, and patients with multiple positive lymph nodes or extracapsular extension.78 The lack of correlation with survival benefit is important, however, as increasing nodal melanoma burden is associated with poorer regional control and distant metastases up to 70% within 1 year. The locoregional benefit of RT must be balanced against the limited impact on distant metastases and melanoma-specific survival and significantly higher rates of RT-related complications in such patients.79

16.6.4 Treatment of Advanced and Systemic Disease

At the present time, surgery with or without postoperative RT remains the mainstay for managing regionally metastatic cSCC, and surgery followed by systemic therapy is typically pursued for regionally metastatic melanoma. Applications of chemotherapy in cSCC of the head and neck continue to evolve, with the emergence of targeted molecular therapies and immunotherapy to supplement and supplant traditional cytotoxic agents, but there is no consensus on the indications and regimens. Vismodegib, a hedgehog signaling pathway inhibitor, has been approved by the FDA for the treatment of locally advanced or metastatic BCC, and it has demonstrated efficacy in controlling disease in patients with basal cell-nevus syndrome.80 Because of the frequent expression of the epidermal growth factor receptor in cSCC of the head and neck, there is significant interest in the use of monoclonal antibodies against its extracellular domain (cetuximab) or the internal tyrosine kinase component (erlotinib, gefitinib).81 82 83 Additional randomized controlled trials should be undertaken, but targeted therapy holds great promise.

The addition of chemotherapy to adjuvant RT for metastatic cSCC is supported by the experience with UADT SCC. However, there is a paucity of data to support its routine use. A recent retrospective study reported an improvement in median RFS to 40.3 months in patients receiving adjuvant, platinum-based chemoradiation therapy versus 15.4 months in patients receiving radiation alone.84 Despite a tendency to regard MCC as similar to other neuroendocrine tumors such as small cell lung cancer, it is a distinct disease, and the role of chemotherapy remains undefined. MCC tends to be initially chemosensitive, but treatment-related toxicities to the commonly used agents and early relapse limit its use as definitive therapy. The roles of adjuvant chemoradiation and targeted therapy also remain unclear.85

Adjuvant therapy use in melanoma is more well defined, but the emergence of newer targeted agents and immunotherapy has altered treatment regimens and provided hope to patients and clinicians. The decision for adjuvant therapy is based on risk stratification by established guidelines. High-risk, node-negative (stage IIb or IIc) patients are generally not recommended to undergo adjuvant therapy due their typically favorable prognosis, treatment toxicity, and lack of inclusion in recent immunotherapy trials.86 Stage III (lymph node involvement without distant metastases) and stage IV (presence of distant metastases) have historically been shown to benefit from adjuvant therapy with interferon-alpha following complete resection, with slight improvements in OS. However, checkpoint inhibitor immunotherapies (nivolumab, ipilimumab, and pembrolizumab) and more targeted therapies (dabrafenib, trametinib, and vemurafenib) have demonstrated modest superiority to interferon.87,88 Current literature points toward the use of adjuvant nivolumab for stage III and stage IV disease, with improved RFS at 12 and 18 months when compared to ipilimumab.89 As a result of these recent innovations, systemic therapy for melanoma is dynamic, and patients should be treated on a clinical trial or according to established guidelines.

16.7 Conclusion

Head and neck skin cancer represents a heterogeneous group of malignancies with numerous treatment challenges related to the aesthetic and functional aspects of the head and neck, its variable lymphatic drainage, and a potential for underestimating the morbidity and mortality of the disease. Appropriate multidisciplinary management of head and neck cutaneous malignancy is predicated on early identification of aggressive lesions with metastatic potential. SLNB has emerged as the standard for assessing regional lymph node status in patients with intermediate-thickness melanoma, and this technique has additional applications in cSCC and MCC. When performed, selective neck dissections may be dictated by the lymphoscintigraphic mapping of the primary lesion, and augmented with adjuvant RT to improve outcomes in cSCC and locoregional control in melanoma. Whether reactive or proactive, neck dissection and sentinel lymph node biopsy in cutaneous malignancy of the head and neck provide valuable information that completes staging, contributes to prognosis, and determines the need for radiation or an evolving array of systemic therapies, making familiarity with these foundational techniques essential in managing these emerging epidemics.

References

[1] American Cancer Society. About Basal And Squamous Cell Skin Cancer. 2016. Available at: https://www.cancer.org/cancer/basal-and-squamous-cell-skin- cancer/about/key-statistics.html. Accessed October 2017

[2] Guy GP, Jr, Machlin SR, Ekwueme DU, Yabroff KR. Prevalence and costs of skin cancer treatment in the U.S., 2002-2006 and 2007-2011. Am J Prev Med. 2015; 48(2):183-187

[3] Ali Z, Yousaf N, Larkin J. Melanoma epidemiology, biology and prognosis. EJC Suppl. 2013; 11(2):81-91

[4] Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Melanoma of the Skin. Bethesda, MD: National Institute of Health; 2017

[5] US Department of Health and Human Services. The Surgeon General's Call to Action to Prevent Skin Cancer. Washington, DC: Office of the Surgeon General; 2014

[6] Iannacone MR, Wang W, Stockwell HG, et al. Patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skin: a case-control study. BMC Cancer. 2012; 12:417

[7] Armstrong BK, Kricker A. How much melanoma is caused by sun exposure? Melanoma Res. 1993; 3(6):395-401

[8] Lallas A, Argenziano G, Zendri E, et al. Update on non-melanoma skin cancer and the value of dermoscopy in its diagnosis and treatment monitoring. Expert Rev Anticancer Ther. 2013; 13(5):541-558

[9] Reed KB, Brewer JD, Lohse CM, Bringe KE, Pruitt CN, Gibson LE. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012; 87(4):328-334

[10] Porceddu SV, Veness MJ, Guminski A. Nonmelanoma cutaneous head and neck cancer and Merkel cell carcinoma: current concepts, advances, and controversies. J Clin Oncol. 2015; 33(29):3338-3345

[11] Brougham ND, Dennett ER, Cameron R, Tan ST. The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors. J Surg Oncol. 2012; 106(7):811-815

[12] Moore BA, Weber RS, Prieto V, et al. Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck. Laryngoscope. 2005; 115 (9):1561-1567

[13] Lai SY, Weinstein GS, Chalian AA, Rosenthal DI, Weber RS. Parotidectomy in the treatment of aggressive cutaneous malignancies. Arch Otolaryngol Head Neck Surg. 2002; 128(5):521-526

[14] Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988; 124(6):869-871

[15] Yalcin O, Sezer E, Kabukcuoglu F, et al. Presence of ulceration, but not high risk zone location, correlates with unfavorable histopathological subtype in facial basal cell carcinoma. Int J Clin Exp Pathol. 2015; 8(11):15448-15453

[16] Penn R, Abemayor E, Nabili V, Bhuta S, Kirsch C. Perineural invasion detected by high-field 3.0-T magnetic resonance imaging. Am J Otolaryngol. 2010; 31 (6):482-484

[17] Frunza A, Slavescu D, Lascar I. Perineural invasion in head and neck cancers - a review. J Med Life. 2014; 7(2):121-123

[18] Sluijter CE, van Lonkhuijzen LR, van Slooten HJ, Nagtegaal ID, Overbeek LI. The effects of implementing synoptic pathology reporting in cancer diagnosis: a systematic review. Virchows Arch. 2016; 468(6):639-649

[19] Hale C. Skin: melanocytic tumor. Miscellaneous: melanocytic tumor. Features to Report. PathologyOutlines.com; 2017. Available at: http://www.pathologyout- lines.com/topic/skintumormelanocyticfeatures.html. Accessed May5,2018

[20] College of American Pathologists. Cancer Protocol Templates. 2018. Available at: http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribu- tion%20Folders/WebContent/pdf/cp-skin-melanoma-17protocol-4001.pdf

[21] Concannon R, Larcos GS, Veness M. The impact of (18)F-FDG PET-CT scanning for staging and management of Merkel cell carcinoma: results from Westmead Hospital, Sydney, Australia. J Am Acad Dermatol. 2010; 62 (1):76-84

[22] Mirk P, Treglia G, Salsano M, Basile P, Giordano A, Bonomo L. Comparison between F-fluorodeoxyglucose positron emission tomography and sentinel lymph node biopsy for regional lymph nodal staging in patients with melanoma: a review of the literature. Radiol Res Pract. 2011; 2011:912504

[23] Perng P, Marcus C, Subramaniam RM. (18)F-FDG PET/CT and melanoma: staging, immune modulation and mutation-targeted therapy assessment, and prognosis. AJR Am J Roentgenol. 2015; 205(2):259-270

[24] Krug B, Crott R, Lonneux M, Baurain JF, Pirson AS, Vander Borght T. Role of PET in the initial staging of cutaneous malignant melanoma: systematic review. Radiology. 2008; 249(3):836-844

[25] Fuster D, Rubello D. PET imaging in melanoma. PET Clinics. 2011; 6:ix-x

[26] Klein JD, Myers JN, Kupferman ME. Posterolateral neck dissection: preoperative considerations and intraoperative technique. Oper Tech Otolaryngol: Head Neck Surg. 2013; 24(1):24-29

[27] Lentsch EJ, Myers JN. Melanoma of the head and neck: current concepts in diagnosis and management. Laryngoscope. 2001; 111(7):1209-1222

[28] O'Brien CJ, Uren RF, Thompson JF, et al. Prediction of potential metastatic sites in cutaneous head and neck melanoma using lymphoscintigraphy. Am J Surg. 1995; 170(5):461-466

[29] Vico P, Fourez T, Nemec E, Andry G, Deraemaecker R. Aggressive basal cell carcinoma of head and neck areas. Eur J Surg Oncol. 1995; 21(5):490-497

[30] Lai SY, Weber RS. High-risk non-melanoma skin cancer of the head and neck. Curr Oncol Rep. 2005; 7(2):154-158

[31] Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017:1024

[32] Rowe DE, Carroll RJ, Day CL, Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992; 26 (6):976-990

[33] Shashanka R, Smitha BR. Head and neck melanoma. ISRN Surg. 2012; 2012:948302

[34] Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol. 1999; 17 (3):976-983

[35] Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001; 19(16):3622-3634

[36] Erman AB, Collar RM, Griffith KA, et al. Sentinel lymph node biopsy is accurate and prognostic in head and neck melanoma. Cancer. 2012; 118(4):1040-1047

[37] O'Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS, Jackson MA. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck. 2002; 24(5):417-422

[38] Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013; 149(4):402-410

[39] Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol. 1992; 26(3)(,)( Pt 2):467-484

[40] Czarnecki D, Staples M, Mar A, Giles G, Meehan C. Metastases from squamous cell carcinoma of the skin in southern Australia. Dermatology. 1994; 189 (1):52-54

[41] Jol JA, van Velthuysen ML, Hilgers FJ, Keus RB, Neering H, Balm AJ. Treatment results of regional metastasis from cutaneous head and neck squamous cell carcinoma. EurJ Surg Oncol. 2003; 29(1):81-86

[42] Cannon RB, Dundar Y, Thomas A, et al. Elective neck dissection for head and neck cutaneous squamous cell carcinoma with skull base invasion. Otolaryngol Head Neck Surg. 2017; 156(4):671-676

[43] Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg (Chicago, Ill.: 1960). 1992; 127(4):392-399

[44] Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol. 2011 ; 29(8):1036-1041

[45] Howle J, Veness M. Sentinel lymph node biopsy in patients with Merkel cell carcinoma: an emerging role and the Westmead hospital experience. Aus- tralas J Dermatol. 2012; 53(1):26-31

[46] Kachare SD, Wong JH, Vohra NA, Zervos EE, Fitzgerald TL. Sentinel lymph node biopsy is associated with improved survival in Merkel cell carcinoma. Ann Surg Oncol. 2014; 21(5):1624-1630

[47] Durham AB, Lowe L, Malloy KM, et al. Sentinel lymph node biopsy for cutaneous squamous cell carcinoma on the head and neck. JAMA Otolaryngol Head Neck Surg. 2016; 142(12):1171-1176

[48] Schmitt AR, Brewer JD, Bordeaux JS, Baum CL. Staging for cutaneous squamous cell carcinoma as a predictor of sentinel lymph node biopsy results: meta-analysis of American Joint Committee on Cancer criteria and a proposed alternative system. JAMA Dermatol. 2014; 150(1):19-24

[49] Schmalbach CE, Nussenbaum B, Rees RS, Schwartz J, Johnson TM, Bradford CR. Reliability of sentinel lymph node mapping with biopsy for head and neck cutaneous melanoma. Arch Otolaryngol Head Neck Surg. 2003; 129(1):61 -65

[50] de Wilt JHW, Thompson JF, Uren RF, et al. Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck. Ann Surg. 2004; 239 (4):544-552

[51] Surasi DS, O'Malley J, Bhambhvani P. 99mTc-Tilmanocept: a novel molecular agent for lymphatic mapping and sentinel lymph node localization. J Nucl Med Technol. 2015; 43(2):87-91

[52] Schmalbach CE, Bradford CR. Is sentinel lymph node biopsy the standard of care for cutaneous head and neck melanoma? Laryngoscope. 2015; 125 (1):153-160

[53] Eldrageely K, Vargas MP, Khalkhali I, et al. Sentinel lymph node mapping of breast cancer: a case-control study of methylene blue tracer compared to iso- sulfan blue. Am Surg. 2004; 70(10):872-875

[54] Daisne JF, Installé J, Bihin B, et al. SPECT/CT lymphoscintigraphy of sentinel node(s) for superselective prophylactic irradiation of the neck in cN0 head and neck cancer patients: a prospective phase I feasibility study. Radiat Oncol. 2014; 9(121):121

[55] Ross AS, Schmults CD. Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature. Dermatol Surg. 2006; 32(11):1309-1321

[56] Doubrovsky A, De Wilt JH, Scolyer RA, McCarthy WH, Thompson JF. Sentinel node biopsy provides more accurate staging than elective lymph node dissection in patients with cutaneous melanoma. Ann Surg Oncol. 2004; 11 (9):829-836

[57] Shpitzer T, Segal K, Schachter J, et al. Sentinel node guided surgery for melanoma in the head and neck region. Melanoma Res. 2004; 14(4):283-287

[58] McMasters KM, Noyes RD, Reintgen DS, et al. Sunbelt Melanoma Trial. Lessons learned from the Sunbelt Melanoma Trial. J Surg Oncol. 2004; 86(4):212-223

[59] Cascinelli N, Morabito A, Santinami M, MacKie RM, Belli F. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet. 1998; 351 (9105):793-796

[60] O'Brien CJ. The parotid gland as a metastatic basin for cutaneous cancer. Arch Otolaryngol Head Neck Surg. 2005; 131(7):551 -555

[61] Veness MJ, Porceddu S, Palme CE, Morgan GJ. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck. 2007; 29(7):621-631

[62] Ebrahimi A, Clark JR, Ahmadi N, et al. Prognostic significance of disease-free interval in head and neck cutaneous squamous cell carcinoma with nodal metastases. Head Neck. 2013; 35(8):1138-1143

[63] Ahmed MM, Moore BA, Schmalbach CE. Utility of head and neck cutaneous squamous cell carcinoma sentinel node biopsy: a systematic review. Otolaryngol Head Neck Surg. 2014; 150(2):180-187

[64] Wang JT, Palme CE, Wang AY, Morgan GJ, Gebski V, Veness MJ. In patients with metastatic cutaneous head and neck squamous cell carcinoma to cervical lymph nodes, the extent of neck dissection does not influence outcome. J Laryngol Otol. 2013; 127 Suppl 1:S2-S7

[65] Rouviere M. Anatomy of the Human Lymphatic System. Ann Arbor, MI: Edward Brothers Inc.; 1938:5-83

[66] Goepfert H, Jesse RH, Ballantyne AJ. Posterolateral neck dissection. Arch Otolaryngol. 1980; 106(10):618-620

[67] Lengele B, Hamoir M, Scalliet P, et al. Anatomic basis for the radiological delineation of lymph node areas. Major collecting trunks, head and neck. Radio- ther Oncol. 2007; 85:146-155

[68] Sheen TS, Chung TT, Snyderman CH. Transverse process of the atlas(C1): an important surgical landmark of the upper neck. Head Neck. 1997; 19 (1):37-40

[69] Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017; 376 (23):2211-2222

[70] Leiter U, Stadler R, Mauch C, et al. German Dermatologic Cooperative Oncology Group (DeCOG). Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016; 17(6):757-767

[71] Madu MF, Franke V, Bruin MM, et al. Immediate completion lymph node dissection in stage IIIA melanoma does not provide significant additional staging information beyond EORTC SN tumour burden criteria. Eur J Cancer. 2017; 87:212-215

[72] Koh CS, Veness MJ. Role of definitive radiotherapy in treating patients with inoperable Merkel cell carcinoma: the Westmead Hospital experience and a review of the literature. Australas J Dermatol. 2009; 50(4):249-256

[73] Khan L, Choo R, Breen D, et al. Recommendations for CTV margins in radiotherapy planning for non melanoma skin cancer. Radiother Oncol. 2012; 104 (2):263-266

[74] Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be considered best practice. Laryngoscope. 2005; 115(5):870-875

[75] Oddone N, Morgan GJ, Palme CE, et al. Metastatic cutaneous squamous cell carcinoma of the head and neck: the Immunosuppression, Treatment, Extranodal spread, and Margin status (ITEM) prognostic score to predict outcome and the need to improve survival. Cancer. 2009; 115(9):1883-1891

[76] Hruby G, Scolyer RA, Thompson JF. The important role of radiation treatment in the management of Merkel cell carcinoma. BrJ Dermatol. 2013; 169(5):975-982

[77] Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol. 2007; 25 (9):1043-1047

[78] Mendenhall WM, Amdur RJ, Grobmyer SR, et al. Adjuvant radiotherapy for cutaneous melanoma. Cancer. 2008; 112(6):1189-1196

[79] Guadagnolo BA, Myers JN, Zagars GK. Role of postoperative irradiation for patients with bilateral cervical nodal metastases from cutaneous melanoma: a critical assessment. Head Neck. 2010; 32(6):708-713

[80] Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012; 366(23):2180-2188

[81] Wollina U. Update of cetuximab for non-melanoma skin cancer. Expert Opin Biol Ther. 2014; 14(2):271-276

[82] Heath CH, Deep NL, Nabell L, et al. Phase 1 study of erlotinib plus radiation therapy in patients with advanced cutaneous squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2013; 85(5):1275-1281

[83] Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res. 2012; 18(5):1435-1446

[84] Tanvetyanon T, Padhya T, McCaffrey J, et al. Postoperative concurrent chemotherapy and radiotherapy for high-risk cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2015; 37(6):840-845

[85] Miller NJ, Bhatia S, Parvathaneni U, Iyer JG, Nghiem P. Emerging and mechanism-based therapies for recurrent or metastatic Merkel cell carcinoma. Curr Treat Options Oncol. 2013; 14(2):249-263

[86] Eggermont AM, Suciu S, MacKie R, et al. EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005; 366(9492):1189-1196

[87] Kirkwood JM, Strawderman MH, ErnstoffMS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996; 14(1):7-17

[88] Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010; 102(7):493-501

[89] Weber J, Mandala M, Del Vecchio M, et al. CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017; 377(19):1824-1835



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