16 Neck Management in Skin Cancer

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.³ 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.

16.3 Patient Evaluation

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 melanoma^19,20

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 metastases. 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 melanoma.^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.

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

Table 16.3 Aggressive features for cutaneous squamous cell carcinoma³¹

Table 16.4 Risk factors for regional metastases in skin cancer of the head and neck^3,12,32,33

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.

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 premalignant—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 metastases—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

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 involved.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 required.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 μCi of ^99mTc sulfur colloid or ^99mTc antimony trisulfide colloid in the four quadrants of the lesion periphery.^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 accumulation.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, cytokeratin 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 false-negative result may lead to delayed detection and treatment of regional metastases, which could negatively impact survival.⁵⁹

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