Shivangi Lohia and Eric J. Lentsch
Cutaneous malignant melanoma (CMM) is an aggressive neoplasm, known for its ability to spread to regional lymphatics as well as distant sites. Although it is less common than basal cell and squamous cell carcinomas, the mortality rates associated with CMM far outstrip those of its less aggressive counterparts. When CMM is detected early, the chance of cure is very high; however, a significant number will have regional or distant spread, and the diagnostic and treatment rationale for these is complex. Herein we describe the diagnosis and treatment of regionally metastatic melanoma of the head and neck—with a focus on the differences in treatment of node-positive (N+) and node-negative (N0) patients. We will describe the central role of neck dissection in the treatment of the N + neck, and the importance of sentinel lymph node biopsy as a diagnostic/thera- peutic procedure in patients with N0 disease.
Keywords: melanoma, metastatic, neck dissection, sentinel node, MSLT-1, MSLT-2
Cutaneous melanoma of the head and neck accounts for up to 20% of all cutaneous malignant melanomas (CMMs). It is aggressive, and in this region the overall prognosis has been reported to be poorer than in other sites.1 During the last 30 years, incidence rates of CMM have increased steadily. Currently, it is estimated that in the United States 87,110 new melanomas will be diagnosed (about 52,170 in men and 34,940 in women) and 9,730 people are expected to die of melanoma.2 Although this is only 10% of all cutaneous malignancies, CMM accounts for more than 75% of all deaths from skin cancer. Despite the advances made for early primary disease, the prognosis for regional metastatic melanoma remains dismal, with overall 5-year survival of 62%.3
17.1.1 Risk Factors for Metastasis
There are several well-known risk factors for spread of melanoma (Table 17.1), the most important of which is the Breslow thickness of the primary tumor. Thicker tumors are more likely to gain access to vascular and lymphatic channels, and therefore to metastasize. Also, since facial skin is often thin, there is also a subgroup of thin melanomas (< 1 mm deep), which have invaded to Clark level IV or beyond, and behave more aggressively as well.
Multiple studies have reported the prognostic significance of anatomic site of the primary on survival rates. In general, patients with head and neck primaries are thought to have a worse prognosis than patients with extremity tumors.4 Several studies have reported that tumors arising in the so-called BANS region (upper back, upper arm, posterior neck and scalp) have worse survival rates than in the non-BANS regions, though this remains controversial.5,6 Within the head and neck, a review from the MD Anderson Cancer Center showed that lesions located on the scalp do significantly worse than lesions on the ear, face, or neck.7 This finding has been corroborated by other investigators.8
Table 17.1 Risk factors for metastatic spread in cutaneous malignant melanoma
• Breslow’s depth (and Clark’s level in thin facial skin)
• ±Clark’s level in thin facial skin
• Scalp or neck
• Presence of histological ulceration
• Mitotic rate > 1mm2
• Lympho/vascular invasion
Histologic factors that increase the risk for metastatic spread include ulceration, mitotic rate greater than 1, and lymphovascu- lar invasion. It is felt that these characteristics enable melanoma cells to invade small vessels or cause ulceration that may be closely tied to the factors that enable it to undergo lymph node metastasis. These factors have been shown to be associated not only with lymph node metastasis, but also with survival. Callery et al found that among clinical and histological node-positive patients, the prognosis was worse for patients with an ulcerated primary tumor, satellitosis, or a high mitotic rate.9 Others have duplicated those findings,10,11 the implication being that the presence of one or more histological risk factors is an important biological tumor marker that can be used in addition to tumor thickness to predict the probability of a primary tumor’s metastatic potential.
17.1.2 Patterns of Spread
The clinical course of cutaneous melanoma is highly variable. Cutaneous melanomas can spread locally through dermal lymphatic channels to form cutaneous satellite lesions (within 2 cm of the primary lesion), as well as in-transit lesions along the course of the draining lymphatics. Most commonly, however, metastatic tumor progression presents as metastasis to draining regional lymph nodes.
The pattern of these lymph node metastases is important to understand as they will greatly affect treatment (Fig. 17.1). In general, tumors located anteriorly on the face and neck generally spread to the facial, submental, submandibular, and deep cervical nodes. Tumors arising on the scalp and forehead, anterior to a coronal line drawn through the external auditory canal, most commonly spread to the parotid/periparotid lymph nodes, and upper jugular lymph nodes. Conversely, tumors arising on the scalp and occiput posterior to this line most commonly spread to the postauricular, suboccipital, and posterior triangle lymph nodes. These drainage patterns have important ramifications for treatment: with facial and anterior scalp lesions requiring a neck dissection addressing those nodes (usually a supraomohyoid or lateral neck dissection) as well as consideration of a parotidectomy, while tumors of the posterior scalp and neck would require a neck dissection that addresses different nodal groups such as a posterolateral neck dissection.
Fig.1-7.1 Predicted patterns of lymphatic drainage from primary sites in the head and neck. (Adapted from Byers RM. Cervical and parotid node dissection. In: Balch CM, Houghton AN, Milton GW, etal, eds. Cutaneous Melanoma. 2nd ed. Philadelphia, PA: JB Lippincott; 1992.)
17.2 Staging of the Neck in Melanoma
In 2017, the American Joint Committee on Cancer (AJCC) Melanoma Task Force revised the staging system for cutaneous melanomas based upon the most current data from multiple trials and studies.12 Staging adheres to the traditional tumor-nodemetastasis (TNM) classification system. This system classifies melanomas on the basis of their local, regional, and distant characteristics, as summarized in Fig. 17.2.
17.3 Treatment of Melanoma of the Neck
Surgery remains the mainstay of treatment for CMM. Primary lesions are surgically excised to achieve negative margins based on tumor thickness. The size of surgical margins has been disputed with some authors advocating for narrow margins (1 cm) and others for wide margins (4-5 cm). However, multiple studies have demonstrated comparable rates of local control and survival with 2-cm margins (for intermediate-thickness melanoma) and 1-cm margins (for thinner lesions).13.14 Of course, primary surgical resection must also be balanced with its cosmetic and functional impacts with adequate understanding of head and neck anatomy. Importantly, appropriate treatment of cutaneous melanoma must include consideration of the neck.
17.4 Management of the Neck
17.4.1 The Node-Positive Neck
Current management of the neck in CMM is guided by the presence or absence of clinically positive neck disease. Nodal disease is associated with poorer disease-specific outcomes; therefore, evidence of regional spread necessitates treatment. Though the decision to treat the neck is not controversial in patients with neck disease, there is some controversy regarding the type of treatment needed.
Traditionally, management of clinically evident nodal disease consisted of a radical neck dissection (RND). Unfortunately, this was associated with significant comorbidities and functional deficits due to sacrifice of key structures. With the advent of more conservative procedures, it became apparent that more aggressive surgical management did not appear to decrease recurrence rates. Thus, surgeons treating melanoma followed the lead of surgeons treating head and neck cancer in becoming more conservative in their neck dissections.
In the 1990s, various authors reported modifications to the RND by limiting lymphadenectomies to nodal groups at highest risk for metastases. O’Brien et al15 observed this trend when they evaluated outcomes for 397 neck dissections performed for malignant melanoma. They noted increasing use of the modified radical neck dissections (MRND) and selective neck dissection (SND), and use of adjuvant radiation therapy. They found an overall regional recurrence rate of 24% regardless of which type of neck dissection was performed. Likewise, Turkula and Woods16 described their experience with 58 patients, all of whom had clinically positive neck disease. Among this group, 34 were treated with RND, 7 underwent MRD, and 17 were treated with SND. There were no significant differences in recurrence or survival rates between the three groups. More recently, these data were confirmed by Andersen et al,17 who retrospectively evaluated a series of 57 patients treated for regional metastases and compared the extent of neck dissection in regard to nodal recurrence and survival. Overall, the rate of recurrence was not statistically different between the groups. Five-year melanoma- specific survival was also similar between the RND, MRND, and SND. The rates of failure or recurrence within the neck were similar to those previously reported within the literature. Finally, a retrospective review sought to evaluate the extent of lymphade- nectomy among patients with regional metastases. Supriya et al18 evaluated 97 patients with pathologically proven melanoma nodal metastases. From this group, 18 patients underwent comprehensive neck dissection (CND) and 79 were treated with SND. Analysis of the outcomes revealed no significant improvement in regional control or 5-year survival with CND.
Fig. 17.2 Melanoma staging as described in the AJCC Staging Manual, eighth edition. (This image is provided courtesy of Dr. M. Gormally.)
Taken together, these findings support a more conservative approach to the management of the clinically positive neck in head and neck melanoma. Specifically, MRND and SND decrease morbidity and risk of functional deficits compared to RND, without adversely affecting risk of regional recurrence or overall survival. Importantly, in SNDs, the extent of lymphadenectomy must be tailored to the disease. As described earlier, consideration must be given to the location of the primary lesion when deciding what nodal groups to remove. Also for certain primary sites, a parotidectomy should be performed in conjunction with the neck dissection. Finally, consideration of adjuvant neck radiation should be given for patients who have multiple positive nodes or extracapsular extension.
17.4.2 The Node-Negative Neck
Management of the clinically negative neck is more controversial than the clinically positive neck. In the case of a patient with known melanoma in the head and neck and no regional lymph node involvement, three strategies have been utilized. The first is observation with treatment of the neck reserved for cases where regional disease manifests later. The second is the use of elective neck dissection (END). The third is the use of sentinel lymph node biopsy (SLNB).
Observation: For stage I disease (thin melanomas: < 1 mm), the risk of occult metastases is relatively low, and management of the neck beyond observation is usually not considered. As the risk of regional metastases increases with increasing stage of the primary, most clinicians would consider some form of treatment; however, observation remains a viable option for some patients, especially those with severe comorbid conditions. Many clinicians argue that few, if any, studies have shown that END improves survival over expectant management of the neck. However, a large preponderance of the evidence suggests a survival benefit for node-positive patients undergoing SLNB as opposed to observation.19
END: Historically, if observation was not chosen, then END was commonly performed. END addresses nodal compartments at highest risk of metastases based on lymphatic drainage pathways. Thus—in the same fashion as treatment of the node-positive neck—a patient with a temporal scalp primary would need to have a parotidectomy and dissection of at least levels I, II, and III, or an MRND.
However, as described earlier, there is no evidence that END improves survival (vs. observation) among patients with CMM. Furthermore, ENDs are associated with functional and cosmetic risks, and increase treatment-related morbidity in patients who are ultimately found to be without occult metastases. For these reasons, ENDs have largely been replaced by the use of SLNB.
SLNB: It is performed with the use of dyes, radiographic contrast, or radioactive tracers to identify the first echelon of nodes receiving lymphatic drainage from the primary lesion. Once identified, these nodes are excised and evaluated for the presence of microscopic metastases, and can guide the decision to perform a more extensive neck dissection (Fig. 17.3).
SLNB provides clinically valuable information regarding treatment and staging. In their landmark paper, Gershenwald et al20 undertook a retrospective review of patients who underwent SLNB, and found sentinel nodal status to be the most important factor in predicting disease-free survival in patients with melanoma. A similar study verified these results in patients with head and neck melanoma.21 While these studies confirmed the validity of SLNB as a diagnostic method, head and neck surgical oncologists were slow to adopt this new diagnostic technique. The complex lymphatic drainage often requires excision of nodes from areas of “danger,” such as the parotid gland where the facial nerve is at risk. However, as later studies showed, there is a high success rate (95%) in identifying the sentinel node(s), with relatively low false-negative rates (< 5%) and very low complication rates with SLNB.22,23
Over the last 20 years, SLNB has shown to be a reliable diagnostic modality to determine which patients had nodal disease, and might be appropriate for completion lymphadenectomy (CND) and/or other adjuvant treatments. However, there has been a question as to whether we are improving the disease course of patients by using SLNB. Though some authors have shown that the use of SLNB and CND could decrease the rate of regional recurrence,24.25.26 whether or not this technique improves survival in melanoma patients remained controversial. This was the question that the Multicenter Selective Lymphade- nectomy Trial 1 (MSLT-1) was designed to answer. Published in 2014, it revealed that patients with intermediate-thickness melanomas with positive SLNB who underwent CND had a disease-free survival advantage compared to patients undergoing observation.19 These data bolstered the clinicians who believed in the efficacy of SLNB and made it the preferred option in patients with intermediate-thickness melanoma.
However, other studies found contradictory evidence in regard to survival following SLNB and CND. In a large SEER database study performed by Sperry et al,27 no survival benefit was seen with SLNB when compared to observation. And most recently, the Multicenter Selective Lymphadenectomy Trial 2 (MSLT-2)26 sought to evaluate the impact of immediate CND on melanoma- related survival. In this large-scale study, patients were randomized to CND or observation following SLNB. Analysis of the results showed no significant difference in melanoma-related death in patients who underwent immediate CND compared to those who underwent observation following positive SLNB. Findings from this study indicate that the performance of CND does not impart a survival advantage to patients beyond any survival the SLNB imparts. Thus, the counseling of patients who have a positive SLNB should include the option of both CND and observation. Currently, however, most national guidelines—including the National Comprehensive Cancer Network (NCCN) guidelines for melanoma—recommend a CND in the context of a positive SLNB.
Fig. 17.3 Sentinel node biopsy for cutaneous malignant melanoma of the head and neck. A 50-year-old patient with a 2.7-mm Clark level IV melanoma of the right cheek. (a) Primary lesion. (b) Preoperative lymphoscintigraphy. (c) Intraoperative blue dye injection. (d) Intraoperative localization of a sentinel-node with hand-held gamma probe. (e) Intraoperative blue dye localization. (f) Identification of four sentinel lymph nodes, one of which was positive for nodal metastasis.
One important caveat should be noted for head and neck melanoma patients in regard to the data supplied by the MSLT- 2. In this trial, head and neck patients comprised only 13% of the study subjects. No subgroup analysis was performed on head and neck patients, yet the hazard ratios were very different for head and neck patients as compared to truncal and extremity, in that they appeared to favor CND. Of course, this cannot be inferred unless a subgroup analysis of the head and neck patients is performed; at this time, that appears unlikely (personal communication with author).
Thus, at the time of this writing, SLNB remains the preferred method to evaluate (and perhaps treat) the node-negative neck. Sentinel-node biopsy has a high value for staging clinically localized, intermediate-thickness melanoma, and provides a more accurate basis for formulating a prognosis than do standard demographic and histopathological factors. The presence or absence of tumor cells in the sentinel node is critical to both accurate AJCC staging and decisions regarding lymphadenectomy and adjuvant therapy. Current NCCN guidelines recommend CND at this time, though that recommendation may weaken as the data from the MSLT-2 are considered.
Treatment of patients with melanoma of the head and neck must take into account the possibility of regional metastatic spread of the disease. The clinician must be able to process the risk factors for this disease as well as the patterns of spread in forming a diagnostic and treatment plan. Treatment should be based on the clinical findings—with clinically positive patients treated with neck dissection, usually in the form of an SND or an MRND. In patients with clinically negative necks, consideration should be given to SLNB, and when this is positive a discussion of CND versus observation should be had with the patient.
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