Survival of Patients With Head and Neck Merkel Cell Cancer: Findings From the Pan-Canadian Merkel Cell Cancer Collaborative.

Importance: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Due to its relatively low incidence and limited prospective trials, current recommendations are guided by historical single-institution retrospective studies. Objective: To evaluate the overall survival (OS) of patients in Canada with head and neck MCC (HNMCC) according to American Joint Committee on Cancer 8th edition staging and treatment modalities. Design, Setting, and Participants: A retrospective cohort study of 400 patients with a diagnosis of HNMCC between July 1, 2000, and June 31, 2018, was conducted using the Pan-Canadian Merkel Cell Cancer Collaborative, a multicenter national registry of patients with MCC. Statistical analyses were performed from January to December 2022. Main Outcomes and Measures: The primary outcome was 5-year OS. Multivariable analysis using a Cox proportional hazards regression model was performed to identify factors associated with survival. Results: Between 2000 and 2018, 400 patients (234 men [58.5%]; mean [SD] age at diagnosis, 78.4 [10.5] years) with malignant neoplasms found in the face, scalp, neck, ear, eyelid, or lip received a diagnosis of HNMCC. At diagnosis, 188 patients (47.0%) had stage I disease. The most common treatment overall was surgery followed by radiotherapy (161 [40.3%]), although radiotherapy alone was most common for stage IV disease (15 of 23 [52.2%]). Five-year OS was 49.8% (95% CI, 40.7%-58.2%), 39.8% (95% CI, 26.2%-53.1%), 36.2% (95% CI, 25.2%-47.4%), and 18.5% (95% CI, 3.9%-41.5%) for stage I, II, III, and IV disease, respectively, and was highest among patients treated with surgery and radiotherapy (49.9% [95% CI, 39.9%-59.1%]). On multivariable analysis, patients treated with surgery and radiotherapy had greater OS compared with those treated with surgery alone (hazard ratio [HR], 0.76 [95% CI, 0.46-1.25]); however, this was not statistically significant. In comparison, patients who received no treatment had significantly worse OS (HR, 1.93 [95% CI, 1.26-2.96)]. Conclusions and Relevance: In this cohort study of the largest Canada-wide evaluation of HNMCC survival outcomes, stage and treatment modality were associated with survival. Multimodal treatment was associated with greater OS across all disease stages.

Practice patterns for positive sentinel lymph node in head and neck melanoma.

BACKGROUND: An international survey was conducted to investigate the preferences for completion lymph node dissection (CLND) in head and neck melanomas. METHODS: A questionnaire was sent through the American Society of Head & Neck Surgery (AHNS) and Canadian Society of Otolaryngology-Head and Neck Surgery (CSO). RESULTS: Hundred and forty-nine surgeons completed the survey. Response rate was 6.3% and 9.7% from AHNS and CSO members, respectively. When presented the scenario of a 47-year-old male with a clinical T3bN0 cheek melanoma, with 1/1 positive sentinel lymph node (SLN) with nodal deposit <2 mm, 72 of respondents (48.3%) would perform a CLND. Reasons for CLND included multiples positive SLN (64.1%), size of nodal deposits (54.2%), and perceived lack of compliance to follow-up (54.2%). Surgeons with access to immunotherapy treatment were less likely to recommend CLND (p = 0.025). CONCLUSIONS: Following SLN biopsy, nearly half of the surveyed head and neck surgeons would recommend CLND, which contrasts with the current melanoma practice patterns in other anatomic locations. However, compared with an earlier study in the literature it does seem that there has been a shift away from completion neck dissection. Further investigation into understanding practice variations is warranted.

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.

BACKGROUND: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes. OBJECTIVES: To provide long-term data on patients with a complete response to IL-2 therapy for ITM. METHODS: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease. RESULTS: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3). CONCLUSION: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

Preoperative Ultrasound Assessment of Regional Lymph Nodes in Melanoma Patients Does not Provide Reliable Nodal Staging: Results From a Large Multicenter Trial.

OBJECTIVE: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging. BACKGROUND: It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low. METHODS: Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen. RESULTS: SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive (1.2%). By basin, the sensitivity of US was 6.6% (95% confidence interval: 4.6-8.7) and the specificity 98.0% (95% CI: 97.5-98.5). Median cross-sectional area of all SN metastases was 0.13 mm2; in US true-positive nodes, it was 6.8 mm2. US sensitivity increased with increasing Breslow thickness of the primary melanoma (0% for ≤1 mm thickness, 11.9% for >4 mm thickness). US sensitivity was not significantly greater with higher trial center volume or with pre-US lymphoscintigraphy. CONCLUSION: In the MSLT-II screening phase population, SN tumor volume was usually too small to be reliably detected by US. For accurate nodal staging to guide the management of melanoma patients, US is not an effective substitute for SN biopsy.

Intraoperative Near-infrared Spectroscopy Correlates with Skin Flap Necrosis: A Prospective Cohort Study.

BACKGROUND: Skin flap necrosis (SFN) is a morbid complication that is disfiguring, leads to acute and chronic wound issues, often requires further surgery, and can delay adjuvant chemotherapy. Although most surgeons rely on the clinical examination, near-infrared (NIR) spectroscopy can extrapolate tissue oxygenation and may serve as an important tool to assess flap perfusion intraoperatively. This cohort study was undertaken to evaluate the capacity of NIR spectroscopy to detect clinically relevant differences in tissue perfusion intraoperatively. METHODS: Patients undergoing oncologic resection of breast cancer, sarcomas, and cutaneous tumors requiring flap reconstruction (local, regional, or free) between January 2018 and January 2019 were analyzed in this study. Clinicians were blinded to device tissue oxygen saturation (StO2) measurements taken intraoperatively after closure and at follow-up appointments in the first 30 days. Measurements were categorized as (1) control areas not affected by the procedure, (2) areas at risk, and (3) areas of necrosis. These areas were retrospectively demarcated by 2 blinded assessors on follow-up images and transposed onto anatomically correlated intraoperative StO2 measurements. Mean StO2 values were compared using a single-sample t test and analysis of variance (ANOVA) to determine differences in oxygenation. RESULTS: Forty-two patients were enrolled, and 51 images were included in the analysis. Oncologic procedures were predominantly breast (22), postextirpative melanoma (13), and sarcoma (3) reconstructions. Flap reconstruction involved 30 regional skin flaps, 3 pedicled flaps, and 3 free flaps. Nine patients (20.9%) and 11 surgical sites developed SFN. Mean intraoperative StO2 measurements for control areas, areas at risk, and areas of SFN were 74.9%, 71.1%, and 58.3%, respectively. Relative to control areas, mean intraoperative StO2 measurements were lower by 17.5% (P = 0.01) in ultimate areas of SFN and in areas at risk by 5.8% (P = 0.003). Relative to areas at risk, mean StO2 measurements from areas of ultimate SFN were lower by 8.3% (P = 0.04). CONCLUSION: These preliminary data suggest that measuring skin flap tissue oxygenation intraoperatively, with NIR spectroscopy, can differentiate objective variations in perfusion that are associated with clinical outcomes.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

How often do level III nodes bear melanoma metastases and does it affect patient outcomes?

BACKGROUND: Limited data exist regarding the necessity of resecting level three nodes as part of an axillary dissection for melanoma. The objective of this study was to determine how often level III nodes have metastases, in patients with sentinel lymph node (SLN) positive, palpable and bulky axillary disease, and to determine patient outcomes. METHODS: A retrospective chart review was completed at two tertiary care centers of patients with melanoma that had level three axillary dissections. At the time of surgery, the level III nodes were sent as a separate specimen. Bulky disease was defined as a large mass in all three levels that could not be separated. RESULTS: A total of 117 patients were identified. Three percent and 18 % of patients with SLN+ and palpable disease, respectively, had further disease in their level III nodes. All bulky patients had level III disease. Those with level III disease had a worse 3-year overall survival than those who did not (15.2 vs. 61.1 %, p < 0.001). For patients with palpable and bulky disease, systemic recurrence rate was 65 and 88 %, with a median time to metastases of 13.6 and 2 months, respectively. CONCLUSIONS: Patients with SLN+ disease rarely have positive level III nodes, questioning the need for routine removal of these nodes. Patients with palpable and bulky lymph node disease have implied occult distant metastases at the time of diagnosis and treatment. With the advent of improved targeted therapies for melanoma, clinical trials evaluating their role in patients with stage III disease may be warranted to improve patient outcomes.