Merkel cell carcinoma in situ: A systematic review of prognosis and management.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported. OBJECTIVE: We present a systematic review to elucidate the prognosis and management of MCCis. METHODS: We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion. RESULTS: We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported. CONCLUSION: This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis.

The role of radiotherapy in the management of non-melanoma skin cancer.

The global incidence of non-melanoma skin cancer continues to increase as the global population ages with the highest incidence in the world occurring in Australian and New Zealand patients. There are numerous treatment options available for non-melanoma skin cancer patients of which radiotherapy is an efficacious and versatile tissue preserving non-surgical (or medical) option. In patients where excision may not be an option (medically/technically inoperable) or considered less ideal (e.g. cosmetic outcome), radiotherapy offers an excellent option. Following surgery, adjuvant radiotherapy in patients with unfavourable pathology can decrease the risk of recurrence and associated morbidity. Elderly and co-morbid patients with poor performance status can benefit from short-course hypofractionated radiotherapy in the setting where surgery is not an option. As with any modality, radiotherapy has advantages and disadvantages and it is therefore important for clinicians to appreciate these. We aim to present an update for clinicians that manage patients with non-melanoma skin cancer on the role of radiotherapy.

Definitive radiotherapy for Merkel cell carcinoma confers clinically meaningful in-field locoregional control: A review and analysis of the literature.

BACKGROUND: Merkel cell carcinoma (MCC) is an uncommon radiosensitive, neuroendocrine malignancy. Treatment often involves surgery; however, older, sicker patients may not be candidates for an operation. Institutions have published data favoring the role of definitive radiotherapy for macroscopic locoregional disease. OBJECTIVE: Our objective was to report the outcome of patients treated with definitive radiotherapy. METHODS: We performed a systematic review of Medline, PubMed, and Embase databases for reported cases or series of definitive radiotherapy for macroscopic locoregional MCC. RESULTS: The mean radiation dose did not significantly differ between primary and regional sites (48.7 ± 13.2 vs 49.4 ± 10.1 Gy, P = .74). The rate of recurrence was calculated on the basis of the site of disease (11.7%) and per patient (14.3%). Recurrence was significantly more likely to occur at regional than at primary irradiated sites (16.3% vs 7.6%, P = .02). There was no association between radiotherapy dose and incidence of recurrence or nonrecurrence; primary (42.7 ± 23 vs 49.3 ± 11.8 Gy, P = .197) and regional (48.6 ± 10 vs 49.5 ± 10.3 Gy, P = .77). LIMITATIONS: A limitation of this report is that most publications were retrospective; heterogeneity was present in the size of MCC and in radiotherapy details. CONCLUSIONS: Definitive radiotherapy for locoregional macroscopic MCC was found to confer clinically meaningful local and regional in-field control.

Prognostic Significance of Lymph Node Ratio in Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck.

BACKGROUND: The prognostic variables in patients with metastatic cutaneous nodal squamous cell carcinoma (SCC) are well documented; however, the relationship between lymph node ratio (LNR) and outcome is not well researched. LNR represents the ratio of positive lymph nodes to total excised lymph nodes. We analyzed the correlation between LNR and outcome in patients who have undergone surgery for metastatic cutaneous nodal SCC of the head and neck. METHODS: Analysis was performed on retrospectively collected data, identifying patients who underwent surgery at Westmead Hospital, Sydney. Pathology reports were reviewed to ascertain LNR. A log-rank test identified a specific LNR value to compare time to disease progression (TTDP) and overall survival (OS). Multivariate proportional hazard regression models were used to review outcome. RESULTS: In total, 193 males and 45 females with a median of age 68 years were identified, with a mean recorded LNR of 0.15. On multivariate analysis, an LNR cutpoint of 0.21 was a significant predictor of decreased TTDP [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 4.40-0.49; p = 0.009] and OS (HR 2.75, 95 % CI 1.57-4.82; p < 0.001). Forty-nine of 238 patients (21 %) developed recurrence, with most recurrences being regional (29 of 49; 59 %). A total of 17 % of patients with an LNR ≤0.21 recurred compared with 40 % for patients with an LNR >0.21. CONCLUSIONS: LNR is potentially an independent predictor of outcome in patients with metastatic cutaneous nodal SCC. The clinical relevance of this finding requires further validation.

Merkel cell carcinoma: A case of palliative upper limb amputation in a patient with refractory in-transit metastases.

We report an unusual case of Merkel cell carcinoma in a 70-year-old woman with the rapid development of left upper limb in-transit and hepatic metastases. The patient had a preceding history of left-sided breast cancer. Palliative chemotherapy with carboplatin and etoposide produced a minimal response. The in-transit metastases rapidly progressed and were refractory to chemotherapy and a single fraction of palliative radiotherapy, leading to a marked impact on her quality of life, secondary to sepsis and bleeding. After lengthy discussion, she consented to an above-elbow amputation resulting in a marked improvement in her well-being. In this case, we believe that palliative amputation of the involved arm was justified and beneficial to the patient.

High-risk cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy: A literature review.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the world. A minority of patients will be given a diagnosis of a high-risk cSCC (HRcSCC) and a proportion of these will have a poor outcome. HRcSCC is characterized by an increase in aggressiveness manifested as locoregional recurrence, and occasionally death. The utility of sentinel lymph node biopsy in this group of patients is unclear without high-level evidence or clear-cut recommendations. If clinicians accept a cutoff threshold of 10% risk of harboring occult nodal metastasis, then a selected group of patients with HRcSCC may benefit from sentinel lymph node biopsy. We performed a review of the currently available evidence, in the form of systematic reviews, meta-analysis, trials, and case series and analyzed the features that define a HRcSCC and the feasibility of performing sentinel lymph node biopsy in this group of patients.

Squamous cell carcinoma of the lip in Australian patients: definitive radiotherapy is an efficacious option to surgery in select patients.

BACKGROUND: In Australia, squamous cell carcinoma (SCC) of the lip is a consequence of chronic sun exposure and treated as a nonmelanoma skin cancer. Patients may be recommended radiotherapy (RT) as a treatment modality. OBJECTIVE: To analyze the outcome of patients with early-stage SCC of the lip treated with definitive RT at Westmead Hospital, Sydney, Australia, between 1980 and 2012. METHODS AND MATERIALS: Ninety-three patients with early-stage SCC of the lip underwent RT. All patients were clinically node negative based on examination and/or relevant investigations. Retrospective chart review was performed. Patients treated since 2000 had data collected and entered prospectively. RESULTS: The most frequently involved site was the lower lip (93%). Fifty-six patients (60%) had T1N0 and 37 patients (40%) had T2N0 disease. Most patients were treated with superficial or orthovoltage RT, with the median RT dose delivered 55 Gy (range, 40 to 70 Gy). Local recurrence occurred in 5 patients (5%), whereas regional metastases developed in 5 patients (5%). One patient developed concurrent local and regional relapse. No patient developed distant metastases. The 5-year recurrence-free survival was 90%. CONCLUSION: The findings confirm the efficacy of RT as an efficacious treatment option in early-stage lip SCC.

Outcome of patients with microscopic and macroscopic metastatic nodal Merkel cell carcinoma: an Australian experience.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with a high rate of nodal metastasis. The American Joint Committee on Cancer staging system subclassifies nodal disease into microscopic and macroscopic groups based on prognosis. OBJECTIVE: To compare the outcome of patients with microscopic and macroscopic nodal metastases. MATERIALS AND METHODS: Patients were identified from a database of 180 patients with MCC who presented to Westmead Hospital, Sydney, Australia, from 1980 to 2013. Disease-free survival (DFS), overall survival (OS), and follow-up were calculated using Kaplan-Meier curves and compared using the log-rank (Mantel-Cox) test. RESULTS: Forty-one patients were diagnosed with node-positive MCC; 11 patients had microscopic nodal metastases, with five (45%) relapsing, and 30 had macroscopic disease, with 17 (57%) relapsing. There was no significant difference in DFS (p = .93) or OS (p = .63) between the two groups. CONCLUSION: The nonsignificant difference in DFS and OS suggest that even microscopic nodal metastases can predict a poor outcome. Because more than half of patients subsequently relapse, often at a distant site, there is a need to develop an effective systemic treatment.

Immunotherapy in advanced cutaneous squamous cell carcinoma: Sydney west cancer network experience.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the Caucasian population. A minority of cases are inoperable at presentation, recur or develop metastatic disease with a historical 5-year overall survival of ~10%. Treatment options in this setting are generally palliative. Immunotherapy has emerged as a new paradigm in managing these patients. METHODS: Patients presenting to Sydney West Cancer Network with locally advanced or metastatic CSCC treated with the anti-PD1 agent cemiplimab were identified. Response to treatment was objectively assessed based on RECIST1.1 or PERCIST criteria. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), therapy toxicity, and predictors of treatment response. RESULTS: A total of 19 patients were identified with a median age of 76 (range 56-94) and 4 immunosuppressed. The longest follow up duration was 28 months. ORR, complete response (CR), and partial response (PR) were 68% (13/19), 53% (10/19), and 16% (3/19), respectively. Median PFS was 12 months (95% CI 9-14) whilst median OS was not reached by end of study. Responders (CR or PR) had significantly superior OS compared to those with no response (P < 0.01). A primary site of head and neck cancer was significantly associated with ORR (P = 0.04). A single patient experienced Grade 3 toxicity with the rest being Grades 0-1. CONCLUSION: This study confirms the clinical efficacy of cemiplimab in patients with advanced CSCC with many experiencing a durable response and an acceptable adverse effect profile.

Analysis and comparison of the 7th edition American Joint Committee on Cancer (AJCC) nodal staging system for metastatic cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: The American Joint Committee on Cancer (AJCC) substantially changed the staging of cutaneous squamous cell carcinoma (cSCC) in the 7th edition of its staging manual. We aim to compare the 7th edition AJCC staging of nodal metastases from cSCC with the N1S3 staging system. METHODS: Analysis of 603 patients from two prospective cancer center databases was performed. Multivariable analysis was performed using a Cox proportional hazards competing risk model adjusting for the effect of immunosuppression, treating institution, adjuvant radiotherapy, nodal margins, and extracapsular spread. Criteria used for comparing staging systems were distribution of patients, stratification of patients according to risk of death from cSCC, and model performance. RESULTS: The N1S3 staging system functioned well in terms of distribution and stratification of patients. The distribution of patients within the AJCC staging system was problematic with three groups (N2a, N2c, and N3) containing less than 10 % of patients without any prognostic relevance. Stratification of patients within the AJCC staging system was poor in terms of monotonicity (N2c) and distinctiveness (N2a). The performance of the AJCC and N1S3 staging systems was similar despite the AJCC staging being more complex. CONCLUSIONS: The N1S3 staging system for cSCC is preferred on the grounds of better distribution, stratification, and parsimony.

Merkel cell carcinoma: an Australian perspective and the importance of addressing the regional lymph nodes in clinically node-negative patients.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy. Nodal status has prognostic significance. OBJECTIVE: We sought to analyze for factors predictive of survival and explore the significance of lymph node status and indication for sentinel lymph node biopsy in patients with MCC. METHODS: A review was undertaken of 136 patients presenting with MCC at our institution between 1980 and 2008. Patient and tumor characteristics, treatment, and patterns of relapse were analyzed. RESULTS: Ninety patients presented with stage I disease, and 46 presented with stage II disease. The median follow-up time was 21 months. In all, 74 patients developed relapse with the commonest site of relapse in the regional lymph nodes. A total of 24 patients developed nodal relapse without prior treatment of the nodal basin. The 5-year survival was 62% and the median disease-free interval was 16 months. Radiotherapy was associated with a better disease-free survival (P < .001) and overall survival was worse as the number of involved lymph nodes increased (P = .03). LIMITATIONS: This was a retrospective review with a prolonged accrual time. CONCLUSION: A high rate of nodal relapse occurred in patients with stage I disease who had undergone treatment of the primary site only. These patients may have benefited from sentinel lymph node biopsy and subsequent treatment of the nodal basin if micrometastatic disease was present, as the number of involved nodes impacted negatively on survival. Conversely, sentinel lymph node biopsy may be used to select those patients with clinical stage I disease who may avoid elective nodal treatment. Radiotherapy should have a routine role in the management of MCC.

Merkel cell carcinoma metastatic to the transverse colon: disease free after six years - cure or just prolonged remission?

Merkel cell carcinoma is an uncommon but highly immunogenic skin malignancy that has the potential to metastasize to any site in the body. Despite treatment many patients experience relapse, often to distant sites beyond the site of initial treatment. The development of distant soft tissue or visceral metastases is considered incurable, despite treatment with prognosis usually being measured in months. We report the case of an elderly man who developed colonic metastases from a head and neck primary and with treatment has survived disease free for over 6 years. Such reports are infrequently documented and highlight the unpredictable nature of this disease.

Immunotherapy in advanced Merkel cell carcinoma: Sydney west cancer network experience.

INTRODUCTION: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with no survival benefit demonstrated using palliative cytotoxic chemotherapy in the setting of metastatic MCC. Recently, immune checkpoint inhibitors (anti-PD-L1/PD1) have been approved in this setting after durable clinical response was demonstrated in several clinical trials. In this series, we present a multicentre real-world experience in using anti-PD-L1/PD1 in advanced MCC. METHODS: A retrospective review was performed of all patients with metastatic MCC who were treated with at least one dose of anti-PD-L1/PD1 presenting to Sydney West Cancer Network (Westmead, Nepean and Blacktown hospitals) was performed between 2016 and 2020. Treatment response was assessed based on morphologic and/or metabolic changes of the disease on FDG-PET/CT scans. Primary end point investigated was objective response rate. Secondary outcomes included therapy toxicity, disease control and overall survival. RESULTS: Thirteen patients received anti-PD-L1/PD1 with a median age of 82 (range 62-89). Two patients had undergone prior palliative chemotherapy. The median follow-up time was 17 months (range 2-34). The overall, complete and partial response rates were 77% (10), 54% (7) and 23% (3), respectively. Treatment-related grade 1 or 2 toxicity was experienced by 69% with only 2 cases of greater severity. The median progression-free survival and overall survival were 18 months (95% CI 10-26 months) and 33 months (95% CI range 7.6-58.4 months), respectively. CONCLUSIONS: Consistent with clinical trial results, anti-PD-L1/PD1 therapy in this small series demonstrated efficacy and safety in patients with metastatic MCC.

Prognostic value of the 8th edition American Joint Commission Cancer nodal staging system for patients with head and neck cutaneous squamous cell carcinoma: A multi-institutional study.

BACKGROUND: The 8th edition American Joint Committee on Cancer staging manual (AJCC8) introduced a separate staging system for head and neck cutaneous squamous cell carcinoma (HNcSCC) which parallels mucosal SCC and incorporates extranodal extension (ENE). This study aims to evaluate its prognostic utility. METHODS: Univariate analysis of 1146 patients with metastatic HNcSCC from four Australian cancer centers was performed according to both AJCC 7th (AJCC7) and the 8th editions. RESULTS: AJCC8 increased classification of 924 (80.6%) patients to either pN2a or pN3b and 341 patients (29.8%) from stage III to IV compared to AJCC7. The disease-specific survival (DSS) was not significantly different between pN1, pN2 or pN3a categories per AJCC8. Estimates of model performance for the AJCC8 pN staging revealed modest predictive capacity (Harrell's C of 0.62 for DSS). CONCLUSIONS: The risk stratification according to pN classification of AJCC8 staging system performed poorly as a prognostic indicator.

Outcomes of patients with metastatic cutaneous squamous cell carcinoma to the axilla: a multicentre cohort study.

BACKGROUND: Metastatic cutaneous squamous cell carcinoma to the axilla is uncommon, with limited data to guide management. We sought to assess the outcomes of patients with this condition after surgery and radiotherapy. METHODS: A retrospective cohort study of patients treated at two Australian hospitals from 1994 through 2016 was performed. RESULTS: A total of 74 patients were identified, including 48 treated curatively with surgery-plus-radiotherapy and 15 with surgery alone. Compared with patients treated with surgery alone, a higher proportion of patients treated with surgery-plus-radiotherapy had lymph nodes larger than 6 cm (53% versus 8%, P = 0.012) and multiple adverse histopathological features (75% versus 47%, P = 0.04). The groups had similar 5-year disease-free survival (45% versus 46%) and overall survival (51% versus 48%). Presence of multiple positive lymph nodes was associated with reduced disease-free survival (hazard ratio 4.57, P = 0.01) and overall survival (hazard ratio 3.53, P = 0.02). Regional recurrence was higher in patients treated with surgery alone (38% versus 22%, P = 0.22) and patients with lymph nodes larger than 6 cm (34% versus 10%, P = 0.03). All recurrences occurred within 2 years following treatment. CONCLUSION: Combined-modality therapy for metastatic cutaneous squamous cell carcinoma to the axilla is recommended for high-risk patients, although outcomes remain modest. The key period for recurrence is within 2 years following treatment.

Managing patients with cutaneous squamous cell carcinoma metastatic to the axilla or groin lymph nodes.

Cutaneous squamous cell carcinoma accounts for 20% of all non-melanoma skin cancer with a minority arising on the trunk and extremities. A small proportion will develop metastases to regional nodes of the axilla or groin. We performed a retrospective review of patients with metastatic cutaneous squamous cell carcinoma to the axilla and groin treated at Westmead Hospital, Sydney. The purpose of this study was to document the treatment and outcome of these patients. We identified 18 men and 8 women with a median age of 73 years. Median follow-up was 18.5 months. Median lesion size was 27 mm (range 3-130 mm) and median thickness was 7 mm (range 3-32 mm). Nine patients developed metastases to the groin, 14 to the axilla, 1 in the epitrochlear, and 2 to both the epitrochlear and axillary lymph nodes. All patients were treated with surgery +/- radiotherapy. Recurrence developed in seven patients (27%) with most developing distant metastases. Most (6/7) patients with recurrence died. Predicting patients that may develop nodal metastatic non-head and neck cutaneous squamous cell carcinoma is difficult. Following diagnosis, surgery remains the primary treatment and select patients with unfavourable features, such as extranodal spread, may benefit from the addition of adjuvant radiotherapy.

Outcomes for elderly patients 75 years and older treated with curative intent radiotherapy for mucosal squamous cell carcinomas of the head and neck.

BACKGROUND: Elderly patients with mucosal squamous cell carcinomas of the head and neck (mHNSCC) represent a challenging clinical dilemma. METHODS: A retrospective review was performed of patients ≥75 years, treated with curative-intent radiotherapy for mHNSCC in two quaternary Sydney hospitals between 2007 and 2017. RESULTS: Ninety-five patients met inclusion criteria. The median age was 79 years (75-94). Patients received radiotherapy alone (n = 24), concurrent chemoradiotherapy (n = 22), surgery and adjuvant radiotherapy (n = 45), or surgery with adjuvant chemoradiotherapy (n = 4). Median follow-up was 4.5 years, median overall survival (OS) was 3.8 years, and 2-year and 5-year OS were 56% and 43%, respectively. Eastern Cooperative Oncology Group performance status of ≥2 (P < .001) was a statistically significant predictor of reduced OS. Thirty-four patients (36%) required hospitalization, 5 (5%) did not complete radiotherapy, and 9 (9%) were feeding tube dependent beyond 6 months. CONCLUSIONS: Appropriately selected elderly patients can achieve durable outcomes from curative intent radiotherapy with acceptable treatment toxicity.

Role of definitive radiotherapy in treating patients with inoperable Merkel cell carcinoma: the Westmead Hospital experience and a review of the literature.

Merkel cell carcinoma (MCC) is an uncommon aggressive primary cutaneous neuroendocrine carcinoma with a propensity to spread to regional lymph nodes and distant sites. The head and neck is the commonest site for presentation (50-60%) and recent evidence suggests patients treated with excision (to achieve a negative microscopic margin) and adjuvant wide-field radiotherapy (RTx) have an improved survival compared with surgery alone. Surgery is often not possible in elderly patients with multiple co-morbidities and in patients with advanced lesions. Definitive RTx therefore remains an option in these inoperable patients, with data to report its benefit. We report the results of eight patients with inoperable MCC treated with RTx alone between 1993 and 2007 at Westmead Hospital, Sydney, Australia, and also review the relevant literature on definitive RTx in the treatment of MCC. The median age at diagnosis was 82.5 years in five women and three men. All patients were Caucasian and none were immunosuppressed. Seven of eight patients were clinically node-positive. The mean duration of follow up was 12 months. A median dose of 50 Gy was prescribed. Seven of eight patients with inoperable MCC achieved in-field control, with most eventually relapsing distantly. Treatment-related toxicity was acceptable. In keeping with our results, other studies also report high rates of in-field locoregional control following RTx alone. These findings highlight the radioresponsiveness of advanced MCC and support a recommendation of moderate-dose RTx alone in select cases. Lower-dose palliative dose fractionation schedules (e.g. 25 Gy in five fractions) may be considered in patients of very poor performance status.

Radiotherapy for early non-melanoma skin cancer.

This article reviews the important role of radiotherapy in the management of early non-melanoma skin cancer, in the definitive and adjuvant settings. Therapeutic considerations and appropriate patient selection will be discussed, as well as evidence for efficacy and potential side-effects. Additionally, we present some recent advances which may improve accessibility and quality of radiotherapy, such as more convenient dose-fractionation, wide-field treatments, electronic brachytherapy and 3D printed bolus.