Cutaneous squamous cell carcinoma metastatic to the axilla and groin: Outcomes and prognostic factors.

PURPOSE: This study examined the clinical outcomes and prognostic factors of patients with metastatic cutaneous SCC metastatic to the axilla and groin when managed with curative-intent lymphadenectomy and received (neo)adjuvant treatment. METHODS AND MATERIALS: We conducted a single institution retrospective review. Patients who had nodal disease without distant spread were 18 years or older with no non-cutaneous primary identified. RESULTS: From January 2000 to July 2015, 78 patients were treated for axilla (64, 82%) or inguinal (14, 18%) involvement with cSCC. The median age was 75.5 years (range: 29-95), and 8 patients (11%) were immunosuppressed. The median size of the largest node was 45 mm (range: 8-135), and extracapsular extension was found in 63 (81%) cases. A majority of patients were treated with surgery alone (21, 26.9%) and surgery with adjuvant radiation therapy (54, 69%). The 2-year OS and PFS were 50% (95% CI: 40%-63%) and 43% (95% CI: 33%-56%), and 5-year OS and PFS were 33% (95% CI:23%-47%) and 32% (95% CI:22%-46%) respectively in the entire cohort. On univariable analysis, factors associated with longer OS were as follows: younger age (HR 1.1, 95% CI: 0.9-1.3 P = 0.021), improved performance status (HR 1.5, 95% CI:1.0-2.3 P = 0.026), lack of immunosuppression (HR 3.3, 95% CI: 1.5-7.3 P = 0.001), lower lymph node ratio (HR 1.2, 95% CI:1.0-1.3 P = 0.007), lower number of positive nodes (HR 1.1, 95% CI:1.0-1.2 P = 0.004) and the use of radiation therapy (HR 0.5, 95% CI:0.3-0.9 P = 0.012). CONCLUSION: Metastasis to the axilla and groin with cSCC has poor outcomes with standard treatment. The addition of immunotherapy warrants investigation.

Retrospective audit of patients referred for further treatment following Mohs surgery for non-melanoma skin cancer.

BACKGROUND/OBJECTIVES: To describe the characteristics, subsequent management and outcomes of patients referred for further management following Mohs micrographic surgery (MMS) for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). METHODS: Retrospective analysis of patients referred to a quaternary cancer centre from 2000 to 2015. RESULTS: In total, 83 lesions in 82 patients were referred for further management; 52 (62%) were SCC and 80 (96%) were located in the head and neck. Reasons for referral included high-risk disease for consideration for adjuvant radiotherapy (37/83, 45%), inadequate resection (28/83, 34%) or recurrence following previous MMS (15/83, 17%). Fewer than 40% of the 69 referrals received from MMS surgeons included photos or an operative report and diagram. There was discordance in pathology opinion in 11 (13%) of cases. Histopathology from MMS was reviewed in eight cases and there was discordance with the in-hospital pathology opinion in six of these. In-hospital re-excision was performed in 19 cases and in five of these the pathology report on the paraffin-sectioned re-excised tissue was discordant with prior MMS assessment. Significantly, two cases were associated with a misinterpretation of lymphocytic infiltrate as residual disease in patients with chronic lymphocytic leukaemia (CLL). CONCLUSION: This study highlights some of the challenges and limitations of MMS. Early referral for multidisciplinary management is recommended when MMS resection margins are inadequate or uncertain, especially for high-risk SCC. We recommend that referrals be accompanied by histological material, as well as a detailed report with operative photos and diagrams. CLL can pose an intraoperative diagnostic challenge. Discrepancies in the interpretation of MMS slides present an opportunity for improvement, and our findings support the role of ongoing quality assurance programs.

Outcomes following management of squamous cell carcinoma of the scalp: A retrospective series of 235 patients treated at the Peter MacCallum Cancer Centre.

BACKGROUND: Squamous cell carcinoma of the scalp is a common clinical problem in an aging population. Despite its high incidence, little has been documented regarding treatment or outcomes. METHODS: We retrospectively analysed 235 cases treated with curative intent at Peter MaCallum Cancer Centre between 1998 and 2010. The cohort was analysed for its characteristics, management, survival and prognostic factors. RESULTS: The patients were primarily male (88%) with a median age of 79 years (range 53-98 years). There was a high proportion of immunosuppressed patients (29%) and stage T2 (48%) tumours. Management included surgery (45%), radiotherapy (28%) and surgery and adjuvant radiotherapy (26%). Median follow up from treatment was 4.5 years. Estimated 5-year overall survival (OS), disease-specific survival and progression-free survival (PFS) were 59, 94 and 51%, respectively. The 5-year cumulative incidence of local and regional relapse was 11 and 7%, respectively. There were four patients who developed distant metastases and died of their disease. Statistically significant prognostic factors identified for poor outcomes for OS and PFS were T2 stage (hazard ratio [1.7 and 2.1) and immunosuppression (HR 3.3 and 3.4). CONCLUSIONS: We conclude the presence of immunosuppression and T2 stage is prognostic for survival. Further research to establish treatment principles is warranted.

p16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary.

BACKGROUND: The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear. METHODS: One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes. RESULTS: The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08; 95% confidence interval [CI], 0.85-1.36; P = .528), cancer-specific (hazard ratio, 1.12; 95% CI, 0.77-1.64; P = .542), or progression-free survival (hazard ratio, 1.03; 95% CI, 0.83-1.29; P = .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status. CONCLUSIONS: p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site.

In-Transit Metastasis From Squamous Cell Carcinoma.

BACKGROUND: In-transit metastasis from cutaneous squamous cell carcinoma (SCC) is an uncommon form of metastasis through lymphatics and occurs more commonly in immunosuppressed patients. OBJECTIVE: To identify cases of in-transit SCC and determine patient characteristics, tumor features, management, and prognosis. METHODS AND MATERIALS: A multicenter case series treated by Australian and New Zealand clinicians. RESULTS: In 31 patients, median age was 72 years (range 52-99) and 68% were immunocompetent. Tumors occurred on the head and neck in 94% of cases, with 71% of all tumors occurring on the scalp, forehead, or temple. The median time to presentation with in-transit SCC from treatment of the initial tumor was 5 months. Management included surgery (94%), radiotherapy (77%), chemotherapy (10%), and reduction of immunosuppression (3%). Median follow-up was 12 months. Overall survival at 3 and 5 years were 27% and 13%, respectively. CONCLUSION: In-transit metastases are described in 31 patients, of whom the majority was immunocompetent. The scalp, forehead, and temple were the most common sites. New clinical and histological diagnostic criteria are proposed. Prognosis was poor with 5-year survival of 13%. Recommended management is a combination of surgery and adjuvant radiotherapy. Reduction of any iatrogenic immunosuppression should be considered.

Identifying the location of locoregional recurrences after definitive radiotherapy for head and neck cancer using metabolic parameters of baseline and mid-treatment 18F-FDG-PET scans.

INTRODUCTION: Tumour recurrences after treatment of head and neck squamous cell carcinoma (HNSCC) are more likely to originate from regions of high-baseline FDG-PET uptake. Mid-treatment functional imaging can potentially predict for higher risk of tumour recurrence. The aim of this study is to correlate the location of locoregional tumour recurrence with baseline FDG-PET metabolic volumes and mid-treatment FDG-PET metabolic volumes in patients with HNSCC following definitive radiotherapy. METHODS: A total of 23 patients with 26 local and/or regional recurrences underwent baseline (W0-PET) and mid-treatment (W3-PET) 18F-FDG PET scans as part of their radiotherapy. FDG-PET-based metabolic volumes (MTV20%, MTV40%, MTV60%, MTV80%, SUV2.5, SUVpeak and PET_EDGE) were delineated onto the FDG-PET scans. The recurrence nidus was identified on FDG-PET at the time of recurrence (REC-PET). DIR-based fusion was performed for REC-PET to W0-PET, and REC-PET to W3-PET. The location of the recurrence nidus was correlated with the FDG-PET volumes. Further analysis included a comparison of the recurrence density to FDG-PET metabolic volumes. RESULTS: Most recurrences occurred within the MTV20%, MTV40% and SUV 2.5 volumes. Sixty-nine per cent of recurrences (18 of 26) occurred within both the W0 MTV40% and W3 MTV40% volumes. A higher recurrence density was seen for iso-SUV contours closer to the maximum SUV for both W0 and W3. For a number of the FDG-PET volumes, including MTV20%, MTV40% and SUV2.5, the recurrence density was improved for W3 compared to W0, however, this improvement was small in magnitude. The average volume of MTV40% contours was considerably smaller than MTV20% and SUV2.5 contours. CONCLUSION: The metabolic parameters of SUV2.5, MTV20% and MTV40% delineated on the baseline and mid-treatment FDG-PET scans encompassed the majority of recurrences. The MTV40% is significantly smaller, hence, we prefer this volume for future dose escalation studies.

Phase I/II trial of concurrent extracranial palliative radiation therapy with Dabrafenib and Trametinib in metastatic BRAF V600E/K mutation-positive cutaneous Melanoma.

BACKGROUND: Concurrent treatment with BRAF inhibitors and palliative radiation therapy (RT) could be associated with increased toxicity, especially skin toxicity. Current Eastern Cooperative Oncology Group (ECOG) consensus guideline recommend ceasing BRAF inhibitors during RT. There is a lack of data regarding concurrent RT with combined BRAF and MEK inhibitors. This single-arm phase I/II trial was designed to assess the safety and tolerability of palliative RT with concurrent Dabrafenib and Trametinib in patients with BRAF-mutant metastatic melanoma. MATERIALS AND METHODS: Patients received Dabrafenib and Trametinib before and during palliative RT to soft tissue, nodal or bony metastases. The RT dose was escalated stepwise during the study period. Toxicity data including clinical photographs of the irradiated area was collected for up to 12 months following completion of RT. RESULTS: Between June 2016 to October 2019, ten patients were enrolled before the study was stopped early due to low accrual rate. Six patients were treated at level 1 (20 Gy in 5 fractions, any location) and 4 patients at level 2a (30 Gy in 10 fractions with no abdominal viscera exposed). All alive patients completed one year of post-RT follow-up. Of the 82 adverse events (AEs) documented, the majority (90%) were grade 1 and 2. Eight grade 3 events (10%) occurred in five patients, only one was treatment-related (grade 3 fever due to Dabrafenib and Trametinib). No patients experienced grade 3 or 4 RT related toxicities, including skin toxicities. One serious AE was documented in relation to a grade 3 fever due to Dabrafenib and Trametinib requiring hospitalisation. CONCLUSIONS: The lack of grade 3 and 4 RT-related toxicities in our study suggests that Dabrafenib and Trametinib may be continued concurrently during fractionated non-visceral palliative RT to extracranial sites.

Cutaneous malignancies in Indigenous Peoples of urban Sydney.

INTRODUCTION: Despite 3% of Australians identifying as Indigenous, cutaneous malignancies in these patients, including incidence, risk factors and outcomes have not been investigated. This is despite recognition that cancer outcomes in this population are significantly poorer. METHODS: We undertook a retrospective case series of Indigenous Peoples who presented to two urban cancer therapy centres for the management of cutaneous malignancies from 2003 to 2017. Risk factors, tumour-specific characteristics, treatments and outcomes were reviewed. RESULTS: Twenty-two patients identified as Aboriginal and/or Torres Strait Islander. The median age at presentation was 61 years and the majority were male (63.6%) and had skin phototype III (86.4%). Patients presented with basal cell carcinoma (50%), squamous cell carcinoma (31.8%), melanoma (9.1%) and cutaneous sarcomas (9.1%). The majority (68.2%) presented with stage II or higher disease, and there were high rates of immunosuppression (45.5%). At the time of reporting, 68.2% patients were alive, 18.2% had died from their skin cancers and 13.6% had died from unrelated causes. CONCLUSION: This cohort has demonstrated late-stage presentation of skin cancers, with substantial morbidity and mortality from potentially treatable cutaneous malignancies. This parallels other health conditions in Indigenous Australians and has highlighted the need for improved data collection of Indigenous status to better quantify the epidemiology of skin cancer in this population. There is an imperative to improve skin cancer awareness in this population to allow earlier detection and management to ensure better outcomes.

Evaluating diffusion-weighted magnetic resonance imaging for target volume delineation in head and neck radiotherapy.

INTRODUCTION: Inter-observer variability (IOV) in target volume delineation is a source of error in head and neck radiotherapy. Diffusion-weighted imaging (DWI) has been shown to be useful in detecting recurrent head and neck cancer. This study aims to determine whether DWI improves target volume delineation and IOV. METHODS: Four radiation oncologists delineated the gross tumour volume (GTV) for ten head and neck cancer patients. Delineation was performed on CT alone as well as fused image sets which incorporated fluorodeoxyglucose (FDG)-positron emission tomography (PET) and magnetic resonance imaging (MRI) in the form of CT/PET, CT/PET/T2W and CT/PET/T2W/DWI image sets. Analysis of the variability of contour volumes was completed by comparison to the simultaneous truth and performance level estimation (STAPLE) volumes. The DICE Similarity Coefficient (DSC) and other IOV metrics for each observer's contour were compared to the STAPLE for each patient and image dataset. A DWI usability scoresheet for delineation was completed. RESULTS: The CT/PET/T2W/DWI mean GTV volume of 13.37 (10.35-16.39)cm3 was shown to be different to the mean GTV of 10.92 (8.32-13.51)cm3 when using CT alone (P < 0.001). The GTV DSC amongst observers for CT alone was 0.72 (0.65-0.79), CT/PET was 0.73 (0.67-0.80), CT/PET/T2W was 0.71 (0.64-0.77) and CT/PET/T2W/DWI was 0.69 (0.61-0.75). CONCLUSION: Mean GTVs with the addition of DWI had slightly larger volumes compared to standard CT and CT/PET volumes. DWI may add supplemental visual information for GTV delineation while having a small impact on IOV, therefore potentially improving target volume delineation.

Number of nodal metastases and prognosis in metastatic cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Existing prognostic systems for metastatic cutaneous squamous cell carcinoma of the head and neck (cSCCHN) do not discriminate between the number of involved nodes beyond single versus multiple. This study aimed to determine if the number of metastatic lymph nodes is an independent prognostic factor in metastatic cSCCHN and whether it provides additional prognostic information to the American Joint Committee on Cancer (AJCC) staging. METHODS: We retrospectively analysed 101 patients undergoing curative intent treatment for metastatic cSCCHN to parotid and/or neck nodes by surgery +/- radiotherapy at Liverpool Hospital, Sydney, Australia. The impact of number of nodal metastases on disease-free survival (DFS) and risk of distant metastases was assessed using multivariate Cox regression. RESULTS: The mean number of nodal metastases was 2.5 (range 1-12). On multivariate analysis, increasing number of nodal metastases significantly predicted reduced DFS (hazard ratio 1.17; 95% confidence interval 1.05-1.30; P = 0.004), with a 17% increased risk of recurrence or death for each additional node. This remained significant in multivariate models adjusted for AJCC 8th edition nodal and TNM stages. Number of nodal metastases was also associated with risk of distant metastatic failure (hazard ratio 1.21; 95% confidence interval 1.05-1.39; P = 0.009). CONCLUSION: Increasing number of nodal metastases is associated with decreased DFS and increased risk of distant metastases in metastatic cSCCHN, with a cumulative risk increase with each additional node. It provides additional prognostic information to the AJCC staging, which may be improved by incorporating information on the number of nodal metastases beyond the current single versus multiple distinction.

Outcomes of cutaneous squamous cell carcinoma of the head and neck with parotid metastases.

INTRODUCTION: Cutaneous squamous cell carcinoma of the head and neck (cHNSCC) metastatic to the parotid has a moderate risk of recurrence despite multimodality treatment. Immunosuppression is associated with lower rates of long-term cure. Our aim was to review outcomes of current management in a tertiary centre with a view to targeting future strategies. METHODS: A retrospective review of clinico-pathological data and outcomes for patients with metastatic cHNSCC involving the parotid gland, undergoing radical surgery and adjuvant radiotherapy during 2000-2014 was conducted. The Kaplan-Meier method was used to determine time-to-event outcomes. RESULTS: One hundred and thirty-two patients met the inclusion criteria. Median follow-up was 5.0 years. Five-year overall (OS), cancer-specific (CSS) and progression free survival (PFS) were 44% (95% Confidence Interval (CI) 34-53%), 64% (95% CI 52-74%) and 37% (95% CI 28-47%) respectively. Locoregional control (LRC) was 68% (95% CI 55-77%) at 5 years. Immunosuppressed patients fared worse (compared with immune-competent) with five-year OS, CSS, and PFS of 14% versus 53% (HR = 3.19; 95% CI 1.91-5.34), 40% versus 71% (Hazard Ratio (HR) = 2.92; 95% CI 1.38-6.19) and 10% versus 46% (HR = 2.51; 95% CI 1.52-4.14) respectively. On multivariate analysis, immune status strongly predicted OS (P < 0.001), CSS (P = 0.003), DMFS (P < 0.001) and PFS (P < 0.001), but not LRC. Largest lymph node size was the only significant factor predictive for LRC on multivariate analysis (P = 0.02). CONCLUSIONS: Despite multimodality treatment metastatic cHNSCC involving the parotid shows moderate rates of recurrence. Immunosuppressed patients with this disease have a particularly poor prognosis, demonstrating lower rates of CSS with similar rates of LRC compared to their immunocompetent counterparts.

Merkel cell carcinoma: emerging biology, current approaches, and future directions.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous cancer that predominantly occurs in patients who are older, and is associated with a high rate of distant failure and mortality. Current management strategies that incorporate surgery and radiotherapy achieve high rates of locoregional control, but distant failure rates remain problematic, highlighting the need for new effective systemic therapies. Chemotherapy can achieve high response rates of limited duration in the metastatic setting, but its role in definitive management remains unproven. Recent developments in our knowledge about the biology of MCC have led to the identification of new potential therapeutic targets and treatments. A key finding has been the discovery that a human polyomavirus may be a causative agent. However, emerging data suggests that MCC may actually be two distinct entities, viral-associated and viral-negative MCC, which is likely to have implications for the management of MCC in the future and for the development of new treatments. In this review, we discuss recent discoveries about the biology of MCC, current approaches to management, and new therapeutic strategies that are being investigated.

Patterns of radiotherapy re-treatment in patients with lung cancer: a retrospective, longitudinal study.

INTRODUCTION: The optimal initial radiotherapy utilization rate for lung cancer is estimated to be 76% of all new cases. The actual re-treatment rate has not been defined. Re-treatment information can aid clinical decision making and resource planning. The aim of this study was to examine the indications for re-treatment in a population cohort and report the proportion of patients who receive more than one radiotherapy treatment for lung cancer throughout their lifetime. METHODS: A retrospective longitudinal analysis of a cohort of patients with lung cancer treated with radiotherapy in the South Western Sydney Area Health Services (SWSAHS) in 1993 and 1996 was performed. The indication for and timing of all episodes of radiotherapy were recorded and analyzed using SPSS Data 3.5 software (SPSS, Inc., Chicago, IL). RESULTS: Of the 527 patients diagnosed with lung cancer in the study period, 279(53%) were treated at least once with radiotherapy. Initial radiotherapy was palliative for 79%, definitive for 14%, and adjuvant for 7%. The most common sites of initial radiotherapy were chest (79%), bone (10%), and brain (9%). Of the 279 patients, 73 (27%) received treatment with a second course of radiotherapy, 19 (7%) had a third radiotherapy episode, and 6 (2%) had a fourth. One patient had five radiotherapy episodes. Overall, there were 328 radiotherapy courses delivered to the 279 patients. DISCUSSION: The re-treatment rate for our cohort was 27%, exceeding other estimations of re-treatment. Common sites re-treated were chest and bone. Re-treatment was 17% of the initial linear accelerator treatment delivery work load for lung cancer.