Does Sentinel Lymph Node Biopsy Accurately Stage the Clinically Negative Neck in Early Oral Cavity Squamous Cell Carcinoma?

PURPOSE: Sentinel lymph node biopsy (SLNB) is being increasingly used worldwide as a minimally invasive option to stage the clinically node-negative neck (N0) in patients with early oral cavity squamous cell carcinomas (OCSCC). We performed this trial to assess the reliability and validity of the technique. METHODS: We did this prospective interventional nonrandomized study in patients with early (cT1-T2 OCSCC) and with negative neck. All patients underwent preoperative lymphoscintigraphy; SLNB was followed immediately by completion neck dissection (CND), thus each patient serving as their own control. The primary outcomes evaluated are sentinel lymph node (SLN) detection rate, SLN retrieval rate, and SLN status (positive or negative) compared with pathology of CND specimen to detect any false negatives. The secondary outcomes included SLN analyses (tumor burden, location in different levels of the neck, laterality, extracapsular spread, and total nodes positive) and overall survival. RESULTS: Of 60 patients, 59 (98%) had successful SLN detection with the lymphoscintigram failing to localize in 1 patient. Of the remaining 59 patients, 58 (96%) had all the SLNs retrieved, resulting in 96.4% sentinel node retrieval rate. In total, 24 (41%) SLNs were positive with 1 false negative. Using a combination of SLN and CND findings as the gold standard for lymph node involvement status, SLNB had a sensitivity of 96% (95% confidence interval [CI]: 80-100%), a specificity of 100% (95% CI: 90-100%), and negative predictive value of 97% (95% CI: 85-100%). CONCLUSION: The results of this study suggest that SLNB is an accurate technique to assess the nodal status in patients with cT1-T2 N0 OCSCC and should be considered for eligible patients.

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.

A critical analysis of the 8th edition TNM staging for head and neck cutaneous squamous cell carcinoma with lymph node metastases and comparison to N1S3 stage and ITEM risk score: A multicenter study.

BACKGROUND AND OBJECTIVES: We performed a critical analysis of the 8th edition American Joint Committee on Cancer (AJCC) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) with nodal metastases and compared the performance to the N1S3 and ITEM systems. METHODS: Multicenter study of 990 patients with metastatic HNcSCC treated with curative intent. The end points of interest were disease-specific (DSS) and overall survival (OS). Model fit was evaluated using Harrell's Concordance Index (C-index), proportion of variation explained (PVE), Akaike information criterion, and Bayesian information criterion. RESULTS: N1S3 and ITEM demonstrated good distribution into risk categories in contrast to the AJCC system, which classified the majority (90.6%) of patients as N2-3 and Stage IV due to the high rate of extranodal extension. The N2c and N3a categories appeared redundant. There was considerable discordance between systems in risk allocation on an individual patient basis. N1S3 was the best performed (DSS: C-index 0.62, PVE 10.9%; OS: C-index 0.59, PVE 4.5%), albeit with relatively poor predictive value. CONCLUSIONS: The AJCC N category and tumor node metastasis stage have poor patient distribution and predictive performance in HNcSCC. The AJCC stage, N1S3, and ITEM score all provide limited prognostic information based on objective measures highlighting the need to develop a staging system specific to HNcSCC.

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.

Hypofractionated radiotherapy in older patients with non-melanoma skin cancer: Less is better.

Radiotherapy is a non-surgical option for patients with non-melanoma skin cancer. Lesions in middle-aged to older patients with good performance status are typically prescribed 4-5 weeks of outpatient weekday treatment. Daily radiotherapy fraction sizes of 2-3 Gy are recommended to decrease the late cutaneous consequences such as in-field hypopigmentation and telangiectasia. In elderly, often unwell patients, these concerns are less of an issue and larger fraction sizes (5-7 Gy), referred to as hypofractionation, can be delivered over a shorter time yet still achieve excellent in-field control and improve a patient's quality of life and avoid the need for surgery. The three case studies presented illustrate this approach along with a review of the evidence to support this.

Education and support needs in patients with head and neck cancer: A multi-institutional survey.

BACKGROUND: Head and neck cancer (HNC) encompasses a diverse group of tumors, and thus providing appropriate and tailored information to patients before, during, and after treatment is a challenge. The objective of the current study was to characterize the experience and unmet needs of patients with HNC with regard to information and support provision. METHODS: A 28-question, cross-sectional survey was completed by patients treated for HNC at 1 of 4 institutions in New South Wales, Australia (Chris O'Brien Lifehouse and Liverpool, Westmead, and Wollongong hospitals). It consisted of the adapted Kessler Psychological Distress Scale and questions assessing information quality, quantity, and format. RESULTS: A total of 597 patients responded. The mean age of the patients was 58 years (range, 21-94 years) with 284 men and 313 women (1:1.1). The majority of patients reported information concerning the disease process (76%), prognosis (67%), and treatment (77%) was sufficient, and approximately 50% reporting having received little or no information regarding coping with stress and anxiety. A substantial percentage of patients reported receiving minimal information concerning psychosexual health (56%) or the availability of patient support groups (56%). The majority of patients preferred access to multiple modes of information delivery (72%), with the preferred modality being one-on-one meetings with a health educator (37%) followed by internet-based written information (19%). CONCLUSIONS: Patients with HNC are a diverse group, with complex educational and support needs. Patients appear to be given information regarding survivorship topics such as psychological well-being, patient support groups, and psychosexual health less frequently than information concerning disease and treatment. Verbal communication needs to be reinforced by accessible, well-constructed, written and multimedia resources appropriate to the patient's educational level. Cancer 2017;123:1949-1957. © 2017 American Cancer Society.

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.

Lack of clinical impact of 18 F-fluorodeoxyglucose positron emission tomography with simultaneous computed tomography for stage I and II Merkel cell carcinoma with concurrent sentinel lymph node biopsy staging: A single institutional experience from Westmead Hospital, Sydney.

BACKGROUND/OBJECTIVE: 18 F-fluorodeoxyglucose (FDG) positron emission tomography with simultaneous computed tomography (PET-CT) FDG PET-CT plays an important clinical role in the staging and management of Merkel cell carcinoma (MCC) although its role in stage I and II disease relative to a sentinel lymph node biopsy (SLNB) is undefined. This study aimed to compare the clinical impact of FDG PET-CT and SLNB on management in stage I and II MCC. METHODS: This was a retrospective observational study. Between 2000 and 2014, 65 patients with biopsy-proven MCC (all stages) underwent a staging FDG PET-CT as part of their investigations in Westmead Hospital, Sydney. Since 2006, 26 patients have had an SLNB and of these, 16 underwent both an SLNB and FDGPET-CT. All 16 patients had a histological diagnosis consistent with MCC without clinical evidence of regional or distant metastases prior to SLNB and FDG PET-CT (stages IB and IIB). These patients were assessed with respect to MCC staging and the subsequent change of patient management post-SLNB and FDG PET-CT. RESULTS: The SLNB identified occult lymph node metastases in 10 patients (63%), with FDG PET-CT positive in only one patient (6%). Of the six SLNB-negative patients, none demonstrated additional metastases on the FDG PET-CT. CONCLUSIONS: In patients with stage I and II MCC, FDG PET-CT is less sensitive than an SLNB in detecting occult metastatic lymph nodes. The routine use of FDG PET-CT in these patients may not be justified.

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.

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.

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.

Management of squamous cell and basal cell carcinomas of the head and neck with perineural invasion.

Perineural invasion (PNI) occurring in non-melanoma skin cancers (NMSC) is associated with an increased risk of locoregional recurrence and reduced disease-free survival. This necessitates early and accurate diagnosis, appropriate risk-stratification and a clear management strategy. The diagnosis of PNI is based on careful clinical assessment, imaging and histopathology. Surgery, preferably with margin control, and definitive or adjuvant radiotherapy (ART) are established treatment strategies for PNI. Clinical uncertainty remains over the role of ART in incidental PNI. This review synthesises current literature to ascertain which clinicopathological features impart a higher risk to individuals with PNI in NMSC, in order to provide treatment algorithms, including the identification of patient subsets that are most likely to benefit from ART. This includes those with extratumoural PNI, involvement of larger-calibre nerves, tumour invasion beyond dermis, recurrent tumour or diffuse intratumoural spread. Patients with clinical PNI may be optimally managed by a multidisciplinary head and neck cancer service that is best placed to offer skull base surgery and intensity-modulated radiation therapy (IMRT). The management options presented are stratified by histological subtype and a new classification of PNI into low-risk, medium-risk and high-risk groups.

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.

Radiotherapy alone in patients with Merkel cell carcinoma: the Westmead Hospital experience of 41 patients.

OBJECTIVES: To review the role of radiotherapy as treatment (RTx) alone in patients with Merkel cell carcinoma (MCC). METHODS: Data on 41 patients with MCC treated with RTx alone between 1993 and 2013 at Westmead Hospital, Sydney, were reviewed and analysed. RESULTS: The patients' median age was 80 (range 45-96 years) among 18 (44%) women and 23 (56%) men. All but one patient were white and six (15%) were immunosuppressed. Most (59%) were irradiated at initial diagnosis with the remainder treated in the relapse setting. The median duration of follow up was 39 months. Head and neck was the most frequently treated site (63%). The median lesion size was 30 mm (range 5-130 mm). The in-field control rate was 85%. Most out-of-field relapses were to visceral organs. Overall survival at 5 years was 40%. CONCLUSIONS: Patients with MCC treated with RTx alone experience a high likelihood of obtaining in-field disease control. Doses of 50-55 Gy in 20-25 fractions are recommended but lower doses (25 Gy in five fractions) are still effective. A minority will be cured with many patients subsequently dying of systemic relapse.

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.

Acute Diabetes-Related Complications in Patients Receiving Chemoradiotherapy for Head and Neck Cancer.

Patients with cancer and diabetes face unique challenges. Limited data are available on diabetes management in patients undergoing concurrent chemoradiotherapy (CCRT), a curative intent anticancer therapy commonly associated with glucocorticoid administration, weight fluctuations and enteral feeds. This retrospective case-control study examined the real-world incidence of acute diabetes-related complications in patients with head and neck cancer receiving CCRT, along with the impact of diabetes on CCRT tolerance and outcomes. METHODS: Consecutive patients with head and neck squamous cell or nasopharyngeal cancer who underwent definitive or adjuvant CCRT between 2010 and 2019 at two large cancer centers in Australia were included. Clinicopathological characteristics, treatment complications and outcomes were collected from medical records. RESULTS: Of 282 patients who received CCRT, 29 (10.3%) had pre-existing type 2 diabetes. None had type 1 diabetes. The majority (74.5%) required enteral feeding. A higher proportion of patients with diabetes required admission to a high-dependency or intensive care unit (17.2 versus 4.0%, p = 0.003). This difference was driven by the group who required insulin at baseline (n = 5), of which four (80.0%) were admitted to a high-dependency unit with diabetes-related complications, and three (60.0%) required omission of at least one cycle of chemotherapy. CONCLUSIONS: Patients with diabetes requiring insulin have a high risk of acute life-threatening diabetes-related complications while receiving CCRT. We recommend multidisciplinary management involving a diabetes specialist, educator, dietitian, and pharmacist, in collaboration with the cancer care team, to better avoid these complications.

Improving accuracy in nodal staging of oral cancer: Proposal of a new system.

BACKGROUND: Despite introduction of extranodal extension (ENE) into the AJCC 8th edition of oral cancer staging, previous criticisms persist, such as limited discrimination between sub-stages and doubtful prognostic value of contralateral nodal disease. The purpose of this study was to compare our novel nodal staging system, based on the number of positive nodes and ENE, to the AJCC staging system in surgically treated patients. METHODS: Retrospective analysis of 4710 patients with oral squamous cell carcinoma (OSCC) treated with surgery±adjuvant therapy in 8 institutions in Australia, North America and Asia. With overall survival (OS) and disease specific survival (DSS) as endpoint, the prognostic performance of AJCC 8th and 7th editions were compared using hazard consistency, hazard discrimination, likelihood difference and balance. RESULTS: Our new nodal staging system (PN) a progressive and linear increase in hazard ratio (HR) from pN0 to pN3, with good separation of Kaplan Meier curves. Using the predetermined criteria for evaluation of a staging system, our proposed staging model outperformed AJCC 8th and 7th editions in prediction of OS and DSS. CONCLUSION: PN was the lymph node staging system that provided the most accurate prediction of OS and DSS for patients in our cohort of OSCC. Additionally, it can be easily adopted, addresses the shortcomings of the existing systems and should be considered for future editions of the TNM staging system.