Implementing structured pathology reporting protocol for non-melanocytic skin cancers: practical considerations.

Non-melanocytic skin cancers (NMSCs) account for five times the incidence of all other cancers combined and cost US $6 billion annually. These are the most frequent specimens encountered in community pathology practice in many Western countries. Lack of standardised structured pathology reporting protocols (SPRPs) can result in omission of critical information or miscommunication leading to suboptimal patient management. The lack of standardised data has significant downstream public health implications, including insufficient data for reliable development of prognostic tools and health-economy planning. The Royal College of Pathologists of Australasia has developed an NMSC SPRP. A multidisciplinary expert committee including pathologists, surgeons, dermatologists, and radiation and medical oncologists from high volume cancer centres was convened. A systematic literature review was performed to identify evidence for including elements as mandatory standards or best practice guidelines. The SPRP and accompanying commentary of evidence, definitions and criteria was peer reviewed by external stakeholders. Finally, the protocol was revised following feedback and trialled in multiple centres prior to implementation. Some parameters utilised clinically for determining management and prognosis including tumour depth, lymphovascular invasion or distance to the margins lack high level evidence in NMSC. Dermatologists, surgeons, and radiation oncologists welcomed the SPRP. Pathologists indicated that the variety of NMSC specimens ranging from curettes to radical resections as well as significant differences in the biological behaviour of different tumours covered by the NMSC umbrella made use of a single protocol difficult. The feedback included that using a SPRP for low risk NMSC was neither clinically justified nor compensated adequately by the Australian Medicare Reimbursement Schedule. Following stakeholder feedback, the SPRP implementation was restricted to excision specimens of head and neck NMSC; and low-risk NMSC, such as superficial basal cell carcinoma, were excluded. Implementing NMSC SPRP fulfils an unmet clinical need. Unlike other cancers, NMSCs generate a range of specimen types and are reported in a wide range of pathology practices. Limiting use of SPRP to NMSC at higher risk of progression and providing formatted templates for easy incorporation into laboratory information systems were essential to successful deployment. In the future, further consideration should be given to implementing the SPRP to include all relevant specimens, including non-head and neck and low-risk NMSC specimens.

Merkel cell carcinoma: a forty-year experience at the Peter MacCallum Cancer Centre.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin malignancy, with Australia having the highest reported incidence in the world. There is currently a lack of consensus regarding optimal management of this disease. METHODS: This was a retrospective audit conducted by reviewing existing medical records of MCC patients presenting to the Peter MacCallum Cancer Centre (PMCC) between 1980 and 2018. The primary endpoint was locoregional recurrence. The secondary endpoints were distant recurrence, disease-free survival (DFS) and overall survival (OS). RESULTS: A total of 533 patients were identified. Locoregional recurrence occurring at one, two and 5 years was 24, 31 and 32%, respectively. The estimated 5-year OS and DFS were 46% (95% Confidence Interval [CI] 41-51%) and 34% (95% CI 30-39%) respectively. Older age at diagnosis (hazard ratio [HR] per year = 1.07, 95% CI 1.06-1.07, p < 0.001), and larger primary tumour diameter (HR =1.16, 95% CI 1.03-1.31, p = 0.019) were associated with worse OS on multivariable analysis. Positive or negative histopathological margin status was not associated with OS or DFS differences in patients treated with post-operative radiotherapy. CONCLUSIONS: In our study, about a third of patients developed locoregional recurrence, distal recurrence or both, and there appears to be no change over the last four decades. If treated with adjuvant radiotherapy, there is no difference in OS or DFS with positive surgical margins. Findings should influence future guidelines.

Long-term control of melanoma adrenal metastasis treated with radiotherapy.

Melanoma remains a large global burden with a significant proportion of patients succumbing to metastatic disease. The adrenal gland is a common area for metastasis with surgical treatment as the main modality. Radiotherapy is less utilised in this setting with uncertainty over deliverability and efficacy. Here, we present the details and outcomes of 20 patients treated with radiotherapy, with or without systemic therapy, for melanoma adrenal metastasis in a single institute. Twenty patients were identified from radiation treatment and medical records from between 2015 and 2019 at our institution. Three patients had bilateral radiotherapy treatments and therefore 23 adrenal lesions were analysed. Demographics, indications for treatment, radiotherapy methodology and outcomes were recorded. Outcomes were based on serial 18F FDG PET/computerized tomography scans reporting using the PERCIST criteria. The most common indication for radiotherapy was oligo-progressive disease (70%) followed by symptom palliation. Eight (35%) of the treatments were delivered by stereotactic ablative body radiotherapy. Twelve (60%) patients had concurrent immunotherapy. Twenty of twenty-three (87%) adrenal lesions had an initial response to treatment with 12 (60%) maintaining local control until death or end of follow-up. Median adrenal-specific progression-free survival was 13 months. Four patients (17%) required salvage adrenalectomy. Symptom palliation was achieved in the majority of patients for which it was indicated and there were no grade three toxicities. The median time from radiotherapy to change of immunotherapy treatment was 4 months. Radiotherapy for melanoma adrenal metastasis is effective and deliverable. With the majority of patients achieving a palliative and clinically relevant durable response, adrenalectomy can be reserved as a salvage option.

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.

γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival.

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4+ or CD8+ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (>20% DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2- γδ T cells. In the context of γδ T-cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T-cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti-PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T-cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions.See related Spotlight on p. 600.

Clinical, FDG-PET and molecular markers of immune checkpoint inhibitor response in patients with metastatic Merkel cell carcinoma.

BACKGROUND: Metastatic Merkel cell carcinoma (mMCC) is an aggressive neuroendocrine malignancy of the skin with a poor prognosis. Immune checkpoint inhibitors (ICIs) have shown substantial efficacy and favorable safety in clinical trials. METHODS: Medical records of patients (pts) with mMCC treated with ICIs from August 2015 to December 2018 at Peter MacCallum Cancer Centre in Australia were analyzed. Response was assessed with serial imaging, the majority with FDG-PET/CT scans. RNA sequencing and immunohistochemistry for PD-L1, CD3 and Merkel cell polyomavirus (MCPyV) on tumor samples was performed. RESULTS: 23 pts with mMCC were treated with ICIs. A median of 8 cycles (range 1 to 47) were administered, with treatment ongoing in 6 pts. Objective responses (OR) were observed in 14 pts (61%): 10 (44%) complete responses (CR) and 4 (17%) partial responses (PR). Median time to response was 8 weeks (range 6 to 12) and 12-month progression-free survival rate was 39%. Increased OR were seen in pts aged less than 75 (OR 80% vs 46%), no prior history of chemotherapy (OR 64% vs 50%), patients with an immune-related adverse event (OR 100% vs 43%) and in MCPyV-negative tumors (OR 69% vs 43%). Pts with a CR had lower mean metabolic tumor volume on baseline FDG-PET/CT scan (CR: 35.7 mL, no CR: 187.8 mL, p=0.05). There was no correlation between PD-L1 positivity and MCPyV status (p=0.764) or OR (p=0.245). 10 pts received radiation therapy (RT) during ICI: 4 pts started RT concurrently (OR 75%, CR 50%), 3 pts had isolated ICI-resistant lesions successfully treated with RT and 3 pts with multisite progression continued to progress despite RT. Overall, 6 pts (26%) had grade 1-2 immune-related adverse events. CONCLUSION: ICIs showed efficacy and safety in mMCC consistent with trial data. Clinical and imaging predictors of response were identified.

The changing paradigm of managing Merkel cell carcinoma in Australia: An expert commentary.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin with an estimated disease-associated mortality of 15-33%. Australia has a higher incidence of MCC compared to the rest of the world, thought to be due to a higher ultraviolet index. The Australian MCC population is distinct from the MCC population of the Northern hemisphere, characterized by a predominantly viral negative etiology with high tumor mutational burden. The optimal management of MCC and the choice of treatment modality vary significantly across the world and even between institutions within Australia. Historically, the treatment for MCC has been resection followed by radiotherapy (RT), though definitive RT is an alternative treatment used commonly in Australia. The arrival of immune checkpoint inhibitors and the mounting evidence that MCC is a highly immunogenic disease is transforming the treatment landscape for MCC. Australia is playing a key role in the further development of treatment options for MCC with two upcoming Australian/New Zealand investigator-initiated clinical trials that will explore the interplay of RT and immunotherapy in the treatment of early and late stage MCC.

Treatment Package Time in Node-Positive Cutaneous Head and Neck Squamous Cell Carcinoma.

PURPOSE: Treatment package time (TPT) prolongation is associated with lower overall survival and locoregional control in mucosal head and neck squamous cell carcinoma (SCC), but there are few reports in cutaneous HNSCC (cHNSCC). We sought to test the effect of TPT in a cohort of patients with cHNSCC. METHODS: This is a single institution retrospective study of node-positive cHNSCC patients involving either the parotid or cervical nodes treated with curative intent surgery with macroscopic tumor clearance followed by standard fractionation postoperative radiation therapy (PORT) from 2001 to 2014. We assessed the effect of TPT and other prognostic variables on overall survival (OS), cHNSCC specific survival (CSS) progression free survival (PFS), and freedom from locoregional failure (FFLRF). RESULTS: In the present study, 152 patients met the inclusion criteria. The 5-year OS, CSS, PFS, and FFLRF were 62% (95% confidence interval [CI], 54-71), 78% (95% CI, 71-87), 54% (95% CI, 46-64), and 76% (95% CI ,68-85), respectively. In a multivariable model, TPT ≥14 weeks was associated with worse outcomes in all endpoints (OS [hazard ratio (HR) 4.93; 95% CI, 2.54-9.56, P < .001], CSS [HR 6.09; 95% CI, 2.33-15.92; P = .001], PFS [HR 4.29; 95% CI, 2.21-8.34; P < .001], and FFLRF [HR 4.63; 95% CI, 1.71-12.51; P = .007]). Immunosuppression and the presence of ≥2 pathologically involved lymph nodes were also significant adverse factors for both OS and FFLRF, although extracapsular extension was also associated with lower FFRLF. Delays to commencing PORT rather than treatment breaks accounted for the majority of cases with prolonged TPT. CONCLUSIONS: Prolongation of TPT to 14 weeks or longer may confer a lower probability of locoregional control and survival in patients with lymph node-positive cHNSCC treated with surgery and PORT. Timely referral and commencement of PORT is necessary to maximize long-term disease outcomes.

A phase II study of induction carboplatin and gemcitabine followed by chemoradiotherapy for the treatment of locally advanced nasopharyngeal carcinoma.

OBJECTIVES: To investigate the tolerability and feasibility of induction gemcitabine and carboplatin chemotherapy followed by radiotherapy with concurrent cisplatin in patients with locally advanced nasopharyngeal carcinoma. PATIENTS AND METHODS: Twenty-eight patients with previously untreated non-keratinising nasopharyngeal carcinoma, with stage IIb to IV disease were enroled to receive three cycles of carboplatin AUC 5 and gemcitabine 1 g/m(2) day 1 and 8 every 21-days, followed by 70 Gy of radiotherapy with concurrent cisplatin 20 mg/m(2)/day for 5 days of weeks 1, 4 and 7. RESULTS: 26/28 (93.0%) patients received all three cycles of induction chemotherapy. All 27 patients who commenced chemoradiotherapy received 70 Gy in 35 fractions of radiotherapy with at least two cycles of concurrent cisplatin. The three-year time to locoregional failure rate was 92.9% (95% CI: 75.5-98.2%) and the three-year overall survival rate was 89.3% (95% CI: 71.6-96.5%). Induction chemotherapy was well tolerated with 5/28 (17.9%) patients experiencing grade 3 non-haematological toxicities and no reported episodes of febrile neutropenia or grade 4 toxicity. For the 27 patients who received radiotherapy, no acute grade 4 radiation toxicities and only 2/27 (7.4%) late grade 4 radiation adverse events were observed. CONCLUSION: The use of induction carboplatin and gemcitabine followed by chemoradiotherapy is feasible, with acceptable toxicity, and is a promising regimen for the treatment of locally advanced nasopharyngeal carcinoma.

Larynx preservation with primary non-surgical treatment for loco-regionally advanced larynx cancer.

INTRODUCTION: The objective of this paper was to review the results of primary non-surgical treatment with the aim of larynx preservation for loco-regionally advanced larynx cancer (LALC). METHODS: All patients with LALC presenting between January 2002 and December 2006 who were selected for primary non-surgical treatment were included in this study. RESULTS: There were 60 patients, 48% with stage III and 52% with stage IV disease. The median follow-up of living patients was 41 months. Larynx preservation with local disease control was achieved in 83% and 77% of patients at 3 and 5 years, respectively. Failure-free survival at 3 and 5 years was 66% and 59%, respectively, and overall survival was 67% and 45%, respectively. All patients with larynx preservation had a functional voice. Two patients became feeding tube dependant. Thirty-nine percent of all deaths were unrelated to LALC. CONCLUSIONS: Primary non-surgical treatment achieves high rates of larynx preservation with a low rate of severe complications but overall survival remains disappointing.

Knowledge, perceptions, and attitudes of Hong Kong Chinese women on screening mammography and early breast cancer management.

In most Western countries, screening mammography and breast-conserving therapy (BCT) are now well-established practices and have been well accepted by women over the last two decades. There are limited data on the acceptability of these strategies by Chinese women in an Oriental society where a population-based screening program has not been established and mastectomy is still commonly practiced. A survey was conducted of 1012 Hong Kong Chinese women, ages 18-69 years, to assess the level of knowledge, perceptions, and attitudes on screening mammography and the surgical management of early breast cancer. Most women (58%) had never heard of mammographic screening, and housewives were more likely to have heard of it than nonhousewives (49% versus 37%; p = 0.0001). The majority (82%) of those who had heard of mammographic screening believe that it can detect early breast cancers and reduce mortality, however, only 58% of these women would participate in yearly screening and clinical breast examination despite acknowledging the potential benefits; a lack of time and the cost were the predominant reasons given. Forty-seven percent of women had the misconception that mastectomy was the only curative treatment; when the alternative was explained, the overall rate for choosing BCT rose from 29% to 49%. There was no correlation between age and the choice of surgery. Most women (75%) felt that breast reconstruction after mastectomy was desirable and acceptable. A lack of knowledge on mammographic screening is prevalent and the concept of preventive health care has a low priority in this Chinese population. Mastectomy is still widely perceived as the only curative treatment; BCT with cosmetic reconstruction is seen as an acceptable alternative. Interventions to improve the accuracy of information and to encourage preventive health care behaviors will have a positive impact on establishing cancer screening programs and providing quality cancer care in the future.

Mycosis fungoides involving the oral cavity.

Mycosis fungoides is a malignant T-cell lymphoproliferative disease with a predilection for cutaneous involvement. Extracutaneous disease is uncommon and oral mucosal involvement is rare. We describe a case of mycosis fungoides involving the hard palate treated with radiotherapy. The relevant literature on this topic is reviewed.

Parotid lymph-node metastases from cutaneous squamous-cell carcinomas: treatment outcome and prognostic factors following surgery and adjuvant radiotherapy.

Australia has the highest incidence of cutaneous squamous cell carcinoma (SCC) in the world. The majority of lesions occur in the head and neck, and regional lymph-node metastases from cutaneous SCCs, though uncommon, reflect an aggressive manifestation. Surgery and adjuvant radiotherapy are currently considered best practice. Fifty-two eligible patients during 1980-1997 were identified in a retrospective review of patients treated within the department of Radiation Oncology, Westmead Hospital, Sydney. Relevant data were extracted from the files, referring clinicians and the New South Wales Cancer Council. The median age at diagnosis was 63 years and the majority were men (87%). Unfavourable pathological features were present in many of the patients. Only extranodal spread (P = 0.02) was identified as an independent predictor for locoregional recurrence on multivariate analysis. The cumulative locoregional recurrence rates were 28 and 45% at 2 and 5 years, respectively. The 5-year cause-specific survival rate in this study was 65%. We conclude that parotid lymph-node metastases from cutaneous SCCs of the head and neck are associated with a high rate of locoregional recurrence and cause-specific mortality despite surgery and adjuvant radiotherapy. The role of altered fractionation after surgery as a means to further enhance locoregional control warrants further investigation.