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.

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAFV600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAFV600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAFV600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAFV600 mutations (including BRAFV600K), which account for ∼10-20% of BRAFV600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.

Assessing the Potential for Patient-led Surveillance After Treatment of Localized Melanoma (MEL-SELF): A Pilot Randomized Clinical Trial.

IMPORTANCE: Patient-led surveillance is a promising new model of follow-up care following excision of localized melanoma. OBJECTIVE: To determine whether patient-led surveillance in patients with prior localized primary cutaneous melanoma is as safe, feasible, and acceptable as clinician-led surveillance. DESIGN, SETTING, AND PARTICIPANTS: This was a pilot for a randomized clinical trial at 2 specialist-led clinics in metropolitan Sydney, Australia, and a primary care skin cancer clinic managed by general practitioners in metropolitan Newcastle, Australia. The participants were 100 patients who had been treated for localized melanoma, owned a smartphone, had a partner to assist with skin self-examination (SSE), and had been routinely attending scheduled follow-up visits. The study was conducted from November 1, 2018, to January 17, 2020, with analysis performed from September 1, 2020, to November 15, 2020. INTERVENTION: Participants were randomized (1:1) to 6 months of patient-led surveillance (the intervention comprised usual care plus reminders to perform SSE, patient-performed dermoscopy, teledermatologist assessment, and fast-tracked unscheduled clinic visits) or clinician-led surveillance (the control was usual care). MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of eligible and contacted patients who were randomized. Secondary outcomes included patient-reported outcomes (eg, SSE knowledge, attitudes, and practices, psychological outcomes, other health care use) and clinical outcomes (eg, clinic visits, skin surgeries, subsequent new primary or recurrent melanoma). RESULTS: Of 326 patients who were eligible and contacted, 100 (31%) patients (mean [SD] age, 58.7 [12.0] years; 53 [53%] men) were randomized to patient-led (n = 49) or clinician-led (n = 51) surveillance. Data were available on patient-reported outcomes for 66 participants and on clinical outcomes for 100 participants. Compared with clinician-led surveillance, patient-led surveillance was associated with increased SSE frequency (odds ratio [OR], 3.5; 95% CI, 0.9 to 14.0) and thoroughness (OR, 2.2; 95% CI, 0.8 to 5.7), had no detectable adverse effect on psychological outcomes (fear of cancer recurrence subscale score; mean difference, -1.3; 95% CI, -3.1 to 0.5), and increased clinic visits (risk ratio [RR], 1.5; 95% CI, 1.1 to 2.1), skin lesion excisions (RR, 1.1; 95% CI, 0.6 to 2.0), and subsequent melanoma diagnoses and subsequent melanoma diagnoses (risk difference, 10%; 95% CI, -2% to 23%). New primary melanomas and 1 local recurrence were diagnosed in 8 (16%) of the participants in the intervention group, including 5 (10%) ahead of routinely scheduled visits; and in 3 (6%) of the participants in the control group, with none (0%) ahead of routinely scheduled visits (risk difference, 10%; 95% CI, 2% to 19%). CONCLUSIONS AND RELEVANCE: This pilot of a randomized clinical trial found that patient-led surveillance after treatment of localized melanoma appears to be safe, feasible, and acceptable. Experiences from this pilot study have prompted improvements to the trial processes for the larger trial of the same intervention. TRIAL REGISTRATION: http://anzctr.org.au Identifier: ACTRN12616001716459.

Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram.

PURPOSE: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity. PATIENTS AND METHODS: Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496). RESULTS: The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model (P < .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%). CONCLUSION: A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au.

The Prognostic and Predictive Value of Melanoma-related MicroRNAs Using Tissue and Serum: A MicroRNA Expression Analysis.

The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are < 15%. Hence, melanoma detection in earlier stages (stages I-III) maximises the chances of patient survival. We measured the expression of a panel of 17 microRNAs (miRNAs) (MELmiR-17) in melanoma tissues (stage III; n = 76 and IV; n = 10) and serum samples (collected from controls with no melanoma, n = 130; and patients with melanoma (stages I/II, n = 86; III, n = 50; and IV, n = 119)) obtained from biobanks in Australia and Germany. In melanoma tissues, members of the 'MELmiR-17' panel were found to be predictors of stage, recurrence, and survival. Additionally, in a minimally-invasive blood test, a seven-miRNA panel (MELmiR-7) detected the presence of melanoma (relative to controls) with high sensitivity (93%) and specificity (≥ 82%) when ≥ 4 miRNAs were expressed. Moreover, the 'MELmiR-7' panel characterised overall survival of melanoma patients better than both serum LDH and S100B (delta log likelihood = 11, p < 0.001). This panel was found to be superior to currently used serological markers for melanoma progression, recurrence, and survival; and would be ideally suited to monitor tumour progression in patients diagnosed with early metastatic disease (stages IIIa-c/IV M1a-b) to detect relapse following surgical or adjuvant treatment.

Treatment and prognostic significance of positive interval sentinel nodes in patients with primary cutaneous melanoma.

BACKGROUND: Interval sentinel nodes (SNs) are lymph nodes receiving direct lymphatic drainage from a primary site and lying between the tumor and a recognized node field. It is not clear what further nodal surgery should be performed when interval nodes are found to contain micrometastatic disease. In this study, the incidence, location, and treatment of interval SNs in melanoma patients were analyzed to develop recommendations regarding the treatment of patients with interval SNs. METHODS: A retrospective review was undertaken of all patients with primary cutaneous melanoma who underwent lymphoscintigraphy at a single institution between 1992 and 2007. Data concerning the primary melanoma, location of SNs, treatment and survival were analyzed. RESULTS: Of 4895 patients who had a lymphoscintigram during the study period, 442 (9.0%) had an interval SN identified on lymphoscintigraphy. Interval SNs occurred significantly more often in patients with melanomas on the posterior trunk than in those with melanomas at other sites (P<0.001). A total of 197 patients (44.6%) with an identified interval SN underwent excision biopsy of the node. Of the 16 patients found to have metastatic melanoma in their interval SN, four also had negative SNs in a recognized lymph node field, and no other positive nodes were found on completion lymphadenectomy. CONCLUSIONS: Interval SNs are present in approximately 1 in 10 melanoma patients but are about half as likely to contain metastases as SNs in recognized node fields. If a positive interval SN is found, completion lymphadenectomy of the recognized lymph node field is only recommended if a SN in this field is also positive.

Elemental bio-imaging of melanoma in lymph node biopsies.

The spatial distribution of trace elements in human lymph nodes partially infiltrated by melanoma cells was determined by elemental bio-imaging. Imaging of (31)P within the nodal capsule and normal lymph node tissue showed a clear demarcation of the tumour boundary, with a significant decrease in relative (31)P concentration within the tumour. The location of the tumour boundary was confirmed by haematoxylin and eosin staining of serial sections and observation by light microscopy. Further enhancement of the tumour boundary was achieved by imaging the (31)P/(34)S ratio. (31)P/(66)Zn ratio images showed a decreasing ratio beyond the tumour boundary that extended into peritumour normal lymph node tissue.