David Speakman

Angiosarcoma of the breast: A difficult surgical challenge

BACKGROUND AND OBJECTIVES Breast angiosarcoma presents following radiotherapy after breast conserving surgery, in the setting of chronic lymphoedema after axillary dissection or as a primary tumour. The Peter MacCallum Cancer Centre has significant experience due to large breast and sarcoma units and as a primary radiotherapy centre. Our aims were to evaluate the management and locoregional and distant outcomes after breast angiosarcoma. METHODS Retrospective study of all patients from the prospective breast and sarcoma databases with a diagnosis of primary or secondary breast angiosarcoma at Peter MacCallum Cancer Centre was performed between January 2000 and December 2010. Mode of presentation, management, loco-regional recurrence and survival rates were reviewed. RESULTS Eight women developed angiosarcoma in the setting of breast conservation with a median latency of 7 years post radiotherapy. Six patients had primary breast angiosarcoma. All breast angiosarcomas were managed with total mastectomy with 5 patients requiring autologous tissue transfer. Four patients had adjuvant radiotherapy and three patients had adjuvant paclitaxel. The median follow-up was 2.5 years (6 month-10 years) with 7 episodes of local recurrence in four patients and 7 patients with distal metastases including two deaths from distant disease. CONCLUSIONS Primary angiosarcoma occurs de novo, presenting as a breast mass. Secondary angiosarcoma presents predominantly as a skin lesion, in the setting post-operative radiotherapy for breast conserving therapy. Angiosarcoma remains a rare and difficult management problem with poor loco-regional and distal control. Secondary AS is an iatrogenic condition that warrants close follow-up and judicial use of radiotherapy in breast conserving therapy.

Atypical Spitzoid neoplasms: a review of potential markers of biological behavior including sentinel node biopsy.

Atypical cutaneous melanocytic lesions, including those with Spitzoid features, can be difficult to categorize as benign or malignant. This can lead to suboptimal management, with potential adverse patient outcomes. Recent studies have enhanced knowledge of the molecular and genetic biology of these lesions and, combined with clinicopathological findings, is further defining their biological spectrum, classification, and behavior. Sentinel node biopsy provides important prognostic information in patients with cutaneous melanoma, but its role in the management of melanocytic lesions of uncertain malignant potential (MELTUMP) is controversial. This paper examines the role of molecular testing and sentinel node biopsy in MELTUMPs, particularly atypical Spitzoid tumors.

CD271 Expression on Patient Melanoma Cells Is Unstable and Unlinked to Tumorigenicity.

The stability of markers that identify cancer cells that propagate disease is important to the outcomes of targeted therapy strategies. In human melanoma, conflicting data exist as to whether hierarchical expression of CD271/p75/NGFR (nerve growth factor receptor) marks cells with enriched tumorigenicity, which would compel their specific targeting in therapy. To test whether these discrepancies relate to differences among groups in assay approaches, we undertook side-by-side testing of published methods of patient-derived melanoma xenografting (PDX), including comparisons of tissue digestion procedures or coinjected Matrigel formulations. We found that CD271(-) and CD271(+) melanoma cells from each of seven patients were similarly tumorigenic, regardless of assay variations. Surprisingly variable CD271 expression patterns were observed in the analyses of sibling PDX tumors (n = 68) grown in the same experiments from either CD271(-) or CD271(+) cells obtained from patients. This indicates unstable intratumoral lineage relationships between CD271(-) and CD271(+) melanoma cells that are inconsistent with classical, epigenetically based theories of disease progression, such as the cancer stem cell and plasticity models. SNP genotyping of pairs of sibling PDX tumors grown from phenotypically identical CD271(-) or CD271(+) cells showed large pairwise differences in copy number (28%-48%). Differences were also apparent in the copy number profiles of CD271(-) and CD271(+) cells purified directly from each of the four melanomas (1.4%-23%). Thus, CD271 expression in patient melanomas is unstable, not consistently linked to increased tumorigenicity and associated with genetic heterogeneity, undermining its use as a marker in clinical studies. Cancer Res; 76(13); 3965-77. ©2016 AACR.

Australian multi-center experience outside of the Sydney Melanoma Unit of isolated limb infusion chemotherapy for melanoma.

Isolated limb infusion (ILI) is a minimally invasive alternative to isolated limb perfusion (ILP) for delivering high‐dose regional chemotherapy to treat locally advanced limb melanoma. The current study aimed to evaluate the applicability of ILI in four Australian tertiary referral centers outside of its originating institution, the Sydney Melanoma Unit (SMU; currently known as the Melanoma Institute Australia).

Intralesional PV‐10 for in‐transit melanoma—A single‐center experience

Patients with in‐transit melanoma metastasis have longer median survival than patients with distant metastatic disease. Furthermore, local disease control is an important endpoint for symptom management. The treatment of unresectable loco‐regional recurrence or in‐transit disease has been historically managed with a combination of treatments including surgery, radiotherapy, isolated limb infusion or perfusion as well as systemic therapies. Intralesional PV‐10 has been used at Peter MacCallum Cancer Centre since 2010, and the current report presents a retrospective analysis of patient outcomes, reporting the response rates, durability of responses, and observed toxicities.

Post‐operative survival following metastasectomy for patients receiving BRAF inhibitor therapy is associated with duration of pre‐operative treatment and elective indication

Introduction Metastasectomy can provide durable disease control for selected patients with metastatic melanoma. Vemurafenib is a BRAF kinase inhibitor which has demonstrated significant improvement in disease-specific survival in patients with metastatic melanoma with a BRAF gene mutation. This study examined the efficacy and safety of metastasectomy during treatment with vemurafenib. Methods A retrospective review was performed of all patients receiving vemurafenib at Peter MacCallum Cancer Centre. Patient records were reviewed to identify patients undergoing surgery within 30 days of vemurafenib therapy. Descriptive statistics and survival analysis were performed. Results Nineteen patients underwent 21 metastasectomies including craniotomy (57%), spinal decompression (14%), small bowel resection (14%), lung resection (9.5%) and neck dissection (4.5%). Indications for surgery were: an isolated residual focus of disease (n = 2); isolated progressive disease in the setting of stability elsewhere (n = 9); and symptomatic disease (n = 8). Grade 2 or higher surgical complications occurred in 19% of cases and there was one peri-operative death. Median post-operative survival was seven months. There was a trend toward improved post-operative survival for patients with longer duration of vemurafenib therapy (P = 0.04) and for those undergoing elective surgery (P = 0.07). Conclusion Resection of oligometastatic disease during BRAF-targeted therapy is safe. Selected patients have durable post-operative disease control. J. Surg. Oncol. 2015 111:980–984.

Quadriceps keystone island flap for radical inguinal lymphadenectomy: a reliable locoregional island flap for large groin defects

Background:  Radical inguinal lymphadenectomy (RIL) for bulky metastatic melanoma and non‐melanoma skin cancers of the inguinal region, while shown to improve morbidity and survival oncologically, can result in substantial morbidity from wound complications. Skin defects cannot be closed primarily and the substantial dead space predisposes to seroma, wound dehiscence and infection. Despite the clear need for reconstructive options, extended series describing reconstruction of large inguinal defects in this setting have not been reported.

Prospective evaluation of prognostic indicators for early recurrence of cutaneous melanoma.

The majority of melanomas are thin lesions with an excellent prognosis; however, significant tumor heterogeneity exists, and a small percentage of patients with early-stage disease may progress to metastatic recurrence. This study aimed to assess whether prognostic factors previously shown to be significant in predicting stage I and stage II melanoma recurrence were consistent in a large prospectively collected patient cohort, and to identify novel prognostic factors associated with early recurrence to inform follow-up protocols. There were 1029 patients with stage I and stage II melanoma included in the analysis, of whom 123 developed a recurrence during follow-up (median 2.13 years). Multivariable analysis identified ulceration, presence of mitoses, Clark level, presence of lymphovascular invasion, and a history of autoimmune disease as factors independently associated with recurrence. These data identified patients with stage I–II melanoma with very low-risk for recurrence: no ulceration, zero mitoses, a low Clark level, no lymphovascular invasion, and possibly no history of autoimmune disease. These patients do not require intensive follow-up: 12 monthly reviews and full skin checks may be appropriate. Ongoing research into prognostic factors for recurrence in early-stage melanoma is important.

The adverse implications of the transition from film to digital mammography for performing surveillance in patients with a history of breast cancer or significant risk factors for the disease.

Aim:  The transition from screen‐film to digital mammography at Peter MacCallum Cancer Centre was investigated, considering the impact on patient management and resource utilization.

Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma

Background As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance. Patients and methods From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were carried out of imaging outcomes. Results One hundred and seventy patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56%-83%. Negative scans had predictive values of 89%-96% for true non-recurrence [negative predictive values (NPV)] until the next scan. A negative PET at 18 months had NPVs of 80%-84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median). Conclusions Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.