BAUSSS biomarker improves melanoma survival risk assessment.

BACKGROUND: The American Joint Committee on Cancer (AJCC) method of staging melanoma is dated and inaccurate. It ignores important prognostic melanoma features, especially the patient's age. BAUSSS is more accurate in determining survival risk for primary cutaneous melanoma patients who have no clinical or imaging evidence of nodal or distant metastases. BAUSSS is an algorithm incorporating analysis of Breslow thickness, Age, Ulceration, Subtype of melanoma, Sex and Site. These are the six features from the patient history along with the details from the melanoma pathology report that are most predictive of mortality outcome. OBJECTIVE: To develop a single-page document that allows the clinician to determine BAUSSS biomarker-predicted prognosis in consultation with the patient. METHOD: From various data sources, we developed an algorithm to predict melanoma mortality using the BAUSSS biomarker system. The single-page algorithm was made available to download at https://globalmelanoma.net/bausss-survival-chart, thus being readily available without charge to all clinicians and their patients. RESULTS: BAUSSS method of determining melanoma prognosis is more accurate and less costly than the AJCC staging system. The only surgery the patient requires is wide local excision of the primary tumour. This method of ascertaining melanoma risk does not require added surgery, costs, hospitalization, tests and anaesthesia, such as would be required if sentinel lymph node biopsy was undertaken. BAUSSS can be a useful tool in determining which primary melanoma patients are at sufficiently high risk to be considered for adjuvant drug therapy. CONCLUSION: We encourage clinicians to download and print in colour this single-page BAUSSS mortality prediction tool, laminate it, and use it face to face with the patient in consultations. Not only will the patient be able to recognize his/her long-term prognosis but will also be able to see how their tumour severity compares with others.

Sentinel lymph node biopsy is unreliable in predicting melanoma mortality for both younger and older patients.

BACKGROUND: Melanoma disease patterns vary with patient age. AIM: To evaluate sentinel lymph node biopsy (SLNB) in managing melanoma at differing patient ages. METHODS: Online prediction tools were applied to compare SLNB positivity (SLNB+) and survival risk at patient ages 20-80. Tübingen melanoma data were used to determine variations in the hazard ratio of SLNB+ for mortality at different patient ages. RESULTS: Regardless of tumour thickness, predicted SLNB+ rates were markedly higher than mortality rates for 20-year-old patients. For 80-year-old patients, it is the opposite. DISCUSSION: If 1000 20-year-olds with a 0.4 mm thickness non-ulcerated melanoma underwent SLNB, 100 would likely be positive. If all 100 were to be offered adjuvant drug therapy (ADT), fewer than three more melanoma deaths in those 1000 patients would be avoided. In total, 97 patients would have received medication they may never have needed. If 1000 80-year-olds with a 3 mm thickness non-ulcerated melanoma underwent SLNB, only 40 would likely be positive. In total, 274 patients would be predicted to die of melanoma, 245 being SLNB negative and 29 SLNB+. ADT linked to SLNB+ could deny treatment to 89% of these high-risk patients. LIMITATIONS: The authors relied on published risk data. CONCLUSION: SLNB has poor specificity at predicting mortality in young melanoma patients and poor sensitivity in older patients. SLNB is not indicated in managing cutaneous melanoma for patients under 40 or over 60 years of age. Many such patients could be managed with wide local excision alone in their clinician's office-based practice. For all cutaneous melanoma patients at all ages, linking ADT to BAUSSS biomarker, (an algorithm of Breslow thickness, age, ulceration, subtype, sex and Site) rather than SLNB+ is likely more appropriate. BAUSSS provides a more accurate melanoma-specific mortality risk assessment for patients without burdening them with added surgery, hospitalization, costs or morbidity risk.

Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial.

BACKGROUND: The necessary margin of excision for cutaneous melanomas greater than 2 mm in thickness is controversial. At a median follow-up of 5 years, findings from our previously published randomised trial of narrow (1 cm) versus wide (3 cm) excision margins in patients with thick cutaneous melanomas showed that narrow margins were associated with an increased frequency of locoregional relapse, but no significant difference in overall survival was apparent. We now report a long-term survival analysis of that trial. METHODS: We did a randomised, open-label multicentre trial in 59 hospitals--57 in the UK, one in Poland, and one in South Africa. Patients with one primary localised cutaneous melanoma greater than 2 mm in Breslow thickness on the trunk or limbs (excluding palms or soles) were randomly assigned (1:1) centrally to receive surgery with either a 1 cm or 3 cm excision margin following an initial surgery. The randomisation lists were generated with random permuted blocks and stratified by centre and extent of initial surgery. The endpoints of this analysis were overall survival and melanoma-specific survival. Analyses were done in the intention-to-treat population. This trial was not registered because it predated mandatory trial registration. FINDINGS: Between Dec 16, 1992, and May 22, 2001, we randomly assigned 900 patients to surgery with either a 1 cm excision margin (n=453) or a 3 cm excision margin (n=447). At a median follow-up of 8·8 years (106 months [IQR 76-135], 494 patients had died, with 359 of these deaths attributed to melanoma. 194 deaths were attributed to melanoma in the 1 cm group compared with 165 in the 3 cm group (unadjusted hazard ratio [HR] 1·24 [95% CI 1·01-1·53]; p=0·041). Although a higher number of deaths overall occurred in the 1 cm group compared with the 3 cm group (253 vs 241), the difference was not significant (unadjusted HR 1·14 [95% CI 0·96-1·36]; p=0·14). Surgical complications were reported in 35 (8%) patients in the 1 cm excision margin group and 65 (15%) patients in the 3 cm group. INTERPRETATION: Our findings suggest that a 1 cm excision margin is inadequate for cutaneous melanoma with Breslow thickness greater than 2 mm on the trunk and limbs. Current guidelines advise a 2 cm margin for melanomas greater than 2 mm in thickness but only a 1 cm margin for thinner melanomas. The adequacy of a 1 cm margin for thinner melanomas with poor prognostic features should be addressed in future randomised studies. FUNDING: Cancer Research UK, North Thames National Health Service Executive, Northern and Yorkshire National Health Service Executive, British United Provident Association Foundation, British Association of Plastic Surgeons, the Meirion Thomas Cancer Research Fund, and the National Institute for Health and Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust.

Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma.

Mucosal melanoma displays distinct clinical and epidemiological features compared to cutaneous melanoma. Here we used whole genome and whole exome sequencing to characterize the somatic alterations and mutation spectra in the genomes of ten mucosal melanomas. We observed somatic mutation rates that are considerably lower than occur in sun-exposed cutaneous melanoma, but comparable to the rates seen in cancers not associated with exposure to known mutagens. In particular, the mutation signatures are not indicative of ultraviolet light- or tobacco smoke-induced DNA damage. Genes previously reported as mutated in other cancers were also mutated in mucosal melanoma. Notably, there were substantially more copy number and structural variations in mucosal melanoma than have been reported in cutaneous melanoma. Thus, mucosal and cutaneous melanomas are distinct diseases with discrete genetic features. Our data suggest that different mechanisms underlie the genesis of these diseases and that structural variations play a more important role in mucosal than in cutaneous melanomagenesis.

Malignancies confined to disused arteriovenous fistulae in renal transplant patients: an important differential diagnosis.

BACKGROUND: Swelling in an arteriovenous fistula (AVF) is commonly caused by thrombosis, aneurysm and infection. However, due to the increased risk of malignancy after transplantation, this should also be considered. PATIENTS: We discuss 4 patients with malignancy confined to an AVF after renal transplantation presenting in a 2-year period. Angiosarcoma was diagnosed in 3 patients and the other had post-transplant lymphoproliferative disorder (PTLD). Angiosarcoma behaves aggressively and 2 of our patients died within 6 months of diagnosis. There are 6 previous cases and 5 died within 16 months of diagnosis. PTLD at AVFs has not been documented previously. CONCLUSION: Malignancy at an AVF is a rare but important differential that can impact significantly on patient morbidity and mortality. Predilection for malignancy at an AVF is not understood. We review the literature and discuss possible aetiologies.

Transmission of donor melanoma by organ transplantation.

Transplant-related malignancies are a major contributor to morbidity and mortality in the organ-recipient population, and most often develop de novo in the immunosuppressed recipient or as recurrent malignancy after transplantation. The least common scenario, and a rare event, is a recipient malignancy derived from the donor organ. Melanoma is one of the most often reported and lethal donor-derived malignancies with a high transmission rate. Donor transmission of melanoma might be related to the biology of melanoma, with regard to tumour dormancy, late recurrence, circulating tumour cells, and the destiny of some micrometastases. Melanoma-cell dormancy explains the late recurrence that can occur after the initial treatment of melanoma, and may be relevant to our understanding and management of some melanoma micrometastasis in the sentinel node. The high incidence of circulating tumour cells in early melanoma should be considered in the context of the transmission of melanoma by apparent disease-free organ donors following removal of a primary melanoma up to 32 years before. This scenario suggests that melanoma cells can remain dormant at distant sites for decades (and possibly forever) in immunocompetent patients, only to reactivate after transplantation into an immunosuppressed recipient. Potential organ donors should be carefully screened for a history of melanoma, and excluded. The current recommendation for treatment of donor-related melanoma includes withdrawal of immunosuppression, graft rejection, and explantation of the allograft after rejection has been established. In non-renal transplant patients with life-sustaining organs, withdrawal of immunosuppression and graft rejection is not feasible, and reduction of immunosuppression or urgent retransplantation are the only possible salvage strategies. The transmission of malignancy by organ donation could be considered "nature's own experiment", but raises questions that our current understanding of the biology of melanoma cannot answer.

Angiosarcoma developing in a non-functioning arteriovenous fistula post-renal transplant.

BACKGROUND: Angiosarcomas comprise less than 1% of all sarcomas, arising from endothelial cells of blood or lymph vessels. Chronic immunosuppression increases the risk of many malignancies and an association between the development of angiosarcoma with an immunosuppressed state is established. A few cases have been reported of angiosarcomas arising in the post-renal transplant patient. Specifically, there have been six cases of an angiosarcoma arising in arteriovenous (AV) fistulae in this patient population. We describe a further case and review the relevant literature with specific emphasis on a possible mechanism for the development of angiosarcoma in the post-transplant patient. CASE PRESENTATION: We report the case of a 48-year-old male who developed an angiosarcoma in a ligated native AV fistula. The lesion arose on the background of immunosuppression following a successful ABO-incompatible renal transplant for chronic renal failure. CONCLUSION: Angiosarcomas are extremely rare tumours but should be considered as a differential diagnosis for an evolving mass near the site of an AV fistula. Diagnosis relies on an index of suspicion and obtaining a definitive histological diagnosis. Both clinicians and patients should be aware that an evolving mass within or around an AV fistula should prompt urgent biopsy.

Prognostic false-positivity of the sentinel node in melanoma.

It is a basic tenet of the sentinel lymph-node biopsy procedure that all positive sentinel lymph nodes will inevitably progress to palpable nodal recurrence if not removed. Comparison of survival is, therefore, considered permissible among patients with positive sentinel lymph nodes who undergo early lymphadenectomy with that among patients who have delayed lymphadenectomy for palpable regional node metastasis, providing that survival is calculated from the date of wide local excision of the primary tumor. Here, that fundamental assumption is contested and evidence is presented to show that a positive sentinel lymph node might have no adverse prognostic relevance in up to one-third of patients. Furthermore, in the same patients, progression to palpable nodal disease might not have occurred even if the positive sentinel node had not been removed. The term prognostic false-positivity is used to describe this phenomenon. Such patients are incorrectly up-staged, are given inaccurate prognostic information and can undergo unnecessary completion lymphadenectomy and unnecessary adjuvant therapy.

Excision margins in high-risk malignant melanoma.

BACKGROUND: Controversy exists concerning the necessary margin of excision for cutaneous melanoma 2 mm or greater in thickness. METHODS: We conducted a randomized clinical trial comparing 1-cm and 3-cm margins. RESULTS: Of the 900 patients who were enrolled, 453 were randomly assigned to undergo surgery with a 1-cm margin of excision and 447 with a 3-cm margin of excision; the median follow-up was 60 months. A 1-cm margin of excision was associated with a significantly increased risk of locoregional recurrence. There were 168 locoregional recurrences (as first events) in the group with 1-cm margins of excision, as compared with 142 in the group with 3-cm margins (hazard ratio, 1.26; 95 percent confidence interval, 1.00 to 1.59; P=0.05). There were 128 deaths attributable to melanoma in the group with 1-cm margins, as compared with 105 in the group with 3-cm margins (hazard ratio, 1.24; 95 percent confidence interval, 0.96 to 1.61; P=0.1); overall survival was similar in the two groups (hazard ratio for death, 1.07; 95 percent confidence interval, 0.85 to 1.36; P=0.6). CONCLUSIONS: A 1-cm margin of excision for melanoma with a poor prognosis (as defined by a tumor thickness of at least 2 mm) is associated with a significantly greater risk of regional recurrence than is a 3-cm margin, but with a similar overall survival rate.

Adult rhabdomyosarcoma: cross-sectional imaging findings including histopathologic correlation.

OBJECTIVE: The purpose of our study was to present the MRI and CT features of adult rhabdomyosarcomas with histopathologic correlation. Forty-nine sequential cases were incorporated over a 5-year period from the sarcoma unit database. Twenty-six patients had adequate imaging (16 MRI, 10 CT) and histopathology available for retrospective review. The alveolar subtype was present in 13 patients, embryonal subtype in four patients, and pleomorphic subtype in nine patients. On both CT and T1-weighted MRI, all tumors were isodense to skeletal muscle, although enhancement was variable after the administration of IV contrast material. Pleomorphic tumors were very high signal on T2-weighted/STIR imaging, and both pleomorphic and alveolar subtypes were extremely heterogeneous. Embryonal tumors were more homogeneous. CONCLUSION: Although adult rhabdomyosarcomas have certain imaging appearances in common with other soft-tissue sarcomas, features at presentation such as tumor heterogeneity, site, regional lymphadenopathy, and pulmonary metastasis should make the radiologist consider this important diagnosis.

A gene expression signature associated with metastatic outcome in human leiomyosarcomas.

Metastasis is a major factor associated with poor prognosis in cancer, but little is known of its molecular mechanisms. Although the clinical behavior of soft tissue sarcomas is highly variable, few reliable determinants of outcome have been identified. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Here, we have chosen leiomyosarcoma as a model for examining the relationship between gene expression profile and the development of metastasis in soft tissue sarcomas. Using cDNA microarray, we have identified a gene expression signature associated with metastasis in sarcoma that allowed prediction of the future development of metastases of primary tumors (Kaplan-Meier analysis P = 0.001). Our finding may aid the tailoring of therapy for individual sarcoma patients, where the aggressiveness of treatment is affected by the predicted outcome of disease.