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.

MEN1 Syndrome and Hibernoma: An Uncommonly Recognised Association?

MEN1 syndrome is known to classically result in parathyroid, pituitary, and pancreatic islet cell tumours. However, the potential association of MEN1 syndrome with hibernoma, a benign tumour with differentiation towards brown fat, is far less well known, despite their genetic profile both being linked to deletion of the MEN1 gene. Herein, we describe a case with its key radiological and pathological findings.

The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis.

Acral melanoma is a subtype of melanoma with distinct epidemiological, clinical and mutational profiles. To define the genomic alterations in acral melanoma, we conducted whole-genome sequencing and SNP array analysis of five metastatic tumours and their matched normal genomes. We identified the somatic mutations, copy number alterations and structural variants in these tumours and combined our data with published studies to identify recurrently mutated genes likely to be the drivers of acral melanomagenesis. We compared and contrasted the genomic landscapes of acral, mucosal, uveal and common cutaneous melanoma to reveal the distinctive mutational characteristics of each subtype.

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.

Retroperitoneal tumours: review of management.

INTRODUCTION: The retroperitoneum can host a wide spectrum of pathologies, including a variety of rare benign tumours and malignant neoplasms that can be either primary or metastatic lesions. Retroperitoneal tumours can cause a diagnostic dilemma and present several therapeutic challenges because of their rarity, relative late presentation and anatomical location, often in close relationship with several vital structures in the retroperitoneal space. MATERIALS AND METHODS: A comprehensive literature search was conducted using PubMed. Relevant international articles published in the last ten years were assessed. The keywords for search purposes included: retroperitoneum, benign, sarcoma, neoplasm, diagnosis and surgery, radiotherapy, chemotherapy. The search was limited to articles published in English. All articles were read in full by the authors and selected for inclusion based on relevance to this article. RESULTS: Tumours usually present late and cause symptoms or become palpable once they have reached a significant size. Retroperitoneal tumours are best evaluated with good quality cross-sectional imaging and preoperative histology by core needle biopsy is required when imaging is non-diagnostic. Sarcomas comprise a third of retroperitoneal tumours. Other retroperitoneal neoplasms include lymphomas and epithelial tumours or might represent metastatic disease from known or unknown primary sites. The most common benign pathologies encountered in the retroperitoneum include benign neurogenic tumours, paragangliomas, fibromatosis, renal angiomyolipomas and benign retroperitoneal lipomas. CONCLUSIONS: Complete surgical resection is the only potential curative treatment modality for retroperitoneal sarcomas and is best performed in high-volume centres by a multidisciplinary sarcoma team. The ability completely to resect a retroperitoneal sarcoma and tumour grade remain the most important predictors of local recurrence and disease-specific survival.

Management of benign retroperitoneal schwannomas: a single-center experience.

BACKGROUND: We describe the presentation, diagnostic pathway, and management of 28 patients with benign retroperitoneal schwannomas. METHODS: A prospectively kept soft-tissue tumor database was reviewed to identify patients who presented to the Royal Marsden Hospital with retroperitoneal schwannomas. RESULTS: From 2001 to 2009, 28 patients presented with retroperitoneal schwannomas. In 13 patients, tumors were identified incidentally, 8 patients presented with pelvic or abdominal symptoms and 7 patients presented with a palpable mass. Seventeen occurred in the pelvis and 11 occurred in the abdominal retroperitoneal space. The median age was 47 years and 21 patients were women; the mean follow-up period was 39 months. Twenty patients underwent resection and 8 patients were managed conservatively with radiologic surveillance. An initial histologic diagnosis was accomplished in 19 of 28 patients. Complete resection was achieved in 17 of 20 patients and 3 patients with pelvic schwannomas underwent a subtotal resection. Resected tumor size ranged from 5 to 23 cm (median, 9 cm), and weighed between 64 and 2,300 g (median, 500 g). There was no surgical mortality. In the 3 subtotal resected tumors, no progression of residual disease or malignant transformation has been noted on follow-up imaging. All 8 patients in the surveillance group had a histologic diagnosis and typical radiologic findings. CONCLUSIONS: An accurate preoperative diagnosis is important because the risks of complicated surgery in the retroperitoneum and pelvis for what is a benign lesion should be considered carefully. Cross-sectional imaging combined with a needle biopsy should in all cases provide the correct diagnosis. Management options include radiologic surveillance in asymptomatic patients or surgical resection in symptomatic patients.

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.

Does the two-week rule pathway improve the diagnosis of soft tissue sarcoma? A retrospective review of referral patterns and outcomes over five years in a regional sarcoma centre.

INTRODUCTION: The NHS Cancer Plan was introduced in 2000 and included guidelines for the rapid assessment and referral of cases of suspected malignancy. We wished to assess the efficiency and appropriateness of patients referred under the Department of Health's general practitioner referral guidelines implemented for sarcomas in December 2000. PATIENTS AND METHODS: A retrospective case-note review was performed of all patients referred to our regional soft tissue sarcoma unit between 1 January 2004 and 31 December 2008. Patients referred under the two-week guidelines and all patients referred routinely were analysed. The main outcome measures were the total number of patients referred on the basis of the two-week guidelines and the proportion they constitute of all referrals. The referring criteria were noted and compared to the observed criteria recorded. The final histological diagnosis of patients referred on the basis of the two-week guidelines are documented. RESULTS: A total of 2746 referrals for suspected sarcoma were made from January 2004 to December 2008. Of these, 154 referrals were made under the two-week rule of which 102 were referred purely on the clinical criteria for suspected soft tissue sarcoma. The remaining patients were referred after non-urgent special investigations indicated the possibility of sarcoma. Twelve patients referred under the two-week rule were proved to have sarcoma, nine after specific investigations including imaging or histological diagnosis. Of the 102 patients referred on clinical suspicion of a sarcoma, two patients had proven soft tissue sarcomas and one patient a cutaneous sarcoma. Between 2004 and 2008, the number of 2-week referrals rose 25-fold but accounted for an increase of less than 1% of the sarcomas treated in this unit. CONCLUSIONS: The numbers of all referrals for suspected sarcoma are increasing; however, the rate of increase of 2-week referrals is increasing faster than routine referrals and will exceed it in 2012 if current trends continue. There has not been a commensurate rise in the detection of sarcoma or, more specifically, diagnosis of the deep sarcomas associated with worse prognosis. Current clinical guidelines have essentially had no impact on the early diagnosis and treatment of soft tissue sarcoma, and may negatively impact on the treatment of patients with proven sarcoma by delaying treatment within a regional centre because of redirection of a large number of patients with benign abnormalities to such centres.

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.