Risk factors for local atypical fibroxanthoma recurrence and progression to pleomorphic dermal sarcoma: A meta-analysis of individualized participant data.

BACKGROUND: Risk factors for local atypical fibroxanthoma (AFX) recurrence and progression to pleomorphic dermal sarcoma (PDS) have not previously been identified. OBJECTIVE: To identify risk factors and provide follow-up suggestions for local AFX recurrence and progression to PDS. METHODS AND MATERIALS: A literature search was performed in the PubMed, EMBASE, and Cochrane databases. The PRISMA and MOOSE guidelines were followed. The risks of local AFX recurrence and progression to PDS were presented as Kaplan-Meier plots and risk factors were presented as hazard ratios (HRs) calculated with univariate and multivariate Cox regression. RESULTS: Five hundred and ninety-eight patients with AFX from 14 studies were included. Age >74 years and male sex significantly increased the risk of local recurrence (HR: 7.31 [95% confidence interval [CI]: 1.78-30.0], p < 0.01 and HR: 2.89 [95% CI: 1.04-8.01], p < 0.05, respectively). There was no difference when comparing wide local excision and Mohs' micrographic surgery (p = 0.89). The risks of local AFX recurrence and progression to PDS after 2 years were <1%. CONCLUSION: A more intensive follow-up regimen could be considered in patients >74 years old and males due to the higher risk of local AFX recurrence.

Genetic predisposition to long telomeres is associated with increased mortality after melanoma: A study of 2101 melanoma patients from hospital clinics and the general population.

Whether there is an association between measured and genetically predicted telomere length and melanoma mortality is unclear. We tested the hypothesis that measured and genetically predicted telomere length is associated with mortality after a melanoma diagnosis. We followed 2,101 patients with melanoma from hospital clinics and the general population for risk of death for up to 26 years. All had telomere length measured in DNA from leukocytes, and 2052 of these were genotyped for the three single nucleotide polymorphisms rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1); all three genotypes are associated with telomere length and combined into an allele count from 0 to 6. For each telomere-lengthening allele, the hazard ratios (HRs) for mortality in the age-adjusted and multivariable-adjusted Cox analysis were 1.12 (95% confidence interval: 1.02-1.23) and 1.11 (1.01-1.23). However, for each standard deviation increase in measured telomere length, HR for mortality was 0.97 (0.88-1.08). In conclusion, in more than 2000 melanoma patients from hospital clinics and from the general population, genetically predicted long telomeres were associated with increased mortality, but measured leukocyte telomere length was not.

Measured and genetically predicted plasma YKL-40 levels and melanoma mortality.

PURPOSE: High plasma levels of YKL-40 might be associated with mortality in patients with melanoma, and it is unknown if YKL-40 is causally related to mortality. EXPERIMENTAL DESIGN: We studied two cohorts: 2618 patients with melanoma from hospital clinics and 1413 general population patients with melanoma, totalling 4031 patients followed up for mortality end-points for up to 20 years. All were genotyped for CHI3L1 rs4950928, highly predictive of lifelong plasma YKL-40, and plasma YKL-40 levels were measured in 2165 patients. We tested the hypotheses that measured and genetically predicted high plasma YKL-40 are associated with increased mortality in patients with melanoma. RESULTS: For the hospital melanoma cohort, age- and sex-adjusted hazard ratios for death in individuals with measured plasma YKL-40 in the 96-100th percentile versus 1-95th percentile and per 10-percentile increase were 1.52 (95% confidence interval, 1.07-2.16) and 1.07 (1.02-1.11), respectively, most pronounced for patients with localised melanomas. Each C-allele of the CHI3L1 rs4950928 genotype was associated with plasma YKL-40 level increases of 32% in the hospital melanoma cohort (p = 6 × 10-48) and 43% in the general population melanoma cohort (p = 7 × 10-13). Multifactorially adjusted ratios for these increases in the combined cohorts were 1.04 (1.00-1.09) observationally for measured plasma YKL-40 and 0.98 (0.86-1.12) for the genetically predicted plasma YKL-40. CONCLUSION: Measured, but not genetically predicted, increasing plasma YKL-40 was associated with increased mortality in patients with melanoma. Plasma YKL-40 is a marker but less likely to be a cause of increased mortality in patients with melanoma.

Targeted ultrasound and fine-needle aspiration cytology for sentinel node diagnostics in early-stage melanoma: a validation study.

Ultrasound-guided fine-needle aspiration cytology (US-FNAC) is used to evaluate the involvement of lymph nodes in various malignant diseases. Its value in detecting sentinel lymph node (SN) metastasis preoperatively in melanoma patients is controversial and is the subject of this study. In this prospective validation study, 91 consecutive patients with melanoma clinical stage I (n=64) and II (n=27) were examined with US-FNAC before SN biopsy from 2012 to 2014 at a tertiary center. All patients underwent lymphoscintigraphy before the US-FNAC. Lymph nodes that showed any of the Berlin morphologic criteria on ultrasonography were examined using FNAC. The median Breslow thickness of the melanomas was 1.22 mm (range: 0.47-11.5 mm). Twenty-two percent of the patients had metastases in their SNs, 90% of which were smaller than 2 mm in largest diameter. The percentages of metastases with a size more than 1 mm were 50 and 29%, respectively, in the true-positive and false-negative US groups. The sensitivity, specificity, positive predictive value, and negative predictive value for overall US examination were 30, 81, 24, and 83%, respectively. None of the FNACs contained conclusive malignant cells. The specificity of the FNAC was 76%. Our results show that US-FNAC was not a useful diagnostic tool in our setting as it did not add significantly to the staging and management of patients with mainly thin cutaneous melanomas, perhaps because of the often small size of the SN metastases. It may be useful in the early diagnosis of lymph node metastases in a subgroup of melanoma patients with larger metastases.

Radionuclide leakage monitoring during hyperthermic isolated limb perfusion for treatment of local melanoma metastasis in an extremity.

INTRODUCTION: The aim is to describe the importance of leakage monitoring in hyperthermic isolated limb perfusion (ILP). It is generally recommended that leakage should not exceed 10% because of risk of systemic toxicity. MATERIAL AND METHODS: Data retrieved by retrospective analysis of 131 perfusions performed in 115 consecutive patients (77 women and 38 men; median age 66 years) with recurrent and/or clinically apparent, cutaneous or subcutaneous melanoma metastases in an extremity. Radionuclide monitoring was performed with continuous, precordial count rate determinations of an intravascular (99m) Tc-labelled tracer infused into the isolated limb circulation. RESULTS: One hundred and sixteen of 131 procedures were completed. In 13%, a leakage of ≥10% was detected; in 6% (n = 8), the cytotoxic drug was never infused because of constant leakage; in 7% (n = 9), leakage ≥10% was measured during the perfusion resulting in two perfusions being terminated before 30 min, 5 perfusions were considered completed though with early termination (after 30 min, before 60 min), and 2 fully completed. No patients had systemic toxicity requiring treatment, whereas considerable or serious local toxicity were observed in 14%. Three of the patients with leakage ≥10% were successfully treated in a repeated procedure. CONCLUSION: Leakage monitoring using a threshold of 10% during ILP saves the patients from systemic toxicity, however, at the expense of early termination or cancellation of ILP treatment in a few patients and repeated ILP procedures in some.

Recurrence and survival after neck dissections in cutaneous head and neck melanoma.

INTRODUCTION: An important prognostic factor in head and neck melanoma is the status of the regional lymph nodes since the presence of metastatic disease in the nodes greatly aggravates the prognosis. There is no consensus on the surgical treatment algorithm for this group. Our aim was to study if there is a difference in nodal recurrence and survival after radical, modified or selective neck dissection. METHODS: A total of 57 patients treated for regional meta-stases of head and neck melanoma were analysed retrospectively with respect to type of neck dissection, use of sentinel node biopsy, nodal recurrence and survival. RESULTS: After a median 127-month (range: 22-290) follow-up period, we showed that there was no significant difference in nodal recurrence between three different dissection groups (11% for radical node dissection, 24% for modified radical node dissection and 23% for selective node dissection, p > 0.05). No significant difference in five-year survival was observed between the dissection types (56% for radical node dissection, 61% for modified radical node dissection and 48% for selective node dissection, p = 0.613). Multivariate and univariate analysis revealed that patients with metastatic deposits in sentinel nodes had a better survival than patients with clinically palpable nodes (five-year survival rate: 70% versus 36%, p = 0.008). CONCLUSION: The extent of neck dissection does not significantly influence the rate of recurrence or survival. This study indicates that there is a survival benefit for patients who undergo completion lymph node dissection following a positive sentinel node biopsy. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Tumour response after hyperthermic isolated limb perfusion for locally advanced melanoma.

INTRODUCTION: The aim was to describe tumour response, complications, recurrence and survival after hyperthermic isolated limb perfusion (ILP) with melphalan or melphalan in combination with tumour necrosis factor-alpha in patients with melanoma metastases confined to an extremity. MATERIAL AND METHODS: A total of 84 perfusions were performed (53 women, 31 men, median age 63 years) from 1993 to 2010. 95% of the perfusions were administered to the lower limbs and 5% to the upper limbs. The inclusion criteria were recurrent and/or clinically apparent cutaneous/subcutaneous extremity in-transit melanoma metastases. RESULTS: The response rate after ILP was 85%; 42% had complete response (CR), 43% partial response (PR), 12% no change (NC) and 3% progression. Two- and five-year survival rates were 57% and 31%, respectively, and they were higher for patients with than without lymph node metastases. Time from ILP to recurrence was a median of seven months (range 1-37 months) for patients with CR or PR. Survival was longer for patients with CR or PR than for patients showing NC or progression. Several patients had mild or moderate local toxicity reactions, two patients developed severe local toxicity. CONCLUSION: ILP induces tumour regression in the vast majority of patients. One patient, i.e. 1% of the group, died from surgical complications. Otherwise, ILP treatment had an acceptable morbidity in this group of very sick patients. We are convinced that the treatment should be offered to improve local disease control in patients with multiple and/or recurrent melanoma confined to an extremity if surgical excision is not possible. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis.

It is possible that reduced function of DNA repair and cell-cycle control genes increases the individual susceptibility to malignant melanoma. As CHEK2 is a cell-cycle master controller, we tested the hypothesis that heterozygosity for the frameshift alteration CHEK2*1100delC is associated with increased risk of malignant melanoma. First, we performed case-control studies of 1,152 Danish and 752 German individuals with malignant melanoma compared with 9,142 Danish and 3,718 German controls. Second, we performed a meta-analysis of CHEK2*1100delC and malignant melanoma, involving 2,619 cases and 17,481 controls. Third, we examined the risk of malignant melanoma associated with CHEK2*1100delC heterozygosity in an analysis stratified for sun exposure, as well as for subtype and location on the body. The odds ratios for malignant melanoma for CHEK2(*)1100del heterozygotes compared with those for noncarriers were 2.01 (95% confidence interval (CI), 1.03-3.91) in Danes, 1.42 (95% CI, 0.46-4.31) in Germans, and 1.79 (95% CI, 1.02-3.17) in Danes and Germans combined. In a meta-analysis, the odds ratio of malignant melanoma for CHEK2*1100delC heterozygotes compared with that for noncarriers was 1.81 (95% CI, 1.07-3.05). Stratifications did not alter these results. CHEK2*1100delC heterozygotes have a twofold risk of malignant melanoma compared with noncarriers.

Extensive screening for primary tumor is redundant in melanoma of unknown primary.

For decades, patients in our institution with metastastic melanoma of unknown primary have been subjected to extensive examinations in search of the primary tumor. This retrospective study questions the results, and thus the feasibility of these examinations. Of 103 patients diagnosed with unknown primary tumor during the period 1986-2006, 39 (38%) presented primarily with a cutaneous or a subcutaneous metastasis, and 63 (61%) with a lymph node metastasis. One patient presented with a bone metastasis (1%). Eighty-seven patients (84%) were examined by an ophthalmologist. A choroidal melanoma was suspected as the primary tumor in one patient. Eighty-four patients (82%) were examined by an oto-rhino-laryngologist, whereby no primary tumor was found. Ninety-five patients (92%) were examined by sigmoideoscopy/rectoscopy. No primary tumor was found. Of the 36 women, 32 had a gynecological examination (89%), revealing no primary tumor. We conclude, that only one possible (but not verified) primary tumor was disclosed by various specialists examinations of 103 patients referred with the diagnosis metastatic melanoma with no primary tumor. Special screenings can thus be considered as redundant. Thus, for patients referred with metastastic melanoma of unknown primary, we recommend that a detailed history is obtained, and a standard physical examination performed, in addition to a histopathological review and CT/PET for staging.

Spontaneous regression of metastases from melanoma: review of the literature.

Regression of metastatic melanoma is a rare event, and review of the literature reveals a total of 76 reported cases since 1866. The proposed mechanisms include immunologic, endocrine, inflammatory and metastatic tumour nutritional factors. We conclude from this review that although the precise mechanisms remain unknown, some event must trigger the immune system to produce a stronger than normal response that results in regression of the melanoma metastases. Immunologic studies of patients with regression may disclose the underlying mechanisms and lead to new therapies of disseminated melanoma.

Radiation exposure to surgical staff during hyperthermic isolated limb perfusion with 99m Technetium labeled red blood cells.

PURPOSE: Hyperthermic isolated limb perfusion (HILP) is an effective method in the treatment of recurrent melanomas and soft tissue sarcomas. To avoid systemic toxicity, leakage from the limb perfusate into the systemic circulation is real-time monitored by administration of a radioactive agent to the limb circuit. This has made HILP safe for the patient. However, the radiation exposure to the surgical staff has never been measured and could be a limiting factor for the use of HILP. The purpose of the present study was to measure and evaluate the radiation exposure to the surgical staff performing HILP with (99m)Technetium labeled red blood cells. MATERIALS AND METHODS: Thirteen patients had HILP performed in 11 lower limbs and two upper limbs at our inpatient clinic between October 2006 and February 2007. The surgeon and nurse had thermoluminescence dosimetry (TLD) chips attached to the finger pulp and to the ring area of the left fourth finger, as well as an electronic dosimeter attached to the anterior lining of the trousers. The anesthesiologist and perfusion technologist also carried electronic dosimeters. RESULTS: The surgeon had the highest radioactive exposure with an average dose per procedure to the finger pulp of 16.2 microSv, to the ring area of 8.5 microSv, and to the abdominal wall of 4.2 +/- 0.6 microSv. CONCLUSIONS: HILP with (99m)technetium-labeled red blood cells does not constitute a safety risk to the operating team with respect to radioactive exposure. Routine dose monitoring of the staff or special precautions for fertile women are not necessary.

Spontaneous regression of metastases from malignant melanoma: a case report.

A case of a 61-year-old male with widespread metastatic melanoma is presented 5 years after complete spontaneous cure. Spontaneous regression occurred in cutaneous, pulmonary, hepatic and cerebral metastases. A review of the literature reveals seven cases of regression of cerebral metastases; this report is the first to document complete spontaneous regression of cerebral metastases from malignant melanoma by means of computed tomography scans. Spontaneous regression is defined as the partial or complete disappearance of a malignant tumour in the absence of all treatment or in the presence of therapy, which is considered inadequate to exert a significant influence on neoplastic disease. The incidence of spontaneous regression of metastases from malignant melanoma is approximately one per 400 patients, and possible mechanisms include immunologic, endocrine, inflammatory and tumour nutritional factors. Our patient engaged in alternative therapies and was taking a number of different dietary supplements, none of which can be medically recommended, but the combination of which possibly strengthened the immune system and thereby the host defense against the melanoma metastases.