melphalan and Carcinoma--Merkel-Cell

Hyperthermic isolated limb perfusion (HILP) has an established role in the management of melanoma, but its role for Merkel cell carcinoma (MCC) is less well defined.. Retrospective review of our institutional experience with HILP for MCC was conducted (2009-2015). Literature search was performed through 04/2015 and 10 studies met inclusion criteria.. Four patients underwent HILP for MCC at our institution. There were no major complications and complete response was achieved in all patients. Early metastatic recurrence developed in two patients. The remaining two had no evidence of disease at last follow-up (36 months) or death (39 months). Systematic review identified an additional 12 pts that underwent HILP for MCC, for a total of 16 cases. Median age was 73 [IQR 69-78] years and 56% were men. Of the patients with reported follow-up, 12 (86%) had complete response, 1 had stable disease, and 1 partial response. Four patients developed local-regional recurrence and six distant metastases, all within 6 months. Overall median follow-up time was 15 [7-36] months.. Among a highly selective group of patients, regional perfusion for MCC is safe and has a high complete response rate. HILP is an acceptable therapeutic modality for obtaining durable loco-regional control but early distant metastatic disease remains a significant cause of mortality. J. Surg. Oncol. 2016;114:187-192. © 2016 Wiley Periodicals, Inc.

Topics: Aged; Aged, 80 and over; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Skin Neoplasms

In-transit metastases of Merkel cell carcinoma (MCC) are an unusual and therapeutically challenging manifestation of the disease. Given the similarity to melanoma, in-transit MCC may be amenable to isolated regional therapy.. To present a case series of 12 patients who underwent isolated limb perfusion (ILP) or isolated limb infusion (ILI) for in-transit MCC.. A literature search was conducted using Medline and Pubmed databases for MCC, ILP, and ILI as key words. Ten cases were identified and reviewed; two cases from our hospital were also included in the series.. Nine patients underwent ILP, and three were treated with ILI. Eleven patients had a complete clinical response, and one had a partial response. All patients avoided limb amputation. Mean follow-up was 25.3 months. Mean duration of response was 21.8 months. Four patients relapsed regionally. Two patients developed distant metastases and died of their disease.. This is the largest case series of in-transit MCC treated with ILP or ILI. Both techniques appear to be a low-morbidity alternative to amputation for the treatment of isolated extremity in-transit MCC. ILI is less invasive than ILP and may be a more practical first-line treatment option. The authors have indicated no significant interest with commercial supporters.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Humans; Infusions, Intra-Arterial; Limb Salvage; Lymphatic Metastasis; Male; Melphalan; Middle Aged; Skin Neoplasms; Treatment Outcome

Merkel cell carcinoma (MCC) is a very rare and aggressive neoplasm. Due to its rarity, therapeutic guidelines are not well established, especially for regionally advanced disease. Hyperthermic isolated limb perfusion (HILP) with Melphalan and either with or without tumor necrosis factor-alpha (TNF-alpha) is becoming more common in clinical practice, yet the long-term response is not clear. Previous reports have established indications for treatment of unresectable MCC as well as the outcome of MCC patients receiving perfusion treatment in combination with other therapies (e.g., radiation).. A review was performed of the most important articles in MEDLINE from the last 20 years related to HILP and MCC. It was possible to collect all cases of HILP from the literature. Details of one case of MCC where HILP was administered was included in the literature review.. A total of nine cases of MCC receiving ILP were identified in the literature; of these, seven achieved a complete response, one a partial response and one no response. All five patients treated without TNF-alpha had a complete response. Of the four patients treated with TNF-alpha, two had complete, one partial and one no response.. Based on the cases described, isolated limb perfusion is an acceptable option to treat regional advanced cases of MCC, and the use of TNF-alpha does not impact the overall response.

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Fatal Outcome; Female; Groin; Humans; Hyperthermia, Induced; Lymph Node Excision; Lymphatic Metastasis; Melphalan; Skin Neoplasms; Tumor Necrosis Factor-alpha

Isolated limb infusion (ILI) is a percutaneous method of delivering regional chemotherapy to patients with recurrent tumors of the extremity. This study determines predictors of response, survival, and limb salvage.. Single institution data from a prospective clinical trial and subsequent ILI experience were reviewed. Limb tumor burden was assessed in melanoma patients with "high" (≥10 lesions or one lesion >3 cm) or "low" burden (<10 lesions and no lesion >3 cm). Response was assessed at 3 months from ILI.. Between 1999 and 2011, 62 patients underwent ILI (58 melanoma, 2 Merkel cell carcinoma (MCC), 2 soft tissue sarcoma (STS)). Low tumor burden patients had more complete responses (CR) (11/23, 48%) than high tumor burden (3/32, 9%, P < 0.001); they had higher 5-year survival (69% vs. 29%, P = .007). Five-year survival rates based on response: 91% CR, 53% partial response (PR), 25% less than PR (P = 0.042, CR vs. PR). 7 patients (11%) underwent amputation due to disease progression; 3 had prior CR or PR.. Low tumor burden is a significant predictor of response in melanoma patients. Response to ILI is a significant predictor of survival. Progression of limb disease requiring amputation is not associated with any factors.

Topics: Adult; Aged; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Disease Progression; Drug Administration Schedule; Extremities; Female; Humans; Kaplan-Meier Estimate; Limb Salvage; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Prospective Studies; Retrospective Studies; Sarcoma; Skin Neoplasms; Treatment Outcome; Tumor Burden

This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant fibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients undergoing regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb malignancies were monitored for intra-operative melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic model which assumed melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no response: 6.7% (n = 1). There was a significant association between tumour response and melphalan concentrations measured over time in subcutaneous microdialysate (P< 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma creatine phosphokinase levels and peak melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportunity for improved drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Histiocytoma, Benign Fibrous; Humans; Melanoma; Melphalan; Microdialysis; Middle Aged; Neoplasms; Osteosarcoma; Treatment Outcome

Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor alpha (TNF-alpha), interferon gamma, and melphalan has proved to be useful in the treatment of recurrent malignant melanoma and of locally advanced soft tissue sarcomas of the extremities.. To determine whether this modality is also effective in the treatment of locally advanced nonmelanoma skin tumors of the extremities.. Fifteen patients with locally advanced primary, recurrent, or metastatic skin tumors of the extremities (12 with squamous cell carcinoma and 3 with Merkel cell carcinoma) underwent HILP with TNF-alpha, interferon gamma, and melphalan. Six tumors were localized in the upper extremity (40%), and 9 in the lower extremity (60%). Treatment-related complications, limb salvage rate, local recurrence, and regional and distant metastases were scored during a median follow-up of 20 months.. After HILP, 9 patients (60%) showed a complete response (with histopathological confirmation). Four patients (27%) showed a partial response (with histopathological confirmation in 1 patient), and 2 patients (13%) showed no change (with histopathological confirmation in 1 patient and with clinical evidence in 1 patient). Two patients (13%) showed treatment-related complications. The limb salvage was achieved in 12 patients (80%), and the local recurrences developed in 4 patients (27%). During follow-up, regional lymph node metastases were observed in 2 patients (13%) and distant metastases in 2 patients (13%).. Based on our results, HILP with TNF-alpha, interferon gamma, and melphalan should be considered as a limb-saving treatment modality in patients with locally advanced nonmelanoma skin tumors of the extremities who would otherwise be candidates for ablative surgery.

Topics: Adult; Aged; Antineoplastic Agents; Arm; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Hot Temperature; Humans; Interferon-gamma; Leg; Male; Melphalan; Middle Aged; Skin Neoplasms; Tumor Necrosis Factor-alpha

Topics: Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Humans; Melphalan; Skin Neoplasms

Topics: Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Humans; Melphalan; Skin Neoplasms

Isolated limb perfusion (ILP) is an established and effective treatment for advanced melanoma and soft tissue sarcomas of the extremities with a high overall response rate. The aim of this study was to describe our experience of ILP for more rare types of tumours.. Patients with Merkel cell carcinoma (MCC) (n = 4), squamous cell carcinoma (SCC) (n = 2), B-cell lymphoma (n = 1), desmoid tumours (n = 3), pigmented villonodular synovitis (PVNS) (n = 1) and giant cell tumour (n = 1) were treated with ILP and analysed retrospectively.. The four patients with in-transit MCC had three complete responses (CR) and one partial response (PR); the two patients with SCC had one CR and one stable disease (SD); the patients with desmoid tumours had two PR and one SD. A CR was also observed for the patient with a giant cell tumour, but the patient with PVNS had a SD. The patient with cutaneous metastases of B-cell lymphoma showed a CR, however with rapid systemic progression. Local toxicity according to Wieberdink was grade II in 10 patients (83%) and grade III in two patients (17%).. These results show that ILP can be used as a treatment option also for more rare disease entities when other treatments have failed.

Topics: Abdominal Neoplasms; Adenomatous Polyposis Coli; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Fibromatosis, Aggressive; Giant Cell Tumors; Humans; Hyperthermia, Induced; Lymphoma, B-Cell; Melphalan; Perfusion; Rare Diseases; Synovitis, Pigmented Villonodular; Tumor Necrosis Factor-alpha

Isolated limb infusion (ILI) for the treatment of in-transit melanoma was originally described more than 10 years ago. Response rates of 45-53% have been reported in U.S. series. Long-term quality of life outcomes after this procedure have not been described. We hypothesized that ILI is rarely associated with long-term limb morbidity.. ILIs performed at our institution between July 2005 and June 2009 were reviewed. Patients were contacted cross-sectionally at 2 time points. During these interviews, response to treatment and postoperative limb function were assessed.. Thirty-two ILIs were performed during the time period. Twenty-seven patients were treated for in-transit melanoma; 5 were treated for recurrent Merkel cell carcinoma. The 30-day mortality was 0%. Three patients (9%) required fasciotomy. Durable complete responses were achieved in 41% of patients, with mean follow-up time of 19.4 ± 9.6 months after infusion; after this period, 53% reported progression of disease. The most common postprocedure symptoms were edema (88%), numbness (59%), and pain (59%). By 3 months and at the time of last follow-up, the most common symptoms were edema (82%), numbness (65%), and stiffness (35%). No patients reported impaired limb function at the time of last follow-up compared to baseline. Median survival was 19.2 ± 4.2 months after infusion.. ILI for melanoma and Merkel cell carcinoma is associated with postprocedure symptoms in most patients, most commonly edema, color change, and numbness. At last follow-up, no ILI patients had residual functional impairment in the treated limb.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Arm; Carcinoma, Merkel Cell; Cross-Sectional Studies; Dactinomycin; Edema; Female; Follow-Up Studies; Humans; Hypesthesia; Infusions, Intravenous; Leg; Length of Stay; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Quality of Life; Skin Neoplasms; Survival Rate

Although studies of melphalan-based isolated limb infusion (ILI) combine data from upper extremity (UE) treatments with those from lower extremity (LE) treatments, differences between the 2 may be clinically important.. Candidates for UE ILI (n = 51) and LE ILI (n = 192) were identified from prospective databases at 2 institutions. The Response Evaluation Criteria in Solid Tumors and Wieberdink toxicity scale were used as appropriate.. The following patients had indications for UE ILI: melanoma, 36 of 47 patients (77%); sarcoma, 5 of 47 patients (11%); Merkel cell sarcoma, 3 of 47 patients (6%), and squamous cell carcinoma, 3 of 47 patients (6%). The patients who underwent UE ILI, as expected, had lower limb volumes (mean, 2.5 L vs 8.6 L; P < .001) and lower mean melphalan doses (20.7 mg vs 49.5 mg; P < .001). On perfusate blood gas analysis, the mean base excess at 30 minutes (-13.9 vs -9.1; P < .001) and the mean pH at 30 minutes (7.06 vs 7.15; P < .001) were lower for UE procedures than for LE procedures, although the mean ischemic time was longer in LE procedures (67.2 minutes) than in UE procedures (61.6 minutes; P = .03). The rate of regional toxicity grade ≥3 for UE ILI was 7% compared with 24% (P = .005) for LE ILI. There was no difference in the complete response rate for melanoma UE procedures (28%; 95% confidence interval, 16%-44%) compared with LE ILI procedures (32%; 95% confidence interval, 25%-39%).. ILI for UE disease was associated with similar complete response rates but lower toxicity than ILI for LE disease and with different physiologic sequelae despite comparable methods. The UE appears relatively resistant to toxic effects of melphalan-based ILI as currently performed, which suggests a potential for further optimization of drug dosing for UE ILI.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Prospective Studies; Sarcoma; Survival Rate; Upper Extremity; Young Adult

To demonstrate the efficacy of isolated limb infusion (ILI) in limb preservation for patients with locally advanced soft-tissue sarcomas and nonmelanoma cutaneous malignant neoplasms.. Locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms, including soft-tissue sarcomas of the extremities, can pose significant treatment challenges. We report our experience, including responses and limb preservation rates, using ILI in cutaneous and soft-tissue malignant neoplasms.. We identified 22 patients with cutaneous and soft-tissue malignant neoplasms who underwent 26 ILIs with melphalan and dactinomycin from January 1, 2004, through December 31, 2009, from 5 institutions. Outcome measures included limb preservation and in-field response rates. Regional toxic effects were measured using the Wieberdink scale and serum creatinine phosphokinase levels.. The median age was 70 years (range, 19-92 years), and 12 patients (55%) were women. Fourteen patients (64%) had sarcomas, 7 (32%) had Merkel cell carcinoma, and 1 (5%) had squamous cell carcinoma. The median length of stay was 5.5 days (interquartile range, 4-8 days). Twenty-five of the 26 ILIs (96%) resulted in Wieberdink grade III or less toxicity, and 1 patient (4%) developed grade IV toxicity. The median serum creatinine phosphokinase level was 127 U/L for upper extremity ILIs and 93 U/L for lower extremity ILIs. Nineteen of 22 patients (86%) underwent successful limb preservation. The 3-month in-field response rate was 79% (21% complete and 58% partial), and the median follow-up was 8.6 months (range, 1-63 months). Five patients underwent resection of disease after an ILI, of whom 80% are disease free at a median of 8.6 months.. Isolated limb infusion provides an attractive alternative therapy for regional disease control and limb preservation in patients with limb-threatening cutaneous and soft-tissue malignant neoplasms. Short-term response rates appear encouraging, yet durability of response is unknown.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Creatine Kinase; Dactinomycin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Length of Stay; Limb Salvage; Male; Melphalan; Middle Aged; Retrospective Studies; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Treatment Outcome; Young Adult

Isolated limb perfusion (ILP) is a surgical technique that enables the administration of high-dose chemotherapy while minimizing serious systemic side effects. The clinical value and indications are well established for skin and soft tissue tumors on limbs. For skin tumors, this technique is mainly indicated for melanoma with in-transit metastasis. For soft tissue tumors--sarcoma and osteosarcoma--it is useful as a palliative technique to reduce the tumoral mass. Limb perfusion can also be an option in other tumors, such as advanced stage squamous cell carcinoma or Merkel cell carcinoma. We present a case report of a 68-year-old man with Merkel cell carcinoma on the right tibiotarsical region, with in-transit metastasis throughout the whole lower limb. Regional chemotherapy involving ILP with melphalan and tumor necrosis factor-alpha (TNFalpha) was performed in order to avoid amputation; the primary tumor was not excised. A steady regression of the disease was observed, with complete resolution of all visible in-transit metastases at the 45th day post-perfusion. However, systemic metastasis leading to fatal outcome occurred 4 months later. Although there was no change in the patient's prognosis, ILP was able to avoid limb amputation as it controlled local-regional disease and produced complete regional remission. The addition of TNFalpha to melphalan in ILP appears to produce greater efficacy in the treatment of patients with bulky tumors or a large number of in-transit metastases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Fatal Outcome; Follow-Up Studies; Humans; Immunohistochemistry; Limb Salvage; Lower Extremity; Male; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Palliative Care; Risk Assessment; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.

Topics: Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Dose-Response Relationship, Drug; Female; Humans; Infusion Pumps; Leg; Male; Melanoma; Melphalan; Middle Aged; Models, Biological; Neoplasm Recurrence, Local; Sarcoma, Kaposi; Skin Neoplasms; Time Factors

Merkel's cell carcinoma is an uncommon neuroendocrine cutaneous neoplasm. An unusual mode of dissemination of this tumor is the phenomenon of in-transit metastases. We report complete resolution of in-transit metastases from a Merkel's cell carcinoma in response to treatment with isolated hyperthermic limb perfusion with melphalan. Limb perfusion appears to be a promising modality for such lesions.

Topics: Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Humans; Hyperthermia, Induced; Lymphatic Metastasis; Male; Melphalan; Skin Neoplasms

An 87-yr-old woman diagnosed with recurrent Merkel's cell carcinoma was treated with therapeutic limb perfusion and underwent PET scanning with 18F-fluorodeoxyglucose (FDG). PET studies were obtained before and after treatment to determine the response to the intervention. A baseline whole-body study was obtained to assess the extent and degree of disease activity. This was followed by a repeat PET scan 2 mo. later after treatment with isolated limb chemotherapy with high-dose melphalan and tumor necrosis factor-alpha. The initial scan demonstrated multiple foci of high FDG uptake in the left calf, a left supraclavicular lesion and also detected concurrent keratinizing squamous cell metastasis in the right axilla. A repeat PET study showed complete metabolic resolution of the lesions in the left calf after treatment. FDG PET may be a useful technique for staging Merkel cell carcinoma and for assessing the tumor response after therapy of this rare tumor.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Female; Fluorodeoxyglucose F18; Humans; Leg; Melphalan; Radiopharmaceuticals; Recurrence; Skin Neoplasms; Tomography, Emission-Computed; Tumor Necrosis Factor-alpha

Merkel cell carcinoma of the skin is a rare malignant tumour first described in 1972 by Toker. The optimal management of this disease has not been clearly defined, especially that of advanced locoregional disease. Surgery, radiotherapy and chemotherapy have been advocated separately or in combination, with less-than-optimal results. Localized high-dose chemotherapy has never been tried, although it would seem to be the logical step forward.

Topics: Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dissection; Humans; Hyperthermia, Induced; Leg; Male; Melphalan; Skin Neoplasms

Two patients with metastatic spread of unusual tumors responded to treatment with high-dose Melphalan and autologous bone marrow transplant. One patient had adenoid cystic carcinoma of a minor salivary gland and the other had Merkel cell tumor of the scalp. Both patients had undergone prior surgery and radiotherapy, but later relapsed with distant metastases. Both patients had progression of their disease despite conventional and salvage chemotherapy. Treatment with high-dose Melphalan and autologous bone marrow transplant resulted in partial responses for both patients. High-dose Melphalan should be considered for therapy earlier in the course of patients with these unusual cancers.

Topics: Adult; Bone Marrow Transplantation; Carcinoma, Adenoid Cystic; Carcinoma, Merkel Cell; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Melphalan; Salivary Gland Neoplasms; Scalp; Skin Neoplasms