Acral lentiginous melanoma histotype predicts outcome in clinical stage I-II melanoma patients: an International multicenter study.

BACKGROUND: In the American Joint Committee on Cancer (AJCC) classification, acral lentiginous melanoma (ALM) histotype ALM is not included as an independent prognostic factor; in small series its negative prognostic impact on disease-free survival (DFS) and overall survival (OS) has been linked to the greater Breslow thickness (BT). PATIENTS AND METHODS: The study was carried out at four referral melanoma centers (three Italian and one Polish). Clinical consecutive patients with stage I-II melanoma, who were diagnosed, treated, and followed up between January 1998 and March 2018 in annotated specific databases were included. RESULTS: Overall, 6734 were evaluable, 4349 with superficial spreading melanoma (SSM), 2132 with nodular melanoma (NM), and 253 with ALM. At univariable analysis, a statistically significant worse DFS [hazard ratio (HR) 2.72, 95% confidence interval (CI) 2.24-3.30; P < 0.001] and OS (HR 2.67, 95% CI 2.15-3.32; P < 0.001) were found in patients with ALM compared with SSM. Similarly, the NM histotype was associated with a worse prognosis compared with the SSM histotype (DFS: HR 2.29, 95% CI 2.08-2.52; P < 0.001 and OS: HR 2.21, 95% CI 1.99-2.46; P < 0.001). At multivariable analysis, after adjusting for age, sex, BT, ulceration, and the sentinel lymph node status, a statistically significant worse DFS [adjusted HR (aHR; ALM versus SSM) 1.25, 95% CI 1.02-1.52; P = 0.028] was confirmed for patients with ALM. For patients with NM, instead, no impact of histology was found in terms of DFS [aHR (NM versus SSM) 1.04, 95% CI 0.93-1.15; P = 0.513] and OS [aHR (NM versus SSM) 0.96, 95% CI 0.86-1.08; P = 0.548]. CONCLUSIONS: ALM is associated with a worse long-term DFS. Our results could have important clinical implications for patients' stratification in future clinical trials and the incorporation of ALM histotype in the new AJCC classification as an independent prognostic factor.

Correction to: NFATc2 is an intrinsic regulator of melanoma dedifferentiation.

In Fig. 6e, the authors noticed that wrong blots for MITF, MART-1 expression/modulation, and for ß-actin were presented, due to the similarity with experiments shown in Figure 5c. Correct MITF, MART-1, and ß-actin blots were added to the revised Fig. 6 shown in the associated Correction. The meaning of the results shown in Fig.6e, as well as the conclusions of this paper were not affected, and the authors regret for this error. These errors have not been fixed in the original Article.

Prognostic factors in Merkel cell carcinoma patients undergoing sentinel node biopsy.

INTRODUCTION: Debate remains about prognostic factors in primary Merkel cell carcinoma (MCC). We investigated clinicopathological factors as determinants of survival in patients with MCC submitted to sentinel node biopsy. METHODS: Sixty-four consecutive patients treated for a primary MCC were identified from a prospectively maintained database at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Time to events outcome were described by product limit estimators and proportional hazards model was used to investigate the association between outcome and potential predictors. RESULTS: The most common site of primary tumor was lower limbs (56.3%). The size of primary lesion was ≤2 cm in 67.2% of cases. Presence of residual disease after the diagnostic surgical excision was observed in 28% of cases. All patients received sentinel node biopsy (SNB) and a SN positivity was detected in 26.6%. The median follow up was 78 months. Disease recurrence occurred in 17 patients (26.6%). In the SN negative group 10 recurrences occurred (21.3%), whereas 7 (41.2%) were found in SN positive one. Nine patients SN negative (19.1%) died of disease and 3 (17.6%) among SN positive. SN status was not associated with survival (p = 0.78). Neither age, gender, size and site of primary tumor resulted predictors of patients' outcome. The presence of residual tumor in the specimen of the wide local excision, after the diagnostic surgical excision, was the only variable associated with survival (p = 0.03). CONCLUSIONS: Presence of residual tumor in the specimen of the wide local excision is the main prognostic factor in MCC patients.

NFATc2 is an intrinsic regulator of melanoma dedifferentiation.

Melanoma dedifferentiation, characterized by the loss of MITF and MITF regulated genes and by upregulation of stemness markers as CD271, is implicated in resistance to chemotherapy, target therapy and immunotherapy. The identification of intrinsic mechanisms fostering melanoma dedifferentiation may provide actionable therapeutic targets to improve current treatments. Here, we identify NFATc2 transcription factor as an intrinsic regulator of human melanoma dedifferentiation. In panels of melanoma cell lines, NFATc2 expression correlated inversely with MITF at both mRNA and protein levels. NFATc2(+/Hi) melanoma cell lines were CD271(+) and deficient for expression of melanocyte differentiation antigens (MDAs) MART-1, gp100, tyrosinase and of GPNMB, PGC1-α and Rab27a, all regulated by MITF. Targeting of NFATc2 by small interfering RNA, short hairpin RNA and by an NFATc2 inhibitor upregulated MITF, MDAs, GPNMB, PGC-1α, tyrosinase activity and pigmentation and suppressed CD271. Mechanistically, we found that NFATc2 controls melanoma dedifferentiation by inducing expression in neoplastic cells of membrane-bound tumor necrosis factor-α (mTNF-α) and that melanoma-expressed TNF-α regulates a c-myc-Brn2 axis. Specifically, NFATc2, mTNF-α and expression of TNF receptors were significantly correlated in panels of cell lines. NFATc2 silencing suppressed TNF-α expression, and neutralization of melanoma-expressed TNF-α promoted melanoma differentiation. Moreover, silencing of NFATc2 and TNF-α neutralization downmodulated c-myc and POU3F2/Brn2. Brn2 was strongly expressed in NFATc2(+/Hi) MITF(Lo) cell lines and its silencing upregulated MITF. Targeting of c-myc, by silencing or by a c-myc inhibitor, suppressed Brn2 and upregulated MITF and MART-1 in melanoma cells. The relevance of NFATc2-dependent melanoma dedifferentiation for immune escape was shown by cytolytic T-cell assays. NFATc2(Hi) MITF(Lo) MDA(Lo) HLA-A2.1(+) melanoma cells were poorly recognized by MDA-specific and HLA-A2-restricted CTL lines, but NFATc2 targeting significantly increased CTL-mediated tumor recognition. Taken together, these results suggest that the expression of NFATc2 promotes melanoma dedifferentiation and immune escape.

Factors predictive of pelvic lymph node involvement and outcomes in melanoma patients with metastatic sentinel lymph node of the groin: A multicentre study.

INTRODUCTION: The optimal extent of the groin lymph node (LN) dissection for melanoma patients with positive sentinel LN biopsy is still debated and no agreement exist on dissection of pelvic LN. This study aimed at investigating predictors of pelvic LN metastasis and prognostic significance of having metastasis in the pelvic LNs. METHODS: Clinicopathologic data of 740 patients with positive groin sentinel LN who underwent ilioinguinal completion LN dissection at four Italian centre were analysed. Multivariable logistic and Cox regression analysis was used to identify independent predictors of pelvic LN metastasis and to adjust prognostic significance of pelvic LN metastasis. RESULTS: More than a quarter (26%) of patients had positive non-SLNs after inguinal and pelvic lymphadenectomy, which were located in their pelvis in the 12% of cases. Older patients [(OR) 1.69; 95% confidence interval (CI) 1.02-2.78] having thick primary (OR 1.6; 95% CI, 1.01-2.53) and ≥ 2 positive SLNs (OR 2.5; 95% CI, 1.4-4.47) were more likely to harbour pelvic LN metastasis. Interestingly, 4% of all patients (34% of patients with positive pelvic LNs) had pelvic LN metastasis with negative inguinal LNs. Pelvic LN metastasis was independently associated with higher risk of recurrence and lower survival. 5-year disease free and overall survival was 30% and 50%, respectively, for patients with pelvic LN metastasis. CONCLUSIONS: Pelvic LNs are frequently positive after ilioinguinal lymphadenectomy and it should be considered for all patients, especially those who are older, have thick primary and ≥ 2 positive SLN. Patients with pelvic LN metastasis have worse prognosis.

Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients.

BACKGROUND: No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study.

BACKGROUND: In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. PATIENTS AND METHODS: This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. RESULTS: Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in 'memory' but not in 'naïve' T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points. BRAF status did not correlate with clinical outcome. CONCLUSIONS: Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. EUDRACT NUMBER: 2010-019356-50. CINICALTRIALSGOV: NCT01654692.

The number of excised lymph nodes is associated with survival of melanoma patients with lymph node metastasis.

BACKGROUND: Although the number of excised LNs has been associated with patient prognosis in many solid tumors, this association has not been widely investigated in cutaneous melanoma. This study aims to evaluate the association between the number of excised regional lymph nodes (LNs) and melanoma-specific survival. PATIENT AND METHODS: Clinico-pathological data from 2507 patients with LN metastasis treated at nine Italian centers were retrospectively collected. RESULTS: The number of excised LNs correlated with younger age (P < 0.001), male sex (P < 0.001), neck LN field (P < 0.001), LN micrometastasis (P < 0.001) and number of positive LNs (P < 0.001). The number of excised LNs was an independent prognostic factor (HR = 0.85; P = 0.002) after adjustment for other staging features. Upon subgroup analysis, the number of excised LNs had a significant prognostic value in patients bearing 1.01-2.00 mm (HR = 0.79; P = 0.032) and 2.01-4.00 mm (HR = 0.71; P < 0.001) thick melanomas, primary tumors showing ulceration (HR = 0.86; P = 0.033) and Clark level V of invasion (HR = 0.86; P = 0.010), LN micrometastasis (HR = 0.83; P = 0.014) and two to three positive LNs (HR = 0.71; P = 0.001). Finally, this study investigated the influence of the number of excised LNs on patient staging: only when ≥11 nodes were excised the AJCC N stage could stratify prognosis (P < 0.001). Considering the number of excised LNs for each lymphatic field, at least 14, 11, 10 and 12 LNs were needed to stage patients according to the AJCC N stage after a lymphadenectomy of the neck, axilla, inguinal and ilioinguinal LN fields, respectively. CONCLUSIONS: The number of excised LNs can be considered for risk stratification of patients with regional LN metastasis from cutaneous melanoma. We demonstrated that a minimum number of LNs is required for the correct staging of patients. Further research is needed to evaluate the effectiveness of the minimum number of LNs to be dissected.

Hyperthermic isolated perfusion with tumor necrosis factor-alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcoma: the experience of the Italian Society of Integrated Locoregional Treatment in Oncology (SITILO).

BACKGROUND: Tumor necrosis factor-alpha (TNFalpha)-based hyperthermic isolated limb perfusion (HILP) is routinely carried out at most oncological institutions in the treatment of locally advanced soft tissue limb sarcoma (STS), employing high TNFalpha dosages. After a phase I-II study, the SITILO (Italian Society of Integrated Locoregional Therapies in Oncology) centers began to employ the lower dose of 1 mg of TNFalpha. The aim of this paper is to report on the results obtained in 75 patients with limb-threatening STS treated with a low TNFalpha dose and doxorubicin (Dx). PATIENTS AND METHODS: HILP with TNFalpha (at a dosage of either 1 mg) and Dx was administered to 75 patients with limb-threatening STS: 37 males and 38 females; median age 50 years; tumor in the lower and upper limbs in 58 and 17 patients, respectively; primary and recurrent tumors in 45 and 30 patients, respectively. Most tumors (77%) were high grade. Tumor resection was carried out 6 to 8 weeks after HILP. RESULTS: The grade of limb toxicity was mild to moderate in the vast majority of patients (76%). Grades IV and V were observed, but only when high muscle temperatures were recorded and high TNFalpha dosages were employed. Systemic toxicity was also mild to moderate and there were no postoperative deaths. Complete and partial tumor responses were 34% and 48%, respectively, with an overall response of 82% . Limb sparing surgery was carried out in 85.3% of patients. At a median follow-up of 28 months, 16 recurrences (21.3%) were recorded, with a 5-year locoregional disease-free survival of 63% . The 5-year disease-free survival and overall survival were 36.7% and 61.6%, respectively. CONCLUSION: HILP with 1 mg of TNFalpha is an effective neoadjuvant therapy resulting in a high rate of limb sparing in limb-threatening STS, with acceptable local reactions and negligible systemic toxicity.

Prognostic factors influencing tumor response, locoregional control and survival, in melanoma patients with multiple limb in-transit metastases treated with TNFalpha-based isolated limb perfusion.

BACKGROUND: In isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNFalpha) and interferon (IFN)-gamma, pioneered by Lienard and Lejenne in 1988, TNFalpha was empirically employed at a dosage (3-4 mg) ten times higher than the systemic maximum tolerable dose (MTD). We previously conducted a phase I/II study in 20 patients with in-transit melanoma metastases, using a combination of melphalan and TNFalpha at dosages ranging from 0.5 to 3.3 mg. The dose of 1 mg of TNFalpha was identified as optimal in terms of both efficacy and toxicity. The aim of the present study was to describe our experience with 113 stage IIIA/IIIAB melanoma patients treated with a TNFalpha-based ILP and identify prognostic factors for response, locoregional control and survival. PATIENTS AND METHODS: Patients at stage IIIA-IIIAB (presence of in-transit metastases and/or regional node involvement) were considered eligible. The disease was bulky (>or=10 nodules3 cm) in 42.5% of the patients and unresectable in 33% . Forty patients were treated with a TNFalpha dosage of >1 mg and 73 with 1 mg. Patients with tumors in the upper and lower limbs were submitted to ILP via axillary and iliac vessels, respectively. TNFalpha was injected in the arterial line of an extracorporeal circuit at the pre-established dose, followed by melphalan (13 and 10 mg/l of limb volume for the upper and lower limbs, respectively) 30 minutes later. RESULTS: Complete responses (CR) and partial responses (PR) were 63% and 24.5%, respectively, with an objective response (OR) of 87.5%. No change (NC) was observed in only 12.5% of the patients. Upon multivariate analysis, only bulky disease maintained its independent value for tumor response with an odds ratio of 4.07 and a p-value of 0.02. The 5-year locoregional disease-free survival was 42.7%. Upon multivariate analysis, the only prognostic factors were stage, age and bulky disease. The 5-year overall survival was 49%. Multivariate analysis showed that only sex, stage and CR maintained their independent values. CONCLUSION: TNFalpha-based ILP was proven to be an effective treatment for melanoma patients with in-transit metastases. The TNFalpha dosage of 1 mg was as effective as 3-4 mg, with lower toxicity and cost. We propose that TNFalpha and melphalan-based ILP should be employed for bulky tumors or after failure of melphalan-based ILP.

Multispectral imaging and artificial neural network: mimicking the management decision of the clinician facing pigmented skin lesions.

Various instruments based on acquisition and elaboration of images of pigmented skin lesions have been developed in an attempt to in vivo establish whether a lesion is a melanoma or not. Although encouraging, the response of these instruments, e.g. epiluminescence microscopy, reflectance spectrophotometry and fluorescence imaging, cannot currently replace the well-established diagnostic procedures. However, in place of the approach to instrumentally assess the diagnosis of the lesion, recent studies suggest that instruments should rather reproduce the assessment by an expert clinician of whether a lesion has to be excised or not. The aim of this study was to evaluate the performance of a spectrophotometric system to mimic such a decision. The study involved 1794 consecutively recruited patients with 1966 doubtful cutaneous pigmented lesions excised for histopathological diagnosis and 348 patients with 1940 non-excised lesions because clinically reassuring. Images of all these lesions were acquired in vivo with a multispectral imaging system. The data set was randomly divided into a train (802 reassuring and 1003 excision-needing lesions, including 139 melanomas), a verify (464 reassuring and 439 excision-needing lesions, including 72 melanomas) and a test set (674 reassuring and 524 excision-needing lesions, including 76 melanomas). An artificial neural network (ANN(1)) was set up to perform the classification of the lesions as excision-needing or reassuring, according to the expert clinicians' decision on how to manage each examined lesion. In the independent test set, the system was able to emulate the clinicians with a sensitivity of 88% and a specificity of 80%. Of the 462 correctly classified as excision-needing lesions, 72 (95%) were melanomas. No major variations in receiver operating characteristic curves were found between the test and the train/verify sets. On the same data set, a further artificial neural network (ANN(2)) was then architected to perform classification of the lesions as melanoma or non-melanoma, according to the histological diagnosis. Having set the sensitivity in recognizing melanoma to 95%, ANN(1) resulted to be significantly better in the classification of reassuring lesions than ANN(2). This study suggests that multispectral image analysis and artificial neural networks could be used to support primary care physicians or general practitioners in identifying pigmented skin lesions that require further investigations.

Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been and is still widely used as an adjuvant in clinical trials of vaccination with autologous tumor cells, peptides and/or dendritic cells in a variety of human neoplasms. This cytokine was administered either as product of gene-transduced tumor cells or as recombinant protein together with the vaccine given subcutaneously or intradermally. Results of these trials were heterogeneous in terms of induction of vaccine-specific immune response and of clinical response. Though in some of these studies GM-CSF appeared to help in generating an immune response, in others no effect or even a suppressive effect was reported. Here, we review the literature dealing with the immune adjuvant activity of GM-CSF both in animal models and clinical trials. As a consequence of such analysis, we conclude that GM-CSF may increase the vaccine-induced immune response when administered repeatedly at relatively low doses (range 40-80 microg for 1-5 days) whereas an opposite effect was often reported at dosages of 100-500 microg. The potential mechanisms of the GM-CSF-mediated immune suppression are discussed at the light of studies describing the activation and expansion of myeloid suppressor cells by endogenous tumor-derived or exogenous GM-CSF.

HSP-70, C-myc and HLA-DR expression in patients with cutaneous malignant melanoma metastatic in lymph nodes.

HSP-70, C-myc and HLA-DR were examined in patients with cutaneous malignant melanoma metastatic to lymph nodes. Lymph-nodal fine-needle aspiration biopsies (FNABs) were analyzed and the results were correlated to other variables, such as the gender of the patients, Clark level and Breslow thickness of the primary tumor. Thirty cases of metastatic melanoma in lymph nodes from 30 patients with cutaneous malignant melanoma were studied. All patients (100%) had microscopic regional nodal metastasis and a recurrence of the lesion during the first two years. The HSP-70, C-myc and HLA-DR expressions were investigated immunocytologically, using the APAAP (alkaline phosphatase) method on the FNAB samples. The immunocytochemical expressions of HSP-70 protein, C-myc oncogene, and HLA-DR antigen were found in 18 cases (60%), in 14 cases (43.3%) and in 12 cases (40%), respectively. Clark levels were significantly associated with HSP-70 protein (< 0.01), C-myc oncogene expression (< 0.05) and HLA-DR antigen (< 0.01) expression. The HLA-DR antigen was also found to be related (< 0.05) to higher Breslow thickness (> 1.5 mm). The clinical course of malignant cutaneous melanoma is related to the expression of these indices, which seem to play a significant role in the metastasis and prognosis of this aggressive tumor. The immunocytochemical expression of HSP-70 in the malignant melanoma tumor could be of particular value in the identification of patients with poor prognosis.

Micro-melanoma detection: a clinical study on 206 consecutive cases of pigmented skin lesions with a diameter < or = 3 mm.

BACKGROUND: Very small pigmented lesions may represent an important diagnostic challenge to the clinician. OBJECTIVES: The aim of the present study was to establish the diagnostic value, in terms of sensitivity and specificity, of both clinical and dermoscopic examinations in a population of patients with unselected consecutive pigmented lesions with a maximum clinical diameter of 3 mm. PATIENTS AND METHODS: Two hundred and four consecutive patients bearing 206 pigmented skin lesions with a maximum diameter of 3 mm were seen and operated on. Twenty-three of these lesions were melanomas. Each lesion was subjected to both clinical and dermoscopic evaluation before surgery. The results were expressed in terms of sensitivity and specificity of both kinds of evaluation. RESULTS: Clinical evaluation produced a diagnostic sensitivity of 43% and a specificity of 91%. Dermoscopy resulted in a sensitivity of 83% and in a specificity of 69%. The comparison between the sensitivity values of the two diagnostic methods showed a significant difference (P < 0.01). A high value of significance was also obtained comparing the respective specificity values (P < 0.001). CONCLUSIONS: Detection of very small melanomas is feasible by accurate visual inspection. Dermoscopy appears to be an important aid to diagnosis, provided that physicians are aware of this type of lesion and maintain the index of suspicion at a high level.

Lymphoscintigraphy with intraoperative gamma probe sentinel node detection: clinical impact in patients with head and neck melanomas.

AIM: The aims of this paper were to evaluate the clinical relevance of lymphoscintigraphy with intraoperative gamma-probe detection in identifying sentinel nodes (SNs) and to study the prognostic value of SN biopsy in head and neck melanoma patients. METHODS: Sixty-one patients had lymphoscintigraphy with intradermal injections of 99mTc-Nanocoll (40 MBq), 24 h before surgery. Tumor-positive SNs patients underwent total lymph node dissection. Postoperative histological examination was performed. Patients were followed up for 1 to 5 years (median 3 years). The tumor relapses and the overall survival were evaluated by means of statistical methods. RESULTS: Lymphoscintigraphy showed lymphatic distribution to more than one basin in 45 patients (74%), in 15 patients one basin was visualized and no basin in 1 patient. In 41 patients the SN was negative for metastases, while in 20 was positive. In a high percentage of patients (30%), metastatic involvement occurred in more than one lymph node basin. During follow-up in the negative SN group, 40 patients remained disease free and 1 relapsed. In the positive SN group, 10 patients remained disease free and 10 relapsed. Recurrence time ranged from 6 to 11 months. The overall survival of the SNs negative group was significantly higher than the positive SN group. CONCLUSIONS: This approach was able to distinguish: a) patients with tumor-negative SNs with a favorable clinical course (98% did not relapse, P<0.001); b) patients with tumor-positive SNs with a high rate of tumor relapse (50%, P<0.001). Therefore SN biopsy may give information about prognosis in head and neck melanoma patients.

Atypical pleomorphic epithelioid angiomyolipoma localized to the pelvis: a case report and review of the literature.

AIMS: Angiomyolipoma is the most common mesenchymal tumour of the kidney. It has been reported in several other sites outside the kidney, mainly in the liver. We report the first case of atypical pleomorphic angiomyolipoma in a man, arising from the pouch of Douglas and extending to the entire abdominal cavity. METHODS: A 17-year-old man underwent a complete resection of a giant abdominopelvic mass. The tissue was formalin fixed and paraffin embedded and 4 micro m thick histological sections were stained with haematoxylin-eosin. Immunohistochemical stains for HMB-45, smooth muscle actin, vimentin, calponin, S100 and desmin were performed. Sections for electron microscopy were also prepared. RESULTS: Microscopic examination revealed a neoplasm composed of pleomorphic epithelioid cells with atypical features, immunoreactive for HMB-45, MART-1, actin, vimentin and calponin, while S100 protein and desmin stains were negative. Ultrastructurally, the tumour cells showed prominent nucleoli, vacuolated cytoplasm, and some premelanosomes. A diagnosis of atypical pleomorphic epithelioid angiomyolipoma was then made. CONCLUSIONS: To date five patients with abdominal epithelioid angiomyolipoma have been described in the literature. All were women. Three of the five patients reported developed metastasis, while our patient is still free of disease at 16 months of follow-up. Clear prognostic pathological features have not been identified.

[Impact of sentinel lymph node biopsy on the treatment of melanoma]. / Impatto della biopsia del linfonodo sentinella sul trattamento del melanoma.

In the National Cancer Institute and S Pio X Hospital series we registered 981 patients with primary cutaneous melanoma and no evidence of clinically detectable regional node metastases underwent sentinel node (SN) dissection to microscopically define the tumor status of the regional lymph nodes. In 62.2% of cases, only one SN was detected; 26.4% of patients had two SNs and 11.4% had three or more SNs. A positive SNB was demonstrated in 18.1%. Analysis of survival indicated that the tumor status of the nodes was the most important prognostic factor. Breslow's thickness had a significant impact on survival in tumors of 4 mm or thicker, and ulceration dropped to a borderline significant P-value. To assess the tumor burden in positive SNB, all slides (148 SN pos) were reviewed. Twenty per cent of these patients had evidence of metastasis in other nodes. Of the remaining 80% with a single tumor-involved SN, 62% had a single metastatic deposit. Preliminary data from this study indicate that several subgroups may be identified among patients with 1 positive node, but adequate analysis of survival requires a larger number of patients and a multicentric study.

World Health Organization experience in the treatment of melanoma.

The method of randomized trials, as performed by the WHO Melanoma Program, has definitely been a legitimate clinical study design in patients with melanoma from about 1970 to the end of the last century. Three important results of these WHO trials have substantially influenced the approach of the clinician towards melanoma: (1) There is no role for elective regional lymph node dissection, (2) narrow local excision of the primary melanoma does not entail additional risks, and (3) adjuvant treatment with chemotherapy or immunotherapy after radical surgery for regional lymph node metastases has not, until now, shown any substantial benefit. A problem arises because randomized clinical studies require long periods of time for patients accrual and completion. Frequently their legitimacy is challenged due to the appearance of new parameters, both regarding staging (eg, the introduction of new technical method such as sentinel node biopsy) and prognosis. Therefore, it would be better to define different clinical study models to quickly test a hypothesis on a small group of selected patients in order to provide quick results. We believe that this is the future of clinical research in the new millennium, because it does not seem reasonable today to plan large clinical trials that need 10 years or more of accrual and follow-up without reaching definite conclusions.

Chordoma: natural history and results in 28 patients treated at a single institution.

BACKGROUND: The natural history of chordoma is characterized by a high failure rate and a poor functional outcome. The purpose of this study was to review the long-term outcome of our institutional experience. METHODS: The clinical features, type of treatment, pathologic assessment, and follow-up of 56 consecutive patients with chordoma were reviewed. RESULTS: Fifty sacral and six mobile spine chordomas (median size, 13 cm; range, 2-30 cm) were treated at our center between January 1933 and December 2000. Twenty-eight patients affected by sacrococcygeal chordoma and operated on after 1977 form the basis of our study. Surgical margins were rated as wide in 11 cases, marginal in 13 cases, and intralesional in 4 cases. The median follow-up was 71 months (range, 15-200 months). Seventeen patients' disease recurred. Ten patients died as a result of disease. Nine patients remained continuously free of disease. The estimated 5- and 10-year overall survival was, respectively, 87.8% and 48.9%; disease-free survival was 60.6% and 24.2%. Radiotherapy was considered for marginal and intralesional resections. CONCLUSIONS: High sacral amputation can achieve a good rate of wide-margin resections for sacrococcygeal chordomas. Adjuvant radiotherapy may offset the negative effect in the prognosis of marginal resections.