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Purpose High-dose interferon (IFN) for 1 year (HDI) is the US Food and Drug Administration–approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. We sought to determine whether a shorter course of biochemotherapy would be more effective. Patients and Methods S0008 (S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma) was an Intergroup phase III trial that enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b (IFN-α-2b) and granulocyte colony-stimulating factor given every 21 days for three cycles. Coprimary end points were relapse-free survival (RFS) and overall survival (OS). Results In all, 432 patients were enrolled. Grade 3 and 4 adverse events occurred in 57% and 7% of HDI patients and 36% and 40% of biochemotherapy patients, respectively. At a median follow-up of 7.2 years, biochemotherapy improved RFS (hazard ratio [HR], 0.75; 95% CI, 0.58 to 0.97; P = .015), with a median RFS of 4.0 years (95% CI, 1.9 years to not reached [NR]) versus 1.9 years for HDI (95% CI, 1.2 to 2.8 years) and a 5-year RFS of 48% versus 39%. Median OS was not different (HR, 0.98; 95% CI, 0.74 to 1.31; P = .55), with a median OS of 9.9 years (95% CI, 4.62 years to NR) for biochemotherapy versus 6.7 years (95% CI, 4.5 years to NR) for HDI and a 5-year OS of 56% for both arms. Conclusion Biochemotherapy is a shorter, alternative adjuvant treatment for patients with high-risk melanoma that provides statistically significant improvement in RFS but no difference in OS and more toxicity compared with HDI.

Associations between HLA class I antigen expression and the efficacy of a melanoma vaccine (Melacine; Corixa Corp.) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for 2 years compared with observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and prespecified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging, and sex. P = 0.01 was considered statistically significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by treatment arm. HLA serotyping was performed on 553 (80%) patients (vaccine, 294; observation, 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n = 178) had marginally improved RFS (adjusted P = 0.02) and significantly improved OS compared with observation arm patients (n = 145), with 10-year OS of 75% and 63%, respectively [hazard ratio (HR), 0.62; 99% confidence interval (CI), 0.37–1.02; P = 0.01]. There was no impact of HLA-A2 and/or HLA-Cw3 expression on observation arm patients. An analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for patients with HLA-A2– and/or HLA-Cw3–expressing melanoma. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted. Cancer Immunol Res; 2(10); 981–7. ©2014 AACR.

Her test results satisfied the criteria for a lupus anticoagulant. What is the most likely diagnosis?

Immunotherapeutics have been applied intratumorally to manage accessible lesions and to induce systemic immunity in malignant melanoma. Intratumoral bacillus Calmette-Guérin (BCG) has been used for 40 years, and intratumoral BCG, IL-2, IFN-α and imiquimod are recommended as treatment options for patients with in-transit melanoma metastases. Regression of cutaneous metastases can be achieved. Subcutaneous metastases are more refractory, and regression of uninjected, visceral metastases is infrequent. Other microbial products, cytokines, chemicals, immune cells, antibody and viral and plasmid vectors expressing immunologically active molecules have been tested. Antitumor activity has not been demonstrated to be superior to that of intratumoral BCG. There are few controlled trials, and whether survival is impacted with any approach has not yet been established. The immunotherapeutics applied and the intratumoral administration procedure itself can activate responses that are immune inhibitory. More rigorous clinical testing and improved understanding and modulation of regulatory immune responses are necessary.

On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting.Based on their physical examination and radiologic imaging studies, patients with a stage IV melanoma judged amenable to complete resection underwent surgery within 28 days of enrollment. All eligible patients were followed with scans (computed tomography or positron emission tomography) every 6 months until relapse and death.Seventy-seven patients were enrolled from 18 different centers. Of those, 5 patients were ineligible; 2 had stage III disease alone; and 3 had no melanoma in their surgical specimen. In addition, 8 eligible patients had incompletely resected tumor. Therefore, the primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. With a median follow-up of 5 years, the median relapse-free survival was 5 months (95% CI, 3-7 months) whereas median overall survival was 21 months (95% CI, 16-34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively.In a prospective multicenter setting, appropriately selected patients with stage IV melanoma achieved prolonged overall survival after complete surgical resection. Although median relapse-free survival was only 5 months, patients could still frequently undergo subsequent surgery for isolated recurrences. This patient population is appropriate for aggressive surgical therapy and for trials evaluating adjuvant therapy.

Pseudolymphomatous folliculitis is a rare entity. We present a 62-year-old man with a recurrent solitary nodule on his nose requiring multiple excisions. Microscopic examination of the excisions showed a dense lymphocytic infiltrate containing numerous histiocytes and S100+, CD1a+ dendritic cells that surrounded and infiltrated hypertrophic hair follicles. Diffuse sheets of CD3+ T cells and nodular clusters of CD20+ B cells were also seen. There was normal reactive pattern of follicular centers. Light chain restriction was not detected. T-cell receptor and immunoglobulin heavy chain gene rearrangements by polymerase chain reaction revealed negative findings. A diagnosis of pseudolymphomatous folliculitis was made based on the hypertrophic hair follicles, periadnexal S100+ and CD1a+ dendritic cells, and negative clonal gene rearrangement study findings. This case of recurrent pseudolymphomatous folliculitis is instructive because of the resemblance to cutaneous lymphomas and cutaneous lymphoid hyperplasias, and the need for correct diagnosis to avoid overtreatment of this indolent condition.

Purpose: Gene copy number alteration (CNA) is common in malignant melanoma and is associated with tumor development and progression. The concordance between molecular cytogenetic techniques used to determine CNA has not been evaluated on a large set of loci in malignant melanoma.Experimental Design: A panel of 16 locus-specific fluorescence in situ hybridization (FISH) probes located on eight chromosomes was used to identify CNA in touch preparations of frozen tissue samples from 19 patients with metastatic melanoma (SWOG-9431). A subset (n = 11) was analyzed using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH) of DNA isolated directly from touch-preparation slides.Results: By FISH, most samples showed loss near or at WISP3/6p21, CCND3/6q22, and CDKN2A/9p21 (>75% of samples tested). More than one third of CDKN2A/9p21 losses were biallelic. Gains of NEDD9/6p24, MET/7q31, and MYC/8q24 were common (57%, 47%, and 41%, respectively) and CNA events involving 9p21/7p12.3 and MET were frequently coincident, suggesting gain of the whole chromosome 7. Changes were confirmed by aCGH, which also uncovered many discreet regions of change, larger than a single BAC. Overlapping segments observed in >45% of samples included many of the loci analyzed in the FISH study, in addition to other WNT pathway members, and genes associated with TP53 pathways and DNA damage response, repair, and stability.Conclusions: This study outlines a set of CNAs at the gene and regional level, using FISH and aCGH, which may provide a benchmark for future studies and may be important in selection of individual therapy for patients with metastatic malignant melanoma.

Some chromosomal alterations can be associated with vascular abnormalities. For instance, Turner syndrome can be complicated by agenesis or hypoplasia of the portal venous system causing presinusoidal portal hypertension. Liver transplantation to treat this condition overcomes portal hypertension and reconstitutes the diminished hepatic function due to severe atrophy of the portal venous inflow.

The development of laboratory tests for the diagnosis and monitoring of graft-vs-host disease (GVHD) is hampered by a lack of knowledge of minor histocompatibility Ags triggering alloresponses. We hypothesized that the unique molecular structure of the TCR could be used as a marker for the unidentified Ags and exploited for molecular monitoring of GVHD posttransplant. To identify alloreactive T cell clones, we performed in vitro allostimulation cultures for a cohort of patients undergoing hemopoietic stem cell transplantation and determined the sequence of the CDR3 of immunodominant alloreactive clones; 10 corresponding clonotypes restricted to activated T cells were identified. As an alternative method for the identification of alloreactive clones, molecular TCR analysis was applied to biopsies of GVHD-affected tissues. Culture- and biopsy-derived clonotypes were used to design sequence-specific quantitative PCR assays to monitor the levels of putative allospecific clonotypes in posttransplant blood samples and subsequent biopsies. Because of the rational design of the methods used to identify immunodominant clonotypes, we were able to follow the behavior of potentially GVHD-specific T cells during the transplant course. Based on our results, we conclude that molecular T cell diagnostics can be a powerful tool for monitoring immune responses posttransplantation.

Clear cell sarcoma of soft tissue (malignant melanoma of soft parts) is a soft tissue sarcoma with melanocytic differentiation that typically occurs in the tendons and aponeuroses of young adults. As demonstrated by cytogenetics and reverse-transcriptase polymerase chain reaction, between 70% and over 90% of clear cell sarcomas have a t(12;22) translocation, fusing the EWS and ATF1 genes on chromosomes 22q12 and 12q13, respectively. Identification of this translocation distinguishes clear cell sarcoma from histologic mimics, most importantly conventional malignant melanoma. We report our experience with a commercially available, dual-color, break-apart fluorescence in situ hybridization (FISH) probe, which allows detection of EWS (22q12) gene rearrangement in formalin-fixed, paraffin-embedded tissues. Histologically and immunophenotypically well-characterized cases of clear cell sarcoma (n = 10) and malignant melanoma (n = 32) were evaluated with a 22q12 dual-color, break-apart probe (Vysis, Downer's Grove, IL, USA), which spans the known common breakpoints in the EWS gene on chromosome 22 (introns 7-10). Signals from tumor cell nuclei were counted under a fluorescence microscope and the presence of red-green break-apart signals was recorded. Of the clear cell sarcoma cases, seven of 10 showed evidence of an EWS gene rearrangement with a mean of 81.6% positive cells per sample (range: 60-95%). All cases of malignant melanoma (n = 32) showed virtually absent break-apart signals in the EWS gene (less than 4% cells per case). FISH detects EWS gene rearrangement in a substantial proportion of clear cell sarcomas, with excellent specificity. Importantly, EWS FISH is negative in malignant melanoma, a clinically dissimilar tumor, which may closely mimic clear cell sarcoma histologically and immunohistochemically. As the studied probe can be utilized in routinely processed tissue, FISH provides an excellent alternative to reverse-transcriptase polymerase chain reaction in cases where fresh tissue is unavailable.

Oncocytosis is defined as a metaplastic change characterized by the presence of cells with finely granular eosinophilic cytoplasm caused by the accumulation of mitochondria. Although this histologic feature can be found in normal tissues, it can also be seen pathologically as a degenerative phenomenon, where an accumulation of mitochondria is thought to compensate for an uncoupling of oxidative metabolism secondary to cellular aging. Oncocytic metaplasia can be observed in a variety of cutaneous lesions but, to our knowledge, has not been described in melanocytic nevi. We retrospectively reviewed 87 melanocytic nevi from 83 patients that showed significant oncocytic change. We obtained patient clinical history through surveys completed by the patients' physicians. Ultrastructural studies were performed on 4 representative nevi to confirm the presence of increased mitochondria. We prospectively reviewed 100 randomly selected nevi looking for oncocytic changes. We subsequently did not find any correlation with patient demographics or medical histories. Histologic evaluation showed granular eosinophilic cytoplasm in 75% or greater of lesional cells in two thirds of cases. This phenomenon occurred in all types of melanocytic nevi. Ultrastructural studies revealed melanocytes with numerous mitochondria in close apposition to melanosomes. Focal oncocytic change was identified prospectively in 38 of 100 randomly selected melanocytic nevi. We conclude that oncocytosis in melanocytic nevi is a relatively common and underrecognized phenomenon.

Defects in expression or activation signal transducer and activator of transcription-1 (Stat1) in response to interferon-alpha2 (IFN-alpha2) have been implicated as a mechanism for IFN resistance in melanoma cells. To further determine the significance of this observation, 17 melanoma cell lines sensitive or resistant to the antiproliferative effects of IFN-alpha2 and IFN-beta, as well as 30 melanoma patient samples, were analyzed for Stat1 levels by either Western blot analysis or immunohistochemistry. Although the expression level varied between samples, all the cell lines except one and all melanoma biopsy specimens expressed Stat1. IFN-stimulated levels of Stat1 and Stat2, which constitute the transcriptional activation complexes, such as, gamma activated factor (GAF) and IFN-stimulated gene factor 3 (ISGF3), for IFN-stimulated gene (ISG) induction were assessed in melanoma cell lines. Both IFN-alpha2 and INF-beta induced equivalent amounts of Stat1 and Stat2 proteins in cell lines, although compared with IFN-alpha2, IFN-beta had greater antiproliferative effects. No significant differences were observed in tyrosine or serine phosphorylation of Stat1 or the formation of GAF or ISGF3 complexes following IFN-alpha2 or IFN-beta treatment of IFN-resistant or IFN-sensitive cell lines. Comparable induction of two ISGs, ISG54 and IFN regulatory factor-1 (IRF-1), was observed in both sensitive WM9 and resistant A375 cells. Therefore, we report that defects in expression or activation of Stat1 or Stat2 were infrequent in melanoma cell lines and tumor samples and did not correlate with IFN resistance. Cellular resistance to IFNs likely results from defective quantitative or qualitative expression of specific ISGs.

Introduction: Alterations in the length of DNA repetitive sequences (microsatellite instability (MSI)) represent distinct tumorigenic pathways associated with several familial and sporadic tumors. Material and methods: To investigate the prevalence and frequency of MSI in melanocytic lesions, the polymerase chain reaction (PCR)-based microsatellite assay was used to examine formalin-fixed, paraffin-embedded tissues of 30 benign melanocytic nevi, 60 melanocytic dysplastic nevi (MDN), and 22 primary vertical growth phase cutaneous malignant melanomas (CMM). Twenty-four microsatellite markers at the 1p, 2p, 3p, 4q and 9p chromosomal regions were used. Results: MSI was found at 1p and 9p in MDN and CMM but not in benign melanocytic nevi. The overall prevalence of MSI was17/60 (28%) in MDN and 7/22 (31%) in CMM. The frequency of MSI ranged from 2/24 (9%) to 4/24 (17%) and was most commonly found at D9S162. There was a statistically significant correlation between degree of atypia and frequency of MSI (p

Immunoperoxidase-staining methods were used to examine the expression of hMLH1, hMSH2, and hMSH6 mismatch repair (MMR) proteins in 50 melanocytic lesions. Microsatellite instability (MSI), screened previously in these lesions by polymerase chain reaction-based microsatellite assay, showed low-level microsatellite instability (MSI-L) in 11 of 22 melanocytic dysplastic nevi (MDN) and two of nine primary cutaneous malignant melanomas (CMMs) but not in the benign melanocytic nevi (BN). Mismatch repair proteins were widely expressed in the epidermis and adnexal structures. All lesions showed positive immunoreactivity with a gradual decrease in the MMR staining values during the progression from BN to MDN to CMMs. The average percentage of positively (PP) stained cells for hMLH1, hMSH2, and hMSH6 in BN was 85.50 +/- 1.95, 77.90 +/- 4.50, and 87.11 +/- 1.85, respectively. The PP cell values in CMMs were significantly reduced as compared with BN (75.22 +/- 3.57, p= 0.01; 56.11 +/- 8.73, p= 0.02; 65.22 +/- 6.47, p = 0.0002 for hMLH1, hMSH2, and hMSH6, respectively). No comparable significant difference was found between microsatellite stable and MSI-L lesions (p = 0.173, p = 0.458, and p = 0.385), suggesting a lack of correlation between MMR expression and MMR function. There was a direct correlation between PP cell values of hMSH2 and hMSH6 (R = 0.39, p = 0.008), implying that their expression could be regulated by a common mechanism. Thus, an important finding of these studies was the reduction of MMR protein levels in CMMs; whether this reflects underlying genetic or epigenetic mechanisms is still to be determined.

Loss of heterozygosity (LOH) of chromosome 1 has been suggested, by karyotyping, to be an initial episode in human hepatocarcinogenesis. However, this alteration has not yet been investigated in cirrhotic nodules (CNs) or dysplastic nodules (DNs). In an initial study from explanted or resected cirrhotic livers, LOH in 1p36-p32 was examined in 31 hepatocellular carcinomas (HCCs), 25 low-grade dysplastic nodules (LGDNs), and 24 high-grade dysplastic nodules (HGDNs). In HCCs, LOH was detected most frequently at loci D1S2843 (1p36.1) (28.6%), D1S513 (1p34.3) (29.2%), and MYCL1 (1p34.1) (28.6%). In HGDN and LGDN, LOH incidences at D1S513 were 11.1% and 13.6%, respectively. To further refine those results and to determine sequential relationships among CN, DN, and HCC, LOH was next studied in an additional 53 HCCs, 56 HGDNs, 30 LGDNs, and 215 CNs from 11 explanted human cirrhotic livers, including 30 "nodule-in-nodule" lesions. Seven markers between D1S2843 (1p36.12) and MYCL1 (1p34.1), and 1 each at D1S484 (1q24.1), IGF2R-3 (6q26), and TP53 (17p13.1) were used. LOH at D1S2843 and D1S513 was detected in HCCs (20.4% and 23.5%, respectively), HGDNs (7.7% and 18.5%), LGDNs (13.6% and 6.9%), and CNs surrounding either HCCs or DNs (7.4% and 8.3%). These results demonstrate that LOH at D1S2843 and D1S513 are early events in human liver carcinogenesis. Data from CN surrounding either HCCs or DN, and also nodule-in-nodule lesions, provide evidence supporting a CN-->DN-->HCC progression. Different deletion patterns from multiple HCCs and DNs suggest independent origins for carcinogenesis in the same individual.

LEARNING OBJECTIVES At the conclusion of this learning activity, physician participants should be able to assess their own diagnostic and patient management skills and use the results of this exercise to help determine personal learning needs that can be addressed through subsequent CME involvement. Instructions for claiming CME credit appear in the front advertising section. See last page of Contents for page number. Instructions: In answering each question, refer to the specific directions provided. Because it is often necessary to provide information occurring later in a series that give away answers to earlier questions, please answer the questions in each series in sequence.

The histologic distinction between dermatofibrosarcoma protuberans (DFSP) and the fibrous type of benign fibrous histiocytoma (dermatofibroma, DF) may be extremely difficult. In this study, we evaluated the extent and pattern of immunoreactivity of both CD34 and factor XIIIa in a large number of DFSPs and DFs in order to determine the utility of these markers in their distinction. Using histologic criteria alone, the authors independently evaluated and agreed upon 30 cases of DF and 24 cases of DFSP, and a representative section was stained with antibodies to both factor XIIIa and CD34. Immunopositivity was evaluated semiquantitatively and assigned a score from 0 to 5. CD34 immunoreactivity was seen in 22 (92%) of 24 DFSPs (mean CD34 score, 4.60 +/- 0.3). Only 12 (40%) of 30 DFs showed CD34 immunopositivity (mean CD34 score, 0.6 +/- 0.1). Factor XIIIa was seen in 29 (97%) of 30 DFs (mean factor-XIIIa score, 4.1 +/- 0.3). In contrast, 18 (75%) of 24 DFSPs stained for factor XIIIa (mean factor-XIIIa score, 1.3 +/- 0.2), but in most of these cases the factor-XIIIa-positive cells were felt to be entrapped nonneoplastic dermal dendrocytes. Thus, an immunoprofile using antibodies to CD34 and factor XIIIa is capable of distinguishing between DFSP and the fibrous type of DF in the vast majority of cases, as long as there is recognition that there may be some CD34-positive cells in DFs, as well as some factor-XIIIa-positive cells in DFSPs.

Objective: To assess the characteristics of patients with perioperative disseminated intravascular coagulation (DIC) and acute ischemic hepatitis after elective aortic aneurysm repair (AAR). Design: A retrospective case-control study. Setting: A single tertiary referral center. Participants: Between 1982 and 1993, 1966 patients underwent elective AAR. Of these, 10 patients (eight with abdominal and two with thoracoabdominal aneurysms) developed DIC and acute elevation of serum transaminases consistent with acute ischemic hepatitis during or shortly after surgery. The control group included 30 patients matched by age, sex, year of surgery, and aneurysm type and size. Interventions: None. Measurements and Main Results: None of the patients in either group had preoperative hemostatic abnormalities or other causes for DIC. There was no difference between the two groups in the duration of aortic cross-clamping. In all study patients, severe coagulopathy or systemic hypotension developed after the aortic cross-clamp was released. This resulted in significantly increased surgery time after unclamping (p < 0.001), and increased estimated blood loss (p < 0.001). DIC developed within 24 hours, and mean concentrations of aspartate transaminase (4,021 ± 3,579 IU/L) and lactate dehydrogenase (4,332 ± 2,903 IU/L) peaked on the second postoperative day. Nine (90%) of the study patients required repeat operations (seven for bleeding), and all of them died; the median survival time was 6 days (mean, 8.3 ± 8.2 days). Only one patient in the control group needed a repeat operation. Liver infarction or necrosis was seen in all seven patients who underwent autopsy or biopsy. Conclusions: The combination of DIC and acute ischemic hepatitis (“hepatohemorrhagic syndrome”) rarely occurs after elective AAR and is associated with a very high mortality rate. DIC was temporally related to the release of the aortic cross-clamp. The cause-effect relationship of this rare syndrome cannot be explained by operative course before the release of the aortic cross-clamp.

A 25-year-old woman presented with a large area of flesh-colored verrucous plaques following the lines of Blaschko on the left side of the body that had been present since 6 months of age. The plaques had been stable and grew proportionately with the patient's body until she reached 20 years of age when they began to thicken and enlarge. Her medical and family history was unremarkable. A shave biopsy revealed a papillomatous epidermis with 3 discrete foci of acantholytic dyskeratosis, with corps ronds and grains that were similar to the histologic findings of Darier disease (DD). Epidermolytic hyperkeratosis was not identified. Our patient's lack of a family history of DD, early-onset disease, and linear presentation along the lines of Blaschko all favored a diagnosis of acantholytic dyskeratotic epidermal nevi (ADEN) versus localized DD.

Sickle-cell trait is a common genetic abnormality in the African American population. A sickle-cell crisis in a patient with sickle-cell trait is uncommon at best. Abdominal painful crises are typical of patients with sickle cell anemia. The treatment for an abdominal painful crisis is usually medical and rarely surgical. We present the case of a cocaine-induced sickle-cell crisis in a sickle-cell trait patient that resulted in splenic, intestinal, and cerebral infarctions and multisystem organ failure necessitating a splenectomy, subtotal colectomy, and small bowel resection. This case highlights the diagnostic dilemma that abdominal pain can present in the sickle-cell population and illustrates the importance of recognizing the potential for traditionally medically managed illnesses to become surgical emergencies.

Reversibility of aberrant methylation via pharmacological means is an attractive target for therapies through epigenetic reprogramming. To establish that pharmacologic reversal of methylation could result in functional inhibition of angiogenesis, we undertook in vitro and in vivo studies of thrombospondin-1 (TSP1), a known inhibitor of angiogenesis. TSP1 is methylated in several malignancies, and can inhibit angiogenesis in melanoma xenografts. We analyzed effects of 5-Aza-deoxycytidine (5-Aza-dC) on melanoma cells in vitro to confirm reversal of promoter hypermethylation and restoration of TSP1 expression. We then investigated the effects of TSP1 expression on new blood vessel formation and tumor growth in vivo. Finally, to determine potential for clinical translation, the methylation status of TSP1 promoter regions of nevi and melanoma tissues was investigated.5-Aza-dC reduced DNA (cytosine-5)-methyltransferase 1 (DNMT1) protein, reversed promoter hypermethylation, and restored TSP1 expression in five melanoma cell lines, while having no effect on TSP1 protein levels in normal human melanocytes. In in vivo neovascularization studies, mice were implanted with melanoma cells (A375) either untreated or treated with 5Aza-dC. Vessels at tumor sites were counted by an observer blinded to treatments and the number of tumor vessels was significantly decreased at pretreated tumor sites. This difference occurred before a significant difference in tumor volumes was seen, yet in further studies the average tumor volume in mice treated in vivo with 5-Aza-dC was decreased by 55% compared to untreated controls. Knockdown of TSP1 expression with shRNA enhanced tumor-induced angiogenesis by 68%. Analyses of promoter methylation status of TSP1 in tumors derived from untreated and treated mice identified 67% of tumors from untreated and 17% of tumors from treated mice with partial methylation consistent with the methylation specific PCR analysis of A375 cells. Examination of methylation patterns in the promoter of TSP1 and comparison of aberrantly methylated TSP1 in melanoma with non-malignant nevi identified a significantly higher frequency of promoter methylation in tumor samples from melanoma patients.Pharmacological reversal of methylation silenced TSP1 had functional biological consequences in enhancing angiogenesis inhibition and inducing antitumor effects to decrease murine melanoma growth. Angiogenesis inhibition is an additional mechanism by which epigenetic modulators can have antitumor effects.

Background. Unusual lesions composed of fibrous tissue, lymphocytes, histiocytes, and plasma cells, called inflammatory pseudotumors (IPT), are being increasingly recognized in many organs and tissues. A hepatic IPT extending into the inferior vena cava has never been reported before to the authors' knowledge. The patient in this study underwent liver resection with cardiopulmonary bypass and circulatory arrest to excise the IPT. Methods. The tissue was studied extensively using histologic, immunohistologic, flow cytometric, and gene rearrangement analysis and electron microscopic methods. Results. On gross examination, the large hepatic tumor resembled a malignancy invading the vena cava. Microscopically, a mixture of T-lymphocytes, B-lymphocytes, and plasma cells were scattered throughout the tumor. DNA flow cytometry did not reveal aneuploidy suggestive of neoplasia. Genetic analysis of the immuno-globulin and T-cell receptor genes did not detect evidence of clonal expansion of B-cells or T-lymphocytes. Conclusions. This experience with the vascular invasive and biliary obstructive nature of IPT and the difficulty in diagnosing it before or during surgery underscores the potentially adverse impact of this lesion on patients. The authors believe that an aggressive approach should be taken when evaluating and treating hepatic masses, even though they may later be confirmed as being IPT.

BACKGROUND—Imatinib mesylate (Gleevec ® ) was evaluated as a treatment for Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) based on the identification of strong c-KIT staining of these neoplasms. METHODS—Eligibility included patients with measurable metastatic or unresectable MCC, c-KIT (CD117) expression and a Zubrod performance status of 0–2. Imatinib 400 mg daily was administered orally in 28-day cycles to 23 patients. RESULTS—Overall, imatinib was well tolerated with Grade 1 or 2 nausea, diarrhea, and hematologic toxicity as the most frequent side effects. A partial response was seen in 1 patient (4%; 95% CI: 0% – 22%). Median progression-free survival was 1 month (95% CI: 1–2 months). Median overall survival was 5 months (95% CI 2–8 months). One patient achieved a partial response and another had prolonged disease stabilization while receiving treatment. CONCLUSIONS—The majority of patients progressed rapidly within 1–2 cycles of treatment. The observed progression-free survival and overall survival were not adequate to conclude that this agent was active in advanced MCC, and thus the planned second stage of patient accrual was not opened.

Two cases of fibrous papule of the nose (FPN) with granular cell features are presented and discussed. Both lesions have classic architectural features of FPN; however, the main stromal cells show large cytoplasmic granules of the type seen in granular cells. We are uncertain of the significance of these findings. Our hypotheses include a perifollicular granular cell reaction and a granular degenerative change of local dermal dendrocytes.

summary Twelve cases were reviewed of squamous cell carcinoma of the nail bed, with emphasis on the aetiological role of human papillomavirus (HPV) infection and radiation damage. Using a hybridization technique, similar HPV genomes were detected in a uterine cervical neoplasia and a subungual squamous cell carcinoma in the same patient.

Summary A case of a severe, locally aggressive fibroblastic reaction to cosmetic silicone injection involving the orbital cone and anterior cranial base is presented. Included is a brief history and description of silicone injection and its complications. Though many facts remain to be discovered, speculation into the possible pathogenesis, with a review of the literature, shows that while silicone continues to be a useful tool for the plastic surgeon, an awareness of the risks, as well as a search for clues to avoid complications, must continue before further liberal use of this material is encouraged.

In order to correlate changes in morphology to changes in molecular attributes, we constructed a tissue microarray of thin and thick melanomas selected to represent progression from dysplasia to early and advanced melanoma. Hematoxylin and eosin (H&E) staining and immunohistology with antibodies to cyclin D1, p16, Ki67, and Bcl-2 were performed. Observations were interpreted using a revised paradigm for the dysplasia-melanoma sequence in which the early steps of melanomatous growth develop in an accretive fashion similar to the growth of the common acquired nevus. The co-expression of cyclin D1 and p16 persisted from dysplasia to early melanomatous vertical growth. Malignant transformation characterized by absence of p16 and presence of increased cyclin D1 and increased Ki67 and confirmed by clinically documented metastasis occurred during the process of evolving melanomatous vertical growth. The interplay of mutated BRAF, cyclin D1, and p16 with anti-apoptosis and failure of senescence may account for the existence of nevi and dysplastic nevi and for their relationship to melanoma, and may indirectly account for the infrequency of nevi in the lentiginous melanomas that lack mutated BRAF. These observations suggest a need for more detailed study of transformation to malignancy in the various subsets of melanoma.

Graft-versus-host disease (GVHD) causes severe morbidity and mortality in allogeneic haematopoietic stem cell transplantation (HSCT) because of destruction of recipient tissues by donor alloreactive T cells. We hypothesized that GVHD-specific T-cell clones are expanded within affected tissue of HSCT patients and can also be detected in blood at the time of active disease. A multiplex polymerase chain reaction (PCR) was used to amplify T-cell receptor (TCR) variable beta (VB) chain rearrangements in skin biopsies from eight allogeneic HSCT patients. Molecular analysis of the complementarity-determining region 3 (CDR3) of amplified products defined expanded, potentially disease-associated 'clonotypes' and enabled the design of clonotype-specific PCR assays. We detected immunodominant clones in seven of eight GVHD-positive skin biopsies. In serial skin biopsies from the same patient, the identical clone was found in each biopsy. In a patient who underwent two successive HSCTs from different donors, distinct clones were identified for each engraftment. Using clonotypic PCR assays, individual tissue-derived clones could be identified in peripheral blood samples obtained during active GVHD. We hypothesize that clonotypic sequences derived from target tissue can serve as markers for GVHD and may have utility in diagnosis and monitoring response to therapy, as well as enable future therapies targeted against pathogenic clones.

Background Oncocytosis is a cellular feature characterized by the presence of a finely granular eosinophilic cytoplasm due to the accumulation of mitochondria. While this histologic trait can be found in normal tissues, it is also seen pathologically as a degenerative phenomenon. We recently reviewed a spectrum of oncocytic melanocytic nevi that did not have clinical significance. We now describe similar changes in melanoma. Methods We retrospectively reviewed 12 melanomas noted to have prominent granular eosinophilic cytoplasm and completed ultrastructural studies. We obtained patient histories and clinical follow-up information from the patients' physicians. Results All cases were primary melanomas and showed prominent oncocytosis in the majority of the lesional melanoma cells. Oncocytosis was observed in both melanoma in situ and invasive melanoma with a wide range of Breslow thicknesses (range, 0.45-5.05 mm). It occurred in the presence and absence of ulceration, regression, vascular invasion, and brisk tumor infiltrating lymphocytes. Ultrastructural studies revealed melanocytes with numerous distorted mitochondria. Conclusion Melanoma is capable of presenting in a variety of histologic guises, including oncocytic change. While our observations are preliminary, this pathologic curiosity likely represents a degenerative phenomenon of little prognostic importance.

We studied 9 clinical and pathologic factors in 259 patients using Cox model regression analysis to determine which factors have independent predictive value. Median follow-up time in all patients still alive was 12.3 years (range, 1.7 to 16.7 years). Tumor-infiltrating lymphocytes (P = .005), primary site (P = .006), and thickness (P = .02) had independent predictive value. Ulceration (P = .06) and age (P = .07) had marginal value. We used 6 of those factors to test the Clark logistic regression prediction model, which accurately predicted 8-year survival in 121 (72.9%) of 166 patients and accurately predicted melanoma-specific mortality in 32 (43%) of 74 patients. The combined or overall accuracy of the Clark model was only 64%.

Little is known about genomic alterations during development of the radial growth phase (RGP) of cutaneous malignant melanomas (CMMs). In this investigation polymerase chain reaction-based microsatellite assays were applied to analyze 13 RGP-CMMs with 18 microsatellite markers at six chromosomal regions: 1p, 3p, 4q, 6q, 9p, and 10q. Loss of heterozygosity (LOH) was found in eight cases (62%), at 9p22, 1p36, and 10q11, suggesting the presence of tumor-suppressor genes at these regions. LOH was encountered frequently at the interferon-alpha (31%) and D10S249 loci (15%). Low-level microsatellite instability (MSI) (11-16% of investigated loci unstable) was noted in three cases (23%). Two MSI banding patterns were seen: band shift and the presence of additional bands. To investigate the underlying mechanisms of the low-level MSI pattern, we analyzed the lesions for expression of mismatch repair (MMR) proteins with immunoperoxidase methods and mouse monoclonal antibodies. The average percentages of positively stained cells for human MutL homolog 1 (hMLH1), human MutS homolog 2 (hMSH2), and human MutS homolog 6 (hMSH6) in RGP-CMM (75.6 +/- 3.4%, 67.20 +/- 7.71%, and 76.6 +/- 2.1%, respectively) were reduced compared with benign nevi. No statistically significant differences in MMR protein expression were found between microsatellite-stable and low-level MSI lesions (P = 0.173, P = 0.458, and P = 0.385 for hMLH1, hMSH2, and hMSH6, respectively). There was a direct correlation between values for percentages of positively stained cells for hMSH2 and hMSH6 (r = +0.9, P = 0.03), suggesting that common mechanisms regulate their expression. In conclusion, LOH, MSI, and reduced MMR protein expression appear to be present in at least some RGP-CMMs and may play a role in their pathogenesis. Further studies are necessary to support these finding and to determine their diagnostic and prognostic significance.

Today, at the beginning of the twenty-first century, most dermatologists, surgeons, and oncologists that deal with melanoma patients have a simple view of pigment lesion pathology. It consists of benign nevus, including dysplastic nevus, in situ melanoma, and invasive melanoma. These are regarded as discrete entities with only minimal reference to a sequence of change from dysplasia to melanoma. Once invasive melanoma is diagnosed, the only additional necessary information is tumor thickness and the presence or absence of ulceration (1,2). However, from a pathologist’ s point of view, the process of changing from a premalignant dysplasia to malignant melanoma is not that simple. A brief history of the past, present, and future of pigment lesion pathology is in order.

We describe a patient with both Muir-Torre syndrome and alpha 1-antitrypsin deficiency. A keratoacanthoma developed after immunosuppressive therapy for necrotizing vasculitis. To our knowledge, this is the first reported case of Muir-Torre syndrome associated with alpha 1-antitrypsin deficiency.

Uterine rhabdomyosarcoma is rare, with only 60 reported cases. We describe an asymptomatic patient with metastatic uterine rhabdomyosarcoma manifested as extensive mediastinal lymphadenopathy. This 73-year-old woman had been previously treated for endometrial rhabdomyosarcoma and was referred to us when a right hilar density was seen on a chest radiograph; computed tomography showed a nodule in the right upper lobe and extensive right hilar and subcarinal lymphadenopathy. The diagnosis of metastatic rhabdomyosarcoma was made by fiberoptic bronchoscopy using transbronchial needle aspiration (TBNA). The patient is well 11 months after completing five cycles of chemotherapy. This is the first reported case of uterine rhabdomyosarcoma with metastasis to the mediastinum and the first case diagnosed with TBNA, which avoided the need for an invasive diagnostic procedure.

BRIEF COMMUNICATION Randomized Trial of Adjuvant Human Interferon Gamma Versus Observation in High-Risk Cutaneous Melanoma: a Southwest Oncology Group Study Frank L. Meyskens, Jr., Kenneth J. Kopecky, Charles W. Taylor, R. Dirk Noyes, Ralph J. Tuthill, Evan M. Hersh, Lynn G. Feun, James H. Doroshow, Lawrence E. Flaherty, Vernon K. Sondak* The prognosis for patients with cu- taneous malignant melanoma worsens considerably if the primary tumor in- vades deeply (>1.5 mm, American Joint Committee on Cancer [AJCC] stage II) and/or spreads to regional lymph nodes (AJCC stage III) (J-3). Such patients are therefore appropriate candidates for studies of postsurgical adjuvant therapy. Several observations suggest a role for immunologic mechanisms in controlling proliferation and spread of melanoma cells (4,5). Nonetheless, clinical trials of nonspecific immunologic stimulants such as BCG, Corynebacterium parvum, le- vamisole, and transfer factor have been disappointing (6-11), leading to con- sideration of more specific immuno- modulatory approaches. Interferon gamma (IFN y) induces a variety of immunomodulatory effects: increased natural killer cell-mediated cytotoxicity, macrophage activation, and enhancement of human leukocyte an- tigen class II antigen expression and shedding (12-15). Phase I studies showed that IFN y was well tolerated and favorably affected immune parameters in patients with completely resected melanoma (16-18). Although IFN y has 1710 BRIEF COMMUNICATION no documented activity against meta- static melanoma, such phase I results ar- gued for its evaluation in the adjuvant setting. Accordingly, the Southwest On- cology Group undertook a randomized, phase III trial (SWOG-8642) to test whether prognosis is improved with recombinant human IFN y (Genentech, Inc., South San Francisco, CA) com- pared with observation following defini- tive surgery for cutaneous melanoma. Eligible patients were 18 years of age or older, had cutaneous melanoma of AJCC stage II (primary thickness of >1.5 mm, NO, MO) or III (any T, Nl-2, MO), and a performance status (Eastern Cooperative Oncology Group scale) of 0 or 1. Patients were required to have had complete excision of their tumors (with at least 1-cm margins) within 4 weeks after registration and to have no prior or concurrent nonsurgical therapy. Staging procedures were required to en- sure that patients were free of detectable residual disease. After giving written in- formed consent, patients were randomly assigned to receive either IFN y or no treatment (observation), stratified by stage. Optimal immunomodulatory ef- fects of IFN y in melanoma patients at high risk of recurrence following sur- gery have been reported at an intra- muscular or subcutaneous dose of 0.1 mg/m 2 per day (19). For practicality, IFN y was given subcutaneously at 0.2 mg per day for 1 year or until disease recurrence. The slides of the tumors of all patients were reviewed by one pa- thologist (R. J. Tuthill), and there was central review of all relevant eligibility criteria, including surgical technique, to determine final eligibility. The protocol was approved by the institutional review boards of the participating institutions. The present analysis was based on data available August 2, 1994, and updates an earlier preliminary report (20). Since the stated aim of the study was to deter- mine whether treatment with IFN y im- proves outcome compared with that seen with observation, one-tailed P values (P\) are reported except for un- planned post hoc analyses using two- tailed P values (P 2 ) that were performed to investigate whether treatment with IFN y might actually be harmful. From October 1987 through Novem- ber 1989, 284 patients were randomly assigned (137 IFN y and 147 observa- tion) by standard cooperative group pro- cedures performed centrally at the Southwest Oncology Group Statistical Center. Eighty-two (29%) were in- eligible, primarily because of failure to obtain required prestudy tests or to meet required histologic or surgical criteria. Results for all 284 patients were similar to those for the 202 eligible patients; the latter are emphasized here. Characteristics of and treatment out- comes for the eligible patients are shown in Table 1. Disease-free survival and overall survival were not sig- nificantly better with IFN y (Fig. 1: for disease-free survival, P\ - .81; for over- all survival, P\ - .91; stage-stratified logrank test). Disease-free survival and overall survival were in fact somewhat poorer with IFN y, but not significantly so in post hoc analyses (disease-free survival, P 2 - .38; overall survival, P 2 = .18). Proportional hazards regression analysis found no significant interac- tions between treatment and stage, gender, age, primary site, body surface area, or weight. The study was original- ly designed for 230 eligible patients. With 202 eligible patients, however, the alternative hypothesis that IFN y reduces the risk of relapse or death by 25% (i.e., relative risk = 0.75) was con- vincingly rejected (Pi = .007), constitut- ing strong evidence against any clinically meaningful beneficial effect. Of the 137 patients randomly as- signed to receive IFN y, 133 were asses- sable for toxic effects. There were no *Affiliations of authors: F. L. Meyskens, Jr., University of California, Irvine; K. J. Kopecky, Southwest Oncology Group Statistical Center, Seattle, WA; C. W. Taylor, E. M. Hersh, Univer- sity of Arizona Cancer Center, Tucson; R. D. Noyes, University of Utah Medical Center, Salt Lake City; R. J. Tuthill, Cleveland Clinic Founda- tion, OH; L. G. Feun, University of Miami School of Medicine, FL; J. H. Doroshow, City of Hope National Medical Center, Duarte, CA; L. E. Flaherty, Wayne State University Medical Center, Detroit, MI; V. K. Sondak, University of Michigan Medical Center, Ann Arbor. Correspondence to: Vernon K. Sondak, M.D., 2920 Taubman Center, 1500 East Medical Center Dr., Ann Arbor, MI 48109-0331. Reprint requests to: Southwest Oncology Group (SWOG-8642), Operations Office, Omicron Dr., San Antonio, TX 78245-3217. See Notes section following References. Journal of the National Cancer Institute, Vol. 87, No. 22, November 15, 1995

Desmoplastic malignant melanoma is an unusual variant of cutaneous melanoma. Arising from either an occult or recognized superficial melanotic lesion, it evolves into an aggressive, locally recurrent and frequently metastasizing, deep, hard, fibrous tumefaction. A highly confusing clinical and histologic picture makes accurate diagnosis especially difficult. Appropriate treatment is often delayed until time of recurrence. Prognosis is invariably poor if the tumor is not adequately treated primarily. Close follow-up is essential. Since its original description by Conley et al. in 1971, in which 7 cases were presented, fewer than 150 additional cases have been cited. We provide a detailed report of 11 cases of this distinct histopathologic entity. Clinical course, histopathology, surgical management, and prognosis are discussed. It is our hope that this comprehensive review will instill a high index of suspicion among surgeon and pathologist alike, enabling earlier diagnosis and definitive therapy.

8504 Background: High-dose interferon for one year (HDI) is the FDA approved adjuvant therapy for patients (pts) with high-risk melanoma (HRM). Efforts to modify IFN dose or schedule have not improved efficacy. A meta-analysis demonstrated that biochemotherapy (BCT) produced superior response rates compared with chemotherapy in pts with stage IV melanoma (Wheatley et al J Clin Oncol 25:5426, 2007). We sought to determine whether a short course of BCT would be more effective than HDI as adjuvant treatment in pts with HRM. Methods: S-0008 (an Intergroup Phase III trial) enrolled pts who were high risk (Stage III A-N2a thru Stage III C N3) and randomized them to receive either HDI or BCT consisting of dacarbazine 800 mg/m2 day 1, cisplatin 20 mg/m2/ days 1-4, vinblastine 1.2 mg/m2 days 1-4, IL-2 9 MIU/m2/day continuous IV days 1-4, IFN 5 MU/m2/day sc days 1-4, 8,10,12, and G-CSF 5 ug/kg/day sc days 7-16. BCT cycles were given every 21 days x 3 cycles (9 weeks total). Pts were stratified for number of involved nodes (1-3 v ≥4), micro v macro metastasis, and ulceration of the primary. Co-primary endpoints were relapse free survival (RFS) and overall survival (OS) using a one-sided log rank test at p= 0.05. Results: 432 pts were enrolled between 8/2000 and 11/2007: 30 were ineligible or withdrew consent. Grade 3 and 4 adverse events occurred in 57% and 7% respectively of HDI pts and 36% and 40% of BCT pts. At a median f/up of 6 yrs, BCT improved RFS (p = 0.02, HR 0.77 [90% CI: 0.62 – 0.96]) with median RFS for BCT of 4.0 yrs (90% CI:1.9 – 5.9) v 1.9 yrs (90% CI: 1.4 – 2.5) and 5 yr RFS of 47% v 39%. Median OS was not different between the two arms (p = 0.49 HR 1.0 [90% CI: 0.78 – 1.27]) with median OS not yet reached for BCT v 8.4 yrs (90% CI: 4.5 – 9.3) for HDI and 5 yr survival 56% for both arms. Conclusions: In HRM pts, BCT provides a statistically significant improvement in RFS compared to HDI, but no discernable difference in OS and more grade IV toxicity. BCT represents a shorter, alternative treatment for pts with HRM, and a potential control arm and basis for future combinations in the adjuvant setting.

SHP-1 phosphatase is a promising target for developing inhibitors as novel cancer immune therapeutics given its key role in negative regulation of immune cells. TPI-1a4 is a small molecule SHP-1 inhibitor identified recently and demonstrated activity for melanoma and colon cancer tumors in mice as a tolerated single oral agent. TPI-1a4 has been further evaluated herein for mechanism of action and potential clinical translation. Oral TPI-1a4 increased (up to 8x) in TILs in K1735 melanoma tumors in syngeneic mice in a dose-dependent manner and in correlation with tumor growth inhibition. The growth of 4-day established K1735 tumors (s.c.) in syngeneic C3H/HeJ mice was inhibited 44% (p < 0.05) by TPI-1a4 at 0.4 mg/kg (5 d/wk, gavage) or 90% (p < 0.01) at 0.8 mg/kg (5 d/wk, gavage) during a treatment period of 4 wks. Evaluation of tumor histology (H.E.) revealed increases (2x and 4x for the two treatments) of tumor-infiltrating lymphocytes (TIL). Immunohistochemistry analyses of the tumor samples demonstrate increases (∼3 and 6x) of CD45+ cells (pan-leukocytes), CD3+ cells (T lineage), B220+ cells (B/NK lineages), and Mac3+ cells (myeloid lineages). Oral TPI-1a4 interacted positively with CTLA4 antibody for survival extension and cure in K1735 melanoma tumor mice. TPI-1a4 (1 mg/kg, 5d/wk, gavage) or CTLA4 antibody (9H10, 100 ug x3, ip) as individual agents delayed tumor growth for ∼1-4 wks in C3H/HeJ mice with 4-day established K1735 tumors (s.c.). Their combination delayed tumor growth for 4-14 wks (4/5 mice) or completely blocked tumor growth (1/5 mice) by 20th wk in association with resistance to re-challenging with the melanoma tumor (s.c.). The combination was more effective in C3H/HeJ mice with 1-day established K1735 tumors, blocked tumor growth in most mice (4/5) comparing to mostly delayed tumor growth for several wks by the individual agents. TPI-1a4 in drinking water ad lib with weekly renewal was effective against the melanoma tumors in mice, suggesting chemical stability. Indeed, mass spectrometry verified structural integrity of TPI-1a4 stored as solid compound or in solvent at room temperature for 2 months. These data provide further evidences designate TPI-1a4 as a novel anti-cancer immune agent and a promising candidate for clinical translation. Our studies demonstrate for the first time the potential of TPI-1a4 to improve the clinical efficacy of CTLA4 antibody and other related cancer therapeutics. Future studies of TPI-1a4 analogs and derivatives are warranted and may lead to more refined and effective SHP-1 inhibitors and immune cell activators. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 868. doi:1538-7445.AM2012-868

PURPOSE A national cooperative group trial was conducted in patients with early-stage cutaneous malignant melanoma to determine if oral vitamin A can increase disease-free survival or survival. PATIENTS AND METHODS Two hundred forty-eight patients with completely resected melanoma of Breslow's thickness greater than 0.75 mm and clinically negative lymph nodes were randomized to oral vitamin A (100,000 IU/d) for 18 months or to observation. Patients were stratified by Breslow's thickness of primary lesion (0.76 to 1.50 mm, 1.51 to 3.00 mm, or > 3.00 mm), sex, and type of therapy (excision, excision plus node dissection, excision plus perfusion, or excision plus both). The median duration of follow-up observation of living patients is greater than 8 years. The relative risk (RR) in disease-free survival and overall survival in the treatment compared with the observation group was calculated using Cox proportional hazards models. RESULTS Overall, there was no difference in disease-free survival or overall survival between the two groups. Examination of treatment by stratification interactions and subset analysis did not show any treatment-effect differences based on sex or type of therapy. There was also no difference between groups in disease-free survival based on Breslow's thickness of the primary lesion. Overall, 12% of patients who received vitamin A experienced grade 3 or 4 toxicities. CONCLUSION Based on the lack of overall survival benefit, further evaluation of vitamin A as adjuvant therapy for melanoma does not appear warranted.

A 65-year-old man presented with a history of a giant blue plaque of the parietal scalp since childhood. Biopsy revealed a cellular blue nevus. The blue nevus was observed for 10 years and thought to be unchanged until a new adjacent lesion was noted. Biopsy of the new lesion revealed metastatic malignant melanoma. A wide excision was performed of the original lesion which revealed malignant melanoma arising in a blue nevus. Areas within the blue nevus were consistent with a pilar neurocristic hamartoma, whereas other areas were consistent with a common blue nevus. Subsequent satellite metastases developed, with early metastases resembling blue nevi except for the absence of a stromal component and the presence of hyperchromatic nuclei. Later metastases were typical of metastatic melanoma. This case illustrates the uncommon evolution of malignant melanoma from a blue nevus. The histological features and relationship between melanoma, blue nevus, and pilar neurocristic hamartoma are reviewed.

In a 57-year-old woman, Crohn's disease involving the gallbladder and duodenum caused biliary tract obstruction and necessitated surgery. The patient's symptoms did not improve postoperatively until corticosteroids provided rapid resolution. Inflammatory bowel disease often involves the hepatobiliary tree, yet the gallbladder is rarely involved directly. This patient highlights a rare complication of Crohn's disease.

8517 Background: Patients (pts) with unknown primary melanoma in regional nodes are widely considered to have a better prognosis, even adjusting for other factors, so many adjuvant trials exclude these pts. Methods: 432 stage IIIB/C pts with known primary (KP) cutaneous and unknown primary (UNK) melanoma went on S0008, a randomized trial of interferon-α2b vs. biochemotherapy. Pooled data blinded to treatment were analyzed for demographics and prognosis of KPC vs UNK. Pts with KP were divided as clinically evident (macromets) versus diagnosed by sentinel node biopsy, and by time from primary diagnosis (dx) to development of nodal metastases (0-6 mos; 6 mos-5 yrs; > 5 yrs). Since UNK pts by definition had macromets, comparative analyses involved only KPC pts with macromets. Results: Of 432 pts entered onto S0008, 33 (7.6%) were UNK, while 222 had KCP macromets. Thus, 13.1% of pts with macromets were UNK. Median age (48) and number of involved nodes (2) was the same for KCP macromets and UNK pts. Overall sur...

9056 Background: Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) frequently stains strongly for c-KIT (CD-117) expression. We therefore evaluated imatinib mesylate as a treatment for MCC. Methods: Eligibility included patients with measurable metastatic or unresectable MCC with CD117 expression by immunostaining. A Zubrod performance status of 0–2, adequate hematologic, renal, and hepatic function was also required. Imatinib 400 mg daily was administered orally in 28-day cycles. Results: A total of 25 patients were accrued to this trial from 13 institutions, with 6 accrued through Intergroup participation by the Eastern Cooperative Oncology Group. Two patients were ineligible (one was found not to express CD117 on central pathology review, and one lacked measurable disease). These 23 patients were included in the analysis. Imatinib was well tolerated with Grade 1 or 2 nausea, diarrhea, and hematologic toxicity as the most frequent side effects. There were no complete responses (0%) and 1 confirmed partial response (4%) in the 23 evaluable patients (4% objective response rate, CI 0 -22%). In addition, stable disease was observed in 3 patients (9, 4 and 3 months). Median progression-free survival was 1 month (95% CI: 1–2 months). Estimated 6 month PFS was 4%. Median overall survival was 5 months (95% CI 2–8 months). The estimated one-year overall survival was 17% (95% CI: 0% - 33%). There were three on-study deaths. All were attributed to tumor progression. One patient achieved a partial response and another had prolonged disease stabilization while receiving treatment. DNA sequencing of c-KIT was performed on tumor tissue from on a non- responding patient and the one patient with long-term stable disease (9 months). Neither demonstrated an activating mutation in c-KIT. Unfortunately, the patient with partial response withdrew consent for the study and DNA sequencing could not be performed. Conclusions: The majority of patients progressed rapidly within 1–2 cycles of treatment. The observed progression-free survival and overall survival were not adequate to conclude that this agent was active in advanced MCC. The planned second stage of patient accrual was not opened. No significant financial relationships to disclose.

Erythromelanosis follicularis faciei et colli is uncommon. Fewer than 20 cases have been reported. Except for one case in a woman and one case of unilateral distribution, all, other reported cases have been bilateral in young male patients. We report the first case of unilateral distribution in a white girl.