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Objective We employed a multidisciplinary approach incorporating theoretical ideas, clinical experience, psychology, physiology, traditional Chinese medicine (CM), modern practice of CM, and oncology to explore the effect of patients’ repression of negative emotions and traumatic events on breast cancer (BC) pathogenesis. Methods BC female patients, older than 18 years of age, with available pathology reports who were treated at Rabin Medical Center were recruited. All participants completed questionnaires regarding medical history, behavioral tendencies, negative emotions, trauma, symptoms, and pathology (from a CM perspective). Data on tumor characteristics were collected from the pathology reports. The associations were examined using hierarchical binary logistic regressions. Results A total of 155 BC patients were enrolled. The median age was 52 years, with a range of 26–79; 95% were mothers; 28% had estrogen receptor (ER)-negative BC, 52% had progesterone receptor (PR)-negative BC, 48% had human epidermal growth factor receptor 2-negative BC, and antigen Ki-67 ≥ 20% was reported for 52% of tumors. Statistically significant associations were found between the emotional markers (sense of motherhood failure, and lack of self-fulfillment), avoidance behavior, and physical symptoms that are related to emotional repression based on CM. Significant associations were also found between variables associated with physical symptoms of emotional repression, which involves the production and accumulation of non-substantial phlegm (i.e., “high-lipid Qi-like microscopic phlegm”), avoidance behavior which unconsciously uses “high-lipid Qi-like microscopic phlegm” in order to achieve emotional repression, and tumor parameters including tumor grade, PR status, and Ki-67. Patients with higher levels of “high-lipid Qi-like microscopic phlegm” were more likely to have tumors with worse prognosis (PR-negative, higher grade, and higher Ki-67). Conclusion We demonstrated a relationship between emotional parameters, behavioral tendencies, CM parameters, and oncologic parameters in BC. Additional research is warranted to explore these associations and their relevance to clinical practice.

The recent success of checkpoint blockade therapies has established immunotherapy as one of the most promising treatments for melanoma. Nonetheless, a complete curative response following immunotherapy is observed only in a fraction of patients. To identify what factors limit the efficacy of immunotherapies, we established mouse models that cease to respond to immunotherapies once their tumors exceed a certain stage. Analysis of the immune systems of the organisms revealed that the numbers of tumor-infiltrating dendritic cells (TIDC) drastically decreased with time. Further, in contrast to the current paradigm, once melanoma was established, TIDC did not migrate into sentinel lymph nodes. Instead, they underwent local cell death due to excessive phagocytosis of lysosomes. Importantly, TIDC were required to license the cytotoxic activity of tumor CD8+ T cells, and in their absence, T cells did not lyse melanoma cells. Our results offer a paradigm shift regarding the role of TIDC and a framework to increase the efficacy of immunotherapies. Significance: This work redefines the role of monocyte-derived dendritic cells in melanoma and provides a novel strategy to increase the efficacy of T-cell–based immunotherapies in nonresponding individuals.

Background The molecular basis of unilesional mycosis fungoides (MF), characterized by a solitary lesion that is clinicopathologically indistinguishable from multifocal patch or plaque MF (early MF), is unknown. Objectives To investigate the microRNA profile in unilesional MF distinguishing it from early MF. Methods Biopsy samples of unilesional MF and early MF were evaluated with the Affymetrix microRNA array, with further comparison with inflammatory dermatosis, using quantitative polymerase chain reaction. NanoString technology was applied to analyse the gene expression of T helper (Th)1 immune markers, and immunohistochemistry was used to evaluate CXCR3 and GATA-binding protein 3 (GATA3) markers for Th1 and Th2 cells, respectively. Results Unilesional MF had a significantly higher level of expression of all members of the microRNA miR-17~92 cluster than early MF. Specifically, unilesional MF had a higher miR-17 level than early MF and inflammatory dermatoses. There was downregulation of the expression of phosphatase and tensin homolog (PTEN) and CREB1, known targets of miR-17~92 members; higher gene expression of interleukin-2 and interferon-γ; and a statistically lower average percentage of GATA3+ dermal cells (6·7% vs. 42·3%), were detected in unilesional MF compared with early MF. High immunoreactivity of CXCR3 was noted in both unilesional and early MF. Conclusions Unilesional MF exhibits a microRNA profile distinct from that of conventional early MF, with a higher level of miR-17~92 members along with Th1 skewing. These findings suggest a robust reactive T-cell immune response in unilesional MF and might account for the localized nature of this disease.

Whole organ perfusion decellularization has been proposed as a promising method to generate non-immunogenic organs from allogeneic and xenogeneic donors. However, the ability to recellularize organ scaffolds with multiple patient-specific cells in a spatially controlled manner remains challenging. Here, we propose that replacing donor endothelial cells alone, while keeping the rest of the organ viable and functional, is more technically feasible, and may offer a significant shortcut in the efforts to engineer transplantable organs. Vascular decellularization was achieved ex vivo, under controlled machine perfusion conditions, in various rat and porcine organs, including the kidneys, liver, lungs, heart, aorta, hind limbs, and pancreas. In addition, vascular decellularization of selected organs was performed in situ, within the donor body, achieving better control over the perfusion process. Human placenta-derived endothelial progenitor cells (EPCs) were used as immunologically-acceptable human cells to repopulate the luminal surface of de-endothelialized aorta (in vitro), kidneys, lungs and hind limbs (ex vivo). This study provides evidence that artificially generating vascular chimerism is feasible and could potentially pave the way for crossing the immunological barrier to xenotransplantation, as well as reducing the immunological burden of allogeneic grafts.

Background/purpose This study examined clinical and histological parameters of primary dermal melanoma (PDM) to aid in its distinction from dermal metastasis. Methods Retrospective analysis of a prospective cohort of PDM patients. Includes patients fulfilling the strict histologic criteria for PDM ( N = 9) and patients who did not, but clinically, unequivocally had an intradermal melanoma—clinical PDM (cPDM; N = 17). Histopathology slides were re-examined. Prognosticators and outcome measures were compared between groups. Sentinel nodes’ retrieval and wide local excision (WLE) were offered to all patients as primary treatment. Results 26 patients identified, 15 females with a median age of 69 years (range 3.5-85). Mean Breslow was 7.9 ± 5.7 mm (median 5.8, range 1.8-25.0), and the mean mitotic rate was 4.9 ± 3.8/mm2 (median 4.0, range 0-17). Initial treatment and follow-up were as for cutaneous melanoma. One patient in each group with a palpable stage III underwent primary radical dissection. Sentinel nodes were retrieved in all 20 lymphatic mappings performed and found to be metastatic in 5 (25%) patients. Treatment consisted of completion lymph-node dissection. At a median postoperative follow-up of 62 months (range 8-132), 20 patients were disease-free, including 6 of 7 patients with stage III disease at presentation. Six patients died all of cPDM; 5 of 6 patients had primary ulcerated or epidermal-abutting melanomas. Conclusions This is the first study to highlight cPDM. Diagnosis requires expert pathology review and a tight correlation to the clinical parameters. Patients seem to benefit from WLE with sentinel node retrieval and complete dissection when appropriate. However, clinical guidelines for dissection have changed since the time period of this retrospective review. Based on this series, complete nodal dissection in these melanomas is associated with better than expected outcome, for stage III disease.

Despite the remarkable success of immunotherapy in cancer, most patients will develop resistant tumors. While the main conceptual paradigm suggests that relapsed clones emerge through a process of clonal selection and immunoediting, currently little evidence directly demonstrates this process in epithelial cancers.To study this process, we established several mouse models in which tumors drastically regress following immunotherapy, yet resistant tumors relapse within a few weeks of treatment cessation. Whole exome analyses indicated that relapsed tumors share hundreds of neo-antigens with the primary tumors and are comparably killed by reactive T cells. Examination of tumor cells that survive immunotherapies revealed that they structure a transient cell-in-cell formation, which is impenetrable to immune-derived cytotoxic compounds and to chemotherapies. This formation is mediated predominantly by a cell-membrane protein on activated T cells, which subsequently induces epidermal growth factor receptors and STAT3 phosphorylation in tumors cells. In contrast to previous reports on cell-in-cell formations, here both cells remain alive and can disseminate into single tumor cells once T cells are no longer present.Overall, this work highlights a powerful resistance mechanism which enable tumor cells to survive immune pressure and provides a new theoretical framework for combining chemotherapies and immunotherapies.

Recent studies suggest that folliculotropic mycosis fungoides (FMF), the most common variant of mycosis fungoides (MF), presents with 2 distinct clinicopathological stages: early indolent stage and more aggressive advanced/tumour stage. To further characterize these stages, miR-155 expression was studied with qRT-PCR and found to be significantly higher in biopsies of tumour-stage FMF compared with early-stage FMF and inflammatory dermatoses. There was no statistically significant difference in miR-155 expression between early-stage FMF and early-stage MF, nor between tumour-stage FMF and tumour-stage MF. Immunohistochemical analysis revealed a significantly increased number of dermal Ki-67+ proliferating lymphocytes in tumour-stage FMF, together with an increased number of CD20+ B cells and CD68+ macrophages compared with early-stage FMF. Thus, similar to classic MF, miR-155, Ki-67 tumour cell immunoreactivity, and certain tumour-infiltrating inflammatory cells are differentially expressed in early- vs tumour-stage FMF. The results of this study corroborate the notion that FMF presents with 2 distinct stages.

Background/objectives Lichen sclerosus is a rare, pruritic, mucocutaneous disease affecting mostly the anogenital area. Reports have occasionally associated lichen sclerosus with overlapping vascular lesions. This study explores this association in children. Methods A retrospective study was conducted in the dermatology unit of a pediatric tertiary care medical center. Electronic medical records were searched for patients diagnosed with lichen sclerosus from 2006 to 2019. Review of the cases was performed to identify overlapping vascular lesions and review the clinical course of overlap cases. Results Of 74 children diagnosed with lichen sclerosus during the study period, five (6.75%) had overlapping vascular lesions and genital lichen sclerosus. Four patients presented with reticular telangiectatic macules and patches (n = 4, 5.4%) that appeared at or shortly after disease onset; resolution occurred a few months after treatment initiation. The fifth patient presented with telangiectases that appeared more than 2 years after the onset of the first symptoms of lichen sclerosus (n = 1, 1.3%). Conclusion Vascular lesions in children with genital lichen sclerosus are common and have variable clinical manifestations. Early appearance of reticular macules, patches, and papules is a variant of the disease and is followed by prompt resolution of these lesions. Pathogenesis is attributed to structural changes and repositioning of the papillary vascular plexus. These changes may be alarming to parents and therefore must be recognized by physicians to prevent unnecessary concern and investigations.

Systemic doxorubicin is effective for desmoid fibromatosis (DF), but its use is limited by dose-dependent cardiotoxicity. A protocol of selective intra-arterial doxorubicin drug-eluting embolization (DEE) was designed to maximize target tissue efficacy of doxorubicin, while minimizing systemic exposure. Four children with recurrent or refractory DF were treated between 2014 and 2017. Tumor volumes were reduced by 54%-97% over a follow-up interval of 6-32 months. A single patient experienced transient lower extremity paresthesia (Common Terminology Criteria for Adverse Events grade I). Further investigation is needed to better establish these promising results for doxorubicin DEE in DF treatment.

Data on the treatment of early folliculotropic mycosis fungoides, a recently defined clinicopathological subgroup of folliculotropic mycosis fungoides with an indolent course, is limited. Treatment outcomes were studied in a retrospective cohort of 47 adults with early folliculotropic mycosis fungoides, with a focus on psoralen plus ultraviolet A (PUVA) monotherapy, including dosimetric data, and the findings were compared with data for PUVA in 18 adults with early-classic mycosis fungoides. PUVA was given to 27 patients with early folliculotropic mycosis fungoides: 70% achieved complete response and 26% partial response. Significantly more treatments were needed to achieve complete response in stage IB compared with stage IA. There was no significant difference in the complete response rate from classic plaque-stage disease, although the early folliculotropic mycosis fungoides group required more treatments to achieve complete response, and a higher cumulative dose of UVA. Thus, PUVA is an effective treatment for early folliculotropic mycosis fungoides. Its complete response rate might be equal to early-classic mycosis fungoides; however, a longer induction phase is needed to achieve complete response.

Nevi and melanocytic proliferations are known to appear in multiple extracutaneous sites, including lymph nodes and meninges. We report a case of an anterior mediastinal mass in a patient with a giant congenital nevus and neurofibromatosis type I. Histologically, the tumor was found to be a malignant melanoma in the thymus arising in association with a nevus that involved most of the thymic tissue. There was no sign of cutaneous melanoma on skin examination. We suggest that the tumor originated from the benign nevus in the thymus, a rare extracutaneous location for nevi and malignant melanoma.

Ependymoma is a malignant pediatric brain tumor, often incurable under the current treatment regimen. We aimed to evaluate the expression of microRNAs (miRs) in pediatric ependymoma tumors in an attempt to identify prognostic molecular markers which would lead to potential therapeutic targets. Following miR-array expression analysis, we focused on 9 miRs that correlated with relapse which were further validated by quantitative real-time PCR (qRT-PCR) in a cohort of 67 patients. Western blotting and immunohistochemistry were used to measure target protein expression in 20 and 34 tumor samples, respectively. High expression of miR-124-3p significantly correlated with the lower progression-free survival (PFS) of 16% compared to 67% in those expressing low levels (P = .002). Interestingly, in the group of patients with local disease (n = 56) expression levels of this miR distinguished 2 subgroups with a significantly different outcome (P = .001). miR-124-3p was identified as an independent prognostic factor of relapse in the multivariate analysis performed in the whole cohort and in the group with localized disease. In the localized group, a patient expressing high levels of miR-124-3p had a 4.1-fold increased risk for relapse (P = .005). We demonstrated the direct binding of miR-124-3p to its target TP53INP1. Negative TP53INP1 protein levels correlated with a poor outcome (P = .034). We propose miR-124-3p and TP53INP1 as new biomarkers for prognostic stratification that may be possible therapeutic targets for ependymoma.

SummaryBackground Primary cutaneous marginal zone B-cell lymphoma (PCMZL) has rarely been reported in patients younger than 20 years. Objectives To report our experience with PCMZL in the paediatric/adolescent age group. Methods Medical records of patients diagnosed with PCMZL before age 20 years and managed at two cutaneous lymphoma clinics in the United States and Israel in 1992-2015 were reviewed. Results The study group included 11 patients (6 girls) of median age 16 years (range 6–19.5); 10 had generalized/multifocal (T3) and 1 had regional/localized (T2) disease. Lesions were located on the limbs in all patients and the trunk in 6; 2 had facial lesions. Staging in all but one was based on whole-body computed tomography or positron emission tomography. Initial management in most patients included non-radiation modalities: 1 patient with localized disease received intralesional steroids; 6 patients with multifocal disease received the following: 3 - topical/intralesional steroids, 2 - excision, 1 - “watch and wait”. No extracutaneous progression was noted during a median follow-up of 5.5 years (mean 7.5, range 0.5-14). At present, 5/11 patients are in complete remission. Conclusions Based on our data (largest series in the literature with the longest follow up); the clinico-pathological presentation and course of PCMZL in the paediatric/adolescent age group are similar to adults. Given the indolent course and the long life expectancy of these young patients, the cumulative risk of imaging studies and the age-related potential toxicity of treatment, especially radiation, should be taken into consideration. This article is protected by copyright. All rights reserved.

We report the unexpected absence of early relapse (before 30 months) in 24 consecutive patients with isolated limb primary Ewing sarcoma treated with an intensified pilot protocol, SCMCIE94. Clinical data for the study were collected retrospectively from the patient files. The protocol included 6 courses of chemotherapy, split radiation, and limb salvage surgery. This SCMCIE94 protocol had been used in almost all the patients described in an earlier report, in whom those with non-pelvic isolated tumors and low/absent CD56 expression in Ewing sarcoma tumor cells were all long-term survivors. The 5-year (10-year) event-free survival rate for the patients with isolated limb primary Ewing sarcoma was 78.95 ± 8.3% (68.6 ± 10.0%) and the overall survival rate was 90.7 ± 6.2% (71.1 ± 11.2%). There were no relapses before 30 months in any of these patients. The intensified SCMCIE94 pilot protocol has been shown previously to cure patients with localized CD56-negative non-pelvic Ewing sarcoma. The present study shows that among all patients with localized extremity disease who were treated with this protocol, there were no cases of early relapse. Although our cohort was small, the difference in results from studies using other protocols is so striking, that it would seem reasonable to assume it is attributable to the changes made in the protocol itself rather than risk factors. Late relapses of isolated limb CD56-positive Ewing sarcoma suggest minimal residual disease warranting additional therapeutic approaches such as autologous stem cell rescue after Busulfan Melfelan.

9045 Background: Immune checkpoint inhibitors (ICI) have become the standard treatment for metastatic NSCLC, although only a small proportion of patients derive durable benefit. PDL1 expression is the only approved biomarker to select NSCLC patients for treatment with single-agent pembrolizumab, however its predictive value is limited and better predictive biomarkers are needed. The spatial arrangement of immune cells in the tumor microenvironment (TME), namely tumor infiltrating lymphocytes (TILs), emerges as a potential biomarker for ICI efficacy. In this work, we utilized deep-learning (DL) models to extract TME features from digitized H&E slides and evaluated their predictive and prognostic role in patients with mNSCLC treated with Pembrolizumab. Methods: NSCLC patients (n=90) treated with single-agent 1st line pembrolizumab in two centers were identified. 47 patients from one center were used to train the model, and 43 patients from another center were used for validating the model. Pre-treatment H&E whole slide images (WSI) were analyzed using a deep-learning model to identify and classify tumor cells, TILs, tumor and stromal areas, and spatial features were calculated. Spatial features were correlated with clinical outcome data to train a binary classifier that identifies patients with a favorable clinical outcome. The resulting classifier combined three spatial features and three clinical features. The classifier was then applied to the validation set and differences in duration of treatment (DOT), and overall survival (OS) between patients with positive and negative scores were assessed. Results: The classifier identified patients in the validation set to have either positive (n=18) or negative (n=25) scores. Baseline patient characteristics and PDL1 score were similar between the positive and negative groups. In a Kaplan-Meier (KM) analysis, OS was significantly higher in patients with a positive score compared to patients with a negative score (HR=0.35, 95% CI 0.13-0.98; p

Aims The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. Methods A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. Results Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). Conclusions A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.

Amelanotic melanomas (AMMs) account for a small proportion of all melanomas. They pose a risk of delayed diagnosis and, consequently, poor prognosis. AMMs may atypically present as a pyogenic granuloma-like lesion. This study sought to investigate the prevalence and clinical and histological features of AMM masquerading as pyogenic granuloma. The database of a tertiary medical center was screened for all patients pathologically diagnosed with melanoma in 2005-2016. Those with a suspected primary (i.e. pre-excision) clinical diagnosis of pyogenic granuloma were identified, and their demographic, clinical, histologic, and outcome data were collected from the medical files. Of 2038 patients diagnosed with melanoma, 10 (∼0.5%) had a pyogenic granuloma-like AMM. The mean±SD age at lesion presentation was 56±18.9 years and the mean time from lesion appearance to diagnosis was 91.5±117.1 months. Nine tumors were located on the skin surface, and one on the oral mucosa. The mean lesion size was 19.6±14.1 mm and the mean Breslow's depth was 6.47±3.1 mm; all tumors presented in the vertical growth phase. Seven (70%) patients had lymph node involvement or metastasis at diagnosis. Two patients died of the disease within 1 year of diagnosis. Given the potential lethality of AMM and the benign nature of pyogenic granuloma, clinician recognition of pyogenic granuloma-like AMMs is crucial. In the presence of a pyogenic granuloma-like lesion, findings of older patient age and large tumor size should raise the index of suspicion and prompt a biopsy study, thereby ensuring early and accurate treatment.

Ewing Sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. microRNAs (miRNAs) are involved in cancer as tumor suppressors or oncogenes. We studied the involvement of miRNAs located on chromosomes 11q and 22q that participate in the most common translocation in ES. Of these, we focused on 3 that belong to the let-7 family. We studied the expression levels of let-7a, and let-7b and detected a significant correlation between low expression of let-7b and increased risk of relapse. let-7 is known to be a negative regulator of the RAS oncogene. Indeed, we detected an inverse association between the expression of let-7 and RAS protein levels and its downstream target p-ERK, following transfection of let-7 mimics and inhibitors. Furthermore, we identified let-7 as a negative regulator of HIF-1α and EWS-FLI-1. Moreover, we were able to show that HIF-1α directly binds to the EWS-FLI-1 promoter. Salirasib treatment in-vitro resulted in the reduction of cell viability, migration ability, and in the decrease of cells in S-phase. A significant reduction in tumor burden and in the expression levels of both HIF-1α and EWS-FLI-1 proteins were observed in mice after treatment. Our results support the hypothesis that let-7 is a tumor suppressor that negatively regulates RAS, also in ES, and that HIF-1α may contribute to the aggressive metastatic behavior of ES. Moreover, the reduction in the tumor burden in a mouse model of ES following Salirasib treatment, suggests therapeutic potential for this RAS inhibitor in ES.

Malignant mesothelioma is an uncommon tumor that usually arises in the pleural cavity of adults with a history of asbestos exposure. Less frequently, it appears in the peritoneum or other mesothelial surfaces. Deciduoid mesothelioma is a rare subtype that has been found at both sites. Of the 3 reported cases in children, 2 originated in the mesenterium and 1 in the pleura. We describe a 4th case of pediatric, malignant, deciduoid mesothelioma and a third case in the mesenteric cavity. The patient was an 8-year-old girl who presented with abdominal pain and fullness. Workup revealed extensive involvement of the abdomen by a serosa-based tumor. The clinical and pathologic findings are described, and the pertinent literature is reviewed.

Acinic cell carcinoma of the parotid gland is a rare low-grade malignant neoplasm. Data on children are sparse. For the present study, the database of a tertiary pediatric medical center was reviewed for all patients with parotid gland acinic cell carcinoma diagnosed and treated between 2004 and 2013. Clinical, histologic, treatment, and outcome parameters were collected from the medical files. Four patients were identified, 3 female and 1 male, aged 13.5 to 18 years (median 15.7) at diagnosis. One patient had a family history of parotid tumor and 1 of hypothyroidism/hyperthyroidism. Two patients had L-thyroxin-treated Hashimoto thyroiditis, and 1 had a thyroid nodule. All presented with a localized parotid mass and negative lymph nodes. Treatment consisted of partial parotidectomy, with no damage to the facial nerve. Histology confirmed the diagnosis of acinic cell carcinoma with low proliferation rate (Ki67 immunostaining 1% to 8%). No evidence of disease was found on any patient with a median follow-up at 83 months (range, 32 to 93 mo) from presentation. In our experience, the prognosis of pediatric parotid gland acinic cell carcinoma is good, and surgery alone is sufficient for treatment of early stage tumors. This is the first report of findings of a family history of thyroid disease and/or thyroid abnormalities in patients with parotid gland acinic cell carcinoma.

Background Unilesional folliculotropic mycosis fungoides (UFMF) has been rarely reported. Objective The aim of this study was to describe our experience with UFMF. Methods Data were collected on all patients with clinicopathological UFMF who attended the Department of Dermatology of a tertiary university-affiliated medical centre in 1996–2013 and were followed prospectively. Results The sample included seven patients (five male, two female) of mean age 38 years at diagnosis; two were aged

Background The literature on mycosis fungoides (MF) in children/adolescents is sparse. Objective We sought to evaluate the characteristics of juvenile MF in a large cohort. Methods Data were collected on all patients with MF, aged 18 years or younger at the time of clinicopathologic diagnosis, who attended the Rabin Medical Center Dermatology Department, Petach Tikva, Israel, between 1994 and 2012 and were followed up prospectively. Results There were 50 patients (30 male; mean age 11.4 years at diagnosis); 18 (36%) had Fitzpatrick skin type IV or higher. All were given a diagnosis of early-stage disease (IA-IIA) except 1 (tumor stage, IIB). Eight had classic MF lesions only and 42 had other variants, alone or in combination; these were mainly hypopigmented MF (n = 29) and cases with subtle but clear clinicopathologic features of folliculotropic MF (FMF) (n = 18). Among the various skin-targeted therapies, psoralen plus ultraviolet A (systemic/bath) proved beneficial for FMF. During a follow-up period of 0.25 to 15 years (mean 4.5), 2 patients progressed from stage IA to IB or IIA. Limitations Relatively short follow-up is a limitation. Conclusions This case series shows that FMF is not uncommon in children and adolescents. It is characterized by more superficial clinical features and less heavy perifollicular lymphocytic infiltrates than adult FMF, and responds well to psoralen plus ultraviolet A. The prognosis of childhood FMF remains unclear.

Background It is generally accepted that folliculotropic mycosis fungoides (FMF) is usually typified by indurated plaques and tumors mainly on the head/neck and an aggressive course. However, its clinical manifestations have long been recognized to be quite variable, and some studies indicate a better prognosis for certain presentations. Objective We sought to summarize our experience with the clinicopathological presentations of FMF and impact on prognosis. Methods Data were collected retrospectively for adults with FMF followed up prospectively at a tertiary medical center in 1995 through 2014. Results In all, 34 patients presented with follicle-based patch/flat plaques, keratosis pilaris–like lesions, and/or acneiform lesions, defined clinically as early stage (IA, IB), and 15 presented with follicle-based infiltrated plaques and/or tumors, defined as advanced stage (IIB). The head/neck was involved in all tumor-stage cases, whereas early-stage lesions involved mainly the trunk/limbs. The tumor stage was characterized by more pruritus, heavier perifollicular infiltrates, greater vertical depth, and more frequent presence of eosinophils. On multivariate analysis, infiltrate density was the only significant histopathological discriminator between the stages. Estimated 5-year survival was 0.94 in the early-stage group and 0.69 in the tumor-stage group. Limitations Lack of long-term follow-up and relatively small sample are limitations. Conclusion FMF presents with 2 distinct patterns of clinicopathologic features, early stage and advanced stage, each with different prognostic implications.

Background Some authorities consider alopecia mucinosa (AM)/follicular mucinosis (FM) to invariably represent mycosis fungoides (MF). This understanding of AM/FM derives from observations in adults. Objectives We sought to explore the clinicopathologic features and natural history of pediatric AM/FM. Methods Medical records were searched for children given the diagnosis of AM/FM from 1998 through 2009. Diagnosis of AM/FM was defined as the presence of well-demarcated hairless plaques with follicular prominence plus an abundance of mucin on histopathologic examination. Results Forty children with a clinical diagnosis of AM/FM were identified. Nine did not meet the inclusion criteria. In the 31 remaining cases (16 boys, 15 girls) the mean age at onset was 9 ± 3.5 years. Histopathologic examination showed folliculotropism in 28 patients (90%) and epidermotropism in 15 (48%). Twelve cases fulfilled the International Society of Cutaneous Lymphomas (ISCL) diagnostic criteria for early MF. The histopathologic findings were typical of MF in only in two of these cases. T-cell receptor gene rearrangement was positive in 3 of 6 (50%) of tested samples, one in a patient who fulfilled the ISCL criteria for early MF. Mean duration of follow-up was 6.2 ± 3.7 years. All skin lesions resolved and none persisted or recurred. Hodgkin lymphoma was diagnosed 6 months after diagnosis of AM/FM in one patient. Limitations This was a retrospective study. Conclusions Although some pediatric cases meet the diagnostic criteria for MF, AM/FM cannot be regarded unequivocally as early follicular MF in this age group. We suggest the current diagnostic criteria for early MF should exclude children with AM/FM. Long-term follow-up of children with AM/FM is nevertheless warranted.

Background. Cancers of unknown primary origin (CUP) constitute 3%–5% (50,000 to 70,000 cases) of all newly diagnosed cancers per year in the United States. Including cancers of uncertain primary origin, the total number increases to 12%–15% (180,000 to 220,000 cases) of all newly diagnosed cancers per year in the United States. Cancers of unknown/uncertain primary origins present major diagnostic and clinical challenges because the tumor tissue of origin is crucial for selecting optimal treatment. MicroRNAs are a family of noncoding, regulatory RNA genes involved in carcinogenesis. MicroRNAs that are highly stable in clinical samples and tissue specific serve as ideal biomarkers for cancer diagnosis. Our first-generation assay identified the tumor of origin based on 48 microRNAs measured on a quantitative real-time polymerase chain reaction platform and differentiated 25 tumor types. Methods. We present here the development and validation of a second-generation assay that identifies 42 tumor types using a custom microarray. A combination of a binary decision-tree and a k-nearest-neighbor classifier was developed to identify the tumor of origin based on the expression of 64 microRNAs. Results. Overall assay sensitivity (positive agreement), measured blindly on a validation set of 509 independent samples, was 85%. The sensitivity reached 90% for cases in which the assay reported a single answer (>80% of cases). A clinical validation study on 52 true CUP patients showed 88% concordance with the clinicopathological evaluation of the patients. Conclusion. The abilities of the assay to identify 42 tumor types with high accuracy and to maintain the same performance in samples from patients clinically diagnosed with CUP promise improved utility in the diagnosis of cancers of unknown/uncertain primary origins.

Background Human herpesvirus (HHV) 8, an essential etiologic agent of Kaposi sarcoma, is also associated with several lymphoproliferative disorders. The involvement of HHV 8 in mycosis fungoides (MF) and large plaque parapsoriasis (LPP) is controversial, with contradictory reports from various countries worldwide. Objective We sought to investigate the presence of the HHV 8 genome in skin lesions of LPP and early-stage sporadic, familial, and juvenile MF in patients in Israel. Methods Archival paraffin-embedded and frozen samples from skin biopsies of untreated patients with LPP and early-stage MF performed in 1990 through 2006 were randomly collected from the department of dermatology of a tertiary medical center in central Israel. DNA was extracted, and a TaqMan-based real-time polymerase chain reaction assay specific for the K6 gene region was used to detect the HHV 8 genome. Results A total of 46 biopsies were sampled from 11 patients with LPP and 35 with early-stage MF (17 adults with sporadic MF, 10 children, and 8 patients with familial MF). In all, 44 samples were negative for HHV 8 DNA; two samples from adults with sporadic MF were positive. Limitations The presence of HHV 8 antibodies or virus sequences was not assessed in peripheral blood. Conclusion The results of this study, conducted in a region relatively endemic for HHV 8, support most earlier studies showing a lack of association of HHV 8 infection with LPP and sporadic adult-type MF. To our knowledge, the lack of association of HHV 8 infection with juvenile and familial MF has not been previously reported.

Background Lentigines are a common pigmentary disorder in adults and in patients treated by psoralen and ultraviolet A (PUVA) radiation. Their appearance following treatment with narrow-band ultraviolet B (NB-UVB) radiation has been reported in only two patients. Objective To describe the clinical and histological features of NB-UVB-induced lentigines their relation to dosimetry and the course of the eruption in patients with mycosis fungoides (MF). Methods The files of all patients with MF treated in our department in 2003–2010 were searched to identify those in whom lentigines appeared following monotherapy with NB-UVB radiation. Results Of the 73 patients with early stage MF identified, 10 met the study criteria. Lentigines were detected in skin previously involved by MF in seven patients, and in both involved and uninvolved skin in three patients. They appeared during therapy in three patients, after a mean of 56 exposures (range 50–61), and several months (mean 7.8) following completion of treatment in seven patients, after a mean of 69 exposures (range 32–157). Histopathological study of lesions from five patients revealed basal hyperpigmentation relative to adjacent normal-looking skin. Two lesions had a slight increased number of normal-looking melanocytes on immunohistochemical staining with melanoma cocktail. One lesion had elongated rete ridges. The lesions persisted throughout follow-up (mean 26.7 months) in 8 patients. Conclusions Patients with MF treated with NB-UVB may acquire lentigines. As opposed to PUVA-induced lentigines which are a known common side-effect of long-term treatment, NB-UVB-induced lentigines are uncommon but appear earlier, even after a few months of treatment.

Ependymoma is a malignant pediatric brain tumor, often incurable with current treatment regimens. We aimed to identify new genes involved in pediatric ependymoma using copy number SNP array analysis. We analyzed 34 primary tumors, in 10 cases we analyzed the paired diagnosis-relapse samples and in 5 of them we also analyzed the corresponding peripheral blood (PB) sample. The most prevalent alterations identified were gain of 8q (18%), deletion of 10q (18%), gain of 11q (12%) and gain of 17q (53%). The locus of the 17q21.31 gain contains only one gene - KANSL1 (KAT8 regulatory NSL complex subunit 1) gene. The gain affected exons 1–4 of the gene. This gain was identified in 9 out of the 10 (90%) relapse samples and in all of the PB samples. The gain was validated at the RNA level and a significant overexpression of KANSL1 mRNA was detected in the samples exhibiting gain versus the samples with normal copy number (p=0.04). KANSL1 is part of the NSL complex which functions as a histone acetyltransferase. The 17q21.31 locus contains a common inversion duplication polymorphism enriched in European populations. Recently, a new fusion was discovered in high frequencies in adult malignancies between KANSL1 and ARL17, termed KANSARL, both located on 17q21.31. KANSARL fusion was detected in 71% of our samples. All the samples that exhibited gain of KANSL1 were positive for the KANSARL fusion. Our results suggest that the gain precedes the formation of the fusion which may be a predisposing event in ependymoma.

Summary Background Cutaneous lymphomas rarely occur in children and adolescents, and are mostly of the T-cell lineage. Low-grade primary cutaneous B-cell lymphoma (CBCL) is extremely rare in individuals under 18 years old. Only 11 patients under 20 years old have been reported in the literature. Objectives To evaluate the number of patients younger than 18 years with primary CBCL diagnosed at our centre and to investigate its clinicopathological features, treatment and course in this age group. Methods We reviewed the files of all 90 patients with primary CBCL who attended the Department of Dermatology of our tertiary care university-affiliated centre from 1992 to 2007. Results Four patients who met study criteria were identified: three girls and one boy. Mean age at diagnosis was 16·6 years (range 16–17). Three patients had cutaneous marginal zone lymphoma (CMZL), and one had a spindle-cell (sarcomatoid) lymphoma, most probably follicular centre cell type. All were treated with the standard regimen used in adults. The mean duration of follow up was 45 months. No extracutaneous progression was noted. At present two of the four patients are in complete clinical remission. Conclusions In Israel, primary CBCL apparently occurs more often in young patients than reported in the literature. CMZL is the most frequent type. Long follow up is mandatory to assess the biological behaviour of CBCL in the paediatric/adolescent age group.

BACKGROUND Acral lentiginous melanoma (ALM) is associated with low survival. OBJECTIVE The aim of the study was to compare the clinical course of ALM, non-ALM hand and foot melanoma, and melanoma of the extremities in nonacral locations. METHODS Data on 168 patients operated on for cutaneous melanoma of the extremities from 1993 to 2005 were examined. Twenty-nine had ALM, 16 non-ALM, and 123 other-extremity melanoma. All known melanoma prognosticators were analyzed for their impact on survival at a median of 53 months' follow-up. RESULTS The ALM group was significantly older (p=.015). No differences between the ALM and non-ALM groups were noted in tumor characteristics, lymph node status, and survival. However, the other-extremity melanoma group presented with significantly thinner lesions, fewer positive sentinel lymph nodes, and lower tumor stage and, consequently, had significantly better disease-specific and disease-free survival (p=.006, p=.0001). The acral lesions were nearly free of peritumoral lymphocytic infiltration. Multivariate analysis identified only tumor thickness (p=.0127), stage (p=.00001), and patient age (p=.012) as independent prognosticators of disease-specific survival. CONCLUSION Cutaneous melanomas in acral sites, regardless of histology, tend to be diagnosed at an advanced stage probably owing to older patient age, difficult-to-see sites, and biologic factors, leading to reduced patient survival.

Background: Dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) occasionally resemble each other histologically but differ in histogenesis and biological behavior. This study sought to determine if these lesions can be differentiated by the quantity or quality of expression of cyclooxygenase-2 (COX-2), an enzyme associated with both reactive and neoplastic processes. Patients and methods: Formalin-fixed and paraffin-embedded samples from 20 DFs and 20 DFSPs were stained immunohistochemically with antibodies directed against COX-2. Staining was evaluated semiquantitatively for percentage and intensity using a three-tiered system. DFs were graded and analyzed by cellularity. Findings within the tumors were compared with fibrocyte staining in adjacent tissue. The results were analyzed. Results: Nineteen DFs (95%) and 15 DFSPs (75%) were immunopositive for COX-2; this difference was not statistically significant. Highly cellular DFs showed more widespread (p = 0.0039; r = 0.614) and more intense (p = 0.0586; r = 0.429) staining than less cellular DFs and more prominent staining in adjacent fibroblasts (p = 0.044; r = 0.608). Conclusions: COX-2 immunostaining does not distinguish DFs from DFSPs. However, the enzyme is expressed more widely and more intensely in more cellular, possibly younger, DFs. The prominent expression of COX-2 in DFSP may have clinical implications for treatment with COX-2 inhibitors in tumors that are not amenable to surgery.

Primary cutaneous apocrine carcinoma is a rare malignancy. This study of 24 examples suggests that the prognosis is not always poor and that grading criteria devised for breast carcinoma may have utility in this group of malignancies. Furthermore, steroid receptor expression should be investigated in these tumors, particularly if a tumor is unlikely to be controlled by surgery alone.

MicroRNAs (miRNAs) belong to a class of noncoding, regulatory RNAs that is involved in oncogenesis and shows remarkable tissue specificity. Their potential for tumor classification suggests they may be used in identifying the tissue in which cancers of unknown primary origin arose, a major clinical problem. We measured miRNA expression levels in 400 paraffin-embedded and fresh-frozen samples from 22 different tumor tissues and metastases. We used miRNA microarray data of 253 samples to construct a transparent classifier based on 48 miRNAs. Two-thirds of samples were classified with high confidence, with accuracy >90%. In an independent blinded test-set of 83 samples, overall high-confidence accuracy reached 89%. Classification accuracy reached 100% for most tissue classes, including 131 metastatic samples. We further validated the utility of the miRNA biomarkers by quantitative RT-PCR using 65 additional blinded test samples. Our findings demonstrate the effectiveness of miRNAs as biomarkers for tracing the tissue of origin of cancers of unknown primary origin.

Recent cases of infants with bullous pemphigoid (BP) prompted us to explore the clinical and laboratory features of childhood BP.We sought to explore the characteristics of infantile BP and compare them with childhood BP.All new consecutive cases of infantile BP referred to dermatologic departments in Israel during 2004 to 2006 were retrospectively reviewed. All reported cases in the English- and foreign-language medical literature were gathered and statistical analysis of all cases was performed.Reports on infantile BP are rapidly increasing. Among 78 reported children with BP, 42 (53%) occurred in the first year of life. The incidence of infantile BP in Israel in the last years is 2.36:100,000/y. Predisposition for acral involvement is significantly higher in infantile BP than in childhood BP (79% vs 17%, P.001), whereas genital involvement is very rare (5% vs 44%, P = .002). Laboratory parameters were not significantly different, except for a more frequent IgM deposition at the dermoepidermal junction in childhood BP (29% vs 10%, P = .042).Statistical analyses of published cases may not be representative and could be affected by possible reporting biases.Infantile BP may not be as rare as commonly stated. Age-related differences in regional distribution of lesions in BP were demonstrated. No major differences regarding laboratory results, treatment, and prognosis were found.

Purpose To compare microRNA (miR) expression between patients with diffuse large B-cell lymphoma (DLBCL) who had a poor prognosis to those who had a favorable prognosis. Methods The study group included 83 patients with diffuse large B-cell lymphoma (DLBCL) treated between the years 1995 and 2003 without rituximab in a single tertiary center for whom adequate tumor content was available. miR signature from tissue biopsies was compared between patients who relapsed within nine months from commencement of treatment (defined as poor prognosis, n = 43) and those with disease-free survival of at least five years (defined as good prognosis, n = 40). RNA was analyzed using custom microarrays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for technical validation of microarray results. An independent set of 13 samples was used for further validation. Results Eight miRs were found to be differently expressed between the two prognostic groups. The expression of the different miRs was verified by qRT-PCR, showing high correlation with the microarray data in both verification and independent set groups. No added value to the clinically based International Prognostic Index was found. Conclusion miR signature from DLBCL biopsies can discriminate between patients with favorable and poor prognoses.

BACKGROUND. Maintenance of telomeres, in most instances by reactivation of telomerase, is obligatory for the indefinite proliferation of tumor cells. The objective of this study was to evaluate telomere length and telomerase activity (TA) as markers for progression and prognosis in neuroblastoma. METHODS. Primary tumor samples from 51 patients were analyzed for telomere length and TA and were correlated with known prognostic parameters and outcome. RESULTS. Telomere length had a highly significant correlation with prognosis (P = .007). Short telomeres were predictive of a favorable prognosis, whereas long or unchanged telomeres were predictive of a poor outcome. For the first time to their knowledge, the authors have shown that, within the high-risk group patients, telomere length could define a favorable subgroup that had a progression-free survival (PFS) rate of 86% compared with a PFS rate of 36% for patients with more adverse disease, which is the expected PFS rate for such patients (P = .04). In a multivariate analysis, telomere length was the most significant prognostic parameter (P = .032). TA was correlated significantly with outcome and with known prognostic factors. High TA and low TA were associated with adverse and favorable outcomes, respectively (P = .01). CONCLUSION. The results of this investigation suggested that telomere length is a highly significant prognostic parameter of clinical relevance in patients with neuroblastoma. In high-risk patients, telomere length was the sole significant parameter that identified a group of patients who had a favorable prognosis. The authors suggest that telomere length should be included in the recommended diagnostic investigations for patients with neuroblastoma. Cancer 2006. © 2006 American Cancer Society.

Biopsy specimens from 23 early stage and 19 tumor-stage mycosis fungoides (MF) patients were evaluated for miR-155 expression by real-time qualitative PCR and compared with 15 biopsy specimens from patients with T-cell-rich inflammatory skin diseases. Significant upregulation of miR-155 was found in MF tumors compared with both early-stage MF lesions and controls. There was no difference in miR-155 expression between early-stage and inflammatory dermatoses. Using laser capture microdissection, it was found that miR-155 was significantly higher in the lymphoma cells in tumor stage compared with the intraepidermal lymphocytes in early stage. In contrast, there was no difference in miR-155 expression between the intraepidermal lymphocytes and the dermal lymphocytes in early-stage MF. These findings suggest that although miR-155 expression cannot serve to discriminate early-stage MF from inflammatory dermatoses; however, it is involved in the switch from the indolent early stage into the aggressive tumor stage of the disease.

Background Climatotherapy at the Dead Sea (CDS) is a well-established therapeutic modality for moderate to severe psoriasis vulgaris, resulting in sustained remissions. It has also been found to be effective for atopic dermatitis, another T-cell–mediated dermatosis. Objective We sought to prospectively evaluate the efficacy of CDS in patch-stage mycosis fungoides. Methods A total of 12 patients with patch-stage mycosis fungoides (6 with stage IA and 6 with stage IB) were treated with CDS as monotherapy for 28 consecutive days according to the protocol for psoriasis, ie, a gradual increase of sun exposure to a maximum of 3 hours daily. Results A total of 9 patients achieved a complete clinical response (CCR), defined as no disease activity present; 2 achieved an almost CCR, defined as the reduction by more than 90% of disease activity; and 1 achieved a partial response, ie, reduction by more than 50% of disease activity. A CCR was achieved in all the patients with stage IA disease and in 3 of the 6 patients with stage IB disease. Of the 9 with a CCR, 6 also showed histopathologic clearing. Duration of the remissions, during which no therapy was allowed except for emollients, lasted from 2 to 9 months (mean: 5 months). No serious short-term side effects were recorded. Conclusion CDS appears to be an effective, well-tolerated therapy for patch-stage mycosis fungoides.

Background Acquired ichthyosis is a known paraneoplastic sign of lymphoproliferative malignancies, with histopathologic findings that are nonspecific, revealing no insinuation of the underlying neoplasm. Ichthyosiform eruption as a specific manifestation of mycosis fungoides (MF), ie, ichthyosiform MF, is, however, regarded as rare and to date has been reported in only a few cases. Objective We sought to study the clinical, histopathologic, immunohistochemical, and genotypic features of patients with ichthyosiform MF. Methods The files of patients with MF seen during the past 8 years in our department were reviewed to search for cases of ichthyosis-like MF. Results Seven patients, comprising 3.5% of the patients seen with MF, had an ichthyosiform eruption with histopathologic features characteristic of early MF. In 2 patients it was the sole manifestation of the disease and in 5 patients it appeared either in conjunction with conventional patches and/or plaques or with follicular lesions. Immunohistochemically, all showed a predominance of CD3 + CD4 + , except for 1 patient in whom the epidermotropic T cells were predominantly CD8 + . In 3 of the 7 patients clonality could be demonstrated by polymerase chain reaction. None had extracutaneous involvement. All had an indolent course of the disease and responded well to skin-targeted therapies. Conclusions Ichthyosiform MF is yet another atypical clinical variant of cutaneous T-cell lymphoma that is not as rare as reflected in the literature. It may be the sole manifestation of the disease but also may appear in conjunction with conventional or follicular MF lesions.

Through a still unclear mechanism, pemphigus vulgaris autoantibodies (PV-IgG) induce intra-epidermal acantholytic lesions responsible for severe to fatal skin wounding. We present evidence that PV lesions contain apoptotic keratinocytes, and that cell death is induced in the lesional tissue apparently before cell separation. These data suggest that apoptosis could be the cause of the acantholytic phenomenon. We show that PV-IgG and an antibody against Fas receptor (anti-FasR) induce lesions in vitro in a similar way, causing: (1) secretion of soluble FasL; (2) elevated cellular amounts of FasR, FasL (soluble and membranal), Bax and p53 proteins; (3) reduction in levels of cellular Bcl-2; (4) enrichment in caspase 8, and activation of caspases 1 and 3; (5) co-aggregation of FasL and FasR with caspase 8 in membranal death-inducing signaling complex (DISC). Hence, the Fas-mediated death signaling pathway seems to be involved in lesion formation. Moreover, we have shown that in skin organ cultures and in keratinocyte cultures, PV-IgG can induce caspase activation and DNA fragmentation, and caspase inhibitors can prevent the formation of PV-IgG-induced epidermal lesions. Altogether, these results suggest that PV-IgG-induced acantholysis may proceed through the death-signaling pathway. They highlight new perspectives on mechanisms of tissue damage in autoimmune diseases.

Background: Basaloid squamous cell carcinoma (BSCC) is a distinct variant of squamous cell carcinoma that was first described by Wain et al in 1986. Since then, about 160 cases have been reported in the literature. Only 40 cases have been described in the larynx. Methods: Four cases of BSCC of the larynx treated in our department between 1986 and 2000 are presented. The clinical features, biological behavior, and histopathological and immunohistochemical characteristics of this uncommon tumor are described, and the relevant literature is reviewed. Results: The main clinical presentation did not differ from other histological types of laryngeal carcinoma. The clinical course, however, was much more aggressive. All the patients received aggressive therapy including radical surgery and radiation. Two patients received chemotherapy. Two of the 4 patients presented died of distant metastasis shortly after diagnosis and treatment. Conclusions: The finding of this study with a limited number of patients supports previous reports suggesting that BSCC is a highly aggressive tumor that presents in older population with male predominance. The frequency of associated regional as well as distant metastases suggests that aggressive treatment is indicated and that systemic chemotherapy should be contemplated.

Malignant melanomas, which produce a large number of substances active in connective tissue modulation, must contend with the dermis to grow and propagate. We studied the morphologic interactions between tumorigenic malignant melanomas and dermal elastin. Formalin-fixed and paraffin-embedded tissues of 108 tumorigenic malignant melanomas were stained for elastic tissue with the Verhoeff-van Gieson method. Various aspects of the relationship between malignant melanoma and dermal elastin were analyzed in relation to the histologic and clinical data using univariate and multivariate analyses. Tumor thickness, mitotic rate, and the presence of elastin remnants within the tumors were found to be independent negative prognostic factors, the latter with borderline significance. Tumors with more remnants of elastin were associated with higher stage of disease and lymph node and distant metastases. Tumor infiltration between the elastic fibers in the tumor depth was associated with high Clark level, greater tumor thickness, high stage of disease, and lymph node metastases. At least partial preservation of elastic fibers in the tumor depth was a relatively good prognostic factor whereas complete absence of elastin was an adverse factor. Focal or multifocal absence of elastin in the midst of the tumors or in their depth was usually associated with lymphocytic infiltrates. We suggest that tumors with remnants of elastic fibers and/or invasion between elastic fibers in their depth may be fast growing and highly invasive. The absence of elastin within tumors and at their advancing edge may be related to the elaboration of elastin-degrading substances by melanoma cells or various inflammatory cells. Our findings indicate that the relationship between malignant melanomas and dermal connective tissue components, specifically elastin, may have prognostic significance.

MicroRNAs (miRs) play a central role in regulating gene expression and are strongly associated with cancer development. This study sought to determine if adrenocortical carcinomas can be differentiated from adenomas by their miR profiles and to correlate the findings with the histologic Weiss system for identifying malignancy in adrenocortical tumors (ACTs). Forty-six primary and 2 recurrent ACTs retrieved from the files of the pathology department of a tertiary medical center were evaluated blindly for the Weiss criteria. High-quality RNA was extracted, and miR expression was evaluated with microarrays and quantitative reverse-transcriptase polymerase chain reaction. The Weiss system defined 17 tumors as carcinomas and 29 as adenomas. On microarray analysis, over a dozen miRs were upregulated or downregulated in carcinomas compared with adenomas. Upregulation of miR-503 was the best single discriminator of malignancy. The combination of miR-34a and miR-497 underexpression discriminated carcinomas from adenomas with 100% sensitivity and 96% specificity. Statistical analysis revealed a high level of correspondence between the Weiss system and miR expression. In conclusion, miR expression can accurately identify malignant ACTs with equal efficiency to the Weiss system. miR analysis may have added value in tumors with borderline features that are difficult to interpret histopathologically.

Male breast cancer is a rare disorder, and little is known about the molecular mechanisms associated with the tumorigenic process. We genotyped 31 Jewish Israeli males with breast cancer for the predominant Jewish BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) germline mutations: 11 individuals from high-risk families and 20 patients unselected for family history of cancer. Two patients of the high-risk group (18.2%) displayed germline mutations: one harbored the 185delAG BRCA1 mutation, and the other the 6174delT mutation in BRCA2. None of the unselected patients displayed any mutation. In 2 patients, complete mutation analysis of the BRCA2 gene did not reveal any disease-associated mutations. We conclude that the predominant Jewish germline mutations in BRCA1/BRCA2 contribute to male breast cancer in Israel, primarily in Ashkenazi individuals with a family history of cancer.

Identification and histologic study of the sentinel node (SN) is an acceptable, yet not firmly established, guide for treating intermediate-thickness melanoma. This study widens the range of applications of this technique. We included 97 patients with intermediate-thickness melanoma lesions or lesions for which there is no standard treatment. Fifty-six underwent preoperative lymphoscintigraphy, and all underwent intraoperative lymphatic mapping (IOLM) using blue dye, followed by frozen section study and total node processing by serial sections. Elective lymph node dissection was performed in cases of metastasis to the sentinel node or technical failures with high risk. Four categories were defined: (A) intermediate-thickness lesions (mean 2.27 mm) (n = 45); (B) thin lesions (mean 1.14 mm) with risk factors of regional failure (n = 27); (C) lesion thickness close to but more than 4 mm (n = 10); and (D) lesions of undetermined thickness (n = 15). Median follow-up was 30 months (range 13-51 months). Intraoperative lymphatic mapping successfully identified the sentinel node (SN) in 93% of basins explored. Metastases were detected in 11 SNs. There were three lymph basin recurrences in patients with previously negative SNs, all salvaged by therapeutic lymph basin dissection and are NED (no evidence of disease). Two SN(+) patients had systemic recurrences; one died of his disease, and the other is alive with disease. One SN(-) patient died NED owing to other cause. This technique spared 83% of category A patients from lymph node dissection. It allowed better staging and better decision making for treatment in categories B and D; and it prevented early regional recurrences in category C patients. Intraoperative lymphatic mapping with SN guidance is a novel, lo