Next-generation sequencing of uveal melanoma with clinical and histological correlations: Prognostic value of new mutations in the PI3K/AKT/mTOR pathway.

BACKGROUND: Uveal melanoma (UM) is the eye's most common primary malignancy and there are no effective therapies for disseminated disease. It is important to try to know the patient's prognosis. The aim of this study was to reflect genetic variants, studied using NGS, of a series of 69 cases of UM and its correlation with histopathology and clinical progression. METHODS: We performed targeted NGS using a 519-gene panel. RESULTS: There were selected 28 different mutated genes, showing a total of 231 genetic variants that affected the function of the protein. The most common secondary mutations occurred in SF3B1 (in 26%), followed by BAP1 (in 23%), LRP1B (22%) and FGFR4 (20%). BAP1 mutation was associated with a greater likelihood of metastases and with greater presence of epithelioid cells. LRP1B was also associated with presence of epithelioid cells SF3B1 mutation was significantly associated with a spindle morphology. We found variants in the RAD51B, TOP2A, PTPRD, TSC2, DHX9, PDK1 and MTOR that have not been previously reported in consulted databases. The presence of a mutation in: CHEK2, DHX9 and PDK1 was associated with metastases. CONCLUSIONS: BAP1 is the most solid biomarker of a poor prognosis in UM and mutations can be detected using NGS. SF3B1 is associated with the spindle cell subtype of UM, which gives it probably a favourable prognostic value. Our study suggests that mutations in DHX9 and PDK1 can have prognostic value. These potential biomarkers are related to the PI3K/AKT/mTOR pathway and makes them candidates for developing new directed therapies.

Difficult to Diagnose Cutaneous Melanoma in a Patient with BAP1 Tumor Predisposition Syndrome.

BRCA1-associated protein 1 (BAP1)-inactivated melanomas can occur sporadically or in germline contexts, particularly in recently recognized BAP1-tumor predisposition syndrome. Diagnosis represents a clinical and histopathological challenge, requiring comprehensive analysis of morphology and sometimes molecular analysis in addition to immunohistochemistry. We report a BAP1-inactivated cutaneous melanoma initially diagnosed as an atypical Spitz tumor on the auricle in a patient with BAP1-tumor predisposition syndrome. Immunohistochemistry, fluorescence in situ hybridization, and comparative genomic hybridization allowed diagnosis. Cutaneous BAP1-inactivated melanocytic tumors, previously classified as atypical Spitz Nevi, may have a dermal mitotic activity that can resemble melanoma and on the other hand, atypical Spitz tumors are sometimes difficult to differentiate from BAP1-inactivated melanoma. Specific criteria, requiring molecular diagnosis have been proposed in order to support melanoma diagnosis.

An Unusual Case of Desmoplastic Melanoma With Monster Cells Imitating an Atypical Fibroxanthoma.

Numerous cells with very large and irregular nuclei ("monster" cells) have not hitherto been reported in desmoplastic melanoma (DM). Their prognostic significance in melanomas is a matter of debate, although some authors have associated them with more aggressive tumor behavior. We report a mixed DM on the scalp of an 88-year-old woman imitating an atypical fibroxanthoma. Tumor cells stained positive for SOX10, S100, and cyclin D1; BRAF mutation status was negative, and fluorescence in situ hybridization analysis showed copy number gains in 11q13 (cyclin D1) and 6p25 (RREB1), and loss in 6q23 (MYB). Cyclin D1 amplification is associated with poor prognosis in melanoma.

Three Cases of Clear Cell Hidradenoma With "Benign" Lymph Node Involvement.

ABSTRACT: The malignant counterpart of cutaneous clear cell hidradenoma (CCH), hidradenocarcinoma, is an aggressive neoplasm that may have a fatal outcome. However, some cases of benign looking CCH with isolated lymph node involvement and excellent prognosis have been described. "CCH-like neoplasm of uncertain malignant potential" or "atypical hidradenoma" have been proposed as designations for these lesions. We report 3 cases of CCH with lymph node involvement. Ages ranged from 29 to 51 years old. All cases involved the inguinal lymph nodes: 2 of them presented with an isolated lymph node lesion, and the third case had lymph node and cutaneous involvement following the resection of a previous cutaneous lesion. Imaging studies showed no systemic involvement. None of the lesions exhibited histopathologic features of malignancy. All neoplasms were well circumscribed, had cystic spaces, did not display atypia or necrosis, and had less than 4 mitoses per high power field. No recurrence has been observed at follow-up after resection in all cases. All published cases of CCH with lymph node involvement so far affected a single lymph node in the axillary or inguinal regions, lacked features of malignancy, and had excellent long-term prognosis. Some cases previously reported as hidradenocarcinoma probably fit into this category. Our series adds more evidence to this rare phenomenon of "benign metastasis." Aggressive treatment should be avoided in these cases, and a long-term follow-up is warranted.

Recurrent Cutaneous Angiosarcoma of the Scalp With Aberrant Expression of S100: A Case Report.

Angiosarcoma (AS) is a malignant mesenchymal neoplasm of endothelial origin with a predominantly lymphatic immunophenotype, which accounts for less than 1% of all sarcomas. Cutaneous AS of the scalp is associated with high rates of local recurrence and a poor prognosis. Histologically, poorly differentiated AS often comprises solid epithelioid cells, although rare variants involving spindle cells have been reported; diagnosis requires immunohistochemical analysis using vascular cell markers. We report on a cutaneous spindle-cell AS of the scalp in a female patient; key features included spontaneous regression after biopsy, local recurrence 2 years later, and aberrant nuclear staining for S100 protein in an area of the tumor not expressing CD34 or D2-40. Tumor cells exhibited positivity for vascular markers CD31, CD34, D2-40, ERG and FLI-1 and were negative for myoid markers (αSMA and desmin), epithelial (EMA and cytokeratin AE1/AE3) and melanocyte markers (HMB45 and melan-A). Cutaneous spindle-cell AS of the scalp is a rare variant with a poor prognosis. Diagnosis of spindle-cell AS was confirmed by immunohistochemical analysis using CD31, CD34, ERG, FLI-1, podoplanin (D2-40), and claudin-5. Although a number of authors have noted aberrant expression of cytokeratins, CD30, CD117 and neuroendocrine markers (synaptophysin and chromogranin A) in AS, intense positive nuclear staining for S100 protein in neoplastic cells has not hitherto been observed. This article reports on a spindle-cell AS of the scalp notable for aberrant expression of S100, spontaneous regression and recurrence 2 years later at the same site and displaying identical histological and immunohistochemical features.

Lipomatosis arborescens en rodilla pediátrica. Resonancia magnética nuclear / Lipoma arborescens in pediatric Knee. Nuclear magnetic resonance

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Controversies in Intrapatient Melanoma BRAFV600E Mutation Status.

Therapies targeting the BRAF oncogene have improved the overall and disease-free survival of patients with advanced melanomas. An unresolved issue in clinical practice is the existence (or not) of BRAF-mutated and BRAF-nonmutated tumors in individual patients (intrapatient BRAF mutation heterogeneity), which may serve as a mechanism of resistance to BRAF inhibitors or lead to diagnostic problems. Different research groups have reported differing results after analyzing the BRAF mutation statuses of multiple melanoma tumors. Herein, we present a brief revision of the literature on this controversial topic and propose a theory to justify the divergence of the results found in the literature.

Association between tumor size and Breslow's thickness in malignant melanoma: a cross-sectional, multicenter study.

The aim of this study was to assess the potential role of tumor diameter in explaining variations in tumoral invasion and in the initial prognosis for patients with malignant melanoma (MM). This was a multicenter, cross-sectional study that recruited between 2000 and 2009 patients with primary in-situ MM (Tis) and invasive cutaneous MM. Tis and MMs with a Breslow's thickness less than 1 mm (T1) were grouped (Tis-T1) and tumors with a Breslow's thickness 1 mm or more were also analyzed in combination (T2-T4). The tumor size was measured after routine formalin tissue fixation. Primary outcomes were the correlation between Breslow's thickness and tumor size, and the role of tumor size in explaining variations in Breslow's thickness, as assessed by the Pearson correlation test and logistic binary regression with calculation of the odds ratios. A total of 1610 MM patients were included and analyzed. The Pearson correlation between tumor size and Breslow's thickness was 0.42, with a determination coefficient of R2=0.18 (P>0.01). Correlations between tumor size and thickness were stronger in patients aged 30-60 years (r=0.42, R2=0.1764, P<0.001) and in tumors arising on the upper limbs (r=0.55, R2=0.3025). The odds ratio of identifying a T2-T4 stage MM in patients with tumors larger than 1 cm in size was 2.76 (95% confidence interval 2.25-3.39, P<0.001). Even though a direct, positive, and strong association between tumoral size and Breslow's thickness might be expected in melanoma cases, the strength of this association has been moderate. Tumor size explains a low burden of the variation observed in the Breslow's thickness.

Intra- and Inter-Tumoral Homogeneity of BRAF(V600E) Mutations in Melanoma Tumors.

The era of targeted therapy has introduced a new therapeutic perspective for melanoma patients. Treatment with BRAFV600 inhibitors has improved overall and disease-free survival in metastatic melanoma patients whose tumors harbor BRAFV600 mutations. Although the BRAFV600E mutation appears to have a critical role in tumor initiation, its expression during tumor progression remains controversial. In fact, various authors claim that BRAFV600E heterogeneity is evident in melanoma tumors. Herein, we investigated the pattern of BRAFV600E expression in matched primary and metastatic samples from 140 patients. Using a combination of real-time PCR and immunohistochemical analyses, we demonstrated that BRAFV600E expression is homogeneous in melanoma tumors and hypothesized that the heterogeneity described by others might be attributable to technical issues when molecular methods are used. We also demonstrated the high efficiency of the anti-BRAFV600E VE1 antibody for the detection of BRAFV600E mutations in melanoma tumors.

Role of age and sex in the diagnosis of early-stage malignant melanoma: a cross-sectional study.

Age and sex have been identified as predictors of outcome in malignant melanoma (MM). This aim of this multicentre, cross-sectional study was to analyse the role of age and sex as explanatory variables for the diagnosis of thin MM. A total of 2430 patients with MM were recruited. Cases of in situ-T1 MM were more frequent than T2-T4 MM (56.26% vs. 43.74%). Breslow thickness increased throughout decades of life (analysis of variance (ANOVA) p < 0.001), with a weak correlation between Breslow thickness and patient's age (r = 0.202, p < 0.001). Breslow thickness was significantly less in women (1.79 vs. 2.38 mm, p = 0.0001). Binary logistic regression showed a significant (p < 0.001) odds ratio for age 0-29 years (1.18), and 30-59 years (1.16), and for women (1.09). Age and sex explained 3.64% of the variation observed in Tis-T1 frequency (R2 = 0.0364). Age and sex appear to explain a low percentage of the variation in the early detection of MM.

The role of accessibility policies and other determinants of health care provision in the initial prognosis of malignant melanoma: a cross-sectional study.

BACKGROUND: The prognostic benefit of health care service provision and delivery policies for patients with malignant melanoma (MM) is not yet clear. OBJECTIVE: To analyze the role of health care provision determinants in the initial prognosis of MM. METHODS: A multicenter cross-sectional study was conducted at 14 public hospitals and recruited 3550 patients with MM between 2000 and 2009. The study variables were analyzed using univariate and multivariate models to identify their role in the variations observed. RESULTS: In a 10-year period, the number of patients with MM increased by 78.54%, with primary in situ MM (Tis) or MMs with a Breslow thickness <1 mm (T1) representing 51.72% of the total number of MMs in 2000, increasing to 62.23% by the end of the study period (P = .005). Among the variables that explained the variation in MM frequency the year of diagnosis after 2004 (univariate odds ratio [OR], 1.43 [P < .001]; multivariate OR, 1.36 [P = .005]) and diagnosis in centers with specific fast-track referral systems (univariate OR, 1.24 [P = .01]; multivariate OR, 1.59 [P = .025]) were shown to explain the increasing frequency of Tis-T1 MM. LIMITATIONS: The primary potential limitation of this study is its retrospective nature. CONCLUSION: Health care provision policies and interventions aimed at improving accessibility to specialized care appear to explain the increasing frequency of Tis-T1 MM.