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  • 1
    In: The American Journal of Dermatopathology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. 4 ( 2020-04), p. 265-271
    Abstract: Melanoma is an aggressive skin malignancy, and the acral lentiginous melanoma (ALM) subtype affects non–sun-exposed sites such as the volar surface of the hands and feet and the subungual region and is most common in Asians, Hispanics, and Afro-descendants. The presence of different clones within the same tumor seems to influence the aggressiveness of tumors. Patients with mutations in the KIT gene have shown a good response to tyrosine kinase inhibitor therapy. We tested the hypothesis of intratumor heterogeneity through analysis of KIT gene mutations in ALM and determined the correlation between KIT mutations and demographic, clinical, and histopathological variables. Twenty-five ALM samples were examined. We selected up to four different regions per tumor for sequencing by the Sanger method for analysis of KIT gene exon 11 and exon 13 mutations. Advanced lesions were predominant, and the main histopathological characteristics of lesions were Breslow index 〉 4.0 mm (17/25, 68%), Clark level IV/V (21/25, 84%), ulceration (16/25, 64%), and 〉 3 mitoses/mm 2 (8/25, 32%). KIT gene mutations were detected in 11/25 cases (44%), and all these 11 cases displayed intratumor heterogeneity, that is, at least 2 tumor regions had different mutational profiles. The predicted effect of most mutations detected was detrimental to protein function. No significant correlations between histopathological variables and either KIT mutations or intratumor heterogeneity were observed. The hypothesis of intratumor heterogeneity of KIT gene mutations in acral lentiginous melanoma was supported.
    Type of Medium: Online Resource
    ISSN: 0193-1091
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2041296-4
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  • 2
    In: Pigment Cell & Melanoma Research, Wiley, Vol. 33, No. 3 ( 2020-05), p. 490-497
    Abstract: Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells. We investigate whether aggressive melanoma tumor cells present IMPDH‐based RR structures. Forty‐five ALM paraffin‐embedded tissue samples and 59 melanocytic nevi were probed with anti‐IMPDH2 antibody. Both the rod‐ and ring‐shaped RR could be observed, with higher frequency in ALM. ROC curve analyzing the proportions of RR‐positive cells in ALM versus nevi yielded a 0.88 AUC. Using the cutoff of 5.5% RR‐positive cells, there was a sensitivity of 80% and specificity of 85% for ALM diagnosis. In ALM, 36 (80%) showed RR frequency above the cutoff, being classified as RR‐positive, compared with only 9 (15%) of the nevi ( p   〈  .001). Histopathology showed that 71% of the RR‐positive specimens presented Breslow thickness  〉  4.0mm, compared with only 29% in the RR‐low/negative ( p  = .039). We propose that screening for RR structures in biopsy specimens may be a valuable tool helping differentiate ALM from nevi and accessing tumor malignancy.
    Type of Medium: Online Resource
    ISSN: 1755-1471 , 1755-148X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2425880-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. e20092-e20092
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 4
    In: The American Journal of Dermatopathology, Ovid Technologies (Wolters Kluwer Health), Vol. 39, No. 2 ( 2017-02), p. 114-120
    Abstract: Samples of acral lentiginous melanomas (ALMs) were obtained from the Department of Pathology at Escola Paulista de Medicina—Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil. Demographic, clinical, and follow-up data were obtained from the charts of Hospital São Paulo. From 2 tissue microarrays containing 60 nevi and quadruplicate samples of ≥1.0-mm of 49 ALM, sections were stained to evaluate SCF, KIT, BRAF, CYCLIND1, MYC, and PTEN immunohistochemical protein expression. Results: Nevi and ALM from 2006 to 2010 were reviewed and collected. All specimens were in the vertical growth phase, and histopathological parameters indicated that tumors were at an advanced stage at diagnosis. Average tumor thickness was 6.95 mm, 63% were ulcerated, average mitotic index was 5 mitotic cells per mm 2 , and 43% were at Clark's level V. Compared with nevi, the χ 2 test showed that ALM significantly correlated with SCF protein expression ( P = 0.001) and expression heterogeneity ( P 〈 0.000). Similar findings were observed for KIT ( P = 0.005, P = 0.003, respectively), MYC ( P 〈 0.000, P 〈 0.000), and PTEN ( P = 0.005, P 〈 0.000). Malignancy did not correlate with BRAF and CYCLIN D1 expression ( P = 0.053 and P = 0.259, respectively), but it did significantly correlate with their heterogeneous expression ( P 〈 0.000, P = 0.024, respectively). Combined protein expression had an odds ratio of greater malignancy when BRAF and MYC were positive and/or heterogeneously expressed (OR of 78 and 95, respectively). Discussion and Conclusion: We show that marker protein expression, when combined with heterogeneous expression as shown by immunohistochemistry, is a powerful indicator of malignancy in ALMs, especially, when protein pairs are combined.
    Type of Medium: Online Resource
    ISSN: 0193-1091
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2041296-4
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  • 5
    In: The American Journal of Dermatopathology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 10 ( 2019-10), p. 733-740
    Abstract: The choice of appropriate therapeutic strategies may be influenced by intratumor heterogeneity and makes cancer treatment considerably more challenging. We aimed to evaluate the heterogeneity of BRAF exon 15 mutations in different areas of acral lentiginous melanoma (ALM). The entire exon 15 was sequenced in 4 different areas of paraffin-embedded samples from 26 patients with ALM. A total of 26 of 49 cases of ≥1 mm in depth of ALM identified by clinical, anatomical, and pathological data fulfilled the inclusion and exclusion criteria for this study. Tumors had a mean Breslow depth of 7.2 mm and an average mitotic index of 3 mitosis/mm 2 . Mutations distinct from the common V600E and V600K were detected in 31%, and intratumor heterogeneity was observed in 31% of samples. Interestingly, 63.5% of all mutations had been previously associated with cancer. Most (62.5%) of the missense BRAF exon 15 mutations found in the ALM samples examined here were deemed “detrimental” for protein function according to at least 2 functional prediction programs, and 3 mutations (37.5%) were predicted to be “neutral,” with no effect on protein function. BRAF exon 15 mutations were detected frequently in ALM and displayed heterogeneity, a finding to be further investigated.
    Type of Medium: Online Resource
    ISSN: 0193-1091
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2041296-4
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