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Abstract Acral melanoma is an aggressive type of melanoma with unknown origins. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. We examine exome sequencing data of 139 tissue samples, spanning different progression stages, from 37 patients. We find that 78.4% of the melanomas display clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These complex genomic aberrations are typically shared across all progression stages of individual patients. TERT activating alterations also arise early, whereas MAP-kinase pathway mutations appear later, an inverted order compared to the canonical evolution. The punctuated formation of complex aberrations and early TERT activation suggest a unique mutational mechanism that initiates acral melanoma. The marked intratumoral heterogeneity, especially concerning MAP-kinase pathway mutations, may partly explain the limited success of therapies for this melanoma subtype.

Background: The early diagnosis of acral lentiginous melanoma (ALM) contributes to clinical outcomes since ALM can be mistaken for acral melanocytic nevus (AMN). ALM occurrence is reported to correlate with stress-bearing areas, which may assist in differential diagnoses. Our objective is to evaluate the distribution patterns of ALMs and AMNs on the palms and soles among Taiwanese patients. Methods: A retrospective analysis was performed by reviewing the charts of 1400 patients diagnosed with benign and malignant pigmented lesions confirmed after excisional biopsy at our institution between 2000 and 2022 in Taiwan. Correlations between lesions and clinicopathological factors were analyzed. Results: 309 AMNs and 177 ALMs were included. Mechanical stress was significantly associated with plantar ALMs (weight-bearing area: 92.65 %, arch: 7.35 %, P

Abstract Background Nanosecond quality‐switched ruby laser (QSRL) and frequency‐doubled 532‐nm picosecond Nd:YAG laser (532‐nm picosecond Nd: YAG laser [PSNYL]) are well‐documented treatments for solar lentigines (SLs). However, no studies have longitudinally tracked the microscopic findings before and after QSRL and 532‐nm PSNYL treatment for SL removal. Objectives To compare the clinical efficacy and dynamic histological changes between QSRL and 532‐nm PSNYL in the treatment of SLs in Asian patients. Method Twenty‐five patients with SLs on both sides of the face were enrolled in this prospective split‐face study. QSRL and 532‐nm PSNYL therapy for SLs on the left and right side of the face, respectively, were performed for each subject. All subjects underwent baseline and follow‐up assessment at Weeks 3 and 6. In vivo harmonic generation microscopy (HGM) imaging was adopted for the noninvasive observation of melanin mass density of basal cells (MMDbasal cell), epidermal melanocyte dendricity, and dermal melanophages before and after laser treatment. Results At Week 6, 60% of the lesions treated with QSRL and 68% with 532‐nm PSNYL had over 75% improvement. Histologically, both lasers resulted in statistically significant decrease of MMDbasal cell in SLs to the level of that in the normal skin at Weeks 3 and 6. Statistically significant increase of dermal melanophages was observed 3 weeks after both laser treatments. Nevertheless, 532‐nm PSNYL led to faster clearance of melanophages than QSRL at Week 6. Moreover, activated melanocytes with enhanced dendrite formation was significantly increased till 6 weeks after both laser treatments. Conclusion Both QSRL and 532‐nm PSNYL were effective treatments for SLs, and there was no statistically significant difference in clinical scoring. However, from histological aspect, 532‐nm PSNYL was associated with lower degree of melanin incontinence and melanophage accumulation. HGM imaging analysis can noninvasively quantitate the cutaneous response to pigmentary laser therapy.

This retrospective cohort study enrolled 385 patients diagnosed with cutaneous melanoma from 1980 to 2021 in National Taiwan University Hospital (NTUH). The aim of this study was to investigate the relationship between thickness of primary melanoma lesions and disease outcome of melanoma patients, in particular, those diagnosed with acral lentiginous melanoma (ALM). The association between important clinicopathological characteristics other than tumor thickness and disease outcome was also analyzed. Survival analyses with the Kaplan-Meier method were utilized to investigate the prognoses of patients with different lesion thickness. The male-to-female ratio was 1.12:1. The median age at diagnosis was 63 years old (mean: 62.2 years). There were 283 cases (73.5%) of acral lentiginous melanoma (ALM) with a male-to-female ratio of 1.04:1. Between patients with primary ALM lesions 4.1 millimeters (mm) to 8.0 mm thick and those with lesions over 8.0 mm thick, significant differences in prognostic outcomes including incidence of second recurrences within 1 year (raw p = 0.003, Bonferroni corrected p = 0.009) and distant metastases within 1 year (raw p = 0.003, Bonferroni corrected p = 0.008), were observed. Significantly worse 1-year (raw p = 0.01, Bonferroni corrected p=0.03) and 2-year survival (raw p = 0.006, Bonferroni corrected p = 0.02) were found in ALM patients with lesions of over 8 mm thick than those with lesions 4.1 mm to 8.0 mm at diagnosis. Vigilant short-term follow-up is warranted in ALM patients with lesions of over 8.0 mm thick at diagnosis due to higher risks of adverse outcome.

Background: Risk factors of lymphatic and hematogenous metastasis in cutaneous melanoma remained unclear in Asian population. This study aimed to identify clinical and histopathological factors to predict metastatic pathways in cutaneous melanoma in Taiwan. Methods: A total of 247 patients diagnosed as stage I and II melanoma, followed at National Taiwan University Hospital were included in this retrospective study from 1980 to 2020. Kaplan–Meier curves and Cox proportional hazards regression were utilized to identify risk factors. Results: During a median follow-up of 143 months, 48 (19.4%) and 62 (25.1%) patients developed lymphatic and hematogenous metastasis respectively. In the univariate analysis, age> 70 years, greater Breslow thickness, ulceration, neurotropism, and NRAS mutation were significant risk factors for lymphatic metastasis in all subtypes of melanoma. Age >70 years, head and neck location, thickness, ulceration, higher mitotic rate, neurotropism, and NRAS mutation were significant predictors of hematogenous metastasis in all subtypes. In the multivariate analysis, greater thickness (HR for 2.0–4.0 mm, 4.5; p = .009 and HR for >4.0 mm, 5.7; p = .003) retained its significance as an independent risk factor for lymphatic metastasis in all subtypes of melanoma. Thickness (HR for >4.0 mm, 5.7; p

Abstract Risk factors of recurrence and distant metastasis of acral lentiginous melanoma (ALM) are of great interest for the high percentage of ALM in cutaneous melanoma in Asian populations. This single-center retrospective cohort including 177 patients with localized melanoma diagnosed from 2004 to 2020 aims to identify adverse predictors in cutaneous melanoma in Taiwan, with a focus on ALM. The relationship between clinicopathological features and outcomes, including incidences of recurrence and distant metastasis in 5 years from diagnosis, was analyzed. This study included 124 patients (70.1%) with ALM and 53 (29.9%) with non-ALM melanoma. Regarding clinicopathological characteristics, ALM patients were diagnosed at an older age and received sentinel lymph node biopsies (SLNBs) more often, while adjacent melanocytic nevi were more prevalent in non-ALM patients. With respect to prognostic implications of clinicopathological features, in ALM, implementation of SLNB was associated with a lower 5-year distant metastasis rate. Thickness of melanoma lesions over 4 mm, ulceration, and neurotropism, were related to both higher 5-year recurrence and distant metastasis rates. With regard to non-ALM patients, diagnoses made at or over 65 years old was linked to a higher 5-year recurrence rate, whereas ulceration was associated with both higher 5-year recurrence and distant metastasis rates. In conclusion, several clinicopathological characteristics have been identified to be associated with poor prognosis of cutaneous melanoma, especially ALM.

Currently, only 14.7% of practicing dermatologists in Taiwan who work at medical centers are dedicated to innovative research. Dermatology departments appear to face steeper challenges with the recruitment and retention of physician‒scientists than other medical specialties. The need to increase the number of physician‒scientists is clear and can be achieved through the provision of good training programs, financial support, early mentorship, and sustained funding.

Abstract The pathogenesis of melanomas emerging in plantar surfaces remains unclear; however, mechanical stress has been reported to increase the formation of melanomas. In this study, we conducted a multicenter retrospective analysis of 153 acral melanomas diagnosed between 2000 and 2015 in Taiwan. The male-to-female ratio of the patients in question was 1:1.28, and the mean age at diagnosis was 68 years. We examined whether melanomas which developed in different areas of the patients’ soles differed in their associations with various clinicopathological characteristics and survival. Testing by goodness of fit indicated that stress-bearing areas were significantly more conducive to the generation of melanomas than non-stress-bearing areas (P

BRAF and NRAS mutations have been described in melanomas among Caucasians and some Asian populations. However, few large-scale studies have investigated the status and clinical significance of BRAF and NRAS mutations in a Taiwanese population. Methods: Melanoma samples (n = 119) were analyzed for mutations in exons 11 and 15 of the BRAF gene, and in exons 1 and 2 of the NRAS gene. The samples were studied in genomic DNA, using polymerase chain reaction amplification and Sanger sequencing. Mutations of the BRAF and NRAS genes were then correlated with clinicopathological features and patients' prognosis. Results: The incidence of somatic mutations within the BRAF and NRAS genes was 14.3% (17/119 patients) and 10.1% (12/119 patients), respectively. Among the 17 patients with BRAF mutations, 15 (88.2%) had V600E mutations. BRAF mutation was frequently detected in younger patients (p = 0.0035), in thin melanomas (p = 0.0181), and in melanomas with less ulceration (p = 0.0089). NRAS mutation was more often seen in patients with lymph node metastasis (p = 0.0332). Both BRAF and NRAS mutations were not significantly correlated with overall survival and disease-free survival. Conclusion: As BRAF and NRAS mutations are rare in Taiwan, BRAF- or NRAS-targeted therapies may be effective only for selected Taiwanese melanoma patients.

Studies surveying melanomas associated with melanocytic nevi in Asia are rare. In this study, we examined whether nevus-associated melanomas differ from de novo melanomas in terms of their associations with clinical factors, histologic characteristics, and patient survival in Taiwan. Using data on cancer cases obtained from the Department of Pathology archives and the Cancer Registry of National Taiwan University Hospital, we conducted a retrospective analysis of 103 consecutive melanoma patients who were diagnosed between 2010 and 2015 and received follow-up through November 2016. Approximately 17.5% of the melanomas in question were associated with a nevus. In patients under 65 years of age, non-acral lentiginous melanomas were significantly associated with a higher percentage of nevus-associated melanomas. The superficial spreading subtype, younger patient age, thinner tumor, intermittent solar exposure, and early stage were significant predictors of a melanoma being histologically associated with a nevus. The appearance of a nevus associated with a melanoma predicted better recurrence-free survival compared with de novo melanomas. Although acral lentiginous melanomas (70.9%) constituted the most common histologic subtype, only 9.6% of the acral lentiginous melanomas were associated with a nevus. Furthermore, there was no statistically significant difference between the nevus-associated and de novo acral lentiginous melanomas with regard to clinicopathological factors and survival. In conclusion, nevus-associated melanomas were uncommon among acral lentiginous melanomas. Relatedly, because over half of all melanomas in Asians are acral lentiginous melanomas, Asians are less likely than Caucasians to have nevus-associated melanomas.

Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3) is an RNA-binding protein expressed in multiple cancers, including melanomas. However, the expression of IMP-3 has not been investigated in acral lentiginous melanoma (ALM). This study sought to elucidate its prognostic value in ALMs. IMP-3 expression was studied in 93 patients diagnosed with ALM via immunohistochemistry. Univariate and multivariate analyses for survival were performed, according to clinical and histologic parameters, using the Cox proportional hazard model. Survival curves were graphed using the Kaplan-Meier method. IMP-3 was over-expressed in 70 out of 93 tumors (75.3%). IMP-3 expression correlated with thick and high-stage tumor and predicted poorer overall, melanoma-specific, recurrence-free and distant metastasis-free survivals (P = 0.002, 0.006, 0.008 and 0.012, respectively). Further analysis showed that patients with tumor thickness ≤ 4.0 mm and positive IMP-3 expression had a significantly worse melanoma-specific survival than those without IMP-3 expression (P = 0.048). IMP-3 (hazard ratio 3.67, 95% confidence intervals 1.35-9.97, P = 0.011) was confirmed to be an independent prognostic factor for melanoma-specific survival in multivariate survival analysis. Positive IMP-3 expression was an important prognostic factor for ALMs.

Background: Reports on the prevalence of different human papillomavirus (HPV) genotypes in male patients with anogenital HPV infection are limited. Methods: We retrospectively analyzed the HPV genotypes of 100 consecutive patients seen in our department with anogenital HPV infection during 2003–2006. History was gathered from the medical records. Results: The most common HPV genotypes among Taiwanese male patients for check of anogenital warts (in descending order) were HPV 6 (46%), HPV 11 (28%), HPV 16 (6%), HPV 33 (5%), HPV 66 (5%), HPV 18 (4%), HPV 53 (4%), and HPV 72 (4%). Coinfections with two, three, and four genotypes of HPV were present in 16%, 7%, and 1% of the patients, respectively. HPV 16 or 18 was found in 10% of cases, with 60% (6/10) coexisting with HPV 6/11. The presence of either HPV 6, 11, 16, or 18 was 77%. HPV 16 was more common in anal compared to genital warts, with an odds ratio of 3.65. Conclusion: The most common genotype of anogenital HPV infection in Taiwanese males was HPV 6, followed by HPV 11. Coinfection with more than one genotype of HPV as well as concurrent low- and high-risk HPV infection was not uncommon.

Multiple myeloma (MM) is characterized by advanced osteolytic lesions resulting from the activation of osteoclasts (OCs) and inhibition of osteoblasts (OBs). OBs are derived from mesenchymal stem cells (MSCs) from the bone marrow (BM), however the pool and function of BMMSCs in MM patients (MM-BMMSCs) are reduced by myeloma cells (MCs) and cytokines secreted from MCs and related anti-MM treatment. Such reduction in MM-BMMSCs currently cannot be restored by any means. Recently, genetic aberrations of MM-BMMSCs have been noted, which further impaired their differentiation toward OBs. We hypothesize that the MSCs derived from adipose tissue (ADMSCs) can be used as alternative MSC sources to enhance the pool and function of OBs. Therefore, the purpose of this study was to compare the osteogenesis ability of paired ADMSCs and BMMSCs in MM patients who had completed intensive therapy. Fifteen MM patients who had received bortezomib-based induction and autologous transplantation were enrolled. At the third month after the transplant, the paired ADMSCs and BMMSCs were obtained and cultured. Compared with the BMMSCs, the ADMSCs exhibited a significantly higher expansion capacity (100% vs 13%, respectively; P = .001) and shorter doubling time (28 hours vs 115 hours, respectively; P = .019). After inducing osteogenic differentiation, although the ALP activity did not differ between the ADMSCs and BMMSCs (0.78 U/µg vs 0.74±0.14 U/µg, respectively; P = .834), the ADMSCs still exhibited higher calcium mineralization, which was determined using Alizarin red S (1029 nmole vs 341 nmole, respectively; P = .001) and von Kossa staining (2.6 E+05 µm2 vs 5 E+04 µm2, respectively; P = .042), than the BMMSCs did. Our results suggested that ADMSCs are a feasible MSC source for enhancing the pool and function of OBs in MM patients who have received intensive therapy.

A random rayburst sampling (RRBS) framework was developed to detect the nucleus and cell membrane boundaries in three-dimensional (3-D) space. Raw images were acquired through a full-field optical coherence tomography system with submicron resolution--i.e., 0.8 µm in lateral and 0.9 µm in axial directions. The near-isometric resolution enables 3-D segmentation of a nucleus and cell membrane for determining the volumetric nuclear-to-cytoplasmic (N/C) ratio of a single cell. The RRBS framework was insensitive to the selection of seeds and image pixel noise. The robustness of the RRBS framework was verified through the convergence of the N/C ratio searching algorithm. The relative standard deviation of the N/C ratio between different randomly selected seed sets was only 2%. This technique is useful for various in vitro assays on single-cell analyses. [ABSTRACT FROM AUTHOR]

In vivo harmonic generation microscopy (HGM) has been applied successfully in healthy human skin and can achieve a submicron resolution, similar to histopathologic examination, even at a penetration depth up to 270 µm. This study aims to investigate the clinical applicability of HGM imaging for differential diagnosis of nonmelanoma pigmented skin lesions. A total of 42 pigmented skin tumors, including pigmented basal cell carcinoma, melanocytic nevus, and seborrheic keratosis were evaluated by HGM ex vivo or in vivo. Based on the standard histopathologic characteristics, we established the corresponding HGM imaging criteria for each pigmented tumor. Diagnostic performance of HGM for differentiating nonmelanoma pigmented skin tumors was evaluated through the observers' direct general assessment (overall evaluation) or the presence of two imaging criteria with the highest sensitivity and specificity (major criteria evaluation). Our results show that, based on the direct general assessment, the sensitivity is 92% [95% confidence interval (CI): 67 to 97%] and the specificity is 96% (95% CI: 83 to 99%); by major criteria evaluation, 94% sensitivity (95% CI: 70 to 99%) and 100% specificity (95% CI: 87 to 100%) are achieved. Our study indicates that HGM serves as a promising histopathological examination tool for noninvasive differential diagnostics of nonmelanoma pigmented skin tumors. [ABSTRACT FROM AUTHOR]