Indeterminate cell histiocytosis in a Chinese patient with progressive and extensive nodular lesions and mixed indeterminate cell and macrophage-monocyte lineage.

Indeterminate cell histiocytosis (ICH) is an extremely rare cutaneous neoplastic disorder. It has the immunophenotypic features of both Langerhans and non-Langerhans cell histiocytosis. We report here a case of a healthy young Chinese woman who presented with disfiguring, thick, infiltrated cutaneous nodules on the face, trunk and extremities which appeared progressively over a period of 4 years. No systemic involvement has been detected so far. Results of a skin biopsy showed diffuse dermal infiltration of histiocytoid cells with indented nuclei and positive staining for S100 and CD1a and negativity for CD207 (langerin). Admixed within were some CD68-positive foamy histiocytes and multinucleated giant cells with focal expression of CD163. Although the clinical presentation is more typical of progressive nodular histiocytosis, the histology and immunoprofile is consistent with ICH. Our report adds to the limited case reports in the current literature of ICH in the Chinese population.

Cutaneous Plasmacytosis: A Clinicopathologic Study of a Series of Cases and Their Treatment Outcomes.

INTRODUCTION: Cutaneous plasmacytosis (CP) is a rare skin disorder characterized by multiple reddish brown nodules with polyclonal plasma cell proliferation. It has most often been reported to affect the trunk but is also known to affect the face and extremities in adults and is predominantly seen in Asians. The etiology is poorly understood, and there is no consensus on treatment methods. METHODS: Five cases diagnosed to have CP were collated from our institution. Their clinicopathologic features and treatment outcomes were reviewed. RESULTS: Four of the 5 patients presented with lesions that affected multiple sites of the body including the trunk, axillae, face, and limbs. The remaining patient had lesions localized to his axillae. The lesions were generally asymptomatic. All patients had hypergammaglobulinaemia but only one had a faint monoclonal band detected on immunofixation. Common findings in the biopsy results for all patients were perivascular plasma cell infiltrates without light chain restriction on kappa/lambda staining, as well as mast cell infiltrates. Partial remission of cutaneous lesions was observed in 3 of the patients, with 2 of them responding well to psoralen and ultraviolet A radiation therapy. CONCLUSION: CP presents with distinctive clinical features and characteristic histological features including polyclonal perivascular plasma cell infiltrates. The axilla seems to be a frequent and characteristic site of involvement and may be a useful clinical clue to the condition. In the management of patients with CP, it is important to exclude secondary causes of plasmacytic infiltrates. While there are no clearly established treatment modalities for CP, psoralen and ultraviolet A radiation therapy may be a viable option in view of the clinical improvement observed in our patients who received it.

Simultaneous Occurrence of Papulonecrotic Tuberculid and Erythema Induratum in an Asian Woman.

A 31-year-old Indonesian woman presented with a 2-month history of recurrent painful nodules on the legs. Review of systems did not reveal any respiratory, gastrointestinal, or abdominal findings. She had been to Singapore working as a domestic helper for close to a year. There was no contact history of tuberculosis.

Basal cell carcinoma in Singapore: a prospective study on epidemiology and clinicopathological characteristics with a secondary comparative analysis between Singaporean Chinese and Caucasian patients.

BACKGROUND/OBJECTIVES: Susceptibility to and clinical presentation of basal cell carcinoma (BCC) differ in Asian and Caucasian populations. This study aims to evaluate the epidemiological and clinicopathological characteristics of BCC in a multiracial Singaporean population, with a secondary comparative analysis between Chinese and Caucasian patients. METHODS: We prospectively studied patients with newly diagnosed, histologically confirmed BCC at the National Skin Centre, Singapore from 2004 to 2008. RESULTS: In total, 274 BCC from 260 patients were studied, with 19 patients having two or more tumours. Their mean age was 67.5 years and 54% were male. Chinese comprised 80% and Caucasians 14%. The Chinese were 1.8-fold as likely as Caucasians to be older than 60 years, and experienced itch thrice more frequently. Caucasians developed multiple BCC threefold and truncal or upper limb BCC 2.9-fold more frequently than the Chinese. In terms of tumour subtype, morphoeic BCC was 2.7-fold more common in Caucasians. Pigmented BCC occurred 2.7-fold more often in the Chinese, most frequently on the head and neck of elderly Chinese. CONCLUSIONS: Compared to the Chinese, BCC occurred more often in younger Caucasians, with a predilection for the trunk and upper limb, suggesting a greater role for recreational sun exposure as a risk factor. Pigmented BCC more commonly occurred on the head and neck of elderly Chinese and may be reflective of cumulative sun exposure as a risk factor. Aggressive morphoeic BCC was more common in Caucasians than in Singaporean Chinese patients.

Pediatric mycosis fungoides in Singapore: a series of 46 children.

Few studies have evaluated Asian children with mycosis fungoides (MF). We report a series of patients from a tertiary dermatologic institution in Singapore. A retrospective review was performed of patients younger than 16 years old diagnosed with MF between 2000 and 2008 at the National Skin Centre, Singapore. Forty-six patients were identified. At initial presentation, a provisional diagnosis of MF was made in 19 patients (41.3%), pityriasis lichenoides chronica (PLC) in 11 (23.9%) and postinflammatory hypopigmentation due to eczema or other causes in 11 (23.9%). After skin biopsy, the hypopigmented variant of MF was diagnosed in 42 patients (91.3%). There was one case each of PLC-like MF, pigmented purpuric dermatosis-like MF, classic MF, and solitary MF. Pityriasis lichenoides coexisted in three cases (6.5%). All except one patient presented with the early patch-plaque stage of disease (stage IA/B). The disease did not progress in any of our patients after a mean follow-up of 71.0 ± 52.5 months. Twenty-seven patients (58.7%) had complete disease clearance after a mean duration of 27.1 ± 28.1 months; 15 (49.7%) of 32 patients who received narrowband ultraviolet B treatment had complete clearance within an average of 8.9 ± 5.3 months, but 7 patients relapsed within 14.9 ± 14.8 months. One patient with solitary MF failed multiple treatment modalities before eventually achieving disease clearance with photodynamic therapy. Hypopigmented MF is the most common MF variant in Asian children. The diagnostic difficulty is in differentiating this from PLC, which may coexist with MF. Long-term prognosis is generally favorable.

A retrospective review of the therapeutic response with remission in patients with newly diagnosed bullous pemphigoid.

We reviewed the clinical characteristics and therapeutic response in cases of newly diagnosed bullous pemphigoid at the National Skin Centre between June 2009 and December 2010. Most (76%, n = 68/90) achieved clinical remission within 6 months of commencement of therapy. Oral mucosal involvement was identified as a risk factor associated with a prolonged duration of treatment beyond 6 months.

Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder associated with sudden cardiac death. Its pathophysiology is still poorly understood. We aimed to produce an in vitro cellular model of ARVC using patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes and determine whether the model could recapitulate key features of the disease phenotype. METHODS AND RESULTS: Dermal fibroblasts were obtained from a 30-year-old man with a clinical diagnosis of ARVC, harbouring a plakophilin 2 (PKP2) gene mutation. Four stable iPSC lines were generated using retroviral reprogramming, and functional cardiomyocytes were derived. Gene expression levels of desmosomal proteins (PKP2 and plakoglobin) in cardiomyocytes from ARVC-iPSCs were significantly lower compared with cardiomyocytes from control iPSCs (P< 0.01); there were no significant differences in the expression of desmoplakin, N-cadherin, and connexin 43 between the two groups. Cardiomyocytes derived from ARVC-iPSCs exhibited markedly reduced immunofluorescence signals when stained for PKP2 and plakoglobin, but similar levels of staining for desmoplakin, N-cadherin, and connexin 43 compared with control cardiomyocytes. Transmission electron microscopy showed that ARVC-iPSC cardiomyocytes were larger and contained darker lipid droplets compared with control cardiomyocytes. After 2 weeks of cell exposure to adiopgenic differentiation medium, ARVC-iPSC cardiomyocytes were found to contain a significantly greater amount of lipid, calculated using Oil Red O staining, compared with controls (734 ± 35.6 vs. 8.1 ± 0.49 a.u., respectively; n = 7, P = 0.001). CONCLUSION: Patient-specific iPSC-derived cardiomyocytes display key features of ARVC, including reduced cell surface localization of desmosomal proteins and a more adipogenic phenotype.

Sun exposure and risk of lymphoid neoplasms in Singapore.

BACKGROUND: Epidemiologic studies have reported an inverse association between sun exposure and non-Hodgkin lymphoma (NHL), but these have been almost exclusively conducted in Western populations residing in temperate locations. We evaluated the association between personal outdoor sun exposure and risk of malignant lymphomas in Singapore. METHODS: A hospital-based case-control study of 541 incident cases of lymphoid neoplasms and 830 controls were recruited during 2004-2008. Participants were interviewed regarding recreational or occupational outdoor activities during childhood and in adulthood. Basic demographics and potential confounders were also collected. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using unconditional logistic regression analysis. RESULTS: Compared with individuals who did not have regular sun exposure, a lower risk of NHL was observed for those who reported regular exposure on non-school days during childhood [OR, 0.62; 95 % CI, 0.46-0.83] and non-working days in adulthood [OR, 0.70; 95 % CI, 0.51-0.97]. The protective effect was more evident among women. CONCLUSION: Our findings support an inverse relationship between intermittent sun exposure and the risk of NHL. These findings are consistent with the growing evidence from various countries, but further studies, especially prospective studies, are needed in Asian populations.

Extramammary Paget disease: Immunohistochemistry is critical to distinguish potential mimickers.

Extra-mammary Paget disease (EMPD) is a rare intra-epithelial carcinoma that is usually found on the apocrine-rich skin of the perineum. We report 2 cases in which EMPD was initially misdiagnosed on the initial punch biopsy as melanoma-in-situ and Bowen disease respectively. Reasons for the misdiagnoses included a rare pigmented axillary variant of EMPD in the first case and atypical bowenoid features on H&E in the second. The cases are described with a critical review of the histopathological findings, along with a review of the current literature. This highlights the necessity of a comprehensive immunohistochemical panel for the assessment of intra-epithelial pagetoid atypical cells.

N-WASP Attenuates Cell Proliferation and Migration through ERK2-Dependent Enhanced Expression of TXNIP.

Neural Wiskott-Aldrich Syndrome Protein (N-WASP) regulates actin cytoskeleton remodeling. It has been known that reduced N-WASP expression in breast and colorectal cancers is associated with poor prognosis. Here, we found reduced N-WASP expression in squamous cell carcinoma (SCC) patient samples. The SCC cell line HSC-5 with reduced N-WASP expression was used to generate HSC-5CN (control) and HSC-5NW (N-WASP overexpression) cells. HSC-5NW cells had reduced cell proliferation and migration compared to HSC-5CN cells. HSC-5NW cells had increased phospho-ERK2 (extracellular signal-regulated kinase 2), phosphorylated Forkhead box protein class O1 (FOXO1) and reduced nuclear FOXO1 staining compared to HSC-5CN cells. Proteasome inhibition stabilized total FOXO1, however, not nuclear staining, suggesting that FOXO1 could be degraded in the cytoplasm. Inhibition of ERK2 enhanced nuclear FOXO1 levels and restored cell proliferation and migration of HSC-5NW to those of HSC-5CN cells, suggesting that ERK2 regulates FOXO1 activity. The expression of thioredoxin-interacting protein (TXNIP), a FOXO1 target that inhibits thioredoxin and glucose uptake, was higher in HSC-5NW cells than in HSC-5CN cells. Knockdown of TXNIP in HSC-5NW cells restored cell proliferation and migration to those of HSC-5CN cells. Thus, we propose that N-WASP regulates cell proliferation and migration via an N-WASP-ERK2-FOXO1-TXNIP pathway.

Extensive hyperpigmented plaques in a chinese singaporean woman: a case of cutaneous plasmacytosis.

Cutaneous plasmacytosis is a rare disease entity presenting with multiple extensive red-brown plaques, histopathology showing marked hyperplasia of mature polyclonal plasma cells, and polyclonal hypergammaglobulinemia on serum protein electrophoresis, in the absence of an underlying secondary cause. We report in this article the first case of cutaneous plasmacytosis from Singapore. A 33-year-old Chinese woman presented with mildly pruritic reddish brown papules and plaques over her trunk and arms for 2 years. Physical examination, laboratory investigations, and radiographic examination were negative for systemic involvement and lymphadenopathy. Serum immunoelectrophoresis showed polyclonal hypergammaglobulinemia with immunoglobulin G and immunoglobulin A. Two sets of skin biopsies performed 2 years apart essentially showed similar histopathological findings of a superficial and deep perivascular infiltrate with numerous mature plasma cells and small typical lymphocytes. There were lymphoid follicles with well-formed germinal centers and mantle zones, surrounded by mature lymphocytes. No light chain restriction was present on immunohistochemistry, and polymerase chain reaction for heavy chain gene rearrangement was negative for monoclonality. Despite potent topical corticosteroids and 8 months of phototherapy with narrow band ultraviolet light, there was no improvement. Intralesional triamcinolone injections to a few lesions afforded temporary relief of itch and flattening of lesions.

Melanoma in Singapore: A 20-year review of disease and treatment outcomes.

INTRODUCTION: Melanomas in Asians have different clinicopathological characteristics and prognosis from melanomas in Caucasians. This study reviewed the epidemiology and treatment outcomes of cutaneous melanoma diagnosed at a tertiary referral dermatology centre in Singapore, which has a multiracial population. The study also determined whether Asians had comparable relapse-free and overall survival periods to Caucasians in Singapore. METHOD: This is a retrospective review of cutaneous melanoma cases in our centre between 1996 and 2015. RESULTS: Sixty-two cases of melanoma were diagnosed in 61 patients: 72.6% occurred in Chinese, 19.4% in Caucasians and 3.2% in Indians, with an over-representation of Caucasians. Superficial spreading melanoma, acral lentiginous melanoma and nodular melanoma comprised 37.1%, 35.5% and 22.6% of the cases, respectively. The median time interval to diagnosis was longer in Asians than Caucasians; median Breslow's thickness in Asians were significantly thicker than in Caucasians (2.6mm versus 0.9mm, P=0.018) and Asians tend to present at a later stage. The mortality rates for Asians and Caucasians were 52% and 0%, respectively. CONCLUSION: More physician and patient education on skin cancer awareness is needed in our Asian-predominant population for better outcomes.

Aggressive subcutaneous panniculitis-like T-cell lymphoma with hemophagocytosis in two children (subcutaneous panniculitis-like T-cell lymphoma).

Subcutaneous panniculitis-like T-cell lymphoma is an uncommon form of cutaneous lymphoma in the pediatric population. It is characterized histologically by subcutaneous infiltration of pleomorphic cytotoxic T cells, mimicking a lobular panniculitis. Although usually described as having an indolent clinical course, the condition may be complicated by systemic involvement and hemophagocytic syndrome, resulting in a poorer prognosis. We present two pediatric patients with aggressive forms of subcutaneous panniculitis-like T-cell lymphoma complicated by hemophagocytic syndrome, and discuss the current literature.

Overexpression of CDC42SE1 in A431 Cells Reduced Cell Proliferation by Inhibiting the Akt Pathway.

Cell division cycle 42 (CDC42), a small Rho GTPase, plays a critical role in many cellular processes, including cell proliferation and survival. CDC42 interacts with the CRIB (Cdc42- and Rac-interactive binding) domain of CDC42SE1, a small effector protein of 9 kDa. We found that the expression of CDC42SE1 was reduced in human skin cancer samples relative to matched perilesional control. Exogenous expression of CDC42SE1 but not CDC42SE1H38A (mutation within CRIB domain) in A431 cells (A431SE1, A431SE1-H38A) reduced cell proliferation. Antibody microarray analysis of A431Ctrl and A431SE1 lysate suggested that reduced A431SE1 cells proliferation was due to inhibition of Akt pathway, which was confirmed by the reduced P-Akt and P-mTOR levels in A431SE1 cells compared to A431Ctrl cells. This suggests that CDC42SE1 modulates the CDC42-mediated Akt pathway by competing with other effector proteins to bind CDC42. A431SE1 cells formed smaller colonies in soft agar compared to A431Ctrl and A431SE1-H38A cells. These findings correlate with nude mice xenograft assays, where A431SE1 cells formed tumors with significantly-reduced volume compared to the tumors formed by A431Ctrl cells. Our results suggest that CDC42SE1 is downregulated in skin cancer to promote tumorigenesis, and thus CDC42SE1 might be an important marker of skin cancer progression.

Late-onset Epstein-Barr virus-negative post-transplant lymphoproliferative disorder presenting as ulcerated necrotic papules and nodules in a renal transplant patient.

We report a case of B-cell post-transplant lymphoproliferative disorder in a 57-year-old female 19 years postrenal transplant patient who presented with multiple, progressive, painful ulcerated necrotic papules and nodules over the left leg. Histopathological examination showed diffuse infiltration of the dermis by large atypical B-lymphoid cells, with a negative in situ hybridization test for Epstein-Barr virus. Gastrointestinal involvement was evident by the presence of atypical lymphoid cells in the peritoneal fluid. She only had partial response to localized radiotherapy and intravenous rituximab and died 4 months later of septicaemia. Unusual features highlighted in this case include the very late onset of disease 19 years post-transplant, Epstein-Barr virus negativity and the aggressive course of disease that did not respond to the reduction of immunosuppression, localized electron beam therapy and intravenous rituximab.

Melanization in basal cell carcinomas: microscopic characterization of clinically pigmented and non-pigmented tumours.

Clinical and microscopic pigmentation may affect the treatment outcomes in basal cell carcinoma. However, there have not been any in-depth histopathological comparisons between clinically pigmented and non-pigmented basal cell carcinomas with regards to microscopic melanization. The aims of our study were to determine the proportion of pigmented basal cell carcinomas presenting to the National Skin Centre in Singapore, to characterize the histological pattern of melanization and to perform a semi-quantitative analysis of the degree of microscopic melanization of the tumours. Patients with clinical features and histologically confirmed basal cell carcinomas were recruited. Demographic data and clinical characteristics were recorded and basal cell carcinoma sections were examined for histological subtype and pattern of melanization. Twenty-five Chinese patients with 30 basal cell carcinomas were recruited. Three of the five clinically non-pigmented and all of the clinically pigmented basal cell carcinomas had microscopic evidence of melanization. Microscopic melanization in clinically non-pigmented basal cell carcinomas was present only focally or in the centre of the tumour mass. Both groups of basal cell carcinomas may be colonized by melanocytes. Two morphological types of melanocytes, a dendritic and round cell type, were identified. Future research is required to evaluate if the degree of microscopic melanization influences the treatment outcome of basal cell carcinomas.

A comparative study of polymerase chain reaction detection of clonal T-cell receptor gamma chain gene rearrangements using polyacrylamide gel electrophoresis versus fluorescence capillary electrophoresis.

INTRODUCTION: Polymerase chain reaction (PCR)-based molecular techniques are useful adjunctive tools in the diagnosis of cutaneous T-cell lymphomas (CTCL). This study compares the sensitivity of PCR analysis of the T-cell receptor-gamma (TCR-gamma) gene rearrangements using conventional polyacrylamide gel electrophoresis (PCR-PAGE) and fluorescent capillary electrophoresis (PCR-FCE). MATERIALS AND METHODS: A total of 22 paraffin blocks were analysed using PCR-PAGE and PCR-FCE. There were 17 cases of mycosis fungoides (MF), 4 cases of non-MF CTCL and 1 case of lymphoblastic leukaemia. RESULTS: Complete agreement was obtained between PCR-PAGE and PCR-FCE in 19 of the 22 cases, giving a concordance rate of 86.4%. PCR-FCE had a higher sensitivity of 77.3%, compared to 63.6% for PCR-PAGE, allowing the detection of 3 additional cases of clonal T-cell rearrangements, which had equivocal or polyclonal bands on PAGE. Two of these 3 cases were in erythrodermic MF patients. PCR-FCE also allowed the detection of matching clones in serial specimens taken from different sites and at different time intervals in patients with MF. However, matching clones from different specimens can be achieved qualitatively in PCR-PAGE by running and comparing these on the same polyacrylamide gel block. CONCLUSIONS: Both PCR-PAGE and PCR-FCE are useful in detecting T-cell clones in CTCL, with both methods being comparable in sensitivity and showing a high concordance rate of 86.4%. PCR-FCE has the added advantage of exhibiting semiquantitative properties, which may be important in early or erythrodermic MF cases, but the requirement for sophisticated and costly machinery limits its availability to high-capacity laboratories. The well-established PCR-PAGE method is a suitable alternative in routine clinical applications.

Hydroa vacciniforme-like lymphoproliferative disorder in an elderly Chinese patient and a literature review of adult cases.

Hydroa vaccinforme-like lymphoproliferative disorder (HVLPD) is a rare T-cell lymphoproliferative disorder driven by the Epstein-Barr Virus (EBV). It was initially designated under the 2008 WHO classification of tumors of hematopoietic and lymphoid tissues as a distinct entity but has been recently reclassified as a lymphoproliferative disorder under the 2016 revision of the 2008 WHO classification of lymphoid malignancies. HVLPD mainly affects Asian, Central, and South American children. It is rarely seen in adults. Although HVLPD may initially be limited to cutaneous involvement and run an indolent course, some patients may develop a rapidly aggressive course. We report a case of an elderly Chinese man with cutaneous-limited disease and a favorable course. A review of adult cases of HVLPD published in the English literature, with comparison to our case, is also presented in this paper.