Three-dimensional histological explanation of the dermoscopy patterns in acral melanocytic lesions.

Dermoscopic images of pigmented lesions have distinct features on the sole where skin ridges and furrows exist. Pigmentation of benign nevus usually locates on the skin furrow, while the malignant melanoma is pigmented on the skin ridge. Correspondence between dermoscopy and pathology in the pigmented lesions on soles have been studied based on conventional vertical pathological images. However, for the full understanding of the correspondence, observation of horizontal histological images would be required, because the epidermis constructs unique horizontal structures, namely crista profunda limitans, crista profunda intermedia, and transverse ridge. In this study, we analyzed basic dermoscopic images of the representative acral melanocytic lesions (nevus, lentigo, and malignant melanoma) by horizonal histological images. We created serial horizontal pathological images by digital reconstruction of a hundred of serial vertical images. We could show that parallel furrow pattern is created by the pigmentation of crista profunda limitans, parallel ridge pattern by the pigmentation of both of crista profunda limitans and crista profunda intermediate, and lattice-like pattern by the pigmentation of transverse ridge. Our results would be useful for the intuitive histological understanding of dermoscopy.

Multimodal therapy with surgery and adjuvant nivolumab for late-onset multiple liver metastases of choroidal malignant melanoma: a case report.

BACKGROUND: Choroidal malignant melanoma is the most common primary malignant tumor of the eye in adults. Prognosis after recurrence of this disease has been dismal because of the absence of an effective therapy. However, resection of recurrent foci and a subsequent treatment with immune-checkpoint inhibitor may improve the prognosis after recurrence of this disease. This study presents a case of late-onset liver metastases of choroidal malignant melanoma, successfully treated with hepatectomy and postoperative adjuvant nivolumab. CASE PRESENTATION: A 53-year-old woman had undergone left ocular enucleation because of choroidal malignant melanoma 13 years prior to admission. She visited a nearby clinic with complaints of epigastric pain. She was referred to our hospital because a giant liver tumor was observed on abdominal ultrasonography. Enhanced computed tomography revealed multiple liver tumors in the right lobe, 49 mm in diameter with ring enhancement in subsegment (S) 5/6, and 14 and 8 mm without any enhancement in S7 and S5, respectively. On magnetic resonance imaging, the main tumor showed high intensity on T1-weighted with fat suppression, suggesting melanin deposition. Based on the diagnosis of multiple liver metastases of choroidal malignant melanoma, right hepatectomy and regional lymphadenectomy were performed. She was discharged without postoperative complications. Histological examination revealed that all tumors were metastatic malignant melanoma. She was treated with nivolumab postoperatively, and no recurrences were observed during 22 months of follow-up. CONCLUSIONS: Aggressive surgery plus adjuvant nivolumab appears to be a promising treatment for choroidal malignant melanoma with late-onset liver metastases.

An intuitive explanation of dermoscopic structures by digitally reconstructed pathological horizontal top-down view images.

Dermoscopy is a convenient tool to diagnose melanocytic lesions, especially nevus and melanoma. Various pigmented structures, including pigment network, dots and globules, and streaks, are observed in dermoscopy. Usually, 2D vertical images are used to explain the correlation of dermoscopy and histopathology. However, because the image of dermoscopy is horizontal, it is difficult for the horizontal view of dermoscopy to refer to the vertical view of histopathology. In our study, we digitally reconstructed 2D horizontal top-down view images and 3D aerial images from 50-100 serial 2D vertical sections by using high-speed scanner and 3D software in 6 cases of melanocytic lesion. Our new technology intuitively explained the histopathological structures corresponding to the dermoscopic structures. This technique could be used as a good educational tool for beginners.

M2 macrophages promote wound-induced hair neogenesis.

BACKGROUND: De novo hair regeneration occurs in scars of normal adult mice. This interesting phenomenon is termed as wound-induced hair neogenesis (WIHN). We hypothesized that M2 macrophages are crucially involved in WIHN. OBJECTIVE: To clarify the contribution of M2 macrophages to WIHN. METHOD: We established a mouse model of WIHN. A full thickness skin excision was implemented on the back of C57BL/6 (B6) mice. Newly developing hair follicles were detected by a whole-mount assay. WIHN took place 2 weeks after wounding. RESULTS: At first, flow cytometry revealed increased infiltration of CD11b+/CD206+ M2 macrophages at the 2nd and 3rd week after wounding. Immunohistochemistry also showed the existence of CD206+ M2 macrophages in the vicinity of regenerated hair follicles. Secondly, the productions of growth factors were confirmed by culturing M2 macrophages isolated from the skin in a comparison with CD11b+ spleen cells. Array for 84 genes revealed increased expressions of various growth factors including Igf1 and Fgf2. Thirdly, we verified the effect of the growth factors on WIHN. WIHN was increased by 2 folds in mice treated with Fgf2 (p=0.05) or by 1.5 folds with Igf1 (p=0.05). Finally, we used B6.Tg(ITGAM-DTR) mice in which macrophages are ablated by diphtheria toxin. We depleted macrophages at one to 2 weeks after wounding when M2 macrophages were dominant. WIHN was attenuated to one third (P=0.05) by the ablation of macrophages. CONCLUSION: Our study suggests that M2 macrophages could promote WIHN through producing a panel of growth factors.

Lymphatic transit rate as a predictive parameter for nodal metastasis in primary limb malignant melanoma.

BACKGROUND: The status of sentinel lymph node (SLN) is one of the most predictive prognostic factors in patients with clinically localized malignant melanomas (MMs). However, since the positive SLN metastatic rate is as low as 20%, it is desirable to minimize SLN biopsy performance with imaging. By dynamic lymphoscintigraphy, we have proposed the lymphatic transit rate (LTR), the value that the distance between the primary lesion and SLN is divided by scintigraphic saturation time. LTR represents the scintigraphic saturation velocity and can be used for evaluation of metastasis of skin cancers. METHODS: Dynamic lymphoscintigraphy data from 36 lymph nodes in 36 patients with primary MM on the limb were analyzed. The initial sites of the MMs were the lower limb in 24 patients and the upper limb in 12 patients. Histopathologically, nodal metastasis was found in 10 patients. RESULTS: In the lower limb MM, the mean LTRs were 3.49 cm/min in histologically non-metastatic SLNs and 4.49 cm/min in histologically metastatic SLNs (P = 0.0056). In the upper limb MM, the mean LTRs were 2.59 cm/min in non-metastatic SLNs and 3.94 cm/min in metastatic SLNs (P = 0.0162). Thus, significantly higher LTRs were obtained in the metastatic SLNs. All SLNs with LTR < 4.0 cm/min in the lower limb MM and those with LTR < 3.0 cm/min in the upper limb MM were non-metastatic. CONCLUSION: LTR is a useful predictive indicator for nodal metastasis and SLN biopsy performance in MMs.

Human T-lymphotropic virus 1 (HTLV-1)-associated lichenoid dermatitis induced by CD8+ T cells in HTLV-1 carrier, HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T-cell leukemia/lymphoma.

Human T-lymphotropic virus type 1 (HTLV-1) induces adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and carrier. ATLL is a mature CD4+ CD25+ CCR4+ T-cell neoplasm, and approximately half of patients have direct skin involvement manifesting patch, plaque, tumor, multiple papules, erythroderma and purpura. However, there exist secondary eruptions without tumor cell infiltration in patients with ATLL or HAM/TSP and carriers of HTLV-1. To clarify the presence of reactive skin eruptions in HTLV-1-infected individuals, we reviewed our patients with HTLV-1-associated diseases. In 2002-2012, we saw 50 ATLL or HAM/TSP patients and HTLV-1 carriers presenting with skin lesions. We retrospectively selected cases that histologically showed lichenoid tissue reactions with predominant infiltration of CD8+ T cells, but not CD4+ tumor cells. The cases included erythroderma (HTLV-1 carrier), lichen planus (HTLV-1 carrier), alopecia areata (HAM/TSP), chronic actinic dermatitis (HTLV-1 carrier to acute ATLL conversion) and discoid lupus erythematosus (smoldering ATLL). They were graft-versus-host disease-like, major secondary lesions and seen in HTLV-1 carriers and patients with HAM/TSP and smoldering ATLL. We coin the term HTLV-1-associated lichenoid dermatitis (HALD) to encompass the conditions. HALD may occur in association with the elevated immunity toward HTLV-1-infected CD4+ T cells, thus sharing the pathogenetic role of cytotoxic T cells with HAM/TSP.

Structural and immunological effects of skin cryoablation in a mouse model.

Cryoablation is therapeutically applied for various disorders in several organs, and skin diseases are typical targets as this cryotherapy has been widely used for viral warts, benign tumors, and actinic keratosis. The main mechanisms of cryoablation consist of direct freezing effect on skin constituents, thrombosis formation in microcirculation, and subsequent immunological responses. Among them, however, the immunological mechanism remains unelucidated, and it is an issue how the direct freezing injury induces immunological consequences. We established a mouse cryoablation model with liquid nitrogen applied to the shaved back skin, and used this system to study the immunological excitement. After application of liquid nitrogen, the thermal decrease ratio was -25°C/sec or less and the lowest temperature was less than -100°C, which was sufficient to induce ulceration. Destruction of cornified layer and necrosis of epidermal cells were observed in transmission electron microscopy image, and increased transepidermal water loss and skin permeability were detected by the functional measurements. By flow cytometry, antigen-presenting dendritic cells (DCs), including PDCA1+B220+CD19- plasmacytoid DCs (pDCs) and CD11c+ myeloid DCs, as well as neutrophils and macrophages were increased in subcutaneous tissue. In parallel, the mRNA expressions of interferon α1 which are known as pDC-producing cytokines, was elevated. We also found marked degranulation of mast cells, providing a possibility that released histamine attracts pDCs. Finally, FITC migration assay revealed that pDCs and CD11c+ DCs emigrated from the cryoablated skin to the draining lymph nodes. Our study suggests that cryoablation induces destruction of the barrier/epidermis, accumulation of pDCs and CD11c+ DCs to the skin, and migration of DCs to regional lymph nodes. Viral elements or tumor cell lysates released from damaged keratinocytes may stimulate the DCs, thereby leading to antiviral or antitumor effect.

Biochemical, cytological, and immunological mechanisms of rhododendrol-induced leukoderma.

Recently, an unexpected outbreak of patients with leukoderma occurred in Japan with the use of brightening/lightening cosmetics containing rhododendrol (RD). Patients developed leukoderma mostly on the skin sites repeatedly applied with RD, but some patients also had vitiligo-like lesions on the non-applied sites. RD is a tyrosinase-competitive inhibiting substance, thereby serving as an inhibitor of melanin synthesis. Upon inhibition of tyrosinase, RD is converted to new products such as tyrosinase-catalyzed hydroxyl-metabolite, which damage melanocytes. The melanocyte cell lysates seem to induce T-cell response. The frequencies of CD8+ T cells in both lesional skin and peripheral blood are significantly higher in the RD leukoderma as well as non-segmental vitiligo patients than in normal controls. In HLA-A*02:01 positive cases, circulating Melan-A-specific cytotoxic T cells can be detected at a high frequency. It is thus suggested that RD-induced leukoderma is induced by not only cytolysis of melanocytes but also subsequent immune reactions toward melanocytes.

Leukoderma in patients with atopic dermatitis.

Atopic dermatitis (AD) is occasionally associated with vitiligo, however, the incidence and conditions of vitiligo or leukoderma, and the characteristics of concurrent AD, remain unclear. We conducted a prospective observational study to investigate the leukoderma-related clinical manifestations and bioparameters of AD. Because vitiligo in AD lesions is occasionally associated with inflammation, we used leukoderma in this study. Enrolled were all AD patients who had been followed up in our AD outpatient clinic and visited within the previous 4 months. During this period, we carefully inspected whether the patients had leukoderma. Eight of 52 patients had leukoderma (15.4%) and were designated as the leukoderma group, and the remaining 44 patients comprised the non-leukoderma group. While the ages were statistically not different between the two groups, female preponderance was significantly observed in the leukoderma group. The leukoderma patients tended to have higher values of SCORAD, CCL17/thymus and activation regulated chemokine and lactate dehydrogenase than the non-leukoderma patients. The leukoderma group was also characterized by a lower frequency of allergic rhinitis and a higher frequency of prurigo lesions. Thus, despite the possession of high AD severity, the leukoderma patients may possibly retain a relatively T-helper 1-skewing state in relation to the development of leukoderma and less association with rhinitis.