Hidradenocarcinoma showing prominent mucinous and squamous differentiation and associated pagetoid cells.

Herein, we report a 63-year-old man presenting with hidradenocarcinoma showing prominent mucinous and squamous differentiation on his back. The tumor was dermal-based, solid and cystic. Tumor cells with squamous differentiation and with keratin pearl formation were identified predominantly in the superficial dermis, and mucinous cells were identified principally in the cystic lesion in the deep dermis. Interestingly, the additional feature of pagetoid cells was identified in the overlying epidermis. Both the mucinous cells in hidradenocarcinoma and pagetoid cells had intracytoplasmic mucin; however, they had different histopathologic findings and immunophenotypes. Mucinous cells in hidradenocarcinoma had small nuclei and abundant intracytoplasmic mucin presenting goblet cells with low rate of positive immunostaining for p53 and Ki67. In contrast, pagetoid cells had larger nuclei with less intracytoplasmic mucin. Both p53- and Ki67-positive cells were increased in pagetoid cells. Additionally, mucinous cells in hidradenocarcinoma were MUC1(+)/MUC2(-)/MUC5AC(+)/MUC6(+), but pagetoid cells were MUC1(+; focal)/MUC2(-)/MUC5AC(-)/MUC6(+; focal). The derivation of pagetoid cells is unclear; however, the localized small region of pagetoid cells over the hidradenocarcinoma in the present case may suggest a common histogenesis of these two malignant neoplasms.

Up-regulated type I collagen expression by the inhibition of Rac1 signaling pathway in human dermal fibroblasts.

Tissue remodeling is known to play important roles in wound healing. Although Rac1 is reported to be one of the key signaling molecules in cutaneous wound healing process, the exact mechanisms of Rac1-mediated tissue remodeling is still unknown. This study investigated the role of Rac1 in the regulation of extracellular matrix in cultured human dermal fibroblasts obtained by skin biopsy from three healthy donors. Protein levels of type I collagen in cultured human fibroblasts were increased by the treatment with Rac1 inhibitor NSC23766 in a dose-dependent manner. However, the mRNA levels of alpha2(I) collagen was not altered by the inhibitor. On the other hand, by the addition of inhibitor, half-lives of type I collagen protein were increased and MMP1 levels were reduced. These data suggest that blockade of Rac1 signaling results in accumulation of type I collagen due to decreased collagenase activity. This study also suggests that controlling Rac1 signaling is a new therapeutic approach to chronic/untreatable ulcer.

The prevalence of melanocytic nevi on the soles in the Japanese population.

BACKGROUND: Acral lentiginous melanoma (ALM) is the most common type of melanoma in Japan. The association between ALM and acral nevus has not been elucidated. OBJECTIVE: To investigate the prevalence and dermatoscopic patterns of plantar melanocytic nevi on the soles in the Japanese and to evaluate the relationship between acral nevi and ALM. METHODS: All outpatients (N = 1697) and melanoma patients (N = 104) were included. We examined the number, size, and dermatoscopic images of nevi. RESULTS: In the control group, the prevalence of plantar nevi was 10.9%, and the mean size was 3.8 +/- 2.4 mm. The prevalence of nevi in patients with ALM and melanoma in situ on the soles was 8.6% and that of patients with melanoma on other sites was 14.5%. The main dermatoscopic pattern was "parallel furrow" in both groups. LIMITATIONS: This was a clinical observational study only. CONCLUSION: The number, size, and dermatoscopic patterns of nevi on the soles of patients with ALM and melanoma in situ on the soles did not differ from those of the control group.

Submental perforator flap: location and number of submental perforating vessels.

The sites and numbers of submental perforator vessels were examined using a Doppler probe in 21 volunteers. The subcutaneous vascular network from each perforator was studied in three cases of dissection of upper-neck lymph nodes among the volunteers. A perforator from the submental vessels was noted in all 21 volunteers: a single perforator in 13 cases, and double perforators in eight. The main perforator, which had some subdermal branches, was located 31.8 (8.3) mm in front of the facial artery that was palpated at the mandible. Five patients who presented with skin defects on the cheek and the chin had the submental perforator flap reconstructed, excluding the platysma muscle. All flaps covered the wounds. The submental perforator flap was useful for reconstructing skin defects on the cheek and the chin, because the site of the submental perforator was stable and raising the flap was easy, and the colour and texture matches were acceptable.

Intramuscular venous malformation in the upper arm with gross calcifications and compression of the ulnar nerve.

We report an unusual case of intramuscular venous malformation with calcifications that presented with features of involvement of the ulnar nerve.

Carbonic anhydrase-related protein VIII increases invasiveness of non-small cell lung adenocarcinoma.

Carbonic anhydrase-related protein VIII (CA-RP VIII) is believed to be an oncofetal antigen and is overexpressed in colorectal and non-small cell lung cancer. However, the pathobiological properties of CA-RP VIII in lung cancer remain unclear. In the present study, we examined ultrastructural changes caused by exogenous CA-RP VIII expression in a well-differentiated lung adenocarcinoma cell line, PC-9. Many vacuoles lined by cilia, sometimes large vacuoles pushing the nuclei to one side, were found in the cytoplasm of CA-RP VIII-expressing PC-9 cells, but not in control PC-9 cells. Moreover, signet-ring cells containing abundant intracytoplasmic mucin were often found among CA-RP VIII-expressing PC-9 cells, but rarely among control PC-9 cells. We subsequently examined CA-RP VIII expression in atypical adenomatous hyperplasia and early-stage lung adenocarcinoma (Stage Ia). Significant expression of CA-RP VIII was observed in invasive lung adenocarcinoma but not in noninvasive adenocarcinoma. Interestingly, CA-RP VIII was strongly expressed in signet-ring cell cancer and invasive mucinous adenocarcinoma components. CA-RP VIII also appeared to enhance the invasiveness of PC-9 cells in Matrigel invasion assay. The present findings suggest that CA-RP VIII expression in lung adenocarcinoma is related to cancer cell invasion.

Giant malignant peripheral nerve sheath tumor of the scalp.

Herein, we describe a rare case of giant malignant peripheral nerve sheath tumor of the head in a 38-year-old Japanese man. The tumor measured 210 mm at its largest diameter and was ulcerated, hemorrhagic, multilocular and non-mobile. It should be noted that the patient stubbornly refused to see a doctor for a long time, resulting in the extreme growth of the tumor. We suspect a psychological basis for this behavior. Dermatohistopathological findings of the biopsy indicated ancient schwannoma and total excision was therefore performed. However, after 4 months, the patient developed multiple metastases and died. Post-mortem skin biopsy revealed features of malignant peripheral nerve sheath tumor. We performed immunohistochemical studies on the primary and recurrent lesions and concluded that there was a difference in the expression of Ki67 and p16. We propose that the expressions of Ki67 and p16 should be checked for all lesions of peripheral nerve sheath tumor for distinguishing benign from malignant forms.

Dermoid cyst at the suprasternal notch: an adult case.

We present a case of a 39-year-old Japanese man with a two-year history of a mass in his suprasternal notch. Histopathologically the diagnosis was confirmed as a dermoid cyst; the cyst wall was almost normal with an epidermal structure consisting of sebaceous and apocrine glands and on the inside there were keratin materials and hair shafts. A dermoid cyst at the suprasternal notch is rare, and in an adult is the first as far as we know.

Multicystic malignant mesothelioma of the tunica vaginalis with an unusually indolent clinical course.

We report an extremely rare case of a multicystic malignant mesothelioma in the tunica vaginalis with an unusually indolent clinical course. A 48-year-old man presented with a one-month history of painless swelling of right scrotal contents. Ultrasonography and computed tomography (CT) revealed a multicystic mass in the right scrotal sac with evidence of neither distant nor lymph node metastases. The testicular tumor markers were within the normal limits. Inguinal orchiectomy was performed under the suspicion of a malignant tumor. The cystic tumor consisted of fibrocellular, microcystic and adenomatoid elements microscopically was diagnosed biphasic malignant mesothelioma of tunica vaginalis but no invasion into the testis, epididymis and also scrotum. The patient has been disease-free for 72 months and is being followed on an outpatient basis with no further adjuvant therapy.

Evaluation of sentinel node biopsy for cutaneous squamous cell carcinoma.

Sentinel lymph node biopsy (SLNB) is a standard care for cutaneous melanoma but its role in cutaneous squamous cell carcinoma (SCC) has not been established. Clinical data was obtained from 54 patients with SCC who received SLNB with the usage of blue dye and radioisotope colloid methods. The positive rate of SLNB in SCC was 7.4%. If the cases were limited to more than T2, the positive rate was 12.9%. Three of 41 patients who was estimated negative LN metastasis by the preoperative tests had micrometastasis (7.3%). Among 13 patients who were suggested to have metastasis in the preoperative tests, only one patient had histological metastasis. One patient with SCC located in the lower lip showed negative SLNB and subsequently developed node recurrence. In conclusion, the efficacy of SLNB in SCC is comparable to that of melanoma in the positive rate. There are two kinds of benefit, avoidance of unnecessary complete lymph node dissection and early detection of metastasis.

Down-regulation of miR-124/-214 in cutaneous squamous cell carcinoma mediates abnormal cell proliferation via the induction of ERK.

Squamous cell carcinoma (SCC) is one of the most common skin cancers. Because its potential to recur and metastasize leads to a poor prognosis and significant mortality, it is necessary to develop new early diagnostic tools and new therapeutic approaches. In this study, we found protein levels of ERK1 and ERK2 were increased in SCC cell lines without changing mRNA levels and that ERK1/2 mediates abnormal cell proliferation in these cells. Then, mechanisms underlying the overexpression of ERK1/2 in SCC were investigated focusing on microRNA. We found that miR-214 is the regulator of ERK1, whereas ERK2 is regulated by miR-124 and miR-214. Expression of miR-124 and miR-214 was significantly down-regulated in SCC in vitro and in vivo. Treatment with 5-aza-deoxycytidine and trichostatin A synergistically recovered the miR-124/-214 down-regulation in SCC cell line. However, bisulphite sequencing revealed the methylation status of miR-124/-214 promoter was not increased in the SCC cell line and tumor tissue. Taken together, the down-regulation of miR-124/-214 in SCC is most likely caused, at least in part, by hypermethylation of other promoter regions rather than the miR-124/-214 promoter. Supplementation of these microRNAs in the SCC cell line reduced the abnormal cell proliferation by normalizing ERK1/2 levels. Additionally, serum concentration of miR-124 was correlated with miR-124 expression levels in the tumor tissues and inversely correlated with tumor progression. On the other hand, miR-214 was not detected in the serum. Investigation of the regulatory mechanisms of keratinocyte proliferation by microRNA may lead to develop new biomarkers and treatments using microRNA.

Evaluation of usefulness of 3D views for clinical photography.

This is the first report investigating the usefulness of a 3D viewing technique (parallel viewing and cross-eyed viewing) for presenting clinical photography. Using the technique, we can grasp 3D structure of various lesions (e.g. tumors, wounds) or surgical procedures (e.g. lymph node dissection, flap) much more easily even without any cost and optical aids compared to 2D photos. Most recently 3D cameras started to be commercially available, but they may not be useful for presentation in scientific papers or poster sessions. To create a stereogram, two different pictures were taken from the right and left eye views using a digital camera. Then, the two pictures were placed next to one another. Using 9 stereograms, we performed a questionnaire-based survey. Our survey revealed 57.7% of the doctors/students had acquired the 3D viewing technique and an additional 15.4% could learn parallel viewing with 10 minutes training. Among the subjects capable of 3D views, 73.7% used the parallel view technique whereas only 26.3% chose the cross-eyed view. There was no significant difference in the results of the questionnaire about the efficiency and usefulness of 3D views between parallel view users and cross-eyed users. Almost all subjects (94.7%) answered that the technique is useful. Lesions with multiple undulations are a good application. 3D views, especially parallel viewing, are likely to be common and easy enough to consider for practical use in doctors/students. The wide use of the technique may revolutionize presentation of clinical pictures in meetings, educational lectures, or manuscripts.

The circulating microRNA-221 level in patients with malignant melanoma as a new tumor marker.

BACKGROUND: MicroRNA-221 (miR-221) is known to be abnormally expressed in malignant melanoma (MM) cells, and it favors the induction of the malignant phenotype through down-modulation of p27Kip1/CDKN1B and the c-KIT receptor. This suggests that the serum level of miR-221 might increase in patients with MM and thus could be used as a new tumor marker. OBJECTIVE: To evaluate the possibility that the serum miR-221 level can be a marker of MM. METHODS: Serum samples were obtained from 94 MM patients and 20 healthy controls. MicroRNAs were purified from serum, and miR-221 levels were measured by quantitative real-time polymerase chain reaction. RESULTS: Circulating miR-221 was detectable and could be quantified in serum samples. MM patients had significantly higher miR-221 levels than healthy controls. Among the MM patients, the miR-221 levels were significantly increased in patients with stage I-IV MM compared to those with MM in situ, and the levels were correlated with tumor thickness. Moreover, a longitudinal study revealed a tendency for the miR-221 levels to decrease after surgical removal of the primary tumor, and to increase again at recurrence. CONCLUSIONS: Serum levels of miR-221 were significantly increased in MM patients and may be useful not only for the diagnosis of MM, but also for the differentiating MM in situ from stage I-IV MM, and for evaluating tumor progression and monitoring patients during the follow-up period. In addition, considering that the serum levels of miR-221 were correlated with tumor thickness, miR-221 might also be useful as a prognostic marker for patients with MM.

Recent progress in studies of infantile hemangioma.

A hallmark of infantile hemangioma, the most common tumor of infancy, is its dramatic growth after birth, by diffuse proliferation of immature endothelial cells, followed by spontaneous regression. The growth and involution of infantile hemangioma is quite different from other vascular anomalies, which do not regress and can occur at any time during life. Some hemangioma lesions can be extremely disfiguring and destructive to normal tissue and may even be life-threatening. Unfortunately, existing therapeutic approaches have limited success and significant adverse effects of some treatment modalities limit their use. Better understanding of the pathogenesis of hemangioma will enable the development of better therapeutic strategies. Here, we review recent studies and new hypotheses on the pathogenesis of the tumor. Detailed mechanisms of activated vascular endothelial growth factor signaling in tumor cells, identification of their origin and characterization of multipotent stem cells that can give rise to infantile hemangioma are shedding new light on this intriguing vascular tumor.

Recent progress in studies of infantile hemangioma.

A hallmark of infantile hemangioma, the most common tumor of infancy, is its dramatic growth after birth, by diffuse proliferation of immature endothelial cells, followed by spontaneous regression. The growth and involution of infantile hemangioma is quite different from other vascular anomalies, which do not regress and can occur at any time during life. Some hemangioma lesions can be extremely disfiguring and destructive to normal tissue and may even be life-threatening. Unfortunately, existing therapeutic approaches have limited success and significant adverse effects of some treatment modalities limit their use. Better understanding of the pathogenesis of hemangioma will enable the development of better therapeutic strategies. Herein, we review recent studies and new hypotheses on the pathogenesis of the tumor. Detailed mechanisms of activated vascular endothelial growth factor (VEGF) signaling in tumor cells, identification of their origin and characterization of multipotent stem cells that can give rise to infantile hemangioma are shedding new light on this intriguing vascular tumor.

Amelanotic malignant melanoma where primary lesion was discovered 5 years after metastasis in the lymph node.

A 53-year-old Japanese man presented with a subcutaneous nodule in his left inguinal region in 2002. He was diagnosed as having a malignant tumor of the soft tissues at a local hospital; however, an exact diagnosis was not obtained. CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine) therapy was done for adjuvant therapy. In 2004, he noticed a nodule on the left heel. Positron emission computed tomography showed abnormal up-take and he consulted our department. He was diagnosed as having amelanotic malignant melanoma and the lesion was resected. There were no metastases in the groin or popliteal lymph nodes. After the evaluation, the tumor was staged at pT3b N1b M0 stage IIIC (Breslow's tumor thickness was 7 mm). In our hospital, we have experienced 16 cases of amelanotic malignant melanoma. Generally, it is reported that the patients with amelanotic malignant melanoma have a poor prognosis, but we have observed no difference in the outcome between the patients with amelanotic malignant melanoma and those with malignant melanoma.

Down-regulation of mir-424 contributes to the abnormal angiogenesis via MEK1 and cyclin E1 in senile hemangioma: its implications to therapy.

BACKGROUND: Senile hemangioma, so-called cherry angioma, is known as the most common vascular anomalies specifically seen in the aged skin. The pathogenesis of its abnormal angiogenesis is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that senile hemangioma consisted of clusters of proliferated small vascular channels in upper dermis, indicating that this tumor is categorized as a vascular tumor. We then investigated the mechanism of endothelial proliferation in senile hemangioma, focusing on microRNA (miRNA). miRNA PCR array analysis revealed the mir-424 level in senile hemangioma was lower than in other vascular anomalies. Protein expression of MEK1 and cyclin E1, the predicted target genes of mir-424, was increased in senile hemangioma compared to normal skin or other anomalies, but their mRNA levels were not. The inhibition of mir-424 in normal human dermal microvascular ECs (HDMECs) using specific inhibitor in vitro resulted in the increase of protein expression of MEK1 or cyclin E1, while mRNA levels were not affected by the inhibitor. Specific inhibitor of mir-424 also induced the cell proliferation of HDMECs significantly, while the cell number was decreased by the transfection of siRNA for MEK1 or cyclin E1. CONCLUSIONS/SIGNIFICANCE: Taken together, decreased mir-424 expression and increased levels of MEK1 or cyclin E1 in senile hemangioma may cause abnormal cell proliferation in the tumor. Senile hemangioma may be the good model for cutaneous angiogenesis. Investigation of senile hemangioma and the regulatory mechanisms of angiogenesis by miRNA in the aged skin may lead to new treatments using miRNA by the transfection into senile hemangioma.