Pigmented epithelioid melanocytoma arising from a teratoma of a Carney complex patient.

A 25-year-old female Carney complex patient with a PRKAR1A mutation who had undergone surgery to remove teratomas visited our dermatology department. She was suspected of having a malignant melanoma in a teratoma. On clinical examination, a black nodule was found within the cyst. On histopathological examination, the black lesion was composed of heavily pigmented round cells with vesicular nuclei and single prominent nucleoli. Additionally, there were large cells with irregularly shaped nuclei. Upon immunohistochemical examination, the large, irregularly shaped cells were positively stained with Melan A, HMB45, S-100 protein, SOX10, CD10 (focally), and BRAFV600E , but negatively stained with PRAME. Based on the histopathological features, we diagnosed the patient with pigmented epithelioid melanocytoma (PEM) in a teratoma of a Carney complex patient. This is the first case of PEM developing from a teratoma. Since PEM lesions may spread to regional lymph nodes, careful follow-up is necessary.

KS-EMPD-1: a novel cell line of primary extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare skin cancer that mainly occurs in apocrine sweat gland-rich areas in elderly people. The prognosis of metastatic EMPD is unfavorable because of the lack of fully effective systemic therapies. However, the difficulty in establishing a model of EMPD has hampered basic research for exploring its pathogenesis and optimal treatments. Here, we established for the first time an EMPD cell line (named KS-EMPD-1) from a primary tumor on the left inguinal region of an 86-year-old Japanese male. The cells were successfully maintained for more than 1 year, with a doubling time of 31.2 ± 0.471 h. KS-EMPD-1 exhibited constant growth, spheroid formation, and invasiveness, and was confirmed to be identical to the original tumor by short tandem repeat analyses, whole exome sequencing, and immunohistochemistry (CK7+CK20-GCDFP15+). Western blotting of the cells revealed the protein expression of HER2, NECTIN4, and TROP2, which have recently attracted attention as potential therapeutic targets for EMPD. KS-EMPD-1 was highly sensitive to docetaxel and paclitaxel on chemosensitivity test. The KS-EMPD-1 cell line is a promising resource for basic and preclinical research on EMPD to better define the tumor characteristics and treatment strategy of this rare cancer.

Histological and immunohistochemical prognostic factors of primary angiosarcoma.

Angiosarcoma is a malignant vascular endothelial neoplasm with various histological patterns. Despite its highly malignant potential, histological prognostic prediction has not been adopted for angiosarcoma. This study aimed to establish a method of predicting the prognosis of primary angiosarcoma. Formalin-fixed, paraffin-embedded samples from 104 primary angiosarcomas were prepared. All the cases were reviewed based on histological examinations with H&E staining. Because the French Fédération Nationale des Centres de Lutte Contre Le Cancer system (FNCLCC) is not adopted for angiosarcoma, we experimentally established a modified version of FNCLCC. Immunohistochemical staining for ERG, CD31, CD34, D2-40, HHV-8, p16, C-MYC, and p53 was performed. Fluorescence in situ hybridization (FISH) was performed for 31 cases to assay c-MYC gene amplification. Multivariate analysis revealed that age (> 70 years old) (p = 0.0011), non-cutaneous angiosarcoma (p = 0.0265), metastasis on diagnosis (p < 0.0001), size ≥ 5 cm (p = 0.0388), no taxane chemotherapy (p = 0.0388), strong nuclear atypia (p = 0.0087), and the presence of luminal structure in ≥ 50% of the tumor volume (p = 0.0009) were independent poor prognostic factors. Among angiosarcomas with luminal formation, mFNCLCC scores were significantly correlated with a poorer prognosis. The overexpression of p16 was associated with less luminal formation (p = 0.0192). Immunohistochemical analysis of C-MYC showed a moderate level of concordance with FISH (Kappa value = 0.45). This study suggested that luminal formation and nuclear atypia may be poor histological prognostic factors of angiosarcoma and that mFNCLCC would be useful for predicting the prognosis of angiosarcoma with luminal formation.

Diagnostic utility of ERG immunostaining in dermatofibroma.

AIMS: Dermatofibroma/fibrous histiocytoma (DF/FH) is a common cutaneous mesenchymal neoplasm exhibiting benign biological behaviour. However, the immunohistochemical utility of erythroblast transformation-specific-related gene (ERG) for diagnosing DF remains unknown. The authors reviewed the immunohistochemical status of ERG in different subtypes of DF and in its differential diagnoses. METHODS: Overall, 97 cases of ordinary DF/FH, 6 cases of aneurysmal FH, 10 cases of cellular FH, 5 cases of angiomatoid FH, 2 cases of epithelioid FH, 64 cases of dermatofibrosarcoma protuberans (DFSP) and 52 cases of fibrous scar were retrieved. As the other histological types of cutaneous neoplasms, 6 cases of myxofibrosarcoma, 4 cases of undifferentiated pleomorphic sarcoma, 11 cases of atypical fibroxanthoma, 19 cases of malignant melanoma, 20 cases of nevocellular nevus, 20 cases of neurofibroma, 19 cases of schwannoma, 8 cases of angioleiomyoma and 1 case of pilar leiomyoma were included. RESULTS: Immunohistochemical positivity for ERG was demonstrated in 87 of 97 cases (89.6%) of ordinary DF/FH, 7 of 10 cases (70%) of cellular FH, 3 of 6 cases (50%) of aneurysmal FH, 1 of 5 cases (20%) of angiomatoid FH and 1 of 52 cases (0.1%) of fibrous scar. All cases of DFSP, epithelioid FH and other types of cutaneous neoplasms included in the current investigation were negative for ERG. The intensity of ERG immunohistochemical staining in spindle-shaped cells appeared weaker than that in endothelial cells. CONCLUSIONS: DF/FH was frequently positive for ERG immunostaining. ERG immunostaining may thus be useful to distinguish DF/FH from DFSP.

TROP2 Expression in Sebaceous and Sweat Gland Carcinoma.

Sebaceous carcinoma and sweat gland carcinoma (malignant tumors with apocrine and eccrine differentiation) are rare malignant skin adnexal tumors that differentiate toward sebaceous gland and eccrine and apocrine glands, respectively. Owing to the rarity of these carcinomas, standard treatments for advanced disease have not been established. Because the prognosis of patients with systemic metastasis is poor, a new treatment for these diseases is eagerly desired. Trophoblast cell surface antigen 2 (TROP2) and sacituzumab govitecan, an antibody-drug conjugate of TROP2, have attracted attention in the treatment of various solid tumors. In the current study, we immunohistochemically investigated TROP2 expression in 14 sebaceous carcinoma and 18 sweat gland carcinoma samples and found strong and relatively homogeneous TROP2 staining in both cancer types. The mean Histoscore, a semi-quantitative scoring ranging from 0 (negative) to 300, was 265.5 in sebaceous carcinoma and 260.0 in sweat gland carcinoma. These observations directly suggest that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with TROP2-targeted antibody-drug conjugates such as sacituzumab govitecan.

The Clinical and Histopathological Features of Cutaneous Immune-Related Adverse Events and Their Outcomes.

Immune checkpoint inhibitors (ICIs) cause a variety of inflammatory eruptions. The understanding of ICI-induced inflammatory eruptions with detailed histopathological findings is not adequate, particularly in Asian populations. In this study, we retrospectively reviewed 51 patients who were histopathologically diagnosed with cutaneous immune-related adverse events (irAEs) following ICI therapy between 2014 and 2020 at the Department of Dermatology of Kyushu University Hospital. Of the 51 patients (30 men, 21 women), maculopapular rash (38/51, 74.5%), erythema multiforme (2/51, 3.9%), lichenoid reaction (3/51, 5.9%), psoriasiform reaction (3/51, 5.9%), bullous pemphigoid (3/51, 5.9%), scleroderma-like reaction (1/51, 2.0%), and Stevens-Johnson syndrome (1/51, 2.0%) were observed. The clinical and histopathological findings of these eruptions were equivalent to typical cases of common drug eruptions. The onset of maculopapular rash was relatively early (more than half of events occurred within 1 month), whereas lichenoid reactions and autoimmune diseases occurred relatively late (4-8 months). With appropriate treatment and/or interruption of ICIs, most rashes improved (50/51, 98.0%). The ICI-induced inflammatory eruptions shared similar clinical and histopathological features with classical inflammatory eruptions, but a variety of inflammatory eruptions may occur with different degrees of severity. Dermatologists play an important role in providing specialized care for cutaneous irAEs.

Frequent MN1 Gene Mutations in Malignant Peripheral Nerve Sheath Tumor.

BACKGROUND/AIM: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue tumor, and its diagnosis is usually made histopathologically. The effectiveness of chemotherapy and radiotherapy has not been established. We elucidated prognostic factors, diagnostic markers, and therapeutic targets. MATERIALS AND METHODS: Cases of MPNST were studied using next-generation sequencing. A total of 24 tumor samples, 11 from von Recklinghausen's disease-associated MPNST (vRH-MPNST), 11 from sporadic non-vRH MPNST, and two neurofibroma (NF) cases were retrieved, on which next-generation sequencing and survival analysis were performed. RESULTS: We identified NF1 gene mutations, including three mutations in two NFs, and 10 mutations in eight MPNSTs (five vRH-MPNSTs and three sporadic MPNSTs). Meningioma 1 (MN1) gene alteration was detected in six cases of vRH-MPNST. It is considered that MN1 gene alteration is related to the tumorigenesis of vRH-MPNST. CONCLUSION: MN1 gene mutation was detected in more than half of our cases, it may have potential for use as a therapeutic target in vRH-MPNST.

Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis.

The current development of BRAF inhibitors has revolutionized the treatment of unresectable melanoma. As the potential heterogeneity of BRAF mutations in melanoma has been reported, accurate detection of BRAF mutations are important. However, the genetic heterogeneity of acral melanoma-a distinct type of melanoma with a unique genetic background-has not fully been investigated. We conducted a retrospective review of our acral melanoma patients. Of the 196 patients with acral melanoma, we retrieved 31 pairs of primary and matched metastatic melanomas. We immunostained the 31 pairs with VE1, a BRAFV600E-mutation-specific monoclonal antibody. Immunohistochemistry with VE1 showed a high degree of sensitivity and specificity for detecting BRAFV600E mutations compared with the real-time polymerase chain reaction method. A total of nine primary (29.0%) and eight metastatic (25.8%) acral melanomas were positive for VE1. In three patients (9.7%), we observed a discordance of VE1 staining between the primary and metastatic lesions. Of note, VE1 immunohistochemical staining revealed a remarkable degree of intra-tumor genetic heterogeneity in acral melanoma. Our study reveals that VE1 immunostaining is a useful ancillary method for detecting BRAFV600E mutations in acral melanoma and allows for a clear visualization of intra- and inter-tumor BRAF heterogeneity.

Early pathology in venom-induced consumption coagulopathy by Rhabdophis tigrinus (Yamakagashi snake) envenomation.

Objective:Rhabdophis tigrinus (Yamakagashi in Japanese) is a venomous non-front-fanged colubroid snake capable of inflicting envenoming with life-threatening defibrinating coagulopathy. However, because of the uncommon incidence of bites and tendency for late development of symptoms/signs, the early effects of the venom on the coagulation system are poorly known. Case report: We describe a boy bitten by a wild R. tigrinus and report his clinical course starting at 30 min after the bite. Results: At 30 min after envenomation, only the thrombin-antithrombin complex (TAT) level was elevated. At 90 min after envenomation, laboratory data revealed a prolonged activated partial thromboplastin time (APTT) and increased prothrombin time international normalized ratio (PT-INR) with elevated fibrinogen degeneration product (FDP). At 5.5 h after envenomation, APTT and PT-INR increased beyond a measurable range, and fibrinogen levels dropped below the detection limit. We administered recombinant human soluble thrombomodulin and antivenom prepared against R. tigrinus antivenom. Venom-induced consumption coagulopathy (VICC), which is sometimes reported as disseminated intravascular coagulation (DIC), subsequently improved rapidly. Discussion: We found that TAT is the earliest marker to detect R. tigrinus envenomation and subsequent VICC occurrence. Although rTM was effective in this case, further studies are necessary to prove its safety and efficacy.

Measurement of trihydroxy-linoleic acids in stratum corneum by tape-stripping: Possible biomarker of barrier function in atopic dermatitis.

Epidermal ceramides are indispensable lipids that maintain the functions of the stratum corneum. Esterified omega-hydroxyacyl-sphingosine (EOS) ceramide with a linoleate moiety is one of the most important ceramide species for forming cornified lipid envelopes. This linoleate moiety is eventually metabolized to trihydroxy-linoleic acid (triol, 9,10,13-trihydroxy-11E-octadecenoic acid). Thus, we assumed that a decrease of triols might reflect skin barrier dysfunction. Against this background, the purposes of this study were to measure the triols by a simple tape-stripping method and to determine the correlation between the amount of triols and transepidermal water loss (TEWL) as an indicator of barrier dysfunction in atopic dermatitis patients. Twenty Japanese subjects with normal skin and 20 atopic dermatitis patients were enrolled in this study. TEWL was measured and triols of the stratum corneum were analyzed by tape-stripping. The results showed for the first time that triols in the stratum corneum could be simply measured using the tape-stripping method. The triol levels in atopic dermatitis patients were much higher than those in healthy subjects. Moreover, the triol levels correlated with TEWL of non-lesional forearm skin in patients with atopic dermatitis. The results suggest that the assaying of triol levels via non-invasive tape-stripping could be beneficial for monitoring barrier function in atopic dermatitis.

Immunohistological Expression of p16INK4a is Commonly Present Both in Benign and Malignant Sweat Gland Neoplasias.

The expression of p16INK4a has been reported to be a significant marker for malignant transformation of epidermal tumors. However, little is known about sweat gland tumors. We examined the immunohistological expression of p16INK4a in benign and malignant sweat gland tumors. The ductal and acrosyringial portion of normal eccrine glands were positively stained with p16INK4a while it was negative in the normal epidermis. Moderate to strong expression of p16INK4a was found in 16 of 17 eccrine poromas, 4 of 5 hidradenomas, 3 of 3 syringocystadenoma papilliferums, 2 of 2 mixed tumors, and 3 of 3 syringomas. The p16INK4a expression was observed focally or diffusely in 4 of 4 porocarcinomas, 4 of 4 apocrine carcinomas and 12 of 17 extramammary Paget's diseases. We conclude that the p16INK4a expression is not a good marker for dictating malignant transformation of sweat gland tumors.

Anterior chamber configuration in patients with glaucoma: MR gonioscopy evaluation with half-Fourier single-shot RARE sequence and microscopy coil.

The purpose of the study was to determine the accuracy of half-Fourier single-shot rapid acquisition with relaxation enhancement high-spatial-resolution magnetic resonance (MR) imaging performed with a microscopy coil in the diagnosis of narrow anterior chamber angle in patients with glaucoma. Slit-lamp biomicroscopy served as the reference standard. The institutional review board approved this study, and written informed consent was obtained from the 20 recruited patients. There was excellent agreement between MR gonioscopy and slit-lamp biomicroscopy in the classification of anterior chamber angles as narrow or open (kappa = 0.89 [95% confidence interval: 0.69, 1.10]). MR gonioscopy has substantial potential as a technique used to evaluate glaucoma.