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Blue nevi are melanocytic tumors originating in the cutaneous dermis. Malignant tumors may arise in association with or resembling blue nevi, so called ‘blue nevus-like melanoma’, which can metastasize and result in patient death. Identifying which tumors will behave in a clinically aggressive manner can be challenging. Identifying genetic alterations in such tumors may assist in their diagnosis and prognostication. Blue nevi are known to be genetically related to uveal melanomas (eg, both harboring GNAQ and GNA11 mutations). In this study, we analyzed a large cohort (n=301) of various morphologic variants of blue nevi and related tumors including tumors diagnosed as atypical blue nevi (n=21), and blue nevus-like melanoma (n=12), screening for all gene mutations known to occur in uveal melanoma. Similar to published reports, we found the majority of blue nevi harbored activating mutations in GNAQ (53%) or GNA11 (15%). In addition, rare CYSLTR2 (1%) and PLCB4 (1%) mutations were identified. EIF1AX, SF3B1, and BAP1 mutations were also detected, with BAP1 and SF3B1 R625 mutations being present only in clearly malignant tumors (17% (n=2) and 25% (n =3) of blue nevus-like melanoma, respectively). In sequencing data from a larger cohort of cutaneous melanomas, this genetic profile was also identified in tumors not originally diagnosed as blue nevus-like melanoma. Our findings suggest that the genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis of blue nevus-like melanoma and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas. Future studies will need to further elucidate the prognostic implications and appropriate clinical management for patients with tumors harboring these mutation profiles.

Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.

SUMMARY Uveal melanoma (UM) is characterized by mutually exclusive activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4, four genes in a linear pathway to activation of PLCβ in almost all tumors and loss of BAP1 in the aggressive subset. We generated mice with melanocyte-specific expression of GNA11Q209L with and without homozygous Bap1 loss. The GNA11Q209L mice recapitulated human Gq-associated melanomas, and they developed pigmented neoplastic lesions from melanocytes of the skin and non-cutaneous organs, including the eye and leptomeninges, as well as at atypical sites, including the lymph nodes and lungs. The addition of Bap1 loss increased tumor proliferation and cutaneous melanoma size. Integrative transcriptome analysis of human and murine melanomas identified RasGRP3 to be specifically expressed in GNAQ/GNA11-driven melanomas. In human UM cell lines and murine models, RasGRP3 is specifically required for GNAQ/GNA11-driven Ras activation and tumorigenesis. This implicates RasGRP3 as a critical node and a potential target in UM., In Brief Moore et al. generate a preclinical mouse model of melanoma that recapitulates features of aggressive uveal melanoma. By comparing murine and human melanomas, they identify a dependency on RasGRP3 in uveal melanoma.

Objectives It is essential to monitor hearing status in children not only as a mandatory requirement during universal newborn hearing screening (UNHS), but also later during preschool and school-age development. The present study considers the appropriateness of the Frequency-specific Animal Sound Test (FAST4) for use in children between the ages of 2.5 and 10 years; the comparability of hearing thresholds determined using FAST4 and those measured by pure tone audiometry (PTA); and the clinical and diagnostic utility of FAST4 in a variety of pediatric settings. Methods 322 children aged 2.6–14.1 years and 41 adults were tested with FAST4. Four animal sounds were presented via headphones and a hearing threshold was determined for the high and low frequency range. In addition, the hearing threshold of each child was measured by PTA. Results Results were analyzed from 156 normal-hearing and hearing-impaired children, mostly above the age of 4 years. In general, FAST4 yielded hearing levels comparable with those from PTA in children and in adults. FAST4 frequently had to be halted prematurely in children under 4 years old. Conclusions FAST4 is a strong candidate for use as an instrument for preschool hearing screening and offers several advantages over other hearing tests. FAST4 permits simple, swift and efficient determination of the hearing threshold and the test can be administered by staff without specialist training. A number of improvements have already been integrated into the successor model known as mFAST.

Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

Cutaneous melanomas are characterized by a range of histological appearances, and several morphological variants have been described. In this study, we report a variant of superficial spreading melanoma that is characterized by large, irregular junctional melanocytic nests. The junctional nests varied in shape and size, showed focal tendency to confluence, and were often surrounded by a cuff of epidermal keratinocytes. The melanocytes comprising the nests showed variable cytological atypia. In most of the cases, scant intraepidermal or junctional single melanocytes were seen, and other well-documented diagnostic criteria for melanoma were lacking, and as a result, histological recognition of these tumors as melanoma was difficult. Some cases were associated with an invasive dermal component or showed evidence of sun damage. To provide supporting evidence for malignancy, we analyzed these tumors for genomic aberrations. Using array comparative genomic hybridization (aCGH), we identified multiple genomic aberrations in all analyzed cases. A similar pattern of genomic aberrations was seen in a control group of bona fide superficial spreading melanomas, suggesting that these 'melanomas composed exclusively or predominantly of large nests' are indeed variants of superficial spreading melanoma. Fluorescence in-situ hybridization (FISH) was positive in 40% of the cases. However, using aCGH, the FISH-negative cases showed multiple genomic aberrations in regions that are not covered by FISH. The low sensitivity of the FISH test can be explained by the fact that FISH only evaluates four genomic loci for aberrations, whereas aCGH surveys the entire genome. In summary, we present histological and molecular genetic evidence for a morphological variant of superficial spreading melanoma. Awareness of the histological features will aid in their correct diagnosis as melanoma, and in difficult cases, judicious application of ancillary tests such as aCGH (rather than FISH) will assist accurate diagnosis.

Recently, initial studies describing the use of multicolor fluorescence in situ hybridization (FISH) for classifying melanocytic skin lesions have been published demonstrating a high sensitivity and specificity in discriminating melanomas from nevi. However, the majority of these studies included neither histologically ambiguous lesions nor a clinical long-term follow up. This study was undertaken to validate a special multicolor FISH test in histologically ambiguous melanocytic skin lesions with known clinical long-term follow up. FISH was scored by three independent pathologists in a series of 22 melanocytic skin lesions, including 12 ambiguous cases using four probes targeting chromosome 6p25, centromere 6, 6q23, and 11q13. The FISH results were compared with array comparative genomic hybridization data and correlated to the clinical long-term follow up (mean: 65 months). Pair-wise comparison between the interpretations of the observers showed a moderate to substantial agreement (kappa 0.47-0.61). Comparing the FISH results with the clinical behavior reached an overall sensitivity of 60% and a specificity of 50% (chi(2)=0.25; P=0.61) for later development of metastases. Comparison of array comparative genomic hybridization data with FISH analyses did not yield significant results but array comparative genomic hybridization data demonstrated that melanocytic skin lesions with the development of metastases showed significantly more chromosomal aberrations (P

Cutaneous lymphomas represent a heterogeneous group of malignant lymphoid diseases with particular tropism for the skin. Prognosis and treatment depend on the type of lymphoma, thus precise diagnosis and classification are of paramount importance. Classification of cutaneous lymphomas relies on a synthesis of all available information, including clinical history and presentation, histopathology, immunophenotype, and molecular data. Thanks to the efforts of the lymphoma groups of both the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC), a joint WHO-EORTC classification for primary cutaneous lymphomas has been proposed in 2005. The WHO-EORTC classification has been adsorbed with minor changes in the 2008 WHO classification of tumours of haematopoietic and lymphoid tissues, thus including for the first time primary cutaneous lymphomas as distinct subtypes of extranodal lymphomas in a general classification of lymphomas.

In January, 2007, a 36-year-old man presented to his derma tologist, with a 3-month history of constant itching of his head, neck, shoulders, and upper limbs. The itch had become so intense that it disturbed the patient’s sleep; it had a burning character, especially when the patient was wearing clothes. Treatment with topical cortico steroids and oral antihistamines produced no improve ment. The patient took no other regular medications, except occa sional nonsteroidal anti-infl ammatory drugs to relieve inter mittent neck pain: he had a 2-year history of neck pain and stiff ness. After 1 month, during which the itch contin ued to worsen, the patient was referred to us for further investigation. Physical examination showed slight redness of the aff ected skin, as well as excoriated fl at papules and erosions on the neck and forearms (fi gure). These signs were considered to be caused by rubbing and scratching. The results of blood tests, including a full blood count, plasma glucose, renal and liver function tests, and infl ammatory markers were all unremarkable. The association of neck pain, cervical stiff ness, and itch localised to areas supplied by the cervical spinal cord, pointed to a neurological cause for the itch. Neurological examination revealed abnormalities of both arms, particularly severe distally and in the right arm: hypoaesthesia, paraesthesia, muscle weakness, and reduced refl exes. Electromyography and nerve conduction tests showed an axonal injury, at the levels of the fi fth and sixth cervical roots. Further sensory testing revealed complete loss of heat sensation, and reduced vibration sense, in the index fi ngers of both hands, corresponding to the sixth cervical root. The symmetrical loss of motor and sensory function led us to suspect a lesion of the cervical spinal cord, aff ecting most or all of its width. Cervical MRI showed a lesion extending from the level of the fi rst to the seventh cervical vertebra, with prominent perifocal oedema. The lesion was excised by a decom pressive laminectomy, and was found to be an ependymoma on histopathological analysis. Irritation of the spinal cord, during the operation, caused weakness of all the patient’s limbs. This weakness decreased during residential rehabilitation; by April, 2007, the patient had regained most of his strength and coordination. The itch was no longer present. In May, 2007, the patient started to receive radiotherapy, to ensure that the tumour was eradicated. Sadly, he then developed a fi stula extending from the spinal cord to the skin—through which cerebrospinal fl uid leaked—and a subse quent infection of the fi stula and the surrounding tissue, though not of the spinal cord itself. The cord was seen on MRI to be oedematous. When last seen, in May, 2007, the patient had severe neurological defi cits—although, ironically, no itch. Itch can be classifi ed into four types: pruritoceptive, psychogenic, neurogenic, and neuropathic. 1