Infantile hemangiomas, the most common tumors of infancy, are vascular tumors characterized by rapid proliferation of endothelial cells during the first few months of postnatal life followed by slow ...spontaneous involution, whose molecular pathogenesis remains unclear. The recent identification of developmental expression of vascular lineage-specific markers prompted us to characterize infantile hemangiomas for the expression of lymphatic endothelial hyaluronan receptor-1 (LYVE-1), Prox-1, CD31 and CD34. We found that LYVE-1, a specific marker for normal and tumor-associated lymphatic vessels, was strongly expressed in tumor cells of infantile hemangiomas (n=28), but not in other vascular tumors including pyogenic granulomas (n=19, P<0.0001) or intramuscular hemangiomas (n=9), using LYVE-1/CD31 double immunostains. Whereas LYVE-1 expression was detected on the endothelial cells of all proliferating infantile hemangiomas, this lymphatic marker was absent from the lesional capillaries during involution in the majority of cases (P=0.0009). The majority of LYVE-1+ endothelial cells also expressed CD34, but were negative for the lymphatic-specific homeobox protein Prox-1. Based on coexpression of both LYVE-1 and the blood vascular marker CD34, we propose that the endothelial cells in proliferating infantile hemangioma are arrested in an early developmental stage of vascular differentiation. The immature, incompletely differentiated immunophenotype of proliferating infantile hemangiomas may contribute to their rapid growth during the first few months of life.
Abstract With the advent of genetic and epigenetic research, molecular techniques could someday be used to discriminate nevus from melanoma so that ambiguous melanocytic lesions could be more ...accurately classified or that prognostication could be improved in melanoma patients. That promised day might be closer than realized. The last 20 years of research in cytogenetic and genetic alterations in melanoma have culminated in defined chromosomal lesions discriminating benign from malignant melanocytic tumors. Exploiting these differences, fluorescence in situ hybridization (FISH) can reproducibly discriminate unequivocal melanomas from melanocytic nevi with high sensitivity and specificity. The discriminating power of FISH in melanocytic tumors with ambiguous histopathology is questionable, however, because there is no standard definition of “malignancy.” Additional FISH studies on ambiguous cases are needed through international collaborations where large collections of such cases are shared and the “proof of malignancy” is established by adequate clinical follow-up. This contribution reviews the diagnostic utility of DNA-based FISH technology as it compares the diagnostic accuracy in melanocytic tumors with unambiguous vs ambiguous histopathology. The melanoma epigenome is further characterized through research into various activities of small interfering RNAs, such as microRNAs, providing the pathway for the application of microRNA-based strategies that could be the basis for future diagnostic biomarkers and molecular therapies in melanoma.
Sarcoidosis is a multisystem disease characterized by non-caseating granulomas present in the involved organ systems. The disease is believed to result from an interaction among genetic factors, ...antigens, and the immune response. Environmental exposures and infectious agents have been implicated as potential causes. Cutaneous sarcoidosis presents clinically in many forms and the lesions are classified as either specific or non-specific. Non-specific lesions show a nondescript inflammatory process whereas specific lesions display typical, non-caseating granulomas. There are many different forms of specific lesions with some being more common than others. Psoriasiform lesions are uncommon. The literature suggests that as few as 0.9% of patients display this type of cutaneous sarcoidosis. Some of these patients present solely with cutaneous sarcoidosis, but others have systemic involvement with pulmonary involvement being the most common concomitant presentation. Plaques appear as round or oval, brownish, red infiltrated lesions, frequently involving the extensor surface of the extremities, face, scalp, back, and buttocks. Multiple configurations, including discrete, confluent, annular, and polycyclic, have been reported. Despite the clinical resemblance to psoriasis, on histological examination, only non-caseating granulomas are seen in the dermis. In rare cases both psoriasiform sarcoidosis and psoriasis were present.
The diagnosis of sebaceous carcinoma presents an important challenge to both clinicians and pathologists, as many cases are initially misdiagnosed both clinically and histopathologically, potentially ...leading to adverse medical and legal outcomes. The distinction of sebaceous carcinoma from benign sebaceous proliferations and other tumors is therefore of utmost importance, and immunohistochemistry may be useful in this differential. We studied the expression of D2-40 (podoplanin) by immunohistochemistry to determine if it can aid in this differential diagnosis and to evaluate the possibility of lymphangiogenesis in sebaceous carcinoma. A total of 36 cases of sebaceous lesions, including 16 sebaceous carcinomas, 7 sebaceous adenomas, 6 sebaceomas, and 7 cases of normal glands and sebaceous hyperplasia, and 17 cases of basal cell carcinoma and 10 cases of squamous cell carcinoma, were also examined. We found no significant increase in tumor lymphangiogenesis by semiquantitative scoring of lymphovascular density per square millimeter of tumoral/peritumoral stroma in sebaceous carcinoma versus benign sebaceous proliferations. However, D2-40 staining showed a different pattern in the benign tumors, which were positive only in the basaloid cells (most pronounced in sebaceoma), versus sebaceous carcinoma, which was either negative or focally positive in a haphazard pattern in most cases, although some cases of basaloid sebaceous carcinomas showed strong positivity. We also found D2-40 to be only weakly and focally positive in basal cell carcinoma and weakly to moderately positive in squamous cell carcinoma, which showed increased staining with decreased differentiation. Therefore, overall, D2-40 is, of limited diagnostic utility in sebaceous lesions but may be useful in distinguishing sebaceoma and basaloid sebaceous carcinoma from basal cell carcinoma.
Mus pahari is a wild-derived, inbred mouse strain. M. pahari colony managers observed fragility of this strain's skin resulting in separation of tail skin from the mouse if handled incorrectly. Tail ...skin tension testing of M. pahari resulted in significantly lowered force threshold for caudal skin rupture and loss in comparison to closely related inbred mouse species and subspecies and even more than a model for junctional epidermolysis bullosa. Histologically, the tail skin separated at the subdermal level with the dermis firmly attached to the epidermis, excluding the epidermolysis bullosa complex of diseases. The dermal collagen bundles were abnormally thickened and branched. Elastin fiber deposition was focally altered in the dermis adjacent to the hair follicle. Collagens present in the skin could not be differentiated between the species in protein gels following digestion with pepsin. Together these data suggest that M. pahari have altered extracellular matrix development resulting in separation of the skin below the level of the dermis with moderate force similar to the African spiny mouse (Acomys spp.).
Differentiated (simplex) vulvar intraepithelial neoplasia (VIN) is an uncommon variant of VIN characterized by highly differentiated morphology, making it a potential diagnostic pitfall. It may arise ...in the background of lichen sclerosus, and unlike most VIN, is not causally associated with human papilloma virus infection. It occurs in an older demographic and is thought to be the precursor of aggressive, invasive vulvar squamous cell carcinoma. For this reason, the timely and accurate diagnosis of this unusual lesion is crucial. The clinical and histologic features of a case of a 70-year-old woman with newly diagnosed differentiated (simplex) VIN arising in a background of long-standing lichen sclerosus is reported, and the historic aspects, current terminology, and diagnostic criteria of differentiated (simplex) VIN are reviewed.
Technology now exists for rapid screening of mutated laboratory mice to identify phenotypes associated with specific genetic mutations. Large repositories exist for spontaneous mutants and those ...induced by chemical mutagenesis, many of which have never been fully studied or comprehensively evaluated. To supplement these resources, a variety of techniques have been consolidated in an international effort to create mutations in all known protein coding genes in the mouse. With targeted embryonic stem cell lines now available for almost all protein coding genes and more recently CRISPR/Cas9 technology, large-scale efforts are underway to create further novel mutant mouse strains and to characterize their phenotypes. However, accurate diagnosis of skin, hair, and nail diseases still relies on careful gross and histological analysis, and while not automated to the level of the physiological phenotyping, histopathology still provides the most direct and accurate diagnosis and correlation with human diseases. As a result of these efforts, many new mouse dermatological disease models are being characterized and developed.
There have been repeated initiatives to produce standard nosologies and terminologies for cutaneous disease, some dedicated to the domain and some part of bigger terminologies such as ICD-10. ...Recently, formally structured terminologies, ontologies, have been widely developed in many areas of biomedical research. Primarily, these address the aim of providing comprehensive working terminologies for domains of knowledge, but because of the knowledge contained in the relationships between terms they can also be used computationally for many purposes.
We have developed an ontology of cutaneous disease, constructed manually by domain experts. With more than 3000 terms, DermO represents the most comprehensive formal dermatological disease terminology available. The disease entities are categorized in 20 upper level terms, which use a variety of features such as anatomical location, heritability, affected cell or tissue type, or etiology, as the features for classification, in line with professional practice and nosology in dermatology. Available in OBO flatfile and OWL 2 formats, it is integrated semantically with other ontologies and terminologies describing diseases and phenotypes. We demonstrate the application of DermO to text mining the biomedical literature and in the creation of a network describing the phenotypic relationships between cutaneous diseases.
DermO is an ontology with broad coverage of the domain of dermatologic disease and we demonstrate here its utility for text mining and investigation of phenotypic relationships between dermatologic disorders. We envision that in the future it may be applied to the creation and mining of electronic health records, clinical training and basic research, as it supports automated inference and reasoning, and for the broader integration of skin disease information with that from other domains.
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