Search

European journal of cancer 154, 227-234 (2021). doi:10.1016/j.ejca.2021.05.026, Published by Elsevier, Amsterdam [u.a.]

Das maligne Melanom ist diejenige Form von Hautkrebs, an der die meisten Menschen sterben. Im Fruhstadium ist das Melanom gut behandelbar, eine Fruherkennung ist also lebenswichtig. Kritiker bemangeln, dass seit der bundesweiten Einfuhrung des Hautkrebs-Screenings haufiger Melanome diagnostiziert werden, die Sterblichkeit am malignen Melanom jedoch nicht zuruckgegangen ist. Sie fuhren dies vor allem auf Uberdiagnosen zuruck. Ein Grund ist die zum Teil komplexe Unterscheidung zwischen benignen und malignen Lasionen. Hinzu kommt, dass es auch Ubergangsformen zwischen eindeutig gut- oder bosartigen Lasionen geben kann, und dass einige bosartige Lasionen so wenig aggressiv wachsen, dass sie nie lebensbedrohlich geworden waren. Bisher kann mangels entsprechender Biomarker nicht festgestellt werden, bei welchen Melanomen dies der Fall ist. Auch die Progressionswahrscheinlichkeit eines In-situ-Melanoms zu einem invasiven Tumor kann bisher nicht sicher beurteilt werden. Die Konsequenzen fur uberdiagnostizierte benigne Lasionen sind unnotige psychische und korperliche Belastungen fur die Betroffenen und anfallende Therapiekosten. Umgekehrt konnen Unterdiagnosen zu gravierenden Einschrankungen der Prognose der Betroffenen und zur Notwendigkeit belastender(er) Therapien fuhren. Prazisere Diagnosemoglichkeiten konnten die Anzahl der korrekten Diagnosen erhohen. Hier haben sich in Studien mit auf kunstlicher Intelligenz basierenden Assistenzsystemen bereits erste Erfolge gezeigt, die allerdings noch in die klinische und pathologische Routine ubertragen werden mussen.

Malignant melanoma is the skin tumor that causes most deaths in Germany. At an early stage, melanoma is well treatable, so early detection is essential. However, the skin cancer screening program in Germany has been criticized because although melanomas have been diagnosed more frequently since introduction of the program, the mortality from malignant melanoma has not decreased. This indicates that the observed increase in melanoma diagnoses be due to overdiagnosis, i.e. to the detection of lesions that would never have created serious health problems for the patients. One of the reasons is the challenging distinction between some benign and malignant lesions. In addition, there may be lesions that are biologically equivocal, and other lesions that are classified as malignant according to current criteria, but that grow so slowly that they would never have posed a threat to patient's life. So far, these "indolent" melanomas cannot be identified reliably due to a lack of biomarkers. Moreover, the likelihood that an in-situ melanoma will progress to an invasive tumor still cannot be determined with any certainty. When benign lesions are diagnosed as melanoma, the consequences are unnecessary psychological and physical stress for the affected patients and incurred therapy costs. Vice versa, underdiagnoses in the sense of overlooked melanomas can adversely affect patients' prognoses and may necessitate more intense therapies. Novel diagnostic options could reduce the number of over- and underdiagnoses and contribute to more objective diagnoses in borderline cases. One strategy that has yielded promising results in pilot studies is the use of artificial intelligence-based diagnostic tools. However, these applications still await translation into clinical and pathological routine.

Journal of medical internet research 23(2), e23436 (2021). doi:10.2196/23436, Published by Healthcare World, Richmond, Va.

Background: Clinicians and pathologists traditionally use patient data in addition to clinical examination to support their diagnoses. Objectives: We investigated whether a combination of histologic whole slides image (WSI) analysis based on convolutional neural networks (CNNs) and commonly available patient data (age, sex and anatomical site of the lesion) in a binary melanoma/nevus classification task could increase the performance compared with CNNs alone. Methods: We used 431 WSIs from two different laboratories and analysed the performance of classifiers that used the image or patient data individually or three common fusion techniques. Furthermore, we tested a naive combination of patient data and an image classifier: for cases interpreted as ‘uncertain’ (CNN output score

Background: Multiple studies have compared the performance of artificial intelligence (AI)–based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice. Objective: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians. Methods: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included. Results: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images. Conclusions: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice. info:eu-repo/semantics/publishedVersion

BACKGROUND An increasing number of studies within digital pathology show the potential of artificial intelligence (AI) to diagnose cancer using histological whole slide images, which requires large and diverse data sets. While diversification may result in more generalizable AI-based systems, it can also introduce hidden variables. If neural networks are able to distinguish/learn hidden variables, these variables can introduce batch effects that compromise the accuracy of classification systems. OBJECTIVE The objective of the study was to analyze the learnability of an exemplary selection of hidden variables (patient age, slide preparation date, slide origin, and scanner type) that are commonly found in whole slide image data sets in digital pathology and could create batch effects. METHODS We trained four separate convolutional neural networks (CNNs) to learn four variables using a data set of digitized whole slide melanoma images from five different institutes. For robustness, each CNN training and evaluation run was repeated multiple times, and a variable was only considered learnable if the lower bound of the 95% confidence interval of its mean balanced accuracy was above 50.0%. RESULTS A mean balanced accuracy above 50.0% was achieved for all four tasks, even when considering the lower bound of the 95% confidence interval. Performance between tasks showed wide variation, ranging from 56.1% (slide preparation date) to 100% (slide origin). CONCLUSIONS Because all of the analyzed hidden variables are learnable, they have the potential to create batch effects in dermatopathology data sets, which negatively affect AI-based classification systems. Practitioners should be aware of these and similar pitfalls when developing and evaluating such systems and address these and potentially other batch effect variables in their data sets through sufficient data set stratification.

Journal of the American Academy of Dermatology : JAAD 86(3), 640-642 (2022). doi:10.1016/j.jaad.2021.02.009, Published by Elsevier, Amsterdam [u.a.]

Background The diagnosis of most cancers is made by a board-certified pathologist based on a tissue biopsy under the microscope. Recent research reveals a high discordance between individual pathologists. For melanoma, the literature reports 25–26% of discordance for classifying a benign nevus versus malignant melanoma. Deep learning was successfully implemented to enhance the precision of lung and breast cancer diagnoses. The aim of this study is to illustrate the potential of deep learning to assist human assessment for a histopathologic melanoma diagnosis. Methods Six hundred ninety-five lesions were classified by an expert histopathologist in accordance with current guidelines (350 nevi and 345 melanomas). Only the haematoxylin and eosin stained (H&E) slides of these lesions were digitalised using a slide scanner and then randomly cropped. Five hundred ninety-five of the resulting images were used for the training of a convolutional neural network (CNN). The additional 100 H&E image sections were used to test the results of the CNN in comparison with the original class labels. Findings The total discordance with the histopathologist was 18% for melanoma (95% confidence interval [CI]: 7.4–28.6%), 20% for nevi (95% CI: 8.9–31.1%) and 19% for the full set of images (95% CI: 11.3–26.7%). Interpretation Even in the worst case, the discordance of the CNN was about the same compared with the discordance between human pathologists as reported in the literature. Despite the vastly reduced amount of data, time necessary for diagnosis and cost compared with the pathologist, our CNN archived on-par performance. Conclusively, CNNs indicate to be a valuable tool to assist human melanoma diagnoses.

Background The diagnosis of most cancers is made by a board-certified pathologist based on a tissue biopsy under the microscope. Recent research reveals a high discordance between individual pathologists. For melanoma, the literature reports on 25–26% of discordance for classifying a benign nevus versus malignant melanoma. A recent study indicated the potential of deep learning to lower these discordances. However, the performance of deep learning in classifying histopathologic melanoma images was never compared directly to human experts. The aim of this study is to perform such a first direct comparison. Methods A total of 695 lesions were classified by an expert histopathologist in accordance with current guidelines (350 nevi/345 melanoma). Only the haematoxylin & eosin (H&E) slides of these lesions were digitalised via a slide scanner and then randomly cropped. A total of 595 of the resulting images were used to train a convolutional neural network (CNN). The additional 100 H&E image sections were used to test the results of the CNN in comparison to 11 histopathologists. Three combined McNemar tests comparing the results of the CNNs test runs in terms of sensitivity, specificity and accuracy were predefined to test for significance (p Findings The CNN achieved a mean sensitivity/specificity/accuracy of 76%/60%/68% over 11 test runs. In comparison, the 11 pathologists achieved a mean sensitivity/specificity/accuracy of 51.8%/66.5%/59.2%. Thus, the CNN was significantly (p = 0.016) superior in classifying the cropped images. Interpretation With limited image information available, a CNN was able to outperform 11 histopathologists in the classification of histopathological melanoma images and thus shows promise to assist human melanoma diagnoses.

Background: There are compelling embryologic and anatomic relationships within adnexal tumors. However, these are mostly perceived within the epithelial component while the stromal component of the tumors is frequently overlooked. In postnatal skin, nestin is almost exclusively expressed in the perifollicular mesenchyme. This study examines the expression of this neuroepithelial stem cell protein in trichoblastoma/trichoepithelioma and in basal cell carcinoma (BCC), which is increasingly being viewed as follicular in nature. Methods: We employed standard immunohistochemical methods with three different antibodies to examine the expression of nestin in 25 BCCs and compared the staining pattern with that of 7 trichoblastomas and 11 trichoepitheliomas. Results: Nestin is expressed in the peritumoral stroma of all tumors examined and is limited to the immediate layer of mesenchymal cells surrounding the tumor epithelium. In BCC, nestin-immunoreactive cells are found as a sheath of thin, spindled fibroblasts, while reactive cells are plump in trichoepitheliomas/trichoblastomas. Conclusions: We postulate that the peritumoral stroma of BCC imitates the perifollicular connective tissue sheath, while in contrast that of trichoepithelioma/trichoblastoma is similar to the papillary and immediate peripapillary follicular mesenchyme. Further functional and animal experimental studies are needed to test this hypothesis. Sellheyer K, Krahl D. Does the peritumoral stroma of basal cell carcinoma recapitulate the follicular connective tissue sheath? A comparative analysis of nestin expression in basal cell carcinoma, trichoepithelioma, trichoblastoma and the hair follicle.

Summary Background Morphoeic basal cell carcinoma (BCC) and desmoplastic trichoepithelioma can often be difficult to differentiate on routine sections and few reliable immunohistochemical markers are currently available. Recent cDNA microarray studies revealed the pleckstrin homology-like domain, family A, member 1 protein (PHLDA1) as a highly reliable marker of the hair follicle stem cells. Given the differentiation of trichoepithelioma along the follicular lineage and the proposed role of PHLDA1 as a follicular stem cell marker, we examined the staining pattern of PHLDA1 in the desmoplastic variant of trichoepithelioma and in its differential diagnostic conundrum, morphoeic BCC. Objectives To describe the expression pattern of PHLDA1 in morphoeic BCC and desmoplastic trichoepithelioma. Methods Evaluation of the staining pattern for PHLDA1 was performed using standard immunohistochemical techniques. For comparison reasons, we analysed staining for PHLDA1 in normal skin structures with particular reference to the hair follicle. Results With the exception of one case, all 16 desmoplastic trichoepitheliomas were immunoreactive with more than 80% of the cells stained, whereas all 14 morphoeic BCCs were PHLDA1-negative with the exception of ulcerated tumours. In the latter, the tumour islands close to the ulcer were PHLDA1-positive whereas the deeper located tumour portions remained immunonegative. PHLDA 1 was prominently expressed in the hair follicle bulge of terminal and vellus hair follicles. Conclusions The hair follicle bulge marker PHLDA1 differentiates between desmoplastic trichoepitheliomas and nonulcerated examples of morphoeic BCCs. We suggest incorporating PHLDA1 in the diagnostic work-up of difficult to differentiate basaloid tumours.

Stem cell-based therapies are expected to have a great impact on the medicine of the 21st century. The focus of dermatologic stem cell research is on the epidermis and the hair follicle. In contrast, the characterization of stem cells in the mesenchymal compartments of the skin has largely escaped the attention of the dermatologic community. This is surprising because the dermis may represent a larger reservoir for adult stem cells than the epidermis and the hair follicle together. In 2001, mesenchymal stem cells residing within the dermis were first isolated. They have the capacity to differentiate into adipocytes, smooth muscle cells, osteocytes, chondrocytes, and even neurons and glia as well as hematopoietic cells of myeloid and erythroid lineage. The perifollicular connective tissue sheath and the papilla crystallize as the likely anatomic niche for these multipotent dermal cells. These previously unidentified mesenchymal stem cells have the potential to function as an easily accessible, autologous source for future stem cell transplantation. Potential therapeutic applications include the treatment of acute and steroid-refractory graft-versus-host disease, systemic lupus erythematosus resistant to currently available therapies, or idiopathic pulmonary fibrosis. The neuronal differentiation potential of cutaneous mesenchymal stem cells may also be exploited in the treatment of neurodegenerative disorders. The most immediate impact can be expected in the field of wound healing. In line with the cancer stem cell hypothesis, the potential contributions to dermatopathology include a conceptual understanding of mesenchymal skin-based neoplasms as evolving from a genetically altered dermal stem cell clone.

Background Whereas keratinocytic bulge stem cells are well characterized, comparably little is known about cutaneous mesenchymal stem cells. The follicular connective tissue sheath is proposed as a niche for dermal stem cells. Objective Because the neuroepithelial stem cell marker nestin represents a marker for mesenchymal stem cells in various tissues, our aim was to characterize its spatiotemporal expression pattern in the skin with special reference to the follicular mesenchyme. Methods We studied immunohistochemically nestin expression over the course of human cutaneous embryogenesis, in postnatal skin, in scalp wounds, and in the peritumoral stroma of basal cell carcinomas and compared its expression with that of other known mesenchymal markers. Results Nestin is expressed throughout the entire early embryonic dermis but confined later during development to the follicular connective tissue sheath, where it can also be found in postnatal human hair follicles. Its expression is up-regulated in scalp wounds and the nestin-positive cells seem to originate from the follicular mesenchyme. Nestin is also expressed in a thin layer of fibroblasts in the immediate vicinity of basal cell carcinomas. Limitations The examination for nestin expression of scalp wounds is considered preliminary, because we examined scalp wounds representing re-excisions of previously diagnosed neoplasms from which we had no exact time table available as to when the original excision took place. Conclusion We propose that nestin functions as a stem cell marker of the follicular mesenchyme and has a major regulatory role in dermal homeostasis, cutaneous neovasculogenesis, and tumor stroma development.

Within the next decade stem cell-based therapies can be expected to be part of clinical medicine. In regard to the skin, the focus of stem cell research is on the epidermis and the hair follicle. In 2001, mesenchymal stem cells residing within the dermis were first isolated which have the capacity to differentiate into adipocytes, smooth muscle cells, osteocytes, chondrocytes and even neurons and glia as well as hematopoietic cells of myeloid and erythroid lineage. The perifollicular connective tissue sheath and the papilla represent the likely anatomical niche for these multipotent dermal cells. They have the potential to function as an easily accessible, autologous source for future stem cell transplantation. Potential therapeutic applications include the treatment of acute and steroid-refractory graft-versus-host disease, systemic lupus erythematosus, idiopathic pulmonary fibrosis and arthritis. The neuronal differentiation potential of cutaneous mesenchymal stem cells may also be exploited in the treatment of neurodegenerative disorders and traumatic spinal injury. The most immediate impact can be expected in the field of wound healing.

Background: The sex-determining gene Sox9 was recently unexpectedly found to have an essential role in outer root sheath differentiation. It was also characterized as a general marker of basal cell carcinoma. Herein, we describe its spatiotemporal expression pattern outside the hair follicle during human cutaneous embryogenesis. Methods: We examined immunohistochemically samples from embryonic and fetal human skin for the expression of SOX9 using standard techniques. For comparison reasons, we also included scalp skin from adults. Results: SOX9 is expressed in the developing nail organ, eccrine glands, blood vessels and melanocytes/melanoblasts. In the nail organ, the nail bed but not the nail matrix was immunoreactive for SOX9. In plantar skin, SOX9 specifically labels the evolving eccrine glands but not the interfollicular keratinocytes. Conclusions: The distinctive expression pattern of SOX9 during human cutaneous embryogenesis indicates a key role in skin homeostasis that includes but goes beyond its role in outer root sheath differentiation. Studying immunohistochemical markers in developing human skin has the potential to further our understanding of adult skin physiology and to deepen our concepts especially of the histogenesis of adnexal tumors (including those of the nail unit) and the relationship of the various adnexal structures to each other. Krahl D and Sellheyer K. Sox9, more than a marker of the outer root sheath: spatiotemporal expression pattern during human cutaneous embryogenesis.

Summary Background Tumour development is frequently described in the basic pathology literature as a recapitulation of embryogenesis. However, a link between the embryology of the skin and the histogenesis of adnexal tumours has been largely overlooked. The low-affinity p75 neurotrophin receptor (p75NTR) has a profound role in hair follicle biology. We therefore speculated that it is involved in the histogenesis of follicular adnexal tumours. One of the most challenging diagnoses in dermatopathology is differentiating morphoeic basal cell carcinoma from desmoplastic trichoepithelioma. Objectives To describe the expression pattern of p75NTR during cutaneous embryogenesis, in the adult hair follicle and in morphoeic basal cell carcinoma and desmoplastic trichoepithelioma. Methods Evaluation of the staining pattern for p75NTR was performed using standard immunohistochemical techniques. For comparison, we examined staining for cytokeratin 20 which highlights Merkel cells. Results All 17 desmoplastic trichoepitheliomas were immunoreactive with > 80% of the cells stained, whereas 12 of the 14 (86%) morphoeic basal cell carcinomas were p75NTR negative. In the two positive cases of morphoeic basal cell carcinoma

Background Trichoadenoma is a rare benign follicular tumor first described by Nikolowski 50 years ago. Both trichoadenoma and desmoplastic trichoepithelioma are composed of cords of epithelial cells and cornifying cysts embedded in sclerotic stroma. In trichoadenoma the cystic component predominates, while desmoplastic trichoepithelioma is a mostly solid neoplasm. Therefore trichoadenoma was suggested to represent a cystic variant of desmoplastic trichoepithelioma. Objective The aim of this study was to investigate whether the morphologic overlap between trichoadenoma and desmoplastic trichoepithelioma translates into a similar immunohistochemical profile. Methods We studied 19 trichoadenomas and 21 desmoplastic trichoepitheliomas for cytokeratin 20, Ber-EP4, and androgen receptor expression. Results Eighteen of 19 trichoadenomas and all desmoplastic trichoepitheliomas demonstrated the presence of Merkel cells as detected by a monoclonal antibody against cytokeratin 20. In contrast, while all desmoplastic trichepitheliomas were positive for Ber-EP4, only 4 of 19 trichoadenomas showed any kind of reactivity for this marker. None of the trichoadenomas or desmoplastic trichoepitheliomas expressed androgen receptor. Limitations This study is limited by the moderate number of these rare tumors available for immunohistochemical analysis. Conclusion Our data demonstrate that trichoadenoma typically retains cytokeratin 20–positive Merkel cells but lacks Ber-EP4 and androgen receptor expression. Trichoadenoma is a distinct follicular tumor related but not identical to desmoplastic trichoepithelioma.

Summary Background The current classification schemes of adnexal tumours are predominantly based on morphological and immunophenotypical similarities to adult skin structures, whereas a link between the embryology of the skin and the histogenesis of adnexal tumours has been largely neglected. Objective To describe the expression patterns of two proteins with proven relevance for hair follicle homeostasis (SOX9 and β-catenin) during human cutaneous embryogenesis and to compare the findings with their expression in basal cell carcinoma (BCC) and pilomatrixoma. Methods Immunohistochemical evaluation with monoclonal antibodies against SOX9 and β-catenin was carried out in embryonic and adult human scalp skin, and BCC and pilomatrixoma samples. Results We found that the expression patterns of SOX9 and β-catenin during human hair follicle embryogenesis mirror the patterns in BCC and pilomatrixoma in spatial distribution within the various follicular subcompartments. Beginning with the hair peg stage, nucleocytoplasmic immunoreactivity of β-catenin is exclusively confined to the emerging matrix (comparable to pilomatrixoma), whereas SOX9 is restricted to the primordial outer root sheath (comparable to BCC). Conclusions An appropriate immunophenotyping validated within the conceptual framework of cutaneous developmental biology allows a logical classification of adnexal neoplasms. Expanding this approach further has the potential to revise the current classification schemes so that not only BCC and pilomatrixoma but all adnexal tumours can be categorized logically.

Summary Background The interface between the inner root sheath (IRS) and the outer root sheath (ORS) represents a slippage plane for the hair shaft to evolve from the pilar canal to the skin surface. Interposed between the IRS and ORS is a single cell layer which is believed to represent the angle point of that slippage plane, termed the companion cell layer (CCL). The CCL is cited in most of the literature as part of the ORS. Objectives To describe the expression pattern of nestin, a neuroepithelial stem cell protein, in the adult and developing human hair follicle. Methods Immunohistochemical evaluation with a monoclonal antibody against nestin was performed using standard techniques. Results Nestin is selectively expressed in the CCL of the adult anagen and late stage fetal hair follicles. Early stages of hair follicle development are negative for nestin expression. Conclusions The selective demarcation of the CCL by nestin highlights the unique feature of this follicular cell layer and raises the question of whether the CCL should not be better conceptualized as a part of the IRS rather than the ORS. The results of the present study, together with published ultrastructural data, also suggest that the slippage plane for the evolving hair shaft may be located at the interface between the CCL and the ORS.

Background: Loss of p16 in melanomas reflects worse outcomes for patients. It is associated with depth of invasion, ulceration, vascular invasion, lymph node metastases, metastases, recurrence of melanoma and decreased 5-year survival. Desmoplastic melanoma is an insidious malignant melanoma subtype that commonly occurs on sun-damaged skin of the head and neck area in elderly patients. The diagnostic conundrum occurs with confusion of desmoplastic melanoma with scars, hyalinizing blue nevi, desmoplastic Spitz nevi and diffuse neurofibromas. Methods: The present study uses immunohistochemistry with a p16 antibody to differentiate desmoplastic Spitz nevi (n = 15 cases) from desmoplastic melanomas (n = 11). To date, no other studies have been published defining the expression pattern of p16 in desmoplastic melanoma. Results: 81.8% of desmoplastic melanomas were negative for p16 and 18.2% were only weakly stained. In contrast, all desmoplastic Spitz nevi were moderately to strongly positive for p16. Conclusions: The staining pattern for p16 in desmoplastic melanomas and Spitz nevi in conjunction with the histopathologic features, S100 staining, Ki67 proliferation index and clinical scenario may aid in the difficult differential diagnosis between these two entities. Further confirmatory studies are indicated.

A two-year-old girl presented with a 20 month history of a facial nodule which had appeared after a vacation on Mallorca. Various topical treatments at other hospitals for the working diagnosis of mastocytoma failed to prevent a slow increase in size and the onset of systemic signs and symptoms. An indurated crusted nodule evolved. Histology, tissue PCR and serologic analysis proved the presence of Leishmania infantum. She was treated with oral miltefosine 10 mg p.o. t.i.d. for 28 days. Regression was apparent after 8 weeks and complete healing after 6 months.

Background Basal cell carcinoma (BCC) is still viewed by many dermatologists as a tumor of the interfollicular epidermis, although references were made early in the dermatopathologic literature to the resemblance of BCC to the hair follicle. Objective Our aim was to characterize the common expression pattern for the epithelial cell adhesion molecule (Ep-CAM) in BCCs, various stages of follicular embryogenesis, and adult hair follicles and, thereby, in analogy point to the similarity between BCC and the hair follicle. Methods We studied immunohistochemically 16 superficial BCCs for Ep-CAM and compared the expression pattern with that during hair follicle, nail, and eccrine gland development in human embryos and fetuses. In addition, we examined terminal scalp and vellus hair follicles. Results All BCCs expressed Ep-CAM similar to the early stages of the embryonic human hair follicle, the secondary hair germ, and the outer root sheath of the vellus hair follicle. The embryonic nail organ and the adult anagen hair follicles were completely negative. Limitations The conclusions are based on the similarity in the immunohistochemical expression profile for a single adhesion molecule. Conclusion BCC expresses the cell-cell adhesion molecule Ep-CAM similar to the embryonic hair germ, the secondary hair germ of the terminal hair follicle, and the outer root sheath of the vellus hair follicle. We suggest that this may be a clue to the adnexal nature of BCC and propose that BCC is the most primitive follicular tumor.

Background: Sclerosing cutaneous neoplasms often represent a diagnostic challenge. The monoclonal antibody Ber-EP4 recognizes two glycopolypeptides found in most human epithelial cells. It is diagnostically highly reliable in the differentiation between basal cell carcinoma and cutaneous squamous cell carcinoma. In this study, we report its application in the differential diagnosis of microcystic adnexal carcinoma, desmoplastic trichoepithelioma and basal cell carcinoma. Methods: Biopsy samples from 28 sclerosing and infiltrating basal cell carcinomas, 13 microcystic adnexal carcinomas and 16 desmoplastic trichoepitheliomas were examined after immunohistochemical staining with Ber-EP4. Results: Ber-EP4 did not label any of the microcystic adnexal carcinomas, whereas all 28 basal cell carcinomas were Ber-EP4 positive. Twenty-seven of the 28 showed moderate or strong staining intensity, with the majority being strong. Only one basal cell carcinoma was weakly positive. Twelve of the 16 desmoplastic trichoepitheliomas were immunoreactive with Ber-EP4 and the staining was more variable than those of basal cell carcinomas. Conclusions: Ber-EP4 reliably differentiates microcystic adnexal carcinoma from basal cell carcinoma to the same extent as it distinguishes the latter tumor from squamous cell carcinoma. While it stains the majority of desmoplastic trichoepitheliomas, these tumors still have to be considered in the differential diagnosis with microcystic adnexal carcinoma, when Ber-EP4 is applied.

The Bcl-2 protein is involved in the regulation of apoptosis. Bax has an antagonistic effect and enhances cell death. We report that in early gestation, Bcl-2 and Bax colocalize to the epidermal portion of the hair follicle. In the more advanced stages, Bax is located in the compartments where a hair canal is excavated and keratinization and holocrine secretion are initiated, in contrast to Bcl-2, which is expressed in the follicular papilla, preventing apoptosis and underscoring its role as a permanent and stable population of specialized fibroblasts. Scattered dendritic cells located in the basal and immediate suprabasal interfollicular epidermis as well as in the outer root sheath of the developing hair follicle, including the bulge, strongly express Bcl-2 and label for HMB-45, identifying them as melanocytes. The spatial and temporal expression pattern of Bcl-2 and Bax during human hair follicle development underscores their importance for hair biology and most likely is disturbed in the evolution of follicular tumors.

Wir berichten uber eine 60jahrige Patientin, welche nach haufigen Zeckenstichereignissen histologisch typische juxta-artikulare fibroide Knoten (JFK) und rotlich-livide Hautschwellungen im Sinne einer Acrodermatitis chronica atrophicans (ACA) zeigte. Es erfolgte eine systemische Antibiose mit Ceftriaxon (Rocephin) 2 g/die parenteral uber 21 Tage. Unerwunschte Nebenwirkungen traten nicht auf.

Background Cutaneous lymphadenoma is a recently recognized unusual tumor. It presents as an indistinct solitary non-ulcerating dermal nodule occuring mostly in the head and neck region of middle aged persons. Its histogenetic definition is controversial and recently it has been proposed that it might represent an unusual inflammatory basal cell carcinoma. We present clinical, histological and immunohistochemistry data of two cases. For the first time lectin-immunohistochemistry of cutaneous lymphadenoma is reported on. Observations One tumor was located on the eyebrow of a 37 years old, the other on the nose of a 75 years old male patient. Slow growth over years occured. Histology showed biphasic pattern of elongated and angulated lobules with peripheral rim of basaloid cells and central network of lymphohistiocytic cells with preponderance of protein S 100-positive cells. Peanut agglutinin (PNA) did not show peripheral staining around tumor lobules as seen in basal cell carcinoma. Conclusions Clinical and histological features as well as absence of peanut agglutinin staining argue in favor of the distinction of cutaneous lymphadenoma from inflammatory basal cell carcinoma. The former probably represents a benign growth of adnexal origin.

Erythrokeratolysis hiemalis, keratolytic winter erythema or Oudtshoorn skin has been reported from the South African district of Oudtshoorn as a dominantly inherited dermatosis beginning in early childhood, in some cases with circinar scaling erythemas. Seasonal manifestation in winter-time and a characteristic multi-form histology distinguish this dermatosis from other childhood scaling erythemas. We present clinical, histological and preliminary immunohistological data of a 4-year-old girl with the attributes of erythrokeratolysis hiemalis. No ancestors from the endemic region were traced. The lack of further cases in the family is interpreted as indicative of a spontaneous dominant new mutation.

Targetoid haemosiderotic haemangioma (THH) can be differentiated from other angiomatous lesions by the characteristic findings on clinical and histological examination. Clinically the solitary lesions is suggestive of a melanocytic or angiomatous origin, surrounded by a haemorrhagic halo in the acute phase. Histological findings vary depending on the duration of the alteration. The pattern has a superficial and a deep dermal component. In the papillary body lesional capillaries are lined by prominent endothelial cells. The surrounding tissue is oedematous and contains masses of erythrocytes or haemosiderin and a lymphocytic infiltrate. Vessels in the deeper dermis have a lymphatic appearance and surround adnexal structures. Further possible similarities with Kaposi sarcoma are dissecting vascular lumina between collagen bundles and spindle cell areas. However, has no atypical cells, eosinophilic globules or apoptotic endothelial cells. Immunohistochemical investigations, which have now revealed BMA 120 for the first time in THH as well as factor VIII-R antigen and Ulex europaeus I lectin, have not so far made any substantial contribution to the differential diagnosis and histogenesis of THH, because markers distinguishing lymphatic from vascular endothelia are still lacking.

Granuloma annulare perforans limited to a thoracic dermatome that was previously involved by herpes zoster occurred in a 51-year-old woman who also had Lennert's lymphoma. Of the various local granulomatous infiltrates described after herpes zoster, granuloma annulare perforans is unique, although ordinary granuloma annulare has been described in a few patients. A high incidence of specific and nonspecific reaction patterns in herpes zoster scars has been described in patients with malignant lymphoma. In contrast to previous patients, all of whom had chronic lymphatic leukemia, our patient had Lennert's lymphoma.

Background: The role of stem cells in maintaining the sebaceous gland throughout the various stages of life is not satisfactorily resolved. In a recent article, the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) was proposed as a marker of a population of unipotent progenitor cells that reside in the sebaceous gland, regulating its size and activity. Methods: We used standard immunohistochemical methods to examine Blimp-1 expression in samples from embryonic, fetal and adult human skin and in 119 sebaceous lesions comprising all major categories of sebocytic lineage, including hamartomas, cysts and benign and malignant neoplasms. Results: Blimp-1 is expressed late in embryonic development and is restricted to the evolving sebaceous gland, the terminally differentiating components of the hair follicle and nail organ and the granular layer. This pattern is preserved into adult life. In all sebaceous lesions, Blimp-1 labels only the most mature cellular constituents. Conclusions: The reported expression pattern is difficult to reconcile with a function of Blimp-1 as a marker for sebocytic progenitor cells but indicates a major role in terminal differentiation. Within the interfollicular epidermis, its exclusive localization to the granular layer suggests a central function in skin barrier homeostasis in the human. Sellheyer K, Krahl D. Blimp-1: a marker of terminal differentiation but not of sebocytic progenitor cells. A comparative analysis of embryonic and adult human skin with sebaceous neoplasms.

Background: The transcription factor GATA-3 was recently identified as a master regulator in the specification of the inner root sheath. Additionally, it seems to play a role in skin barrier physiology. p63 binds and transactivates the GATA-3 promoter. While the expression profile of GATA-3 is delineated for the mouse, little is known about its expression in the adult human hair follicle and no studies are published about its distribution during human cutaneous embryogenesis. Methods: We examined samples from embryonic, fetal and adult human skin for the expression of GATA-3 using immunohistochemistry. Results: GATA-3 is expressed late during human skin development. Its expression pattern is comparable to the mouse and confined to the Huxley layer and inner root sheath cuticle but sparing the Henle layer. In addition, GATA-3 localizes to the spinous cell layer of the interfollicular epidermis. Conclusions: From the described expression pattern, it is highly probable that GATA-3 plays a role in follicular and epidermal morphogenesis. What the anatomically confined expression of GATA-3 to the spinous layer means biologically for the physiology of the skin is still unclear. Likewise, it still needs to be shown if GATA-3 could be exploited in the diagnosis of adnexal neoplasms.

Summary Background There is an increasing body of evidence suggesting that malignancies arise from mutated stem cells, which has led to the formulation of the cancer stem cell hypothesis. It has also been suggested that cutaneous malignancies originate from a mutated stem cell. To date, mesenchymal tumours of the skin have not been the focus of the cancer stem cell hypothesis. A population of mesenchymal stem cells has recently been identified in the dermal compartment of the skin. These proposed stem cells are positive for the neuroepithelial stem cell marker nestin. Objectives To describe the expression pattern of nestin, a neuroepithelial stem cell protein, in dermatofibrosarcoma protuberans (DFSP). Methods Immunohistochemical evaluation of DFSP with a monoclonal antibody against nestin was performed using standard techniques. For comparison we also analysed dermatofibromas (DF). In addition, we used antibodies against CD34 and Factor XIIIa; the proliferation marker Ki67 was also used. Results Strong immunoreactivity for nestin was found in DFSP whereas all DF cases were nestin-negative. Conclusions We propose that DFSP may represent a clonal expansion of a nestin-positive mesenchymal stem cell which would put this tumour in line with other neoplasms for which the cancer stem cell hypothesis was formulated. We suggest the use of nestin as an additional marker for DFSP, especially in cases of negative immunoreactivity for CD34. Nestin may also be employed for margin evaluation of DFSP in micrographic (Mohs) surgery.

The expression of p16 in cutaneous neoplasms is upregulated in melanocytic neoplasms, ultraviolet radiation―induced neoplasms, such as actinic keratoses and squamous cell carcinomas, and in lesions related to human papillomavirus, such as Bowen's disease and bowenoid papulosis. In cervical dysplasia and tonsillar carcinoma, there is such a close relationship between p16 and human papillomavirus (HPV) to the extent that p16 immunostaining is used as a surrogate marker for the presence of HPV proteins. In this study we were interested in the expression pattern of p16 in trichilemmomas. Twenty-six conventional and 19 desmoplastic trichilemmomas were immunohistochemically stained for p 16. p16 immunostaining was noted in the majority of conventional (80.8%) and desmoplastic trichilemmomas (73.7%). The staining pattern was both nuclear and cytoplasmic. The staining intensity was more pronounced in the desmoplastic variant. We describe for the first time p16 expression in trichilemmomas and discuss our findings in conjunction with p 16 expression found in other cutaneous neoplasms. Additionally, the relationship of p16 to HPV infection is critically evaluated.

Non-infectious ulcerative oral mucous membrane diseases are difficult to separate at first glance: they can appear as aphthous, bullous, lichenoid, drug-induced or toxic-irritative reactions. The overall considerations of history, localization of lesions, clinical and histological features, as well as direct and indirect immunofluorescence examination are required for the correct diagnosis. Some disorders start preferably at the oral mucosa, like pemphigus vulgaris and Adamantiades-Behcet disease, while others, such as cicatricial pemphigoid and habitual aphthosis generally are confined to the mucous membranes. This overview summarizes clinical and diagnostic features, differential diagnoses and current therapeutic possibilities of non-infectious inflammatory stomatopathies, which possess a specific position among skin diseases in distinction to infectious or neoplastic oral ulcers. This group of diseases includes aphthous lesions, lichen planus mucosae, lupus erythematosus, disorders with intraepidermal or subepidermal formation of blisters including pemphigus, bullous pemphigoid, erythema multiforme and variants as well as allergic or toxic contact stomatitis.