[Dermoscopic changes in melanocytic nevi during use of melanotan II]. / Dermatoskopische Veränderungen von melanozytären Nävi unter Verwendung von Melanotan II.

For cosmetic reasons, a 24-year-old man performed subcutaneous autoinjections with a preparation having alpha-MSH-like effects (melanotan II) purchased via the internet. The changes of patient's nevi were documented by sequential videodermoscopy before and during treatment. The observed dermoscopic changes made it difficult to differentiate a nevus from a melanoma.

PHLDA1 (TDAG51) is a follicular stem cell marker and differentiates between morphoeic basal cell carcinoma and desmoplastic trichoepithelioma.

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.

Gongylolepis martiana, an Asteraceae pollinated by bats in the Amazon.

Most Asteraceae species are pollinated by insects, mainly bees and butterflies, although pollination by birds has been documented and pollination by bats has been suggested for some species. Here, we investigated the pollination of Gongylolepis martiana, a species supposedly pollinated by bats. We assessed floral traits and visitors in a population of G. martiana in the Brazilian Amazon, measuring pollen removal from anthers and deposition on stigmas by diurnal and nocturnal visitors. Florets opened at dusk and lasted for 4 days, with the male phase starting on the first night and the female phase on the third night. Accumulated nectar per capitulum was 69.6 µl per night and sugar concentration was 15%. Nectar-feeding bats and hummingbirds contacted the sexual parts, but pollen removal and deposition were greater throughout the night than during the day, when Meliponini bees considerably reduced pollen availability. Other nocturnal visitors of G. martiana were rare, including nocturnal bees and moths that foraged for pollen and nectar, respectively. Our results support that nectarivorous bats are the main pollinators of G. martiana, confirming Vogel's hypothesis of bat pollination in Asteraceae, particularly in the genus Gongylolepis. Since anthesis and each sexual floral phase started in the evening, nectarivorous bats and diurnal bees caused additive priority effects, preventing hummingbirds from being efficient pollinators. The high density of flowering individuals of G. martiana in patches from white-sand forests likely increases bat attraction, while the small amount of nectar per plant favours cross-pollination.

Basal cell carcinoma and pilomatrixoma mirror human follicular embryogenesis as reflected by their differential expression patterns of SOX9 and ß-catenin.

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 ß-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 ß-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 ß-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 ß-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.

p75 Neurotrophin receptor differentiates between morphoeic basal cell carcinoma and desmoplastic trichoepithelioma: insights into the histogenesis of adnexal tumours based on embryology and hair follicle biology.

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 < 30% of cells were labelled. In the late bulbous hair peg stage and in the postnatal anagen hair follicle p75NTR highlights the outer root sheath. CONCLUSIONS: Our results support the classification of desmoplastic trichoepithelioma as a follicular hamartoma mimicking the outer root sheath. In contrast, the lack of p75NTR expression in morphoeic basal cell carcinoma favours a concept of this tumour as a more primitive follicular lesion with the characteristics of a carcinoma and not a hamartoma. We suggest including p75NTR as a tool in the differential diagnosis between morphoeic basal cell carcinoma and desmoplastic trichoepithelioma.

[Cutaneous mesenchymal stem cells. Current status of research and potential clinical applications]. / Mesenchymale Stammzellen der Haut. Gegenwärtiger Stand der Forschung, potenzielle klinische Anwendungen.

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.

The neuroepithelial stem cell protein nestin is a marker of the companion cell layer of the adult and developing human hair follicle.

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.

Dermatofibrosarcoma protuberans: a tumour of nestin-positive cutaneous mesenchymal stem cells?

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.

Water jet-assisted liposuction for patients with lipoedema: histologic and immunohistologic analysis of the aspirates of 30 lipoedema patients.

Lipoedema is a fat distribution disorder causing massive, bilaterally symmetrical enlargement of the lower and in some cases the upper extremities in women. The atraumatic, anatomically appropriate procedure of water jet-assisted liposuction available today represents a promising treatment for these patients who generally suffer from severe subjective and objective impairment. Liposuction treatment can bring long-term improvement if the operative technique focuses on lymph vessel preservation. Immunohistologic analyses show minimal evidence of lymph vessel structures in lipoaspirates. The histologic analysis of the aspirates documents a relatively specific removal ("apheresis") of primarily intact lipocytes with low vascular amount.

What causes hidradenitis suppurativa?

Hidradenitis suppurativa (HS)--a rather common, very chronic and debilitating inflammatory skin appendage disorder with a notoriously underestimated burden of disease--has long been a playground for the high priests of nomenclature: Ask a bunch of eminent dermatologists and skin pathologists to publicly share their thoughts on what causes HS, and they will soon get entrenched in a heated debate on whether this historical term is a despicable misnomer. Fortunately, the recently founded Hidradenitis Suppurativa Foundation (HSF; http://www.hs-foundation.org), to which EXP DERMATOL serves as home journal, has broken with this unproductive tradition and has encouraged publication of the current CONTROVERSIES feature. This is exclusively devoted to discussing the pathobiology of this chronic neutrophilic folliculitis of unknown origin. Although traces of terminological bickering remain visible, it does the HS experts in our virtual debate room credit that they engage in a constructive and comprehensive dissection of potential pathogenesis pathways that may culminate in the clinical picture we know under the competing terms HS or acne inversa. These experts sketch more often complementary than mutually exclusive pathogenesis scenarios, and the outlines of a conceivable consensus on the many open pathobiology questions begin to emerge in these CONTROVERSIES. Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy.

Combined positive/negative purging and transplantation of peripheral blood progenitor cell autografts in breast cancer patients: a pilot study.

This trial studied the feasibility and efficiency of a novel procedure of double purging to eliminate tumor cells from leukapheresis products of stage IV breast cancer patients. After induction and mobilization therapy, 35 leukapheresis products from 16 breast cancer patients were subjected to CD34+ enrichment (i.e., positive selection) with the Isolex 300 device and subsequent immunomagnetic depletion of tumor cells (i.e., negative selection) using a cocktail of three monoclonal antibodies directed against epithelial antigens. Patients with clinical response to induction chemotherapy proceeded to tandem high-dose chemotherapy, which consisted of melphalan (140 mg/m2) followed by retransfusion of the purged graft. After hematologic recovery, patients received ifosfamide 14 g/m2, carboplatin 1.5 g/m2, and etoposide 1.5g/m2 (ICE), again followed by autografting. After positive selection, a median purity of 96.6% CD34+ cells (range 48.4-99.2%) and a recovery of 56.8% (range 25.8-92.6%) were achieved. Subsequent negative purging resulted in a median CD34+ purity of 97.2%. Overall CD34+ recovery after both purging procedures was 51.1% (range 18.5-82.4%). Tumor cells were detectable in 8 of 16 (50%) starting fractions before purging. After both purging cycles, only 1 of 16 autografts remained positive for tumor cells compared to 3 of 16 after CD34+ selection. A calculated purging efficiency of 2 to >4 log was achieved. Engraftment was rapid, reaching > or =500/microL neutrophils on day +10 after melphalan and on day +9 after ICE. A platelet count of > or =20.000/microL was reached on day +12 after melphalan and on day +11 after ICE. Thus, combining positive and negative purging is feasible, further enhances purging efficiency, and does not compromise the quality of the graft, leading to rapid engraftment after high-dose chemotherapy.

Salvage therapy for relapsed mediastinal B-cell lymphoma with allogeneic HLA-identical related donor bone marrow transplantation, donor lymphocyte infusion and IDEC-C2B8.

Primary B-cell lymphoma of the mediastinum is an aggressive non-Hodgkin's lymphoma with distinct clinicopathologic features. Response rates are between 60-80% following intensive chemotherapy regimens. Poor responders or patients with an early relapse usually do not achieve a prolonged second remission with conventional salvage therapy protocols and therefore qualify for intensive or experimental approaches. Here we describe two patients of same age, gender and stage with primary mediastinal B-cell lymphoma and an early relapse after the first courses of combination chemotherapy and irradiation of the mediastinum. One patient relapsed after a salvage therapy with allogeneic donor-related bone marrow transplantation and donor lymphocyte infusion but responded again with a continuing good partial remission after infusion of the chimeric anti-CD20 antibody IDEC-C2B8. For the other patient an allogeneic bone marrow transplantation was not possible. He finally failed to respond to salvage therapy with IDEC-C2B8 and died of progressive disease. The anti-CD20 antibody IDEC-C2B8 induced a partial remission in a patient with primary mediastinal B-cell lymphoma refractory to other therapeutic approaches, including allogeneic bone marrow transplanatation (alloBMT), donor lymphocyte infusion (DLI) and irradiation. The role of IDEC-C2B8 as a component of salvage regimens appears to be worthy for further evaluation in high-risk patients with primary mediastinal B-cell lymphoma

Tumor inhibition by metallocenes: ultrastructural localization of titanium and vanadium in treated tumor cells by electron energy loss spectroscopy.

The intracellular distribution patterns of the metal atoms titanium and vanadium after in vivo as well as in vitro treatment of Ehrlich ascites tumor with the antitumor agents titanocene dichloride (TDC) or vanadocene dichloride (VDC) have been investigated by use of electron energy loss spectroscopy (EELS). The metals were found mainly accumulated in the nuclear heterochromatin and, to a minor extent, in the nucleolus and in the cytoplasmic ribosomes. In connection with other experimental results it is argued that this accumulation is indicative of the molecular interaction of the metal-containing species with the nucleic acids, especially with the DNA.

A TV system for image recording and processing in conventional transmission electron microscopy.

An image processing system for a CTEM is described which is particularly suited for the imaging of radiation-sensitive objects. It consists of an image intensifier device for single electron counting, a digital storage unit and a video recorder for intermediate storage of low-dose image series. During on-line operation the information can be transferred to a computer for further processing. The output can be transferred onto a second digital storage unit and observed on a monitor. The influence on the DQE of the pulse height distribution of the single electron video signals and of a multiple counting are eliminated by means of special electronic components. Various modes of operation and application possibilities of the image processing system are discussed.

[Chancre of the finger. A circuitous route to diagnosis]. / Primäraffekt am Finger unter dem Bild einer chronischen Paronychie. Umwege zur Diagnose.

A 33-year-old woman presented with a 4-months history of a granulating ulcer on the right index finger. Paronychia was suspected and nail extraction with subsequent histopathologic examination of the removed tissue was performed. Two months later, it became known that the patient's sexual partner had been treated for syphilis. The patient's serology was also positive. Subsequent examination of the original tissue sample by polymerase chain reaction, immunohistochemistry using Treponema pallidum-specific antibodies, and silver staining revealed large numbers of syphilis bacteria, confirming the diagnosis of extragenital chancre.

[Chronic otitis externa from the dermatologic viewpoint]. / Chronische Otitis externa aus dermatologischer Sicht.

Chronic external otitis may be divided into several diagnostic categories. Disposition for psoriasis, seborrhoeic and atopic eczema are main endogenous reasons. Exogenous pathogens for external otitis are microbes and allergens. There are numerous interrelations by coincidence of dispositional diseases, e.g. psoriasis and atopic eczema and by combination of exogenous and endogenous pathogens. This holds good for the yeast Pityrosporum ovale vs. orbiculare in seborrhoeic eczema and for the susceptibility to contact (type IV) and respiratory (type I) allergy in atopic individuals as well. Mycotic and bacterial, especially gram negative external otitis are linked to predisposing factors like eczema, long-term microbicidal therapy, hot and humid environment. Contact allergic external otitis may occur during long lasting local therapy with various substances including vehicles, the most common allergen being neomycin. Mucosal allergic reactions (Type I) in the upper respiratory tract may impair ventilation of the Eustachian tube and middle ear and therefore epithelial migration, as a drainage mechanism of the auditory canal. Examination should include functional assessment of the Eustachian tube and middle ear and allergy testing (patch, prick test). Preparations for local therapy should contain a limited number of constituents and avoid common allergens. Surgical procedures to reestablish ventilation of the middle ear are also a therapy for chronic external otitis.

[Sterile eosinophilic pustulosis (Ofuji)--Mediterranean and endemic case]. / Sterile eosinophile Pustulose (Ofuji)--mediterraner und einheimischer Fall.

Sterile eosinophilic pustulosis (Ofuji's disease) is very rare in Europe compared with Japan. We describe a Turkish and a German case. Clinical and histopathological findings do not allow a clearcut diagnosis. Many differential diagnoses have to be excluded, mainly by histopathological investigations. Careful examination of the heart and other internal organs is also necessary, since Ofuji's disease belongs to the group of hypereosinophilic diseases. Transitions from cutaneous to internal manifestations of hypereosinophilic disease may exist.

[Target-like hemosiderotic hemangioma. Further differential diagnosis of Kaposi sarcoma]. / Targetoides hämosiderotisches Hämangiom. Eine weitere Differentialdiagnose des Kaposi-Sarkoms.

Targetoid haemosiderotic haemangioma (THH) can be differentiated from other angiomatous lesions by the characteristic findings on clinical and histological examination. Clinically the solitary lesion 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.

Distribution of Bcl-2 and Bax in embryonic and fetal human skin: antiapoptotic and proapoptotic proteins are differentially expressed in developing skin.

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.