Fibroepithelioma of Pinkus is a true basal cell carcinoma developing in association with a newly identified tumour-specific type of epidermal hyperplasia.

BACKGROUND: Fibroepithelioma of Pinkus (FEP) has long been viewed as a subtype of basal cell carcinoma (BCC). Recently, however, the proposal has been made that FEP represents a fenestrated trichoblastoma/trichoepithelioma. One of the main arguments is the presence of Merkel cells in FEP, which typically do not occur in BCC. OBJECTIVES: As the new stem cell marker, PHLDA1 (TDAG51), labels trichoepithelioma but not BCC, our aim was to characterize its staining pattern in FEP. Because adnexal tumours have been viewed as recapitulating embryogenesis, we also examined PHLDA1 immunoreactivity in the skin of human embryos and fetuses. METHODS: We studied immunohistochemically PHLDA1 staining in 31 FEPs, 14 BCCs and 16 trichoepitheliomas and compared this with its staining pattern in embryonic skin and with the distribution of Merkel cells. RESULTS: In FEP, PHLDA1 labels the anastomosing network of thin cellular strands but not the basaloid nubbins. During embryogenesis, PHLDA1 stains the basal cell layer of the epidermis, as long as adnexal structures develop. Immunoreactivity for PHLDA1 correlates positively with the presence of Merkel cells. CONCLUSIONS: We propose that the thin anastomosing network of PHLDA1-positive cells represents a type of epidermal hyperplasia specific to FEP. The multifocal BCCs that are PHLDA1-negative develop from this network which becomes incorporated into the tumour. Viewing the anastomosing network as a tumour-specific form of epidermal hyperplasia explains the hitherto enigmatic presence of Merkel cells in FEP.

Basal cell carcinoma: cell of origin, cancer stem cell hypothesis and stem cell markers.

Cancer stem cells have recently been described in several high-grade neoplasms. It is still unclear if they also occur in cutaneous malignancies. Cancer stem cells are not identical with somatic stem cells. The presence of tumour stem cells in a neoplasm does not in itself equal that the tumour derives from a somatic stem cell. A cell originally lacking stem cell characteristics could also acquire those features during the course of carcinogenesis and then becomes the clonal founder cell of a tumour. Basal cell carcinoma (BCC) is the most common cutaneous malignancy. A plethora of various stem cell markers has been applied to study its cellular origin. Intriguingly, the anatomical origin of BCC is still uncertain. This review will discuss the various stem cell markers used in BCC and the cellular origin of this tumour, and touches briefly on the possibility of cancer stem cells in BCC. If BCC or other skin cancers harbour tumour stem cells, these cells could be specifically targeted, making use of specific cell surface molecules such as receptor proteins. Novel drugs directed against those receptor proteins could replace currently available shotgun approaches including imiquimod.

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.

[Basal cell carcinoma and stem cell markers : Contribution to possible histogenesis?]. / Basalzellkarzinom und Stammzellmarker : Beitrag zur möglichen Histogenese?

The prevalence and incidence of basal cell carcinoma are on the rise. Yet, its histogenesis is still controversial. Hitherto discussed concepts are largely based on morphological analogies. Historically, basal cell carcinoma was named after its similarity to the epidermal basal cell layer which is viewed as its histogenetic origin. On the other hand, a primitive follicular origin is postulated due to the morphological similarity of basal cell carcinoma to the embryonic hair germ. In 1990, the hair follicle bulge was characterized as the anatomical niche for follicular stem cells. Early studies employing stem cell markers suggested a follicular origin of basal cell carcinoma. Since then an explosion of stem cell markers has occured in dermatology. In this review, the stem cell markers employed in the examination of basal cell carcinoma up to now are critically evaluated. Initially, studies on the histogenesis of this common dermatological tumor are reviewed.

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.

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.

Transgenic models of skin diseases.

BACKGROUND: Transgenic animals have greatly enhanced our understanding of the contribution of various structural and regulatory components to epidermal biology. The expression of mutant versions of these components in the epidermis of transgenic mice has generated animal models of specific human skin diseases. OBSERVATIONS: The expression of mutant keratin genes has produced animal models of epidermolysis bullosa simplex and epidermolytic hyperkeratosis and, in doing so, has focused attention on the genetics of keratins in these and other skin disorders. Similarly, the generation of mice overexpressing growth factors and/or oncogenes, exclusively in the epidermis, has identified the role of these factors in normal skin and produced models of disease states where the regulation of these factors is perturbed. CONCLUSIONS: These models of keratin disorders and other diseases not only enable the determination of the cause of these disorders, but also allow evaluation of novel therapeutic techniques for the amelioration of these skin diseases.

Development of the choroid and related structures.

The development of the choriocapillaris and the choroid is described using light and electron microscopy. Up to the seventh week after conception, the endothelium of the choriocapillaris is thick and contains many cytoplasmic vesicles. By the ninth week the endothelium flattens and becomes vesiculated. Fenestrations are found as early as the seventh week, whereas the continuous basement membrane is only observed at the ninth week. The first choroidal arterioles and venules can be seen during the fifteenth week and the arteries and veins become distinguishable at the twenty-second week. Haller's and Sattler's layers are both venous and arterial at the time of their first appearance.

[Transgenic mice as models for skin diseases]. / Transgene Mäuse als Modelle für Hautkrankheiten.

Naturally occurring animal models are not available even for most common skin diseases. Transgenic technology developed during the 1980s is closing this gap. It was initially used as a tool by scientists in basic research, but during the last 5 years it has increasingly been applied by clinically oriented basic researchers in dermatology. This technique, has made it possible to imitate HIV-associated diseases and genodermatoses in the murine model and to elucidate their pathogenesis. Owing to specifically induced epidermally localized overexpression of growth factors and cytokines, the skin of transgenic mice exhibited similarities to those of the psoriatic epidermis. Such animals are also useful for studying wound healing. Furthermore, transgenic technology enables us to induce cutaneous tumors selectively. The availability of animal models for human skin diseases is also of value in elucidating experimental therapeutic approaches, e.g., the somatic gene therapy.

Ultrastructure of the human posterior tunica vasculosa lentis during early gestation.

In human embryos with a gestational age of from 7.6 to 14.0/15.0 weeks, the posterior tunica vasculosa lentis (TVL) was examined by both scanning and transmission electron microscopy. Even at the very early age of 7.6 weeks the tunica was found to be fully developed. It consisted of a radiating network of tortuous capillaries. Their walls were composed of a continuous layer of endothelial cells, surrounded by a basement membrane and a discontinuous sheath of pericytes. The thickness of the basement membrane increased with increasing gestational age. As opposed to previous studies, the endothelial cells exhibited transitory fenestrations. In the neighborhood of the posterior TVL macrophages were found.

The fine structure of the developing human choriocapillaris during the first trimester.

In human embryos with a gestational age ranging from 6.5 to 13 weeks the development of the choriocapillaris was studied by electron microscopy. A continuous maturation process was observed over the whole period, which was most pronounced between weeks 6.5 and 9.7. During the earlier weeks, the endothelium appeared to be rather thick and contained many cytoplasmic vesicles; it was markedly flattened and less vesiculated than at week 9.7. This process was accompanied by an enlargement in the vascular lumina. Fenestrations directed towards the primitive Bruch's layer were found to be already present at week 7.2 but increased in number from week 9.7 to week 13. In the early weeks, basement membrane structures were present in small, discontinuous tufts of cloudy material adjacent to the endothelium. These structures became continuous at week 9.7 and increased in thickness towards week 13. In the earlier weeks, punctate junctions were seen. Beginning with week 9.7, adultlike tight junctions between the endothelial cells became observable. Pericytes were already present at week 6.5. It is suggested that both pericytes and endothelial cells are derived from the differentiating mesenchymal cells of the surrounding ocular stroma.

Surface morphology of the human ciliary body during prenatal development. A scanning electron microscopic study.

The development of the ciliary body was examined by scanning electron microscopy in human embryos and fetuses with a gestation age of 9.5 to 24 weeks. During this period it was possible to follow up the main morphogenetical events, beginning with the appearance of the first radial folds up to the occurrence of ciliary processes with a rather adultlike arrangement. The ciliary processes observed during week 24 differed from those of the adult eye only by their dimensions and the lack of surface infoldings. A primitive pars plana could only be identified during week 24. The morphological basis for aqueous humor production is discussed.

Development of the human sclera. A morphological study.

Differentiation of the sclera in human embryos and fetuses with a gestation age from 6.4 to 24.0 weeks was studied by light and electron microscopy. The developmental route was found to be anteroposterior and directed from inside outwards. Continuous cytological maturation begins anteriorly during week 7.2 with a loss of free ribosomes and polysomes and an increase in the amount of rough-surfaced endoplasmic reticulum (rER) and Golgi complex components. From the region of the future limbus, these cytodevelopmental events progress posteriorly. By week 13 there are no marked differences between anterior and posterior localization. The cytodevelopmental events directed from inside outwards were found to begin during week 7.2, with a marked increase in the addition of glycogen and lipid droplets in the choroidal half of the anterior scleral condensation and from there progressing to the outer (episcleral) half. With the beginning of week 10.9 no more differences were identified between the outer and the inner portions of the sclera. Portions of the ER denuded of ribosomes close to the plasmalemma were observed during the whole gestational period studied. The role of these structures and the involvement of the Golgi complex for the biosynthesis of collagen are discussed. In week 24, the diameter of the collagen fibrils had increased more than three times in comparison with week 6.4. Elastic microfibrils were found beginning with week 7.2, whereas the elastic deposits with central electron-translucent cores were characterized for the first time beginning with week 18.

[Light and electron microscopy studies of the development of the human ciliary body]. / Licht- und elektronenmikroskopische Untersuchungen zur Entwicklung des menschlichen Ziliarkörpers.

In human embryos and fetuses with a gestation age of 9.5 to 24 weeks, differentiation of the ciliary muscle was examined by both light and transmission electron microscopy, and the surface morphology of the ciliary body was analyzed by scanning electron microscopy. Smooth muscle cells develop from mesenchymal elements or early fibroblasts located at the anterior rim of the optic cup. Musclelike cells exhibiting dense bodies and myofilaments were first distinguished during week 12 and smooth muscle cells with an adultlike appearance become apparent during week 15/16. A cellular maturation process can be observed up to week 22. Fibroblasts separating the muscle cell layers from each other also derive from the same precursor cells, as do smooth muscle cells, thereby pointing out the close relationship between the two cell types. The first radial ciliary folds could be observed at week 10.3 by scanning electron microscopy. However, true ciliary processes have only been described at week 24. The ciliary processes observed during week 24 only differed from those of the adult eye by the dimensions and lack of surface infoldings. A primitive pars plana was first identified during week 24. The morphological basis for aqueous humor production is discussed.

Differentiation of the ciliary muscle in the human embryo and fetus.

In human embryos and fetuses with a gestation age of 10.3 to 22 weeks, differentiation of the ciliary muscle was examined both by light and transmission electron microscopy. The smooth muscle cells develop from mesenchymal elements or early fibroblasts located in the region between the anterior scleral condensation and the ciliary pigment epithelium. The first musclelike cells exhibiting myofilaments and dense bodies could be distinguished during week 12. Smooth muscle cells with an adultlike appearance become apparent during week 15/16. Up to week 22, a cellular maturation process can be observed. Fibroblasts separating the muscle cell layers from each other also derive from the same precursor cells, as do the smooth muscle cells, thereby pointing to the close relationship between the two cell types.