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The CHILD syndrome (MIM 308050), an acronym for congenital hemidysplasia with ichthyosiform nevus and limb defects, is an X-linked dominant trait with lethality for male embryos. Recently, we elucidated the underlying gene defect by demonstrating point mutations in NSDHL (NAD[P]H steroid dehydrogenase-like protein) at Xq28 in 6 patients with classic CHILD syndrome. The most striking clinical feature is an inflammatory nevus that usually shows a unique lateralization with strict midline demarcation. Ipsilateral defects involve all skeletal structures and internal organs such as the brain, the lung, the heart, or the kidney. As an exception to this rule, in some cases the CHILD nevus may occur in a more or less bilateral distribution. In 1997 Fink-Puches et al described a case of CHILD nevus with an almost symmetric arrangement. To test the correctness of the diagnosis, we now examined blood lymphocytes of this patient by single-strand conformation analysis and genomic sequencing. We identified a novel missense mutation in NSDHL that potentially may impair protein function. We conclude that a diagnosis of CHILD syndrome can be based on clinical features such as the highly characteristic morphology of the CHILD nevus. A symmetric distribution of this nevus can exceptionally be seen in patients with CHILD syndrome, and this bilateral involvement should not mislead the clinician to any other diagnosis. Apparently, the effect of random X-inactivation is responsible for different patterns of cutaneous involvement in female carriers of NSDHL mutations.

Classification of primary cutaneous lymphomas (PCLs) is the subject of ongoing controversy. Based on a series of 556 patients, the applicability of the European Organization for Research and Treatment of Cancer (EORTC) classification for PCLs was assessed and compared to the proposed World Health Organization (WHO) classification of hematologic malignancies. The large majority of patients could be properly classified according to the scheme proposed by the EORTC. Comparison of estimated 5-year survival for specific diagnostic categories of PCLs demonstrated nearly complete concordance of the present results with those of the EORTC study for most of the indolent cutaneous T-cell lymphomas and cutaneous B-cell lymphomas, whereas differences were found for mycosis fungoides-associated follicular mucinosis and Sezary syndrome. A few patients with newly described entities (CD8(+) epidermotropic cytotoxic T-cell lymphoma, primary cutaneous natural killer/T-cell lymphoma) could not be classified according to the EORTC scheme. Comparison of the EORTC with the WHO classification showed that the EORTC scheme allows a more precise categorization of the patients, especially for cutaneous B-cell lymphoma. In conclusion, the study confirmed that the EORTC classification allows a better management of patients with PCL. Small amendments to that classification should be carried out to account for recently described entities and to unify some of the diagnostic categories.

Context: Beginning in 1957, patients have been described with localized alopecia characterized histopathologically by mucin deposition within hair follicles (follicular mucinosis [FM]). At least 2 distinct diagnostic entities have been proposed: one occurring in children and young adults without association with other diseases ("idiopathic" FM), the other occurring in elderly patients and associated with mycosis fungoides or Sézary syndrome ("lymphoma-associated" FM)., Objective: To determine whether idiopathic and lymphoma-associated FM are distinct or related entities., Design: Case series., Setting: Department of Dermatology, University of Graz, Graz, Austria., Patients: Forty-four patients with FM were divided into 2 groups. Group 1 comprised 16 patients (mean age, 37.5 years) with no associated mycosis fungoides or Sézary syndrome; group 2 was made up of the other 28 (mean age, 52.2 years), who had clinicopathologic evidence of cutaneous T-cell lymphoma., Results: Mean age was lower in patients with idiopathic FM, but a considerable overlapping among the 2 groups was present. Location on the head and neck region was common in both groups, but most patients with lymphoma-associated FM had lesions also on other body sites. In fact, solitary lesions at presentation were common in patients with idiopathic FM (11 [68.8%] of 16 patients), but uncommon in those with lymphoma-associated FM (2 [7.1%] of 28 patients). Histopathologic findings did not allow clear-cut differentiation of the 2 groups. Finally, a monoclonal rearrangement of the T-cell receptor gamma gene was demonstrated by polymerase chain reaction analysis in about 50% of tested cases from each group., Conclusions: Criteria previously reported to differentiate idiopathic from lymphoma-associated FM proved ineffective. In analogy to localized pagetoid reticulosis (Woringer-Kolopp disease), small-plaque parapsoriasis, and so-called solitary mycosis fungoides, idiopathic FM may represent a form of localized cutaneous T-cell lymphoma.

Primary B-cell lymphomas of the skin are defined as malignant B-cell proliferations presenting with cutaneous involvement alone and no evidence of extracutaneous manifestations over a period of at least six months when complete staging has been performed. The major subtypes are follicle center-cell lymphoma, marginal zone lymphoma and large B-cell lymphoma of the leg (EORTC classification 1997). Primary B-cell lymphomas of the skin differ significantly from nodal lymphomas especially with respect to their clinical behavior. Pseudolymphomas of the skin are inflammatory diseases that simulate malignant lymphomas either clinically, histopathologically, or both. Particular pseudolymphomas may mimic cutaneous B-cell lymphomas. The most important examples are: lymphomatoid drug reactions, lymphocytoma (borrelia burgdorferi as causative agent), arthropod reactions, pseudolymphomas associated with vaccinations or tattoos and inflammatory pseudotumors. In recent years, new immunohistological and molecular techniques have added important criteria for the differentiation of cutaneous lymphomas from pseudolymphomas.

Background: Recent studies have demonstrated the expression of the c-erbB-2 (HER-2/neu) oncoprotein in several malignant tumors and have related its overexpression with poor prognosis. Because cutaneous melanoma is a malignant tumor associated with poor prognosis, we investigated the expression of c-erbB-2 protein in cutaneous melanoma and in melanoma metastatic to the skin., Materials and Methods: The expression of c-erbB-2 protein in 20 primary cutaneous melanomas and in 10 melanomas metastatic to the skin was investigated using a semi-quantitative immunohistochemical assay., Results: No specific staining with c-erbB-2 antibody was observed in any of the 20 cases of primary malignant melanoma or 10 cases of melanoma metastatic to the skin., Conclusion: c-erbB-2 overexpression does not appear to play a role in the development of primary cutaneous melanoma or in the development of metastatic melanoma, indicating that mechanisms other than c-erbB-2 overexpression are involved in the pathogenesis of cutaneous melanoma.

The morphologic spectrum of large B-cell lymphoma is broad. Several unusual variants have been described such as lymphoma with myxoid stroma, sclerosing B-cell lymphoma, signet ring-cell lymphoma, and multilobated B-cell lymphoma among others. We report on five cases of cutaneous large B-cell lymphoma in which the neoplastic cells were spindle-shaped. In two cases, the clinical features fulfilled those of a primary cutaneous lymphoma; in the three other cases, the lymphoma most likely arose primarily in the skin, but incomplete clinical workups precluded definite categorization. The patients ranged in age from 30 to 89 years and presented with solitary lesions on the trunk or head. Histopathologic examination revealed nodular or dense diffuse infiltrates involving the entire dermis as well as the subcutaneous fat in some cases. Thickened collagen bundles between the spindled cells were present in one case. Cytomorphologic analysis showed the presence of round or oval medium-sized and large-sized lymphocytes with features of centrocytes and centroblasts in some foci, with others dominated by cells with spindle-shaped, elongated, twisted nuclei with dispersed chromatin and scant cytoplasm. Immunohistologic analysis revealed that both round or oval and spindled cells were positive for CD20 in all cases; in all cases tested, these cells were also positive for MIB-1 and were negative for CD3, CD5, CD43, CD45RO, CD21, CD30, CD68, S-100, HMB-45, actin, smooth-muscle actin, and cytokeratin. Bcl-2 was expressed in one of three cases tested. Analysis of the rearrangement of the J(H) gene by polymerase chain reaction performed in one case showed a monoclonal pattern. Spindle-cell large B-cell lymphoma represents a distinctive rare subtype of the cutaneous large B-cell lymphoma and can arise primarily in the skin in some cases. Recognition of this variant is necessary to avoid misdiagnosis of other cutaneous malignant spindle-cell tumors.

Background and Objectives: Angiosarcomas of the skin arise almost exclusively in the following clinical settings: 1. the face and scalp, usually in elderly individuals, 2. lymphedematous regions (lymphedema-associated angiosarcomas), and 3. skin that has been previously irradiated (post-radiation angiosarcomas). Clinical and histopathologic diagnosis of angiosarcoma is difficult often resulting in great delay that obviates against early and possibly successful treatment of these very aggressive neoplasms. Diagnostic problems are described, and prognostic factors as well as the effect of different forms of treatment on the outcome are discussed., Patients/methods: Retrospective study of 11 patients with cutaneous angiosarcomas. Clinical presentation, histopathology, therapy and survival time are analysed., Results: Only 1 of 11 cases cutaneous angiosarcoma was clinically identified. Survival time was 1-24 months. Three patients who received radical surgery have not developed metastases and are still alive., Conclusions: Clinical and histopathologic diagnosis of cutaneous angiosarcomas is often very difficult. Prognosis is very bad; radical surgery seems to be the best therapeutical option.

We report a young girl with an unusual manifestation of CHILD syndrome in whom skin lesions showed involvement of the right side of her neck as well as symmetrically distributed ptychotropic involvement of the large body folds. Excision resulted in improvement and finally healing of skin lesions within the submammary folds, where breast reduction was also performed, whereas excision of axillary lesions and subsequent grafting with split skin turned out to be unsuccessful.

Background and Objective: Primary cutaneous B-cell lymphomas (PCBCL) represent a unique type of extranodal B-cell lymphomas. Recently, the "European Organization for Research and Treatment of Cancer (EORTC)-Cutaneous Lymphoma Study Group" classified PCBCL into two major groups: one with low-grade malignancy and excellent prognosis (follicle center cell lymphoma, immunocytoma/marginal zone B-cell lymphoma) and the other with intermediate malignancy and worse prognosis (large B-cell lymphoma of the leg). The clinical course and the prognosis of both groups clearly distinguish them from nodal lymphomas with similar morphological aspects, thus underlying the need for different treatment modalities., Patients/methods: We investigated retrospectively the therapeutic data from 51 patients with PCBCL (40 low grade lymphomas, 11 large B-cell lymphomas). Several treatment modalities were used: total excision, radiotherapy, polychemotherapy, systemic corticosteroids, systemic antibiotics, as well as a variety of combination treatments., Results: Recurrence, dissemination and/or death of the patients were not significantly related to any single treatment modality., Conclusions: In our opinion, the choice of treatment for PCBCL depends on the histologic classification, the number, spread and localization of the infiltrates, and on the general condition of the patient.

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that usually begins with cutaneous patches that evolve into plaques and tumors. A few recent reports describe a solitary variant of MF distinct from localized pagetoid reticulosis, a disease in which solitary verrucous lesions occur on acral skin. Solitary skin lesions with some of the histopathologic features of MF rarely occur during treatment with several drugs, especially antidepressants or antihistamines. We analyzed the clinicopathologic features of 20 patients with solitary skin lesions showing histopathologic features of patch- or early plaque-stage MF. Eight men and 12 women (mean age 50.6, range 23-82, median 49) had solitary, small erythematous patches or plaques located on the trunk (16 cases, 6 of them on the breast), upper extremities (3 cases), and inguinal region (1 case). Ten patients were treated with one or more drugs; only two of them received antidepressants or antihistamines. Histopathologic examination revealed in all cases a band-like infiltrate in the upper dermis, frequently with epidermotropism of solitary lymphocytes. Atypical lymphocytes were present in a minority of cases. Immunohistology showed a predominance of CD3+ T lymphocytes, in most cases admixed with clusters of CD20+ B-cells. Only a small proportion of the infiltrate was CD8+. Molecular analysis of the rearrangement of the T-cell receptor genes was performed in 16 cases using the polymerase chain reaction (PCR) technique and revealed a monoclonal band in 8 of them. After surgical excision, 2/14 patients had a recurrence near the surgical scar. In 18 patients with complete follow-up data, no evidence of "classic" MF could be observed after a mean follow-up of 31.9 months. Solitary skin lesions with the histopathologic features of MF can be considered as a distinct clinicopathologic entity, probably representing a solitary variant of mycosis fungoides.

Lymphoblastic leukemia/lymphoma (LBL) is a malignant neoplasm of precursor lymphocytes of B- or T-cell phenotype. Involvement of the skin is relatively uncommon. We examined retrospectively the clinicopathologic, immunophenotypic, and molecular genetic features of six patients with cutaneous involvement of LBL (B-LBL=5; T-LBL=1). Patients presented clinically with solitary, large tumors located on the head (3 cases) or the back (1 case), or with generalized tumors (2 cases). Ulceration was uncommon. In two patients the onset of skin lesions was concomitant to the diagnosis of lymphoblastic leukemia. Histopathologic examination showed in all cases a dense, diffuse, monomorphous infiltrate located in the entire dennis and subcutaneous fat. A typical "starry sky" pattern was observed in the majority of the lesions. In some areas neoplastic cells were aligned in a "mosaic-like" fashion. Cytomorphologically, medium sized lymphoid cells with round or convoluted nuclei, inconspicuous nucleoli and scant cytoplasm predominated. There were no significant differences in the histopathologic features of skin lesions in T- and B-LBL. In B-LBL, CD79a was more useful than CD20 in determining the phenotype of neoplastic cells (4/5 cases positive for CD79a as compared to 2/5 cases positive for CD20). TdT, CD10 and CD43 were positive in 4 cases, CD34 in 2. The case of T-LBL revealed positivity for CD1a, CD3, CD43 and TdT, and negativity for CD34 and for B-cell markers. All neoplasms were positive for CD99 and bcl-2, and showed a high proliferation rate. Molecular genetic analysis of J(H) and T-cell receptor (TCR) genes performed using a polymerase chain reaction technique revealed a monoclonal rearrangement of J(H) genes in all five B-LBLs. One of these cases showed also a concomitant TCR-gamma gene rearrangement. A monoclonal rearrangement of the TCR-gamma gene was detected in the case of T-LBL. Our study shows that skin lesions of LBL present characteristic clinicopathologic and molecular features allowing the differentiation from other cutaneous lymphomas, even in cases without clinical history of previous precursor lymphoblastic leukemia/lymphoma.

The importance of tumor-stroma interaction in many solid tumors of the skin has been demonstrated in recent years. Invasion and metastasis require multiple interactions of the tumor cells with the surrounding stroma. In malignant melanoma most studies concerning tumor-stroma interaction focus on the peritumoral infiltrate, whereas other aspects of tumor-stroma interactions have not been considered. We investigated two morphologic criteria of tumor-stroma interaction in melanocytic skin tumors. Simple infiltration into the surrounding dermis or subcutis without evident stromal reaction (DERMSIMPLE) and the existence of morphologically intact collagen bundles of the reticular dermis within the tumor bulk (PRECOLL) were examined in 373 benign common nevi, 239 dysplastic nevi, 322 Spitz nevi, 368 primary malignant melanomas, and 344 melanoma lesions metastatic to the skin. Our results showed that there is a highly significant difference in the expression of DERMSIMPLE and PRECOLL between benign and malignant melanocytic skin tumors. Concerning DERMSIMPLE, 13.3% of benign skin lesions compared with 28.2% of malignant lesions were positive for this feature; PRECOLL was found in 13.8% benign and 37.1% malignant lesions (chi-squared test; p = 0.0001 for both features). Furthermore, it could be demonstrated that simple infiltration into the surrounding stroma as well as the existence of morphologically intact collagen bundles of the reticular dermis within the tumor bulk increases with tumor progression; between primary malignant melanoma and melanoma metastatic to the skin, for example, there was a highly significant difference for DERMSIMPLE, as well as for PRECOLL (chi-squared test; p = 0.00001). These data indicate that morphologic aspects of tumor-stroma interactions in different benign and malignant melanocytic skin lesions may reflect biological behavior of tumor cells. The analysis of further aspects of tumor-stroma interaction and the relation to the patient's outcome may lead to the development of further prognostic parameters in malignant melanoma.

Objective: To investigate the immediate and long-term effects of photodynamic therapy with delta-aminolevulinic acid (ALA-PDT) on superficial basal cell carcinomas (BCC) and superficial squamous cell carcinomas (SCC)., Design: Retrospective study with 60 months of maximal follow-up., Setting: University-based hospital in Graz, Austria., Patients: Forty-seven subjects with a total of 95 superficial BCC and 35 superficial SCC., Interventions: A compound of 20% delta-aminolevulinic acid was topically applied under an occlusive and light-shielding dressing before exposure to either UV-A or different wave bands of polychromatic visible light (full-spectrum visible light, >515, >570, or >610 nm)., Main Outcome Measures: Primary tumor responses and recurrence rates in the long-term follow-up, as well as histological changes associated with ALA-PDT, were studied., Results: The complete primary response rate for all wave bands of light was 86% (82/95) for superficial BCC and 54% (19/35) for superficial SCC. There was no statistically significant difference among the response rates to the different wave bands of light. After a median follow-up of 19 months (range, 3-60 months) for BCC and 8 months (range, 3-47 months) for SCC, the overall recurrence rate was 44% (36/81) and 69% (11/16), respectively. At 36 months after therapy, the projected disease-free rate was 50% (95% confidence interval, 43%-57%) for BCC vs 8% (95% confidence interval, 7%-9%) for SCC (P<.001, log-rank test). Histopathologic studies revealed a significant increase of fibrosis in the dermis after ALA-PDT and appearance of a sharp border between fibrotic and nonfibrotic tissue. In 15 of 16 BCC examined, the border between fibrotic and nonfibrotic tissue was deeper in the dermis than the maximum tumor thickness before therapy (P<.001, Wilcoxon signed rank test). Similar histopathologic observations were made in SCC., Conclusions: Our study revealed poor long-term cure rates for superficial BCC and SCC treated with topical ALA-PDT and visible light. The histopathologic observations showing remarkable fibrosis in the dermis indicated that the effect of ALA-PDT reached deeper than the initial depth of invasiveness of the neoplastic tissue, suggesting in turn that the poor long-term results of ALA-PDT cannot be explained by insufficient penetration of the therapy effect.

The object of this study was to evaluate the prognostic impact of a cross-sectional area measured in routinely stained slides of cutaneous melanoma using fully automated image analysis. Hematoxylin-eosin stained slides of 238 specimens of primary cutaneous melanoma with Clark levels III to V were evaluated by digital image analysis using color video images, a scanning stage, and autofocus equipment. The cross-sectional area was significantly related to metastasis-free survival. Lesions with a cross-sectional area < or = 12 mm2 showed a 2-year metastasis-free survival rate of 92+/-2% compared with 41+/-8% in lesions with a cross-sectional area > 12 mm2 (log rank test: z = 71, p < 0.0001). The same was true for overall survival (98+/-1% compared with 82+/-6%; z = 42.12, p < 0.0001). In multivariate analysis, the cross-sectional area seems to provide prognostic information in addition to that provided by Breslow's index. In cases with regression and in small melanomas with vertical growth, however, metastatic spread may occur in lesions with a small cross-sectional area. It was concluded that automated measurement of the cross-sectional area may be helpful in assessing prognosis in cutaneous melanoma.

The microtubular system as one part of the cellular cytoskeleton is not only necessary for mitotic activity of malignant cells but also for invading neighboring tissues and for the formation of distant metastases. In the present study, the amount and distribution of tubulin in two murine melanoma cell lines (K1735-M2: high metastatic clone; K1735-c116: low metastatic clone) were determined quantitatively using an indirect immunofluorescence technique, confocal laser scanning microscopy (CLSM) and computer-assisted image analysis. Additionally, qualitative and quantitative changes after application of the microtubule-inhibitor nocodazole were investigated. Quantitative analysis showed a significant difference between the high and low metastatic cell line for the parameter TEXTURE, indicating a finer structured network within the high metastatic cells. After treatment with nocodazole the parameters TEXTURE and DENSITY were reduced, suggesting a decrease of assembled tubulin and a less delicate structure of the remaining microtubules. Our study shows that CLSM combined with computer-assisted image analysis provides a new method to examine quantitative variations of the cytoskeleton possibly related to cell function.

The CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects) is usually characterized by lateralization of all associated anomalies. It has been assumed that the event of X-inactivation coincides and interferes with a clone of organizer cells controlling a large developmental field. A 16-year-old girl with bilateral manifestations of CHILD syndrome is described. The inflammatory skin lesions affected the body folds (ptychotropism) in a symmetrical distribution, although only the right side of the neck was involved. In addition, absence of several facial muscles, vertebral defects, and shortening of the leg on the right side were noted, and a ventricular septum defect was present. This unusual case may be explained by the assumption that X-inactivation did not coincide with the origin of inducer cell clones controlling large morphogenetic fields on either side of the body.

Intercellular communication and the active movement of malignant cells into and through host tissue barriers play a critical role during the complex process of tumor invasion. Motile activity, cytoskeletal actin and vinculin organization as well as gap junctional communication of in vivo benign and malignant melanocytes were compared and related to in vitro invasiveness. Normal melanocytes, Melan-a, showed significantly less motile activity, a higher organization of the actin cytoskeleton and more vinculin-containing cell-substratum adhesion plaques than highly metastatic melanoma cells, K1735-M2. There was no pronounced difference in gap junctional communication under comparable culture conditions. However, cultivation of Melan-a cells in a conventional melanocyte growth medium containing the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) enhanced intercellular communication. Melanocytes were less invasive than melanoma cells both in the embryonic chick heart model and in the Matrigel invasion assay. The least invasive activity was determined for melanocytes cultivated in TPA-deficient medium indicating that the medium supplement TPA stimulates invasion. The comparison of certain in vitro properties of both melanocytic cell lines revealed a positive correlation of motility with in vitro invasion, whereas an inverse correlation was found for the degree of actin filament organization as well as for the number of vinculin plaques. Gap junctional communication was not directly related to in vitro invasiveness.

Stromal relationships are crucial to metastatic spread of solid malignancies. Some aspects of this stroma interaction are obviously associated with particular morphological features, which may carry prognostic significance. In cutaneous melanoma, level of invasion, arrangement of cells (horizontal or vertical growth phase), neovascularization, vessel invasion, architecture of the border, and inflammatory infiltrate have been examined. Expression of adhesion molecules, signalling factors, cytoskeletal components, extracellular matrix molecules and matrix-degrading enzymes have been assessed by immunohistology and in situ hybridization. Besides providing prognostic information, a thorough evaluation of stromal relationships may help to increase our knowledge about factors mediating the growth and metastatic spread of malignancies.

Cancer cell surface glycosphingolipids are considered to play a critical role in tumor growth and metastasis. However, the implications of glycoconjugates in the control of cell motility, which is considered to be involved in tumor invasion, are not fully understood. In this study, the effects of a series of synthetic sphingosine derivatives, obtained by the chemical transformation of azidosphingosines, on directional migration of K1735-M2 melanoma cells grown on type I collagen-coated surfaces were investigated. Following the application of 60 microM (2R, 3S, 4E)-2, 3-epimino-4-octadecen-3-ol (S4) the migration rate was 94 +/- 10 microns/day, compared with 377 +/- 22 microns/day in the control experiment. Six other analogues were not as potent. S4 also considerably down-modulated melanoma single cell motility. Inhibition of motile activity was associated with changes in the actin filament organization as well as with changes in the number and distribution of vinculin plaques. Moreover, the compound reduced the attachment abilities of melanoma cells to basement membrane Matrigel. Tumor cell invasion, however, was less affected and proliferation remained unimpaired after treatment with S4. These data suggest at least one intracellular mode of action of this particular synthetic sphingosine derivative by modulation of cytoskeletal organization. Melanoma cell motility and growth may be controlled independently via glycosphingolipids.

Objective: There is abundant evidence that patterning in life sciences may be closely related to the functional properties of the constitutive elements. In order to estimate some of these functional properties by examining the static pattern evolved, pattern interpretation by cellular automata (PICA) was introduced and applied to the mechanisms of tumor growth. Previously it was shown that the estimates concerning tumor cell proliferation and motility were consistent with those obtained by other methods., Study Design: Morphologic patterns obtained by growing two variants of the C4 cervical carcinoma cell lines with different in vitro adhesive properties in the hamster cheek pouch were evaluated by PICA., Results: PICA estimates of tumor cell cohesion turned out to be significantly higher in tumors derived from the C4-I cell line (0.73 +/- 0.02 SD) with high in vitro cohesiveness than in tumors derived from the less adhesive C4-II cell line (0.32 +/- 0.04 SD; t test, P = .001)., Conclusion: These results indicate that functional estimates concerning tumor cell cohesion obtained by PICA may be in good agreement with in vitro observations of the same cellular property and further underscore that PICA may be a useful tool for the functional interpretation of static histologic patterns.

Nevoid basal cell carcinoma (BCC) syndrome is a genetically linked disorder characterized by multiple BCCs associated with various skeletal abnormalities and sometimes with mental retardation. Because of the large number of lesions, treatment of BCCs in these patients may be extremely difficult. The value of different therapeutic options was assessed in a patient with multiple, disfiguring nevoid BCC syndrome. Surgical excision and split-skin grafting was used to remove three larger tumors. Photodynamic therapy led to healing of flat lesions; small papules within the treated areas, however, did not respond to this type of management. Three nodular BCCs treated with intralesional application of interferon alfa-2b were markedly reduced in size. Still, complete healing could not be achieved. Nodular lesions vaporized with the CO2 laser disappeared and showed no recurrence after 2 years of follow up. Our experience indicates that CO2 laser vaporization of BCCs allows the treatment of a large number of lesions in a single session, and is indicated when surgical treatment is not feasible for all lesions. Photodynamic therapy with 5-amino-levulinic acid may be a valid therapeutic option for flat lesions only. Intralesional application of interferon alfa-2b removes papular lesions of small size.

Invasion of a tissue by distinct cell types is common to various biological processes including embryonic development and tumour growth. Active movement is usually considered to be a prerequisite for invasiveness. Using a computer simulation program based on a stochastic cellular automata model, we provide evidence that invasive patterns may evolve in the absence of active cellular motility. Cells characterized by low proliferation, a high rate of cell loss, pronounced tumour-stroma adhesion and an expansive instead of a destructive behaviour invade the surrounding matrix, despite a complete lack of active movement. The resulting morphological patterns are similar to those obtained with motile cells. Thus invasion does not necessarily indicate the presence of motility.

Cell motility and the ability to grow invasively are crucial properties within the metastatic cascade. The relation of cell motility in vitro and metastatic behaviour of tumour cells in animal experiments indicates that they are directly correlated. We undertook this study to see whether a quantitative correlation could be found in complex in vitro systems. Using the assay of directional migration and a newly developed image analysis system to measure cell motility of K1735-M2 mouse melanoma cells and the embryonic chick heart assay of Mareel to follow invasion, we examined the influence of eight compounds on cell motility seven compounds on invasion. For stationary motility we calculated the change of density, area of change, area of ruffling sites (representing only changes at the leading edge and tail of the cell), number of ruffling sites, area of changing intracellular particles and number of intracellular particles. Velocity of single tumour cells and directional migration were also measured. In the invasion assay the parameters STRCSTR and INVASLOG, expressing different forms of stromal (i.e. embryonic chick heart) disintegration and degradation, were calculated. Directional migration and all parameters of stationary motility except number of ruffling sites, changing intracellular particles and number of changing intracellular particles correlated significantly (p < 0.05) with STRCSTR and INVASLOG. For velocity, area of change and area of ruffling we found the most significant correlation with parameters of invasion indicating that both stationary and translocative motility contribute to invasion. Our systems also showed that the compounds tested exerted differential effects on various aspects of motility.(ABSTRACT TRUNCATED AT 250 WORDS)

Confocal laser scanning microscopy (CLSM) is a new optical microscopic technique, which offers significant advantages over conventional microscopy. CLSM is microscopy of optical sections. Light, which is emitted from regions other than the focal plane, is cut off by introducing a diaphragm in the beam path. The result is an optical "slice", which shows more details because the blurring from out of focus haze disappears. It has been repeatedly used in experimental, but also in diagnostic dermatopathology. The "in vivo" confocal microscopy, applied directly to the intact skin provides details of living cells in the superficial layers comparable to that of fixed and stained tissue. While the extent of its future applications is hard to predict, its potential for applications in dermatology appears enormous, particularly for studies of fixed or living tissues, where it is desirable to obtain clear images many micrometers below the surface of the tissue under examination.

Chemoprevention, the use of drugs to prevent invasive neoplasia, has gained increasing significance in recent years. Especially for the skin, chemoprevention will become of importance, because large areas of the skin are exposed to environmental carcinogenic factors. Furthermore, many skin diseases predispose to the development of multiple skin tumors. One group of chemopreventive agents are the retinoids, which are effective modulators of cell proliferation and differentiation in normal as well as in transformed tissues. Though the mechanism of action of retinoids is not yet fully understood at the molecular level, chemoprevention studies have demonstrated the ability of retinoids to prevent the development of skin cancer, particularly in patients with xeroderma pigmentosum, multiple basal cell carcinoma and oral leukoplakia. A better understanding of the carcinogenic process should improve our ability to develop effective chemoprevention strategies.

A 20-year-old female patient with the typical signs of Wissler's subsepsis allergica (Wissler-Fanconi syndrome) is described. This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia. In the early stages it is difficult to differentiate from septicaemia. This syndrome has sometimes been considered equivalent to or an initial stage of Still's disease (juvenile rheumatoid arthritis) progressing to degenerative arthritis in many patients, whereas other authors have classified it as a separate entity with good prognosis. The present case demonstrates that Wissler's subsepsis allergica should be considered when ever transient polymorphous exanthema is accompanied by high recurrent fever, leucocytosis and arthralgia.

Melanoma cell invasion in vitro was tested by means of confrontation cultures of melanoma multicellular spheroids with rounded fragments of embryonic chick heart tissue. Quantitative determination of invasion was performed using a computerized image analysis program, facilitating the evaluation of the efficacy of potentially anti-invasive compounds. Retinoic acid (RA; 1 microM) [corrected] considerably impaired K1735-M2 melanoma cell invasion, as demonstrated by various measuring parameters. Parameter TUMAREA, expressing the amount of tumor tissue, indicates a growth inhibitory effect and the invasion parameter STRCSTR shows that after treatment with RA the stromal component was better preserved than in untreated controls. Besides the inhibitory effect of RA on melanoma cell invasion in confrontation cultures, RA increased the dynamics of adhesion of melanoma cells to the extracellular matrix components type I collagen and laminin, and slightly impaired melanoma cell directional migration. Fluorescence microscopy using rhodamine-labeled phalloidin showed that RA also modulated the organization of the actin cytoskeleton by inducing the formation of actin-containing stress fibers. Our data show that 1 microM RA exhibited a pronounced anti-invasive effect on highly metastatic melanoma cells in vitro. Impairment of host tissue degradation, altered adhesion abilities, changes in the actin cytoskeleton, as well as the antiproliferative effect may all account for inhibition of melanoma cell invasion.

In the present study we investigated whether there is a correlation between Langerhans cell density, peritumoral infiltrate or intraepithelial T-lymphocyte density within 17 epithelial skin tumors using immunohistologic and morphometric methods. We found a significant difference between seborrheic keratosis, basal cell carcinoma, and squamous cell carcinoma. No correlation was found between the Langerhans cell density and the number of intraepithelial T lymphocytes or between Langerhans cell density and the peritumoral infiltrate. A significant (inverse) correlation was found between mean nuclear area of the epithelial tissue and the number of Langerhans cells. These data might indicate that the number of Langerhans cells does not influence the extent of the anti-tumoral immune response, but that there is an association between the differentiation state of the epithelium and Langerhans cell density.

Tumor cell motility and tumor cell proliferation are supposed to be essential for tumor invasion. The cytoskeleton, which consists of different components, is considered to be important for maintaining cell shape and facilitating cell movement. Numerous data are available about tumor cell motility in vitro, but the behavior of tumor cells in vivo is as yet poorly understood. In the present study, estimates of tumor cell motility and proliferation were statistically derived from morphological tumor patterns in human melanocytic skin tumors, and their relationship to expression of certain cytoskeletal components was evaluated. Overexpression of vimentin within tumor cells correlated with low actual tumor cell motility and proliferation, indicating a structurally stabilizing function of these filaments. An overexpression of actin was found within tumor cells of high motility and proliferation, suggesting the contribution of cytocontractile elements to active tumor cell locomotion in situ. Concerning the cytoskeleton of the stromal cells, expression of actin, myosin and tubulin correlated with a high number of motile tumor cells and high mitotic counts. Thus increased tumor cell motility seems to be associated with cytoskeletal changes not only of the tumor cells themselves but also of the surrounding stromal cells.

In malignant melanoma active movement of cancer cells is considered to be essential for tissue invasion. Various mechanisms, such as the Ca(2+)-calmodulin-proteinkinase C cascade or G-protein-dependent processes are considered to play a role in tumor cell functions. The assay of directional migration, combined with computer-assisted image analysis, was used to evaluate the antimigratory efficacy of drugs interfering with different steps of signal transduction pathways. Treatment with different compounds showed a more or less concentration-dependent reduction of migration rates: The Ca(2+)-channel blockers verapamil and devapamil showed a slight reduction of motility. The effect was more pronounced when the calmodulin antagonist flunarizine was used or the proteinkinase C inhibitors dequalinium, tamoxifen and H-7 were applied. A marked inhibition of motility was found with the G-protein antagonist L 651582. Thus, our results indicate that different signal transduction pathways are involved in the regulation of directional migration of K1735-M2 melanoma cells.

Cationic lipophilic compounds have an antiproliferative effect on certain tumour systems in vitro and in vivo. We have investigated whether the cationic lipophilic compound dequalinium affects not only proliferation but also motility and invasion of the highly metastatic and highly invasive melanoma cell line K1735-M2. Proliferation was assessed in monolayer cultures and in multicellular spheroids, motility was estimated in the assay of directional migration, and invasiveness was tested through confrontation cultures of tumour multicellular spheroids with embryonic chick heart tissue evaluated by computerized image analysis. 2 mumol/l dequalinium impaired melanoma cell proliferation, reduced directional migration and significantly blocked invasion in vitro. On the ultrastructural level, dequalinium caused obvious changes in mitochondria of both melanoma and embryonic chick heart cells. The mechanisms of the antiproliferative, antimigrating and antiinvasive effects remain to be determined. Inhibition of protein kinase C, calmodulin antagonism, DNA intercalation and/or direct effects on mitochondrial functions may be considered.