Tumor-infiltrating T cells in primary cutaneous B-cell lympho-proliferative disorders.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are considered to play an important role in the antitumoral immune response. The presence and percentage of CD8-positive tumor-infiltrating T cells have been shown to correlate with differentiation and prognosis in various neoplasms. The aim of this study was to determine the number of CD8-positive T cells in various primary cutaneous B-cell lymphoproliferative disorders and to evaluate its correlation with the histological type of tumor. METHODS: Fifty-three lesions were examined by immunohistochemistry with antibodies targeting CD3, CD4, CD8 and TIA-1. Thirty-two lesions had been diagnosed as primary cutaneous B-cell lymphomas (CBCL) and 21 as B-cell pseudolymphomas (B-PSL). CBCLs included 15 follicular lymphomas (FL), 6 marginal zone lymphomas (MZL), and 11 diffuse large B-cell lymphomas (LCL). The number of CD8-positive cytotoxic T cells was determined by computer-assisted morphometrical microscopy. RESULTS: No significant difference could be detected in the density of CD8-positive T cells in B-PSL (101/105 microm(2)), FL (110/105 microm(2)), and MZL (122/105 microm(2)). In contrast, the number of CD8-positive cells (55/105 microm(2)) in LCL was significantly lower (p<0.01) compared to B-PSL, FL and MZL. CONCLUSIONS: In summary the number of CD8-positive T cells in B-cell lymphoproliferative disorders differs in regard to tumor type and differentiation with lowest numbers in diffuse large B-cell lymphomas. However, due to an overlap of the number of TILs, this parameter cannot be employed as a diagnostic parameter for individual cases.

[Multiple miliary osteomata cutis. Excision with "front lift" approach]. / Multiple miliäre Osteomata cutis. Exstirpation mittels "front-lift"-Zugang.

Multiple miliary osteomata of the skin commonly occur on the face and the upper trunk of young healthy women. The mechanism of bone formation is unknown. There is no adequate therapy, which reduces or reverses the growth of osteomatas. Those tumours which are cosmetically disturbing may be excised by a small incision through the skin. For the first time we report their removal via the subcutaneous "front-lift" approach.

[Immuno-intervention in cutaneous lymphomas]. / Immunintervention bei kutanen Lymphomen.

Cutaneous lymphomas are a heterogeneous group of lymphoproliferative disorders. Most of the cutaneous lymphomas present a rather good prognosis because they disseminate to internal organs late in the disease process, if at all. Since radiotherapy and intensive chemotherapy have limited efficacy, immunological interventions are regularly used in this disease group. These interventions include unspecific treatment modalities such as Interferon-alpha, Interleukin-2, but also rather specific interventions like photopheresis, fusion toxins and as a new development, antigen-loaded dendritic cells. A new humanized anti CD20-antibody can be used for patients with cutaneous B-cell lymphomas, expressing the B-cell antigen CD20 in most of the cases. We expect that new information on the immunobiology of these diseases will allow more specific immunological interventions, providing the basis for a better therapy with optimal tolerability for patients suffering from cutaneous lymphomas.

Angiogenesis in cutaneous lymphoproliferative disorders: microvessel density discriminates between cutaneous B-cell lymphomas and B-cell pseudolymphomas.

The role of angiogenesis in neoplastic disorders is supported by the evidence that tumor growth beyond a certain size requires induction of new blood vessels. The extent of tumor-associated angiogenesis, measured as microvessel density (MVD), has shown to correlate with aggressiveness and the prognostic outcome in several malignant neoplasms. Few data have been reported on the angiogenic response in lymphoproliferative diseases. In this study, the MVD has been assessed in benign and malignant primary cutaneous B-cell lymphoproliferative disorders. MVD was determined in formaldehyde-fixed, paraffin-embedded specimens of primary cutaneous B-cell lymphomas (CBCL; n = 18) and cutaneous B-cell pseudolymphomas (B-PSL; n = 22) according to previously described protocols but was performed using computer-aided microscopic morphometry. The endothelial cells of microvessels were identified by immunohistochemical staining for factor VIII-related antigen and CD31. The MVD was 99 dots/mm2 for CBCL and 68 dots/mm2 for PSL, and a MVD of 115 dots/mm2 for CBCL and 73 dots/mm2 for PSL by using an antibody against factor VIII-related antigen and CD31 antigen, respectively. Univariate analysis revealed statistically highly significant differences in MVD between CBCL and B-PSL (P = 0.0036 with staining for factor VIII-related antigen and P = 0.0002 with staining for CD31 antigen). This study analyzes for the first time the angiogenic response in CBCL compared with that of B-PSL and demonstrates that MVD discriminates between CBCL and B-PSL. However, because of an overlap in the ranges of MVD in CBCL and PSL, the MVD is not useful as a diagnostic tool in individual cases.

Intralesional therapy with anti-CD20 monoclonal antibody rituximab in primary cutaneous B-cell lymphoma.

BACKGROUND: We report the use of a new treatment modality in 2 patients with primary cutaneous B-cell lymphoma. In a 58-year-old woman with progressive nodular lesions on the scalp and face, several treatment attempts either failed or could not be used because of severe adverse effects and underlying epilepsy. The patient declined radiotherapy. A 30-year-old man presented with recurrence of tumor nodules occipitally, thoracically, on the arm, and on the right thigh after several excisions. OBSERVATIONS: Intralesional injection of rituximab, a chimeric antibody directed against the CD20 transmembrane antigen present in malignant and normal B cells, resulted in partial regression of tumor nodules. No adverse effects occurred except pain during or shortly after injection and, in one patient, a slight rise in body temperature. Due to the treatment a prolonged complete disappearance of B cells from peripheral blood samples was observed. CONCLUSION: Intralesional rituximab therapy is a nontoxic and effective treatment for cutaneous B-cell lymphoma that deserves further investigation in larger clinical trials.

Tumor burden index as a prognostic tool for cutaneous T-cell lymphoma: a new concept.

OBJECTIVES: To introduce a prognostic tool for cutaneous T-cell lymphoma that takes into account the tumor burden and to compare the prognostic value of this tumor burden index (TBI) with that of other prognostic factors. DESIGN: Retrospective clinical and statistical study. PATIENTS: One hundred sixteen patients with cutaneous T-cell lymphoma. METHODS: A TBI was designed that takes into account the types, numbers, and severity of skin lesions with the use of the Cox proportional hazard model. RESULTS: Models of the TBI were developed to test the relative contributions of patches, plaques, and tumors to the total tumor burden and, hence, survival time. Weighting factors reflecting the severity of each skin lesion were tested and incorporated. The best prognostic correlation was a dichotomized index with the following formula: TBI = 1 + (patches x 2) + (plaques x 2) + (tumor x 1.3), where the patches factor equals 0 if 30% or less of the skin area is involved and 1 if greater than 30% of the skin area is involved and where the plaque or tumor factor equals 1 if plaques or tumors are present. Both the TBI and TNM provided predictive information. Discrimination of survival curves and significance of differences was better for TBI (P < .001) than for TNM (P = .009). Sex was also statistically related to survival (males had a better prognosis; P < .04), whereas neither age at first symptoms (P = .35) nor age at time of diagnosis (P = .36) was of prognostic value. CONCLUSIONS: The TBI offers a simple prognostic index for the evaluation of cutaneous T-cell lymphoma. It may become a valuable tool for designing therapeutic strategies for patients according to their specific survival expectancies. However, this model is preliminary and has to be validated on a larger number of patients.

[An unusual hemorrhagic variant of Stevens-Johnson syndrome in an HIV-infected patient]. / Ungewöhnliche hämorrhagische Variante eines Stevens-Johnson-Syndroms bei einem HIV-infizierten Patienten.

Cutaneous adverse drug reactions in HIV-positive patients with their wide spectrum of manifestations remain a diagnostic and therapeutic challenge. Skin diseases as erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis belong to this group. The typical primary lesions are erythematous macules and papules, which rapidly extend to the entire body and may be accompanied by a extensive epidermal detachment. Diagnosis and immediate therapy is indispensable because of the possible fulminant course of the disease. We report a HIV-positive patient with a cutaneous adverse drug reaction showing predominantly hemorrhagic lesions.

Pyoderma gangrenosum associated with the secondary antiphospholipid syndrome.

A 64-year-old woman with an 11-year history of systemic lupus erythematosus and amputation of her left lower leg as a consequence of arterial embolism, presented with two large, non-healing ulcers on her right shank. Pyoderma gangrenosum associated with secondary antiphospholipid syndrome was diagnosed based upon the typical clinical features and increased antibodies to cardiolipin. Although an aggressive therapy with corticosteroids and cyclosporine was started, her condition continued to worsen. She finally died as a result of sepsis. We discuss the difficulties in diagnosis and therapy of SLE combined with the antiphospholipid syndrome and pyoderma gangrenosum.

[Allergy to shrimp. A contribution to reactions after ingestion of seafood and fishes]. / Zur Allergie auf Krevetten. Ein Beitrag über Reaktionen nach Genuss von Meeresfrüchten und Fischen.

Adverse reactions to seafood are common and may cause many types of symptoms that are difficult to define. The nature of these reactions are variable including allergic and toxic reactions as well as infectious diseases. The differentiation between these entities is essential in choosing therapy. We describe 9 patients with IgE mediated allergic reactions due to crustaceans and fish diagnosed from case history, clinical findings, skin tests and specific IgE antibodies. Most symptoms of a IgE mediated allergic reaction appear within 30 minutes after ingestion. Characteristics clinical features may include an urticarial rash, gastrointestinal symptoms and even anaphylaxis. In this case immediate therapy with intravenous glucocorticoids, antihistamine and perhaps subcutaneous epinephrine is required.

Acne conglobata and Klinefelter's syndrome.

Acne conglobata has been reported to be more common and more severe in XYY chromosomal aberration than in normal subjects. Whereas only exceptional cases have been observed in the more common XXY Klinefelter karyotype. We report a 17-year-old male with both Klinefelter's syndrome and acne conglobata, spreading from face to upper arms, trunk, buttocks and upper legs. The serum level of testosterone was normal, whereas luteinizing hormone and follicle-stimulating hormone were elevated. Skin lesions responded well to a combined therapeutic regimen including oral isotretinoin and prednisolone. An overview of severe acne in relation to chromosomal abnormalities is given and diagnostic and therapeutic options discussed.

Juvenile amyopathic dermatomyositis.

We report a 15-year-old girl with a 10-year-old history of typical skin features of dermatomyositis (DM) without evidence of muscle involvement. Amyopathic dermatomyositis (ADM) is defined by the presence of biopsy confirmed classic cutaneous findings of dermatomyositis in the absence of any clinical or laboratory signs of muscle disease for at least 2 years after onset of skin pathology. To exclude muscle involvement muscle enzymes should be normal; moreover additional use of magnetic resonance imaging and muscle ultrasound is currently being proposed. It is as yet undetermined, whether early aggressive immunosuppressive treatment of ADM might prevent the development of myositis at a later date or influence the course of the skin disease. In a paediatric patient with ADM we advocate a more expectant attitude with careful and regular monitoring for possible development of muscle disease.

[Current therapy concepts in cutaneous T-cell lymphomas]. / Moderne Therapiekonzepte bei kutanen T-Zell-Lymphomen.

Cutaneous T-cell-lymphomas (CTCL) include a group of rare diseases that are characterized by an accumulation of clonal T-lymphocytes in skin. The various disease entities may be classified by an adapted Kiel classification. For staging purposes the TNM system is most commonly used. Treatment modalities depend on the extent and the aggressiveness of the disease (low- or high-grade lymphoma) and on the individual situation of the patient. Stage-adapted therapy is currently recommended. Early stages of low-grade CTCL are successfully treated with PUVA, retinoids or interferon-alpha. Extracorporeal photopheresis is the treatment of choice in stage III patients with Sézary syndrome. Alternative therapeutic modalities for CTCL, such as radiotherapy, chemotherapy or various experimental protocols, are discussed.

Topical glucocorticoids with improved risk-benefit ratio. Rationale of a new concept.

Topical glucocorticoids for dermal application were introduced more than 40 years ago and revolutionised the treatment of inflammatory skin diseases. Today these drugs are frequently administered, although systemic and local adverse drug reactions, especially skin atrophy, are feared complications of their use. This literature review evaluates the present state of topical glucocorticoid therapy for inflammatory skin diseases. Several attempts have been made to increase the safety of topical glucocorticoid treatment. With respect to conventional compounds, new application schedules, as well as new vehicles, have been proposed. New derivatives have also been synthesized, forming the novel group of nonhalogenated double-ester-type glucocorticoids. Among these latter compounds, prednicarbate and 6-methyl-prednisolone aceponate have been characterised most thoroughly. According to in vivo studies, their anti-inflammatory activity is in the order of that of betamethasone valerate (a frequently used medium potency glucocorticoid, which is obtained by halogenation of the pregnane nucleus of the steroid molecule). Furthermore, these new congeners induce less skin atrophy than conventional glucocorticoids, as determined by in vivo and in vitro studies. Qualitative and quantitative assessment of the therapeutic and adverse effects of non-halogenated double-ester-type glucocorticoids suggests an increased benefit-to-risk ratio.

Interaction of cultured human keratinocytes with liposomes encapsulating silver sulphadiazine: proof of the uptake of intact vesicles.

There is evidence to suggest that human keratinocytes grown in vitro are capable of engulfing and subsequently disintegrating intact liposomes. However, as the liposomes used in this context did not carry an electron-dense marker, the possibility that the lamellar structures seen within the keratinocytes were composed of material produced within the cell could not be excluded. We therefore decided to investigate liposome-keratinocyte interaction using an electron-dense marker. Human keratinocytes obtained from juvenile foreskins were cultured in a serum-free medium, and subconfluent cultures were exposed to liposomally encapsulated and free silver sulphadiazine 1% (SSD), and a corresponding vehicle, for 5 min to 24 h. After fixation ultra-thin sections were analysed electron microscopically at magnifications of up to x85,000. Many keratinocytes treated with liposomal and free SSD showed marked damage to the plasma membranes and the cell organelles. The phagocytosis of intact liposomes was demonstrated by the appearance of silver-labelled unilamellar vesicles within the cytoplasm of undamaged keratinocytes. The labelled liposomes were found enclosed in cellular unit membranes, i.e. in lysosomes. In addition, perinuclear disintegration and release of the entrapped marker were observed. Silver particles, as present in liposomally encapsulated SSD, were found to be adequate markers for electron microscopy. Our results confirm the phagocytosis of intact liposomes by keratinocytes in vitro. In addition, the cytotoxic effects of liposomal (intended for the treatment of burns) and free SSD on human keratinocytes were studied in detail. Many keratinocytes treated for 10 min or more were severely affected.

[Three-quadrant syndrome in Klippel-Trenaunay syndrome and primary lymphedema of both legs]. / Drei-Quadranten-Syndrom bei Klippel-Trenaunay-Syndrom und primären Lymphödemen beider Beine.

A 34-year-old woman with extensive Klippel-Trenaunay syndrome is presented. Clinical and radiological tests demonstrated that three quadrants are affected with haemangiomas, varicose veins and bone abnormalities. In addition, our patient suffers from congenital lymphoedema of both legs. Associated findings such as intestinal haemangiomata, vascular hamartomas, lipoma or arteriovenous abnormalities of the spinal cord were not apparent. The treatment is only symptomatic with compression bandages and an orthopaedic appliance for compensation of the different leg length.

Coal tar, pine tar and sulfonated shale oil preparations: comparative activity, efficacy and safety.

BACKGROUND: Tar and sulfonated shale oil preparations are used in the treatment of a variety of inflammatory skin diseases, including psoriasis vulgaris; due to the high polycyclic aromatic hydrocarbon (PAH) content of tars, a possible relationship with cancer in humans has been postulated. On the other hand, the purity of sulfonated shale oils concerning PAHs guarantees a good tolerability during dermatologic therapy. AIM: In this review, it is attempted to compare activity, efficacy and safety of coal tar, pine tar and sulfonated shale oil preparations which currently play a role in dermatologic treatment. RESULTS AND CONCLUSIONS: Primary sources of PAHs in the normal human environment are forest fires, cigarette smoke and combustion of fossil fuels for heating and energy. Thermal processing of fossil substances is also required for the production of tars and sulfonated shale oils. Due to individual manufacturing techniques, tars and sulfonated shale oils differ completely in their chemical composition. Still, sulfonated shale oils are often falsely grouped as tars because of their related origin and similar dermatologic indications. There is at least limited evidence of the activity and efficacy of various tars as well as sulfonated shale oil preparations in different frequent inflammatory skin diseases. This includes psoriasis vulgaris and atopic eczema of glabrous as well as hairy skin. There is still some concern about the long-term tolerability of tar preparations at least in some contexts. This, however, does not apply to sulfonated shale oil preparations. Consequently, at least their use should still be considered a rational drug treatment in dermatology.

Interaction of liposomes with human epidermis reconstructed in vitro.

Upon topical application of liposomes of the large unilamellar vesicle type to human epidermis reconstructed in vitro, there is a dose-dependent alteration of the morphology of both the stratum corneum and the living part of the epidermis. In particular, shrunken lipid droplets are found between corneocytes and keratinocytes. Sometimes, corneocytes show inclusions reminiscent of 'cholesterol crystals'. Corneocytes, moreover, show a decreased density. Both corneocytes of the various layers of the stratum corneum and keratinocytes belonging to the uppermost layer of the living epidermis show particularly osmophilic membranes, indicating lipid transfer. Intact liposomes or their remnants can sometimes be seen between corneocytes of the upper strata. The presence of liposomal lipid within the stratum corneum is supported by the presence of gold particles used as a marker. There is, however, no evidence for the uptake of intact liposomes by the living epidermis, or their passage through this compartment of the skin.

The concept of the acid mantle of the skin: its relevance for the choice of skin cleansers.

Whereas soap has long been the only cleansing agent, a new generation of cleansers, the so-called synthetic detergents or syndets, has been developed during the last decades. They offer a wide variety of formulations and are therefore becoming more and more important for cleansing of diseased and healthy skin. Among the syndets, especially those with a pH of about 5.5 seem to be relevant. In contrast to alkaline soap, they do not interfere with the cutaneous microflora, whose composition is linked to the skin surface pH. As their irritancy potential might be even lower than that of soap, the benefit-to-risk ratio of syndets appears favorable.