Histopathologic and ultrastructural study of lupus-like skin lesions in a patient with Bloom syndrome.

The histopathology of the lupus-like skin lesions associated with Bloom syndrome has been sporadically described. Skin biopsies from a 2-year-old boy with the classical features of Bloom syndrome, including lupus-like skin lesions, demonstrated marked interface changes with basal liquefaction degeneration, a moderate superficial mononuclear infiltrate, pigmentary incontinence, and capillary dilation in the papillary dermis. Immunophenotyping of the dermal infiltrate revealed predominance of T-cells. Basement membrane thickening on periodic acid-Schiff examination was not seen. Direct immunofluorescence failed to demonstrate deposits of immunoglobulin other than nonspecific IgM deposition along the basement membrane zone of lesional skin. Ultrastructurally, the most striking findings were disintegration of basal cell cytoplasm and tubuloreticular inclusions in vascular endothelia. Taken together, the histologic and ultrastructural features of lupus-like lesions associated with Bloom syndrome mimic those of cutaneous lupus erythematosus, with the exception of paucity of immune deposits at the dermoepidermal junction.

Expression of intercellular adhesion molecule 3 (CDw50) on endothelial cells in cutaneous lymphomas. A comparative study between nodal and cutaneous lymphomas.

Advances in the molecular definition of surface proteins (adhesion molecules) involved in tumor metastasis may help to explain the invasive behavior of malignant tumors, that is, the migration of tumor cells involving reversible adhesive contacts, their release in the circulation, and their extravasation into distant sites. Intercellular adhesion molecule-3 (ICAM-3), the third receptor for the lymphocyte function-associated antigen molecule-1 (LFA-1) was recently characterized. We investigated fresh frozen skin biopsies from 10 patients with mycosis fungoides, four with pleomorphic T-cell lymphoma, six with Sézary syndrome, 10 with primary cutaneous B-cell lymphoma, and 10 with eczematous lesions as controls. The biopsies were compared with lymph node biopsies of five patients with known cutaneous T-cell lymphoma (CTCL), 10 with primary nodal B-cell lymphoma, and 11 with lymph-node specimens showing dermatopathic lymphadenopathy as controls. The specimens were stained with ICAM-3 antibody (Bender Medical Science) using the alkaline phosphatase antialkaline phosphatase method. Using cytomorphologic criteria, neoplastic lymphocytes could be differentiated from smaller reactive cells. Staining intensities were classified semiquantitatively as follows: 4, strong expression in 75 to 100% of the tumor cells; 3, 50 to 75%; 2, 25 to 50%; 1, 5 to 25%; and 0 fewer than 5% of the tumor cells. The endothelial cells in skin biopsies of seven of 30 primary cutaneous lymphomas expressed ICAM-3. In contrast, no expression of ICAM-3 could be demonstrated on endothelial cells in lymph nodes infiltrated with tumor cells of CTCL. Finally, endothelial cells of lymph nodes infiltrated with primary nodal B-cell lymphomas showed expression of ICAM-3 in three of 10 patients. The endothelial cells in the 11 control patients presenting with both eczematous lesions and dermatopathic lymphadenopathy showed no staining for ICAM-3. Every patient who expressed ICAM-3 on endothelial cells showed systemic spread of this disease. The findings suggest that ICAM-3 expression may be induced on endothelial cells in late-stage cutaneous lymphomas, probably by a cytokine-mediated mechanism.

A realistic approach to the sensitivity of PCR-DGGE and its application as a sensitive tool for the detection of clonality in cutaneous T-cell proliferations.

The practical value of the detection of clonality within the T-cell receptor gamma locus by polymerase chain reaction for the diagnosis of cutaneous T-cell lymphomas is well known. However, studies dealing with this subject so far, with special emphasis on the sensitivity of the technique in comparison to, for example, Southern blotting have used mixtures of DNA in various concentrations instead of using mixtures of the cells involved, which would reflect the in vivo situation in a more realistic scope. The purpose of this study was therefore to determine the sensitivity and the limitations of the PCR assay by dilution experiments, using mixtures of cells. Furthermore we studied its applicability to cutaneous T-cell proliferative disorders. Two clonal T-cell lines (MyLa and Jurkat) served as positive control. Dilutions of MyLa cells, cultured normal human keratinocytes and peripheral blood mononuclear cells from lymphoma negative volunteers were used to assess the sensitivity of the PCR-DGGE assay. Skin samples from 4 patients with cutaneous T-cell lymphoma, 1 lesional lymph node, 2 blood samples from a patient with Sézary syndrome and 4 lymphoma-negative tissue samples were analysed. Two samples were uncertain for diagnosis of lymphoma. The PCR-DGGE assay consisted of a 2-round nested PCR with consensus primers within the TCR-gamma locus followed by electrophoretic separation of the product along a denaturing urea/formamide gradient gel. PCR-DGGE sensitivity was, to our knowledge, for the first time investigated for mixtures of lymphocytes (clonal and polyclonal) and keratinocytes. Clonal T-cells were detected in a concentration between 1-0.1% in keratinocytes, whereas the sensitivity was generally lower upon dilution in peripheral blood mononuclear cells or in a mixture of keratinocytes and peripheral blood mononuclear cells. Nevertheless, T-cell clonality was detected in 2 blood samples of a patient with Sézary syndrome, which were negative by Southern blot analysis. The crucial point of this work was the new approach to establish the sensitivity of the PCR-DGGE, in a way which more closely mimics the condition of clinical specimens. Instead of mixing and amplifying DNA extracted from clonal T-cell lines and polyclonal bone marrow cells, we amplified DNA from clonal and polyclonal cells which had been mixed in various ratios before DNA extraction. Polymerase chain reaction in conjunction with denaturing gradient gel electrophoresis is a sensitive and versatile molecular tool for the assessment of clonality of suspect cutaneous lesions. The determination of sensitivity using DNA extracted from premixed cells more closely corresponds to the actual test situation when testing skin samples.

Clonal disease in extracutaneous compartments in cutaneous T-cell lymphomas. A comparative study between cutaneous T-cell lymphomas and pseudo lymphomas.

Extracutaneous involvement is a sign of poor prognosis in cutaneous T-cell lymphomas (CTCL). Unfortunately it becomes clinically and histologically manifest only late in the course of the disease. It was the purpose of this study to detect clonality in peripheral blood, lymph nodes and bone marrow samples at times when extracutaneous involvement cannot otherwise be demonstrated. In addition to skin biopsies, peripheral blood, lymph node and bone marrow samples from a total of 25 patients were analysed by Southern blotting for clonal gene rearrangement of the T-cell receptor beta-chain. Six of the patients were suffering from mycosis fungoides (MF), four from non-MF CTCL (pleomorphic T-cell lymphomas), seven from Sézary syndrome (SS), eight from pseudolymphoma (insect bites) (PSL), and one from lymphomatoid papulosis (LP). Clonal TcR b gene rearrangements were found in patients with MF in four of five skin probes as well as in two of two lymph node samples and in one of two peripheral blood samples. In SS patients, all skin probes (seven of seven), lymph node samples (six of six), peripheral blood samples (six of six) and one bone marrow specimen had a clonal TcR beta gene rearrangement. In patients with non-MF CTCL, two of four skin, zero of two peripheral blood and one of one bone marrow samples with clonal T cells were detected. All investigated patients showed exactly the same rearrangement pattern at extranodal sites and in the skin, which is proof for the same clone in all compartments. In contrast, no rearrangements were detected in LP and PSL (zero of eight skin probes, zero of two peripheral blood samples). Our results provide strong evidence for an early systemic spread of neoplastic cells in CTCL. However, an initial tumour burden has to be reached in order to lead to a clinically and prognostically relevant manifestation.

[Adhesion molecules in dermato-oncology]. / Adhäsionsmoleküle in der Dermatoonkologie.

Adhesion molecules are cell surface proteins responsible for cell-cell and cell-matrix interactions. They represent a basis for physiologic and pathologic processes, especially for homing behavior, homeostasis of the immune response, inflammations and tumor metastasis. Recently, adhesions molecules such as CD44v6 have been shown to be expressed on tumor cells of cutaneous lymphomas with systemic tumor spread and thus play an important role in metastasis.

Necrotizing herpes zoster mimicking relapse of vasculitis in angioimmunoblastic lymphadenopathy with dysproteinaemia.

An 81-year-old man presented with a generalized maculopapular rash, lymphadenopathy, conjunctivitis and arthritis. Vasculitis was confirmed by skin biopsy and by direct immunofluorescence, which showed perivascular C3 and granular IgM accumulation. Histology of an inguinal lymph node was diagnostic for angioimmunoblastic lymphadenopathy with dysproteinaemia (AILD), and this was confirmed by the finding of hypergammaglobulinaemia and elevated IgE levels. Immunohistology on a lymph node biopsy showed a T-helper cell (CD4) infiltrate expressing the interleukin (IL)-2 receptor alpha and beta chains. While receiving prednisone 100 mg/day, the patient developed new lesions, mimicking a relapse of vasculitis, which were subsequently shown to be necrotizing herpes zoster. Serum IL-2 and IL-6 levels were elevated. To our knowledge, this is the first report of simultaneous elevation of IL-2 and IL-6 in AILD: IL-2 may be involved in proliferation of the malignant cell clone, and IL-6 in the pathogenesis of both the vasculitis (via endothelial cell activation) and the hypergammaglobulinaemia.

Primary cutaneous T-cell-rich B-cell lymphoma. A case report with a 13-year follow-up.

Cutaneous B-cell lymphomas constitute approximately 20% of primary cutaneous lymphomas. Most histologic subtypes of nodal B-cell lymphomas also occur primarily in the skin. The recently described T-cell-rich B-cell lymphomas (TCRBCLs) manifest mainly in the lymph nodes. This article presents a case of TCRBCL arising primarily in the skin, the origin of which could be traced back 13 years. The patient is a 59-year-old man. Plaque-like and nodular skin infiltrates had first appeared in the left preauricular region. Repeated examinations never found any extracutaneous involvement. A skin biopsy and a retrospectively studied 10-year-old skin specimen showed identical histologic features. Immunohistochemistry identified the TCRBCL previously considered as cutaneous Hodgkin's disease or a diffuse centroblastic centrocytic non-Hodgkin's lymphoma. A clonal B-cell population was detected by polymerase chain reaction, showing a rearrangement of IgH gene. The case of this patient shows that primary cutaneous TCRBCLs, similarly to other B-cell lymphomas in the skin, may have a good prognosis, in contrast to their nodal counterparts.

Pathology of cutaneous T-cell lymphoma.

Clinical features as well as histomorphology and cytomorphology are the golden standard for the differentiation of the various nosologic entities of cutaneous lymphomas, consisting of pre-lymphomas and pseudolymphomas, abortive lymphoma, latent lymphoma, definite low grade malignant lymphoma, and high grade malignant lymphoma. Histomorphologic and cytomorphologic criteria allow additional subtyping of lymphoproliferative T-cell infiltrates of the skin.

CD44v6 is a marker for systemic spread in cutaneous T-cell lymphomas. A comparative study between nodal and cutaneous lymphomas.

Adhesion molecules are involved in leukocyte recruitment, lymphocyte recirculation, and in several aspects of tumour biology. Recent discoveries of surface proteins on tumour cells involved in tumour metastasis may explain the invasive behaviour, the migration involving reversible adhesive contacts, the release into the circulation and the extravasation of tumour cells. CD44 is a family of glycoproteins involved in cell-cell and cell-matrix interactions. The v6 (variant exon v6) form of CD44 confers a metastatic potential onto some carcinoma cells. In the present study, the expression of CD44v6 on skin biopsies of 10 inflammatory skin diseases, 30 cutaneous lymphomas (CL), 11 reactive lymph nodes, 10 primary nodal non-Hodgkin's lymphomas (NHL) and 5 secondary nodal NHL was investigated immunohistochemically. None of the 10 nodal NHL were CD44v6 positive for the neoplastic B- or T-cells, whereas 11/12 CL with systemic spread showed a distinct CD44v6 expression in the skin. CD44v6 was not expressed on the tumour cells of skin biopsies of patients without systemic spread (18 cases of CL). In conclusion, CD44v6 expression is connected to an aggressive behaviour of CL.

New perspectives in experimental and clinical research for cutaneous T cell lymphomas.

Cutaneous T cell lymphomas (CTCL) are lymphoproliferative disorders, which can be classified by an adaptation of the Kiel classification. The most common CTCL, Mycosis fungoides (MF) and Sézary syndrome (SS), are monoclonal T helper memory lymphomas. They belong to the group of peripheral T cell lymphomas. However, CTCL includes other disease entities such as granulomatous slack skin, pagetoid reticulosis, and lipotropic CTCL. Polymerase chain reaction of the T cell receptor (TCR)-gamma and screening of the PCR products for sequence-specific mobility in acrylamide gels has increased the detection limit for clonal T cells in the skin. This method will help to define the relationship of CTCL to other lymphoproliferative disorders and may contribute to the early diagnosis of CTCL. In SS, the malignant CTCL clone secretes a T helper-2 cytokine pattern, which might be responsible for the systemic immunosuppression in CTCL patients. New treatment modalities (IL-12) might correct these immunologic abnormalities. Cutaneous B cell lymphomas mostly are follicular center cell derived and usually have a good prognosis. Therapy of cutaneous lymphomas should take into account prognostic factors, the most reliable of which in CTCL is the tumor mass expressed by the tumor burden index.

Lymphomatoid papulosis--treatment with recombinant interferon alfa-2a and etretinate.

Lymphomatoid papulosis is a rare cutaneous lymphoproliferative disorder with nodular, papulonecrotic or plaque-like lesions. Although it is clinically benign, the histology shows large, atypical lymphoid cells that display antigenic markers of activated T-helper lymphocytes and express CD30. There is a close relationship to Hodgkin's disease and to Ki-1-positive anaplastic large-cell lymphoma of the skin. For therapy, various modalities such as PUVA, steroids and acyclovir have been used. We report on a patient with a 10-year history of disease. Treatment with interferon alfa-2a, 3 MU 3 times/week for 4 weeks, and etretinate, 50 mg/day for 5 months, was initially successful, but lesions further relapsed 5 months after cessation of the therapy.

[Actinobacillus actinomycetemcomitans isolated from a mycetoma (of the forearm)]. / Actinobacillus actinomycetemcomitans isoliert aus einem Mycetom (des Vorderarms).

Mycetomas are subacute or chronic infections usually localized on unprotected skin areas and caused by fungi or Actinomyces. We report the case of a patient who suffered a splinter injury on his wrist after a motor accident. Six months later a cutaneous abscess with Actinobacillus actinomycetemcomitans developed on his wrist. Complete healing was obtained within 1 month after administration of ceftriaxon and doxycycline. The therapeutic management will be discussed.

Semimalignant ("pseudolymphomatous") cutaneous B-cell lymphomas.

Almost 50% of cutaneous B-cell lymphoproliferative infiltrates are derived from follicular center cells. Among these, about 25% show a rapidly progressive course, whereas about 75% account for flattening of the survival curve after about 7 years. This group is referred to as semimalignant ("pseudolymphomatous") cutaneous B-cell lymphoma (SM-CBCL). Clinical, histologic, and phenotypical criteria for their differentiation from B-cell pseudolymphoma and from CBCL have been investigated in 60 patients (11 CBCL, 30 SM-CBCL, 19 PSL). Semimalignant CBCL are different from malignant CBCL because they do not tend to disseminate to extracutaneous sites or to transform into high-grade malignant blast-type lymphomas; follicular center cell formation with CD21 positive dendritic reticulum cells is usually present; and normal survival time is not affected. On the other hand, SM-CBCL differ from PSL in that complete cure of the usually multiple and disseminated skin manifestations is not possible and that follicular center formation and the network of CD21-positive cells in conjunction with a kappa or lambda light chain restriction of cellular surface immunoglobulins is seen. If these and other criteria are taken together, differentiation of these various nosologic entities demanding different therapeutic approaches can be achieved with significant reliability.

[Malignant lymphoma of the skin]. / Maligne Lymphome der Haut.

Extranodal non-Hodgkin lymphomas preferentially involve the skin. Among them, 65% are T-cell lymphomas, 25% B-cell lymphomas and about 10% rare variants or nonclassifiable lymphomas. Mycosis fungoides is the most common form of low-grade malignant peripheral cutaneous T-cell lymphoma (CTCL): Lymphomas originating from follicular center cells are the most common types of cutaneous B-cell lymphomas (CBCL). Only 15 to 25% of cutaneous lymphomas show extracutaneous manifestations at time of diagnosis. The prognosis is relatively good, since the average survival time from diagnosis is 12 to 14 years. For making the diagnosis, clinical, histo- and cytomorphological parameters often have to be supplemented by phenotypic, genotypic and molecular biologic techniques in order to establish the correct diagnosis. An important problem still is the early diagnosis and early evaluation of prognostic parameters in CTCL. The therapeutic approach is control of the disease according to stage and prognostic parameters.