Gyde Staib

Subcutaneous T-cell lymphoma

We describe a patient with severe fatal histiocytic phagocytic panniculitis caused by a pleomorphic T-cell lymphoma. Analysis by polymerase chain reaction revealed clonality for both the T-cell receptor gamma-chain gene and the immunoglobulin heavy-chain gene. We also review 44 reported cases of primary or secondary lymphoma affecting the subcutaneous fat.

Management of Refractory Early-Stage Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin’s lymphomas that manifest primarily in the skin. Mycosis fungoides is recognized as the most common type of CTCL. Patients with early-stage CTCL usually have a benign and chronic disease course. However, although there is a wide array of therapeutic options for early-stage CTCL, not all patients respond to these individual therapies, resulting in refractory cutaneous disease over time. Refractory early-stage CTCL poses an important therapeutic challenge, as one of the principal treatment goals is to keep the disease confined to the skin, thereby preventing disease progression.Much of the focus of current research has been on the evaluation of already available skin-directed therapies and biologic response modifiers and combination regimens thereof, such as the combination of psoralen and UVA (PUVA) with interferon-α or retinoids. Recent novel developments include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL and has been shown to be effective in patients with refractory early-stage disease as well as advanced-stage disease. Likewise, the topical gel formulation of bexarotene has proved to be an important therapeutic option in patients with refractory or relapsed lesions. Oral bexarotene and topical bexarotene have been approved by the US FDA for the treatment of refractory CTCL. Systemic chemotherapy is typically reserved for advanced-stage CTCL and is usually not recommended for early-stage, skin-limited disease. However, recent exploratory studies indicate that low-dose methotrexate may represent an overall well tolerated therapy in a subset of patients with refractory early-stage CTCL, as may pegylated liposomal doxorubicin, which is currently being investigated in this specific clinical setting. Another recently FDA-approved therapy is the interleukin-2 fusion toxin denileukin diftitox, which is now well established to play a role in the treatment of refractory CTCL, including early-stage extensive plaque disease. The value of other agents, such as topical tazarotene, topical methotrexate, and topical imiquimod, and of novel immunomodulatory approaches including monoclonal antibodies, still needs to be assessed for refractory early-stage CTCL.

Use of Polymerase Chain Reaction in the Detection of Clones in Lymphoproliferative Diseases of the Skin

Early-stage mycosis fungoides shows similar clinical symptoms and histological and immunophenotypical features to several benign lymphoproliferative skin disorders. We analyzed T cell receptor gamma gene rearrangement by polymerase chain reaction in the search for monoclonal lymphoid subpopulations in skin infiltrates. Totally, 283 skin biopsies (paraffin-embedded and frozen material) from patients with different malignant and reactive skin diseases were investigated. Using primers for the T cell receptor gamma chain gene, monoclonality was detected in 59 out of 66 (89%) cases of pleomorphic cutaneous lymphoma, in 60 out of 78 (77%) patients with mycosis fungoides, in 11 out of 22 (50%) cases of parapsoriasis en plaques, in five out of 35 (14%) cases of pseudolymphoma, in six out of 15 (40%) patients with lymphomatoid papulosis, and in none out of 64 patients with inflammatory skin diseases. The results show that clonal T cell population can be detected in the majority of patients with cutaneous T cell lymphoma, but the findings have to be correlated with the histological and morphological features.

Systemic treatment for cutaneous lymphomas.

Primary malignant T cell lymphomas of the skin form a heterogenous group. Relevant classifications were recently made to separate different entities by various criteria. This is of great importance, because one should only rely on those therapeutical trials in which patients were included according such classifications. In this paper, we will mainly focus on therapeutic modalities for mycosis fungoides, which is the most frequent cutaneous T cell lymphoma and which may serve as a model disease. In principle, local (e.g., psoralens and ultraviolet A, PUVA) and systemic therapies (e.g., interferon-alpha 2a) can be applied. Very recently, we were able to demonstrate that even in initial stages of mycosis fungoides, the T cell clone is not restricted to the skin, but rather is present in low amounts in the peripheral blood. Therefore, systemic therapeutic modalities alone or in combination with local strategies (interferon-alpha 2a and acitretin/PUVA and interferon-alpha 2a) should be more effective, which will be proven by currently running clinical trials.

Evidence for a paracrine pathway of B-cell stimulation in hairy cell leukaemia

It is a well‐known phenomenon that the growth of malignant B‐lymphocytes, i.e. hairy cells, is regulated by cytokines. Several investigators have suggested that the stimulating cytokines are produced by the malignant B cells themselves, indicating an autocrine growth regulation. In this paper we demonstrate that T‐lymphocyte clones produce soluble mediators which stimulate the growth of malignant B lymphocytes. The incidence of the growth‐stimulating T‐cell clones derived from peripheral blood is identical in patients with hairy cell leukaemia (HCL) and healthy controls. About 50% of the clones stimulate the growth of hairy cells, but not the growth of purified B lymphocytes of healthy donors. The stimulating activity of a single clone varies when tested on different hairy cells. Interferon alpha (IFNa), but not antibodies against tumour necrosis factor alpha (TNFQ) or interleukin‐2 (IL‐2), completely inhibit the growth‐stimulating activity. Our results indicate that a paracrine growth regulation has to be considered in addition to the postulated autocrine loop in the growth regulation of malignant B cells.

New molecular biology aspects in the diagnosis of cutaneous malignant lymphoma

Zusammenfassung. Die Diagnosestellung primär kutaner maligner Lymphome stützt sich neben den klinischen, histomorphologischen und immunhistochemischen Befunden seit jüngster Zeit auch auf molekularbiologische Analysen des Genotyps eines Lymphominfiltrates. Dabei wird mit Hilfe der Polymerase-Ketten-Reaktion (PCR) linienspezifisch für die Immunglobulin- oder T-Zell-Rezeptorgene eine monoklonale maligne Zellpopulation im Infiltrat nachgewiesen. Dieses Verfahren ist innerhalb von 3 Tagen an kleinen, paraffingebetteten Haut- und Lymphknotenbiopsaten sowie herparinisiertem Blut der Patienten durchführbar, erfordert keine Radioaktivität und weist deshalb gegenüber herkömmlichen Techniken, z. B. dem Southern-Blot deutliche Vorteile auf. Desweiteren wäre durch derartige PCR-Analysen ein patientenspezifisches Monitoring unter einer entsprechenden Therapie möglich, das frühzeitig ein Rezidiv der malignen lymphoproliferativen Erkrankung aufzeigen könnte.Abstract. The diagnosis of cutaneous malignant lymphoma is based on clinical, histo-morphological and immunochemical findings and, nowadays, on molecular biology analyses of the genotyp in the lymphocytic infiltrate. By using the polymerase chain reaction (PCR) with specific primers for the Ig heavy chain gene and the T-cell receptor gamma chain gene, the detection of monoclonal cell populations in the skin infiltrate is possible. Since this method produces results within 3 days, since paraffin-embedded skin and lymph node biopsies and heparinized peripheral blood can be used and since no radioactivity is necessary, this technique has important advantages over traditional techniques such as Southern blot analyses. In addition, specific PCR analyses may allow a patient-specific monitoring during therapy and also may detect early relapses of the lymphoproliferative malignant disease.

C1-INH and C3/C4 levels do not correlate with long-term danazole dosage and HAE-1 attack-free interval.

References 1. Johri S, Shetty S, Soni A, Kumar S. Anaphylaxis from intravenous thiamine-long forgotton? Am J Emerg Med 2000;18:642– 643. 2. Proebestle TM, Gall H, Jugert FK, Merk HF, Sterry W. Specific IgE and IgG serum antibodies to thiamine associated with anaphylactic reaction. J Allergy Clin Immunol 1995;95:1059–1060. 3. Stephen JM, Grant R, Yeh CS. Anaphylaxis from administration of intravenous thiamine. Am J Emerg Med 1992;10:61–63. 4. Van Haecke P, Ramaekers D, Vanderwegen L, Boonen S. Thiamine-induced anaphylactic shock. Am J Emerg Med 1995;13:371–372. 5. Wrenn KD, Slovis CM. Is intravenous thiamine safe? Am J Emerg Med 1992;10:165. 6. Burge PS, Pantin CF, Newton DT et al. Development of an expert system for the interpretation of serial peak expiratory flow measurements in the diagnosis of occupational asthma. Occup Env Med 1999;56:758–764.