EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma.

Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.

Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC).

BACKGROUND: Granulomatous cutaneous T-cell lymphomas (CTCLs) are rare and represent a diagnostic challenge. Only limited data on the clinicopathological and prognostic features of granulomatous CTCLs are available. We studied 19 patients with granulomatous CTCLs to further characterize the clinicopathological, therapeutic, and prognostic features. OBSERVATIONS: The group included 15 patients with granulomatous mycosis fungoides (GMF) and 4 with granulomatous slack skin (GSS) defined according to the World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas. Patients with GMF and GSS displayed overlapping histologic features and differed only clinically by the development of bulky skin folds in GSS. Histologically, epidermotropism of lymphocytes was not a prominent feature and was absent in 9 of 19 cases (47%). Stable or progressive disease was observed in most patients despite various treatment modalities. Extracutaneous spread occurred in 5 of 19 patients (26%), second lymphoid neoplasms developed in 4 of 19 patients (21%), and 6 of 19 patients (32%) died of their disease. Disease-specific 5-year survival rate in GMF was 66%. CONCLUSIONS: There are clinical differences between GMF and GSS, but they show overlapping histologic findings and therefore cannot be discriminated by histologic examination alone. Development of hanging skin folds is restricted to the intertriginous body regions. Granulomatous CTCLs show a therapy-resistant, slowly progressive course. The prognosis of GMF appears worse than that of classic nongranulomatous mycosis fungoides.

Cutaneous malignant lymphomas: update 2006.

Cutaneous lymphomas represent a unique group of lymphomas and are the second most frequent extranodal lymphomas. As with other neoplasias, the pathogenesis is based mainly on a stepwise accumulation of mutations of suppressor genes and oncogenes caused by genetic, environmental or infectious factors. The diagnostic work-up includes clinical, histological, imaging and hematological investigations and in many cases immunohistochemical and molecular biological analyses. The current WHO/EORTC classification of cutaneous lymphomas differentiates "mature T-cell and NK-cell lymphomas", "mature B-cell lymphomas" and "immature hematopoietic malignancies", their variants and subgroups. It is compatible with the WHO classification for neoplasias of the hematopoietic and lymphoid tissue and respects the organ-specific peculiarities of primary cutaneous lymphomas. The assignment of the various types of cutaneous lymphomas into prognostic categories (pre-lymphomatous "abortive" disorders; definite malignant lymphomas of low-grade malignancy; definite malignant lymphomas of high-grade malignancy) provides essential information on the biological behavior and allows an appropriate planning of the therapeutic strategy, which may be topical or systemic and aggressive or non-aggressive. Besides the classical options for therapy, there are new and "experimental" strategies, the efficacy of which has to be studied in clinical trials.

Primary cutaneous lymphoproliferative disorders with dual lineage rearrangement.

We present a series of 15 cases of cutaneous lymphoma and pseudolymphoma with dual lineage rearrangement identified among approximately 1200 cases of cutaneous lymphoproliferative disorders assessed in our 4 institutions during the last 8 years in which the results of both T-cell receptor and immunoglobulin heavy chain rearrangement investigations were available. On the basis of the clinicopathologic information, the cases were retrospectively subdivided into 2 categories: (1) cases with definite features of cutaneous lymphoma or pseudolymphoma (n = 11) and (2) cases with unclassifiable disease (n = 4). The detection of dual genotype in the first group did not influence the final diagnosis; 7 cases represented cutaneous B-cell lymphomas, 3 pseudolymphomas, and 1 case lymphomatoid papulosis. The presence of monoclonal T-cell receptor-gene rearrangements in these cases may be explained either by monoclonal or oligoclonal expansion of exuberant T cells (or B cells in case of lymphomatoid papulosis) or by lineage infidelity. Three patients with unclassifiable disease had several clinical and histopathologic features in common. They were elderly, presented with solitary lesions, were in good general health and histopathologically demonstrated a dense multinodular infiltrate containing approximately an equal number of T and B cells and a high number of histiocytes forming granulomas, with prominent granulomatous features in 2 cases. B cells were either scattered with the infiltrate or formed collections vaguely resembling follicles; Reed-Sternberg-like cells were seen in 2 cases. B cells showed expression neither of immunoglobulin light chain. The T-cell component was represented mainly by small, well-differentiated lymphocytes or slightly pleomorphic cells, with some medium-sized convoluted cells. Epstein-Barr virus was not detected by polymerase chain reaction. The exact classification of these cases is unknown; they differ histopathologically from previously published cases of bigenotypic cutaneous lymphomas. They may merely represent a growth or reactive pattern, but, on the other hand, may be low-grade lymphomas. If so, they may be histopathologically related to cutaneous Hodgkin disease, T-cell/histiocyte-rich large B-cell lymphoma, or composite lymphomas. Further reports are needed to identify these lesions to clarify their nature and biologic potential.

Intra-lesional low-dose interferon alpha2a therapy for primary cutaneous marginal zone B-cell lymphoma.

Primary cutaneous marginal zone lymphomas (pcMZL) belong to the primary cutaneous B-cell lymphoma (pCBCL) group. They are characterized by their restriction to the skin and a high likelihood of recurrence after various treatment modalities. First-line therapy consists of surgery and radiotherapy. These therapies may not always be indicated in young patients or in patients with pCBCL located in the face, where surgery or radiotherapy may leave disfiguring scars or radioderma. Eight patients with pcMZL were treated with intra-lesional injections of 3 million units of recombinant IFNalpha2a three times per week. The patients either did not want to undergo or did not qualify for surgical excision or radiotherapy due to inappropriate localization or age. All patients experienced complete tumor regression after a mean of 8.5 weeks (range 3 - 20). Two patients relapsed 4 and 12 months after treatment, respectively, but tumor regression was repeated after additional cycles of intra-lesional IFNalpha2a. All other patients remained free of disease. Thus, intra-lesional IFNalpha2a may represent a valuable alternative to surgery and radiotherapy as first-line treatment of pcMZL.

Extracutaneous transformation into a high-grade lymphoma: a potential pitfall in the management of patients with Sézary syndrome.

BACKGROUND: Transformation into a high-grade lymphoma in cutaneous T-cell lymphoma (CTCL) occurs in approximately 25% of cases and is associated with an aggressive clinical course. METHODS: We identified four cases of transformation of Sézary syndrome (SS) into pleomorphic T-cell lymphoma. RESULTS: In all patients, transformation occurred first in the lymph nodes, an average of 43 months after the diagnosis of SS. These high-grade lymphomas were composed of CD30-positive (two patients) and CD30-negative (two patients) pleomorphic large cells. All patients died of lymphoma an average of 29 months after nodal transformation. CONCLUSION: Because of an apparently poorer prognosis, the early recognition of transformation, especially by lymph node biopsy, is important for adequate therapy.

Febrile ulceronecrotic Mucha-Habermann disease with clonality: a cutaneous T-cell lymphoma entity?

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a severe variant of pityriasis lichenoides et varioliformis acuta (PLEVA). PLEVA patients only very rarely have systemic signs; the cutaneous lesions are usually asymptomatic, but may be pruritic and may heal with scarring. FUMHD often starts out as classic PLEVA, but goes on to develop widespread ulceronecrotic lesions and is associated with a high mortality rate. Whether Pityriasis lichenoides chronica (PLC) and PLEVA form a spectrum rather than single entities of clonal lymphoproliferative diseases has been discussed. Recently, it has been proposed that FUMHD, too, is a clonal lymphoproliferative disorder. Here, we report two cases of FUMHD with monoclonal T-cell population, as detected by Southern blot analysis. We propose that clonal FUMHD represents a cutaneous T-cell lymphoma entity.

Hepatitis C and G viruses in B-cell lymphomas of the skin.

BACKGROUND: The etiology of B-cell lymphoproliferative disorders (LPDs) of the skin has still to be elucidated. So far, Borrelia sp. has been identified as the causative agent of some cases of B-cell LPDs of the skin. Apart from bacterial pathogens, recent studies suggested that also flaviviruses, in particular hepatitis C (HCV) and G (HGV) viruses, may be involved in the pathogenesis of B-cell non-Hodgkin's lymphomas (NHLs). Most studies were performed in patients with known HCV infection, but the overall frequency of HCV- and HGV-RNA in tumoral tissue of primary cutaneous B-cell lymphomas (CBCLs) is unknown. METHODS: We examined 23 tumor biopsies of various forms of CBCLs by reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing for the presence of HCV and HGV. RESULTS: HCV-RNA sequences were detected in seven of 23 (30%) of the tumor biopsies. In contrast, RNA sequences of HGV were not detected in any of the tumors. CONCLUSIONS: Interestingly, the presence of HCV in our series of primary CBCLs was not restricted to a distinct clinicopathologic subform. HCV which can infect B cells, may play a role in pathogenesis of one-third of CBCLs, whereas HGV is not involved in CBCLs. Further molecular studies and therapeutic trials are needed to clarify the putative pathogenetic role of HCV in CBCLs.

Study of HHV-8 DNA sequences in archival biopsies from lesional skin of Kaposi's sarcoma, various mesenchymal tumors and related reactive conditions.

BACKGROUND: HHV-8 has been identified as the causative agent of Kaposi's sarcoma (KS) and some lymphoproliferative disorders. In addition, there are anecdotal reports on the presence of HHV-8 in other tumors, especially cutaneous epithelial and mesenchymal neoplasms. The aim of the study was to ascertain the value of identification of HHV-8 viral DNA sequences in routinely processed, formalin-fixed, paraffin-embedded tissues for the diagnosis of Kaposi's sarcoma and other mesenchymal tumors. METHODS: The presence of HHV-8 sequences in archival material was studied by nested PCR using specific primers for amplification of a 233-bp long fragment of HHV-8 (ORF 26). RESULTS: Thirty-three patients with KS (18 classic/sporadic, six post-transplant and nine AIDS-related) and various mesenchymal tumors and related conditions (n = 76) were studied. HHV-8 DNA sequences were detected in 29 of the 33 cases of KS and in one case of multiple eruptive dermatofibroma (MEDF). CONCLUSIONS: Identification of HHV-8 DNA sequences in routinely processed tissue is a useful diagnostic marker for KS. Although other mesenchymal tumors are usually not associated with HHV-8, its presence is not fully specific for KS since HHV-8 sequences were also found in one case of MEDF. Therefore, PCR analysis for the detection of HHV-8 should only be used as an additional diagnostic marker for KS and in the context of other tools such as routine histology.