Acyclovir in mycosis fungoides and lymphomatoid papulosis

A survey is given on 23 patients (10 of our own, 13 reported in personal communications and in the literature) suffering from lymphoproliferative diseases and treated with acyclovir (ACV). In 5 patients (3 of 18 with cutaneous T-cell lymphomas, 2 of 5 with lymphomatoid papulosis) partial remission could be achieved. Since herpes simplex virus, cytomegalovirus and viruses like Epstein-Barr and varicella-zoster do not play an etiologic role and since HTLV-I virus, due to its lack of thymidine kinase, cannot activate ACV, the following mechanisms should be discussed regarding the possible effectiveness of ACV in lymphoproliferative diseases: a direct cytopathic effect; activation of ACV by the thymidine kinase of viruses not yet detected in cutaneous lymphoproliferative disorders; ACV activation by cellular thymidine kinase, which has been found to be elevated in lymphoproliferative disorders. Preliminary clinical observations suggest that ACV may exhibit an antiproliferative effect intravenously in some patients with lymphomatoid papulosis.     

Infection with parapoxvirus induces CD30-positive cutaneous infiltrates in humans

Expression of CD30 is a distinct feature of B- or T-cell activation, found in Hodgkin's disease, large cell anaplastic lymphoma, lymphomatoid papulosis, as well as in certain viral infections such as human T-lymphotropic virus type I, HIV, hepatitis B and C virus, and Epstein-Barr virus. Here, we report highly proliferative CD30-positive cutaneous infiltrates in 3 patients with Milkers's nodules, adding parapoxvirus infection to the spectrum of CD30-positive benign lympho-proliferations.     

Lymphomatoid papulosis: a follow-up study

A follow-up study has been performed on 16 patients with lymphomatoid papulosis diagnosed at the Finsen Institute during the years 1970-81. In none of the patients did malignant lymphoma develop during the observation period (7 months to 22 years). During this period the nature of the lesions and the tendency to recurrence were unchanged in 11 patients, spontaneous remission took place in 4, and 1 patient went into complete remission after PUVA treatment (8-methoxsalen followed by UVA). The histological material (32 punch biopsies) could be divided into two major groups diagnosed as either typical (16 biopsies) or consistent with lymphomatoid papulosis (16 biopsies). Based on our present knowledge, we suggest the following classification of lymphomatoid papulosis: 1) "classical" lymphomatoid papulosis, 2) lymphomatoid papulosis associated with parapsoriasis en plaque or mycosis fungoides and 3) primary cutaneous T-cell lymphoma.     

Lymphomatoid papulosis associated with mycosis fungoides: clinicopathological and molecular studies of 12 cases

The association of mycosis fungoides and a primary cutaneous CD30+ lymphoproliferative disorder has been reported and probably represents different clinical aspects of a unique T-cell monoclonal expansion. In this study, 12 patients (6 men and 6 women) presented with lymphomatoid papulosis and mycosis fungoides. A TCRgamma gene rearrangement study was performed by an automated high-resolution PCR fragment analysis method on skin biopsy specimens taken from the different clinical lesions in each patient. An indolent clinical course was observed in the majority of patients. T-cell clonality was identified in 7 of 12 lymphomatoid papulosis lesions (58%) and in 6 skin biopsies of plaque stage mycosis fungoides (50%). In each individual case, where T-cell clonality was detected, both mycosis fungoides and lymphomatoid papulosis specimens exhibited an identical peak pattern by automated high-resolution PCR fragment analysis, confirming a common clonal origin. Only one case showed a clonal TCRgamma rearrangement from the lymphomatoid papulosis lesion, which could not be demonstrated in the mycosis fungoides specimen. The demonstration of an identical clone seems to confirm that both disorders are different clinical manifestations of a unique T-cell monoclonal proliferation. Our results also seem to confirm that the association of mycosis fungoides with a primary cutaneous CD30+ lymphoproliferative disorder usually carries a favourable prognosis.     

Human T-cell leukemia virus in cutaneous T-cell lymphoma in Denmark. A possible association of HTLV and aneuploidy

Cutaneous T-cell lymphomas (CTCL) are neoplasias of mature T-cells and comprise Sezary syndrome, mycosis fungoides and some cases of lymphomatoid papulosis. Clinically this group of disorders differ from the more aggressive neoplasias of mature T-cells known as adult T-cell leukemia/lymphoma and T-cell lymphosarcoma leukemia which are associated with human T-cell leukemia virus (HTLV). We have found that of 68 patients from Denmark with CTCL ten were positive for HTLV antibodies and that the neoplastic T-cells from skin specimens in seven of eight HTLV-antibody positive patients studied by DNA flow cytometry exhibit DNA aneuploidy. Either one or two hyperdiploid cell clones were present. Aneuploidy was found in two patients with histologically verified mycosis fungoides, in four patients with histological non-diagnostic mycosis fungoides, and in one patient with lymphomatoid papulosis. The present data indicate that further seroepidemiologic survey studies of cutaneous T-cell lymphomas should include the early histological non-diagnostic stages, especially when aneuploidy is present.     

Primary and isolated cutaneous lymphomatoid granulomatosis following heart-lung transplantation

BACKGROUND: Lymphomatoid granulomatosis is an Epstein-Barr virus-associated B-cell lymphoproliferative disease. It is angiocentric and angiodestructive and involves the lungs, central nervous system and skin. Exclusive cutaneous involvement is rare and may be associated with a better outcome. Contrarily to the extra-cutaneous forms of lymphomatoid granulomatosis, it is difficult or impossible to detect Epstein-Barr virus DNA sequences in primary and isolated cutaneous lymphomatoid granulomatosis. CASE REPORT: A 54-year-old woman developed erythemato-violaceous lesions on both legs 3 years after a heart-lung transplantation. The diagnosis of erythema multiforme and of drug-induced vasculitis were first made. Because of fever and of the rapid extension of the lesions, the patient was hospitalized. The histologic examination of the first lesions showed a perivascular infiltrate, without epidermotropism, composed of histiocytes, lymphocytes and plasma cells. Immunohistochemistry revealed the presence of a predominantly T-cell infiltrate with some large B cells. Subsequent biopsies were diagnosed as high grade B-cell lymphoma. Polymerase chain reaction analysis as well as in situ hybridation study showed the presence of Epstein-Barr virus load in the lesions. There was however no serologic evidence of viral reactivation. Extensive systemic evaluation revealed no visceral or bone marrow involvement. Despite antiviral treatment and CHOP polychemotherapy, the patient died 3 months after her admission. DISCUSSION: This observation of lymphomatoid granulomatosis is particular because of its exclusive cutaneous involvement associated with a fulminant evolution to high grade B lymphoma. The presence of a context of iatrogenic immunosuppression underlies the role of altered immune cellular functions in the initiation and/or progression of lymphomatoid granulomatosis and strengthens the role of a viral agent in its pathogenesis. We suggest that the presence of Epstein-Barr virus, which is generally not associated with the isolated cutaneous forms of lymphomatoid granulomatosis, may have played a role in this fulminant evolution to high grade B lymphoma.     

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.     

Primary cutaneous T-cell lymphoma occurring after organ transplantation

Lymphoma occurring after organ transplantation has been well described. The majority of cases are B-cell lymphomas and are usually associated with Epstein-Barr virus. Only a minority of posttransplant lymphomas are of T-cell origin, and primary cutaneous T-cell lymphoma (CTCL) is extremely rare. In this article, we report a case of cutaneous peripheral T-cell lymphoma, pleomorphic CD30+ large-cell type, and review the literature relating to posttransplant primary CTCL. Of the 23 cases of posttransplant primary CTCL, 5 patients had erythrodermic disease, and 8 had primary cutaneous anaplastic large cell lymphoma. In addition, there are two cases of mycosis fungoides, one case of subcutaneous panniculitis-like T-cell lymphoma, one case of CD30+ lymphomatoid papulosis, and 6 cases of peripheral T-cell lymphoma, of which 3 were CD30+ large cell lymphomas. Seventeen cases had renal transplants and the majority received both cyclosporine and azathioprine. No consistent viral association was noted among these cases. The sex ratio was 18:5 (male/female), and the mean age at diagnosis was 53 years. Mean time from transplantation to diagnosis is 6.4 years and mean survival time from diagnosis is 14.5 months. The prognoses normally associated with particular subsets of CTCL do not apply in the posttransplant setting.     

Clinical features of cutaneous T-cell lymphoma

The distinctive clinical features and natural history of mycosis fungoides, an epidermotropic variant of cutaneous T-cell lymphoma, are presented. These findings are compared with certain non-mycosis fungoides T-cell lymphomas that occasionally occur in the skin. Clinical staging and evaluation of patients with cutaneous lesions including plaques, tumors, or erythroderma, with or without nodal involvement and disseminated disease, are considered. Associated disorders such as follicular mucinosis, actinic reticuloid, lymphomatoid papulosis, and secondary primary malignancies are also presented.     

Lymphomatoid papulosis and human herpesviruses--A PCR-based evaluation for the presence of human herpesvirus 6, 7 and 8 related herpesviruses

BACKGROUND: Lymphomatoid papulosis (LyP) is a chronic, recurrent lymphoproliferative disorder of the skin that belongs to the group of primary cutaneous CD30-positive T-cell lymphomas. Ultrastructural and clinical features of LyP suggest that it has a viral etiology. Human herpesviruses have been proposed as causative cofactors for LyP because of their oncogenic potential and their association with other lymphomas. METHODS: LyP skin lesions and a LyP-derived cell line were examined for the presence of the recently discovered oncogenic human herpesvirus 8 (HHV-8) and the two T-lymphotropic human herpesviruses 6 and 7 (HHV-6 and HHV-7) by nested polymerase chain reaction (PCR) using virus-specific oligonucleotide primers. Furthermore, a recently described method involving degenerate PCR primers was applied to detect highly conserved DNA sequences shared by a variety of herpesviruses, especially oncogenic gamma-herpesviruses, in an attempt to identify a yet undiscovered herpesvirus associated with LyP. RESULTS: HHV-6 and 8 could not be found in 26 archival and 11 snap-frozen LyP lesions and a LyP tumor cell line. HHV-7 DNA sequences were detected in 14% (5 of 37) of LyP samples. HHV-6 was found in 23% (3 of 13) and HHV-7 in 8% (1 of 13) of normal skin samples from healthy individuals, respectively. Using degenerate PCR primers to amplify the highly conserved polymerase region of herpesviruses, no DNA sequences related to human herpesviruses could be detected. CONCLUSIONS: LyP is not associated with HHV-6, HHV-7 and HHV-8. In addition, the studies using degenerate PCR primers do not indicate the presence of a previously undescribed human herpesvirus in LyP.     

Cutaneous angiocentric T-cell lymphoma associated with Epstein-Barr virus.

BACKGROUND: Two unusual cases of cutaneous angiocentric T-cell lymphoma were found to be associated with Epstein-Barr virus infection. OBJECTIVE: The objective was to study the clinical course and the response of the disease to conventional chemotherapy. METHODS: Histologic specimens from both patients were studied. Clonal proliferation was assessed by Southern blot hybridization. RESULTS: The disease in both patients was rapidly progressive and responded poorly to aggressive treatment. Biopsy specimens showed infiltration of atypical lymphoid cells with angiocentricity and angiodestruction, which probably resulted in the observed tissue necrosis. Clonal proliferation of Epstein-Barr virus DNA was detected in tissue from primary skin lesions and disseminated nasal lesions. CONCLUSION: Epstein-Barr virus-associated angiocentric T-cell lymphoma in our patients was characterized by an aggressive course and resistance to conventional chemotherapy. A search for Epstein-Barr virus and the human T-lymphotropic virus should be performed in patients with atypical features of cutaneous T-cell lymphoma.     

Lymphomatoid papulosis in a patient with atopic eczema on long-term ciclosporin therapy

We report a 36-year-old man with atopic eczema who developed lymphomatoid papulosis while taking ciclosporin. Latent membrane protein 1 and in situ hybridization for Epstein-Barr virus were negative. There are only two reports in the literature of patients taking ciclosporin to control atopic eczema who developed primary cutaneous CD30+ T-cell lymphoproliferative disorders. The development of T-cell lymphoproliferative disorders including lymphomas is well described in patients with solid organ transplants who are taking ciclosporin. Also, it has been noted in patients taking ciclosporin for rheumatological conditions or psoriasis.     

Survival data for 299 patients with primary cutaneous lymphomas: a monocentre study

The aim of this study was retrospectively to assess the validity of the 2005 WHO-EORTC classification for primary cutaneous lymphomas (PCL) in a large cohort of patients of a single German skin cancer unit. All patients with PCLs consecutively visiting our hospital between January 1980 and December 2005 were included in a retrospective monocentre study, analysing their histological and clinical data. A total of 312 patients fulfilled the inclusion criteria for PCL. In 299 patients clinical information and paraffin material were sufficient for detailed classification. Of the 299 patients, 63% expressed a T-cell and 37% a B-cell phenotype. Mycosis fungoides was the entity with the highest frequency (30.9%), followed by primary cutaneous follicle centre lymphomas (16.9%) and lymphomatoid papulosis (15.9%). The mean follow-up period was 38.4 months. Five-year disease-specific survival was 80.5% for mycosis fungoides, 92.5% in primary cutaneous anaplastic large cell lymphoma, 100% in lymphomatoid papulosis, 98.1% in primary cutaneous follicle center lymphoma, 100% in primary cutaneous marginal zone lymphoma and 63.2% in diffuse large B-cell lymphoma, leg type. Our data are in line with the data collected by the WHO-EORTC. This is further evidence for the reliability of the WHO-EORTC classification and staging system.     

Cutaneous lymphomas in Tokyo: analysis of 62 cases in a dermatology clinic

BACKGROUND: The epidemiology of cutaneous lymphomas revealed that the incidence of lymphomas differed depending on various factors including area, race, and sex, among others. OBJECTIVE: This study was undertaken to analyse the incidence of cutaneous lymphomas in Tokyo. METHODS: The clinical records and histologic material from 50 patients with lymphomas of the skin and 12 patients with lymphomatoid papulosis seen during the last 10 years at the Department of Dermatology, The Jikei University School of Medicine, Tokyo, have been reviewed. RESULTS: T-cell lymphomas including mycosis fungoides (MF)-Sézary's syndrome (SS) complex and adult T-cell leukemia/lymphoma (ATL) were more frequent than B-cell lymphomas. The incidence of ATL is associated with the number of human T-cell lymphotropic virus type 1 (HTLV-1) carriers in the general population. Cutaneous B-cell lymphoma (CBCL) is not as rare as previously thought in Japan. CONCLUSIONS: Although the frequency of these cases depends on many unrelated factors, these values can provide a rough indication of the incidence of cutaneous lymphomas in Tokyo. The incidence of cutaneous lymphomas may be influenced by changes in environmental factors including viral infections.     

Examination of mycosis fungoides for the presence of Epstein–Barr virus and human herpesvirus-6 by polymerase chain reaction

BACKGROUND: The aetiology of cutaneous T-cell lymphoma (CTCL) remains unknown despite numerous investigations. In recent years, retroviruses and human herpesviruses have been implicated to play a causal part in CTCL. OBJECTIVE: The aim of this study was to elucidate the possible aetiopathogenetic role of human herpesviruses (HHV) in mycosis fungoides (MF). METHODS: Polymerase chain reaction was used to study formalin-fixed, paraffin-embedded lesional skin biopsies from 92 subjects with MF to evidence possible presence of Epstein-Barr virus (EBV) and HHV-6. RESULTS: Biopsy specimens from nine subjects (9.8%) evidenced EBV DNA, whereas all except one of the subjects (1.1%) lacked HHV-6 DNA. CONCLUSIONS: Although these findings do not support a primary aetiological role for EBV and HHV-6 in classical CTCL, the possibility remains that both viruses, particularly EBV, may act as potential cofactors in the development of CTCL.     

Human T-cell leukemia (lymphoma) virus (HTLV-I) antibodies in Danish patients with cutaneous T-cell lymphoma

HTLV-I antibodies were found in 10 out of 68 patients with cutaneous T-cell lymphoma (14%). HTLV antibodies were found in the earliest pre-diagnostic stage [Mycosis fungoides I (MF I), histologically non-diagnostic] as well as in the later stages (MF-III), where tumour cells are histologically apparent and the skin lesions have progressed from the plaque stage to the tumour stage. Of 4 patients with lymphomatoid papulosis, only 1 had positive HTLV antibody sera. Sequential studies of 6 patients demonstrated that the presence of HTLV-I antibodies was independent of the clinical remission - relapse stages in these patients. The present results show that HTLV-I or a related virus is found in Denmark and probably more widely distributed than was previously thought.     

Granulomatous and eccrinotropic lymphomatoid papulosis

Lymphomatoid papulosis has been classically described as a chronic, recurrent and self-healing papulonecrotic or papulonodular skin eruption, which is clinically benign and histopathologically malignant. The histologic characteristics of lymphomatoid papulosis are suggestive of a cluster of differentiation 30+ (CD30+) malignant lymphoma, and it is best regarded as a low grade cutaneous T cell lymphoma (CTCL). We hereby report a case of granulomatous and eccrinotropic lymphomatoid papulosis in a 40- year-old male. There was no systemic involvement. The patient was treated with low dose oral methotrexate with good response.     

T-cell clonality of peripheral blood lymphocytes in patients with lymphomatoid papulosis

Six patients with lymphomatoid papulosis demonstrated a clonal T-cell population in skin lesions by polymerase chain reaction methods. Two of these patients showed identical T-cell clones in their peripheral blood T cells as well. In one case, the clone persisted in the blood despite clearing of skin lesions with methotrexate.