Cutaneous involvement by angioimmunoblastic T-cell lymphoma with remarkable heterogeneous Epstein-Barr virus expression

INTRODUCTION: Initially described as an abnormal immune reaction, most cases of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-like T-cell infiltrates are now regarded as a peripheral T-cell lymphoma (AILD T-NHL). AILD T-NHL is characterized clinically with constitutional symptoms, generalized lymphadenopathy, hepatosplenomegaly, skin rash, and polyclonal hypergammaglobulinemia. Epstein-Barr virus (EBV) is frequently detected in involved lymph nodes, but the presence of EBV in cutaneous infiltrates of AILD T-NHL has rarely been examined. We present a patient with AILD T-NHL with cutaneous involvement that shows marked heterogeneity of EBV expression in the lymph node and skin biopsies, and review the histological findings of AILD T-NHL in the skin. METHODS: Two skin biopsies of a diffuse maculopapular rash and a lymph node were examined and immunophenotyped. In situ hybridization for detection of EBV in the lymph node and skin biopsies was utilized. In order to attempt to delineate which lymphocytes were EBV positive, skin biopsies were dual labeled with CD3, CD45RO, CD20 and EBV. The skin biopsies and lymph node were submitted for gene rearrangement studies by polymerase chain reaction (PCR). Capillary electrophoresis of fluorescently labeled PCR products was utilized for PCR product quantitation. RESULTS: The histological features of the lymph node were diagnostic of AILD T-NHL and a T-cell clone was identified by PCR. The skin biopsies showed an atypical superficial and deep perivascular polymorphous infiltrate consistent with cutaneous involvement by AILD T-NHL. Both skin biopsies showed the same clonal T-cell receptor gene rearrangement as the lymph node. In situ hybridization of the lymph node and one skin biopsy showed a few scattered EBV-positive lymphocytes (<1% of the infiltrate). A second skin biopsy revealed 40-50% of the lymphocytes as EBV positive. Dual staining for CD20 and EBV identified a minority of EBV-infected lymphocytes as B-cells, but most of the EBV-positive cells lacked staining for CD3 and CD45RO. CONCLUSIONS: In our patient, the same T-cell receptor gene rearrangement was found by PCR in all three biopsy sites. Most cases of AILD T-NHL contain only a few EBV-positive cells, but in our patient the extent of EBV expression ranged from <1% to 40-50% of the AILD T-NHL cutaneous infiltrate. To our knowledge, this case is the most extensive and heterogeneous expression of EBV in cutaneous AILD T-NHL to date.     

免疫母细胞性淋巴结病样T细胞淋巴瘤伴皮肤损害1例

免疫母细胞性淋巴结病样Ｔ细胞淋巴瘤（ＩＢＬ－ＴＣ）是特殊类型的周围Ｔ细胞淋巴瘤。临床特征为发热;淋巴结、肝脾肿大;皮疹及高γ球蛋白血症。皮疹呈多种形态,随其发展主要为二型：丘疹结节型和红皮病型。淋巴结病理示淋巴结结构破坏,有异形淋巴样细胞、免疫母细胞和浆细胞样的所谓淡染细胞（ｐａｌｅｃｅｌｌｓ）浸润。免疫学示Ｔ细胞标记。     

Lymphomatoid papulosis followed by large-cell lymphoma: immunophenotypical and genotypical analysis

The immunophenotype and genotype of atypical cells in skin and lymph node infiltrates were investigated in a patient with lymphomatoid papulosis (LyP) complicated by anaplastic large-cell lymphoma of the lymph nodes. The large atypical cells in both skin and lymph nodes displayed an almost identical immunophenotype, i.e. CD30+ and CD25+. Southern blot analysis for T-cell receptor beta-chain gene rearrangement revealed an identical gene configuration in DNA extracted from skin and lymph node. Our results strongly support the hypothesis that clonal populations of T cells arising in cutaneous LyP lesions may undergo malignant transformation, spread into regional lymph nodes, and give rise to secondary malignant lymphomas, such as anaplastic large-cell lymphoma.     

Phenytoin-induced pseudolymphoma. A report of a case and review of the literature

We report a patient with phenytoin-induced pseudolymphoma mimicking cutaneous T-cell lymphoma (CTCL). Despite withdrawal of phenytoin, there was persistence of the cutaneous eruption and lymphadenopathy. Southern blot analysis of immunoglobulin and T-cell receptor genes was therefore used to assess whether there was a clonal lymphoid expansion. However, no rearrangement of the beta T-cell receptor gene or immunoglobulin heavy-chain gene was detected in tissue DNA from skin and lymph nodes. One year later the patient became asymptomatic, although he is still at risk of developing a true malignant lymphoma in the future, a condition known as pseudo-pseudolymphoma. It is suggested that genotypic studies may help in the initial diagnosis and the subsequent management of such patients.     

Cutaneous presentation of recurrence of lymphoepithelioid T-cell lymphoma (Lennert's lymphoma)

Lennert's lymphoma (LL) is a T-cell lymphoma characterized by the presence of atypical T lymphocytes, admixed with histiocytes and epithelioid granulomas. Patients present with superficial lymph node involvement, mainly in the cervical areas; thoracic adenopathies and involvement of deep abdominal lymph nodes are rare. Cutaneous involvement is infrequent, reported to occur in only 4-11% of patients, and even rarer is the onset of cutaneous lesions as first sign of a recurrence. We report a female patient who presented with papules and nodules on the trunk and upper limbs as the first manifestation of recurrent LL.     

Cutaneous involvement in patients with angioimmunoblastic lymphadenopathy with dysproteinemia: a clinical, immunohistological, and molecular analysis

OBJECTIVE: To determine whether cutaneous involvement in patients with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is related to a clonal T-cell proliferation. DESIGN: Retrospective study. SETTING: University hospitals. PATIENTS: Ten patients with AILD and cutaneous involvement. MAIN OUTCOME MEASURE: The T-cell receptor-gamma (TCRG)gene rearrangement was studied with the use of polymerase chain reaction and denaturing gradient gel electrophoresis in blood, nodal, and skin samples. Skin and nodal samples were investigated also for the presence of Epstein-Barr virus (EBV) RNA by in situ hybridization. RESULTS: A transient morbilliform eruption of the trunk was seen most often. Other cutaneous features were infiltrated plaques and purpuric or urticarial lesions. A clonal TCRG gene rearrangement was detected in 7 skin samples, corresponding to a maculopapular eruption with a histological pattern of nonspecific mild lymphoid dermal infiltrate in 6 patients, and to erythematous plaques with histological findings of typical cutaneous lymphoma in 1 patient. In the 5 patients in whom a TCRG gene rearrangement was evidenced in skin and lymph node samples, identical clones were detected in both. Five patients died by the end of the study, with a mean survival of 33.2 months. Four of these 5 patients had a clonal infiltrate in skin and lymph nodes. The EBV RNA was detected in only 1 of 10 skin biopsy specimens and in 5 of 8 lymph nodes tested. CONCLUSIONS: Cutaneous involvement is often related to a clonal T-cell proliferation in AILD, even when clinical and histological features are nonspecific. Cutaneous infiltrate seems to be clonally related to the nodal T-cell proliferation. The role of EBV infection in skin lesions was not evidenced.     

Cutaneous CD8+ epidermotropic cytotoxic T-cell lymphoma with aggressive course

BACKGROUND: Cutaneous CD8+ epidermotropic cytotoxic T-cell lymphoma is a recently described rare primary cutaneous lymphoma exhibiting aggressive clinical behavior. Only about twenty cases have been described in the literature. Below we report a case involving unusual association of cutaneous vasculitis and lymphoproliferation. CASE REPORT: A 42-year-old senegalese man was hospitalized for cutaneous nodular lesions, which rapidly spread and became necrotic and ulcerated. he had recent weight loss with fever and multiple enlarged lymph nodes. Cutaneous histological analysis showed epidermotropic dermal infiltrate comprising medium and large cd8+ cytotoxic t-cells of unusual angiocentricity with cutaneous vasculitis and fibrinoid necrosis. the patient died 4 months after initiation of treatment with multi-agent chemotherapy. DISCUSSION: This patient presented the characteristics of primary cutaneous CD8+ epidermotropic cytotoxic T-cell lymphoma described by Berti. The clinical findings in most cases consist of nodular and ulcerative cutaneous lesions. Histologically, the cutaneous infiltrate is composed of pleomorphic lymphocytes with marked and constant epidermotropism. Immunohistochemistry shows lymphocytes expressing a CD8+ phenotype and cytotoxic proteins, which probably accounts for the local and systemic aggressiveness of the disease, as well as the angiodestructive nature of the infiltrate and the necrotic lesions.     

A case of malignant lymphoma of the nodular, poorly differentiated lymphocytic type.

A case of malignant lymphoma of the nodular, poorly differentiated lymphocytic type was presented. The patient, a 72-year-old woman, exhibited cutaneous nodules, generalized lymphadenopathy and splenomegaly. Treatment with two courses of steroid therapy and radiotherapy was carried out. After this therapy, skin tumors responded excellently. Histopathological findings of lymph nodes included proliferating forms of lymphoid tumor cells consisting of nodular and diffuse patterns. Peripheral lymphoid tumor cells, which had cleaved nuclei, clear nucleoli and mitoses were 30% increased in peripheral lymphocytes. Furthermore, the percentage of B cells in the subpopulation of peripheral lymphocytes was high, and that of T cells was low. In the present report, the histopathological and autopsy findings were studied, and some aspects of the classification of malignant lymphoma were discussed.     

Cutaneous histopathologic, immunohistochemical, and clinical manifestations in patients with hemophagocytic syndrome. Military Medical Consortium for Applied Retroviral Research (MMCARR).

BACKGROUND AND DESIGN--The hemophagocytic syndrome (HPS) is characterized by fever, wasting, generalized lymphadenopathy, hepatosplenomegaly, and pancytopenia, often with associated coagulopathy. The most common cutaneous manifestations are panniculitis and purpura. Cytophagic histiocytic panniculitis fits within the spectrum of HPS, and the most consistent histopathologic feature in HPS is a proliferation of mature histiocytes that exhibit prominent erythrophagocytosis and cytophagocytosis. The clinical spectrum, the underlying causes, and the histopathologic features found in HPS are broad. The characteristic phagocytic histiocytes seen in HPS have been confused with malignant histiocytes in the past, but are now known to be reactive. The clinical findings, histologic, and immunohistochemical features of 10 cases of HPS with cutaneous lesions were reviewed. Immunohistochemical markers included KP-1, beta F-1, UCHL-1, L-26, MAC-387, factor XIIIa, and S100 protein. RESULTS--The HPS was associated with T-cell lymphoma and/or viral infection. Most biopsy specimens showed edema and hemorrhage with a lymphohistiocytic infiltrate and prominent histiocytic cells showing erythrophagocytosis and, in some cases, cytophagocytosis. The histiocytic cells showed positive reactions for KP-1 and negative reactions for the lymphoid markers. In all cases the lymphoid cells showed a mixed pattern with most cells positive for beta F-1 and UCHL-1, and a small percentage positive for L-26. CONCLUSION--In HPS, the prominent phagocytic histiocytes are reactive and are stimulated by T-cell lymphocytes, either neoplastic or in response to viral infection. Many of the findings in the HPS may also be due directly or indirectly to cytokines produced by proliferating T-cell lymphocytes and/or reactive phagocytic histiocytes.     

Primary cutaneous CD56 positive lymphoma: a diagnostic conundrum in an unusual case of lymphoma

We present an unusual case of a CD56-positive T-cell lymphoma exhibiting immunophenotypic characteristics of both γδ T-cell lymphoma and extranodal NK/T-cell lymphoma, nasal-type. The patient presented with a 2-month history of rapidly progressive, pruritic and cutaneous nodules on his arms. A biopsy showed a dense pan-dermal infiltrate of markedly atypical CD3-positive lymphocytes, compatible with tumor stage cutaneous T-cell lymphoma. Retrospective review of a preceding biopsy and flow cytometric analysis, performed at an outside institution, showed strong expression of surface CD3, CD7, CD43 and γδ T-cell receptor (TCR), findings consistent with a diagnosis of cutaneous γδ T-cell lymphoma. In light of these data, we performed additional studies that showed diffuse positive staining of the atypical lymphocytes for CD56, CD4 and CD43 as well as Epstein-Barr virus-encoded small nonpolyadenylated RNA (EBER). Interestingly, this case displays characteristic features of γδ T-cell lymphoma, with strong surface expression of CD3 and γδ-TCR, as well as characteristics of natural killer (NK)/T-cell lymphoma, including expression of CD4 and EBER positivity, that represent two separate categories in the current classification of cutaneous lymphomas. Taken together, these findings underscore the difficulty of rendering an unambiguous classification of the presented neoplasm given the close ontogenetic relationship between NK and cytotoxic T-cells and highlight the need for continued reevaluation of the current classification system.     

Specific skin lesions occurring in a patient with Hodgkin's lymphoma

A 47-year-old man presented with a several month history of non-specific acquired ichthyosis, an unknown period of generalized lymphadenopathy and a short history of erythematous papules and nodules affecting the cutaneous drainage area of his right axillary lymph nodes. Histology confirmed these lesions to be specific lesions of Hodgkin's lymphoma; that is, metastatic retrograde lymphatic spread from his axillary lymph nodes of CD30+, CD15+, Reed-Sternberg cells as well as mononuclear Hodgkin's cells. This is the most common site and mode of spread of Hodgkin's disease to the skin. As is typical of advanced Hodgkin's disease, as evidenced by specific cutaneous involvement, this patient died shortly after definitive diagnosis was made.     

Analysis of T-cell receptor gene rearrangement for predicting clinical outcome in patients with cutaneous T-cell lymphoma: a comparison of Southern blot and polymerase chain reaction methods

OBJECTIVE: To extend previous observations regarding the prognostic value of analyzing lymph node DNA from patients with cutaneous T-cell lymphoma for the presence of a monoclonal T-cell population by Southern blot vs polymerase chain reaction (PCR) methods. DESIGN: Inception cohort study from 1982 to 1998. Recruitment of new patients ended in 1994. SETTING: A tertiary care referral center in Seattle, Wash.Patients Fifty-five uniformly staged patients with the diagnosis of cutaneous T-cell lymphoma who underwent a lymph node biopsy, 21 with clinically abnormal nodes and 34 with normal nodes.Interventions Lymph nodes were evaluated for T-cell receptor (TCR) gamma-chain gene rearrangement by 2 PCR methods: capillary electrophoresis and denaturing gradient gel electrophoresis. The same lymph nodes were evaluated by Southern blot analysis for TCR beta-chain gene rearrangement and examined histopathologically on the basis of the National Cancer Institute lymph node classification system. Patients were observed clinically for a mean of 9.5 years. MAIN OUTCOME MEASURES: Skin stage, clinical lymph node examination, lymph node histologic examination, Southern blot analysis, and PCR analyses were evaluated as potential prognostic predictors by univariate and multivariate analyses. The statistical association of TCR analysis and clinical outcome was determined among all patients. Hazard ratios (HRs) by Cox proportional hazards regression analysis were used to estimate the risk of a poor clinical outcome. Cumulative survival rates were analyzed by the Kaplan-Meier method. RESULTS: A skin stage of T3 (tumors) or T4 (erythroderma) was the most powerful predictor of a poor clinical outcome (HR, 31.3 vs T1; P<.001). Patients with detectable TCR gamma-chain gene rearrangement in lymph node DNA by PCR also were more likely to have a poor outcome (HR, 5.1; P<.001), but it was a less powerful predictor than skin stage. Even when the skin stage, presence or absence of lymphadenopathy, and histologic lymph node score were known for the patient, Southern blot analysis still added to prediction of a poor outcome (HR, 9.3; P = .007), whereas PCR provided no statistically significant additional information on outcome. CONCLUSIONS: Detection of a monoclonal T-cell population by PCR in lymph nodes of patients with cutaneous T-cell lymphoma does not enhance prediction of clinical outcome and probability of survival beyond what can be determined from clinical examination and histologic lymph node scores. Skin stage and the presence or absence of lymphadenopathy remain the most important determinants of clinical outcome.     

Sezary syndrome--without erythroderma

Sezary syndrome (SS), is described as the classical triad of pruritic erythroderma, lymphadenopathy, and presence of more than 10% of circulating Sezary cells in the peripheral blood. We report on unusual case of advanced cutaneous T - cell lymphoma with classical haematological and histopathological features of Sezary syndrome, but lacking the clinical features of erythroderma. A 66 year old man presented with asymptomatic multiple papules, plaques and nodules and with generalized lymphadenopathy. Peripheral smear showed more than 60% of Sezary cells. Skin and lymph node biopsy showed typical features of T-cell lymphoma and immunohistochemistry and CD marker studies showed the cells to be atypical T-lymphocytes. This unusual case is highlighted to denote that erythroderma need not be taken as a hard and fast criterion for diagnosing Sezary syndrome.     

Cutaneous composite lymphoma of mycosis fungoides and Hodgkin lymphoma: Response to sequential therapy

Composite lymphoma is defined as two or more morphologically and immunophenotypically distinct lymphoma clones that occur in the same tissue site. The occurrence of cutaneous composite lymphoma (CCL) is extremely rare. Here we report a unique case of CCL consisting of Hodgkin lymphoma (HL) and mycosis fungoides (MF). Our patient presented with longstanding erythematous plaques on the skin and later developed axillary lymph node enlargement. Histopathologically, the skin lesions were characterized by a dense dermal lymphocytic infiltrate with prominent epidermotropism of pleomorphic T-cells, consistent with typical MF. Nonetheless, scattered large atypical cells resembling Reed-Sternberg (R-S) cells were interspersed among these atypical T-cells in the deep dermis. Immunophenotyping suggested a HL origin of these R-S cells. Monoclonality of T-cell receptor beta gene was detected in the skin, monoclonal immunoglobulin heavy chain gene rearrangement was identified in these R-S cells microdissected from the deep dermis, confirming the origin from HL. The lymph node biopsy showed nodular sclerosis classic Hodgkin lymphoma. Therefore, CCL of HL and MF, with lymph node HL was diagnosed. The lesions of this patient responded to a sequential treatment to HL and MF. Being aware of this rare CCL facilitates correct diagnosis and proper clinical management.     

CD56-Positive cutaneous lymphoma with multicentric Castleman's disease-like systemic manifestations.

We report a 55-year-old Japanese male with CD56+ cutaneous lymphoma. The patient had multiple cervical lymphadenopathy, a red nodule on his neck, and parotid gland nodularity. Histologic features of the biopsied cervical lymph node showed follicular hyperplasia with numerous plasma cells. A biopsied skin specimen of the nodule on his neck demonstrated dense infiltration of atypical large lymphocytes into the dermis. Immunohistochemical study of this specimen revealed CD3+, CD4+, and CD56+ expression in the majority of neoplastic cells. Polymerase chain reaction assays for the detection of Epstein-Barr virus sequences were positive for lymph node and skin DNA. Laboratory examinations showed polyclonal gammopathy, pancytopenia, and high serum interleukin-6 levels. These clinical and histological findings resembled those of multicentric Castleman's disease.     

Transient CD30+ nodal transformation of cutaneous T-cell lymphoma associated with cyclosporine treatment

BACKGROUND: Mycosis fungoides (MF) may evolve from pre-existing chronic atopic or psoriasiform dermatitis and the histology can be equivocal. Early patch and plaque lesions of MF may evolve into tumors, disseminate to lymph nodes, bone marrow, and internal organs, and/or undergo transformation to a large cell size. METHODS: A patient with a history of "atopic dermatitis" followed by "psoriasis" rapidly developed exfoliative erythroderma and axillary lymphadenopathy following treatment with cyclosporine. At presentation, biopsy specimens of skin lesions and lymph nodes and staging were obtained. We present the treatment and follow-up of this patient and review the medical literature for similar cases. RESULTS: Multiple skin biopsy specimens from lesions revealed changes consistent with low-grade, cutaneous, T-cell lymphoma (MF) without evidence of large cell transformation and psoriasiform epidermal hyperplasia. CD30+ large cell transformation was present in the lymph node. Adenopathy and erythroderma resolved without systemic therapy following discontinuation of cyclosporine and treatment with psoralen/ultraviolet A (PUVA), isotretinoin, interferon-alpha, and antimicrobials. CONCLUSIONS: This case documents a close relationship between atopy, psoriasis, and the development of cutaneous T-cell lymphoma, and illustrates that an immunosuppressive agent, cyclosporine, can dramatically alter the course of the disease.     

A rare case of the cutaneous form of adult T-cell leukaemia/lymphoma: assessment of remission by PCR for clonal T-cell receptor gamma gene rearrangements in an electron beam-irradiated cutaneous lesion

Adult T-cell leukaemia/lymphoma is a lymphoproliferative disorder aetiologically associated with human T-cell lymphotropic virus type I infection. A cutaneous lesion often develops in the disease, and in rare cases, is even the only manifestation. Here we report a rare case of 'cutaneous' adult T-cell leukaemia/lymphoma with neither atypical cells in the peripheral blood nor lymph node involvement. All nodular lesions were completely eliminated after local electron beam irradiation (20 Gy/nodule in total). To evaluate whether or not there were residual lymphoma cells in the skin, we performed PCR to detect clonal T cell receptor gamma gene rearrangements. The sample from the nodule before irradiation showed evidence of a rearranged band, which was not detected at the same site after treatment nor in any peripheral blood. The findings suggest that this procedure is useful for the evaluation of therapeutic effects and the early detection of lymphoma recurrence.     

Micosis fungoide folicular cutánea y ganglionar

—Follicular mycosis fungoides is an unusual variant of mycosis fungoides characterized by atypical lymphocytes showing a predilection for hair follicles (folliculotropism). Epidermotropism of lymphocytes and mucin deposition may be present to varying degrees. This malignant lymphocytic infiltrate results in follicular disruption, typically occuring as plaques, comedo-like lesions, epidermal cysts and follicular keratoses with or without alopecia.We report a 33-year-old man who presented two plaques of alopecia located on his left arm and on his right thigh for 10 years and an enlarged lymph node on inguinal region. Histology of a plaque showed an exclusive folliculotropism of atypical lymphocytes sometimes forming follicular Pautrier's microabscesses, and the lack of epidermotropism and follicular mucinosis. Histopathological study of the enlarged inguinal lymph node revealed infiltration by T-cell lymphoma. A total body CT scan demonstrated multiple enlarged lymph nodes. The patient was treated with chemotherapy, which induced a complete resolution of his patches and lymph nodes.     

Cutaneous graft-versus-host-like reaction in systemic T-cell lymphoma

We report a case of systemic T-cell lymphoma with cutaneous lesions showing histological features of a cutaneous graft-versus-host-like-reaction. Histology from liver, lymph node and bone marrow showed a malignant T-cell infiltrate. T-cell receptor gene rearrangement studies confirmed the diagnosis. A cutaneous graft-versus-host-like reaction has been reported with disseminated malignancy and one case has been reported with systemic lymphoma. Graft-versus-host disease normally occurs when lymphocytes from an immunocompetent donor are introduced into a histo-incompatible recipient who is incapable of rejecting them. In our patient a similar reaction may have occurred if the lymphoma was composed of cytotoxic cells or if a cell-mediated immune response against the malignant T-cells cross-reacted with epidermal keratinocytes. Alternatively the malignant T-cells could have been functionally active and induced a lichenoid reaction in the skin.