Expression and function of the natural cytotoxicity receptor NKp46 on circulating malignant CD4+ T lymphocytes of Sézary syndrome patients

The natural cytotoxicity receptors NKp30, NKp44, and NKp46 were identified as activating receptors mainly expressed by natural killer (NK) lymphocytes. In this study we show that peripheral blood malignant CD4(+) T lymphocytes from patients with Sézary syndrome, an aggressive form of cutaneous T-cell lymphoma, express NKp46 at their cell surface. Although NKp46 does not behave as an independent functional receptor, its engagement provides a strong inhibiting signal on the malignant T lymphocyte CD3-induced proliferation. We show that this inhibition is correlated with a decreased phosphorylation of the CD3ζ chain associated with NKp46 and/or the TCR/CD3 complexes. Our results reveal that in addition to KIR3DL2/CD158k expression, NKp46 could represent an additional marker on the circulating malignant T lymphocytes of Sézary patients, where it displays an as yet unreported function of inhibitory co-receptor able to interfere with the processes governing their CD3-dependent proliferation.     

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.     

Primary cutaneous aggressive epidermotropic CD8(+) cytotoxic T-cell lymphoma with atypical presentation

Primary cutaneous aggressive epidermotropic CD8(+) cytotoxic T-cell lymphoma is characterized by a proliferation of epidermotropic CD8(+) cytotoxic T cells and an aggressive clinical behavior. Patients present with localized or disseminated eruptive papules, nodules and tumors. We report a case of primary cutaneous aggressive epidermotropic CD8(+) cytotoxic T-cell lymphoma with unusual clinical manifestation. The lesion occurred as multiple brownish macules and flat-topped papules on the hands, feet and face in a 25-year-old woman.     

Primary cutaneous CD8+ cytotoxic T‐cell lymphoma involving the epidermis and subcutis in a young child

CD8+ cytotoxic T‐cell lymphoma involving the skin represents a heterogeneous group of diseases that include subcutaneous panniculitis‐like T‐cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T‐cell lymphoma, and ‘type D’ lymphomatoid papulosis. In this report, we describe a case of CD8+ cytotoxic T‐cell lymphoma involving both the epidermis and subcutis. The patient was a 6‐year‐old girl who presented with a 3‐year history of multiple plaques on her trunk and legs. The lesions had relapsed twice but responded well to prednisone. Histopathologic examination showed the proliferation of atypical lymphocytes in the epidermis, dermis and subcutaneous tissue. On immunohistochemical analysis, the atypical lymphocytes were positive for βF1, CD3, CD8, perforin, granzyme B and TIA‐1, but negative for T‐cell receptor (TCR) γ, CD4, CD30 and CD56. It was difficult to classify this tumor in terms of the known types of cutaneous lymphoma, and this case should be differentiated with subcutaneous panniculitis‐like T‐cell lymphoma and primary cutaneous aggressive epidermotropic CD8+ T‐cell lymphoma.     

New developments in Sézary syndrome

Sézary syndrome (SS) represents 3% of cutaneous T-cell lymphomas (CTCL). It is an aggressive epidermotropic CTCL with a 5-year survival rate of 24%. According to EORTC (European organization for research and treatment of cancer), SS is defined by erythroderma, diffuse lymphadenopathy, atypical T lymphocytes (>1000/mm(3)), and the presence of a major blood, cutaneous and nodal T cell clone. A specific marker for atypical tumoral T lymphocytes known as Sézary cells was identified in 2001, namely KIR3DL2 (CD158k) receptor, which allows more specific diagnosis of SS; levels of this marker are highly correlated with the clinical course of the disease. In therapeutic terms, clinical trials are being conducted on new molecules that point towards an improved prognosis for this disease. We propose a review of Sézary syndrome, which is currently the subject of scientific papers concerning both physiopathology and therapeutics, with new prospects of targeted therapy.     

Primary cutaneous aggressive epidermotropic CD8+ T cell lymphoma with a chronic and indolent course. Is this different from peripheral T cell lymphoma?

Cutaneous T cell lymphomas most commonly have a CD4+ memory T cell phenotype and exhibit a relatively indolent course, but may in rare cases present with a CD8+ cytotoxic phenotype with a strikingly more aggressive clinical behavior. Primary cutaneous aggressive epidermotropic CD8+ T cell lymphoma is an extremely rare entity with distinct clinicopatological features. The clinical features and prognosis of the recently-described CD8+ peripheral lymphoma are very different from cytotoxic CD8+ epidermotropic lymphoma, but the histological and phenotypic characteristics are very similar. We report a new case of CD8+ epidermotropic lymphoma with a chronic course and suggest the possibility of an overlap between these two types of lymphoma.     

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma with a CD15(+)CD30(-) phenotype

Primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma (CD8(+)TCL) is an extremely rare entity with distinct clinicopathological features. While the CD15 antigen is typically associated with classic Hodgkin's lymphoma, aggressive peripheral T-cell lymphomas, including advanced stage cutaneous T-cell lymphomas, rarely express this molecule. We report a case of primary cutaneous aggressive epidermotropic CD8(+)TCL, in which lymphoma cells are CD15(+)CD30(-) with a medium-to-large pleomorphic phenotype. Although the functional characteristics of CD15 expression in the cutaneous lymphomas are not fully understood, the poor prognosis of primary cutaneous aggressive epidermotropic CD8(+)TCL might be associated with the presence of this molecule in our case.     

Aggressive T cytotoxic CD8+ epidermotropic cutaneous lymphoma: a case in a patient with Steinert's myotonic dystrophy

INTRODUCTION: Primary cutaneous "aggressive" CD8-positive epidermotropic cytotoxic T-cell lymphoma is a rare subset of cutaneous cytotoxic T/NK lymphomas that clearly differs from mycosis fungoides, whether CD4+ or CD8+, by the presence of rapidly evolving tumoral cutaneous lesions, foci of keratinocytes necrosis, a cytotoxic T phenotype and a poor prognosis. CASE REPORT: A 33-year-old man with Steinert's myotonic dystrophy was referred for evaluation of rapidly worsening cutaneous tumors along with marked deterioration of general status. Clinical, histological and immunohistological data led to the diagnosis of primary cutaneous CD8+ epidermotropic cytotoxic T-cell lymphoma. CHOP chemotherapy was effective despite cardiac toxicity in the setting of Steinert's dystrophy, but the patient relapsed and died of pulmonary sepsis after chemotherapy was resumed. DISCUSSION: The treatment of primary cutaneous epidermotropic CD8+ cytotoxic T-cell lymphoma is not codified. CHOP chemotherapy is usually the first-line therapy but relapses are frequent with median survival of no more than 34 months. In our patient, an additional difficulty was the cardiac toxicity of cytostatic drugs linked to the myopathy which prevented the use of high dosages, requiring a change of therapeutic regimen.     

Erythema multiforme‐like lesions in primary cutaneous aggressive cytotoxic epidermotropic CD8+ T‐cell lymphoma: A diagnostic and therapeutic challenge

Primary cutaneous aggressive cytotoxic epidermotropic CD8+ T‐cell lymphoma is an extremely rare, rapidly progressing, cutaneous lymphoma, with frequent systemic involvement and poor prognosis, that still represents a diagnostic and therapeutic challenge, especially in the early stage. Herein, we report a case of an elderly woman with a fulminant course, who at onset presented with clinical and pathological features mimicking erythema multiforme (EM) and treated with cyclosporine that led to rapid deterioration with fatal outcome 6 months after disease onset. Histopathology showed a lichenoid, epidermotropic and nodular, angiocentric, dermal and subcutaneous infiltrate of sF1, CD8+, CD45RA+ small to medium‐sized atypical lymphoid cells, which strongly expressed cytotoxic markers. Monoclonal T‐cell‐γ receptor was clonally rearranged and array‐CGH showed numerous chromosomal imbalances. This case evidences the clinical, pathological and therapeutic challenges involved in this tumor. The first biopsy showed an interface dermatitis‐like pattern, revealing the deceptive features that early cutaneous infiltrates of this aggressive lymphoma may have. A high suspicion for aggressive CTCL and a low threshold for repeat biopsies should be maintained when faced with rapidly progressing and/or ulcerative EM‐like lesions, especially if immunomodulatory therapy is being considered.     

Indolent CD8-positive T-cell lymphoid proliferation of the ear: a report of two cases

The current classification of primary cutaneous T-cell lymphoma (CTCL) of the World Health Organization (WHO) includes primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma as a provisional entity awaiting cumulative data. Recent reports identify CD3/CD8-positive clonal T-cell lymphoid proliferations arising in the ear and nose that behave indolently and therefore defy currently established subclassification. Here, we report two cases of clonal CD8-positive/granzyme-B-negative T-cell lymphoid proliferations that arose in the ear and behaved indolently. Collectively, these cases suggest that an additional category of cutaneous indolent CD8-positive T-cell lymphoma may be necessary among the existing classification schemes.     

多脏器累及的亲表皮CD8~+ T细胞淋巴瘤1例

患者男,46岁,全身渗出性红斑、头皮脓肿9月。入院检查发现累及肺、肝脏,皮肤组织病理示:表皮海绵水肿,真皮弥漫淋巴细胞,异型细胞具亲表皮性,免疫组化示:LCA(+),CD8(+),TIA(+),TCR基因重排阳性,诊断:亲表皮CD8+皮肤T细胞淋巴瘤。予以2次CHOP化疗,无效死亡。本病在国内首次报道,具有独特临床病理特点,早期累及皮外,侵袭性高,无有效治疗方法,预后差。     

Cutaneous CD30‐positive lymphoproliferative disorders with CD8 expression: a clinicopathologic study of 21 cases

Lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma (ALCL) belong to the spectrum of cutaneous CD30+ lymphoproliferative disorders, an indolent form of T‐cell lymphoproliferative disease. We reviewed 21 cases of CD30+ lymphoproliferative lesions expressing cytotoxic profile (CD8+). Seven cases of cutaneous ALCL, 2 cases of systemic ALCL involving the skin, and 12 cases of LyP. The cases of LyP were predominated by small lymphocytes exhibiting a prominent epidermotropic pattern consistent with either type B or type D LyP. Four cases showed co‐expression of CD56. The ALCL cases included myxoid features, pseudoepitheliomatous change, and an intravascular component. In all cases that were primary in the skin an indolent clinical course was seen while one patient with systemic myxoid ALCL is in remission following systemic multiagent chemotherapy. The paucity of other neutrophils and eosinophils and concomitant granulomatous inflammation were distinctive features in cases of type B and type D LyP. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful differentiating features from an aggressive cytotoxic CD8+ T cell lymphoma. In all cases that were primary in the skin an indolent clinical course was observed. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful in preventing a misdiagnosis of an aggressive cytotoxic CD8+ T cell lymphoma.     

Primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma: Proposed diagnostic criteria and therapeutic evaluation

Primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma is a rare cytotoxic lymphoma characterized clinically by aggressive behavior and histologically by prominent epidermotropism of atypical CD8(+) lymphocytes. Despite the continuous addition of new case reports, no definite diagnostic criteria have been established, and an optimum treatment is still awaiting. Herein, we study and analyze the different clinical, histopathological, and immunohistochemical features described in the reported cases. Different therapeutic modalities and their impact on the prognosis of the tumor are also evaluated and presented. We propose two sets of diagnostic criteria. The first comprises constant clinical, histopathological, and immunohistochemical features that are always present in every case, and the combination of which is necessary for the diagnosis. The second set helps to avoid missing cases and includes variable features that may be present in some cases, and to which any emerging finding could be added. Although different therapeutic options have been used, either as single agents or in combinations, there is no standard therapy for primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma and the tumor still represents a therapeutic challenge with very poor prognosis.     

Epidermotropic CD8+ cytotoxic T-cell lymphoma exhibiting a transition from the indolent to the aggressive phase, accompanied by emergence of CD7+ cells and formation of neutrophilic pustules

A 47-year-old-man presented with rashes on his trunk and limbs, and a diagnosis of parapsoriasis was made. Ten years later, the rashes had progressed gradually to form plaques and tumours. Gene rearrangement studies revealed monoclonality of the T-cell receptor β-chain (TCR-Jβ)1 gene, and results of flow cytometry and immunohistochemical examination confirmed a diagnosis of epidermotropic CD8+ cytotoxic T-cell lymphoma. The clinical course of the disease remained indolent for some time, but about 2 years later, neutrophilic pustules formed on the surface of the skin lesions, and tumours developed in the patient's testes. Using flow cytometry, emergence of CD7+ cells was found. The patient died the following year of respiratory failure due to brain herniation. On postmortem examination, CD8+ tumour cells were found in the brain. This case demonstrates an unusually protracted indolent phase in a patient with cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; its transition into the aggressive phase was accompanied by emergence of CD7+ cells and formation of neutrophilic pustules.     

Extrafacial indolent CD8‐positive cutaneous lymphoid proliferation with unusual symmetrical presentation involving both feet

Indolent CD8+ cutaneous lymphoid proliferation represents a recently described entity among cutaneous T‐cell lymphomas that typically presents with solitary skin lesions on the face or at acral sites and usually follows an indolent clinical course. Histopathologically, this entity is characterized by a dense dermal infiltrate of non‐epidermotropic, small‐ to medium‐sized pleomorphic CD8+ T‐cells of the non‐activated cytotoxic phenotype showing a clear‐cut grenz zone and a low proliferation index. Distinction from otherwise aggressive T‐cell lymphomas bearing a cytotoxic CD8+ phenotype is fundamental. We herein present an unusual case of indolent CD8+ cutaneous lymphoid proliferation presenting in bilateral symmetrical distribution on both feet and lacking the otherwise described grenz zone. Our case widens the spectrum of possible clinical and histomorphological variations of this entity. Taking into account the distinctive and unique clinical and microscopic features of all hitherto published cases of indolent CD8+ cutaneous lymphoid proliferation we suppose that this lymphoma subtype has to be included as a new and distinct entity in the World Health Organisation (WHO)‐/European Organisation for Research and Treatment of Cancer (EORTC)‐classification of cutaneous lymphomas.     

Absolute CD3+ CD158k+ lymphocyte count is reliable and more sensitive than cytomorphology to evaluate blood tumour burden in Sézary syndrome

Background CD158k/KIR3DL2 is a specific marker for Sézary cells which can be used to diagnose Sézary syndrome (SS) in erythrodermic patients with abnormal circulating T cells. Objectives To evaluate the suitability of CD158k/KIR3DL2 for detecting and evaluating blood tumour load during the follow up of patients with SS. Methods The absolute CD3+ CD158k+ lymphocyte count was compared with the absolute count of cytomorphological Sézary cells and was correlated with clinical flares in a cohort of patients with SS. Twenty‐five patients were included in the study and 48 blood samples were analysed. Results The absolute count of CD3+ CD158k+ cells strongly correlated with the absolute count of atypical circulating cells (r = 0·97, P < 10^?15). The CD3+ CD158k+ lymphocyte cell count was in eight cases more sensitive than cytomorphology for detecting atypical circulating cells especially for small‐sized tumour cells. The tumour burden evaluated by CD3+ CD158k+ immunostaining was significantly associated with clinical flare (P < 10^?4). Conclusions CD3+ CD158k+ phenotyping is a reliable and objective test to monitor the blood tumour burden in patients with SS under systemic therapy.     

Cutaneous EBV‐positive γδ T‐cell lymphoma vs. extranodal NK/T‐cell lymphoma: a case report and literature review

Primary cutaneous γδ T‐cell lymphoma and extranodal natural killer (NK)/T‐cell lymphoma (ENKTL), nasal type are two distinct lymphoma entities in the World Health Organization (WHO) classification. We report the case of an aggressive cutaneous lymphoma of γδ T‐cell origin showing overlapping features of both lymphomas. A 78‐year‐old female presented with confluent erythematous plaques with ulcerations over her right thigh. Microscopically, section of the skin showed a diffuse dermal and subcutaneous lymphocytic infiltration with tumor necrosis and angioinvasion. The medium‐ to large‐sized tumor cells expressed CD3, CD8, cytotoxic molecules and T‐cell receptor (TCR)‐γ but not CD4, CD20, CD30, CD56 or βF1. In situ hybridization for Epstein‐Barr virus‐encoded mRNA (EBER) was diffusely positive. Polymerase chain reaction‐based clonality assay showed a clonal TCR‐γ chain gene rearrangement. The features compatible with γδ T‐cell lymphoma include dermal and subcutaneous involvements, cytotoxic phenotype, expression of TCR‐γ, as well as an aggressive course. On the other hand, the diffuse EBER positivity, angioinvasion, tumor necrosis and cytotoxic phenotype may also fit in the diagnosis of an ENKTL of T‐cell lineage. We review the literature on EBER‐positive γδ T‐cell lymphoma and discuss the diagnostic dilemma using the current WHO classification system.     

Fatal CD8+ epidermotropic cytotoxic primary cutaneous T-cell lymphoma with multiorgan involvement

A 70-year-old woman presented with a 3-month history of two ulcerated erythematous-violaceous nodular lesions over the nose and forehead, respectively. The patient's history included a similar cutaneous nodule on the glabella diagnosed as pseudolymphoma 2 years ago.At that time, despite the diagnosis of a benign disease, an adequate staging was performed, ruling out any extracutaneous involvement. During hospitalization, multiple purpuric papules developed over the abdomen, and the disease spread to mediastinal lymph nodes, lungs and the central nervous system. Based on the histologic, immunophenotypic and molecular biology findings, a diagnosis of CD8+ epidermotropic cytotoxic primary cutaneous T-cell lymphoma was made. Secondary skin involvement by a CD8+ extracutaneous T-cell lymphoma could not be excluded with certainty, but seemed to be unlikely because of the negativity of the initial workup. The patient died from complications of right femoral artery thrombosis before starting specific polychemotherapy 21 months after onset of the disease. Among primary cutaneous T-cell lymphomas, the CD8+ epidermotropic cytotoxic subset comprises rare, highly aggressive forms characterized by metastatic spread to unusual sites such as the oral cavity, lungs, testis and the central nervous system but usually not to the lymph nodes. These cases seem to be distinct from mycosis fungoides with CD8+ phenotype, which shows a nonaggressive clinical behavior.