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.     

Relapsed hepatosplenic T-cell lymphoma heralded by a solitary skin nodule

Hepatosplenic T-cell lymphoma (HSTL) represents a rare form of peripheral T-cell lymphoma composed of lymphocytes that typically express the γδ T-cell receptor. This form of lymphoma rarely involves the skin. We report the case of a 23-year-old man with a history of HSTL that was presumed to be in remission who presented with a solitary cutaneous nodule. Skin biopsy showed an atypical lymphocytic infiltrate arranged in a perivascular and periappendageal pattern with associated vacuolar epidermal interface change. The constituent T cells expressed CD2, CD3, CD7, CD8, β-F1, γδ T-cell receptor, Tia-1 and granzyme B. The cells lacked the expression of CD4, CD5 and CD56. Fluorescence in situ hybridization (FISH) showed a characteristic chromosomal abnormality, namely isochromosome 7q, which confirmed the diagnosis of cutaneous HSTL. On restaging his disease, widespread progression was noted. To our knowledge, this report provides the first detailed account of cutaneous involvement by HSTL. We show the novel utility of FISH to identify isochromosome 7q in the lesional skin of HSTL patients.     

Cutaneous involvement by colonic extranodal NK/T-cell lymphoma mimicking mycosis fungoides: a case report*

We report a 51-year-old woman with cutaneous involvement by extranodal NK/T-cell lymphoma (TCL) of the colon that microscopically mimicked mycosis fungoides (MF). She had a history of fever of unknown origin for 2 months and then developed multiple erythematous papules on her trunk and extremities. A skin biopsy revealed superficial infiltration by atypical small to medium-sized lymphocytes with epidermotropism and Pautrier collections. Immunohistochemical studies showed expression of CD3 and TIA-1 with lack of expression (double negative) of CD4 and CD8. Initially, we reported the diagnosis as MF, cytotoxic variant. Thereafter, computerized tomography scan incidentally identified a colonic mass. A colonic biopsy revealed infiltration of atypical lymphoid cells with the same morphology and immunophenotype as those found in the skin. Additionally, CD56 and Epstein-Barr virus-encoded RNA in situ hybridization in both skin and colonic biopsies were diffusely positive. Thus, extranodal NK/TCL was diagnosed. Delta T-cell receptor (TCR) gene rearrangement was documented in the skin biopsy by polyacrylamide gel electrophoresis and fluorescence capillary gel electrophoresis methods. There was no TCR gene rearrangement detected in the colonic biopsy. Unfortunately, the patient died within 2 months of diagnosis.     

Pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma in a case of CD56‐positive cytotoxic T‐cell lymphoma

We present the case of an 84‐year‐old patient with a cutaneous CD56 positive cytotoxic T‐cell lymphoma associated with substantial pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma (SCC). The patient presented with a 7‐month history of several progressive, ulcerated plaques on his right forearm. An initial biopsy showed changes consistent with a diagnosis of SCC for which the patient underwent surgical treatment. Several months later, the patient developed recurrent ulcerated plaques on the right forearm of which several biopsies were performed. The biopsies repeatedly showed marked pseudocarcinomatous hyperplasia resembling SCC. Deeper punch biopsies, however, showed a dense superficial and deep infiltrate of markedly atypical lymphocytes. Immunohistochemical analysis revealed strong positive staining for CD3, CD8, CD56 with negative stains for CD30 and Epstein‐Barr virus‐encoded small non‐polyadenylated RNAs (EBER). Staining for beta F1 and gamma‐delta T‐cell receptor (γδ TCR) were both negative. This constellation was most consistent with a diagnosis of cutaneous peripheral T‐cell lymphoma, unspecified in association with marked pseudocarcinomatous hyperplasia. Our case adds cutaneous peripheral T‐cell lymphoma, unspecified to the list of conditions associated with pseudocarcinomatous hyperplasia (PCH) and illustrates once again the potential pitfalls of distinguishing marked pseudocarcinomatous hyperplasia from SCC.     

TCR gene-rearranged,extranodal NK/T-cell lymphoma,nasal type,presenting as gyrate patches

In the CD56+ cutaneous nasal-type NK/T-cell lymphoma strongly associated with latent EBV infection, subcutaneous or dermal nodules are the most common skin findings, but great morphologic heterogeneity has been noted including papules, infiltrated plaques, and ulcerated tumors, and TCR genes are mostly germline. We describe a case of nasal and nasal-type NK/T-cell lymphoma featuring multiple erythematous polycyclic patches on the trunk, which is similar to patch stage mycosis fungoides or other cutaneous T cell lymphoma. Immunohistochemical study of a skin biopsy specimen revealed CD2+, CD3epsilon+, CD56+, and CD45RO+ expression in the neoplastic cells. In situ hybridization using an anti-sense Epstein Barr virus early regions probe showed a positive reaction. However, clonal TCR beta gene rearrangement was found.     

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.     

皮肤的结外鼻型NK/T细胞淋巴瘤1例及文献复习

目的报道1例皮肤结外鼻型NK/T细胞淋巴瘤,以引起临床和病理医师对此病的关注。方法通过临床病理分析结合免疫组化染色、EB病毒原位杂交及T细胞受体基因重排的PCR检测分析确诊。结果左膝内后方皮损初次活检诊断为结节性脂膜炎,1个月内再次活检示真皮和皮下脂肪内肿瘤大片坏死,瘤细胞异型性明显,血管中心性浸润和血管坏死。瘤细胞表达CD2,CD8,CD45RO,CD56,TIA-1,GranzymeB和LMP-1,EB病毒(+);未检测到TCR-γ的克隆性基因重排。诊断为皮肤的结外鼻型NK/T细胞淋巴瘤。结论皮肤的结外鼻型NK/T细胞淋巴瘤恶性度高、易误诊、预后差;诊断有赖于常规组织病理结合分子病理技术。     

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.     

Cutaneous gamma‐delta T‐cell lymphoma with central nervous system involvement: report of a rarity with review of literature

Primary cutaneous gamma‐delta (γδ) T‐cell lymphoma is an extremely rare and aggressive variant of cutaneous lymphoma. Central nervous system (CNS) involvement, a rare finding, and hemophagocytic syndrome are two complications that are commonly fatal. We describe a 58‐year‐old patient presenting with skin plaque who subsequently developed subcutaneous nodules diagnosed as cutaneous T‐cell lymphoma (CTCL), clinically resembling ‘mycosis fungoides’. The patient was treated with repeat topical radiation therapies but had frequent relapsed disease. Approximately 4.5 years after, the patient presented with third and sixth cranial nerve palsies and was found to have CNS involvement by lymphoma per positron emission tomography—computed tomography (PET/CT) and a biopsy of foramen magnum. Phenotypically, the tumor cells were CD3(+)/CD4(?)/CD8(?)/CD7(+)/CD5(?)/CD30(?)/TCRαβ(?)/TCRγδ(+). Despite aggressive strategies taken, the patient expired 3 months after the diagnosis of the CNS lesion. A retrospective investigation proved the original CTCL to be γδ T‐cell in origin, confirming an indolent cutaneous γδ T‐cell lymphoma with eventual CNS manifestation. We present this case to draw attention to the entity, which can occasionally present with misleading histopathologic and clinical features. In addition, we provide a review of the literature to summarize clinical and pathologic features of the reported similar cases.     

Primary cutaneous γδ-T-cell lymphoma treated with low-dose methotrexate and narrowband ultraviolet B irradiation: report of a case with testicular involvement

Primary cutaneous γδ-T-cell lymphoma (CGD-TCL) is a rare entity of cutaneous T-cell lymphomas (CTCL) and is characterized by tumoral growth of mature γδ-T-cell expressing cytotoxic molecules. The prognosis of CGD-TCL is generally worse than other CTCL. However, relatively indolent patch/plaque lesions have been described suggesting the heterogeneous nature of this entity. Here, we present a case of CGD-TCL with various skin manifestations, such as erythematous plaques/tumors and subcutaneous panniculitis-like lesions. During the follow up, testicular involvement was detected, which was surgically removed. Histopathology showed mixed features from epidermotropism, dermal infiltration and subcutaneous panniculitis-like lesions depending on the clinical manifestations. The tumor cells were positive for CD3 and revealed cytotoxic markers, TIA-1 and perforin, but not for CD4, CD8, CD20, CD56, TCRβF1 or EBER. Topical glucocorticoid ointment, narrowband ultraviolet B (NB-UVB) irradiation and low-dose methotrexate (MTX) were effective to control these skin lesions. No visceral involvement was detected thereafter. While CGD-TCL is usually associated with poor prognosis, it seems to be composed of various clinical manifestations, and NB-UVB and low-dose MTX could be a choice for indolent patch/plaque and possibly nodular lesions, especially for the aged.     

Blastic natural killer cell and extranodal natural killer cell-like T-cell lymphoma presenting in the skin: report of six cases from the UK

BACKGROUND: Some lymphomas express natural killer (NK)-cell markers such as the neural cell adhesion molecule, which is recognized by the CD56 antibody. These lymphomas may present in the skin, but do not represent a homogeneous group. The new World Health Organization classification of lymphoma/leukaemia recognizes several types of NK/T-cell neoplasm, including blastic NK-cell lymphoma, which characteristically presents with cutaneous lesions. OBJECTIVES: To describe the clinical, pathological and molecular features in six cases of CD56+ lymphoma with cutaneous presentation. METHODS: The clinical, histopathological and immunophenotypic features of six patients were reviewed. In addition, in situ hybridization (ISH) to identify Epstein-Barr virus (EBV) mRNA, and polymerase chain reaction analysis to identify the presence of a clonal population of T cells or B cells were performed on lesional skin. RESULTS: All patients presented with widespread nodules and plaques, which in five cases were a characteristic purple colour. Four patients developed disseminated disease, three with neurological involvement. These four patients died between 14 and 46 months following diagnosis (median 30 months). In four of six cases the histopathological and immunohistological features were in keeping with a blastic NK-cell lymphoma. No clonal immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement was detected in the four cases consistent with an origin from NK cells. A further case fitted the criteria for an extranodal NK/T-cell lymphoma of nasal type and was also the only case to show evidence of EBV mRNA by ISH. A clonal T-cell population was identified in the final case. This patient also exhibited molecular evidence of a clonal B-cell population and a t(14;18) translocation confirmed by sequence analysis. CONCLUSIONS: Our data confirm that NK-cell lymphomas presenting in the skin are a heterogeneous group, and that in the U.K., blastic NK-cell lymphoma is more common than extranodal NK/T-cell lymphoma of nasal type. These lymphomas pursue an aggressive course, with rapid development of disseminated disease, and resistance to chemotherapy. Detailed immunophenotyping is needed to distinguish the different types. Our molecular data indicate that blastic NK-cell lymphoma cases lack clonal TCR/IgH gene rearrangements consistent with an NK-cell origin. Our ISH findings indicate that EBV plays a pathogenetic role only in extranodal NK/T-cell lymphoma of nasal type.     

Primary cutaneous γδ T-cell lymphoma with unusual immunophenotype: A case report and review of published work

Primary cutaneous γδ T-cell lymphoma (CGD-TCL) is a rare form of primary cutaneous lymphoma. The histopathological features of CGD-TCL are still unclear because of its rarity. Here, we report a case of a 77-year-old Japanese man who presented with a 9-month history of erythematous plaques on his left forearm. Skin biopsy specimens revealed the infiltration of atypical medium/large-sized lymphocytes from the epidermis to the deep dermis. Atypical lymphocytes were positive for CD3, CD5, CD8 and Vδ1, and negative for CD4, CD7, CD56, EBER-ISH, intracellular antigen-1, granzyme B and perforin. CD30 was partially expressed. We also reviewed 246 cases of CGD-TCL from the published work. CD4⁻CD8⁻ double-negative cases were 113 of 196 cases (57.6%), followed by CD4⁻CD8⁺ cases (52/196, 26.5%). CD5 was expressed in 25.8% of the cases (34/132). At least one cytotoxic molecule marker was expressed in 150 of 160 cases (93.8%). Some cases showed an indolent clinical course, especially in mycosis fungoides-like CGD-TCL cases. CD5 positivity and lack of cytotoxic molecule expression could be associated with a better prognosis. In addition, CD30 expression was found in approximately half of CGD-TCL cases (51/112 cases), suggesting that brentuximab vedotin could be a good treatment option for such patients. Further studies with more cases with detailed clinical and pathological information are necessary to elucidate the etiology and prognostic markers of this entity.     

Cutaneous CD30 (Ki-1)-positive anaplastic large cell lymphoma preceded by Hodgkin's disease

A 38-year-old female was diagnosed as Hodgkin's disease of the axillar lymph nodes, nodular sclerosis type, as evidenced by the presence of Reed-Sternberg cells positive for CD30 and CD15 and negative for CD3, CD20, and CD45. She achieved complete remission after combination chemotherapy. Two years later, she noticed a red papule on her public area without any lymph node involvement. The biopsy specimens showed diffuse proliferation of large-sized atypical lymphoid cells positive for CD30 and CD45, and negative for CD3, CD20 and CD15. These findings were mostly compatible with CD30 (Ki-1)-positive anaplastic large cell lymphoma (Ki-1 lymphoma). Our case is considered to be cutaneous Ki-1 lymphoma preceded by Hodgkin's disease.     

原发皮肤结外NK/T细胞淋巴瘤一例并文献复习

报道1例原发皮肤结外NK/T细胞淋巴瘤,并复习文献。患者,女,42岁。全身皮肤瘀斑、皮下结节20余天,发热4 d。右股内侧皮损组织病理示:大量淋巴细胞及浆细胞呈弥漫性浸润。免疫组化结果:CD3、CD43、CD56、颗粒酶B(Granzyme B,GгB)、细胞毒性蛋白(TIA)-1均(+)、Ki-67 LI约60%阳性;原位杂交EBER(+)。本病恶性程度高,需尽早进行组织病理检查及免疫组化染色以帮助诊断。     

伴噬血细胞综合征的皮肤NK/T细胞淋巴瘤鼻型一例

患者男,48岁,反复面颈、躯干、四肢丘疱疹10年,加重10 d,发热4 d。皮损组织病理检查示真皮内大量小到中等异形淋巴样细胞浸润,以血管及附属器周围明显,伴血管结构的破坏,并可累及皮下脂肪小叶间隔。免疫组化标记示真皮及皮下组织浸润的异形细胞CD45RO（+++）、CD3（-）、CD4（-）、CD8（+）、CD56（+）、TIA-1（++）、粒酶B（+）、EBER（++）、CD3ε胞质（++）、CD20（-）、CD79a（-）、CD30（-）。实验室检查示外周血红细胞、白细胞、血小板进行性下降,转氨酶、胆红素持续性升高,高甘油三酯血症及纤维蛋白原降低,腹部B超示肝脾肿大。诊断：皮肤NK/T细胞淋巴瘤鼻型伴噬血细胞综合征。     

牛痘样水疱病样皮肤淋巴瘤与慢性活动性EB病毒感染的关系

目的 报道6例牛痘样水疱病样皮肤淋巴瘤,并研究其与慢性活动性EB病毒感染的关系.方法 临床病理分析、皮损免疫组织化学染色、血清学分析、EB病毒编码RNA原位杂交、外周血EB病毒DNA测定.结果 6例患者皮损均为反复发作的丘疹、丘疱疹、坏死、痘疮样瘢痕,其中4例还伴有程度不同的颜面、手足水肿.所有患儿均有长期间断发热等症状.皮损病理可见表皮多房性水疱,真皮全层大量淋巴细胞浸润,细胞形态异形,可见病理分裂象.4例皮损病理免疫组化染色,可见大量CD56阳性细胞,散在的CD3和CD45RO阳性细胞,T细胞内抗原-1和粒酶B染色阳性,诊断为牛痘样水疱病样皮肤NK/T细胞淋巴瘤;2例组化染色CD3和CD45RO阳性,CD56阴性,诊断为牛痘样水疱病样皮肤T细胞淋巴瘤.6例皮损均可见EB病毒编码RNA原位杂交阳性肿瘤细胞,血清学检查EB病毒衣壳抗原IgG抗体滴度升高,其中2例滴度为1:5120,2例为1:2560,2例为1:1280;2例患者外周血EB病毒DNA拷贝数高于正常.6例患儿均证实患有慢性活动性EB病毒感染.结论 牛痘样水疱病样皮肤淋巴瘤主要表现为颜面手足肿胀、水疱、痘疮样瘢痕,病理表现主要为真皮异形淋巴细胞浸润和血管中心坏死,免疫表型以NK/T型多见.慢性活动性EB病毒感染与该型淋巴瘤发病密切相关.     

以胃肠道症状首发伴有皮肤表现的血管内NK/T细胞淋巴瘤一例

患者男,51岁,上腹部胀痛4个月,颈项、躯干、双大腿结节、斑块1个月。当地多家医院行胃肠道相关检查,并予对症处理,治疗效果不佳。腹部皮肤结节组织病理检查：真皮下层和皮下脂肪小叶内大量增生的小血管腔内填塞中等偏大异形淋巴样细胞;免疫组化标记：血管腔内异形细胞CD2（+++）、CD4（-）、CD8（-）、CD3ε胞质（++）、CD99（++）、CD43（+++）、CD56（+++）、细胞毒颗粒相关蛋白（TIA-1）（++）、穿孔素（++）、EBER（+++）、CD20（-）、CD79a（-）、CD30（-）、细胞角蛋白（-）、S100（-）、CD68（-）、血管内皮细胞CD31（+）、CD34（+）。诊断：以胃肠道症状首发伴有皮肤表现的血管内NK/T细胞淋巴瘤。给予环磷酰胺、长春新碱、柔红霉素、地塞米松 + 依托泊苷方案化疗,病情得到迅速控制,目前仍在随访中。     

Cutaneous extranasal NK/T-cell lymphoma

Malignant neoplasm from natural killer (NK) cells are characterized by their positivity for CD56 and absence of monoclonal TCR gene rearrangement. We present the case of a 54-year-old man with a fungous mass in his left flank whose histological examination was consistent with cutaneous extranasal T/NK cell lymphoma. We review the literature and also discuss the prognosis and treatment of this variety of lymphoma.     

CD8‐positive peripheral T‐cell lymphoma with aberrant expression of CD20 and concurrent in situ follicular lymphoma

A case of a 78‐year‐old woman with a CD8‐positive peripheral T‐cell lymphoma with aberrant expression of CD20 associated with follicular lymphoma in situ (FLIS) is reported. The neoplasm presented initially as cutaneous macules, papules, plaques and nodules. A skin biopsy was performed and the diagnosis of peripheral T‐cell lymphoma (PTCl) with aberrant expression of CD20 was made. The staging procedures included an excisional inguinal lymph node biopsy that showed findings similar to those of the previous diagnosis. In addition, FLIS was identified. The clinicopathologic features of PTCLs with aberrant CD20 expression involving the skin as well as this uncommon association are reviewed.     

Human herpesvirus 8-associated lymphoma mimicking cutaneous anaplastic large T-cell lymphoma in a patient with human immunodeficiency virus infection

Primary effusion lymphoma, a human herpesvirus 8 (HHV8)-associated lymphoma, is uncommon, and it is usually seen in human immunodeficiency virus (HIV)-infected patients. It presents as a body cavity-based lymphomatous effusion, but several cases of the so-called solid primary effusion lymphoma presenting as solid tumors without associated lymphomatous effusion have been reported. They have similar clinical, histopathological and immunophenotypical features. Most of them have a B-cell genotype. This suggests the solid variant may represent a clinicopathological spectrum of primary effusion lymphoma. We report a case of HHV8-associated lymphoma histopathologically and immunophenotypically mimicking cutaneous anaplastic large cell lymphoma. The patient was a 31-year-old HIV-seropositive man presenting with skin nodules over his right thigh. Biopsy of the nodules showed anaplastic large cells infiltrating the dermis. These malignant cells strongly expressed CD3, CD30 and CD43. Cutaneous anaplastic large T-cell lymphoma was initially diagnosed, but further tests, including immunoreactivity for HHV8 protein and clonal rearrangements of immunoglobulin genes, confirmed the diagnosis of HHV8-associated B-cell lymphoma with aberrant T-cell marker expression. This case provides an example of solid primary effusion lymphoma mimicking cutaneous anaplastic large T-cell lymphoma and highlights the importance of HHV8 immunohistochemistry and molecular tests in the diagnosis of HHV8-associated lymphoma with a cutaneous presentation.