皮肤NK/T细胞淋巴瘤的临床病理及其与EB病毒关系的研究

目的探讨皮肤 NK/T细胞淋巴瘤的临床病理特点、免疫表型及与 EB病毒感染的关系。方法应用免疫组织化学染色,选用 CD45RO、 CD3ε、 TIA－ 1、 CD20、 Ki－ B5、 CD68和 LMP1等抗体;用 EBER1/2原位杂交检测 EB病毒编码的小分子 RNA。结果 5例皮肤 NK/T细胞淋巴瘤患者占同期皮肤恶性淋巴瘤的 5.68％;男 4例,女 1例,平均年龄 34岁,主要表现为皮肤无症状肿块, 2例有溃疡形成;组织学特征为肿瘤在真皮和皮下脂肪内,易形成血管浸润性和破坏性病变,瘤细胞大小、形态各异;瘤细胞表达 T细胞标记（ 5/5）和 NK细胞或细胞毒性 T细胞标记 TIA－ 1（ 4/4）, EBER1/2（ 3/4）。结论皮肤 NK/T细胞淋巴瘤具有临床病理独特性,与 EB病毒感染有较强的相关性。     

蚊咬超敏与儿童皮肤T/NK细胞淋巴瘤

儿童发生的皮肤T/NK细胞淋巴瘤在发生前可有蚊咬超敏现象,蚊咬超敏、慢性EBV感染、T/NK细胞淋巴瘤形成一个临床三联征,称之为HMB-EBV-NK病或Tokura-Ishihara病,属于儿童EBV阳性T细胞淋巴增殖性疾病。EB病毒慢性感染是蚊咬超敏和T/NK细胞型淋巴增殖性疾病共同的病因。在慢性EB病毒感染的基础上,蚊唾液腺变应原刺激CD4阳性T细胞反应,诱导EB病毒癌基因活化,进展为儿童皮肤T/NK细胞淋巴瘤。蚊咬超敏和儿童皮肤T/NK细胞淋巴瘤是EBV阳性T细胞淋巴增殖性疾病这一疾病谱系的不同阶段。     

皮肤的结外鼻型NK/T细胞淋巴瘤1例

对1例皮肤的结外鼻型NK/T细胞淋巴瘤临床病理结合免疫组化染色、EB病毒原位杂交及T细胞受体基因重排进行分析.右胫后多发结节,组织病理特征为肿瘤组织在真皮及皮下组织内弥漫性浸润,肿瘤组织具有血管中心性及血管破坏性特点,肿瘤细胞具有异型性.瘤细胞表达CD2,CD56,颗粒酶B,EBER阳性,未检测到TCR克隆性基因重排.诊断为皮肤的结外鼻型NK/T细胞淋巴瘤.皮肤的结外鼻型NK/T细胞淋巴瘤恶性度高、预后差;诊断有赖于组织病理及免疫表型检测及EBER原位杂交技术.     

鼻NK/T细胞淋巴瘤1例

报道1例以皮肤为首发症状的鼻NK／T细胞淋巴瘤。患者男，48岁。双下肢、躯干、双上肢陆续出现红色斑丘疹、结节及溃疡4月余，鼻腔发现新生物1月余。皮肤及鼻部组织病理示中、小淋巴样细胞弥漫浸润；免疫组化染色：CD56（＋），LCA（＋），UCLH－1（＋），26(-),CD57(-);EBER( )。     

儿童皮下脂膜炎样T细胞淋巴瘤临床病理特点及其与EB病毒关系的研究

目的：研究儿童皮下脂膜炎样T细胞淋巴瘤（SPTCL）的临床和病理特点及与EB病毒感染的关系。方法：选用CD20、CD5RO．CD68．CD30、CD56、TIA—1等抗体作免疫组织化学ABC法染色；应用EBER1／2原位杂交检测EB病毒，结果：13例SPTCL占同期观察的皮肤非何杰金淋巴瘤的36．1％，其中男8例，女5例；发病年龄平均4．8岁；主要表现为下肢、躯干无症状性结节或肿块，常伴发热和肝脾肿大。组织学特点为肿瘤花皮下脂肪内呈脂膜炎样浸润，瘤细胞大小不等、形态各异，瘤内可见上皮样肉芽肿、多核巨细胞、豆袋细胞、小片坏死。免疫表型：TIA—1抗体表达12例，13例CD5RO均为阳性，CD20、CD30、CD56均为阴性；EB病毒EBER1／2原位杂交阳性率38．5％。13例中随访10例，死亡5例，其中4例合并噬血细胞综合征（HPS），4例中EBER阳性3例。结论：SPTCL在儿童皮肤非何杰金淋巴瘤中并不少见．儿童SPICL可能与EB病毒潜伏感染有一定的相关性。与EB病毒相关的SPTCL具有更大的侵袭性，常伴有HPS．预后较差。     

皮下脂膜炎样T细胞淋巴瘤与皮肤结外鼻型NK/T细胞淋巴瘤的鉴别

皮下脂膜炎样T细胞淋巴瘤和皮肤结外鼻型NK/T细胞淋巴瘤是两类特殊而少见的皮肤淋巴瘤.当后者累及皮下脂肪组织时,二者在临床表现、组织病理、免疫表型上有重叠,鉴别非常困难.该文对这两种皮肤淋巴瘤与EB(Epstein-Barr)病毒感染的关系、临床表现、组织病理学特点、免疫表型、分子遗传学特征及预后等方面作一对比性综述.     

鼻部NK/T细胞淋巴瘤1例

报告1例鼻部NK/T细胞淋巴瘤患者。患者男,16岁。鼻腔糜烂、出血6个月,鼻尖溃疡、穿孔,伴发热3个月。体格检查：T38.8℃,外鼻部塌陷、表面皮肤呈干性坏死,沿中线对称性分布;鼻尖部穿孔、双鼻下甲、中隔糜烂;免疫组化染色;LCA（＋）CD（＋）,CD45RO（＋）,CD56（＋）;组织病理诊断;鼻部NK/T细胞淋巴瘤。     

第三讲原发性皮肤大细胞淋巴瘤的分类

原发性皮肤大细胞淋巴瘤（PCLC）可分为T细胞性和B细胞性两类。T细胞表型PCLCL[PCLCL(T)]可以CD30阳性与否预期其预后。CD30^＋PCLCL(T)和CD30^ 非皮肤原发性LCL（T）的预后差。从蕈样肉芽肿转化成的CD30^ 皮肤LCL的预后一般差，从淋巴瘤样丘疹病演变成的CD30^ -LCL仅系统性的预后差而皮肤CD30^ -LCL的预后则不差。原发性皮肤多形T细胞性淋巴瘤，大细胞型和原发性皮肤T－免疫母细胞性淋巴瘤的预后差。B细胞表型原发性皮肤大细胞淋巴瘤中绝大多数为原发性皮肤滤泡中心细胞性淋巴瘤，其预后较淋巴结滤泡中心细胞性淋巴瘤为好。     

皮肤原发性间变性大细胞淋巴瘤—附1例报告

报道1例皮肤原发性间变性大细胞淋巴瘤。运用HE染色观察组织学形态及LCA、UCHL1、L26、CD30、EMA等抗体的免疫组化染色,以确定本例肿瘤的免疫表型。结果本例瘤细胞表达CD30、EMA及T细胞相关抗原。皮肤原发性间变性大细胞淋巴瘤临床经过缓慢,预后良好。     

以皮肤损害为首发表现的结外鼻型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,分析其临床表现、组织病理特点及治疗和预后,以提高皮肤科临床医生对本病的诊治水平.方法:通过临床表现、组织病理分析,结合免疫组化染色、EB病毒原位杂交确诊.结果:颈后皮损组织病理示真皮浅中层血管附属器周围几大灶淋巴样细胞浸润,细胞核大,胞浆透明,异型性明显.瘤细胞表达CD2、CD3、CD5、CD7、CD8、GranzymeB、Ki-67,而不表达CD56,EB病毒( + ).诊断为皮肤的结外鼻型NK/T细胞淋巴瘤.结论:结外鼻型NK/T细胞淋巴瘤具有独特的组织病理及免疫组化特征,恶性度高、易误诊、预后差.     

Nasal natural killer/T cell lymphoma with cutaneous involvement: case report and Chinese literature review reported in China mainland

Nasal natural killer (NK)/T cell lymphoma is an Epstein-Barr virus (EBV) associated lymphoma that arises in the nasal area and aggressively invades surrounding tissues. Our patient was a 48-year-old male who had had nasal obstruction and nasal discharge for 2 years and infiltrating plaques and necrosis on his nasal dorsum for three months. He developed fever and fatigue two weeks before admission. Biopsy from both skin and nasal mucosa revealed atypical medium-sized tumor cells infiltrating into the dermis. Immunohistochemical studies revealed that the tumor cells were UCHL-1, cytoplasmic CD3, CD56, TIA-1, and granzyme B positive, and CD8 and CD20 negative. In situ hybridization for EBV-DNA was positive. Clonal TCRb and TCRg gene rearrangement were negative. The patient was treated with cyclophosphamide, vincristine, and prednisone (COP) and with local radiotherapy, but he died 20 days later. We reviewed the cases of nasal NK/T cell lymphoma reported in mainland China in the Chinese literature during the last 5 years.     

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.     

Cutaneous presentation of nasal/nasal type T/NK cell lymphoma: clinicopathological findings of four cases

Epstein–Barr virus (EBV)-associated T/natural killer (NK) cell lymphoma mainly shows nasal lesions, and has recently been shown to be associated with cutaneous T-cell lymphoma (CTCL). The detailed features of CTCL nasal metastasis have yet to be elucidated. We report clinicopathological findings for four cases of cutaneous T/NK cell lymphoma with metastasis to the nose. The four patients presented progressive involvement of nasal lesions of CTCL, an aggressive course and poor outcome. Their pathological and immunohistological findings were consistent with peripheral T/NK cell neoplasm and, in three of four cases, EBER-1 were apparently detected in lymphoma cells by in situ hybridization, and two of four cases were also positive for TIA-1. The polymerase chain reaction (PCR) results showed the identical band from the skin and nasal lesions of the two patients. We also reviewed the cases of similar clinical course and attempted to elucidate clinical, pathological, immunological and genotypic features. The 10 reported cutaneous T/NK cell lymphomas with nasal metastasis revealed a poor prognosis (nine of 10 died at 3–108 months). Six cases of nine showed a positive reaction to EBV, and six cases revealed T-cell receptor β or -γ rearrangement. These findings suggest that most cutaneous T/NK cell lymphoma with nasal metastasis are similar to nasal T-cell lymphoma associated with EBV infection. This type of cutaneous T/NK cell lymphoma likely to involve nasal lesions and skin cases seemed to have a poor prognosis.     

Blastoid NK cell leukemia/lymphoma with cutaneous involvement

Malignant neoplasms from natural killer (NK) cells are characterized by their positivity for CD56 and absence of monoclonal TCR gene rearrangement. Recently, they have been classified into four main types (nasal and nasal-type NK cell lymphoma, aggressive NK cell leukemia/lymphoma, and blastoid NK cell leukemia/lymphoma), based on clinical features, racial predisposition, presence of azurophilic granules, immunophenotype and association with Epstein-Barr virus (EBV) infection. A 72-year-old Caucasian man presented with a malignant neoplasm comprised of blastoid cells without azurophilic granules in the Giemsa stain, with positivity for CD2, CD4, HLA-DR, CD45 and CD56, and negativity for CD3 (surface and cytoplasmic) and CD5. In situ hybridization for EBV and PCR analysis of rearrangement of the T cell receptor gene were negative. Based on these results, a diagnosis of blastoid NK cell lymphoma was made. In this case the first clinical manifestations were the cutaneous lesions, and, although the disease was already advanced at the diagnosis, the patient responded completely to the treatment and remains asymptomatic 14 months after diagnosis.     

CD56-positive (nasal-type T/NK cell) lymphoma arising on the skin

Several authors have reported cases of patients with malignant lymphoma with unique characteristics, designated nasal-type T/NK cell lymphoma, which expresses the natural killer (NK) cell marker and shows frequent extra-nodal involvement and poor prognosis. We report 2 cases of this type of lymphoma which were CD56-positive and showed a histopathologically angiocentric pattern with cutaneous and subcutaneous tumorous lesions. Patient 1 had extensive invasion of skin, underlying skeletal muscle, spleen and bone marrow, and died of sepsis 34 months after onset. Patient 2 had multiple subcutaneous nodules and invasion to mammary gland, lung, lymph node and spleen at the time of her first visit. She died of a rapid invasion of lymphoma cells to the liver 5 months after onset. Both patients showed similar immunophenotypes of tumor cells (CD2+, CD3−, CD4−, CD8−, CD20−, CD56+) and germ line configuration of the heavy chain of immunoglobulin (JH), T-cell receptor C beta-1 subunit DNA and T-cell receptor J gamma subunit DNA. Epstein-Barr virus early regions RNA was demonstrated in the nuclei of tumor cells of both patients with in situ hybridization. The histopathological examination of the skin lesions of both patients revealed the features of angiocentric lymphoma. The detection of CD56 in the tumor cells of cutaneous lymphomas should be routinely performed for the early diagnosis of this type of lymphoma with extremely poor prognosis.     

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。     

A case of primary cutaneous CD56+, TdT+, CD4+, blastic NK-cell lymphoma in a 19-year-old woman.

The classification of blastic or blastoid natural killer (NK)-cell lymphoma is controversial. Reports of primary cutaneous blastic CD56+ NK-cell lymphoma are rare, which necessitates further clinicopathologic definition of this type of lymphoma. Most CD56+ lymphomas display angiocentric histologic features, especially in Asian patients, and these are mostly associated with the presence of Epstein-Barr virus (EBV) genome and with an aggressive clinical course. We report on a young woman with a primary cutaneous blastic NK lymphoma which showed no angiocentric features but showed an unusual immunophenotype; CD56+, TdT+, CD4+, EBV-, and germline configuration of T-cell receptor gene. This unusual lymphoblastic lymphoma seems to have an immature or progenitor NK cell lineage.     

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.     

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.