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.     

Analysis of T-cell antigen receptor gamma chain gene rearrangement by polymerase chain reaction in combination with denaturing gradient gel electrophoresis in the differential diagnosis of cutaneous T-lymphoproliferative diseases

A polymerase chain reaction (PCR)-based strategy has been developed for analysis of clonal rearrangement of the T-cell receptor gamma gene (TCR gamma) and was shown to be useful for detection of clonal T-cell populations. In this study, we performed PCR combined with denaturing gradient gel electrophoresis (DGGE) on fresh frozen biopsy samples from 16 patients with cutaneous T-lymphoproliferative diseases in whom a definite diagnosis was difficult to make on morphological and immunohistochemical grounds alone. Ages of the patients at biopsy ranged from 28 to 81 (median 62) years, and the subjects consisted of 8 men and 8 women. They presented with erythema on the extremities in 5 cases, trunk in 7, buttock in 2, and papules on the trunk and face in one case each. Clonal rearrangement of TCR gamma was observed in 3 of 16 cases. Clinical diagnoses of these three cases were mycosis fungoides, cutaneous invasion of adult T-cell leukemia (ATL), and large granular lymphocytic leukemia (LGL) of T-cell type, respectively, but they were histologically difficult to differentiate from reactive cutaneous T-cell proliferation. The skin lesions of the LGL case worsened, and this patient died two years after biopsy. Another patient with suspected mycosis fungoides in the plaque stage died due to dissemination of tumors 22 months after biopsy. The remaining one patient with ATL survived with cutaneous lesions for over four years. Clonality was not demonstrated in the remaining 13 cases, and their clinical courses were favorable. These findings showed that demonstration of clonal TCR gamma gene rearrangement using the PCR-DGGE method is very helpful for diagnosis of cutaneous T-cell neoplasms.     

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.     

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.     

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.     

Minimal residual disease in mycosis fungoides follow-up can be assessed by polymerase chain reaction

BACKGROUND: T-cell receptor (TCR) gene rearrangement analysis, i.e. T-cell clonality, using polymerase chain reaction (PCR) is a routine method used to assess the presence of a cutaneous dominant T-cell clone in mycosis fungoides (MF). OBJECTIVES: To compare the outcome of cutaneous lesions of MF after treatment with the fate of the cutaneous T-cell clonality, and to determine whether minimal residual disease can be detected in patients in clinical complete remission. METHODS: Fifty-one patients histologically diagnosed as having MF (17 stage IA, 21 stage IB and 13 stage III) were included in this retrospective study. T-cell clonality was analysed by GC-clamp multiplex PCRgamma-denaturing gradient gel electrophoresis. Every patient had two cutaneous biopsies at least 3 months apart. The second biopsy was performed at the site of a treated lesion. RESULTS: The presence or absence of a dominant T-cell clone in the skin remained identical in 26 of the 31 (84%) patients with persistent disease. Thirteen patients with a detectable dominant T-cell clone at diagnosis went into complete clinical remission. In nine of these 13 (69%) patients, the T-cell clone was no longer detectable after treatment. The remaining four (31%) patients had an unchanged T-cell clonality. CONCLUSIONS: The TCR gene rearrangement imprint is a stable and reliable tumour marker of MF disease. One-third of patients in complete clinical remission had a cutaneous molecular residual disease, the prognostic value of which will be analysed in an ongoing prospective study.     

Lymphomatoid papulosis with associated cerebellar lesion of similar histology and T‐cell clonality

A 9‐year old boy presented with a 4‐month history of a truncal monomorphic eruption with self‐healing papulonecrotic lesions. A skin biopsy revealed a dermal infiltrate of CD4, CD8 and CD30‐positive T‐cells, consistent with lymphomatoid papulosis. He responded to 4 months of treatment with narrowband UVB phototherapy (311 nm) which stabilised his disease. Five years later he presented with an acute onset of nausea and vomiting, dizziness, headache and ataxia. Magnetic resonance imaging of the brain revealed a lesion in the cerebellum and stereotactic resection was undertaken. Histology showed CD4, CD8 and CD30‐positive T‐cells similar to his skin lesions, with a monoclonal T‐cell receptor (TCR) gamma gene rearrangement. Subsequent analysis of the skin detected a monoclonal band of the same size as the cerebellar lesion. Treatment was initiated for a primary central nervous system (CNS) lymphoma but ceased after one course of high‐dose methotrexate. Opinion on the pathology was divided as to whether the cerebellar lesion represented an atypical reactive T‐cell lymphoproliferative response or a T‐cell lymphoma. On follow‐up 2 years later, the patient remains clinically and radiologically clear, making CNS lymphoma unlikely.     

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。     

Intravascular cytotoxic T-cell lymphoma: A case report and review of the literature

Intravascular lymphoma (IVL) is a rare subtype of extranodal diffuse large B-cell lymphoma in the World Health Organization classification. Although the majority of cases are of B-cell lineage, cases of IVL with a T-cell phenotype and, rarely, histiocytic and natural killer (NK)-cell phenotypes have been reported. We report a case of T-cell IVL with a cytotoxic phenotype. A 62-year-old male presented with erythematous patches and plaques on the lower extremities, and a biopsy revealed IVL with an activated cytotoxic phenotype (CD56(+), perforin+, granzyme B+, TIA-1+, CD3epsilon(+), CD20(-), CD4(-), CD8(-), CD5(-), and T-cell receptor [TCR] betaF1(-)), consistent with either NK-cell or T-cell origin. TCR gene analysis showed a monoclonal T-cell population, supporting the diagnosis of a T-cell IVL. Although the patient's skin lesions were refractory to combination chemotherapy and salvage chemotherapy regimens, there has been no evidence of disease progression in 24 months of follow-up.     

Cutaneous peripheral T-cell lymphoma of cytotoxic phenotype mimicking extranodal NK/T-cell lymphoma

Cutaneous peripheral T-cell lymphoma unspecified is a rare neoplasm that is infrequently associated with Epstein-Barr virus (EBV) infection. In contrast, extranodal natural killer (NK)/T-cell lymphoma, although also rare, is known to be strongly associated with EBV and occurs most commonly in the nasal region. We report the case of a 55-year-old male who presented with fever and an indurated cutaneous plaque with ulceration. This cutaneous neoplasm showed diffuse dermal lymphomatous infiltration and tumor necrosis, with neoplastic cells expressing CD2, cytoplasmic CD3 (CD3ε), CD8, CD16, CD30, T-cell intracellular antigen-1, and granzyme B but not CD56, BF1, or T-cell receptor (TCR) δ1. Furthermore, the tumor cells were noted to be diffusely positive for EBV by in situ hybridization. A monoclonal TCR gene rearrangement was demonstrated. The disease showed an aggressive clinical course, and the patient died within 3 weeks of diagnosis without complete staging or chemotherapy. According to the 2005 World Health Organization/European Organization for Research and Treatment of Cancer scheme for cutaneous lymphoma and the 2008 WHO classification for lymphoid neoplasms, our case would have been classified as a nasal type extranodal NK/T-cell lymphoma with T-cell lineage. However, the expressions of CD8 and CD16, in addition to a monoclonal TCR gene rearrangement, are unusual findings in NK/T-cell lymphoma, and we believe such a phenotype/genotype should be more appropriately classified as an EBV-positive peripheral T-cell lymphoma, unspecified with a cytotoxic phenotype. Detailed clinicopathologic and molecular studies of similar cases may shed light on the prognostic impact of NK vs. T-cell lineage on extranodal NK/T-cell lymphomas.     

Hydroa vacciniforme-like primary cutaneous CD8-positive T-cell lymphoma

An 8-year-old Taiwanese girl had a 6-month history of a relapsing papulovesicular eruption on her face that resembled hydroa vacciniforme (HV). Histologically, there was a dense infiltration of large atypical lymphocytic cells expressing CD8. TCR-gamma gene rearrangement study revealed a monoclonal band present in the DNA extracted from the specimen. A diagnosis of CD8+ cutaneous T-cell lymphoma (CTCL) was made. The patient was treated with Chinese herbal drugs and her skin lesions waxed and waned. At this writing, 11 months after establishment of the diagnosis, the skin lesions have been limited to the facial area and no definite evidence of systemic involvement is noted. To our knowledge, this is the first case of CD8+ primary CTCL with clinical features resembling HV.     

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.     

The significance of multiplex PCR/heteroduplex analysis-based TCR-γ gene rearrangement combined with laser-capture microdissection in the diagnosis of early mycosis fungoides

Background: The diagnosis of early mycosis fungoides (MF) is a big challenge to dermatologists and dermatopathologists because it lacks specific clinicopathologic features. Methods: Fifty‐two paraffin‐embedded skin samples from 50 patients, including 31 with suspected MF, 10 with typical MF and 9 with benign inflammatory dermatosis (BID), were obtained from our archives. DNA was extracted both by traditional phenol‐chloroform method and by the laser‐capture microdissection (LCM)‐proteinase K approach. The T_VG/T_JG, V_2–5/V_8–12/JGT₁ and BIOMED‐2‐TCR‐γ primers were used to assess TCR‐γ monoclonal rearrangement as measured by polymerase chain reaction (PCR). Results: In the suspected MF group, clonal TCR‐γ gene rearrangements were detected in 11/31 cases (35.5%) by phenol‐chloroform DNA extraction and in 25/31 cases (80.7%) by LCM‐proteinase K extraction (p < 0.05). While T‐cell clonality was detected in 8/10 cases (80%) by the phenol‐chloroform method and 10/10 cases (100%) by LCM (p > 0.05) in the typical MF group, no TCR‐γ monoclonal rearrangement was detected in the BID group. Conclusions: The strategy of multiple PCR/heteroduplex analysis for TCR‐γ gene rearrangement combined with LCM increases the detection rate of clonal TCR‐γ gene rearrangement in early MF cases and could provide strong evidence to confirm the diagnosis of early MF. Yang H, Xu C, Tang Y, Wan C, Liu W, Wang L. The significance of multiplex PCR/heteroduplex analysis‐based TCR‐γ gene rearrangement combined with laser‐capture microdissection in the diagnosis of early mycosis fungoides.     

Nasal-type T/natural killer cell angiocentric lymphoma, Epstein-Barr virus-associated, and showing clonal T-cell receptor gamma gene rearrangement

Nasal-type T/natural killer (NK) cell lymphoma, which often shows an angiocentric growth pattern, is a distinct clinicopathological entity highly associated with the Epstein-Barr virus (EBV). This tumour has a characteristic immunophenotype, whereas the cytological spectrum is broad. It is known that a clonal T-cell receptor (TCR) gene rearrangement is not found in this tumour. However, it is still unresolved as to whether the finding of a clonal TCR gene rearrangement excludes the diagnosis of nasal-type T/NK cell lymphoma. We describe a case of nasal-type T/NK cell angiocentric lymphoma, EBV-associated, and showing clonal TCR gamma gene rearrangement. The patient died of sepsis 5 months after diagnosis in spite of aggressive chemotherapy.     

CD30+ large cell transformation of mycosis fungoides after psoralen plus ultraviolet A photochemotherapy

Psoralen plus ultraviolet A (PUVA) photochemotherapy is widely used for the therapy of mycosis fungoides (MF). Clinical progression of MF is often associated with an increase in the size of tumour cells known as transformation. We report two patients with CD30+ large cell transformation that appeared after low-dose PUVA therapy for MF. Clinical data, histopathology, immunohistopathology and T-cell receptor gene rearrangement were studied. Nodules consisted of atypical large cells that expressed CD30. Monoclonal rearrangement of T-cell receptors was observed in one case. Low-dose PUVA therapy may be associated with CD30+ large cell transformation in patients with MF.     

Evaluation of a new paraffin-reactive CD7 T-cell deletion marker and a polymerase chain reaction-based T-cell receptor gene rearrangement assay: implications for diagnosis of mycosis fungoides in community clinical practice

BACKGROUND: T-cell deletion and T-cell receptor (TCR) gene rearrangement studies are helpful in the early diagnosis and subsequent management of mycosis fungoides (MF). However, this often requires fresh-frozen tissue that can be difficult to obtain and evaluate in community clinical practice. A new CD7 antibody, the most sensitive and specific T-cell deletion marker, and a new TCR-gamma gene rearrangement polymerase chain reaction (PCR) assay (TCR-gamma PCR) are now available on routine paraffin-embedded biopsy specimens. OBJECTIVE: Our purpose was to assess the utility of CD7 deletion and TCR-gamma PCR in the diagnosis of MF using routine paraffin-embedded biopsy material. METHODS: Cases of MF (n = 17) with matching frozen tissue immunohistochemistry and benign reactive dermatoses (lichen planus; n = 27) were assessed for CD7 (Clone: CD7-272) deletion and TCR-gamma PCR using paraffin-embedded biopsy specimens. RESULTS: Excellent concordance comparing frozen and paraffin embedded CD7 immunostaining (88%) was observed. CD7 deletion and TCR-gamma PCR was sensitive (94%) and specific (96%) for a diagnosis of MF using paraffin-embedded biopsy specimens. CONCLUSION: In the diagnosis of MF, detection of CD7 deletion and monoclonal TCR rearrangements can be successfully performed in a cost-effective, timely fashion using routine formalin-fixed paraffin-embedded biopsy specimens.     

非霍奇金淋巴瘤1例

报告1例以皮肤肿瘤为首发表现的儿童非霍奇金淋巴瘤。患儿女，8岁。右侧鼻翼出现肿块3个月余，伴进行性增大1个月就诊。体格检查示局部淋巴结不增大，系统检查无异常。皮损组织病理检查示真皮内有异形淋巴样细胞浸润，免疫组化染色结果示：CD45RO（＋），CD20，HMB45，CK，CD30和CD68均阴性，证实为T细胞淋巴瘤。     

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。     

Mycosis fungoides involving an acrochordon: a case report

We present the case of a 77‐year‐old male undergoing treatment for mycosis fungoides (MF) who presented for removal of an acrochordon on his mid back. Histopathologic examination of the acrochordon revealed a dense, band‐like lymphocytic inflammatory infiltrate in the dermis with epidermotropism of single lymphocytes and small nests of lymphocytes into the lower epidermis. Immunohistochemical staining characterized the dermal and epidermal lymphocytic population as CD3‐positive T lymphocytes with a predominance of CD4‐positive over CD8‐positive lymphocytes. These findings were consistent with the patient's known MF and molecular identification of a clonal T‐cell receptor gene rearrangement further supported the diagnosis. Our unusual case reports MF involving an acrochordon and provides evidence to support the importance of submitting acrochordons for histopathologic examination.     

Subcutaneous panniculitis-like T-cell cutaneous lymphoma

Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma classified in the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification as a unique extranodal lymphoma with characteristic by T cell receptor (TCR) gene rearrangement. We report here a case of SPTCL in a 22 year-old woman who had presented with variably sized multiple nodules on both her legs. Initial differential diagnoses considered were panniculitis and lupus panniculitis. The histopathology showed a predominantly subcutaneous lobular infiltrate with atypical lymphocytes, karyorrhexis and rimming of adipocytes by lymphoid cells. Immunohistochemistry showed CD4-, CD8+, CD56- T-cell phenotype. Although TCR rearrangement studies were not done, the above T-cell phenotype and sparing of epidermis and dermis suggested the possibility of an SPTCL alpha/beta type. The patient received five cycles of a cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen which resulted in the regression in her skin lesions and constitutional symptoms.