Cutaneous natural killer/T-cell lymphoma

Lymphomas are classified as either Hodgkin's or non-Hodgkin's. The 2 subtypes of non-Hodgkin's lymphoma that can present primarily in the skin are cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, both of which tend to be low-grade malignant neoplasms. Recently another distinct subtype of lymphoma was discovered, the natural killer (NK)/T-cell lymphoma, which can involve the skin in a primary or secondary fashion. The NK/T-cell subtype of lymphoma is characterized by the expression of the NK-cell antigen CD56. These CD56(+) lymphomas are further subdivided into nasal NK/T-cell lymphomas that commonly present as midfacial destructive disease and non-nasal NK/T-cell lymphomas that often arise in extranodal locations, including the skin. We report a case of aggressive NK-cell leukemia/lymphoma with numerous secondary cutaneous lesions and review the clinical and histopathologic spectrum of non-nasal CD56(+) lymphomas, with an emphasis on the dermatologic findings.     

A Case of Aggressive NK/T-cell Lymphoma/Leukemia with Cutaneous Involvement in Adolescence

NK/T-cell lymphoma (NKTCL) is characterized by the expression of the NK-cell antigen CD56. Non-nasal NK/T-cell lymphomas are subdivided into primary cutaneous and 4 subtypes of secondary cutaneous lymphomas; nasal type, aggressive, blastic (blastoid), and other specific NK-like cell lymphoma. Aggressive NK/T-cell lymphoma/leukemia is a rare leukemic variant of nasal type NKTCL. We herein report a rare case of aggressive NK/T-cell lymphoma/leukemia with cutaneous involvement in adolescence.     

Cutaneous presentation of steroid responsive blastoid natural killer cell lymphoma

CD56+ lymphomas derived from natural killer (NK) cell lineage are rarely encountered in Western populations and their clinical and pathological features have not been fully defined. The majority of reported cases are lymphomas of the nasal cavity, which are most commonly seen in Asia. A subtype of CD56+ lymphoma has recently been described (blastoid NK-cell lymphoma) which characteristically presents in older patients with cutaneous infiltrates and disease at other nodal and extranodal sites. We describe a case that correlates well with the clinicopathological features of blastoid NK-cell lymphoma. An unusual feature in our patient was that the cutaneous features of the lymphoma showed complete resolution shortly following commencement of oral steroid therapy.     

Relative frequency of the different types of cutaneous T cell and natural killer cell lymphomas in Korea based on the proposed WHO classification and the EORTC classification

The R.E.A.L. classification was largely adopted recently by the proposed WHO classification. The usefulness of this classification in cutaneous T cell and natural killer (NK) cell lymphomas in Korea was evaluated compared to that of the European Organization for Research and Treatment of Cancer (EORTC) classification. Overall, 78 patients with cutaneous T cell and NK cell lymphomas were diagnosed in Asan Medical Center in the 1990's. The clinical records, slides of H&E and immunohistochemical stainings were reviewed. By the proposed WHO classification, mycosis fungoides (20 cases), lymphomatoid papulosis (13 cases), nasal type NK/T-cell lymphoma (10 cases), CD30+ anaplastic large cell lymphoma (8 cases), subcutaneous panniculitis-like T-cell lymphoma (6 cases), peripheral T-cell lymphoma, unspecified (3 cases), Sézary syndrome (1 case) and blastic NK cell lymphoma (1 case) comprised the primary cases. Secondary or undetermined cases included peripheral T-cell lymphoma, unspecified (10 cases), nasal type NK/T-cell lymphoma (5 cases), and angioimmunoblastic T-cell lymphoma (1 case). EORTC classification for cutaneous T cell and NK cell lymphomas did not include nasal and nasal type NK/T-cell lymphomas, unspecified non-pleomorphic T-cell lymphoma, undetermined cases among primary or secondary ones and some rare types of skin lymphomas which can be classified by WHO. The WHO classification is more useful for skin lymphomas in Korea since it encompassed all the various types of skin T cell and NK cell lymphomas in Korea.     

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.     

Skin is the frequent site for involvement of peripheral T-cell and natural killer cell lymphomas in Korea

We have studied the clinicopathological features of 19 Korean cases of peripheral T-cell and natural killer (NK) cell lymphomas, not including mycosis fungoides. Primary cutaneous involvement was demonstrated in eight of these 19 cases, and we recognized four clinicopathologic subtypes among these eight patients: nasal type NK/T cell lymphoma, three cases; primary cutaneous CD30 positive anaplastic large cell lymphoma, two cases; subcutaneous panniculitis-like T-cell lymphoma, one case; lymphoma with hydroa vacciniforme-like cutaneous lesions, two cases. We did not, however, encounter any cases of HTLV-associated adult T-cell lymphoma/leukemia, which is common in Taiwan and Japan. EBV-associated lymphoma is the most prominent type of peripheral T-cell and NK cell neoplasm involving the skin in Korea.     

Blastic CD56+ natural killer-cell lymphoma with primary cutaneous manifestation

T/natural killer-cell lymphomas belong to a heterogeneous group of non-Hodgkin lymphomas with predominant extranodal, often cutaneous, manifestations. In contrast to B- and T-cell lymphomas, T/NK-cell lymphomas were only recently regarded as a distinct entity. These rather aggressive malignancies arise from cytotoxic T cells, NK-cells or NK-like T cells, which share several phenotypic and functional properties. We report a man with a blastic NK-cell lymphoma with nodular skin infiltrations as the leading clinical manifestation of the disease. Complicated of tuberculosis, the patient died within 9 months of diagnosis, despite aggressive polychemotherapy.     

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.     

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.     

Rimming of adipocytes by neoplastic lymphocytes: a histopathologic feature not restricted to subcutaneous T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma of the skin presenting with histopathologic features simulating those of a lobular panniculitis. The presence of neoplastic T-lymphocytes forming a rim around the individual fat cells in the subcutaneous lobules, so-called "rimming" of adipocytes, is considered a characteristic morphologic feature of this type of cutaneous lymphoma. In this study we reviewed a series of 45 biopsy specimens of primary and secondary cutaneous B- and T-cell lymphomas and one of myeloid leukemia involving the subcutaneous tissues and showing rimming of adipocytes (subcutaneous panniculitis-like T-cell lymphoma: n = 16; mycosis fungoides, tumor stage: n = 3; aggressive epidermotropic CD8(+) T-cell lymphoma: n = 2; cutaneous gamma/delta T-cell lymphoma: n = 4; extranodal NK/T-cell lymphoma, nasal type: n = 4; cutaneous medium-large pleomorphic T-cell lymphoma, NOS: n = 5; CD4(+)/CD56(+) hematodermic neoplasm (blastic NK-cell lymphoma): n = 7; secondary cutaneous large B-cell lymphoma: n = 3; secondary cutaneous lymphoplasmacytic lymphoma: n = 1; specific cutaneous manifestations of acute myelogenous leukemia: n = 1). We could demonstrate that rimming of adipocytes by neoplastic cells can be recognized not only in subcutaneous panniculitis-like T-cell lymphoma, but also in several different entities of malignant lymphoma with skin involvement. Precise classification of cases with prominent involvement of the subcutaneous tissues can only be achieved upon precise correlation of clinicopathologic and phenotypic features. Rimming of adipocytes should not be considered specific of subcutaneous panniculitis-like T-cell lymphoma.     

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.     

A case of primary cutaneous extranodal natural killer/t-cell lymphoma, nasal type, with a 22-year indolent clinical course

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare type of cytotoxic lymphoma involving mainly the upper aerodigestive tract and associated with Epstein-Barr virus. The disease has usually a poor prognosis related to several factors. The skin is the second most common affected organ, and cases may be localized to the skin only without any other extracutaneous manifestations. Although primary cutaneous cases may have a better prognosis, survival usually is still poor. We report a case of primary cutaneous extranodal NK/T-cell lymphoma, nasal type, in a 77-year-old woman with an indolent course for more than 22 years and still limited to the skin.     

Retrospective analysis of 133 patients with cutaneous lymphomas from a single Japanese medical center between 1995 and 2008

In 2008, a revised World Health Organization (WHO) system of hematological neoplasm classification was promulgated. Between January 1995 and December 2008, 133 new patients with cutaneous lymphomas were seen at the dermatology clinic of Okayama University Hospital. All patients were re-classified according to the revised WHO system. The incidence rates were analyzed and the survival was estimated. Of 133 patients, 106 (79.7%) had primary cutaneous lymphomas (PCLs) and 27 (20.3%) were skin invasion from extracutaneous origin of systemic lymphoma. Compared with several reports from western countries, "mature T-cell and NK-cell neoplasms" was frequent in this study (87% vs. 77 or 72%) because of the occurrence of adult T-cell leukemia/lymphoma (ATLL) and "extranodal NK/T cell lymphoma, nasal type", with less frequent occurrence of "mature B-cell neoplasms" (13% vs. 23 or 28%). Estimated survival of patients with mycosis fungoides was favorable (5-year survival rate 90.6%), but that of the patients with primary cutaneous anaplastic large cell lymphoma (C-ALCL) was extremely less favorable than previously reported (5-year survival rate of 47.4%).     

CD-3 positive extranodal T-cell lymphoma of nasal type with skin involvement

A 40-year-old previously healthy lady presented with nasal obstruction and localized plaques over the right arm. She developed complete nasal obstruction due to a mass in the right nasal cavity and skin lesions that ulcerated to present as ecthyma gangrenosum like lesions. Patient's condition deteriorated fast and she developed icterus with fatal outcome within 4 weeks of developing skin lesions. Nasal and skin biopsy revealed angiocentric T-cell lymphoma, which on immuno-phenotyping revealed CD-3 positive; and CD-20, CD-30, ALK and EMA negativity. She was seronegative for HIV. Final diagnosis of CD-3 positive extranodal T-cell lymphoma of nasal type was made. Extranodal T-cell lymphomas are very aggressive NHLs with poor prognosis. Prognosis depends on histology, stage of the disease and sites of involvement. NK/T cell lymphoma of nasal type is common with EBV association. Skin involvement is rare and is also an indicator of poor prognosis.     

CD4+/CD56+ hematodermic neoplasm: report of a rare variant with a T-cell receptor gene rearrangement

CD4+/CD56+ hematodermic neoplasm (HN), formerly known as a blastic natural killer (NK) cell lymphoma, is a rare subtype of a cutaneous dendritic cell neoplasm notable for highly aggressive behavior. The characteristic features are: expression of the T-helper/inducer cell marker CD4 and the NK-cell marker CD56 in the absence of other T cell or NK-cell specific markers. In particular, CD3 (surface or cytoplasmic) and CD2 are not expressed. Although T-cell receptor (TCR) genes are generally reported to be in a germline configuration, we present an unusual variant of a CD4+/CD56+ HN with a clonal rearrangement of TCR genes. This feature of a CD4+/CD56+ HN has been only rarely reported. Recognition of the presence of clonal TCR gene rearrangements in a small subset of CD4+/CD56+ HN is important to avoid misdiagnosis of this entity as an unusual variant of a cutaneous T-cell lymphoma.     

Extranodal NK / T-cell lymphoma with cutaneous involvement: 'nasal' vs. 'nasal-type' subgroups— a retrospective study of 18 patients

Background  Extranodal natural killer T (NK/T) cell lymphoma is subcategorized into 'nasal' and 'nasal-type' NK/T-cell lymphomas according to the primary sites of anatomical involvement.
Objectives  The aim of this study was to characterize the cutaneous manifestations of the skin involving extranodal NK/T-cell lymphoma and to define the distinctive features of 'nasal' and 'nasal-type'. In addition, the prognostic factors that affect overall survival were investigated.
Methods  A retrospective case study of 18 patients with extranodal NK/T-cell lymphoma with cutaneous involvement was performed.
Results  The NK/T-cell lymphomas usually occurred in middle-aged, male patients. Most of the patients presented with either cellulitis or ulcer. A facial predilection for the location of the lesion was noted. The characteristic features of the 'nasal-type' compared with the 'nasal' were a localized involvement of the skin, less aggressive clinical course and better survival outcome.
Conclusions  Extranodal NK/T-cell lymphomas are extremely aggressive regardless of their subgroup. However, the 'nasal-type' NK/T-cell lymphoma was clinically less aggressive, more localized and had a better outcome compared with the other type. Cellulitis and ulcer were the major cutaneous manifestations.     

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.     

皮肤淋巴瘤与EB病毒潜伏感染的关系及病毒亚型的分析

目的 探讨EB病毒潜伏感染及其亚型与皮肤淋巴瘤的相关性.方法 标本来源于41例淋巴瘤患者的皮肤组织和38例健康成人咽部洗漱液.采用原位杂交、PCR、巢式PCR、Southern杂交方法检测EB病毒及其亚型.通过Southern杂交对5例自然杀伤/T细胞淋巴瘤病例中EB病毒末端重复序列进行分析.结果 8例自然杀伤/T细胞淋巴瘤、4例皮下脂膜炎型淋巴瘤、1例自然杀伤/T淋巴细胞增生症、1例血管免疫母细胞恶性淋巴瘤和1例组织细胞样淋巴瘤EB病毒原位杂交和PCR结果均阳性.38例正常人中有14例咽部携带有EB病毒.15例蕈样肉芽肿、5例Sézary综合征病例中,EB病毒原位杂交和EB病毒BMRF1基因PCR扩增均为阴性.除1例淋巴细胞增生症患者为EB病毒亚型1和2双重感染外,其它病例均为亚型1感染.正常人群咽部携带亚型1EB病毒.5例自然杀伤/T细胞淋巴瘤与EB病毒末端重复序列特异性探针杂交后,均只产生一条杂交带.结论 EB病毒潜伏感染与皮肤自然杀伤/T细胞淋巴瘤及皮下脂膜炎型淋巴瘤相关,但与蕈样肉芽肿和Sézary综合征无明显相关性.肿瘤细胞中的EB病毒与正常人群咽部所携带的病毒亚型相同,均为亚型1.肿瘤细胞单克隆增殖发生于EB病毒感染之后,此结论支持EB病毒在自然杀伤/T细胞淋巴瘤中的致病作用.     

Nasal‐type extranodal natural killer/T‐cell lymphoma presenting with extensive leg ulcers

Primary cutaneous T‐cell lymphomas are rare and can be difficult to classify precisely. We present a case of extranodal natural killer (NK)/T‐cell lymphoma in a previously healthy, immunocompetent man who presented with extensive necrotic leg ulcers and disseminated skin nodules. Immunohistochemical studies revealed that the tumour cells were positive for CD3, CD30, granzyme B and T‐cell intracellular antigen‐1, and negative for CD5 and CD56, with positive staining for Epstein–Barr virus (EBV) RNA on in situ hybridization. A diagnosis of extranodal NK/T‐cell lymphoma was made, based on the presence of cytotoxic granules and positive EBV RNA staining. The patient was treated with a regimen of chemotherapy comprising corticosteroids, intravenous methotrexate, ifosphamide, L‐asparginase and etoposide with initial response.     

Genomic alterations in blastic natural killer/extranodal natural killer-like T cell lymphoma with cutaneous involvement

Natural killer and natural killer-like T cell lymphomas represent a rare type of non-Hodgkin's lymphoma originally described to involve the upper aerodigestive tract. This malignancy has been increasingly observed in other extranodal sites, particularly in the skin. Patients with cutaneous natural killer cell lymphoma generally have a poor prognosis; however, the etiology and the underlying molecular pathogenesis remain unclear. This study aimed to investigate comprehensively genomic changes in blastic natural killer and extranodal natural killer-like T cell lymphoma with cutaneous involvement. Comparative genomic hybridization showed chromosome imbalances in six of eight cases studied (75%). The mean number of chromosome imbalances per sample was 2.18+/-1.63 with similar number of gains (1.18+/-1.17) and losses (1.00+/-1.34). The most frequent DNA copy number changes observed were losses of 9/9p (83%), followed by loss of 13q and gain of 7 (67%). Similar patterns of chromosome imbalances were observed in both blastic natural killer and cutaneous natural killer-like T cell lymphomas. Loss of the RB1 gene at 13q14.2 was detected in one blastic natural killer cell lymphoma with 13q loss using a gene dosage assay, and in one cutaneous natural killer-like T cell lymphoma without 13q loss using fluorescent in situ hybridization. Genomic microarray analysis identified oncogene copy number gains of PAK1 and JUNB in three of four cases studied, and gains of RAF1, CTSB, FGFR1, and BCR in two cases. Real-time polymerase chain reaction detected amplification of CTSB and RAF1 in four of five cases analyzed, JUNB and MYCN in three cases, and REL and YES1 in two cases, respectively. In conjunction with this study, an extensive literature search for the published G-banded karyotypes of four subsets of natural killer cell lymphomas was conducted, which showed a nonrandom pattern of multiple chromosome aberrations. These results reveal consistent genetic alterations in cutaneous natural killer cell lymphomas, and provide a basis for further investigation of molecular pathogenesis in this malignancy.