[Interpretation of T-cell and NK-cell lymphoid proliferations and lymphomas in the 5th edition of the WHO classification of haematolymphoid tumours].

The 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumours used the hierarchical system to classify T-cell and NK-cell lymphoid proliferations and lymphomas (T/NK-LPD/LYM) based on research advances and clinicopathological characteristics of the diseases. In this edition of classification, tumour-like lesions were included, some tumors were added/deleted, the names or terms of certain diseases were refined, and the diagnostic criteria or subtypes of some diseases were revised. This group of diseases was reintegrated from non-clonal hyperplasia to highly aggressive lymphoma, which would further reflect the nature of T/NK-LPD/LYM and benefit to clinical application.

The bidirectional increased risk of B-cell lymphoma and T-cell lymphoma.

Lymphoma survivors have a significantly higher risk of developing second primary lymphoma than the general population; however, bidirectional risks of developing B- and T-cell lymphomas (BCLs and TCLs) specifically are less well understood. We used population-based cancer registry data to estimate the subtype-specific risks of second primary lymphoma among patients with first BCL (n = 288 478) or TCL (n = 23 747). We observed nearly fivefold increased bidirectional risk between BCL and TCL overall (TCL following BCL: standardized incidence ratio [SIR] = 4.7, 95% confidence interval [CI] = 4.2-5.2; BCL following TCL: SIR = 4.7, 95% CI = 4.1-5.2), but the risk varied substantially by lymphoma subtype. The highest SIRs were observed between Hodgkin lymphoma (HL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (PTCL-NOS following HL: SIR = 27.5; HL following PTCL-NOS: SIR = 31.6). Strikingly elevated risks also were notable for angioimmunoblastic T-cell lymphoma (AITL) and diffuse large B-cell lymphoma (DLBCL) (AITL following DLBCL: SIR = 9.7; DLBCL following AITL: SIR = 15.3). These increased risks were strongest within the first year following diagnosis but remained persistently elevated even at ≥5 years. In contrast, SIRs were <5 for all associations of TCL with chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. These patterns support etiologic heterogeneity among lymphoma subtypes and provide further insights into lymphomagenesis.

American Registry of Pathology Expert Opinions: Recommendations for the diagnostic workup of mature T cell neoplasms.

The diagnosis of T-cell lymphomas is highly challenging and requires an integrated approach in which clinical, morphologic, immunophenotypic and molecular data are incorporated into the diagnosis. Under the auspices of the American Registry of Pathology, the authors met to discuss this topic with the goal to provide practical and useful recommendations for pathologists when evaluating T-cell lymphomas. In this review, we discuss the diagnostic findings and workup for the various types of nodal T-cell lymphoma including anaplastic large cell lymphoma, nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), and PTCL with a T follicular helper (TFH) phenotype. We review clinicopathologic and immunophenotypic features (including flow cytometry panels) helpful in the differential diagnosis of mature T-cell lymphomas presenting in the peripheral blood and bone marrow, and we discuss some of the more common extranodal-based T-cell lymphomas including extranodal natural killer/T-cell lymphoma of nasal and non-nasal type, gamma delta T cell lymphomas, and aggressive and indolent T- and NK-lymphoproliferative disorders involving the gastrointestinal tract. Mycosis fungoides and most other cutaneous T-cell lymphomas are not the focus of this review, although the differential diagnosis of Sezary syndrome from mycosis fungoides is covered. We do not intend for these recommendations to be anything other than suggestions that will hopefully spur on additional discussion, and perhaps eventually evolve into a consensus approach for the workup of T-cell lymphomas.

A clinicopathologic study of the spectrum of systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood: A single tertiary care pediatric institution experience in North America.

BACKGROUND: Systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood (S-EBV-T-LPD) comprise three major forms: EBV-positive hemophagocytic lymphohistiocytosis (EBV-HLH), systemic EBV-positive T-cell lymphoma (S-EBV-TCL), and systemic chronic active EBV infection (S-CAEBV). These disorders occur rarely in children in Western countries. Here, we described eight children of such entities. DESIGN: Eight cases (six clinical and two autopsy) with S-EBV-T-LPD of childhood were retrospectively identified from 1990 to 2015. Clinicopathologic parameters including histomorphology, immunophenotype, EBV studies, and T-cell receptor gene rearrangement studies were recorded. RESULTS: Patients include five females and three males of Hispanic, Asian, and Caucasian origins with an age range of 14 months to 9 years. Fever, hepatosplenomegaly, cytopenias, abnormal EBV serologies, and very high EBV viral loads were common findings. Histologic findings showed EBV+ T-cell infiltrates with variable degrees of architectural distortion and cytologic atypia ranging from no to mild cytologic atypia to overt lymphoma and tissue hemophagocytosis. All showed aberrant CD4+ or CD8+ T cells with dim to absent CD5, CD7, and CD3, and bright CD2 and CD45 by flow cytometry or loss of CD5 by immunohistochemistry. TCR gene rearrangement studies showed monoclonal rearrangements in all clinical cases (6/6). Outcomes were poor with treatment consisting of chemotherapy per the HLH-94 or HLH-2004 protocols with or without bone marrow transplant. CONCLUSION: In this large pediatric clinicopathologic study of S-EBV-T-LPD of childhood in the United States, EBV-HLH, S-EBV-TCL, and S-CAEBV show many overlapping features. Diagnosis is challenging, and overall outcome is poor using current HLH-directed therapies.

Subcutaneous Panniculitis-Like T-cell Lymphoma in Dogs: Morphologic and Immunohistochemical Classification.

Canine nonepitheliotropic cutaneous T-cell lymphomas (NECTCL) are poorly characterized. In humans, a number of distinct subtypes of NECTCL have been recognized, including subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Five dogs with subcutaneous T-cell lymphomas histologically similar to SPTCL in humans are herein described. The mean age was 8.5 years (5.5 to 12 years). No breed or sex predilection was identified in this small cohort. Two dogs presented with an acute onset of multiple skin masses and 3 dogs had solitary masses with subsequent development of multiple smaller masses within 0.5 to 2 months post-diagnosis without treatment. Locations, when specified, included shoulder, neck, and ventral abdomen. Two dogs were euthanized following diagnosis and one dog treated with chemotherapy (CCNU) survived 7 months post-diagnosis. Histologically, all cases were characterized by proliferations of either small to intermediate or large sized, CD3-positive T cells that infiltrated the subcutis in a lace-like pattern and frequently rimmed adipocytes. No epitheliotropism was observed, neoplastic cells were often karyorrhectic, and there were regions of extensive necrosis. Heavy infiltrates of histiocytes with prominent phagocytosis masked the lymphoid neoplastic cell population in some sections. A clonal T-cell receptor gamma gene rearrangement was found in 4 of the 5 cases. While SPTCLs typically have a less aggressive clinical course in humans, their biological behavior in dogs remains to be determined. In summary, SPTCL may represent a distinct entity in dogs and needs to be accurately diagnosed to better determine clinical behavior.

Intestinal T-cell and NK/T-cell lymphomas: A clinicopathological study of 27 Chinese patients.

BACKGROUND: Intestinal T-cell and NK/T- cell lymphomas are rare and aggressive. The diagnosis is quite difficult, especial in biopsy specimens. This study investigates the clinicopathological features of intestinal T-cell and NK/T-cell lymphomas to aid their differential diagnosis. METHODS: Clinical data of 27 cases were collected. Including extranodal NK/T-cell lymphoma, nasal type (ENKTCL-N), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), anaplastic large-cell lymphoma, ALK+ (ALCL, ALK+) and angioimmunoblastic T-cell lymphoma (AITL). The histologic features, immunohistochemical findings, T-cell receptor gene rearrangement results, and follow-up data were analyzed, with review of literature. RESULTS: The age of the patients (N = 27) was 15-85 years (mean, 47.5 years), and male:female ratio, 3.5:1. Abdominal pain and B symptoms were the most common symptoms. Although 85.2% of the patients were in clinical stage I-II, 59.3% died within 1 year. MEITL showed certain distinctive clinic opathological features from ENKTCL-N. Compared to lesions at other sites, there were no differences in the morphological features, immunophenotype and TCR gene rearrangement of intestinal ENKTCL-N, PTCL, NOS, ALCL, ALK+ and AITL. CONCLUSION: Intestinal T-cell and NK/T-cell lymphomas are a heterogeneous group of lymphomas. They could be classified to 5 histological subtypes in our study. ENKTCL-N and MEITL formed the majority of the tumor types. Each subtype has distinctive pathological features, but most of them have diamal prognosis.

Follicular helper T-cell-related lymphomas.

In this issue of Blood, Wang et al describe the occurrence and pathogenetic relevance of IDH2R172 mutations in angioimmunoblastic T-cell lymphoma (AITL).

IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2(R172) mutations demonstrated a distinct gene expression signature characterized by downregulation of genes associated with TH1 differentiation (eg, STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2(R172K) in the Jurkat cell line and CD4(+) T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysine methylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2 mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.

FoxP3-positive T cell lymphoma arising in non-HTLV1 carrier: clinicopathological analysis of 11 cases of PTCL-NOS and 2 cases of mycosis fungoides.

AIMS: Forkhead box protein 3-positive (FoxP3(+) ) T cell lymphoma, in the absence of human T cell lymphotrophic virus type 1 (HTLV-1) infection, is rare and its clinicopathological characteristics still remain unclear. The aim of this study was to elucidate its characteristics. METHODS AND RESULTS: We describe here 11 cases of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) and two cases of mycosis fingoides (MF) which were positive for FoxP3. The median age of the 11 PTCL-NOS cases was 65 years (range: 48-80 years), and all the patients were male. Eight patients (80%) showed stages III/IV disease, and six (60%) were categorized as high-intermediate/high-risk groups according to the International Prognostic Index. Two cases of MF were 57- and 59-year-old males. Both cases were categorized as stage IA, according to International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) classification. Immunohistochemically, all the cases were negative for cytotoxic molecule marker, and nine (75%) were αß T cell type. Scattered Epstein-Barr virus (EBV)-infected cells were detected in four cases of PTCL-NOS, implying the reactivation of EBV caused by the immunodeficient status of the patients. CONCLUSIONS: FoxP3(+) PTCL-NOS constitute a minor phenotypical subtype with poor prognosis and EBV reactivation in some. Conversely, two cases of MF showed an indolent clinical course which was different from previously reported cutaneous T cell lymphoma (CTCL) cases.

Gamma-delta t-cell lymphomas.

Gamma-delta T-cell lymphomas are aggressive and rare diseases originating from gamma-delta lymphocytes. These cells, which naturally play a role in the innate, non-specific immune response, develop from thymic precursor in the bone marrow, lack the major histocompatibility complex restrictions and can be divided into two subpopulations: Vdelta1, mostly represented in the intestine, and Vdelta2, prevalently located in the skin, tonsils and lymph nodes. Chronic immunosuppression such as in solid organ transplanted subjects and prolonged antigenic exposure are probably the strongest risk factors for the triggering of lymphomagenesis. Two entities are recognised by the 2008 WHO Classification: hepatosplenic gamma-delta T-cell lymphoma (HSGDTL) and primary cutaneous gamma-delta T-cell lymphoma (PCGDTL). The former is more common among young males, presenting with B symptoms, splenomegaly and thrombocytopenia, usually with the absence of nodal involvement. Natural behaviour of HSGDTL is characterised by low response rates, poor treatment tolerability, common early progression of disease and disappointing survival figures. PCGDTL accounts for <1% of all primary cutaneous lymphomas, occurring in adults with relevant comorbidities. Cutaneous lesions may vary, but its clinical behaviour is usually aggressive and long-term survival is anecdotal. Available literature on gamma-delta T-cell lymphomas is fractioned, mostly consisting of case reports or small cumulative series. Therefore, clinical suspicion and diagnosis are usually delayed, and therapeutic management remains to be established. This review critically analyses available evidence on diagnosis, staging and behaviour of gamma-delta T-cell lymphomas, provides recommendations for therapeutic management in routine practice and discusses relevant unmet clinical needs for future studies.

Follicular helper T-cell lymphoma: a B-cell-rich variant of T-cell lymphoma.

Follicular helper T-cell lymphoma is a recently described variant of T-cell lymphoma sharing the cell of origin with angioimmunoblastic T-cell lymphoma and with primary cutaneous CD4-positive small/medium T-cell lymphoma. To better characterize the morphologic and immunophenotypic features of follicular helper T-cell lymphoma, a series of 4 confidently diagnosed cases are analyzed. The overall morphologic pattern significantly overlaps with that of progressive transformation of germinal centers in 3 cases and with follicular hyperplasia in 1. Detection of large, clustered, atypical T-cells is an important feature differentiating follicular T-cell lymphoma from benign, reactive processes such as progressive transformation of germinal centers. The abnormal T-cells have an immunophenotype identical to that of follicular helper T-cells in all cases. Clonal T-cell populations are detected in all cases. A characteristic setting follicular T-cell lymphomas apart from most other T-cell lymphomas is the abundance of small, mature B-cells. Differences from angioimmunoblastic T-cell lymphoma include the absence of proliferating vessels or of Epstein-Barr virus-positive immunoblasts.

Non-Hodgkin's lymphoma by immunohistochemistry.

Non Hodgkin's lymphomas (NHL) constitute a heterogeneous group of neoplasm of the lymphoid system. There are many histological subtype of NHL based on WHO classification of hematopoietic and lymphoid neoplasm. This cross-sectional study was carried out in the department of Pathology, Dhaka Medical College, Dhaka from January 2009 to December 2010 to observe the different subtypes of NHL using immunohistochemistry (IHC) with CD3. A total of 50 microscopically diagnosed case of NHL irrespective of age and sex were included in the study. The diagnostic morphologic criteria of each lymphoma subcategory were compiled and diagnosis was made. Mean age of the study subjects were 42.0±19.7 years with range 3-75 years and male female ratio was 1.8:1. Nodal NHL was 66% and extranodal cases were 34%. Maximum number of histolgic subtypes belonged to diffuse large B-cell lymphoma (DLBCL) and male was predominant in all histological subtypes, except peripheral T-cell lymphoma (PTCL). DLBCL was predominant in all B-cell NHL whereas PTCL was predominant in all T-cell NHL. The most childhood patients belonged to lymphoblastic lymphoma. Regarding cell lineage B-cell NHL was more common than T-cell NHL (88% vs. 12%), but high grade pattern was more predominant in T-cell type (83.3% vs. 65.9%). Among 50 study subjects histological (H & E) diagnosis reveals 46 cases as B-cell NHL and 4 as T-cell NHL but IHC confirms 6 cases as T-cell NHL.

CUTANEOUS EPITHELIOTROPIC T-CELL LYMPHOMA WITH METASTASES IN A VIRGINIA OPOSSUM (DIDELPHIS VIRGINIANA).

A 2-yr-old, captive, intact female Virginia opossum ( Didelphis virginiana ) with a 7-mo history of ulcerative dermatitis and weight loss was euthanatized for progressive worsening of clinical signs. Initially the opossum was treated with several courses of antibiotics, both topically and systemically; systemic nonsteroidal anti-inflammatory medication; and, later, systemic glucocorticoids, with no improvement in clinical signs. Histopathologic samples of skin lesions taken 3 mo into the course of disease revealed no evidence of neoplasia; however, cytologic samples of a skin lesion taken 5 mo into the course of disease revealed mature lymphocytes, and were suggestive of cutaneous lymphoma. Postmortem histopathology revealed neoplastic cells consistent with lymphoma; these were found in the haired skin of the forearm, axilla, hind limb, face, and lateral body wall, as well as the liver, kidney, axillary lymph node, heart, and spleen. Multifocal neutrophilic and eosinophilic ulcerative and necrotizing dermatitis and folliculitis of the haired skin were also present. To the authors' knowledge, this is the first documented case of cutaneous lymphoma in a Virginia opossum and the first documented case with visceral metastases in a marsupial.

Endoscopic and clinical analysis of primary T-cell lymphoma of the gastrointestinal tract according to pathological subtype.

BACKGROUND AND AIM: Little is known about the clinicopathological characteristics of primary gastrointestinal T-cell lymphomas (PGITL). This study evaluated the clinical and endoscopic features of the pathological subtypes of PGITL. METHODS: Forty-two lesions in 36 patients with PGITL were assessed, including 15 enteropathy-associated T-cell lymphomas (EATL), 13 peripheral T-cell lymphomas (PTCL), 10 NK/T-cell lymphomas (NK/TL), and four anaplastic large cell lymphomas (ALCL). RESULTS: PTCL occurred more frequently in the stomach and duodenum and NK/TL more frequently in the small and large intestines (P = 0.009). The endoscopic features of the four subtypes were similar (P = 0.124). Fifteen of 41 lesions (36.6%) were Epstein-Barr virus (EBV) positive, with NK/TL more likely to be EBV positive than the other types (P < 0.001). First endoscopy and first computed tomography (CT) scan indicated that 65.4% and 51.4% of the lesions, respectively, were malignant, and that 43.2% and 42.3%, respectively, were GI lymphomas. The two modalities together correctly diagnosed about half of the lesions before biopsy. Intestinal perforation was associated with small bowel location (P < 0.001) and infiltrative type (P = 0.009), and was more common in NK/TL than in the other subtypes (P = 0.015). Multivariate analysis showed that higher international prognosis index (P = 0.008) and the presence of complications (P = 0.006) were associated with poor prognosis. Survival was poorer in patients with small bowel lesions than with lesions at other locations (P = 0.048). CONCLUSIONS: The four main pathological types of PGITL differed in clinical characteristics. As PGITL was often not diagnosed by initial endoscopic or radiological examination, a high index of suspicion is necessary to ensure its early diagnosis.

Characteristics of primary cutaneous lymphoma according to WHO-EORTC classification in Korea.

BACKGROUND: Primary cutaneous lymphoma (PCL) is an extranodal non-Hodgkin lymphoma with primary involvement of the skin. Epidemiological data on PCLs according to the World Health Organization/European Organization for Research and Treatment of Cancer classification (WHO-EORTC) has not been investigated in Korea to date. AIM: To evaluate the demographic characteristics, clinical and histological features, and survival data of patients with PCL according to the WHO-EORTC classification. METHODS: In total, 93 patients with PCL were retrospectively identified from an extensive review of medical records over a 16-year period. RESULTS: The tumours found included primary cutaneous CD30+ lymphoproliferative disorders, extranodal natural killer/T-cell lymphoma and primary cutaneous diffuse large B-cell lymphoma. We found that 81.6% of the patients had primary cutaneous T-cell and natural killer-cell lymphoma, and 16.2% had primary cutaneous B-cell lymphoma, with 2.2% having precursor haematological neoplasms. The median age was 52 years (range 3-95) and the male : female ratio was 1: 1.16. The 5-year survival rate was 92.5%. CONCLUSIONS: The incidence rates of many PCL subtypes in Koreans differ from those of other countries.

Molecular profiling reveals prognostically significant subtypes of canine lymphoma.

We performed genomewide gene expression analysis of 35 samples representing 6 common histologic subtypes of canine lymphoma and bioinformatics analyses to define their molecular characteristics. Three major groups were defined on the basis of gene expression profiles: (1) low-grade T-cell lymphoma, composed entirely by T-zone lymphoma; (2) high-grade T-cell lymphoma, consisting of lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified; and (3) B-cell lymphoma, consisting of marginal B-cell lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. Interspecies comparative analyses of gene expression profiles also showed that marginal B-cell lymphoma and diffuse large B-cell lymphoma in dogs and humans might represent a continuum of disease with similar drivers. The classification of these diverse tumors into 3 subgroups was prognostically significant, as the groups were directly correlated with event-free survival. Finally, we developed a benchtop diagnostic test based on expression of 4 genes that can robustly classify canine lymphomas into one of these 3 subgroups, enabling a direct clinical application for our results.

Hepatosplenic and hepatocytotropic T-cell lymphoma: two distinct types of T-cell lymphoma in dogs.

The clinical, clinicopathologic, and pathological findings of 9 dogs with T-cell lymphoma that involved the liver in the absence of peripheral lymphadenopathy were assessed. Seven dogs had hepatosplenic T-cell lymphoma (HS-TCL). Dogs with HS-TCL presented with hepato- and/or splenomegaly, regenerative anemia, thrombocytopenia, and hypoproteinemia. The clinical course was rapidly progressive with all dogs but 1 dead within 24 days of initial presentation. Neoplastic lymphocytes were centered on hepatic and splenic sinusoids and had a CD3+ (5/7), TCRαß- (5/5), TCRγδ+ (3/5), CD11d+ (6/7), granzyme B+ (5/7) immunophenotype. Bone marrow and lungs were consistently but variably involved. These findings closely resemble the human disease and support the classification of HS-TCL as a distinct World Health Organization entity in dogs. The remaining 2 dogs markedly differed in the pattern of hepatic involvement by neoplastic lymphocytes, which were not confined to hepatic sinusoids but invaded hepatic cords. In addition, neoplastic cells had a CD11d- immunophenotype, and clinicopathologic data indicated marked cholestasis and mild to absent anemia. Based on the distinct tropism of neoplastic lymphocytes for hepatocytes, the name hepatocytotropic T-cell lymphoma (HC-TCL) is proposed. Given the histomorphologic, clinicopathologic, and immunophenotypic differences, HC-TCL likely represents a separate biological entity rather than a histomorphologic variant of HS-TCL.

Mucosal CD30-positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders.

CD30-positive T-cell lymphoproliferative disorders are classified as cutaneous (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis) or systemic. As extent of disease dictates prognosis and treatment, patients with skin involvement need clinical staging to determine whether systemic lymphoma also is present. Similar processes may involve mucosal sites of the head and neck, constituting a spectrum that includes both neoplasms and reactive conditions (eg, traumatic ulcerative granuloma with stromal eosinophilia). However, no standard classification exists for mucosal CD30-positive T-cell lymphoproliferations. To improve our understanding of these processes, we identified 15 such patients and examined clinical presentation, treatment and outcome, morphology, phenotype using immunohistochemistry, and genetics using gene rearrangement studies and fluorescence in situ hybridization. The 15 patients (11 M, 4 F; mean age, 57 years) had disease involving the oral cavity/lip/tongue (9), orbit/conjunctiva (3) or nasal cavity/sinuses (3). Of 14 patients with staging data, 7 had mucosal disease only; 2 had mucocutaneous disease; and 5 had systemic anaplastic large cell lymphoma. Patients with mucosal or mucocutaneous disease only had a favorable prognosis and none developed systemic spread (follow-up, 4-93 months). Three of five patients with systemic disease died of lymphoma after 1-48 months. Morphologic and phenotypic features were similar regardless of extent of disease. One anaplastic lymphoma kinase-positive case was associated with systemic disease. Two cases had rearrangements of the DUSP22-IRF4 locus on chromosome 6p25.3, seen most frequently in primary cutaneous anaplastic large cell lymphoma. Our findings suggest mucosal CD30-positive T-cell lymphoproliferations share features with cutaneous CD30-positive T-cell lymphoproliferative disorders, and require clinical staging for stratification into primary and secondary types. Primary cases have clinicopathologic features closer to primary cutaneous disease than to systemic anaplastic large cell lymphoma, including indolent clinical behavior. Understanding the spectrum of mucosal CD30-positive T-cell lymphoproliferations is important to avoid possible overtreatment resulting from a diagnosis of overt T-cell lymphoma.

Intramucosal variant of nasal natural killer (NK)/T cell lymphoma has a better survival than does invasive variant: implication on loss of E26 transformation-specific sequence 1 (ETS-1) and T-box expressed in T cells (T-bet) with invasion.

AIMS: Nasal natural killer/T cell lymphoma (NNKTCL) arises from the nasal mucosa, and spreads to adjacent tissues via local invasion or to regional lymph nodes and distant sites via metastasis. The aims of this study were to determine the impact of invasion on the prognosis of NNKTCL, and correlate invasion with the expression of cytotoxic markers of lymphoma cells. METHODS AND RESULTS: Histopathological evaluations of invasion and immunohistochemistry for cytotoxic markers, including E26 transformation-specific sequence 1 (ETS-1), T-box expressed in T cells (T-bet), signal transducer and activator of transcription (STAT-1), CD56 and granzyme B (GB), were performed in 64 NNKTCLs. There were 17 stage I cases without invasion (stage Ia or intramucosal), 21 stage I cases with invasion (stage Ib), 16 stage II cases and 10 stages III/IV cases. Stage Ia NNKTCLs had a better 5-year overall survival rate than that of stages Ib, II or III/IV NNKTCLs (85%, 38%, 33% and 20%, respectively, P < 0.001 by log-rank test). Loss of ETS-1 was found in 24% (four of 17) stage Ia NNKTCLs and in 65% (28 of 43) stages Ib/II/III/IV NNKTCLs (P = 0.04, Fisher's exact test); loss of T-bet was found in 29% (five of 17) stage Ia NNKTCLs and in 67% (30 of 45) stages Ib/II/III/IV NNKTCLs (P = 0.02, Fisher's exact test). CONCLUSIONS: NNKTCL is classically an aggressive lymphoma, but the intramucosal variant is less aggressive. Loss of ETS-1 or T-bet correlated weakly with invasion, a finding that requires further confirmation.

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.