Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas

Peripheral T‐ or natural killer (NK)‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between NK cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and NK‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase (ALK)‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal NK/T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive NK‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal NK/T‐cell lymphoma, nasal type lacked these NK‐cell receptors, indicating different cell origin from NK and innate‐like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test, P = .024). We propose that the presence of activating NK‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm.     

Phase 2 trial of combined cisplatin,etoposide, gemcitabine,and methylprednisolone (PEGS) in peripheral T‐cell non‐Hodgkin lymphoma

BACKGROUND:

Patients with peripheral T‐cell lymphomas (PTCLs) have inferior progression‐free survival (PFS) and overall survival (OS) compared with patients who have aggressive B‐cell non‐Hodgkin lymphoma. Because PTCLs over express multidrug resistance gene 1/P‐glycoprotein (MDR‐1/P‐gp), we devised platinum, etoposide, gemcitabine, and methylprednisolone (PEGS) with agents that are not substrates of the efflux pump. Gemcitabine was included because of its excellent single‐agent activity in PTCL.

METHODS:

Patients who had PTCL with stage II bulky disease, stage III or IV disease with extra‐nodal, nodal, and transformed cutaneous presentations were eligible. Patients received intravenous cisplatin 25 mg/m² on days 1 through 4, etoposide 40 mg/m² on days 1 through 4, gemcitabine 1000 mg/m² on day 1, and methylprednisolone 250 mg on days 1 through 4 of a 21‐day cycle for 6 cycles.

RESULTS:

In total, 34 patients were enrolled, 33 were eligible, and 79% were newly diagnosed. Histologic types were PTCL not otherwise specified (n = 15), anaplastic lymphoma kinase (ALK)‐negative anaplastic large cell lymphoma (n = 4), angioimmunoblastic T‐cell lymphoma (n = 6), or other T‐cell non‐Hodgkin lymphomas (n = 8). Adverse events included 1 grade 5 infection with grade 3 or 4 neutropenia and 9 grade 4 hematologic toxicities. The overall response rate was 39% (47% in PTCL not otherwise specified, 33% in angioimmunoblastic T‐cell lymphoma, 25% in ALK‐negative and 38% in other T‐cell non‐Hodgkin lymphomas). The PFS rate at 2 years was 12% (95% confidence interval, 0.1%‐31%), and the median PFS was 7 months. The OS rate at 2 years was 30% (95% confidence interval, 8%‐54%), and the median OS was 17 months. Immunohistochemical analysis of P‐gp expression revealed strong positivity in a subset of lymphoma cells (n = 6) and tumor endothelium (n = 25).

CONCLUSIONS:

Overall, PEGS was well tolerated, but OS was not considered promising given the design‐specified targets. These results may serve as a benchmark for future comparisons for non‐CHOP regimens. Cancer 2013. © 2012 American Cancer Society.     

Indolent T‐ and NK‐cell lymphoproliferative disorders of the gastrointestinal tract: a review and update

Primary gastrointestinal (GI) T‐ and NK‐cell lymphomas are usually aggressive neoplasms associated with high morbidity and mortality. Over the past two decades, however, cases of primary GI lymphoproliferative disorders (LPDs) or lymphomas of T‐ or NK‐cell derivation with indolent behavior have been reported. These LPDs are rare and they can be challenging to diagnose as they share clinical and pathological features with both, inflammatory disorders and aggressive T‐ and NK‐cell lymphomas. Primary, indolent clonal T‐cell proliferations of the GI tract, which can be CD4+, CD8+ or CD4? CD8?, have been included as a provisional entity in the newly revised World Health Organization (WHO) classification of lymphoid neoplasms and designated ‘indolent T‐cell LPD of the GI tract’. It is currently unclear whether the indolent NK‐cell LPDs represent reactive or neoplastic proliferations. In this review, we describe the clinical, morphologic, immunophenotypic and genetic features of indolent GI T‐ and NK‐cell LPDs and provide guidance in differentiating them from other inflammatory and neoplastic diseases. We believe that greater awareness of these LPDs amongst physicians and the research community will lead to timely and accurate diagnoses, stimulate investigations into the pathogenetic mechanisms underlying different entities thereby enhancing our understanding of disease biology and enable the development of effective therapeutic regimens. Copyright © 2016 John Wiley & Sons, Ltd.     

Impact of comorbidity on survival in peripheral T‐cell lymphomas: A Swedish Lymphoma Registry study

Comorbidity impacts survival in B‐cell lymphoma patients, but the influence in peripheral T‐cell lymphomas (PTCLs) has been little studied. To investigate the impact of comorbidity on outcome in PTCL, we identified adult patients with newly diagnosed PTCL from 2000 to 2009 in the Swedish Lymphoma Registry. Data on comorbidity at diagnosis were retrospectively collected according to the Charlson Comorbidity Index (CCI). Comorbid conditions were present in 263 out of 694 (38%) patients. A CCI score of ≥2 was associated with inferior overall survival (OS) (hazard ratio [HR] 1.63, P < .001) and progression‐free survival (HR 1.54, P < .001) in multivariate analysis. In patients undergoing front‐line autologous stem cell transplantation (auto SCT), CCI >0 was associated with inferior OS (HR 2.40, P = .013). Chemotherapy regimens were classified as curative or low‐intensity treatments. Among patients aged ≥75 years (n = 214), low‐intensity and curative treatment groups had similar OS (HR 0.8, P = .6), also when adjusted for CCI. In summary, our results demonstrate CCI to be independently associated with survival in PTCLs. Even limited comorbidity impacted survival after front‐line auto SCT, which needs to be considered in treatment decisions. Intensive anthracycline‐based chemotherapy in elderly PTCL patients might be of limited benefit.     

Occult recurrence of monomorphic epitheliotropic intestinal T‐cell lymphoma and the role of MATK gene expression in diagnosis

Monomorphic epitheliotropic intestinal T‐cell lymphomas (MEITL), formerly Type II enteropathy‐associated T‐cell lymphomas (EATL), are rare peripheral T‐cell lymphomas. They are associated with poor survival outcomes, in part because of their late diagnosis. Although MEITLs may be reliably diagnosed based on histological and immunophenotypic findings, overlaps with other NK/T and T‐cell lymphomas may confound the diagnosis. The distinctive high‐level nuclear staining of the novel marker Megakaryocyte‐associated tyrosine kinase (MATK) in MEITLs is an invaluable tool in distinguishing MEITL from classical EATL and other NK/T or T‐cell lymphomas. 18‐Fluorine‐2‐fluorodeoxyglucose positron emission tomography (¹⁸F‐FDG PET) has been shown to be a useful tool in the staging and follow‐up of aggressive lymphomas. Herein, we describe an unusual case of occult hepatic recurrence of MEITL that was non‐avid on ¹⁸F‐FDG PET, in which diagnosis was confirmed based on the expression of MATK in tumour cells. Copyright © 2016 John Wiley & Sons, Ltd.     

Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is rare in most parts of the world. Therefore, we have evaluated the 96 cases of PTCL diagnosed within the Non-Hodgkin's Lymphoma Classification Project (NHLCP) (1378 cases) for their geographical distribution, pathologic features and diagnostic reliability, as well as clinical presentation and outcome. MATERIALS AND METHODS: Diagnoses of all cases were rendered independently by five experienced hematopathologists based on morphology only, and after introduction of the immunophenotype and clinical data. Divergent diagnoses were jointly discussed and a final consensus diagnosis was established in each case. Reliability of the diagnoses was evaluated statistically, and the clinical features and outcome were analyzed according to the consensus diagnoses. RESULTS: Seven per cent of all non-Hodgkin's lymphoma (NHL) cases reviewed were classified as PTCL and the frequency varied from 1.5% to 18.3% in different countries. The interobserver agreement with the consensus diagnosis of PTCL was 86% in the Revised European-American Lymphoma (REAL) classification, but the designation of subtypes was less reliable. Diagnostic reliability improved from 41% to 86% after immunophenotyping, but did not improve further with the addition of detailed clinical data. Clinically, angiocentric nasal lymphoma presented in young females (median age 49 years) at extranodal sites, but with few adverse risk factors, whereas angioimmunoblastic lymphoma presented most often in older males (median age 65 years) at nodal and extranodal sites with numerous risk factors. The 5-year overall and failure-free survivals for patients with PTCL treated with doxorubicin (Adriamycin)-containing regimens were only 26% and 20%, respectively. Both failure-free and overall survival were strongly correlated with the performance status and International Prognostic Index scores at presentation, but differences in survival were not observed between the major histological types. However, within the PTCL 'not otherwise specified' category, but not angioimmunoblastic lymphoma, the number of transformed blasts was prognostically relevant. CONCLUSIONS: PTCLs can be diagnosed reliably by experienced hematopathologists, but immunophenotyping is absolutely necessary. Currently, all types of PTCL should be considered high-grade lymphomas. An increased ability to distinguish T-lymphocyte subsets is needed in order to better subclassify the PTCLs for therapeutic and prognostic purposes.     

Classification and treatment of rare and aggressive types of peripheral T-cell/natural killer-cell lymphomas of the skin.

BACKGROUND: The classification of cutaneous lymphomas has been contentious. Two major competing classifications were the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC). The principal authors met for a consensus meeting resulted in a combined classification called WHO-EORTC Classification of Cutaneous Lymphoma. METHODS: We review the classification of "mature" or peripheral T-cell lymphoma (PTCL) with high predilection to the skin as published by the WHO-EORTC. We also highlight new information and changes from the previous classifications of cutaneous PTCL according to the WHO classification or the EORTC classification. Finally, the salient findings are compared with similar-looking nodal PTCLs with a high frequency of skin involvement. RESULTS: This review focuses on a rare group of cutaneous PTCLs other than mycosis fungoides or its variants. Changes from the previous classifications are discussed, and the rare group of nodal PTCLs with high predilection to the skin are presented. The salient findings, diagnostic features, and treatments are included, along with summary tables and clinical-histopathologic images. CONCLUSIONS: This review may serve as a guide for hematologists, oncologists and dermatologists in the diagnosis and management of these rare, aggressive, and often difficult to diagnose lymphomas. Although cutaneous lymphomas are morphologically identical to systemic lymphomas, the former behave differently, require divergent management, and should be recognized as separate entities. The consensus WHO-EORTC classification presents unified terminology and definitions to promote conformity in diagnosing and treating these cases, to foster a multidisciplinary approach to these often-obscure diseases, and to lead to more advances in identifying molecular targets specific to these entities.     

Update: Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are a group of biologically heterogeneous but typically aggressive diseases. Progress in understanding and developing optimal therapies for PTCLs has been hampered by disease rarity and only relatively recent recognition of the importance of the T-cell phenotype. The International Peripheral T-cell Lymphoma Project was a large collaborative effort to provide a broader understanding of prognosis. Recently, several new therapies have shown promise in the treatment of PTCLs.     

Birt‐Hogg‐Dubé syndrome‐associated renal cell carcinoma: Histopathological features and diagnostic conundrum

Birt‐Hogg‐Dubé (BHD) syndrome is associated with the development of hereditary renal cell carcinoma (RCC) and is caused by a germline mutation in the folliculin gene. Most cases of BHD syndrome‐associated RCC (BHD‐RCC) are less aggressive than sporadic clear cell RCC and multifocal. Therefore, it is critical to distinguish BHD‐RCC from its sporadic counterparts to identify and monitor affected families and to preserve renal function for as long as possible. The World Health Organization/International Society of Urological Pathology consensus classification defined distinct entities for certain hereditary RCC; however, BHD‐RCC was not included in this classification. Although the clinical features and molecular mechanisms of BHD‐RCC have been investigated intensively over the last two decades, pathologists and urologists occasionally face difficulties in the diagnosis of BHD‐RCC that require genetic testing. Affected patients usually have miscellaneous benign disorders that often precede renal carcinogenesis. In the present review, we summarize the current understanding of the histopathological features of BHD‐RCC based on our epidemiological studies of Japanese families and a literature review. Pathological diagnostic clues and differential diagnosis of BHD‐RCC from other hereditary RCC are also briefly discussed.     

c-kit Expression and mutations in peripheral T cell lymphomas, except for extra-nodal NK/T cell lymphomas

The present study evaluated the expression and mutations of c-kit in peripheral T-cell lymphomas (PTCLs), except for extra-nodal NK/T cell lymphomas, as a potential target for treatment with imatinib mesylate. Fifty-two patients diagnosed with PTCLs (peripheral T-cell lymhoma, unspecified, 38 cases; angioimmunoblastic T-cell, 7 cases; anaplastic large cell, 7 cases) were enrolled. The immunohistochemistry was performed using standard procedures with anti-c-kit monoclonal IgG, while the c-kit mutations were analysed on paraffin-embedded specimens using PCR-single-stranded conformational polymorphism followed by direct DNA sequencing. The median age of the patients was 52 years (19 to approximately 75 years) with a male-to-female ratio of 69%:31%. Weak expression of c-kit was found in 16 (30.8%) patients, while only 3 (5.8%) patients exhibited mutations in exon 11 or exon 13. The c-kit mutations in exon 11 occurred at codon 558 (AAG --> TAG; Lys --> Stop) and at codon 571 (CTA --> ATA; Leu --> Ile), respectively, while the mutation in exon 13 occurred at codon 634 (CGG --> CGA; Arg --> Arg). The current study only found c-kit mutations in a few patients with PTCLs, except for extra-nodal NK/T cell lymphomas. Therefore, c-kit would not seem to be a good target for a new therapeutic approach to PTCLs.     

Biweekly THP‐COP therapy for newly diagnosed peripheral T‐cell lymphoma patients

Pirarubicin tetrahydropyranyl adriamycin (THP‐ADR) is an analogue of doxorubicin. This agent exhibits activity against some doxorubicin‐resistant cell lines. We performed a phase II study of biweekly THP‐COP [50 mg/m² pirarubicin, 750 mg/m² cyclophosphamide, 1.4 mg/m² vincristine (2.0 mg maximum) on day 1, and 100 mg/body predonisolone on days 1–5] in patients with peripheral T‐cell lymphoma (PTCL). Seventeen patients with newly diagnosed PTCL were enrolled. Histological diagnoses were of PTCL, not otherwise specified (n = 5), or angioimmunoblastic T‐cell lymphoma (n = 12). All diagnostic specimens including those of the historical control group were centrally reviewed by hematological pathologists. All patients received six cycles of biweekly THP‐COP. The patient group included 13 male and 4 female patients, with a median age of 62 years. The median follow‐up time in surviving patients was 30 months. Overall response rate was 94% with 15 cases of complete remission (88%). The 3‐year progression‐free survival and overall survival rates were 57% and 75%, respectively. The most frequent adverse events associated with biweekly THP‐COP were leukocytopenia (100%), neutropenia (100%), and lymphopenia (100%), followed by alopecia (92%) and anaemia (88%). All of these occurred only transiently, and the patients subsequently recovered. Biweekly THP‐COP is a safe and promising therapy for patients with newly diagnosed PTCL. This study is registered in a public database (UMIN000010485). Copyright © 2014 John Wiley & Sons, Ltd.     

Prognostic Value of Interim Positron Emission Tomography in Patients With Peripheral T‐Cell Lymphoma

The definition of the role of positron emission tomography (PET) in peripheral T‐cell lymphomas (PTCLs) is still under investigation. The purpose of the present observational retrospective study was to assess the early prognostic value of PET after the first three cycles of therapy (PET+3), evaluating visual data in de novo PTCL patients treated in first line with standard chemotherapy and followed by both PET and computed tomography scan. Of 27 PET+3‐negative patients, 19 also had a negative PET at the end of treatment (PET+6), whereas 8 of 27 had a positive final one; 6 of 7 PET+3‐positive patients had a positive PET+6, whereas only 1 patient had a negative PET+6. Estimated overall survival plotted according to PET+3 results showed 78.6% for negative patients and 21.4% for positive patients at 88.7 months with a significant difference. Patients with negative PET+3 had superior progression‐free survival of 72.6% compared with 16.7% of PET+3‐positive patients. At the time of this analysis, 17 of 19 (89.5%) patients with negative PET+3 are in continuous complete response (CCR) and only 1 of 7 (14.2%) patients with positive PET+3 is still in CCR. In conclusion, our results indicate that positive PET+3 is predictive of a worse outcome in PTCL, and this significant statistical difference between the two curves could be clinically informative. Larger and prospective studies and harmonization of PET reading criteria are needed.     

Managing the toxicities of CAR T‐cell therapy

Chimeric antigen receptor (CAR) T‐cell therapy has the potential to revolutionize the management of B‐cell lymphomas and possibly other cancers. Two anti‐CD19 CAR T‐cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for the management of relapsed/refractory large B‐cell lymphoma after two lines of systemic therapy. Additional trials are ongoing to evaluate these and other CAR T products at earlier stages of the disease course as well as in other lymphomas. While the potential to induce durable remissions with a single CAR T‐cell infusion even in patients who are chemorefractory has generated much enthusiasm in the field, practitioners need to familiarize themselves with the unique toxicities associated with these therapies. This review will discuss the grading and management of the two most common toxicities, cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS), observed acutely after this therapy. In addition, late toxicities including prolonged cytopenias and on‐target off‐tumor effects will be reviewed.     

Cutaneous lymphomas—An update 2019

Primary cutaneous lymphomas (CL) are the second most common form of extranodal lymphomas. Cutaneous T‐cell lymphomas represent the majority. They are classified according to the WHO classification 2017 and the updated WHO‐EORTC 2018 published in the fourth edition of the WHO classification for Skin Tumors monograph. Primary cutaneous acral CD8+ T‐cell lymphoma and EBV‐positive mucocutaneous ulcer have been listed as new provisional entities. Moreover, the histological and genetic spectrum of lymphomatoid papulosis has been expanded. Recently, prognostic subtypes were delineated for some entities and subtypes of CL such as folliculotropic mycosis fungoides and marginal zone lymphoma. Since CL show overlapping histological features, clinico‐pathological correlation is of outmost importance for the diagnosis. Recent studies revealed new biomarkers and genetic alterations underlying the pathogenesis of CL. Moreover, targeted therapies have widened the treatment options particularly for aggressive lymphomas.     

Update on the World Health Organization classification of peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of lymphoproliferative disorders of postthymic origin. Progress in elucidating the pathobiology and appropriate therapy of these neoplasms has been slow, primarily because of their rarity, but also because until the early 1990s, they were generally grouped together and combined with B-cell lymphomas. It is now understood that most PTCLs are highly aggressive and respond poorly to standard chemo therapy, and thus they have a significantly poorer prognosis than their B-cell counterparts. In 1994, the Revised European and American Lymphoma classification provided the first uniform system to classify lymphoproliferative disorders on the basis of morphology, phenotype, genetics, and clinical features. Since then, the World Health Organization (WHO) has refined this system as additional information has evolved to further elucidate the origin of these neoplasms. More recently, several new distinct and provisional categories in the updated WHO classification have been defined. This review summarizes the changes in the fourth edition of the WHO classification of lymphoid tumors, with particular focus on the aggressive subtypes.     

Detecting clonal rearrangement in non-Hodgkin's lymphomas in Taiwan by polymerase chain reaction

The detection of monoclonal expansions of the immunoglobulin heavy chain (IgH) or the T-cell receptor-gamma (TCRgamma) chain genes is an important supplement for the diagnosis of the non-Hodgkin's lymphomas (NHLs). Detection of monoclonality by polymerase chain reaction (PCR) method has offered an efficient approach for rapid diagnosis and monitoring of the therapeutic effects. Here we conducted a retrospective PCR clonality study on 49 cases of NHLs including 23 B-cell lymphomas (BCLs), 20 peripheral T-cell lymphomas (PTCLs), 6 natural killer (NK)/T-cell lymphomas and 3 reactive lymphoid tissues from southern Taiwan. Genomic DNAs from paraffin sections were extracted and analyzed by the IgH- and TCR-specific PCR reactions. The results showed that 20 of 23 (87.5%) BCLs exhibited IgH gene rearrangements and were all germline for TCRgamma. 15 of 20 (75.0%) PTCLs exhibited TCRgamma gene rearrangements while 1 case (5%) was positive for IgH gene rearrangement. The 6 NK/T-cell lymphomas and 3 reactive lymphoid tissues were all germline for either IgH or TCRgamma genes. Our results were similar to other Western reports in terms of sensitivity and cell-lineage specificity. This is the first large series of PCR clonality study of IgH and TCRgamma gene rearrangements on NHLs from Taiwan. We have confirmed that this rapid method is a sensitive diagnostic tool for NHLs.     

Interim report of a phase 2 clinical trial of lenalidomide for T‐cell non‐Hodgkin lymphoma

BACKGROUND:

Novel therapies are needed to improve outcomes in T‐cell lymphomas. The authors report the interim results of a prospective multicenter trial evaluating lenalidomide in T‐cell lymphomas.

METHODS:

Patients with recurrent and refractory T‐cell lymphomas other than mycosis fungoides and untreated patients ineligible for combination chemotherapy were prescribed oral lenalidomide (25 mg daily) on Days 1 to 21 of each 28‐day cycle until disease progression, death, or unacceptable toxicity. The primary endpoint was overall response rate. Secondary endpoints were progression‐free survival (PFS), overall survival (OS), and safety. The 2‐stage design allows for up to 40 patients.

RESULTS:

At the time of this interim analysis, 24 patients were enrolled in this study, and 23 were evaluable for response. The median age was 65 years. The overall response rate was 7 (30%) of 23; all were partial responses. Two patients had stable disease for ≥5 cycles. Responses were seen in anaplastic, angioimmunoblastic, and peripheral T‐cell unspecified histologies. Median PFS was 96 days (range, 8‐696+ days). Median OS was 241 days (range, 8‐696+ days). The most common grade 4 adverse event was thrombocytopenia (33%). The most common grade 3 adverse events were neutropenia (21%), febrile neutropenia (17%), and pain not otherwise specified (17%). Rash correlated with response to therapy (P = .003).

CONCLUSIONS:

In patients with recurrent and refractory T‐cell lymphomas, oral lenalidomide monotherapy has clinical activity, and toxicity is consistent with the known safety profile of lenalidomide. Further study of lenalidomide in these diseases is warranted. Cancer 2010. © 2010 American Cancer Society.     

Comparison of peripheral T-cell lymphomas and diffuse large B-cell lymphoma

BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are a biologically heterogeneous subgroup of lymphomas with poor prognosis. In this study, the authors analyzed the clinical behaviors of PTCLs and diffuse large B-cell lymphoma (DLBCL). METHODS: The authors compared the characteristics and outcomes of 59 patients with PTCLs, including 33 angioimmunoblastic T-cell lymphomas and 26 unspecified peripheral T-cell lymphomas, with the characteristics and outcomes of 193 patients with DLBCLs who were treated in the era before rituximab. RESULTS: Based on the clinical characteristics, elevated lactate dehydrogenase (LDH), poor PS, advanced stage, higher International Prognostic Index score, and B symptoms were more common in patients with PTCLs, and bulky mass was more common in patients with DLBCL. The rates of complete response (CR) or an unconfirmed CR (CRu) were higher in patients with DLBCL (72%) than in patients with PTCLs (56%; P = .03). The 5-year overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) rates were 31%, 26%, and 47%, respectively, in patients with PTCLs and 59%, 55%, and 73%, respectively, in patients with DLBCL (P = .001, P < .001, and P = .003, respectively). Although multivariate analysis identified several risk factors that were significant in PTCLs, but not in DLBCLs, for the CR/CRu, OS, PFS, and DFS rates, the immunophenotype was not identified as a risk factor. CONCLUSIONS: The poor response and survival of patients who had PTCLs, compared with patients who had DLBCL, was caused by numerous initial risk factors. T-cell phenotype itself did not appear to have a significant impact on either response or survival.     

Expert review of non-Hodgkin's lymphomas in a population-based cancer registry: reliability of diagnosis and subtype classifications.

Incidence rates of non-Hodgkin's lymphomas (NHLs) have nearly doubled in recent decades. Understanding the reasons behind these trends will require detailed surveillance and epidemiological study of NHL subtypes in large populations, using cancer registry or other multicenter data. However, little is known regarding the reliability of NHL diagnosis and subtype classification in such data, despite implications for the accuracy of incidence statistics and studies. Expert pathological re-review was completed for 1526 NHL patients who were reported to the Greater Bay Area Cancer Registry and who participated in a large population-based case-control study. Agreement of registry diagnosis with expert diagnosis and with International Classification of Diseases for Oncology-2 (Working Formulation) subtype classifications was measured with positive predictive values and kappa statistics. Agreement of registry and expert diagnoses was high (98%). Thirty patients were found on review not to have NHL; most of these had leukemia. For subtypes, agreement of registry and expert classification was more moderate (59%). Agreement varied substantially by subtype from 5% to 100% and was 77% for the most common subtype, diffuse large cell lymphoma. Seventy-seven percent of 128 registry-unclassified lymphomas were assigned a subtype on re-review. Our analyses suggest excellent diagnostic reliability but poorer subtype reliability of NHL in cancer registry data information that is critical to the interpretation of lymphoma time trends. Thus, overall NHL incidence and survival statistics from the early 1990s are probably accurate, but subtype-specific statistics could be substantially biased, especially because of high (15-20%) proportions of unclassified lymphomas.     

STX11 functions as a novel tumor suppressor gene in peripheral T‐cell lymphomas

Peripheral T‐cell lymphomas (PTCL) are a heterogeneous group of non‐Hodgkin lymphomas with poor prognosis. Their molecular pathogenesis has not been entirely elucidated. We previously showed that 6q24 is one of the most frequently deleted regions in primary thyroid T‐cell lymphoma. In this study, we extended the analysis to other subtypes of PTCL and performed functional assays to identify the causative genes of PTCL that are located on 6q24. Genomic loss of 6q24 was observed in 14 of 232 (6%) PTCL cases. The genomic loss regions identified at 6q24 always involved only two known genes, STX11 and UTRN. The expression of STX11, but not UTRN, was substantially lower in PTCL than in normal T‐cells. STX11 sequence analysis revealed mutations in two cases (one clinical sample and one T‐cell line). We further analyzed the function of STX11 in 14 cell lines belonging to different lineages. STX11 expression only suppressed the proliferation of T‐cell lines bearing genomic alterations at the STX11 locus. Interestingly, expression of a novel STX11 mutant (p.Arg78Cys) did not exert suppressive effects on the induced cell lines, suggesting that this mutant is a loss‐of‐function mutation. In addition, STX11‐altered PTCL not otherwise specified cases were characterized by the presence of hemophagocytic syndrome (67% vs 8%, P = 0.04). They also tended to have a poor prognosis compared with those without STX11 alteration. These results suggest that STX11 plays an important role in the pathogenesis of PTCL and they may contribute to the future development of new drugs for the treatment of PTCL.