Variant Of Peripheral T-cell Lymphoma Research Articles

Primary extranodal soft tissue Lennert lymphoma (lymphoepithelioid variant of peripheral T-cell lymphoma, unspecified): a case report and review of the literature

Lennert lymphoma (LeL) is a rare variant of peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS) that is rich in epithelioid histiocytes. LeL may pose great diagnostic and therapeutic challenges to the pathologist and clinician. Primary extranodal soft tissue LeL is even rarer and has not been reported. Herein, we report a case of LeL arising from soft tissue.A 65-year-old male presented for evaluation of a painless mass in the subcutaneous soft tissue of the left forehead. There was no invasion of the bone and no ulceration on the surface of the skin. The surrounding skin was erythematous and swollen. Grossly, the tumor was gray-red and 30 mm × 20 mm × 10 mm in size.Microscopically, the demarcation between the lesion and surrounding tissues was unclear without a capsule. The tumor invaded the surrounding striated muscle and adipose tissue. The tumor had a diffuse proliferation of small-sized atypical lymphocytes and numerous large clusters of epithelioid histiocytes. Plasma cells, eosinophils, and Hodgkin-Reed-Sternberg (HRS) cells were not identified. Rare multinucleated histiocytes were noted, and well-formed granulomas were not present. Rare mitotic figures were noted, but no necrosis. The immunophenotypic features in this case were as follows: CD2+/CD3+/CD5low+/CD7+/CD4low+/ CD8+/CD30−/CD56− in neoplastic lymphocytes; CD163+/CD31+/CK(pan)− in epithelioid histiocytes; and CD20−/CD30−/TdT−/CD5−/ALK−/S-100−/CD1α−/CD21 + 23−/SSTR2− in neoplastic lymphocytes and epithelioid histiocytes. Epstein-Barr virus (EBV)-encoded RNA in situ hybridization (EBER-ISH) was negative. The Ki-67 index was elevated to 60%. PCR showed a polyclonal pattern for IgH and a monoclonal TCR γ-chain rearrangement.The final diagnosis was PTCL/NOS, lymphoepithelioid cell variant (LeL), which arose from soft tissue and had a rare double-positive CD4low+/CD8+ immunophenotype. The patient received four cycles of cyclophosphamide, doxorubicin liposomes, vincristine, and prednisone tablets (CHOP) and was followed for 20 months. Overall treatment efficacy was achieved without lymphadenopathy, and no other discomfort or illnesses were reported.

Classification and diagnostic evaluation of nodal T- and NK-cell lymphomas.

Nodal T- and NK-cell lymphomas are among the most frequent T-cell malignancies and most subtypes have aggressive clinical behavior. Evolving understanding of the biology and molecular characteristics of these lymphomas, as well as the development of new precision therapy approaches, underscores the importance of ongoing updates to the classification and diagnostic evaluation of this group of malignancies. Here, we discuss the classification of nodal T- and NK-cell lymphomas based on the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC). Lymphomas of T-follicular helper cell origin are now grouped into a single entity, follicular helper T-cell lymphoma (TFH lymphoma), with three subtypes (angioimmunoblastic-type, follicular-type, and not otherwise specified), reflecting their common cellular origin and shared molecular and clinical characteristics. Classification of anaplastic large cell lymphoma (ALCL) remains essentially unchanged; DUSP22-rearranged cases are now considered a genetic subtype of ALK-negative ALCL. Primary nodal EBV-positive T-/NK-cell lymphoma is introduced as a new provisional entity; these cases were previously considered a variant of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). PTCL, NOS remains a diagnosis of exclusion, with evolving molecular data indicating the presence of distinct subgroups, including PTCL-TBX21, PTCL-GATA3, and EBV-negative cytotoxic PTCLs. We also discuss diagnostic strategies to facilitate the 2022 ICC classification among nodal T- and NK-cell lymphomas and the distinction from nodal involvement by extranodal neoplasms.

Rare Case of Double-Positive CD4/CD8 Immunophenotype in Lennert Lymphoma With Cutaneous Involvement: A Case Report

Lennert lymphoma is a lymphoepithelioid variant of peripheral T-cell lymphoma (not otherwise specified) with characteristics that do not fit into other peripheral T-cell lymphoma categories. Lennert lymphoma is primarily a nodal disease, and skin involvement may be exhibited. Cutaneous manifestations in Lennert lymphoma are nonspecific and include erythematous papules, nodules, and small plaques. Histological examination of cutaneous involvement characteristically presents epithelioid histiocytes and atypical small lymphocytes around vessels or appendages. A lymph node (LN) biopsy is essential for Lennert lymphoma diagnosis. In Lennert lymphoma, immunohistochemistry of both LNs and the involved skin reveals T-cell marker positivity. Although most Lennert lymphoma cases present with a single-positive CD4/CD8 immunophenotype, few cases present with a double-positive CD4/CD8 immunophenotype. We report a case of a 54-year-old woman presenting with fever, chills, general weakness, and a skin rash of erythematous patches on the trunk, extremities, and buttocks. A skin biopsy of the buttocks revealed atypical lymphocytes around the dermal vessels. In immunohistochemistry, these atypical lymphocytes stained positive for CD3, CD4, CD8, and CD68 but negative for CD20, CD30, and granzyme B. Similarly, a biopsy of the axillary LN revealed numerous epithelioid cells with atypical lymphocytes, exhibiting positivity for CD3, CD4, CD8, and CD68 but negativity for CD20, CD30, and S-100. Ki-67 was overexpressed in both the skin and LN. The final diagnosis of the patient was Lennert lymphoma with cutaneous involvement and a rare double-positive CD4/CD8 immunophenotype. The patient was transferred to another hospital for chemotherapy as per her request.

Lennert Lymphoma (lymphoepithelioid lymphoma) with Extensive Necrosis: A Case Report

Lennert lymphoma (lymphoepitheloid lymphoma) is an extremely rare variant of peripheral T-cell lymphoma, not otherwise specified. Here we report a case of Lennert lymphoma diagnosed in a 57-year-old woman. She had a three-year history of waxing and waning lymphadenopathy with a rapid increase in size in the past four months before presentation. A needle biopsy and a fine needle aspiration were non-diagnostic due to extensive necrosis. The patient underwent a right neck lymph node excisional biopsy which showed the lymph node architecture was effaced by numerous and sometimes confluent clusters of epithelioid histiocytes and infiltration of small lymphocytes. Extensive necrosis was present. Immunohistochemical stains revealed a mixed population of B- and T-cells with the T-cells showing diminished T-cell markers CD3, CD5, and CD7. Flow cytometric analysis detected a small population (7% of total lymphocytes) of CD4-positive T-lymphocytes with loss of CD3, CD5, and CD7 expressions. PCR-based T-cell receptor gene rearrangement studies showed positive results (clonal peaks) in both gamma and beta genes. Stains for microorganisms were negative. The overall findings indicate Lennert lymphoma. To our knowledge, this is the first reported case of Lennert lymphoma with extensive necrosis. The patient is undergoing chemotherapy. The diagnosis of Lennert lymphoma can be challenging, particularly in cases with extensive necrosis. Our case highlights that adequate sampling is important in the investigation of patients with suspected Lennert lymphoma. A careful pathologic examination with ancillary studies including flow cytometry, immunohistochmistry, and cytogenetic and molecular studies leads to the accurate diagnosis.

Transcriptional Analysis of Lennert Lymphoma Reveals a Unique Profile and Identifies Novel Therapeutic Targets.

Lennert lymphoma (LL) is a lymphoepithelioid morphological variant of peripheral T-cell lymphoma—not otherwise specified (PTCL/NOS), clinically characterized by better prognosis if compared with other PTCL/NOS. Although well characterized as far as morphology and phenotype are concerned, very little is known regarding its molecular features. In this study, we investigated the transcriptional profile of this tumor aiming 1) to identify its cellular counterparts; 2) to better define its relation with other PTCLs—and, therefore, its possible position in lymphoma classification; and 3) to define pathogenetic mechanisms, possibly unveiling novel therapeutic targets. To address these issues, we performed gene and microRNA expression profiling on LL and other PTCL/NOS cases; we identified different genes and microRNAs that discriminated LL from other PTCL/NOS. Particularly, LL revealed a molecular signature significantly enriched in helper function and clearly distinguishable from other PTCL/NOS. Furthermore, PI3K/Akt/mTOR pathway emerged as novel potential therapeutic target. In conclusion, based on the already known particular morphological and clinical features, the new molecular findings support the hypothesis that LL might be classified as a separate entity. Preclinical and clinical studies testing the efficacy of PI3K/MTOR inhibitors in this setting are warranted.

Adult T-cell leukemia/lymphoma can be indistinguishable from other more common T-cell lymphomas. The University of Miami experience with a large cohort of cases

AbstractAdult T-cell leukemia/lymphoma, an aggressive T-cell neoplasm, is causally linked to human T-cell lymphotropic virus type 1 and based on this association has a distinct geographic distribution. In our United States-based practice, whose population is enriched for immigrants from human T-cell lymphotropic virus type 1 endemic areas, we have identified that a subset of adult T-cell leukemia/lymphoma, in the absence of human T-cell lymphotropic virus type 1 identification, are indistinguishable from other more common T-cell neoplasms. We retrospectively gathered serology results for anti-human T-cell lymphotropic virus type 1/2 antibody in patients diagnosed with T-cell neoplasms at our institution. A total of 220 human T-cell lymphotropic virus type 1/2 positive patients with T-cell neoplasms were identified; 199 (91%) were correctly classified as adult T-cell leukemia/lymphoma or provisionally as peripheral T-cell lymphoma (serology testing pending). Twenty-one cases (9%) were initially misclassified, including the following: 13 presenting with skin +/− peripheral blood involvement and misclassified as mycosis fungoides/Sezary syndrome; 7 with lymphomatous disease, absence of leukemic involvement, and diffuse CD30 expression, misclassified as ALK- negative anaplastic large-cell lymphoma; 1 thought to represent T-prolymphocytic leukemia with TCL-1 gene rearrangement and diffuse marrow involvement. We also present an example of adult T-cell leukemia/lymphoma, which mimicked lymphoepithelioid variant of peripheral T-cell lymphoma also with diffuse marrow involvement. A subset of adult T-cell leukemia/lymphoma can closely mimic a variety of other more common T-cell neoplasms. Due to its extreme clinicopathologic heterogeneity, identification of adult T-cell leukemia/lymphoma requires a high level of suspicion based on patient demographic alone, which should prompt anti-human T-cell lymphotropic virus type 1/2 serology testing in all T-cell neoplasms developing in patients of appropriate demographic. Absence of high level of suspicion, adult T-cell leukemia/lymphoma is easily misclassified.

Mogamulizumab for the treatment of relapsed or refractory adult T-cell leukemia-lymphoma

ABSTRACTIntroduction: Adult T-cell leukemia-lymphoma (ATL) is an aggressive variant of peripheral T-cell lymphoma of CD4+ T-malignant cells caused by human T-lymphotropic virus type-1. Despite aggressive treatment with multidrug combination chemotherapies, ATL confers a poor prognosis and commonly develops resistance to conventional treatments.Areas covered: Mogamulizumab is a humanized, defucosylated monoclonal antibody that acts by targeting the CC chemokine receptor 4 (CCR4) on malignant cells of ATL. In phase I and II clinical trials, it has achieved overall response rates of 31–50% in CCR4+ malignancies. The most commonly observed hematologic and non-hematologic adverse events included lymphocytopenia, neutropenia, leukocytopenia, infusion reaction, rash, and pyrexia.Expert commentary: Mogamulizumab has shown significant efficacy in treating ATL with moderately high response rates and has been approved in Japan for use in ATL. It may serve as a bridge therapy to achieve disease control prior to allogeneic hematopoietic stem cell transplantation. It also offers potential for use in combination with conventional chemotherapy. Determining the optimal combination of mogamulizumab with conventional and novel therapies remains an important strategy to improve the prognosis of patients with ATL.

A Clinicopathologic Study of Lennert Lymphoma and Possible Prognostic Factors: The Importance of Follicular Helper T-cell Markers and the Association With Angioimmunoblastic T-cell Lymphoma.

Lennert lymphoma (LeL) is a variant of peripheral T-cell lymphoma, not otherwise specified. Few clinicopathologic studies have investigated LeL, which is a rare disease. Here, we analyzed the clinicopathologic features of 26 patients with LeL to identify potential prognostic factors. Neoplastic cells positive for CD4, CD8, CD4/CD8, TIA-1, and granzyme B were observed in 21 (80.8%), 4 (15.4%), 1 (3.8%), 4 (15.3%), and 0 (0.0%) patients, respectively. Regarding follicular helper T-cell (TFH) markers, neoplastic cells positive for programmed cell death-1 (PD-1), CXCL13, CD10, and BCL6 were observed in 14 (53.8%), 13 (50.0%), 1 (3.8%), and 0 (0.0%) patients, respectively. Patients with positivity for at least 1 TFH cell marker (PD-1, CXCL13, CD10, and/or BCL6) were defined as being TFH cell marker-positive (n=15) and had a worse prognosis than TFH cell marker-negative patients (n=11) (P=0.011). Clinicopathologic characteristics did not differ significantly between TFH cell marker-positive and marker-negative LeL patients. Moreover, prognosis did not differ significantly between TFH cell marker-positive LeL patients and patients with angioimmunoblastic T-cell lymphoma (AITL) (n=42). Nevertheless, as compared with AITL, TFH cell marker-positive LeL was associated with significantly lower frequencies of B symptoms, skin rash, high-intermediate-risk or high-risk international prognostic index values, expanded follicular dendritic cell meshworks, polymorphic infiltrate, clear cells, and positivity for CD10 and BCL6. Although it may be difficult to definitively distinguish between TFH cell marker-positive LeL and AITL, our results suggest that TFH cell markers are useful for identifying LeL patients who will experience unfavorable outcomes.

Follicular variant of peripheral T-cell lymphoma: a clinicopathologic and genetic study of 2 cases

To observe the clinicopathologic and genetic features of follicular variant of peripheral T-cell lymphoma (FV-PTCL), with particular attention to the relationship of this type of lymphoma with angioimmunoblastic T-cell lymphoma (AITL). The clinical data, hematoxylin and eosin-stained sections of lymph node biopsies from 2 FV-PTCL cases were reviewed. Immunohistochemical phenotyping and detection of EBV-encoded RNAs (EBER) through in situ hybridization (ISH) were performed. The EnVision two-step method was used for all antibodies except CXCL13 (by using three-step streptavidin immunoperoxidase method). Analysis of clonality and ITK/SYK gene rearrangement was conducted using PCR and RT-PCR assays, respectively. Clinically, the two patients presented with superficial lymphadenopathy similarly. Histologically, case 1 showed a follicular/nodular lymphoid proliferation without marked germinal centers. The neoplastic cells comprised mainly medium sized cells with abundant, sometimes clear cytoplasms. Similar histologic findings were seen in case 2 in addition to a concurrent component mimicking typical AITL noticed. Of both cases, the neoplastic cells showed positive reactivity to CD3, CD4, CD10, PD1, and CXCL13. Positive hybridization signals for EBER were only seen in case 2, and double stains demonstrated that those EBV-positive cells were mostly the reactive transformed B-cells. Monoclonal T-cell proliferation was proved by the rearranged TCR gene detection in both cases. Neither of the current cases expressed ITK/SYK fusion transcripts. FV-PTCL shows the similar or overlapped morphological and immunophenotypic features to those of AITL, possibly suggesting the presence of a potential relationship between these two types of lymphomas.

Cutaneous manifestations of angioimmunoblastic T-cell lymphoma: clinical and pathological characteristics.

Angioimmunoblastic T-cell lymphoma (AITL), an uncommon variant of peripheral T-cell lymphoma, affects the skin in approximately 50% of cases. Its protean clinical and histopathological cutaneous manifestations pose a challenge in diagnosis, particularly when these precede the diagnosis of AITL on a lymph node biopsy. In this retrospective study, we compared 11 cases of AITL with cutaneous manifestations (mean age 67 years; male:female ratio 1:0.8; 24 skin biopsies) with 20 control cases of inflammatory and non-AITL lymphomatous diseases (mean age 52 years; male:female ratio 1:1.5; 26 skin biopsies). Clinical, histopathological, immunohistochemical, and molecular data were documented. New insights into the clinical evolution of cutaneous involvement by AITL (C-AITL), from early macular, through papular to nodular stages, were observed. Microscopically, a parallel increment in the density of the dermal infiltrate and in the detection of lymphocyte cytological atypia was noted over time. Identification and quantification of follicular T-helper cells (Tfh), the neoplastic lineage, by immunohistochemistry helped to separate cases of C-AITL from inflammatory controls, offering promise as a useful diagnostic adjunct. The presence of T-cell clonality did not have discriminatory value between the 2 groups. Our work suggests that the early maculopapular phase of C-AITL eludes identification on pathological grounds alone and that features such as cytological atypia and high endothelial venules lack diagnostic specificity. In the context of (1) a rash that simulates a drug/viral exanthem or an acute manifestation of a connective tissue disorder, but proves recalcitrant, (2) constitutional abnormalities and/or lymphadenopathy that persist, and (3) a Tfh cell-rich perivascular dermatitis, the diagnosis of early C-AITL can be suspected, but not confirmed, without the benefit of a lymph node biopsy. The later nodular phase of C-AITL occurring in a similar constitutional background, can usually be discerned as lymphomatous, clinically and pathologically. Here a Tfh cell-rich infiltrate is a clue to the specific diagnosis, but confirmation by a nodal evaluation remains mandatory. Despite the difficulty in establishing a diagnosis of C-AITL in its early stages, and speculation that the initial eruptions might be reactive in nature, our sequential data support the concept that these are lymphomatous ab initio. To address the diagnostic challenge presented by this disease, meaningful integration of clinical and pathological data is imperative.

Perifollicular Variant of Peripheral T-Cell Lymphoma, UNS: A Distinct Lymphoma Type with Cytogenetic andcytogenetic and Clinical Findings Different from Those of Angio-Immunoblastic Lymphoma

Perifollicular variant of peripheral T-cell lymphoma, UNS: a distinct lymphoma type with cytogenetic and clinical findings different from those of angio-immunoblastic lymphoma.A. Bassarova, F. Micci, G. Trzen, H. Holte, J. DelabiePeripheral T-cell lymphoma, unspecified (PTCL-U), represents approximately 30% of all peripheral T-cell lymphomas (PTCL) in adults, excluding primary cutaneous lymphomas. PTCL-U represents approximately 12–15% of lymphomas in the Western population. The disease has a five-year overall survival of about 30%. PTCL-U is currently an amalgam of T-cell lymphomas with a mature immunophenotype that cannot be classified into other well-characterized types of PTCL. However, within PTCL-U several variants are tentatively recognized, among which the follicular or perifollicular variant. This entity is histologically characterized by its localization within the B-cell area of the lymph node and by its T follicular helper cell immunophenotype. In view of the latter, it has been argued that the follicular variant of PTCL-U is an early stage of angio-immunoblastic T-cell lymphoma, a well-characterized type of PTCL of T follicular helper cell origin.To better study perifollicar T-cell lymphoma as compared to AITL, we retrieved 47 cases of PTCL with these diagnoses from the archive of the Department of Pathology at Oslo University Hospital collected in a time period from 1999 to 2013 and reviewed the morphological, immunophenotypic, cytogenetic and clinical findings. Immunophenotypic analysis was completed when necessary. Diagnoses were made according to the W.H.O. criteria that included those published by our group previously. Cytogenetic data were available for 39 cases.Nineteen cases of perifollicular TCL and 23 cases of AITL were retrieved and 4 cases with features between perifollicular TCL and AITL were identified. By cytogenetic analysis, perifollicular TCL showed a complex karyotype with structural and numerical abnormalities. The most frequently observed aberrations were loss of 4p16 and 6q22 as well as gains of 1q21 and 3q11q12 (Fig. 1). AITL was characterized by predominantly numerical chromosomal aberrations and less structural abnormalities. The most frequent detected abnormalities were gains of chromosome 3, 5, 7, 9 and 19 (Fig. 2).The patients with perifollicular TCL had normal to high lymphocytic counts (p<0.05), platelet counts greater than 145 (p<0.001), normal LDH levels, albumin levels above the median (p<0.05) normal or slightly elevated sedimentation ratios (p<0.05), normal or above median hemoglobin levels (p<0.001) and infrequent bone marrow involvement at presentation. The majority of patients had international prognostic index (IPI) scores of 0, 1 or 2 (p<0.05) and a W.H.O. performance status between 0 and 2. Bulky disease as well as extranodal involvement at presentation was rare in this group of patients. By contrast patients with AITL presented with B-symptoms, high sedimentation ratios (p<0.05), lymphopenia (p<0.05), thrombocytopenia (p<0.001), elevated LDH and low hemoglobin levels (p<0.001) and hypoalbuminemia (p<0.05). The patients had IPI scores between 3 and 5 at presentation (p<0.05). All patients with AITL had bulky disease and 40 % had multiple extranodal localizations at presentation. Importantly, patients with perifollicular TCL showed better response to therapy and had significantly longer overall survival when compared with AILT (Fig. 3).In conclusion, the cytogenetic findings showing a complex karyotype with predominantly structural alterations, the less severe symptoms and signs at presentation and the longer overall survival are features that distinguish perifollicular TCL from AITL. Together these features do not favor the hypothesis that perifollicular TCL is an early stage of AITL but indicate that perifollicular TCL is a distinct type of PTCL. The identification of four cases with histological features between those of perifollicular TCL and AITL in our series may indicate that better methods are needed to reliably separate these entities. Therefore, detailed genetic characterization of perifollicular TCL in comparison with AITL is currently being undertaken. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Involvement of FER and FES in the Pathogenesis of Follicular Variant of Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma - not otherwise specified (PTCL-NOS) is the largest, most common and very heterogeneous category of PTCL. To date three PTCL variants have been described, including follicular variant (PTCL-F), a rare and poorly understood entity. Cytogenetically, PTCL-F is associated with a recurrent t(5;9)(q33;q22) resulting in the fusion of two protein tyrosine kinase (PTK) genes, ITK and SYK, showing constitutive activation of SYK. Transforming capacities of ITK-SYK were documented both in vitro and in vivo. Involvement of other PTK genes in the pathogenesis of PTCL-F has been postulated, but is thus far, not evidenced.We present cytogenetic, molecular and functional studies of two PTCL-F cases recently identified in our institution. The first case was characterized by complex chromosomal rearrangements involving several chromosomal regions harboring PTK genes. Extensive FISH analysis eventually identified FES involvement in t(15;16)(q26;q22). Further RNA-sequencing of this sample detected an in-frame fusion of exon 24 of RLTPR (16q22) to exon 11 of FES. The rearrangement was confirmed by subsequent Sanger sequencing of the 500 bp fragment obtained by RLTPR-FES nested RT-PCR. The predicted chimeric protein likely consists of the SH2 and Kinase domain of FES fused to the LRR domain of RLTPR. The second case showed a sole t(1;5)(p34;q21) masking the FER-involving inv(5)(q21q33) identified by FISH. By RNA-sequencing, an in-frame fusion of exon 8 of ITK/5q33 to exon 12 of FER/5q21 was identified. The rearrangement was confirmed by Sanger sequencing of the 402 bp fragment obtained by ITK-FER nested RT-PCR. The predicted chimeric protein likely contains the SH2 and Kinase domain of FER fused to a part of the SH2 domain of ITK.Oncogenic potential of RLTPR-FES was studied in vitro and in vivo. We designed a chimeric expression construct, introduced it into the murine hematopoietic IL3-dependent Ba/F3 cell line and showed that RLTPR-FES was able to transform Ba/F3 cells to growth factor-independent growth upon IL3 withdrawal. In addition, we demonstrated that NVP-TAE684, a small molecule ATP-competitive inhibitor of ALK and FES, abrogates the activity of the novel RLTPR-FES chimera. Western blot analysis confirmed a decrease of a phosphotyrosine protein of approximately 131kDa, corresponding to the predicted molecular weight of RLTPR-FES, with an increasing dose of NVP-TAE684 inhibitor. In vitro study of the ITK-FER fusion is ongoing.In order to assess the in vivo role of RLTPR-FES, a murine bone marrow transplantation model was established. Between 42-88 days after BMT, 4 mice transplanted with RLTPR-FES-transduced bone marrow developed a fatal disease and were sacrificed. Histological examination showed a massive infiltration of myeloid origin in all tissues examined (i.e. spleen, liver, thymus, bone marrow and lymph nodes). FACS analysis also confirmed this strong enrichment of cells of myeloid origin. Taken together, these data pointed toward the development of a myeloproliferative malignancy in all mice.Overall, our study confirms the critical role of PTKs in the pathogenesis of PTCL-F. In addition to SYK, we found FER and FES as targets of chromosomal aberrations in this tumor, and ITK, as a recurrent partner involved in the PTK fusions. Of note, FER and FES are the only two members of a distinct family of non-receptor PTKs, and thus far, their involvement in cancer-driving rearrangements has not been reported. Given that PTKs are ideal targets in the search for ‘molecularly-targeted’ cancer chemotherapy, PTCL-F patients may benefit from these novel therapeutic strategies. DisclosuresNo relevant conflicts of interest to declare.

Angioimmunoblastic T-cell lymphoma in taiwan showed a frequent gain of ITK gene

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoma of follicular helper T-cell origin exhibiting overlapping features with the follicular variant of peripheral T-cell lymphoma (PTCL-F). Around one fifth of PTCL-F exhibits t(5;9)(q33;q22)/ ITK-SYK chromosomal translocation, which is essentially absent in AITL. We retrospectively investigated 35 cases of AITL from Taiwan, so far the largest, including FISH for t(5;9)(q33;q22)/ITK-SYK. Twenty-six cases of not otherwise specified PTCL (PTCL-NOS) were also examined by FISH. Most AITL patients were male and elderly with frequent marrow involvement, high Ann Arbor stages, and elevated serum lactate dehydrogenase. Most cases (80%) showed a typical CD4+/CD8- phenotype and in 90% cases there were scattered EBV-positive B-cells. None of these cases showed t(5;9)(q33;q22)/ITK-SYK translocation. Gain of ITK and SYK gene was identified in 38% and 15% tumors, respectively, but both were not associated with overall survival. Performance status < 2 was associated with a better outcome but not the other clinicopathological factors. All PTCL-NOS cases were negative for ITK-SYK translocation and similar rates (38% and 12%, respect-ively)ofgainsatITK and SYK lociasthatofAITL. Morestudies are warranted to elucidate the roles of SYK and ITK and other genes in the lymphomagenesis of AITL in Taiwan.

Noduläres lymphozytenprädominantes Hodgkin-Lymphom und seine Differenzialdiagnosen

Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare subtype of Hodgkin's lymphoma. The histological patterns of NLPHL variants are characterized by different localizations of the tumor cells, intranodular and perinodular and by the varying composition of the microenvironment. T-cell/histiocyte-rich B-cell lymphoma may be the result of an aggressive transformation of NLPHL. Classical lymphocyte-rich Hodgkin's lymphoma can usually be clearly distinguished from NLPHL by the immunophenotype of the tumor cells. Further differential diagnoses include follicular lymphoma and the follicular variant of peripheral T-cell lymphoma. Angioimmunoblastic T-cell lymphoma with CD20-positive blasts represents a differential diagnosis to the diffuse variants of NLPHL.

Peripheral T-cell and NK-cell lymphomas in the WHO classification: pearls and pitfalls

Peripheral T-cell and NK-cell lymphomas are functionally, pathologically, and clinically complex. Most nodal T-cell lymphomas belong to the adaptive immune system, whereas many extranodal T-cell and NK-cell lymphomas are derived from innate immune cells. The pathological manifestations often reflect the functional attributes of the neoplastic cells. Several forms of peripheral T-cell lymphoma are derived from T-follicular helper cells (TFH), and include angioimmunoblastic T-cell lymphoma, the follicular variant of peripheral T-cell lymphoma, not otherwise specified, and primary cutaneous small/medium CD4-positive T-cell lymphoma. TFH-derived neoplasms are often associated with atypical and clonal B-cell proliferations, which take a number of forms, sometimes mimicking classical Hodgkin's lymphoma, and sometimes showing marked plasmacytic differentiation. Most extranodal T-cell lymphomas are cytotoxic and often arise in mucosal-associated sites. They can be derived from either αβ or γδ cytotoxic T cells, and include subcutaneous panniculitis-like T-cell lymphoma, and enteropathy-associated T-cell lymphomas, both Type I and Type II. Type I enteropathy-associated lymphomas occur in association with celiac disease, whereas Type II lymphomas are more often sporadic. For some T-cell lymphomas, such as hepatosplenic T-cell lymphoma, immunophenotypic heterogeneity is seen within a single disease entity. New data are emerging on the molecular pathogenesis of T-cell and NK-cell lymphoma, but most tumor types remain poorly characterized.

Lennert′s lymphoma: Clinicopathological profile of five cases

Lennert's lymphoma is a rare variant of peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS) rich in epithelioid histiocytes. This study aims to analyze the clinical, morphologic, and immunophenotypic profile of cases of Lennert's lymphoma from our country and determines the utility of T-cell receptor (TCR) gene rearrangement in the diagnosis. All cases diagnosed as Lennert's lymphoma during the period of January 2001 to August 2011 were included in this study. Hematoxylin and eosin (H and E) stained slides and immunohistochemistry results were analyzed and TCR gene rearrangement was performed. There were five cases of Lennert's lymphoma diagnosed in our institution during this period, which included two males and three females. All cases showed effacement of lymph node architecture by diffuse infiltration of small lymphoid T cells [CD3+, CD4+, CD8+, T-cell intracellular antigen 1 (TIA-1+), Granzyme B-] and clusters of epithelioid histiocytes throughout the lymph node and scattered large transformed cells (CD20-, CD30+, CD15-/+). TCR rearrangement was done in three cases by polymerase chain reaction (PCR) and showed the presence of a clonal T-cell population. Lennert's lymphoma constituted 0.11% of all non-Hodgkin lymphomas (NHLs) in our institution. Differentiation from classical Hodgkin's lymphoma is sometimes difficult by morphology and immunohistochemistry alone and TCR gene rearrangement was extremely useful in diagnosis.

Follicular T-cell lymphoma: a member of an emerging family of follicular helper T-cell derived T-cell lymphomas

Unlike B-cell lymphomas, where knowledge of normal B-cell origin and differentiation has greatly contributed to their classification, the current classification of peripheral T-cell lymphomas is limited by a lack of understanding of their cellular origin. In the current World Health Organization classification of lymphomas, follicular T-cell lymphoma was formally recognized as a morphologic variant of peripheral T-cell lymphoma, not otherwise specified. There is growing evidence, however, that follicular T-cell lymphoma may be a unique clinicopathologic entity based on its morphologic features and derivation from follicular helper T-cells. In addition, there are abundant recent data supporting the concept that follicular helper T-cells can give rise to other types of T-cell lymphoma, including angioimmunoblastic T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoma, and a subset of neoplasms, in addition to follicular T-cell lymphoma, currently classified as peripheral T-cell lymphoma, not otherwise specified. In this review, we focus primarily on the clinicopathologic, immunophenotypic, and molecular features of follicular T-cell lymphoma and discuss its potential relationship with other types of T-cell lymphoma thought to be derived from follicular helper T-cells.

Revising the historical collection of epithelioid cell-rich lymphomas of the Kiel Lymph Node Registry: what is Lennert’s lymphoma nowadays?

Lennert's lymphoma is a rare variant of peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS). The aim of this study was to further characterize this tumour. Historical material of 97 lymphomas with a high content of epithelioid cells, collected at the Kiel Lymph Node Registry were reviewed, by applying immunohistochemistry and current diagnostic criteria. Among all cases revised, various B-cell lymphoma entities (25 cases), Hodgkin lymphomas (21 cases) and PTCL subtypes (48 cases) could be identified. A distinctive subgroup of eight PTCLs was found that were regarded as genuine Lennert's lymphomas. These cases were characterized by mild atypia, a non-activated cytotoxic phenotype [TIA1 cytotoxic granule-associated RNA binding protein (TIA1)-positive(+) and granzyme B-negative], and a substantial lack of follicular T-helper (T(FH) ) cell markers. Among the other PTCLs, including angioimmunoblastic T-cell lymphoma and PTCL NOS, many cases with positivity for more than three T(FH) cell-associated molecules were recorded. Our study shows that, according to current criteria, Lennert's lymphoma is a rare but distinctive entity among epithelioid cell-rich lymphomas, differing on grounds of morphology and immunophenotype from other PTCL subtypes. An additional finding is the broad morphological spectrum of epithelioid-cell rich PTCLs showing a T(FH) cell phenotype.

A rare case of Lennert’s type peripheral T-cell lymphoma with t(14;19)(q11.2;q13.3)

Although most patients with peripheral T-cell lymphoma (PTCL) show clonal rearrangement of T-cell receptor genes, few PTCLs show recurrent chromosomal abnormalities. We describe here a rare chromosomal rearrangement, t(14;19)(q11.2;q13.3), in a Lennert's lymphoma, a variant of PTCL, not otherwise specified. Sequential fluorescence in situ hybridization assays showed that the breakpoint in 19q13.3 was located distal to the BCL3 and PVRL2 genes, both of which may be candidate proto-oncogenes. These findings suggest that another gene is involved in the pathogenic characteristics observed in this patient with Lennert's lymphoma.

Follicular variant of peripheral T-cell lymphoma mimicking follicular lymphoma: A case report with a review of the Literature

Peripheral T-cell lymphoma (PTCL) with a follicular growth pattern is very rare. Herein, a case of follicular variant of PTCL in a 50-year-old man who complained of tonsillar and generalized lymph node swelling is reported. The resected tonsil revealed a vague nodular growth pattern of atypical cells, medium to large in size, with abundant pale cytoplasm. The lymphoma cells were CD3(+) CD4(+) CD5(+) CD8(-) CD10(+) CD56(-) CD57(-) BCL6(+) PD-1(+) CXCL13(+) and were associated with a meshwork of CD21(+) follicular dendritic cells. Molecular studies revealed clonal rearrangement of the T-cell receptor gamma chain gene but not of the immunoglobulin gene. Cytogenetic analysis disclosed a complex abnormality in 18 of 20 cells with the exclusion of t(5; 9). These findings suggest that the present case is a follicular variant of PTCL derived from follicular T-helper cells.