The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. The NF-κB transcription factor family is activated by 2 main pathways, the canonical and the alternative NF-κB activation pathway, with different functions. The alternative NF-κB pathway leads to activation of the transcriptionally active RelB NF-κB subunit. Alternative NF-κB activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their activated B-cell-like or germinal center B-cell-like subtype. RelB activity defines a new subset of patients with DLBCL and a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for activated B-cell-like tumors carrying MYD88L265P and CD79B mutations that cooperatively activate canonical NF-κB, thus indicating that current genetic tools to evaluate NF-κB activity in DLBCL do not provide information on the alternative NF-κB activation. Furthermore, the newly defined RelB-positive subgroup of patients with DLBCL exhibits a dismal outcome after immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA damage-induced apoptosis in response to doxorubicin, a genotoxic agent used in the front-line treatment of DLBCL. We also show that RelB positivity is associated with high expression of cellular inhibitor of apoptosis protein 2 (cIAP2). Altogether, RelB activation can be used to refine the prognostic stratification of DLBCL and may contribute to subvert the therapeutic DNA damage response in a segment of patients with DLBCL.

Baseline circulating tumour DNA and total metabolic tumour volume as early outcome predictors in aggressive large B-cell lymphoma. A real-world 112-patient cohort.

Approximately 20%-50% of patients with large B-cell lymphoma (LBCL) experience poor outcomes. We aimed to evaluate the combined prognostic value of circulating tumour DNA (ctDNA) and total metabolic tumour volume (TMTV) in LBCL. This observational single-centre study included 112 newly diagnosed LBCL patients, receiving R-CHOP/R-CHOP-like chemotherapies. CtDNA load was calculated following next-generation sequencing of cell-free DNA (cfDNA) using a targeted 40-gene lymphopanel. TMTV was measured using a fully automated artificial intelligence-based method for lymphoma lesion segmentation. CtDNA was detected in cfDNA samples from 95 patients with a median concentration of 3.15 log haploid genome equivalents per mL. TMTV measurements were available for 102 patients. The median TMTV was 501 mL. High ctDNA load (>3.57 log hGE/mL) or high TMTV (>200 mL) were associated with shorter 1-year PFS (44% vs. 83%, p < 0.001 and 64% vs. 97%, p = 0.002, respectively). When combined, three prognostic groups were identified. The shortest PFS was observed when both TMTV and ctDNA load were high (p < 0.001). Even with a short follow up, combining ctDNA load with TMTV improved the risk stratification of patients with aggressive LBCL. In the near future, very high-risk patients could benefit from CAR T-cell therapy or bispecific antibodies as first-line treatments.

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma.

To date, genomic analyses of hepatocellular carcinoma (HCC) have been limited to early stages obtained from liver resection. We aim to describe the genomic profiling of HCC from early to advanced stages. We analyzed 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) for 190 gene expressions and for 31 gene mutations. Forty-one advanced HCC and 156 whole exome of Barcelona Clinic Liver Cancer (BCLC) 0/A were analyzed by whole-exome sequencing. Genomic profiling was correlated with tumor stages, clinical features, and survival. Our cohort included patients classified in BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the overall 801 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT-rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced-stage HCC (BCLC B/C) showed higher frequencies of splicing factor 3b subunit 1 (SF3B1) (P = 0.0003), TP53 (P = 0.0006), and RB Transcriptional Corepressor 1 mutations (P = 0.03). G1-G6 transcriptomic classification and the molecular prognostic 5-gene score showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5-gene score predicted survival in patients treated by resection (P < 0.0001) and ablation (P = 0.01) and in advanced HCC (P = 0.04). Twenty-two percent of advanced HCC harbored potentially druggable genetic alterations, and MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Conclusion: Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies.

PTPN11 mutations in canine and human disseminated histiocytic sarcoma.

In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS (7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS: the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti-proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans.

Composite and sequential lymphoma between classical Hodgkin lymphoma and primary mediastinal lymphoma/diffuse large B-cell lymphoma, a clinico-pathological series of 25 cases.

Composite and sequential lymphomas involving both classical Hodgkin lymphoma (CHL) and primary mediastinal B-cell lymphoma (PMBCL) are rare phenomena. Beyond the relevant biological interest raised by these cases, treatments and outcome data are poorly covered in the recent literature. This retrospective analysis describes the pathological and clinical characteristics of 10 composite and 15 sequential cases included after a central pathological review. At diagnosis, 70% of the composite lymphomas presented a disseminated and extranodal disease. Among the 15 sequential lymphomas, 12 were CHL at first occurrence and three were PMBCL. Based on their clinical evolution, these sequential lymphomas could be divided into early (i.e., diagnosis of second lymphoma within a year) and late [(i.e., a second lymphoma occurrence occurring after a long period of complete remission]). All composite cases were alive in complete remission after a median follow-up of 34 months. If the early sequential lymphoma presented a particularly poor outcome with a median overall survival shorter than one year, the late cases were efficiently salvaged. Further molecular studies are needed to describe the underlying biology of these rare diseases, possibly representing the extreme of tumour cell plasticity found in grey-zone lymphoma.

Defining signatures of peripheral T-cell lymphoma with a targeted 20-marker gene expression profiling assay.

Peripheral T-cell lymphoma comprises a heterogeneous group of mature non-Hodgkin lymphomas. Their diagnosis is challenging, with up to 30% of cases remaining unclassifiable and referred to as "not otherwise specified". We developed a reverse transcriptase-multiplex ligation-dependent probe amplification gene expression profiling assay to differentiate the main T-cell lymphoma entities and to study the heterogeneity of the "not specified" category. The test evaluates the expression of 20 genes, including 17 markers relevant to T-cell immunology and lymphoma biopathology, one Epstein-Barr virus-related transcript, and variants of RHOA (G17V) and IDH2 (R172K/T). By unsupervised hierarchical clustering, our assay accurately identified 21 of 21 ALK-positive anaplastic large cell lymphomas, 16 of 16 extranodal natural killer (NK)/T-cell lymphomas, 6 of 6 hepatosplenic T-cell lymphomas, and 13 of 13 adult T-cell leukemia/lymphomas. ALK-negative anaplastic lymphomas (n=34) segregated into one cytotoxic cluster (n=10) and one non-cytotoxic cluster expressing Th2 markers (n=24) and enriched in DUSP22-rearranged cases. The 63 TFH-derived lymphomas divided into two subgroups according to a predominant TFH (n=50) or an enrichment in Th2 (n=13) signatures. We next developed a support vector machine predictor which attributed a molecular class to 27 of 77 not specified T-cell lymphomas: 17 TFH, five cytotoxic ALK-negative anaplastic and five NK/T-cell lymphomas. Among the remaining cases, we identified two cell-of-origin subgroups corresponding to cytotoxic/Th1 (n=19) and Th2 (n=24) signatures. A reproducibility test on 40 cases yielded a 90% concordance between three independent laboratories. This study demonstrates the applicability of a simple gene expression assay for the classification of peripheral T-cell lymphomas. Its applicability to routinely-fixed samples makes it an attractive adjunct in diagnostic practice.

Whole-Body Diffusion-weighted MR Imaging of Iron Deposits in Hodgkin, Follicular, and Diffuse Large B-Cell Lymphoma.

Purpose To analyze the frequency and distribution of low-signal-intensity regions (LSIRs) in lymphoma lesions and to compare these to fluorodeoxyglucose (FDG) uptake and biologic markers of inflammation. Materials and Methods The authors analyzed 61 untreated patients with a bulky lymphoma (at least one tumor mass ≥7 cm in diameter). When a LSIR within tumor lesions was detected on diffusion-weighted images obtained with a b value of 50 sec/mm2, a T2-weighted gradient-echo (GRE) sequence was performed and calcifications were searched for with computed tomography (CT). In two patients, Perls staining was performed on tissue samples from the LSIR. LSIRs were compared with biologic inflammatory parameters and baseline FDG positon emission tomography (PET)/CT parameters (maximum standardized uptake value [SUVmax], total metabolic tumor volume [TMTV]). Results LSIRs were detected in 22 patients and corresponded to signal void on GRE images; one LSIR was due to calcifications, and three LSIRS were due to a recent biopsy. In 18 patients, LSIRs appeared to be related to focal iron deposits; this was proven with Perls staining in two patients. The LSIRs presumed to be due to iron deposits were found mostly in patients with aggressive lymphoma (nine of 26 patients with Hodgkin lymphoma and eight of 20 patients with diffuse large B-cell lymphoma vs one of 15 patients with follicular lymphoma; P = .047) and with advanced stage disease (15 of 18 patients). LSIRS were observed in spleen (n = 14), liver (n = 3), and nodal (n = 8) lesions and corresponded to foci FDG uptake, with mean SUVmax of 9.8, 6.7, and 16.2, respectively. These patients had significantly higher serum levels of C-reactive protein, α1-globulin, and α2-globulin and more frequently had microcytic anemia than those without such deposits (P = .0072, P = .003, P = .0068, and P < .0001, respectively). They also had a significantly higher TMTV (P = .0055) and higher levels of spleen involvement (P < .0001). Conclusion LSIRs due to focal iron deposits are detected in lymphoma lesions and are associated with a more pronounced biologic inflammatory syndrome. © RSNA, 2017 Online supplemental material is available for this article.

MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study.

Diffuse large B-cell lymphoma (DLBCL) with MYC rearrangement (MYC-R) carries an unfavorable outcome. We explored the prognostic value of the MYC translocation partner gene in a series of MYC-R de novo DLBCL patients enrolled in first-line prospective clinical trials (Groupe d'Etudes des Lymphomes de l'Adulte/Lymphoma Study Association) and treated with rituximab-anthracycline-based chemotherapy. A total of 774 DLBCL cases characterized for cell of origin by the Hans classifier were analyzed using fluorescence in situ hybridization with BCL2, BCL6, MYC, immunoglobulin (IG)K, and IGL break-apart and IGH/MYC, IGK/MYC, and IGL/MYC fusion probes. MYC-R was observed in 51/574 (8.9%) evaluable DLBCL cases. MYC-R cases were predominantly of the germinal center B-cell-like subtype 37/51 (74%) with no distinctive morphologic and phenotypic features. Nineteen cases were MYC single-hit and 32 cases were MYC double-hit (MYC plus BCL2 and/or BCL6) DLBCL. MYC translocation partner was an IG gene in 24 cases (MYC-IG) and a non-IG gene (MYC-non-IG) in 26 of 50 evaluable cases. Noteworthy, MYC-IG patients had shorter overall survival (OS) (P = .0002) compared with MYC-negative patients, whereas no survival difference was observed between MYC-non-IG and MYC-negative patients. In multivariate analyses, MYC-IG predicted poor progression-free survival (P = .0051) and OS (P = .0006) independently from the International Prognostic Index and the Hans classifier. In conclusion, we show in this prospective randomized trial that the adverse prognostic impact of MYC-R is correlated to the MYC-IG translocation partner gene in DLBCL patients treated with immunochemotherapy. These results may have an important impact on the clinical management of DLBCL patients with MYC-R who should be routinely characterized according to MYC partner gene. These trials are individually registered at www.clinicaltrials.gov as #NCT00144807, #NCT01087424, #NCT00169143, #NCT00144755, #NCT00140660, #NCT00140595, and #NCT00135499.

Whole exome sequencing of relapsed/refractory patients expands the repertoire of somatic mutations in diffuse large B-cell lymphoma.

Despite the many efforts already spent to enumerate somatic mutations in diffuse large B-cell lymphoma (DLBCL), previous whole-genome and whole-exome studies conducted on patients of mixed outcomes failed at characterizing the 30% of patients who will relapse or resist current immunochemotherapies. To address this issue, we performed whole-exome sequencing of normal/tumoral DNA pairs in 14 relapsed/refractory (R/R) patients subclassified by full-transcriptome arrays (six activated B-cell like, three germinal center B-cell like, and five primary mediastinal B-cell lymphomas), from the LNH-03 LYSA clinical trial program. Aside from well-known DLBCL features, gene and pathway level recurrence analyses proposed several interesting leads including TBL1XR1 and activating mutations in IRF4 or in the insulin regulation pathway. Sequencing-based copy number analysis defined 23 short recurrently altered regions involving genes such as REL, CDKN2A, HYAL2, and TP53. Moreover, it highlighted mutations in genes such as GNA13, CARD11, MFHAS1, and PCLO as associated with secondary variant allele amplification events. The five primary mediastinal B-cell lymphomas (PMBL), while unexpected in a R/R cohort, showed a significantly higher mutation rate (P = 0.003) and provided many insights on this classical Hodgkin lymphoma related subtype. Novel genes such as XPO1, MFHAS1, and ITPKB were found particularly mutated, along with various cytokine-based signaling pathways. Among these analyses, somatic events in the NF-κB pathway were found preponderant in the three DLBCL subtypes, confirming its major implication in DLBCL aggressiveness and pinpointing several new candidate genes.

[A rare endolaryngeal tumor]. / Une tumeur rare endolaryngée.

We report the case of a 65-year-old woman who presented with a dysphonia. ENT tomography and laryngoscopy showed an endolaryngeal tumoral lesion extended to the right supraglottis. Biopsy of the lesion revealed dense lymphoid infiltrate in the lamina propria, without necrosis or ulceration of the mucosa. The infiltrate showed many CD3+, CD5+, CD4+, CD8+ lymphocytes and plasmocytes. Larger lymphoid cells with cytologic atypia expressed CD56 and cytotoxicity markers such as TIA1 and granzyme B. In situ hybridization for EBV revealed numerous positive cells. The diagnosis of extranodal NK/T cell lymphoma was proposed. The primary laryngeal localization of this disease is exceptionally rare. Heavy admixture of inflammatory cells may mimic inflammatory process and delay the diagnosis.

Pulmonary mucosa-associated lymphoid tissue lymphoma revisited.

This general review sought to clarify the pathophysiological, diagnostic, prognostic, and therapeutic features of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma.MALT lymphoma is the most common pulmonary B-cell lymphoma, which usually occurs in the context of acquired MALT. The disease is slow-growing with an asymptomatic chronic alveolar opacity visible on radiography. Diagnosis requires tissue samples that should be retrieved using minimally invasive techniques, such as bronchoscopy or computed tomography-guided biopsies. The pathophysiology includes cytogenetic abnormalities and autoimmune diseases, whereas an association with a chronic pulmonary infection is still suspected but not yet demonstrated. Disease prognosis is typically excellent and the current available treatments are discussed in this review, including the decision not to treat, surgery, and single- or double-agent chemotherapy.

Immune-checkpoint expression in Epstein-Barr virus positive and negative plasmablastic lymphoma: a clinical and pathological study in 82 patients.

Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma commonly associated with Epstein-Barr virus co-infection that most often occurs in the context of human immunodeficiency virus infection. Therefore, its immune escape strategy may involve the upregulation of immune-checkpoint proteins allowing the tumor immune evasion. However, the expression of these molecules was poorly studied in this lymphoma. We have investigated 82 plasmablastic lymphoma cases of whom half were Epstein-Barr virus positive. Although they harbored similar pathological features, Epstein-Barr virus positive plasmablastic lymphomas showed a significant increase in MYC gene rearrangement and had a better 2-year event-free survival than Epstein-Barr virus negative cases (P=0.049). Immunostains for programmed cell death-1, programmed cell death-ligand 1, indole 2,3-dioxygenase and dendritic cell specific C-type lectin showed a high or moderate expression by the microenvironment cells in 60%-72% of cases, whereas CD163 was expressed in almost all cases. Tumor cells also expressed programmed cell death-1 and its ligand in 22.5% and 5% of cases, respectively. Both Epstein-Barr virus positive and negative plasmablastic lymphomas exhibited a high immune-checkpoint score showing that it involves several pathways of immune escape. However, Epstein-Barr virus positive lymphomas exhibited a higher expression of programmed cell death-1 and its ligand in both malignant cells and microenvironment as compared to Epstein-Barr virus negative cases. In conclusion, plasmablastic lymphoma expresses immune-checkpoint proteins through both malignant cells and the tumor microenvironment. The expression of programmed cell death-1 and its ligand constitutes a strong rationale for testing monoclonal antibodies in this often chemoresistant disease.

Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-ß nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc.

Personalized risk prediction for event-free survival at 24 months in patients with diffuse large B-cell lymphoma.

We recently defined event-free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1,348 patients with DLBCL and treated with anthracycline-based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease, and sex was identified. The model was then applied to an independent validation dataset of 1,177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c-statistic = 0.671) in the validation dataset compared to the IPI (c-statistic = 0.649) or the NCCN-IPI (c-statistic = 0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12-88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be used via electronic apps.

Chronic inflammation and extra-nodal marginal-zone lymphomas of MALT-type.

Extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) is an indolent B-cell non-Hodgkin lymphoma (NHL) arising in lymphoid populations that are induced by chronic inflammation in extra nodal sites. The stomach is the most commonly affected organ, and MALT lymphoma is clearly associated with a gastroduodenitis induced by a microbial pathogen, Helicobacter pylori, thus gastric MALT lymphoma represents a paradigm for evaluating inflammatory-associated lymphomagenesis. Variable levels of evidence have indicated a possible association between other microorganisms and non-gastric MALT lymphomas. In addition to infectious etiology, chronic inflammation arising as a result of autoimmune diseases such as Sjogren's syndrome or Hashimoto thyroiditis, poses a significant risk factor for developing NHL. Recently, genetic alterations affecting the NF-κB pathway, a major signaling pathway involved in many cancers, have been identified in MALT lymphoma. This review will present MALT lymphoma as an example of the close pathogenetic link between chronic microenvironmental inflammation and tumor development, showing how these observations can be integrated into daily clinical practice, also in terms of therapeutic implications, with particular focus on the NF-κB pathway.

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue of the Salivary Glands: A Multicenter, International Experience of 248 Patients (IELSG 41).

BACKGROUND: The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). A large series of patients with long-term follow-up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma. METHODS: Patients with biopsy-confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long-term outcomes were evaluated. RESULTS: A total of 247 patients were evaluated; 76% presented with limited-stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty-seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression-free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first-line management. On multivariate analysis, age <60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS. CONCLUSION: Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long-term complications must be weighed when determining initial therapy.

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract.

Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years). Presenting symptoms included abdominal pain, diarrhea, vomiting, food intolerance, and dyspepsia. The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4(-)/CD8(+), 1 was CD4(+)/CD8(-), and another was CD4(-)/CD8(-). T-cell receptor-γ chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. We propose the name "indolent T-LPD of the GI tract" for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy.

Atypical fibrous histiocytoma of the skin with CD30 and p80/ALK1 positivity and ALK gene rearrangement.

We report the case of a two patients who presented with a solitary, asymptomatic, angiomatoid nodule on the right thigh. Histopathological finding showed a poorly circumscribed lesion, located in the dermis. The morphological aspect strongly suggested the diagnosis of atypical fibrous histiocytoma (AFH), but surprisingly, the neoplastic cells were diffusely CD30+, with a membrane staining devoid of paranuclear dot. The lesions were tested for p80/ALK1 expression. Surprisingly, we found a diffuse cytoplasmic positivity. Interestingly, using break-apart fluorescent in situ hybridization (FISH), we evidenced an ALK rearrangement in nearly 50% of the neoplastic cells. The expression of CD30 and ALK1 with ALK gene rearrangement raised the possibility of three diagnoses: a primary cutaneous anaplastic large cell lymphoma (ALCL), a cutaneous inflammatory myofibroblastic tumor (IMT), an AFH of the skin associated with ALK gene rearrangement and CD30 positivity. The three hypotheses were discussed and finally, although p80/ALK1 expression and cytogenetic abnormalities in fibrous histiocytoma (FH) are not yet reported to the best of our knowledge, we favored the diagnosis of AFH.