Follicular lymphoma (FL) is the second most common B-cell lymphoma subtype in the world wide. Although around 85-90% of FL harbors t(14;18)/IGH-BCL2 translocation, this entity is clinically and ...genetically heterogenous from in situ lesion to advanced stage disease. Also, a part of FL transforms to aggressive lymphomas such as diffuse large B-cell lymphoma and rarely lymphoblastic lymphoma.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of ...HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression.
We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data.
We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non-light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive-transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested.
We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.
Patients with rheumatoid arthritis often develop methotrexate‐associated lymphoproliferative disorders (MTX‐LPD) during MTX treatment. MTX‐LPD occasionally regresses spontaneously after simply ...discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non‐spontaneous regression have yet to be elucidated. To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTX‐LPD (diffuse large B‐cell lymphoma DLBCL‐type n = 34 and classical Hodgkin lymphoma CHL‐type n = 17). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL‐type MTX‐LPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL‐type MTX‐LPD patients (76%) required additional chemotherapy. This difference was statistically significant (P = 0.001). However, overall survival was not significantly different between DLBCL‐type and CHL‐type (91% vs 94%, respectively; P > 0.05). Thus, the morphological differences in the pathological findings of MTX‐LPD may be a factor for spontaneous or non‐spontaneous regression after discontinuation of MTX.
Many of the DLBCL‐type MTX‐LPD patients showed spontaneous remission and a better survival rate after methotrexate discontinuation. In contrast, more of the CHL‐type MTX‐LPD patients did not show spontaneous remission, and required additional chemotherapy. These findings are clinically relevant because the morphological differences in the pathological histology of MTX‐LPD might be a prognostic factor after methotrexate discontinuation.
IgG4‐related diseases comprise a recently recognized systemic syndrome characterized by mass‐forming lesions in mainly exocrine tissue that consist of lymphoplasmacytic infiltrates and sclerosis. ...There are numerous IgG4‐positive plasma cells in the affected tissues, and the serum IgG4 level is increased in these patients. The present study describes the history, autoimmune pancreatitis (AIP), IgG4‐related lymphadenopathy and lymphomagenesis based upon ocular adnexal IgG4‐related disease. Lymphoplasmacytic sclerosing pancreatitis, a prototypal histological type of AIP, is now recognized as a systemic IgG4‐related disease. Lymph node lesions can be subdivided into at least five histological subtypes, and systemic IgG4‐related lymphadenopathy should be distinguished from multicentric Castleman's disease. Interleukin‐6 and CRP levels are abnormally high in multicentric Castleman's disease, but are normal in the majority of systemic IgG4‐related lymphadenopathy. Ocular adnexal IgG4‐related disease frequently involves bilateral lacrimal glands swelling, and obliterative phlebitis is rare. Moreover, some malignant lymphomas, especially mucosa‐associated lymphoid tissue lymphoma, arise from ocular adnexal IgG4‐related disease. In addition, IgG4‐producing lymphoma also exists.
IgG4‐related disease is a recently proposed clinical entity with several unique clinicopathological features. Ocular adnexal IgG4‐related disease, however, has not well been clarified. The purpose of ...the present study was to examine 21 patients (10 men, 11 women; age range, 39–86 years) with ocular adnexal IgG4‐related disease. In 17 out of 21 patients (81%), the lacrimal glands were involved and bilateral lacrimal gland swelling was frequently observed (n = 12; 70.6%). In contrast, the conjunctiva was not involved in any of the patient. Histology was uniform with marked lymphoplasmacytic infiltration admixed with dense fibrosis, similar to previous reports of IgG4‐related disease. Immunostaining detected numerous aggregates of IgG4‐positive plasma cells. Serum IgG4 was higher than normal in 10 of the 13 patients tested, although it was measured after treatment in almost all cases. Interestingly, immunoglobulin heavy chain gene rearrangement was detected in two of 17 patients (12%) examined. The present results show that ocular adnexal IgG4‐related disease has uniform clinicopathology: that is, disease involving the bilateral lacrimal glands with lymphoid hyperplasia and fibrosis, but not the conjunctiva. And presence of immunoglobulin heavy chain gene rearrangement suggests the possibility of B‐cell lymphoma arising in a background of IgG4‐related chronic inflammation.
The gastrointestinal (GI) tract is the most commonly involved site of extranodal follicular lymphoma (FL). GI‐FL shows very indolent clinical behavior and localized at GI tract without any ...progression or transformation compared to nodal FL. The most frequently involved site of the GI tract was the duodenum followed by the jejunum and ileum, and only 15% of FL arising in the second part of the duodenum were localized there without scattered very small daughter lesions in other GI tract examined by double‐balloon endoscopy. The typical macroscopic appearance of GI‐FL was multiple white nodules. Microscopically, neoplastic cells were small‐ to medium‐sized lymphoid cells and formed neoplastic follicles. Most of the cases (>95%) were histologically Grade 1 to 2 (low grade). Several pathological and molecular characteristics were seen in GI‐FL (especially duodenal FL) compared with nodal FL: immunoglobulin heavy chain deviation to VH4 and VH5; memory B‐cell immunophenotype; and molecular features shared by mucosa‐associated lymphoid tissue lymphoma. Considering the pathological and molecular uniqueness of this disease, GI‐FL should be separately managed from nodal FL.
Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between ...malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4
helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1
CXCL13
T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5
normal B cells in close proximity to CXCL13
T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1
CXCL13
T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL (
= 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1
CXCL13
T cells as a treatment target in LR-CHL.
Myeloid sarcoma (MS) is a condition characterized by a tumor mass of myeloid blasts in any site of the body other than the bone marrow, with or without acute myeloid leukemia. A 93-year-old man ...underwent laparoscopy-assisted distal gastrectomy with D1 lymphadenectomy for advanced gastric cancer. Other than metastatic foci of gastric cancer cells, some dissected lymph nodes showed destructive architecture with proliferation of small- to medium-sized atypical hematopoietic cells. Those cells were focally positive for naphthol AS-D chloroacetate esterase. Immunohistochemically, positive results were obtained for CD4, CD33, CD68 (KP1), Iba-1, lysozyme, myeloperoxidase, and PU.1, with focally positive results for CD13, CD14, CD68 (PGM1), CD163, and CD204, and negative results for AE1/AE3, CD1a, CD3, CD20, and S-100 protein. These results suggested MS with phenotypically myelomonocytic differentiation. We report a rare case of MS incidentally found in specimens resected for other purposes. Careful diagnosis and consideration of differential diagnoses including MS using an adequate panel of antibody markers for dissected lymph nodes is warranted.
We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients ...with stage I and II1 GI–FL. Of the 125 patients, the small intestine was examined in 70 patients, with double‐balloon endoscopy and/or capsule endoscopy. The most frequently involved GI–FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP‐positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression‐free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI–FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course. (Cancer Sci 2011; 102: 1532–1536)
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