The gastrointestinal tract (GIT) is the most common (30–40%) extranodal site involved in lymphoma. Although primary gastrointestinal lymphoma (PGIL) is a rare disease, comprising only 1–4% of gastrointestinal (GI) malignant tumors, its incidence is increasing. Different regions of the GIT are involved in different subtypes of PGIL with a various frequency that reflects the diversity of the causative agents and predisposing factors for each site and subtype of PGIL. Even though these malignant diseases are categorized under the common term of “lymphoma” they represent a heterogeneous group of malignant neoplasms which are different entities in terms of etiologic factors, predisposing conditions, pathogenesis, immunohistochemical profile, treatment strategy and prognosis. In this chapter the epidemiology of all subtypes of PGIL, factors and disorders contributing to the development of them, non-inherited and inherited conditions associated with a higher risk of them, diagnostic difficulties and pitfalls, and novel treatment strategies were comprehensively and concisely illuminated.
Follicular lymphoma (FL) is one of the most common type of indolent non- Hodgkin’s lymphoma. It originates from germinal center B cells and has characteristic translocation t(11,14) involving immunoglobulin heavy chain gene (chromosome 14q32) and Bcl2 gene (chromosome 18q21) in 90% of patients. FL presents with lymphadenopathy and/or bone marrow involvement. Diagnosis is confirmed by histological examination of lymph nodes. FL is a slow growing tumor with frequent remission and relapses. Follicular lymphoma international prognostic index (FLIPI) and progression of disease within 24 months (POD24) are most important prognostic markers. Early-stage disease is usually treated with radiotherapy. Management of advanced stage depends on disease burden. Patients with advanced stage disease may be observed in case of low burden disease and those with high disease load require treatment with chemo-immunotherapy.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases of the lymphatic system, which is represented by de novo and secondary tumors resulting from the transformation of indolent lymphomas. In the absence of a long history of the disease at the stage of histological transformation (HT), it is difficult to distinguish between de novo and secondary diffuse large B-cell lymphoma. According to the data of a randomized study, we obtained clinical and laboratory data that are not typical for de novo diffuse large B-cell lymphoma. These include exclusive, predominant retroperitoneal localization, compression of the ureters/kidneys with or without the development of acute renal failure (ARF), unilateral lymphostasis of the leg due to compression of the inguinal, iliac lymph nodes by the conglomerate, intratumor in the central nervous system (CNS) at the onset/relapse/progression of the disease, discordant bone marrow involvement, blood involvement, paraprotein secretion.
Cancer is the biggest health problem worldwide due to its high mortality rate. Lymphoma is defined as a group of malignant diseases that is caused by clonal proliferation of lymphocytes and is classified under two major groups: Hodgkin lymphoma and non-Hodgkin lymphoma. Genetic predisposition and some environmental factors constitute risk factors. Symptoms of the disease include unexplained fever, swelling of lymph glands, swollen abdomen, tiredness, loss of appetite, frequent infections, and weight loss. Positron emission tomography (PET) and computed tomography (CT) scans, along with MRI, are widely used for the diagnosis of lymphoma. Advanced blood and lymph node biopsy tests are used to evaluate treatment effect on blood cells and to confirm the diagnosis of lymphoma, respectively. Current treatment options include chemotherapy, radiotherapy, and bone marrow/stem cell transplantation. Development of new treatment options for cancer medications includes small molecules and monoclonal antibodies for immunotherapy. In addition, the discovery of new phytochemical agents used in complementary and alternative medicine adds perspective to the treatment of lymphoma.
Early suspicion, withholding steroids, stereotactic biopsy, and high-dose methotrexate (HD-MTX) are essential for the treatment of primary CNS lymphoma (PCNSL) making its management in lower-middle-income countries (LMIC) challenging. Novel radiological methods, clinician awareness about the disease, and utilization of drugs like thiotepa and ibrutinib which can be given on an outpatient basis may allow better management of these patients in resource-poor settings. Combined with a late presenting demographic, this results in poorer outcomes in the Indian subcontinent as compared to its western counterparts. In this review, we summarize the currently available data on PCNSL in the Indian subcontinent. We also review the current standard of care for PCNSL and present potential modifications or research areas that may potentially improve outcomes in LMIC.
This chapter aims to provide a complete knowledge over the primary intraocular lymphoma (PIOL) and a correct clinical approach towards this rare condition, to avoid delays in diagnosis, which is considered the most important prognostic factor. A PIOL arises with no specific symptoms and could mimic both inflammatory and non-inflammatory ocular conditions. Also known as reticulum cell sarcoma in the past, PIOL is an ocular malignant condition, with a strong bond with primary central system lymphoma (PCNSL). This linkage is underlined by the fact that approximately 30% of the patients with PIOL have also PCNSL at presentation, while 45–90% will develop PCSNL in the following months. A correct diagnosis is currently achieved by the means of many different techniques: cytology, flow cytometry, immunohistochemistry, molecular analysis, and cytokines assay. Treatment of this condition has been completely revolutionized with the introduction of monoclonal antibodies directed against specific proteins present on the surface of lymphomatous cells.
This chapter explores the testicular involvement of lymphoma. Testicular lymphoma may either represent secondary involvement by systemic disease or primary malignancy. Regarding primary testicular lymphoma (PTL), it is a rare form of extranodal lymphoma and the most frequent malignant testicular neoplasm in men over the age of 60 years. The diffuse large B-cell lymphoma (DLBCL) accounts for the majority of cases. The morphologic manifestation of PTL on imaging may be in the form of a localized mass or a diffuse enlargement of the testis. On ultrasonography, PTL usually appears as a hypoechoic area with hypervascularity. MRI and positron emission tomography with computed tomography (PET/CT) are useful diagnostic tools. The latter is crucial in staging and follow-up of these patients. The treatment of PTL is based on orchiectomy, chemotherapy, and radiotherapy. The prognosis is poor and PTL exhibits a propensity to relapse in the central nervous system (CNS) and in the opposite testis. Secondary involvement of the testis by non-Hodgkin lymphoma (NHL) is more frequent than PTL. Patients may develop the relapsed or refractory disease in the testis in the context of disseminated lymphomas due to the existence of the blood-testis barrier. This chapter discusses the treatment of secondary involvement by lymphoma.
Splenic B-cell lymphoma/leukemia, which is unclassifiable, includes low-grade B-cell lymphoproliferative disorders that do not fit into any other splenic lymphoid neoplasm based on current WHO classification. Presently, two provisional entities, splenic diffuse red pulp small B-cell lymphoma (SDRPL) and hairy-cell leukemia variant (HCL-v), are the most recognizable members of this group. SDRPL is an uncommon malignancy representing less than 1% of all non-Hodgkin lymphomas. Frequent clinical manifestations include splenomegaly and lymphocytosis. SDRPL is currently considered a diagnosis of exclusion and requires clinical and paraclinical correlation, including blood smear, bone marrow and spleen morphology, and the correct immunophenotype (typically positive for CD20, DBA.44, and IgG; and negative for CD5, CD10, CD23, CD43, annexin A1, CD11c, CD25, CD103, and CD123), and cytogenetic findings. Cyclin D3 is expressed in the majority of SDRPL in contrast to other types of small B-cell lymphomas. HCL-v is a less common disease accounting for 0.4% of all chronic lymphoproliferative disorders. It resembles classical HCL and SDRPL by diffusely infiltrating the splenic red pulp but is considered biologically unrelated. Splenomegaly and atypical lymphocytosis without monocytopenia are common. Distinguishing features of HCL-v include morphology, immunophenotype (the absence of CD25, CD200, CD123, annexin A1, and TRAP), genotype (wild-type BRAF), and prognosis.
Hydroa vacciniforme (HV)-like cutaneous T-cell lymphoma (HVLL) is a controversial skin pathology because some cases appear as hydroa vacciniforme, whereas others progress to cutaneous T-cell lymphoma with or without angiocentricity. It is usually associated with infections of Epstein Barr viruses and NK-cell lymphomas and typically affects the pediatric population. Symptoms include facial edema, papules, vesicles, and blisters in the facial region, arms, legs, and areas exposed to sunlight that leave varioliform scars. There may be infiltration of the lips, eyelids, and nose, usually accompanied by comorbid infections and hypersensitivity to insect bites. Frequency is rare, but HVLL more commonly affects patients from South America and Asia. Its clinical management can be difficult and accompanied by a high index of malignancy, thus early diagnosis is essential for effective and timely management.
Lymphoma is a significant clinical entity because of its high incidence and complicated etiology and pathology. In this chapter, we discussed lymphoma in general and made focus in our previous studies in which we found unique features linking the interaction of EBV with sex steroid hormones in lymphoma cells. Sex steroid hormones included estrogen receptor and progesterone receptors that were investigated for their expression in malignant lymphoid cells. The localization of EBV in malignant lymphoid cells was also investigated. The two main types of lymphoma, Hodgkin Lymphoma, and non-Hodgkin lymphoma, were investigated for the interaction of EBV with sex steroid hormones. Unique features were obtained in terms of a bridge-linking estrogen receptor with EBV in Hodgkin lymphoma and progesterone receptor with EBV in non-Hodgkin lymphoma. The interactions between EBV and lymphoma are classic, but the reasons beyond this are not well established. The results of our studies highlighted new features by the existence of expressed sex steroid receptors. We think that the dissociation of combination between sex steroid hormones and EBV bears the link to design new therapeutic strategies for lymphoma.
Breast implant-associated anaplastic large cell lymphoma is a rare disease first described in 1997. Since then, its incidence has continued to increase. Current estimated lifetime risk in women with textured breast implants range from 1:1000 to 1:30,000. Most cases present with rapid and dramatic breast swelling resulting from peri-implant fluid collection. Palpable mass, pain, and skin lesions also occur. A high index of suspicion in patients who develop a seroma around the breast implant more than one year after implant placement is required. The combination of clinical history, physical exam findings, and appropriate imaging workup can lead to a timely and accurate diagnosis. The disease has excellent prognosis when it is diagnosed earlier, and complete surgery is performed. Radiologists, particularly those involved in breast imaging, can play an essential role in early diagnosis. This chapter presents an overview of the disease, including relevant imaging findings.
The overall approach to the management of Hodgkin lymphoma has undergone a rapid revolution. The Ann Arbor staging, proposed more than half a century ago, is still valid to guide treatment intensity, but all the invasive methods originally proposed have been replaced by a single high-performing tool of functional imaging: the Positron Emission Tomography coupled with Computed-Tomography (PET/CT). Apart from improving the overall accuracy of the Ann Arbor staging, new PET-derived metrics to measure the tumor burden such as metabolic tumor volume, total lesion glycolysis and tumor spread such as the Tumor Distance (Dmax), are ready to take over the classical four-level lymphoma staging. PET/CT has also downsized the role of radiation in the classic “combined modality treatment” for HL. PET/CT performed early during treatment (interim PET) for advanced-stage HL remains the standard of care in Europe to escalate treatment in patients starting with ABVD or to de-escalate treatment for patients starting with BEACOPP escalated. Finally, the therapeutic offer for patients failing first-line chemotherapy has been completely renewed by the advent of new non-chemotherapy agents such as Brentuximab Vedotin and Immune Checkpoint Inhibitors (CPI) which are now the standard of care along with autologous stem cell transplant (ASCT).
ABSTRACT Epstein-Barr virus (EBV)-positive diffuse large B cell lymphoma (DLBCL) is known for distinct clinical features. This disease was formerly designated as EBV-positive DLBCL of the elderly, but the restriction to elderly patients has been removed, and the World Health Organization classification revised 4th edition lists EBV-positive DLBCL, not otherwise specified (NOS). The frequency of EBV-positive DLBCL among DLCBL is about 2.5–14.0%, with higher incidence among East Asians. Most cases occur in patients aged over 50 years old with male predominance. The clinical characteristics of EBV-positive DLBCL, compared to those with EBV-negative DLBCL, include association with older age, more advanced clinical stage, a higher rate of extranodal involvement, and worse performance status. It is usually treated with R-CHOP, consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. EBV-positive DLBCL shows an inferior prognosis with R-CHOP as compared with EBV-negative DLBCL. Furthermore, high EBV-DNA load and positivity of EBV-encoded RNA in biopsy specimens are associated with a worse prognosis.
In 2014, a committee of clinicians and nuclear medicine experts issued the recommendations for lymphoma staging and restaging based on the use of positron emission tomography/computed tomography (PET/CT). These recommendations were immediately adopted in the Western countries and have become part of the routine clinical use. In contrast, the adoption of these recommendations has been gradual in many non Western countries, and around the world in general, depending on the availability of dedicated and skilled technicians and doctors, and on the accessibility to economic resources in the healthcare system for the reimbursement of the cost of the procedure. This chapter presents a portrait of the adoption and accessibility of PET/CT in Uruguay, Argentina, Ukraine, and Saudi Arabia. The chapter concludes with a section on the reproducibility of SUV-related indexes for PET/CT reporting in lymphoma.
Imaging has a pivotal role in the management of lymphoma patients, from the diagnosis to the therapy assessment. Its importance has grown exponentially in the last years thanks to the introduction of 18F-fluoro deoxy-glucose positron emission tomography/computed tomography (18FDG-PET/CT) that permitted to design clinical trial in which treatment was adapted on the basis of metabolic response obtained in the early phase of treatment, usually after two cycles of chemotherapy. This approach has been successfully translated in clinical practice thanks to the introduction of the Deauville criteria, which is currently the standard method for PET/CT imaging reporting and metabolic response assessment. The introduction of quantitative evaluation of baseline PET/CT images provided new functional indices such as metabolic tumor volume (MTV) that demonstrated good value in predicting patient outcome. Recently, radiomic analysis has allowed the extraction of a wide variety of quantitative data that reflect biological characteristics of disease providing additional promising prognostic biomarkers in lymphomas.
Lymphoma is the third most common pediatric neoplasm. In the United States, there are close to 2000 new lymphoma cases diagnosed in children every year. Common pediatric lymphomas include Hodgkin lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma. Advances in understanding the biology of these lymphomas have led to significantly improved therapeutic outcome and made lymphoma one of the most curable pediatric cancers. There are a few newly proposed or revised entities of lymphoma in the most recent WHO classification, which include Burkitt-like lymphoma with 11q aberration, large B-cell lymphoma with IRF4 rearrangement, pediatric type follicular lymphoma and systemic EBV (Epstein-Barr virus) + T-cell lymphoma of childhood. These new entities are relatively common in children and are not well known. They can be a diagnostic challenge to a pathologist who is not familiar with them. This chapter describes common pediatric lymphomas as well as these new WHO entities with the focus on the epidemiology, pathogenesis, and pathology.
SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) is the only human gene encoding the histone methyltransferase responsible for trimethylation of lysine 36 of histone H3. SETD2 protein is involved in multiple important cellular processes that include transcriptional regulation, DNA damage repair, alternative RNA splicing, genomic stability, apoptotic response, and interferon response. As a tumor suppressor, SETD2 loses its activities by loss-of-function mutations in a wide spectrum of tumors. The alterations of SETD2 are the most common genetic changes detected in monomorphic epitheliotropic intestinal T-cell lymphoma, seen in over 90% of the cases. SETD2 is the commonest silenced gene detected in hepatosplenic T-cell lymphoma, seen in 25% of the cases. SETD2 alterations have been detected in approximately 10% of precursor B-cell lymphoblastic leukemia/lymphoma cases, and commonly gained in the relapse of this disease. SETD2 alterations have also been found in about 10% of early-T-precursor lymphoblastic leukemia, up to 10% of diffuse large B cell lymphoma, up to 7% of chronic lymphoblastic leukemia/small lymphocytic lymphoma, and in a small portion of other lymphoid malignancies. Experimental loss of SETD2 can promote tumor cell proliferation and result in chemotherapy resistance. Targeting SETD2 may offer a potential therapeutic strategy for these lymphoid malignancies.
Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OII-LPD) is defined by the World Health Organization classification 2016 as lymphoid proliferations or lymphomas that arise in patients treated with immunosuppressive drugs for autoimmune disease or conditions other than in the post-transplant setting. OII-LPD patients have a relatively high incidence of extranodal disease (40–50%). The distinct feature of OII-LPD is spontaneous regression after discontinuation of immunosuppressive drugs. The clinical course of OII-LPD after discontinuation of immunosuppressive drugs can be roughly divided into three categories: regression, transient regression followed by relapse or recurrence, and progression. Regression after discontinuation of immunosuppressive drugs was seen in 70% of OII-LPD patients. About 33% of these patients who experienced transient regression had experienced relapse or recurrence. The remaining 30% of patients were without regression even after discontinuation of immunosuppressive drugs. Higher absolute lymphocyte count in peripheral blood at the time of development of OII-LPD and Epstein-Barr virus-encoded RNA (EBER)-positivity are predictive factors of regression.
A majority of B-cell lymphomas, including diffuse large B-cell lymphomas (DLBCLs) and follicular lymphomas (FLs), arise from germinal center (GC) B cells. GC B cells are highly proliferative and manifest genomic instability as a byproduct of immunoglobulin affinity maturation. These characteristics make GC B cells particularly prone to malignant transformation such that DLBCLs and FLs inherit and are dependent on mutations in proteins that are also required for normal GC B cells. For example, the BCL6 transcriptional repressor is required to establish the GC phenotype in both normal B-cell development and GC B-cell malignancy through its effect on silencing expression of plasma cell differentiation and checkpoint genes. GC B cells feature a unique transcriptional program featuring upregulation of genes involved in cell proliferation and other growth pathways. Cell context-specific gene expression is largely mediated through gene enhancers. Hence we hypothesized that transcription factors that activate GC specific gene enhancers would play a critical role in formation of these cells, and would likely be required in turn to maintain the survival of GC-derived lymphoma cells. To address this question we first mapped gene enhancers in primary human resting B cells and purified GC B cells by performing ChIP-seq to map the distribution of H3K27Acetyl, H3K4me1, and H3K4me3. This procedure allowed us to identify several thousand GC-specific enhancers. We next examined these enhancers using bioinformatic approaches to identify transcription factor binding sites and identified a list of fifteen putative GC enhancer regulators. Of these potential GC enhancer regulators, only SOX9 was highly induced in GC B cells as compared to resting B cells, pointing to SOX9 as a candidate master enhancer regulator of the GC transcriptome with potential relevance to lymphomas. Indeed, in addition to the well-known role of SOX9 as a stem cell self-renewal and cell-differentiation regulator during development, SOX9 has also been described as playing a role in colon, breast, and prostate carcinogenesis through inhibition of apoptosis, and promoting proliferation, invasion, and metastasis. We confirmed that SOX9 is highly induced in GC cells using QPCR and Western blots. To determine whether SOX9 would indeed bind to these enhancer sites, we next performed SOX9 ChIP-seq in GC B-cell derived lymphoma cell lines. These experiments validated and showed that SOX9 binds to 1,668 upstream distal enhancer regions (-5 to -100 kb upstream from TSS) associated with 963 genes. These target genes were significantly enriched in cell cycle regulation (CCND2, CDC25B, CDK1), transcription regulation (BCOR, NCOR2), epigenetic regulation (BMI1, DNMT3A, MLL2, SUZ12, TET3), and MAPK signaling (MAP2K3, MAP3K7) and also for B-cell activation and BCL6 repressed pathways (p We next wished to determine whether SOX9 was also expressed in GC-derived lymphoma clinical samples. Therefore we next examined RNA-seq gene expression profiles derived from cohorts of FL and DLBCL patients. We found that SOX9 is expressed at higher levels in FL patient samples, but lower levels in most DLBCLs compared to naive B cells. These data raise the possibility that SOX9 might be differentially relevant to FL more than DLBCLs, perhaps contributing to the biologic distinction between these two GC-derived lymphomas. To determine if SOX9 protein was also expressed in these tumors, we examined protein expression by immunohistochemistry using tissue microarrays (TMAs) containing both FLs and DLBCLs. We found that 88 of the 242 FL TMA samples (36.4%) were positive for SOX9 staining. Eleven of the 114 DLBCL TMA samples (10%) were positive for SOX9 staining, among which 80% (9/11) were GC-type DLBCL and 45% (5/11) had a prior FL history. To determine if any of the currently available GC derived lymphoma cell lines manifest high SOX9 levels, we performed a series of Western blot experiments. These studies show high levels of SOX9 protein in the GC-type DLBCL cell lines HT, Karpas422, DB, and Farage, but not in any of the eight ABC-DLBCLs subtypes. Ongoing studies are assessing the biologic relevance of SOX9 for the GC reaction and possible contribution to lymphomagenesis using gain- and loss-of-function studies in human cells and mouse models. These data will determine whether this apparently key enhancer regulatory protein is a novel lineage factor for follicular lymphoma and potentially suitable as a therapeutic target. Citation Format: Angela A. Fachel, Yanwen Jiang, Wayne Tam, Ashlesha S. Muley, Cem Meydan, Xabier Agirre, Ari M. Melnick, Kristy L. Richards. SOX9 enhancer regulator may play an oncogenic role in B-cell lymphomas [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 30.
Introduction. Non-Hodgkin lymphoma (NHL) is the most frequent malignancy associated with primary immune deficiency disease (PID). We aimed to present the clinical characteristics and outcomes of Belarusian children with PID who developed NHL. Procedure. We reviewed 16 patients with PID and NHL. Eight patients had combined PID: 5—Nijmegen breakage syndrome, 1—Bloom syndrome, 1—Wiskott-Aldrich syndrome, and 1—Х-linked lymphoproliferative syndrome. Results. In 75% cases PID was diagnosed simultaneously or after the NHL was confirmed. PID-associated NHL accounted for 5.7% of all NHL and was characterized by younger median age (6.3 versus 10.0 years, P<0.05) and by prevalence of large-cell types (68.8% versus 24.5%, P<0.001). Children with combined PID had median age of 1.3 years; 5 of them developed EBV-associated diffuse large B-cell lymphoma with lung involvement. Five of 6 patients with chromosomal breakage syndrome developed T-NHL. Six patients died of infections; two died after tumor progression; one child had early relapse; two died of second NHL and one of secondary hemophagocytic syndrome. Overall, 4 children are alive and disease-free after a follow-up from 1.4 to 5.7 years. Conclusions. PID needs to be diagnosed early. Individualized chemotherapy, comprehensive supportive treatment, and hematopoietic stem cell transplantation may improve survival of children with PID and NHL.
