# Lecture 10: Lymphomas ## Unit 2.9: Hematology/Oncology --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe the classification of lymphomas 2. Explain the clinical features and staging of Hodgkin lymphoma 3. Describe the treatment and prognosis of Hodgkin lymphoma 4. Explain the classification and features of non-Hodgkin lymphomas 5. Describe the treatment of aggressive and indolent lymphomas 6. Explain special types of lymphomas and their management --- ## Lecture Outline ### I. Lymphoma Overview Lymphoma encompasses a diverse group of malignancies arising from lymphocytes, including B cells, T cells, and rarely natural killer cells, that predominantly manifest as solid tumors within lymph nodes, spleen, or extranodal tissues rather than as circulating malignant cells in the blood and bone marrow. The fundamental distinction between lymphoma and leukemia lies in the primary site of disease, with lymphoma originating in lymph nodes or extranodal sites and leukemia arising in the blood and bone marrow, though considerable overlap exists as some diseases demonstrate features of both, such as CLL which is the same disease as small lymphocytic lymphoma differing only in the predominant site of involvement. The two major categories of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma, which differ in their pathologic features, clinical behavior, treatment approaches, and prognosis. Understanding this classification is essential because the distinction between Hodgkin and non-Hodgkin lymphoma fundamentally determines the diagnostic workup, treatment strategy, and expected clinical outcomes. The classification of lymphoma begins with the division into Hodgkin lymphoma, characterized by the pathognomonic Reed-Sternberg cell of B-cell origin, and non-Hodgkin lymphoma, a far more heterogeneous group in which approximately 85 percent of cases arise from B cells, 15 percent from T cells, and a small minority from natural killer cells. Hodgkin lymphoma is relatively uncommon compared to non-Hodgkin lymphoma, with approximately 8,000 new cases per year in the United States compared to approximately 80,000 cases of non-Hodgkin lymphoma annually. The age distribution differs substantially, with Hodgkin lymphoma demonstrating a characteristic bimodal distribution with peaks in the 20s and again after age 60, while non-Hodgkin lymphoma incidence increases progressively with advancing age. The prognosis of Hodgkin lymphoma is generally favorable with high cure rates, while non-Hodgkin lymphoma prognosis varies enormously by subtype, ranging from indolent diseases with years of survival without treatment to highly aggressive forms requiring immediate intensive therapy. The clinical presentation of lymphoma shares several common features regardless of the specific subtype, with painless, firm lymphadenopathy being the most characteristic presenting finding across all categories. B symptoms, defined as fever exceeding 38 degrees Celsius, drenching night sweats, and unintentional weight loss exceeding 10 percent of body weight over the preceding 6 months, are important prognostic indicators that affect staging and treatment decisions in both Hodgkin and non-Hodgkin lymphoma. Pruritus is another systemic symptom that occurs particularly in Hodgkin lymphoma and may precede the diagnosis by months. Extranodal involvement may occur at various sites including the gastrointestinal tract, central nervous system, skin, and bone, and is more characteristic of non-Hodgkin lymphoma than Hodgkin lymphoma. Splenomegaly is variably present depending on the subtype and extent of disease, and may be the dominant clinical finding in certain lymphoma types. Panel A: Classification tree showing division of lymphoma into Hodgkin and non-Hodgkin types with B-cell and T-cell subcategories. Panel B: Clinical presentation with painless firm lymphadenopathy in cervical and supraclavicular regions. Panel C: B symptoms defined as fever greater than 38 degrees Celsius, drenching night sweats, and greater than 10% unintentional weight loss. Panel D: Extranodal involvement sites including gastrointestinal tract, CNS, skin, and bone with relative frequencies. --- ### II. Hodgkin Lymphoma - Pathology The pathologic hallmark of Hodgkin lymphoma is the Reed-Sternberg cell, a large malignant cell with a distinctive bilobed nucleus creating the classic "owl eyes" appearance with two prominent eosinophilic nucleoli surrounded by a clear halo. Reed-Sternberg cells are derived from germinal center B cells that have undergone aberrant immunoglobulin gene rearrangement and express the characteristic immunohistochemical markers CD15 and CD30 while typically lacking CD20 expression, a pattern that distinguishes them from most other B-cell malignancies. A paradoxical feature of Hodgkin lymphoma is that the malignant Reed-Sternberg cells constitute only a minority of the tumor mass, typically less than 1 to 2 percent, with the vast majority of cells representing a reactive inflammatory infiltrate of lymphocytes, histiocytes, eosinophils, and plasma cells. This inflammatory background reflects the extensive cytokine network produced by Reed-Sternberg cells that recruits and maintains the reactive cellular milieu, and the composition of this background forms the basis for subtype classification. Classical Hodgkin lymphoma encompasses four histologic subtypes that differ in the composition of the reactive background, clinical associations, and to some extent prognosis. Nodular sclerosis is the most common subtype, accounting for approximately 70 percent of cases, and characteristically affects young adults, frequently presents with a mediastinal mass, and demonstrates broad bands of collagen fibrosis creating a nodular architecture. Mixed cellularity represents approximately 25 percent of cases, is more commonly associated with HIV infection and older adult age, and shows a mixed inflammatory background without prominent fibrosis. Lymphocyte-rich classical Hodgkin lymphoma is rare and carries a favorable prognosis, while lymphocyte-depleted Hodgkin lymphoma is also rare, tends to present at advanced stage, and is associated with HIV infection and immunocompromised states. These subtypes share the same immunophenotype and treatment approach but differ in their clinical presentations and epidemiologic associations. Nodular lymphocyte-predominant Hodgkin lymphoma represents a biologically distinct entity that differs from classical Hodgkin lymphoma in its pathology, immunophenotype, clinical behavior, and treatment approach. The malignant cells in this subtype are called lymphocyte-predominant cells or "popcorn cells" due to their multilobed nuclei, and they express CD20 but lack CD15 and CD30, an immunophenotypic profile essentially opposite to classical Hodgkin lymphoma Reed-Sternberg cells. The clinical behavior of nodular lymphocyte-predominant Hodgkin lymphoma is typically indolent with a tendency for late relapses, but the disease may undergo transformation to aggressive large B-cell lymphoma in a subset of patients. Treatment of this subtype differs from classical Hodgkin lymphoma, with observation appropriate for some patients and rituximab-based approaches leveraging the CD20 expression of the malignant cells. Epstein-Barr virus plays an important etiologic role in a subset of Hodgkin lymphoma cases, with the degree of association varying by histologic subtype and patient immune status. Mixed cellularity Hodgkin lymphoma demonstrates the strongest EBV association, with the virus detectable in approximately 75 percent of cases, while nodular sclerosis shows EBV positivity in approximately 25 percent of cases. In immunocompromised patients, including those with HIV/AIDS, EBV is detected in more than 90 percent of Hodgkin lymphoma cases, reflecting the critical role of immune surveillance in controlling EBV-driven lymphoproliferation. The mechanism involves expression of viral oncogenes including latent membrane proteins that activate survival pathways in infected B cells, contributing to the malignant transformation that generates Reed-Sternberg cells. Panel A: Reed-Sternberg cell morphology showing large binucleated cells with owl-eye appearance and prominent eosinophilic nucleoli. Panel B: Comparison of classical Hodgkin lymphoma subtypes showing nodular sclerosis with fibrous bands, mixed cellularity with diverse inflammatory infiltrate, and lymphocyte-depleted variant. Panel C: Immunohistochemistry panel demonstrating CD15 and CD30 positivity with CD20 negativity in classical HL. Panel D: Nodular lymphocyte-predominant HL with popcorn cells (LP cells) showing CD20 positivity and different marker profile. --- ### III. Hodgkin Lymphoma - Clinical and Staging The clinical presentation of Hodgkin lymphoma most commonly begins with painless lymphadenopathy in the cervical or supraclavicular regions, which is the most frequent initial site of involvement. A mediastinal mass is a characteristic finding particularly associated with nodular sclerosis subtype, and may be detected on chest radiograph obtained for respiratory symptoms or as part of the diagnostic workup. A distinctive feature of Hodgkin lymphoma that differentiates it from most non-Hodgkin lymphomas is its pattern of contiguous spread, progressing in an orderly fashion through adjacent lymph node groups rather than the non-contiguous dissemination more typical of non-Hodgkin lymphoma. B symptoms including fever, night sweats, and weight loss are present in 30 to 40 percent of patients at diagnosis and carry prognostic significance. Pel-Ebstein fever, a cyclical pattern of days to weeks of fever alternating with afebrile periods, is rare but considered a classic association with Hodgkin lymphoma, and alcohol-induced pain in involved lymph nodes is another rare but pathognomonic symptom. The Ann Arbor staging system provides the framework for staging both Hodgkin and non-Hodgkin lymphoma based on the anatomic extent of disease involvement. Stage I indicates involvement of a single lymph node region, stage II indicates two or more lymph node regions on the same side of the diaphragm, stage III indicates lymph node involvement on both sides of the diaphragm, and stage IV indicates diffuse or disseminated involvement of extralymphatic organs including liver or bone marrow. Important stage modifiers include the suffix A for absence of B symptoms and B for their presence, E for direct extranodal extension from an involved lymph node site, and X for bulky disease defined as a mass greater than 10 cm in diameter or occupying more than one-third of the thoracic diameter. These staging designations directly influence treatment decisions, with early-stage disease receiving less intensive therapy than advanced-stage disease. The diagnostic workup for Hodgkin lymphoma begins with an excisional lymph node biopsy to provide adequate tissue for architectural and immunohistochemical analysis, as fine needle aspiration alone is insufficient to diagnose Hodgkin lymphoma reliably. PET-CT has become the cornerstone of staging and response assessment, providing functional imaging that identifies metabolically active disease sites with greater sensitivity than CT alone. Bone marrow biopsy, previously routine in staging, is usually not required when PET-CT shows no marrow involvement, as PET has high sensitivity for detecting marrow disease. Laboratory evaluation includes complete blood count, lactate dehydrogenase, erythrocyte sedimentation rate, and comprehensive metabolic panel, while pulmonary function tests and echocardiography are obtained before treatment to establish baseline organ function given the pulmonary toxicity of bleomycin and cardiotoxicity of anthracyclines used in standard regimens. Prognostic factors in advanced Hodgkin lymphoma are captured by the International Prognostic Score, which identifies seven adverse features that predict worse outcomes. These adverse factors include age greater than 45 years, stage IV disease, hemoglobin less than 10.5 g/dL, white blood cell count greater than 15,000 per microliter, lymphocyte count less than 600 or less than 8 percent of the white cell differential, male sex, and serum albumin less than 4 g/dL. Each factor present adds one point to the score, with higher scores indicating worse prognosis and potentially guiding treatment intensification. The overall prognosis of Hodgkin lymphoma remains excellent, and even patients with multiple adverse prognostic factors achieve meaningful cure rates with modern therapy. Panel A: Ann Arbor staging diagram showing stages I through IV based on lymph node region involvement above and below the diaphragm. Panel B: PET-CT scan demonstrating FDG-avid lymphadenopathy in mediastinum and neck with staging implications. Panel C: Contiguous spread pattern characteristic of Hodgkin lymphoma with predictable progression through adjacent lymph node groups. Panel D: Stage modifiers including A/B for symptoms, E for extranodal extension, and X for bulky disease definitions. --- ### IV. Hodgkin Lymphoma - Treatment The treatment of Hodgkin lymphoma is tailored to the stage and risk category of the disease, following well-established protocols that have achieved among the highest cure rates of any malignancy. Early favorable-stage disease is treated with 2 cycles of ABVD followed by involved-site radiation therapy, achieving cure rates exceeding 90 percent with minimal treatment burden. Early unfavorable-stage disease, defined by the presence of certain risk factors, receives 4 cycles of ABVD followed by involved-site radiation therapy. Advanced-stage disease is treated with 6 cycles of either ABVD or the newer A+AVD regimen, which substitutes brentuximab vedotin for bleomycin, and the BV-AVD regimen incorporating brentuximab vedotin represents an alternative approach with demonstrated superiority in advanced-stage disease. The ABVD regimen consists of four drugs, each contributing unique mechanisms of action and carrying distinct toxicity profiles that must be monitored throughout treatment. Adriamycin (doxorubicin) is an anthracycline with significant cardiotoxicity risk that requires monitoring of cumulative dose and cardiac function. Bleomycin carries the risk of pulmonary fibrosis, a potentially fatal complication that necessitates baseline and interval pulmonary function testing and prompt discontinuation if pulmonary toxicity develops. Vinblastine is a vinca alkaloid that may cause peripheral neuropathy affecting both sensory and motor function. Dacarbazine is an alkylating agent that commonly causes nausea and vomiting requiring antiemetic prophylaxis. The balanced toxicity profile of ABVD, with no single agent dominating the side effect spectrum, has contributed to its durability as the standard regimen for over three decades. Response-adapted therapy using interim PET-CT scanning has emerged as a key strategy for optimizing treatment intensity in Hodgkin lymphoma, allowing therapy to be tailored based on individual response rather than applied uniformly to all patients. When interim PET scanning performed after 2 cycles demonstrates a negative result indicating excellent treatment response, therapy may be de-escalated by reducing the number of cycles or omitting radiation, sparing patients from unnecessary toxicity. Conversely, when interim PET scanning shows persistent metabolically active disease, treatment may be escalated to a more intensive regimen such as BEACOPP to improve outcomes. End-of-treatment PET scanning determines the final response assessment and guides decisions about surveillance versus additional therapy, making PET imaging an integral component of modern Hodgkin lymphoma management. The management of relapsed or refractory Hodgkin lymphoma follows a stepwise approach that has been enriched by the introduction of novel agents over the past decade. First relapse is typically treated with salvage chemotherapy followed by autologous stem cell transplantation, which remains the standard curative approach for patients who relapse after initial treatment. For patients who relapse following autologous transplant, brentuximab vedotin, an anti-CD30 antibody-drug conjugate that targets the CD30 molecule expressed on Reed-Sternberg cells, provides an effective treatment option. Further relapse or refractory disease is treated with checkpoint inhibitors, specifically pembrolizumab or nivolumab, which exploit the characteristic amplification of the PD-L1 locus found in Hodgkin lymphoma to achieve high response rates. CAR-T cell therapy represents an emerging option for multiply relapsed disease. The overall prognosis for Hodgkin lymphoma remains excellent, with cure rates exceeding 90 percent for early-stage disease, 70 to 80 percent for advanced-stage disease, and an overall cure rate of approximately 85 percent. Panel A: ABVD regimen components showing adriamycin, bleomycin, vinblastine, and dacarbazine with administration schedule and key toxicities. Panel B: PET-adapted treatment algorithm with interim PET guiding therapy intensification or de-escalation based on response. Panel C: Survival curves demonstrating greater than 90% cure rate for early stage and 70-80% for advanced stage Hodgkin lymphoma. Panel D: Relapsed disease treatment pathway through salvage chemotherapy, autologous transplant, brentuximab vedotin, and checkpoint inhibitors. --- ### V. Non-Hodgkin Lymphoma - Classification Non-Hodgkin lymphomas are classified by their clinical behavior into three categories that determine the urgency of treatment and the goals of therapy. Indolent lymphomas, including follicular lymphoma, marginal zone lymphoma, and CLL/SLL, grow slowly over years and may not require immediate treatment, but are generally incurable with standard therapy despite their favorable short-term prognosis. Aggressive lymphomas, exemplified by diffuse large B-cell lymphoma and mantle cell lymphoma, progress over weeks to months and require prompt treatment, but have the potential for cure with appropriate therapy. Highly aggressive lymphomas, including Burkitt lymphoma and lymphoblastic lymphoma, can progress over days to weeks and represent medical emergencies requiring immediate intensive treatment, but paradoxically are curable if treated aggressively with appropriate protocols. The B-cell non-Hodgkin lymphomas account for the vast majority of cases and encompass a wide spectrum of diseases with distinct biology, clinical behavior, and treatment approaches. Diffuse large B-cell lymphoma is the most common subtype at approximately 30 percent of all NHL, followed by follicular lymphoma at approximately 20 percent. Marginal zone lymphoma accounts for approximately 8 percent, CLL/SLL for approximately 7 percent, mantle cell lymphoma for approximately 6 percent, and Burkitt lymphoma for approximately 2 percent of cases. Each subtype is defined by a combination of characteristic histologic features, immunophenotypic markers, and genetic abnormalities that determine its classification and guide treatment selection. The recognition that these are biologically distinct diseases requiring different treatment approaches underscores the importance of accurate pathologic diagnosis in lymphoma management. T-cell non-Hodgkin lymphomas are less common than B-cell lymphomas and generally carry worse prognosis due to limited treatment options and lower response rates to standard chemotherapy. Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is the most common T-cell NHL subtype and carries a poor prognosis. Anaplastic large cell lymphoma is subdivided into ALK-positive disease, which occurs in younger patients and carries a significantly better prognosis with approximately 70 percent cure rates, and ALK-negative disease occurring in older patients with worse outcomes. Mycosis fungoides is a cutaneous T-cell lymphoma that follows an indolent course progressing through patch, plaque, and tumor stages. Adult T-cell leukemia/lymphoma is associated with HTLV-1 viral infection and represents a geographically restricted disease endemic to certain regions. The World Health Organization classification of lymphomas integrates multiple diagnostic modalities to define biologically and clinically meaningful disease entities. Morphologic assessment evaluates cell size and growth pattern to provide initial classification clues. Immunophenotyping using flow cytometry and immunohistochemistry identifies lineage-specific and disease-defining surface and intracellular markers. Cytogenetic analysis detects characteristic translocations that define specific entities, such as the t(14;18) of follicular lymphoma and the t(8;14) of Burkitt lymphoma. Molecular testing identifies gene mutations and expression profiles that further refine classification and prognosis. Clinical features including site of involvement and disease behavior complete the classification, recognizing that the same histologic entity may behave differently depending on the anatomic context of disease presentation. Panel A: Clinical behavior spectrum showing indolent lymphomas with years-long course, aggressive lymphomas progressing over weeks to months, and highly aggressive forms with days to weeks timeline. Panel B: Pie chart of NHL subtypes showing DLBCL at 30%, follicular at 20%, and distribution of other subtypes. Panel C: Comparison of B-cell versus T-cell lymphomas with relative frequencies and representative subtypes. Panel D: WHO classification framework integrating morphology, immunophenotype, cytogenetics, and molecular features. --- ### VI. Diffuse Large B-Cell Lymphoma Diffuse large B-cell lymphoma is the most common non-Hodgkin lymphoma, accounting for approximately 30 percent of all cases, and behaves as an aggressive malignancy requiring prompt diagnosis and treatment. The median age at presentation is 60 to 70 years, and patients typically present with a rapidly enlarging lymph node mass or extranodal tumor, with extranodal involvement present in approximately 40 percent of cases at diagnosis. The rapid growth kinetics of DLBCL mean that delays in diagnosis and treatment can result in significant disease progression, making timely biopsy and workup essential. Despite its aggressive behavior, DLBCL is a potentially curable disease, and the treatment approach is undertaken with curative intent in most patients. Molecular classification of DLBCL has identified biologically distinct subtypes based on the cell of origin that carry different prognoses and may eventually guide treatment selection. The germinal center B-cell (GCB) subtype arises from germinal center B cells and carries a better prognosis with standard therapy. The activated B-cell (ABC) subtype, derived from post-germinal center B cells, demonstrates worse outcomes and has been the focus of efforts to develop subtype-specific therapies. Double-hit lymphomas harboring concurrent MYC and BCL2 or BCL6 rearrangements, and triple-hit lymphomas with all three rearrangements, represent a particularly aggressive subset with worse prognosis that requires more intensive treatment approaches. These molecular distinctions are increasingly incorporated into treatment algorithms as the field moves toward precision medicine for lymphoma. The International Prognostic Index provides a validated prognostic scoring system for DLBCL based on five clinical factors that can be readily assessed at diagnosis. The adverse prognostic factors include age greater than 60 years, stage III or IV disease, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status of 2 or greater, and involvement of more than one extranodal site. The IPI score stratifies patients into four risk groups with markedly different 5-year survival rates: low risk with 0 to 1 factors achieving 75 percent survival, low-intermediate risk with 2 factors at 50 percent, high-intermediate risk with 3 factors at 45 percent, and high risk with 4 to 5 factors at 30 percent survival. These prognostic distinctions help guide treatment decisions, inform patient counseling, and identify patients who may benefit from clinical trials of novel approaches. The standard treatment for DLBCL is R-CHOP, consisting of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone, administered for 6 cycles with curative intent. The addition of rituximab, an anti-CD20 monoclonal antibody, to CHOP chemotherapy represented a major advance that improved cure rates by approximately 10 to 15 percent across all risk groups. Double-hit lymphomas are treated with more intensive regimens, typically dose-adjusted EPOCH-R (DA-EPOCH-R), which includes etoposide and infusional dosing to overcome the aggressive biology. Patients who relapse after initial R-CHOP therapy or have primary refractory disease are treated with salvage chemotherapy followed by autologous stem cell transplantation if chemosensitive disease is demonstrated. For patients with refractory DLBCL who fail salvage therapy, CAR-T cell therapy targeting CD19 has emerged as a transformative treatment option achieving durable remissions in a significant proportion of otherwise incurable patients. Panel A: Cell of origin classification showing germinal center B-cell (GCB) versus activated B-cell (ABC) subtypes with prognostic implications. Panel B: International Prognostic Index calculation with five factors: age, stage, LDH, performance status, and extranodal sites. Panel C: R-CHOP regimen components showing rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone with dosing schedule. Panel D: Double-hit lymphoma with concurrent MYC and BCL2 rearrangements requiring intensified DA-EPOCH-R treatment. --- ### VII. Follicular and Marginal Zone Lymphomas Follicular lymphoma is the second most common non-Hodgkin lymphoma and represents the prototypical indolent B-cell malignancy, characterized by a slow growth pattern, long natural history, and the paradox of being generally incurable with standard therapy despite prolonged survival. The genetic hallmark of follicular lymphoma is the t(14;18) translocation that juxtaposes the BCL2 gene on chromosome 18 with the immunoglobulin heavy chain locus on chromosome 14, resulting in constitutive overexpression of the BCL2 anti-apoptotic protein that prevents normal programmed cell death. Histologically, follicular lymphoma demonstrates a nodular or follicular growth pattern that recapitulates the architecture of normal germinal centers. The clinical presentation is typically painless lymphadenopathy, often generalized, and bone marrow involvement is frequently present at diagnosis, reflecting the widespread nature of this indolent disease. Follicular lymphoma is graded based on the proportion of centroblasts within the neoplastic follicles, a distinction that has important treatment implications. Grades 1 and 2 represent low-grade indolent disease that is managed conservatively, while grade 3A represents an intermediate category. Grade 3B follicular lymphoma is treated as aggressive lymphoma similar to DLBCL rather than as indolent disease, reflecting its more aggressive clinical behavior. A critically important aspect of follicular lymphoma biology is its capacity for histologic transformation to diffuse large B-cell lymphoma, occurring at a rate of approximately 2 to 3 percent per year, which converts an indolent disease into an aggressive one requiring immediate treatment. Clinical signs suggesting transformation include sudden rapid growth of lymph nodes, new or worsening B symptoms, and rising lactate dehydrogenase levels. The treatment of follicular lymphoma is highly stage-dependent and reflects the paradoxical nature of this disease. Limited-stage follicular lymphoma may be treated with radiation alone, which is potentially curative in this select minority of patients. Advanced-stage asymptomatic follicular lymphoma is managed with a watch-and-wait approach, deferring treatment until symptoms develop or disease progresses, as early treatment has not been shown to improve overall survival. When treatment is indicated for advanced symptomatic disease, rituximab-based regimens such as bendamustine-rituximab (BR) or R-CHOP are standard first-line options. Maintenance rituximab administered every 2 months for 2 years following initial treatment prolongs progression-free survival. Relapsed follicular lymphoma has multiple treatment options including lenalidomide with rituximab, PI3K inhibitors, and newer targeted agents, reflecting the chronic relapsing nature of this disease that typically requires sequential therapies over many years. Marginal zone lymphomas arise from the marginal zone of lymphoid follicles and are classified into three distinct subtypes based on the anatomic site of origin. MALT (mucosa-associated lymphoid tissue) lymphoma is the most common subtype and occurs at extranodal sites including the stomach, lungs, and skin, reflecting the acquisition of lymphoid tissue at mucosal surfaces in response to chronic antigenic stimulation. Splenic marginal zone lymphoma involves the spleen and bone marrow, while nodal marginal zone lymphoma affects lymph nodes. Gastric MALT lymphoma is of particular clinical importance because of its strong association with Helicobacter pylori infection, present in approximately 90 percent of cases, and the remarkable observation that eradication of H. pylori with antibiotic therapy produces lymphoma regression in the majority of patients. When gastric MALT lymphoma is refractory to H. pylori eradication, radiation therapy or rituximab may be employed, and the presence of the t(11;18) translocation predicts poor response to antibiotic therapy alone, indicating the need for alternative treatment approaches. Panel A: Follicular architecture on histology with t(14;18) translocation resulting in BCL2 overexpression preventing apoptosis. Panel B: Grading system based on centroblast count showing grade 1-2 indolent behavior versus grade 3B treated as aggressive lymphoma. Panel C: Treatment algorithm from watch and wait for asymptomatic disease through rituximab-based regimens to maintenance therapy. Panel D: Transformation risk to DLBCL at 2-3% per year with clinical indicators of sudden growth and rising LDH. --- ### VIII. Mantle Cell and Burkitt Lymphoma Mantle cell lymphoma arises from B cells of the mantle zone surrounding normal germinal centers and is defined by the t(11;14) translocation that leads to overexpression of cyclin D1, a cell cycle regulatory protein that drives proliferation. Despite its origin from a defined anatomic compartment of the lymph node, mantle cell lymphoma typically behaves as an aggressive disease, though some patients demonstrate a more indolent clinical variant. Patients commonly present at advanced stage with gastrointestinal involvement, which is a characteristic feature of mantle cell lymphoma that distinguishes it from many other lymphoma subtypes. The immunophenotype includes CD5 positivity, similar to CLL, but critically CD23 is negative in mantle cell lymphoma, a distinction that helps differentiate it from CLL which is CD23 positive. Treatment for young, fit patients involves intensive chemotherapy followed by autologous stem cell transplantation to achieve durable remissions, while older patients are treated with less intensive bendamustine-rituximab with or without maintenance rituximab. Relapsed mantle cell lymphoma is treated with BTK inhibitors such as ibrutinib, venetoclax, or increasingly with CAR-T cell therapy, reflecting the ongoing challenge of this difficult-to-cure lymphoma. Burkitt lymphoma is the prototypical highly aggressive lymphoma, characterized by an extraordinarily rapid doubling time of approximately 24 hours that makes it one of the fastest-growing human malignancies and a genuine medical emergency requiring immediate diagnosis and treatment. The defining genetic abnormality is the t(8;14) translocation that places the MYC oncogene under control of the immunoglobulin heavy chain enhancer, resulting in dramatic MYC overexpression that drives relentless cellular proliferation. Histologically, Burkitt lymphoma demonstrates a characteristic "starry sky" pattern created by benign macrophages engulfing apoptotic debris scattered among sheets of rapidly dividing tumor cells. The disease exists in three clinical variants: endemic Burkitt lymphoma, found primarily in Africa, that characteristically involves the jaw and facial bones and is strongly associated with Epstein-Barr virus; sporadic Burkitt lymphoma, more common in Western countries, that typically presents as a gastrointestinal or abdominal mass with less frequent EBV association; and immunodeficiency-associated Burkitt lymphoma occurring in the setting of HIV infection. The treatment of Burkitt lymphoma requires intensive multi-agent chemotherapy regimens such as DA-EPOCH-R or Hyper-CVAD that are administered with curative intent, recognizing that the extremely rapid growth rate demands immediate and aggressive intervention. Central nervous system prophylaxis is mandatory in all patients with Burkitt lymphoma due to the high risk of leptomeningeal spread, administered as intrathecal chemotherapy and incorporated into systemic regimens. Tumor lysis syndrome prevention is critical given the massive tumor burden and rapid cell death induced by effective therapy, requiring aggressive hydration, allopurinol, and frequently rasburicase for rapid uric acid reduction in high-risk patients. Despite the aggressive nature of Burkitt lymphoma, high cure rates are achievable when treatment is initiated promptly and administered at full intensity with appropriate supportive care. The key distinctions between mantle cell lymphoma and Burkitt lymphoma highlight important differences in genetics, biology, and clinical approach that guide diagnostic workup and treatment selection. Mantle cell lymphoma is defined by the t(11;14) translocation driving cyclin D1 overexpression, while Burkitt lymphoma carries the t(8;14) translocation activating MYC. Both are aggressive diseases, but Burkitt lymphoma is classified as highly aggressive with a near-100 percent Ki-67 proliferation index compared to the high but less extreme Ki-67 seen in mantle cell lymphoma. CD5 is positive in mantle cell lymphoma but negative in Burkitt lymphoma, providing an important immunophenotypic distinction. Treatment intensity also differs, with mantle cell lymphoma requiring transplant consolidation in fit patients and Burkitt lymphoma requiring intensive chemotherapy regimens with mandatory CNS prophylaxis and vigilant tumor lysis syndrome prevention with rasburicase. Panel A: Mantle cell lymphoma with t(11;14) cyclin D1 translocation, CD5 positivity, and characteristic GI involvement on endoscopy. Panel B: Burkitt lymphoma showing t(8;14) MYC-IGH translocation with starry sky histology from macrophages containing apoptotic debris. Panel C: Comparison of endemic Burkitt with jaw involvement versus sporadic form with abdominal presentation. Panel D: Treatment intensity comparison with mantle cell requiring transplant consolidation and Burkitt requiring CNS prophylaxis and TLS prevention with rasburicase. --- ### IX. T-Cell and Special Lymphomas Peripheral T-cell lymphoma not otherwise specified is the most common T-cell non-Hodgkin lymphoma and carries a notably poor prognosis with only approximately 30 percent 5-year survival, reflecting both the aggressive biology of T-cell malignancies and the limited efficacy of standard chemotherapy regimens. Treatment typically follows the CHOP regimen used in B-cell lymphomas, followed by consolidation with stem cell transplantation in eligible patients to improve outcomes beyond what chemotherapy alone can achieve. Newer agents including romidepsin, pralatrexate, and brentuximab vedotin have provided additional options for relapsed or refractory disease, though complete and durable responses remain challenging to achieve. The overall inferior outcomes in T-cell lymphomas compared to B-cell lymphomas have driven intensive research efforts to develop more effective targeted therapies. Anaplastic large cell lymphoma is an important T-cell lymphoma subtype that is divided into two biologically distinct entities based on expression of the anaplastic lymphoma kinase (ALK) protein. ALK-positive anaplastic large cell lymphoma occurs in young patients and carries a significantly better prognosis with approximately 70 percent cure rates, driven by the ALK fusion protein that serves as a targetable oncogenic driver. ALK-negative disease occurs in older patients, demonstrates worse prognosis, and lacks the favorable biology conferred by ALK expression. Treatment includes CHOP-based chemotherapy for both subtypes, with brentuximab vedotin, an anti-CD30 antibody-drug conjugate, providing an important addition that exploits the characteristic CD30 expression shared by all anaplastic large cell lymphomas. Mycosis fungoides is the most common cutaneous T-cell lymphoma and follows a characteristic clinical progression through distinct stages of skin involvement. The disease begins in the patch stage with flat, scaly lesions that may mimic eczema or other benign dermatoses, progressing to the plaque stage with raised, thicker lesions, and ultimately to the tumor stage with nodular lesions that may ulcerate. Sezary syndrome represents the leukemic variant of cutaneous T-cell lymphoma, characterized by erythroderma with generalized skin redness and involvement of the peripheral blood by malignant T cells with characteristic cerebriform nuclei. Treatment is stage-dependent, with early-stage disease managed using topical therapies including corticosteroids, nitrogen mustard, and phototherapy, while advanced-stage disease requires systemic therapy with agents including brentuximab vedotin, mogamulizumab, and histone deacetylase inhibitors (HDACi). Primary central nervous system lymphoma is a rare and challenging form of lymphoma that arises within the brain, spinal cord, eyes, or leptomeninges without evidence of systemic disease. The vast majority of primary CNS lymphomas are diffuse large B-cell lymphoma, and the disease is strongly associated with HIV/AIDS and other forms of immunosuppression, though it also occurs in immunocompetent patients. Treatment is fundamentally different from systemic DLBCL because standard R-CHOP does not adequately penetrate the blood-brain barrier, and instead relies on high-dose methotrexate-based regimens that achieve sufficient CNS drug levels. Whole brain radiation therapy, while effective, is avoided when possible due to significant neurotoxicity including cognitive impairment, particularly in older patients. The prognosis of primary CNS lymphoma remains worse than that of systemic DLBCL despite therapeutic advances. Panel A: Peripheral T-cell lymphoma histology with poor prognosis and treatment approach including CHOP followed by transplant. Panel B: Mycosis fungoides progression from patch stage through plaque stage to tumor stage with Sezary syndrome showing erythroderma. Panel C: Anaplastic large cell lymphoma comparison of ALK-positive with good prognosis versus ALK-negative with worse outcomes. Panel D: Primary CNS lymphoma management with high-dose methotrexate-based regimens and avoidance of whole brain radiation when possible. --- ### X. Supportive Care and Complications Tumor lysis syndrome represents the most acute metabolic emergency in lymphoma management and occurs most frequently with Burkitt lymphoma due to its extreme proliferative rate, though it can complicate treatment of any aggressive lymphoma with high tumor burden. Prevention is the cornerstone of management and includes aggressive intravenous hydration to maintain high urine output, allopurinol to inhibit uric acid production, and rasburicase for rapid enzymatic degradation of uric acid in patients at highest risk. Careful monitoring of potassium, phosphate, uric acid, calcium, and creatinine is essential during the initial treatment period, as the metabolic derangements of tumor lysis syndrome can cause fatal cardiac arrhythmias from hyperkalemia, acute renal failure from uric acid and calcium phosphate crystal precipitation, and seizures from hypocalcemia. Early recognition and aggressive electrolyte management are critical, with dialysis reserved for severe cases unresponsive to medical therapy. Infectious complications pose a significant risk throughout lymphoma treatment, with the nature of infection risk varying by treatment phase and the specific agents used. During periods of chemotherapy-induced neutropenia, patients are susceptible to bacterial and fungal infections requiring prompt empiric antibiotic therapy for febrile neutropenia. Post-rituximab therapy carries a specific risk of hepatitis B virus reactivation, making screening with hepatitis B surface antigen and core antibody testing mandatory before initiating any rituximab-containing regimen, with prophylactic antiviral therapy for patients with evidence of prior infection. Certain chemotherapy regimens also necessitate prophylaxis against Pneumocystis jirovecii pneumonia (PJP) with trimethoprim-sulfamethoxazole, as the combination of disease-related and treatment-induced immunosuppression creates significant risk for this opportunistic infection. Late effects of lymphoma treatment represent an increasingly important consideration as cure rates improve and more patients become long-term survivors who must live with the consequences of their therapy. Anthracycline chemotherapy, particularly doxorubicin, carries a cumulative dose-related risk of cardiomyopathy that may manifest years after treatment completion. Bleomycin, used in the ABVD regimen for Hodgkin lymphoma, can cause pulmonary fibrosis that may be progressive and life-threatening. Radiation therapy is associated with second malignancies in the radiation field, coronary artery disease from mediastinal irradiation, and hypothyroidism from neck irradiation. Alkylating agents including cyclophosphamide carry risks of secondary myelodysplastic syndrome and acute myeloid leukemia, typically developing 5 to 10 years after exposure, as well as infertility from gonadal toxicity. Survivorship care for lymphoma patients requires a structured approach that addresses the multiple domains of potential long-term morbidity. Surveillance for second cancers is essential, with screening programs tailored to the specific exposures received during treatment. Cardiac monitoring with echocardiography and cardiovascular risk factor management is important for patients who received anthracyclines or mediastinal radiation. Pulmonary function testing should be performed for symptomatic patients who received bleomycin. Fertility should be discussed before treatment initiation and preservation options offered, as both alkylating agents and radiation can cause permanent gonadal damage. Psychosocial support addressing quality of life, anxiety about recurrence, and the long-term psychological impact of cancer diagnosis and treatment represents an essential component of comprehensive survivorship care. Panel A: Tumor lysis syndrome prevention protocol with hydration, allopurinol, and rasburicase for high-risk patients with electrolyte monitoring. Panel B: Post-rituximab HBV reactivation risk requiring hepatitis B screening and prophylaxis with antiviral therapy. Panel C: Late effects of treatment showing anthracycline cardiotoxicity, bleomycin pulmonary fibrosis, and radiation-induced second malignancies. Panel D: Survivorship care plan elements including cardiac surveillance, pulmonary function monitoring, fertility assessment, and psychosocial support. --- ## Summary - Hodgkin lymphoma: Reed-Sternberg cells; CD15+/CD30+; contiguous spread; highly curable - Classical HL: ABVD is standard; PET-adapted therapy; 85% cure rate - NHL: Heterogeneous; B-cell (85%) vs T-cell (15%); indolent vs aggressive - DLBCL: Most common NHL; R-CHOP standard; IPI for prognosis; CAR-T for refractory - Follicular: t(14;18) BCL2; indolent; watch and wait or rituximab-based; not curable - Marginal zone (MALT): H. pylori associated gastric; treat infection first - Mantle cell: t(11;14) cyclin D1; aggressive; transplant in fit patients - Burkitt: t(8;14) MYC; highly aggressive; intensive chemo + CNS prophylaxis - T-cell lymphomas: Generally worse prognosis; newer targeted agents available --- ## Key Terms | Term | Definition | |------|------------| | Reed-Sternberg cell | Large cells with owl-eye nuclei; pathognomonic of HL | | B symptoms | Fever, night sweats, >10% weight loss | | Indolent lymphoma | Slow-growing; often incurable but long survival | | DLBCL | Diffuse large B-cell lymphoma | | R-CHOP | Rituximab + CHOP chemotherapy | | t(14;18) | BCL2 translocation in follicular lymphoma | | t(8;14) | MYC translocation in Burkitt lymphoma | | CAR-T | Chimeric antigen receptor T-cell therapy | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*