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7. Lymphogranulomatosis
Kebekova Aizat Ashimzhanovna
Teacher, Clinical Discipline 1, International Medical Faculty, Osh state university, Osh Kyrgyzstan
Prayag Das
Prayagdas191101@gmail.com
5th Year, Student, International Medical Faculty, Osh state university, Osh Kyrgyzstan
Abstract
Hodgkin Lymphoma (HL), historically termed Lymphogranulomatosis maligna, represents a distinct B-cell malignancy characterized by the scarcity of neoplastic Hodgkin and Reed-Sternberg (HRS) cells within an extensive inflammatory microenvironment. This treatise traces the evolution of HL from its initial anatomical description by Thomas Hodgkin in 1832 through the histological definition by Sternberg and Reed, to the modern era of precision oncology. It examines the unique pathobiology of the HRS cell, including its "crippled" germinal center origin and reliance on the PD-1/PD-L1 axis for immune evasion. The report details current WHO classification systems and the paradigm shift in therapeutic management for advanced-stage disease, highlighting the transition from traditional chemotherapy (ABVD, BEACOPP) to antibody-drug conjugates (Brentuximab Vedotin) and checkpoint inhibitors (Nivolumab) as evidenced by the landmark ECHELON-1, SWOG S1826, and HD21 trials. Finally, it addresses the critical domain of survivorship, focusing on the mitigation of late effects such as secondary malignancies and cardiovascular disease in a population with high cure rates.
Keywords: Hodgkin Lymphoma, Lymphogranulomatosis, Reed-Sternberg Cell, Immunotherapy, Nivolumab, Brentuximab Vedotin, BrECADD, SWOG S1826, Survivorship.
The entity historically designated as Lymphogranulomatosis maligna, and universally recognized in contemporary medicine as Hodgkin Lymphoma (HL), represents one of the most intellectually compelling chapters in the annals of human pathology. It is a disease that has defied simple categorization for nearly two centuries, straddling the conceptual boundary between an inflammatory granulomatous reaction and a true neoplastic process.1 Unlike the vast majority of malignancies, where the tumor mass is composed almost exclusively of clonal cancer cells, the hallmark of Lymphogranulomatosis is a tumor microenvironment wherein the malignant cells—the Hodgkin and Reed-Sternberg (HRS) cells—are a distinct minority, often constituting less than 1% of the cellular infiltrate.2 This unique histological architecture, characterized by a sea of non-neoplastic inflammatory cells surrounding isolated islands of malignant giants, fueled decades of debate regarding its etiology and necessitated the archaic term "lymphogranulomatosis" to describe its granuloma-like appearance.5
Today, Hodgkin Lymphoma stands as a paradigm of success in modern oncology. Once an invariably fatal diagnosis with a trajectory of relentless adenopathy and cachexia, it is now a highly curable malignancy, with five-year survival rates exceeding 88% in developed nations.6 This transformation from a death sentence to a manageable condition was not serendipitous but the result of rigorous, stepwise scientific inquiry—from the anatomical descriptions of Thomas Hodgkin and Samuel Wilks to the microscopic elucidations of Carl Sternberg and Dorothy Reed, and finally to the therapeutic revolutions led by Henry Kaplan and Vincent DeVita.8
This report provides an exhaustive analysis of the disease, tracing its journey from the 19th-century descriptive era to the 21st-century era of precision immunotherapy. It integrates data from seminal medical textbooks, including Williams Hematology and Wintrobe’s Clinical Hematology, alongside landmark clinical trials such as ECHELON-1, SWOG S1826, and HD21, to offer a definitive reference on the current state of the science.10
To understand the complexity of Hodgkin Lymphoma, one must appreciate the historical context of its discovery and the etymological struggle to define it. The term Lymphogranulomatosis is not merely an old synonym; it reflects the profound biological confusion that persisted for a century regarding the nature of the disease.
The narrative begins in 1832 at Guy’s Hospital in London, where Thomas Hodgkin, a pathologist and Quaker physician committed to humanitarian causes, published his seminal paper, On Some Morbid Appearances of the Absorbent Glands and Spleen, in the Medico-Chirurgical Transactions.14 In this text, Hodgkin described seven patients who presented with simultaneous enlargement of the lymph nodes (absorbent glands) and spleen. His critical insight was the differentiation of this condition from typical inflammation or suppuration; he noted that the glandular enlargement appeared to be a primary pathology rather than a secondary reaction to adjacent infection.16
It is a point of historical nuance that Hodgkin likely did not describe a single disease entity. Retrospective analyses of his preserved specimens suggest that his case series included examples of tuberculosis, non-Hodgkin lymphoma, and syphilitic adenitis, in addition to true Hodgkin lymphoma.9 Nevertheless, his recognition of a primary system-wide disorder of the lymphatic system was revolutionary. The condition remained largely obscure until 1865, when Samuel Wilks, also of Guy’s Hospital, independently described similar cases. Upon discovering Hodgkin’s earlier publication, Wilks magnanimously named the condition "Hodgkin's disease," securing his predecessor's legacy.8
As the 19th century closed, the focus shifted from gross anatomy to microscopy. In 1898, the Austrian pathologist Carl Sternberg published a detailed description of the giant multinucleated cells that characterize the disease. However, Sternberg interpreted these cells as a variant of tuberculosis, influenced by the high prevalence of TB at the time. Consequently, the disease was widely referred to in Germanic literature as Lymphogranulomatosis maligna or Paltauf-Sternberg disease, reflecting the belief that it was a granulomatous inflammatory process caused by an infectious agent.1
In 1902, Dorothy Reed, an American pathologist at Johns Hopkins Hospital, definitively refuted the tubercular origin. In her paper, On the Pathological Changes in Hodgkin Disease, with Especial Reference to its Relation to Tuberculosis, she provided clear illustrations of the diagnostic cells and demonstrated through animal inoculation that the tissue was not infectious for tuberculosis.3 She argued that the condition was a distinct pathological entity, separate from both TB and other malignancies. Her work cemented the eponymous "Reed-Sternberg cell" in the medical lexicon, although the term Lymphogranulomatosis persisted in Europe well into the mid-20th century as a nod to the inflammatory background of the tumor.1
The early management of Hodgkin disease was palliative, utilizing agents such as arsenic and Fowler’s solution with minimal success.8 The first breakthrough occurred with the advent of radiation therapy. In 1902, shortly after Roentgen’s discovery of X-rays, Pusey and Senn noted remarkable regression of lymph nodes in HL patients.8 This was refined in the 1960s by Henry Kaplan at Stanford, who utilized the linear accelerator to deliver curative doses of radiation to extended fields (Mantle field), proving that localized disease could be eradicated.8
Simultaneously, the development of combination chemotherapy at the National Cancer Institute (NCI) transformed the outlook for advanced-stage patients. In 1964, Vincent DeVita and colleagues introduced the MOPP regimen (Mustard, Vincristine, Procarbazine, Prednisone), the first regimen to cure advanced cancer in adults.8 This was later superseded by the ABVD regimen (Doxorubicin, Bleomycin, Vinblastine, Dacarbazine) developed by Bonadonna in Italy, which offered equal efficacy with reduced leukemogenic and sterility risks.20 These historical milestones are not merely footnotes; they established the paradigms of combined modality therapy and salvage protocols that underpin modern guidelines.
The biological distinctiveness of Hodgkin lymphoma lies in the complex interplay between the malignant HRS cell and its supportive microenvironment. This relationship explains the "granulomatous" appearance that confounded early pathologists and provides the targets for modern immunotherapy.
The pathognomonic cell of classical Hodgkin Lymphoma (cHL) is the Reed-Sternberg cell, a large (20–50 micrometers) cell with abundant cytoplasm and a bilobed or multilobed nucleus containing prominent, eosinophilic, inclusion-like nucleoli.3 This morphology gives the nucleus an "owl’s eye" appearance. Mononuclear variants are termed Hodgkin cells.
For decades, the cellular origin of the HRS cell was a mystery. It expressed markers of various lineages (T-cell, myeloid, B-cell) inconsistently. It was not until the advent of single-cell microdissection and polymerase chain reaction (PCR) techniques in the 1990s that researchers definitively established the HRS cell as a clonal B-cell.3 However, it is a "crippled" B-cell. These cells originate from germinal center B-cells that have acquired disadvantageous somatic hypermutations in their immunoglobulin variable region genes. In a physiological state, such cells would undergo apoptosis. In HL, however, they escape this fate through various mechanisms, including latent EBV infection or constitutive activation of the NF-kappaB signaling pathway.3
Crucially, the HRS cell undergoes a process of reprogramming where it downregulates typical B-cell lineage markers. It frequently loses expression of CD20, CD79a, and the B-cell receptor (BCR), while upregulating markers typically associated with other lineages or activation states, such as CD15 and CD30.4
Table 1: Immunophenotypic Profile of Classical Hodgkin Lymphoma (cHL)
The HRS cells do not grow in isolation; they actively recruit and educate a supportive niche. They secrete a constellation of cytokines (e.g., IL-5, IL-13, CCL17, CCL22) that attract a specific infiltrate of T-cells, eosinophils, macrophages, fibroblasts, and plasma cells.22 This infiltrate is not merely a host reaction against the tumor; it is a tumor-promoting scaffold.
● T-Regulatory Cells (Tregs): HRS cells recruit Tregs to suppress cytotoxic T-cell responses, creating an immunologically privileged site.
● Checkpoint Ligands: A defining molecular feature of cHL is the near-universal alteration of the 9p24.1 genetic locus, which leads to the amplification of the CD274 (PD-L1) and PDCD1LG2 (PD-L2) genes. Consequently, HRS cells massively overexpress PD-L1, which binds to PD-1 on surrounding T-cells, inducing T-cell exhaustion and preventing immune elimination.20 This mechanism is the "Achilles' heel" targeted by checkpoint inhibitors like Nivolumab.
● CD30-CD30L Interaction: The interaction between CD30 on HRS cells and CD30 Ligand on mast cells and eosinophils provides reciprocal survival signals.22
The classification of Hodgkin lymphoma has been refined over decades to reflect the distinct biological and clinical behaviors of its subtypes. The 5th Edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours (2022/2024) divides the disease into two broad categories: Classical Hodgkin Lymphoma (cHL) and Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL).25
Accounting for approximately 95% of all cases, cHL is characterized by CD30+/CD15+ HRS cells. It is subdivided into four histological variants:
1. Nodular Sclerosis cHL (NSCHL):
○ Epidemiology: The most common subtype (60-70%), particularly prevalent in adolescents and young adults, with a slight female predominance.2
○ Pathology: Characterized by broad, bi-refringent collagen bands that divide the lymphoid tissue into circumscribed nodules. The neoplastic cells often appear as "lacunar cells," a fixation artifact where the cytoplasm retracts, leaving the cell sitting in an empty space or lacuna.27
○ Clinical: Frequently involves the mediastinum (80% of cases) and supraclavicular nodes.23
2. Mixed Cellularity cHL (MCCHL):
○ Epidemiology: Accounts for 20-25% of cases. More common in older adults, males, and patients with HIV.
○ Pathology: A heterogeneous infiltrate without sclerotic bands. It has a strong association with EBV positivity (approx. 75% of cases).6
○ Clinical: Patients often present with advanced stage (III/IV) and systemic B-symptoms.23
3. Lymphocyte-Rich cHL (LRCHL):
○ Epidemiology: Uncommon (~5%).
○ Pathology: Features scattered HRS cells in a background of abundant small lymphocytes. It can be morphologically difficult to distinguish from NLPHL, but immunophenotyping (CD30+, CD20-) confirms the cHL diagnosis.2
○ Clinical: Usually presents with early-stage peripheral lymphadenopathy and has an excellent prognosis.27
4. Lymphocyte-Depleted cHL (LDCHL):
○ Epidemiology: Rare (<1%). Historically overdiagnosed; many cases classified as LDCHL in the past are now recognized as diffuse large B-cell lymphoma (DLBCL) or anaplastic large cell lymphoma.
○ Pathology: Characterized by a paucity of lymphocytes and a relative abundance of HRS cells and sarcomatoid variants. Reticulin fibrosis is common.27
○ Clinical: Associated with HIV infection and elderly patients; typically presents with widespread abdominal disease and aggressive behavior.2
This entity represents about 5% of cases and is biologically distinct from cHL, bearing a closer resemblance to indolent B-cell non-Hodgkin lymphomas.2
● Neoplastic Cell: The "Lymphocytic and Histiocytic" (L&H) cell, colloquially known as the "popcorn cell" due to its multi-lobated, vesicular nucleus.2
● Immunophenotype: In sharp contrast to cHL, L&H cells retain the B-cell program. They are CD20 positive, CD45 positive, Bcl-6 positive, and usually CD30/CD15 negative.4
● Clinical Course: The disease typically presents as localized, slow-growing lymphadenopathy (often stage I/II). While highly treatable, it has a tendency for late relapses and a higher rate of transformation to diffuse large B-cell lymphoma (DLBCL) compared to cHL.29
● Management: Because of its CD20 expression, therapy often incorporates Rituximab (an anti-CD20 monoclonal antibody), unlike standard cHL therapy.29
Hodgkin lymphoma exhibits a unique bimodal age distribution in industrialized nations. The first peak occurs in young adulthood (ages 15–35), and the second peak occurs in later life (ages 55+).6 This pattern is less pronounced in developing countries, where the early peak often occurs in childhood rather than young adulthood.
The epidemiology of young-adult cHL shares similarities with paralytic poliomyelitis, leading to the "delayed infection" hypothesis. In childhood, exposure to common pathogens (like EBV) is usually asymptomatic. However, in individuals with higher socioeconomic status (SES) and smaller family sizes, exposure to these pathogens may be delayed until adolescence or young adulthood. At this later age, the immune system's response is more vigorous, potentially leading to the aberrant germinal center reaction that triggers Hodgkin lymphoma.1 This model explains why the incidence of the Nodular Sclerosis subtype (the young adult form) rises with industrialization and SES.6
● Epstein-Barr Virus (EBV): EBV is a crucial cofactor. The virus is detected in the tumor cells of approximately 40% of cHL cases in the West and nearly 100% of cases in parts of Africa and Latin America.1 The viral Latent Membrane Protein 1 (LMP1) mimics a constitutive CD40 signal, and LMP2A mimics the B-cell receptor signal. Together, these viral proteins provide the survival signals necessary to rescue the "crippled" germinal center B-cell from apoptosis.22
● HIV: Patients with HIV have a 5- to 15-fold increased risk of HL. Interestingly, the incidence of HL in HIV patients has not decreased significantly with the advent of antiretroviral therapy (ART), unlike other AIDS-defining cancers. HIV-associated HL is almost always EBV-positive and presents with aggressive features.6
The classic presentation of Hodgkin lymphoma is the detection of a painless, enlarging mass in the neck (cervical) or supraclavicular region. The nodes are typically firm and rubbery.6
● Constitutional "B" Symptoms: Systemic symptoms are critical for staging and prognosis. They include:
○ Fever: Unexplained temperature >38 degrees C (100.4 degrees F), sometimes following a cyclic pattern known as Pel-Ebstein fever (days of high fever alternating with days of normal temperature), though this classic sign is rarely seen today.6
○ Night Sweats: Drenching sweats that require changing bedclothes.2
○ Weight Loss: Unexplained loss of >10% of body weight over 6 months.6
● Pruritus: Severe, generalized itching is a frequent paraneoplastic symptom, often preceding the diagnosis by months. It is not considered a "B" symptom for staging purposes but is clinically significant.6
● Alcohol-Induced Pain: A rare but specific symptom where ingestion of alcohol causes immediate pain in the involved lymph nodes, likely due to vasodilation within the fibrous capsule.2
Staging describes the anatomical extent of the disease and guides treatment intensity. The Lugano Classification (2014) has replaced the older Ann Arbor system, incorporating modern imaging capabilities (PET/CT).28
Table 2: The Lugano Staging Classification for Hodgkin Lymphoma
● Modifiers:
○ A: No systemic symptoms.
○ B: Presence of fever, night sweats, or weight loss.
○ X (Bulky Disease): A nodal mass >10 cm in diameter or a mediastinal mass exceeding one-third of the transthoracic diameter on chest X-ray/CT. Bulky disease is an independent risk factor requiring more intensive therapy.33
Current guidelines mandate 18F-FDG PET/CT for initial staging and response assessment. Hodgkin lymphoma is intensely FDG-avid. The response to treatment is graded using the Deauville 5-Point Scale, which compares tumor uptake to the uptake in the mediastinal blood pool and liver.34
● Scores 1-3: Considered a complete metabolic response (Negative).
● Scores 4-5: Considered treatment failure or residual active disease (Positive).
● This metabolic assessment allows for "response-adapted therapy," where treatment is escalated or de-escalated based on early PET results.20
The treatment of Hodgkin lymphoma has undergone a paradigm shift in the 2020s. While traditional chemotherapy remains the backbone, the integration of antibody-drug conjugates (Brentuximab Vedotin) and immune checkpoint inhibitors (Nivolumab, Pembrolizumab) has redefined the standard of care, particularly for advanced stages.
The goal in early-stage disease is to maintain the high cure rate (>90%) while minimizing long-term toxicity. The standard approach is Combined Modality Treatment (CMT).
1. Favorable Disease: Typically treated with 2 cycles of ABVD followed by Involved-Site Radiation Therapy (ISRT) at a low dose (20 Gy).
2. Unfavorable Disease: Defined by risk factors such as bulky disease, elevated ESR, or multiple nodal sites. Treated with 4 cycles of ABVD + ISRT (30 Gy).27
3. PET-Adapted Strategy: If the PET scan after 2 cycles (PET-2) is negative, Bleomycin (the component responsible for lung toxicity) is often dropped for the remaining cycles (regimen becomes AVD). In select favorable patients, radiation may be omitted entirely to spare breast and heart tissue, though this slightly increases the risk of local relapse.20
This represents the area of most rapid change. For decades, the choice was between the less toxic ABVD regimen (US/UK standard) and the more toxic but more effective escalated BEACOPP regimen (German standard). Recent trials have introduced a third and fourth option that are now preferred.
1. The ECHELON-1 Era (BV-AVD)
The ECHELON-1 phase 3 trial compared standard ABVD against BV-AVD (Brentuximab Vedotin + AVD). Brentuximab is an antibody-drug conjugate that delivers a microtubule poison (MMAE) directly to CD30+ cells.
● Outcome: BV-AVD showed a superior Overall Survival (OS) benefit compared to ABVD.20
● Toxicity: BV-AVD eliminates Bleomycin (removing pulmonary risk) but increases the rate of peripheral neuropathy and neutropenia requiring growth factor support.29
2. The SWOG S1826 Revolution (Nivo-AVD)
Published in the New England Journal of Medicine in late 2024, the SWOG S1826 trial is considered practice-changing. It compared Nivolumab-AVD (N-AVD) against BV-AVD in patients with Stage III/IV disease.
● Mechanism: Nivolumab blocks PD-1, allowing the patient's T-cells to attack the PD-L1-expressing HRS cells.
● Efficacy: At a median follow-up of 2.1 years, N-AVD demonstrated a 92% Progression-Free Survival (PFS) compared to 83% for BV-AVD.12 This benefit was seen across all ages and prognostic scores.
● Safety: N-AVD was significantly less toxic than BV-AVD. It caused less peripheral neuropathy and fewer treatment discontinuations.12
● Current Status: The NCCN Guidelines (2025 version) now list Nivo-AVD as a preferred Category 1 recommendation for primary treatment of advanced cHL.37
3. The European Approach (HD21 and BrECADD)
The German Hodgkin Study Group (GHSG), having long championed escalated BEACOPP, sought to reduce its toxicity while maintaining its high efficacy. The HD21 trial compared eBEACOPP against BrECADD (Brentuximab, Etoposide, Cyclophosphamide, Doxorubicin, Dacarbazine, Dexamethasone).
● Outcome: BrECADD was non-inferior to eBEACOPP in efficacy (PFS >90%) but drastically superior in tolerability. Crucially, it significantly reduced gonadal toxicity, preserving fertility in both men and women.13
● Administration: BrECADD is given for only 4-6 cycles (guided by PET), completing therapy in just 3-4 months compared to the longer ABVD or N-AVD courses.39
Table 3: Comparison of Modern Frontline Regimens for Advanced HL
For the 10-15% of patients who fail frontline therapy, the standard of care remains salvage chemotherapy (e.g., ICE, DHAP) followed by High-Dose Chemotherapy and Autologous Stem Cell Transplantation (ASCT).29
● Post-Transplant: Patients at high risk of relapse after ASCT are often placed on maintenance therapy with Brentuximab Vedotin, which has been shown to improve progression-free survival.29
● Multiply Relapsed: For patients who relapse after transplant or are ineligible, PD-1 inhibitors (Pembrolizumab, Nivolumab) are highly effective, inducing remissions in >65% of cases.20 Novel therapies like CD30-directed CAR-T cells and bispecific antibodies (AFM13) are currently showing promise in clinical trials for this population.40
The high cure rates of Hodgkin lymphoma have created a large population of survivors, making the management of late effects a critical component of care. The concept of "Survivorship" in HL is distinct because the patients are often cured in their 20s and live for another 50-60 years, allowing ample time for the delayed toxicities of chemotherapy and radiation to manifest.
Survivors of HL have a significantly elevated risk of developing second cancers.
● Breast Cancer: Young women treated with mantle field radiation have a risk of breast cancer similar to BRCA mutation carriers. Screening with MRI typically begins 8-10 years post-treatment.41
● Lung Cancer: The risk is dose-dependent on radiation and alkylating agents (procarbazine) and is multiplicatively increased by smoking.
● Leukemia (t-AML/MDS): Therapy-related myeloid neoplasms can occur 2-10 years after treatment with alkylating agents or topoisomerase II inhibitors (etoposide, doxorubicin).6
Cardiotoxicity is the leading non-malignant cause of death in HL survivors.
● Anthracyclines (Doxorubicin): Cause direct myocyte damage.
● Radiation: Mediastinal radiation accelerates coronary artery atherosclerosis, valvular fibrosis, and conduction defects. Modern techniques like Deep Inspiration Breath Hold (DIBH) and Proton Therapy are used to minimize the dose to the heart.41
The older regimens (MOPP, escalated BEACOPP) caused permanent azoospermia in most men and premature ovarian failure in women. The shift to ABVD, and more recently BrECADD (which replaces procarbazine with dacarbazine), has drastically improved fertility preservation rates.38
The trajectory of Lymphogranulomatosis—from a confusing "granulomatous" inflammation to a curable neoplasm—parallels the maturity of modern medicine. We have moved from the era of non-specific poisons (nitrogen mustard) to the era of precision medicine (anti-CD30, anti-PD-1).
The immediate future of Hodgkin lymphoma management lies in "de-escalation for the many and escalation for the few." Techniques like liquid biopsy (circulating tumor DNA or ctDNA) are currently being validated to detect molecular residual disease (MRD) with greater sensitivity than PET scans.42 This may allow oncologists to identify the subset of patients who are cured after just 2 cycles of therapy, sparing them the toxicity of a full course, while intensifying therapy for those with molecular persistence.
Furthermore, the results of SWOG S1826 and HD21 suggest that the era of "chemotherapy-heavy" regimens may be ending. The exceptional efficacy of Nivolumab-AVD raises the question of whether traditional cytotoxic agents like doxorubicin and vinblastine can eventually be replaced entirely by combinations of immunotherapies (e.g., Nivolumab + Brentuximab). As we approach the bicentennial of Thomas Hodgkin’s 1832 paper, the disease that bears his name stands as a beacon of hope, demonstrating that even the most complex malignancies can be deciphered and defeated.
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