Hodgkin Lymphoma: Symptoms, Types, Causes and Treatment

Hodgkin lymphoma (HL) is a unique and highly curable cancer of the lymphatic system that stands apart from other lymphomas due to its distinctive cellular features and clinical presentation. Over the past decades, breakthroughs in understanding its biology and advances in therapy have significantly improved outcomes. However, HL can still pose diagnostic, therapeutic, and survivorship challenges. In this comprehensive guide, we explore the symptoms, types, causes, and treatment strategies for Hodgkin lymphoma, synthesizing insights from the latest research and clinical experience.

Symptoms of Hodgkin Lymphoma

Hodgkin lymphoma often announces itself with subtle, sometimes confusing symptoms. Recognizing these early signs can make a critical difference in diagnosis and outcomes.

Main Symptom	Description	Clinical Relevance	Source(s)
Lymphadenopathy	Enlarged, painless lymph nodes	Most common presentation	2 14
B Symptoms	Fever, night sweats, weight loss	Indicate systemic disease	3 14
Fatigue	Persistent tiredness	Long-term effect, impacts QoL	1 2
Pruritus	Unexplained itching	Less common, paraneoplastic	3
Pain	Unexplained pain, sometimes after alcohol	Occasional, diagnostic clue	2 14

Table 1: Key Symptoms

Common Presenting Symptoms

Lymphadenopathy
The hallmark of HL is painless swelling of lymph nodes, often in the neck, underarms, or groin. The swelling is typically discovered incidentally and may or may not be accompanied by discomfort. As the disease progresses, the enlarged nodes can become more noticeable or cause pressure symptoms in nearby tissues 2 14.

B Symptoms
A subset of patients experience systemic symptoms known as "B symptoms," which include:

• Unexplained fever (often intermittent)
• Profuse night sweats (drenching)
• Unintentional weight loss (over 10% in 6 months)

These symptoms are important for staging and prognosis, indicating a more extensive disease process 3 14.

Fatigue
Fatigue is both an acute and chronic issue in HL. It can persist even after successful treatment, affecting daily activities and quality of life. Long-term survivors may face ongoing, clinically significant fatigue due to treatment and disease sequelae 1.

Other Symptoms

• Pruritus (itching): Some patients experience generalized itching, which can be severe and is considered a paraneoplastic phenomenon 3.
• Pain: Rarely, patients report pain in affected lymph nodes after alcohol consumption—a classic but uncommon feature 2 14.

Uncommon Manifestations

HL can involve organs outside the lymphatic system (extranodal involvement), leading to unusual symptoms depending on the site. Rare paraneoplastic syndromes may affect the nervous system, skin, or cause autoimmune phenomena such as anemia or kidney dysfunction 3.

Types of Hodgkin Lymphoma

Hodgkin lymphoma is not a single disease but a group of related subtypes, each with unique characteristics and implications for treatment.

Type/Subtype	Defining Feature	Typical Demographics	Source(s)
Classical HL (cHL)	Reed-Sternberg cells; inflammatory milieu	Most HL cases (young adults)	6 7 14
Nodular Sclerosis cHL	Bands of fibrosis in lymph nodes	Young adults, females	4 6 14
Mixed Cellularity cHL	Mixed inflammatory background	Older adults, children	4 6 14
Lymphocyte-Rich cHL	Abundant lymphocytes; rare RS cells	Less common	4 6
Lymphocyte-Depleted cHL	Few lymphocytes; many RS cells, aggressive	Elderly, immunosuppressed	4 6
Nodular Lymphocyte Predominant HL (NLPHL)	Popcorn (L&H) cells, B-cell markers	Males, indolent course	6 7 14

Table 2: Major HL Types and Subtypes

Classical Hodgkin Lymphoma (cHL)

Overview
Classical HL accounts for the vast majority of cases and is defined by the presence of Reed-Sternberg (RS) cells in a background of inflammatory cells. There are four main subtypes 6 7 14:

• Nodular Sclerosis (NS): Characterized by bands of fibrosis dividing lymph node tissue. Most common in young adults, especially women. Often presents with mediastinal involvement 4 6.
• Mixed Cellularity (MC): Features a heterogeneous mixture of inflammatory cells. More frequent in older adults and children, and often associated with Epstein-Barr virus (EBV) infection 4 6.
• Lymphocyte-Rich (LR): Contains abundant normal lymphocytes and relatively few RS cells. It is less common and generally has a favorable prognosis 4 6.
• Lymphocyte-Depleted (LD): Marked by fewer lymphocytes and a higher number of RS cells. This rare and aggressive subtype is seen more often in older or immunocompromised patients 4 6.

Nodular Lymphocyte Predominant HL (NLPHL)

Distinct Entity
NLPHL is a rarer form, presenting with "popcorn" (L&H) cells that express typical B-cell markers, unlike RS cells in cHL. It usually runs a more indolent course and has a different treatment approach 6 7 14.

The Tumor Microenvironment

HL is notable for a distinctive microenvironment rich in immune cells, which play a role in tumor growth, immune evasion, and even response to therapy. This cellular interplay is especially relevant in classical HL and is the focus of ongoing research into targeted treatments 3 5 7 8.

Causes of Hodgkin Lymphoma

Understanding what causes Hodgkin lymphoma remains a complex puzzle involving viral, genetic, and environmental factors.

Cause/Factor	Role in HL	Evidence Summary	Source(s)
Epstein-Barr Virus	Directly implicated in some HL cases	Strong association, causality supported	10 12 13 14
Genetic Alterations	Chromosomal gains (e.g., 2p, 9p24.1)	Pathogenesis, oncogene activation	4 3 14
Immune Dysfunction	Increased risk in immunosuppressed hosts	HIV, transplant recipients	10 12
Unknown/Other	Majority of cases remain idiopathic	Multifactorial, under study	12 15

Table 3: Main Causes and Risk Factors

Viral Infections: The Role of Epstein-Barr Virus (EBV)

A significant proportion of HL cases, especially the mixed cellularity subtype, are associated with latent EBV infection. EBV can transform B cells and is considered a direct cause in many cases, particularly in children, the elderly, and immunosuppressed individuals 10 12 13 14. Studies confirm a strong epidemiological and molecular link between EBV and HL, although not all HL cases are EBV-positive 13.

Genetic and Molecular Alterations

Reed-Sternberg cells, the malignant cells in HL, frequently display genetic abnormalities:

• Gains in chromosomes 2p, 9p24.1: Lead to overexpression of genes like REL and PD-L1, promoting cell survival and immune evasion 3 4.
• Activation of signaling pathways: Such as NF-kappaB, JAK-STAT, and c-MYC, which drive proliferation and resist cell death 3 4 14. These genetic alterations are central to HL pathogenesis and are targets for emerging therapies.

Immune Dysfunction

HL risk is higher in individuals with immune deficiencies, such as HIV infection or after organ transplantation. Chronic immune stimulation or immunosuppression can create a permissive environment for malignant transformation 10 12.

Other and Unknown Factors

Despite extensive research, the precise cause of most HL cases remains unclear, suggesting contributions from environmental, genetic, and possibly occupational exposures 12 15. Ongoing studies aim to clarify these factors and their interplay.

Treatment of Hodgkin Lymphoma

Treatment of HL is one of the major success stories in oncology, with cure rates exceeding 80%. Therapy is tailored to disease type, stage, and individual risk factors, and new options continue to expand the therapeutic landscape.

Treatment Approach	Indication/Stage	Key Features/Drugs	Source(s)
Chemotherapy (ABVD, BEACOPP)	All stages	ABVD standard; BEACOPP for high-risk	6 14 15 16
Radiation Therapy	Early/limited disease	Often combined with chemo (CMT)	6 14 15 16
High-dose Chemo + Autologous SCT	Relapsed/refractory	Salvage for resistant/relapsed HL	6 14 15 17
Targeted Therapy	Relapsed/refractory	Brentuximab vedotin, checkpoint inhibitors	6 14 17
Immunotherapy	Relapsed/refractory	PD-1 inhibitors (nivolumab, pembrolizumab)	14 17
Clinical Trials/Novel Agents	Selected patients	CAR T-cells, HDAC inhibitors	17

Table 4: Main Treatment Modalities

Standard First-Line Therapy

• Early-Stage HL: Typically treated with a short course of chemotherapy (most commonly ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine) followed by involved-field radiation therapy. Combined-modality therapy offers high cure rates with minimized toxicity 6 14 15 16.
• Advanced-Stage HL: Managed with more extended chemotherapy regimens. ABVD remains the standard, but escalated BEACOPP may be used in higher-risk patients to improve disease control at the expense of increased side effects 14 15.

Risk-Adapted and Response-Adapted Therapy

Recent advances utilize PET/CT imaging during treatment to tailor intensity, aiming to reduce long-term side effects without compromising cure rates 16.

Salvage Therapy for Relapsed/Refractory HL

• High-dose Chemotherapy with Autologous Stem Cell Transplant (SCT): The standard for patients whose disease returns after initial therapy or does not respond. It offers a chance of cure for a significant proportion 6 14 15 17.
• Allogeneic SCT: Considered for selected patients, especially after failure of autologous SCT 6 15.

Targeted and Novel Therapies

• Brentuximab Vedotin: An antibody-drug conjugate targeting CD30 on RS cells, effective in relapsed/refractory HL and as consolidation post-transplant 6 14 17.
• Immune Checkpoint Inhibitors: Nivolumab and pembrolizumab (PD-1 inhibitors) have shown high response rates in heavily pretreated patients, exploiting the immune-evasive microenvironment of HL 14 17.
• Emerging Agents: Clinical trials are exploring CAR T-cells, HDAC inhibitors, and combination immunotherapies for patients with resistant disease 17.

Survivorship and Long-Term Management

Long-term follow-up is critical to monitor for late effects of treatment, including secondary cancers, cardiovascular disease, and chronic fatigue. Survivorship care, psychosocial support, and management of late complications are integral components of HL care 1 16.

Conclusion

Hodgkin lymphoma is a complex but highly treatable malignancy with unique clinical, pathological, and therapeutic features. Understanding its diverse symptoms, subtypes, causes, and the evolving landscape of therapy empowers patients and clinicians to achieve the best possible outcomes.

Key Points:

• HL often presents with painless lymph node swelling and "B symptoms" (fever, night sweats, weight loss).
• There are distinct HL subtypes; classical HL is the most common, with several variants.
• Causes include EBV infection, genetic alterations, and immune dysfunction, but most cases are multifactorial.
• Modern therapy achieves high cure rates, with chemotherapy, radiation, and stem cell transplantation forming the backbone.
• Targeted therapies and immunotherapies offer new hope for patients with relapsed or refractory disease.
• Long-term survivorship care is essential to manage late effects and optimize quality of life.

If you or a loved one are facing Hodgkin lymphoma, know that research and treatment continue to advance, offering more effective and less toxic therapies than ever before.