How to Distinguish Between Types of Hodgkin Lymphoma

The fight against cancer is often a journey into the intricate and sometimes perplexing world of cellular anomalies. Among the many forms of cancer, lymphomas stand out due to their origin in the lymphatic system, a critical part of our immune defense. Within the broad category of lymphomas, Hodgkin lymphoma (HL) holds a distinct place. While often more treatable than many other cancers, understanding its nuances, particularly the different types, is paramount for accurate diagnosis, effective treatment, and ultimately, improved patient outcomes.

This comprehensive guide delves into the fascinating and crucial distinctions between the various types of Hodgkin lymphoma. We’ll go beyond superficial descriptions, offering a deep dive into their microscopic features, clinical presentations, and the implications these differences have for personalized care. By the end of this article, you’ll possess a profound understanding of how medical professionals meticulously differentiate these subtypes, equipping you with valuable knowledge in the complex realm of hematological malignancies.

Unveiling the Enigma: What is Hodgkin Lymphoma?

Before we dissect the individual types, let’s establish a foundational understanding of Hodgkin lymphoma itself. Hodgkin lymphoma is a cancer of the lymphatic system, specifically originating from B lymphocytes (a type of white blood cell). The hallmark of Hodgkin lymphoma is the presence of a unique, often multi-nucleated giant cell known as the Reed-Sternberg cell, or variants thereof, within an inflammatory cellular background. These cells, though typically sparse, are essential for diagnosis.

The lymphatic system is a vast network of vessels, nodes, and organs (like the spleen, tonsils, and bone marrow) that transport lymph – a fluid containing white blood cells – throughout the body. Its primary role is to filter waste products and pathogens, and to mount immune responses. When HL develops, these abnormal B cells proliferate uncontrollably, often accumulating in lymph nodes, leading to their enlargement.

While the exact cause of Hodgkin lymphoma remains unknown, several risk factors have been identified, including certain viral infections (notably Epstein-Barr virus), a weakened immune system, and a family history of the disease. It commonly affects two age groups: young adults (15-35 years old) and older adults (over 55 years old), though it can occur at any age.

The Microscopic Menagerie: Distinguishing Classical Hodgkin Lymphoma Subtypes

The vast majority of Hodgkin lymphoma cases, approximately 95%, fall under the umbrella of Classical Hodgkin Lymphoma (CHL). CHL is further subdivided into four distinct histological types, each with its own unique microscopic appearance and, to some extent, clinical behavior. The accurate identification of these subtypes relies heavily on meticulous pathological examination of biopsy specimens, primarily lymph node biopsies. This process involves sophisticated staining techniques and expert interpretation by hematopathologists.

1. Nodular Sclerosis Classical Hodgkin Lymphoma (NSCHL)

Nodular Sclerosis Hodgkin Lymphoma is the most common subtype of CHL, accounting for 70-80% of all cases. Its name perfectly describes its key features: “nodular” referring to the formation of distinct nodules within the lymph node, and “sclerosis” indicating the presence of fibrous bands of collagen that compartmentalize these nodules.

Microscopic Hallmarks:

Lacunar Cells: The characteristic Reed-Sternberg variant in NSCHL is the lacunar cell. These cells have multi-lobed or folded nuclei, inconspicuous nucleoli, and abundant, pale-staining cytoplasm that often retracts during tissue processing, creating a clear “lacuna” or space around the nucleus. Imagine a dried-up puddle, leaving a distinct outline – that’s the lacuna effect.
Collagen Bands: Thick, birefringent bands of collagen tissue are a defining feature, dividing the lymph node into distinct nodules. These bands can be visualized under a microscope as wavy, sometimes pinkish-blue structures. Think of the internal structure of an orange, with fibrous divisions segmenting the fruit; NSCHL lymph nodes exhibit a similar, albeit microscopic, compartmentalization.
Mixed Inflammatory Background: Within the nodules, there’s a varied infiltrate of reactive lymphocytes (small, mature lymphocytes), eosinophils (white blood cells with bright red granules), plasma cells (antibody-producing cells), and histiocytes (macrophage-like cells). This reactive background is crucial for diagnosis, as it helps differentiate HL from other lymphomas that might have similar large cells but lack this characteristic cellular milieu.
Variable Cellularity: The cellularity within the nodules can vary from paucicellular (few cells) to hypercellular (many cells). Some cases can be very cellular, while others might be dominated by the fibrous component.

Clinical Presentation and Prognosis:

Demographics: NSCHL is most frequently observed in adolescents and young adults, particularly women.
Location: It commonly presents in the mediastinum (the area between the lungs) and the lower cervical and supraclavicular lymph nodes. Mediastinal involvement can sometimes lead to symptoms like cough or shortness of breath due to compression of airways or vessels.
Clinical Course: NSCHL typically presents as localized disease (Stage I or II) and has a generally favorable prognosis with modern treatment regimens. While it can be bulky, its tendency for contiguous spread makes it more amenable to localized therapies.
Examples: A 22-year-old female presents with a persistent cough and a palpable mass in her neck. Imaging reveals enlarged mediastinal and cervical lymph nodes. A biopsy shows characteristic lacunar cells amidst broad collagen bands and a mixed inflammatory infiltrate, leading to a diagnosis of NSCHL.

2. Mixed Cellularity Classical Hodgkin Lymphoma (MCCHL)

Mixed Cellularity Hodgkin Lymphoma is the second most common subtype, accounting for approximately 15-30% of CHL cases. Its name reflects the highly diverse and often abundant inflammatory cell infiltrate within the affected lymph node, with less prominent fibrosis compared to NSCHL.

Microscopic Hallmarks:

Classic Reed-Sternberg Cells: MCCHL is characterized by a higher prevalence of classic Reed-Sternberg (RS) cells. These are large cells with bilobed or multi-lobed nuclei, prominent eosinophilic (red-staining) nucleoli that resemble “owl’s eyes,” and abundant cytoplasm. Imagine an owl staring directly at you – the prominent eyes are analogous to the nucleoli of a classic RS cell.
Polymorphous Inflammatory Infiltrate: The background is a rich and diverse mixture of reactive cells, including small lymphocytes, eosinophils, plasma cells, and histiocytes. Unlike NSCHL, there’s a more diffuse pattern of infiltration, with less emphasis on nodule formation or fibrous bands. This “mixed bag” of cells is what gives the subtype its name.
Absence of Nodularity or Significant Sclerosis: While some minimal fibrosis might be present, it does not form the distinct collagen bands seen in NSCHL. The architecture of the lymph node is generally effaced (replaced) by the tumor and its reactive infiltrate, rather than compartmentalized.
Increased RS Cell Variants: Besides classic RS cells, other variants like mononuclear RS cells (single-lobed nucleus) or mummified RS cells (pyknotic, darkly stained nucleus) can also be seen.

Clinical Presentation and Prognosis:

Demographics: MCCHL can occur at any age but is more common in older adults and in patients with underlying immune deficiencies, such as those with HIV infection. It also has a slightly higher incidence in men.
Location: It often presents with widespread lymphadenopathy (enlarged lymph nodes) and can involve extranodal sites (outside lymph nodes) more frequently than NSCHL, including the spleen, liver, and bone marrow. Mediastinal involvement is less common than in NSCHL.
Clinical Course: MCCHL generally presents at a more advanced stage (Stage III or IV) than NSCHL. Despite this, it remains highly curable with contemporary chemotherapy regimens, though the prognosis can be slightly less favorable than localized NSCHL.
Examples: A 60-year-old male presents with unexplained fever, night sweats, and weight loss (B symptoms). Physical examination reveals generalized lymphadenopathy. A lymph node biopsy shows numerous classic Reed-Sternberg cells amidst a diffuse, mixed inflammatory background of lymphocytes, eosinophils, and plasma cells, without significant nodularity or broad fibrous bands. This leads to a diagnosis of MCCHL.

3. Lymphocyte-Rich Classical Hodgkin Lymphoma (LRCHL)

Lymphocyte-Rich Classical Hodgkin Lymphoma is the least common subtype of CHL, accounting for approximately 5% of cases. As its name suggests, it is characterized by an abundance of small, reactive lymphocytes in the background, with relatively few Reed-Sternberg cells. This can sometimes make diagnosis challenging, as it might be mistaken for other benign or malignant lymphoid proliferations.

Microscopic Hallmarks:

Prominent Lymphocytic Background: The predominant cell type in the biopsy is small, mature lymphocytes, often forming a nodular or diffuse pattern. This dense lymphocytic infiltrate almost “masks” the presence of the malignant cells.
Scattered Classic Reed-Sternberg Cells: Classic RS cells are present but are typically sparse. Their identification requires careful searching by the pathologist. RS cell variants may also be present.
Few Eosinophils or Plasma Cells: Unlike MCCHL, the inflammatory background in LRCHL contains significantly fewer eosinophils, plasma cells, or histiocytes. The reactive infiltrate is almost exclusively lymphocytic.
Absence of Nodularity or Sclerosis: Similar to MCCHL, there is no significant nodularity or broad fibrous bands. The architecture is usually effaced by the dense lymphocytic infiltrate.

Clinical Presentation and Prognosis:

Demographics: LRCHL tends to affect males more often and typically presents in older adults.
Location: It usually presents as localized lymphadenopathy, often in the cervical, supraclavicular, or axillary regions. Mediastinal involvement is rare.
Clinical Course: LRCHL often presents at an early stage (Stage I or II) and has an excellent prognosis, often considered the most favorable among the CHL subtypes, largely due to its early presentation and responsiveness to treatment.
Examples: A 65-year-old male discovers an isolated, painless enlarged lymph node in his neck. A biopsy reveals a dense infiltrate of small lymphocytes with only a handful of scattered classic Reed-Sternberg cells, and notably, very few eosinophils or plasma cells. This picture is consistent with LRCHL.

4. Lymphocyte-Depleted Classical Hodgkin Lymphoma (LDCHL)

Lymphocyte-Depleted Classical Hodgkin Lymphoma is the rarest and historically considered the most aggressive subtype of CHL, comprising less than 1% of cases. Its characteristic feature is a paucity of reactive lymphocytes and an abundance of Reed-Sternberg cells and their variants, often accompanied by diffuse fibrosis or necrosis.

Microscopic Hallmarks:

Paucity of Reactive Lymphocytes: As the name implies, there’s a marked reduction in the number of small, reactive lymphocytes in the background. The normal lymphoid architecture is effaced by the tumor cells and associated fibrosis.
Abundant Reed-Sternberg Cells and Variants: There is a relatively high number of classic Reed-Sternberg cells and various atypical RS cell variants, which can sometimes be pleomorphic (varied in shape and size) and anaplastic (lacking differentiation). These cells can form cohesive sheets, making differentiation from other aggressive lymphomas challenging without specific immunohistochemical markers.
Diffuse Fibrosis or Necrosis: Significant diffuse fibrosis, often disorderly and haphazard, or areas of necrosis (tissue death) are common findings. This fibrosis is not compartmentalizing like in NSCHL, but rather replaces the normal lymphoid tissue.
Scattered Other Inflammatory Cells: While lymphocytes are depleted, some plasma cells, histiocytes, and occasionally eosinophils might still be present, but they are overwhelmed by the tumor cells and fibrosis.

Clinical Presentation and Prognosis:

Demographics: LDCHL is more common in older adults, particularly males, and in individuals with underlying immune suppression, such as HIV/AIDS or organ transplant recipients.
Location: It often presents with advanced-stage disease, including widespread lymphadenopathy, significant extranodal involvement (especially bone marrow, liver, and spleen), and systemic symptoms (B symptoms).
Clinical Course: Historically, LDCHL had the poorest prognosis among CHL subtypes due to its advanced presentation and aggressive nature. However, with modern intensive chemotherapy regimens, the prognosis has significantly improved, although it generally remains less favorable than the other CHL subtypes.
Examples: An 80-year-old male with a history of HIV presents with severe fatigue, significant weight loss, and widespread, rapidly enlarging lymph nodes. A biopsy reveals numerous highly atypical, pleomorphic Reed-Sternberg cells forming sheets, with very few background lymphocytes and diffuse, haphazard fibrosis. This aggressive microscopic picture points towards LDCHL.

Beyond the Classical: Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

While the Classical Hodgkin Lymphoma subtypes dominate, there’s a distinct entity that, despite sharing the “Hodgkin lymphoma” moniker, stands apart both microscopically and clinically: Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL). NLPHL accounts for approximately 5% of all Hodgkin lymphoma cases. It was previously considered a subtype of CHL but is now recognized as a separate disease entity within the World Health Organization (WHO) classification due to its unique cellular origin, immunological profile, and clinical course.

Microscopic Hallmarks of NLPHL:

Popcorn Cells (LP Cells): The hallmark malignant cell in NLPHL is the “lymphocytic and histiocytic” (L&H) cell, often referred to as a “popcorn cell” due to its multi-lobed, delicate nucleus that resembles popped corn. These cells are typically mononuclear, with relatively inconspicuous nucleoli and abundant, pale cytoplasm. They are distinctly different from classic Reed-Sternberg cells.
Nodular Growth Pattern: The tumor cells typically reside within reactive nodules, which are rich in small lymphocytes, histiocytes, and epithelioid histiocytes (macrophage-like cells with abundant pink cytoplasm). These nodules are often surrounded by a network of follicular dendritic cells, which can be highlighted by immunohistochemical stains.
Absence of Classic Reed-Sternberg Cells: Importantly, classic Reed-Sternberg cells are typically absent. Their presence should raise suspicion for CHL or a composite lymphoma.
Reactive Background: The background is predominantly composed of small B-lymphocytes forming follicles, often with germinal centers. There are very few, if any, eosinophils, plasma cells, or neutrophils, which are common in CHL.

Immunophenotyping: The Definitive Distinguisher

While morphology provides crucial clues, the definitive distinction between CHL subtypes and NLPHL often relies on immunohistochemistry (IHC). IHC uses antibodies to detect specific proteins (antigens) expressed on the surface or within the cytoplasm of cells. This allows pathologists to “fingerprint” the malignant cells and differentiate them based on their unique protein expression profiles.

Immunophenotype of Classical Hodgkin Lymphoma (CHL) (all subtypes):

The malignant Reed-Sternberg cells and their variants in all four CHL subtypes typically show the following immunophenotype:

Positive for CD30: CD30 is a transmembrane glycoprotein and a highly characteristic marker for RS cells in CHL. It’s almost universally expressed. Think of CD30 as the unique barcode for classical Hodgkin lymphoma.
Positive for CD15: CD15 is another crucial marker, usually expressed on the cell surface or in the Golgi apparatus of RS cells. It’s positive in the majority of CHL cases, though sometimes absent.
Negative for CD45 (Leukocyte Common Antigen): This is a critical differentiating feature. CD45 is expressed on most hematopoietic cells, but it is typically absent or weakly expressed on RS cells. This negativity helps distinguish CHL from most other lymphomas.
Negative for B-cell markers (CD20, CD79a): While CHL originates from B cells, the RS cells typically lose the expression of most conventional B-cell markers during their malignant transformation. This “loss of lineage markers” is a hallmark.
Variable for PAX5: PAX5 is a transcription factor important for B-cell development. RS cells show weak and aberrant nuclear expression of PAX5, which can be helpful but isn’t as definitive as CD30/CD15/CD45.
Variable for EBV (EBER): In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) is positive in a significant proportion of CHL cases, particularly in MCCHL and LDCHL, and more commonly in patients from certain geographical regions or with immunodeficiency.

Immunophenotype of Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL):

The popcorn cells (L&H cells) of NLPHL have a distinctly different immunophenotype, which reflects their origin from germinal center B-cells:

Positive for CD20: Unlike CHL, the L&H cells in NLPHL are strongly positive for CD20, a pan-B-cell marker. This is a crucial distinguishing feature.
Positive for CD45: The L&H cells are also typically positive for CD45, another major differentiator from CHL.
Positive for CD79a: Another pan-B-cell marker, CD79a, is also usually positive in L&H cells.
Positive for PAX5: L&H cells show strong nuclear expression of PAX5, unlike the weak and aberrant expression in CHL.
Positive for BCL6: BCL6 is a marker associated with germinal center B-cells, and its expression is characteristic of L&H cells.
Negative for CD30: This is a key negative marker. L&H cells are typically negative for CD30. This is the most significant differentiating factor from CHL.
Negative for CD15: L&H cells are also typically negative for CD15.
Negative for EBV (EBER): NLPHL is almost universally negative for EBV.

Concrete Example of Immunophenotyping in Action:

Imagine a pathologist examining a lymph node biopsy. They see some large, atypical cells.

Scenario A: If these large cells are CD30+, CD15+, and CD45-, the diagnosis strongly points towards Classical Hodgkin Lymphoma. Further morphological evaluation will then determine which CHL subtype it is (e.g., presence of lacunar cells and collagen bands suggests NSCHL).
Scenario B: If the large cells are CD20+, CD45+, and CD30-, the diagnosis is almost certainly Nodular Lymphocyte-Predominant Hodgkin Lymphoma. The specific “popcorn” morphology will then confirm this.

This clear distinction provided by immunohistochemistry is indispensable for accurate diagnosis and, consequently, for guiding treatment decisions.

The Broader Diagnostic Toolkit: Beyond Morphology and IHC

While morphology and immunohistochemistry are the cornerstones of Hodgkin lymphoma diagnosis and subtyping, other diagnostic tools contribute to a comprehensive understanding of the disease, aiding in staging and prognosis.

Clinical Presentation and Patient History

A thorough patient history and physical examination provide invaluable initial clues. Symptoms such as persistent fever ( >38∘C), drenching night sweats, and unexplained weight loss ( >10% of body weight in 6 months) are known as “B symptoms” and are associated with a more advanced stage and sometimes a less favorable prognosis. The presence and location of enlarged lymph nodes (cervical, axillary, inguinal, mediastinal) are also crucial.

Examples:

A young adult with a painless lump in the neck and no B symptoms might suggest early-stage NSCHL or LRCHL.
An older adult with generalized lymphadenopathy, significant weight loss, and fatigue might suggest advanced MCCHL or LDCHL.

Imaging Studies

Imaging techniques are essential for staging the disease – determining the extent of its spread.

Computed Tomography (CT) Scans: CT scans of the neck, chest, abdomen, and pelvis are routinely used to identify enlarged lymph nodes and assess involvement of organs like the liver and spleen.
Positron Emission Tomography (PET) Scan with CT (PET-CT): PET-CT is a highly sensitive imaging modality. It uses a radioactive tracer (FDG) that is taken up by metabolically active cancer cells. This allows for the identification of all active disease sites, including those not visible on conventional CT, and is critical for accurate staging and response assessment during and after treatment. A positive PET scan lights up areas where the cancer is metabolically active, like a beacon in the night.
Magnetic Resonance Imaging (MRI): MRI may be used in specific situations, such as evaluating bone marrow involvement or assessing spinal cord compression.

Bone Marrow Biopsy

While not always required for all patients with Hodgkin lymphoma, a bone marrow biopsy and aspiration are performed, particularly for advanced stages (Stage III/IV) or if there are unexplained blood count abnormalities or B symptoms. Bone marrow involvement can indicate a more disseminated disease.

Blood Tests

Routine blood tests, including a complete blood count (CBC), erythrocyte sedimentation rate (ESR), and liver and kidney function tests, provide information about the patient’s overall health, presence of inflammation, and potential organ involvement. An elevated ESR, for instance, can be a non-specific indicator of inflammation or disease activity.

Implications for Treatment and Prognosis

The accurate distinction between Hodgkin lymphoma types is not merely an academic exercise; it has profound implications for treatment planning and predicting patient outcomes. While most types of Hodgkin lymphoma are highly curable, understanding the nuances allows for a personalized and optimized approach.

Treatment Modalities:

Chemotherapy: Chemotherapy is the cornerstone of Hodgkin lymphoma treatment. The specific regimen and intensity depend on the disease stage, subtype, and patient-specific factors. For example, ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) is a widely used and highly effective regimen for most CHL subtypes. More intensive regimens like escalated BEACOPP (Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone) might be considered for advanced-stage disease or less favorable subtypes.
Radiation Therapy: Radiation therapy is often used in conjunction with chemotherapy, particularly for localized disease, bulky lymphadenopathy, or residual disease after chemotherapy.
Immunotherapy and Targeted Therapies: For relapsed or refractory Hodgkin lymphoma, newer therapies like checkpoint inhibitors (e.g., Nivolumab, Pembrolizumab) and antibody-drug conjugates (e.g., Brentuximab Vedotin) have shown significant promise, targeting specific proteins on the cancer cells.
Stem Cell Transplantation: For patients with relapsed or refractory disease, high-dose chemotherapy followed by autologous stem cell transplantation (using the patient’s own stem cells) can be a curative option.

Prognostic Considerations:

Classical Hodgkin Lymphoma: In general, classical Hodgkin lymphoma has an excellent prognosis, with overall survival rates exceeding 80-90% for early-stage disease and 70-80% for advanced-stage disease.
- Nodular Sclerosis CHL (NSCHL): Generally has the most favorable prognosis, especially when localized.
- Lymphocyte-Rich CHL (LRCHL): Also has an excellent prognosis, often presenting at early stages.
- Mixed Cellularity CHL (MCCHL): While often presenting at more advanced stages, it remains highly curable with modern therapies.
- Lymphocyte-Depleted CHL (LDCHL): Historically, it had the least favorable prognosis, but advancements in treatment have significantly improved outcomes. However, it still often requires more intensive therapy.
Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): NLPHL often has an indolent (slow-growing) course with an excellent long-term prognosis. It has a high cure rate, often requiring less intensive therapy than CHL. However, it has a higher tendency to relapse, but these relapses are typically treatable. A small percentage of NLPHL cases can transform into aggressive large B-cell lymphomas, which requires a different treatment approach.

The distinctions in treatment for NLPHL versus CHL are notable. For example, while CD30-targeted therapies like Brentuximab Vedotin are highly effective in CHL, they are not typically used in NLPHL because the L&H cells do not express CD30. Conversely, Rituximab, an anti-CD20 antibody, is a key component of NLPHL treatment due to the consistent CD20 expression on L&H cells, whereas it has no role in CHL.

The Future of Distinction: Precision Medicine in Hodgkin Lymphoma

The journey of distinguishing Hodgkin lymphoma types is continuously evolving. Advances in molecular diagnostics are beginning to offer even deeper insights into the biology of these cancers, paving the way for more precise and personalized medicine.

Gene Expression Profiling: Research is ongoing to identify specific gene expression patterns that might further refine classification, predict response to therapy, and identify patients at higher risk of relapse.
Genomic Sequencing: Understanding the specific genetic mutations within the Reed-Sternberg cells or L&H cells could lead to the development of novel targeted therapies that directly address these genetic vulnerabilities.
Liquid Biopsies: The analysis of circulating tumor DNA (ctDNA) from blood samples holds promise for non-invasive monitoring of disease progression, detection of minimal residual disease, and potentially guiding treatment decisions in the future.

These emerging technologies represent the next frontier in cancer diagnostics, promising even greater accuracy in distinguishing between Hodgkin lymphoma types and ultimately leading to even better outcomes for patients.

Conclusion

Distinguishing between the types of Hodgkin lymphoma is a sophisticated process that requires a multifaceted approach, combining meticulous microscopic examination, precise immunohistochemical profiling, and a thorough understanding of clinical presentations. From the fibrosis-laden nodules of NSCHL and the diverse cellular milieu of MCCHL, to the lymphocyte-rich background of LRCHL and the lymphocyte-depleted, aggressive nature of LDCHL, each classical subtype tells a unique story under the microscope. Separately, NLPHL stands alone with its distinct “popcorn cells” and unique immunophenotype.

This comprehensive guide has illuminated the intricate features that allow medical professionals to accurately categorize these diseases. This precision in diagnosis is not an academic exercise but a critical step that directly informs treatment strategies, predicts prognosis, and ultimately empowers patients and their healthcare teams to navigate the complexities of Hodgkin lymphoma with clarity and confidence. The relentless pursuit of understanding these distinctions is a testament to the dedication of the medical community in its ongoing fight against cancer, continually striving for more targeted, effective, and personalized care.