Classic Hodgkin Lymphoma: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 14, 2026

Classic Hodgkin lymphoma is a type of cancer that starts in the lymph nodes — small bean-shaped glands distributed throughout the body that are part of the immune system. It is defined by the presence of distinctive abnormal cells called Reed-Sternberg cells, which are much larger than normal immune cells and have a characteristic appearance under the microscope. Classic Hodgkin lymphoma is one of the most treatable cancers, and most people — even those with advanced-stage disease — achieve long-term remission or cure with modern treatment. This article will help you understand the findings in your pathology report, what each term means, and why it matters for your care.

What are the symptoms of classic Hodgkin lymphoma?

The most common presenting symptom is painless swelling of one or more lymph nodes, most often in the neck, chest, or armpits. The swelling is usually firm and rubbery, unlike swollen lymph nodes from infection, which usually go away on their own. A large mass in the chest — called a mediastinal mass — is a particularly common finding in classic Hodgkin lymphoma, and in some people it can cause cough, shortness of breath, or chest pressure before a lymph node lump is noticed elsewhere.

Many people also experience general symptoms known as B symptoms: unexplained fever, drenching night sweats, and unintentional weight loss of more than 10% of body weight over six months. Fatigue is also common. Some people notice alcohol-induced pain — discomfort in affected lymph nodes shortly after drinking alcohol — which is an unusual symptom considered characteristic of classic Hodgkin lymphoma when present, though it occurs in only a minority of patients. The B symptoms are important because they are included in staging and can influence treatment planning.

What causes classic Hodgkin lymphoma?

The exact cause is not fully understood. Classic Hodgkin lymphoma arises from a specific type of B cell — a white blood cell that normally develops and matures inside the germinal center, the region of a lymph node where B cells learn to recognize and respond to infections. Through a combination of genetic changes, this cell loses much of its normal B cell identity and transforms into a Reed-Sternberg cell, the defining feature of the disease.

Several factors are associated with an increased risk. Infection with Epstein-Barr virus (EBV) — the virus responsible for infectious mononucleosis — is found inside the Reed-Sternberg cells in approximately 30–40% of classic Hodgkin lymphoma cases overall, and in a higher proportion of mixed cellularity and lymphocyte-depleted subtypes. EBV promotes B cell survival and proliferation, contributing to lymphoma development in these cases. A weakened immune system — from HIV infection, organ transplantation, or other causes — substantially increases the risk of EBV-associated classic Hodgkin lymphoma. A personal or family history of infectious mononucleosis or having a sibling with classic Hodgkin lymphoma also increases risk. In most people, however, no single identifiable cause is found.

Classic Hodgkin lymphoma has a bimodal age distribution — it is most common in young adults between 15 and 35 years old, with a second smaller peak in adults over 55. It affects men slightly more often than women overall, though the nodular sclerosis subtype is roughly equally common in both sexes.

How is the diagnosis made?

The diagnosis of classic Hodgkin lymphoma is made by examining lymph node tissue under the microscope. An excisional biopsy — removal of an entire lymph node — is the preferred approach because the full architecture of the node is needed to identify the growth pattern and subtype. A core needle biopsy may be used when an excisional biopsy is not readily accessible, though it provides less tissue. Fine needle aspiration alone is not sufficient. The pathologist examines the tissue to identify Reed-Sternberg cells and characterize the surrounding immune cell background, which defines the subtype. Immunohistochemistry is routinely performed to confirm the protein expression profile of the Reed-Sternberg cells and to distinguish classic Hodgkin lymphoma from other lymphomas that can look similar under the microscope. Testing for EBV using a special test called EBER in situ hybridization is also performed. Once the diagnosis is confirmed, PET/CT imaging, blood tests, and sometimes a bone marrow biopsy are used to determine the stage of disease.

What are the subtypes of classic Hodgkin lymphoma?

Classic Hodgkin lymphoma is divided into four subtypes based on the appearance of the tissue under the microscope — specifically, the characteristics of the Reed-Sternberg cells and the types of surrounding immune cells. Identifying the subtype is important because subtypes differ in their typical age of presentation, their association with EBV, and, in some cases, their behavior and treatment implications.

Nodular sclerosis classic Hodgkin lymphoma (NSCHL)

Nodular sclerosis is the most common subtype, accounting for approximately 60–80% of all classic Hodgkin lymphoma cases. It is most frequently diagnosed in adolescents and young adults and is equally common in men and women. It has a particular predilection for the lymph nodes in the chest (mediastinum), and a large mediastinal mass at diagnosis is characteristic of this subtype.

Under the microscope, nodular sclerosis is defined by two hallmark features: bands of dense scar-like tissue (sclerosis) that divide the lymph node into nodules, and a distinctive variant of Reed-Sternberg cell called the lacunar cell. Lacunar cells appear to sit in empty spaces or holes — called lacunae — which are actually an artifact created when the cytoplasm (the body of the cell) contracts during tissue processing. The nodules between the sclerotic bands contain a mixture of lacunar cells, normal inflammatory cells, and non-cancerous lymphocytes. A rare aggressive variant called the syncytial variant shows sheets of Reed-Sternberg cells with areas of cell death (necrosis). EBV is found in a minority (approximately 10–30%) of nodular sclerosis cases. This subtype generally has a very good prognosis with modern treatment.

Mixed cellularity classic Hodgkin lymphoma (MCCHL)

Mixed cellularity is the second most common subtype, accounting for approximately 20–25% of cases. It has a broader age distribution than nodular sclerosis, occurring more commonly in children and in older adults than in young adults. It is more common in men and is the subtype most frequently associated with HIV infection and with populations outside North America and Western Europe.

Under the microscope, mixed cellularity shows a diffuse pattern in which Reed-Sternberg cells are scattered throughout the lymph node among a varied background of inflammatory cells — including small lymphocytes, eosinophils, histiocytes, and plasma cells. The sclerotic bands seen in nodular sclerosis are absent. EBV is present in the Reed-Sternberg cells in approximately 50–75% of cases, significantly more often than in nodular sclerosis. Despite its aggressive-sounding name, mixed cellularity classic Hodgkin lymphoma responds well to treatment and the prognosis is generally good.

Lymphocyte-rich classic Hodgkin lymphoma (LRCHL)

Lymphocyte-rich classic Hodgkin lymphoma is uncommon, accounting for approximately 5% of cases. It tends to occur in older adult men and usually presents at an early stage without mediastinal involvement. EBV is found in approximately 30–40% of cases.

Under the microscope, the lymph node is replaced by a dense background of normal-appearing small lymphocytes, with Reed-Sternberg cells present but relatively few in number. The pattern may be nodular, in which the lymphocytes form round nodules containing shrunken germinal centers with the Reed-Sternberg cells located just outside them, or diffuse. Eosinophils and neutrophils are typically absent or sparse. Because of its abundant lymphocyte background and few Reed-Sternberg cells, lymphocyte-rich classic Hodgkin lymphoma can be mistaken for nodular lymphocyte-predominant Hodgkin lymphoma — a related but distinct disease — and immunohistochemistry is essential to distinguish the two. This subtype has a very favorable prognosis.

Lymphocyte-depleted classic Hodgkin lymphoma (LDCHL)

Lymphocyte-depleted classic Hodgkin lymphoma is the rarest subtype, accounting for fewer than 2% of cases. It is strongly associated with EBV infection (present in the Reed-Sternberg cells in up to 80–90% of cases), with older age at presentation, and with HIV infection. It has a particular tendency to involve abdominal lymph nodes and bone marrow in addition to peripheral lymph nodes, and patients often present with more advanced disease and B symptoms.

Under the microscope, this subtype shows either sheets of numerous Reed-Sternberg cells with very few surrounding lymphocytes, or diffuse fibrous replacement of the lymph node with scattered Reed-Sternberg cells. The relative absence of the normal background immune cell reaction — which is what “lymphocyte-depleted” refers to — gives the tissue a markedly different appearance from the other subtypes. Despite its association with advanced presentation and EBV, outcomes are improving with modern chemotherapy regimens, though this remains the most challenging subtype to treat.

What do Reed-Sternberg cells look like under the microscope?

Reed-Sternberg cells are the defining diagnostic feature of classic Hodgkin lymphoma and are present in all four subtypes. Understanding their appearance helps explain why pathologists look for them so carefully and why they are so recognizable.

Classic Reed-Sternberg cells are very large — typically much larger than any normal lymphocyte or immune cell in the tissue — and have at least two nuclear lobes (two separate compartments inside the cell containing the DNA), each with a single very large, prominent red-staining nucleolus. This gives them an “owl-eye” appearance: the two pale nuclei with their large central nucleoli resemble two owl eyes looking directly at the observer. This appearance is so characteristic that it is essentially diagnostic of Hodgkin lymphoma when seen in the right clinical context.

Several related cell types are also associated with classic Hodgkin lymphoma and may be described in the pathology report:

Hodgkin cells — Mononuclear (single-nucleus) variants of Reed-Sternberg cells that are also enlarged with a prominent nucleolus. They represent a variant form of the same malignant cell.
Lacunar cells — The variant Reed-Sternberg cell characteristic of nodular sclerosis, which appears to sit in an empty space due to cytoplasmic retraction during tissue processing.
Mummified cells — Reed-Sternberg cells that have undergone cell death (apoptosis), appearing dense and shrunken with pyknotic (contracted, darkly staining) nuclei.

Critically, Reed-Sternberg cells typically make up only a very small fraction — often less than 1–5% — of all the cells seen in the lymph node. The vast majority of cells in classic Hodgkin lymphoma tissue are non-cancerous reactive immune cells (T cells, B cells, eosinophils, histiocytes, plasma cells, and neutrophils) that have been recruited into the lymph node in response to the Reed-Sternberg cells. This surrounding immune cell population is called the tumor microenvironment, and its composition varies by subtype and influences both the diagnosis and the patient’s immune response to the lymphoma.

Immunohistochemistry

Immunohistochemistry (IHC) is performed on all cases of classic Hodgkin lymphoma to confirm the diagnosis and exclude other lymphomas that can look similar under the microscope. The protein profile of Reed-Sternberg cells is highly characteristic and is essential for the diagnosis.

CD30 — Positive. CD30 is expressed on the surface of Reed-Sternberg cells in essentially all cases of classic Hodgkin lymphoma and is the most important diagnostic marker. CD30 is a protein that normally appears on activated immune cells; in Reed-Sternberg cells it is constitutively expressed (always switched on), helping the cells survive. CD30 is also the target of brentuximab vedotin, an antibody-drug conjugate used in treatment. Staining is typically strong and located on the cell membrane and in the Golgi region (a processing area inside the cell), creating a characteristic pattern.
CD15 — Positive in approximately 75–85% of cases. CD15 is a carbohydrate marker expressed on the surface of Reed-Sternberg cells. Its expression may be focal or variable but when present it strongly supports the diagnosis.
PAX5 — Positive but weak. PAX5 is a transcription factor (a protein that switches genes on or off) that is normally expressed strongly in B cells. Reed-Sternberg cells retain PAX5 expression as evidence of their B cell origin, but it is consistently dimmer than the PAX5 staining in the surrounding normal B cells — a characteristic finding that helps identify Reed-Sternberg cells when they are subtle.
CD20 — Negative in most cases, though a minority (approximately 10–20%) of cases show variable CD20 expression. CD20 is normally strongly expressed in B cells; its relative loss in Reed-Sternberg cells reflects the partial loss of normal B cell identity that defines classic Hodgkin lymphoma.
CD45 — Negative. CD45 is expressed on all normal lymphocytes and most B cell lymphomas; its absence from Reed-Sternberg cells is a key distinguishing feature that helps separate classic Hodgkin lymphoma from non-Hodgkin lymphomas.
IRF4 (MUM1) — Positive. This transcription factor is expressed by Reed-Sternberg cells and is useful in some diagnostic contexts.
OCT2 and BOB1 — Negative or weak in most cases. These B cell transcription factors are strongly expressed in normal B cells and in nodular lymphocyte-predominant Hodgkin lymphoma (the related but distinct disease), and their absence or weak expression in classic Hodgkin lymphoma is an important distinguishing feature.
CD3 — Negative in Reed-Sternberg cells (positive only in the background T cells). Occasionally a small number of classic Hodgkin lymphoma cases express T cell markers, which requires additional testing to characterize.

EBV testing

Testing for Epstein-Barr virus is performed on all classic Hodgkin lymphoma biopsies using a test called EBER in situ hybridization — a technique that detects small RNA molecules produced by EBV inside infected cells. When EBER is positive, EBV is present inside the Reed-Sternberg cells. When EBER is negative, EBV is not involved in this particular case.

EBV status has implications for understanding the biology of the lymphoma and may have some prognostic relevance in specific clinical settings (for example, EBV-positive disease tends to be more common in immunocompromised patients and in certain subtypes). However, EBV status does not currently change the standard treatment approach in most patients. Your report will record whether EBV was detected or not, and your care team can explain what this finding means in your specific context.

Staging

Classic Hodgkin lymphoma is staged using the Lugano classification (a modification of the Ann Arbor staging system), which describes how widely the lymphoma has spread in the body. Staging is determined by PET/CT imaging, blood tests, and sometimes bone marrow biopsy, and is essential for selecting the right treatment intensity.

Stage I — A single lymph node region or a single extranodal site is involved.
Stage II — Two or more lymph node regions on the same side of the diaphragm (the muscle separating the chest from the abdomen) are involved.
Stage III — Lymph node regions on both sides of the diaphragm are involved.
Stage IV — The lymphoma has spread to one or more organs outside the lymphatic system, such as the bone marrow, liver, or lung.

The letters A and B are added to the stage to indicate whether B symptoms are absent (A) or present (B). The designation E is added when a single extranodal site adjacent to a nodal region is involved. Bulky disease — typically defined as a mass measuring 10 cm or more, or a mediastinal mass exceeding one third of the chest diameter on imaging — is also noted because it influences treatment decisions. Stages I and II are considered limited or early-stage disease; stages III and IV are considered advanced-stage disease. PET/CT is the preferred imaging modality because it identifies areas of metabolically active disease and, crucially, allows assessment of treatment response during and after therapy.

What is the prognosis?

Classic Hodgkin lymphoma has one of the highest cure rates of any cancer, including among cancers that have spread widely at diagnosis. Overall, approximately 85–90% of patients with classic Hodgkin lymphoma are cured with modern treatment. Even in patients with advanced-stage disease (stage III–IV), long-term remission rates exceed 70–80% with current chemoimmunotherapy regimens.

Prognosis varies by stage, subtype, and individual patient factors. Specific features associated with outcomes include:

Stage — Limited-stage (I–II) disease without bulky disease has a cure rate approaching 90–95%. Advanced-stage disease (III–IV) has a somewhat lower cure rate but remains highly treatable, with most patients achieving long-term remission.
Bulky disease — Large mediastinal or nodal masses are associated with a higher risk of relapse and typically require more intensive treatment.
B symptoms — The presence of fever, night sweats, or significant weight loss at diagnosis (B symptoms) is associated with a modestly less favorable prognosis than A-stage disease at the same stage.
EBV status — In immunocompromised patients, EBV-positive disease is generally associated with a more aggressive course; in immunocompetent patients, EBV status has a smaller prognostic impact with modern therapy.
Subtype — Lymphocyte-rich and nodular sclerosis subtypes generally have excellent prognoses. Lymphocyte-depleted subtype has historically had a less favorable prognosis, though outcomes have improved with modern regimens.
Response to initial treatment — PET/CT after the first two cycles of chemotherapy (called interim PET) is one of the strongest predictors of outcome. Patients who achieve a complete metabolic response early in treatment have a much better prognosis than those with persistent disease.

It is important to know that for patients who relapse after first-line treatment, salvage chemotherapy followed by autologous stem cell transplantation — where a patient’s own stem cells are collected, preserved, and returned after intensive chemotherapy — is effective in approximately 50% of relapsed cases. Newer agents including brentuximab vedotin (targeting CD30) and checkpoint inhibitors such as pembrolizumab and nivolumab (targeting the PD-1/PD-L1 pathway) have transformed the management of relapsed and refractory disease.

What happens after the diagnosis?

After the diagnosis of classic Hodgkin lymphoma is confirmed, staging evaluation is completed before treatment begins. Most patients are referred to a hematologist or lymphoma oncologist. Treatment is highly effective and the goal in most patients is cure.

For limited-stage disease (stage I–II) without unfavorable features, the standard approach is a short course of combination chemotherapy — most commonly ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for two to four cycles — followed by involved-site radiation therapy to the areas where lymphoma was present. In selected patients, chemotherapy alone (without radiation) may be considered to reduce long-term radiation-related side effects. An interim PET/CT after the first two cycles guides whether the treatment plan needs adjustment.

For limited-stage disease with unfavorable features (such as bulky disease, B symptoms, or multiple lymph node regions involved), a more prolonged chemotherapy course is used, typically four to six cycles, often with radiation to bulky sites.

For advanced-stage disease (stage III–IV), the standard treatment is six cycles of ABVD chemotherapy, or an intensified regimen called BV-AVD (brentuximab vedotin replacing bleomycin). Interim PET after two cycles guides ongoing treatment. Radiation therapy is used selectively in patients with residual PET-positive disease after chemotherapy.

For relapsed or refractory disease, salvage chemotherapy regimens are used to achieve a second remission, followed by autologous stem cell transplantation in eligible patients. Brentuximab vedotin and checkpoint inhibitors (pembrolizumab, nivolumab) are important options in relapsed settings. Allogeneic stem cell transplantation is considered for selected patients with multiply relapsed disease.

Long-term follow-up is important after treatment for classic Hodgkin lymphoma, not only to monitor for relapse but also to screen for late effects of treatment — including cardiovascular disease, secondary cancers, and endocrine effects — which become relevant particularly for patients treated with radiation or certain chemotherapy agents at a young age.

Questions to ask your doctor

What subtype of classic Hodgkin lymphoma do I have — nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted?
Was EBV found in my biopsy, and what does that mean for my treatment and prognosis?
What stage is my lymphoma, and do I have bulky disease or B symptoms?
What treatment regimen are you recommending, and how many cycles will I need?
Will I need radiation therapy, and if so, to which areas?
How will you know if the treatment is working — will I have a PET scan after the first two cycles?
What are the most important short-term and long-term side effects of the treatment plan?
What is the expected cure rate for my stage and subtype?
What happens if my lymphoma does not respond or comes back after treatment?
Should I consider fertility preservation before starting chemotherapy?
What follow-up will I need after completing treatment, and what late effects should I be monitored for?
Are there clinical trials I should consider?