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Hodgkin lymphoma Last updated: September 14, 2021

Summary

Hodgkin lymphoma (HL) is a malignant lymphoma that is typically of B-cell origin. The incidence of HL has
a bimodal age distribution, with peaks in the 3rd and 6th–8th decades of life. The WHO classifies HL into
two types: classical HL (CHL) and nodular lymphocyte-predominant HL (NLPHL). CHL is further divided
into four subtypes, which are nodular sclerosis (most common), mixed cellularity, lymphocyte-depleted,
and lymphocyte-rich CHL. Risk factors for developing HL include a history of infectious mononucleosis
caused by the Epstein-Barr virus (EBV) and immunodeficiency (e.g., HIV infection). HL typically presents
with painless cervical lymphadenopathy, fever, night sweats, and involuntary weight loss. Pel-Ebstein
fevers (cyclical fever with periods of both high and normal temperature) and alcohol-induced pain at
affected lymph nodes are less common but specific for HL. Suspicious lymph nodes are excised and
definitive diagnosis is made via histological analysis, which characteristically reveals pathognomonic
Reed-Sternberg cells (malignant B-cells). The modified Ann Arbor classification (Cotswold staging
system) is used to stage HL based on both the localization of the lymphoma with respect to the diaphragm
and on the presence of systemic symptoms. Treatment is typically initiated with curative intent. In early
stages, treatment is generally limited to involved-field radiation and chemotherapy. In later stages, when
local radiation is often unsuccessful or not feasible due to tumor spread, polychemotherapy is the
mainstay of treatment.

Epidemiology

Incidence

2–3/100 000 per year [1]

Subtype variance with age (see “Pathology” below)

Young adults: nodular sclerosing HL

Elderly adults: mixed-cellularity HL

Age: bimodal distribution [2]

1st peak: 25–30 years

2nd peak: 50–70 years

[2]
Sex: ♂ > ♀

Male predominance, especially in pediatric cases

Exception: ♀ = ♂ in nodular sclerosing HL (most common type)

Epidemiological data refers to the US, unless otherwise specified.

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Etiology

The exact causes are unknown, but several risk factors have been associated with HL. [3][4]

Strong association with Epstein-Barr virus (EBV)

Immunodeficiency: e.g., organ or cell transplantation, immunosuppressants, HIV infection ,

chemotherapy

Autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis)

Clinical features

Painless lymphadenopathy

Cervical lymph nodes (in ∼ 60–70% of patients) > axillary lymph nodes (in ∼ 25–35% of patients) >
[5]
inguinal lymph nodes (in ∼ 8–15% of patients)

Involvement of a single group of lymph nodes

Contiguous pattern of lymph node spread

Mediastinal mass → chest pain, dry cough, and shortness of breath

Splenomegaly or hepatomegaly may occur if the spleen or liver are involved.

B symptoms [5]

Night sweats, weight loss > 10% in the past 6 months, fever > 38°C (100.4°F)

Can occur in a variety of diseases (see “Differential diagnosis of B symptoms” below)

In the case of confirmed HL, the presence of a single B symptom suffices for a positive diagnosis of
B symptoms.

Pel-Ebstein fever: Intermittent fever with periods of high temperature for 1–2 weeks, followed by
afebrile periods for 1–2 weeks. Relatively rare but very specific for HL.

Alcohol-induced pain: Pain in involved lymph nodes after ingestion of alcohol. Relatively rare but
highly specific for HL.

Pruritus (focal or generalized)

Stages

Lugano classification (based on the Cotswolds modified Ann Arbor system) [6][7][8]

Stage Description

I Involvement of 1 lymph node area (IN), or 1 extranodal (IE) focus

II Confined to one side of the diaphragm: Involvement of ≥ 2 (IIN) lymph node areas or extranodal foci (IIE)

III On both sides of the diaphragm: Involvement of ≥ 2 (IIIN) lymph node areas or extranodal foci (IIIE)

IV Disseminated spread into one or more extralymphatic organs independent of lymph node involvement

Additional modifiers
Primarily involved tissue: nodal (N) or extranodal (E)

Symptoms
A: if asymptomatic
B: if B symptoms present
Bulky disease (X)

Staging is based on the number of affected nodes, the presence or absence of B symptoms,
and whether or not the disease is present on both sides of the diaphragm.

Diagnostics

Diagnosis of HL is primarily based on medical history and clinical features (B symptoms, localization of
lymph node involvement) and is confirmed with lymph node biopsy.
Blood tests

Complete blood count

Elevated or decreased WBC count

Anemia

Eosinophilia

Serum chemistry

↑ LDH

Hypercalcemia; : most commonly due to paraneoplastic production of 1,25-dihydroxyvitamin D

Histology

Obligatory diagnostic step

Lymph node excision

Reed-Sternberg cells (RSCs)

Tumor cells that are pathognomonic of HL

Originate from B cells

Large cells with binuclear/bilobed nuclei with dark centers of chromatin and pale halos, which
results in an owl-eye appearance on histopathologic examination.

CD15/CD30-positive

Hodgkin cells: mononuclear, malignant B lymphocytes

Inflammatory background containing the following cell types in varying numbers: lymphocytes,
neutrophils, eosinophils, macrophages/histiocytes, plasma cells, and fibroblasts

Granuloma formation

Reed-Sternberg cells are bi(2)nucleate with CD15/CD30 positivity. To recall the cell
markers, remember that 2 x 15 = 30.

Imaging

Chest x-ray or CT-scan: detection and measurement of masses and enlarged lymph nodes in chest,
abdomen, and pelvis

Bone scintigraphy or PET-CT: performed before treatment to assess disease spread

Pathology

Histological classification of Hodgkin lymphoma (WHO)

Classification Subtype Characteristics Prognosis Pathology

Classical Nodular Most common Good Nodules of Reed-Sternberg cells

subtype (> 60%) within lacunae, separated by
Hodgkin sclerosing
collagenous tissue with sclerosing
Localization: mostly
lymphoma classical HL ( appearance (hence the name
mediastinal and
(95%) NSHL) “nodular sclerosing”).
cervical
Lymphocyte rich.

Mixed- Commonly found in Good Nodules with numerous

immunocompromised (but Reed-Sternberg cells, and
cellularity
patients (e.g., HIV- slightly increased number of histiocytes,
classical HL ( positive individuals) worse eosinophils, and plasma cells
MCHL) than (hence the name “mixed-
Localization: mostly
NSHL) cellularity”).
abdominal and
splenic

Lymphocyte- Rare Very Presence of Reed-Sternberg cells,

good and reactive lymphocytosis that
rich classical Localization: mostly
causes distortion of the
cervical and axillary
HL (LRHL) lymph node architecture.

Lymphocyte- Very rare (< 1%) Poor Numerous Reed-Sternberg cells,

and decreased number of
depleted Commonly found in
lymphocytes.
immunocompromised
classical HL (
patients
LDHL)
Localization: mostly
below the diaphragm

Lymphocyte Nodular Rare (5%) Very Presence of popcorn cells: a

good variant of a Reed-Sternberg cell
predominant lymphocyte Localization: mostly
(but characterized by polylobulated
neck, axillary, and
Hodgkin predominant slightly nuclei that resemble popcorn.
inguinal [9]
lymphoma HL (NLPHL) worse Lymphocyte predominant (LP)
(5%) than cells express CD20, CD79a, and
LRHL)
CD45. [10]

Unlike in classical Hodgkin

lymphoma, tumor cells are
negative for CD15 and CD30. [10]

Differential diagnoses

Hodgkin vs Non-Hodgkin lymphoma

Hodgkin lymphoma vs non-Hodgkin lymphoma

Feature Hodgkin lymphoma Non-Hodgkin lymphoma

Age distribution Bimodal (late adolescence and older Increases with age (peak > 50 years)
adulthood)

Etiology Immunosuppression (e.g., HIV) Chromosomal translocation, commonly t(14;18)

EBV infection Autoimmune diseases (e.g., Hashimoto thyroiditis,

rheumatic disease)
Infections (HIV, EBV, HTLV-1)

Lymph node Lymph node groups localized above Multiple lymph node groups
the diaphragm
involvement Noncontiguous spread
Contiguous spread Extranodal involvement common
Extranodal involvement rare

Histology Reed-Sternberg cells Majority are neoplastic cells of B-cell lineage

Prognosis Good Worse .

Differential diagnoses of lymphadenopathy

Examining lymph nodes can yield important diagnostic clues. Generalized lymphadenopathy is usually a
sign of systemic illness, such as HIV, mycobacterial infection (e.g., tuberculosis), infectious mononucleosis,
systemic lupus erythematodes, or serum sickness. Signs of malignancy include rapid growth, painlessness,
hardness/coarseness, and being fixed to underlying or surrounding tissue. Most often, though, there is no
discernible cause or pathology.

Feature Normal Infection Malignancy

Size < 1 cm > 1 cm > 1 cm

Consistency Soft Hard (various malignancies)

Rubbery (typical of lymphoma)

Tender/nontender Nontender Tender Nontender

Fixation Freely movable May be fixed or freely movable Fixed to the underlying tissue

Differential diagnosis of B symptoms

Non-Hodgkin lymphomas, Hodgkin lymphomas

Other hematopoietic malignancies (e.g. CML, ALL)

Solid tumors

Tuberculosis

HIV

Differential diagnosis of granulomatous disease

See differential diagnosis of granulomatous disease

The differential diagnoses listed here are not exhaustive.

Treatment

Early stage (I and II): combination of chemotherapy and radiation therapy

The most widely used chemotherapy approach is ABVD: adriamycin (doxorubicin), bleomycin,
vinblastine, dacarbazine

Advanced stage (III and IV and often II with bulky disease): combination chemotherapy with
radiation therapy in select cases

Three possible treatment approaches are commonly considered:

ABVD

Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide,

prednisone

BEACOPP: bleomycin, etoposide, adriamycin (doxorubicin), cyclophosphamide, oncovin (

vincristine), procarbazine, prednisone

Primary refractory or relapsed disease: trial of alternative chemotherapy or consideration of high-dose

chemotherapy and autologous stem cell transplantation

Independent of stage, treatment is typically initiated with curative intent.

Prognosis

Good prognosis

5-year survival rate ∼ 80–90% (in children > 90%)

Best prognosis: lymphocyte-rich classical HL and (LRHL) and nodular lymphocyte predominant HL (
NLPHL)

Prognosis is largely determined by disease stage (i.e., lower stage has a better prognosis)

∼ 10–20% of patients will develop secondary malignancies (especially lung cancer; related to
radiation therapy and chemotherapy) [11]

Unfavorable factors for Hodgkin lymphoma (relevant when selecting a treatment regimen)

High ESR

High LDH

Involvement of three or more lymph node areas

Large mediastinal tumor

Bulky disease (tumors measuring ≥ 10 cm across) [12][13]

International Prognostic Score (IPS): evaluation of prognosis in patients with advanced disease (for
each factor present, the patient receives one point)

IPS factors

Albumin < 4 g/dL

Hemoglobin < 10.5 g/dL

Gender ♂

Age ≥ 45 years

Stage IV disease

Leukocytosis: white cell count (WBC) > 15,000/μL

Lymphopenia: lymphocyte count < 8% of WBC count and/or absolute lymphocyte count < 600
cells/μL

IPS categories: Based on the calculated IPS, patients can be categorized as follows:

Good prognosis (IPS 0–1)

Fair prognosis (IPS 2–3)

Poor prognosis (IPS 4–7)

References

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