Hodgkin Lymphoma
by D. Grenzelias, M.D., Hematologist


The term lymphoma describes a heterogeneous group of malignancies of the immune system. In general, lymphomas are divided into 2 large groups of neoplasms: 

  • Non-Hodgkin lymphoma (comprising 85% of all malignant lymphomas)
  • Hodgkin Lymphoma.

Hodgkin Lymphoma is a cancer of lymph tissue. This lymphoid malignancy involves usually peripheral lymph nodes but can also affect organs such as liver, lung and bone marrow.



It is one of the most common lymphomas in the Western world, with 3 cases per 100,000 individuals every year. Across age groups, Hodgkin Lymphoma peaks in young adults (aged 15-34) and older individuals (older than 55). Compared with North America and Europe, Hodgkin Lymphoma is relatively rare in Japan and China. Overall, the disease is somewhat more common in males than in females, with this difference being more evident in children.


Etiology and risk factors

Hodgkin Lymphoma does not have known causes, but there are some risk factors that increase the chance that a person will develop the disease.

Specifically, past infection with the Epstein-Barr virus (EBV) is thought to contribute to some cases of the disease, since epidemiologic studies have shown an increased risk of EBV-positive Hodgkin Lymphoma in patients with a self-reported history of infectious mononucleosis in adolescence.

Also, individuals with HIV infection are at increased risk to develop Hodgkin Lymphoma compared to the general population, although Hodgkin Lymphoma is not considered an acquired immunodeficiency syndrome (AIDS)-defining neoplasm.

Other risk factors for Hodgkin Lymphoma are the suppression of the immune system (called immunosuppression, inherited or caused by immunosuppressant treatment usually following an organ transplant) and family history. Family members of a person with Hodgkin Lymphoma may also have an increased chance of developing the disease.

Clearly, a person with characteristics from one or more of the above risk factors will not necessarily develop Hodgkin Lymphoma.  



According to the World Health Organization (WHO), Hodgkin Lymphoma is sub-classified into the following 5 types:

  1. nodular sclerosis
  2. mixed cellularity
  3. lymphocyte depleted
  4. lymphocyte rich
  5. nodular lymphocyte predominant Hodgkin disease (NLPHD).

The first four subtypes are collectively called classical Hodgkin Lymphoma


Signs and Symptoms

Symptoms that may occur with this disease are:

  • Painless enlargement of lymph glands more often in the neck and the armpits and less often in the groins
  • Fatigue
  • Fever and chills that come and go
  • Soaking night sweats
  • Weight loss that cannot be explained
  • Fever, night sweats and weight loss represent the constitutional symptoms of the disease known as “B symptoms”.
  • Itching all over the body that cannot be explained
  • Chest pain, cough, shortness of breath if there are swollen lymph nodes in the chest
  • Pain or feeling of fullness below the ribs due to swollen spleen or liver
  • Pain at disease sites, precipitated by drinking alcohol (specific for Hodgkin lymphoma)
  • Rarely, back or bone pain

The physical findings in Hodgkin lymphoma are:

  • Palpable, painless lymph nodes in the neck, armpits, or groin
  • Palpable spleen and/or liver
  • Superior Vena Cava Syndrome: in patients with massive lymph node enlargement in the chest pressure in the veins of the face and arms causes swelling in these areas
  • Rarely, central nervous system signs due to paraneoplastic syndromes


Diagnosis of Hodgkin Lymphoma

If Hodgkin Lymphoma is suspected from the medical history and physical examination, the doctor may order:

  1. Laboratory tests:
  • Full Blood Count and Erythrocyte Sedimentation Rate (ESR).
  • Biochemistry tests, including Lactate Dehydrogenase (LDH), serum creatinine and alkaline phosphatase (ALP).
  • A test for HIV infection since antiviral therapy can improve disease outcome in HIV positive patients.
  • Screening for hepatitis B and C.
  1. Imaging studies, including:
  • Chest x-rays to check for swollen glands in the mediastinum and measure any mediastinal mass related to thoracic diameter.
  • Computed Tomography (CT), which has largely replaced chest x-ray. CT scans of neck, chest, abdomen, and pelvis may reveal enlarged lymph nodes, lesions in the liver and/or spleen, nodules or infiltrates in the lung, and pleural effusions.
  • Positron Emission Tomography (PET) scanning is nowadays considered essential to the initial staging of Hodgkin Lymphoma.
  1. A lymph node biopsy is recommended, since biopsy is the only reliable way to diagnose Hodgkin Lymphoma. The biopsy may remove an entire lymph node (excisional biopsy) or only part of a lymph node (incisional biopsy). A thin needle biopsy (known as fine needle aspiration) cannot remove a good enough specimen for the pathologist to confirm Hodgkin Lymphoma diagnosis.
  2. If a diagnosis of Hodgkin Lymphoma is confirmed, bone marrow biopsies are indicated in some cases, especially in advanced-stage or high-risk disease.


Stages of Hodgkin Lymphoma

For Hodgkin Lymphoma staging following classification is used:

  • Stage 1: Hodgkin Lymphoma affects one only group of lymph nodes. Rarely, the disease may be found in an organ other than a lymph node and in only that one organ.
  • Stage 2: Lymphoma is found in at least two lymph node groups, which are on the same side of the diaphragm.
  • Stage 3: Lymphoma cells are in lymph nodes on both sides of the diaphragm. The spleen may also be affected.
  • Stage 4: Disseminated disease or multiple involvement of organs others than lymph nodes such as liver and lung. Other less common sites of Hodgkin Lymphoma involvement include bone, bone marrow, skin, kidneys, digestive tract, ovaries or testicles

Each stage may be further described as either A or B:

A: without symptoms, such as weight loss, drenching night sweats, or fevers.

B: with one or more of the above symptoms

The stage can also be described with an E, S or both:

E: Extranodal or outside the lymph system.

S: The spleen is affected by Hodgkin Lymphoma.

There is another set of 3 subgroups, which is important for the therapeutic approach followed. These subgroups are defined based on the clinical scenario, the stage and the degree of end-organ damage, as follows:

  • Early-stage favorable Hodgkin Lymphoma: Stage 1 or 2 and no risk factors (with small differences among different organizations as risk factors are considered ESR, B symptoms, age, bulky mediastinal mass, number of nodal sites and extranodal disease).
  • Early-stage unfavorable Hodgkin Lymphoma (bulky and non bulky): Stage 1 or 2, and one or more of the above risk factors.
  • Advanced-stage Hodgkin Lymphoma (includes patients with stages 3 and 4).


Further categorization for advanced disease patients

Patients with advanced disease are further risk stratified using the “International Prognostic Score” (IPS), which includes the following risk factors (each factor present corresponds to 1 point in the scale):

  • Serum albumin < 4 g/dL
  • Hemoglobin < 10.5 g/dL
  • Male gender
  • Age ≥ 45y
  • Stage 4 disease
  • Leukocytosis: white cell count (WBC) > 15,000/μL
  • Lymphopenia: lymphocyte count < 8% of WBC count and/or absolute lymphocyte count < 600 cells/μl

Based on the IPS score from the above factors, patients with advanced disease can be categorized as follows:

  • Good risk (IPS 0-1)
  • Intermediate risk (IPS 2-3)
  • Poor risk (IPS 4-7)


Treatment of Hodgkin Lymphoma

General treatment principles include the following:

  • Radiation therapy
  • Induction chemotherapy
  • Salvage chemotherapy
  • Hematopoietic stem cell transplantation


Early-stage favorable Hodgkin Lymphoma

The standard of care is chemotherapy regimen consisting of “ABVD”, a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine, on days 1 and 15; every 28 days for 2 cycles.


  1. If after these 2 cycles, a PET-CT confirms complete remission, two additional cycles of ABVD are administered, without any radiation.
  2. Alternatively, this is followed by radiation to the sites of disease localization at diagnosis (called Involved Field Radiation Therapy-IFRT).


Early-stage, unfavorable, nonbulky/bulky Hodgkin Lymphoma
  • ABVD regimen, as above, for 4 cycles, and Involved Field Radiation Therapy-IFRT.
  • Alternatively, patients with nonbulky disease can be treated with 6 cycles in total of systemic ABVD chemotherapy, if after the first two courses a PET-CT confirms complete remission.


Advanced-stage Hodgkin Lymphoma
  • Systemic chemotherapy with ABVD for 6 cycles with or without Involved Field Radiation Therapy.
  • Involved Field Radiation Therapy (IFRT) is strongly considered for those patients with bulky disease or those exhibiting a slow response to therapy by PET-CT.
  • Patients with advanced Hodgkin Lymphoma and International Prognostic Score (IPS) ≥ 4 may be treated with dose-escalated “BEACOPP” scheme (Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) for 4 cycles, followed by 4 standard doses of BEACOPP for early responders.
  • For slow responders, 4 additional dose-escalated BEACOPP are recommended.

An alternative and effective treatment option for patients interested in completing therapy earlier is the “Stanford V” regimen, a treatment combining chemotherapy and radiation. It consists of administration of systemic chemotherapy delivered over 8 weeks for early-stage disease or over 12 weeks for advanced-stage disease, followed by Involved Field Radiation Therapy (IFRT).


Relapsed/refractory Hodgkin Lymphoma

Although the prognosis of Hodgkin Lymphoma nowadays is excellent, it has been estimated that approximately 20-30% of all patients do not achieve a long lasting remission with front-line therapy or present refractory disease. These patients can be treated by salvage chemotherapy followed by High-Dose Chemotherapy and Autologous Stem Cell Transplantation (HDC-ASCT), leading to cure for approximately 50% of these patients.

The best timing for HDC-ASCT is after the first relapse.


Salvage Chemotherapy

The goal of salvage regimens is to reduce tumor burden in preparation for High-Dose Chemotherapy and Autologous Stem Cell Transplantation (HDC-ASCT), in an attempt to improve its outcome. A large number of regimens are used in the treatment of patients with relapsed/refractory Hodgkin Lymphoma, based on chemotherapy agents that are not resistant to those used in the front-line treatment.

For example, there is the ESHAP regimen (Etoposide, methylprednizolone, cisplatin, cytarabine), the DHAP regimen (Dexamethasone, cytarabine, cisplatin), ICE regimen (ifosfamide, carboplatin, etoposide), GVD (Gemcytabine, Vinorelbine, Liposomal Doxorubicin), etc.

There is no evidence in support of the superiority of any of the above regimens over the others. During recovery from the hematological toxicity usually after the second salvage chemotherapy course, hematopoietic stem cells from peripheral blood are collected and stored in order to support the HDC-ASCT.

After the maximum response with salvage chemotherapy has been achieved (usually 2-4 cycles) the patient proceeds to HDC-ASCT. The usual high dose regimen is called BEAM (BiCNU, Etoposide, Cytarabine and Melphalan); subsequently, the stored peripheral hematopoietic stem cells are re-infused in order to support bone marrow recovery.

For patients who are not eligible for HDC=ASCT (i.e. age above 65-70 years, with serious health conditions beyond the Lymphoma), salvage treatment remain a therapeutic challenge. Gemcytabine, Virinelbine and Vinblastine have shown an antitumor activity in relapsed/refractory patients. Bendamustine is also emerging as a potential therapeutic agent in relapsed/refractory setting, whereas targeted therapy with Brentuximab Vedotin holds a great promise for these patients. Other options for heavily pretreated patients with Hodgkin Lymphoma include Histone deacetylase inhibitors, immunomodulatory drugs and adoptive cell transfer.


Targeted therapy

Brentuximab-vedotin is a new class targeted agent for Hodgkin Lymphoma. This agent is indicated for treatment of Hodgkin Lymphoma after failure of Autologous Stem Cell Transplantation, or after failure of at least 2 prior chemotherapy regimens in patients who are not ASCT eligible.



Patient prognosis is largely based on the stage of the disease and various prognostic factors, which may be defined differently across various groups.

In general, the prognosis of Hodgkin Lymphoma is good, with an overall 5-year survival rate at 84.7%.



After treatment for Hodgkin Lymphoma, regular checkups (such as every 3 or 4 months for the first year and less often after that) are needed. Checkups help ensure that any health changes are noted and treated if needed.

Hodgkin Lymphoma may relapse after treatment. Checkups also help detect health problems related to treatment, such as heart disease, thyroid disease, or cancer. They may include a physical examination, blood tests, chest x-rays, CT scans, or other tests.


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