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Hodgkin’s lymphoma overview

Published: July 07, 2009. Updated: July 29, 2009

Hodgkin's disease is a type of lymphoma described by Thomas Hodgkin in 1832. The classical subtype is characterized by the presence of Reed-Sternberg cells.

The estimated new cases and deaths from Hodgkin's lymphoma in the United States in 2005 are:

  • New cases: 7,350

  • Deaths: 1,410

Due to the advances of therapy for Hodgkin's lymphoma over the past 4 decades more than 75% of all newly diagnosed patients can expect a disease-free normal life span.


It is slightly more common in males with a male-to-female ratio of Hodgkin's disease is 1.3 to 1.


Unlike other lymphomas, whose incidence increases with age, Hodgkin's lymphoma has a bimodal incidence curve: that is, it occurs more frequently in two separate age groups, the first being young adulthood (age 15-35), the second being in those over 50 years old.

Race and ethnicity

Hodgkin's disease occurs less commonly in African-Americans (2.3 cases per 100,000 persons) than in Caucasians (3.0 per 100,000 persons).


The age-specific incidence of Hodgkin's disease differs markedly in different countries. In Japan, the overall incidence is low and the early peak is absent. In some developing countries, there is a downward shift of the first peak into childhood.

Causes and risk factors

There are no well-defined risk factors for development of Hodgkin's lymphoma and its causes remain unknown. Certain associations have been noted that provide clues to possible etiologic factors. Familial aggregation may imply genetic factors, but other epidemiologic findings suggest an abnormal response to an infective agent. Both factors may play a role in the pathogenesis of the disease.

Familial factors

  • Same-sex siblings of patients with Hodgkin's disease have a 10 times higher risk for the disease. Patient-child combinations are more common than spouse pairings.
  • The monozygotic twin sibling of a patient with Hodgkin's disease has a 99 times higher risk of developing Hodgkin's disease than a dizygotic twin sibling of a patient with Hodgkin's disease.
  • Higher risk for Hodgkin's disease is associated with few siblings, single-family houses, early birth order, and fewer playmates all of which decrease exposure to infectious agents at an early age.


  • EBV: Epstein-Barr virus has been implicated in the etiology of Hodgkin's disease by both epidemiologic and serologic studies, as well as by the detection of the EBV genome in 20%-80% of tumor specimens.

  • HIV: Hodgkin's disease in HIV-positive patients is associated with an advanced stage and poor therapeutic outcome. However, there have been no conclusive studies regarding the possible increased frequency of Hodgkin's disease in patients with human immunodeficiency (HIV) infection.

Symptoms and signs

When to suspect

Consider HD in patients with unexplained lymphadenopathy that presents as follows:

  • In young adults with cervical, supraclavicular, or mediastinal lymphadenopathy
  • When accompanied by "B symptoms" which include pruritus, fevers, night sweats, or unexplained weight loss (>10% in <6 months), especially when signs or symptoms persist longer than 1 month.
  • Consider occult HD in patients with severe, persistent, unexplained fevers or night sweats, even if detailed investigation shows no lymphadenopathy or hepatosplenomegaly.
  • Consider HD in an asymptomatic patient if an anterior mediastinal mass is found on routine chest x-ray.

1. Lymph node enlargement

Hodgkin's disease is primarily a disease of the lymph nodes and commonly presents as an asymptomatic lymphadenopathy that may progress to predictable clinical sites.

Location of lymphadenopathy

There is considerable evidence that HL begins in a single group of lymph nodes and then spreads to contiguous lymph nodes, especially in NSHL or MCHL.[1] This important observation, first made over 50 years ago, continues to form the basis for determination of treatment strategies in patients with apparently localized HL treated with radiation therapy alone.

  • Cervical and/or supraclavicular involvement (94%).[2]
  • Mediastinal involvement (70%).
  • Axillary involvement (36%).
  • Inguinal involvement (9%).
  • All patients with axillary or inguinal involvement also had neck disease.

  • Disseminated lymphadenopathy is rare in patients with Hodgkin's disease, as is involvement of Waldeyer's ring and occipital, epitrochlear, posterior mediastinal, presacral, popliteal, hypogastric and mesenteric sites.
  • Most patients with NSHL or MCHL have a central pattern of lymph node involvement (cervical, mediastinal, paraaortic).

2. Extranodal involvement (rare)

Hodgkin's disease may affect extranodal tissues by direct invasion (contiguity; the so-called E lesion) or by hematogenous dissemination (stage IV disease). The most commonly involved extranodal sites are the spleen, lungs, liver, and bone marrow.

  • The spleen is involved more frequently in patients with adenopathy below the diaphragm, systemic symptoms, and MC histologic type.
  • Involvement of the liver in an untreated patient is rare and almost always occurs with concomitant splenic involvement.
  • Infiltration of the bone marrow is usually focal and almost invariably associated with extensive disease and systemic symptoms.

3. Systemic symptoms

About 30% of patients experience systemic symptoms. They include fever, drenching night sweats, or weight loss >10% in < 6 months (so-called B symptoms) and chronic pruritus. These symptoms occur more frequently in older patients and have a negative impact on prognosis.

Clinical manifestations of subtypes

1. Nodular sclerosis

  • Incidence: 80%
  • Gender: Females have a slightly higher incidence.
  • Age: 15-40yrs.
  • Mediastinal and supradiaphragmatic lymphadenopathy is common.
  • The disease mainly presents in the earlier stages (I-III).

2. Mixed cellularity

  • Incidence: 20%
  • Age: 30-50yrs.
  • Abdominal lymphadenopathy and splenic involvement is common.
  • The disease mostly presents in later stages (II-IV).

3. Lymphocyte predominant

  • Incidence: 5%.
  • Gender: Males.
  • Age: 20-40yrs.
  • Commonly presents as localized disease. Characterized by late relapses and transformation to high-grade B-NHL.
  • The disease mainly presents as stage I-IIA.

4. Lymphocyte depletion

  • Incidence: <5%.
  • Gender: Males.
  • Age: 40-80yrs.
  • Underdeveloped countries.
  • HIV positive individuals.
  • Commonly presents as late stage disease with organ involvement (liver and bone marrow) and without lymphadenopathy.
  • The disease mainly presents as stage III-IVB.


Hodgkin's disease must be distinguished from non-cancerous causes of lymph node swelling (such as various infections) and from other types of cancer especially Non-Hodgkin's lymphoma. Definitive diagnosis is by lymph node biopsy (removal of a lymph node for pathological examination). The pathological diagnosis of Hodgkin's lymphoma depends on the presence of Reed-Sternberg cells and their variants in the biopsy material.

Excisional biopsy

Because the lymph node architecture is important for histological classification, an excisional lymph node biopsy is recommended.

Fine needle aspiration

When a patient presents with neck lymphadenopathy that may be due to a head and neck cancer, a fine-needle aspiration is usually advised as the initial diagnostic step, followed by excisional biopsy if squamous cell histology is excluded. A concern exists that an incisional or a needle-core biopsy will result in regional spread of a head and neck squamous cell carcinoma.


The World Health Organization classification system combines nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted subtypes of HD under the subheading "classic HD".[3] Immunohistochemistry may be required in the diagnosis of some cases.

Classical Hodgkin's Lymphoma (CD15+, CD30+, CD20-, CD45-)

  • H-RS cells frequently express CD30 and CD15 (80% of cases)
  • expression of CD20 on a minor sub-population of H-RS cells in up to 2/3 of cases
  • vast majority of cases show expression of a 55kD actin-bundling protein termed FASCIN in the H-RS cells.
  • evidence of Epstein-Barr virus either by LMP1 immunohistochemistry or by EBER in situ hybridisation in up to 30% of cases in UK
  • lymphoid population shows a predominance of CD4+ peripheral T-cells adjacent to the H-RS cells, around which they may form rosettes.

Nodular Lymphocyte Predominant Hodgkin's Lymphoma (CD20+, CD45+, CD15-, CD30-)

  • nodules are composed of mantle zone B-cells expressing IgM and IgD, with admixed follicular dendritic cells
  • L&H cells have a B-cell phenotype expressing CD20 and CD79a, and show evidence of immunoglobulin-synthetic capacity with expression of cytoplasmic J-chain
  • epithelial membrane antigen is frequently expressed by the L&H cells
  • numerous T-cells are also present with a CD4 predominance, some co-expressing the germinal centre-associated T-cell marker CD57. T-cells form rosettes around the L&H cells.


The cytogenetics of both Classical HL and the rare cases of Nodular Lymphocyte Predominant HL which have been karyotyped show complex numerical and structural abnormalities affecting all chromosomes, with as yet no identifiable non-random cytogenetic abnormality.

Molecular genetics

  • molecular genetic analysis of micro-dissected single H-RS cells from cases of classical HL demonstrate clonal hypermutated immunoglobulin heavy chain genes with 'crippling' mutations.
  • similar analysis of L&H cells from cases of Nodular Lymphocyte Predominant HL show somatically hypermutated immunoglobulin heavy chain genes without crippling mutations and ongoing antigen-driven hypermutation in an identical fashion to the follicle centre lymphomas.

Differential diagnosis

Non-Hodgkin's lymphoma is the most important item in the differential diagnosis of Hodgkin's lymphoma. A biopsy usually settles the confusion. However, there is occasional difficulty differentiating HD from T-cell rich B-cell NHL, anaplastic large cell lymphoma or peripheral T-cell lymphoma, because of overlapping clinical and pathologic characteristics.



Classical Hodgkin's Lymphoma (95%)

CHL is defined by the presence of classic, diagnostic RS cells in a background of either nodular sclerosis (NS), MC, or lymphocyte depletion, with (when studied) the immunophenotype of CHL (CD15+ CD30+, T- and B-cell associated antigens usually negative). CHL includes NSHL, MCHL, and LDHL, as well as the proposed new category of LRCHL. The immunophenotype, genetic features, and postulated normal counterpart are the same for all of the classic types.

I) Nodular sclerosis (80%)

  • Characterized by nodular growth pattern with fibrous bands separating the nodules in most cases; diffuse areas are common, as is necrosis. Capsular fibrosis frequently seen.
  • A cytological spectrum of diseases ranging from an abundance of lymphocytes with scanty Hodgkin's Reed-Sternberg (H-RS) cells to a lymphocyte-depleted appearance with abundant tumor cells.
  • predominant morphology of the H-RS cells is the lacunar cell, characterized by lobulated nucleus, prominent eosinophillic nucleolus and abundant clear cytoplasm.
  • grading system devised by British National Lymphoma Investigation recognized 2 grades:
    • Grade II: an aggressive subtype that is characterized by 25% or more of cellular nodules showing lymphocyte depleted or pleomorphic cytological features.
    • Grade I: All other cases including borderline cases categorized as grade I (low grade).

II) Lymphocyte-rich classical Hodgkin's Lymphoma (5%)

Some cases of HL with RS cells of classic type, both by morphology and immunophenotype, may have a background infiltrate that consists predominantly of lymphocytes, with rare or no eosinophils.

  • Characterized by lymphocyte-rich cellular background containing typical H-RS cells, maybe nodular or diffuse.
  • when nodular, it is characterised by expanded mantle zone regions colonized by H-RS cells. There is a relative paucity of H-RS cells, histiocytes, plasma cells and eosinophils.

III) Lymphocyte depletion (1%)

The infiltrate in LDHL is diffuse and often appears hypocellular, due to the presence of diffuse fibrosis and necrosis. There are large numbers of RS cells and bizarre "sarcomatous" variants, with a paucity of other inflammatory cells. Confluent sheets of RS cells and variants may occur and rarely predominate (reticular variant or Hodgkin's sarcoma).

  • includes diffuse fibrosis and reticular Hodgkin's disease from the Lukes and Butler classification.
  • now very rarely diagnosed, and it is recognized that many cases previously diagnosed as HD (lymphocyte-depletion) are in fact examples of non-Hodgkin's lymphoma, commonly of anaplastic large cell type Anaplastic Large Cell Lymphoma.
  • the majority of cases of show morphological features of diffuse fibrosis characterized by a hypocellular background containing bizarre H-RS cells and associated with non-collagenous fibrosis.

IV) Mixed cellularity (20%)

  • Classical Hodgkin's Lymphoma lacking histological features which would otherwise permit classification as a specific subtype.

Nodular Lymphocyte Predominant Hodgkin's Lymphoma (5%)

  • may show partial or total nodal effacement by a nodular, or nodular and diffuse proliferation of small lymphoid cells.
  • a characteristic H-RS cell variant is present termed the L&H (or 'popcorn') cell characterized by a lobulated and twisted nucleus, and a nucleolus which is typically smaller than that seen in H-RS cells of Classical HL.
  • the number of popcorn cells is variable and may comprise up to 10% of the cellular population within the nodules. Collagenous fibrosis is uncommon.
  • classical H-RS cells are extremely rare and are not required for the diagnosis.

Transformation and progression

Classical HL

  • relapsing cases have a tendency to increase the numbers of H-RS cells present which maybe associated with depletion of lymphoid cells
  • the development of secondary NHL occurs in about 0.8% of cases at 25yrs.

Nodular Lymphocyte Predominant HL

  • relatively high frequency of developing secondary NHL (3.8% at 25yrs), most of which are diffuse large B-cell lymphoma, but rare cases of peripheral T-cell lymphoma have been described.
  • the development of secondary non-Hodgkin's lymphoma is usually associated with multiple relapses.

Staging and prognostic factors

Staging techniques -

Supradiaphragmatic involvement

Chest x-ray

Over 60% of patients with newly diagnosed HL have radiographic evidence of intrathoracic involvement. Frontal and lateral chest radiographs should be routinely ordered and also represent a low-cost method for subsequent surveillance.

Computed (axial) tomography (CT)

Computed (axial) tomography (CT) has become the standard thoracic staging examination for patients with HL, both for determination of sites of initial involvement in the chest and for determination of the extent of the mediastinal adenopathy.


  • CT scan has a sensitivity of 80% and a specificity of 70% in detection of lymphoma.

Subdiaphragmatic involvement

Computed (axial) tomography (CT)

CT scan of the abdomen and pelvis is essential in staging of lymphoma (enlarged lymph nodes, splenomegaly, filling defects in liver and spleen).


  • CT scan has a sensitivity of 80% and a specificity of 70% in detection of lymphoma. The detection of Hodgkin's disease in normal-size nodes is problematic.

  • CT, MRI have a 20% to 25% false-negative rate as a consequence of the inability to detect occult Hodgkin's disease in the spleen.

PET scan

PET (FDG-glucose) scanning is gaining wider acceptance as a potential diagnostic approach for staging at diagnosis, response assessment, and relapse.

Hematologic involvement

Complete blood count (CBC)

A complete blood count with differential should be performed. A moderate to marked leukemoid reaction and thrombocytosis are common, particularly in symptomatic patients, and usually disappear with treatment.

Laboratory findings such as leukopenia, anemia and thrombocytopenia are indications for performing a bone marrow biopsy.

Bone marrow biopsy

Core-needle biopsy of bone marrow from the posterior iliac crest is indicated in patients with stages IIB to IV disease.

Laboratory findings such as leukopenia, anemia, thrombocytopenia, and an elevated alkaline phosphatase level may give indications of bone marrow infiltration.

Surgical laparotomy

Staging laparotomy is no longer recommended routinely; it should be considered only when the results will allow substantial reduction in treatment. It should not be done in patients who require combination chemotherapy. If the laparotomy is required for treatment decisions, the risks of potential morbidity should be considered.


Erythrocyte sedimentation rate (ESR)

An elevated ESR level has prognostic significance (see below). Some physicians use ESR levels in the follow up of patients with Hodgkin's disease. A sustained elevation in ESR may be a predictor of an early relapse following chemotherapy.[4]

CNS involvement

Hodgkin's disease (now referred to as Hodgkin's lymphoma by the WHO) involves the CNS in 0.2% to 0.5% of cases either by contiguous or hematogenous spread. CSF cytology and CT/MRI of the brain is only warranted if there is suspicion based on symptoms.

Staging of Hodgkin's disease

On the basis of this staging, the patient will be classified according to a staging classification (the Ann Arbor staging classification scheme is a common one):

  • See staging system for Hodgkin's disease

Prognostic factors

Among the patients with early-stage disease, who had previously continued to receive radiotherapy alone, an "unfavorable" subgroup is often defined to select patients for combined modality therapy.

Prognostic Factors for Early Stages

  • Advanced age: correlates with the presence of occult abdominal disease and with poor results of salvage therapy; may also be associated with treatment complications leading to reduced or delayed treatment
  • Male gender: small effect only
  • Histologic MC subtype: associated with presence of occult abdominal disease
  • B symptoms: associated with presence of occult abdominal disease
  • Large mediastinal mass: some evidence of increased relapse rate in thorax (little data, because few patients with large mediastinal masses were treated with radiotherapy alone)
  • Greater number of involved nodal regions
  • Elevated erythrocyte sedimentation rate (ESR)
  • Anemia
  • Low serum albumin level

Prognostic Factors for Advanced Stages

In its most basic form, stage IIIB or IV, or advanced-stage, disease has been associated with the poorest prognosis, and these patients have been assigned an intensive chemotherapy protocol, sometimes followed by adjuvant radiotherapy. Further prognostic factors were often used to assign patients with stage IIIA or IIB disease to the advanced-stage group.

- The International Prognostic Index (IPI)

In 1996, an international effort identified seven prognostic factors that accurately predict the success rate of conventional treatment in patients with locally extensive or advanced stage Hodgkin's disease.

The prognostic factors identified in the international study are:

  • Age >= 45 years
  • Male sex
  • Stage IV disease
  • White blood count >= 15,000/ul
  • Lymphocyte count < 600/ul or < 8%
  • Hemoglobin < 10.5 mg/dl
  • Albumin < 4.0 mg/dl

Freedom from progression (FFP) at 5 years was directly related to the number of factors present in a patient. The 5-year FFP for patients with zero factors is 84%. Each additional factor lowers the 5-year FFP rate by 7%, such that the 5-year FFP for a patient with 5 or more factors is 42%.

A number of other factors have been shown to correlate with prognosis in advanced stages, but their independent importance is not proven due to conflicting results or lack of confirmation in a large data set. These include higher pathologic grade in NSHL, tissue eosinophilia, inguinal involvement, and high levels of serum lactate dehydrogenase and beta-2-microglobulin.



Hodgkin's disease is sensitive to radiation and many chemotherapeutic drugs, and, in most stages, there is more than one effective treatment option. Disease stage is the most important determinant of treatment options and outcome. All patients, regardless of stage, can and should be treated with curative intent.

  • Early stages with favorable prognostic factors: combined modality therapy / radiation alone (extended field)
  • Early stages with unfavorable prognosis: combined modality therapy
  • Advanced stages: extensive chemotherapy (typically eight cycles) with or without consolidatory (usually local) radiation

Currently, ABVD is the gold standard chemotherapy regimen for treatment of Hodgkin's disease. Developed in Italy in the 1970s, the ABVD treatment typically takes between six and eight months, although longer treatments may be required.

1. Classic Hodgkin's disease

Stage I-II

In younger patients with early-stage HD, most oncologists recommend short-course chemotherapy followed by limited radiation therapy to minimize the long-term risks of both modalities. Radiation alone is preferable in patients above the age of 60 years old (extended-field radiotherapy) and young patients with lymphocyte-predominant histology (involved-field radiotherapy).

1. Combined-modality therapy

Brief chemotherapy followed by involved-field irradiation is considered by many to be the treatment of choice for patients with both favorable early-stage disease and unfavorable early-stage disease (bulky and/or with B symptoms, more than four sites of involvement).

In cases with stage I to II mediastinal HD early trials using only radiation therapy or chemotherapy alone for relapse rates were 50% in those with bulky disease. With a regimen of chemotherapy (ABVD / Stanford V chemotherapy regimen) followed by radiation therapy, relapse rates are <25%.


For favorable disease:

Complete remission was achieved in 100% and in 97% of patients, respectively. The 12-year freedom from progression rates were 93% (95% CI, 83% to 100%) after ABVD and STNI, and 94% (95% CI, 88% to 100%) after ABVD and IFRT, whereas the figures for overall survival were 96% (95% CI, 91% to 100%) and 94% (95% CI, 89% to 100%), respectively. Apart from three patients who developed second malignancies in the STNI arm, treatment-related morbidities were mild.[5]

For unfavorable disease:

Five years after random assignment, the overall survival (OSran) for all eligible patients was 91% and freedom from treatment failure (FFTFran) was 83%. Survival rates at 5 years after start of radiotherapy revealed no differences for arms A and B, respectively, in terms of FFTF (85.8% and 84.2%) and OS at 5 years (90.8% and 92.4%). There also were no differences between arms A and B, respectively, in terms of complete remission (98.5% and 97.2%), progressive disease (0.8% and 1.9%), relapse (6.4% and 7.7%), death (8.1% and 6.4%), and secondary neoplasia (4.5% and 2.8%).[6]


  • young women to avoid radiating the breast tissue (see below),
  • patients above 60 years of age (extended-field radiotherapy) and
  • young patients with lymphocyte-predominant histology (involved-field radiotherapy).

2. Chemotherapy alone

Alternatively, consider treatment with six cycles of ABVD alone, especially in women between the ages of 15 and 25, to avoid radiating breast tissue.


Median follow-up is 4.2 years. In comparison with ABVD alone, 5-year freedom from disease progression is superior in patients allocated to radiation therapy (P = .006; 93% v 87%); no differences in event-free survival (P = .06; 88% v 86%) or overall survival (P = .4; 94% v 96%) were detected.[7]

3. Radiotherapy

Radiotherapy remains an adequate alternative treatment of clinically or pathologically staged favorable (nonbulky and without B symptoms) early stage Hodgkin's disease (stages I-II). This is especially applicable to patients above 60 years of age (extended-field radiotherapy) and young patients with lymphocyte-predominant histology (involved-field radiotherapy).

When irradiation is used as the sole therapeutic modality, the standard radiation field used in patients with early-stage disease who did not undergo a staging laparotomy is subtotal lymphoid irradiation. Subtotal lymphoid irradiation involves treatment of the mantle and para-aortic fields only. This approach is considered because clinically staged patients who were irradiated to a small field had a high relapse rate. The term "total lymphoid irradiation" refers to treatment of the mantle, para-aortic, and pelvic fields.

Patients in whom results of laparotomy were normal may be treated safely with mantle-field irradiation alone. A different approach can be used for patients with lymphocyte-predominant histology, namely, less extensive irradiation without surgical staging.


  • In patients who underwent pathologic staging (laparotomy) and were treated with primary irradiation alone, several large series reported a 15-to 20-year survival rate of nearly 90% and relapse-free survival rate of 75%-80%.[8]
  • Most relapses (75%) occurred within 3 years after the completion of therapy; very late relapses were uncommon. Importantly, more than half of the patients who relapsed after radiotherapy alone were still curable with standard chemotherapy.

Stage III-IV

1. Combination chemotherapy alone

Treat patients with advanced-stage HD with six to eight cycles of ABVD chemotherapy. For those with very high-risk disease treatment with escalated-dose BEACOPP may provide an advantage.


  • In a randomized phase III trial undertaken by the Cancer and Leukemia Group B (CALGB)it was shown that there were higher complete response rates with ABVD and ABVD/MOPP (82% and 83%, respectively) than with MOPP alone (65%).
  • ABVD has been shown to be more effective and less toxic than MOPP, particularly with respect to sterility and secondary leukemia.


CALGB trial

The overall response rate was 93 percent, with complete responses in 77 percent: 67 percent in the MOPP group, 82 percent in the ABVD group, and 83 percent in the MOPP-ABVD group (P = 0.006 for the comparison of MOPP with the other two regimens, both of which contained doxorubicin). The rates of failure-free survival at five years were 50 percent for MOPP, 61 percent for ABVD, and 65 percent for MOPP-ABVD. Age, stage (III vs. IV), and regimen influenced failure-free survival significantly. Overall survival at five years was 66 percent for MOPP, 73 percent for ABVD, and 75 percent for MOPP-ABVD (P = 0.28 for the comparison of MOPP with the doxorubicin regimens). MOPP had more severe toxic effects on bone marrow than ABVD and was associated with greater reductions in the prescribed dose.[9]

At a median follow-up of 14.1 years, we tested for equality of the failure-free and overall survival distributions in the three treatment groups using the Cox proportional-hazards model. We found a significant difference in the failure-free survival distributions (score test, P=0.03) but not in the overall survival distributions (score test, P=0.35). Patients who were randomly assigned to ABVD have continued to have a higher rate of failure-free survival than those treated with MOPP alone and a similar rate of failure-free survival to those treated with MOPP alternating with ABVD (Figure 1A). Overall survival is not significantly different among the groups, reflecting the ability of salvage therapy to prolong survival or to cure the disease.[10]

b. escalated-dose BEACOPP

The German Hodgkin's Lymphoma Study Group study

1,201 patients with advanced-stage disease were randomized to COPP/ABVD, BEACOPP, or to increased-dose BEACOPP, with most patients receiving consolidative radiation therapy to sites of initial bulky disease (more than or equal to5 cm). The 5-year overall survival was 83% for COPP/ABVD, 88% for BEACOPP, and 91% for increased-dose BEACOPP (P = .16 for the comparison of COPP/ABVD with BEACOPP, P = .06 for the comparison of BEACOPP with increased-dose BEACOPP, and P = .002 for the comparison of COPP/ABVD with increased-dose BEACOPP).[11]

b. Clinical trials

Consider enrolling patients in a clinical trial using newer chemotherapy regimens, especially if they have high-risk disease as defined by the International Prognostic Index.

2. Involved field radiation

Although the role of consolidation radiotherapy after induction chemotherapy remains controversial, irradiation is routinely added in patients with advanced-stage disease who present with bulky disease or who remain in uncertain complete remission after chemotherapy.

Stage III-IV

Relapsed disease (30% of advanced cases)

Relapse after radiation therapy

Patients with early-stage Hodgkin's disease who relapse after initial therapy with irradiation alone have excellent complete remission rates and long term survival rates when treated with MOPP or ABVD.


Combination chemotherapy results in 10-year disease-free and overall survival rates of 60% to 80% and 60% to 90%, respectively.

In patients who relapse following extended-field radiation therapy, combination chemotherapy is curative in 50% to 60%.[12]

Relapse after combination chemotherapy

Among patients with advanced-stage Hodgkin's disease, 70%-90% will have complete responses to treatment; however, up to one-third of patients with stage III or IV disease will relapse, usually within the first 3 years after therapy.

For patients who experience a relapse after initial combination chemotherapy, prognosis is determined more by the duration of the first remission than by the specific induction or salvage combination chemotherapy regimen.

  • Patients whose initial remission after chemotherapy was longer than 1 year (late relapse) have long-term survivals with salvage chemotherapy of 22% to 71%.
  • Patients whose initial remission after chemotherapy was shorter than 1 year (early relapse) do much worse and have long-term survivals of 11% to 46%.

In addition to duration after remission, resistant disease (see below), the presence B symptoms at relapse and extranodal disease are significant prognostic factors.[12]

A variety of treatment regimens have been used for patients with relapsed Hodgkin's disease. In addition to MOPP or ABVD in patients who received the opposite regimen initially, a number of other treatments have been used:

  • BEACOPP: bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone.
  • COPP/ABVD: cyclophosphamide + vincristine + procarbazine + prednisone/doxorubicin + bleomycin + vinblastine + dacarbazine.
  • Stanford V: doxorubicin + vinblastine + mechlorethamine + etoposide + vincristine + bleomycin + prednisone.
  • MINE: mitoxantrone + ifosfamide + etoposide.

High-dose therapy with autologous stem cell transplantation

The preferred salvage method for patients who relapsed after combined-modality therapy or chemotherapy alone or remained refractory to those programs is high-dose chemoradiotherapy with autologous stem-cell transplantation (ASCT). Two randomized trials have compared aggressive conventional chemotherapy versus high-dose chemotherapy with autologous hematopoietic stem cell transplantation for relapsed chemosensitive Hodgkin's lymphoma. Both trials show improvement in freedom from treatment failure at 3 years for the transplantation arm (75% vs. 45%, 55% vs. 34%); but no difference in overall survival.

  • Although most patients have a poorly responsive disease, the complete response rate has ranged from 50%-80%, with approximately 40%-80% of responding patients achieving durable remissions.

Patients who relapse after initial combination chemotherapy usually undergo reinduction with the same or another chemotherapy regimen followed by high-dose chemotherapy and autologous bone marrow or peripheral stem cell or allogeneic bone marrow rescue.

This therapy has resulted in a 3- to 4-year disease-free survival rate of 27% to 48%.

Patients who are responsive to reinduction chemotherapy may have a better prognosis.

Limited disease

For the small subgroup of patients with only limited nodal recurrence following initial chemotherapy, radiation therapy with or without additional chemotherapy may provide long-term survival for about 50% of these highly selected patients.

Resistant disease

Patients who do not respond to induction chemotherapy (about 10%-20% of all presenting patients) have <10% survival at 8 years. For these patients, high-dose chemotherapy and autologous bone marrow or peripheral stem cell or allogeneic bone marrow rescue are under clinical evaluation. These trials have resulted in a 3- to 4-year disease-free survival rate of 27% to 48%.

2. Lymphocyte predominant Hodgkin's disease


Involved Field Radiotherapy (IFRT) alone


LPHD is an indolent disease that is associated with prolonged survival and late relapses. It does not have a contiguous pattern of spread, and rarely involves the mediastinum. This makes it unnecessary to use regional (involved sites plus all contiguous sites) or extended-field radiotherapy. More than half of the deaths in patients with LPHD were due to either second malignancies or cardiovascular disease, and were probably related to previous (extended-field) radiotherapy (37; 38; 39).


  • More than 80% of patients with LPHD have stage I or II disease (37; 38; 39).

  • Despite the frequency of relapses, the 20-year survival rate for LPHD is >90%.

Watch and wait

Some have argued that, in patients with fully resected stage I disease, a "watch and wait" approach may even be considered (39; 40).


For patients with more extensive disease, treatment with combined-modality chemotherapy is recommended.

There are also a few reports of responses to the anti-CD20 monoclonal antibody rituximab in patients with LPHD. Responses tend to be short lived, and rituximab is still considered investigational. Larger studies evaluating rituximab both as initial therapy and as therapy for relapsed disease in patients with LPHD are underway.


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