Mehdi Hamadani and Elaine S. Jaffe
EPIDEMIOLOGY
Hodgkin lymphoma (HL) is a common lymphoid malignancy, representing 11% of all lymphomas. Approximately 9,000 patients were diagnosed with HL in 2012 in the United States. Median age at the time of diagnosis is 38 years, with a bimodal age distribution in resource-rich countries, showing a first peak at 15 to 35 years and a second peak after the age of 50 years. The age-adjusted incidence rate of HL is 2.8 per 100,000 individuals per year. Unlike non-Hodgkin lymphoma, HL incidence has not increased over the past decades. The male to female ratio is 1.3:1.0. In the United States, it affects African Americans less commonly than Caucasians.
ETIOLOGY AND RISK FACTORS
The cause of HL remains unknown.
■Epstein-Barr virus (EBV) has been postulated to play a role in the pathogenesis of classical HL (CHL) (particularly mixed cellularity and lymphocyte-depleted subtypes).
■Loss of immune surveillance in immunodeficiency states (e.g., HIV infection, allogeneic stem cell transplantation, and solid organ transplantation) may predispose to development of HL.
■Twofold increased risk of HL is seen in smokers.
■Family history of classical HL increases the risk to develop disease by threefold to ninefold. Identical twin sibling of a HL patient has a 99-fold higher risk of developing HL.
PATHOLOGY
HL is a neoplastic disease of B-cell origin. CHL is characterized by the presence of Reed-Sternberg (RS) cells and mononuclear variants, amidst an inflammatory background that is composed of lymphocytes, eosinophils, monocytes, and histiocytes. Nodular lymphocyte predominance HL (NLPHL) is characterized by LP cells in a background of lymphocytes and histiocytes but without other inflammatory cells.
RS and LP cells are derived from the follicular center B cells with clonally rearranged V heavy-chain genes. RS cells often exhibit two mirror-image nuclei (owl’s eyes appearance) (Fig. 29.1). RS cells are positive for CD30 and CD15 and typically negative for CD20 and CD45, whereas LP cells more fully express a normal B-cell program.
FIGURE 29.1 (A) Diagnostic Reed-Sternberg (RS) cell, seen in classic types of Hodgkin lymphomas (mixed cellularity, nodular sclerosis, lymphocyte depletion). (B) Variants of RS cells seen in nodular lymphocyte-predominant Hodgkin lymphomas: popcorn cells or L and H cells (lymphocytic or histiocytic predominance). RS cells of the classic type generally are not seen in a nodular lymphocyte-predominant Hodgkin lymphoma.
Pathologic Classification
The World Health Organization (WHO) classification divides HL into two main types (Table 29.1):
■CHL
•CHL is characterized by the presence of RS cells in an inflammatory background and is divided into four histologic subtypes.
–Nodular sclerosis HL
–Mixed cellularity HL
–Lymphocyte-rich HL
–Lymphocyte-depleted HL
■NLPHL
•NLPHL lacks RS cells but is characterized by LP cells, which are sometimes referred to as popcorn cells.
Table 29.2 summarizes the clinical and pathologic features of the disease subtypes.
CLINICAL FEATURES
■Lymphadenopathy: Most commonly above the diaphragm (cervical, axillary, or mediastinal). Enlarged nodes are not tender with a characteristic firm rubbery consistency. Lymph node pain may occasionally be precipitated by alcohol intake.
■Chronic pruritus.
■Most common extranodal sites of involvement are lung, bone marrow, liver, and bones.
■B symptoms.
–Unexplained weight loss (>10% body weight over 6 months before diagnosis)
–Fever of >38°C, intermittent with 1- to 2-week cycles
–Drenching night sweats
Staging
The modified Ann Arbor staging of lymphoma is used to clinically stage HL (Table 29.3).
Diagnostic Evaluation
Excisional biopsy of an enlarged lymph node is strongly recommended for initial diagnosis. A core biopsy may be appropriate if adequate tissue can be obtained to avoid major surgery. A fine-needle aspiration is not recommended for initial diagnosis.
Laboratory Tests
■Complete blood count (CBC), differential, and platelets.
■Erythrocyte sedimentation rate (ESR): Adverse prognostic biomarker, if elevated.
■Lactate dehydrogenase (LDH) and albumin.
■Liver function tests: If abnormal, may be associated with liver involvement.
■Alkaline phosphatase: May be nonspecifically high or associated with bone involvement.
■BUN, creatinine, electrolytes, and uric acid.
■Pregnancy test: Women of childbearing age.
■HIV testing in patients with risk factors for HIV.
Radiologic Studies
■Chest radiograph.
■Computerized tomography (CT) scan of the chest, abdomen, and pelvis are required for staging. CT-scan of the neck may sometimes be needed.
■Positron emission tomography (PET) CT-scan.
Unilateral Bone Marrow Biopsy and Aspiration
Required in clinical stage IB, IIB, III, or IV.
Evaluation/Procedures for Specific Treatments and Counseling
■MUGA scan or echocardiography to evaluate left ventricular ejection fraction before anthracycline treatment.
■Pulmonary function tests (including DLCO) are recommended prior to bleomycin-containing treatment.
■Fertility counseling (to discuss sperm, ovarian tissue, and/or oocyte cryopreservation).
■Smoking cessation counseling.
■Vaccination (pneumococcal, hemophilus influenza, and meningococcal) prior to splenic irradiation is recommended.
MANAGEMENT
■HL is sensitive to radiation and many chemotherapeutic agents. All patients, regardless of stage, should be treated with a curative intent. Cure rates are high (>80%), thus limiting long-term toxicities is a major consideration of treatment.
■Early-stage disease may be treated with combined-modality chemotherapy and radiation treatment (RT), or chemotherapy alone.
■Advanced-stage disease is usually treated with chemotherapy alone.
■In advanced-stage disease radiation consolidation can be considered for PET-positive areas following a full course of chemotherapy, but should be omitted in patients with PET-negative residual masses. Based on pre-PET era studies, routine radiation consolidation in patients with bulky (≥10 cm or one-third the diameter of the chest on CXR) disease is widely practiced in North American centers; however, radiation consolidation may not be necessary in PET-negative bulky masses.
Principles of Chemotherapy
■The standard regimen for HL in North America is ABVD since it superseded MOPP regimen in the large randomized trial of the Cancer and Leukemia Group B (CALGB) in 1992 (Table 29.4). ABVD was associated with less myelosuppression and reduced risk of secondary leukemias and infertility compared to MOPP regimen. Growth factors are not required with ABVD. Treatment delay and/or dose reduction due to leukopenia is not recommended.
■The German Hodgkin Lymphoma Study Group (GHSG) developed the dose-escalated BEACOPP regimen and showed it to be superior to COPP-ABVD and standard-dose BEACOPP in advanced HL. However the significant associated toxicities of dose-escalated BEACOPP (3% rate of treatment-related death, 2% to 3% rate of secondary leukemias, and nearly universal infertility) has precluded its widespread use in North America. Dose-escalated BEACOPP is not recommended for elderly HL patients (≥60 years).
■Stanford V is a dose-intense 12-week regimen. Involved field radiation to macroscopic splenic disease and all lymph nodes measuring ≥ 5 cm in size is an integral part of Stanford V. The cumulative doses of doxorubicin and bleomycin in Stanford V are less than those in ABVD, with potentially less risk for cardiac and pulmonary toxicity. In the three randomized prospective trials (from Italy, United Kingdom, and United States) compared to ABVD, Stanford V had inferior complete remission rates and was associated with more hematologic and neurologic toxicity.
Chemotherapy regimens are described in Table 29.5.
Principles of Radiotherapy
■Radiation therapy for HL targets sites with either clinical disease (involved field or involved nodal) or involved plus adjacent areas (extended field). Extended fields are either “mantle field” for the cervical, axillary, and mediastinal regions or “inverted Y field” for spleen, para-aortic, and pelvic regions. When inverted Y field radiation is given together with mantle field radiation, the combination is called total nodal radiation.
■Dose of RT depends on the extent of the disease. In combined-modality therapy, RT is initiated ideally within 3 weeks of finishing chemotherapy.
Treatment Response Evaluation
All patients (early and late stages) should receive interim restaging (after two and/or four cycles of chemotherapy) to evaluate the response to treatment. Restaging should be repeated 3 months after the end of treatment if complete remission is not achieved in the interim assessment.
TREATMENT OF EARLY DISEASE (STAGES I AND II)
Early CHL should be treated with intent to cure. Poor risk factors have been identified in this subset of patients.
GHSG Unfavorable Prognostic Features for Early-Stage Disease (I and II)
Any of the following four features:
■Extranodal disease
■Bulky disease: A mass >10 cm in diameter or high mediastinal mass ratio (> one-third of maximum intrathoracic diameter)
■ESR >50 with no B symptoms, or >30 with B symptoms
■More than 2 nodal areas
Early-stage patients with bulky disease and stage IIB patients are best treated like advanced-stage (stage III/IV) disease. The remaining early-stage patients can be managed as following:
■Favorable early disease (by GHSG criteria): These patients are treated with ABVD × two cycles followed by 20 Gy of involved field radiation. The cure rate of these patients is >90%.
■Unfavorable early disease (by GHSG criteria): These patients are treated with ABVD × four cycles followed by 30 Gy of involved field radiation.
■An alternative for early-stage disease is chemotherapy with four to six cycles of ABVD alone without involved field radiation. This option is especially attractive for patients with abdomen only disease and in young patients where involved field radiation to chest or axillae is associated with a high risk of subsequent second cancers (particularly breast cancer in young female patients) and premature coronary artery disease.
■Rarely in patients who are unfit for chemotherapy, treatment with subtotal nodal or mantle field radiation alone may be considered.
TREATMENT OF ADVANCED DISEASE (STAGES III AND IV)
Aggressive histology (e.g., mixed cellularity or lymphocyte-depleted) is more common among patients with advanced CHL. In North America, subjects with bulky stage I or II disease and those with stage IIB are managed like patients with advanced-stage (III/IV) disease.
Unfavorable Prognostic Features for Advanced Stages (III and IV)
Hasenclever index (also called international prognostic score [IPS]) identifies seven adverse prognostic factors:
■Stage IV disease
■Age >45 years
■Male gender
■WBC ≥15,000/mm3
■Lymphopenia (<600/mm3 or <8% of total WBC)
■Hemoglobin <10.5 g/dL
■Albumin level <4 g/dL
The 5-year overall survival decreases with higher IPS scores as follows: 0 factor (89%), 1 factor (90%), 2 factors (81%), 3 factors (78%), 4 factors (61%), and 5 or more factors (56%).
Increased number of tumor-associated (CD68+) macrophages is strongly associated with shortened survival in patients with CHL. The 10-year survival of HL patients with <5% CD68+ macrophages in lymph node biopsy is 88%, compared to only 59% in those with >25% CD68+ cells.
The goal of treatment in advanced CHL should be curative. The primary treatment of advanced disease is chemotherapy. ABVD is the standard of care in North American centers. The recommended initial treatment is six cycles of ABVD. Nonbulky advanced-stage patients with a negative PET-CT at the end of chemotherapy do not need radiotherapy consolidation. RT can also be omitted in bulky disease patients with a negative CT or PET-CT after finishing chemotherapy, but this is an area of significant controversy. Bulky HL patients with a positive PET-CT after finishing chemotherapy can be offered 36 Gy of involved field RT. While not commonly used in North America, dose-escalated BEACOPP is an alternative option in younger patients with high-risk disease (e.g., ≥4 unfavorable factors). The recommended initial treatment is six cycles of BEACOPP. Stanford V is not recommended outside the setting of a clinical trial.
TREATMENT OF NODULAR LYMPHOCYTE–PREDOMINANT HODGKIN LYMPHOMA
The NLPHL subtype represents 5% of HL. Unlike CHL, NLPHL is strongly CD20 positive and typically behaves like an indolent non-Hodgkin lymphoma. While conventional HL approaches continue to be applied to NLPHL, as outlined below, there are compelling biologic and clinical arguments for a different therapeutic approach.
Conventional Treatment Approaches
■Stages IA and IIA can be treated with 30 to 36 Gy of involved field radiation alone.
■Stages IA, IB, IIA, and IIB can be managed with a combined-modality approach (e.g., two to four cycles of ABVD or R-CHOP followed by involved field radiation).
■Watchful waiting in patients with asymptomatic stage III/IV disease is reasonable. Patients with symptomatic advanced-stage disease are managed with systemic chemotherapy. The optimal chemotherapy regimen for NLPHL remains unknown. While ABVD is the “historical” standard, regimens designed for non-Hodgkin lymphomas such as CHOP, CVP, or dose-escalated EPOCH with rituximab (because of strong CD20 expression on LP Hodgkin cells) are also appropriate. Single-agent rituximab is also active in NLPHL and can be considered in patients with low bulk disease. It is important to recognize the “aggressive” presentations of NLPHL such as those with disseminated disease, including cases involving the bones and bone marrow and transformation to aggressive histologies. Such cases should be managed like aggressive non-Hodgkin lymphomas.
Follow-up after Completion of Treatment
The purpose of follow-up is detection of disease relapse and late treatment-related complications.
■Clinical evaluation with CBC, ESR, chemistry panel every 3 months for 2 years, then every 6 months for 5 years
■CT of chest, abdomen, and pelvis should be done every 3 to 6 months for 3 years, then annually for up to 5 years. Surveillance PET-CT-scan is controversial because of high false-positive results.
■Annual influenza vaccination.
■TSH annually if neck RT was given (risk of hypothyroidism).
■Annual mammogram screening should start 8 to 10 years after or at age of 40 years, whichever is earlier, for patients who received RT above the diaphragm. Annual breast MRI is also recommended by the American Cancer Society in addition to mammogram in female patients who received radiation to chest or axillae between the ages 10 and 30 years. Breast self-exam should be encouraged.
LATE TREATMENT–RELATED COMPLICATIONS
■Hypothyroidism can occur after neck or mediastinal RT.
■Breast cancer can occur in females after chest or axillary RT. The risk is higher in patients who receive RT at younger age. It occurs after an average of 15 years after finishing treatment.
■Lung cancer: High risk is evident in patients who received RT to chest, received alkylating agents, and smoke cigarettes.
■Infertility risk is high after pelvic RT, MOPP regimen, BEACOPP regimen, and autologous transplantation.
■Leukemia and myelodysplastic syndromes (especially with MOPP, BEACOPP, RT, and autologous transplantation).
■Pulmonary toxicity after bleomycin treatment: Risk may be increased when G-CSF is used during treatment; hence G-CSF use is discouraged with ABVD.
■Cardiac toxicity secondary to anthracycline is uncommon (total cumulative anthracycline dose is not high). The risk for premature coronary artery disease and cerebrovascular accidents is increased after mediastinal and cervical RT, respectively.
■Lhermitte sign: It is an infrequent complication that can occur 6 to 12 weeks after neck RT and resolves spontaneously. Patients feel electric-like shock sensation radiating down the back and extremities when neck is flexed. This sign is attributed to transient spinal cord demyelinization.
■Capsulated organism infection (pneumococcal, meningococcal, and hemophilus) can occur in patients not vaccinated after splenic RT or splenectomy (rarely used now).
TREATMENT OF RELAPSED HODGKIN LYMPHOMA
■Relapsed disease must be confirmed by repeat biopsy.
■CHL:
–In rare cases where RT was the first-line treatment, conventional chemotherapy (ABVD) at the time of relapse without autologous transplantation can be very effective treatment.
–If conventional chemotherapy (with or without RT) was the primary treatment, salvage chemotherapy such as ICE, DHAP, ESHAP, and GND (Table 29.6) followed by autologous transplantation is curative for about 50% of the patients.
–Brentuximab vedotin, an antibody-drug conjugate, is an attractive option for HL patients relapsing after autologous transplantation, or ones who are not a candidate for autologous transplantation. The drug consists of an anti-CD30 chimeric monoclonal antibody; brentuximab, linked to the antimitotic agent; monomethyl auristatin E (MMAE). The antibody portion of the drug attaches to CD30 on the surface of HL cells, delivering MMAE which is exerts anti-HL activity.
–A small proportion of heavily pretreated, but otherwise healthy HL patients relapsing after an autologous transplant can be cured with an allogeneic stem cell transplant.
■NLPHL: Relapsed disease is best approached as an indolent lymphoma. Reasonable options include observation, rituximab alone or with chemotherapy, and/or RT.
Palliative Treatment
■Sequential single-agent chemotherapy such as gemcitabine, vinblastine, bendamustine, or lenalidomide.
■RT can be used to relieve pain or pressure symptoms of bulky masses.
■Investigational treatment is encouraged through enrollment in clinical trials.
Future Directions
■Interim-negative PET-CT (after two to three cycles of chemotherapy) is a strong predictor of an excellent outcome, and might be a useful tool to identify patients with a high likelihood of cure. Ongoing studies are using interim PET-CT to develop “tailored” therapies for individual patients. Trials are deescalating treatment length and intensity in good-risk patients with a negative interim PET-CT (e.g., omitting RT in early-stage patients, or treating with only two or four cycles of ABVD alone) to reduce the long-term treatment-related complications, while in the poor-risk patients who have a positive interim PET-CT, trials are examining the role of escalating therapy (e.g., switching from ABVD to dose-escalated BEACOPP).
■Recently completed trials (e.g., EORTC 20012 study) comparing ABVD against BEACOPP in patients with high IPS score advanced-stage disease, in the coming years, will clarify if these high-risk patients benefit from more aggressive approaches upfront.
■Phase III studies are being planned to combine brentuximab vedotin in a first-line setting to improve patient outcomes.
REVIEW QUESTIONS
1.A 19-year-old heterosexual, single African American male presented with a two-month history of right supraclavicular lymph node enlargement. He denied weight loss, night sweats, or unexplained fevers. Physical examination showed a 2 cm firm lymph node in the right supraclavicular fossa and a 3 cm lymph node in the right axilla. An excisional biopsy of the right axillary node was consistent with nodular sclerosis CHL. A PET/CT-scan showed hypermetabolic activity confined to nonbulky right supraclavicular and right axillary nodal areas. His CBCs, differential, and chemistries were within normal limits. ESR was 22. Echocardiogram showed a left ventricular ejection fraction of 65% and pulmonary function tests showed normal spirometric parameters. What is the next best step in this patient’s management before starting treatment?
A.Unilateral bone marrow aspiration and biopsy
B.Bilateral bone marrow aspiration and biopsy
C.Sperm banking
D.MRI brain with and without contrast
E.Infuse-A-port insertion
2.What is the best therapy option for the 19-year-old African American man in question 1?
A.Four cycles of ABVD followed by 30 Gy of involved field radiation therapy
B.Two cycles of ABVD followed by 20 Gy of involved field radiation therapy
C.Six cycles of chemotherapy with R-CHOP
D.Subtotal nodal radiation therapy
E.Four cycles of dose-escalated BEACOPP followed by 30 Gy of involved field radiation therapy
3.A 45-year-old schoolteacher with stage IIIA mixed cellularity CHL is undergoing first-line chemotherapy with ABVD. She is tolerating chemotherapy well. A PET/CT-scan performed after two cycles showed complete remission. She presents now to start cycle 4 of chemotherapy with ABVD. She reports no nausea, vomiting, or fevers with the previous cycle. Her blood work today showed normal hepatic and renal function. Blood counts showed an absolute neutrophil count (ANC) of 880/μL and platelet count of 145/μL. What is the best next step in management?
A.Delay chemotherapy until ANC >1,000/μL
B.Delay chemotherapy until ANC >1,000/μL and add growth factor support to the next cycle of chemotherapy
C.Continue ABVD without delay and add growth factor support
D.Continue ABVD without delay and without growth factor support
E.Continue ABVD with 25% dose reduction in doxorubicin and bleomycin
4.A 55-year-old man with advanced-stage nodular sclerosis CHL presented with new-onset right axillary lymph node enlargement. He was treated with six cycles of ABVD 3 years ago. An excisional biopsy of the right axillary node confirmed relapsed disease. A PET/CT-scan showed widespread hypermetabolic lymphadenopathy above and below the diaphragm. Bone marrow biopsy was negative. He goes on to achieve a second complete remission after three cycles of salvage chemotherapy with ICE. He has four siblings. You now recommend
A.High-dose therapy and autologous hematopoietic cell transplantation
B.Matched sibling allogeneic hematopoietic cell transplantation
C.Six cycles of ICE followed by watchful waiting
D.Six cycles of ICE followed by brentuximab vedotin maintenance therapy
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