The Bethesda Handbook of Clinical Oncology

Robert Dean and Matt Kalaycio

EPIDEMIOLOGY

Hodgkin lymphoma (HL) is a common lymphoid malignancy, representing 10% of all lymphomas. The National Cancer Institute SEER registry estimates that approximately 8,500 patients will be diagnosed with HL in 2016 in the United States. Median age at the time of diagnosis is 39 years, with a peak incidence at age 20 to 35 years. The age-adjusted incidence rate of HL is 2.6 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 slightly 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 some cases 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.

Two-fold increased risk of HL is seen in smokers.

Family history of classical HL increases the risk to develop disease by 3-fold to 9-fold. 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. Classical HL (CHL) is characterized by the presence of Reed-Sternberg (RS) cells and mononuclear variants, amidst an inflammatory background consisting of lymphocytes, eosinophils, monocytes, and histiocytes. Nodular lymphocyte predominant HL (NLPHL) is characterized by RS variants termed LP cells in a background of lymphocytes and histiocytes but without other inflammatory cells.

RS and LP cells are derived from follicular center B cells with clonally rearranged V heavy-chain genes. RS cells often exhibit symmetrical bilobed 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 express B-cell markers including CD20, CD45, and CD79a but are negative for CD30 and CD15.

FIGURE 29.1Diagnostic Reed-Sternberg (RS) cell, with Owl’s Eye nucleus, seen in classic types of Hodgkin lymphomas (mixed cellularity, nodular sclerosis, lymphocyte depletion).

Pathologic Classification

The World Health Organization (WHO) classification divides HL into two main types (Table 29.1):

TABLE 29.1Immunophenotypic Features of Hodgkin Lymphoma

	Classical Hodgkin Lymphoma	Nodular Lymphocyte Predominant Hodgkin Lymphoma
CD45	Negative	Positive
CD30	Positive	Negative^a
CD15	Positive (80% of cases)	Negative
CD20	Variable^b	Positive
CD79a	Negative^a	Positive
EMA	Majority of cases positive	Negative

aPositive in rare cases.

bPresent in up to 40% of the cases but usually expressed on minority of tumor cells with variable intensity.

Classical Hodgkin lymphoma (CHL)

•CHL is characterized by the presence of RS cells in an inflammatory background and is divided into four histologic subtypes, based mainly on the characteristics of the non-neoplastic reactive infiltrate.

•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.

TABLE 29.2Classification of Hodgkin Lymphoma

Pathologic Type	Pathologic Features	Clinical Features
Classical Hodgkin lymphoma
Nodular sclerosis	Nodular growth pattern with broad bands of fibrosis	Most common type; and has a better prognosis. Common in resource-rich countries. Peak incidence at ages 15–34 y
Mixed cellularity	Typical RS cells in a rich inflammatory background and fine reticular fibrosis; 70% are positive for Epstein-Barr virus	Second most common type; more common in patients with HIV infection and in developing countries. Median age is 38 y, with a male predominance
Lymphocyte-rich	Scattered RS cells in a usually nodular background consisting of small lymphocytes	Common in elderly; has good prognosis
Lymphocyte-depleted	Relative predominance of RS cells with depletion of background lymphocytes	Rare, often associated with HIV infection; has poor prognosis. Median age ranges from 30 to 37 y
Nodular lymphocyte predominant
	No RS cells, but characterized by “popcorn” or LP cells (lobulated nucleus)	More common in adult males; often presents with early stage and has good prognosis, but late relapses are not uncommon. Peak incidence at ages 30–50 y

CLINICAL FEATURES

Lymphadenopathy: Most commonly above the diaphragm (cervical, axillary, or mediastinal). Enlarged nodes are non-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).

TABLE 29.3Cotswolds Modified Ann Arbor Staging of Lymphoma

Stage I	Single lymph node region, lymphoid structure (e.g., spleen, thymus, or Waldeyer ring), or a single extralymphatic site (IE)
Stage II	Two or more lymph node regions on the same side of the diaphragm, or localized extranodal extension (contagious to a nodal site) plus one or more nodal regions (IIE)
Stage III	Lymph node regions on both sides of the diaphragm. This may be accompanied by localized extranodal site (IIIE), or splenic involvement (IIIS), or both (IIIE+S)
Stage IV	Diffuse or disseminated involvement of one or more extranodal organs or tissue beyond that designated E, with or without associated lymph node involvement
	Each stage is designated A or B, where B means presence and A means absence of B symptom
	X: A mass >10 cm or a mediastinal mass larger than one-third of the thoracic diameter
	E: Extranodal contiguous extension, which can be encompassed within an irradiation field appropriate for nodal disease of the same anatomic extent. More extensive extranodal disease is designated stage IV

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, but this may limit accurate classification among CHL subtypes. 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 (PA and lateral views) for assessment of mediastinal disease bulk.

Diagnostic computerized tomography (CT) scan of the chest, abdomen, and pelvis are recommended for staging. CT scan of the neck may be needed for objective assessment of palpable lymphadenopathy, or in obese patients.

Positron emission tomography/computerized tomography (PET/CT) scan.

Unilateral Bone Marrow Biopsy and Aspiration

Recommended if PET/CT shows focal areas of skeletal uptake, or if unexplained cytopenias are present. Generally not needed in clinical stage 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.

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, particularly in patients who are poor candidates for intensive second-line therapy including autologous transplantation. Radiation consolidation 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 (doxorubicin, bleomycin, vinblastine, dacarbazine) since it superseded MOPP (mechlorethamine, vincristine, procarbazine, prednisone) 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. Prophylactic use of growth factors may increase the risk of pulmonary toxicity with ABVD and is therefore discouraged. Treatment delay and/or dose reduction due to uncomplicated leukopenia is not recommended, given that febrile neutropenia is uncommon with ABVD.

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) have precluded its widespread use in North America. Dose-escalated BEACOPP is not recommended for older 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.

TABLE 29.4CALGB Study Comparing Different Regimens in Hodgkin Lymphoma

Regimen	Complete Response Rate (%)	5-y Overall Survival Rate (%)
MOPP	67	66
ABVD	82	73
Alternating MOPP/ABVD	83	75

Chemotherapy regimens are described in Table 29.5.

TABLE 29.5Commonly Used Chemotherapy Regimens for Hodgkin Lymphoma

ABVD (every 28 d)	Doxorubicin 25 mg/m²/dose IV on days 1 and 15
	Bleomycin 10 units/m²/dose IV on days 1 and 15
	Vinblastine 6 mg/m²/dose IV on days 1 and 15
	Dacarbazine (DTIC) 375 mg/m²/dose IV on days 1 and 15
Dose-escalated BEACOPP (every 3 wk)	Bleomycin 10 international units/m² IV on day 8
	Etoposide (VP-16) 200 mg/m² IV on days 1–3
	Doxorubicin (driamycin) 35 mg/m² on day 1
	Cyclophosphamide (Cytoxan) 1,200 mg/m² on day 1
	Vincristine 1.4 mg/m² (max 2 mg) on day 8
	Procarbazine 100 mg/m² PO on days 1–7
	Prednisone 40 mg/m² PO on days 1–14
	Filgrastim (G-CSF) support is needed
Stanford V (every 4 wk) × three cycles (12 wk)	Nitrogen mustard 6 mg/m² IV day 1
	Doxorubicin (Adriamycin) 25 mg/m² IV days1 and 15
	Vinblastine 6 mg/m² IV days 1 and 15
	Vincristine 1.4 mg/m² IV days 8 and 22 (maximum dose is 2 mg/dose).
	Bleomycin 5 units/m² IV days 8 and 22
	Etoposide (VP-16) 60 mg/m² IV days 15 and 16
	Prednisone 40 mg PO qod × 10 wk, then taper by 10 mg every other day between weeks 10 and 12
	For patients older than 50, reduce vinblastine to 4 mg/m² and vincristine to 1 mg/m² in cycle 3

Principles of Radiotherapy

Radiation therapy for HL targets sites with radiographic disease (involved nodal or involved site). Historical approaches included involved areas alone (involved field), 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 with PET/CT after two cycles of chemotherapy to evaluate the response to treatment. Restaging may be repeated after four cycles of chemotherapy to evaluate ongoing response, where applicable. Restaging should be repeated 2 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-stage CHL is stratified as favorable or unfavorable disease, and treatment varies accordingly. Unfavorable risk factors in this subset of patients vary somewhat among international clinical trial groups and are also summarized in guidelines from the National Comprehensive Cancer Network (NCCN).

NCCN Unfavorable Prognostic Features for Early-Stage Disease (I and II)

Any of the following features:

Bulky disease: A mass >10 cm in diameter, or mediastinal mass ratio exceeding one-third of maximum intrathoracic diameter

ESR >50 or presence of B symptoms

More than 3 nodal areas

Early-stage patients with unfavorable risk factors are best treated like advanced-stage (stage III/IV) disease. The remaining favorable-risk early-stage patients are managed as follows:

Favorable early-stage disease (by NCCN criteria): These patients may be treated with ABVD × two cycles followed by 20 Gy of involved nodal or involved site radiation. The cure rate of these patients is >90%.

An alternative for favorable 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 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.

Unfavorable early-stage disease (by NCCN criteria): Patients with bulky stage I or II disease without B symptoms are treated with ABVD × four cycles followed by 30 Gy of involved nodal or involved site radiation. Patients with stage IB or IIB disease, or with stage II disease encompassing more than 3 nodal areas, are treated with ABVD x six cycles, usually followed by 30 Gy of involved nodal or involved site radiation to sites of initial bulky 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.

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%).

The primary treatment of advanced-stage CHL is chemotherapy. ABVD is the standard of care in North American centers. The recommended initial treatment is six cycles of ABVD. In a phase III trial, initial treatment of advanced-stage CHL with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine was associated with improved progression-free survival, decreased pulmonary toxicity, and a trend toward lower overall mortality compared with ABVD. Brentuximab vedotin is not currently approved for primary treatment of CHL. Initial therapy with dose-escalated BEACOPP does not improve survival and increases the risk of subsequent myelodysplastic syndrome. Stanford V is also not recommended as initial therapy outside the setting of a clinical trial.

Treatment decisions are increasingly being made on the basis of PET scans obtained after chemotherapy has begun (Interim PET).

Evidence supports continuing ABVD if a PET or PET/CT scan is negative following two cycles of ABVD chemotherapy. Current data indicate that bleomycin may be discontinued in patients who achieve PET-negative response after two cycles of ABVD, continuing with AVD to complete six cycles with outcomes comparable to ABVD. This approach merits particular consideration in older adults, who are at higher risk for pulmonary toxicity and mortality with bleomycin-based therapy.

If a PET or PET/CT scan is positive according to the Deauville criteria, then evidence supports intensification of treatment with either 1) 6 cycles of dose-escalated BEACOPP or 2) ifosfamide-based rescue chemotherapy followed by high-dose chemotherapy with autologous hematopoietic cell rescue.

Nonbulky advanced-stage patients with a negative PET/CT at the end of chemotherapy do not need radiotherapy consolidation, particularly if interim restaging with PET or PET/CT scan was negative following 2 cycles of chemotherapy. 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.

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 the 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.

There is no evidence to support routine radiographic surveillance following completion of treatment and confirmation of complete remission. Surveillance PET/CT imaging should be avoided because of frequent false-positive results.

Annual influenza vaccination.

Thyroid stimulating hormone (TSH) annually if neck RT was given (risk of hypothyroidism).

Annual mammogram screening should start 8 to 10 years after RT 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 and thyroid cancer 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. Supplemental oxygen should be used sparingly when needed, to minimize the risk of inducing pneumonitis.

Cardiac toxicity secondary to anthracycline is uncommon (total cumulative anthracycline dose is not prohibitive). 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.

Encapsulated 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 curative.

•If conventional chemotherapy (with or without RT) was the primary treatment, salvage chemotherapy such as ICE, DHAP, ESHAP, or GND (Table 29.6) followed by autologous transplantation is curative for about 50% of the patients.

•Brentuximab vedotin 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 exerts anti-HL activity. In patients with relapsed or refractory Hodgkin lymphoma after autologous transplant, brentuximab vedotin induces remission in 75% with estimated 3-year overall survival and progression-free survival rates of 73% (95% confidence interval [CI]: 57%, 88%) and 58% (95% CI: 41%, 76%), respectively.

•For brentuximab naïve HL patients, brentuximab vedotin added as maintenance therapy following autologous stem cell transplant improves progression-free survival compared to placebo, particularly in high-risk HL patients who do not achieve complete remission with rescue chemotherapy before autologous stem cell transplant.

•In patients with relapsed and refractory HL, the PD-1 inhibitor nivolumab induced remission in 87% resulting in a progression-free survival of 86% with 6 months of follow-up. Similarly, the PD-1 inhibitor pembrolizumab induced responses in 69% of patients with previously treated HL, with 63.4% progression-free survival at 9 months of follow-up.

•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 with better results obtained in those achieving remission first.

•NLPHL: Relapsed disease is best approached as an indolent lymphoma. Reasonable options include observation, rituximab alone or with chemotherapy, and/or RT.

TABLE 29.6Salvage Chemotherapy Regimen for Hodgkin Lymphoma

ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin)

ICE (ifosfamide, carboplatin, and etoposide)

DHAP (dexamethasone, high-dose cytarabine, and cisplatin)

GND (gemcitabine, vinorelbine, and liposomal doxorubicin)

GCP (gemcitabine, cisplatin, and methylprednisolone)

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

Phase III studies are underway or planned to combine standard chemotherapy with novel agents such as brentuximab vedotin and checkpoint inhibitors like nivolumab in the first-line setting to improve patient outcomes.