AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

Background

Hodgkin disease (Hodgkin's lymphoma) is a potentially curable malignant lymphoma with distinct histology, biologic behavior, and clinical characteristics. Thomas Hodgkin first described Hodgkin disease (Hodgkin's lymphoma) in 1832. The disease is defined in terms of its microscopic appearance (histology) and the expression of cell surface markers (immunophenotype).

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Lymphoma.

Related eMedicine topics:
Hodgkin Disease [in the Pediatrics: General Medicine section]
Lymphoma, B-Cell
Lymphoma, Diffuse Large Cell
Lymphoma, Malignant Anaplastic (Ki 1+)
Lymphoma, Mantle Cell
Lymphoma, Non-Hodgkin

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Resource Center Cancer: Biologic Therapies
Resource Center Stem Cell Research & Therapy
Specialty Site Hematology-Oncology
High-Dose Therapy and Stem Cell Transplant Useful for Resistant Hodgkin Disease
Hodgkin's Lymphoma: Current Treatment Strategies and Novel Approaches

Pathophysiology

Histology and classification

As classified by the World Health Organization (WHO), Hodgkin disease (Hodgkin's lymphoma) exists in 5 types.¹ Four of these, nodular sclerosis, mixed cellularity, lymphocyte depleted, and lymphocyte rich, are referred to as classic Hodgkin disease (Hodgkin's lymphoma). The fifth type, nodular lymphocyte predominant Hodgkin disease (NLPHD), is a distinct entity with unique clinical features and a different treatment paradigm. 

In classic Hodgkin disease (Hodgkin's lymphoma), the neoplastic cell is the Reed-Sternberg (RS) cell.^{2, 3} Reed-Sternberg cells compose only 1-2% of the total tumor cell mass. The remainder is composed of a variety of reactive, mixed inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes. Most Reed-Sternberg cells are of B-cell origin, derived from lymph node germinal centers but no longer able to express antibodies. 

Some Hodgkin disease (Hodgkin's lymphoma) cases have been identified in which the Reed-Sternberg cell is of T-cell origin, but these are rare, accounting for 1-2% of classic Hodgkin disease (Hodgkin's lymphoma). The Reed-Sternberg cells consistently express the CD30 (Ki-1) and CD15 (Leu-M1) antigens. CD30 is a marker of lymphocyte activation that is expressed by reactive and malignant lymphoid cells and was originally identified as a cell surface antigen on Reed-Sternberg cells. CD15 is a marker of late granulocytes, monocytes, and activated T cells that is not normally expressed by B-lineage cells. 

• Nodular sclerosis Hodgkin disease (NSHD) (60-80% of all cases): The morphology shows a nodular pattern. Broad bands of fibrosis divide the node into nodules. The capsule is thickened. The characteristic cell is the lacunar-type Reed-Sternberg cell, which has a monolobated or multilobated nucleus, a small nucleolus, and abundant pale cytoplasm. NSHD is frequently observed in adolescents and young adults and usually involves the mediastinum and other supradiaphragmatic sites.
• Mixed-cellularity Hodgkin disease (MCHD) (15-30% of cases): Histologically, the infiltrate is usually diffuse. Reed-Sternberg cells are of the classic type (large, with bilobate, double or multiple nuclei, and a large, eosinophilic nucleolus). MCHD commonly affects the abdominal lymph nodes and spleen. Patients with this histology typically have advanced-stage disease with systemic symptoms. MCHD is the histologic type most commonly observed in patients with human immunodeficiency virus (HIV) infection.
• Lymphocyte-depleted Hodgkin disease (LDHD) (less than 1% of cases): The infiltrate in LDHD is diffuse and often appears hypocellular. Large numbers of Reed-Sternberg cells and bizarre sarcomatous variants are present. It is associated with older age and HIV-positive status. Patients usually present with advanced-stage disease. Epstein-Barr virus (EBV) proteins are expressed in many of these tumors. Many cases of LDHD diagnosed in the past were actually were non-Hodgkin lymphomas, often of the anaplastic large-cell type.
• Lymphocyte-rich classic Hodgkin disease (LRHD) (5% of cases): In this type of Hodgkin disease (Hodgkin's lymphoma), Reed-Sternberg cells of the classic or lacunar type are observed, with a background infiltrate of lymphocytes. It requires immunohistochemical diagnosis. Some cases may have a nodular pattern. Clinically, the presentation and survival patterns are similar to those for MCHD.
• Nodular lymphocyte-predominant Hodgkin disease (NLPHD) (5% of cases): In contrast to the other histologic subtypes, the typical Reed-Sternberg cells in NLPHD are either infrequent or absent. Instead, lymphocytic and histiocytic (L&H) cells, or "popcorn cells" (their nuclei resemble an exploded kernel of corn), are seen within a background of inflammatory cells, which are predominantly benign lymphocytes. Unlike Reed-Sternberg cells, L&H cells are positive for B-cell antigens, such as CD19 and CD20, and are negative for CD15 and CD30. A diagnosis of NLPHD needs to be supported by immunohistochemical studies, because it can appear similar to LRHD or even some non-Hodgkin lymphomas.

Frequency

United States

Information regarding the incidence and mortality of Hodgkin disease (Hodgkin's lymphoma) in the United States can be found at the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER) database Website (www.seer.cancer.gov). Data are also collected by the American Cancer Society (ACS).⁴

The NCI estimates 8,220 new cases and 1,350 deaths from Hodgkin disease (Hodgkin's lymphoma)in 2008. The age-adjusted incidence of Hodgkin disease (Hodgkin's lymphoma) is 2.8 cases per 100,000 individuals.

International

Hodgkin disease (Hodgkin's lymphoma) had a worldwide incidence of 62,000 cases in 2002. Compared with North America and Europe, Hodgkin disease (Hodgkin's lymphoma) is relatively rare in Japan (age-adjusted incidence of 0.3 per 100,000 males) and China (age-adjusted incidence of 0.2 per 100,000 males). In developing countries, the incidence of the mixed-cellularity (MCHD) and lymphocyte-depleted (LDHD) subtypes is higher. In contrast, the nodular-sclerosis (NSHD) subtype is most frequent in developed countries.

Mortality/Morbidity

The 5-year disease-specific survival for patients with stages I and II Hodgkin disease (Hodgkin's lymphoma) is 90%; III, 84%; and IV, 65%.

Race

Hodgkin disease (Hodgkin's lymphoma) incidence rates in the United States vary by race and sex. The incidence in cases per 100,000 individuals is 3.3 for white males, 2.7 for white females, 2.9 for black males, 2.3 for black females, 1.4 for Asian/Pacific Islander males, and 1.0 for Asian/Pacific Islander females.

Sex

Overall, Hodgkin disease (Hodgkin's lymphoma) is somewhat more common in males than in females. The observed male predominance is particularly evident in children, in whom 85% of the cases are in males.

Age

Age-specific incidence rates of Hodgkin disease (Hodgkin's lymphoma) have a bimodal distribution in both sexes, peaking in young adults (aged 15-34 y) and older individuals (>55 y). In the United States, young adults typically have NSHD, whereas children (aged 0-14 y) and older individuals more commonly have the MCHD subtype.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

History

Clinical history features of Hodgkin disease (Hodgkin's lymphoma)

• Asymptomatic lymphadenopathy may be present (above the diaphragm in 80% of patients).
• Constitutional symptoms (eg, unexplained weight loss, fever, night sweats) are present in 40% of patients. Collectively, these are known as "B symptoms."
• Intermittent fever is observed in approximately 35% of cases. Infrequently, the classic Pel-Ebstein fever is observed (high fever for 1-2 wk followed by an afebrile period of 1-2 wk).
• Chest pain, cough, shortness of breath, or a combination of these things may be present due to a large mediastinal mass or lung involvement. Rarely, hemoptysis is observed.
• Patients may present with pruritus.
• Alcohol-induced pain at sites of nodal disease is specific for Hodgkin disease (Hodgkin's lymphoma) and occurs in less than 10% of patients.
• Back or bone pain occurs rarely.

Related Medscape topic:
Specialty Site Pulmonary Medicine

Physical

Physical examination findings in Hodgkin disease (Hodgkin's lymphoma) 

• Palpable painless lymphadenopathy occurs in the cervical area (60-80%), axilla (6-20%), and, less commonly, in the inguinal area (6-20%). It is described as rubbery adenopathy.
• Involvement of the Waldeyer ring or occipital or epitrochlear areas is infrequently observed.
• Splenomegaly may be present.
• Patients may have hepatomegaly.
• Superior vena cava syndrome resulting from massive mediastinal lymphadenopathy can also be seen.
• Central nervous system (CNS) symptoms or signs may be due to paraneoplastic syndromes, including cerebellar degeneration, neuropathy, Guillain-Barré syndrome, or multifocal leukoencephalopathy.

Related Medscape topic:
Specialty Site Neurology & Neurosurgery

Causes

The etiology of Hodgkin disease (Hodgkin's lymphoma) is unknown.

• Infectious agents, particularly EBV, may be involved in the pathogenesis of Hodgkin disease (Hodgkin's lymphoma).
• In as many as 50% of Hodgkin disease (Hodgkin's lymphoma) cases, the tumor cells are EBV-positive; EBV positivity is higher with MCHD (60-70%) than with NSHD (15-30%). Almost 100% of HIV-associated Hodgkin disease (Hodgkin's lymphoma) cases are EBV-positive.
• An epidemiologic study from Denmark and Sweden showed an increased risk of EBV-positive Hodgkin disease (Hodgkin's lymphoma) in patients with a self-reported history of infectious mononucleosis (IM) in adolescence.⁵ The average incubation time from IM to symptoms of Hodgkin disease (Hodgkin's lymphoma) was 2.9 years.
• Patients with HIV infection have a higher incidence of Hodgkin disease (Hodgkin's lymphoma) compared with the population without HIV infection. However, Hodgkin disease (Hodgkin's lymphoma) is not considered an acquired immunodeficiency syndrome (AIDS)-defining neoplasm.
• Genetic predisposition may play a role in the pathogenesis of Hodgkin disease (Hodgkin's lymphoma). Approximately 1% of patients with Hodgkin disease (Hodgkin's lymphoma) have a family history of the disease. Siblings of an affected individual have a 3- to 7-fold increased risk for developing Hodgkin disease (Hodgkin's lymphoma). This risk is higher in monozygotic twins.
• Human leukocyte antigen (HLA)-DP alleles are more common in Hodgkin disease (Hodgkin's lymphoma).

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

Other Problems to Be Considered

• Any disease presenting with lymphadenopathy and constitutional symptoms
• HIV infection
• Hypersensitivity reaction
• Other solid tumors

Occasionally, Hodgkin disease (Hodgkin's lymphoma) can present with hemophagocytic syndrome (hemophagocytic lymphohistiocytosis).⁶ Hemophagocytic syndrome is associated with EBV antigen expression by Reed-Sternberg cells and is clinically characterized by pancytopenia; fever; hepatosplenomegaly with liver function test abnormalities; elevated serum levels of ferritin and triglycerides; and phagocytosis of hematopoietic lineage cells by benign macrophages. 

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

Lab Studies

• Erythrocyte sedimentation rate (ESR) (a general marker of inflammation) measurements may be elevated in Hodgkin disease (Hodgkin's lymphoma). An elevated ESR has been associated with worse prognosis. However, the ESR is a nonspecific test that should not be used for Hodgkin disease (Hodgkin's lymphoma) screening.
• Lactate dehydrogenase (LDH) may be increased. LDH may correlate with the bulk of disease.
• Complete blood cell (CBC) count studies (for anemia, lymphopenia, neutrophilia, or eosinophilia) should be performed. Hodgkin disease (Hodgkin's lymphoma)–associated anemia is most commonly the anemia of chronic disease. However, it may result from bone marrow involvement by tumor or from the presence of an autoantibody (positive findings on a warm Coombs test). Cytopenias are common in advanced Hodgkin disease (Hodgkin's lymphoma) disease. Platelet counts may be increased or decreased.
• Serum creatinine in Hodgkin disease (Hodgkin's lymphoma) has a rare association with nephrotic syndrome.
• Alkaline phosphatase (ALP) may be increased due to the presence of liver or bone involvement. Other uncommon laboratory findings include hypercalcemia, hypernatremia, and hypoglycemia (due to the presence of insulin autoantibodies).
• An HIV test is important in the workup of Hodgkin disease (Hodgkin's lymphoma) and non-Hodgkin lymphomas, because antiviral therapies can improve disease outcomes in HIV-positive patients.⁷
• Serum levels of cytokines (interleukin [IL]-6, IL-10) and soluble CD25 (IL-2 receptor) correlate with tumor burden, systemic symptoms, and prognosis, but these studies are generally obtained only in special situations or in the context of a clinical trial.

Imaging Studies

Imaging studies for Hodgkin disease (Hodgkin's lymphoma) 

• Computed tomography (CT) scans of the chest, abdomen, and pelvis
• • Possible abnormal findings include enlarged lymph nodes, hepatomegaly and/or splenomegaly (with or without focal parenchymal abnormalities), lung nodules or infiltrates, and pleural effusions.
  • A mediastinal mass, representing mediastinal lymphadenopathy, is a very common finding in classic Hodgkin disease (Hodgkin's lymphoma), although it is uncommon in NLPHD.
• Positron emission tomography (PET) scanning is now considered to be essential to the initial staging of Hodgkin disease (Hodgkin's lymphoma).⁸

Other Tests

Sampling of a pleural effusion by thoracentesis and examination of the cells obtained may be useful in the evaluation of Hodgkin disease (Hodgkin's lymphoma). The pleural fluid may be an exudate or transudate, or it may be chylous.

CNS evaluation by lumbar puncture and magnetic resonance imaging (MRI) should be performed if symptoms or signs of CNS involvement are present. CNS involvement with Hodgkin disease (Hodgkin's lymphoma) is exceedingly rare, but it has been reported.

Procedures

• A histologic diagnosis of Hodgkin disease (Hodgkin's lymphoma) is always required.
• • An excisional lymph node biopsy is recommended, because the lymph node architecture is important for histologic classification.
  • When a patient presents with neck lymphadenopathy that may be due to a head and neck cancer, a fine-needle aspiration (FNA) is usually advised as the initial diagnostic step, followed by excisional biopsy if squamous cell histology is excluded.
• Bone marrow biopsies
• • Because Hodgkin disease (Hodgkin's lymphoma) in the bone marrow is often patchy, bilateral bone marrow biopsies are advised to improve the identification of advanced disease (stage IV).
  • Bone marrow involvement is more common in elderly individuals, in patients with advanced-stage disease, in the presence of systemic symptoms, and in patients with a high-risk histology.
  • A bone marrow biopsy can be omitted in patients with stage I Hodgkin disease (Hodgkin's lymphoma) and some patients with stage II disease without hematologic abnormalities. 
• A staging laparotomy is a surgical procedure that includes splenectomy with biopsies of the liver and lymph nodes in the para-aortic, mesenteric, portal, and splenic hilar regions. At present, a staging laparotomy procedure is very rarely indicated, because even early-stage Hodgkin disease (Hodgkin's lymphoma) is most often treated with combination chemotherapy. The procedure can be helpful in rare cases in which radiation therapy is under consideration as the sole treatment of early-stage Hodgkin disease (Hodgkin's lymphoma).

Staging

The Ann Arbor classification (1971) is used most often for cases of Hodgkin disease (Hodgkin's lymphoma). Clinical staging involves assessment of disease extent by clinical examination, history, and imaging techniques. When staging laparotomies are used as part of staging, the disease extent is designated as pathologic staging.

• Stage I denotes a single lymph node area or single extranodal site.
• Stage II denotes 2 or more lymph node areas on the same side of the diaphragm.
• Stage III denotes lymph node areas on both sides of the diaphragm.
• Stage IV denotes disseminated or multiple involvement of the extranodal organs. Involvement of the liver or the bone marrow is considered stage IV disease. For staging classifications, the spleen is considered to be a lymph node area. Involvement of the spleen is denoted with the S suffix (ie, IIB_S).
• A or B designations denote the absence or presence of B symptoms.
• • A "B" designation includes the presence of 1 or more of the following:
  • • Fever (temperature >38°C)
    • Drenching night sweats
    • Unexplained loss of more than 10% of body weight within the preceding 6 months
  • An "A" designation is the absence of the above.
  • An "X" designation is sometimes used to indicate the presence of bulky disease.
• Approximately one third of new patients have splenic involvement based on laparotomy data. However, this depends on the histologic subtype. Two thirds of patients with the mixed cellularity subtype have splenic involvement, compared with only one third of patients with the lymphocyte-depleted or nodular sclerosis histology. When liver or bone marrow involvement is present, the spleen is likely to be involved.
• Spread of Hodgkin disease (Hodgkin's lymphoma) takes place via the lymphatics, hematogenous routes, and direct extension.
• Contiguous involvement of extranodal sites (eg, involvement of the lung parenchyma due to direct extension of large mediastinal lymphadenopathy) is not considered stage IV disease. Rather, it is designated with the E suffix (ie, IIB_E).

Unfavorable factors in limited-stage Hodgkin disease (Hodgkin's lymphoma)

Many factors that can be assessed at the time of the disease diagnosis can help to determine whether a patient's Hodgkin disease (Hodgkin's lymphoma) has a high or low risk of proving resistant to therapy. Such an estimate is important for treatment planning. In addition, it can help identify patients who would potentially benefit from participating in clinical trials that seek to either minimize therapy in low-risk patients or intensify therapy in high-risk patients.

In patients with stage I or II disease, the following factors are considered unfavorable and, if present, will increase the intensity of the recommended initial therapy:

• Bulky disease, defined as a mediastinal mass greater than one third of the intrathoracic diameter (on a chest radiograph) or greater than 35% of the thoracic diameter at vertebral level T5-6. Hodgkin disease (Hodgkin's lymphoma) also qualifies as bulky disease if it is greater than 10 cm in diameter on a CT scan.
• An ESR result (a general marker of inflammation) 50 mm/h or higher, if the patient is otherwise asymptomatic
• More than 3 sites of disease involvement
• The presence of B symptoms
• The presence of extranodal disease

• Serum albumin less than 4 g/dL
• Hemoglobin less than 10.5 g/dL
• Male sex
• Stage IV disease
• Age 45 years or older
• White blood cell (WBC) count greater than 15,000/mm³
• Lymphocyte count less than 600/mm³ or less than 8% of the total WBC count

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

Medical Care

Principles of therapy for Hodgkin disease (Hodgkin's lymphoma)

• Published guidelines from the National Comprehensive Cancer Network (NCCN),¹⁰ the European Society of Medical Oncology (ESMO),¹¹ and the International Harmonization Project¹² provide consensus opinions from leading experts on evidence-based approaches to the diagnosis and treatment of Hodgkin disease (Hodgkin's lymphoma).
• Hodgkin disease (Hodgkin's lymphoma) is considered to be a curable malignancy, but therapies for this disease can have significant long-term toxicity. Therefore, advances in treatment protocols have sought to (1) minimize the treatment given to patients with early stage, low-risk disease and (2) safely maximize the treatment given to patients with disease that is likely to be refractory to standard therapies.
• Combined-modality therapy (radiation therapy [XRT] and chemotherapy) is frequently the preferred approach in for most patients. In early stage disease, combined-modality therapy provides a synergistic effect while limiting the total exposure to any particular agent.¹³ In patients with advanced Hodgkin disease (Hodgkin's lymphoma), involved-field XRT can be used for sites of persistent disease following chemotherapy. XRT to sites of disease that were bulky at diagnosis is a standard feature of the Stanford V regimen (see Chemotherapy, Stanford V regimen, below).
• The high sensitivity of positron emission tomography (PET) scanning for classic Hodgkin disease (Hodgkin's lymphoma) has this imaging modality a prominent role in the assessment of treatment response in affected patients. A positive PET scan following therapy correlates strongly with a high risk of relapse. An early attainment of a negative PET scan during therapy is a positive prognostic indicator, but studies have not yet provided information on whether a course of therapy can be safely shortened in this situation.^{14, 15}

  PET/CT scans should be obtained at least 3 weeks, and preferably 6-8 weeks following the last therapy in order to lessen the risk of false-positive scans resulting from nonmalignant inflammatory responses.¹⁶ Biopsies of PET-positive lesions are typically done in order to test for persistent Hodgkin disease (Hodgkin's lymphoma).

• The goal of therapy is to induce a complete remission (CR), which is defined as the "disappearance of all evidence of disease," as evaluated by PET/CT scanning, physical examination, and bone marrow examination (if appropriate). A partial remission (PR) is defined as "regression of measurable disease and no new sites" of disease. 
• Despite the high rate of cure for this disease, many cases Hodgkin disease (Hodgkin's lymphoma) do relapse. In most of these cases, salvage chemotherapy followed by high-dose chemotherapy (HDC) with autologous hematopoietic stem cell support is indicated.¹⁷
• The role of allogeneic hematopoietic stem cell transplantation for Hodgkin disease (Hodgkin's lymphoma) is being explored.¹⁸ It is possible that a graft-vs-lymphoma effect may contribute to favorable outcomes in affected patients, but mortality directly resulting from the transplant procedure has been unacceptably high. Newer transplant protocols that use less-intensive conditioning regimens (chemotherapy) offer the potential for long-term disease-free survival (DFS) with less transplant-related mortality.¹⁹ Allogeneic hematopoietic stem cell transplantation should ideally be pursued only in the context of a clinical trial.
• Because of the limited number of patients with Hodgkin disease (Hodgkin's lymphoma) and the importance of the clinical questions that remain about optimal disease management, patient involvement in clinical trials is strongly encouraged.
• NLPHD is clinically distinct from classic Hodgkin disease (Hodgkin's lymphoma) in that it generally presents as early stage disease that can be treated with local measures (surgery, radiation) or followed expectantly. Some cases of NLPHD can transform to aggressive non-Hodgkin lymphomas that are treated using standard paradigms.

For treatment of classic Hodgkin disease (Hodgkin's lymphoma), XRT is generally administered in combination with chemotherapy. Radiation fields and doses are selected to minimizing the potential side effects of therapy, while maximizing the potential for long-term DFS. Involved-field therapy encompasses only the areas of observed disease. Regional-field therapy extends the involved field to include adjacent lymph regions. 

Other fields that have been used historically and may be used in exceptional clinical circumstances include the mantle field, covering the mediastinal, cervical, and axillary nodes, and the inverted Y field, covering the para-aortic, pelvic, and inguinal nodes. Subtotal nodal irradiation involves the mantle field plus the para-aortic nodes. The mantle field is shaped in order to reduce radiation exposure to the heart and lungs. Careful avoidance of the spinal cord can reduce the risk of myelitis. Shielding the testes and oophoropexy (temporary surgical suspension of the ovaries [eg, outside of a radiation field]) are important during the reproductive years.

The dose of radiation to be administered is tailored to the specific clinical scenario. Doses used in combined modality therapy are 30-36 Gy for bulky disease sites and 20-30 Gy for nonbulky disease sites. When used alone, doses may range from 30-44 Gy.   

In the NLPHD subtype of Hodgkin disease (Hodgkin's lymphoma), involved-field XRT may be recommended for stage IA and IIA disease.

Chemotherapy

Induction regimens are those given as initial treatment for Hodgkin disease (Hodgkin's lymphoma).

• MOPP regimen (mechlorethamine, vincristine, procarbazine, prednisone) was the first effective combination chemotherapy developed for Hodgkin disease (Hodgkin's lymphoma). It is a 4-drug regimen developed by Vincent DeVita and colleagues at the NCI in the mid 1960s and is primarily of historical importance.
• The ABVD regimen (Adriamycin, bleomycin, vinblastine, dacarbazine) was designed in Italy by Gianni Bonadonna and his colleagues in the early 1970s. This combination has now become the standard chemotherapy regimen for Hodgkin disease (Hodgkin's lymphoma). ABVD is superior to MOPP in terms of DFS and has a lower incidence of sterility and secondary leukemia.²⁰ 
• The Stanford V regimen (doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide, prednisone) is a multidrug regimen created at Stanford University by Sandra Horning and colleagues.²¹ The drugs are administered weekly, alternating myelosuppressive and nonmyelosuppressive agents, for 12 weeks. Involved-field XRT at the conclusion of the 12-week regimen is an important part of this regimen. A potential advantage of the Stanford V regimen is that its use of a broad spectrum of chemotherapy drugs can limit the exposure (and potential side-effects) of any single drug.
• The BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) was developed in Germany by Volker Diehl and colleagues.²² A dose-intensified version of BEACOPP (escalated BEACOPP), with higher doses of etoposide, Adriamycin, and cyclophosphamide and the addition of granulocyte colony-stimulating factor (G-CSF) for neutrophil support, has also been developed, which may be useful for unfavorable, advanced-stage Hodgkin disease (Hodgkin's lymphoma). However, escalated BEACOPP is associated with greater hematologic toxicity and a higher incidence of secondary malignancies, including acute myelogenous leukemia (AML).

Salvage chemotherapy

For patients whose disease has failed induction chemotherapy, salvage chemotherapy is generally given. Salvage regimens incorporate drugs that are complementary to those that failed during induction therapy. Commonly used salvage regimens include ICE (ifosfamide, carboplatin, etoposide), DHAP (cisplatin, cytarabine, prednisone), and ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin). 

HDC with bone marrow transplantation

HDC at doses that ablate the bone marrow is feasible with reinfusion of the patient's previously collected hematopoietic stem cells (autologous transplantation) or infusion of stem cells from a donor source (allogeneic transplantation). Historically, hematopoietic stem cells have been obtained from bone marrow, but they are now typically obtained by pheresis of peripheral blood lymphocytes. A validated and relatively safe conditioning regimen for autologous transplantation is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan).¹⁷

Specific Regimens

Each of the medications in all of the regimens described in the article are given intravenously, except for prednisone and procarbazine, which are given orally.

Induction (for initial disease treatment)

MOPP regimen
Every 28 days for 6 or more cycles.

• Mechlorethamine: 6 mg/m², days 1 and 8
• Vincristine: 1.4 mg/m², days 1 and 8
• Procarbazine: 100 mg/m², days 1-14
• Prednisone: 40 mg/m², days 1-14, cycles 1 and 4 only

ABVD regimen 
Every 28 days for 6 or more cycles.

• Adriamycin: 25 mg/m², days 1, 15
• Bleomycin: 10 mg/m², days 1, 15
• Vinblastine: 6 mg/m², days 1, 15
• Dacarbazine: 375 mg/m², days 1, 15

Stanford V regimen 
XRT is administered to bulky sites 2-4 weeks following the end of chemotherapy.

• Vinblastine: 6 mg/m², weeks 1, 3, 5, 7, 9, 11
• Doxorubicin: 25 mg/m², weeks 1, 3, 5, 9, 11
• Vincristine: 1.4 mg/m², weeks 2, 4, 6, 8, 10, 12
• Bleomycin: 5 units/m², weeks 2, 4, 8, 10, 12
• Mechlorethamine: 6 mg/m², weeks 1, 5, 9
• Etoposide: 60 mg/m² twice daily, weeks 3, 7, 11
• Prednisone: 40 mg/m², every other day, weeks 1-10, tapered weeks 11, 12

Escalated BEACOPP regimen 
Every 3 weeks for 8 cycles.

• Bleomycin: 10 mg/m², day 8
• Etoposide: 200 mg/m², days 1-3
• Doxorubicin: 35 mg/m², day 1
• Cyclophosphamide: 1,250 mg/m², day 1
• Vincristine: 1.4 mg/m², day 8
• Procarbazine: 100 mg/m², days 1-7
• Prednisone: 40 mg/m², days 1-14

Salvage Therapy (for primary refractory or relapsed disease)

ICE regimen

• Ifosfamide: 5 g/m², day 2
• Mesna: 5 g/m², day 2
• Carboplatin: AUC 5, day 2
• Etoposide: 100 mg/m², days 1-3

DHAP regimen

• Cisplatin: 100 mg/m², day 1
• Cytarabine: 2 g/m², given twice on day 2
• Dexamethasone: 40 mg, days 1-4

EPOCH regimen – In this regimen, etoposide, vincristine, and doxorubicin are given together over a total of 96 hours in a continuous intravenous infusion.

• Etoposide: 50 mg/m², days 1-4
• Vincristine: 0.4 mg/m², days 1-4
• Doxorubicin: 10 mg/m², days 1-4
• Cyclophosphamide: 750 mg/m², day 5
• Prednisone: 60 mg/m², days 1-6

Myeloablative Regimens (high-dose therapy requires hematopoietic stem cell support for recovery)

BEAM regimen

Different schedules for BEAM exist that vary primarily in the dose of etoposide administered.  This is the version used by Schmitz et al  in a key randomized, prospective clinical trial.¹⁷ Following this chemotherapy, autologous hematopoietic stem cells are administered on day 0.

• BCNU 300 mg/m², day –7
• Etoposide 150 mg/m², every 12 hours, total of 8 doses, days –7 to –4
• Cytarabine 200 mg/m², every 12 hours, total of 8 doses, days –7 to –4
• Melphalan 140 mg/m², day –3

Treatment of Hodgkin disease (Hodgkin's lymphoma) is tailored to disease type, disease stage, and an assessment of the risk of resistant disease. Two sets of consensus guidelines currently help guide the standard of care for Hodgkin disease (Hodgkin's lymphoma), written by the NCCN and the ESMO. 

The guidelines are very similar, but the NCCN guidelines have more specific recommendations for response evaluation and follow-up. In addition, a set of revised response criteria for malignant lymphoma, including Hodgkin disease (Hodgkin's lymphoma), and recommendations for using PET scanning to monitor Hodgkin disease (Hodgkin's lymphoma) were published by the International Harmonization Project. Together, these provide specific guidance for evaluating the response of disease therapy.

Goals of therapy

The primary goal of therapy is to induce a CR, which is defined as the "disappearance of all evidence of disease," as evaluated by PET/CT scanning, physical examination, and bone marrow examination (if appropriate).¹² PET/CT scanning should be obtained at least 3 weeks and preferably 6-8 weeks following the last therapy in order to lessen the risk of false-positive scans resulting from nonmalignant inflammatory responses. A PR is defined as "regression of measurable disease and no new sites" of disease. A failure to achieve a CR with initial therapy or a relapse after having attained a CR is an indication for additional HDC and/or XRT, often with autologous hematopoietic stem cell support.

Early stage, low-risk disease

This group is defined as patients with clinical stages IA or IIA classic Hodgkin disease (Hodgkin's lymphoma) who do not have unfavorable factors (bulky disease, elevated ESR, >3 sites of involvement, B symptoms, extranodal disease).^{13, 25} These patients generally should receive 4 cycles of the ABVD regimen or 8 weeks of the Stanford V regimen, followed by involved-field XRT. Radiation alone has been shown to be inferior to the combined modality approach in early stage, low-risk disease. If XRT is contraindicated or not possible, then chemotherapy should continue for 2 additional cycles following the attainment of a CR. 

Early stage disease with unfavorable factors

This group is defined as patients with clinical stages I or II with bulky disease, with or without unfavorable factors (elevated ESR, >3 sites of involvement, B symptoms, extranodal disease). These patients are candidates for 4-6 cycles of the ABVD regimen or 12 weeks of the Stanford V regimen, followed by involved-field XRT. 

Advanced and/or high-risk disease

These patients have stage I or II disease with B symptoms (IB, IIB), or stages III or IV. The NCCN recommends either 4 cycles of the ABVD regimen or 12 weeks of the Stanford V regimen, followed by restaging with PET/CT scanning. If a patient has positive results on PET scans following the ABVD regimen, an additional 2 cycles are administered. Once a CR has been achieved, involved-field XRT is given. If, after 12 weeks of the Stanford V regimen, a patient is in a CR or PR has been attained, then involved-field XRT is standard. 

EMSO recommends that patients with this category of disease receive either 8 cycles of the ABVD regimen or the standard-dose BEACOPP regimen, with involved-field XRT applied only to tumors initially more than 7.5 cm or to sites of residual disease following chemotherapy. For patients with advanced-stage disease, the use of the escalated BEACOPP regimen has support in the literature.

NLPHD

Early-stage NLPHD can be treated with local excision, involved-field XRT, or expectant management (close observation).²⁶ Advanced-stage disease may represent histologic transformation to T-cell rich B-cell lymphoma (TCR-BCL) or diffuse large cell B-cell lymphoma (DLCBL). These are types of non-Hodgkin lymphoma that should be treated with a typical non-Hodgkin regimen, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).

Rituximab is a humanized monoclonal antibody that is specific for CD20, a cell-surface antigen expressed by the malignant L&H cells in NLPHD. It has shown activity as a single agent in NLPHD. The German Hodgkin Lymphoma Study Group (GHSG) published long-term follow-up data on the use of rituximab in patients with relapsed/refractory NLPHD.²⁷ The investigators observed a 94% overall response rate, with 8 complete remissions from their population of 15 patients.²⁷ Therefore, rituximab is a promising agent for advanced NLPHD, although the use of rituximab in NLPHD, especially in early-stage disease, should ideally be pursued in the context of a clinical trial.

Hodgkin disease (Hodgkin's lymphoma) with concomitant HIV infection

In patients with advanced Hodgkin disease (Hodgkin's lymphoma) and HIV, the results with standard chemotherapy (eg, ABVD, BEACOPP) can be dramatically improved by simultaneous treatment with highly active antiretroviral therapy (HAART). Such therapy generally involves 3 drugs: 2 nucleoside reverse transcriptase inhibitors combined with either a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor, or a viral fusion inhibitor.

Relapsed or primary refractory disease

Hodgkin disease (Hodgkin's lymphoma) that has never entered a CR or that has relapsed after the attainment of a CR is associated with a very poor prognosis when treated with standard chemotherapy and radiation. Therefore, for patients with relapsed or refractory disease, HDC with autologous stem cell transplantation is recommended.²⁸ In this procedure, salvage chemotherapy is first administered to help reduce the size of the persistent disease and obtain a CR, if possible. The number of cycles to be administered depends on how well the disease is responding to therapy. An optimal situation is one in which the disease enters a CR with negative PET scan findings, although one study demonstrated that patients may achieve long-term DFS, even if their condition has little or no response.²⁹
 
Following one of the cycles of salvage chemotherapy, hematopoietic stem cells are collected from the peripheral blood by leukapheresis and are stored frozen. Following the administration of myeloablative chemotherapy (eg, BEAM), the stored hematopoietic stem cells are thawed and reinfused into the patient to facilitate hematopoietic recovery. HDC with autologous stem cell transplantation can provide better than 50% long-term, progression-free survival for patients with relapses, although specific predicted outcomes vary widely depending on patient-specific risk factors.

Many questions relating to salvage and HDC therapy for patients with Hodgkin disease (Hodgkin's lymphoma) need to be addressed and are the subject of ongoing clinical trials. These include (1) the optimal salvage regimen or regimens, (2) the ideal conditioning regimen or regimens, (3) the potential benefits of twin transplants compared with single transplants, and (4) how to prospectively identify those patients who are unlikely to benefit from HDC and how to best manage their disease.

In some cases in which HDC fails, allogeneic stem cell transplantation may be a viable option. In this method, myeloablative therapy (chemotherapy and sometimes XRT) is followed by the infusion of hematopoietic stem cells from a genetically matched donor.¹⁸ This offers the potential for an immunologic antitumor effect from T cells provided by the hematopoietic stem cell donor, which may improve the chances for cure of the disease. 

Historically, allogeneic stem cell transplantation for Hodgkin disease (Hodgkin's lymphoma) has been considered too high risk for most patients due a high transplant-related mortality. However, new transplant protocols use less toxic conditioning regimens and may be safer and more effective for patients with refractory Hodgkin disease (Hodgkin's lymphoma).¹⁹

Consultations

The following consultations should be sought in cases of Hodgkin disease (Hodgkin's lymphoma)

• Hematologist/oncologist
• Radiation oncologist
• Social worker
• Tertiary care center for consideration of clinical trial enrollment

FOLLOW-UP

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

Further Outpatient Care

Follow-up for the patient in complete remission

NCCN and ESMO both provide recommendations for the long-term follow-up of treated patients with Hodgkin disease (Hodgkin's lymphoma).^{10, 11}

• Most relapses occur in the first 3 years after therapy. Follow-up visits are recommended every 2-4 months for the first 1-2 years and every 3-6 months for the next 3-5 years.
• Follow-up examinations include the following:
• • History and physical examination
  • CBC counts and chemistry panel, including LDH, ESR, glucose, and lipid levels
  • Thyroid-stimulating hormone (TSH) levels (at least annually if the patient has had neck XRT)
  • Chest x-ray or CT scans of the chest every 6-12 months in the first 2-5 years. Abdominal and pelvic CT scans may be added every 6-12 months in the first 2-3 years, especially if the disease had originally occurred below the diaphragm. 
  • PET scans obtained for surveillance following CR is specifically not encouraged by the NCCN due to the possibility that false-positive results may occur.
  • Spiral chest CT scans may be appropriate annually, starting 5 years after therapy to screen patients at increased risk for lung cancer.
• Female patients with a history of chest irradiation should be screened annually with mammography, starting at age 40 years or 5-8 years following the XRT. 
• Vaccinations against pneumococcus (especially in patients who have had splenectomy), Haemophilus influenzae, meningococcus, and influenza (annually, especially in patients who have received bleomycin or chest XRT), should be maintained.

Complications

Late complications of therapy in Hodgkin disease (Hodgkin's lymphoma) survivors

Survivors of Hodgkin disease (Hodgkin's lymphoma) may have long-term sequelae from their therapy.³⁰ With the current widespread use of nonleukemogenic chemotherapy (ABVD) and the use of smaller radiation fields and doses, the rate of treatment-related deaths is expected to decrease.

• Cardiac disease
• • Mantle radiotherapy increases the risk the risk of coronary artery disease, chronic pericarditis, pancarditis, valvular heart disease, and defects in the conduction system.³¹
  • Patients with history of mediastinal radiation have a 3-fold increase in their risk of cardiac death.
  • A study of patients who had previously undergone mediastinal irradiation for Hodgkin disease (Hodgkin's lymphoma) but who had no clinical evidence of heart disease demonstrated a significant incidence of silent coronary artery obstruction and previous ventricular damage.³² Based on these results, it is reasonable to initiate functional screening 5 years after XRT in patients with Hodgkin disease (Hodgkin's lymphoma).
• Pulmonary disease
• • The ABVD regimen contains bleomycin, a drug associated with dose-related pulmonary toxicity, mainly interstitial pneumonitis, which may lead to fibrosis.
  • The addition of mantle irradiation enhances lung injury. Pulmonary symptomatology, such as cough or dyspnea upon exertion, is observed in 50% of patients, and declining pulmonary function parameters are observed in approximately one third of patients during ABVD chemotherapy, with or without XRT. This may lead to dose reductions or even discontinuation of bleomycin.
  • Baseline tests and follow-up evaluation with pulmonary function tests are recommended. The best parameter to follow is the carbon monoxide diffusion capacity.
  • Although acute toxicity is common, the incidence of severe long-term pulmonary toxicity is low. Fatal pulmonary toxicity has been reported in up to 2-3% of patients treated with the ABVD regimen.
• Secondary cancers – Secondary leukemias and solid tumors are significant causes of morbidity and mortality for patients who have received early therapies, including the MOPP regimen and mantle XRT. With modern therapies that emphasize the widespread use of the ABVD and Stanford V regimens and the application of radiation to involved fields only, the incidence of secondary cancers is expected to be much lower.
• • Myelodysplastic syndromes (MDS) /acute leukemia
  • • In the Stanford case series, the projected risk for developing MDS or acute leukemia over a follow-up period of 35 years was 2%, and the relative risk compared with matched controls was 38%. The MOPP regimen is associated with an approximately 5% incidence of MDS/leukemia. With the ABVD regimen, such risk is lower, less than 1%. 
    • MDS/AML is usually seen in the first 3-8 years following treatment for Hodgkin disease (Hodgkin's lymphoma); subsequently, the risk appears to decline. These findings are consistent with the biology of secondary leukemias following alkylator therapy. 
    • MDS/AML usually develops in the context of an MDS with cytogenetic abnormalities in chromosomes 5 and/or 7. Exposure to alkylating agents (eg, the mechlorethamine used in the MOPP regimen) has been implicated. 
    • Exposure to epipodophyllotoxins (etoposide and teniposide) may also result in AML, which generally develops within 3 years and is associated with chromosomal abnormalities at band 11q23.
  • Breast cancer
  • • Patients treated with mantle XRT when they are younger than 30 years are 19 times more likely to develop breast cancer. If women are exposed to chest XRT when they are younger than 15 years, this relative risk increases to 136.
    • MOPP chemotherapy also produces an increased risk for breast cancer when combined with XRT.
  • Other solid tumors
  • • The most common secondary malignancy following treatment for Hodgkin disease (Hodgkin's lymphoma) is lung cancer. Both chemotherapy with alkylating agents and irradiation are associated with a 10-fold increased relative risk of lung cancer. Smoking can further increase the risk. 
    • Patients in the Stanford case series were also found to have increased risks of developing melanoma, non-Hodgkin lymphoma, soft-tissue sarcoma, salivary gland cancers, pancreatic cancers, and thyroid cancers.
• Infertility
• • MOPP chemotherapy causes permanent infertility in at least 80% of males and approximately 50% of females. Young females may maintain their ovarian function, and some studies suggest that this may be improved by the use of oral contraceptives.³³ The escalated BEACOPP regimen is also likely to impair fertility.³⁴
  • The ABVD and Stanford V regimens pose a lower risk of permanent sterility than regimens that contain an alkylating agent (eg, MOPP chemotherapy).³⁵ The EORTC Lymphoma Group reported an 82% rate of recovery of fertility in male patients who were treated without alkylating agents.³⁶ Male patients who are considering bearing children may consider sperm banking before initiating therapy. 
• Infectious complications
• • Patients who have undergone splenectomy are predisposed to bacterial sepsis secondary to encapsulated microorganisms (especially Streptococcus pneumoniae). Empiric antibiotic therapy should be instituted promptly in patients who have undergone splenectomy and present with fever. Pneumococcal vaccination before splenectomy and every 5-7 years thereafter is also recommended.
  • Influenza vaccination annually may help to reduce the incidence and/or complications of influenza in patients who have received bleomycin or chest XRT.
  • Herpes zoster usually appears in previously irradiated dermatomes, but this condition may also occur in patients who have not been irradiated.
• Hypothyroidism – Elevation of thyroid stimulating hormone (TSH) occurs in one third of adult patients after neck/mediastinal XRT.
• Lhermitte syndrome – Patients with this syndrome describe an electric shock sensation that radiates along the back and legs upon flexion of the neck. It can occur in approximately 15% of patients after mantle irradiation. Lhermitte syndrome is not associated with the development of radiation myelitis, and it does not require treatment. This syndrome may last for many months, but eventually, it resolves without long-term sequelae.
• Psychosocial sequelae – Survivors of Hodgkin disease (Hodgkin's lymphoma) have an increased incidence of fatigue, psychiatric distress (anxiety, depression), employment problems, family issues, and sexual functioning problems, as compared with individuals without this disease or relative to survivors of acute leukemia.^{37, 38}

Patient Education

• Before the initiation of HDC, patients with Hodgkin disease (Hodgkin's lymphoma) should be counseled about the risk of infertility, and sperm banking should be considered for males.
• Patients should be counseled on health habits that may help reduce the risk of cancer and cardiovascular disease, including avoidance of smoking, control of lipids, and the use of sunscreen.
• Female patients who have received chest XRT should be encouraged to perform regular breast self-examinations.
• Patients should also be advised about the long-term risk of infection after undergoing splenectomy and the importance of calling their physician if they experience a fever.
• Patients should understand the risk of psychosocial problems that may affect survivors of Hodgkin disease (Hodgkin's lymphoma). Consultations with social workers, psychologists, and psychiatrists may be helpful to manage some of these issues.

MISCELLANEOUS

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

Medical/Legal Pitfalls

• Because Hodgkin disease (Hodgkin's lymphoma) is considered to be a curable malignancy, medicolegal problems may arise from failure to diagnose the disease in a timely manner, possibly attributable to the following factors:
• • The misinterpretation of B symptoms
  • A lack of follow-up for abnormal chest radiographs or physical examination findings
  • A missed pathologic diagnosis because a needle biopsy was obtained rather than an excisional lymph node biopsy
• Treatment for Hodgkin disease (Hodgkin's lymphoma) seeks to balance the risk of treatment failure with the risk of treatment side effects. Medicolegal liability may therefore result from overtreatment of low-risk disease or undertreatment of high-risk disease.
• Patients with refractory or relapsed Hodgkin disease (Hodgkin's lymphoma) should be promptly referred to centers capable of HDC with hematopoietic stem cell support.
• In the case of survivors of Hodgkin disease (Hodgkin's lymphoma), problems may arise in the following scenarios:
• • Failure to identify secondary cancers in a timely manner
  • Failure to consider sepsis as a possible cause for fever in a splenectomized patient
  • Failure to diagnose and treat predictable complications of Hodgkin disease (Hodgkin's lymphoma) treatment, such as coronary artery, pulmonary, or thyroid disease
• Failure to warn patients about potential complications of Hodgkin disease (Hodgkin's lymphoma) therapy, including the risk of cardiac disease, lung toxicity, and secondary cancers. Patients should also be apprised of the potential loss of fertility that may arise from MOPP chemotherapy, escalated BEACOPP chemotherapy, pelvic irradiation, or HDC, so that they may explore fertility-preserving options such as sperm banking, oral contraceptive use, or oophoropexy.

Related Medscape topics:
Resource Center Medical Malpractice and Legal Issues
Specialty Site Hematology-Oncology

FURTHER READING

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

• Hoppe RT, Hira Advani R, Ambinder RF, et al, for the NCCN Hodgkin Disease/Lymphoma Panel Members. NCCN clinical practice guidelines in oncology. Hodgkin disease/lymphoma. v2. 2009. Available at: http://www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf. Accessed October 31, 2008.
• Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. Mar-Apr 2006;56(2):106-30. [Medline]. [Full Text].
• National Cancer Institute. Adult Hodgkin's lymphoma treatment (PDQ) [health professionals version]. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/healthprofessional/. Accessed October 31, 2008.
• National Cancer Institute. Adult Hodgkin's lymphoma treatment (PDQ) [patient version]. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/patient/. Accessed October 31, 2008.
• National Cancer Institute. Search for clinical trials: basic search. Available at: http://www.cancer.gov/clinicaltrials/search. Accessed October 31, 2008.
• National Cancer Institute. Surveillance Epidemiology and End Results (SEER) [database]. Available at: http://www.seer.cancer.gov/. Accessed October 31, 2008.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

We are grateful to Virginia Kaklamani, MD, and Christine Wasilewski, MD, MPH, for help on prior versions.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• References

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