Pathophysiology: HD is a disease of the reticuloendothelial and lymphatic systems. As with other malignant disease, invasion of other organ systems can occur. Clustering of cases within families or racial groups has supported the idea of a genetic predisposition or common environmental link. Identical twins of patients with HD are noted to have an elevated risk of HD. Additionally, HD has been observed with greater frequency in patients with congenital or acquired immunodeficiency syndromes.

Several epidemiologic studies have suggested links between HD and certain viral illnesses. The strongest case to date relates to Epstein-Barr virus (EBV), where viral DNA has been noted in Reed-Sternberg cells. The possible role of human herpes virus 6 (HHV6) is also under investigation. While the connection between these infectious agents and HD is intriguing, further study is necessary to define the role these agents might play in the pathogenesis of this malignancy.

Frequency:

• In the US: Annually, 750-800 new cases of pediatric HD are diagnosed in the United States. For children younger than 15 years, the incidence is 5.5 cases per million children. For those aged 15-20 years, the incidence is 12.1 cases per million.

• Internationally: Differences exist among countries with different levels of economic development, with a higher incidence in younger children of less developed countries. Over time, this observation is becoming less pronounced. In the United States and Western Europe, the childhood rate is lower than the young adult rate. In Eastern Europe, the young adult rate is similar to that observed in the United States and Western Europe but the childhood rate is higher. Latin American countries have patterns of incidence approaching those of the United States. Incidence is relatively low in Asia, with the exception of South Asia where a relatively high incidence is found. Nodular sclerosis HD is the most common type in developed countries.

Mortality/Morbidity: The 5-year survival rate for HD of all stages is 91%. Patients with lower-stage disease have survival rates greater than 90%, whereas those with higher-stage disease have survival rates as low as 70%.

Race: Within the United States, the incidence among white and black people is essentially the same; however, the ratio is 1.4:1 in children older than 10 years.

Sex: A slight male predominance exists in children younger than 15 years, which is 1.3. In children aged 15 years and older, the male-to-female ratio decreases to 0.8.

History: The most common presenting symptom for HD is asymptomatic cervical or supraclavicular lymphadenopathy. Two thirds of these patients have mediastinal involvement as well. Constitutional (B symptoms, see below) are observed in 20-30% of patients with this malignancy.

• Localized symptoms: Painless adenopathy, which is usually nontender, is present.

• Respiratory symptoms: Cough or chest pain may be present as a result of mediastinal involvement.

• Systemic symptoms: B symptoms result in the upgrading of stage, which is denoted by the suffix B appearing after the numeric stage (eg, stage IIB). Patients without any of these symptoms have the suffix A added after the numeric stage (eg, IIIA). This designation is important because the presence or absence of the following B symptoms has bearing on the prognosis:

• Unexplained fever with temperature above 38°C for 3 consecutive days

• Unexplained weight loss of 10% or more within the previous 6 months

• Drenching night sweats

• Other systemic symptoms: These include pruritus, urticaria, and fatigue.

Physical:

• Nontender lymphadenopathy in the cervical or supraclavicular region is common; therefore, evaluate all sites of lymphoid tissue (eg, lymph nodes, Waldeyer ring, spleen). Measure enlarged nodes to monitor response to treatment.

• Splenomegaly may be observed with abdominal involvement. Isolated disease in the abdomen is unusual. Superior vena cava syndrome due to impeded blood return secondary to a mediastinal mass can be observed.

• Respiratory findings are found in cases of extensive mediastinal involvement with narrowing of the airways; therefore, evaluate the patient for stridor or decreased breath sounds on auscultation.

Causes: As with most malignancies, the following factors may contribute to development of HD:

• Genetic predisposition

• Environmental factors (eg, infectious agents): The EBV is found in approximately 50% of cases of HD in the United States and Western Europe.

• Immune dysregulation

Lab Studies:

• Hemoglobin/hematocrit: Anemia can be observed in the absence of bone marrow disease, usually because of a destructive process (ie, hemolytic anemia, which may be Coombs positive). Anemia of chronic disease can also be observed depending on duration of disease prior to diagnosis.

• Platelet count: Thrombocytopenia and an idiopathic thrombocytopenia purpura (ITP)–type picture may be present.

• White blood cell count/differential: Abnormalities such as lymphopenia, eosinophilia, and monocytosis may be present.

• Erythrocyte sedimentation rate (ESR) is usually elevated.

• Full serum chemistry panel: Other studies that may demonstrate elevated findings are lactate dehydrogenase (LDH), serum copper, and ferritin, suggesting activation of the reticuloendothelial system.

Imaging Studies:

• A chest radiograph (CXR) with anteroposterior and lateral projections often shows a mediastinal mass. A mass that occupies more than one third of the intrathoracic diameter carries a poorer prognosis than a smaller mass.

• CT imaging: Scan the head to include Waldeyer ring, neck, chest, abdomen, and pelvis for sites of disease.

• Gallium scan: Pay particular attention to the subdiaphragmatic regions. It may also be useful in long-term follow-up care of these patients.

• Bone scan

• Lymphangiogram (when CT imaging is not available)

Procedures:
 

• Bone marrow aspirate and biopsy

• Tissue biopsy

• A tissue biopsy is needed for diagnosis.

• Histopathologic studies consist of hematoxylin and eosin staining and special immunohistochemical staining for surface markers such as CD15, CD20, CD30, and CD45.

• Cytogenetic abnormalities, immunoglobulin gene rearrangements, and oncogene rearrangements are being studied; however, they are not currently used in the diagnostic workup of HD.

Histologic Findings: Several histologic classifications of HD now exist since the first by Jackson and Parker in 1947 (eg, those by Lukes and Butler and the Rye Conference). The most recent are the revised European-American lymphoma (REAL) classification and the World Health Organization (WHO) classification, both of which describe 2 distinct diseases classified as HD under the older classifications.

REAL/WHO classification

• Classic
   

   

• Nodular sclerosis (NS)
   

   

• Mixed cellularity (MC)
   

   

• Lymphocyte-rich (LR)
   

   

• Lymphocyte-depleted (LD)
   

   

• Unclassifiable
   

   

• Nodular lymphocyte–predominant (NLP)

Morphology

Medical Care: Treat children with HD at a pediatric oncology center where pediatric oncologists, radiation therapists, and full ancillary services for children with malignancies are available.

In pediatric patients, treatment consists of multiagent chemotherapy and possible radiation therapy. The specifics of both of these regimens vary with the stage of disease. With chemotherapy used in conjunction with radiation therapy, patients with early stage HD have long-term survival rates of close to 100%. Patients with more advanced disease, especially those with B symptoms, have survival rates of greater than 80%.

Current areas of interest in improving outcome for children with HD include decreasing long-term adverse effects such as cardiomyopathy, fertility problems, and secondary malignancies. Further reduction in radiation dose is being considered because of the association of radiation therapy with secondary malignancies. On the therapeutic front, better therapies for relapsed patients, including high-dose chemotherapy with autologous stem cells rescue have been used. Treatment with EBV-cytotoxic T cells is also being considered in the relapse setting.

• Chemotherapy: Many different combinations of chemotherapy are used. In general, advanced-stage disease requires more cycles of chemotherapy than localized disease. Recent protocols have focused on decreasing the long-term toxicity of therapy. This has been accomplished by alternating courses of active multichemotherapies, as well as substitution of newer less toxic agents for some members of the traditional MOPP regimen (mechlorethamine, vincristine, procarbazine, prednisone).

• Radiation therapy: Involved-field and extended-field radiation is used depending on the extent of disease. Because of the effects of radiation therapy on musculoskeletal growth in children as well as the increased risk of second malignancies in the radiation field (such as breast cancer in adult survivors of HD who were treated with mantle radiation), low-dose radiation is used in conjunction with chemotherapy.

Surgical Care: A staging laparotomy and splenectomy is currently not routinely performed in patients with HD. In patients with suspicious lesions on imaging performed for staging, biopsy is sometimes necessary if the findings may alter the treatment regimen.

Consultations:

• Placement of a central venous catheter for chemotherapy and supportive care is suggested. Not all patients require a central venous catheter; therefore, base the decision on the intensity of the treatment, level of supportive care anticipated, state of peripheral venous access, and patient preference.

• Radiation oncologist

• Psychosocial support for the family

Diet: No special diet is required.

Multiple chemotherapeutic agents in various combinations are used to treat HD. The combinations vary by stage of disease and by treating institution. In patients with relapsed or unresponsive disease, the use of autologous stem cell transplantation has been shown to result in significant disease-free survival. A variety of drug combinations has been employed with stem cell rescue.

Although the intended target is the malignant cell of HD, the effects of chemotherapy on normal cells of the body are considerable and account for the adverse effects observed with these agents. Because most patients with HD are long-term survivors, one of the goals of current therapy is to decrease the long-term adverse effects while maintaining excellent cure rates. Using different therapeutic agents with nonoverlapping toxicities is one way to achieve this. Various combinations of the following drugs are used to treat HD.

Although adverse effects vary with each drug, some are common to many drugs. These include nausea, vomiting, alopecia, bone marrow suppression, and, less commonly, secondary malignancies.
 

Drug Category: Antineoplastics agents -- Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).

Cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy and is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Further Inpatient Care:

• Initial evaluation, staging, and subsequent treatment can be performed on an outpatient basis; however, at times, admission is indicated for supportive medical care.

Further Outpatient Care:

• The patient requires regular monitoring for response to therapy and development of adverse effects of treatment.

Deterrence/Prevention:

• During periods of decreased blood cell counts due to bone marrow suppressive effects of treatment, neutropenic and thrombocytopenic precautions should be observed.

Complications:

• Most complications are due to recurrence of disease or adverse effects of treatment as noted above.

Prognosis:

• The overall 5-year survival rate for HD is 91%. Patients with localized disease have a higher rate (>90%) than those with advanced-stage disease (as low as 70%).

Patient Education:

• Refer the patient and family for psychosocial counseling.