Epidemiology

The worldwide incidence of HL is approximately 2-4 new cases/100,000 population/year; there is a bimodal age distribution, with peaks at 15-35 yr of age and again after 50 yr. In developing countries, the early peak tends to occur prior to adolescence. A male:female predominance is found among young children but lessens with age. Several studies suggest that infectious agents may be involved, such as human herpes virus 6, cytomegalovirus, and Epstein-Barr virus (EBV). The role of EBV is supported by prospective serologic studies and confers a fourfold higher risk of developing HL and may precede the diagnosis by years. EBV antigens have been demonstrated in HL tissues, although EBV status is not prognostic of outcome.

Pathogenesis

The Reed-Sternberg (RS) cell, a pathognomonic feature of HL, is a large cell (15-45 µm in diameter) with multiple or multilobulated nuclei. This cell type is considered the hallmark of HL, although similar cells are seen in infectious mononucleosis, NHL, and other conditions. The Reed-Sternberg cell is clonal in origin and arises from the germinal center B cells. HL is characterized by a variable number of RS cells surrounded by an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils in different proportions, depending on the HL histologic subtype. Other features that distinguish the histologic subtypes include various degrees of fibrosis and the presence of collagen bands, necrosis, or malignant reticular cells (Fig. 490-1). The distribution of subtypes varies with age (Fig. 490-2).

Figure 490-1 Histologic subtypes of Hodgkin lymphoma. A, Hematoxylin & eosin stains of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) demonstrating a nodular proliferation with a moth-eaten appearance. B, High-power view demonstrating the neoplastic L and H cells found in NLPHL. C, Classic Hodgkin lymphoma, nodular sclerosis subtype. Large mononuclear and binucleate Reed-Sternberg cells are seen admixed in the inflammatory cell background. D, Classic Hodgkin lymphoma, mixed cellularity subtype, demonstrating increased numbers of Reed-Sternberg cells in a mixed inflammatory background without sclerotic changes. E, High-power view of a classic Reed-Sternberg cell showing binucleate cells with prominent eosinophilic nucleoli and relatively abundant cytoplasm.

Figure 490-2 Comparative distribution of Hodgkin lymphoma in children, adolescents, and adults.

(Adapted from Hochberg J, Waxman IM, Kelly KM, et al: Adolescent non-Hodgkin lymphoma and Hodgkin lymphoma: state of the science, Br J Haematol 144:24–40, 2008.)

The Revised World Health Organization (WHO) Classification of Lymphoid Neoplasms (Table 490-1) includes two modifications of the older Rye system. HL appears to arise in lymphoid tissue and spreads to adjacent lymph node areas in a relatively orderly fashion. Hematogenous spread also occurs, leading to involvement of the liver, spleen, bone, bone marrow, or brain, and is usually associated with systemic symptoms.

Clinical Manifestations

Patients commonly present with painless, nontender, firm, rubbery, cervical or supraclavicular lymphadenopathy and usually some degree of mediastinal involvement. Clinically detectable hepatosplenomegaly is rarely encountered. Depending on the extent and location of nodal and extranodal disease, patients may present with symptoms and signs of airway obstruction (dyspnea, hypoxia, cough), pleural or pericardial effusion, hepatocellular dysfunction, or bone marrow infiltration (anemia, neutropenia, or thrombocytopenia). Disease manifesting below the diaphragm is rare and occurs in approximately 3% of all cases. Systemic symptoms, classified as B symptoms that are considered important in staging, are unexplained fever >39°C, weight loss >10% total body weight over 3 mo, and drenching night sweats. Less common and not considered of prognostic significance are symptoms of pruritus, lethargy, anorexia, or pain that worsens after ingestion of alcohol. Patients also exhibit immune system abnormalities that often persist during and after therapy.

Diagnosis

Any patient with persistent, unexplained lymphadenopathy unassociated with an obvious underlying inflammatory or infectious process should undergo chest radiography to identify the presence of a large mediastinal mass before undergoing lymph node biopsy. Formal excisional biopsy is preferred over needle biopsy to ensure that adequate tissue is obtained, both for light microscopy and for appropriate immunohistochemical and molecular studies. Once the diagnosis of HL is established, extent of disease (stage) should be determined to allow selection of appropriate therapy (Table 490-2). Evaluation includes history, physical examination, and imaging studies, including chest radiograph; CT scans of the chest, abdomen, and pelvis; and either gallium scan or positron emission tomography (PET) scan. Laboratory studies should include a complete blood cell count (CBC) to identify abnormalities that might suggest marrow involvement; erythrocyte sedimentation rate (ESR); and measurement of serum ferritin, which is of some prognostic significance and, if abnormal at diagnosis, serves as a baseline to evaluate the effects of treatment. A chest radiograph is particularly important for measuring the size of the mediastinal mass in relation to the maximal diameter of the thorax (Fig. 490-3). This determines “bulk” disease and becomes prognostically significant. Chest CT more clearly defines the extent of a mediastinal mass if present and identifies hilar nodes and pulmonary parenchymal involvement, which may not be evident on chest radiographs (Fig. 490-4). Bone marrow aspiration and biopsy should be performed to rule out advanced disease. Bone scans are performed in patients with bone pain and/or elevation of alkaline phosphatase. Gallium scan can be particularly helpful in identifying areas of increased uptake, which can then be re-evaluated at the end of treatment. Fluorodeoxyglucose (FDG)–PET imaging has advantages over gallium scanning, as it is a 1-day procedure with higher resolution, better dosimetry, less intestinal activity, and the potential to quantify disease. PET scans are being evaluated as a prognostic tool in HL enabling therapy to be reduced in those predicted to have a good outcome.

Table 490-2 ANN ARBOR STAGING CLASSIFICATION FOR HODGKIN LYMPHOMA*

* The absence or presence of fever >38°C for 3 consecutive days, drenching night sweats, or unexplained loss of ≥10% of body weight in the 6 months preceding admission are to be denoted in all cases by the suffix letter A or B, respectively.

Figure 490-3 A, Anterior mediastinal mass in a patient with Hodgkin disease before therapy. B, After 2 mo of chemotherapy, the mediastinal mass has disappeared.

Figure 490-4 CT for the diagnosis of mediastinal disease in Hodgkin lymphoma. A, Chest radiograph, findings of which were interpreted as normal. B, Contrast-enhanced CT scan reveals marked widening of the mediastinum by an irregular enhancing mass (arrows) that is displacing the great vessels posteriorly. Right-sided paratracheal adenopathy is also present posterior to the superior vena cava. LSA, left subclavian artery.

(From Slovis TL, editor: Caffey’s pediatric diagnostic imaging, ed 11, vol 1, Philadelphia, 2008, Mosby/Elsevier.)

The staging classification currently used for HL was adopted at the Ann Arbor Conference in 1971 and was revised in 1989 (see Table 490-2). HL can be subclassified into A or B categories: A is used to identify asymptomatic patients and B is for patients who exhibit any B symptoms. Extralymphatic disease resulting from direct extension of an involved lymph node region is designated by category E. A complete response in HL is defined as the complete resolution of disease on clinical examination and imaging studies or at least 70-80% reduction of disease and a change from initial positivity to negativity on either gallium or PET scanning because residual fibrosis is common.

Treatment

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