Pediatric Hodgkin Lymphoma Workup

Hematological and blood chemistry evaluation may reveal nonspecific findings in patients with Hodgkin lymphoma that may be associated with disease extent. Several of these findings have been used as prognostic factors.

Chest radiography is used to assess the bulk of the mediastinal mass, and CT, MRI, or ultrasonography of the neck, chest or abdomen may be indicated for further assessment. Positron emission tomography (PET) is used with increasing frequency to identify the extent of disease at diagnosis and for follow up.

Lymph node biopsy findings may be helpful. Bilateral bone marrow biopsy is necessary in all patients with suspected involvement of the bone marrow and in those with stage IIB, III, or IV disease. Staging laparotomy is no longer advocated in pediatric Hodgkin lymphoma.

The complete blood cell count may reveal the following:

• Hemolytic anemia (Coombs positive), anemia of chronic disease, or anemia secondary to involvement of the bone marrow
• Leukocytosis, lymphopenia, eosinophilia, monocytosis
• Thrombocytopenia due to marrow infiltration or idiopathic thrombocytopenia purpura

Assessment of acute-phase reactants may show elevations in the erythrocyte sedimentation rate (ESR) and C-reactive protein, serum copper, and ferritin levels.

A full serum chemistry panel may aid in evaluating levels of serum electrolytes; lactate dehydrogenase levels (LDH), which reflects bulk of disease; alkaline phosphatase, which indicates bony metastasis; as well as liver and kidney function.

In addition to stage and male sex, the International Prognostic Factors for advanced Hodgkin lymphoma include certain laboratory findings as poor prognostic factors. The following findings may indicate a poor prognosis:

• ESR of more than 50 mm/h
• Hemoglobin concentration less than 10.5 g/dL
• WBC count of 15,000/μL or less
• Absolute lymphocyte count less than 800/μL
• Albumin level less than 4 g/dL

Urinalysis may reveal proteinuria. Nephrotic syndrome may be associated with Hodgkin lymphoma.

Chest radiography is performed with anteroposterior and lateral projections to assess the bulk of the mediastinal mass. Mediastinal mass with a thoracic ratio of 33% or greater is of prognostic importance.

CT or MRI of neck, chest, abdomen, and/or pelvis are indicated to assess sites of disease (nodal and extranodal) as well as to assess liver and spleen involvement. Ultrasonography can be used to assess the abdominal and pelvic structures in centers with limited resources in which CT scanning or MRI is not available. The minimal feasible amount of ionizing radiation should be used for diagnostic imaging in order to limit the future incidence of secondary malignancy.

On PET scanning, uptake of the radioactive glucose analog 2-[18F]fluoro-2-deoxy-D-glucose (FDG) is correlated with proliferative activity in tumors undergoing anaerobic glycolysis. PET scans are used with increasing frequency to identify the extent of disease at diagnosis and for follow up. After 2 cycles of therapy with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), a positive PET scan finding may be predictive of poor outcome. However, confirmation of its utility with other regimens is pending.

PET scanning is becoming an important modality to guide involved-field radiation therapy in adult Hodgkin lymphoma,^[5] and its role in guiding involved-field radiation therapy in pediatrics is being explored.

Gallium scanning is rarely used and has been replaced by PET scanning. Bone scanning has been used when bony metastases are suspected because of an elevated alkaline phosphatase level, but the same information may be obtained with PET scanning.

Lymph node biopsy findings may be helpful. Histopathologic studies consist of hematoxylin and eosin staining and special immunohistochemical staining for surface markers such as CD15, CD20, CD30, and CD45. Consider other immunohistochemical staining to ensure that they are negative and to rule out non-Hodgkin lymphoma, such as CD3 and anaplastic lymphoma kinase (ALK).

Clinicians must use care when recommending diagnostic biopsies in patients with mediastinal lymphadenopathy. Performing a diagnostic biopsy under local analgesia is preferable; if this is not possible, these patients must be carefully evaluated by an anesthesiologist. These patients may be difficult to intubate or, if intubated, may be unable to be taken off respirator support.

Bilateral bone marrow biopsy is necessary in all patients with suspected involvement of the bone marrow and in those with advanced-stage disease.

Fine-needle aspiration is not recommended because of lack of stromal tissue and the difficulty of classifying Hodgkin lymphoma into one of the classic subtypes versus nodular lymphocyte–predominant (NLP) subtype.

The most recent and currently accepted classification is the Revised European-American Lymphoma (REAL) classification as modified and adopted by the WHO. The REAL classification distinguishes 5 classes of Hodgkin lymphoma, as follows^[6] :

• Nodular sclerosing
• Mixed cellularity
• Lymphocyte depleted
• Lymphocyte rich
• Nodular lymphocyte predominant (NLP)

The first 4 types are referred to as classic Hodgkin lymphoma. Nodular lymphocyte predominant Hodgkin lymphoma is a distinct entity with unique clinical features and a different treatment approach. On immunophenotyping, the classic subtypes of Hodgkin lymphoma are positive for CD15 and CD30 and may be positive for CD20, whereas NLP Hodgkin lymphoma is negative for CD15 and CD30 but positive for CD20 and CD45.

Nodular sclerosing Hodgkin lymphoma is notable for fibrous bands that result in a nodular pattern and lacunar-type Hodgkin-Reed-Sternberg (HRS) cells wherein the cytoplasm in formalin-fixed specimens retracts, forming a lacuna around the nucleus. This is the most common type in all age groups (77% of adolescents and 72% of adults), although it affects only 44% of younger children.

Mixed cellularity Hodgkin lymphoma may have interstitial fibrosis, but fibrous bands are not observed. HRS cells are classic in appearance or mononuclear. Lymphocytes may predominate in the cellular background (see the image below). This subtype is more common in young children (33%) than in adolescents (11%) or adults (17%).

Lymphocyte-rich Hodgkin lymphoma has classic or lacunar-type HRS cells with rare or absent eosinophils on a cellular background. This type is extremely rare.

Lymphocyte-depleted Hodgkin lymphoma has large numbers of HRS cells with sarcomatous variants and a hypocellular background because of fibrosis and necrosis. This type is also extremely rare.

NLP may be nodular, but fibrosis is unusual. The HRS cell variants are known as lymphocytic and histiocytic (L&H) or popcorn cells (because their nuclei resemble an exploded kernel of corn). The nuclei are multilobed and vesicular with small nucleoli. The characteristic halo of the classic H-RS cell is absent. The background consists of histiocytes and lymphocytes with a B-cell predominance, in contrast to the cellular background in classic Hodgkin lymphoma, which has a T-cell predominance.