At a Glance
Classical Hodgkin lymphoma (CHL) comprises about 10% of all lymphomas in North America. It has a bimodal age distribution, with peak incidences between 15 and 35 years of age and again between 65 and 86 years of age; it is rare in children under 10 years of age.
The typical presentation of CHL in an immunocompetent patient is as localized, painless, peripheral lymphadenopathy (most commonly affecting cervical or supraclavicular lymph nodes) in a teenager or young adult. Splenomegaly is usually absent but can be seen in a minority of cases. Systemic B symptoms are seen in less than one-half of the patients at presentation. In developing countries and in immunocompromised patients, presentation of CHL often reflects disseminated disease, including diffuse lymphadenopathy, systemic B symptoms, and/or symptoms related to cytopenias secondary to bone marrow infiltration by CHL. Pruritus and alcohol-induced pain have been reported in up to one-third of CHL patients at presentation, although these symptoms are nonspecific.
Younger patients, particularly males, often present with a bulky mediastinal mass due to thymic involvement and manifest symptoms related to compression of mediastinal structures, such as cough, chest pain, dyspnea, and/or stridor. However, superior vena cava syndrome is a relatively uncommon presentation of CHL.
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Older adult patients (>60 years of age) more frequently present with disseminated disease, systemic B symptoms, and an elevated erythrocyte sedimentation rate. A bulky mediastinal mass is less common in patients older than 60 years of age.
Although not an AIDS-defining disease, CHL has a 10-fold increased incidence in HIV-infected individuals. HIV-positive patients with CHL often present with disseminated disease and systemic B symptoms. Unlike CHL in immunocompetent patients, involvement of extranodal sites at presentation, such as bone marrow and liver, are frequent.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
A biopsy of involved tissue should be performed to confirm clinical suspicion of CHL.
The characteristic morphologic appearance of CHL on tissue biopsy is that of neoplastic Reed-Sternberg cells and their variants set in a variable inflammatory background. The Reed-Sternberg cell is a large lymphoid cell with a bilobed or multilobed, vesicular nucleus, and 2 or more very prominent nucleoli; the cytoplasm is abundant and pale-staining. Mononuclear variant Reed-Sternberg cells are more frequent in the involved tissue than are true Reed-Sternberg cells; they have similar nuclear and nucleolar features to true-Reed-Sternberg cells, but have a single nucleus.
The neoplastic Reed-Sternberg cells of CHL have a unique immunophenotype: CD30 positive, CD15 positive (most cases), and positive for the B-cell marker PAX5 but negative for most other B-cell markers and negative for all T-cell markers.
The nonneoplastic inflammatory background that surrounds the neoplastic Reed-Sternberg cells is highly variable, depending on the particular histologic subtype (see chapters on Nodular Sclerosis CHL, Mixed Cellularity CHL, Lymphocyte-depleted CHL, and Lymphocyte-rich CHL). The background lymphocytes are mostly small T-cells in the majority of CHL cases, with CD4+ T cells predominating over CD8+ T cells.
Once the diagnosis of CHL is confirmed, the disease should be staged according to the Ann Arbor staging system. The stage is based on the disease distribution on radiologic studies (full body CT scans), physical exam (extent of peripheral lymphadenopathy), and bone marrow exam. (Table 1)
Table 1.
| Tissue Biopsy | Immunohistochemistry on tissue biopsy |
| Presence of Reed-Sternberg cells in a variable inflammatory background. |
Reed-Sternberg are CD30+, usually CD15+, and PAX5+, but usually negative for other B-cell markers |
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
When a lymph node biopsy is obtained to investigate a clinical suspicion of CHL, biopsy of a superficial or smaller lymph node in an involved lymph node group may yield false-negative results. Lymph nodes surrounding the nodes frankly involved by CHL can show nonspecific reactive changes or only partial involvement that may be difficult to diagnose; this problem is compounded if the presentation is atypical and CHL is not considered upfront (e.g., in an elderly patient or an individual with potentially distracting comorbid conditions).
Limited tissue samples, such as needle core biopsies or fine-needle aspiration, frequently yield false-negative results in CHL.
What Lab Results Are Absolutely Confirmatory?
A biopsy of involved tissue with pathologic examination is required to confirm a diagnosis of CHL. The biopsy should demonstrate the presence of diagnostic Reed-Sternberg cells in an inflammatory background environment (whose constitution depends on the particular CHL subtype).
Ideally, immunohistochemistry should be performed to confirm the expected Reed-Sternberg cell immunophenotype (always CD30 positive, usually CD15 and PAX5 positive, and usually CD20 negative or only partially positive).
What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?
The role of fine needle aspiration (FNA) in the diagnosis of suspected CHL is controversial. FNA may be a reasonable first approach: it could yield an alternative definitive diagnosis (e.g., metastatic carcinoma or an infection) or yield findings highly suspicious for CHL, guiding a prompt confirmatory tissue biopsy.However, false-negative rates of up to 40% have been reported for FNA diagnosis of CHL. In general, excisional biopsies of involved lymph nodes are preferred over core biopsies, as assessment of the tissue architecture is an important feature to both diagnose CHL and determine the histologic subtype.
Given the unique immunophenotype of the Reed-Sternberg cells of CHL, this disease should be theoretically amenable to diagnosis by flow cytometry. However, these neoplastic cells typically constitute less than 1% of the cells in the tissue infiltrate, and they may be underrepresented due to tissue fibrosis and sampling artifact. Thus, flow cytometry has not been considered useful in the diagnosis of CHL. Recently, new protocols using multicolor flow cytometry show promise in detecting even very small numbers of Reed-Sternberg cells, and, in the future, this technique may improve the sensitivity of FNA diagnosis of CHL.
One immunophenotypic clue to the diagnosis of CHL is an elevated CD4:CD8 ratio (>7:1) in the background T cells. Although nonspecific, it can support a suspicion of CHL over viral infections and other reactive processes in which CD8+ T cells often predominate.
In staging CHL, bone marrow exam may be omitted in patients with very low risk of involvement (Ann Arbor Stage I or II disease without systemic B symptoms). Bone marrow exam may also be omitted in some patients already shown to have advanced disease on radiologic studies, if the presence of bone marrow involvement would not alter clinical management. When performing a staging bone marrow for CHL, it is critical to obtain an adequate bone marrow core biopsy. Bone marrow aspirate smears and flow cytometry are not useful in assessing for bone marrow involvement by CHL, as the associated fibrosis in the involved marrow usually leads to sampling artifact and false-negative results in the aspirate.
A number of laboratory tests at the time of diagnosis have been associated with disease outcome. For early stage disease, an elevated erythrocyte sedimentation rate has been associated with a higher risk of disease recurrence. For advanced stage patients, several clinical tests factor into the International Prognostic Score (IPS) that is associated with patient outcome. The components of the IPS include serum albumin, hemoglobin, total white blood count, and absolute lymphocyte count. However, in recent years, with improvements in therapeutic approaches to CHL, the IPS score may not be as relevant in predicting outcome. The neoplastic Reed-Sternberg cells in CHL express CD30 and elevated serum soluble CD30 levels have been associated with adverse outcome.
Certain features assessable in the tissue biopsy are also associated with disease prognosis in CHL. In particular, qualities of the nonneoplastic background inflammatory cells appear to influence the biologic behavior of the disease. An important recent finding is the observation that increased CD68+ tumor-infiltrating macrophages (>5% of total tumor cellularity) are associated with adverse disease-free survival. This finding may prove particularly useful in early-stage CHL patients in whom low pretreatment CD68 cell numbers could identify a subset of patients with excellent prognosis who could be adequately treated with less intensive regimens. Other studies have shown improved outcome in patients with higher numbers of tumor-infiltrating nonneoplastic CD20+ B cells. Higher numbers of background FOXP3+ regulatory T cells and CD117+ mast cells, as well as lower numbers of TIA1+ cytotoxic T cells, have been correlated with favorable outcome in CHL.
About 50% of CHL cases (with wide variation depending on patient immune status and geography) contain Epstein-Barr Virus (EBV) genome in the neoplastic Reed-Sternberg cells. Although this finding has been associated with superior disease-free survival in young, immunocompetent CHL patients, it is associated with a worse prognosis in elderly patients. A high percentage of CHL cases in tropical regions of the world are EBV positive.
Although Reed-Sternberg cells are clonal B cells, due to their relative rarity in the prevalent nonneoplastic polyclonal background cells, polymerase chain reaction (PCR) studies for immunoglobulin heavy chain (IGH) gene rearrangement are almost always negative and are not generally used in the diagnostic workup of CHL.
What Factors, If Any, Might Affect the Confirmatory Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
There is a small but significant interobserver variability (up to 10%) in the diagnosis of CHL. This reflects differences in opinion as to whether a limited sample is diagnostic (versus only suspicious) of CHL, as well as difficulties in distinguishing CHL from morphologic mimics, such as a florid reactive hyperplasia and certain non-Hodgkin’s lymphomas. Thus, if the diagnosis of CHL does not fit the clinical picture, the clinician and pathologist should communicate to discuss possible reasons for such a discrepancy. Conversely, if CHL is strongly suspected clinically but a different diagnosis is rendered on biopsy, the clinician and pathologist should communicate.
If the patient has received steroids prior to the biopsy (e.g., to treat impending airway obstruction due to a large mediastinal mass), this may render the pathologic diagnosis of CHL more difficult because of alteration of the characteristic morphology.
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