Early-Stage Hodgkin Lymphoma
PATHOLOGIC CLASSIFICATION
According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.24 These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.25
The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.26 B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.27
Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.7 Patients diagnosed with NSHL generally have a very good prognosis.
,Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.24
Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.28 The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.23,29
Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.30 HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.
NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.28 NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.34
PRESENTATION
Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.35 A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.
