This category accounts for 95% of HL cases and encompasses the following histologic subtypes: nodular sclerosis (NSHL), mixed cellularity (MCHL), lymphocyte-rich (LRHL), and lymphocyte-depleted (LDHL) Hodgkin lymphoma. Pathologically, CHL is characterized by the presence of few neoplastic Reed-Sternberg (RS) cells surrounded by a dominant population of nonmalignant polyclonal host inflammatory cells. The RS cells are usually CD15 positive and CD30 positive but negative for CD45 and traditional B-cell and T-cell markers.

Nodular sclerosis disease is the most common subtype, particularly among younger patients, and accounts for approximately 70% of cases, with a slight female predominance. It usually presents clinically as early-stage disease (I or II) in the mediastinum or cervical lymph nodes, but it may be locally aggressive, compressing local structures and causing pleural or pericardial effusion. Systemic “B” symptoms (fever >38°C, drenching night sweats, or unintentional weight loss of >10% of body weight over the preceding 6 months) are present in approximately one third of patients at diagnosis.

Mixed cellularity disease accounts for approximately 20% to 25% of cases; it is the most common subtype in the elderly, in HIV-infected patients, and in persons living in developing countries. It has a male predominance and commonly presents at advanced stages with “B” symptoms. Peripheral lymph nodes are most frequently involved; mediastinal disease is uncommon, in contrast to NSHL.

Lymphocyte-rich disease is an uncommon variant, accounting for 5% of cases. Like MCHL, it occurs predominantly in peripheral lymph nodes without mediastinal involvement, but presentation is usually at limited stage and without symptoms. There is a male predominance.

Lymphocyte-depleted disease is a very rare variant, notable pathologically for a dominant RS cell population with few of the infiltrating host inflammatory cells. Many cases previously diagnosed as LDHL would now likely be classified as variants of NHL.

NLPHL accounts for only 5% of HL overall and is distinguished from the classical HL subtypes by distinct biology, natural history, and approach to therapy. NLPHL occurs at a slightly older median age than does classical HL (median age in the fourth decade) and has a strong male predominance. The disease is limited in stage (I to II) in 75% of cases, in contrast to CHL, which occurs only slightly more frequently at limited stage. It presents most often in peripheral nodes that are palpable on physical examination but rarely within the mediastinum, abdomen, or extranodal sites. Systemic “B” symptoms are rarely present. Unlike CHL, NLPHL follows a distinctly indolent natural history, with an excellent overall prognosis of approximately 80% to 90% of patients alive 10 years after diagnosis, regardless of treatment.

Pathologically, NLPHL is similar to CHL; however, the infiltration is nodular rather than diffuse, and the reactive cells are predominantly small lymphocytes. The tumor cells are distinguished from classical RS cells by immunohistochemistry. They strongly express CD45 and the B-cell marker CD20 and do not express the traditional RS cell markers CD15 and CD30.

HL presents most commonly with painless lymphadenopathy or less commonly with symptoms of cough, chest pain, shortness of breath, or the radiographic finding of mediastinal lymphadenopathy or a prominent mediastinal mass. Involved nodes are typically firm, mobile, and nontender and may be discrete or matted. Hodgkin lymphoma may involve the spleen, with involvement of extranodal locations such as lung, liver, and bone marrow being less frequent. Involvement of other extranodal sites is uncommon. Systemic “B” symptoms (fever >38°C, drenching night sweats, or unintentional weight loss of >10% of body weight over the preceding 6 months) may be present, as may rare findings of pruritus or alcohol-induced pain in involved nodal sites.

The prognosis and treatment of HL depend on the extent of disease, making classification by stage an important part of HL management (Table 84-2). Staging in HL uses the so-called Ann Arbor staging system:

Symptoms are incorporated into the staging system because they are important determinants of prognosis, particularly in limited-stage disease. Approximately 20% of patients present with at least one “B” symptom. When they are absent, the
designation is “A”; when any of the three is present, the designation is “B.” Pruritus is not considered a “B” symptom due to minimal influence on prognosis.

Clinical staging begins with ascertaining important findings in the history and physical examination. Physical exam concentrates on careful palpation of all peripheral lymph nodes and the assessment of liver and spleen size (although organ enlargement or its absence is not necessarily a definitive indicator).

Imaging studies, beginning with a plain film of the chest during workup, provide important staging information. Chest and abdominal/pelvic computed tomographic (CT) scanning heighten imaging sensitivity, which is further enhanced by adding positron emission tomography (PET) scanning (combined PET/CT scan, which further enhances test sensitivity for both nodal and extranodal disease). (PET scanning is also used during and after treatment to assess the response to therapy.) Magnetic resonance imaging offers no advantage over CT and is relegated to staging patients who are unable to undergo CT imaging (e.g., patients who are pregnant at diagnosis).

Bone marrow biopsy is indicated only in select circumstances as PET/CT scans have proven highly sensitive and specific for bone marrow involvement in Hodgkin lymphoma and have reduced the necessity for invasive staging techniques. Pathologic staging with laparotomy is also no longer performed due to the sensitivity of modern radiographic techniques, as well as the incorporation of systemic therapy in limited-stage disease.

As important as staging is to the determination of prognosis, it is not sufficient fully to predict the outcome of treatment, especially in persons presenting with advanced disease. Prognostic risk factors have been identified, but the validity of modifying treatment based on these risks remains to be proven and is the subject of ongoing randomized clinical trials. The ultimate goal is to decrease treatment intensity and treatment-related toxicities in low-risk patients and increase the dose intensity and the cure rate in high-risk patients.

Prognosis has improved dramatically with the advent of careful staging and improved radiation technology and chemotherapy programs. The overall 5-year survival is 80% when all stages of disease are combined. Although it is a highly treatable and curable disease, many patients experience disease recurrence and some prove refractory. Prognosis in NLPHL is generally more favorable than that in classical HL, owing to a significantly more indolent natural history. Although late relapses are more common than in classical subtypes of HL, very few patients die from NLPHL.

Although the selection of a treatment regimen is the responsibility of the oncologist, it is important for the primary physician to be cognizant of the major treatment regimens and their outcomes. The treatment of classical HL is a function of disease stage and associated prognostic factors but not of histologic subtype. The treatment of NLPHL is approached differently. Therapies for HL achieve a substantial cure rates despite stage of the disease.

Combination chemotherapy is the mainstay of the treatment, both for advanced-stage disease and for limited-stage disease, where it may be combined with local/regional irradiation.

Radiation therapy achieves a substantial cure rate in persons with localized early-stage disease; however, adverse late effects (especially when applied to young persons; see later discussion) and recurrences outside the field of irradiation have stimulated the development of chemotherapy programs for use with radiation. The resultant significant decreases in recurrence rates have led to combined-modality therapy becoming the standard approach to limited-stage HL. Treatment with ABVD chemotherapy (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) followed by radiation therapy to all involved sites of disease represents an enduring standard of care in most patients with limited-stage classical HL.

Patients with a very low-risk disease (zero adverse risk factors) may be treated with as few as two cycles of chemotherapy followed by low-dose radiation. However, patients with adverse risk factors require a minimum of four cycles of chemotherapy, followed by consolidative radiation. Randomized trials have demonstrated no incremental benefit favoring additional radiation beyond the involved fields (i.e., extended field or subtotal nodal irradiation) or increased cycles of chemotherapy beyond four when followed by radiation. Given the late risks of radiation treatment in young patients with HL (see later discussion), treatment with chemotherapy alone in limited-stage patients without bulky disease is being studied. The initial results of two randomized trials have showed no difference in overall survival, suggesting a similar efficacy with the omission of radiotherapy. Long-term data from the largest trial comparing ABVD alone to ABVD plus subtotal nodal radiotherapy now shows a 12-year overall survival favoring patients who received chemotherapy alone, due primarily to an excess of late events related to radiation. It must be noted, however, that patients in that trial received more extensive radiotherapy than routinely employed today, thus likely overestimating the late radiation risks. Despite that limitation, patients treated with ABVD chemotherapy alone enjoyed a remarkable 12-year overall survival of 92%, speaking to excellent outcomes with a radiation-sparing approach. Based on these and other supporting data, chemotherapy alone with six cycles of ABVD may be considered for patients with nonbulky, limited-stage, classical HL. Patients with bulky disease at presentation (>10 cm), were not represented in these trials, and so should still routinely receive consolidative radiotherapy as part of standard therapy. All patients should be counseled on the short- and long-term risks and benefits of treatment in order to make informed decisions in concert with their care team.

Combination chemotherapy is the cornerstone of treatment, offering long-term survival to nearly three fourths of patients. ABVD is the most widely used regimen based on improved efficacy and tolerability over its predecessor, MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone). ABVD offers a complete remission rate of greater than 80% and long-term failurefree and overall survival rates of approximately 75% and 85%, respectively. ABVD is administered on an outpatient basis every 2 weeks for a total of 6 months. There is no role for radiation therapy in advanced-stage patients who are in complete remission after chemotherapy alone, but radiation is used for patients in a partial remission following the completion of chemotherapy.