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Chapter 75 Hodgkin Lymphoma 1217

of routine staging for all patients with newly diagnosed HL. However, anatomic stage, are widely used for risk stratification and subsequent
because of the high sensitivity of PET/CT for bone marrow involve- selection of appropriate initial therapy.
ment, bone marrow biopsy is no longer mandated for the routine HL patients have traditionally been divided into two distinct
staging of patients with newly diagnosed HL, unless PET/CT imaging prognostic groups according to clinical stage at diagnosis: early-stage
is unavailable. 2 disease, accounting for 45% of newly diagnosed patients, and
In addition to excisional node biopsy and staging with PET/CT, advanced-stage disease, accounting for 55% of newly diagnosed
assessment of the peripheral blood represents an important part of patients.
the diagnostic workup for patients with newly diagnosed HL with
particular respect to risk stratification and treatment choice. Com-
plete blood count, erythrocyte sedimentation rate (ESR), and serum Early Stage Disease
biochemistry including C-reactive protein, alkaline phosphatase,
lactate dehydrogenase, liver function tests, renal function tests, and The category of early-stage HL includes patients with stages I or II.
albumin are required as part of standard care, and screening for HIV Early-stage disease may also include patients with B symptoms, bulky
and hepatitis is strongly advised. In addition, given the potentially disease, or extension to adjacent sites. Limited stage disease is usually
damaging effects of chemotherapy and RT, certain pretreatment confined to nodes above the diaphragm nodes and less frequently
investigations including cardiac and pulmonary function tests, presents in only subdiaphragmatic sites.
thyroid function tests, reproductive counseling, and serum pregnancy Data from large clinical studies in which HL patients with variable
testing, may also be warranted in selected patients. disease characteristics were treated uniformly and closely followed
As advances continue to be made with regards to imaging modal- have allowed additional prognostic factors to be identified. These
ity, molecular profiling, and improved disease characterization, additional prognostic factors have led to the more accurate stratifica-
further modifications to the current staging approach for patients tion of early-stage disease into early “favorable” and early “unfavor-
with HL are expected. However, at present, the principles of the able” disease subgroups, with regards to outcome. Early stage I or II
Cotswold-modified Ann Arbor staging system still apply and provide HL is considered “favorable” if it is limited to an area above the
the backbone for management decisions and clinical trial design diaphragm and is not associated with other risk factors. Early stage I
worldwide. or II HL is considered “unfavorable” in the presence of other risk
factors related to age, tumor burden, ESR, and number of involved
nodal areas (Table 75.3).
CLINICAL FEATURES The criteria for early-unfavorable stage HL vary slightly according
to international cooperative group. Since 1982 the European Orga-
The importance of an accurate clinical history in facilitating the nization for Research and Treatment of Cancer (EORTC) has defined
management of patients with HL should not be underestimated. early-unfavorable HL as clinical stage I−IIA disease with one or more
Certain symptoms may provide clues as to the likely stage of disease of the following: age greater than 50 years; ESR >50 mm/h in the
or lead to further investigations that might identify additional sites absence of symptoms; ESR >30 mm/h in the presence of B symp-
of disease. This may result in important treatment modifications. An toms; large mediastinal mass. The German Hodgkin Study Group
accurate past medical history, particularly with regards to lung, heart, (GHSG), however, refined these criteria in 1988 to include clinical
and kidney function, is also crucial in highlighting those organs that stage I−IIA patients with any of the following risk factors: mediastinal
might benefit from further investigation before commencing therapy, mass greater than one-third of the maximum thoracic diameter;
to ensure that treatment choices are both effective and safe for the greater than three affected nodal areas; elevated ESR and localized
individual. extranodal disease infiltration. Early-unfavorable disease is often also
Systemic symptoms that are known to influence prognosis in referred to as Intermediate stage disease and these terms may be used
patients with HL include night sweats, fever, and weight loss. These interchangeably (see Table 75.3). Thus, early-stage HL is a heteroge-
constitutional symptoms have come to be known as “B symptoms” neous group and treatment algorithms have been developed for dif-
and their importance in HL is reflected by their inclusion as key ferent subgroups based on these prognostic factors and response
components of the Cotswold-modified Ann Arbor staging system (see criteria (see Treatment of Early-Stage Hodgkin Lymphoma section,
Staging section, earlier). B symptoms are a presenting feature in later).
approximately 30% of patients with HL and may predate lymphade-
nopathy in some cases. Fever in HL may take any form, from con-
tinuous low-grade pyrexia to intermittent spikes exceeding 38°C Advanced-Stage Disease
(101°F), whereas night sweats are typically drenching. A particular
type of fever that is considered characteristic of HL historically, is the The criteria for advanced-stage HL again vary slightly according to
Pel-Ebstein fever, which typically follows a swinging pattern, occur- international cooperative group. Whereas the EORTC defines
ring on a daily basis for many weeks, with intermittent afebrile advanced stage as those patients with clinical stage III−IV disease
periods occurring between episodes. In reality, however, this phenom- only, the GHSG also includes those patients with clinical stage IIB
enon features rarely in the modern clinical setting. B symptoms may disease and a large mediastinal mass and/or extranodal disease
occur in isolation or simultaneously, and incidence tends to increase involvement in their definition (see Table 75.3).
with more advanced disease. Following the identification of more specific and more widely
Other well-described clinical features associated with HL include applicable prognostic factors, the International Prognostic Score
fatigue, chronic pruritus, which may be an early sign of disease in up (IPS) was developed as an internationally accepted means of distin-
to 15% of patients, and the presence of a pain localized to the site guishing those patients with newly diagnosed advanced HL who
of involved lymphadenopathy that is precipitated by the consump- might be cured by standard treatment, and therefore avoid overtreat-
tion of alcohol. ment, from those in whom standard treatment might fail. In 1998
based on a multivariate analysis of survival data from 5141 patients
PROGNOSTIC FACTORS, RISK STRATIFICATION, AND with newly diagnosed advanced HL treated between 1983 and 1992,
seven adverse prognostic factors were identified as being statistically
TREATMENT GROUPS meaningful when predicting 5-year freedom from progression (FFP)
and overall survival (OS): age ≥45 years, male sex, albumin <40 g/L,
Prognostic factors have helped to predict the likely outcome for hemoglobin <10.5 g/dL, Ann Arbor stage IV, leucocytosis ≥15 ×
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individual patients with HL at diagnosis. Clinical stage, presence of 10 /L, and lymphocyte count <0.6 × 10 /L. Five-year FFP was 84%
systemic symptoms, and tumor burden continue to be important for those patients with no adverse prognostic factors, and each
prognostic factors in HL, and, in addition to disease histology and additional factor reduced FFP by 7%, with four to seven factors