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Chapter 84 Malignant Lymphomas in Childhood 1339

The EBV protein LMP1 may be the key in the oncogenic process Treatment
because it can elicit B-lymphocyte transformation in vitro. 127
There is also a relationship between the development of HL and Despite the excellent outcomes for children with HL, there is still no
cell-mediated immune deficiency, with an increased incidence in ideal therapeutic approach. Generally, combination chemotherapy
128
patients with HIV, patients on chronic immunosuppressive therapy with low-dose involved-field radiation is used with varying intensities
following SOT, and common variable immune deficiency. It remains and durations, usually depending on disease stage and prognostic
unclear whether the underlying immune deficiency commonly seen factors such as disease bulk and B symptoms. However, studies of late
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in HL is primary, secondary, or both. 127 effects in these patients have fueled cooperative groups in particular
to explore regimens with decreased radiation and/or chemotherapy
doses, especially for children with low-risk disease. Risk stratification
Pathobiology for treatment assignment varies considerably between the pediatric
HL research groups, thus limiting comparisons between trial results.
HL is generally considered to be slow-growing with a tendency to The general consensus, however, is that chemotherapy should be
spread to contiguous lymph nodes. Only in advanced stages is there given to all patients with HL, with or without radiation. The excep-
129
evidence of blood vessel invasion and spread to more distant organs. tion to this approach is patients with stage I, completely resected,
Over the past 30 years, significant advances have been made in the nodular lymphocyte-predominant HL, who can achieve cure with
treatment of pediatric HL, such that over 85% of children are cured surgery alone. 133
with chemotherapy and/or radiation even with stage III/IV disease. Chemotherapeutic agents used for the initial treatment of pediat-
HL is notable for the characteristic B cell–derived HRS cells found ric HL are similar to those used in adults and include alkylating
in a background of an inflammatory microenvironment usually agents, corticosteroids, vinca alkaloids, antimetabolites, doxorubicin,
comprising regulatory T cells, Th2 T cells, macrophages, and eosino- bleomycin, dacarbazine, and etoposide. However, doxorubicin (or
phils. The REAL and WHO classification systems identify two main Adriamycin) is associated with cardiac toxicity; bleomycin can lead
subtypes: classical HL and lymphocyte-predominant HL. Classical to pulmonary fibrosis; and alkylators may impair fertility. Therefore,
HL accounts for the majority of cases in adolescents and young adults many cooperative group studies have developed hybrid regimens
+
+
and is characterized by HRS cells that are usually CD15 and CD30 . using lower cumulative doses of alkylators, doxorubicin, and bleomy-
HRS cells do not express B-cell markers such as CD19 and CD79A, cin, especially for low-risk (stages I–IIA, no bulk, no B symptoms)
although CD20 is expressed in approximately 5% to 10% of cases. and intermediate-risk (all stages I and II patients not classified as early
Mixed cellularity HL accounts for approximately one-third of cases stage; stage IIIA; and variably stage IVA) disease. Results of clinical
diagnosed in children younger than 10 years old. The histopathology trials conducted by the major international pediatric HL study groups
shows frequent HRS cells on a background of normal reactive are summarized in Table 84.8. Trials differ by the use of chemotherapy
immune cells, including T lymphocytes, plasma cells, eosinophils, regimens of varying dose intensity, as well as the criteria for omission
macrophages, and histiocytes. Lymphocyte-predominant HL and of radiotherapy. The German Society of Pediatric Oncology, and now
lymphocyte-rich classical HL may both have nodular appearances, in conjunction with other European pediatric oncology centers
−
but the former is more commonly CD15 and usually has strong (Euronet Consortium), has investigated OEPA (vincristine, etopo-
CD20 and CD45 positivity, thus distinguishing it from classical side, prednisone, doxorubicin) for low risk groups and OEPA with
HL. 130 COPDac (cyclophosphamide, vincristine, prednisone, dacarbazine)
134
for intermediate- and high-risk groups. In North America, the
COG has primarily evaluated ABVE-PC (doxorubicin, bleomycin,
Clinical Manifestations vincristine, etoposide, prednisone, cyclophosphamide) and its deriva-
tives across the risk groups. 135–138
The majority of pediatric patients with HL present with painless, Radiotherapy use varies considerably. In the only recent large
firm, “rubbery” lymphadenopathy, most commonly in the cervical/ randomized trial to evaluate omission of radiotherapy, the COG
supraclavicular regions. Over 70% of adolescents and young adults reported that radiotherapy may be safely omitted in intermediate-risk
present with mediastinal disease, which can be asymptomatic. This patients who have a rapid reduction in tumor dimensions by CT after
presentation is less frequent in younger children, possibly related to two cycles of chemotherapy. 142,143 The European consortium has
a lower incidence of nodular sclerosis HL and a greater frequency of omitted radiotherapy for low-risk patients achieving a complete
134
mixed cellularity or lymphocyte-predominant HL in this group. response after two cycles of OEPA. The utility of response by posi-
Approximately one-fourth of patients present with systemic “B” tron emission tomography (PET) has been evaluated in trials recently
symptoms, including fevers, weight loss, and drenching night sweats. completed or in progress by all the major groups. In general, pediatric
The majority of pediatric patients presenting with HL have stages radiotherapy approaches use lower doses (15–25 Gy) and fields
I–III disease (involvement of lymph nodes and/or the spleen only) (involved field or node).
with a minority (approximately 15%) presenting with stage IV Therapies targeting CD30, a transmembrane glycoprotein that is
disease (noncontiguous extranodal involvement such as BM, lung, present on Reed-Sternberg cells but is not expressed in most normal
liver, and/or bone). tissue, have been an area of significant interest as a means of improv-
ing efficacy and replacing agents with long-term toxicities. Brentux-
imab vedotin is an antibody drug conjugate composed of a monoclonal
Staging anti-CD30 antibody linked to the antimitotic agent monomethyl
auristatin E. In a phase II study evaluating brentuximab vedotin in
Pediatric HL is staged using the Ann Arbor staging system (with relapsed HL, the overall response rate was 75%, with complete remis-
144
subsets A and B used for the absence or presence of B symptoms, sion achieved in 34%. Incorporation of brentuximab vedotin in
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respectively). Briefly, stage I involves a single lymph node region. frontline chemotherapy regimens is currently under investigation in
Stage II involves two or more lymph node regions on the same a phase II trial of pediatric high-risk HL by the Stanford, St. Jude,
side of the diaphragm. Stage III involves lymph node regions above Dana-Farber Cancer Institute consortium and a randomized phase
and below the diaphragm. For stages I–III, if there is extension to III trial by the COG.
an adjacent extralymphatic region/organ, then this is designated E
(for example, stage IIE). For stage III, if there is splenic involve-
ment, this is designated stage IIIS. Finally, for Stage IV disease, Management of Relapsed Hodgkin’s Lymphoma
there is noncontiguous involvement of one or more extralymphatic
organs or tissues with or without involvement of associated For patients who relapse, response depends on whether they had
lymph nodes. favorable disease at diagnosis and whether the relapse is confined to