non-hodgkin lymphomas in children · 2010-12-18 · node tumors are most common; in alcl, skin,...

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Non-Hodgkin Lymphomas in Children

Lead contributors:

Guillermo Chantada, MDHospital JP Garrahan

Buenos Aires, Argentina

Raul C. Ribeiro, MDSt. Jude Children’s Research Hospital

Memphis, Tennessee, United States of America

A. Introduction

Non-Hodgkin lymphomas (NHL), clonal disorders of the immune system,

are caused by the transformation of lymphoid progenitor cells at a particular

stage of differentiation.

The significant variations in the clinical and biological characteristics of

lymphoid malignancies among young patients reflect the fact that the lymphoid

system is functionally diverse, has a wide anatomic distribution, interacts with

other cellular systems, and undergoes continuous remodeling during childhood

and adolescence.

NHL is classified according to the lymphoid lineage involved. B-lineage

NHL (Burkitt, lymphoblastic, and large B-cell lymphomas) represents about 50%

of cases; T-lineage accounts for the remaining half (lymphoblastic and

anaplastic large-cell lymphomas).

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B. Epidemiology and Risk Factors

In the U.S., 800 (6.5%) of the 12,400 new cases of cancer diagnosed

annually in children, adolescents, and adults younger than 20 years are NHL.1

NHL represents 3% of all cases of pediatric cancer affecting children younger

than 5 years of age and 9% of the cases of those 15 to 19 years of age

(B.Figure 1).

B. Figure 1

Age-specific rates, for all races and both sexes, of NHL. Data from theSurveillance Epidemiology End Results (SEER; used with permission)1

During the past 20 years, the incidence of NHL appears to have increased

in the U.S, while the incidence of NHL in children younger than 15 years

remained stable from 1975 through 1995, that of adolescents increased for

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unknown reasons from 10.7 per million (1975-1979) to 16.3 per million (1990-

1995).1 The incidence of NHL is higher among boys, and the rate of NHL in all

age groups is markedly higher for white American children than for black

American children.

International variation in the incidence of NHL has been reported that

Burkitt lymphoma is more common in tropical areas such as Equadorial Africa.2,3

In this part of the world, endemic Burkitt lymphoma usually affects the jaw and

it’s geographical distribution is similar to malaria.

The incidence of pediatric NHL is likely to be affected by the environment

since the disease typically originates in immune-system structures that come in

contact with the environment, such as the Peyer follicles in the bowel and the

lymphoid nodules at airway branch points. Such a relation has already been

observed between Epstein-Barr virus (EBV) infection (with malaria as a co-factor)

and the incidence of Burkitt lymphoma.4 Moreover, AIDS (acquired

immunodeficiency syndrome), which is cause by human immunodeficiency virus

(HIV) infection, has been associated with an increased risk of NHL. However, in

developing countries, the lack of population registries makes estimation of this

incidence very difficult.

Causes of childhood lymphoid malignancies are largely unknown; and

most children with NHL do not appear to have predisposing factors. However,

certain factors and specific constitutional syndromes have been associated with

an increased predisposition to lymphoid malignancies.5 For example, increased

risk of NHL has been associated with congenital immunodeficiencies such as

Wiskott-Aldrich syndrome,6 X-linked lymphoproliferative syndrome, ataxia

telangiectasia and other chromosomal breakage syndromes and severe

combined immunodeficiency.7,8

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B. References1Percy CL, Smith MA, Linet M, et al. Lymphomas and reticuloendothelial Neoplasms. In: RiesLAG, Smith MA, Gurney JG, et al., eds. Cancer Incidence and Survival among Children andAdolescents: United States SEER Program 1975-1995. (Bethesda, MD: National Cancer Institute,SEER Program, 1999) 35-48.2Parkin DM, Stiller CA, Draper GJ, et al. International Incidence of Childhood Cancer. (Lyon,France: IARC Scientific Publications No. 87, 1988).3McNally RJ, Cairns DP, Eden OB, et al. Examination of temporal trends in the incidence ofchildhood leukaemias and lymphomas provides aetiological clues. Leukemia. 2001;15(10):1612-18.4Magrath IT. Non-Hodgkin's lymphomas: epidemiology and treatment. Ann N Y Acad Sci.1997;824:91-106.5Vessey CJ, Norbury CJ, Hickson ID. Genetic disorders associated with cancer predisposition andgenomic instability. Prog Nucleic Acid Res Mol Biol. 1999; 63:189-221.6Kersey JH, Shapiro RS, Filipovich AH. Relationship of immunodeficiency to lymphoidmalignancy. Pediatr Infect Dis J. 1988; 7(5 Suppl):S10-S12.7Filipovich AH, Mathur A, Kamat D, et al. Primary immunodeficiencies: genetic risk factors forlymphoma. Cancer Res.1992; 52(19 Suppl):5465s-7s.8Knowles DM. Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol.1999;12(2):200-17.

C. Diagnosis and Classification

A definitive diagnosis of NHL requires examination of the tumor mass

(nodal or extranodal). When NHL is suspected, it is best to sample the most

accessible, representative nodal or extranodal tumor. When patients have a

large mediastinal mass and they are at very high risk of complications during

anesthesia, pleural effusion can provide an adequate number of tumor cells for

diagnosis. Alternatively, fine needle aspiration of regional lymph nodes or

mediastinal masses, which can be performed without general anesthesia, may

also yield adequate material for diagnosis if a complete immunocytological

panel can be done. However, in most cases, an open biopsy procedure is

needed to yield sufficient material for an accurate diagnosis.

Cytologic diagnosis of pediatric lymphoma is justified only in emergency

cases, and results should be confirmed at least by immunophenotyping.

Although the classification of NHL in general is very complex and the process is

still evolving, the classification of pediatric NHL is considered to be simpler

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than that of its adult counterpart. The classification developed by the WHO is

the current standard classification in use

Virtually all childhood NHL can be classified into one of three types:

Burkitt, lymphoblastic, and large-cell. Each type exhibits diffuse histologic

characteristics. In a study of 1,336 children and adolescents, histologic

examination indicated that only 17 cases (1.3%) were follicular (nodular) NHL.1

Rarely, other subtypes of NHL are seen in children, and many can cause a

diagnostic dilemma (see section on uncommon forms of pediatric NHL).

Burkitt lymphoma is characterized by sheets of monomorphic lymphoid

cells. Commonly, macrophages dispersed throughout the tumor give it the

classic “starry sky” appearance. In the bone marrow or blood, the Burkitt cells

(in FAB L3 subtype ALL, C. Figure 1) are relatively uniform in shape, and have a

moderate amount of deeply basophilic cytoplasm containing sharply defined,

clear vacuoles, and round nuclei containing coarsely reticular chromatin.

The cells express monotypic surface immunoglobulin (either IgM k or l

light chains) and harbor specific chromosomal translocations involving the C-

MYC oncogene. The most common of these cytogenetic abnormalities, present

in 80% of cases, is the t(8;14)(q24;q32) translocation. In the remaining cases,

t(2;8)(p12;q24) and t(8;22)(q24;q11) translocations are observed.2

Even though cytogenetic abnormalities are a hallmark of Burkitt

lymphoma, it is not always possible to do a complete study. In such cases,

fluorescence in situ hybridization (FISH) analysis performed in paraffin

embedded tissue, may give additional important information.

Lymphoblastic NHL arises from transformed, immature T or B cells.

Lymphoblastic NHL that arises from T cells, which accounts for more than 80%

of all cases of the disease, expresses an immunophenotypic profile similar to

that of normal thymocytes at an intermediate or late stage of differentiation. As

with Burkitt NHL, T-cell malignancy is characterized by several cytogenetic

abnormalities that cause activation of transcription factors due to specific

translocations in the T-cell receptor genes. Typically, these translocations are

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juxtaposed with a small number of developmentally important transcription

factor genes, including HOX11 (TLX1), TAL1 (SCL), TAL2, LYL1, BHLHB1, LMO1,

and LMO2.3 Recent studies suggest that loss of heterocygocity of 6q14-q24 may

have a negative impact in prognosis of lymphoblastic lymphoma4 and the

pattern of this aberration is different in cases of T-ALL from those seen in T-cell

lymphoblastic lymphoma.5 B-cell precursor lymphoblastic lymphoma

occasionally represents a diagnostic dilemma. It is important to identify

accurately this entity since it may be confused with a mature B cell malignancy

that would need a different treatment.6 Usually, B-cell precursor lymphoblastic

lymphoma express tdt as well as a more immature B cell precursor phenotype

and they usually don’t express surface immunoglobulins.

C. Figure 1FAB L3 cells showing basophilic cytoplasm containing sharply defined, clearvacuoles (May-Grunwald-Giemsa staining X 100).

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Large-cell NHL is the most heterogeneous pediatric NHL subtype.7

Immunophenotypic analysis of large-cell NHL shows that the neoplastic cells

can be of T-cell or B-cell lineage or occasionally, they have no lineage-specific

markers (null cells). However, anaplastic large cell lymphoma and B cell difuse

large cell lymphoma are the most common subtypes. 7 According to the

classification system adopted by the WHO, most pediatric large-cell lymphomas

can be classified as diffuse B-cell or anaplastic large-cell lymphoma (ALCL). 7

Classification as ALCL requires the co-expression of CD30, the expression

of anaplasic lymphoma kinase (ALK) and the membrane epithelial antigen in

lymphoma cells expressing usually T-cell markers.8 Anaplastic lymphomas with

B cell phenotype and ALK expression have been reported infrequently.9

Approximately 80% of ALCL cases identified on the basis of this criterion harbor

the t(2;5)(p23;q35) chromosomal rearrangement.14 This translocation

juxtaposes the gene encoding anaplastic lymphoma kinase (ALK) with

regulatory elements of the gene encoding nucleophosmin (NPM), a

nonribosomal nucleolar phosphoprotein.15 Rarely, the ALK gene is involved in

other translocations, including t(1;2), t(2;3), inv(2), and t(2;22). Importantly,

ALK protein expression can be detected by immunohistochemical study. The

use of polyclonal and monoclonal antibodies to detect these proteins aids in

diagnosis. Children with ALK-positive ALCL appear to have a better prognosis

than do those with other forms of large cell NHL.

C.1 Clinical Manifestations

Childhood NHL manifests in extremely diverse ways. The dominant

clinical manifestations depend on the tumor’s location and the extent of the

disease. Virtually any lymphoid tissue can be affected, including peripheral

lymph nodes, tonsils, thymus, spleen, and intestinal lymphoid aggregates

(Peyer’s patches). In addition, pediatric NHL commonly extends to the bone

marrow, CNS, bone, and skin.

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Generally, the primary tumor site is associated with a particular histologic

subtype. In patients with Burkitt NHL, an abdominal mass is most common; in

lymphoblastic or diffuse, large B-cell NHL, mediastinal and peripheral lymph

node tumors are most common; in ALCL, skin, bone, and soft tissue tumors are

most common. When disease is disseminated, it is often impossible to

determine the tumor’s primary site. Less-common presentations of NHL include

subcutaneous lesions, thyroid and parotid enlargement, proptosis, and spinal

cord compression. Although rare, spinal cord compression should be

considered a medical emergency, and it should be treated urgently to prevent

permanent neurologic deficits. Painless enlargement of the cervical lymph

nodes is the most common clinical presentation. In a retrospective chart review

conducted at St. Jude Children’s Research Hospital16, one-third of children with

NHL had palpable lymph nodes in the head and neck region. Another third

presented with primary mediastinum involvement, which is commonly

associated with supraclavicular and axillary adenopathy (C. Figure 2).

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C. Figure 2Mediastinal involvement by lymphoblastic lymphoma.

The clinical presentation of patients with a large mediastinal mass and anterior

vena cava syndrome can be seen in

https://www.cure4kids.org/ums/oncopedia/case_detail/?id=240.

Abdominal presentation of childhood NHL is associated with a palpable

mass. Tumors in the gastrointestinal tract usually affect the distal ileum,

cecum, and mesenteric nodes (C. Figure 3).

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C. Figure 3Massive intraperitoneal invasion by Burkitt lymphoma.

C. Figure 4Retroperitoneal and renal extension is also common

Patients with a large abdominal mass complain of intermittent pain in the

periumbilical region or right iliac fossa. Nausea, vomiting, and weight loss are

also common features. Occasionally, signs of an acute abdomen due to

intussusception are the dominant feature.

See case in: https://www.cure4kids.org/ums/oncopedia/case_detail/?id=310

Burkitt lymphoma should always be considered in the differential

diagnosis of intussusception in children older than 2 years.

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Occasionally, Burkitt lymphoma may present with bowel perforation, or it may

develop after the initiation of chemotherapy.


Less frequently, rectal prolapse was described

See https://www.cure4kids.org/ums/oncopedia/case_detail/?id=314

The histologic, immunophenotypic, and cytogenetic characteristics of childhood

NHL are listed in C. Table 1.

C. Table 1Clinically Relevant Histologic Types, Immunophenotype, and CytogeneticFeatures of NHL in Children

Histologictypea Immunophenotype

Cytogeneticabnormality Fusion gene

Burkitt B-cell (mature) t(8;14)(q24;q32) MYC-IgHt(8;22)(q24;q11) MYC-IgLt(2;8)(p12;q24) MYC-IgK

Lymphoblastic T-cell Same as T-cellALL

Pre-B–cell Same as pre-B–cell ALL

Diffuse large-cell

B-cell

Anaplasticlarge-cell

T-cell, t(2;5)(p23;q32) NPM-ALK

t(1;2)(q21;p23) TPM3-ALKt(2;3)(p23;q21) TFG-ALKInv(2)(p23q35) ATIC-ALKt(2;22)(p23;q11) CTCL-ALKt(X;2)(q11;p23) MOESIN-ALKt(2;19)(p23;13) TPM4-ALK

aWorld Health Organization classification

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C.2 Laboratory Findings

In patients with NHL, blood counts are usually normal. In those with bone

marrow involvement, anemia and thrombocytopenia are common, and

circulating lymphomatous cells may be present, but hyperleukocytosis is

infrequent. As in patients with ALL, serum concentrations of uric acid and

lactate dehydrogenase activity (LDH) can be elevated. Although CNS

involvement is rare at presentation of NHL, particularly in those with large-cell

lymphoma, all patients should undergo lumbar puncture and CSF examination.

A prompt radiologic investigation is required to demonstrate areas of tumor

involvement and is used to monitor the tumor’s response to therapy.

Whole-body computed tomography (CT) is the imaging modality of choice

to determine tumor extent. The roles of magnetic resonance imaging, photon

emission CT, and thallium scanning in childhood NHL have not yet been

defined. However, in the initial evaluation, bilateral bone marrow examination is

mandatory. Occasionally bone marrow involvement is unilateral. Bone marrow

biopsy may reveal tumor involvement that is not clear from examination of the

bone marrow aspirate; therefore, to determine disease stage, most

investigators recommend bone marrow biopsy as part of the work-up. However,

children with massive mediastinal involvement may not tolerate the anesthetic

procedure needed to perform bilateral bone marrow aspirations, and biopsies

and a single aspirate may be sufficient. Suspected cases of pediatric lymphoma

should be diagnosed promptly, and treatment should begin without delay.

C.3 Differential Diagnosis

Because of its varied clinical and laboratory manifestations, childhood

NHL can mimic several nonmalignant and malignant diseases. Differentiating

between a reactive lymphoproliferative process and NHL is rarely difficult.

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However, diagnosis of NHL is occasionally delayed in patients with localized,

painless adenopathy when results of histologic studies of the lymph nodes are

inconclusive for the presence of malignancy. Patients with persistent, painless

enlargement of the lymph nodes after a 10- to 14-day trial of antibiotic therapy

should undergo a lymph node biopsy, preferably surgically, to provide adequate

tissue for immunophenotyping and for molecular and conventional studies.

Persistently enlarged lymph nodes in patients with acquired or congenital

immunodeficiency represent a substantial diagnostic dilemma. Collectively,

these abnormalities have been classified as lymphoproliferative disorders, and

they range from reactive polyclonal hyperplasia to true monoclonal malignant

lymphomas. Children presenting with an isolated mediastinal mass present a

diagnostic challenge because a mediastinal mass can be present at diagnosis

of several malignant and nonmalignant conditions, including histoplasmosis,

sarcoidosis, Hodgkin disease, germ cell tumor, thymic carcinoma,

neuroblastoma, and myeloblastoma. Results of serologic studies can provide

evidence of some of these diseases, but a CT-guided needle biopsy procedure is

usually necessary to provide tissue for diagnosis.

Primary lymphoma of the bone is commonly misdiagnosed.10,11 Indeed, in

one St. Jude study, 10 of the 11 patients with biopsy-confirmed primary

lymphoma of the bone had previously received an alternative initial diagnosis.11

To differentiate between primary lymphoma of the bone and other small blue

cell tumors, immunohistochemical studies with an extensive panel of markers

are required to supplement histologic studies.

C.4 Prognostic Factors

In NHL, staging systems have been used to identify groups of patients

with diverse prognoses. The most commonly used, a system introduced by St.

Jude Children’s Research Hospital, applies to all subtypes of NHL (C. Table 2)12

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However, in recent years, a review an update of such classification is being

discussed.

To view a poll on this topic visit:

https://www.cure4kids.org/ums/oncopedia/polls/

C. Table 2The St. Jude Staging System for NHL in Children.12

Stage DescriptionI A single tumor (extranodal) or single anatomic area

(nodal), excluding mediastinum or abdomenII A single tumor (extranodal) with regional node

involvement, On same side of the diaphragm:

(a) Two or more nodal areas(b) Two single extranodal tumors, with or without

regional node involvement A primary gastrointestinal tract tumor (usually

ileocecal) with or without associated mesentericnode involvement, grossly completely resected

III On both sides of the diaphragm:(a) Two or more nodal areas(b)Two single extranodal tumorsAll primary intrathoracic tumors (mediastinal, pleuralthymic)

All extensive primary intra-abdominal disease;unresectable

All primary paraspinal or epidural tumors, regardlessof other sites

IV Any of the above with initial CNS or bone marrowinvolvement (< 25%)

Its main value is in separating patients with localized disease from those

with advanced disease. More recently, information on immunophenotype and

molecular findings has been incorporated into classification schemes. This

approach has established a foundation on which investigators can develop

treatment regimens specific to immunophenotype and disease stage.

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Recently many groups of investigators have used LDH level as a surrogate

value for tumor burden in making treatment decisions regarding B-cell NHL.13

Response to therapy has been used similarly. In patients with B-cell lymphoma,

French investigators have proposed the use of imaging studies to estimate the

reduction in tumor mass after one week of cyclophosphamide, vincristine, and

prednisone treatment. Patients whose primary tumor was reduced by less than

20% received more intensive treatment.14 Recently, more attention has been

paid to the molecular kinetics of response to chemotherapy detecting minimal

residual disease by molecular techniques or flow cytometry.15,16

The most important prognostic factor in pediatric NHL is an accurate

diagnosis and evaluation of the extent of disease, so every effort should be

made to correctly characterize disease biology before treatment.

C. References1Ribeiro RC, Pui CH, Murphy SB, et al. Childhood malignant non-Hodgkin lymphomas ofuncommon histology. Leukemia. 1992;6(8):761-765.2Ferry JA. Burkitt's lymphoma: clinicopathologic features and differential diagnosis. Oncologist.2006;11(4):375-383.3Ferrando AA, Neuberg DS, Staunton J, et al. Gene expression signatures define novel oncogenicpathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1(1):75-87.4Burkhardt B, Bruch J, Zimmermann M, et al. Loss of heterozygosity on chromosome 6q14-q24is associated with poor outcome in children and adolescents with T-cell lymphoblasticlymphoma. Leukemia. 2006;20(8):1422-1429.5Burkhardt B, Moericke A, Klapper W, et al. Pediatric precursor T lymphoblastic leukemia andlymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity atchromosome 6q and their prognostic impact. Leuk Lymphoma 2008;49(3):451-461.6Neth O, Seidemann K, Jansen P, et al. Precursor B-cell lymphoblastic lymphoma in childhoodand adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. MedPediatr Oncol 2000;35(1):20-27.7Reiter A, Klapper W. Recent advances in the understanding and management of diffuse large B-cell lymphoma in children. Br J Haematol. 2008.8Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood.2007;110(7):2259-2267.9Lee HW, Kim K, Kim W, et al. ALK-positive diffuse large B-cell lymphoma: report of three cases.Hematol Oncol. 2008;26(2):108-113.10Coppes MJ, Patte C, Couanet D, et al. Childhood malignant lymphoma of bone. Med PediatrOncol. 1991;19(1):22-27.11Furman WL, Fitch S, Hustu HO, et al. Primary lymphoma of bone in children. J Clin Oncol.1989;7(9):1275-1280.

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12Murphy SB, Fairclough DL, Hutchison RE, et al. Non-Hodgkin's lymphomas of childhood: ananalysis of the histology, staging, and response to treatment of 338 cases at a singleinstitution. J Clin Oncol. 1989;7(2):186-193.13Reiter A, Schrappe M, Parwaresch R, et al. Non-Hodgkin's lymphomas of childhood andadolescence: results of a treatment stratified for biologic subtypes and stage--a report of theBerlin-Frankfurt-Munster Group. J Clin Oncol. 1995;13(2):359-372.14Patte C, Auperin A, Michon J, et al. The Societe Francaise d'Oncologie Pediatrique LMB89protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initialresponse in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood2001;97(11):3370-3379.15Coustan-Smith E, Sandlund JT, Perkins SL, et al. Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the children's oncology group. J Clin Oncol.2009;27(21):3533-3539.16Mussolin L, Pillon M, Conter V, et al. Prognostic role of minimal residual disease in mature B-cell acute lymphoblastic leukemia of childhood. J Clin Oncol. 2007;25(33):5254-5261.

D. Treatment

Progress in the treatment of children and adolescents with NHL parallels

that of childhood acute lymphoblastic leukemia. Investigators of most

contemporary clinical trials report survival estimates approaching 90% in more

developed countires.1-4 Moreover, the relevance of clinical and biologic

prognostic factors has been practically eliminated by the use of risk-adapted

strategies specific to disease stage and immunophenotype in conjunction with a

wide range of effective agents, which are largely responsible for the improved

survival estimates.

Adequate treatment has emerged as the single most important

determinant of successful outcome of NHL. Clinical and biologic features that

guide the therapeutic strategy include the extent of the disease at the time of

diagnosis, sites of involvement, immunophenotype, morphology and

immunohistochemistry of tumor cells, and early response to therapy. The BFM

group evaluated the impact of age and gender in the prognosis of pediatric and

adolescent lymphomas.5 In their study of 2084 patients the probability of event-

free survival was significantly superior for males with T lymphoblastic

lymphomas and diffuse B large cell lymphomas. When age-groups were

compared dividing in groups between 0-4, 5-9, 10-14 and 15-18 years, the

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outcome was poorer for the youngest patients only in the precursor B-

lymphoblastic lymphomas and anaplastic large cell lymphomas.

Adolescent females with T lymphoblastic lymphomas and diffuse large cell B

cell lymphomas had worse outcome than younger girls while age had no impact

on pEFS for boys.5

Most groups developed different strategies for treatment of patients

according to biological subgroups, that encompass about 90% of the cases.

These include:

1) Lymphoblastic lymphoma

2) Mature B-cell malignancies

3) Anaplastic large cell lymphoma

D.1 Lymphoblastic lymphoma

Investigators developing treatment for lymphoblastic NHL have assumed

that this form of the disease behaves the same as does T-cell ALL. Their

assumption is based on results of the seminal Children’s Cancer Group study,

reported more than 20 years ago, showing that the LSA2L

2regimen, an ALL-type

therapy, was significantly more effective than pulse chemotherapy (COMP) in

the treatment of lymphoblastic NHL.6 However, because most lymphoblastic

NHL is of T-cell immunophenotype, ALL regimens that have not been

particularly successful in the treatment of T-cell ALL are expected to yield poor

results in the treatment of lymphoblastic NHL. So, most of the groups use BFM-

based protocols that have been highly effective in ALL.1 The BFM-90 protocol for

NHL incorporates treatment components found to be effective in T-cell ALL.7

These regimens include an induction phase with steroids, vincristine, L-

asparaginase and anthracyclines followed by cyclophosphamide, cytarabine and

mercaptopurine. The original BFM study included a consolidation phase

including high dose methotrexate (5 g/m2 in 24 hour infusion) and 6-

mercaptopurine.7 However, a recently completed study from the COG and yet

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unpublished, failed to show any benefit from high dose methotrexate for

patients with lymphoblastic lymphoma treated with a modified BFM-based

protocol. A re-induction phase should be prescribed for these patients followed

by maintenance therapy to complete 2 years of therapy. However, children with

limited disease (stages I and II) might not need it.


Cranial radiotherapy for patients with no initial CNS involvement is

probably not necessary if an intensive intrathecal chemotherapy is used.8 The

NHL-BFM-90 protocol was associated with a 5-year event-free survival (EFS)

estimate of 92% in more than 100 patients with lymphoblastic lymphoma—a

truly remarkable achievement.7 However, results from other groups using a

similar strategy were not as remarkable.9

D.2 Mature B-cell malignancies

The highly successful protocol (LMB89)10 developed by French

investigators and the BFM studies developed by the German-Austrian groups to

treat mature B-cell NHL (Burkitt, Burkitt-like, and large B-cell lymphomas)2 have

become the benchmark for other protocols. For such subtypes, intensive, high-

dose treatment of short total duration (5 to 8 months) and a reduced interval

between treatment cycles are the hallmark of all effective types of combination

therapy. CNS-directed therapy is mandatory, and patients with evidence of CNS

involvement or those in the high-risk category should receive intensive

therapy.11

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D.2.1 Treatment of localized disease

The results of the treatment of localized mature B cell malignancies are

excellent and current efforts are directed to use the less intensive therapy

possible that could preserve these excellent results while reducing the acute

and late side effects associated with therapy. Even though, it can be generalized

that patients with stage I and II disease constitute those with localized disease,

most groups have used their own risk groups based in other prognostic factors

such as the completeness of resection. Thus, based on the classification used

by the French LMB group, the FAB (French, American, British consortium) they

defined lower risk patients as those with completely resected Stage I disease

and also those abdominal stage II that underwent complete resection of their

tumor manifestations.12 The definition used by the BFM group was similar.2 The

results of the FAB group for the treatment of Group A disease showed that a

survival rate of 99% can be achieved with the use of only 2 cycles of COPAD

chemotherapy (Cyclophosphamide, Prednisone, Doxorubicin and Vincristine)

and no intrathecal chemotherapy.12 These results were obtained in a large

cohort in a multicentric study, involving many institutions from developed

countries.

Similar results were obtained by the BFM group in their protocol 95 in a

smaller cohort2 and using a slightly more intense protocol with intermediate

dose methotrexate and prophylactic intrathecal chemotherapy. The results

from less developed countries are also encouraging with survival rates over

90%, but most results from mid income countries came from single institutions

with few patients included.13-15 It is essential that patients should be

meticulously staged in order to give them a reduced-dose regimen. This is

important to be emphasized, especially in less developed countries, where

staging procedures might be not accurate in all institutions and patients with

more advanced disease might be missed.

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A typical example is the case with intususception, operated in a local hospital

with reportedly completely resected disease. Since it is often impossible to be

completely sure about the completeness of the resection in some of these

cases, and they might benefit from a more intense regimen if the tumor was

not completely resected. Reduced dose chemotherapy should be used only

when there is absolute certainty of the completeness of the resection.

D.2.2 Treatment of advanced disease

Patients who are not classified as having limited or low-risk disease are

collectively grouped as high-risk patients. Naturally, patients placed in this

category have a wide range of tumor burdens and are likely to have diverse

prognoses. Due to this diversity, treatments vary greatly on the basis of the

staging system used. For example, a patient with Burkitt lymphoma without

CNS involvement and < 25% blast cells in the bone marrow is considered to

have stage IV disease according to the St. Jude system; but the patient is placed

in group B in the French Society of Pediatric Oncology (SFOP) staging system,

which stipulates 70% or more of bone marrow involvement for group C.

Treatment of group C disease is much more intensive than that of group B.16

Other investigators define risk categories associated with advanced-stage

disease on the basis of serum LDH concentrations.2 Berlin-Frankfurt-Munster

(BFM) protocols also stratify patient groups according to their LDH values.

Those whose values exceed 1,000 U/L are at highest risk and receive a more

intensive therapy.2 However, because what is considered a normal range of LDH

values may vary by institution, relative, rather than absolute values of LDH

should be considered as a basis for making treatment decisions. Therefore,

other investigators in cooperative groups used an elevation of LDH greater than

2 times the institutional normal values as a basis for stratification of patient

groups.

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Therefore, regardless of the definition used, these patients need intensive

chemotherapy to achieve a high cure rate. The results of the FAB and BFM series

of studies were excellent with the use of high intensity chemotherapy.2,3,16 There

does not seem to be a significant difference between the effectiveness of each

of these strategies and different treatment groups or institutions should use

the strategy with which they are familiar with. With these regimens, it is

expected that over 85% of the patients could be cured with tailored intensive

therapy. Only CNS invasion and poor response to chemotherapy remain as

significant risk factors.11,16 In recent years, children with primary mediastinal

(thymic) B cell lymphoma have been identified as an independent subtype with

poorer prognosis. Therefore, they are analyzed separately in most current

series.17

The BFM series of studies classified patients according to stage, tumor

burden based on serum LDH levels and the presence of CNS invasion. In the

study BFM 95, the use of a higher dose of methotrexate (5g/m2) in a prolonged

infusion (24 hours) for patients with abdominal primaries and high tumor

burden obtained better results.18 With that classification patients of Risk group

R3 (stage III abdominal primary with LDH greater than 500 IU/L but lower than

1000 IU/L and those of stage IV and B-ALL with the same LDH values but with

negative CNS involvement) and those with Risk group 4 (those with stage III or

IV and LDH >1000 IU/L or CNS involvement) achieved an overall survival rate

greater than 85%.2 So, the major conclusion of that study was that the dose and

the duration of Methotrexate infusion are important in advanced B-cell

lymphomas. Therefore, higher dose and prolonged infusions of Methotrexate

were associated to a reduced relapse rate, but at the same time, they were less

toxic. This information is important for less developed countries where

induction mortality is still a problem. So, each institution should analyze their

own results, so that if toxic mortality is a greater problem, they might benefit

from shorter infusions, associated to lower toxicity.

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D.3 Anaplastic large cell lymphoma

The third largest group of childhood NHL (ALCL) comprises

approximately 15% of all cases of pediatric NHL, and it includes tumors mostly

with T-cell markers.19 Because the clinical and biologic characterization of this

NHL subtype is still evolving,20 treatment programs for this disease have

differed vastly. Only a few pediatric cooperative treatment groups have reported

results of studies in which patients were selected by using the contemporary

definition of ALCL. Remarkably, the results, albeit inferior to those noted in

pediatric B-cell or lymphoblastic NHL, have shown that approximately survival

rates from 60% to 80% can be achieved with either treatment strategy.

The French Society of Pediatric Oncology used a protocolbased on the

treatment of B-cell NHL that prescribes 2 cycles of COPDAM (methotrexate,

cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by 5 to 7

months of maintenance chemotherapy.21 Complete responses were achieved in

95% of the patients; 21/82 patients experienced an adverse event.21 By using a

strategy developed for B-cell NHL, BFM investigators also reported improved

results.22 The 5-year EFS estimate for 55 patients with stage III disease was 76%;

for 6 patients with stage IV NHL, 50%. In the BFM study, treatment lasted only 5

months; in the others, 10 to 24 months.23

A recently completed study from multinational European and Japanese

investigators showed in a randomized fashion that the BFM treatment strategy

was reproducible in a larger cohort of patients.24,25 That study was designed to

test in a randomized factorial design the effectiveness and toxicity of two

different doses and schedules of methotrexate and the impact of maintenance

with Vinblastin. Vinblastin was identified as a candidate active drug based upon

the observations of French investigators in relapsed patients where single drug

Vinblastine was associated to a high response rate.26 The results of that study

showed that the preferred methorexate schedule was 3 g/m2 in a 3 hour

infusion followed by leucovorin rescue.

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The alternative schedule of 1 g/m2 in 24 hour infusion was equally effective but

more toxic. With the use of the 3g/m2 schedule, no intrathecal prophylaxis was

necessary. The preliminary results of the randomized question of the

effectiveness of vinblastin for maintenance failed to show any benefit, but final

results have not been published at the time of this report. In that study, 2-year

event-free survival for the whole cohort was around 70-75%, but many patients

could be rescued after relapse. Most tumor failures occur in the first year of

diagnosis.

That seminal study also contributed to shed light on prognostic factors

for this subtype. Prognostic factors are related to treatment, so the conclusions

of that study are valid only for treatment with a similar strategy. Mediastinal,

visceral (including lung, liver and spleen) and skin involvement were identified

as poor prognostic factors in that study.25

Other groups also reported encouraging results. The POG reported the

effectiveness of the APO regimen and the impact of methothrexate and

cytarabine was inconclusive in that population. However, that regimen has a

high cumulative dose of anthracyclines.27 Similar results were reported by Italian

investigators with a leukemia-based therapy.28 In these cases where a lower

intensity regimen is used, occasional late relapses may be seen.28

D.4 Salvage Therapy (Partial Responses or Relapse)

Persistent or relapsed NHL presents serious management problems.

Because contemporary, risk-directed therapies are usually very intensive, the

overall prognosis for such cases is dismal.

In patients with a residual mass after induction and consolidation

therapy, persistent disease should be confirmed by biopsy, as imaging studies

commonly detect nonviable tumor. The use of PET scans is under evaluation for

this situation.

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When persistent disease during therapy or relapse is documented, the

options for salvage therapy depend on the intensity and types of agents used in

the primary therapy, histologic disease type, and timing of the relapse. Because

primary therapy for Burkitt lymphoma or large B-cell lymphoma includes most

of the known effective agents, salvage therapy is usually based on regimens

containing cisplatin or carboplatin, such as the widely used combination of

ifosfamide, carboplatin, and etoposide. Monoclonal antibodies to B-cell

antigens, successfully used to treat B-cell lymphomas, have been combined with

conventional chemotherapy or conjugated to radioisotopes. The monoclonal

anti-CD20 (rituximab), for example, has been widely used in combination with

standard chemotherapy.29,30 A report of the combination of Rituximab and the

ICE (Ifosfamide, Carboplatin and Etoposide) combination showed encouraging

results with a response rate of 60%.31 The response of relapsed B cell

malignancies to second line chemotherapy is usually short lived, and patients

showing at least a partial response to second line chemotherapy should

undergo intensification with high dose chemotherapy and stem cell rescue. The

results of autologous stem cell rescue seem to parallel those of allogeneic

transplantation and it is usually feasible in a shorter period of time in patients

without bone marrow involvement. However, even in the favorable situations

where a response to second line chemotherapy occurred and the patient could

undergo a stem cell transplant, relapse usually occurs and the survival rate is

usually below 30%.32 Preparative regimens usually include chemotherapy only

regimens since B-cell malignancies are usually not sensitive to radiotherapy.32

The principles of management of relapsed lymphoblastic NHL are similar

to those of relapsed ALL. When a second remission is achieved, HSCT is also

indicated. However, the results of rescue therapy for lymphoblastic lymphoma

are poor, even with high dose chemotherapy and stem cell rescue.33 The

outcome of residual disease after salvage therapy is very poor. Allogeneic

transplantation is usually preferred for relapsed lymphoblastic lymphoma,

however registry data from adults report a comparable result after autologous

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transplantation.34 Preparative regimens usually contain total body irradiation

along with chemotherapy.

Contrary to what is observed in Burkitt and lymphoblastic NHL, in ALCL,

second remission is usually possible. Salvage treatment has included intensive

chemotherapy with stem cell rescue. In a recent SFOP study, a second remission

was achieved in 36 of 41 cases of relapsed ALCL.26 Eight of 13 patients

receiving a single agent, (vinblastine administered weekly) experienced

prolonged remission, which suggests that several relapses of ALCL do not

preclude a long period of disease-free survival. BFM investigators have reported

the use of allogeneic BMT for 20 patients with relapsed/resistant ALCL30. Event-

free survival 3 years after BMT was 75%; and outcome was not influenced by

donor type or conditioning regimens.

D.5 Supportive Care

Patients with lymphoid malignancies often present with respiratory,

cardiovascular, neurologic, renal, hemorrhagic, infectious, and metabolic

complications. Intense tissue remodeling—cell proliferation and cell death—

results in a large tumor burden and rapid turnover of nucleoproteins, both of

which are responsible for the dysfunction of these organ systems. The rate of

mortality due to these complications has been reduced to less than 1% by

prompt recognition of signs and symptoms, careful clinical and laboratory

evaluation to determine the presence of these complications, and early

intervention. However, in less developed countries, it is still a significant

problem. Mortality resulting from these complications is defined as death not

due directly to the leukemia or lymphoma. Respiratory distress from

compression of mediastinal structures is common in lymphoblastic NHL. 35

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See video with a case:

https://www.cure4kids.org/ums/oncopedia/case_detail/?id=240

Compression of the vessels of the mediastinum can lead to intraluminal

thrombosis and sudden death.35 In cases of severe compression, general

anesthesia is not recommended because of an increased risk of complete,

irreversible airway block. In an emergency it is sometimes necessary, before

diagnosis is made, to reduce the risk of airway compression by administration

of corticosteroids or local radiotherapy (or both). Massive ascites and intra-

abdominal involvement in Burkitt lymphoma can cause compression of the

bowel and ureter.36 In addition, abdominal blood and lymphatic vessels can

become compressed, which results in reduced blood flow and lymphatic return

and in edema of the lower extremities.

Patients with NHL are at particularly high risk of biochemical

complications because of the high rate of cell turnover and the high sensitivity

of the malignant cells to chemotherapy.37 Biochemical abnormalities, often

present before chemotherapy begins, are induced by fever, processes

associated with infection, dehydration, and even spontaneous cell lysis. These

metabolic abnormalities, which include hyperuricemia, hyperphosphatemia,

hypocalcemia, hyperkalemia, and azotemia, characterize tumor lysis syndrome

(TLS). The pathogenetic consequences of this syndrome result from the release

of cellular breakdown products that exceed the hepatic and renal anabolic and

catabolic capacities. The deposition of phosphorus, uric acid, and its precursors

(hypoxanthine and especially xanthine or both) in the lumina of the renal

tubules is believed to be central to the development of renal insufficiency. If

these metabolic abnormalities become severe, renal failure, cardiac arrhythmia,

respiratory distress, and death can follow.

Features associated with increased risk of TLS include hyperleukocytosis,

massive organomegaly, renal enlargement, extrinsic compression of the

genitourinary tract, and elevated serum LDH activity.

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Patients with established TLS or those at high risk for TLS should be monitored

carefully. Preferably, they should be admitted to an intensive care unit and

cared for by a multidisciplinary team. The team must ensure adequate urinary

flow before chemotherapy is started. To determine the adequacy of renal

function, a slightly hypotonic solution without potassium should be

administered intravenously at a rate of 2 to 5 L/m2 per day. Administration of

fluids dilutes intravascular solutes such as urates and phosphates, increases

renal blood flow and glomerular filtration, and flushes precipitated solutes from

the renal tubules. The availability of recombinant urate oxidase (rasburicase)

has greatly facilitated the prevention and management of hyperuricemia.38,39

It is important to consider the outcome of tumor lysis and the presence

of renal failure at the time of initiating chemotherapy especially in children with

B cell lymphomas. Since renal failure leads to disturbances in the

pharmacokinetics of many drugs used in these malignancies, it may be prudent

to consider delaying the chemotherapy or giving a prolonged pre-phase in

children with renal abnormalities. Occasionally, renal failure is caused by tumor

invasion of the renal parenchyma or obstruction of the urinary tract, so a

careful evaluation is needed in these cases.

D. References

1Reiter A. Diagnosis and treatment of childhood non-hodgkin lymphoma. Hematology Am SocHematol Educ Program 2007:2007:285-296.2Woessmann W, Seidemann K, Mann G, et al. The impact of the methotrexate administrationschedule and dose in the treatment of children and adolescents with B-cell neoplasms: a reportof the BFM Group Study NHL-BFM95. Blood 2005:105(3):948-958.3Patte C, Auperin A, Gerrard M, et al. Results of the randomized international FAB/LMB96 trialfor intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible toreduce treatment for the early responding patients. Blood 2007:109(7):2773-2780.4Grenzebach J, Schrappe M, Ludwig WD, et al. Favorable outcome for children and adolescentswith T-cell lymphoblastic lymphoma with an intensive ALL-type therapy without localradiotherapy. Ann Hematol 2001:80 Suppl 3:B73-76.

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5Burkhardt B, Zimmermann M, Oschlies I, et al. The impact of age and gender on biology,clinical features and treatment outcome of non-Hodgkin lymphoma in childhood andadolescence. Br J Haematol 2005:131(1):39-49.6Anderson JR, Wilson JF, Jenkin DT, et al. Childhood non-Hodgkin's lymphoma. The results of arandomized therapeutic trial comparing a 4-drug regimen (COMP) with a 10-drug regimen(LSA2-L2). N Engl J Med 1983:308(10):559-565.7Reiter A, Schrappe M, Ludwig WD, et al. Intensive ALL-type therapy without local radiotherapyprovides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFMgroup report. Blood 2000:95(2):416-421.8Burkhardt B, Woessmann W, Zimmermann M, et al. Impact of cranial radiotherapy on centralnervous system prophylaxis in children and adolescents with central nervous system-negativestage III or IV lymphoblastic lymphoma. J Clin Oncol 2006:24(3):491-499.9Pillon M, Piglione M, Garaventa A, et al. Long-term results of AIEOP LNH-92 protocol for thetreatment of pediatric lymphoblastic lymphoma: a report of the Italian Association of PediatricHematology and Oncology. Pediatr Blood Cancer 2009:53(6):953-959.10Patte C, Auperin A, Michon J, et al. The Societe Francaise d'Oncologie Pediatrique LMB89protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initialresponse in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood2001:97(11):3370-3379.11Salzburg J, Burkhardt B, Zimmermann M, et al. Prevalence, clinical pattern, and outcome ofCNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin'slymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 2007:25(25):3915-3922.12Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of COPADchemotherapy in children and adolescents with resected localized B-cell non-Hodgkin'slymphoma: results of the FAB/LMB 96 international study. Br J Haematol 2008:141(6):840-847.13Klumb CE, Schramm MT, De Resende LM, et al. Treatment of children with B-cell non-Hodgkin'slymphoma in developing countries: the experience of a single center in Brazil. J Pediatr HematolOncol 2004:26(7):462-468.14Chantada G, Casak S, Alderete D, et al. Treatment of B-cell malignancies in children with amodified BFM-NHL 90 protocol in Argentina. Med Pediatr Oncol 2003:41(5):488-490.15Kutluk T, Varan A, Akyuz C, et al. Clinical characteristics and treatment results of LMB/LMTregimen in children with non-Hodgkin's lymphoma. Cancer Invest 2002:20(5-6):626-633.16Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-riskcentral nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia inchildren and adolescents. Blood 2007:109(7):2736-2743.17Seidemann K, Tiemann M, Lauterbach I, et al. Primary mediastinal large B-cell lymphoma withsclerosis in pediatric and adolescent patients: treatment and results from three therapeuticstudies of the Berlin-Frankfurt-Munster Group. J Clin Oncol 2003:21(9):1782-1789.18Reiter A, Schrappe M, Tiemann M, et al. Improved treatment results in childhood B-cellneoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-MunsterGroup Trial NHL-BFM 90. Blood 1999:94(10):3294-3306.19Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood2007:110(7):2259-2267.20Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically andimmunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not

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otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood2008:111(12):5496-5504.21Brugieres L, Deley MC, Pacquement H, et al. CD30(+) anaplastic large-cell lymphoma inchildren: analysis of 82 patients enrolled in two consecutive studies of the French Society ofPediatric Oncology. Blood 1998:92(10):3591-3598.22Reiter A, Schrappe M, Tiemann M, et al. Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: a prospective analysis of 62 patients enrolled in three consecutiveBerlin-Frankfurt-Munster group studies. J Clin Oncol 1994:12(5):899-908.23Seidemann K, Tiemann M, Schrappe M, et al. Short-pulse B-non-Hodgkin lymphoma-typechemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report ofthe Berlin-Frankfurt-Munster Group Trial NHL-BFM 90. Blood 2001:97(12):3699-3706.24Brugieres L, Le Deley MC, Rosolen A, et al. Impact of the methotrexate administration dose onthe need for intrathecal treatment in children and adolescents with anaplastic large-celllymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol 2009:27(6):897-903.25Le Deley MC, Reiter A, Williams D, et al. Prognostic factors in childhood anaplastic large celllymphoma: results of a large European intergroup study. Blood 2008:111(3):1560-1566.26Brugieres L, Quartier P, Le Deley MC, et al. Relapses of childhood anaplastic large-celllymphoma: treatment results in a series of 41 children--a report from the French Society ofPediatric Oncology. Ann Oncol 2000:11(1):53-58.27Laver JH, Kraveka JM, Hutchison RE, et al. Advanced-stage large-cell lymphoma in children andadolescents: results of a randomized trial incorporating intermediate-dose methotrexate andhigh-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Groupphase III trial. J Clin Oncol 2005:23(3):541-547.28Rosolen A, Pillon M, Garaventa A, et al. Anaplastic large cell lymphoma treated with aleukemia-like therapy: report of the Italian Association of Pediatric Hematology and Oncology(AIEOP) LNH-92 protocol. Cancer 2005:104(10):2133-2140.29de Vries MJ, Veerman AJ, Zwaan CM. Rituximab in three children with relapsed/refractory B-cellacute lymphoblastic leukaemia/Burkitt non-Hodgkin's lymphoma. Br J Haematol2004:125(3):414-415.30Attias D, Weitzman S. The efficacy of rituximab in high-grade pediatric B-celllymphoma/leukemia: a review of available evidence. Curr Opin Pediatr 2008:20(1):17-22.31Griffin TC, Weitzman S, Weinstein H, et al. A study of rituximab and ifosfamide, carboplatin,and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkinlymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children'sOncology Group. Pediatr Blood Cancer 2009:52(2):177-181.32Attarbaschi A, Dworzak M, Steiner M, et al. Outcome of children with primary resistant orrelapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment:a population-based analysis of the Austrian Cooperative Study Group. Pediatr Blood Cancer2005:44(1):70-76.33Mitsui T, Mori T, Fujita N, et al. Retrospective analysis of relapsed or primary refractorychildhood lymphoblastic lymphoma in Japan. Pediatr Blood Cancer 2009:52(5):591-595.34De Witte T, Awwad B, Boezeman J, et al. Role of allogenic bone marrow transplantation inadolescent or adult patients with acute lymphoblastic leukaemia or lymphoblastic lymphoma infirst remission. Bone Marrow Transplant 1994:14(5):767-774.35Ricketts RR. Clinical management of anterior mediastinal tumors in children. Semin PediatrSurg 2001:10(3):161-168.

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36Hendrick JM, Kaste SC, Tamburro RF, et al. Abdominal compartment syndrome in a newlydiagnosed patient with Burkitt lymphoma. Pediatr Radiol 2006:36(3):254-257.37Wossmann W, Schrappe M, Meyer U, et al. Incidence of tumor lysis syndrome in children withadvanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic useof urate oxidase. Ann Hematol 2003:82(3):160-165.38Patte C, Sakiroglu C, Ansoborlo S, et al. Urate-oxidase in the prevention and treatment ofmetabolic complications in patients with B-cell lymphoma and leukemia, treated in the SocieteFrancaise d'Oncologie Pediatrique LMB89 protocol. Ann Oncol 2002:13(5):789-795.39Hummel M, Reiter S, Adam K, et al. Effective treatment and prophylaxis of hyperuricemia andimpaired renal function in tumor lysis syndrome with low doses of rasburicase. Eur J Haematol2008:80(4):331-336.

E. Uncommon Forms of Pediatric Non-HodgkinLymphoma

Although the overwhelming majority of patients with pediatric lymphoma

fall into the three categories, (Burkitt, lymphoblastic and large cell), some

patients occasionally present with less common disease subtypes that pose

diagnostic and treatment challenges. Many times, pathologists in children’s

hospitals do not have the experience or reagents needed to precisely

characterize these uncommon forms of lymphomas. It is crucial for pediatric

oncologists to have a high index of suspicion for these rare lymphomas, and

collaboration among pediatric and adult pathologists is often necessary to

reach the correct diagnosis.

E.1 Follicular lymphoma

Follicular pediatric NHL, which occurs in about 3% of all pediatric cases,

differs substantially from its adult counterpart.1 In adults, follicular NHL is

disseminated, has a low histologic grade, and is incurable with current

therapies. Conversely, pediatric NHL is typically localized with intermediate or

high histologic grade (grade 2 or 3), and highly curable. Pediatric cases are

more common in males. Head and neck lymph nodes or tonsils are the most

common primary sites. Extranodal sites include the gastrointestinal tract,

parotid, kidney, epididymis, and testes, but the BFM series failed to show any

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case of testicular location.1,2 Approximately 70% of the pediatric cases have

localized (Stage I or II) disease. CD10 is expressed in most tumor cells; in a

minority, CD34 is expressed.2 The Bcl-6 protein is occasionally present, as the

Bcl-2 protein, but the typical t(14;18) translocation seen in adults is not.1

Furthermore, in contrast to the adult counterpart, in the most cases of pediatric

follicular NHL, the t(14;18) rearrangement is not present.1

NHL involvement of the testes is rare; most involvement is present at

diagnosis in patients with disseminated lymphoblastic or Burkitt NHL. Primary

testicular lymphoma is usually of follicular histiotype. Of the approximately 12

cases reported,3 the median age at diagnosis was 5 years; tumors were small

(2-4 cm), and the histologic grade was III. CD10 was expressed in 6 of 9 cases

tested, and the Bcl-6 protein was expressed in 10 of 11 cases tested. In that

series, the Bcl-2 protein was not expressed in any of the cases tested, and the

t(14;18) rearrangement was not evident in 8 cases tested.3

The treatment of pediatric follicular NHL is controversial. Investigators

from the United Kingdom Children Cancer Study Group (UKCCSG) have even

suggested that children with localized and completely resected tumors do not

need further therapy.4 Their recommendation is based on a very small number

of patients. Patients with more advanced disease or those who had incomplete

resections received a short course of chemotherapy in accordance with the

UKCCSG protocol 10.4 At St. Jude, patients with follicular NHL are treated

according to disease stage. Patients with Murphy disease stage I or II receive

chemotherapy. Those children with the rare diagnosis of advanced-stage

follicular NHL usually receive more intensive treatment. A recent report from

the BFM group also showed excellent results with B-cell based chemotherapy. It

seems that, as opposed to the clinical behavior in adults, follicular lymphoma in

children does not follow an indolent clinical course with multiple relapses and

behaves more like a B-cell diffuse large cell lymphoma.1

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E.2 Marginal Zone B-cell Lymphomas

Marginal zone lymphomas are relatively rare forms of B-cell malignancies

derived from post-germinal B-cells.5 They are much more common in older

patients (median age, 60 years) than in children or in young adults. Pediatric

cases are very rare and have been associated with autoimmune disorders such

as Sjögren syndrome, Hashimoto thyroiditis, and systemic lupus

erythematosus. The primary sitevaries considerably and includes nodal and

extranodal regions.

Approximately 8% to 10% of adult cases of NHL are classified as

extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid

tissue type (MALT). The stomach is the most commonly affected among the

extranodal sites. Other extranodal sites include the salivary glands, orbit, and

lungs. In the etiology of MALT-associated gastric lymphoma, infection with the

bacterium Helicobacter pylori has been implicated. Isolated cases of MALT

lymphoma have been reported in pediatric patients who are HIV-infected. Only

four patients (<0.1%) of the 2,703 admitted on NHL BFM studies between 1986

and 2004 received a diagnoses of MALT lymphoma.6 All four cases had

extranodal sites: lower lid, breast, conjunctiva, and stomach. In another, 32 of

48 children and young adults with marginal zone B-cell lymphoma (67%) had

nodal presentation.7 They ranged in age from 2 to 27 years (median, 16 years);

21 patients (66%) were 18 years of age or younger and the disease

predominated in males.

Most patients (88%) presented with isolated, painless, peripheral

adenopathy in the head and neck region that lasted from a few weeks to 2

years. None of these patients were HIV positive or showed signs of autoimmune

disorder. In 19 of these patients, examination of bone marrow did not indicate

the presence of tumor. Only one patient had stage III disease, with cervical,

supraclavicular, and mesenteric nodes involvement.

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Treatment approaches varied among 28 patients. Surgery only, with

completely excised tumors, was reported in 19 patients; 5 received local

radiotherapy; 3 received systemic chemotherapy; and 1 patient received a

combination of radiotherapy and chemotherapy.

Only one disease recurrence was reported, and that was in a patient who

underwent surgery and received no other treatment. At the time of the report

(four years of follow-up), the patient was free of disease.

Sixteen of the 48 patients (33%) had extranodal marginal zone

lymphoma. The median age was 24.5 years, 4 of 16 cases were pediatric, and

there was no gender preponderance. The most common disease sites at

presentation were the ocular adnexa (5 of 16, 31%), the salivary glands (4 of 16,

25%), and skin (3 of 16, 19%). Only one patient had gastric involvement. Three

patients with salivary gland involvement (two females) had a history of

autoimmune disease. Two had Sjögren syndrome, and one had systemic lupus

erythematosus. In addition, the single patient with gastric involvement had a

history of Helicobacter pylori gastritis and gastric ulcers.

More than 70% of evaluable patients had stage I disease. Concomitant

regional lymph node involvement was evident in two cases, but dissemination

to other nodal or extranodal sites was not observed. In all five cases in which

bone marrow was examined, involvement was not present.

Information on treatment and outcome was available for nine patients.

Five were treated with local radiotherapy, two with excision alone, and two with

chemotherapy. Follow-up ranged from 1 to 24 months. Only one patient

experienced a local relapse of disease. He had a large conjunctival mass at

presentation, and had been treated with excision only. The accurate diagnosis

of these conditions requires experienced pathologists and sophisticated

immunologic and molecular diagnostic tools often not available in developing

countries. In this setting, the treating physician should also consider that other

more common types of lymphoma may extend to the stomach, orbit, and

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tonsils. Therefore, every effort should be made to biologically characterize

these lymphomas to ensure adequate treatment.

E.3 Cutaneous lymphoma

The skin may be involved in patients with systemic lymphomas [8]but

occasionally, primary cutaneous occur in children. There is little published

about their outcome in children and most of the knowledge of these entities

comes from the adult experience.9-11 The most frequently seen entities include

primary cutaneous CD30+ anaplastic large T-cell (ALTC) lymphoma and

lymphomatoid papulosis are rarely seen in children. In recent years, they have

been recognized as different expressions of a distinct clinicopatholgical entity

different from other lymphoproliferative disorders such as mycosis fungoides

(E. Figure 1), and subcutaneous panniculitis-like T-cell lymphoma12 (E. Figure 2)

(E.Table 1)39–41. Primary cutaneous lymphomas have been recently re-classified

including these new entities by the EORTC.13 Most patients with CD30+ ALCT

present with isolated or multifocal nodules, papules, or tumors that are

frequently ulcerated. Multifocal lesions are seen in approximately 20% of the

patients. The skin lesions may regress spontaneously, but they do not wax and

wane as do those in lymphomatoid papulosis. Disease extension to other

organs is rare (10%) and typically involves the lymph nodes.

The prognosis of CD30+ ALTC is favorable (E. Figure 3). Conversely,

children with systemic CD30+ large cell lymphoma with secondary skin

involvement have much worse prognosis and require intensive systemic

chemotherapy.

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E. Figure 1Child with typical plaques of mycosis fungoides

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E. Figure 2Skin nodules of panniculitis like T-cell lymphoma. These nodules underwent awax and wane presentation.

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E. Figure 3Primary cutaneous anaplastic large cell lymphoma (ALK -) in a 13-year-old girl.Treatment included surgical resection alone.

Lymphomatoid papulosis is a chronic condition characterized by

recurrent papulonecrotic skin lesions that wax and wane. Its malignant nature

has not been definitively proved. However, progression to cutaneous ALTC has

been documented. Lymphomatoid papulosis has also been associated with

other types of malignancy, including Hodgkin disease. The typical lesions,

which can be localized or generalized, are red-brown papules and nodules in

different stages of evolution. The lesions evolve with central hemorrhage,

necrosis, and crusting, and wax and wane (the hallmark of this condition). The

pathologic distinction between lymphoid papulosis and cutaneous CD30+ ALTC

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is often difficult to see; therefore, the dermatologic features and natural history

have usually been used to make that distinction.

No uniform guidelines have been developed for the management of these

interrelated disorders. The correct diagnosis and classification are crucial to

treatment planning. Being able to distinguish between primary cutaneous

CD30+ ALTC and systemic large cell lymphoma with secondary cutaneous

involvement requires careful disease staging. For primary cutaneous ALTC, the

type of treatment depends on the extent of the disease. A solitary or a few

regional lesions can be treated with local radiotherapy. If a solitary lesion has

been completely excised, no further treatment is recommended, unless it

recurs. Some of these cases of primary cutaneous ALTC and those involving

residual disease can been treated with a short course of chemotherapy such as

that used for low-stage NHL.

Management of multifocal primary cutaneous ALTC is controversial.

Intensive chemotherapy has been used, but it appears to be ineffective. In some

cases, low-dose methotrexate has been successfully used. A treatment regimen

for lymphomatoid papulosis has not been defined. Intensive chemotherapy or

radiotherapy is not indicated because the lesions will reappear after a period of

“remission.” When the lesions regress without scarring, specific treatment is not

necessary. When scarring occurs, low-dose methotrexate can be administered

orally. Other less common primary cutaneous lymphomas in children include

subcutaneous panniculitis-like lymphoma,12 mycosis fungoides,10 CD4-CD56

hematodermic neoplasm, which has recently been characterized as a dendritic

cell neoplasm.14

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E. 4 Mature T- and Natural Killer-cell non-Hodgkin Lymphomas

E.4.1 Extranodal NK/T-cell Lymphoma, Nasal Type

Nasal extranodal NK/T-cell lymphoma, a distinct clinicopathologic entity,

is characterized by chronic midfacial processes.15-17 It most commonly presents

clinically as a destructive nasal or midline facial tumor within one year of

evolution.

The lesion usually develops in the nasal cavity, causing nasal obstruction,

rhinorrhea, epistaxis, and facial edema. Palatal destruction and orbital swelling

may also occur. Less commonly, extranodal NK/T-cell lymphomas involve

cervical nodes, skin, soft tissues, testicles, and the gastrointestinal and

respiratory tracts. Other names by which this entity is known include Stewart

granuloma, lethal midline granuloma, angiocentric lymphoma, idiopathic

midline destructive disease, pseudolymphoma, malignant midline granuloma,

non-healing midline granuloma, polymorphic reticulosis, and lymphomatoid

granulomatoses. It occurs more often in male patients in Asian and Central

American countries and Native Americans. This disease is highly associated

with EBV and distinctly more common in Southeast Asia and some areas in Latin

America.18,19 In the early stages, extranodal NK/T-cell lymphoma is difficult to

characterize histologically. The lesion is composed of an atypical polymorphic

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infiltrate with a broad spectrum ranging from small cells to large transformed

cells with a propensity to invade and destroy blood vessels. In situ hybridization

studies with probes to EBV-encoded small nuclear RNA can detect even small

numbers of neoplastic cells; such studies are invaluable in diagnosis and follow

up.18 Analysis of immunohistochemistry usually reveals T cell–associated

antigens, including CD2, the intracytoplasmic CD3-εchain, and the NK-

associated antigen CD56. Results of molecular studies do not indicate the

presence of the T-cell gene rearrangement in malignant cells.

This malignancy may also appear at extra-nasal sites. This entity shares

biological features with the nasal counterpart.20 Treatment of extranodal NK/T-

cell lymphoma is still evolving. Anthracycline and asparaginase-based therapy

plus local radiotherapy is typically used.15,16,21 Because the disease is rare in

children and adolescents outside endemic areas, prognostic factors have not

been established in this age group. In adults treated with chemotherapy and

radiotherapy, predictors of poor outcome include constitutional “B” symptoms,

high lactated dehydrogenase levels, and regional nodal involvement. Patients

without any of the risk factors (localized disease) had an approximately 50%

probability of survival, whereas patients with disseminated disease had a dismal

outcome.

E.4.2 Aggressive NK-Cell Leukemia

Aggressive NK-cell leukemia is characterized by a fulminant clinical

course. Immunophenotype and molecular genetic findings are similar to those

of nasal-type NK/T-cell lymphoma.22 Patients are typically from Asian countries

who present with fever, hepatosplenomegaly, leukopenia, and coagulopathy.

This may lead to multiple organ failure followed by death within weeks of the

initial signs and symptoms. As was the case with extranodal NK/T-cell

lymphoma, aggressive NK-cell leukemia is highly associated with EBV.18

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A closely related condition also seen in children and adolescents has

been designated EBV+ fulminant T-cell lymphoproliferative disorder (fatal

mononucleosis). It can occur after acute EBV infection, or more commonly after

chronic EBV infection.19,23 However in this case, the malignant cells express true

T-cell immunophenotype, including expression of clonality by rearranged T-cell

receptor studies. In a manner similar to that of aggressive NK-cell leukemia,

fatal mononucleosis is also characterized by severe hemophagocytic syndrome,

from which the patient usually dies.

E.4.3 Hepatosplenic T-cell Lymphoma

Hepatosplenic T-cell lymphoma is a rare, extranodal, and usually fatal,

disorder resulting from the malignant transformation of cytotoxic T-cells,

usually of γδT-cell receptor type. It occurs very rarely in children and most often

affects young adults.24 Typically, patients with hepatosplenic T-cell lymphoma

present with marked hepatosplenomegaly and various degrees of cytopenia.

Adenopathy and circulating blasts are usually absent. Bone marrow involvement

is frequent. The neoplastic cells, typically γδT-cells, are present in the

sinusoids of the bone marrow. In most cases, CD4 and CD8 are not expressed

in neoplastic cells, while CD56 is. Also, TIA-1, a cytoxic T-cell marker, is usually

expressed. T-cell variants with an αβphenotype have been described as well.

Isochromosome 7q and trisomy 8 are consistent cytogenetic abnormalities.25

Although a few cases have been successfully treated with chemotherapy alone,

the overall prognosis of this disease is dismal. Hematopoietic stem cell

transplantation (HSCT) has been effective in a small number of patients.

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E.4.4 Primary Mediastinal (thymic) Large B-cell Lymphoma

Primary mediastinal (thymic) large B-cell lymphoma (PMLBCL) has been

recently recognized as a distinct clinicopathologic entity with a molecular gene-

expression signature reminiscent of nodular sclerosis subtype of classical

Hodgkin disease26 Although it develops more commonly in adults, it can

develop in children, predominantly adolescent girls.26

Tumor cells arise from the medullary thymic B cells and often express

CD79a, CD19, CD20, and CD22, but not surface immunoglobulin. CD30 may

also be expressed by these tumors, but it is not as frequent as in ALCL. Patients

often present with a rapidly growing mediastinal (thymic) mass, usually without

involvement of other areas; the kidney, the adrenal glands and the ovaries may

also be involved.

Limited information is available on this disorder in children. In adults,

regimens with polychemotherapy combined with local radiotherapy were used.

Other adult studies suggest a benefit from therapy intensification and

autologous stem cell rescue. The BFM group reported its experience in

successive trials (30 patients) in which results were relatively poorer than those

of studies of other types of B-cell malignancy. The group reported a probability

of event-free survival of 0.7 for the whole group, and elevated LDH values were

correlated with prognosis.26 Therefore, the most effective treatment of this

condition in children it is not currently known, and the utility of radiotherapy in

children is debatable.

E.4.5 Treatment of Non-Hodgkin Lymphoma in Developing Countries

Pediatric NHL in developing countries is associated with some

peculiarities. In an INCTR study, Naresh et al. evaluated the distribution of

lymphomas in several developing countries and found regional variation of

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subtypes.27 The archetypical example is Burkitt lymphoma, which is endemic to

Equatorial Africa, and which typically involves the jaw or the orbit in younger

children. In Africa, Burkitt lymphoma accounts for 45% of all cases of childhood

malignancy.27 In Africa and other developing areas of the world treatment is still

inadequate. For example, in Malawi, only approximately 50% of children with

localized Burkitt lymphoma survive disease free, in sharp contrast with the

greater than 90% survival estimates of comparable groups of patients in the

more developed countries.28,29

To improve the outcome in Malawi, the International Society of Pediatric

Oncology (SIOP) launched a series of studies in which attempts to use a

modification of the high-dose regimens proposed by the SFOP caused

unacceptable number of deaths due to toxicity and had to be discontinued.30 A

low-intensity regimen is prescribed in this setting because of poor patient

tolerance caused by malnutrition, malaria, parasitosis, and lack of compliance

for longer therapies.28,31

Although many African children with NHL have no access to

chemotherapy, encouraging results have been reported in South Africa.32 In

other emerging nations, non-Hodgkin lymphoma also represents a challenge.

In some Latin American countries, such as Brazil and Argentina, encouraging

results have been reported by those using adapted BFM therapies.29,33 In Turkey

and Venezuela, SFOP protocols have been used with success.34,35 However, death

due to toxicity is higher than that reported in developed nations. Physicians

working in developing countries should also consider that B-cell lymphoma

might behave differently in their areas and that treatment tailored to these

differences should be developed.

In developing countries, only tertiary-care centers can provide the quality

of care needed for patients with B-cell lymphoma when they receive high

intensity therapy. In the developed nations, uncommon subtypes might be

more prevalent than in developing countries. In some Latin American countries,

hydroa vacciniforme such as skin lymphoma has long been recognized and has

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recently been included in the WHO-EORTC classification for skin lymphomas.12

In Asia, NK-cell malignancies are more frequent.19

E. References

1Oschlies I, Salaverria I, Mahn F, et al. Pediatric follicular lymphoma - a clinico-pathological studyof a population-based series of patients treated within the NHL-BFM (Berlin-Frankfurt-Munster)multicenter trials. Haematologica 2009.2Ribeiro RC, Pui CH, Murphy SB, et al. Childhood malignant non-Hodgkin lymphomas ofuncommon histology. Leukemia 1992:6(8):761-765.3Swerdlow SH. Pediatric follicular lymphomas, marginal zone lymphomas, and marginal zonehyperplasia. Am J Clin Pathol 2004:122 Suppl:S98-109.4Atra A, Meller ST, Stevens RS, et al. Conservative management of follicular non-Hodgkin'slymphoma in childhood. Br J Haematol 1998:103(1):220-223.5Shaye OS, Levine AM. Marginal zone lymphoma. J Natl Compr Canc Netw 2006:4(3):311-318.6Claviez A, Meyer U, Dominick C, et al. MALT lymphoma in children: a report from the NHL-BFMStudy Group. Pediatr Blood Cancer 2006:47(2):210-214.7Taddesse-Heath L, Pittaluga S, Sorbara L, et al. Marginal zone B-cell lymphoma in children andyoung adults. Am J Surg Pathol 2003:27(4):522-531.8Muljono A, Graf NS, Arbuckle S. Primary cutaneous lymphoblastic lymphoma in children: seriesof eight cases with review of the literature. Pathology 2009:41(3):223-228.9Chan YF, Lee KC, Llewellyn H. Subcutaneous T-cell lymphoma presenting as panniculitis inchildren: report of two cases. Pediatr Pathol 1994:14(4):595-608.10Peters MS, Thibodeau SN, White JW, Jr., et al. Mycosis fungoides in children and adolescents. JAm Acad Dermatol 1990:22(6 Pt 1):1011-1018.11Hutchison RE, Laver JH, Chang M, et al. Non-anaplastic peripheral t-cell lymphoma in childhoodand adolescence: a Children's Oncology Group study. Pediatr Blood Cancer 2008:51(1):29-33.12Willemze R, Jansen PM, Cerroni L, et al. Subcutaneous panniculitis-like T-cell lymphoma:definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Studyof 83 cases. Blood 2008:111(2):838-845.13Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research and Treatment ofCancer and International Society for Cutaneous Lymphoma consensus recommendations for themanagement of cutaneous B-cell lymphomas. Blood 2008:112(5):1600-1609.14Weaver J, Hsi ED. CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma). J CutanPathol 2008:35(10):975-977.15Yong W, Zheng W, Zhu J, et al. Midline NK/T-cell lymphoma nasal-type: treatment outcome, theeffect of L-asparaginase based regimen, and prognostic factors. Hematol Oncol 2006:24(1):28-32.16Wang ZY, Li YX, Wang WH, et al. Primary radiotherapy showed favorable outcome in treatingextranodal nasal-type NK/T-cell lymphoma in children and adolescents. Blood. 2009.

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