Case Report, NHL

7/28/2019 Case Report, NHL

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CHAPTER I

Introduction

NHL accounts for approximately 60% of all lymphomas in children and adolescents.

It represents 810% of all malignancies in children between 519 yr of age. Although

>70% of patients present with advanced disease at diagnosis, the prognosis has

improved dramatically, with survival rates of 9095% for localized disease and 60

90% with advanced disease.

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CHAPTER II

2.1 EPIDEMIOLOGY

While most children and adolescents with NHL present with de novo disease,

a small number of patients develop NHL secondary to specific etiologies, including

inherited or acquired immune deficiencies (e.g., severe combined immunodeficiency

syndrome, Wiskott-Aldrich syndrome), viral etiologies (e.g., HIV, EBV) or as part of

genetic syndromes (e.g., ataxia-telangiectasia, Bloom syndrome). Most children who

develop NHL, however, have no obvious genetic or environmental etiology.

2.2 PATHOGENESIS

The four major pathological subtypes of childhood and adolescent NHL are

Burkitt lymphoma (BL), constituting 40% of NHL; lymphoblastic lymphoma (LL),

accounting for 30%; diffuse large B-cell lymphoma (DLBCL), constituting 20%; and

anaplastic large cell lymphoma (ALCL), accounting for 10% ( Fig. 496-3 ). Most

childhood and adolescent NHLs are high-grade tumors with an aggressive clinical

behavior compared to those of adult NHL, which usually are low- to intermediate-

grade indolent tumors. Almost all childhood and adolescent NHL is derived from

germinal center aberrations. Almost all forms of BL and DLBCL are of B cell origin;

cases of LL are 80% T cell and 20% B cell; and cases of ALCL are 70% T cell, 20%

null cell, and 10% B cell in origin. Some pathological subtypes have specific

cytogenetic aberrations. Children with BL commonly have a t(8;14) translocation

(90%) or, less commonly, a t(2;8) or t(8;22) translocation (10%). Patients with ALCL

commonly have a t(2;5) translocation (5%). Patients with DLBCL and LL have a

variety of different cytogenetic abnormalities.

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Histopathology of DLCL. Image by KGH.

Malignant B-cell lymphocytes seen in Burkitt's lymphoma

image by Louis Staudt,NCI

Follicular lymphoma grade I.

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http://commons.wikimedia.org/wiki/User:KGHhttp://visualsonline.cancer.gov/details.cfm?imageid=4156http://commons.wikimedia.org/wiki/User:KGHhttp://visualsonline.cancer.gov/details.cfm?imageid=4156


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2.3 CLINICAL MANIFESTATIONS

The clinical manifestations of childhood and adolescent NHL depend

primarily on pathological subtype and primary and secondary sites of involvement.NHLs are rapidly growing tumors and can cause symptoms based on size and

location. Approximately 70% present with advanced disease of stages III or IV

( Table 496-4 ), including extranodal disease that manifests as gastrointestinal, bone

marrow, and central nervous system (CNS) involvement. BL commonly presents

with abdominal (sporadic type) or head and neck (endemic type) disease with

involvement of the bone marrow or CNS. LL commonly presents with an

intrathoracic or mediastinal supradiaphragmatic mass, and also has a predilection for

spreading to the bone marrow and CNS. DLBCL commonly presents with either an

abdominal or mediastinal primary and, rarely, dissemination to the bone marrow or

CNS. ALCL presents either with a primary cutaneous manifestation (10%) or with

systemic disease (fever, weight loss) with dissemination to liver, spleen, lung,

mediastinum, or skin; spread to the bone marrow or CNS is rare.

TABLE 1. St. Jude Staging System for Childhood Non-Hodgkin Lymphoma

STAGE DESCRIPTION

I A single tumor (extranodal) or single anatomic area (nodal), with the

exclusion of mediastinum or abdomen

II A single tumor (extranodal) with regional node involvement

Two or more nodal areas on the same side of the diaphragm

Two single (extranodal) tumors with or without regional node involvement

on the same side of the diaphragm

A primary gastrointestinal tract tumor, usually in the ileocecal area, with or

without involvement of associated mesenteric nodes only, which must be

grossly (>90%) resected

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STAGE DESCRIPTION

III Two single tumors (extranodal) on opposite sides of the diaphragm

Two or more nodal areas above and below the diaphragm

Any primary intrathoracic tumor (mediastinal, pleural, or thymic)

Any extensive primary intra-abdominal disease

IV Any of the above, with initial involvement of central nervous system or bone

marrow at time of diagnosis

From Murphy SB: Classification, staging and end results of treatment of childhood

non-Hodgkin's lymphomas: Dissimilarities from lymphomas in adults. Semin Oncol

1980;7:332339.

Site-specific manifestations include painless, rapid lymph node enlargement;

cough, superior vena cava (SVC) syndrome, dyspnea with thoracic involvement;

abdominal (massive and rapidly enlarging) mass, intestinal obstruction,

intussusception-like symptoms, ascites with abdominal involvement; nasal stuffiness,

earache, hearing loss, tonsil enlargement with Waldeyer ring involvement; and

localized bone pain (primary or metastatic).

Three clinical manifestations that require special alternative treatment

strategies include SVC syndrome secondary to a large mediastinal mass obstructing

various blood flow or respiratory airways; acute paraplegias secondary to spinal cord

or central nervous system compression from neighboring localized NHL; and tumor

lysis syndrome (TLS) secondary to severe metabolic abnormalities, including

hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia from massive

tumor cell lysis.

2.4 LABORATORY FINDINGS

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Recommended laboratory and radiologic testing includes: complete blood

count (CBC); electrolytes, uric acid, calcium, phosphorus, bilirubin urea nitrogen,

creatinine, alanine aminotransferase, and aspartate aminotransferase; bilateral bone

marrow aspiration and biopsies; lumbar puncture with CSF cytology, cell count and

protein; chest x-ray; and neck, chest, abdominal, and pelvic CT scans, PET scan and

bone scan (optional), and head CT scan (optional). The tumor tissue (i.e., biopsy,

bone marrow, CSF, or pleural/paracentesis fluid) should be tested by flow cytometry

for immunophenotypic origin (T, B, or null) and cytogenetics (karyotype). Additional

tests might include fluorescent in situ hybridization (FISH) or quantitative RT-PCR

for specific genetic translocations, T and B cell gene rearrangement studies, and

molecular profiling by oligonucleotide microarray. Excision biopsy andhistopathological examination remain the gold standard for primary diagnosis and

classification of non-Hodgkin's lymphoma

TABLE 2-- Pretreatment Studies for Staging Pediatric Non-Hodgkin

Lymphoma

Complete blood cell count

Serum electrolytes, uric acid, lactate dehydrogenase, creatinine, calcium,

phosphorus

Liver function tests (ALT, AST)

Chest radiograph

Neck, chest, abdominal, pelvic CT

Positive emission tomography scan

Bilateral bone marrow aspirate and biopsy

Cerebrospinal fluid cytology, cell count, protein

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

2.5 DIFFERENTIAL DIAGNOSIS

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Head and neck lymphadenopathy should be differentiated from infectious

nodal etiologies; mediastinal masses from HD and germ cell tumors; abdominal

involvement from other abdominal malignant masses such as Wilms tumor,

neuroblastoma, and rhabdomyosarcoma; and bone marrow involvement from

precursor B (Pre-B) acute lymphoblastic leukemia and T-cell acute lymphoblastic

leukemia. CT and PET scans, along with flow cytometry, cytogenetic and molecular

genetics on biopsy and tumor tissue, usually differentiate NHL from other entities.

2.6 TREATMENT

The primary modality of treatment for childhood and adolescent NHL is

multiagent systemic chemotherapy and intrathecal chemotherapy. Surgery is used

mainly for diagnostic and/or biologic specimens and staging but rarely is used for

debulking large masses. Radiation therapy is rarely, if ever, used, except in special

circumstances such as CNS involvement in LL or occasionally BL, acute SVC, and

acute paraplegias. Patients at diagnosis and at risk of TLS, especially advanced/bulky

BL or LL, require vigorous hydration and either a xanthine oxidase inhibitor

(allopurinol, 10 mg/kg/day PO divided tid) or, more often, recombinant urate oxidase

(rasburicase, 0.2 mg/kg/day PO once daily for 13 days).

Specific treatment for localized and advanced disease is similar for BL and

DLBCL. Localized BL and DLBCL require 6 wk to 6 mo of multiagent

chemotherapy. Common regimens include COPAD (cyclophosphamide, vincristine,

prednisone and doxorubicin), as demonstrated by the recent international B-NHL

study (FAB/LMB 96 [French-American-British Lymphoma, mature B cell]) or

COMP (cyclophosphamide, vincristine, methotrexate, 6-mercaptopurine and

prednisone). Advanced disease usually is treated by 46 mo of multiagent

chemotherapy such as FAB/LMB 96 protocol therapy or BFM (Berlin Frankfurt

Munich) NHL90 protocol therapy.

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Localized and advanced LL usually require almost 24 mo of therapy. The best

results in advanced LL have been obtained using the BFM NHL 90 protocol, which

uses therapeutic approaches similar to those for childhood acute leukemia, which

includes an induction cycle of chemotherapy, consolidation phase, interim

maintenance phase, reinduction phase (advanced disease only), and a year of

maintenance therapy with 6- mercaptopurine and methotrexate.

Localized ALCL may require only cutaneous excision or more aggressive

therapy similar to that for advanced ALCL. Advanced ALCL commonly is treated

with a BFM NHL 90 protocol or with a COG protocol of APO (doxorubicin,

prednisone and vincristine) with additional VP-16, Ara-C, or vinblastine.

Intrathecal chemotherapy is administered to moderate to advanced disease in

all subtypes of childhood and adolescent NHL and may include intrathecal

methotrexate, hydrocortisone, or Ara-C.

Patients with NHL who develop progressive or relapsed disease require

reinduction chemotherapy and either allogeneic or autologous stem cell

transplantation. The specific reinduction regimen or transplant depends on the

pathologic subtype, previous therapy, site or reoccurrence, and stem cell donor

availability.

2.7 SUPPORTIVE CARE

Some patients require G-CSF prophylaxis to prevent fever and neutropenia

following myelosuppressive chemotherapy and prophylactic antibiotics to prevent

infections. Indwelling central venous catheters routinely are placed to facilitate

frequent blood draws, chemotherapy and transfusion administration, and parenteral

nutrition to prevent weight loss and nutritional debilitation.

2.8 COMPLICATIONS

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Patients receiving multiagent chemotherapy for advanced disease are at acute

risk for serious mucositis, infections, cytopenias requiring red cell and platelet blood

product transfusions, electrolyte imbalance, and poor nutrition. Long-term

complications may include growth retardation, cardiac toxicity, gonadal toxicity with

infertility, and secondary malignancies.

2.9 PROGNOSIS

The prognosis is excellent for most forms of childhood and adolescent NHL.

Patients with localized disease have a 90100% chance of survival, and patients with

advanced disease have a 6095% chance of survival. The variation in survival

depends on pathological subtype, tumor burden at diagnosis as reflected in serum

LDH level, presence or absence of CNS disease, and specific sites of metastatic

spread. Specific cytogenetic and molecular genetic subtyping also may be important

in predicting outcome and influencing specific therapeutic strategies.

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Case Report, NHL