AUTHOR INFORMATION

Section 1 of 11

Authored by Stuart S Winter, MD, Associate Professor, Department of Pediatrics, University of New Mexico Health Sciences Center

Stuart S Winter, MD, is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, New Mexico Pediatric Society, Pediatric Oncology Group, and Society for Pediatric Research

Edited by Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Stuart S Winter, MD
Editor's Email:	Kathleen Sakamoto, MD

eMedicine Journal, December 20 2006, VOLUME 7, Number 12

INTRODUCTION

Section 2 of 11

Background: Lymphoproliferative disorders (LPDs) in children represent a heterogeneous group of expanding, monoclonal or oligoclonal, and lymphoid neoplasms that only occur in the setting of immune dysfunction. The risk of true malignancy in affected children is 10- to 300-fold higher than the risk in immunocompetent children. Treatment must be tailored to the child's underlying immune disorder, to the aggressiveness of the clone, and to the likelihood of causing clinically significant toxicity. In this article, underlying immunodeficiency disorders are reviewed in the context of the type of LPD encountered.

Pathophysiology: Over the past 3 decades, scientific understanding of the human immune system has extraordinarily grown. Not all lymphocytes are the same, and they are broadly categorized as thymus-derived lymphocytes (T cells) or bone marrow–derived lymphocytes (B cells). Today, lymphocytes are easily measured and quantified from either peripheral blood or bone marrow by using panels of monoclonal antibodies that specifically recognize B- or T-cell antigens.

The 2 main functions of normal T cells are effector and regulatory. Effector functions include regulation of cell-mediated cytotoxicity, delayed hypersensitivity, and recognition of foreign antigens. Regulatory function includes cell-mediated and humoral immunity. Activated T cells produce a number of soluble factors termed chemokines and cytokines. These molecules locally and distantly modulate immune function in a wide variety of cell types. B cells are largely responsible for the synthesis and secretion of antibodies into blood, lymph, milk, and other interstitial tissues. T cells and B cells both undergo proliferation and then maturation, when rearrangements of T-cell receptors and immunoglobulin genes occur. These rearrangements allow for the complex interplay between the many cell subsets that make up the lymphocyte superfamily.

Although normal B cells synthesize immunoglobulins, B cells can undergo an abnormal expansion into a monoclonal B-cell lymphocytosis, which is morphologically indistinguishable from chronic lymphocytic leukemia (CLL). Longitudinal studies are required to determine whether monoclonal B cells are a heralding feature of CLL or other types of B-lymphoproliferative disease.

When any of the numerous control points of the immune system become dysfunctional, immunodeficiency or deregulation is likely to develop. LPDs in children occur in the setting of immunodysfunction.

Frequency:

• In the US: LPDs only occur in children with immunodysfunction. The occurrence is difficult to track in children with inherited immunodeficiency states, but best estimates indicate that it represents <1 case per million children.

Mortality/Morbidity: Mortality and morbidity in children vary considerably and depend on the underlying immunodeficiency syndrome. As supportive care improves for patients after transplantation, the incidence of LPDs after transplantation is rising.

Race: Severe combined immune deficiency (SCID) syndrome appears to be slightly more prevalent in persons of Navajo descent than in others. However, no other evidence for racial predilection is reported.

Sex: The overall male-to-female ratio is 1:1, except for X-linked immunodeficiency syndromes, which primarily affect male individuals. Of interest, X-linked immunodeficiency syndrome occasionally affects female individuals. In scenarios such as this, hypermorphic mutations in the gene encoding NFkappaB essential modifier (NEMO), which can be inherited in autosomal dominant fashion, lead to immunodeficiency syndromes in members of both sexes.

Age: LPDs can occur in any age group, but they are relatively uncommon in infants and toddlers. They are progressively more common with age.

CLINICAL

Section 3 of 11

Physical:

• Physical findings most commonly include adenopathy, splenomegaly, or symptoms attributable to organ infiltration by an expanding lymphoid clone.



• Because the GI tract or lungs may be affected preferentially in certain subtypes, abdominal bloating or pulmonary findings may dominate the physical examination.

Causes:

• Childhood immunodeficiency syndromes


• • Although the clinical features are somewhat similar among patients, the predisposing abnormalities of lymphocyte-mediated immune function stems from a heterogeneous group of childhood immunodeficiency syndromes.
  
  
  
  • These inherited, acquired, or iatrogenically induced immunodeficiency syndromes predispose the person to the formation of a pool of lymphocytes that proliferate unchecked, that infiltrate a variety of lymphoid organs, and that have the distinct ability to undergo malignant transformation into true lymphoid malignancies.
  
  
  
  • Indeed, the risk of mortality from cancer is 10- to 300-fold higher in affected patients than in immunocompetent children.
  
  
  
  • Approximately 60% of the tumors identified in patients in the Immunodeficiency Disease Registry are lymphoid neoplasms, most of which manifest by the age of 11 years.
  
  
  
• Inherited molecular causes of LPDs


• • X-linked LPDs
    • In boys with X-linked LPD, an overwhelming T-cell–mediated response to the Epstein-Barr virus (EBV) often leads to death from marrow failure, irreversible hepatitis, and malignant lymphoma.

    • The 3 phenotypes associated with the diagnosis of X-linked LPD are severe and mostly fatal infectious mononucleosis (58%), LPDs of B-cell origin (30%), and/or dysgammaglobulinemia (31%).

    • Mutations in the SH2-domain on band Xq25, which contains gene 1A (SH2D1A), result in X-linked LPD. This gene, also known as DSHP, or SAP, encodes a protein primarily expressed in T and NK cells. The protein functions as an intracellular adapter that transduces T- and NK-cell activation. SAP protein is expressed in T cells, natural killer (NK) cells, and NK T cells, on which it binds to the cytoplasmic domain of the surface receptor SLAM (CD150) and the related receptors, 2B4 (CD244), CD84, Ly9 (CD229), NK-T-B-antigen, and CD2-like receptor-activating cytotoxic T cells. SH2D1A elicits cellular activation by means of SLAM, a T-cell costimulatory molecule, or by means of 2B4, an NK-cell activator receptor.

    • Experimental data suggest that these molecules regulate important aspects of lymphocyte function, such as proliferation, cytokine secretion, cytotoxicity, and antibody production. These signaling abnormalities likely contribute to the phenotypes of X-linked LPD, which include fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia.

    • Approximately 55% of EBV-negative patients eventually develop dysgammaglobulinemia or LPDs later in life. This finding suggests that the initial EBV infection is merely a powerful trigger for the immunologic abnormalities observed in X-linked LPD. The characterization of genetic abnormalities in SH2D1A enables the identification of affected male and female carriers.
  
  
  
  • Autosomal LPDs
    • Some children with autoimmune lymphoproliferative syndrome have heterozygous mutations in the Fas receptor (CD95), a key component of a major apoptotic pathway. As a consequence of these mutations, a primitive population of T cells proliferates in an uncontrolled manner, leading to the clinical sequelae of lymphoid infiltration, autoantibodies, and autoimmune disease.

    • Both of these models demonstrate the importance of the regulatory balance that must exist between T cells and B cells and other components of the immune system and which, when dysregulated, can lead to uncontrolled proliferation in cell populations that are immunologically active.
  
  
  
• Other inherited causes


• • Most LPDs in children with X-linked agammaglobulinemia are non-Hodgkin lymphoreticular B cell neoplasms. This immunodeficiency syndrome is caused by a defect in the BTK gene, a member of the SRC gene family localized to Xq21.3-Xq22. This genetic abnormality impairs B-cell maturation. Boys with X-linked immunodeficiency syndrome are at high risk for mortality associated with EBV infections, and they are predisposed to develop LPDs and lymphoma.
  
  
  
  • Among children with common variable immune deficiency (CVID), the incidence of lymphoreticular malignancies also increases and frequently results in intestinal lymphomas. Approximately 30% of children with CVID have splenomegaly, diffuse adenopathy, and even extranodal infiltration into intestinal tissue that mimics lymphoma. EBV-containing B-cell LPDs commonly occur in children with SCID. Of interest, immunoreconstitution with bone marrow transplantation in children with SCID can prevent LPDs and other sequelae of extreme immunodysfunction.
  
  
  
  • Chédiak-Higashi syndrome is transmitted as an autosomal recessive disorder characterized by giant lysosomes in neutrophils and other leukocytes. Patients also have incomplete oculocutaneous albinism, photophobia, and severe recurrent infections. Approximately 85% eventually enter an accelerated lymphomatous phase in which lymphoid and histiocytic cells infiltrate visceral tissue and in which they are likely to develop opportunistic infections. In addition, lymphadenopathy, hepatosplenomegaly, and pancytopenia frequently occur, possibly as the result of chronic EBV infection. The LYST gene is mutated in patients with Chédiak-Higashi syndrome. This gene is located at a 1q locus, but screening for mutations in this gene is difficult because of its large size.
  
  
  
  • Wiskott-Aldrich syndrome is an X-linked recessive disorder characterized by a triad of recurrent pyogenic infections, thrombocytopenia, and severe atopic dermatitis. The dermatitis can be associated with painful vasculitis and predispose to severe skin infections. As the child ages, T-cell function declines, with LPDs occurring in approximately 15% of patients. Extranodal and brain involvement with LPDs are commonplace. Again, chronic EBV infections are thought to play an important role in the development of this disorder.
  
  
  
  • Ataxia telangiectasia is inherited as an autosomal recessive disorder due to genetic mutations of the ATM gene on band 11q22-23. ATM is a member of the large phosphatidylinositol-3 kinase family and plays an important role in mediating the cellular response to DNA damage. As a result of ATM mutations, patients with ataxia telangiectasia present with cerebellar degeneration, immunodeficiency, sensitivity to radiation, and a predisposition to develop LPDs bearing a T-cell phenotype. Mutations also result in abnormalities in cell-cycle control because of S-phase progression. This syndrome is due to increased chromosomal breakage, which commonly affects rearrangement of lymphoid antigen-receptor genes.
  
  
  
  • Of interest, unlike other disorders related to mutations of DNA damage repair genes, even heterozygotes for ataxia telangiectasia have an increased risk of developing cancer, while the risk of homozygotes to develop leukemia or lymphoma may be as high as 40% over a lifetime.
  
  
  
• Acquired causes


• • Congenital HIV infection is the most common cause for acquired immunodeficiency in children.

  • Affected children can present with diffuse adenopathy as a prodrome of AIDS, but cases of lymphadenopathic forms of Kaposi sarcoma have been reported.
  
  
  
• Iatrogenic causes


• • LPDs associated with organ transplantation and concomitant immunosuppressive therapy are increasingly common. Posttransplantation LPDs are varied and somewhat depend on the nature of the allograft and on the immunosuppressive agents used to prevent graft (or host) rejection. In most cases, the LPD is of B-cell origin; however, in rare cases, T-cell LPDs are described.
  
  
  
  • Most posttransplantation LPDs occur in the setting of a solid organ transplantation, especially cardiac transplantation. In these cases, posttransplantation LPD is likely the consequence of prolonged therapy with sirolimus, tacrolimus, cyclosporine A, or other profound inhibitors of T-cell function.

  • LPDs have been described as posttransplant complications when alemtuzumab (antiCD52 monoclonal antibody) is included in the preparative regimen.
  
  
  

DIFFERENTIALS

Section 4 of 11

Non-Hodgkin Lymphoma

Other Problems to be Considered:

Castleman disease
Lymphomatoid papulosis
Anaplastic large cell lymphoma

WORKUP

Section 5 of 11

Lab Studies:

• General tests


• • Clinical findings indicate local or distant adenopathy and hepatosplenomegaly.
  
  
  
  • In certain conditions, the GI tract or lung tissue may also be affected.
  
  
  
• Biochemical panel


• • Perform serologic tests for cytomegalovirus and EBV.
  
  
  
  • Measure the erythrocyte sedimentation rate.
  
  
  
  • Evaluate electrolyte, BUN, creatinine, phosphate, calcium, and uric acid levels to rule out tumor-lysis syndrome.
  
  
  
  • Assess lactate dehydrogenase levels to assess the neoplastic burden.
  
  
  

Imaging Studies:

• Radiography


• • CT scans obtained with intravenous or oral contrast material can help in determining the true extent of abdominal adenopathy, infiltration of the bowel wall, and the accurate sizes of tumorous masses. This information is important for staging and assessing therapeutic response.
  
  
  
  • MRI studies of soft-tissue infiltrative processes can refine the clinician's understanding of the tumor burden and the potential that vital structures might be compromised.
  
  
  
  • Chest radiography is performed in patients with pulmonary lesions to follow the progression or regression of disease. In some patients, pulmonary functional tests can provide further objective evidence of disease progression or a therapeutic response.
  
  
  
• Bone scanning



• Ultrasonography: Sonography is sometimes helpful.



• Small bowel follow-through study: In children with GI lesions, this test helps in diagnosing ileal disease.

Other Tests:

• As with all neoplastic processes, "the tissue is the issue." In rapidly growing tumors, areas of necrotic tissue may complicate morphologic use of fine-needle aspirates.



• EBV detection by means of Southern blot hybridization or polymerase chain reaction (PCR) can be helpful. The in situ hybridization of the EBV-encoded RNA (EBER) test has become a useful adjunct in the diagnosis of EBV-related LPDs.

Procedures:

• Examination of the bone marrow may help in differentiating metastatic disease from other diseases.



• Diagnostic spinal tap is used in children with primary tumors involving the head or neck region to exclude spread to the neuraxis.



• Surgical resection does not play an important role in the control of LPDs. Most lymphoproliferative tumors are not easily resectable and, given the underlying nature of the affected cell type, rapid lymphatic spread to distant sites is common.

TREATMENT

Section 6 of 11

Medical Care:

• Children with inherited immunodeficiency syndromes


• • Truly malignant neoplasms are sometimes difficult to differentiate from nonmalignant LPDs with aggressive features. When the underlying immunodeficiency manifested to only a minor degree and when the histologic features are marked nuclear atypia and other features of a high-grade neoplasm, standard chemotherapeutic regimens are usually recommended. These regimens include cyclophosphamide, prednisone, vincristine, and doxorubicin.
  
  
  
  • In other cases, local control of the LPD by using surgical resection or irradiation with adjunctive interleukin-2 or monoclonal antibody therapy may prove beneficial.
  
  
  
  • Boys with X-linked immunodeficiency syndrome appear to benefit from immunoglobulin therapy.

  • A word of caution: If cytotoxic therapy is chosen in child with an underlying immunodeficiency syndrome, myelosuppressive therapy may worsen their immunocompromise beyond what is ordinarily expected. Therefore, care should be taken to begin support for febrile neutropenia and other infections in a timely fashion. As described above, bone marrow reconstitution with an immunocompetent donor appears to be the best method to prevent LPDs in children with severe inherited immunodeficiency syndromes.
  
  
  
• Patients with LPDs after transplantation


• • LPDs after transplantation are varied and somewhat depend on the nature of the allograft and on the immunosuppressive agents used to prevent graft (or host) rejection. The histologic grades of LPDs can vary widely in this setting and range from a benign oligoclonal expansion of lymphoid cells to a high-grade neoplastic process. Low-grade tumors usually respond favorably to a reduction in immunosuppression, whereas high-grade tumors may require chemotherapy, irradiation, and/or surgery.

  • Cyclosporin A and antithymocyte globulin are associated with the development of LPDs within months of transplantation, often in the GI tract. In many instances, EBV DNA transcripts can be identified with Southern blotting, anti-EBER staining, or PCR, but results of serologic tests are frequently nonreactive. The lymphocytic infiltration into transplanted organs can often mimic organ rejection.

  • In contrast to the LPDs observed in primary immunodeficiency syndromes, the most successful means of control after transplantation are diminishing or discontinuing immunosuppressive drug therapy.
  
  
  

Surgical Care:

• Surgical resection plays a role in managing LPDs. Circumstances are limited to obtaining enough tissue to make a diagnosis and to debulking large tumors that compromise surrounding vital structures. However, in most cases, the primary means to control LPDs is medical management.

Consultations:

• In children with a suspected LPD, consultation with a physician familiar with the underlying immunodeficiency syndrome is indicated, in addition to consultation with a pediatric oncologist.



• Consider an infectious process with appropriate consultation with a pediatric infectious disease specialist.

Diet:

• In children, diet does not appear to play a role in the pathogenesis or treatment of LPDs.

Activity:

• Activity does not appear to play a role in the treatment or pathogenesis of LPDs.

MEDICATION

Section 7 of 11

Drug Category: Antineoplastic agents -- Prescribe chemotherapeutic agents only to children with the help of clinicians who are experienced with the doses and toxicities of these drugs. The drugs detailed below are those used in standard cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine (Oncovin), and prednisone (CHOP) therapy.

Drug Name	Doxorubicin (Adriamycin) -- Alkylating agent with several mechanisms of action (eg, DNA intercalation, topoisomerase-mediated DNA strand breaks, oxidative damage by producing free radicals).
Adult Dose	40 mg/m2 IV days 1 and 22
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function (cumulative anthracycline dose >450 mg/m2 is relative contraindication); preexisting myelosuppression
Interactions	Increased risk of cardiotoxicity when combined with chest irradiation; may decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in impaired hepatic function; may cause nausea, diarrhea, or alopecia

Drug Name	Cyclophosphamide (Cytoxan) -- Exerts cytotoxic effect by alkylation of DNA, leading to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks and inhibition of DNA replication.
Adult Dose	750 mg/m2 IV on days 1 and 22 Administer with mesna, 400 mg/m2 IV with first dose; repeat after 3 h and after each dose of cyclophosphamide
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; nephropathy, hemorrhagic cystitis, and myelosuppression
Interactions	Coadministration of phenobarbital may enhance metabolic activation of cyclophosphamide (prodrug); inhibits cholinesterase, potentiating effect of succinylcholine; allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase toxicity; may increase effect of anticoagulants; thiazide diuretics may prolong cyclophosphamide-induced leukopenia
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in bone marrow suppression and impaired renal or hepatic function; may need to modify dosage; may cause myelosuppression (ie, leukopenia, hemolytic anemia, thrombocytopenia), alopecia, hemorrhagic cystitis (monitor for hematuria), cardiotoxicity (at high doses), impaired fertility, headache, darkening of skin and fingernails; moderate-to-high emetogenic potential (based on the dose) causes anorexia, diarrhea, stomatitis, and mucositis

Drug Name	Vincristine (Oncovin) -- Plant-derived vinca alkaloid. Inhibits mitosis by binding tubulin. Inhibits microtubule formation in mitotic spindle, arresting metaphase.
Adult Dose	1.5 mg/m2 IV; not to exceed 2 mg/dose and not > 1 time/wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; patients with demyelinating form of Charcot-Marie-Tooth syndrome; universally fatal if delivered intrathecally
Interactions	Acute pulmonary reaction may occur when taken concurrently with mitomycin-C; asparaginase, cytochrome P450 (CYP) 3A4 inhibitors (eg, itraconazole, quinupristin-dalfopristin, sertraline, ritonavir), granulocyte-macrophage colony-stimulating factor (GM-CSF, eg, sargramostim, filgrastim), or nifedipine increase toxicity; CYP3A inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects
Pregnancy	D - Unsafe in pregnancy
Precautions	Dosage modification required in patients with impaired hepatic function, patients receiving other neurotoxic drugs, or patients with preexisting neuromuscular disease; avoid extravasation (can cause tissue damage); severe constipation and/or peripheral neuropathy are relative contraindications

Drug Name	Prednisone (Deltasone, Meticorten, Orasone, Sterapred) -- Combines ubiquitous uses and likely to downregulate inflammatory proteins by directly signaling with intrachromosomal binding sites.
Adult Dose	40 mg/m2/d PO qd for 30 d; not to exceed 60 mg/d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; serious infections (excluding meningitis and septic shock) and fungal or varicella infections
Interactions	Barbiturates, phenytoin, rifampin may decrease effectiveness; coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Administer with meals to decrease GI upset; abrupt discontinuation of glucocorticoids may cause adrenal crisis Early-onset adverse effects include glucose intolerance, hypertension, agitation and indigestion Late-onset adverse effects include immune suppression and increased susceptibility to sepsis, adrenal suppression, hypertension, urinary calcium loss and osteopenia, gastric irritation, and bleeding

Drug Category: Antiemetic agents -- Antineoplastic-induced vomiting is stimulated through the chemoreceptor trigger zone, which then stimulates the vomiting center in the brain. Increased activity of central neurotransmitters, dopamine in the chemoreceptor trigger zone or acetylcholine in the vomiting center appears to be major mediators for inducing vomiting. After the administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With release of 5-HT and its subsequent binding to 5-HT3-receptors, vagal neurons are stimulated and transmit signals to the vomiting center, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and after cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Drug Name	Ondansetron (Zofran) -- Selective 5-HT3–receptor antagonist that blocks 5-HT peripherally and centrally. Ameliorates chemotherapy-induced nausea and vomiting.
Adult Dose	0.3 mg/kg/d IV; not to exceed 24 mg/d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Although CYP inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) change half-life and clearance, dosage adjustment usually not required
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Headache (common adverse drug reaction)

Drug Category: Uroprotective antidote -- Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide.

In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, which is the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

Drug Name	Mesna (Mesnex) -- Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.
Adult Dose	Dose depends on ifosfamide or cyclophosphamide, typically 60-100% of antineoplastic agent used; may be administered as initial bolus, followed by continuous or intermittent IV infusions before and after chemotherapy regimen
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	May increase warfarin affect, adjust dose according to international normalized ratio (INR) target
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor morning urine for hematuria before ifosfamide or cyclophosphamide dose; common adverse effects include hypotension, headache, GI toxicity, and limb pain

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Follow-up care of a child can range from simple (eg, watchful observation) to very complex (bone marrow transplantation). Coordinate with a team of subspecialists familiar with immunodeficiency disorders and the management of potentially toxic drug therapy.

In/Out Patient Meds:

• Inpatient and outpatient drugs depend on the nature of the underlying immunodeficiency syndrome.

Deterrence/Prevention:

• The best preventive measure is to correct the underlying immunodeficiency syndrome.



• Children who have had a bone marrow transplant with an immunocompetent graft are unlikely to develop problems with a LPD.

Prognosis:

• LPD prognoses are determined by the prevalence of immunodeficiency in the patient. Ordinarily, a favorable response in a relatively immunocompetent patient augurs well for long-term survival. LPDs of low-grade histological features tend to remit with a reduction of immunosuppression, whereas higher-grade LPDs require a more aggressive therapeutic approach and often require several cycles of CHOP therapy with close follow-up.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Treatment of LPDs in immunocompromised hosts is best left to healthcare personnel who are accustomed to treating the diseases, drug toxicities associated with chemotherapeutic agents or immune suppressants, and who are able to ensure adequate follow-up care. For instance, the long-term follow-up of affected patients is coordinated by a Transplant Program where the needs of a patient with a LPD can be balanced against graft/organ rejection.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A 15-year-old female adolescent with ataxia telangiectasia has worsening symptoms of respiratory distress. A CT scan of the chest reveals parenchymal nodularities. What is the next best step in the evaluating this patient?

A: Start a trial course of antibiotics
B: Start a trial course of antifungal therapy
C: Perform skin testing including a purified protein derivative of tuberculin (PPD) test
D: Schedule pulmonary bronchoscopy and, possibly, lung biopsy
E: All of the above

The correct answer is D: Immunocompromised patients are at risk for developing infiltrative diseases and opportunistic infections, each of which require a tissue diagnosis likely to be confirmed with pulmonary bronchoscopy.

CME Question 2: A 6-year-old child is receiving cyclosporine for a renal graft. The child develops an infiltrating gastric lymphoproliferative disorder. What is most likely complication if the dosage of cyclosporine is reduced?

A: Renal graft rejection
B: Progression of the lymphoproliferative process
C: Elevation of the serum creatinine
D: Hypertensive encephalopathy
E: All of the above

The correct answer is A: Rejection of the transplanted organ is most likely to occur when dosages of antirejection agents are reduced.

Pearl Question 1 (T/F): In an immunocompromised host, the most likely clinical manifestation of a lymphoproliferative disorder is adenopathy or organomegaly.

The correct answer is True: Progressive organomegaly or adenopathy is the most common feature of an expanding clone of lymphoid cells.

Pearl Question 2 (T/F): An analysis of surface markers and cytogenetic abnormalities is not helpful in distinguishing a lymphoproliferative disorder from a frankly neoplastic process.

The correct answer is False: True lymphoid malignancies often show clonal karyotypic abnormalities and a clonal phenotypic pattern on flow cytometric analyses.

Pearl Question 3 (T/F): The most effective means of preventing a lymphoproliferative disorder is to increase immunosuppression in the patient to inhibit growth of the lymphoproliferative clone.

The correct answer is False: The best means of controlling lymphoproliferative disorder is to treat the underlying cause of the immunodeficiency by reducing drug therapy or by performing transplantation with immunocompetent bone marrow.

Pearl Question 4 (T/F): Surgical resection ordinarily plays an important role in reducing bulky tumor associated with lymphoproliferative disorder.

The correct answer is False: Lymphoproliferative disorders are primarily managed with antibody or drug therapy.

BIBLIOGRAPHY

Section 11 of 11

• Baehner RL: Lymphocytes. In: Miller DR, Baehner RL, eds. Blood Diseases in Infancy and Childhood. St Louis: CV Mosby; 1990: 578-603.
• Bird AG, Britton S: The relationship between Epstein-Barr virus and lymphoma. Semin Hematol 1982 Oct; 19(4): 285-300[Medline].
• Brusamolino E, Pagnucco G, Bernasconi C: Secondary lymphomas: a review on lymphoproliferative diseases arising in immunocompromised hosts: prevalence, clinical features and pathogenetic mechanisms. Haematologica 1989 Nov-Dec; 74(6): 605-22[Medline].
• Buck BE, Scott GB, Valdes-Dapena M, Parks WP: Kaposi sarcoma in two infants with acquired immune deficiency syndrome. J Pediatr 1983 Dec; 103(6): 911-3[Medline].
• Certain S, Barrat F, Pastural E, et al: Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak-Higashi syndrome. Blood 2000 Feb 1; 95(3): 979-83[Medline].
• Cotelingam JD, Witebsky FG, Hsu SM, et al: Malignant lymphoma in patients with the Wiskott-Aldrich syndrome. Cancer Invest 1985; 3(6): 515-22[Medline].
• Craig FE, Gulley ML, Banks PM: Posttransplantation lymphoproliferative disorders. Am J Clin Pathol 1993 Mar; 99(3): 265-76[Medline].
• Fiorilli M, Carbonari M, Crescenzi M, et al: T-cell receptor genes and ataxia telangiectasia. Nature 1985 Jan 17-23; 313(5999): 186[Medline].
• Kempf W: CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators. J Cutan Pathol 2006 Feb; 33 Suppl 1: 58-70[Medline].
• Kirsch IR, Brown JA, Lawrence J, et al: Translocations that highlight chromosomal regions of differentiated activity. Cancer Genet Cytogenet 1985 Oct; 18(2): 159-71[Medline].
• Le Deist F, Emile JF, Rieux-Laucat F, et al: Clinical, immunological, and pathological consequences of Fas-deficient conditions. Lancet 1996 Sep 14; 348(9029): 719-23[Medline].
• Lim DS, Kim ST, Xu B, et al: ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 2000 Apr 6; 404(6778): 613-7[Medline].
• Locker J, Nalesnik M: Molecular genetic analysis of lymphoid tumors arising after organ transplantation. Am J Pathol 1989 Dec; 135(6): 977-87[Medline].
• Loughrey M, Trivett M, Lade S, et al: Diagnostic application of Epstein-Barr virus-encoded RNA in situ hybridisation. Pathology 2004 Aug; 36(4): 301-8[Medline].
• Lundell R, Elenitoba-Johnson KS, Lim MS: T-cell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient. Am J Surg Pathol 2004 Jul; 28(7): 967-73[Medline].
• Maia DM, Garwacki CP: X-linked lymphoproliferative disease: pathology and diagnosis. Pediatr Dev Pathol 1999 Jan-Feb; 2(1): 72-7[Medline].
• Marti GE, Rawstron AC, Ghia P, et al: Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol 2005 Aug; 130(3): 325-32[Medline].
• Merino F, Henle W, Ramirez-Duque P: Chronic active Epstein-Barr virus infection in patients with Chediak- Higashi syndrome. J Clin Immunol 1986 Jul; 6(4): 299-305[Medline].
• Neudorf SM, Filipovich AH, Kersey A: Immunoreconstitution by bone marrow transplantation decreases lymphoreticular malignancies in Wiskott-Aldrich and SCID syndromes. In: Purtillo DT, ed. Immune Deficiency and Cancer: EBV and Lymphoreticular Malignancies. New York: Plenum; 1984: 471-80.
• Nichols KE: X-linked lymphoproliferative disease: genetics and biochemistry. Rev Immunogenet 2000; 2(2): 256-66[Medline].
• Okano M, Thiele GM, Purtilo DT: Variable presence of circulating cytokines in patients with sporadic or X-linked lymphoproliferative disease with fatal infectious mononucleosis. Pediatr Hematol Oncol 1993 Jan-Mar; 10(1): 97-9[Medline].
• Paller AS: Immunodeficiency syndromes. X-linked agammaglobulinemia, common variable immunodeficiency, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, and X-linked lymphoproliferative disorder. Dermatol Clin 1995 Jan; 13(1): 65-71[Medline].
• Sanal O, Wei S, Foroud T, et al: Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region. Am J Hum Genet 1990 Nov; 47(5): 860-6[Medline].
• Sander CA, Medeiros LJ, Weiss LM, et al: Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Am J Surg Pathol 1992 Dec; 16(12): 1170-82[Medline].
• Schuster V, Kreth HW: X-linked lymphoproliferative disease is caused by deficiency of a novel SH2 domain-containing signal transduction adaptor protein. Immunol Rev 2000 Dec; 178: 21-8[Medline].
• Seemayer TA, Gross TG, Egeler RM, et al: X-linked lymphoproliferative disease: twenty-five years after the discovery. Pediatr Res 1995 Oct; 38(4): 471-8[Medline].
• Seibel NL, Cossman J, Magrath IT: Lymphoproliferative disorders. In: Pizzo PA, Poplack DG, eds. Principles and Practices of Pediatric Oncology. Philadelphia, Pa: JB Lippincott; 1993: 595-616.
• Snyder MJ, Stenzel TT, Buckley PJ, et al: Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation. Am J Surg Pathol 2004 Jun; 28(6): 794-800[Medline].
• Spector BD, Perry GS III, Kersey JH: Genetically determined immunodeficiency diseases (GDID) and malignancy: report from the immunodeficiency--cancer registry. Clin Immunol Immunopathol 1978 Sep; 11(1): 12-29[Medline].
• Straus SE, Sneller M, Lenardo MJ, et al: An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med 1999 Apr 6; 130(7): 591-601[Medline].
• Uzel G: The range of defects associated with nuclear factor kappaB essential modulator. Curr Opin Allergy Clin Immunol 2005 Dec; 5(6): 513-8[Medline].
• Vetrie D, Vorechovsky I, Sideras P, et al: The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993 Jan 21; 361(6409): 226-33[Medline].

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