AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Lymphoblastic leukemias/lymphomas are neoplasms of precursor T cells and B cells, or lymphoblasts. The term lymphoblastic lymphoma (LBL) has been used to describe predominantly lymph node–based disease; however, clinical distinction between lymphoblastic lymphoma and acute lymphoblastic leukemia (ALL) has been arbitrary and has varied among different studies and institutions.^{1, 2}

Because it is now known that lymphoblastic lymphoma and ALL represent the same disease entity based on morphologic, genetic, and immunophenotypic features, the World Health Organization (WHO) classification has unified these entities as precursor B-cell and T-cell lymphoblastic leukemia/lymphoma. However, because this unification is relatively recent and the majority of the clinical literature describing these entities has treated these entities as distinct, this article focuses on the disease entity previously designated as lymphoblastic lymphoma.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Lymphoma.

Related eMedicine topics:
Lymphoma, B-Cell
Lymphoma, High-Grade Malignant Immunoblastic
Lymphoma, Non-Hodgkin

Related Medscape topics:
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JAK2 Mutations Seen With Down's Syndrome-Associated Leukemia

Pathophysiology

Lymphoblastic lymphoma arises from immature T cells in 85-90% of cases and immature B cells in the remainder of cases. The lymphoblasts infiltrate nodal structures or extranodal structures, especially the bone marrow, spleen, and central nervous system (CNS).¹

Lymphoblastic lymphoma is aggressive and progresses rapidly, presenting as stage IV disease in more than 70% of patients. Gross lymphadenopathy impairs immunity, allows opportunistic infections, and may compress adjacent structures. In 30-50% of patients, the lymphoblasts infiltrate bone marrow, causing ineffective hematopoiesis. Many investigators have suggested that both lymphoblastic lymphoma and ALL may be part of one clinical spectrum of a single malignant lymphoproliferative disorder.

Pathogenesis

Much of what is known about the molecular pathogenesis of lymphoblastic lymphoma has arisen from T-cell receptor analysis as well as nonrandom, recurrent chromosomal translocations. Approximately one third of tumors have translocations involving the alpha and delta T-cell receptor loci at band 14q11.2, the beta locus at band 7q35, and the gamma locus at band 7p14-15. These translocations result in juxtaposition T-cell receptor promoter and enhancer elements with various transcription factors, such as HOX11/TLX1, TAL1/SCL, TAL2, and LYL1, which lead to high levels of expression in precursor thymocytes. Molecular array studies have identified subtypes of the above noted abnormalities that may have distinct prognoses.^{3, 4}

Frequency

United States

Lymphoblastic lymphoma is relatively rare, comprising only 2% of all non-Hodgkin lymphomas (NHLs). The T-cell phenotype accounts for 80-90% of cases, with the remainder of B-cell origin.

T-lymphoblastic lymphoma (T-LBL) accounts for 25-30% of childhood NHL and is closely related to T-lymphoblastic leukemia (T-ALL).⁴ Lymphoblastic lymphoma predominates in young adults and adolescents with a median age at diagnosis of 20 years and a slight male predominance.

International

• In a Brazilian study in 96 districts of Sao Paolo that evaluated 507 children aged 0-14 years who were diagnosed with ALL between 1997 and 2002, the investigators found a correlation between the children's Social Exclusion Index (SEI) categories—based on the district of residence at diagnosis, as well as 4 categories from high to low that included the indicators of poverty, employment, inequality, education, and violence—and the districts of residence and areas in which there were high percentages of crowded households.⁵
• • The age-adjusted incidence rate was 3.68/100,000 for males and 2.87/100,000 for females.⁵
  • Children who lived in areas with the lowest SES had a significantly lower risk of ALL compared with those living in the wealthiest districts.⁵
  • There was a strong correlation between SEI and crowding (rho = -0.95, P <0.001). Lower incidence rates of childhood ALL were noted in areas with high percentages of households with >7 persons (>5.7%) compared with those in which there had percentages less than or equal to 2.2%.⁵
  • The authors concluded that population-based attributes for SES and household size may be useful surrogate markers of early exposure to childhood infections, which has been found to decrease the risk of ALL.⁵

Mortality/Morbidity

• With current treatments, the overall survival rate at 5 years in children with lymphoblastic lymphoma is 80-90%, and the overall survival rate in adults is 45-55%.
• Disease-free survival rates at 5 years range from 70% to 90% in children and from 45% to 55% in adults.

Race

No racial predilection exists for lymphoblastic lymphoma.

Sex

The male-to-female ratio of those with lymphoblastic lymphoma is 2:1.

Age

• Lymphoblastic lymphoma is more common in children and adolescents than in adults.
• In adults, the median age at presentation is 27 years for men and 50 years for women.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients with lymphoblastic lymphoma usually present with painless lymphadenopathy.
• A mediastinal mass occurs in 50-75% of patients and may cause dyspnea and chest pain or may progress to life-threatening compression of the superior vena cava or tracheobronchial tree. B-cell subtypes usually lack a mediastinal mass.
• Constitutional B symptoms include 1 or more of the following:
• • Fever higher than 38ºC
  • Drenching night sweats
  • Weight loss of more than 10% of body weight within 6 months
• Patients may have fatigue from anemia or bleeding and bruising from thrombocytopenia.
• Dyspnea or chest pain may result from pleural disease.
• Neurologic deficits may be present from central nervous system (CNS) disease.
• Patients may have a gonadal mass or gonadal dysfunction.

Physical

Mediastinal adenopathy in a young adult is the predominant finding (60-70% of patients with lymphoblastic lymphoma, likely reflecting the thymic origin of most of these lymphomas and, therefore, is an uncommon feature of B-cell lymphoblastic lymphoma. Pleural, pericardial, and superior vena cava syndrome are also frequent presenting features. Peripheral lymph node involvement is present in 60-80% of patients at diagnosis.

Lymphoblastic lymphoma has a predilection for the bone marrow with a reported incidence at diagnosis of 21%, as well as a reported incidence of 5-10% for the CNS. CNS involvement is more frequent at relapse, particularly in the absence of adequate CNS prophylaxis, with one series reporting 31% CNS involvement at relapse.⁶

Peripheral blood involvement is also common, but the true incidence is confounded by the previous inconsistencies in the distinction between lymphoblastic lymphoma and ALL.

Other rarer sites of involvement include the liver, spleen, and testes. Skin and oropharyngeal involvement is more common in children with B-cell LBL. Signs of involvement include the following:

• Painless lymphadenopathy
• Pallor
• Petechiae
• Ecchymoses
• Splenomegaly
• Neurologic deficits
• Gonadal masses

Causes

Like all NHLs, LBL is associated with exposure to radiation or pesticides and congenital or acquired immunosuppression.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to Be Considered

Small, noncleaved cell lymphoma⁷

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

In patients suspected of having lymphoblastic lymphoma, the following studies should be included:

• Obtain a complete blood cell (CBC) count with examination of the peripheral smear to evaluate for peripheral blood involvement.
• Evaluate the electrolytes, creatinine, lactate dehydrogenase (LDH), and uric acid (UA) levels, with careful attention to assessment of the risk for tumor lysis syndrome (most highly correlated with LDH).
• • Tumor lysis syndrome is a phenomenon observed most commonly in lymphomas with bulky masses. Tumor lysis occurs when cytotoxic agents kill high numbers of cells simultaneously, releasing large amounts of intracellular enzymes and electrolytes. The sudden osmotic load overwhelms the patient’s kidneys; renal typically occurs, with a rising creatinine level, hyperkalemia, and hyperuricemia, and may progress to oliguria and hypotension.

    Treatment for tumor lysis syndrome is immediate intensive care with cardiac monitoring. Dialysis may be necessary. Continue chemotherapy because the lysing of tumor cells resolves as the tumor burden decreases. If tumor lysis is anticipated, patients should be hydrated aggressively and observed in the intensive care unit (ICU) during the first chemotherapy treatment.

• Complete a bone marrow aspiration and biopsy with studies for cytogenetic and flow cytometric analysis.
• If not contraindicated due to severe thrombocytopenia and/or coagulation disorders, complete a lumbar puncture and send for standard analysis and cytopathology to exclude CNS involvement.

Imaging Studies

• Obtain computed tomography (CT) scans of the chest, abdomen, and pelvis. Consider functional imaging (positron emission tomography [PET] scanning or gallium scanning), particularly in patients with bulky disease.
• Obtain magnetic resonance imaging (MRI) of the CNS system if it is clinically indicated.

Related Medscape topic:
Specialty Site Radiology

Procedures

• Excisional lymph node biopsy
• • The diagnosis of lymphoblastic lymphoma is based on excisional lymph node biopsy.
  • Fine-needle aspirate (FNA) or core-needle biopsy usually provides inadequate tissue for diagnosis.
  • Immunophenotyping: Lymphoblastic lymphoma is nearly always positive for terminal deoxynucleotidyl transferase (TdT), whereas small noncleaved cell lymphoma is negative for TdT.
• Bone marrow biopsy and aspirate
• • Bone marrow is involved at presentation in 30-50% of cases of lymphoblastic lymphoma, and lymphoblasts may comprise up to 25% of marrow elements.
  • If lymphoblasts involve more than 25% of the marrow, patients are arbitrarily diagnosed with ALL.
• Incisional biopsy of an extramedullary site
• • Some patients present with extramedullary disease. One example is a breast mass. In these patients the diagnosis could be made by biopsy of that site. A large sample must be obtained for proper diagnosis. Cytologic analysis is not appropriate.
• Lumbar puncture: The CNS is involved in one third of cases at some point during the clinical course.
• Diagnostic aspiration of pleural effusion (if present)
• • This aspiration is especially useful in children who present with a mediastinal mass and respiratory difficulty.
  • If a pleural effusion is present and aspiration fluid is positive for lymphoma, it may obviate the need for further biopsy. However, often, further tissue is necessary to obtain a specific diagnosis of lymphoblastic lymphoma.

Histologic Findings

Morphologically, lymphoblastic lymphoma is indistinguishable from L1 ALL, as defined in the French-American-British (FAB) classification of ALL. Lymphoblastic lymphoma is composed of medium-sized cells with finely dispersed chromatin and scant cytoplasm. The nuclei are round or highly convoluted, and the nucleoli are inconspicuous.

Based on the rapid growth and cell turnover, mitotic figures and apoptotic bodies are abundant. The apoptotic bodies are often phagocytosed by macrophages, imparting a starry sky appearance, which is characteristic of high-grade lymphomas. The differential diagnosis includes L2 ALL, Burkitt lymphoma, lymphocyte-rich thymoma, and especially in children, small round–cell tumors such as Ewing sarcoma. Modern molecular and immunophenotypic analysis generally provides reliable distinction.

Typical flow cytometric findings for B-lymphoblastic lymphoma are as follows: CD19⁺ CD10 bright, CD20^+/–, CD22^+/–, TdT⁺, HLA-DR⁺, CD34^+/–, slg^–. Findings for T-lymphoblastic lymphoma are as follows: sCD3^–, but CD3⁺, CD4⁺CD8⁺ or CD4^-CD8^–, CD2^+/–, CD5^+/–, CD7^+/–, TdT⁺, CD34^+/–, CD10^+/–.

Staging

• The Ann Arbor staging system (see below) is the widely used staging system for most subtypes of NHL, including lymphoblastic lymphoma. However, the Murphy staging system is commonly used in pediatric lymphoblastic lymphoma and has been shown to provide more useful prognostic information. Comparison of the Ann Arbor and Murphy staging systems in adults with lymphoblastic lymphoma demonstrated that the Ann Arbor system provided more accurate prediction of survival.
• Ann Arbor staging system
• • Stage I – One site on 1 side of the diaphragm
  • Stage II – Multiple sites on 1 side of the diaphragm
  • Stage III – Sites on both sides of the diaphragm
    • Mediastinal mass
    • Pleural effusion
    • Unresectable abdominal disease
  • Stage IV – Disseminated disease, marrow, or CNS
  • Subsets
  • • E – Extranodal
    • S – Spleen
    • B symptoms – Temperature >38°C, weight loss >10% within 6 months, drenching night sweats
• Identification of prognostic factors for patients with lymphoblastic lymphoma has been inconsistent in part because of the lack of a clear distinction between ALL and lymphoblastic lymphoma, as well as distinguishing between adult and pediatric cases. Based on the potential for early treatment intensification, identification of reliable prognostic factors for clinical trial risk stratification is crucial. Some of the commonly used prognostic factors are included in the following list:
• • Adverse clinical prognostic factors
  • • Age older than 30 years
    • Advanced Ann Arbor stage (stage III or IV)
    • Bone marrow involvement
    • CNS involvement
    • Peripheral blood involvement/leukemic component
    • B symptoms
    • Advanced international prognostic index score more than 2
    • Time to achieve a complete response
    • LDH that is more than 1.5 times normal

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Combination chemotherapy produces an excellent response, but relapse is common. In children with lymphoblastic lymphoma, regimens similar to treatments for ALL have produced 5-year disease-free survival rates ranging from 60% to 80%. ALL regimens may be equally effective in adults, although many adults are treated with regimens traditionally designed for diffuse intermediate-grade lymphoma (which were predominantly diffuse large B-cell lymphoma in the new WHO classification), such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens. Depending on the regimen, response rates in adults ranged from 55% to 95%, with leukemia-type regimens producing rates greater than 70%.

A randomized trial in children compared the LSA₂-L₂ leukemia regimen with a more traditional CHOP-like regimen (COMP, M = additional methotrexate) and found the LSA₂-L₂ regimen superior in terms of response and overall survival rates. Subsequently, a number of studies have used chemotherapy/radiotherapy LSA₂-L₂–like regimens in adults with lymphoblastic lymphoma. Most are characterized by the standard leukemia-like sequence of intensive remission induction, CNS prophylaxis, consolidation, and prolonged maintenance. Most of these studies produced long-term disease-free survival rates of 40-60% in adults.

Encouraging results have been obtained with another regimen commonly used for ALL, hyper-CVAD (fractionated cyclophosphamide vincristine, adriamycin, and dexamethasone), which was used in patients with lymphoblastic lymphoma.⁶ This regimen generated responses in 100% of patients, 91% being complete and producing a 3-year progression-free of 66% and an overall survival of 70%.

Despite high initial remission rates, 40-60% of adults eventually relapse, with relapse rates considerably higher in patients with poor prognostic features. Several studies have examined the role of both autologous and allogeneic stem cell transplantation in first and second remission, as well as in patients with refractory disease.

Surgical Care

• Excisional lymph node biopsy
• Placement of double-lumen central venous catheter

Consultations

• Radiation oncologist
• • Radiation is useful both for prophylaxis of CNS disease and treatment of CNS disease. It may also be required for palliation of symptomatic masses, such as a mediastinal mass with compression.
  • Radiation is never the sole treatment modality.
• Anesthesiologist or critical care medicine specialist: Emergent endotracheal intubation may be necessary if a mediastinal mass compresses the tracheobronchial tree or the superior vena cava and compromises respiration.

Diet

A regular diet is usually adequate in individuals with lymphoblastic lymphoma. Patients who are neutropenic should not eat any raw fruits or vegetables.

Activity

The following restrictions apply to patients with thrombocytopenia or neutropenia:

• Instruct all persons to wash their hands before entering the room. 
• Use Toothette swabs for cleaning teeth.
• Do not shave with a razor.
• No intramuscular (IM) injections should be administered.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Begin chemotherapy as soon as possible for patients with lymphoblastic lymphoma. Supportive medications help control nausea, vomiting, tumor lysis syndrome, and infections.

Drug Category: Antineoplastic Drugs

Antineoplastic drugs inhibit cell growth and proliferation. Refer to established guidelines and the product information for each agent regarding the administration schedule for induction, consolidation phase, and maintenance therapy.

Drug Category: Enzymes

Enzymes are used to digest amino acids that are essential for cell proliferation.

Drug Category: Corticosteroids

Corticosteroids inhibit the immune system and reduce inflammation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit patients with lymphoblastic lymphoma for neutropenic fever.

Further Outpatient Care

• Monitor the CBC count of patients with lymphoblastic lymphoma during the treatment nadir.
• For patients with asymptomatic anemia or thrombocytopenia, arrange for outpatient transfusions. The most commonly used arbitrary thresholds for transfusion are a hemoglobin of 8 g/dL or a hematocrit of 25% and a platelet count of 10,000/mm³, if the patient is not bleeding, anemic, or febrile.

In/Out Patient Meds

• Consolidation and maintenance therapy of patients with lymphoblastic lymphoma may be performed on an outpatient basis.

Transfer

Patients with lymphoblastic lymphoma should be managed at a facility experienced in the diagnosis and treatment of high-grade lymphomas.

Complications

• Neutropenic fever
• Opportunistic infections
• Bleeding
• Tumor lysis syndrome

Prognosis

• Response rates in adults with lymphoblastic lymphoma range from 55-95%, with leukemia-type regimens producing rates higher than 70%.
• • The 5-year disease-free survival rate is 45-55% in adults and 70-90% in children.
  • Since 1982, increasing use of leukemia-type regimens has increased the 5-year overall survival rate from 26% to 45% in adults lymphoblastic lymphoma.
• For any NHL, the prognosis for survival may be estimated according to the International Index.
• • This index scores 1 point each for age older than 60 years, high serum LDH, poor performance status, or tumor stage III or IV. Patients older than 60 years with more than 1 extranodal site receive an additional point.
  • Five-year overall survival rates by index risk factor score are as follows:
  • • 0 (zero) points – Low risk (83%)
    • 1 point – Low-intermediate risk (69%)
    • 2 points – Intermediate-high risk (46%)
    • 3 or more points – High risk (32%)
• Relapse may occur locally or in extranodal sites such as the bone marrow or CNS.

Patient Education

• During a period of neutropenia, advise patients with lymphoblastic lymphoma of the following:
• • Contact a physician if fever, bleeding, or infection occurs.
  • Avoid raw fruits or vegetables.
  • Avoid crowds of people.
  • Avoid contact with people who are ill.
  • Always protect the site of an indwelling catheter from contamination.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Diagnosis of any lymphoma requires an excisional biopsy to preserve the architecture of the lymph node. An FNA disrupts the natural lymph node structure and often alters the appearance, resulting in an incorrect diagnosis (eg, carcinoma).

Related Medscape topics:
Resource Center Medical Malpractice and Legal Issues
Specialty Site Hematology-Oncology
Specialty Site Pathology & Lab Medicine

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 2^nd ed. New York, NY: Churchill-Livingstone; 1995.
2. Head DR, Behm FG. Acute lymphoblastic leukemia and the lymphoblastic lymphomas of childhood. Semin Diagn Pathol. Nov 1995;12(4):325-34. [Medline].
3. Tauchi H, Tomizawa D, Eguchi M, et al. Clinical features and outcome of MLL gene rearranged acute lymphoblastic leukemia in infants with additional chromosomal abnormalities other than 11q23 translocation. Leuk Res. Oct 2008;32(10):1523-9. [Medline].
4. Smock KJ, Nelson M, Tripp SR, et al. Characterization of childhood precursor T-lymphoblastic lymphoma by immunophenotyping and fluorescent in situ hybridization: a report from the Children's Oncology Group. Pediatr Blood Cancer. Oct 2008;51(4):489-94. [Medline].
5. Ribeiro KB, Buffler PA, Metayer C. Socioeconomic status and childhood acute lymphocytic leukemia incidence in São Paulo, Brazil. Int J Cancer. Oct 15 2008;123(8):1907-12. [Medline].
6. Thomas DA, O'Brien S, Cortes J, et al. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. Sep 15 2004;104(6):1624-30. [Medline]. [Full Text].
7. Magrath IT. Management of high-grade lymphomas. Oncology (Williston Park). Oct 1998;12(10 suppl 8):40-8. [Medline].
8. Bailey LC, Lange BJ, Rheingold SR, Bunin NJ. Bone-marrow relapse in paediatric acute lymphoblastic leukaemia. Lancet Oncol. Sep 2008;9(9):873-83. [Medline].
9. Digiuseppe JA. Acute lymphoblastic leukemia: diagnosis and detection of minimal residual disease following therapy. Clin Lab Med. Sep 2007;27(3):533-49, vi. [Medline].

Article Last Updated: Oct 1, 2008