Lymphoblastic Lymphoma 

Updated: Sep 10, 2019
  • Author: Joseph M Tuscano, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Practice Essentials

Lymphoblastic leukemias/lymphomas are neoplasms of precursor T cells and B cells or lymphoblasts. The term lymphoblastic lymphoma (LBL) is used to describe predominantly lymph node–based disease; however, because lymphoblastic lymphoma and acute lymphoblastic leukemia (ALL) are known to represent the same disease entity, the World Health Organization (WHO) classification has unified these entities as precursor B-cell and T-cell lymphoblastic leukemia/lymphoma. These entities are futher categorized based on morphologic, genetic, and immunophenotypic features. [1]

When the disease is restricted to primary nodal and extranodal sites with minimal involvement of bone marrow (< 20% lymphoblasts in marrow), a diagnosis of lymphoblastic lymphoma is made.  Conversely, a diagnosis of ALL requires at least 20% lymphoblasts in marrow. [2]

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Etiology and Pathophysiology

Lymphoblastic lymphoma is associated with exposure to radiation or pesticides and congenital or acquired immunosuppression and is more common in children and young adults. This condition arises from immature T cells in more than 80% of cases and immature B cells in the remainder of cases. The lymphoblasts infiltrate nodal structures or extranodal structures and is commonly associated with large mediastinal masses with a high predilection for disseminating to bone marrow and the central nervous system (CNS). [3]

Lymphoblastic lymphoma is aggressive and progresses rapidly, presenting as stage IV disease in more than 70% of patients (see Staging). 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 acute lymphoblastic leukemia (ALL) may be part of one clinical spectrum of a single malignant lymphoproliferative disorder. [4]

Although several subtypes of T-cell lymphoblastic leukemia/lymphoma exist, early T-cell precursor lymphoblastic leukemia (ETP-ALL) is the only subtype recognized as an entity in the revised 2016 WHO tumor classification. [1]  ETP-ALL frequently has mutations in RUNX1 and/or ETV6 in addition to genes that are more commonly associated with myeloid neoplasms and are otherwise rare in T-cell lymphoblastic leukemia/lymphoma (such as FLT3IDH1/2TET2, and DNMT3A mutations). [5]

Non-ETP subtypes of T-cell lymphoblastic leukemia/lymphoma, in contrast, are associated with activating NOTCH1 mutations in over half of all patients and an additional 10% to 15% of cases have FBXW7 mutations, which also result in increased NOTCH signaling. Mutations in PHF6 are also seen in 20% to 40% of T-ALL and are largely restricted to non-ETP cases. Chromosomal alterations are also common and include loss of CDKN2A/B through chromosome 9 deletion in 50% to 60% of non-ETP T-ALL patients. Finally, translocations and noncoding region mutations such as TAL1, TAL2, LYL1, LMO1LMO2TLX1TLX3ZEB2MYB, and MYC are common but their clinical relevance is not known. [5]

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Epidemiology

In the United States, lymphoblastic lymphoma is relatively rare, comprising only 2% of all non-Hodgkin lymphomas (NHLs). The T-cell phenotype accounts for more than 80% 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). [6] Lymphoblastic lymphoma predominates in young adults and adolescents with a median age at diagnosis of 20 years (in adults: median age, 27 y for men; 50 y for women) and a slight m  ale predominance (male-to-female ratio, 2:1).

The estimated overall incidence of acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma in Europe is 1.28 per 100 000 individuals annually, with significant age-related variations (0.53 at 45–54 years, ∼1.0 at 55–74 years and 1.45 at 75–99 years). [7]

Population-based attributes for Social Exclusion Index (SEI) and household size may be useful surrogate markers of early exposure to childhood infections, which has been found to decrease the risk of acute lymphoblastic leukemia (ALL). [8] In a Brazilian study in 96 districts of Sao Paolo, investigators evaluated 507 children aged 0-14 years who were diagnosed with ALL between 1997 and 2002 and found a correlation between the children's SEI categories—based on the district of residence at diagnosis, as well as four 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. Their findings included the following [8] :

  • The age-adjusted incidence rate was 3.68/100,000 for males and 2.87/100,000 for females.

  • Children who lived in areas with the lowest SEIs had a significantly lower risk of ALL compared with those living in the wealthiest districts.

  • There was a strong correlation between SEI and crowding: Lower incidence rates of childhood ALL were noted in areas with high percentages of households with >7 persons (5.7% or greater) compared with those in which there had percentages of 2.2% or less.

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Clinical Evaluation

As many as 75% of patients with T-cell lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck. [9] B-cell subtypes usually lack a mediastinal mass. [10]

Constitutional B symptoms include any of the following:

  • Fever higher than 38°C

  • 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; and patients may have a gonadal mass or gonadal dysfunction.

On physical examination, 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 central nervous system (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. [11]

Peripheral blood involvement is also common, but the true incidence is confounded by the previous inconsistencies in the distinction between lymphoblastic lymphoma and acute lymphoblastic leukemia (ALL). Other more rare sites of involvement include the liver, spleen, and testes. Skin and oropharyngeal involvement is more common in children with B-cell lymphoblastic lymphoma. Signs of involvement include the following:

  • Painless lymphadenopathy

  • Pallor

  • Petechiae

  • Ecchymoses

  • Splenomegaly

  • Neurologic deficits

  • Gonadal masses

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Staging

The Ann Arbor staging system is the widely used staging system for most subtypes of non-Hodgkin lymphoma (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.

The Ann Arbor staging system is as follows:

  • 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 central nervous system (CNS)

  • Subsets (E – Extranodal; S – Spleen; B symptoms – Temperature >38°C, weight loss >10% within 6 mo, drenching night sweats)

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Prognosis and Prognostic Factors

Identification of prognostic factors for patients with lymphoblastic lymphoma has been inconsistent in part because of the lack of a clear distinction between acute lymphoblastic leukemia (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. [10] Some of the commonly used prognostic factors are as follows:

  • Age older than 30 years

  • Advanced Ann Arbor stage (stage III or IV)

  • Bone marrow involvement

  • Central nervous system (CNS) involvement

  • Peripheral blood involvement/leukemic component

  • B symptoms

  • Advanced international prognostic index score more than 2

  • Time to achieve a complete response

  • Lactate dehydrogenase (LDH) level that is more than 1.5 times normal

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. [2]

Treatment 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 non-Hodgkin lymphoma (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 level, 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.

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Differential Diagnosis

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Routine Laboratory Studies

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).

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CT Scanning and MRI

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 central nervous system (CNS) if it is clinically indicated.

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Specimen Collection and Analyses

This section will briefly review biopsy and specimen collection procedures/analyses such as excisional lymph node biopsy, bone marrow biopsy and aspirate, incisional biopsy of an extramedullary site, lumbar puncture, and diagnostic aspiration of a pleural effusion.

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.

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

Immunophenotyping of the lymphoblastic lymphoma specimen is nearly always positive for terminal deoxynucleotidyl transferase (TdT), whereas small noncleaved cell lymphoma is negative for TdT.

Bone marrow biopsy and aspirate

Complete a bone marrow aspiration and biopsy with studies for cytogenetic and flow cytometric analysis. [13, 14, 15] 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 acute lymphoblastic leukemia (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 central nervous system (CNS) is involved in one third of cases at some point during the clinical course of lymphoblastic lymphoma. 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.

Diagnostic aspiration of pleural effusion

Diagnostic 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.

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Histologic Features

Morphologically, lymphoblastic lymphoma is indistinguishable from L1 acute lymphoblastic leukemia (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, [16] lymphocyte-rich thymoma, and especially in children, small round–cell tumors such as Ewing sarcoma (see also Differential Diagnosis). Modern molecular and immunophenotypic analysis generally provides reliable distinction.

Typical flow cytometric findings for B-lymphoblastic lymphoma are as follows [13, 17] : CD19+ CD10 bright, CD20+/–, CD22+/–, TdT+, HLA-DR+, CD34+/–, slg. Findings for T-lymphoblastic lymphoma are the following: sCD3, but CD3+, CD4+ CD8+ or CD4- CD8, CD2+/–, CD5+/–, CD7+/–, TdT+, CD34+/–, CD10+/–.

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Management of Lymphoblastic Lymphoma

Patients with lymphoblastic lymphoma should be managed at a facility experienced in the diagnosis and treatment of high-grade lymphomas. [7, 2] Patients with lymphoblastic lymphoma and neutropenic fever should be admitted to the hospital.

Begin chemotherapy as soon as possible; combination chemotherapy produces an excellent response for lymphoblastic lymphoma, but relapse is common. [12, 18] Placement of double-lumen central venous catheter may be needed to facilitate the administration of the chemotherapeutic agents. Supportive medications help control nausea, vomiting, tumor lysis syndrome, and infections.

CHOP

In children with lymphoblastic lymphoma, chemotherapy regimens similar to treatments for acute lymphoblastic leukemia (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 World Health Organization [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 than70%.

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 leukemialike sequence of intensive remission induction, central nervous system (CNS) prophylaxis, consolidation, and prolonged maintenance. Most of these studies produced long-term disease-free survival rates of 40-60% in adults.

Hyper-CVAD

Encouraging results have been obtained with another regimen commonly used for ALL, hyper-CVAD (fractionated cyclophosphamide vincristine, Adriamycin [doxorubicin], and dexamethasone), which was used in patients with lymphoblastic lymphoma. [11] 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 (see Prognosis and Prognostic Factors). 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.

Targeted agents under investigation

With NOTCH1 being the major oncogene in T-ALL and with drugs available that can interfere with the activation of NOTCH1 by the gamma-secretase complex, a number of clinical trials have been initiated with gamma-secretase inhibitors (GSIs). However, these trials led to disappointing clinical results due to the dose-limiting toxicity and low response rates. [19] Promising responses to second generation GSIs have been reported and with milder toxicities. [20, 21]

Tumor lysis syndrome

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 failure 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.

Complications

Potential complications of lymphoblastic lymphoma include neutropenic fever (admit the patient), opportunistic infections, bleeding, and tumor lysis syndrome.

Consultations

Because radiation is useful both for prophylaxis of CNS disease and treatment of CNS disease, a radiation oncologist should be consulted. Radiation may also be required for palliation of symptomatic masses, such as a mediastinal mass with compression. Note that radiation is never the sole treatment modality.

Consult an anesthesiologist or critical care medicine specialist, as emergent endotracheal intubation may be necessary if a mediastinal mass compresses the tracheobronchial tree or the superior vena cava and compromises respiration.

Diet and activity

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

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Outpatient Management

Consolidation and maintenance therapy of patients with lymphoblastic lymphoma may be performed on an outpatient basis. Monitor the complete blood cell (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 cells/µL, if the patient is not bleeding, anemic, or febrile.

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.

For patient education information, see eMedicineHealth's Cancer Center, as well as Lymphoma.

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Questions & Answers

Overview

What is lymphoblastic lymphoma?

What is the pathophysiology of lymphoblastic lymphoma?

What is the prevalence of lymphoblastic lymphoma in the US?

What is the global prevalence of lymphoblastic lymphoma?

Which socioeconomic factors may increase the risk for lymphoblastic lymphoma?

Which clinical history findings are characteristic of lymphoblastic lymphoma?

Which physical findings are characteristic of lymphoblastic lymphoma?

How is lymphoblastic lymphoma staged?

Which factors affect the prognosis of lymphoblastic lymphoma?

What is the prognosis of lymphoblastic lymphoma?

Which conditions are included in the differential diagnoses of lymphoblastic lymphoma?

What is the role of lab testing in the workup of lymphoblastic lymphoma?

What is the role of imaging in the workup of lymphoblastic lymphoma?

What is the role of excisional lymph node biopsy in the workup of lymphoblastic lymphoma?

What is the role of bone marrow biopsy in the workup of lymphoblastic lymphoma?

What is the role of incisional biopsy of an extramedullary site in the workup of lymphoblastic lymphoma?

What is the role of lumbar puncture in the workup of lymphoblastic lymphoma?

What is the role of pleural effusion aspiration in the workup of lymphoblastic lymphoma?

Which histologic findings are characteristic of lymphoblastic lymphoma?

How is lymphoblastic lymphoma treated?

What is the role of the CHOP regimen in the treatment of lymphoblastic lymphoma?

What is the role of the hyper-CVAD regimen in the treatment of lymphoblastic lymphoma?

What is the role of targeted agents in the treatment of lymphoblastic lymphoma?

What is tumor lysis syndrome and how is it treated in patients with lymphoblastic lymphoma?

What are the possible complications of lymphoblastic lymphoma?

Which specialist consultations are beneficial to patients with lymphoblastic lymphoma?

Which dietary and activity modifications are used in the treatment of lymphoblastic lymphoma?

What is included in the long-term outpatient care for lymphoblastic lymphoma?

What is included in patient education about lymphoblastic lymphoma?

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