WORKUP	Section 5 of 10
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Lab Studies:

• Obtain a CBC with examination of the peripheral smear to evaluate for peripheral blood involvement.

• Evaluate the electrolytes, creatinine, lactate dehydrogenase (LDH), and uric acid levels, with careful attention to assessment of the risk for tumor lysis syndrome (most highly correlated with LDH).

• Complete a bilateral bone marrow biopsy with studies for cytogenetic and flow cytometric analysis.

• Complete a lumbar puncture and send for standard analysis and cytopathology to exclude CNS involvement.

Imaging Studies:

• Obtain CT scans of the chest, abdomen, and pelvis. Consider functional imaging (positron emission tomography [PET] or gallium scans), particularly in patients with bulky disease.

Procedures:

• Excisional lymph node biopsy

• Diagnosis is based on excisional lymph node biopsy.

• Fine-needle aspirate or core-needle biopsy usually provides inadequate tissue for diagnosis.

• Immunophenotyping: LBL is nearly always positive for terminal deoxynucleotidyl transferase (TdT), whereas small noncleaved cell lymphoma is negative.

• Bone marrow biopsy and aspirate

• Bone marrow is involved at presentation in 30-50% of cases, 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.

• Lumbar puncture: 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 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.

Staging:

• The Ann Arbor staging system (see below) is the widely used staging system for most subtypes of NHL, including LBL. However, the Murphy staging system is commonly used in pediatric LBL and has been shown to provide more useful prognostic information. Comparison of the Ann Arbor and Murphy staging systems in adults with LBL demonstrated that the Ann Arbor system provided more accurate prediction of survival.

• Ann Arbor staging system

• I - One site on 1 side of the diaphragm

• II - Multiple sites on 1 side of the diaphragm

• III - Sites on both sides of the diaphragm
  • Mediastinal mass

  • Pleural effusion

  • Unresectable abdominal disease

• 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 LBL has been inconsistent in part because of the lack of a clear distinction between ALL and LBL, as well as distinguishing between adult and pediatric cases. Based on the potential for early treatment intensification, identification of reliable prognostic factors for clinical trail risk stratification is crucial. Some of the commonly used prognostic factors are included in the following list:

	TREATMENT	Section 6 of 10
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Medical Care: Combination chemotherapy produces excellent response, but relapse is common. In children with lymphoblastic lymphoma (LBL), regimens similar to treatments for ALL have produced 5-year disease-free survival rates ranging from 60-80%. 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). Response rates in adults ranged from 55-95%, with leukemia-type regimens producing rates greater than 70%.

Recently, 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 LBL. Most are characterized by the standard leukemialike 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.

Despite high initial remission rates, 40-60% of adults eventually relapse, with relapse rates being 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.

Stem cell transplantation

As a whole, intensive chemotherapy regimens, with or without irradiation in adult LBL, have improved complete remission (CR) rates compared with previous lymphoma regimens. Further attempts to improve long-term outcome have resulted in chemotherapy programs that integrate consolidation with intensification followed by high-dose therapy and either autologous or allogeneic SCT.

The high CR rate and high subsequent relapse rate provided the rationale for the use of high-dose therapy and stem cell transplantation (SCT) to consolidate first remission in patients with LBL. Available data (in a satisfactory number of cases) suggest that intensive consolidation therapy followed by autologous or allogeneic SCT may improve the long-term prognosis of this disease, but which patients may benefit from SCT remains unclear.

The use of autologous SCT in adults with LBL in first remission produced a trend for improved relapse-free survival but did not improve overall survival significantly compared with conventional-dose therapy in a small randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group. However, studies from single centers and registries have resulted in 31-77% long-term disease-free survival by using autologous SCT and in 39-91% disease-free survival in patients receiving allogeneic bone marrow transplant (BMT) in first remission.

More recently, Levine et al published, on behalf of the Lymphoma Study Writing Committee, the outcomes of 204 patients who underwent autologous (n = 128) or HLA-identical sibling (n = 76) SCT from 1989-1998 and were reported to the International Bone Marrow Transplant Registry (IBMTR) or Autologous Blood and Marrow Transplant Registry (ABMTR). This is the largest series of patients with LBL ever reported. Of 204 patients, 183 were adult patients as defined as older than 16 years. Among adults, 118 (64.5%) patients received allogeneic SCT, and 65 (35.5%) received autologous SCT. Allogeneic SCT recipients had higher treatment-related mortality (TRM) at 6 months (18% vs 3%; P=.002), and this disadvantage persisted at 1 and 5 years.

Graft-versus-host disease (GVHD) was reported as the cause of death in only 2 (7%) of the allogeneic transplant recipients. Infection, pneumonitis, and organ failure accounted for most TRM for both autologous and allogeneic transplant recipients. Early relapse rates after allogeneic SCT and autologous SCT were similar, but significantly lower relapse rates were observed in allogeneic SCT recipients at 1 and 5 years (32% vs 46%, [P=.05] and 34% vs 56% [P=.004], respectively). The 5-year cumulative incidences of relapse were 34% after allogeneic SCT and 56% after autologous SCT (P=.004).

No statistically significant effect of acute or chronic GVHD was noted on the risk of relapse for allogeneic transplant recipients. Multivariate analysis revealed that donor source, lymphomatous involvement of the bone marrow at transplantation, and disease status at transplantation were independent predictors of persistent or recurrent lymphoma after SCT. No differences were noted in lymphoma-free survival rates between allogeneic SCT and autologous SCT (5-y rates, 36% vs 39%; P=.82).

Management of CNS disease

CNS involvement may be present in up to 20% of adult T-cell LBL patients at presentation, and the CNS is a frequent site of relapse in the absence of CNS prophylaxis. Cytologic evaluation of the spinal fluid and administration of intrathecal prophylactic CNS chemotherapy is mandatory for all patients with LBL at the time of diagnosis.

In a series by Coleman et al, earlier administration of intrathecal methotrexate and the addition of prophylactic cranial irradiation reduced the incidence of CNS relapse from 29% to 3%, but no significant improvement in survival was noted.

Taken as a whole, CNS relapse rates range from 3-42% in studies using intrathecal chemotherapy prophylaxis alone, from 3-15% in studies using a combination of cranial radiation and intrathecal therapy, and from 42-100% in studies not incorporating any CNS-directed therapy.

A Pediatric Oncology Group study found that the CNS relapse rate was similar whether prophylaxis was intrathecal therapy alone or cranial radiation and intrathecal therapy, and, therefore, many centers have abandoned the use of cranial radiation caused by concerns of long-term neurologic sequelae, at least in children.

Management of mediastinal disease

Although mediastinal radiotherapy is certainly effective local treatment, it carries several potentially serious risks, including the development of cardiac disease, radiation pneumonitis, secondary malignancies (eg, breast cancer, bone sarcomas in the radiation field, myelodysplasia, acute myeloid leukemia), and other long-term sequelae, especially in long-surviving children. Because of short- and long-term morbidity, as well as locoregional relapses, mediastinal radiotherapy has been eliminated from most pediatric LBL protocols. Because of concerns about increased toxicity with concomitant doxorubicin in 2 earlier pediatric LBL studies, mediastinal irradiation was reserved for respiratory compromise or vascular obstruction due to adenopathy.

Steroid therapy alone often leads to rapid alleviation of signs and symptoms, although mediastinal irradiation may sometimes be needed. Hence, if mediastinal disease results in respiratory distress or superior vena cava syndrome, an effort should be made to establish a tissue diagnosis before the initiation of therapy. The incidence of isolated mediastinal relapse in the absence of prophylactic or consolidative radiotherapy ranges from 5-10%. The routine administration of mediastinal radiotherapy for all patients with mediastinal disease remains controversial.

The management of residual mediastinal masses in LBL is also controversial. The options include local radiotherapy, surgical resection of the residual mass or close observation if the patient is receiving maintenance chemotherapy or if SCT is being planned. The contribution of mediastinal radiotherapy to disease-free survival in chemotherapy-treated patients may depend on the efficacy of the chemotherapy.

Many studies suggest a possible role of appropriate dose-consolidative mediastinal irradiation in adults; however, because some patients experience early progression in the mediastinum, consolidative irradiation (30-36 Gy) involving the entire extent of the original mediastinal tumor may be tried earlier in the course of the dose-intensive phase, especially for slow responders.

Surgical Care:

• Excisional lymph node biopsy

• Placement of double-lumen central venous catheter

Consultations:

• Radiation oncologist

• Radiation is useful for both prophylaxis of CNS disease and treatment CNS disease. It also may 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 usually is adequate. If the patient is neutropenic, they should not eat any raw fruits or vegetables.

Activity: The following restrictions apply to patients with thrombocytopenia or neutropenia:

• Isolate the patient in a private room. Instruct all persons to wash their hands before entering the room. Gowns or gloves are not necessary unless the patient is undergoing a BMT.

• Use Toothette swabs for cleaning teeth.

• Do not shave with a razor.

	MEDICATION	Section 7 of 10
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Begin chemotherapy as soon as possible for patients with lymphoblastic lymphoma (LBL). Supportive medications help control nausea, vomiting, tumor lysis syndrome, and infections.

	MISCELLANEOUS	Section 9 of 10
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Medical/Legal Pitfalls:

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