Non-hodgkin's Lymphoma

Investigations

Table 3 Evaluation of Patient with Non-Hodgkin's Lymphoma

• History and physical examination
• Blood count
• Serum electrolytes: blood urea nitrogen (BUN), creatinine, liver chemistries, calcium,phosphorus, magnesium
• Viral studies: HIV antibody, hepatitis A,B, C serology, cytomegalovirus (CMV) antibody,varicella antibody, herpes simplex virus (HSV) antibody
• Bone marrow aspiration and biopsy*
• Spinal fluid, peritoneal, pericardial, or pleural fluid examination - cytochemical, immunologic,cytogenetic, and molecular
• Adequate surgical biopsy for cytochemical, immunologic, cytogenetic, and molecular studies
• Evaluation of hepatic function (bilirubin, alkaline phosphatase, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum protein electrophoresis)
• Lactic dehydrogenase (LDH) levels
• Soluble interleukin-2 receptor (IL-2R) levels (if possible)
• Evaluation of renal function (urinalysis, BUN, uric acid, creatinine)
• Chest radiograph
• Computed tomography (CT) scan of the chest (when indicated)
• Ultrasonography of the abdomen
• CT Scan of the abdomen with contrast
• Plain radiograph and CT scan of afflicted site as deemed necessary on clinical grounds
• Gallium scan
• Diphosphonate bone scan: bone scan prior to gallium scan, because gallium will obscure the diphosphonate (if bone scan positive, radiographs or CT scan of bone or MRI of involved area indicated)
• Magnetic resonance imaging (MRI) especially for bone involvement (e.g. vertebrae)
• Dental evaluation in patients with Burkitt's lymphoma

* May establish the diagnosis without lymph node biopsy.

Note: Avoid undue delay in carrying out investigations because of the risk of rapid dissemination of the disease, especially to the bone marrow. In urgent medical situations (e.g. cord compression, cranial nerve palsy, or renal failure), minimum investigations prompted by the patient's particular clinical problems should be carried out and the patient should be treated on the day of admission.

Staging

Staging of NHL requires an expeditious investigation to determine the clinical extent of the disease, the degree of organ impairment, and the biochemical disturbance present.

Table 4 Staging System for Childhood Non-Hodgkin's Lymphoma: Murphy Classification

Stage I

• A single tumor (extranodal) or single anatomic area (nodal) with the exclusion of mediastinum or abdomen

Stage II

• A single tumor (extranodal) with regional lymph node involvement
• Two or more nodal areas on the same side of the diaphragm
• Two single (extranodal) tumors with or without regional lymph node involvement on the same side of the diaphragm
• A resectable primary gastrointestinal tract tumor, usually in the ileocecal area, with or without involvement of associated mesenteric nodes only

Stage III

• Two single tumors (extranodal) above and below the diaphragm
• Two or more nodal areas above and below the diaphragm
• All primary intrathoracic (mediastinal, pleural, thymic) tumors
• All extensive primary intra-abdominal disease
• All paraspinal or epidural tumors, regardless of other tumor site (or sites)

Stage IV

• Any of the above with initial involvement of central nervous system or bone marrow or both.

Staging laparotomy to determine precise pathologic staging of the disease is not indicated. Radiation therapy alone, with fields determined by an anatomic stating system, is not employed. Chemotherapy is the mainstay because of the multicentric origin of NHL.

Non-Hodgkin's Lymphoma - Diagnosis

Excellent cytologic and histologic preparations are essential for precise diagnosis; accurate classification of lymphomas and special precautions must be taken in handling the lymph node. Most diagnostic problems result from improperly and poorly prepared material and crushing artifacts. The selection of the appropriate node and histologic material is important. Histologic material that is obviously necrotic and that has been subject to vascular compromise creates major diagnostic problems.

Treatment

There are two potentially life-threatening complications seen in children with NHL: superior vena cava syndrome and/or mediastinal tumor with airway obstruction most often seen in lymphoblastic lymphoma; and tumor lysis syndrome, most often seen in small noncleaved cell NHL.

Supportive care of children with NHL consists of:

• Complications arising from the space-occupying nature of the tumor
• Metabolic complications of chemotherapy (i.e. tumor lysis syndrome)

Management of Complications Due to Space-occupying Nature of the Tumor at Specific Anatomic Sites

Intrathoracic:

• Size of mass
• Degree of airway compression
• Presence of significant amounts of pleural and/or pericardial effusions

Echocardiogram for evaluation of pericardial effusion and cardiac function.

Biopsy of a clinically involved peripheral lymph node under local anesthesia or from aspiration of pleural effusion, when present. If the disease is present exclusively in the anterior mediastinum, attempt biopsy (under local anesthesia) through a small suprasternal incision, or if possible, obtain a fine needle biopsy.

It is possible that all of the aforementioned procedures may be prohibitive because of the patient's poor clinical condition. Under these circumstances, treat the patient with corticosteroid with or without a limited radiation field until the mass is sufficiently small to permit a safe biopsy under general anesthesia. Corticosteroid and/or local radiotherapy can bring about rapid resolution of SVC obstruction.

Management of Pericardial Effusion

Pericardial effusion can cause life-threatening cardiac tamponade. Pericardial rub, S-T segment elevation on an electrocardiogram (ECG), a globular-shaped heart on a chest radiograph, and cardiac ultrasonography establish the diagnosis. When signs of cardiac tamponade (pulsus paradoxus, elevated venous pressure, or hypertension) are present, pericardiocentesis should be performed. The cytology of the fluid should be examined. Prompt treatment with chemotherapy is necessary to prevent the reaccumulation of fluid.

Management of Gastrointestinal Complications

The abdominal disease is more commonly observed in patients with small noncleaved non-Hodgkin's lymphoma. The following complications are of immediate significance:

Small bowel obstruction: NHL of the GI tract commonly involves the terminal ileum and the cecum. The tumor can cause bowel obstruction, either by compression of the bowel lumen or by intussusception. In about 25% of patients, the tumor can be resected completely. Chemotherapy should begin within a few days of surgery.

Gastric bleeding or perforation: Endoscopic examination should be performed to identify patients at high risk for massive bleeding and/or perforation by noting the extent of involvement of the stomach wall, degree of ulceration, and necrosis. High-risk patients should be treated with resection of the tumor (involving total or partial gastrectomy, depending on the extent of the tumor) before starting chemotherapy.

Management of Tumor Lysis Syndrome

In patients with high tumor burden, especially those with stage III and stage IV small noncleaved cell lymphoma, B-cell acute lymphoblastic leukemia, and T-cell leukemia/lymphoma syndrome, the following metabolic complications can occur before starting chemotherapy:

• Renal failure
• Hyperuricemia
• Hyperphosphatemia
• Hypocalcemia
• Hyperkalemia

These complications are observed in the previously mentioned conditions because these tumors have high growth fractions and they are exclusively sensitive to chemotherapy. As a consequence, there is a rapid release of intracellular metabolites (such as phosphorous, potassium, and uric acid) in quantities that exceed the excretory capacity of the kidneys.

Renal failure: Mechanism of renal failure:

• Precipitation of urates in the acid environment of urine
• Precipitation of hypoxanthine when the urine pH exceeds 7.5
• Increase in the hypoxanthine levels after starting treatment with allopurinol
• Precipitation of calcium phosphate in renal microvasculature and renal tubules when the calcium x phosphate values exceed 60 (lymphoblasts contain four times the amount of phosphate present in normal lymphocytes).

Treatment

Hemodialysis or arteriovenous (A-V) hemofiltration should be used when renal failure occurs. Peritoneal dialysis should not be used. Chemotherapy such as cyclophosphamide is given immediately after dialysis and not before. Renal dialysis usually needs to be repeated every 12 hours because of continuous rapid tumor lysis.

Indications for renal dialysis are:

• An estimated glomerular filtration rate (GFR) less than 50%[ Estimated GFR = {Height (in cm) x 0.5}/Serum creatinine in (mg/dl)]
• Congestive heart failure
• Anuria
• Symptomatic hypocalcemia with hyperphosphatemia
• Hyperkalemia with QRS interval widening and/or potassium greater than 6.0 mEq/l.
• High creatinine with poor urinary output
• Blood pressure (BP) higher than 150/90 and urinary output inadequate at 10 hours from the start of treatment

Hyperuricemia (>8 mg/dl)

• Allopurinol: 100 mg/m2/dose tid.
• Hydration: Begin hydration at 3000 ml/m2/24 h and increase as needed to maintain urine output. The aim is to maintain urine output at 5 ml/kg/h or more before initiating chemotherapy and at 3 ml/kg/h or more once chemotherapy is begun. Strict measurement of intake and output should be carried out and verified every 2-4 hours. Insert a Foley catheter for continuous monitoring of urinary output. If urine output falls (i.e. less than 75% of input), increase hydration fluid and/or administer diuretics (furosemide/Lasix 0.5-1 mg/kg/dose or mannitol 5-15 g/m2 as 25% solution over 5-10 minutes, repeated every 6 hours as necessary). If, at 10 hours from the start of treatment, the BP is less than 130/90 and the urinary output is still inadequate, dopamine 5 mcg/kg/min should be started.
• Alkalinization of urine: To increase the solubility of the urates, alkalinize the urine with sodium hydrocarbonate (NaHCO3), which will maintain the urine pH between 6.5 and 7.5. A urine pH greater than 7.5 is associated with the precipitation of hypoxanthine and calcium phosphate in renal tubules and should be avoided. Administer NaHCO3 120 mEq/m2/24 h in IV hydration fluid.
• If the urine pH is less than 6.5 increase NaHCO3 and/or start Diamox 300 mg/m2 q6h.

Hyperphosphatemia (>6.5 mg/dl)

• Prescribe a low phosphate diet
• Administer aluminum hydroxide 150 mg/kg/day PO divided q4-6h
• Maintain urine output at 3 ml/kg/h or more

Hypocalcemia (ionized calcium <1.5 mEq/l)

• When calcium x phosphate is greater than 60 due to hyperphosphatemia, a compensatory hypocalcemia occurs to maintain the calcium phosphate product at 60.
• For symptomatic hypocalcemia (e.g. tetany), give 10 mg/kg of elemental calcium (i.e. 0.5-1.0 ml/kg 10% calcium gluconate). Discontinue administration when symptoms resolve. Consider dialysis if hyperphosphatemia is present. (Caution: Do not administer calcium in the same intravenous line as NaHCO3).

Hyperkalemia (>6.0 mEq/l)

• High potassium (K+) results from tumor cell lysis and/or renal failure.
• Do not administer K+ until tumor lysis is controlled.

Use the following measures to drive K+ into the cells:
NaHCO3: 1-2 mEq/kg IV. For every increase in 0.1 pH unit, K+ is decreased by about 1 mEq/l. The onset of action is within ½ hour and the duration of activity lasts several hours.

Insulin and glucose: Use dextrose 0.5 g/kg/h with insulin 0.1 unit/kg/h. Monitor serum glucose closely. In case of emergency, glucose can be used at 1 ml/kg of 50% dextrose through a central line. The onset of action is within 20-30 minutes and the duration of activity lasts several hours.

For life-threatening arrhythmias, administer calcium as calcium chloride 10 mg/kg IV. The onset of action is within minutes and the duration of action lasts about ½ hour. (Caution: Do not administer calcium in the same line as NaHCO3).

Administer sodium polystyrene sulfonate (kayexalate) to remove 1 mEq K/1/g resin over 24 hours. Give as 1 g/kg PO q6h with sorbitol 50-150 ml. The duration of action depends on the rate of endogenous K+ release.

Adjust antibiotics and other drug dosages appropriate for the level of renal failure as determined by blood urea nitrogen (BUN) and creatinine.

Treatment Groups

Treatment groups can be divided into the following categories:

• Localized NHL
• Stage III small noncleaved NHL
• Stage IV small noncleaved NHL, including B-cell acute lymphoblastic leukemia
• Stage III and IV lymphoblastic NHL
• Stage III and IV Ki-1+ Anaplastic large cell lymphoma

Localized Non-Hodgkin's Lymphoma

Patient eligibility criteria include:

• Less than or equal to 21 years of age at the time of diagnosis.
• Histology-proven diagnosis of diffuse, non-Hodgkin's lymphoma: In the working formulations - lymphoblastic, diffuse small noncleaved cell (Burkitt's and non-Burkitt's types), diffuse large cell (cleaved, non-cleaved, and immunoblastic subtypes), and large cell anaplastic lymphoma Ki-1+ subtype. In the Rapport classification - lymphoblastic (convoluted or non convoluted) diffuse, histiocytic, or diffuse undifferentiated (Burkitt's and non-Burkitt's types).
• Stage I or II by the Murphy staging system. In this staging system, the following patients are eligible:
  

  1. One or more nodal areas on the same side of the diaphragm
  2. One or more extranodal tumors with or without regional nodes on the same side of the diaphragm
  3. A primary gastrointestinal tumor (usually ileocecal) with or without mesenteric nodules
  4. Primary NHL of skin localized to a single site with or without regional nodes
  5. Involvement of single bone
  6. Primary head and neck
  7. The base of skull involvement without cranial nerve involvement, negative brain CT or MRI, and negative cerebrospinal fluid cytology.

Table 5: Treatment Regimens for Patients with Localized Non-Hodgkin's Lymphoma

Consolidation begins on day 43

Optional: give Mesna 400 mg/m2 i.v. push 15 minutes prior to and 3 hours after cyclophosphamide administration

Continuation therapy (i.e. maintenance therapy) starts on day 64,; only for patients with lymphoblastic lymphoma

Central nervous system therapy: triple intrathecal chemotherapy only for patients with head and neck primaries.

Note: Diagnostic lumbar puncture is performed on days 1 and 64. Remission status is assessed on day 64 with a physical examination, radio imaging studies, bone marrow, and lumbar puncture.

Results:

• Localized nonlymphoblastic lymphoma: 5-year rate of continuous complete remission 90%

• Localized lymphoblastic lymphoma: 5-year rate of continuous remission 65%

• Stage III Small noncleaved Non-Hodgkin's Lymphoma: 80% event-free 5-year survival.

• Stage IV Small noncleaved Non-Hodgkin's Lymphoma including B-cell Acute Lymphoblastic Leukemia: 80% event-free 5 year survival.

  Stage III and IV Lymphoblastic Non-Hodgkin's Lymphoma: Event-free survival at 6 years is 79+6% and 79+9%, respectively.

Treatment of Recurrent Non-Hodgkin's Lymphoma

Aggressive treatment should be considered for patients who relapse after completion of therapy. Following induction of remission, allogeneic, or autologous bone marrow transplantation should be considered.

Radiation Therapy

Generally, radiotherapy is not indicated on an elective basis. It is only indicated for acute life-threatening complications, such as superior vena cava syndrome, ureteric obstruction from the tumor, or hyperbilirubinemia from severe liver involvement, which might preclude initiation of chemotherapy at diagnosis. In B-cell NHL with central nervous system (CNS) involvement, cranial irradiation should not be used. The use of cranial irradiation for CNS prophylaxis is controversial. However, it is used in many of the protocols to treat advanced-stage lymphoblastic lymphoma.

Surgical Therapy

The role of surgery in NHL treatment is limited. It should be performed on patients in whom there is good reason to believe that total resection can be achieved (e.g. localized bowel disease) without a mutilating procedure (e.g. amputation, extensive faciomaxillary surgery, exenterations) or an excessively risky procedure. Patients with widespread lymphoma are not eligible for surgical resection, but the presence of a single nonresectable mass in addition to a totally resectable mass will not exclude patients from surgical treatment.

Non-Hodgkin's Lymphoma - Prognosis

Table 6. Factors Associated with Favorable and Unfavorable Prognosis

Favorable Prognosis

• Primary site

• Stage I and II: Head and neck (non-parameningeal)

• Peripheral nodes

• Abdominal site: 80% or greater 2-year survival (recurrence after 2 years rare)

Unfavorable Prognosis

• Stage of disease: Stage III or IV

• Stage IV with CNS involvement: Worst prognosis

• Site of disease: Parameningeal stage II, all stages of extranodal, extralymphatic NHL in head and neck area (sinus, jaw, orbit, scalp), presence of pleural effusion in stage III small noncleaved cell lymphoma

• Incomplete initial remission within 2 months

• Soluble IL-2R level: >1000 units/ml

• Lactic dehydrogenase (LDH) level: >1000 units/l

• Uric acid level: >7.1 ug/dl