AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

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

INTRODUCTION

Section 2 of 9  

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

Background

Anaplastic large cell lymphomas (ALCLs) are distinguished from other lymphomas by their anaplastic cytology and constant membrane expression of the CD30 antigen. Striking clinical features include frequent cutaneous and extranodal involvement, young age at presentation, and male predominance. This malignancy was recognized in 1985, when tumor cells consistently demonstrated labeling by the monoclonal antibody Ki-1, a marker later shown to recognize the CD30 receptor. In 1988, ALCL was added as a distinct entity to the revised Kiel classification, and, in 1994, it was included in the Revised European-American Lymphoma (REAL) classification.

In the late 1980s, an unusual chromosomal translocation, t(2,5), was noted in many of these CD30-positive tumors. In 1994, the discovery of its chimeric protein product served as an additional diagnostic and subclassification tool for this lymphoma. Several different clinical and pathologic variants of CD30-positive large cell lymphoma and other diseases with pathologic similarities to ALCL exist. The overlap and heterogeneity have led to controversy over which diagnostic criteria should be used in ALCL and whether certain subtypes should be considered as completely separate diseases.

Pathophysiology

ALCL can be divided clinically into primary and secondary subforms, with the de novo type further subclassified into systemic, cutaneous, and HIV-related forms. The primary systemic and cutaneous forms are the predominant subtypes. All types strongly express the CD30 antigen on cell membranes, and histologic review reveals the characteristic tumor cells. In addition to various clinical forms, pathologic variants exist that differ with respect to morphology, immunophenotype, and other antigen markers.

Histologically, ALCL is characterized most commonly by sheets of large pleomorphic cells, abundant cytoplasm, horseshoe- or wreath-shaped nuclei, and multiple prominent nucleoli. These hallmark tumor cells may be multinucleated and can be similar to Reed-Sternberg cells in appearance. The growth pattern in lymph nodes (LNs) is diffuse, and, for partially involved nodes, it shows a predilection for paracortical and sinusoidal regions.

Additional morphologic subforms distinct from the above classic type do not appear to represent separate disease entities. Morphologic variants include the following:

• The monomorphic subtype demonstrates a rather nonanaplastic appearance.
• The small cell subtype contains a mixture of small and large lymphocytes, with the CD30 antigen expression mainly limited to the larger cells. This subtype is more common in children and can transform into the common type and vice versa.
• The lymphohistiocytic type has a predominance of histiocytes and a minority of hallmark cells and, therefore, can present a diagnostic challenge. Tumor cells in the giant cell–rich type are frequently multinucleated.
• The Hodgkinlike type refers to ambiguous cases in which the tumor histologically resembles both ALCL and Hodgkin disease.
• Rare additional histologic types exist that include sarcomatoid, neutrophil-rich, eosinophil-rich, and signet-ring forms. In addition, as many as 15% of patients have features of more than one morphologic subtype.

Immunophenotyping in ALCL exhibits consistently strong CD30 expression in all clinical and pathologic subtypes. Most tumor cells are of the null or T-cell phenotype, and the demonstration of clonally rearranged TCR genes, in most cases of both T-type and null-type ALCL, suggest that null-type ALCL is a variant of T-type ALCL. B-cell antigenic expression is rare and is commonly observed in the HIV-related clinical form. In fact, these B-cell cases are classified separately in the Kiel classification, and, in the REAL and World Health Organization classifications, they are grouped under diffuse, large, B-cell lymphoma. Epithelial membrane antigen (EMA) expression is strongly positive in the most common morphologic types of ALCL, which include the classic, small cell, and lymphohistiocytic types. EMA analysis is also useful in the clinical subtype distinction, with strong expression observed in the primary systemic form and little or no expression in the other clinical forms.

Most patients with the primary systemic clinical subtype of ALCL have an unusual 2;5 translocation, expressing a fusion protein that joins the N-terminus of nucleophosmin (NPM) to the C-terminus of anaplastic lymphoma kinase (ALK). The wild-type NPM protein demonstrates ubiquitous expression and functions as a carrier of proteins from the cytoplasm into the nucleolus. The ALK wild type has its postnatal expression limited to a few cells in the nervous system and functions as a tyrosine kinase receptor. The 2;5 translocation brings the ALK gene portion encoding the tyrosine kinase on chromosome 2 under control of the NPM promoter on chromosome 5, producing permanent expression of the chimeric NPM-ALK protein (p80).

The resultant aberrant tyrosine kinase presumably triggers malignant transformation via constitutive phosphorylation of intracellular targets. The NPM/ALK rearrangements are very specific, and within the non-Hodgkin lymphoma (NHL) spectrum, they are restricted to T-cell lineage ALCL. Various other less common ALK fusion proteins are associated with ALCL, including those resulting from t(1;2), t(2;3), inv(2), and t(2;22). All variants demonstrate linkage of the ALK tyrosine kinase domain to an alternative promotor that regulates its expression. The other clinical subtypes of ALCL, including the primary cutaneous form, are almost never ALK positive.

Frequency

United States

Approximately 50,000 cases of NHL are diagnosed annually in the United States, which accounts for 4% of all cancers and cancer-related deaths per year.

International

Primary systemic ALCL represents 2-8% of adult NHL cases and as many as 30% of childhood NHL cases. Primary cutaneous ALCL is demonstrated in 9% of cutaneous lymphomas. ALCL constitutes approximately 2% of all lymphomas and approximately 9% of high-grade lymphomas in the Kiel registry. It represents approximately 12% of childhood lymphomas and 70% of large cell pediatric lymphomas.

Sex

A male predominance occurs in cases of primary systemic ALCL that express the ALK fusion protein and in patients whose disease is limited to the skin.

Age

Primary systemic ALCL demonstrates a bimodal age distribution, with the first peak representing primarily ALK-positive patients who present during the second and third decades of life. The second peak occurs in individuals older than 60 years and mainly consists of ALK-negative patients.

• Of all cases, 15-20% occur in persons younger than 20 years.
• The mean age at presentation of primary cutaneous ALCL is 60 years, and it occurs only rarely in children and adolescents.

CLINICAL

Section 3 of 9  

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

History

• Primary systemic ALCL is typically in an advanced stage at patient presentation, and the disease is rapidly progressive. These patients demonstrate an increased frequency of bone marrow involvement (30%) and extranodal involvement, including skin (21%), bone (17%), soft tissues (17%), lung (11%), liver (8%), and, rarely, the gastrointestinal tract and central nervous system. Systemic symptoms are observed in 75% of patients, with fever the most common symptom.
• Primary cutaneous ALCL usually manifests as a single or localized cluster of erythematous skin nodules, some of which may demonstrate superficial ulcerations. As many as 25% of patients have some degree of spontaneous regression of these lesions. Although most cases present with local involvement, patients may rarely present with disseminated cutaneous disease and are at higher risk of developing spread to other organs.
• Most cases of HIV-related ALCL are actually of B-cell origin and seem instead to be related to the anaplastic variant of diffuse large B-cell lymphoma. Many patients demonstrate infection with the Epstein-Barr virus, which is absent in those with the T-cell or null-cell types of ALCL.
• Secondary ALCL evolves from other lymphomas, most frequently from peripheral T-cell lymphomas, mycosis fungoides, Hodgkin disease, or lymphomatoid papulosis. This form of ALCL tends to arise in older adults, is commonly ALK negative, and carries a poor prognosis.
• Patients with ALCL present with either a primary cutaneous form or a systemic form of the illness. Patients may present with isolated lymphadenopathy or with extranodal disease at any site, including the gastrointestinal tract and bone. Patients with infiltration into musculoskeletal tissues (eg, psoas muscle) can present with backache.

Physical

The initial diagnostic evaluation of patients with any lymphoproliferative malignancy should include a careful history and physical examination, with close attention to the presence of systemic B symptoms, LN involvement, organomegaly, and evidence of cutaneous involvement.

Causes

The etiology of ALCL is unknown. Unlike most lymphomas, a normal counterpart to this malignancy has yet to be recognized.

DIFFERENTIALS

Section 4 of 9  

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

Other Problems to be Considered

Metastatic carcinoma
Metastatic melanoma
Malignant histiocytosis
Lymphomatoid papulosis

WORKUP

Section 5 of 9  

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

Lab Studies

• The necessary imaging and laboratory tests to appropriately evaluate a patient who may have ALCL are similar to those recommended in the standard evaluation of aggressive NHLs and are described briefly, as follows:
• • Hematology: Complete blood cell count, peripheral smear review, bone marrow aspiration, and biopsy are standard.
  • Chemistry: Electrolyte evaluations, renal function studies, liver function tests and liver-associated enzyme tests, and uric acid evaluations are appropriate. Serum lactic dehydrogenase (LDH), beta2-microglobulin, and albumin values are useful for prognostic categorization. The LDH and beta2-microglobulin levels also serve as indirect indicators of tumor burden and proliferative activity.

Imaging Studies

• Chest radiographs are used to assess for lymphadenopathy, pleural effusions, and parenchymal lesions.
• CT scans of chest, abdomen, and pelvis should be performed, with close attention to lymphadenopathy, pleural effusions, pulmonary parenchymal lesions, splenomegaly, and hepatic and splenic filling defects.
• Ultrasound of the liver is indicated in patients who have abnormal results from laboratory liver function tests and normal hepatic imaging findings on CT scan images.
• Gallium scans, although not as useful in the initial staging workup, can be helpful for evaluating the response to treatment because continued positive uptake in a residual mass after completion of treatment is an indicator of persistent disease.
• MRI can be useful for detecting occult bone marrow lymphoma involvement, which is displayed as patchy distribution and thus will be missed on bone marrow biopsy findings. A spinal study is indicated for patients with epidural involvement and possible spinal cord compression.
• A bone scan is indicated if musculoskeletal symptoms are present or if the alkaline phosphatase level is elevated.
• Positron emission tomography scanning is gaining wider approval as a potential staging modality at both diagnosis and relapse.

Procedures

• Excisional biopsy of lymphadenopathy is necessary to confirm the diagnosis of ALCL. Critical assessments of cell morphology, LN architecture, immunophenotype, and molecular and cytogenetic analyses are indicated.
• Bone marrow aspiration and biopsy are performed to search for occult lymphoma involvement. Bilateral biopsies are routinely performed to increase the diagnostic yield.
• Immunophenotyping and immunohistochemistry study of the lymphoma cells is critical in the definitive diagnosis of ALCL. The major features of immunophenotype of ALCL typically include CD30⁺, CD15^-, and CD45⁺. (Hodgkin lymphoma typically expresses CD30⁺ and CD15⁺.) Sixty percent of cases express one or more T-cell antigens (CD3⁺, CD43, or CD45RO). ALK protein may be detected in most cases (60-70%) by immunohistochemistry.

Histologic Findings

The morphology of ALCL is similar within its major clinical subforms, the primary systemic and cutaneous varieties. The tumor cells are usually large, with abundant cytoplasm. They manifest prominent nucleoli, display an eccentrically located and pleomorphic nucleus that is often kidney-shaped, and tend to infiltrate LNs in a sinusoidal and paracortical pattern.

The malignant cells stain positive for the CD30 antigen, a very sensitive but nonspecific test result that is also positive in other lymphomas, including Hodgkin disease. Most cases exhibit either T-cell or null phenotype, with frequent CD3 expression, cytotoxic protein expression, clonal T-cell receptor gene rearrangements by polymerase chain reaction (PCR), and lack of B cell–associated markers. The primary systemic form, unlike the primary cutaneous form, generally stains positive for EMA and usually displays the t(2;5) translocation and the chimeric p80 protein with PCR and antibody studies.

Staging

The Cotswold modification of the Ann Arbor staging system is the standard anatomic staging system for NHL and Hodgkin disease and is used to evaluate the extent of disease in patients with ALCL. Accurate staging allows appropriate therapeutic selection and contributes to predicting the prognosis. Staging is as follows:

• Stage I - Involvement of a single LN region or lymphoid structure
• Stage II - Involvement of 2 or more LN regions on the same side of the diaphragm
• Stage III - Involvement of LN regions or structures on both sides of the diaphragm
• Stage IV - Involvement of extranodal sites beyond that designated as E (see below)
• Further staging designations include the following:
• • Suffix A - No symptoms (any disease stage)
  • Suffix B - Fever (temperature >38°C); drenching sweats; unexplained weight loss, eg, 10% of body weight within preceding 6 months (any disease stage)
  • Suffix E - Involvement of a single extranodal site that is contiguous or proximal to the known nodal site (stages I-III)
• Cotswold modifications are as follows:
• • Suffix X - Denotes bulky disease (a widening of the mediastinum by more than one third or the presence of a nodal mass with a maximal dimension of >10 cm)
  • Subscripts - Used to indicate the number of anatomic regions
  • Stage III subdivisions - May be subdivided to include III(1), with or without splenic, hilar, celiac, or portal nodes and III(2), with para-aortic, iliac, or mesenteric nodes
  • Further identification - Staging identified as clinical stage (CS) or pathological stage (PS)

TREATMENT

Section 6 of 9  

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

Medical Care

• Primary systemic ALCL
• • The current treatment approach for primary systemic ALCL is identical to that for other types of diffuse aggressive NHLs. Patients usually present in advanced stages, and intensive anthracycline-based chemotherapy offers a high chance of durable complete responses.
  • A combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the standard first-line treatment. If CD20 antigens are positive, rituximab should be added. Alternatively, substitution of mitoxantrone for doxorubicin (CNOP) or an equivalent third-generation regimen (eg, m-BACOD [ie, moderate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone], ProMACE/CytaBOM [ie, prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin calcium, concomitant trimethoprim/sulfamethoxazole DS], MACOP-B [ie, methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin], ACVB [ie, doxorubicin, cyclophosphamide, vindesine, bleomycin) can be used.
  • Radiation therapy to bulky sites of disease may be necessary after completion of chemotherapy.
  • Compared to patients with other types of diffuse aggressive lymphomas, patients with ALCL have increased and more prolonged response rates, with improved overall survival. The better prognosis holds particularly true for patients who are ALK positive, who have demonstrated significantly better survival rates than those who are ALK negative.
  • A recent prospective trial using high-dose chemotherapy and autologous stem cell transplantation (ASCT) as front-line treatment revealed an excellent 5-year overall survival rate of 87%, which was significantly better than for aggressive nonanaplastic lymphomas. To date, no published randomized trials compare ASCT to conventional combination chemotherapy regimens.
• Secondary forms of ALCL: These forms are associated with a poor prognosis and also warrant treatment with a regimen containing doxorubicin.
• Primary cutaneous ALCL
• • As many as one fourth of patients with primary cutaneous ALCL experience spontaneous regression of skin lesions.
  • Those with persistent localized disease can undergo surgical excision with or without radiation therapy and achieve excellent long-term survival. Those with disseminated skin involvement are more likely to experience progression to extracutaneous sites and thus may benefit from systemic combination chemotherapy.
  • The distinction of primary cutaneous ALCL from lymphomatoid papulosis, although difficult by pathologic means, should be attempted clinically because lymphomatoid papulosis tends to run a benign clinical course despite cycles of regression followed by relapse.

MEDICATION

Section 7 of 9  

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

The goals of pharmacotherapy are to induce remission, to reduce morbidity, and to prevent complications.

Drug Category: Antineoplastic agents

Intensive anthracycline-based chemotherapy offers a high chance of durable, complete responses. CHOP is the standard first-line treatment. The regimen consists of (1) cyclophosphamide, doxorubicin, vincristine, and prednisone q21d, (2) restaging after first 2 cycles to document response, and (3) continuing with 2 additional cycles after complete remission is documented (not to exceed 6-8 cycles).

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 9  

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

Further Outpatient Care

• Although late relapses can occur, patients with diffuse aggressive lymphomas usually experience recurrence within 2 years of completion of treatment. Early detection allows identification of potential candidates for high-dose therapy and stem cell transplantation. Periodic physical examinations and reimaging are recommended as follow-up care for those in remission. Long-term survivors need continued surveillance for potential treatment-associated complications.

Complications

• Tumor lysis syndrome (TLS) is a common complication of treatment for any high-grade, bulky, treatment-sensitive lymphoma and occurs after intracellular contents are released rapidly into the blood. The syndrome manifests as renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia; these metabolic derangements may lead to sudden death if left uncorrected. Prophylactic and treatment measures include allopurinol, alkaline diuresis, and correction of potassium and phosphate abnormalities. Patients with bulky or advanced-stage ALCL are at high risk of TLS and should receive prophylaxis, with close monitoring of fluid status, urine output, electrolytes, and renal function.
• Untreated or treatment-resistant systemic ALCL, like other aggressive systemic lymphomas, ultimately results in death, with variable earlier complications depending on the bulk and sites of disease.
• Long-term survivors of NHL are at increased risk of second malignancies, including all solid tumors, melanoma, Hodgkin disease, and acute myelogenous leukemia.

Prognosis

• Primary systemic ALCL: The prognostic factors applied to other NHLs are also relevant to ALCL and include age, LDH values, performance status, number of extranodal sites, and stage. These features are compiled in the International Prognostic Index, which provides stratification into risk groups and serves to identify patients for whom early experimental approaches may be considered. ALK status is also an important prognostic indicator because ALK-positive cases have demonstrated a significantly improved 5-year overall survival rate of 70-80%, versus 15-45% reported for those without ALK expression.
• Primary cutaneous ALCL: Localized skin presentation in those with pure cutaneous disease is associated with good long-term survival.
• Secondary ALCL: This is associated with poor prognosis.

Patient Education

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

REFERENCES

Section 9 of 9

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

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Article Last Updated: Aug 25, 2006