eMedicine Specialties > Hematology > Stem Cells and Disorders
Lymphoma, Malignant Anaplastic (Ki 1+)
Updated: Dec 12, 2008
Introduction
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.1,2,3
Anaplastic large cell lymphoma (ALCL) 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, anaplastic large cell lymphomas (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, npm-alk, served as an additional diagnostic and subclassification tool for this lymphoma. Approximately 85% of these tumors express a chimeric protein, with 70% expressing npm-alk (nucleophosmin-anaplastic lymphoma kinase), and the other 15% expressing x -alk, due to variant translocations other than t(2,5). ALK, a tyrosine kinase, is believed to be directly involved in lymphomagenesis through its interactions with the substrates in multiple signaling pathways.
Several different clinical and pathologic variants of CD30-positive large cell lymphoma and other diseases with pathologic similarities to anaplastic large cell lymphoma (ALCL) exist.1,2,3,4,5,6 The overlap and heterogeneity have led to controversy over which diagnostic criteria should be used in anaplastic large cell lymphoma (ALCL) and whether certain subtypes should be considered as completely separate diseases.
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Related eMedicine topics:
Cutaneous CD30+ (Ki-1) Anaplastic Large-Cell Lymphoma
Lymphoma, Non-Hodgkin
Malignant Lymphoma
Pathophysiology
Anaplastic large cell lymphoma (ALCL) can be divided clinically into primary and secondary subforms, with the de novo type further subclassified into systemic, cutaneous, and human immunodeficiency virus (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, anaplastic large cell lymphoma (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 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 anaplastic large cell lymphoma (ALCL) 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 anaplastic large cell lymphoma (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 anaplastic large cell lymphoma (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 anaplastic large cell lymphoma (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 anaplastic large cell lymphoma (ALCL) have translocation between chromosomes 2 and 5, resulting in a fusion protein that joins the N-terminus of NPM to the C-terminus of 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 anaplastic large cell lymphoma (ALCL). Various other less common ALK fusion proteins are associated with anaplastic large cell lymphoma (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 promoter that regulates its expression. The other clinical subtypes of anaplastic large cell lymphoma (ALCL), including the primary cutaneous form, are almost never ALK positive.
ALK– ALCLs tend to be more aggressive and are more likely to relapse. ALK+ and ALK– ALCLs have been found to have different gene-expression profiles. BCL6, PTPN12, CEBPB, and SERPINA1 genes were overexpressed preferentially in ALK+ ALCLs, whereas CCR7, CNTFR, IL22, and IL21 genes were overexpressed in ALK– ALCLs.6
Frequency
United States
Approximately 50,000 cases of non-Hodgkin lymphoma are diagnosed annually in the United States, which accounts for 4% of all cancers and cancer-related deaths per year.
International
Primary systemic anaplastic large cell lymphoma (ALCL) represents 2-8% of adult non-Hodgkin lymphoma cases and as many as 30% of childhood non-Hodgkin lymphoma cases.7,8,9,10,11 Primary cutaneous anaplastic large cell lymphoma (ALCL) is demonstrated in 9% of cutaneous lymphomas.
Anaplastic large cell lymphoma (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 anaplastic large cell lymphoma (ALCL) that express the ALK fusion protein and in patients whose disease is limited to the skin.
Age
Primary systemic anaplastic large cell lymphoma (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 anaplastic large cell lymphoma (ALCL) is 60 years, and it occurs only rarely in children and adolescents.
Clinical
History
- Primary systemic anaplastic large cell lymphoma (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 anaplastic large cell lymphoma (ALCL) usually manifests as a single or localized cluster of erythematous skin nodules, some of which may demonstrate superficial ulcerations.12,13,14 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 anaplastic large cell lymphoma (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 anaplastic large cell lymphoma (ALCL).
- Secondary anaplastic large cell lymphoma (ALCL) evolves from other lymphomas, most frequently from peripheral T-cell lymphomas, mycosis fungoides, Hodgkin disease, or lymphomatoid papulosis. This form of anaplastic large cell lymphoma (ALCL) tends to arise in older adults, is commonly ALK negative, and carries a poor prognosis.
- Patients with anaplastic large cell lymphoma (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, lymph node involvement, organomegaly, and evidence of cutaneous involvement.
Causes
The etiology of anaplastic large cell lymphoma (ALCL) is unknown. Unlike most lymphomas, a normal counterpart to this malignancy has yet to be recognized.
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References
Dalla-Favera R, Gaidano G. Lymphomas. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Vol 2. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:2215-387.
Rodriguez J, Pugh W, Romaguera J, Cabanillas F. Anaplastic Ki-1 + large-cell lymphoma. Cancer Invest. 1993;11(5):554-8. [Medline].
Stein H, Foss HD, Durkop H, et al. CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood. Dec 1 2000;96(12):3681-95. [Medline]. [Full Text].
Zinzani PL, Bendandi M, Martelli M, et al. Anaplastic large-cell lymphoma: clinical and prognostic evaluation of 90 adult patients. J Clin Oncol. Mar 1996;14(3):955-62. [Medline].
Benharroch D, Meguerian-Bedoyan Z, Lamant L, et al. ALK-positive lymphoma: a single disease with a broad spectrum of morphology. Blood. Mar 15 1998;91(6):2076-84. [Medline]. [Full Text].
Lamant L, de Reynies A, Duplantier MM, et al. Gene-expression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. Blood. Mar 1 2007;109(5):2156-64. [Medline]. [Full Text].
Gaidano G, Dalla-Favera R. Pathobiology of non-Hodgkin lymphomas. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:1213-29.
Coiffier B. Treatment of aggressive non-Hodgkin's lymphoma. Semin Oncol. Oct 1999;26(5 suppl 14):12-20. [Medline].
Lister TA, Armitage JO. Non-Hodgkin's lymphomas. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE, eds. Clinical Oncology. 2nd ed. Philadelphia, Pa: Churchill Livingstone; 2000:2658-719.
Pugh WC, McBride JA. The pathologic basis for the classification of non-Hodgkin lymphomas. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:1263-93.
van Besien K, Cabanillas F. Clinical manifestations, staging, and treatment of non-Hodgkin lymphoma. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:1293-339.
Beljaards RC, Kaudewitz P, Berti E, et al. Primary cutaneous CD30-positive large cell lymphoma: definition of a new type of cutaneous lymphoma with a favorable prognosis. A European Multicenter Study of 47 patients. Cancer. Mar 15 1993;71(6):2097-104. [Medline].
Paulli M, Berti E, Rosso R, et al. CD30/Ki-1-positive lymphoproliferative disorders of the skin -- clinicopathologic correlation and statistical analysis of 86 cases: a multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J Clin Oncol. Jun 1995;13(6):1343-54. [Medline].
Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. Jul 1 1997;90(1):354-71. [Medline]. [Full Text].
Porrata LF, Ristow K, Witzig TE, et al. Absolute lymphocyte count is independent of the anaplastic lymphoma kinase and predicts survival in primary anaplastic large cell lymphoma [abstract]. Blood. 2007;110:abstract 1335. [Full Text].
Foss HD, Anagnostopoulos I, Araujo I, et al. Anaplastic large-cell lymphomas of T-cell and null-cell phenotype express cytotoxic molecules. Blood. Nov 15 1996;88(10):4005-11. [Medline]. [Full Text].
Deconinck E, Lamy T, Foussard C, et al. Autologous stem cell transplantation for anaplastic large-cell lymphomas: results of a prospective trial. Br J Haematol. Jun 2000;109(4):736-42. [Medline].
Brugieres L, Deley MC, Pacquement H, et al. CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood. Nov 15 1998;92(10):3591-8. [Medline]. [Full Text].
Chabner BA, Allegra CJ, Curt GA, Calabresi P. Antineoplastic agents. In: Goodman LS, Limbird LE, Milinoff PB, et al, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:1273.
Longo G, Federico M, Pieresca C, et al. Anaplastic large cell lymphoma (CD30+/Ki-1+). Analysis of 35 cases followed at GISL centres. Eur J Cancer. Oct 1995;31A(11):1763-7. [Medline].
Reiter A, Schrappe M, Tiemann M, et al. Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: a prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies. J Clin Oncol. May 1994;12(5):899-908. [Medline].
Tilly H, Gaulard P, Lepage E, et al. Primary anaplastic large-cell lymphoma in adults: clinical presentation, immunophenotype, and outcome. Blood. Nov 1 1997;90(9):3727-34. [Medline]. [Full Text].
Zhang M, Yao Z, Zhang Z, et al. Effective therapy for a murine model of human anaplastic large-cell lymphoma with the anti-CD30 monoclonal antibody, HeFi-1, does not require activating Fc receptors. Blood. Jul 15 2006;108(2):705-10. [Medline]. [Full Text].
Zinzani PL, Pileri S, Bendandi M, et al. Clinical implications of serum levels of soluble CD30 in 70 adult anaplastic large-cell lymphoma patients. J Clin Oncol. Apr 1998;16(4):1532-7. [Medline].
Further Reading
Keywords
malignant anaplastic lymphoma, Ki-1+ anaplastic lymphoma, anaplastic large-cell lymphoma, Ki-1 lymphoma, CD30+, ALCL, anaplastic lymphoma kinase-positive lymphoma, ALK-positive lymphoma, anaplastic Ki-1+ large cell lymphoma, lymphoma, large cell anaplastic CD30+ Ki-1 lymphoma, Ki-1 large cell lymphoma, cutaneous and nodal Ki-1 positive anaplastic large cell lymphoma, cutaneous lymphoma, skin cancer, cancer, extranodal lymphoma, extra-nodal lymphoma, systemic lymphoma, systemic cancer, anaplastic lymphoma, systemic anaplastic large-cell lymphoma
