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Anaplastic large cell (CD30+) lymphoma

1. GENERAL INFORMATION

1.1 Definition

Anaplastic large cell lymphoma (ALCL) is the currently accepted term to define a unique type of lymphoma that strongly expresses the CD30 antigen, which can be recognized by the use of Ki67 antibody. Although other lymphomas express this antigen, there is sufficient evidence that the anaplastic type is a distinct clinicopathologic entity. This lymphoma has not been listed in the Working Formulation classification, while it was formerly recognized as large cell anaplastic lymphoma in the Kiel classification (Banks 1992; Lennert 1978). Anaplastic large cell lymphoma has been termed malignant histiocytosis, sinusoidal large cell lymphoma or regressing atypical histiocytosis. The postulated normal counterpart of ALCL is the presence of extrafollicular CD30+ blasts (Andreesen 1984).

1.2 Incidence

Anaplastic large cell lymphoma (ALCL) is a relatively infrequent tumour accounting for about 5% of all NHLs and 10% – 20% of the high-grade lymphomas (Delsol 1997).

1.3 Risk factors

No particular risk factor has been clearly identified for ALCL. Presently, there is no convincing evidence that viruses causing NHL in humans, such as Epstein-Barr virus, human T-cell leukemia/lymphoma virus family, or others, could be involved in the origin of ALCL. The pathogenesis implications of t(2;5) and NPM/ALK fusion product are matter of study. No particular correlation between ALCL and inherited immunological deficiency disease, or other immunological disorders has been reported. There are no convincing data concerning the role of chronic antigenic stimulation in the genesis of ALCL. Several chemical substances such as solvents, pesticides and fertilizers as well as dusts and particles, hair dye, smoking and diet have been suggested as possible aetiological factors in NHL (Weisenburger 1985). Among other pesticides, 2,4-D (Zahm 1990), organophosphate insecticides (Woods 1987) and phenoxy herbicides (La Vecchia 1989) have been suggested as aetiological agents, mainly of large-cell lymphomas. Although specific studies have not been undertaken in ALCL patients, all histotypes of NHL have been described as occurring in people whose work involves application of pesticides (Scherr 1992; Weisenburger 1990).

2. PATHOLOGY and BIOLOGY

2.1 Morphology

Anaplastic large cell lymphoma (ALCL) is composed of large blastic cells with pleomorphic, often horseshoe-shaped or multiple nuclei with multiple or single prominent nucleoli. Multinucleated forms may resemble Reed-Sternberg cells. The tumour cells are typically much larger than the cells of usual large cell lymphomas, with more abundant cytoplasm. The cells grow in a cohesive pattern and often preferentially involve the lymph node sinuses, as well as extranodal sites, such as soft tissue, bone and skin. There is a variable admixture of granulocytes and macrophages. A lymphohistiocytic variant occurs, in which reactive histiocytes predominate and the rare neoplastic cells may be smaller than classic ALCL cells (Pileri 1990), and a small cell variant has been described recently, whose relationship to classic ALCL remains to be determined (Kinney 1993). Many cases of ALCL were previously diagnosed as malignant histiocytic tumours, regressing atypical histiocytosis, metastatic carcinoma, melanoma, sarcoma, or lymphocyte-depleted Hodgkin’s disease. The majority of the tumours with the morphology described above express one or more T-cell-associated antigens, many express neither T- nor B-cell-associated antigens and in some cases express B-cell antigens. Although the literature is confusing, some evidence seems to suggest that T and “null” cases represent different antigenic expressions of the same malignancy. Several morphological variants of this malignancy such as common type, monomorphic, small cell predominant, lymphohistiocytic, neutrophil rich, and sarcomatoid variants have been described (Kadin 1997).

2.2 Immunophenotype

From an immunophenotyping point of view, ALCL cells are CD30+, CD45+/-, CD25+/-, EMA+/-, CD15-/+, CD3-/+, other T-cell-associated antigens variable, CD43-/+, CD45RO-/+, CD68- (PGM1-, KP1-/+), or lysozyme- (Leoncini 1990). H and Y blood group antigens have been observed in half the cases (Delsol 1991). Primary cutaneous cases are reported to lack EMA and express the cutaneous lymphocyte antigen (CLA) (de Bruin 1993a).

2.3 Genetic features

2.3.1

t(2;5) has been observed in a small series of systemic cases (Mason 1990). The gene at the 2p23 breakpoint encodes a tyrosine kinase, ALK (anaplastic lymphoma kinase). The gene rearranged at 5q35, the nucleophosmin gene (NPM) encodes a nucleolar phosphoprotein also known as nucleolar protein B23 or numatrin. The resulting fusion gene encodes a chimaeric protein, NPM/ALK (p80), consisting of a N-terminal portion of NPM fused to the catalytic domain of ALK (Landanyi 1997;Morris 1994). The NPM/ALK protein was independently isolated by Shiota el al. (Shiota 1994) in a screen for aberrant tyrosine kinases in a cell line of Ki-1 anaplastic large-cell lymphoma. True cytogenetic variants represent the rearrangement of one translocation partner with another gene, typically homologous to the usual translocation partner. Examples include the t(8;22) and t(2;8) variants of the t(8;14) (q24;q32), where MYC rearranges with one of the immunoglobulin light chain genes instead the IgH. Several cytogenetic variants of the t(2;5) have been reported. In the absence of molecular studies, the possibility that these represent masked or complex variants of t(2;5) resulting in a conventional NPM/ALK fusion could not be excluded. TCR rearrangement has been reported in 50% – 60% of cases, while 40% to 60% have no rearrangement of TCR or Ig genes.

3. DIAGNOSIS

3.1 Clinical presentations

Anaplastic large cell lymphoma (ALCL) is a rare tumour, but may be diagnosed with increasing frequency as its features are more widely recognized. Cases have been reported in all age groups; 15% to 30% of the cases in unselected series are under age 20. Most cases arise “de novo”, while some patients have a history of other lymphomas including mycosis fungoides or Hodgkin’s disease (Kaudewitz 1991). There are two major forms of ALCL that should be considered distinct categories: the systemic form, which may involve lymph nodes or extranodal sites, including the skin, but is not localized to the skin, and a primary cutaneous form, without extracutaneous spread at the time of the diagnosis (Mason 1990). ALCLs that present with systemic extracutaneous disease (with or without skin involvement) have a bimodal age distribution in children and adults, are clinically more aggressive, and are EMA+ and CLA-. In systemic ALCL, the clinical findings at the onset of disease differ according to histotype. The common and lympho-histiocytic variants most often present with multiple lymphadenopathies stage III-IV disease and fever (Pileri 195). Less frequent findings include mediastinal mass, bulky disease, bone lesions, spleen or skin infiltration, and raised LDH values (Pileri 1994). Bone marrow is rarely involved and the disease usually spares the central nervous system. A leukemic phase has been reported anecdotally (Anderson 1996). The primary cutaneous form occurs predominantly in adults, as a solitary, asymptomatic cutaneous or subcutaneous reddish-violet tumour, which is frequently located on upper or lower limbs, can be ulcerated, shows rapid growth, and at times may spontaneously regress. This form lacks EMA and expresses CLA, and may represent a continuous spectrum with lymphomatoid papulosis type A. The ALCL lympho-histiocytic type is more often observed in the first or second decade of life, although it is not exclusive to young people. The primary cutaneous form appears to be indolent and incurable, lacks the t(2;5)(p23;q35) and is ALK protein-negative. The systemic form appears to behave similarly to other large cell lymphomas, being moderately aggressive but potentially curable with aggressive therapy (Greer 1991; Mason 1990). ALCLs show different clinical presentation according to the ALK protein expression. ALK+ ALCLs mostly occur in children and young adults (mean age 22 years) with a male predominance, aggressive course, advanced disease, systemic symptoms, and extranodal involvement. ALK- ALCLs occur in older individuals, without gender predominance, and lower incidence of systemic symptoms and extranodal disease (Falini 1999).

3.2 Diagnostic criteria

Cases of ALCL have been reported in all age groups; 15% to 30% of the cases in unselected series are under age 20. Most cases arise “de novo”, while some patients have a history of other lymphomas including mycosis fungoides or Hodgkin’s disease (Kaudewitz 1991). There are two major forms of ALCL: the systemic form, which may involve lymph nodes or extranodal sites, including the skin, but is not localized to the skin, and a primary cutaneous form, without extracutaneous spread at the time of the diagnosis (Mason 1990). ALCL that present with systemic extracutaneous disease (with or without skin involvement) have a bimodal age distribution in children and adults, are clinically more aggressive, and are EMA+ and CLA-. In systemic ALCL, the clinical findings at the onset of disease differ according to histotype. The common and lympho-histiocytic variants most often present with multiple lymphadenopathies, stage III-IV disease and fever (Pileri 1995). Less frequent findings include mediastinal mass, bulky disease, bone lesions, spleen or skin infiltration, and raised LDH values (Pileri 1994). Bone marrow is rarely involved and the disease usually spares the central nervous system. The primary cutaneous form occurs predominantly in adults, as a solitary, asymptomatic cutaneous or subcutaneous reddish-violet tumour, which is frequently located on upper or lower limbs, can be ulcerated, shows rapid growth, and at times may spontaneously regress. This form lacks EMA and expresses CLA, and may represent a continuous spectrum with lymphomatoid papulosis type A. The ALCL lympho-histiocytic type is more often observed in the first or second decade of life, although it is not exclusive to young people. Although the primary cutaneous form appears to be indolent and incurable, the systemic form appears to behave similarly to other large cell lymphomas, being moderately aggressive but potentially curable with aggressive therapy (Greer 1991; Mason 1990). A single gold standard for the diagnosis of ALCL does not exist; the diagnosis requires both morphology and immunophenotype and, at least at present, restricting the diagnosis to ALK+ cases does not seem to be justified (Harris 1999). From a morphological point of view, ALCL could be suspected when the tumour is composed of large blastic cells with pleomorphic, often horseshoe-shaped or multiple nuclei with multiple or single prominent nucleoli. Multinucleated forms may resemble Reed-Sternberg cells. The tumour cells are typically much larger than the cells of usual large cell lymphomas, with more abundant cytoplasm. The cells grow in a cohesive pattern and often preferentially involve the lymph node sinuses, as well as extranodal sites, such as soft tissue, bone and skin. There is a variable admixture of granulocytes and macrophages. A lymphohistiocytic variant occurs, in which reactive histiocytes predominate and the rare neoplastic cells may be smaller than classic ALCL cells (Pileri 1990), and a small cell variant has been described recently, whose relationship to classic ALCL remains to be determined (Kinney 1993). From an immunophenotyping point of view, the ALCL cells are CD30+, CD45+/-, CD25+/-, EMA+/-, CD15-/+, CD3-/+, other T-cell-associated antigens variable, CD43-/+, CD45RO-/+, CD68- (PGM1-, KP1-/+), and lysozyme- (Leoncini 1990). H and Y blood group antigens have been observed in half the cases (Delsol 1991). Primary cutaneous cases are reported to lack EMA and express the cutaneous lymphocyte antigen (CLA) (de Bruin 1993a). Cytogenetic studies could contribute to diagnosis considering the presence of t(2;5) in several ALCL cases(Mason 1990). The gene at the 2p23 breakpoint encodes a tyrosine kinase, ALK (anaplastic lymphoma kinase). The gene rearranged at 5q35, the nucleophosmin gene (NPM) encodes a nucleolar phosphoprotein also known as nucleolar protein B23 or numatrin. The resulting fusion gene encodes a chimaeric protein, NPM/ALK (p80), consisting of a N-terminal portion of NPM fused to the catalytic domain of ALK (Ladanyi 1997; Morris 1994). The NPM/ALK protein was independently isolated by Shiota el al. (Shiota 1994) in a screen for aberrant tyrosine kinases in a cell line of Ki-1 anaplastic large-cell lymphoma. Several cytogenetic variants of the t(2;5) have been reported. TCR rearrangement has been reported in 50% – 60% of cases, while 40% to 60% have no rearrangement of TCR or Ig genes.

3.3 Additional useful tests

3.3.1

The consistency of the NPM/ALK rearrangement provides the basis for reliable and highly sensitive detection of the gene fusion by reverse transcriptase-polymerase chain reaction (Morris 1994). These procedure using NPM and ALK primers closely bracketing the fusion point of the chimaeric transcript has been reported to detect the fusion product in all Ki-1 anaplastic large-cell lymphoma cases with the translocation, with few exceptions (10%) (Shiota 1994; Weisenburger 1996). Negative cases may represent currently undescribed molecular variants of NPM/ALK lacking one or both of the usual primer sites, technical problems, insufficient sample, lack of amplifiable RNA template, or difficulties in karyotype interpretation. Other detection methods for the NPM/ALK rearrangement include Southern blotting, long range DNA polymerase chain reaction and fluorescence in situ hybridization (Hutchison 1997). Indirectly, the presence of the fusion has also been detected by demonstration of the ALK portion of the molecule by immunohistochemistry or in situ hybridization. A polyclonal antiserum to a peptide from the ALK kinase domain, the p80 antibody, has been found useful in the immunohistochemical detection of NPM/ALK in both frozen and formalin fixed paraffin embedded material (Shiota 1994). A monoclonal antibody, ALK1, has been developed and shown to be more effective in detecting NPM/ALK than the polyclonal p80 antibody (Pulford 1997).

4. STAGING

4.1 Staging procedures

Complete staging and work-up for ALCL is similar to that routinely used for nodal NHL. It includes an accurate physical examination, complete haematological and biochemical exams, total-body computerized tomography, gastrointestinal tract examination, and bone marrow aspirate and biopsy. Lymphangiography has been completely replaced by abdominal computerized tomography considering the higher sensitivity of tomography to detect mesenteric nodes and its capacity to show a true estimation of nodes size, which usually are underestimated with lymphangiography. Since the clinical relevance of marrow involvement and general statements for all NHL , marrow biopsy should be bilateral. Laparoscopy with multiple liver biopsies should be done only when there is a strong suspicion of liver involvement in a patient who would otherwise have stage I-II disease. Staging laparotomy and splenectomy should never be performed in ordinary clinical practice as a routine staging procedure. Although laparotomy-related mortality is lower than 1%, morbidity has been reported in up to 40% of patients (Herman 1977). The major factor that accounts for the limited need for laparotomy is the high yield of information from less morbid procedures and the recognition that precise definition of involvement probably has limited importance in treatment planning for most patients. Under certain circumstances, special procedures are required. CNS MRI or CT scan and CSF cytology examination is indicated in patients with neurological symptoms. Although extremely rare, bone lesions should be investigated by skeleton scanning, confirmed by routine X-ray studies, and biopsied if possible. Some particular sites of disease frequently involved by ALCL require special diagnostic procedures, such as gastrointestinal tract radiologic and endoscopic assessment. The staging of stomach and colon-rectum requires gastroscopy with several biopsy samples of macroscopically evident lesions, while the small intestine should be studied with contrasted radiological techniques. Ultrasonography and magnetic resonance imaging are useful to investigate the involvement of breast, soft tissue, salivary glands or orbits.

4.2 Staging system

The standard staging system used for ALCL is the same as that proposed for Hodgkin’s disease at the Ann Arbor Conference in 1971 (Carbone 1971). This system is currently used for all non-Hodgkin’s lymphomas, even if other staging systems are used in some extranodal lymphomas with particular biological behavior. The Ann Arbor staging system reflects both the number of sites of involvement and the presence of disease above or below the diaphragm. This staging system considers four stage of disease: Stage I: involvement of a single lymph node region (I) or a single extranodal site (IE). Stage II: involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic site (IIE). Stage III: involvement of lymph nodes regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic site (IIIE) or spleen (IIIs) or both (IIIEs). Stage IV: diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement. Localized involvement of liver or bone marrow is also considered stage IV. Patients are divided in two subsets according to the presence (A) or absence (B) of systemic symptoms. Fever of no evident cause, night sweats and weight loss of more than 10% of body weight are considered systemic symptoms. Even though it is a frequent accompanying symptom, itch should not be considered as a systemic symptom. The presence of bulky mass, such as a lesion of 10 cm or more in the longest diameter is signaled as “X”, while the extranodal involvement should be identified by a symbol (O: bone, L: lung, D: skin, etc.).

4.3 Molecular analysis of minimal residual disease

Molecular monitoring of minimal residual disease is not routinely used in ALCL.

4.4 Restaging procedures

Restaging should include all the diagnostic procedures positive at time of diagnosis and initial staging.

5. PROGNOSIS

5.1 Natural history

5.1.1

The cutaneous form or primary ALCL at times spontaneously regresses, perhaps as a result of a suppressive effect of tumour growth by transforming growth factor b. The tumour remains restricted to the skin for a long period, while evolution to a systemic disease occurs in the 25% of cases. Tumours respond well to local treatment (surgery, radiotherapy) and are associated with a good prognosis: median survival 42 months (Beljaards 1993). On the other hand, when ALCL develops in the skin as a secondary form or represents an example of skin involvement in patients with systemic disease, it tends to be quite aggressive. Lymphomatoid papulosis and regressing atypical histiocytosis are two distinct clinical entities related to cutaneous ALCL. Both of them undergo spontaneous regression and show, respectively, scattered and relatively high numbers of CD30+ large atypical cells carrying T-cell phenotype and clonal TCR-b gene rearrangements. Lymphomatoid papulosis, regressing atypical, and cutaneous ALCL might represent a spectrum of one disease, whose histologic and clinical characteristics depend on the host immune response or the aggressiveness of the neoplastic component (Kadin 1994). The systemic form of ALCL was long regarded as being a very aggressive, incurable disease. This was due to the fact that all the studies had been carried out retrospectively and included cases originally diagnosed and treated as non-lymphoid tumours. Furthermore, treatment was frequently delayed due to the difficulties in making a definite diagnosis. More recent studies show that primary systemic ALCL, common, and a lympho-histiocytic type are very sensitive to aggressive chemotherapy and achieve the same complete remission and overall survival rates as the other variants of high-grade NHLs. In particular, the occurrence in childhood is usually associated with a very favorable prognosis, with a 5-year overall survival of 80%. Secondary ALCL runs a much more aggressive clinical course than the primary forms, with a 4-yr overall survival rate of 20% (Kadin 1994; Stein 1991).

5.2 Prognostic factors

The main prognostic indicators for ALCL are age, Ann Arbor stage, bulky disease, LDH level, performance status, histology, B symptoms, serum albumin level, bone marrow involvement, and extranodal involvement (Tilly 1997; Zinzani 1996). The serum soluble CD30 levels have been reported as negative prognostic indicators in these patients (Zinzani 1998a). The International Prognostic Index developed for aggressive lymphomas in general predicts survival in patients with ALCL, with a 5-year survival of 82% for the low risk group, 78% for the low-intermediate risk group, 50% for the intermediate-high risk group, and 26% for the high-risk group (Tilly 1997). The ALK protein expression has been proposed as an independent predictor of survival in ALCLs (Falini 1999). Overall survival of ALK+ ALCLs is far better than that of ALK- ALCLs with a 5-yr OS of 71% and 15%, respectively. Within the good prognostic group of ALK+ ALCLs, survival is significantly different among subgroups divided according to the International Prognostic Index (Falini 1999).

6. TREATMENT

6.1 Treatment of primary ALCL

Combined treatment with primary systemic conventional-dose anthracycline-containing polychemotherapy which may or may not be followed by radiation therapy is the standard option for patients with primary ALCL. The use of third-generation regimens produces a complete remission and overall response rates in the range of 80% to 90% of cases (Zinzani 1996). The overall relapse rate in complete responders is approximately 25%. With this strategy, 5-yr overall survival is 60% – 65% and the 5-yr relapse-free survival 65% – 80% (Zinzani 1996). No significant differences in the effectiveness of chemotherapeutic regimens were observed in a series of 90 patients with ALCL registered in a randomized trial that compared F-MACHOP and MACOP-B regimens in a large group of patients with aggressive lymphomas (Zinzani 1996). In patients with residual mediastinal masses, radiotherapy is recommended on a type R basis (Zinzani 1998b), while consolidation radiotherapy in complete responders is suitable for individual clinical use on a type 3 level of evidence (Zinzani 1998b; Zinzani 1996; Fanin 1996a). Primary systemic conventional-dose polychemotherapy followed by autologous bone marrow transplantation (ABMT) is investigational . In a series of 16 patients with primary systemic ALCL, primary F-MACHOP chemotherapy followed by ABMT and radiation therapy to residual mediastinal masses produced a complete response rate of 100% and an overall survival rate of 100% after a median follow-up of 45 months (Fanin 1996a).

6.2 Treatment of secondary ALCL

Although most ALCL cases arise “de novo”, some patients affected by this malignancy have a history of other lymphomas including mycosis fungoides or Hodgkin’s disease (Kaudewitz 1991). Secondary ALCL runs a much more aggressive clinical course than the primary forms, with a 4-yr overall survival rate of 20% (Kadin 1994; Stein 1991). In these patients, primary systemic conventional-dose anthracycline-containing polychemotherapy is suitable for individual clinical use on a type 3 level of evidence.

6.3 Treatment of relapsed or refractory disease

High-dose chemotherapy supported by autologous bone marrow transplantation is suitable for individual clinical use on a type R basis in patients relapsed after conventional-dose first-line chemotherapy (Zinzani 1998b; Fanin 1996a).

INDEX

Akhtar M, al-Dayel F, Siegrist K, Ezzat A. Neutrophil-rich Ki-1-positive anaplastic large cell lymphoma presenting as a testicular mass. Mod Pathol 1996; 9: 812-815 [Medline]

Amagai M, Kawakubo Y, Tsuyuki A, Harada R. Lymphomatoid papulosis followed by Ki-1 positive anaplastic large cell lymphoma: proliferation of a common T-cell clone. J Dermatol 1995; 22: 743-746 [Medline]

Anderson MM, Ross CW, Singleton TP, Sheldon S, Schnitzer B. Ki-1 anaplastic large cell lymphoma with a prominent leukemic phase. Hum Pathol 1996; 27: 1093-1095 [Medline]

Andreesen R, Osterholz J, Lohr GW, Bross KJ. A Hodgkin cell-specific antigen is expressed on a subset of auto- and alloactivated T (helper) lymphoblasts. Blood 1984; 63: 1299-1302 [Medline]

Arber DA, Sun LH, Weiss LM. Detection of the t(2;5)(p23;q35) chromosomal translocation in large B- cell lymphomas other than anaplastic large cell lymphoma. Hum Pathol 1996; 27: 590-594 [Medline]

B. Falini, S. Pileri, P. L. Zinzani, A. Carbone, V. Zagonel, C. Wolf-Peeters, et al. ALK+ lymphoma: clinico-pathological findings and outcome. Blood 93 (8):2697-2706, 1999. [Medline]

Banks PM. Incorporation of immunostaining data in anatomic pathology reports. American Journal of Surgical Pathology 1992; 16: 808 [Medline]

Beljaards RC, Kaudewitz P, Berti E, Gianotti R, Neumann C, Rosso R, 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 1993; 71: 2097-2104 [Medline]

Brice P, Cazals D, Mounier N, Verola O, Neidhart-Berard AM, Remenieras L, et al. Primary cutaneous large-cell lymphoma: analysis of 49 patients included in the LNH87 prospective trial of polychemotherapy for high-grade lymphomas. Groupe d’Etude des Lymphomes de l’Adulte. Leukemia 1998; 12: 213-219 [Medline]

Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1860-1861 [Medline]

Chen GS, Chang YF, Chang MC, Tsan KW. Response of Epstein-Barr virus-associated Ki-1+ anaplastic large cell lymphoma to 13-cis retinoic acid and interferon alpha. J Formos Med Assoc 1998; 97: 420-424 [Medline]

Clavio M, Rossi E, Truini M, Carrara P, Ravetti JL, Spriano M, et al. Anaplastic large cell lymphoma: a clinicopathologic study of 53 patients. Leuk Lymphoma 1996; 22: 319-327 [Medline]

de Bruin PC, Beljaards RC, van Heerde P, Van Der Valk P, Noorduyn LA, Van Krieken JH, et al. Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology 1993a; 23: 127-135 [Medline]

Decoteau JF, Butmarc JR, Kinney MC, Kadin ME. The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large-cell lymphoma of nodal origin. Blood 1996; 87: 3437-3441 [Medline]

Delsol G, Blancher A, al Saati T, Ralfkiaer E, Lauritzen A, Bruigeres L, et al. Antibody BNH9 detects red blood cell-related antigens on anaplastic large cell (CD30+) lymphomas. Br J Cancer 1991; 64: 321-326 [Medline]

Delsol G, Lamant L, Mariame B, Pulford K, Dastugue N, Brousset P, et al. A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2; 5 translocation. Blood 1997; 89: 1483-1490 [Medline]

Falini B, Liso A, Pasqualucci L, Flenghi L, Ascani S, Pileri S, et al. CD30+ anaplastic large-cell lymphoma, null type, with signet-ring appearance. Histopathology 1997; 30: 90-92 [Medline]

Falini B, Pileri S, Zinzani PL, Carbone A, Zagonel V, Wolf-Peeters C, et al. ALK+ lymphoma: clinico-pathological findings and outcome. Blood 1999; 93: 2697-2706 [Medline]

Fanin R, Silvestri F, Geromin A, Cerno M, Infanti L, Zaja F, et al. Primary systemic CD30 (Ki-1)-positive anaplastic large cell lymphoma of the adult: sequential intensive treatment with the F-MACHOP regimen (+/- radiotherapy) and autologous bone marrow transplantation. Blood 1996a; 87: 1243-1248 [Medline]

Fanin R, Silvestri F, Geromin A, Cerno M, Infanti L, Zaja F, et al. Sequential intensive treatment with the F-MACHOP regimen (+/- radiotherapy) and autologous stem cell transplantation for primary systemic CD30 (Ki-1)–positive anaplastic large cell lymphoma in adults. Leuk Lymphoma 1997; 24: 369-377 [Medline]

Fanin R, Silvestri F. Therapy of primary systemic CD30-positive anaplastic large-cell lymphoma of the adult. J Clin Oncol 1996b; 14: 3049-3050 [Medline]

Fraga M, Brousset P, Schlaifer D, Payen C, Robert A, Rubie H, et al. Bone marrow involvement in anaplastic large cell lymphoma. Immunohistochemical detection of minimal disease and its prognostic significance. Am J Clin Pathol 1995; 103: 82-89 [Medline]

Greer JP, Kinney MC, Collins RD, Salhany KE, Wolff SN, Hainsworth JD, et al. Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma. J Clin Oncol 1991; 9: 539-547 [Medline]

Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. World health organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting-airlie house, virginia, november 1997. J Clin Oncol 1999; 17: 3835-3849 [Medline]

Herman TS, Jones SE. Systematic re-staging in the management of non-Hodgkin’s lymphomas. Cancer Treat Rep 1977; 61: 1009-1015 [Medline]

Hutchison RE, Banki K, Shuster JJ, Barrett D, Dieck C, Berard CW, et al. Use of an anti-ALK antibody in the characterization of anaplastic large- cell lymphoma of childhood. Ann Oncol 1997; 8 Suppl 1:37-42: 37-42 [Medline]

Kadin ME. Anaplastic large cell lymphoma and its morphological variants. Cancer Surv 1997; 30:77-86: 77-86 [Medline]

Kadin ME. Primary Ki-1-positive anaplastic large-cell lymphoma: a distinct clinicopathologic entity. Ann Oncol 1994; 5 Suppl 1:25-30: 25-30 [Medline]

Kaudewitz P, Herbst H, Anagnostopoulos I, Eckert F, Braun-Falco O, Stein H. Lymphomatoid papulosis followed by large-cell lymphoma: immunophenotypical and genotypical analysis. Br J Dermatol 1991; 124: 465-469 [Medline]

King JA, Martino RL, Tucker JA. Anaplastic large-cell lymphoma (Ki-1 lymphoma) and diffuse large-cell immunoblastic lymphoma: two diagnostic problem cases. Ultrastruct Pathol 1998; 22: 55-62 [Medline]

Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME. A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. Am J Surg Pathol 1993; 17: 859-868 [Medline]

Kuze T, Nakamura N, Hashimoto Y, Abe M, Wakasa H. Clinicopathological, immunological and genetic studies of CD30+ anaplastic large cell lymphoma of B-cell type; association with Epstein- Barr virus in a Japanese population. J Pathol 1996; 180: 236-242 [Medline]

La Vecchia C, Negri E, D’Avanzo B, Franceschi S. Occupation and lymphoid neoplasms. Br J Cancer 1989; 60: 385-388 [Medline]

Ladanyi M. The NPM/ALK gene fusion in the pathogenesis of anaplastic large cell lymphoma. Cancer Surv 1997; 30:59-75: 59-75 [Medline]

Lamant L, Meggetto F, al Saati T, Brugieres L, de Paillerets BB, Dastugue N, et al. High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin’s disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. Blood 1996; 87: 284-291 [Medline]

Lennert K. Malignant lymphomas: other than Hodgkin’s disease: histology, cytology, ultrastructure, immunology. Berlin: Springer-Verlag. 1978 [Medline]

Leoncini L, Del Vecchio MT, Kraft R, Megha T, Barbini P, Cevenini G, et al. Hodgkin’s disease and CD30-positive anaplastic large cell lymphomas–a continuous spectrum of malignant disorders. A quantitative morphometric and immunohistologic study. Am J Pathol 1990; 137: 1047-1057 [Medline]

Longo G, Federico M, Pieresca C, Avanzini P, Iannitto E, Di Prisco AU, et al. Anaplastic large cell lymphoma (CD30+/Ki-1+). Analysis of 35 cases followed at GISL centres. Eur J Cancer 1995; 31A: 1763-1767 [Medline]

Mann KP, Hall B, Kamino H, Borowitz MJ, Ratech H. Neutrophil-rich, Ki-1-positive anaplastic large-cell malignant lymphoma. Am J Surg Pathol 1995; 19: 407-416 [Medline]

Mason DY, Bastard C, Rimokh R, Dastugue N, Huret JL, Kristoffersson U, et al. CD30-positive large cell lymphomas (‘Ki-1 lymphoma’) are associated with a chromosomal translocation involving 5q35. Br J Haematol 1990; 74: 161-168 [Medline]

McCluggage WG, Walsh MY, Bharucha H. Anaplastic large cell malignant lymphoma with extensive eosinophilic or neutrophilic infiltration. Histopathology 1998; 32: 110-115 [Medline]

Mitev L, Christova S, Hadjiev E, Guenova M, Oucheva R, Valkov I, et al. A new variant chromosomal translocation t(2;2)(p23;q23) in CD30+/Ki-1+ anaplastic large cell lymphoma. Leuk Lymphoma 1998; 28: 613-616 [Medline]

Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994; 263: 1281-1284 [Medline]

Mysore V, Bhusnurmath SR, Banodkar DD, al Suwaid AR. Ki-1 anaplastic large cell lymphoma. Int J Dermatol 1996; 35: 583-584 [Medline]

Nadali G, Vinante F, Stein H, Todeschini G, Tecchio C, Morosato L, et al. Serum levels of the soluble form of CD30 molecule as a tumor marker in CD30+ anaplastic large-cell lymphoma. J Clin Oncol 1995; 13: 1355-1360 [Medline]

Nakagawa A, Nakamura S, Ito M, Shiota M, Mori S, Suchi T. CD30-positive anaplastic large cell lymphoma in childhood: expression of p80npm/alk and absence of Epstein-Barr virus. Mod Pathol 1997; 10: 210-215 [Medline]

Nakamura S, Aoyagi K, Ohkuni A, Kimura Y, Tsuneyoshi M, Fujishima M. Rapidly growing primary gastric CD30 (Ki-1)-positive anaplastic large cell lymphoma. Dig Dis Sci 1998; 43: 300-305 [Medline]

Ott G, Bastian BC, Katzenberger T, Decoteau JF, Kalla J, Rosenwald A, et al. A lymphohistiocytic variant of anaplastic large cell lymphoma with demonstration of the t(2;5)(p23;q35) chromosome translocation. Br J Haematol 1998; 100: 187-190 [Medline]

Pileri S, Bocchia M, Baroni CD, Martelli M, Falini B, Sabattini E, et al. Anaplastic large cell lymphoma (CD30 +/Ki-1+): results of a prospective clinico-pathological study of 69 cases. Br J Haematol 1994; 86: 513-523 [Medline]

Pileri S, Falini B, Delsol G, Stein H, Baglioni P, Poggi S, et al. Lymphohistiocytic T-cell lymphoma (anaplastic large cell lymphoma CD30+/Ki-1 + with a high content of reactive histiocytes). Histopathology 1990; 16: 383-391 [Medline]

Pileri SA, Piccaluga A, Poggi S, Sabattini E, Piccaluga PP, de Vivo A, et al. Anaplastic large cell lymphoma: update of findings. Leuk Lymphoma 1995; 18: 17-25 [Medline]

Pileri SA, Pulford K, Mori S, Mason DY, Sabattini E, Roncador G, et al. Frequent expression of the NPM-ALK chimeric fusion protein in anaplastic large-cell lymphoma, lympho-histiocytic type. Am J Pathol 1997; 150: 1207-1211 [Medline]

Pittaluga S, Wiodarska I, Pulford K, Campo E, Morris SW, Van den Berghe H, et al. The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements. Am J Pathol 1997; 151: 343-351 [Medline]

Pulford K, Lamant L, Morris SW, Butler LH, Wood KM, Stroud D, et al. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 1997; 89: 1394-1404 [Medline]

Reinhold U, Frick M, Fischer J, Schupp G, Kreysel HW. High-dose chemotherapy with autologous stem cell transplantation in a patient with a CD30+ anaplastic large cell lymphoma of the skin. Br J Dermatol 1996; 134: 811-813 [Medline]

Romaguera JE, Garcia-Foncillas J, Cabanillas F. 16-year experience at M. D. Anderson Cancer Center with primary Ki-1 (CD30) antigen expression and anaplastic morphology in adult patients with diffuse large cell lymphoma. Leuk Lymphoma 1995; 20: 97-102 [Medline]

Scherr PA, Hutchison GB, Neiman RS. Non-Hodgkin’s lymphoma and occupational exposure. Cancer Res 1992; 52: 5503s-5509s [Medline]

Sgrignoli A, Abati A. Cytologic diagnosis of anaplastic large cell lymphoma. Acta Cytol 1997; 41: 1048-1052 [Medline]

Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori S. Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene 1994; 9: 1567-1574 [Medline]

Stein H, Herbst H, Anagnostopoulos I, Niedobitek G, Dallenbach F, Kratzsch HC. The nature of Hodgkin and Reed-Sternberg cells, their association with EBV, and their relationship to anaplastic large-cell lymphoma. Ann Oncol 1991; 2 Suppl 2:33-8: 33-38 [Medline]

Stenier C, Bourlond A, Humblet Y. Ki-1 anaplastic primary cutaneous large-cell lymphoma. Dermatology 1995; 190: 332-334 [Medline]

Takimoto Y, Tanaka H, Tanabe O, Kuramoto A, Sasaki N, Nanba K. Anaplastic large-cell lymphoma (Ki-1 lymphoma) with expression of IL-5 mRNA and eosinophilic invasion. Acta Haematol 1996; 96: 245-248 [Medline]

Tilly H, Gaulard P, Lepage E, Dumontet C, Diebold J, Plantier I, et al. Primary anaplastic large-cell lymphoma in adults: clinical presentation, immunophenotype, and outcome. Blood 1997; 90: 3727-3734 [Medline]

Tomaszewski MM, Lupton GP, Krishnan J, May DL. A comparison of clinical, morphological and immunohistochemical features of lymphomatoid papulosis and primary cutaneous CD30(Ki-1)- positive anaplastic large cell lymphoma. J Cutan Pathol 1995; 22: 310-318 [Medline]

Weisenburger DD, Gordon BG, Vose JM, Bast MA, Chan WC, Greiner TC, et al. Occurrence of the t(2;5)(p23;q35) in non-Hodgkin’s lymphoma. Blood 1996; 87: 3860-3868 [Medline]

Weisenburger DD. Environmental epidemiology of non-Hodgkin’s lymphoma in eastern Nebraska. Am J Ind Med 1990; 18: 303-305 [Medline]

Weisenburger DD. Lymphoid malignancies in Nebraska: a hypothesis. Nebr Med J 1985; 70: 300-305 [Medline]

Woods JS, Polissar L, Severson RK, Heuser LS, Kulander BG. Soft tissue sarcoma and non-Hodgkin’s lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington. J Natl Cancer Inst 1987; 78: 899-910 [Medline]

Wyss M, Dummer R, Dommann SN, Joller-Jemelka HI, Dours-Zimmermann MT, Gilliet F, et al. Lymphomatoid papulosis–treatment with recombinant interferon alfa-2a and etretinate. Dermatology 1995; 190: 288-291 [Medline]

Zahm SH, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Cantor KP, et al. A case-control study of non-Hodgkin’s lymphoma and the herbicide 2,4- dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska. Epidemiology 1990; 1: 349-356 [Medline]

Zinzani PL, Bendandi M, Martelli M, Falini B, Sabattini E, Amadori S, et al. Anaplastic large-cell lymphoma: clinical and prognostic evaluation of 90 adult patients. J Clin Oncol 1996; 14: 955-962 [Medline]

Zinzani PL, Martelli M, Magagnoli M, Zaccaria A, Ronconi F, Cantonetti M, et al. Anaplastic large cell lymphoma Hodgkin’s-like: a randomized trial of ABVD versus MACOP-B with and without radiation therapy. Blood 1998b; 92: 790-794 [Medline]

Zinzani PL, Pileri S, Bendandi M, Buzzi M, Sabattini E, Ascani S, et al. Clinical implications of serum levels of soluble CD30 in 70 adult anaplastic large-cell lymphoma patients. J Clin Oncol 1998a; 16: 1532-1537 [Medline]

Prof. Bernard Coiffier (Reviewer)
Centre Hospitalier Lyon Sud – Lyon, France
mail: bertrand.coiffier@chu-lyon.fr

Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
mail: ferreri.andres@hsr.it

Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy
mail: carlo.tondini@ospedaliriuniti.bergamo.it