Anaplastic Large T-cell Lymphoma Research Articles

The Mobilisation of Peripheral Blood Stemcells in Patients with High Risk or Relapsed Non-Hodgkin Lymphoma Does Not Lead to the Presence of Detectable Tumour Cells in the Stem Cell Harvest.

Consolidation treatment with high dose chemotherapy in combination with an autologous peripheral blood stem celll transplant. is widely used in patients with high risk non-Hodgkin lymphoma (NHL). Also this treatment has its place in patients with relapsed intermediate lymphoma. Earlier studies in patients with breast cancer or multiple myeloma showed evidence for (minimal) tumour contamination in the graft that might lead to the occurence of relapse. For patients with NHL this is less clear. For the present analysis 60 patients (pts) were included: 18 pts with primary high risk NHL, 6 patients with mantle cell lymphoma, and 36 pts with primary refractory or relapsed intermediate NHL. Patients with high risk NHL were treated with induction chemotherapy according to the Hovon-27 or Hovon-40 protocol(www.hovon.nl). Two patients (1 pt with T-Lymphoblastair lymphoma, 1 pt with Burkitt Lymphoma ) received intensive induction chemotherapy according to our leukemia protocols. Stem cells were collected as early as possible, provided the peripheral blood and bone marrow showed no histological evidence of NHL and < 20% lymfocytes. In the patients with mantle cell lymphoma stem cells were collected during the induction chemotherapy (Hovon-45 protocol:www.hovon.nl), irrespective of their presence in the bone marrow. The patients with primary refractory or relapsed intermediate NHL received reinduction chemotherapy with DHAP (Dexamethason, Cytarabin, Cisplatin) or EMP (Etopside, Mitoxantrone, Prednisone). After two or three courses peripheral blood stem cells were mobilised with G-CSF (Neupogen, Amgen) 10 μg/kg sc daily starting day 5 and harvested for autologous stem cell transplant. Before the start of mobilisation patients were required to be responsive to the induction chemotherapy and to have a bone marrow without histological and immunological detectable tumour cells. In all patients a sample of the first day stem cell collection was analyzed with the use of three or four colour Flowcytometry. The sensitivity of the assay was 1/ 104–105 lymphoma cells. Only in 3 pts tumour cells were found at a level > 0.05 %. Interestingly two patients had a primary diagnosis of diffuse large B-cell lymphoma T-cell/ histiocyte rich variant. Both pts relapsed: one within 6 months and the other one within 12 months.The third patient suffered from a anaplastic large cell T-cell lymphoma and relapsed after 15 months. In all other patients no lymphoma cells were detectable in the stemcell harvest at a minimum level of <0.02%. Follow up showed a relapse within 12 months in 16 of 36 patients with relapse or primary refractory NHL (44%) and 6 of 24 patients with high risk NHL (25%). In conclusion, in the vast majority of the above patients, no circulating lymphoma cells were detectable with the use of flowcytometry in the stemcell harvest. Therefore we conclude that with the present techniques and sensitivity immunological analysis of the graft does not give additional information and therefore is not necessary in this patient group. Provided the bone marrow before collection is free of lymphoma cells, we feel that the currently used mobilisation regimen is safe in these patients and does not lead to the presence of detectable tumour cells in the collected stemcells.

Prevalence and characterization of anaplastic large cell lymphoma and its association with Epstein-Barr virus in Pakistani patients

Anaplastic large cell lymphoma (ALCL), CD30+, is a subtype of T-non-Hodgkin's lymphoma (NHL). Its most common form is a classical systemic type that involves multiple nodal and extranodal sites. In this study, morphologic, immunohistologic, and genetic studies were performed on ALCL cases in Pakistani patients. The median age of the patients in this study was 45 years (age range: 5–70 years), with a male to female ratio of 3.4:1. Thirty-seven (37) patients were diagnosed to have Ki-1 (CD30+) ALCL, which constituted 2% of all NHLs and 12.6% of all T-NHLs, over a period of 11 years (January 01, 1992–December 31, 2002). The tumors were of either T- or null-cell type with constant (100%) expression of CD30 (Ki-1). The majority of the cases (89.2%) expressed EMA, whereas 40.5% of the cases expressed either CD45 (LCA), CD45RO (UCHL1), or ALK. The mean age of ALCL patients with null-cell phenotype was 33.8 years as compared to those with T-cell phenotype having a mean age of 36.3 years. Out of the 37 cases diagnosed as ALCL, amplifiable DNA was isolated from 28 cases, which were further assessed for T-cell clonality for T-cell receptor (TCR)-β, γ, and immunoglobulin heavy chain (IgH) for the FR2 and FR3 regions. The polymerase chain reaction (PCR) technique demonstrated clonal rearrangement of the TCR β, γ, and IgH regions in 15 (53.6%), 11 (39.3%), and 2 (7.1%) ALCL cases, respectively, out of 28 cases. Association of Epstein-Barr virus (EBV) was noted in seven out of 28 cases (25%) of ALCL by PCR, whereas ISH for EBV-encoded nuclear RNA-1 (EBER-1) detected the presence of EBV in two (16.7%) out of 12 cases, where one was T-cell ALCL and the other null-cell ALCL. Immunostaining for LMP-1 could not be performed, because tissue material was not available. In conclusion, our study demonstrated that the prevalence of ALCL in Pakistan is comparable to that reported for some of the Asian communities and by the International Lymphoma Study Group and that EBV could be partly responsible for the pathogenesis of ALCL.

The Spectrum of Cutaneous Lymphomas in Patients Less than 20 Years of Age

Cutaneous lymphomas are rare in young patients and are mostly represented by mycosis fungoides and its variants and CD30+ lymphoproliferative disorders (lymphomatoid papulosis [LYP] and anaplastic large T-cell lymphoma). We report our observations in a series of 69 patients less than 20 years of age who presented either with primary cutaneous lymphoma (n = 62) or with secondary manifestations of extracutaneous disease (n = 7). Clinicopathologic features permitted classification of the cases into the following diagnostic categories: mycosis fungoides (n = 24, all primary cutaneous), anaplastic large T-cell lymphoma (n = 13, all primary cutaneous), LYP (n = 11, all primary cutaneous), subcutaneous "panniculitis-like" T-cell lymphoma (n = 1, primary cutaneous), small-medium pleomorphic T-cell lymphoma (n = 2, all primary cutaneous), natural killer (NK)/T-cell lymphoma, nasal-type (n = 1, secondary cutaneous), follicle center cell lymphoma (n = 1, primary cutaneous), marginal zone B-cell lymphoma (n = 7, all primary cutaneous), B-lymphoblastic lymphomas (n = 6, 3 primary and 3 secondary cutaneous), specific cutaneous manifestations of Hodgkin disease (n = 1, secondary cutaneous), and acute myeloid leukemia (n = 2, both secondary cutaneous). Cutaneous lymphoma in children should be differentiated from benign skin disorders that may simulate them. In particular, mycosis fungoides and LYP in this age group may present with clinicopathologic features reminiscent of inflammatory disorders such as pityriasis alba, vitiligo, pityriasis rosea, and pityriasis lichenoides et varioliformis acuta. Even in secondary cutaneous lymphomas, skin manifestations may be the first sign of the systemic disease, and a diagnosis may be achieved on examination of histopathologic specimens of a cutaneous lesion. Our study illustrates the wide spectrum of cutaneous lymphomas and leukemias in patients less than 20 years of age and underlines the need for proper interpretation of these lesions by dermatologists and dermatopathologists.

Genomic Profiling of Peripheral T-Cell Lymphoma, Unspecified, and Anaplastic Large T-Cell Lymphoma Delineates Novel Recurrent Chromosomal Alterations

To characterize genetic alterations in peripheral T-cell lymphoma, not otherwise specified (PTCL NOS), and anaplastic large T-cell lymphoma (ALCL), 42 PTCL NOS and 37 ALCL [17 anaplastic large cell kinase (ALK)-negative ALCL, 9 ALK-positive ALCL, 11 cutaneous ALCL] were analyzed by comparative genomic hybridization. Among 36 de novo PTCL NOS, recurrent chromosomal losses were found on chromosomes 13q (minimally overlapping region 13q21, 36% of cases), 6q and 9p (6q21 and 9p21-pter, in 31% of cases each), 10q and 12q (10q23-24 and 12q21-q22, in 28% of cases each), and 5q (5q21, 25% of cases). Recurrent gains were found on chromosome 7q22-qter (31% of cases). In 11 PTCL NOS, high-level amplifications were observed, among them 3 cases with amplification of 12p13 that was restricted to cytotoxic PTCL NOS. Whereas cutaneous ALCL and ALK-positive ALCL showed few recurrent chromosomal imbalances, ALK-negative ALCL displayed recurrent chromosomal gains of 1q (1q41-qter, 46%), and losses of 6q (6q21, 31%) and 13q (13q21-q22, 23%). Losses of chromosomes 5q, 10q, and 12q characterized a group of noncytotoxic nodal CD5+ peripheral T-cell lymphomas. The genetics of PTCL NOS and ALK-negative ALCL differ from other T-NHLs characterized genetically so far, among them enteropathy-type T-cell lymphoma, T-cell prolymphocytic leukemia, and adult T-cell lymphoma/leukemia.

Mutations of the 5' noncoding region of the BCL-6 gene in primary bone lymphomas.

Somatic point mutations of the 5' noncoding region of the BCL-6 gene have been described as genetic alterations in non-Hodgkin lymphomas (NHL). They are more frequent in diffuse large B cell (DLBCL) and follicular lymphomas (FL). This study aims to analyse the presence and distribution of BCL-6 gene mutations in a large series of primary bone lymphomas (PBL), a rare extranodal presentation of NHL frequently associated with diffuse large cell morphology. Fifty-three cases of PBL were examined. Mutations were detected with non-radioisotopic polymerase chain reaction-single strand conformation polymorphism and visualized with fluorescent cycle sequencing. Among stage I(E) PBL, there were 30 cases of DLBCL and one each of follicular, anaplastic large cell and peripheral T-cell lymphoma. The stage II(E) PBL included six DLBCL and one lymphoplasmacytic lymphoma, whereas within stage IV PBL there were 12 DLBCL and one Burkitt lymphoma. Fifteen patients (28%) displayed mutational events. In nine cases there were more than one BCL-6 mutation. Only DLBCL displayed mutations (31%). Mutations included single base-pair substitutions (16 transitions and ten transversions) and a single point insertion (ins A 427-28). The frequency of mutations resulted lower in DLBCL of the PBL category than in the majority of other extranodal large cell lymphomas. The prevalence of mutations was higher in stage I(E) PBL than in more advanced stages of the disease (II(E) + IV) ( p=0.02). Our results reinforce the observation of heterogeneity of the DLBCL included in the clinical category of PBL.

Endogenous retroviral elements, but not exogenous retroviruses, are detected in CD30-positive lymphoproliferative disorders of the skin.

Primary cutaneous CD30-positive lymphoproliferative disorders (LPD) comprise a spectrum of disorders including lymphomatoid papulosis (LyP) and CD30+ pleomorphic or anaplastic large T-cell lymphomas ( 1 – 3 ). LyP is a chronic, recurrent lymphoproliferative disorder which manifests clinically as papulonodular, spontaneously regressing skin lesions ( 4 ). Histologically, large pleomorphic and anaplastic tumor cells are found which are activated T-lymphocytes expressing the CD30 antigen ( 5 , 6 ). Viruses are known etiologic factors in the pathogenesis of non-Hodgkin’s lymphomas (NHL) ( 7 ). In particular, retroviruses such as human T-lymphotropic virus 1 and 2 (HTLV-1 and 2) have been linked to adult T-cell leukemia/lymphoma (ATLL) and other forms of NHL (for review see refs 8 and 9). Primary cutaneous lymphomas, especially cutaneous T-cell lymphomas, have been considered to be caused by viruses. Several reports of the detection of HTLV-1 or 2 sequences in cutaneous T-cell lymphomas (CTCL) ( 10 – 13 ) have not been confirmed in other studies ( 8 , 9 , 14 , 15 ).

Comparison of Fascin Expression in Anaplastic Large Cell Lymphoma and Hodgkin Disease

Diagnostic difficulties sometimes arise in distinguishing anaplastic large cell lymphoma (ALCL) from Hodgkin disease (HD), especially the syncytial variant. Study of the biologic features of diagnostic Reed-Sternberg cells in HD, in search of specific markers for Reed-Sternberg cells, has suggested fascin as a relatively specific and sensitive marker. We studied the frequency of fascin expression in 30 ALCLs and 34 cases of classic HD, including 17 cases of the syncytial variant. Staining with CD30 and anaplastic lymphoma kinase (ALK)-1 also was performed in all cases. All ALCL and HD cases showed membranous and Golgi zone CD30 positivity. Fascin stained all HD cases but also stained 67% (20/30) of the ALCLs in a cytoplasmic pattern. Fascin positivity was observed in 59% (10/17) of T-cell ALCLs and 77% (10/13) of null-cell ALCLs; ALK-1–positive ALCLs, regardless of origin, were usually fascin-positive (91% [10/11]). In conclusion, fascin shows strong positivity in all cases of classic HD but also is positive in the majority of ALCLs, including ALK-1–positive and ALK-1–negative cases. Positive staining for fascin is not useful for distinguishing ALCL from HD. In some cases, fascin negativity may help rule out classic HD.

Peripheral T-cell Lymphomas: Clinical Features and Prognostic Factors of 92 Cases Defined by the Revised European American Lymphoma Classification

The purpose of this study was to better define the clinical features and natural history of peripheral T-cell lymphomas (PTCL) entities included in the Revised European American lymphoma (REAL) classification. Cases of PTCL were retrieved from the records of the Department of Pathology and classified according to the REAL classification. In addition, cases of anaplastic large cell lymphoma (ALCL) were divided into classical, small cell, and primary cutaneous subtypes, and immunostaining for the anaplastic large-cell kinase (ALK) protein was performed on all cases of ALCL. Clinical features, response to therapy and survival were abstracted. Ninety-two cases of PTCL with adequate clinical information were retrieved. There were 40 cases of ALCL (30 classical, 7 small cell variant, 3 primary cutaneous), 28 PTCL, unspecified, 13 angioimmunoblastic T-cell lymphoma and 11 with other entities. The patients had a median age of 48 years with a range of 6-84 and had an estimated overall survival (OS) of 49% and progression-free survival (PFS) of 22% at 5 years. The International Prognostic Index (IPI) was a significant prognostic factor for both progression-free and OS. Histology was a significant predictor of PFS with anaplastic large cell having the best prognosis. ALK expression was not associated with an improved progression-free or overall-survival in patients with systemic T-cell ALCL. In conclusion, the REAL classification describes distinct PTCL entities. The IPI is the most important predictor of progression-free and OS in patients with PTCL. ALK expression may not provide prognostic information for systemic ALCL.

A single-centre study of treatment outcomes and survival in 120 patients with peripheral T-cell non-Hodgkin's lymphoma.

We conducted a retrospective study of treatment outcomes and survival in 120 consecutive, unselected patients with peripheral T-cell non-Hodgkin's lymphoma, presenting at a single centre over a 20-year period. Cases met the criteria of the Revised European-American Lymphoma (REAL) Classification and patients with peripheral T-cell lymphoma of the following subtypes were included: anaplastic large T-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AILD), peripheral T-cell lymphoma unspecified (PTCLu), and intestinal T-cell lymphoma (ITCL). The study population consisted of 120 patients with a presenting diagnosis of peripheral T-cell lymphoma. Cases that had been previously confirmed as T-cell lymphoma at formal pathology review were identified from the lymphoma database of this institution. Staging investigations, treatment type and outcomes were taken from patient records. For each subtype, clinical characteristics, response to initial treatment, duration of response and any subsequent relapse were recorded. Overall, relapse, and progression-free survival figures were calculated. The ALCL group had the best response rate to first line treatment 19 of 22 (86 percent) while the AILD group had the lowest response 12 of 29 (41 percent). Relapse rates were PTCLu 13 of 35 (37 percent), ITCL 10 of 34 (29 percent), ALCL 6 of 22 (27 percent) and AILD 7 of 29 (24 percent). In terms of median overall survival, a significantly superior survival was demonstrated for the ALCL group (7.05 years) compared to the remaining three groups. The ALCL group had the lowest risk of death while the ITCL group had the highest risk (hazard ratio: 2.82). Five-year survival rates were estimated to be ALCL 60 percent, PTCLu 40 percent, AILD 30 percent and ITCL 25 percent. This single-centre study demonstrated different outcomes for each group with significant differences in overall survival rates. These findings support the clinical utility of the REAL lymphoma classification in respect to the PTCL subgroups included in this study.

PTCL: lessons from adult T-cell leukemia.

Peripheral T-cell lymphoma (PTCL) is a neoplastc disease of peripheral T-lymphocytes/NK cells, including PTCL unspecified, anaplastic large T-cell lymphoma (ALCL), IBL-like T-cell lymphoma (AILD), intestinal T-cell lymphoma (ITCL) and adult T-cell leukemia/lymphoma (ATL). The incidence of PTCL is relatively uncommon although its incidence shows significant variations in the geographical regions and racial populations. In Asia, its incidence is high due to HTLV-I infection in Japan. Molecular mechanisms of oncogenesis of PTCLs remain unknown. Therefore, analyses of ATL will give us a clue to clarify the molecular mechanism.

Lymphoma of the Skin

This chapter describes the various ways in which the non-Hodgkin's lymphomas can involve the skin, how these diseases should be assessed, standard treatments available in 2002, and new directions in research. The goal of the session is to succinctly review recent developments in lymphoma classification and treatment as they apply to the unique aspects of lymphoma when manifest in the skin. In Section I, Dr. Eric Hsi reviews the special characteristics of the lymphomas seen when they proliferate in the skin and the application of the new World Health Organization classification system to the cutaneous lymphomas, emphasizing the unique challenges of recognizing and correctly classifying these diseases. He summarizes the evidence in favor of including the skin lymphomas in the overall lymphoma classification scheme and concludes with a practical description of the specific skin lymphoma entities. In Section II, Dr. Joseph Connors describes the current optimal treatment of the B-cell lymphomas when they present in or metastasize to the skin. Building on the classification scheme described by Dr. Hsi, Dr. Connors outlines a treatment approach based on current understanding of pathophysiology of these diseases and application of each of the effective modalities available for cutaneous lymphoma including radiation, chemotherapy, and immunotherapy. In Section III, Dr. Francine Foss concludes the session with a discussion of the different T-cell lymphomas that start in or spread to the skin concentrating on mycosis fungoides, cutaneous anaplastic large cell lymphoma and peripheral T-cell lymphoma. She includes comments on the newer anti-T-cell chemo- and immuno-therapeutics focusing on agents and techniques specific for cutaneous T-cell lymphomas.

ALK-positive Anaplastic Large T-cell Lymphoma Preceded by Epstein-Barr Virus Infection Complicated by Development of an Aorto-esophageal Fistula

We report an unusual case of aggressive ALK-positive anaplastic large cell lymphoma with widespread mediastinal involvement immediately preceded by an acute Epstein-Barr virus (EBV) infection. Following initiation of chemotherapy and radiological evidence of significant tumor regression, the patient suffered a fatal massive upper gastrointestinal hemorrhage from an aorto-esophageal fistula. The relevant literature relating to EBV in the pathogenesis of ALK-lymphomas and literature relating to aorto-enteric fistula (AEF) in mediastinal lymphoma is reviewed.

Ovarian Non-Hodgkin's Lymphoma: A Clinicopathologic Study of Eight Primary Cases

Primary (localized) non-Hodgkin's lymphoma (NHL) of the ovary is rare. We studied eight cases of primary ovarian NHL to better understand the clinicopathologic and immunophenotypic features of these tumors. The patients ranged in age from 29 to 62 years (mean 47 years). Pelvic complaints were the most common symptoms; however, three of eight neoplasms were discovered incidentally. All tumors were unilateral and Ann Arbor stage IE. The three incidental NHL were microscopic (largest 1.2 cm), whereas the grossly evident lesions ranged from 7.5 to 20 cm (mean 13.3). Each tumor was classified according to the World Health Organization Classification as follows: diffuse large B-cell lymphoma (three cases), follicular lymphoma (two cases), Burkitt lymphoma (one case), T-cell anaplastic large cell lymphoma (one case), and precursor T-lymphoblastic lymphoma (one case). Six tumors were of B-cell lineage, and two tumors were of T-cell lineage. All three diffuse large B-cell lymphomas were positive for BCL-6, two were positive for CD10, and two were positive for BCL-2. Estrogen and progesterone receptors were negative in all NHLs assessed. Patients were treated by various combinations of surgery, chemotherapy, and radiotherapy. Clinical follow-up ranged from 1.3 to 11.7 years (mean 5.2) and all patients were alive without disease at last follow-up. We conclude that most patients with primary ovarian NHL present with symptoms attributable to an ovarian mass, but in a subset of patients ovarian NHL may be detected incidentally. With appropriate therapy, patients appear to have a favorable prognosis although follow-up is short for some patients in this study.

Langzeitergebnisse mit MACOP-B und Strahlentherapie bei aggressiven Non-Hodgkin-Lymphomen

Long-Term Results with MACOP-B and Radiation Therapy for Aggressive Lymphomas Background: Long-term results are needed to evaluate chemotherapy regimens and prognostic factors in non-Hodgkin’s lymphomas (NHL). We report the 10-year follow-up data of aggressive NHL classified according to the Kiel classification and treated with MACOP-B. Patients and Methods: Between 1985 and 1991, 71 patients with aggressive NHL were treated in a single institution with MACOP-B and adjuvant radiotherapy as first-line therapy. NHL subtypes were classified according to the updated Kiel classification. Follow-up data were available until 1998. Results: The overall survival (OS) at 10 years is 45% (confidence interval 33–57%), the progression-free survival 42% (30–54%), and the relapse-free survival of the 59 patients (82%) in complete remission is 52% (39–65%). The Kiel classification combined with the International Prognostic Index (IPI) identified diffuse large B-cell and anaplastic large T-cell lymphomas with IPI 0–2 as subgroups with very favorable prognosis after MACOP-B (OS 84% and 80% at 10 years). Late relapses (>2 years after therapy) did occur in these patients but had a good prognosis after second remission. Only 3 of 24 relapses were in the radiation field. Three patients died of toxicity, 1 during MACOP-B (1.3%). Risk factors for therapy-related death were age and pulmonary toxicity. Most patients suffered from chemotherapy-associated mucositis. Osteoporosis was a common late toxicity (39%). Three second cancers but no leukemias or myelodysplastic syndromes were observed during follow-up. Conclusions: MACOP-B in combination with adjuvant radiotherapy is highly effective in diffuse large B-cell or anaplastic large T-cell-lymphomas with IPI 0–2. Patients with IPI >2 or with centrocytic or secondary centroblastic B-cell or non-anaplastic T-cell lymphomas need more intensive therapy or novel approaches. Regarding the toxicity profile, MACOP-B should be replaced by VACOP-B.

Anaplastic large cell lymphoma arising in bone: report of a case of the monomorphic variant with the t(2;5)(p23;q35) translocation.

Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all non-Hodgkin lymphomas according to the recent Non-Hodgkin Lymphoma Classification Project. As defined in the revised European-American classification of lymphoid neoplasms (REAL), ALCL is a neoplasm of T-cell or null-cell lineage; 20% to 60% of cases are associated with the t(2;5)(p23;q35) translocation. ALCL commonly involves nodal as well as a wide variety of extranodal sites, although primary or secondary involvement of bone is rare. We describe the case of a 71-year-old man with stage IE T-cell ALCL, monomorphic variant, arising in the left anterior fifth rib and involving adjacent soft tissue without other sites of disease. The monomorphic histologic features hindered the initial recognition of this neoplasm as ALCL. However, strong uniform CD30 antigen expression and subsequent demonstration of the t(2;5)(p23;q35) translocation and anaplastic lymphoma kinase (ALK) immunoreactivity led to the correct diagnosis. We identified only 5 reported cases of T-cell and null-cell ALCL arising in bone and only 2 of these cases involved a single bone site. All 5 previously reported cases were ALCL of the classic type. We report a case of ALCL that is unique to our knowledge. This case of monomorphic ALCL was localized to bone and tumor cells contained the t(2;5)(p23;q35) translocation.

Rarity of genomic instability in pathogenesis of systemic anaplastic large cell lymphoma (ALCL) in immunocompetent patients

Microsatellite instability (MSI) is a recently described type of genetic alteration resulting from defects in the DNA mismatch repair genes that appears to play an integral role in neoplastic transformation. MSI has been described in a wide variety of malignancies; however, data regarding the role of MSI in the pathogenesis of non-Hodgkin's lymphoma (NHL) are limited. MSI appears to be important in some T-cell lymphomas, including ALCL arising in immunocompromised patients. In addition, MSI has recently been identified in CD30 + cutaneous lymphoproliferative processes and lymphoblastic lymphoma. In this study, we have analyzed five well-characterized cases of systemic T-cell ALCL arising in immunocompetent patients for the presence of MSL Genomic DNA isolated from paired normal and tumor tissue was analyzed at seven microsatellite loci by polymerase chain reaction. We were unable to identify MSI or loss of heterozygosity (LOH) in our cases, suggesting that abnormalities in the DNA mismatch repair system do not play a major role in the pathogenesis of most systemic ALCL. Our data provide additional molecular evidence that the various subgroups of lymphoma with ALCL morphology are biologically distinct processes.

Transformation of the small cell variant Ki-1+ lymphoma to anaplastic large cell lymphoma: pathologic and clinical features.

The disease spectrum of anaplastic large cell lymphoma (ALCL) includes a biologically aggressive small cell variant (SCV). The SCV may progress to ALCL, but little is known about the transformation process and its significance. The goals of this study were (1) to identify the clinical and pathologic features that characterize ALCL arising in SCV and (2) to determine whether some cases with ALCL histologic appearance at the outset arose from an SCV. Seventeen SCV were reviewed, and four cases (24%) transformed to ALCL as shown by subsequent biopsy. The ALCLs were predominantly monomorphic (3 cases) rather than pleomorphic (1 case). Residual SCV was detected at transformation in 3 of 4 cases. Twenty-one de novo T-cell ALCLs were reviewed for an SCV component; such a component was identified in two ALCLs with monomorphic features, suggesting a preceding SCV phase. There was no change in the immunophenotype between the SCV and ALCL, all marking as EMA+ T cells. Expression of p80 was detected in 3 of 4 (75%) SCV with transformation and 10 of 12 (77%) SCV without transformation. Chromosomal abnormalities involving the sex chromosomes and 6, 7, 9, and 15, in addition to the characteristic t(2;5)(p23;q35), were present in 2 cases at transformation. Times to transformation ranged from 1 to 146 months (mean: 63 months) after diagnosis. Transformation to ALCL signaled a rapid clinical course, with 75% of patients dying in less than a year; one patient remains alive at 15 months. In summary, some ALCLs, particularly those with monomorphic features, arise from an SCV. Transformation to ALCL signals a rapid course, with death occurring in less than a year in most cases. Necrosis in the SCV may be predictive of transformation. Chromosomal abnormalities in addition to the t(2;5)(p23;q35) are present at transformation, suggesting that multiple genetic alterations are involved in disease progression.

Utility of flow cytometry in subtyping composite and sequential lymphoma

Composite lymphoma (CL) is defined as more than one distinct lymphoma variant occurring in the same anatomic site, and sequential lymphoma (SL) is defined as different lymphoma variants occurring at different sites or at different times in the same patient. The utility of flow cytometry immunophenotyping in evaluating CL and SL has only been investigated in a few single-case studies. To further define the utility of flow cytometry in evaluating these tumors, records were searched at two institutions. Cases representing high-grade progression of low-grade lymphoma were excluded. For each CL/SL, clinical data was obtained and morphology was evaluated in routinely processed H&E-stained tissue sections. Tumor components were subtyped using revised European-American classification (REAL) criteria. Follicle center components were graded using modified Rappaport criteria. Immunophenotype was determined using two-color flow cytometry and paraffin-section immunostains. Four cases were identified. Case 1, nodal follicle center, follicular, grade III plus marginal zone CL, showed two discrete populations of monoclonal B-cells that differed in their expression of CD10. Case 2, cutaneous lymphoplasmacytoid lymphoma followed by mesenteric non-Hodgkin's lymphoma (lymphoplasmacytoid plus follicle center, follicular, grade III) plus Hodgkin's disease CL, showed CD5-/CD10-/CD19+/kappa+ cells by flow cytometry in both tissue samples. The Hodgkin's disease component showed CD3-/CD15-/CD20-/CD30+ Reed-Sternberg cell variants in paraffin-section immunostains. Case 3 represented nodal follicle center lymphoma, follicular, grade I (CD3-/CD5-/CD10-/CD19+/kappa+) followed by cutaneous anaplastic large T-cell lymphoma (CD2+/CD4+/CD5+/CD19- cells with partial expression of CD3 and CD7). Case 4 represented cutaneous follicle center lymphoma, follicular, grade I (CD5-/CD10+/CD19+/CD23+/lambda+) followed by bone marrow B-cell small lymphocytic lymphoma (CD5+/CD10-/CD19+/CD23+/kappa+). Results show that flow cytometry is a potentially useful adjunct in characterizing CL and SL.

Most Primary Cutaneous CD30-Positive Lymphoproliferative Disorders Have a CD4-Positive Cytotoxic T-Cell Phenotype

Primary cutaneous CD30-positive (anaplastic) large T-cell lymphomas and lymphomatoid papulosis are closely related types of cutaneous T-cell lymphoma with a favorable prognosis. The neoplastic T cells in these conditions have the phenotype of activated CD3+, CD4+, CD8-, CD30+ skin homing T cells, but their normal counterpart has not yet been defined. To further characterize the cellular origin of the neoplastic T cells, skin biopsies from 14 patients with primary cutaneous CD30-positive (anaplastic) large T-cell lymphomas, nine patients with lymphomatoid papulosis, and six patients with primary cutaneous CD30-negative pleomorphic large T-cell lymphomas were stained with monoclonal antibodies against cytotoxic cell-associated molecules granzyme B and T-cell restricted intracellular antigen. In nine of nine lymphomatoid papulosis and in 10 of 14 CD30-positive primary cutaneous large T-cell lymphomas, expression of granzyme B and T-cell restricted intracellular antigen by variable numbers of neoplastic cells was found. Expression of granzyme B by the neoplastic CD30-positive T cells was confirmed by double-staining for granzyme B and CD30 (three cases) and by the detection of granzyme B mRNA using RNA in situ hybridization (one case). In most cases equal numbers of granzyme-B-positive and T-cell restricted intracellular antigen positive tumor cells were observed. In five of six CD30-negative primary cutaneous large T-cell lymphomas the neoplastic cells did not express these proteins, whereas in one case a sporadic positive tumor cell was found. These results demonstrate that, in contrast to primary cutaneous CD30-negative pleomorphic large T-cell lymphomas, the neoplastic cells in most primary cutaneous CD30-positive (anaplastic) large T-cell lymphomas and lymphomatoid papulosis have a unique CD4+, CD8-, cytotoxic T-cell phenotype.

Anaplastic Large-Cell Lymphomas of T-Cell and Null-Cell Phenotype Express Cytotoxic Molecules

To further specify the cellular origin and nature of anaplastic large-cell lymphoma (ALCL) and its relationship to other lymphoid neoplasms, particularly Hodgkin's disease (HD), we investigated the presence of cytotoxic molecules in a large well-characterized series of these tumors. For expression of the cytotoxic molecules perforin and granzyme B, in situ hybridization (ISH) and immunohistology were used, respectively. Overall, 23 of 25 ALCLs of T/null phenotype and five (three mixed cellularity and two nodular sclerosis) of 57 HD cases showed the presence of perforin transcripts and/or granzyme B molecules in neoplastic cells. Polymerase chain reaction (PCR) analysis of ALCLs showed that most (10 of 11) cases of null-cell ALCL (null-ALCL) contained a clonal rearrangement of T-cell receptor beta-chain genes, as did T-cell ALCL (T-ALCL; 9 of 10 cases). However, both cytotoxic molecules and clonally rearranged T-cell receptor beta-chain genes were absent in seven of seven and eight of nine cases of B-cell ALCL (B-ALCL), respectively. These data show that all or nearly all T-ALCLs, irrespective of the clinical subform or the lack of T-cell-associated molecules, are derived from activated cytotoxic T cells. The same appears to be true for the neoplastic cells of rare HD cases. These findings indicate that T-ALCLs are different from B-ALCLs and the majority of HD cases, and suggest that some HD cases, especially those with T-cell antigen-positive tumor cells, may be closely related to T-ALCL, at least in terms of cellular origin.