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Background
This lymphoma is characterized by a distinctive morphology as well as specific genetic abnormalities and immunohistochemical profile. Like its counterpart in the skin, these CD30 positive lymphomas show immunopositivity for the CD30 antibody. Unlike its skin counterpart, the specific t(2;5) translocation is usually consistently found in these nodal based tumors. This translocation is critical in the distinction of clinical behavior and prognosis.
OUTLINE
PATHOGENESIS CHARACTERIZATION ALK MUTATIONS
Specific t(2;5) translocation
Am J Pathol 1998;153:875-886
Science 1994;263:1281-1284
Fuses the ALK (anaplastic lymphoma kinase) geen with the NPM (nucleophosmin) gene leading to production of a chimeric NPM-ALK protein (p80)ALK protein is not expressed in normal or reactive lymphoid cells
Found in 53-84% of anaplastic large cell lymphomas
- Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas.
Thompson MA, Stumph J, Henrickson SE, Rosenwald A, Wang Q, Olson S, Brandt SJ, Roberts J, Zhang X, Shyr Y, Kinney MC.
Hum Pathol. 2005 May;36(5):494-504. Abstract quote
Summary Anaplastic large cell lymphoma (ALCL) is an aggressive large T- or null-cell lymphoma. Most ALCLs arising in children and young adults express a constitutively active receptor tyrosine kinase, anaplastic lymphoma kinase (ALK). Anaplastic large cell lymphomas lacking ALK are clinically heterogeneous and their pathogenesis is unknown.
This study is the first complementary DNA (cDNA) microarray analysis using RNA extracted from tumor tissue (7 ALK+ ALCLs and 7 ALK- ALCLs) to identify genes differentially expressed or shared between the ALK+ and ALK- tumors. Unsupervised hierarchical clustering using the top 11 most statistically significant discriminator cDNAs correctly grouped all ALK+ and ALK- tumors. Hierarchical clustering analysis using the 44 cDNAs with the greatest differential expression between ALK+ and ALK- RNAs grouped 6 of 7 ALK+ ALCLs together and 1 ALK+ ALCL with the ALK- group. In general, ALK+ tumors overexpress genes encoding signal transduction molecules ( SYK , LYN , CDC37 ) and underexpress transcription factor genes (including HOXC6 and HOX A3 ) compared with the ALK- group. Cyclin D3 was overexpressed in the ALK+ group and the cell cycle inhibitor p19INK4D was decreased in the ALK- group, suggesting different mechanisms of promoting G 1 /S transition. Both groups had similar proliferation rates.
Genes highly expressed in both ALK- and ALK+ ALCLs included kinases ( LCK , protein kinase C, vav2, and NKIAMRE ) and antiapoptotic molecules, suggesting possible common pathogenetic mechanisms as well.
Xiayuan Liang, MD, etal.
To evaluate t(2;5) and its variants, we studied 21 pediatric cases of anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) by using immunohistochemical staining, fluorescence in situ hybridization, cytogenetics, and reverse transcriptase–polymerase chain reaction.
Results showed 7 (33%) cases with t(2;5), 6 (29%) with variant gene rearrangements, 7 (33%) with uncharacterized rearrangements, and 1 with ALK protein expression but no ALK rearrangement. Among 6 variant gene rearrangements, 1 had TPM4-ALK/t(2;19)(p23;p13) and 2 had inv(2) with the breakpoint proximate to ATIC-ALK and an unknown partner gene separately.
The genetic features of the remaining 3 cases were as follows: ins(8;2) with an unknown partner gene; conversion from ALK– at diagnosis to ALK+ at recurrence with unspecified gene rearrangement; complex karyotype without involvement of 2p23, suggesting a cryptic translocation. Concordance between different laboratory results varied from 47% to 81%.
These data suggest that ALK variants are not uncommon and underscore the necessity of integrating immunohistochemical, cytogenetic, and molecular genetic approaches to detect, characterize, and confirm t(2;5) and its variant translocations.ALK NEGATIVE TUMORS
- Extra copies of chromosome 2 are a recurring aberration in ALK-negative lymphomas with anaplastic morphology.
Kansal R, Sait SN, Block AW, Ward PM, Kelly FL, Cheney RT, Czuczman M, Brecher ML, Barcos M.
[1] 1Department of Pathology, Buffalo General Hospital, The State University of New York, Buffalo, NY, USA [2] 4Department of Pathology and Laboratory Medicine.
Mod Pathol. 2005;18:235-243 Abstract quote
The purpose of this study was to evaluate fluorescence in situ hybridization abnormalities of the 2p23 anaplastic lymphoma kinase (ALK) gene loci in lymphomas with anaplastic morphology.
We studied 24 anaplastic large cell lymphomas (ALCL) classified by World Health Organization criteria [17 primary nodal/systemic (10 ALK+, 7 ALK-), seven primary cutaneous], and 17 additional non-Hodgkin's lymphomas [one ALK+ B-lineage lymphoma, 14 ALK- diffuse large B-cell lymphomas (seven anaplastic variants, five nonanaplastic, two secondary CD30+), two follicular lymphomas]. ALK- lymphomas with anaplastic morphology showed extra nonrearranged anaplastic lymphoma kinase gene loci (P=0.004) due to trisomy 2 irrespective of the following factors: B or T/null phenotype (P=0.315), diagnostic categories of systemic or cutaneous ALCL or the above-mentioned B-cell lymphomas (P=0.131), and CD30 positivity by immunohistochemistry (P=1.000). Trisomy 2 was absent in all ALK+ lymphomas (P=0.009), which showed rearranged ALK gene loci (P<0.001).
Whether trisomy 2 is a primary or secondary event that leads to ALK- lymphomas cannot be determined from this study. Its presence in secondary B-cell lymphomas suggests that trisomy 2 may be a secondary cytogenetic aberration in lymphomas in general. Further investigation of this finding is necessary to further our understanding of the heterogeneous group of ALK- lymphomas.CYCLIN D3
- Differential expression of cyclin D3 in ALK+ and ALK- anaplastic large cell lymphoma.
Dalton RR, Rassidakis GZ, Atwell C, Wang S, Oyarzo MP, Medeiros LJ.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hum Pathol. 2005 Jul;36(7):806-11 Abstract quote
As defined in the World Health Organization classification, anaplastic large cell lymphoma (ALCL) is a distinct type of non-Hodgkin lymphoma of T/null cell lineage, a subset of which is associated with translocations involving 2p23 resulting in expression of anaplastic lymphoma kinase (ALK). The most common translocation, the t(2;5)(p23;q35), results in expression of nucleophosmin (NPM)-ALK. NPM-ALK has been shown to activate signal transducer and activator of transcription (STAT) 3, a transcriptional regulator of cyclin D3.
In this study, we assessed cyclin D3 expression in 2 ALK+ ALCL cell lines (Karpas 299 and SU-DHL1) and 1 ALK- ALCL cell line (Mac2A) by Western blot analysis. We also assessed cyclin D3 expression in 52 ALCL tumors (32 ALK+, 20 ALK-) by immunohistochemistry using tissue microarrays. These results were compared with phosphorylated (activated) STAT3 (pSTAT3) expression. Both ALK+ ALCL cell lines, but not the ALK- ALCL cell line, expressed cyclin D3 and pSTAT3. Cyclin D3 was expressed in 25 (78%) of 32 ALK+ ALCL tumors and in 4 (20%) of 20 ALK- ALCL tumors (P < .001, Fisher exact test ). In ALK+ ALCL tumors, the mean percentage of cyclin D3-positive tumor cells was 40.6% compared with 5.1% in ALK- ALCL tumors (P < .001, Mann-Whitney U test). The percentages of cyclin D3-positive and pSTAT3-positive tumor cells were positively correlated (Spearman R = 0.35, P = .036).
We conclude that cyclin D3 is differentially expressed in ALK+ and ALK- ALCL and that high expression levels of cyclin D3 in ALK+ ALCL may be attributable to STAT3 activation.EPSTEIN-BARR VIRUS
Absence of Epstein-Barr virus in anaplastic large cell lymphoma: a study of 64 cases classified according to World Health Organization criteria.
Herling M, Rassidakis GZ, Jones D, Schmitt-Graeff A, Sarris AH, Medeiros LJ.
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Hum Pathol. 2004 Apr;35(4):455-9. Abstract quote
The frequency of Epstein-Barr virus (EBV) in anaplastic large cell lymphoma (ALCL) has been controversial. The interpretation of previous studies is complicated by the use of nonuniform EBV detection methods and the inclusion of cases of CD30-positive diffuse large B-cell lymphoma and so-called "ALCL, Hodgkin-like," as defined in the Revised European-American Lymphoma classification scheme. In the current World Health Organization (WHO) classification system, both of these tumors are excluded from the ALCL category. Also, recently developed antibodies (eg, the antibody specific for PAX-5/B-cell-specific activator protein [BSAP]) provide new, sensitive tools for identifying neoplasms of B-cell lineage that can morphologically resemble ALCL.
In this study we evaluated 64 cases of ALCL of T- or null-cell lineage, defined according to the WHO classification system, for the presence of EBV. All tumors were negative for B-cell antigens, including PAX-5/BSAP and CD20 or CD79a. The study group included 27 (42%) anaplastic lymphoma kinase (ALK)-positive (18 T-cell and 9 null-cell) and 37 (58%) ALK-negative (30 T-cell and 7 null-cell) tumors analyzed by in situ hybridization for EBV-encoded RNA (EBER) or immunohistochemistry for EBV-latent membrane protein type 1. All 64 cases were negative for EBV.
We conclude, based on the current definition of ALCL in the WHO classification, there is no role for EBV in ALCL arising in Western patients. We suggest that published reports of EBV in a small proportion of ALCL cases in Western patients can be explained by the inclusion of tumors no longer considered to be in the current classification of ALCL, such as CD30-positive anaplastic tumors of B-cell origin.
Epstein-Barr virus association and ALK gene expression in anaplastic large-cell lymphoma.Agarwal S, Ramanathan U, Naresh KN.
Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, India.
Hum Pathol 2002 Feb;33(2):146-52 Abstract quote Anaplastic large cell lymphoma of T/null-cell type (ALCL) is associated with a characteristic genetic abnormality t(2;5) that results in the NPM-ALK chimeric gene and the protein product derived thereof.
In 10% to 20% of ALCLs, the translocation partners of the ALK gene are genes other than NPM (variant translocations). ALK gene expression limited to the cytoplasm implies a variant translocation. In this study, we have investigated 46 cases of ALCL for expression and localization of ALK protein and its association with Epstein-Barr virus (EBV) (by hybridization to EBV-encoded nuclear RNA-1 [EBER-1] and immunostaining for LMP-1).
ALCL patients with a null cell phenotype were significantly younger as compared with those of T-cell phenotype (mean age: 28 years v 42 years; P =.018). Sixteen of 46 ALCL cases (34%) were ALK positive. ALK-positive patients were significantly younger (mean age: 25 years for those with both cytoplasmic and nuclear staining; 22 years for those with exclusive cytoplasmic staining; and 41 years for those negative for the ALK gene; P =.023). EBER-1 was detected in 9 of 46 cases (20%), and LMP-1 expression was noted in 5 of them. By polymerase chain reaction analysis, all EBV-associated cases that were investigated showed type I EBV.
Whereas 2 of 23 T-cell ALCLs (9%) were EBER-1+, and 7 of 23 null-cell ALCLs (30%) showed EBV association (P =.057). EBV association was seen in 20% of ALK-negative cases, in 0% of cases with ALK gene expression in both nucleus and cytoplasm, and in 60% of cases with ALK gene expression exclusively in the cytoplasm (P =.02).
Further, although ALK-positive-EBER-1+ cases were LMP-1 negative, ALK-negative-EBER-1+ cases were LMP-1 positive. Our study raises the question whether EBV might have an etiological role in the evolution of ALCLs that lack classical t(2;5).
PARTNER GENE CYTOGENETIC ALTERATION FREQUENCY NPM t(2;5) 70-80% TPM3 t(1;2) 10-20% TRK FUSION GENE (TFG) t(2;3) 2-5% ATIC Inv2 2-5% CLATHRIN HEAVY CHAIN t(2;17) 2-5% MOESIN (MSN) t(X;2) ?
OTHER MECHANISMS CASPASE-3
Caspase-3 activation in systemic anaplastic large-cell lymphoma.
Drakos E, Rassidakis GZ, Lai R, Herling M, O'Connor SL, Schmitt-Graeff A, McDonnell TJ, Medeiros LJ.
1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mod Pathol. 2004 Jan;17(1):109-16 Abstract quote.
Anaplastic large-cell lymphoma (ALCL), as currently defined, includes a subset of tumors that have abnormalities of chromosome 2p23 (alk gene) resulting in overexpression of anaplastic lymphoma kinase (ALK).
We have previously shown differences in apoptotic rate and expression of apoptosis-related proteins between ALK-positive and ALK-negative ALCL. In this study, we assessed for activated caspase-3 (aC-3), an executioner of apoptotic cell death, in ALCL cell lines and tumors.
We used the Karpas 299 and SU-DHL-1 cell lines, and the caspase inhibitors Boc-D-FMK and DEVD-FMK to investigate the role of caspase-3 activation in tumor cell death after treatment with doxorubicin. Cell viability and apoptosis were assessed by trypan blue and Annexin-V methods. A caspase-3 assay was used to evaluate caspase-3 enzymatic activity. Caspase-3 activity was significantly increased in Karpas-299 and SU-DHL-1 cells treated with doxorubicin, but remained as low as control levels with addition of Boc-D-FMK or DEVD-FMK. Expression of aC-3 was also assessed immunohistochemically in 57 ALCL tumors. The mean percentage of aC-3 positive tumor cells was 3.2% in ALK-positive ALCL compared with 1.2% in ALK-negative ALCL (P=0.0003, Mann-Whitney test), and inversely correlated with BCL-2 expression (P=0.01, Mann-Whitney test). aC-3 expression did not correlate with patient outcome in either the ALK-positive or ALK-negative ALCL groups.
In conclusion, doxorubicin-induced cell death of ALK-positive ALCL cells involves caspase-3 activation in vitro. aC-3 levels correlate with ALK expression in ALCL tumors.Jak3 ACTIVATION
- Jak3 activation is significantly associated with ALK expression in anaplastic large cell lymphoma.
Lai R, Rassidakis GZ, Lin Q, Atwell C, Medeiros LJ, Amin HM.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hum Pathol. 2005 Sep;36(9):939-44 Abstract quote.
Janus kinase 3 (Jak3) is a tyrosine kinase that activates signal transducer and activator of transcription 3 (Stat3) in response to cytokine stimulation. Stat3 is an oncogene. In previous studies of anaplastic large cell lymphoma (ALCL), we showed that inhibition of Jak3 down-regulates activated/phosphorylated Stat3 (pStat3), decreases anaplastic lymphoma kinase (ALK) enzymatic activity, and induces cell-cycle arrest and apoptosis in ALK-positive ALCL. These findings implicate Jak3 as playing a significant role in the pathogenesis of ALK-positive ALCL; most likely via Stat3 and ALK activation.
To assess this possibility, we used immunohistochemical staining to evaluate the frequency of expression of Jak3 and its activated/phosphorylated form (pJak3) in 48 systemic ALCL tumors included in a tissue microarray. pJak3 was detected in 17 (81%) of 21 ALK-positive tumors, compared with 3 (11%) of 27 ALK-negative tumors (P < .0001, Fisher exact test). pStat3 was present in 12 (86%) of 14 ALK-positive tumors and in 10 (40%) of 25 ALK-negative tumors assessed (P = .0078). Of 12 ALK-positive/pStat3-positive tumors, 8 (67%) expressed pJak3, but none of 10 ALK-negative/pStat3-positive tumors expressed pJak3.
We conclude that Jak3 activation is predominantly restricted to ALK-positive ALCL tumors. Most likely, Jak3 collaborates with ALK in activating Stat3, leading to cell survival, cell-cycle progression, and tumor growth. In contrast, the mechanism of Stat3 activation in ALK-negative ALCL tumors appears to be independent of Jak3.
Jun B
- JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis.
Rassidakis GZ, Thomaides A, Atwell C, Ford R, Jones D, Claret FX, Medeiros LJ.
1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mod Pathol. 2005 Oct;18(10):1365-70. Abstract quote
JunB is a member of the Jun family of proteins that are components of the AP-1 transcription factor complex. AP-1 is involved in cell proliferation and apoptosis. Recent evidence suggests that Hodgkin and Reed-Sternberg cells overexpress JunB and that JunB facilitates constitutive CD30 expression by binding to an AP-1 site in the CD30 promoter.
In this study we surveyed JunB expression in a variety of CD30+ lymphoma types including 42 cases of anaplastic large cell lymphoma, 36 classical Hodgkin lymphoma, 15 cutaneous anaplastic large cell lymphoma, and 11 CD30+ diffuse large B-cell lymphoma. In addition, seven cases of nodular lymphocyte-predominant Hodgkin lymphoma and 42 diffuse large B-cell lymphoma, known to be CD30-, were analyzed. JunB expression was assessed using tissue microarrays, immunohistochemistry and a monoclonal antibody specific for JunB. Expression of JunB was observed in 41 of 42 cases of anaplastic large cell lymphoma, including all 21 cases positive for anaplastic lymphoma kinase and 20 of 21 (95%) negative for anaplastic lymphoma kinase. JunB was also expressed in all cases of classical Hodgkin lymphoma, cutaneous anaplastic large cell lymphoma and CD30+ diffuse large B-cell lymphoma, and in lymphomatoid papulosis. By contrast, all nodular lymphocyte-predominant Hodgkin lymphomas and diffuse large B-cell lymphomas that were CD30- were also JunB-.
We conclude that JunB is expressed in virtually all CD30+ lymphomas and is a potential target for experimental therapy in patients with these tumors.THYMUS AND ACTIVATION REGULATED CHEMOKINE
Differential Expression of Thymus and Activation Regulated Chemokine and Its Receptor CCR4 in Nodal and Cutaneous Anaplastic Large-Cell Lymphomas and Hodgkin's Disease.Vermeer MH, Dukers DF, Ten Berge RL, Bloemena E, Wu L, Vos W, De Vries E, Tensen CP, Meijer CJ, Willemze R.
Departments of Dermatology (MHV, EdV, CPT, RW) and Pathology (DFD, RLtB, EB, WV, CJLMM), Vrije Universiteit Amsterdam, the Netherlands.
Mod Pathol 2002 Aug;15(8):838-44 Abstract quote Recent studies demonstrated that Hodgkin/Reed-Sternberg (H/RS) cells in Hodgkin's disease (HD) express thymus and activation-regulated chemokine (TARC), whereas reactive lymphocytes surrounding H/RS cells express its ligand, CC-chemokine receptor 4 (CCR4). Because in vitro studies showed that CCR4 expression is a marker for lymphocytes bearing a T-helper 2 (Th2) phenotype, it was suggested that expression of TARC is a new immune escape mechanism in HD.
To find out whether this mechanism might also be operative in CD30+ malignant lymphomas other than HD, TARC and CCR4 expression was investigated by immunohistochemistry on paraffin and frozen-tissue sections of 39 nodal CD30+ anaplastic large cell lymphomas (ALCL), including 27 ALK-negative and 12 ALK-positive ALCL, 25 primary cutaneous CD30+ ALCL, including 11 patients with lymphomatoid papulosis, and 31 cases of HD. TARC was expressed by the neoplastic cells in 12/27 (44%) nodal ALK-negative ALCL and all cases of classic HD, but not in nodal ALK-positive ALCL (0/12) and only rarely in primary cutaneous CD30+ ALCL (3/25). In contrast, CCR4 was expressed by the neoplastic cells in 9/9 cutaneous CD30+ ALCL, and in 9/15 (60%) nodal ALK-negative ALCL, but only in 1/4 (25%) nodal ALK-positive ALCL and not by the H/RS cells in HD (0/8). Apart from three cases of HD showing 10 to 15% CCR4-positive lymphocytes surrounding TARC-positive H/RS cells, CCR4-positive reactive T cells were few (<5%) in all other cases studied.
Our results demonstrate a differential expression of TARC and CCR4 in different types of CD30+ malignant lymphomas. The small number of CCR4-positive reactive T cells in most cases studied argues against an important role of TARC expression in the evasion of antitumor responses.
HISTOLOGICAL TYPES CHARACTERIZATION General Large cells with eccentric embryo-like or reniform nuclei, multiple small nucleoli, and distinct eosinophilic Golgi zone VARIANTS HODGKIN DISEASE-LIKE
- ALK-Positive Anaplastic Large Cell Lymphoma Mimicking Nodular Sclerosis Hodgkin's Lymphoma: Report of 10 Cases.
Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P, Delsol G.
From *Centre de Physiopathologie de Toulouse-Purpan, Department of Oncogenesis and Signalling in Hematopoietic Cells and Laboratory of Pathology, Hopital Purpan, Centre Hospitalier Universitaire, University of Toulouse, Toulouse, France; daggerDepartment of Pathology of the Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil; double daggerInstitut Gustave Roussy, Villejuif Cedex, France; section signDepartment of Pathology, Centre Hospitalier Universitaire de Nantes, France; and parallelLaboratory of Pathology, Hospital Clinic, University of Barcelona, Spain.
Am J Surg Pathol. 2006 Feb;30(2):223-229. Abstract quote
Anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) are recognized as biologically distinct entities. However, occasionally, these two entities may share some morphologic features responsible for diagnostic difficulties.
In the last 10 years, we have collected 380 cases of ALK-positive ALCL of which 10 cases were originally diagnosed as nodular sclerosis classic HL (NSHL) on conventional histopathological examination. After immunostaining, these cases proved to be ALK-positive ALCL mimicking HL (so-called Hodgkin-like ALCL). These cases account for 2.6% of our cases of ALK-positive ALCL (10 of 380 cases). Median age was 11 years (3-92 years) with a female predominance (male/female ratio, 3:7). Characteristically, these lesions showed thick nodular fibrosing bands highly suggestive of NSHL. Neoplastic cells were scarce in 6 cases, whereas in the 4 remaining cases, sheets of tumor cells were also present. A perivascular and a sinusoidal growth pattern was observed in various degrees in all cases. Few binucleated Reed-Sternberg-like cells were present in every case in a background of small lymphocytes. Inflammatory cells (ie, granulocytes, eosinophils, and histiocytes) were rare. Neoplastic cells were positive for CD30 (10 of 10 cases), ALK protein (10 of 10 cases), epithelial membrane antigen (EMA) (9 of 9 cases), CD43 (6 of 9 cases), and perforin (8 of 8 cases), but negative for CD15 (10 of 10 cases), CD20 (10 of 10 cases), Pax5/BSAP (6 of 6 cases), and EBV (8 of 8 cases). In addition, in 7 cases, neoplastic cells were of T-phenotype, whereas the 3 remaining cases were considered to be of null/undetermined phenotype.
Although rare, Hodgkin-like ALCL may mimic NSHL, and it is advisable to include EMA in the first line panel and to ask for ALK staining in EMA-positive, CD15-negative lesions with morphologic features suggestive of NSHL.Hypocellular Anaplastic Large Cell Lymphoma Mimicking Inflammatory Lesions of Lymph Nodes
W. Cheuk, M.B.B.S.; Robert W. Hill, M.D., F.R.C.P.A.; Carlos Bacchi, M.D.; Marco Antonio Dias, M.D.; John K. C. Chan, M.B.B.S., F.R.C.Path.
From the Departments of Pathology, Queen Elizabeth Hospital, Hong Kong (W.C., J.K.C.C.), Wellington Hospital, Wellington South, New Zealand (B.H.), University of Sao Paulo, Brazil (C.B.), and Faculdade de Ciencias Medicas de Minas Gerais, Brazil (M.A.D.).
Am J Surg Pathol 2000;24:1537-1543 Abstract quote
The subgroup of T/null-cell primary systemic anaplastic large cell lymphoma that expresses anaplastic lymphoma kinase (ALK) constitutes a distinctive clinicopathologic entity that exhibits a broad morphologic spectrum. The examples predominated by small cells or showing a mixed cell population can be difficult to recognize as being neoplastic.
We report four such cases with a remarkably hypocellular granulation tissue-like appearance, mimicking an inflammatory or reparative process.
All patients were young and presented with lymphadenopathy in multiple sites. The lymph node biopsies showed a hypocellular appearance, with wide separation of the small to medium-sized lymphoid cells by edematous or fibromyxoid stroma. There were interspersed spindly neoplastic cells resembling myofibroblasts, sometimes forming short, sweeping fascicles, as well as histiocytes. Occasional large cells with atypical nuclei were identified. The larger lymphoid cells tended to form cuffs around the venules. In two cases, the capsule and fibrous trabeculae were markedly broadened with increased spindly cells, mimicking inflammatory pseudotumor of lymph node. Immunostaining showed dispersed and clustered CD30+ ALK+ cells, confirming a diagnosis of anaplastic large cell lymphoma.
In conclusion, a diagnosis of hypocellular anaplastic large cell lymphoma requires a high index of suspicion. The young age of the patients and the presence of perivascular cuffs of larger lymphoid cells should provide the strongest clues to the correct diagnosis.
LEUKEMIC INVOLVEMENT ALK-Positive Anaplastic Large Cell Lymphoma With Leukemic Peripheral Blood Involvement Is a Clinicopathologic Entity With an Unfavorable Prognosis Report of Three Cases and Review of the Literature
Mihaela Onciu, MD, Frederick G. Behm, MD, Susana C. Raimondi, PhD, Sheila Moore, MD, Emma L. Harwood, MD, Ching-Hon Pui, MD, and John T. Sandlund, MDAm J Clin Pathol 2003;120:617-625 Abstract quote
Leukemic peripheral blood involvement in anaplastic large cell lymphoma (ALCL) is uncommon. We describe 3 children with such manifestations and review the features of 9 pediatric and adult patients previously described in the literature. Leukemic involvement in ALCL may occur at the time of initial diagnosis or develop during the course of disease. It most often is associated with the small cell histologic features and the t(2;5)(p23;q35).
Clinical features commonly include significant respiratory distress, diffuse lung infiltrates or pleural effusions, and hepatosplenomegaly. Most cases have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens, most often CD11b or CD13. Ten of the 12 cases reviewed had a poor response to therapy or early relapse.
Thus, while anaplastic lymphoma kinase–positive ALCL and young patient age generally are associated with a favorable prognosis, leukemic involvement seems to identify a high-risk malignant neoplasm that requires more aggressive therapy, including hematopoietic stem cell transplantation.NEUTROPHIL-RICH Neutrophil-Rich Ki-1–Positive Anaplastic Large Cell Lymphoma
A Study by Fine-Needle Aspiration Biopsy
Andrew J. Creager, MD, Kim R. Geisinger, MD, and Simon Bergman, MDAm J Clin Pathol 2002;117:709-715 Abstract quote
Fine-needle aspiration biopsy (FNAB) is an accurate, cost-effective method of evaluating lymphomas. The neutrophil-rich variant of anaplastic large cell lymphoma (NR-ALCL) is a rare non-Hodgkin lymphoma.To our knowledge, we present the first study of NR-ALCL by FNAB cytology. Histologic confirmation was available for both patients. Both cases were positive for Ki-1 (CD-30) and were either T-cell or null-cell phenotype. FNAB specimens were highly cellular with a single-cell pattern composed of pleomorphic tumor cells, "hallmark" tumor cells, and a background rich in neutrophils that occasionally obscured tumor cells. Diagnosis on FNAB is difficult owing to the rarity of this tumor, its resemblance to Hodgkin lymphoma and other non-Hodgkin lymphomas that express CD30, its similarity to an infectious process, and its occasional confusion with metastatic carcinoma and melanoma.
Reproducible cytologic features usually are present, and the diagnosis can be made conclusively by FNAB in conjunction with ancillary studies.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Special stains Immunoperoxidase Positive for:
CD30
CD45RO
EMAOriginally, B cell lymphomas were included in this category. In the REAL classification, these are now classified under diffuse large B cell lymphoma
Thus only T cell and null cell types remainCLUSTERIN
Alessandra F. Nascimento, MD, Jack L. Pinkus, PhD, and Geraldine S. Pinkus, MD
We evaluated the immunohistochemical staining profile of clusterin in paraffin sections of 143 neoplasms (non-Hodgkin lymphoma, 83, including 41 anaplastic large cell lymphomas [ALCLs]; Hodgkin lymphoma, 17; primary and metastatic carcinoma, 30; and other neoplasms, 13). In 40 of 41 ALCLs (34 systemic, 7 cutaneous), neoplastic cells revealed clusterin reactivity characterized by a Golgi staining pattern.
The proportion of reactive cells varied with more than 25% positive cells in the majority of cases. In 7 non-Hodgkin lymphomas of other types, fine cytoplasmic (3 cases) or strong membranous reactivity (4 cases) was observed for clusterin. In Hodgkin lymphoma, rare Reed-Sternberg cells exhibited focal cytoplasmic or membranous clusterin positivity. In the nonhematopoietic neoplasms, a Golgi staining pattern was apparent in only 2 cases, 1 lobular carcinoma of the breast and 1 poorly differentiated colonic carcinoma; however, cytoplasmic reactivity was noted in 12 of 30 carcinomas and 1 of 5 neuroendocrine neoplasms.
A Golgi pattern of reactivity for clusterin seems highly characteristic of ALCL among hematopoietic neoplasms, but also might be observed in rare nonhematopoietic tumors, necessitating the use of a broad immunohistochemical panel for evaluation of poorly differentiated neoplasms of indeterminate derivation.Clusterin Is Widely Expressed in Systemic Anaplastic Large Cell Lymphoma but Fails to Differentiate Primary From Secondary Cutaneous Anaplastic Large Cell Lymphoma
Marick E. Lae, MD
Iftikhar Ahmed, MD
and William R. Macon, MDAm J Clin Pathol 2002;118:773-779 Abstract quote
A recent study by Wellmann et al (Blood. 2000;96:398-404) detected clusterin expression in all 36 systemic anaplastic large cell lymphomas (ALCLs) tested, but not in any of 9 primary cutaneous ALCLs.
Our purpose was to confirm the diagnostic usefulness of clusterin in systemic ALCL and to evaluate its efficacy in distinguishing primary cutaneous ALCL from secondary skin involvement by systemic ALCL.We examined clusterin expression by paraffin immunohistochemical analysis in 41 systemic ALCLs (18 ALK-1+ and 23 ALK-1–), 9 primary cutaneous ALCLs, and 4 secondary cutaneous ALCLs. Clusterin was positive in 95% of systemic ALCLs (39/41), including 100% (18/18) of the ALK-1+ cases and 91% (21/23) of the ALK-1– cases. Five (56%) of 9 primary and 3 (75%) of 4 secondary cutaneous ALCLs were positive for clusterin.
Our observations confirm the diagnostic usefulness of clusterin in systemic ALCL, especially in the ALK-1– cases. However, our data fail to demonstrate its value in distinguishing primary from secondary cutaneous ALCL.
FASCIN
Comparison of fascin expression in anaplastic large cell lymphoma and Hodgkin disease.Fan G, Kotylo P, Neiman RS, Braziel RM.
Department of Pathology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Mail Code L471, Portland, OR 97201, USA.
Am J Clin Pathol 2003 Feb;119(2):199-204 Abstract quote 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.
TARC TARC, a CC Chemokine, Is Frequently Expressed in Classic Hodgkin's Lymphoma But Not in NLP Hodgkin's Lymphoma, T-Cell-Rich B-Cell Lymphoma, and Most Cases of Anaplastic Large Cell Lymphoma
S. C. Peh, M.B.B.S., F.R.C.Path.; L. H. Kim, B.BMed.Sc.; S. Poppema, M.D., Ph.D., F.R.C.P.
From the Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur and Department of Pathology and Laboratory Medicine, University Hospital Groningen, The Netherlands.
Am J Surg Pathol 2001;25:925-929 Abstract quote
Thymus and activation-regulated chemokine (TARC) has been identified as a lymphocyte-directed CC chemokine that attracts activated T-helper type 2 (Th2) cells in humans. Recent studies showed that the T cells surrounding Reed-Sternberg cells in Hodgkin's lymphomas (HL) are Th2 type. Anaplastic large cell lymphomas (ALCL), T-cell-rich B-cell lymphoma (TCRBCL) can mimic HL in some instances.
This study aimed to establish the pattern of TARC expression in these diseases. Immunohistochemical stain using a polyclonal goat anti-human antibody to TARC was performed on 119 cases of confirmed HL; 99 were classical type (43 mixed cellularity, 43 nodular sclerosis, 5 lymphocyte depleted, 4 lymphocyte rich, 4 unclassifiable) and 20 lymphocyte predominant HL. Additional 27 ALCL (9 T-, 18 null-cell phenotype), 16 T-cell and 8 B-cell non-Hodgkin's lymphoma (NHL) were studied.
A total of 85.8% of the classical HL, one case of ALCL, and one case of large cell B-cell lymphoma with anaplastic morphology showed positive TARC expression in the tumor cells. The expression was paranuclear and/or diffuse in the cell cytoplasm. The tumor cells in all cases of lymphocyte predominant HL, TCRBCL, null ALCL, and T-NHL did not express TARC.
The high frequency of TARC expression in the Reed-Sternberg cells of classical HL may explain the characteristic T-cell infiltrate in this disease. The absence in other types that may be morphologically similar indicates that staining for TARC may aid in differential diagnosis.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Anaplastic carcinoma Anaplastic sarcoma Malignant melanoma Hodgkin's lymphoma Hodgkin's lymphoma of T-cell type: Clonal association with a CD30+ cutaneous lymphoma
Marshall E. Kadin, MD
Reed Drews, MD
Andrew Samel, MD
Annalyn Gilchrist, BS
Olivier Kocher, MDHum Pathol 2001;32:1269-1272. Abstract quote
The derivation of Reed-Sternberg cells in Hodgkin's lymphoma has been a subject of great interest. In most cases, Reed-Sternberg cells seem to be derived from germinal center B cells. In few sporadic cases, a T-cell origin has been shown.
This article supports the concept of a T-cell derivation for rare cases of Hodgkin's lymphoma and provides evidence of a novel mechanism of pathogenesis from chronic inflammation in the skin.
KSHV/HHV8-ASSOCIATED LYMPHOMA
KSHV/HHV8-associated Lymphoma Simulating Anaplastic Large Cell Lymphoma.
Huang Q, Chang KL, Gaal KK, Weiss LM.
Division of Pathology, City of Hope National Medical Center, Duarte, CA
Am J Surg Pathol. 2004 May;28(5):693-7. Abstract quote
We report a unique, previously undescribed case of KSHV/HHV8-associated lymphoma in a 49-year-old HIV-seropositive patient. The cervical lymph node-based lymphoma displayed distinctive characteristic features of preferential sinusoidal infiltrate and anaplastic cellular morphology, closely resembling classic anaplastic large cell lymphoma of the WHO classification both histologically and immunophenotypically.
Paraffin immunohistochemical study showed that the lymphoma cells were strongly positive for KSHV/HHV8 latency-associated nuclear antigen, and PCR analysis confirmed the presence of KSHV/HHV8 infection. Epstein-Barr virus in situ hybridization was negative. Molecular study clearly demonstrated B-cell lineage with immunoglobulin heavy and kappa light chain gene rearrangements.
This case may add to the spectrum of the heterogeneous category of KSHV/HHV8-associated B-cell lymphomas.LYMPHOMA
ALK+, CD30-, CD20- large B-cell lymphoma containing anaplastic lymphoma kinase (ALK) fused to clathrin heavy chain gene (CLTC).Chikatsu N, Kojima H, Suzukawa K, Shinagawa A, Nagasawa T, Ozawa H, Yamashita Y, Mori N.
Department of Internal Medicine, Hitachi General Hospital, Hitachi, Ibaraki, USA.
Mod Pathol. 2003 Aug;16(8):828-32. Abstract quote Pathological features and genomic basis of a rare case of ALK(+), CD30(-), CD20(-) large B-cell lymphoma were analyzed. A 36-year-old Japanese female was admitted because of lumbago and constitutional symptoms.
Physical examination and laboratory tests showed anemia (hemoglobin, 7.5 g/dL), mild hepatosplenomegaly, and immunoglobin G (IgG) lambda-type monoclonal gammopathy (IgG, 2782 mg/dL). The lymphoma spread exclusively in extranodal sites such as bone marrow, liver, spleen, ovary, and muscle. Biopsy specimens obtained from the ovary showed monomorphic proliferation of large immunoblastic cells with basophilic cytoplasm, round-shaped nuclei with a high nuclear to cytoplasmic ratio, and prominent single nucleolus.
Immunostaining with anti-anaplastic lymphoma kinase (ALK) antibody, ALK1, showed finely granular cytoplasmic staining pattern. These cells were also positive for epithelial membrane antigen, CD4, CD19, CD38, CD138, cytoplasmic IgG, and lambda chain, but negative for CD30 (Ber-H2), CD56, CD57, and other T- and B-cell markers. Southern blot analyses revealed that Ig heavy and lambda light chain genes, but not T-cell receptor (TCR) beta gene, were clonally rearranged. Chromosomal analyses by conventional G-banding, spectral karyotyping, and fluorescence in situ hybridization showed complex abnormality involving 2p23, and chromosome 2 was translocated to chromosome 17. As 2;17 translocation resulting in the fusion of clathrin heavy chain (CLTC) gene with ALK was previously reported in inflammatory myofibroblastic tumor, we performed reverse transcriptase-polymerase chain reaction and demonstrated that the lymphoma cells contained CLTC-ALK fusion transcript. Under the diagnosis of ALK(+), CD30(-), CD20(-) large B-cell lymphoma, she was treated with conventional combination chemotherapies. However, the lymphoma was primarily chemotherapy resistant, and the patient died 11 months after admission.
We consider that this case confirms the existence of ALK(+), CD30(-), CD20(-) large B-cell lymphomas proposed by Delsol et al. (16) and further provides relevant information regarding their clinicopathological features and cytogenetics.Sinusoidal CD30-positive large B-cell lymphoma: a morphologic mimic of anaplastic large cell lymphoma.
Lai R, Medeiros LJ, Dabbagh L, Formenti KS, Coupland RW.
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Mod Pathol 2000 Mar;13(3):223-8 Abstract quote
Anaplastic large cell lymphoma (ALCL) has been recognized recently as a distinct clinicopathologic entity, restricted to a subset of CD30-positive diffuse large cell lymphomas of T/null lineage. Some of the characteristic features of ALCL, such as CD30 antigen expression and the presence of large pleomorphic lymphoid cells infiltrating lymph node sinuses, can be found rarely in diffuse large B-cell lymphomas.
We collected 11 such cases, and their clinical, morphologic, and immunophenotypic features are reviewed. The age of the patients ranged from 36 to 82 years (mean, 63.2 years) with a male to female ratio of 1:1.2. All neoplasms were nodal with a sinusoidal infiltrative pattern, although four neoplasms also had foci of confluent growth. Eight tumors were composed predominantly of large pleomorphic cells with occasional Reed-Sternberg-like cells. The other three tumors had a higher proportion of large monomorphic lymphoid cells. Necrosis and admixed granulocytes were other common features. Immunophenotypically, all cases were positive for CD30 and CD20 or CD79a. All eight cases examined for anaplastic lymphoma kinase-1 immunoreactivity were negative. In situ hybridization for Epstein-Barr virus RNA was performed in eight cases; two were positive. Excluding one consultation case with no available clinical follow-up data, six patients died of the disease within 3 years and one had disease relapse within 1 year.
We conclude that an unusual variant of diffuse large B-cell lymphoma can closely mimic ALCL. However, these neoplasms can be distinguished from ALCL by virtue of their B-lineage and lack of anaplastic lymphoma kinase-1 expression. Evidence of Epstein-Barr virus infection can be found in a small subset of these neoplasms.
REACTIVE HYPERPLASIA
CD30 antigen expression in florid immunoblastic proliferations. A clinicopathologic study of 14 cases.Segal GH, Kjeldsberg CR, Smith GP, Perkins SL.
Department of Pathology, University of Utah School of Medicine, Salt Lake City.
Am J Clin Pathol 1994 Sep;102(3):292-8 Abstract quote Reactive immunoblastic proliferations may be confused with certain types of non-Hodgkin's lymphoma and Hodgkin's disease on morphologic grounds. In addition, a characteristic antigen, CD30 (Ki-1; BerH2) on these neoplastic entities may be observed in morphologically atypical yet reactive florid immunoblastic proliferations such as those associated with acute infectious mononucleosis. Although it has been documented, a large series determining the frequency and extent of CD30 antigen expression on a variety of nonneoplastic immunoblastic proliferations is lacking.
The authors studied 14 florid immunoblastic proliferations (9 in lymph nodes and 5 in tonsils) for CD30 antigen expression and for B- and T-cell paraffin markers. In situ hybridization to determine the presence of Epstein-Barr virus (EBV) genomes also was performed. Cases were classified into monospot-positive acute infectious mononucleosis (4 cases), EBV-related lymphoproliferative disorder suggestive of acute infectious mononucleosis (5 cases), and other etiologies (5 cases). CD30 Antigen expression was found on the immunoblasts in cases from all three categories and overall in 9 (64%) of 14 specimens. CD30 reactivity in the positive cases varied from occasional to numerous positive cells; 4 samples (3 EBV-related lymphoid proliferations and 1 vaccine-related lymphadenopathy) had numerous CD30-reactive immunoblasts. Expression of CD30 antigen on B or T cells and prominence of B or T cells within a proliferation were variable. Significant "atypia" of immunoblasts was found only in EBV-related disorders and correlated with B-cell prominence of the infiltrate.
Appropriate clinical correlation and ancillary laboratory data are necessary to assist in differentiating these CD30(+)-reactive disorders from similar-appearing malignant lymphomas. Most important, a fresh tissue sample should be procured and adequately processed to allow for comprehensive determination of clonality and cellular lineage.
SCABIES
CD30 antigen expression in cutaneous inflammatory infiltrates of scabies: a dynamic immunophenotypic pattern that should be distinguished from lymphomatoid papulosis.Gallardo F, Toll A, Pujol RM; Carlos Barranco.
Department of Dermatology, Hospital del Mar, IMAS, Barcelona, Spain Department of Dermatology, Pathology, Hospital del Mar, IMAS, Barcelona, Spain.
J Cutan Pathol 2002 Jul;29(6):368-73 Abstract quote Background: Expression of CD30 antigen is a distinct marker of lymphocyte activation that was originally described in the Reed-Sternberg cells of Hodgkin's disease. The observation of CD30+ cells has been considered a diagnostic feature of cutaneous CD30 lymphoid proliferations. However, CD30 expression has also been reported in some cutaneous benign inflammatory infiltrates.
Methods: Eleven skin biopsies from patients with scabies were double-blindly and retrospectively analysed. A panel of histopathological parameters and immunophenotypic expression of CD4, CD8, CD30 and S-100 antigens was studied. CD30 and S-100 antigens expression were related to clinical features.
Results: Large CD30+ cells were demonstrated in eight (8/11) biopsies, corresponding to patients with long-standing lesions (3 months or longer). However, no expression of the CD30 antigen was observed in all biopsy specimens (3/11) corresponding to early lesions (2 months or less). The presence of S-100 positive cells in the papillary dermis was an almost constant feature.
Conclusions: CD30+ large cells seem to be a common feature in long-standing infiltrates of scabies. CD30 expression in scattered cells of a cutaneous lymphoid infiltrate cannot be assessed as a strong diagnostic argument of neoplastic cutaneous CD30+ lymphoid proliferation (lymphomatoid papulosis/cutaneous CD30+ lymphoma). Therefore, the possibility that large atypical CD30+ cells may be also present in several benign inflammatory diseases should be always considered.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS *Am J Surg Pathol 1997;21:1420-1432 (Included some B-cell lymphomas)
*Blood 1999;93:2697-2706 (only T and null cell types)Aggressive chemotherapy may leade to 5 year survival of 70% p80/ALK+ p80/ALK- Median Age 17 years 60 years EMA 95% 33% EBV (EBER) 0% 21% Median survival 165 months 35 months 2-yr survival 84% 52% 5-yr survival 72% 30% ALK+ group (n=53) ALK- group (n=25) Age Children and young adults with mean age of 22 years Older, with mean age of 43.4 years M:F ratio 3:1 (reaching 6.5:1 for 2-3rd decades) 0.9:1 Stage Usually stage III-IV Less frequently high stage Systemic symptoms Common (75%) Less common Extranodal disease Common (60%), especially skin, bone, and soft tissue Less common Overall survival 71% +/- 6% 15% +/- 11% Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001.|
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