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(EMA) Is Preferentially Expressed by ALK Positive Anaplastic Large Cell Lymphoma, in The J Clin Pathol 2001;54:933–939 933 MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly J Clin Pathol: first published as on 1 December 2001. Downloaded from hypoglycosylated form R L ten Berge*, F G M Snijdewint*, S von MensdorV-Pouilly, RJJPoort-Keesom, J J Oudejans, J W R Meijer, R Willemze, J Hilgers, CJLMMeijer Abstract 30–50% of cases, a chromosomal aberration Aims—To investigate whether MUC1 such as the t(2;5)(p23;q35) translocation gives mucin, a high molecular weight trans- rise to expression of the anaplastic lymphoma membrane glycoprotein, also known as kinase (ALK) protein,2 identifying a subgroup epithelial membrane antigen (EMA), dif- of patients with systemic ALCL with excellent fers in its expression and degree of glyco- prognosis.3–6 ALK expression seems specific for sylation between anaplastic large cell systemic nodal ALCL; it is not found in classic lymphoma (ALCL) and classic Hodgkin’s Hodgkin’s disease (HD)7–11 or primary cutane- disease (HD), and whether MUC1 ous ALCL.7101213Morphologically, these lym- immunostaining can be used to diVerenti- phomas may closely resemble systemic ALCL, ate between CD30 positive large cell being also characterised by CD30 positive lymphomas. tumour cells with abundant cytoplasm, large Methods/Results—Using five diVerent irregular nuclei, and a prominent single monoclonal antibodies (E29/anti-EMA, nucleolus or multiple nucleoli.1 Clinically, DF3, 139H2, VU-4H5, and SM3) that however, classic HD and primary cutaneous distinguish between various MUC1 glyco- ALCL have a more favourable prognosis than 12 14–16 Department of forms, high MUC1 expression (50–95% of ALK negative systemic ALCL. Because Pathology, University tumour cells positive) was found in 13 of of the diVerences in clinical behaviour and Hospital Vrije 17 anaplastic lymphoma kinase (ALK) subsequent therapeutic strategies, diVerentiat- Universiteit, De positive systemic nodal ALCLs, and in one ing ALK negative systemic ALCL from classic Boelelaan 1117, 1081 of 20 cases of classic HD. Scattered or HD or primary cutaneous ALCL is very http://jcp.bmj.com/ HV Amsterdam, The focal staining (< 25% of tumour cells) was important. Netherlands R L ten Berge seen in two additional ALK positive sys- Several markers can be used in the diVeren- J J Oudejans temic ALCLs, two additional classic HD tial diagnosis of ALCL and other CD30 CJLMMeijer cases, and in three of 20 cases of ALK positive lymphomas. One such marker is negative systemic nodal ALCL. Primary MUC1 mucin, also known as epithelial mem- Department of cutaneous ALCL showed no staining with brane antigen (EMA).17 18 MUC1 is a high Obstetrics and the anti-MUC1 antibodies. Antibodies molecular weight transmembrane glycopro- on September 25, 2021 by guest. Protected copyright. Gynaecology, University Hospital detecting hypoglycosylated MUC1 were tein, usually expressed on the luminal surface 18–20 Vrije Universiteit found to be absent in all lymphomas of glandular epithelia. It consists of protein F G M Snijdewint (SM3) or present in only six of 15 ALK core with a constant cytoplasmic domain of 69 S von MensdorV-Pouilly positive ALCLs (VU-4H5). amino acids, and an extracellular domain with RJJPoort-Keesom Conclusions—MUC1 is preferentially ex- a variable number of 20 amino acid tandem pressed by a subtype of systemic nodal repeats, containing serine and threonine resi- Department of Dermatology, ALCL, characterised by ALK expression, dues, to which multiple oligosaccharide side 21–24 University Hospital but is found in only a few cases of classic chains are O-linked (fig 1). Vrije Universiteit HD and ALK negative ALCL. Therefore, Since the first rabbit polyclonal antisera R Willemze although MUC1 could be used in a panel raised against human milk fat globule,17 and the of markers for CD30 positive lymphomas, first monoclonal antibodies designated Department of it is probably not a valuable tool to diVer- HMFG1 and HMFG225 were described, many Pathology, Rijnstate Hospital, 6815 AD entiate between ALK negative CD30 posi- anti-MUC1 monoclonal antibodies have been 26 Arnhem, The tive large cell lymphomas. Finally, the generated and characterised. Most react with Netherlands degree of MUC1 glycosylation in lympho- a dominant epitope within the variable number J W R Meijer mas is relatively high, compared with the of tandem repeats of the protein core; namely, aberrant hypoglycosylation found in ad- the hydrophilic sequence of PDTRPAP.26–28 Biotech and Research enocarcinomas. The specificity of antibody binding to the pro- Division, Sanbe Fama, ( 2001;54:933–939) Bandung, Indonesia J Clin Pathol tein core depends largely on the extent of MUC1 glycosylation; during the ISOBM J Hilgers Keywords: MUC1 (epithelial membrane antigen) glycoforms; anaplastic large cell lymphoma; ALK; TD-4 workshop, clusters of monoclonal anti- *These authors contributed Hodgkin’s disease bodies were identified that distinguish between equally to this study. the various glycoforms of MUC1.29 30 Correspondence to: Although MUC1 is defined as an epithelial Dr ten Berge Systemic (nodal) anaplastic large cell antigen, in 1984 Delsol et al reported that lym- [email protected] lymphoma (ALCL) is a CD30 positive non- phoid cells and malignancies express EMA.31 Accepted for publication Hodgkin’s lymphoma of T cell or null cell Since then, EMA (or more appropriately, 1 May 2001 phenotype, mainly arising in lymph nodes.1 In MUC1) has been found to be consistently www.jclinpath.com 934 ten Berge, Snijdewint, von MensdorV-Pouilly form,22 38 39 and is related to tumour progres- sion and increased metastatic potential.40–42 In our present study, we used the E29 antibody and four other MUC1 monoclonal antibodies that distinguish between the various MUC1 mucin glycoforms of MUC1. We investigated whether J Clin Pathol: first published as on 1 December 2001. Downloaded from the expression and extent of glycosylation of MUC1 diVers between ALCL of systemic and primary cutaneous origin and classic HD, and whether MUC1 is a valid tool in the diVerential diagnosis of these lymphomas. In addition, peripheral blood T and B cells, as well as a small number of T cell and B cell lymphomas, were investigated for MUC1 expression. MUC1 mucin 20 mer tandem repeat Methods with O-linked glycosylation TISSUE SAMPLES Formalin fixed, paraYn wax embedded tumour biopsies of ALK positive (n = 17) and H SA G ALK negative (n = 20) systemic nodal ALCL, V Gal T primary cutaneous ALCL (n = 10), nodular o GalNAc SA c o GalNA S sclerosing (NS) (n = 14), and mixed cellularity Gal Tn A GlcNAc (MC) (n = 6) subtypes of classic HD were P D selected from the files of the Comprehensive T o Cancer Center Amsterdam, and from the R GalNAc Gal P department of pathology, Rijnstate Hospital, A P T or TF Arnhem, The Netherlands. We also selected GalNAc G o S samples of peripheral T cell lymphoma not SA Tn T o G otherwise specified (PTCL-NOS) (n = 5), T alNAc A lymphoblastic lymphoma (T-LB) (n = 2), and P STn P nodal diVuse large B cell lymphoma (DLBCL) A (n = 5). Cases were classified according to the proposed WHO classification43 and systemic ALCL was subtyped as described previ- ously.44 45 ALK positive systemic ALCL could http://jcp.bmj.com/ thus be divided into common type (n = 13), Figure 1 Extended MUC1 mucin molecule on a cell surface membrane with O-linked and small cell variant (n = 3), and lymphohistio- N-linked glycosylated side chains. The insert shows a MUC1 20 mer single repeat peptide cytic type (n = 1); whereas ALK negative with O-linked hypoglycosylated side chains. ALCL comprised common type (n = 11), expressed on plasma cells20 31–32 and immature small cell variant (n = 1), lymphohistiocytic erythroid cells in normal haematolymphoid type (n = 6), and giant cell rich variant (n = 2). tissues,33 34 but not on CD34+ progenitor cells Standard immunophenotyping included on September 25, 2021 by guest. Protected copyright. or resting T cells.32 34 Among peripheral blood CD30, ALK, CD15, B cell markers CD20/L26 mononuclear cells (PBMCs), B cells show and CD79A, and T cell markers CD3 and variable MUC1 expression,32 34 but T cells CD45RO/UCHL-1. By definition, systemic nodal ALCL, primary cutaneous ALCL, and express MUC1 only after activation, for classic HD were all CD30 positive. Two cases instance, by stimulation with phytohaemagglu- of DLBCL showed CD30 expression in a sub- tinin (PHA).31 35 Cumulative experience on set of the tumour cells. ALK expression was MUC1 expression in lymphoid malignancies, 36 absent in all cases of classic HD, primary cuta- recently reviewed by Chittal et al, shows that neous ALCL, PTCL-NOS, T-LB, and plasma cell neoplasms and T/null cell ALCLs DLBCL. have the highest expression of MUC1 (ap- proximately 85% and 60% of cases, respec- PBMC STIMULATION AND CELL SUBSET ISOLATION tively). In contrast, MUC1 expression was PBMCs were isolated from the peripheral found to be low in classic HD and in cutaneous blood of healthy volunteer donors by density ALCL. Thus, based on the literature, MUC1 centrifugation on Ficoll-Hypaque (1.077 g/ml; would seem a valuable tool for diVerentiating Pharmacia, Uppsala, Sweden). Cells were systemic nodal ALCL from classic HD or pri- washed three times with HBSS (Gibco, Paisley, mary cutaneous ALCL. UK) supplemented with 2% fetal calf serum However, data on MUC1 expression in lym- (FCS; HyClone Laboratories, Logan, Utah, phomas are skewed in favour of the commer- USA) and cryopreserved in IMDM (Gibco) cially available E29 (anti-EMA) monoclonal with 50% FCS and 10% DMSO until use. antibody37 because this is the anti-MUC1 anti- PBMCs were thawed, washed three times in body used most frequently in haematopathol- HBSS with 2% FCS, and cultured in IMDM ogy.
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