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• W2129663642 abstract "Granzyme B (GrB) and T-cell-restricted intracellular antigen (TIA-1) are cytotoxic proteins that are specifically expressed by cytotoxic CD4 or CD8 positive T cells and natural killer cells. Recent studies demonstrated frequent expression of GrB and TIA-1 by neoplastic cells in primary cutaneous CD30+ large T-cell lymphomas and lymphomatoid papulosis but not in CD30− large T-cell lymphomas. In the present study, 74 biopsies from 54 patients with mycosis fungoides (MF) were investigated for the expression of GrB and TIA-1 using immunohistochemistry on paraffin sections. Staining of more than 10% of the neoplastic T cells for GrB or TIA-1 was considered positive. All but two follow-up biopsies had been obtained from patients without extracutaneous disease at the time of biopsy. Expression of TIA-1 and GrB was found in 33 (45%) and 14 (19%) of 74 MF biopsies, respectively. Comparison of biopsies from T3NoMo-stage MF (n = 27) and T2NoMo-stage MF (n = 45) showed increased expression of TIA-1 (55 versus 37%) and GrB (33 versus 9%) in T3NoMo-stage MF. Evaluation of multiple sequential biopsies from successive stages of MF also revealed an increase in the GrB/TIA-1 expression with tumor progression in five of eight cases. A clearcut relation between the expression of TIA-1 and/or GrB and the type of skin lesion biopsied was found. Considering all 74 biopsies, expression of TIA-1 and GrB was found in 18 of 50 (35%) and 5 of 50 (10%) patches or plaques, 9 of 16 (55%) and 3 of 16 (20%) tumors without blastic transformation, and 6 of 8 (75%) and 6 of 8 (75%) tumors with blastic transformation (defined as >50% blast cells). Correlation between GrB/TIA-1 expression in first diagnostic biopsies from patches or plaques from 40 patients with T2NoMo-stage MF and clinical follow-up data did not reveal differences in clinical behavior and survival between patients with (n = 14) or without (n = 26) expression of cytotoxic proteins, indicating that MF expressing cytotoxic proteins should not be considered as a separate group. Granzyme B (GrB) and T-cell-restricted intracellular antigen (TIA-1) are cytotoxic proteins that are specifically expressed by cytotoxic CD4 or CD8 positive T cells and natural killer cells. Recent studies demonstrated frequent expression of GrB and TIA-1 by neoplastic cells in primary cutaneous CD30+ large T-cell lymphomas and lymphomatoid papulosis but not in CD30− large T-cell lymphomas. In the present study, 74 biopsies from 54 patients with mycosis fungoides (MF) were investigated for the expression of GrB and TIA-1 using immunohistochemistry on paraffin sections. Staining of more than 10% of the neoplastic T cells for GrB or TIA-1 was considered positive. All but two follow-up biopsies had been obtained from patients without extracutaneous disease at the time of biopsy. Expression of TIA-1 and GrB was found in 33 (45%) and 14 (19%) of 74 MF biopsies, respectively. Comparison of biopsies from T3NoMo-stage MF (n = 27) and T2NoMo-stage MF (n = 45) showed increased expression of TIA-1 (55 versus 37%) and GrB (33 versus 9%) in T3NoMo-stage MF. Evaluation of multiple sequential biopsies from successive stages of MF also revealed an increase in the GrB/TIA-1 expression with tumor progression in five of eight cases. A clearcut relation between the expression of TIA-1 and/or GrB and the type of skin lesion biopsied was found. Considering all 74 biopsies, expression of TIA-1 and GrB was found in 18 of 50 (35%) and 5 of 50 (10%) patches or plaques, 9 of 16 (55%) and 3 of 16 (20%) tumors without blastic transformation, and 6 of 8 (75%) and 6 of 8 (75%) tumors with blastic transformation (defined as >50% blast cells). Correlation between GrB/TIA-1 expression in first diagnostic biopsies from patches or plaques from 40 patients with T2NoMo-stage MF and clinical follow-up data did not reveal differences in clinical behavior and survival between patients with (n = 14) or without (n = 26) expression of cytotoxic proteins, indicating that MF expressing cytotoxic proteins should not be considered as a separate group. Recently, monoclonal antibodies against components of the cytotoxic granules present in the cytoplasm of cytotoxic granules present in the cytoplasm of cytotoxic T-lymphocytes (CTL) and natural killer (NK) cells have become available. These cytotoxic molecules include perforin,1Lichtenheld MG Olsen KJ Lu P Lowrey DM Hameed A Hengartner H Podack ER Structure and function of human perforin.Nature. 1988; 335: 448-451Crossref PubMed Scopus (283) Google Scholar the serine proteases granzyme A and B,2Krahenbuhl O Rey C Jenne D Lanzavecchia A Groscurth P Carrel S Tschopp J Characterization of granzymes A and B isolated from granules of cloned human cytotoxic T lymphocytes.J Immunol. 1988; 141: 3471-3477PubMed Google Scholar, 3Griffiths GM Mueller C Expression of perforin and granzymes in vivo: potential diagnostic markers for activated cytotoxic cells.Immunol Today. 1991; 12: 415-419Abstract Full Text PDF PubMed Scopus (166) Google Scholar and the T-cell restricted intracellular antigen (TIA-1).4Anderson P Nagler-Anderson C O'Brien C Levine H Watkins S Slayter HS Blue ML Schlossman SF A monoclonal antibody reactive with a 15-kDa cytoplasmic granule-associated protein defines a subpopulation of CD8+ T lymphocytes.J Immunol. 1990; 144: 574-582PubMed Google Scholar, 5Anderson P TIA-1: structural and functional studies on a new class of cytolytic effector molecule.Curr Top Microbiol Immunol. 1995; 198: 131-143Crossref PubMed Scopus (84) Google ScholarAfter target cell recognition, cytotoxic lymphocytes reorient their cytoplasmic granules to the area of the target cell followed by vectorial exocytosis of granule contents into a tightly apposed, synaptosomal-like space between the cells. After interaction with specific binding sites, granzymes are endocytozed with adjacent sublytic perforin pores. The role of perforin lies in the delivery of granzymes to the cytosol by compromising the integrity of the endocytosed vesicle.6Froelich CJ Hanna WL Poirier GG Duriez PJ Damours D Salvesen GS Alnemri ES Earnshaw WC Shah GM Granzyme B perforin-mediated apoptosis of Jurkat cells results in cleavage of poly (ADP-ribose) polymerase to the 89-kDa apoptotic fragment and less abundant 64-kDa fragment.Biochem Biophys Res Commun. 1996; 227: 658-665Crossref PubMed Scopus (90) Google Scholar, 7Froelich CJ Orth K Turbov J Seth P Gottlieb R Babior B Shah GM Bleackley RC Dixit VM Hanna W New paradigm for lymphocyte granule-mediated cytotoxicity: target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis.J Biol Chem. 1996; 271: 29073-29079Crossref PubMed Scopus (313) Google Scholar, 8Froelich CJ Dixit VM Yang XH Lymphocyte granule-mediated apoptosis: matters of viral mimicry and deadly proteases.Immunol Today. 1998; 19: 30-36Abstract Full Text PDF PubMed Scopus (115) Google Scholar Once in the cytosol, granzymes can initiate apoptosis by activation of caspases and induction of intranuclear cyclin A/kinase complexes.9Shi LF Chen G He DL Bosc DG Litchfield DW Greenberg AH Granzyme B induces apoptosis and cyclin A-associated cyclin-dependent kinase activity in all stages of the cell cycle.J Immunol. 1996; 157: 2381-2385PubMed Google Scholar, 10Alnemri ES Livingston DJ Nicholson DW Salvesen G Thornberry NA Wong WW Yuan JY Human ICE/CED-3 protease nomenclature.Cell. 1996; 87: 171Abstract Full Text Full Text PDF PubMed Scopus (2129) Google Scholar, 11Zou H Henzel WJ Liu XS Lutschg A Wang XD APAF-1, a human protein homologous to c-elegans CED-4, participates in cytochrome C-dependent activation of caspase-3.Cell. 1997; 90: 405-413Abstract Full Text Full Text PDF PubMed Scopus (2725) Google ScholarInitial studies on the components of cytotoxic granules were focused primarily on the expression of these molecules by CTL and NK cells considered to play an important role in immunesurveillance and antitumor responses. However, studies in malignant lymphomas demonstrated that not only reactive cytotoxic leukocytes but also the neoplastic cells in various types of malignant lymphomas expressed these cytotoxic proteins.12De Bruin PC Kummer JA Van der Valk P Van Heerde P Kluin PM Willemze R Ossenkoppele GJ Radaszkiewicz T Meijer CJ Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa-associated lymphoid tissue localization.Blood. 1994; 84: 3785-3791PubMed Google Scholar, 13De Bruin PC Connolly CE Oudejans JJ Kummer JA Jansen W McCarthy CF Meijer CM Enteropathy-associated T-cell lymphomas have a cytotoxic T-cell phenotype.Histopathology. 1997; 31: 313-317Crossref PubMed Scopus (59) Google Scholar, 14Daum S Foss HD Anagnostopoulos I Dederke B Demel G Araujo I Riecken EO Stein H Expression of cytotoxic molecules in intestinal T-cell lymphomas: the German Study Group on intestinal non-Hodgkin lymphoma.J Pathol. 1997; 182: 311-317Crossref PubMed Scopus (32) Google Scholar Apart from rare NK/T-cell lymphomas,15Van Gorp J De Bruin PC Siego DS Van Heerde P Ossenkoppele GJ Rademakers LM Meijer CM Vandentweel JG Nasal T-cell lymphoma: a clinicopathological and immunophenotypic analysis of 13 cases.Histopathology. 1995; 27: 139-148Crossref PubMed Scopus (54) Google Scholar, 16Ohshima K Suzumiya J Shimazaki K Kato A Tanaka T Kanda M Kikuchi M Nasal T/NK cell lymphomas commonly express perforin and Fas ligand: important mediators of tissue damage.Histopathology. 1997; 31: 444-450Crossref PubMed Scopus (65) Google Scholar expression of granzyme B (GrB), TIA-1, and perforin was noted in 70 to 90% of noncutaneous CD30+ anaplastic large cell lymphomas (ALCL) of T- or null-cell phenotype and in sporadic cases of Hodgkin's disease.17Foss HD Anagnostopoulos I Araujo I Assaf C Demel G Kummer JA Hummel M Stein H Anaplastic large-cell lymphomas of T-cell and null-cell phenotype express cytotoxic molecules.Blood. 1996; 88: 4005-4011PubMed Google Scholar, 18Oudejans JJ Kummer JA Jiwa M Van der Valk P Ossenkoppele GJ Kluin PM Kluin-Nelemans JC Meijer CM Granzyme B expression in Reed-Sternberg cells of Hodgkins disease.Am J Pathol. 1996; 148: 233-240PubMed Google Scholar, 19Krenacs L Wellmann A Sorbara L Himmelmann AW Bagdi E Jaffe ES Raffeld M Cytotoxic cell antigen expression in anaplastic large cell lymphomas of T- and null-cell type and Hodgkin's disease: evidence for distinct cellular origin.Blood. 1997; 89: 980-989PubMed Google Scholar In primary cutaneous lymphomas, recent studies demonstrated expression of GrB and TIA-1 proteins in variable proportions of neoplastic cells in most cases of lymphomatoid papulosis and primary cutaneous CD30+ ALCL, but not or rarely in CD30− primary cutaneous large T-cell lymphomas.20Kummer JA Vermeer MH Dukers D Meijer CJ Willemze R Most primary cutaneous CD30-positive lymphoproliferative disorders have a CD4-positive cytotoxic T-cell phenotype.J Invest Dermatol. 1997; 109: 636-640Crossref PubMed Scopus (113) Google Scholar Because these primary cutaneous CD30+ lymphoproliferations may coexist or progress from typical mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL), we wondered if the neoplastic cells in MF also express TIA-1 and GrB. Therefore, immunohistochemical stainings for GrB and TIA-1 were performed on paraffin sections from 74 biopsies of 54 MF patients. The results were correlated with clinical stage according to the TNM classification and with the type of skin lesion biopsied. To establish whether cases of MF expressing TIA-1 and/or GrB should be regarded as a distinct subgroup of MF, expression of cytotoxic proteins was correlated with clinical behavior and survival.Material and MethodsPatientsSeventy-four paraffin-embedded skin specimens from 54 patients with MF were selected from the tissue bank of the Dutch Cutaneous Lymphoma Working Group. The diagnosis was based on a combination of clinical, histological, and immunophenotypical data as described previously.21Willemze R Kerl H Sterry W Berti E Cerroni L Chimenti S Diazperez JL Geerts ML Goos M Knobler R Ralfkiaer E Santucci M Smith N Wechsler J Van Vloten WA Meijer CM EORTC classification for primary cutaneous lymphomas: a proposal from the cutaneous lymphoma study group of the European organization for research and treatment of cancer.Blood. 1997; 90: 354-371PubMed Google Scholar Biopsies had been obtained from untreated skin lesions at the time of diagnosis (57 biopsies) or at the time of relapse or disease progression (17 biopsies). For all 74 biopsies, both the clinical stage at the time of biopsy, which was assessed according to the staging criteria proposed by the National Cancer Institute workshop on cutaneous T-cell lymphomas (TNM classification),22Diamandidou E Cohen PR Kurzrock R Mycosis fungoides and Sezary syndrome.Blood. 1996; 88: 2385-2409PubMed Google Scholar as well as the type of skin lesion from which the biopsy was taken, are presented in Table 1. With respect to the clinical stage, it should be noted that at the time of biopsy only two patients (Table 1; patients 44 and 54) had concurrent lymph node involvement (T3N3Mo). Because all but these two follow-up biopsies had been obtained from patients without evidence of extracutaneous disease at the time of biopsy the clinical stage was determined only by the type of skin lesions, defined as the presence of patches and plaques covering more than 10% of the skin surface (T2) or the presence of tumors (T3). Because previous studies demonstrated unequivocally that skin tumors showing blastic transformation have a significantly worse prognosis than tumors without blastic transformation23Dmitrovsky E Matthews MJ Bunn PA Schechter GP Makuch RW Winkler CF Eddy J Sausville EA Ihde DC Cytologic transformation in cutaneous T cell lymphoma: a clinicopathologic entity associated with poor prognosis.J Clin Oncol. 1987; 5: 208-215PubMed Google Scholar, 24Greer JP Salhany KE Cousar JB Fields JP King LE Graber SE Flexner JM Stein RS Collins RD Clinical features associated with transformation of ceribriform T-cell lymphoma to a large cell process.Hematol Oncol. 1990; 8: 215-227Crossref PubMed Scopus (59) Google Scholar within the T3 category, distinction was made between tumors with and tumors without blastic transformation, defined by the presence of more than 50% blast cells. Therefore, we will refer primarily to the type of skin lesion (patches/plaques, tumors without, and tumors with blastic transformation). Whenever appropriate, the TNM categories will be indicated as well.Table 1Stage of Disease (TNM Classification)22Diamandidou E Cohen PR Kurzrock R Mycosis fungoides and Sezary syndrome.Blood. 1996; 88: 2385-2409PubMed Google Scholar and Type of Skin Lesion of 74 Biopsies in 54 Patients with Mycosis FungoidesBiopsy at time of diagnosisBiopsy at time of relapse/progressionSkin lesionsSkin lesionsPatientTNMPLT−T+TNMPLT−T+1–29T2N0M0+30–34T2N0M0+T2N0M0+35–37T2N0M0+T3N0M0+38T2N0M0+T3N0M0+*Two tumors biopsied 2 years apart.39T2N0M0+T3N0M0+40T2N0M0+T3N0M0++41T3N0M0++42–43T3N0M0++44T3N0M0++T3N3M0+45–50T3N0M0+51T3N0M0+T3N0M0+52T3N0M0+T3N0M0+53T3N0M0+54T3N3M0+Total number of skin biopsies44103665Definitions of TNM classification: T1, patches/plaques covering <10% of skin surface; T2, patches/plaques covering 10% or more of skin surface; T3, tumor(s); T4, erythroderma; N0, no clinically enlarged peripheral lymph nodes, histology (if performed) negative; N1, clinically abnormal peripheral lymph nodes, pathology negative for CTCL; N2, clinically nonpalpable, pathologically positive lymph nodes; N3, clinically abnormal, pathology positive for CTCL; M0, no visceral involvement; M1, visceral involvement (biopsy documented); PL, plaque; T−, tumor without transformation; T+, tumor with blastic transformation, defined by the presence of >50% blast cells.* Two tumors biopsied 2 years apart. Open table in a new tab Skin biopsies had been obtained from typical patches (cases 1 through 4; Table 1), plaques (n = 46), and tumors without (n = 16) or tumors with blastic transformation (n = 8) (see Table 1). Multiple biopsies were available in 17 of 54 patients. In five cases (patients 30 to 34) biopsies from two different plaques of patients with T2NoMo stage disease were studied. The time interval between the first and second biopsy ranged between 6 and 45 months (median, 21 months). In 10 patients biopsies from both plaques and tumors obtained at the same time at diagnosis (patients 41 to 44) and/or during follow-up (patients 35 to 40 and 44) were studied. In three patients (patients 44, 51, and 52) skin biopsies from two tumorous lesions, biopsied 12 to 15 months apart, were available for examination.All cases had been immunophenotyped previously as part of routine diagnostic procedures both on paraffin material and fresh material, the latter either on another part of the same biopsy or on another biopsy from a similar lesion concurrently taken. Sixty-seven of 74 biopsies had a CD3+, CD4+, and CD8− immunophenotype, 6 of 74 had a CD3+, CD4−, and CD8− immunophenotype, and one biopsy had a CD3+, CD4−, and CD8+ immunophenotype. This latter patient was included because both the clinical presentation, the histological appearance, and the clinical course were all characteristic of MF. In none of the cases the neoplastic T cells expressed CD56 or CD57.ImmunohistochemistryImmunostaining on formalin-fixed, paraffin-embedded sections with monoclonal antibodies against granzyme B (GrB7)25Kummer JA Kamp AM Van Katwijk M Brakenhoff JP Radosevic K van Leeuwen AM Borst J Verweij CL Hack CE Production and characterization of monoclonal antibodies raised against recombinant human granzymes A and B and showing cross reactions with the natural proteins.J Immunol Methods. 1993; 163: 77-83Crossref PubMed Scopus (79) Google Scholar, 26Kummer JA Kamp AM Tadema TM Vos W Meijer CJ Hack CE Localization and identification of granzymes A and B-expressing cells in normal human lymphoid tissue and peripheral blood.Clin Exp Immunol. 1995; 100: 164-172Crossref PubMed Scopus (61) Google Scholar and TIA-1 (Coulter Immunology, Hialeah, FL)4Anderson P Nagler-Anderson C O'Brien C Levine H Watkins S Slayter HS Blue ML Schlossman SF A monoclonal antibody reactive with a 15-kDa cytoplasmic granule-associated protein defines a subpopulation of CD8+ T lymphocytes.J Immunol. 1990; 144: 574-582PubMed Google Scholar was performed using a streptavidin-biotin-peroxidase technique following antigen retrieval with microwave heating, as described previously.18Oudejans JJ Kummer JA Jiwa M Van der Valk P Ossenkoppele GJ Kluin PM Kluin-Nelemans JC Meijer CM Granzyme B expression in Reed-Sternberg cells of Hodgkins disease.Am J Pathol. 1996; 148: 233-240PubMed Google Scholar In addition, in all cases serial sections were stained with monoclonal antibodies against CD4 (Novocastra, Newcastle upon Tyne, UK), CD8 (144B; a gift from Dr. Mason, Oxford, UK), Ber-H2/CD30 (DAKO, Glostrup, Denmark), and polyclonal antibodies against CD3 (DAKO).Interpretation of Immunohistochemical StainingIdentification of neoplastic T cells, including medium-sized to large cerebriform cells and blast cells, was based on a combination of morphology and phenotype. In the early plaque lesions the neoplastic T-cells could be recognized rather easily by their cerebriform nuclear morphology, their haloed appearance and their typical lining-up at the dermal-epidermal junction. In addition, in all cases, examination of serial sections stained with monoclonal antibodies against CD3, CD4, and CD8 were used as an additional tool to differentiate the neoplastic T cells from reactive CD8+ T cells and dendritic cells/macrophages (Figure 1). Because interpretation of cases showing only occasional GrB and/or TIA-1+, neoplastic T cells may be difficult in particular in cases containing many admixed GrB+, TIA-1+, and CD8+ T cells; cases with less than 10% GrB+ or TIA-1+ neoplastic cells were considered negative. The percentage of neoplastic cells positive for GrB and TIA-1 were scored as follows: −, no or occasional (<10%) tumor cell stained; +, 10 to 50%; and ++, >50% positive tumor cells.Statistical AnalysisThe relationship between the expression of TIA-1 and GrB and TNM-stage was evaluated with Fisher's exact test by comparing all biopsies from stage T2NoMo and T3NoMo, irrespective of the type of skin lesion biopsied. The increase of expression of TIA-1 and GrB in relation to the type of skin lesion biopsied was evaluated with the nonparametric Spearman rank correlation test. Disease-related survival probabilities for T2NoMo-stage MF were estimated using Kaplan-Meier survival analysis.27Kaplan EL Meier P Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481Crossref Scopus (47662) Google Scholar Survival of patients without TIA-1 and GrB expression was compared with cases expressing TIA-1 or expressing TIA-1 and GrB with the log rank test. Observations were considered statistically significant if P < 0.05.ResultsIn 33 of 74 biopsies, more than 10% of the neoplastic cells showed a clear granular cytoplasmic staining for GrB and/or TIA-1 (Figure 1, Figure 2). Tumor cells expressing TIA-1 and/or GrB included both neoplastic T cells with cerebriform nuclei and blast cells. Expression of TIA-1 was more frequent (33 of 74) than GrB (14 of 74). Whereas 14 of 33 TIA-1+ biopsies also expressed GrB in more than 10% of the neoplastic cells, biopsies showing tumor cells reactive with GrB but negative for TIA-1 were not observed. Moreover, in most biopsies TIA-1+ neoplastic T cells outnumbered GrB+ tumor cells. In 21 and 17 of 74 biopsies occasional tumor cells (<10%) expressing TIA-1 or GrB, respectively, were observed. In 20 biopsies, staining of neoplastic T cells for both TIA-1 and GrB was completely negative. In these biopsies, the reactive T lymphocytes expressing GrB and TIA-1 acted as a positive control. Correlation between the expression of cytotoxic proteins and the phenotype of the neoplastic cells showed expression of GrB and/or TIA-1 by more than 10% of the neoplastic cells in 28 of 67 (40%) of CD3+, CD4+, and CD8− MF, in four of six (60%) of CD3−, CD4−, and CD8− MF, and in the single case with a CD3+, CD4−, and CD8+ immunophenotype.Figure 2Mycosis fungoides, tumor. Diffuse proliferation of neoplastic cells that show a diffuse granular cytoplasmic staining for both TIA-1 (A) and GrB (B). Streptavidin-biotin-peroxidase technique; hematoxylin counterstain; original magnification, ×400.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Increased Expression of GrB and TIA-1 with Progression from Plaque to Tumor Stage MFThe results of TIA− and GrB staining in the different clinical stages and in the different types of skin lesions are presented in Table 2. Comparison between the 45 biopsies obtained from patients with T2NoMo-stage MF with the 27 biopsies obtained from patients with T3NoMo-stage MF showed expression of TIA-1 and GrB by the neoplastic cells in 17 of 45 (37%) and 4 of 45 (9%) skin lesions in T2NoMo-stage MF, and in 15 of 27 (55%) and 9 of 27 (33%) skin lesions in T3NoMo-stage MF, respectively. Thus, the expression of cytotoxic proteins was higher in T3NoMo-stage MF than in T2NoMo-stage MF, and this increased expression reached statistical significance for GrB (P = 0.01) but not for TIA-1. Within T3NoMo-stage MF, a clearcut relation between the expression of TIA-1 and GrB and the type of skin lesion biopsied was found. TIA-1 and GrB were expressed by one in five (20%) plaques, by 10 in 16 (62%), and 3 in 16 (18%) tumors without transformation, respectively, and by 5 in 6 (80%) tumors with blastic transformation. Thus, no significant differences in the expression of TIA-1 and GrB were found between patches/plaques in patients with (T3NoMo) or without (T2NoMo) concurrent tumors. Consistently, evaluation of four patients presenting with T3NoMo-stage MF (patients 41 to 44), in whom both plaques and tumors could be investigated, both TIA-1 and GrB were expressed by 20% of the neoplastic cells in one of four plaques, whereas both proteins were expressed by more than 75% of the neoplastic cells in three of four concurrent tumors. In one of these four cases both plaque and tumor were completely negative for TIA-1 and GrB. In another eight cases, in which multiple biopsies from successive stages of MF were available, an increase in the percentages of neoplastic cells expressing GrB and/or TIA-1 was observed in five of the eight (Table 3). In all five cases, in which two plaques biopsied 6 to 45 months apart were studied, no major differences in GrB and TIA-1 expression between the first and the second biopsy were found.Table 2Expression of Cytotoxic Molecules in Relation to Different Stages of Mycosis Fungoides (TNM Classification) and the Type of Biopsied Skin LesionTIA-1*−, no positive cells or <10% positive neoplastic cells; +, 10–50% positive neoplastic cells; ++, >50% positive neoplastic cells;Granzyme B*−, no positive cells or <10% positive neoplastic cells; +, 10–50% positive neoplastic cells; ++, >50% positive neoplastic cells;TNM classification at time of biopsyType of skin lesionn−+++−+++T2N0M0Patch/plaque4528 (62%)12 (27%)5 (11%)41 (91%)2 (4%)2 (4%)T3N0M0Plaque54 (80%)1 (20%)04 (80%)1 (20%)0Tumor228 (36%)5 (23%)9 (41%)14 (64%)6 (27%)2 (9%)T3N3M0Tumor21 (50%)01 (50%)1 (50%)01 (50%)Type of skin lesion†Statistical analysis with Spearman rank correlation coefficient is 0.35 (P = 0.002) for TIA-1 and 0.39 (P = 0.0006) for GrB.Patch/plaque5032 (64%)13 (26%)5 (10%)45 (90%)3 (6%)2 (4%)Tumor without transformation167 (44%)5 (31%)4 (25%)13 (81%)2 (13%)1 (6%)Tumor with transformation‡Transformation is defined by the presence of >50% blast cells.82 (25%)06 (75%)2 (25%)4 (50%)2 (25%)* −, no positive cells or <10% positive neoplastic cells; +, 10–50% positive neoplastic cells; ++, >50% positive neoplastic cells;† Statistical analysis with Spearman rank correlation coefficient is 0.35 (P = 0.002) for TIA-1 and 0.39 (P = 0.0006) for GrB.‡ Transformation is defined by the presence of >50% blast cells. Open table in a new tab Table 3Expression of Cytotoxic Proteins in Sequential Biopsies from Successive Stages of Mycosis FungoidesBiopsy at time of diagnosisBiopsy after disease progressionNumber (patient number)TNMSkin lesionTIA-1/GrB*TNMSkin lesionTIA-1/GrBExpression of GrB/TIA-1†Result over sequential biopsies.1 (35)T2N0M0Plaque−/++T3N0M0Tumor+/++↑2 (36)T2N0M0Plaque−/−T3N0M0Tumor−/−≈3 (37)T2N0M0Plaque−/−T3N0M0Tumor−/+↑4 (38)T2N0M0Plaque−/−T3N0M0Tumor−/−‡Confirmed on an additional biopsy two years later.≈5 (39)T2N0M0Plaque−/−T3N0M0Tumor (+Tr)+/++↑6 (40)T2N0M0Plaque−/−T3N0M0Tumor (+Tr)−/−≈7 (44)T3N0M0Plaque+/+T3N3M0Tumor (+Tr)++/++↑Tumor+/+8 (52)T3N0M0Tumor−/+T3N0M0Tumor (+Tr)+/++↑Abbreviations: *−, No positive cells or <10% positive neoplastic cells; +, 10 to 50% positive neoplastic cells; ++, >50% positive neoplastic cells.Tr, transformation, defined as >50% blast cells.† Result over sequential biopsies.‡ Confirmed on an additional biopsy two years later. Open table in a new tab Taken together, these results demonstrate an increase in the expression of TIA-1 and GrB with progression from plaque stage (T2N0M0) to tumor stage (T3N0M0) MF. In addition, a clearcut relationship between the expression of cytotoxic molecules and the type of skin lesion biopsied was observed. Evaluation of all 74 biopsies confirmed that the increase in TIA-1/GrB expression strongly correlated with the development of tumors (P = 0.03 for TIA-1 and P = 0.007 for GrB). Thus, TIA-1 expression by more than 10% of the neoplastic cells was detected in 18 of 50 (35%) patches or plaques, in 9 of 16 (55%) tumors without transformation, and in six of eight (75%) tumors with blastic transformation. Similarly, the expression of GrB in more than 10% of neoplastic cells increased from 5 in 50 (10%) of patches or plaques and 3 of 16 (20%) tumors without transformation to six of eight (75%) tumors with transformation. In the nonparametric Spearman rank correlation test, this increase in the expression of TIA-1 and GrB was statistically significant with a correlation coefficient of 0.35 (P = 0.002) and 0.39 (P = 0.0006), respectively (Table 2).Correlation of GrB/TIA-1 Expression with Clinical Behavior and OutcomeTo study whether cases of MF expressing cytotoxic molecules have a different clinical behavior and prognosis compared with GrB−/TIA-1− cases, the results of staining for GrB/TIA-1 in the first diagnostic biopsy of 40 patients with T2N0M0-stage MF (patients 1 to 40; Table 1) were correlated with the clinical follow-up data, including the development of tumors, the development of nodal or visceral involvement, and survival. In 16 of 40 biopsies more than 10% of the neoplastic cells expressed both TIA-1 and GrB (four patients) or only TIA-1 but not GrB (12 patients), whereas in 24 of 40 biopsies no or occasional tumor cells stained for GrB and/or TIA-1. The follow-up data did not show major differences in disease progression or prognosis between these three groups, neither between the first two positive groups together compared with the negative group (Table 4). Also the four cases, in which more than 50% of the neoplastic cells expressed cytotoxic molecules, did not show another clinical behavior as compared with the GrB−/TIA-1− cases (data not shown). Thus, no significant differences in disease progression and survival were found between patients with and without expression of cytotoxic molecules in T2NoMo-stage MF.Table 4Disease Pr" @default.
• W2129663642 created "2016-06-24" @default.
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• W2129663642 date "1999-04-01" @default.
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• W2129663642 title "Expression of Cytotoxic Proteins by Neoplastic T Cells in Mycosis Fungoides Increases with Progression from Plaque Stage to Tumor Stage Disease" @default.
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