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Microvessel density of mantle cell lymphoma. A retrospective study of its prognostic role and the correlation with the Ki-67 and the mantle cell lymphoma international prognostic index in 177 cases

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Abstract

The clinical course and therapy of mantle cell lymphoma (MCL) are heterogeneous and often unsatisfactory. Prognostic factors are needed to stratify the patients. Microvessel density (MVD) has prognostic significance in some malignancies. There is little information about the vasculature of MCL, although some antiangiogenic drugs are in use. We studied MVD using systematic uniform random sampling and unbiased counting frames in immunohistochemical reactions with anti-CD34 antibody in pre-therapeutic extramedullary MCL samples of 177 patients. We analyzed the relationship of MVD to overall survival (OS) and progression-free survival (PFS), as well as to proliferative activity (Ki-67), mantle cell lymphoma prognostic index (MIPI), morphological variant, pattern of growth, and localization. MVD varied widely: range 54.6–503.6 vessels/mm2, median 158.2 vessels/mm2. Higher MVD was associated with bone marrow infiltration at the time of diagnosis (P = 0.001). High MVD was associated with significantly worse OS (P = 0.04) only in patients treated with non-intensive (conventional) therapy. MVD correlated positively with MIPI scores but not with the proliferation, morphological variant, growth pattern, or localization. Univariate analysis identified a prognostic influence of morphological variant, MIPI, and proliferative activity on OS and PFS and a prognostic influence of bone marrow infiltration at the time of diagnosis on PFS. Multivariate analysis showed prognostic influence of MIPI and proliferative activity on OS and PFS only. In conclusion, this is the first clinicopathological study of MVD of MCL with long-term follow-up showing negative prognostic trends of high MVD in MCL and positive correlation of MVD and MIPI.

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References

  1. Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, Kluin-Nelemans HC, Pfreundschuh M, Reiser M, Metzner B, Einsele H, Peter N, Jung W, Wörmann B, Ludwig WD, Dührsen U, Eimermacher H, Wandt H, Hasford J, Hiddemann W, Unterhalt M (2008) A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 111:558–565

    Article  PubMed  CAS  Google Scholar 

  2. Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E (2008) Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood 112:2687–2693

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, Stilgenbauer S, Thieblemont C, Vehling-Kaiser U, Doorduijn JK, Coiffier B, Forstpointner R, Tilly H, Kanz L, Feugier P, Szymczyk M, Hallek M, Kremers S, Lepeu G, Sanhes L, Zijlstra JM, Bouabdallah R, Lugtenburg PJ, Macro M, Pfreundschuh M, Prochazka V, Raimondo FD, Ribrag V, Uppenkamp M, André M, Klapper W, Hiddemann W, Unterhalt M, Dreyling MH (2012) Treatment of older patients with mantle-cell lymphoma. N Engl J Med 367:520–531

    Article  PubMed  CAS  Google Scholar 

  4. Swerdlow SH, Campo E, Seto M, Müller-Hermelink HK (2008) Mantle cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds) WHO classification of tumours of haematopoietic and lymphoid tissue. IARC Press, Lyon, pp 229–232

    Google Scholar 

  5. Fernández V, Salamero O, Espinet B, Solé F, Royo C, Navarro A, Camacho F, Beá S, Hartmann E, Amador V, Hernández L, Agostinelli C, Sargent RL, Rozman M, Aymerich M, Colomer D, Villamor N, Swerdlow SH, Pileri SA, Bosch F, Piris MA, Montserrat E, Ott G, Rosenwald A, López-Guillermo A, Jares P, Serrano S, Campo E (2010) Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res 70:1408–1418

    Article  PubMed  Google Scholar 

  6. Geisler CH, Kolstad A, Laurell A, Räty R, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Nilsson-Ehle H, Kuittinen O, Lauritzsen GF, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E (2010) The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT). Blood 115:1530–1533

    Article  PubMed  CAS  Google Scholar 

  7. van de Schans SA, Janssen-Heijnen ML, Nijziel MR, Steyerberg EW, van Spronsen DJ (2010) Validation, revision and extension of the Mantle Cell Lymphoma International Prognostic Index in a population-based setting. Haematologica 95:1503–1509

    Article  PubMed  PubMed Central  Google Scholar 

  8. Salek D, Vesela P, Boudova L, Janikova A, Klener P, Vokurka S, Jankovska M, Pytlik R, Belada D, Pirnos J, Moulis M, Kodet R, Michal M, Janousova E, Muzik J, Mayer J, Trneny M (2014) Retrospective analysis of 235 unselected patients with mantle cell lymphoma (MCL) confirms prognostic relevance of MIPI (MCL international prognostic index), and Ki-67 in the era of rituximab: long-term data from the Czech Lymphoma Project Database. Leuk Lymphoma 55:802–810

    Article  PubMed  CAS  Google Scholar 

  9. Hoster E, Klapper W, Hermine O, Kluin-Nelemans HC, Walewski J, van Hoof A, Trneny M, Geisler CH, Di Raimondo F, Szymczyk M, Stilgenbauer S, Thieblemont C, Hallek M, Forstpointner R, Pott C, Ribrag V, Doorduijn J, Hiddemann W, Dreyling MH, Unterhalt M (2014) Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol 32:1338–1346

    Article  PubMed  Google Scholar 

  10. Shah JJ, Fayad L, Romaguera J (2008) Mantle Cell International Prognostic Index (MIPI) not prognostic after R-hyper-CVAD. Blood 112:2583

    Article  PubMed  CAS  Google Scholar 

  11. Ott G, Kalla J, Ott MM, Schryen B, Katzenberger T, Müller JG, Müller-Hermelink HK (1997) Blastoid variants of mantle cell lymphoma: frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones. Blood 89:1421–1429

    PubMed  CAS  Google Scholar 

  12. Katzenberger T, Petzoldt C, Höller S, Mäder U, Kalla J, Adam P, Ott MM, Müller-Hermelink HK, Rosenwald A, Ott G (2006) The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood 107:3407

    Article  PubMed  CAS  Google Scholar 

  13. Determann O, Hoster E, Ott G, Wolfram Bernd H, Loddenkemper C, Leo Hansmann M, Barth TE, Unterhalt M, Hiddemann W, Dreyling M, Klapper W (2008) Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood 111:2385–2387

    Article  PubMed  CAS  Google Scholar 

  14. Klapper W, Hoster E, Determann O, Oschlies I, van der Laak J, Berger F, Bernd HW, Cabeçadas J, Campo E, Cogliatti S, Hansmann ML, Kluin PM, Kodet R, Krivolapov YA, Loddenkemper C, Stein H, Möller P, Barth TE, Müller-Hermelink K, Rosenwald A, Ott G, Pileri S, Ralfkiaer E, Rymkiewicz G, van Krieken JH, Wacker HH, Unterhalt M, Hiddemann W, Dreyling M (2009) Ki-67 as a prognostic marker in mantle cell lymphoma—consensus guidelines of the pathology panel of the European MCL Network. J Hematop 2:103–111

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ruan J, Hajjar K, Rafii S, Leonard JP (2009) Angiogenesis and antiangiogenic therapy in non-Hodgkin’s lymphoma. Ann Oncol 20:413–424

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Wang L, Shi WY, Wu ZY, Varna M, Wang AH, Zhou L, Chen L, Shen ZX, Lu H, Zhao WL, Janin A (2010) Cytostatic and anti-angiogenic effects of temsirolimus in refractory mantle cell lymphoma. J Hematol Oncol 3:30

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wang M, Rule SA, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, McGreivy J, Clow F, Stevens-Brogan M, Kunkel L, Blum KA (2012) Interim results of an international, multicenter, phase 2 study of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): durable efficacy and tolerability with longer follow-up. ASH Annu Meet Abstr 120:904

    Google Scholar 

  18. Zaja F, De Luca S, Vitolo U, Orsucci L, Levis A, Salvi F, Rusconi C, Ravelli E, Tucci A, Bottelli C, Balzarotti M, Brusamolino E, Bonfichi M, Pileri SA, Sabattini E, Volpetti S, Monagheddu C, Vacca A, Ria R, Fanin R (2012) Salvage treatment with lenalidomide and dexamethasone in relapsed/refractory mantle cell lymphoma: clinical results and effects on microenvironment and neo-angiogenic biomarkers. Haematologica 97:416–422

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Bono AV, Celato N, Cova V, Salvadore M, Chinetti S, Novario R (2002) Microvessel density in prostate carcinoma. Prostate Cancer Prostatic Dis 5:123–127

    Article  PubMed  CAS  Google Scholar 

  20. Uzzan B, Nicolas P, Cucherat M, Perret GY (2004) Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res 64:2941–2955

    Article  PubMed  CAS  Google Scholar 

  21. Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Wellik LA, Fonseca R, Lust JA, Witzig TE, Kyle RA, Greipp PR, Rajkumar SV (2004) Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy. Bone Marrow Transplant 34:235–239

    Article  PubMed  CAS  Google Scholar 

  22. Gratzinger D, Zhao S, Tibshirani RJ, Hsi ED, Hans CP, Pohlman B, Bast M, Avigdor A, Schiby G, Nagler A, Byrne GE Jr, Lossos IS, Natkunam Y (2008) Prognostic significance of VEGF, VEGF receptors, and microvessel density in diffuse large B cell lymphoma treated with anthracycline-based chemotherapy. Lab Invest 88:38–47

    Article  PubMed  CAS  Google Scholar 

  23. Cardesa-Salzmann TM, Colomo L, Gutierrez G, Chan WC, Weisenburger D, Climent F, González-Barca E, Mercadal S, Arenillas L, Serrano S, Tubbs R, Delabie J, Gascoyne RD, Connors JM, Mate JL, Rimsza L, Braziel R, Rosenwald A, Lenz G, Wright G, Jaffe ES, Staudt L, Jares P, López-Guillermo A, Campo E (2011) High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy. Haematologica 96:996–1001

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Tzankov A, Heiss S, Ebner S, Sterlacci W, Schaefer G, Augustin F, Fiegl M, Dirnhofer S (2007) Angiogenesis in nodal B cell lymphomas: a high throughput study. J Clin Pathol 60:476–482

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Lasota J, Franssila K, Koo CH, Miettinen M (1996) Molecular diagnosis of mantle cell lymphoma in paraffin-embedded tissue. Mod Pathol 9:361–366

    PubMed  CAS  Google Scholar 

  26. Tonar Z, Egger GF, Witter K, Wolfesberger B (2008) Quantification of microvessels in canine lymph nodes. Microsc Res Tech 71:760–772

    Article  PubMed  Google Scholar 

  27. Wolfesberger B, Tonar Z, Witter K, Guija de Arespacohaga A, Skalicky M, Walter I, Thalhammer JG, Egger GF (2008) Microvessel density in normal lymph nodes and lymphomas of dogs and their correlation with vascular endothelial growth factor expression. Res Vet Sci 85:56–61

    Article  PubMed  CAS  Google Scholar 

  28. Ruan J, Martin P, Coleman M, Furman RR, Cheung K, Faye A, Elstrom R, Lachs M, Hajjar KA, Leonard JP (2010) Durable responses with the metronomic regimen RT-PEPC in elderly patients with recurrent mantle cell lymphoma. Cancer 116:2655–2664

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Ridell B, Norrby K (2001) Intratumoral microvascular density in malignant lymphomas of B-cell origin. AMPIS 109:66–72

    CAS  Google Scholar 

  30. Koster A, van Krieken JH, MacKenzie MA, Schraders M, Borm GF, van der Laak JA, Leenders W, Hebeda K, Raemaekers JM (2005) Increased vascularization predicts favorable outcome in follicular lymphoma. Clin Cancer Res 11:154–161

    PubMed  CAS  Google Scholar 

  31. Taskinen M, Jantunen E, Kosma VM, Bono P, Karjalainen-Lindsberg ML, Leppä S (2010) Prognostic impact of CD31-positive microvessel density in follicular lymphoma patients treated with immunochemotherapy. Eur J Cancer 46:2506–2512

    Article  PubMed  Google Scholar 

  32. Argatoff LH, Connors JM, Klasa RJ, Horsman DE, Gascoyne RD (1997) Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood 89:2067–2078

    PubMed  CAS  Google Scholar 

  33. Räty R, Franssila K, Joensuu H, Teerenhovi L, Elonen E (2002) Ki-67 expression level, histological subtype, and the International Prognostic Index as outcome predictors in mantle cell lymphoma. Eur J Haematol 69:11–20

    Article  PubMed  Google Scholar 

  34. Kimura Y, Sato K, Arakawa F, Karube K, Nomura Y, Shimizu K, Aoki R, Hashikawa K, Yoshida S, Kiyasu J, Takeuchi M, Nino D, Sugita Y, Morito T, Yoshino T, Nakamura S, Kikuchi M, Ohshima K (2010) Mantle cell lymphoma shows three morphological evolutions of classical, intermediate, and aggressive forms, which occur in parallel with increased labeling index of cyclin D1 and Ki-67. Cancer Sci 101:806–814

    Article  PubMed  CAS  Google Scholar 

  35. Pittaluga S, Verhoef G, Criel A, Maes A, Nuyts J, Boogaerts M, De Wolf Peeters C (1996) Prognostic significance of bone marrow trephine and peripheral blood smears in 55 patients with mantle cell lymphoma. Leuk Lymphoma 21:115–125

    Article  PubMed  CAS  Google Scholar 

  36. Alexandrakis MG, Passam FH, Dambaki C, Pappa CA, Stathopoulos EN (2004) The relation between bone marrow angiogenesis and the proliferation index Ki-67 in multiple myeloma. J Clin Pathol 57:856–860

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Schaffel R, Hedvat CV, Teruya-Feldstein J, Persky D, Maragulia J, Lin D, Portlock CS, Moskowitz CH, Zelenetz AD (2010) Prognostic impact of proliferative index determined by quantitative image analysis and the International Prognostic Index in patients with mantle cell lymphoma. Ann Oncol 21:133–139

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Tiemann M, Schrader C, Klapper W, Dreyling MH, Campo E, Norton A, Berger F, Kluin P, Ott G, Pileri S, Pedrinis E, Feller AC, Merz H, Janssen D, Hansmann ML, van Krieken H, Möller P, Stein H, Unterhalt M, Hiddemann W, Parwaresch R (2005) Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. Br J Haematol 131:29–38

    Article  PubMed  Google Scholar 

  39. Schrader C, Meusers P, Brittinger G, Teymoortash A, Siebmann JU, Janssen D, Parwaresch R, Tiemann M (2004) Topoisomerase IIα expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome. Leukemia 18:1200–1206

  40. Romaguera JE, Fayad LE, Feng L, Hartig K, Weaver P, Rodriguez MA, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Cabanillas F, Kantarjian H, Kwak L, Wang M (2010) Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol 150:200–208

    PubMed  CAS  Google Scholar 

  41. Oberley MJ, Rajguru SA, Zhang C, Kim K, Shaw GR, Grindle KM, Kahl BS, Kanugh C, Laffin J, Yang DT (2013) Immunohistochemical evaluation of MYC expression in mantle cell lymphoma. Histopathology 63:499–508

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The help of many participating physicians and data managers providing clinical information and pathological specimens is greatly acknowledged. This study was supported in part by research grants of the Ministry of Education and Youth of the Czech Republic MSM0021620819 (LB), by the Charles University in Prague, Project No. P36 (ZT), and by the grant of the Internal Grant Agency of the Ministry of Health of the Czech Republic IGA MZ CR NT 12193-5 (LB, PV, DS, MT, on behalf of CLSG).

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Veselá, P., Tonar, Z., Šálek, D. et al. Microvessel density of mantle cell lymphoma. A retrospective study of its prognostic role and the correlation with the Ki-67 and the mantle cell lymphoma international prognostic index in 177 cases. Virchows Arch 465, 587–597 (2014). https://doi.org/10.1007/s00428-014-1632-4

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