Abstract
Although the long-term disease control of classical Hodgkin lymphoma (cHL) is relatively high, significant treatment-related morbidities are common. These include secondary cancers, cardiopulmonary complications, stroke, peripheral neuropathy, and infertility. In the 20 % of patients who do not respond to first-line agents, prolonged exposure to suboptimal therapy can induce chemoresistance. Patients with a rapid response may be overtreated and might benefit from a truncated treatment regimen. Accurate risk stratification is needed in order to optimally treat cHL. However, this requires defined predictive and treatment response markers. Existing clinical parameters have limited prognostic value prior to therapy, and the only established marker of value once treatment has commenced is 18-fluorodeoxyglucose positron emission tomography (FDG-PET) combined with computerized tomography (CT). Although PET/CT is currently the most important tool used, interpretation is imperfect with low false-negative rates countered by high false positives. Furthermore, PET/CT is unavailable in many rural or underprivileged centers and, even in the most advantaged centers, is impractical for frequent testing. In order to risk-stratify patients once therapy has commenced, clinicians need an accurate marker of treatment response that can be performed throughout the therapy, prior to each follow-up visit. This chapter focuses on two newly identified serum disease response biomarkers, CD163 and TARC, for cHL that have the potential to greatly assist clinical decision making and aid interpretation of PET/CT.
Abbreviations
- cDNA:
-
Complementary DNA
- cHL:
-
Classical Hodgkin Lymphoma
- CR:
-
Complete Remission
- CT:
-
Computerized Tomography
- CTL:
-
Cytotoxic T Lymphocyte
- DSS:
-
Disease-Specific Survival
- EBNA:
-
Epstein-Barr Virus Nucleic Acid
- EBV:
-
Epstein-Barr Virus
- EFS:
-
Event-Free Survival
- EIA:
-
Enzyme Immunoassay
- ELISA:
-
Enzyme-Linked Immunosorbent Assay
- ESR:
-
Erythrocyte Sedimentation Rate
- FACS:
-
Fluorescence-Activated Cell Sorter
- FDG:
-
18-Fluorodeoxyglucose
- FFS:
-
Failure-Free Survival
- FFTF:
-
Freedom from First-Line Treatment Failure
- GHSG:
-
German Hodgkin Study Group
- HL:
-
Hodgkin Lymphoma
- HRS:
-
Hodgkin and Reed-Sternberg
- IHC:
-
Immunohistochemistry
- IM:
-
Infectious Mononucleosis
- IPS:
-
International Prognostic Score
- ISH:
-
In Situ Hybridization
- LD:
-
Lymphocyte Depleted
- LDH:
-
Lactate Dehydrogenase
- LMP:
-
Latent Membrane Protein
- LP:
-
Lymphocyte Predominant
- LR:
-
Lymphocyte Rich
- MC:
-
Mixed Cellularity
- NLPHL:
-
Nodular Lymphocyte-predominant HL
- NS:
-
Nodular Sclerosis
- OS:
-
Overall Survival
- PBMC:
-
Peripheral Blood Mononuclear Cell
- PET:
-
Positron Emission Tomography
- PFS:
-
Progression-Free Survival
- PR:
-
Partial Remission
- PTLD:
-
Posttransplant Lymphoproliferative Disorder
- qRT-PCR:
-
Quantitative Real-Time Polymerase Chain Reaction
- ROC:
-
Receiver Operating Characteristic
- sCD163:
-
Serum CD163
- sTARC:
-
Serum TARC
- TAMs:
-
Tumor-Associated Macrophages
- TARC:
-
Thymus and Activation-Related Chemokine
- TILs:
-
Tumor-Infiltrating Lymphocytes
- WHO:
-
World Health Organization
References
Alvaro T, Lejeune M, et al. Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res. 2005;11(4):1467–73.
Alvaro-Naranjo T, Lejeune M, et al. Tumor-infiltrating cells as a prognostic factor in Hodgkin’s lymphoma: a quantitative tissue microarray study in a large retrospective cohort of 267 patients. Leuk Lymphoma. 2005;46(11):1581–91.
Azambuja D, Natkunam Y, et al. Lack of association of tumor-associated macrophages with clinical outcome in patients with classical Hodgkin’s lymphoma. Ann Oncol. 2012;23(3):736–42.
Caporaso NE, Goldin LR, et al. Current insight on trends, causes, and mechanisms of Hodgkin’s lymphoma. Cancer J. 2009;15(2):117–23.
Chetaille B, Bertucci F, et al. Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood. 2009;113(12):2765–3775.
Christiansen I, Enblad G, et al. Soluble ICAM-1 in Hodgkin’s disease: a promising independent predictive marker for survival. Leuk Lymphoma. 1995;19(3–4):243–51.
Christiansen I, Sundstrom C, et al. Soluble vascular cell adhesion molecule-1 (sVCAM-1) is an independent prognostic marker in Hodgkin’s disease. Br J Haematol. 1998;102(3):701–9.
Claviez A, Tiemann M, et al. Impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin’s lymphoma. J Clin Oncol. 2005;23(18):4048–56.
Diehl V, Stein H, et al. Hodgkin’s lymphoma: biology and treatment strategies for primary, relapsed disease. Hematology Am Soc Hematol Educ Program. 2003:225–47.
Diehl V, Thomas RK, et al. Part II: Hodgkin’s lymphoma–diagnosis and treatment. Lancet Oncol. 2004;5(1):19–26.
Diepstra A, van Imhoff GW, et al. HLA class II expression by Hodgkin Reed-Sternberg cells is an independent prognostic factor in classical Hodgkin’s lymphoma. J Clin Oncol. 2007;25(21):3101–8.
Diepstra A, van Imhoff GW, et al. Latent Epstein-Barr virus infection of tumor cells in classical Hodgkin’s lymphoma predicts adverse outcome in older adult patients. J Clin Oncol. 2009;27(23):3815–21.
Doussis-Anagnostopoulou IA, Vassilakopoulos TP, et al. Topoisomerase IIalpha expression as an independent prognostic factor in Hodgkin’s lymphoma. Clin Cancer Res. 2008;14(6):1759–66.
Drouet E, Brousset P, et al. High Epstein-Barr virus serum load and elevated titers of anti-ZEBRA antibodies in patients with EBV-harboring tumor cells of Hodgkin’s disease. J Med Virol. 1999;57(4):383–9.
Evens AM, Hutchings M, et al. Treatment of Hodgkin lymphoma: the past, present, and future. Nat Clin Pract Oncol. 2008;5(9):543–56.
Fischer M, Juremalm M, et al. Expression of CCL5/RANTES by Hodgkin and Reed-Sternberg cells and its possible role in the recruitment of mast cells into lymphomatous tissue. Int J Cancer. 2003;107(2):197–201.
Gallagher A, Armstrong AA, et al. Detection of Epstein-Barr virus (EBV) genomes in the serum of patients with EBV-associated Hodgkin’s disease. Int J Cancer. 1999;84(4):442–8.
Gallamini A, Kostakoglu L. Interim FDG-PET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials? Blood. 2012;120(25):4913–20.
Gallamini A, Hutchings M, et al. Early interim 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. J Clin Oncol. 2007;25(24):3746–52.
Gandhi MK, Tellam JT, et al. Epstein-Barr virus-associated Hodgkin’s lymphoma. Br J Haematol. 2004;125(3):267–81.
Gandhi MK, Lambley E, et al. Plasma Epstein-Barr virus (EBV) DNA is a biomarker for EBV-positive Hodgkin’s lymphoma. Clin Cancer Res. 2006;12(2):460–4.
Gause A, Pohl C, et al. Clinical significance of soluble CD30 antigen in the sera of patients with untreated Hodgkin’s disease. Blood. 1991;77(9):1983–8.
Gause A, Jung W, et al. Soluble CD8, CD25 and CD30 antigens as prognostic markers in patients with untreated Hodgkin’s lymphoma. Ann Oncol. 1992;3 Suppl 4:49–52.
Glavina-Durdov M, Jakic-Razumovic J, et al. Assessment of the prognostic impact of the Epstein-Barr virus-encoded latent membrane protein-1 expression in Hodgkin’s disease. Br J Cancer. 2001;84(9):1227–34.
Greaves P, Clear A, et al. Expression of FOXP3, CD68, and CD20 at diagnosis in the microenvironment of classical Hodgkin lymphoma is predictive of outcome. J Clin Oncol. 2013;31(2):256–62.
Harris JA, Jain S, et al. CD163 versus CD68 in tumor associated macrophages of classical Hodgkin lymphoma. Diagn Pathol. 2012;7:12.
Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506–14.
Herbst H, Dallenbach F, et al. Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells. Proc Natl Acad Sci U S A. 1991;88(11):4766–70.
Hijnen D, De Bruin-Weller M, et al. Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell- attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis. J Allergy Clin Immunol. 2004;113(2):334–40.
Hohaus S, Santangelo R, et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17(9):2885–92.
Hutchings M, Mikhaeel NG, et al. Prognostic value of interim FDG-PET after two or three cycles of chemotherapy in Hodgkin lymphoma. Ann Oncol. 2005;16(7):1160–8.
Hutchings M, Loft A, et al. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood. 2006;107(1):52–9.
Jarrett RF, Gallagher A, et al. Detection of Epstein-Barr virus genomes in Hodgkin’s disease: relation to age. J Clin Pathol. 1991;44(10):844–8.
Jerusalem G, Beguin Y, et al. Whole-body positron emission tomography using 18F-fluorodeoxyglucose for posttreatment evaluation in Hodgkin’s disease and non-Hodgkin’s lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging. Blood. 1999;94(2):429–33.
Jones K, Nourse JP, et al. Tumor-specific but not nonspecific cell-free circulating DNA can be used to monitor disease response in lymphoma. Am J Hematol. 2012;87(3):258–65.
Jones K, Vari F, et al. Serum CD163 and TARC as disease response biomarkers in classical Hodgkin lymphoma. Clin Cancer Res. 2013;19(3):731–42.
Kamper P, Bendix K, et al. Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica. 2011a;96(2):269–76.
Kamper P, Ludvigsen M, et al. Proteomic analysis identifies galectin-1 as a predictive biomarker for relapsed/refractory disease in classical Hodgkin lymphoma. Blood. 2011b;117(24):6638–49.
Kanakry JA, Li H, et al. Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood. 2013;121(18):3547–53.
Kuppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9(1):15–27.
Kurzrock R, Redman J, et al. Serum interleukin 6 levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin’s disease and with B symptoms. Cancer Res. 1993;53(9):2118–22.
Mao Y, Lu MP, et al. Prognostic significance of EBV latent membrane protein 1 expression in lymphomas: evidence from 15 studies. PLoS One. 2013;8(4):e60313.
Meignan M, Gallamini A, et al. Report on the Second International Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8–9 April 2010. Leuk Lymphoma. 2010;51(12):2171–80.
Niens M, Visser L, et al. Serum chemokine levels in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22. Br J Haematol. 2008;140(5):527–36.
Oudejans JJ, Jiwa NM, et al. Activated cytotoxic T cells as prognostic marker in Hodgkin’s disease. Blood. 1997;89(4):1376–82.
Ouyang J, Plutschow A, et al. Galectin-1 serum levels reflect tumor burden and adverse clinical features in classical Hodgkin lymphoma. Blood. 2013;121(17):3431–3.
Pallesen G, Hamilton-Dutoit SJ, et al. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin’s disease. Lancet. 1991;337(8737):320–2.
Peh SC, Kim LH, et al. 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. Am J Surg Pathol. 2001;25(7):925–9.
Pileri SA, Ascani S, et al. Hodgkin’s lymphoma: the pathologist’s viewpoint. J Clin Pathol. 2002;55(3):162–76.
Plattel WJ, van den Berg A, et al. Plasma thymus and activation-regulated chemokine as an early response marker in classical Hodgkin’s lymphoma. Haematologica. 2012;97(3):410–5.
Reynolds GM, Billingham LJ, et al. Interleukin 6 expression by Hodgkin/Reed-Sternberg cells is associated with the presence of ‘B’ symptoms and failure to achieve complete remission in patients with advanced Hodgkin’s disease. Br J Haematol. 2002;118(1):195–201.
Sanchez-Espiridion B, Martin-Moreno AM, et al. Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin lymphoma. Haematologica. 2012;97(7):1080–4.
Seymour JF, Talpaz M, et al. Clinical correlates of elevated serum levels of interleukin 6 in patients with untreated Hodgkin’s disease. Am J Med. 1997;102(1):21–8.
Shim HK, Lee WW, et al. Relationship between FDG uptake and expressions of glucose transporter type 1, type 3, and hexokinase-II in Reed-Sternberg cells of Hodgkin lymphoma. Oncol Res. 2009;17(7):331–7.
Shimada Y, Takehara K, et al. Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis. J Dermatol Sci. 2004;34(3):201–8.
Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood. 2002;99(12):4283–97.
Spacek M, Hubacek P, et al. Plasma EBV-DNA monitoring in Epstein-Barr virus-positive Hodgkin lymphoma patients. Acta Pathol Microbiol Immunol Scand. 2011;119(1):10–6.
Steidl C, Lee T, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875–85.
Steidl C, Diepstra A, et al. Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma. Blood. 2012;120(17):3530–40.
Swerdlow SH, Campo E, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008.
ten Berge RL, Oudejans JJ, et al. Percentage of activated cytotoxic T-lymphocytes in anaplastic large cell lymphoma and Hodgkin’s disease: an independent biological prognostic marker. Leukemia. 2001;15(3):458–64.
Tubiana M, Henry-Amar M, et al. Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin’s disease. The EORTC Lymphoma Group controlled clinical trials: 1964–1987. Blood. 1989;73(1):47–56.
Tzankov A, Meier C, et al. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica. 2008;93(2):193–200.
van den Berg A, Visser L, et al. High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltrate in Hodgkin’s lymphoma. Am J Pathol. 1999;154(6):1685–91.
Vassilakopoulos TP, Nadali G, et al. Serum interleukin-10 levels are an independent prognostic factor for patients with Hodgkin’s lymphoma. Haematologica. 2001;86(3):274–81.
Wagner HJ, Schlager F, et al. Detection of Epstein-Barr virus DNA in peripheral blood of paediatric patients with Hodgkin’s disease by real-time polymerase chain reaction. Eur J Cancer. 2001;37(15):1853–7.
Weihrauch MR, Manzke O, et al. Elevated serum levels of CC thymus and activation-related chemokine (TARC) in primary Hodgkin’s disease: potential for a prognostic factor. Cancer Res. 2005;65(13):5516–9.
Yamamoto R, Nishikori M, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111(6):3220–4.
Yoon DH, Koh YW, et al. CD68 and CD163 as prognostic factors for Korean patients with Hodgkin lymphoma. Eur J Haematol. 2012;88(4):292–305.
Zinzani PL, Magagnoli M, et al. The role of positron emission tomography (PET) in the management of lymphoma patients. Ann Oncol. 1999;10(10):1181–4.
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Jones, K., Seymour, L., Gandhi, M.K. (2014). Circulating Biomarkers in Hodgkin Lymphoma. In: Preedy, V., Patel, V. (eds) Biomarkers in Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7744-6_5-1
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