SPARC-positive macrophages are the superior prognostic factor in the microenvironment of diffuse large B-cell lymphoma and independent of MYC rearrangement and double-/triple-hit status.
BACKGROUND
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC).


PATIENTS AND METHODS
We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME.


RESULTS
The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank] <0.001, P[trend] < 0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)].


CONCLUSIONS
SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.
['Croci|G A|GA|', 'Au-Yeung|R K H|RKH|', 'Reinke|S|S|', 'Staiger|A M|AM|', 'Koch|K|K|', 'Oschlies|I|I|', 'Richter|J|J|', 'Poeschel|V|V|', 'Held|G|G|', 'Loeffler|M|M|', 'Trümper|L|L|', 'Rosenwald|A|A|', 'Ott|G|G|', 'Spang|R|R|', 'Altmann|B|B|', 'Ziepert|M|M|', 'Klapper|W|W|']
D000971:Antineoplastic Combined Chemotherapy Protocols D006801:Humans D016403:Lymphoma, Large B-Cell, Diffuse D008264:Macrophages D015676:Osteonectin D011379:Prognosis D011446:Prospective Studies D019253:Proto-Oncogene Proteins c-bcl-2 D051560:Proto-Oncogene Proteins c-bcl-6 D016271:Proto-Oncogene Proteins c-myc D015203:Reproducibility of Results D059016:Tumor Microenvironment
lymphoma DLBCL tumor microenvironment biomarker SPARC pathology