Immunohistochemical Double-Hit Score Is a Strong Predictor of Outcome in Patients With Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Green, Tina Marie; Young, Ken H.; Visco, Carlo; Xu-Monette, Zijun Y.; Orazi, Attilio; Go, Ronald S.; Nielsen, Ole; Gadeberg, Ole; Mourits-Andersen, Torben; Frederiksen, Mikael; Pedersen, Lars Møller; Møller, Michael

doi:10.1200/jco.2011.41.4342

Cited by 606 publications

(711 citation statements)

References 34 publications

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“…CD10 was positive in 28 of 39 (72%), BCL6 in 25 of 27 (93%), MUM1 in 5 of 16 (31%, all negative for CD10), and BCL2 in 33 of 35 (95%) cases. MYC expression was observed in 14 of 20 (70%) cases by using a 40% cutoff, 28,30 or 17 of 20 (85%) cases by using 10% as cutoff as reported by a recent study. 31 On the basis of these results and by Survival of patients with atypical double-hit lymphoma.…”

Section: Resultssupporting

confidence: 60%

“…Data showing that DLBCL patients with MYC and BCL2 coexpression shown by immunohistochemistry have a poor prognosis in the absence of concurrent MYC and BCL2 translocations indirectly supports this hypothesis. 28,30,[34][35][36] In this study, similar proportions of 31 However, this study included only three cases with MYC amplification (44 copies). Our results suggest that patients with atypical double-hit lymphoma that had three to four copies of MYC showed similar OS to patients with atypical DHL with more than four copies of MYC.…”

Section: Discussionmentioning

confidence: 99%

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B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Seegmiller

Lin

et al. 2015

Modern Pathology

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Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n ¼ 14) or more aggressive chemotherapy regimens (n ¼ 17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P ¼ 0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P ¼ 0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (Po0.01), less frequently expressed CD10 (Po0.01), and patients less often had an elevated serum lactate dehydrogenase level (P ¼ 0.01). In aggregate, these results support expanding the category of MYC/ BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations.

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Section: Resultssupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Seegmiller

Lin

et al. 2015

Modern Pathology

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“…[9][10][11][12][13] These studies have shown that cases of diffuse large B-cell lymphoma with concurrent overexpression of MYC and BCL2 proteins have a dismal prognosis similar to those with double-hit lymphomas. The rate of so-called double-hit lymphoma-like cases as determined by immunohistochemistry is larger than the one detected by FISH.…”

mentioning

confidence: 99%

“…The rate of so-called double-hit lymphoma-like cases as determined by immunohistochemistry is larger than the one detected by FISH. 9,10 Evaluation of MYC expression in these studies is performed by estimating the percentage of MYC protein expressing tumor cells. In the majority of studies, a cutoff of Z40% is used to define MYC protein overexpression.…”

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confidence: 99%

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Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

et al. 2015

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Recent studies have shown that immunohistochemical evaluation of MYC protein expression in diffuse large B-cell lymphoma is a useful prognostic tool with high concordance rate among pathologists. Concordance in these studies was assessed among few pathologists from one institution by scoring tissue microarrays. In daily practice, MYC evaluation is performed on entire tumor sections by a diverse group of pathologists. In our study, nine hematopathologists from two institutions scored whole-tissue sections of two sets of cases. The training set included 13 cases of diffuse large B-cell lymphoma and 4 cases of Burkitt lymphoma. The validation set included 18 cases of diffuse large B-cell lymphoma and 1 case of Burkitt lymphoma. MYC positivity was defined as Z40% of tumor cells demonstrating nuclear staining similar to prior studies. The mean score for each case was used to determine MYC status with discrepant cases defined as having any score causing a different MYC status designation. Discrepant cases from the training set were characterized by staining heterogeneity, extensive necrosis or crush artifact and had mean scores within 15 percentage points of 40%. Cases from the validation set that demonstrated any of these features were scored twice on two different days. Overall concordance was moderate (Kappa score: 0.68, P-valueo0.001) with no significant change between the two sets (Kappa scores: 0.69 vs 0.67). Thirty-nine percent of cases were discrepant. The findings indicate that a significant number of diffuse large B-cell lymphomas are inherently difficult to score due to staining heterogeneity. The effect of heterogeneity can be under-represented when concordance is measured among few pathologists scoring tissue microarrays. Careful scoring strategy in our study failed to improve concordance. In the absence of specific instructions on how to deal with heterogeneity, caution is advised when evaluating MYC expression in diffuse large B-cell lymphoma.

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MYC and therapy resistance in cancer: risks and opportunities

Donati

Amati

2022

Molecular Oncology

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The MYC transcription factor, encoded by the c-MYC proto-oncogene, is activated by growth-promoting signals, and is a key regulator of biosynthetic and metabolic pathways driving cell growth and proliferation. These same processes are deregulated in MYC-driven tumors, where they become critical for cancer cell proliferation and survival. As other oncogenic insults, overexpressed MYC induces a series of cellular stresses (metabolic, oxidative, replicative, etc.) collectively known as oncogenic stress, which impact not only on tumor progression, but also on the response to therapy, with profound, multifaceted consequences on clinical outcome. On one hand, recent evidence uncovered a widespread role for MYC in therapy resistance in multiple cancer types, with either standard chemotherapeutic or targeted regimens. Reciprocally, oncogenic MYC imparts a series of molecular and metabolic dependencies to cells, thus giving rise to cancerspecific vulnerabilities that may be exploited to obtain synthetic-lethal interactions with novel anticancer drugs. Here we will review the current knowledge on the links between MYC and therapeutic responses, and will discuss possible strategies to overcome resistance through new, targeted interventions.

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Immunohistochemical Double-Hit Score Is a Strong Predictor of Outcome in Patients With Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Abstract: The immunohistochemical DHS defined a large subset of DLBCLs with double-hit biology and was strongly associated with poor outcome in patients treated with R-CHOP.

Cited by 606 publications

References 34 publications

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

MYC and therapy resistance in cancer: risks and opportunities

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