Large tumour cell group, combinations of CMYC+ or PD-1+ tumour cells and intense PD-L1+ cell reaction are important prognostic factors in nodal T-cell lymphomas with T follicular helper markers

doi:10.21203/rs.3.rs-850494/v1

Download PDF

Research

Large tumour cell group, combinations of CMYC+ or PD-1+ tumour cells and intense PD-L1+ cell reaction are important prognostic factors in nodal T-cell lymphomas with T follicular helper markers

https://doi.org/10.21203/rs.3.rs-850494/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background

The clinicopathological characteristics and prognostic factors in nodal T-cell lymphomas with T follicular helper markers (TFH+) are not adequately investigated.

Methods

Immunohistologically, we selected 22 patients with TFH + lymphoma in 47 of peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS), and subclassified into large and small cell groups. We compared the two groups with 39 angioimmunoblastic T-cell lymphoma (AITL) and seven follicular T-cell lymphoma (F-TCL) patients. Prognostic factors were analysed by overall survival in patients with three types of TFH + lymphomas.

Results

Thirteen large cell and nine small cell PTCL patients had more than two TFH markers including programmed cell death-1 (PD-1). Large cell TFH + PTCL showed CMYC expression in 10 patients (76.9%), and four of 11 large cell group (36.4%) had somatic RHOA G17V gene mutation by Sanger sequencing. In TFH + lymphomas, large cell TFH + PTCL patients showed significantly worse prognosis than those of the small cell group, AITL, and F-TCL (p < 0.05). CMYC + tumour cells, and combined PD-1 ligand 1 (PD-L1) + tumour cells and intense reaction of PD-L1 + non-neoplastic cells (high PD-L1 + cell group) were significantly poor prognostic factors (p < 0.05). Combinations of CMYC + or PD-1 + tumour cells and high PD-L1 + cell group indicated significantly poor prognosis (p < 0.01).

Conclusion

Large cell TFH + PTCL indicated poor prognosis in TFH + lymphomas. These data suggested that CMYC + tumour cells and intense PD-L1 + cell reaction influenced tumour cell progression in TFH + lymphomas, and PD-1 + tumour cell/intense PD-L1 + cell reactions may play a role in immune evasion.

Laboratory Diagnostics

Pathology

AITL

CMYC

PD-1

PD-L1

peripheral T-cell lymphoma-NOS

T follicular helper cell

T follicular helper (TFH) cells are mainly located in germinal centres and frequently express CD4, programmed cell death-1 (PD-1), CD10, chemokine (C-X-C motif) ligand (CXCL) 13, BCL6 and inducible T-cell co-stimulator [1]. In peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL) and follicular T-cell lymphoma (F-TCL) are derived from TFH cells and defined by expression of two or more TFH markers (TFH+) [2, 3]. Furthermore, PTCL-not otherwise specified (NOS) frequently exhibits TFH phenotype and shows similar incidences of gene mutations of TET2 and RHOA G17V to AITL [4–6]. No prognostic differences have been reported among TFH + and TFH − PTCL-NOS patients and AITL. In PTCL-NOS, more than 70% large tumour cells and international prognostic index were significant poor prognostic factors (p = 0.008, p < 0.001, respectively) [7].

Transcription factor CMYC plays a role in tumour cell proliferation and progression in high grade B-cell lymphoma, T-acute lymphoblastic leukaemia (T-ALL) and adult T-cell leukaemia/lymphoma (ATLL) [8–12]. More than 30% CMYC expression in lymphoma cells was a significant prognostic factor in AITL patients (p = 0.008), but not in PTCL-NOS [13]. CMYC controls the function of PD-1 ligand 1 (PD-L1), which has immunosuppressive effects and promotes tumour cell growth in mouse and human T-ALL, and in solid tumour cells [14]. CMYC expression in non-small cell lung cancer significantly correlated with PD-L1, and patients with CMYC + and PD-L1 + tumour cells had a worse prognosis than other subgroups (p < 0.05) [15].

Interactions between PD-1 and PD-L1 play a role in immune suppression during inflammatory processes, and PD-L1 expression induces an immune evasion mechanism exploited by various malignancies [1, 16]. In T/natural killer (NK) cell neoplasia, PD-L1 + tumour cells were frequently found in anaplastic lymphoma kinase (ALK) + and ALK − systemic anaplastic large cell lymphoma (sALCL), occasionally in PTCL-NOS, and rarely in AITL [17–20]. Patients demonstrating combined PD-L1 + tumour cells and intense reaction of PD-L1 + non-neoplastic cells (high PD-L1 + group) showed significantly poorer prognosis compared with the low PD-L1 + group in the above four types of PTCL [19]. The combination of PD-1 + tumour cells and high PD-L1 + group was related to shorter survival in AITL patients (p = 0.051), but not PTCL-NOS [21].

In the current study, we initially selected TFH + PTCL from PTCL-NOS by immunohistology, and subclassified patients into large and small cell groups. We then compared clinicopathological findings of the two groups of TFH + PTCL with those of AITL and F-TCL. The large cell TFH + PTCL patients sometimes had the RHOA G17V mutation, which indicated a group with poor prognosis in TFH + lymphomas [22]. Furthermore, CMYC + tumour cells and the combination of PD-1 + tumour cells and high PD-L1 + group indicated significantly poor prognostic factors in patients with TFH + lymphomas by uni- and multivariate analyses. It was highly suggested that histology, CMYC + tumour cells and PD-1 + tumour cell/intense PD-L1 + cell reactions were significantly influential on tumour progression and patient prognosis in TFH + lymphomas.

Patient selection, histological classification and clinical findings

Registered patients were retrieved retrospectively from the Department of Pathology, Fukuoka University, from 1990 to 2019. Histological classification was performed according to the WHO classification in 2017 [2. 23]. Forty-seven nodal PTCL-NOS, 39 AITL and seven F-TCL patients were selected in this study. Criteria of small, medium and large tumour cell sizes were in accordance with those of mantle cells, centrocytes and centroblasts in lymphoid follicles. Among PTCL-NOS, the large cell group was characterised by diffusely non-cohesive proliferation of ≥ 50% large lymphoma cells with distinct nucleoli. The small cell group consisted of predominantly medium-sized (n = 7) and small cell (n = 20) lymphomas. The small cell group included 10 cases of Lennert lymphoma. TFH+ PTCL was defined by more than two TFH markers and lacking AITL features. Diffuse infiltrate of atypical CD4+ lymphocytes with more than two TFH markers, clear cell nests, prominent proliferation of high endothelial venules and CD21+ dendritic cell nests were main criteria of AITL. Scattered and patchy infiltrates of plasma cells and eosinophils were additional criteria of AITL. Follicular TCL was definite by nodular proliferation of atypical TFH+ lymphocytes and lacing AITL features. Corresponding medical records were reviewed to obtain clinical information, including Ann Arbor stage, treatments and overall survival.

Histology, immunohistology, and detection of EBV-encoded RNA

Excised tissue specimens were fixed in 10% formalin to generate formalin-fixed and paraffin embedded (FFPE) wax samples and stained with haematoxylin and eosin. Immunohistology was performed on the tumour tissues using the Leica Bond III automated stainer (Leica Biosystems, Buffalo Grove, IL, USA). Antibodies against the following proteins were used: CD3 (PS1, Leica, Newcastle, UK), CD4 (4B12, Leica), CD8 (C81/44B, Leica), CD10 (56C6, Leica), CD25 (interleukin 2 receptor [IL2R], 4C9, Leica), CD30 (BerH2, DakoCytomation, Glostrup, Denmark), PD-1 (NAT105, Abcam, Cambridge, MA), CXCL13 (BLC, R&D, Minneapolis, MN), BCL6 (LN22, Leica), CMYC (Y69, Abcam), MIB1 (MIB1, Dako), PD-L1 (E1L3N, Cell Signaling, Danvers, MA), CD20 (L26, Nichirei, Tokyo), and CD21 (1F8, Dako). Tumour cell counts were semi-quantitatively calculated by two pathologists and percentages of antibody-positive cells were determined (0%, 5%, and 10%–100% in 10% increments) in over five high power fields [12]. For the four TFH markers (PD-1, BCL6, CD10 and CXCL13), samples with ≥ 20% labelling of the tumour cells were considered positive [4]. Expression of CMYC, MIB1 and PD-L1 in ≥ 50% atypical lymphoid cells was estimated as positive (n+) [17], and staining intensity of PD-L1 in histiocytes and dendritic cells was scored as follows: R0 (no staining), R1+ (a few cells to < 5%), R2+ (≥ 5% – < 20%) and R3+ (≥ 20%). For the other antibodies, samples with ≥ 30% labelling of the tumour cells were considered positive. The presence of EBV infection was determined by in situ hybridisation of EBV-encoded RNA (EBERs)+ nuclear signals (BOND EBER probe, Leica)

Quantitative real time polymerase chain reaction

Total RNAs were extracted from FFPE tumour specimens of 42 patients using the NucleoSpin total RNA FFPEXS (Macherey-Nagel, Duren, Germany), according to the manufacturer’s instructions, on a real-time PCR machine (Mini OpticonTM, BioRad, Hercules, CA, USA). All samples were tested for expression of CMYC (assay ID: Hs00905030_m1, amplicon size 87 bp) [12]. In addition, samples were analysed for expression of GUSB (Hs99999908_m1), TBP (Hs00427620_m1), and ABL1 (Hs00245443_m1), which were used for normalisation in the final analysis.

Detection of RHOA G17V mutation by Sanger sequencing

DNA samples from FFPE tumour tissue were extracted using a GenElute™ Mammalian DNA Miniprep Kit (Sigma-Aldrich, St. Louis, MO, USA). Detection of RHOA G17V mutation and wild type were assessed by allele-specific PCR. For RHOA amplification, PCR was performed with AmpliTaq gold (Thermo Fisher Scientific, Waltham, MA, USA) using 40 ng genomic DNA, 0.3 μM primers, and 2 μL AmpliTaq gold master mix. A PCR-amplified product of 244 bp, including the codon for the 17th amino-acid, was obtained in 53 patients, and direct sequencing of these products was performed. The coding DNA position 50G>T mutation of the RHOA gene predicted change of the wild-type G (Gly) to the mutant type V (Val) [22].

Statistical analysis

All pairwise comparisons of categorised variables between the histological groups and types of PTCL were performed using the χ² or Fisher’s exact test. Of the 93 recruited patients, 87 PTCL patients were examined for clinical outcome. Outcome was determined by calculating cumulative survival from time of diagnosis to date of the last follow up or death. Overall survival (OS) curves were generated using the Kaplan–Meier method with log-rank tests, and analysed by the proportional Hazard model. A p value < 0.05 was considered statistically significant. Analyses were performed using software JMP 10 (SAS Institute, Cary, NC, USA).

Clinical features

The clinical features and immunohistological findings of 22 patients with TFH+ PTCL and 25 with TFH− PTCL-NOS, 39 AITL and seven F-TCL are shown in table 1. Thirteen of 22 TFH+ PTCL patients (59.1%) were composed of large cell lymphoma and the remaining nine (40.9%) were small cell. Six of 11 large cell TFH+ PTCL patients (54.6%) showed ≥ 5000 U/ml sIL2R, which was significantly higher than that observed in small cell TFH− PTCL (12.5%) and F-TCL (0%) (p = 0.008, p = 0.039, respectively). Patients in the four groups of TFH+ lymphomas frequently showed advanced clinical stages III and IV.

Histological, immunohistological, and genetic findings, and EBV infection

Large cell TFH+ PTCL patients had significantly lower populations of clear neoplastic cells and fewer reactions of eosinophils and plasma cells than those of AITL (figure 1a, b; both p < 0.01). Large cell TFH+ PTCL expressed more than two TFH markers; among them PD-1 was positive in 12 patients (92.3%; figure 2a), BCL6 in 12 (92.3%), CXCL13 in seven (53.9%; figure 2b) and CD10 in seven (53.9%). Small cell TFH+ lymphoma showed frequent expressions of PD-1 (100%) and BCL6 (88.9%), but rarely of CD10 (11.1%). Four of 10 Lennert lymphoma patients showed more than two TFH markers (figure 1c, f). Large cell TFH+ PTCL showed frequent expression of CD25 in eight patients (61.5%) and CD30 in five (38.5%; figure 1d, e), which were significantly higher than one (11.1%) and 0 (0%), respectively, in small cell TFH+ PTCL, and eight (20.5%) and one (3.6%), respectively, in AITL (p < 0.05, p < 0.01, respectively). Scattered and patchy infiltrates of CD30+ lymphoma cells were detected in the five large cell TFH+ PTCL patients. Large cell TFH+ PTCL was frequently positive for CMYC in 10 patients (76.9%, figure 2c) and MIB1 in 13 (100%), which were significantly higher than 0 (0%) and seven (77.8%), respectively, in small cell TFH+ PTCL, and 12 (30.8%) and 29 (74.4%), respectively, in AITL (p < 0.05, p < 0.01, respectively). Mean CMYC mRNA was 4.1 in tumour specimens of 42 patients, and ≥ 4.1 CMYC mRNA was detected in six of seven large cell TFH+ PTCL patients (85.7%), which was significantly higher than in small cell TFH+ PTCL (0/5, 0%) and F-TCL (0/5, 0%) (both p < 0.05). The combination of PD-L1+ tumour cells and intense reaction (R3+) of PD-L1+ non-neoplastic cells (high PD-L1+ group) was found in eight large cell TFH+ PTCL patients (61.5%), which was significantly higher than in F-TCL (0%) (p = 0.036; figure 2d). Scattered EBERs+ lymphocytes in the background were found in large cell (92.3%) and small cell (88.9%) TFH+ PTCL patients, compared with large cell (28.6%) and small cell (55.6%) TFH− groups (p < 0.01, p < 0.05, respectively).

RHOA p.G17V mutation by Sanger sequencing

By Sanger sequencing, four of 11 large cell TFH+ PTCL patients (36.4%), one of six small cell TFH+ PTCL (16.7%), eight of 19 of AITL (42.1%), two of four F-TCL (50%) and one of 13 TFH− PTCL (7.7%) patients showed the RHOA p.G17V mutation (figure 3), but no significant differences were found among the groups.

Prognostic factors in TFH+ lymphomas

Of the total cohort, we examined clinical outcome in 87 patients. The examined 20 TFH+ PTCL, 23 TFH− PTCL, 38 AITL and six F-TCL patients showed no prognostic differences between groups (figure 4a). Twelve patients with large cell TFH+ PTCL showed significantly poorer OS than eight small cell TFH+ PTCL, 16 small cell TFH− PTCL, 38 AITL and six F-TCL patients (p = 0.045, p = 0.014, p = 0.047 and p = 0.012, respectively; figure 4b). Table 2 shows the univariate analysis of risk factors for OS in the examined 64 patients with TFH+ lymphomas. In TFH+ lymphomas, ≥ 300 IU/L lactate dehydrogenase (LDH; n = 28) and clinical stages III and IV (n = 50) were significant poor prognostic factors (p = 0.04, p = 0.022, respectively). Presence of CMYC+ tumour cells (n = 23) was a significantly poor OS factor (p = 0.029; figure 4c). Presence of the high PD-L1+ group (n = 23) showed a significantly poor OS compared with presence of the low (R1+, R2+) PD-L1+ group (n = 41) (p = 0.0004; figure 4d). Furthermore, 21 patients with the combination of PD-1+ tumour cells and high PD-L1+ group showed significantly poorer OS than the other groups (n = 43) (p = 0.005; figure 4e). The combination of CMYC+ tumour cells and high PD-L1+ group (n = 10) also indicated prominently poor OS compared with the other groups (n = 54) (p < 0.0001; figure 4f). The RHOA p.G17V mutation was not a prognostic factor in examined 40 patients with TFH+ lymphomas. Multivariate analysis indicated that presence of CMYC+ tumour cells (p = 0.03) and high PD-L1+ group (p = 0.001) were significantly associated with OS in TFH+ lymphoma patients in Table 2.

Other researchers have reported that lymphoma cells in 18 of 41 PTCL-NOS patients (43.9%) showed TFH phenotype [6]. Although BCL6 expression and RHOA G17V mutation were significantly higher in AITL patients than in PTCL-NOS (both p < 0.01), neither definite clinical nor prognostic differences were found among patients with TFH + and TFH − PTCL and AITL. The current study also demonstrated no prognostic differences among the above three groups of T-cell lymphoma. The examined 13 large cell TFH + PTCL patients had a similar incidence of RHOA G17V mutation (36.4%) to those with AITL (42.1%), but showed higher expressions of CD25 (IL2R), CD30, CMYC, and CMYC mRNA, than small cell TFH + PTCL patients and AITL (p < 0.01 or p < 0.05). Other researchers have reported that CD30 + giant cells or large tumour cells were detected in 64 of 217 PTCL-NOS patients (32%) and six of 25 TFH + PTCL cases (24%) [3, 7]. CD30 as well as CD25 (IL2R) may be one of the activation molecules in large cell TFH + PTCL. Furthermore, large cell TFH + PTCL patients showed significantly poorer OS compared with small cell TFH + PTCL, AITL and F-TCL (all p < 0.05). Patients with F-TCL were frequently found to be of advanced clinical stages III and IV, but showed relatively indolent prognosis compared with AITL [24, 25]. These findings, together with our results demonstrated that the large cell group of TFH + PTCL indicated distinct pathological and immunohistological features and poor prognosis in groups of TFH + lymphoma patients.

CMYC protein and mRNA expressions in aggressive type ATLL patients were significantly higher than those of smouldering and chronic types (p < 0.01), and CMYC may accelerate the conversion from indolent to aggressive type ATLL [12]. In the current study, CMYC + tumour cells were frequently detected in 10 of 13 large cell TFH + PTCL patients (76.9%), and was a significantly poor prognostic factor in patients with TFH + lymphomas by the uni- and multivariate analyses (both p = 0.03). Other researchers have reported that expressions of CMYC and Th2-cell transcription factor GATA3 were frequently found in 128 nodal PTCL patients with AITL, PTCL-NOS and sALCL, and CMYC + tumour cells indicated significantly poor prognosis in the above three types of PTCL and in only AITL (all p < 0.01) [13]. GATA3 + PTCL-NOS patients showed frequent copy number gains/amplifications of CMYC and STAT3, and loss of CDKN2A, having inferior OS compared with the GATA3 − group [8]. CMYC and GATA3 may be important transcription factors that significantly affect the prognosis of TFH + lymphoma patients.

Sun et al reported that the presence of the high PD-L1 + group (45.8%) including PD-L1 + tumour cells, resulted in significantly poorer prognosis compared with presence of the low PD-L1 + group (54.2%) in 144 patients with AITL, PTCL-NOS, ALK + and ALK − sALCL (p < 0.05) [19]. However, PD-L1 + tumour cells were frequently found in 34 of 45 ALK+ (76%) and 21 of 50 ALK− (42%) sALCL patients [20]. In addition, sALCL also showed less frequent expression of TFH markers [26, 27]. The results supported sALCL as a distinct disease from AITL and PTCL-NOS. In the current study, presence of the high PD-L1 + group was a significant poor prognostic factor in 64 patients with TFH + lymphomas by the uni- and multivariate analyses (p = 0.0004, p = 0.001, respectively). Furthermore, the combination of PD-1 + tumour cells and high PD-L1 + group also indicated significantly poor prognosis (p = 0.005). A recent report showed that the combination of PD-1 + tumour cells and the high PD-L1 + group significantly correlated with elevated serum LDH in AITL and PTCL-NOS patients (p = 0.03), and was related to shorter OS in patients with AITL (p = 0.051), being significant in clinical stage IV of AITL (p = 0.007) [21]. It was highly suggested that the combination of PD-1 + tumour cells and PD-L1 + cells induced intrinsic immune escape and poor prognosis in patients with TFH + lymphomas.

JQ1, a bromodomain and extra-terminal protein (BET) inhibitor, blocks acetylation of N-terminal histone tails and suppresses tumour initiating cells. JQ1 treatment resulted in growth arrest and apoptosis in mouse and human T-ALL and solid tumour cells due to CMYC inactivation and immune reactivation by downregulation of PD-L1 [28, 29]. CMYC and PD-L1 double expression in pancreas cancer in 87 patients was significantly associated with poor histological grade and poor OS (p < 0.01) [30]. Furthermore, JQ1 combined with anti-PD-L1 treatment suppressed both CMYC and PD-L1 in cancer cell lines and mouse models, and exerted synergistic inhibition of pancreas cancer growth. In the current study, the combination of CMYC + tumour cells and high PD-L1 + group was a significant poor prognostic factor in TFH + lymphomas (p < 0.0001). Inactivation of CMYC pathways and immune reactivation by downregulation of PD-L1 may be effective therapeutic strategies for tumour cell reduction in patients with TFH + lymphomas.

In conclusion, differentiating large and small cell TFH + PTCL is necessary. Large cell TFH + PTCL patients showed frequent expression of activation molecules and sometimes RHOA G17V mutation, and pursued a progressive clinical course in types of TFH + lymphomas. Presence of CMYC + tumour cells or the high PD-L1 + group, and the combination of these two were significantly poor prognostic factors in patients with TFH + lymphomas (p = 0.029, p = 0.0004, or p < 0.0001, respectively). Furthermore, the combination of PD-1 + tumour cells and high PD-L1 group induced significantly poor prognosis (p = 0.005). CMYC inactivation and immune checkpoint inhibitors might improve patient prognosis in TFH + lymphomas. Further study is necessary to confirm the clinicopathological characteristics of TFH + PTCL because of the small number of patients in the current study.

AITL: Angioimmunoblastic T-cell lymphoma, ALK: Anaplastic lymphoma kinase, ALL: Acute lymphoblastic leukaemia, ATLL: Adult T-cell leukaemia/lymphoma, EBV: Epstein-Barr virus, EBER: EBV-encoded RNA, F-TCL: Follicular T-cell lymphoma, NOS: Not otherwise specified, PD-1: Programmed cell death-1, PD-L1: Programmed cell death-1 ligand 1, PTCL: Peripheral T-cell lymphoma, TFH: T follicular helper.

Acknowledgments. We are grateful to Tomomi Okabe and Tomoko Fukushige for their technical assistance with the immunohistochemistry and genetic study. We thank Gillian Campbell, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

Consent for publication

Not applicable.

Author contribution statement.

Y. M., S. K. and M. T. designed and performed the research. Y. M., Y. O., S. K., and S. S. collected and summarised pathological data, and conducted the statistical analysis. H. I., Y. T. and K. I. conducted treatment and collected clinical data. Y. M., S. K., and M. T. wrote the manuscript.

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Ethics Committee of Fukuoka University and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Fukuoka University, Faculty of Medicine.

Availability of date and materials

The datasets used and analysed in the current study are available from the corresponding author on reasonable request.

Competing interests

The author declare that they have no competing interests.

Conflict of interest

The authors declare that they have no significant relationships with, or financial interest in, any commercial activities pertaining to this article.

Funding

This work was supported in part by a Grant-in-Aid for Scientific Research © (No.17K08732) from the Ministry of Education, Science and Culture of Japan.

Ueno H. T follicular helper cells in human autoimmunity. Current Opin Immunol. 2016;43:24-31. https://doi: 10.1016/j.coi.2016.08.003
Dogan A, Gaulard P, Jaffe ES, Müller-Hermelink HK, de Leval L. Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of T follicular helper cell origin. In: Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer; 2017. pp. 407–12.
Rodrıguez-Pinilla SM, Atienza L, Murillo C, Pérez-Rodríguez A, Montes-Moreno S, et al. Peripheral T-cell lymphoma with follicular T-cell markers. Am J Surg Pathol. 2008;32:1787–99. doi. 10.1097/PAS.0b013e31817f123e.
Basha BM, Bryant SC, Rech KL, Feldman AL, Vrana JA, et al. Application of a 5 marker panel to the routine diagnosis of peripheral T-cell lymphoma with T-follicular helper phenotype. Am J Surg Pathol. 2019;43:1282–90. doi. 10.1097/PAS.0000000000001315.
Dobay MP, Lemonnier F, Missiaglia E, Bastard C, Vallois D, et al. Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. Haematologica. 2017;102:e148-51. https://doi.org/10.3324/haematol.2016.158428.
Manso R, Gonzalez-Rincon J, Rodriguez-Justo M, Roncador G, Gómez S, et al. Overlap at the molecular and immunohistochemical levels between angioimmunoblastic T-cell lymphoma and a subgroup of peripheral T-cell lymphomas without specific morphological features. Oncotarget. 2018;9:16124–33. doi. 10.18632/oncotarget.24592.
Weisenburger DD, Savage KJ, Harris NL, Gascoyne RD, Jaffe ES, et al. Peripheral T-cell lymphoma, not otherwise specified: are port of 340 cases from the International peripheral T-cell lymphoma project. Blood. 2011;117:3402–08. https://doi.org/10.1182/blood-2010-09-310342.
Heavican TB, Bouska A, Yu J, Lone W, Amador C, et al. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood. 2019;133:1664–76. https://doi: 10.1182/blood-2018-09-872549.
Chisholm KM, Bangs CD, Bacchi CE, Molina-Kirsch H, Cherry A, Natkunam Y. Expression profiles of MYC protein and MYC gene rearrangement in lymphomas. Am J Surg Pathol. 2015;39:294–303. doi. 10.1097/PAS.0000000000000365.
Green TM, Nielsen O, de Stricker K, Xu-Monette ZY, Young KH, Møller MB. High levels of nuclear MYC protein predict the presence of MYC rearrangement in diffuse large B-cell lymphoma. Am J Surg Pathol. 2012;36:612–19. doi. 10.1097/PAS.0b013e318244e2ba.
Starza RL, Borga C, Barba G, Pierini V, Schwab C, et al. Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations. Blood. 2014;124:3577–82. doi. 10.1182/blood-2014-06-578856.
Mihashi Y, Mizoguchi M, Takamatsu Y, Ishitsuka K, Iwasaki H, et al. C-MYC and its main ubiquitin ligase, FBXW7, influence cell proliferation and prognosis in adult T-cell leukaemia/lymphoma. Am J Surg Pathol. 2017;41:1139–49. doi. 10.1097/PAS.0000000000000871.
Manso R, Bellas C, Martin-Acosta P, Mollejo M, Menarguez J, et al. C-MYC is related to GATA3 expression and associated with poor prognosis in nodal peripheral T-cell lymphomas. Haematologica. 2016;101:e336-8. https://doi.org/10.3324/haematol.2016.143768.
Casey SC, Tong L, Li Y, Do R, Walz S, et al. MYC regulates the antitumour immune response through CD47 and PD-L1. Science. 2016;352:227–31. https://doi:10.1126/science.aac9935.
Zhou C, Che G, Zheng X, Qiu J, Xie Z, et al. Expression and clinical significance of PD-L1 and c-Myc in non-small cell lung cancer. J Cancer Res Clin Oncol. 2019;145:2663–74. https://doi: 10.1007/s00432-019-03025-8.
Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ. PD-L1. J Clin Pathol. 2018;71:189–94. http://dx.doi.org/10.1136/jclinpath-2017-204853.
Sakakibara A, Kohno K, Eladl AE, Klaisuwan T, Ishikawa E, et al. Immunohistological assessment of the diagnostic utility of PD-L1: a preliminary analysis of anti-PD-L1 antibody (SP142) for lymphoproliferative diseases with tumour and non-malignant Hodgkin-Reed Sternberg (HRS)-like cells. Histopathol. 2018;72:1156–63. doi. 10.1111/his.13475.
Tiemann M, Samoilova V, Atiakshin D, Buchwalow I. Immunophenotyping of the PD-L1-positiv cells in angioimmunoblastic T cell lymphoma and Hodgkin disease. BMC. 2020;13:139. doi. 10.21203/rs.2.22304/v2.
Sun M, Su W, Qian J, Meng H, Ji H, et al. The prognostic value of toll-like receptor5 and programmed cell death-ligand1 in patients with peripheral T-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2019;60:2646–57. doi. 10.1080/10428194.2019.1602266.
Shen J, Li S, Medeiros LJ, Lin P, Wang SA, et al. PD-L1 expression is associated with ALK positivity and STAT3 activity, but not outcome in patients with systemic anaplastic large cell lymphoma. Mod Pathol. 2020;33:324–33. https://doi.org/10.1038/s41379-019-0336-3.
Kim S, Kwon D, Koh J, Nam SJ, Kim YA, et al. Clinicopathological features of programmed cell death-1 and programmed cell death-ligand-1 expression in the tumor cells and tumor microenvironment of angioimmunoblastic T cell lymphoma and peripheral T cell lymphoma not otherwise specified. Virch Arch. 2020;447:131–42. https://doi:10.1007/s00428-020-02790-z.
Nagao R, Kikuchi YY, Carreras J, Kikuchi T, Miyaoka M, et al. Clinicopathologic analysis of angioimmunoblastic T-cell lymphoma with or without RHOA G17V mutation using formalin-fixed paraffin-embedded sections. Am J Surg Pathol. 2016;40:1041–50. doi. 10.1097/PAS.0000000000000651.
Pileri SA, Weisenburger DD, Sng I, Nakamura S, Müller-Hermelink HK, Chan WC, Jaffe ES. Peripheral T-cell lymphoma, NOS. In: Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer. Lyon, 2017;403-06.
Huang Y, Moreau A, Dupuis J, Petit B, Le Gouill S, et al. Peripheral T-cell lymphomas with a follicular growth pattern are derived from follicular helper T cells (TFH) and may show overlapping features with angioimmunoblastic T-cell lymphoma. Am J Surg Pathol. 2009;33:682–90. https://doi:10.1097/PAS.0b013e3181971591.
Hartmann S, Goncharova O, Portyanko A, Sabattini E, Meinel J, et al. CD30 expression in neoplastic T cells of follicular T cell lymphoma is a helpful diagnostic tool in the differential diagnosis of Hodgkin lymphoma. Mod Pathol. 2019;32:37–47. https://doi: 10.1038/s41379-018-0108-5.
Krishnan C, Warnke RA, Arber DA, Natkunam Y. PD-1 expression in T-cell lymphomas and reactive lymphoid entities: Potential overlap in staining patterns between lymphoma and viral lymphadenitis. Am J Surg Pathol. 2010;34:178–89. https://doi:10.1097/PAS.0b013e3181cc7e79.
Manso R, Rodríguez-Perales S, Torres-Ruiz R, Santonja C, Rodríguez-Pinilla SM. PD-L1 expression in peripheral T-cell lymphomas is not related to either PD-L1 gene amplification or rearrangements. Leuk Lymph. 2021;62:1648–56. doi. 10.1080/10428194.2021.1881511.
Schubbert S, Cardenas A, Chen H, Garcia C, Guo W, Bradner J, Wu H. Targeting the MYC and PI3K pathways eliminates leukaemia-initiating cells in T-cell acute lymphoblastic leukaemia. Cancer Res. 2014;74:7048–59. doi. 10.1158/0008-5472.
Casey S, Baylot V, Felsher DW. The MYC oncogene is a global regulator of immune response. Blood. 2018;131:2007–15. doi. 10.1182/blood-2017-11-742577.
Pan Y, Feia Q, Xiong P, Yang J, Zhang Z, et al. Synergistic inhibition of pancreatic cancer with anti-PD-L1 and c-Myc inhibitor JQ1. Oncoimmunology. 2019;8:e1581529. doi. 10.1080/2162402X.2019.1581529.

Due to technical limitations, Table 1 and 2 are only available as a download in the Supplemental Files section.

Download PDF

Review #1 received at journal
11 Sep, 2021
Editorial decision: Major Revision
11 Sep, 2021
Review #2 received at journal
07 Sep, 2021
Reviewer #2 agreed at journal
01 Sep, 2021
Reviewers invited by journal
31 Aug, 2021
Reviewer #1 agreed at journal
31 Aug, 2021
Editor assigned by journal
29 Aug, 2021
Submission checks completed at journal
29 Aug, 2021
Editor invited by journal
29 Aug, 2021
First submitted to journal
26 Aug, 2021

You are reading this latest preprint version

Large tumour cell group, combinations of CMYC+ or PD-1+ tumour cells and intense PD-L1+ cell reaction are important prognostic factors in nodal T-cell lymphomas with T follicular helper markers

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Background

Methods

Results

Discussion

Abbreviations

Declarations

References

Tables

Supplementary Files

Status:

Version 1