Clinical Characteristics and Prognostic Analysis of 24 Cases with Breast Diffuse Large B-cell Lymphoma

doi:10.21203/rs.3.rs-3395542/v1

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Clinical Characteristics and Prognostic Analysis of 24 Cases with Breast Diffuse Large B-cell Lymphoma

https://doi.org/10.21203/rs.3.rs-3395542/v1

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Aim: We collected and analyzed the clinical characteristics and treatment methods of breast diffuse large B-cell lymphoma (B-DLBCL), and analyzed its prognosis to find the best treatment plan for B-DLBCL.

Methods: We collected clinical data of 24 patients with B-DLBCL treated at Zhejiang Cancer Hospital between July 2003 and November 2014, and performed prognostic analysis according to the patients' pathological types and treatments, as well as plotting the Progression-free survival (PFS) and overall survival (OS) curves.

Results: The included patients were all female (100%), with 92% (22/24) of patients presenting with breast masses, the majority (58%) presenting with left breast masses, and a very small portion presenting with bilateral breast masses; After a median follow-up of 51 (5-123) months, the PFS and OS of 24 patients were 72% and 80%, respectively; Among them, there were 14 cases of primary breast diffuse large B-cell lymphoma (PB-DLBCL), with corresponding PFS and OS of 85% and 83%, and their prognosis level is higher than that of secondary breast diffuse large B-cell lymphoma(SB-DLBCL); Among them, 13 patients underwent surgical treatment, and the prognosis of non-surgical patients was worse than that of surgical patients (PFS: 61% vs 80%; OS: 70% vs 87%); The 11 patients on rituximab had a non-significant improvement in PFS and OS compared with those not on rituximab (PFS: 72% vs 73%; OS: 79% vs 83%).

Conclusion: B-DLBCL is a group of heterogeneous diseases. In our retrospective study, we found that the prognosis of PB-DLBCL is better than that of SB-DLBCL. What’s more, surgical treatment can improve the prognosis, but the use of Rituximab has no effect on the prognosis.

Breast cancer (BC)

Diffuse large B-cell lymphoma (DLBCL)

Treatments

Prognosis

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL), accounting for about 1/3 of all NHLs. DLBCL is a heterogeneous entity composed of intermediate and high-grade B-cell lymphomas with different molecular backgrounds, clinical courses, and treatment responses. DLBCL occurs in approximately 30% of organs outside of lymph nodes, mostly involving the gastrointestinal tract, soft tissues, breast, and uterus[1]. Although the incidence of diffuse large B-cell lymphoma of the breast (B-DLBCL) is less than 1% of breast tumors, it is the main pathological type of breast lymphoma [2–4]. Currently, the main treatments for B-DLBCL include surgery, chemotherapy, radiotherapy, and rituximab, although rituximab combined with chemotherapy is the standard treatment for DLBCL, 30–40% of patients still do not respond or relapse[5]. In addition, breast lymphoma also has a high propensity for CNS recurrence, it indicates that the patient has a poor prognosis when CNS recurrence occurs and there is no better prevention method [6]. B-DLBCL is an extra-nodal lymphoma, which can be divided into primary breast diffuse large B-cell lymphoma (PB-DLBCL) and secondary breast diffuse large B-cell lymphoma (SB-DLBCL), the difference between PB-DLBCL and SB-DLBCL is that the latter involves not only the breast and its regional lymph nodes, but also other lymph nodes and organs. Besides, DLBCL can also be divided into germinal center B-cell (GCB) and non-GCB types by cellular origin. Although there is still significant tumor heterogeneity among the same types through this classification, overall, patients with GCB subtypes typically have a better prognosis than those with non-GCB subtypes. Due to the low incidence rate of breast DLBCL, it is difficult to conduct large-scale clinical trials for research, so the best treatment scheme for breast DLBCL has not yet been determined. Therefore, it is urgent to find a safe and effective treatment option to address the challenges of poor prognosis and high recurrence rate of breast lymphoma. We collected the data of B-DLBCL patients admitted to the Department of Breast Surgery of Zhejiang Cancer Hospital in the past 15 years, and conducted a comprehensive analysis of the clinical characteristics, treatment options, and prognosis of B-DLBCL patients, hoping to be helpful for the treatment progress of breast lymphoma.

2.1 Cases

We retrospectively analyzed 32 patients of breast lymphoma diagnosed and treated in our hospital from July 2003 to November 2014. Among them, 24 cases (75%) were diagnosed with B-DLBCL, and 19 cases received complete follow-up data. The clinical data included: gender, age, pathological type, site of disease, lump size, lymph node infiltration, B symptoms (fever; night sweats; weight loss), Eastern Cooperative Oncology Group (ECOG) score, Lactic dehydrogenase (LDH) level at presentation, Ann Arbor stage, and International Prognostic Index (IPI) score.

2.2 Pathological Diagnosis

DLBCL can be classified by gene expression profiling into two clinically distinct subtypes: germinal center B cell (GCB) and non-GCB. Immunohistochemical staining was performed on patient specimens using CD10, Bcl-6, and MUM1 antibodies. When at least 30% of tumor cells expressed the aforementioned antibodies, the tumor was considered positive, and the results were evaluated using the Hans algorithm[7]. If CD10 alone was positive or both Bcl-6 and CD10 were positive, they were classified into the GCB group; If both Bcl-6 (-) and CD10 (-), the case was classified in the non-GCB subgroup; If Bcl-6 (+) and CD10 (-), the expression of MUM1 determined the group: if MUM1 (-), the case was assigned to the GCB group; if MUM1 (+), the case was assigned to the non-GCB group [7, 8].

24 patients in this study had pathological specimens obtained by biopsy or surgical resection, and the diagnosis of DLBCL was confirmed by morphology and immunohistochemistry (Fig. 1). 14 patients of them were analyzed by immunohistochemical staining for the expression levels of CD10, MUM1, and Bcl-6.

2.3 Treatments

Treatments for B-DLBCL include surgery, chemotherapy, rituximab combined with chemotherapy, and radiation therapy. Surgical options include tumor resection and mastectomy, combined with or without axillary lymph node dissection (ALND). The chemotherapy regimen was mainly a combination of CHOP (E) [doxorubicin, cyclophosphamide, vincristine, prednisone (etoposide) ± rituximab (375 mg/m2)] for 6 cycles, with one patient treated with the IHOP (doxorubicin, ifosfamide, vincristine, prednisone). All drug doses were calculated according to the standard dose of the DLBCL treatment regimen of the 2016 edition of the NCCN guidelines, based on body surface area. After chemotherapy, radiation therapy was administered, and the dose of radiotherapy for the involved area was 20Gy-36Gy.

2.4 Follow-up Visits

The follow-up period ended in July 2016 with a median follow-up time of 51 (5-123) months. Progression-free survival (PFS) was defined as the time from the start of treatment until the patient experienced tumor progression or died from any causes; overall survival (OS) was defined as the time from the start of treatment until the patient died from any causes.

2.5 Statistical Analysis

The survival curves are drawn with GraphPad 5 and analyzed by log-rank (Mantel-Cox) method. The differences will be statistically significant when the P value is lower than 0.05.

3.1 Clinical Characteristics and Pathological Typing

All 24 patients with B-DLBCL were female whose median age is 49 (24–69). There were 14 cases of PB-DLBCL, and the majority of patients had an ECGO score of 0 (16/24); At the onset of the disease, only 21% of patients had elevated LDH levels; Out of 24 patients, only 1 patient showed symptoms of B; Among the 14 patients with GCB subtypes detected by immunohistochemistry, there were 7 patients with both GCB and non-GCB subtypes. Their general clinical characteristics and pathological typing are shown in Table 1 as follows.

Table 1

Clinical Characteristics of Patients
Characteristics	Quantity	Percentage
Age (n = 24)
≥60	5	21%
<60	19	79%
Pathological Type (n = 24)
PB-DLBCL	14	58%
SB-DLBCL	10	42%
ECOG Scores (n = 24)
0	16	67%
1	6	25%
2	2	8%
3	0	0%
4	0	0%
5	0	0%
LDH Level (n = 24)
Normal	19	79%
Increase	5	21%
B Symptoms (n = 24)
Yes	1	4%
No	23	96%
Involvement (n = 24)
Left	8	33%
Right	14	58%
Bilateral	2	8%
Lump Size (n = 22)*
≥4cm	13	59%
༜4cm	9	41%
Infiltration of Lymph Nodes (n = 24)
No	5	21%
Axilla	8	33%
Clavicle and/or Axilla	2	8%
Others	9	38%
Ann Arbor stage (n = 24)
Ⅰ	5	21%
Ⅱ	12	50%
Ⅲ	4	17%
Ⅳ	3	13%
IPI (n = 24)
0	7	29%
1	10	42%
2	4	17%
3	2	8%
4	1	4%
Pathological Type (n = 14) #
GCB	7	50%
Non-GCB	7	50%

*: Data about the lump size of 22 patients have been obtained. #: Expression level of CD10, MUM1, and Bcl-6 is detected for 14 patients who can be classified. PB-DLBCL: Primary breast diffuse large B-cell lymphoma; SB-DLBCL: Secondary breast diffuse large B-cell lymphoma; ECOG: Eastern Cooperative Oncology Group; LDH: Lactic dehydrogenase; IPI: International Prognostic Index; GCB: Germinal center B cell.

3.2 Therapeutic Regimes

Among the 24 patients included, 13 underwent surgical treatment, and 1 patient only underwent surgical treatment without undergoing chemotherapy or radiotherapy. Besides, among patients undergoing surgical treatment, only one underwent total mastectomy; All 4 patients with radiotherapy received chemotherapy, of which 3 patients did not receive surgery, and 1 patient received Mastectomy combined with axillary lymph node dissection. In addition, among the 23 patients undergoing chemotherapy, 11 underwent Rituximab treatment. (Table 2)

Table 2

Therapeutic Regimes
Therapeutic Regimes	Quantity	Percentage
Surgery (n = 24)
Yes	13	54%
No	11	46%
Surgical Approaches (n = 13)
Breast Lump Removal ± Axillary Regional Lymph Node Dissection	12	92%
Mastectomy ± Axillary Regional Lymph Node Dissection	1	8%
Chemotherapy (n = 24)
Yes	23	96%
No	1	4%
Use of Rituximab (n = 23)
Yes	11	48%
No	12	52%
Radiotherapy (n = 24)
Yes	4	17%
No	20	83%

3.3 Prognostic Analysis

Complete follow-up data were obtained in 19 of 24 patients with B-DLBCL, of which 6 patients suffered disease progression and 4 patients died. The PFS and OS of 24 patients were 72% and 80%, respectively (Fig. 2).

Primary diffuse large B-cell lymphoma of the breast (PB-DLBCL) is a rare primary site of extra-nodal malignant lymphoma, meaning that it only infiltrates the breast and its regional lymph nodes, accounting for only 2.2% of extra-nodal malignant lymphomas. However, secondary diffuse large B-cell lymphoma of the breast (SB-DLBCL) is part of systemic lymphoma or a recurrent site of lymphoma in other organs, and its pathogenetic features and the extent and sequence of infiltration are very different from those of PB-DLBCL, which is a higher type of DLBCL with Ann Arbor stage. Therefore, we divided 24 patients into two groups: PB-DLBCL and SB-DLBCL, and plotted the PFS and OS curves, which were 85% and 83% for PB-DLBCL; 53% and 75% for SB-DLBCL, respectively. We found that the PFS and OS of SB-DLBCL were lower than that of PB-DLBCL (P > 0.05). (Fig. 3)

In the past, surgery was a common method for the diagnosis and treatment of B-DLBCL, but it is controversial whether surgery is beneficial for the clinical prognosis of the disease. We plotted the PFS and OS curves of surgical patients and non-surgical patients in Fig. 4, and the results showed that the PFS and OS of non-surgical patients were 61% and 70%, respectively. while the PFS and OS of surgical patients were 80% and 87%, respectively. In this study, we found that the prognosis of non-surgical patients was worse than that of surgical patients (P > 0.05). (Fig. 4)

At present, most of the clinical data on B-DLBCL came from Pre-clinical application of rituximab. At that time, the impact of Rituximab on the prognosis of B-DLBCL was unclear. Therefore, we divided 23 chemotherapy patients into Rituximab group and non-Rituximab group, and drew PFS and OS curves respectively. The results showed that the PFS and OS of the rituximab group were 72% and 79% respectively, while those of the non-Rituximab group were 73% and 83% respectively. (Fig. 5)

Breast Non-Hodgkin’s lymphoma is a highly heterogeneous disease, with DLBCL being the most common pathological type. Related studies have shown that the 5-year OS of breast NHL ranges from 50–75%. In our study, the 5-year OS of patients was 80%, slightly higher than previous literature reports[2, 3]. According to the diagnostic criteria developed by Wiseman et al. in 1972, B-DLBCL can be divided into two categories: PB-DLBCL and SB-DLBCL. PB-DLBCL is defined as only involving the breast, including or excluding the ipsilateral axillary and supraclavicular lymph nodes, while the rest are defined as SB-DLBCL[9]. Based on this standard, the Ann Arbor staging of PB-DLBCL is in stages I-II, with primary lesions mostly located in the breast, belonging to a type of disease with limited involvement in the region; On the contrary, the Ann Arbor staging of SB-DLBCL is in stages III-IV, with primary lesions mostly located in other parts and involving breast tissue during the disease development process. It belongs to the type of disease that involves a wide range of areas and spreads throughout the body; In theory, PB-DLBCL has a better prognosis than SB-DLBCL. In our study, the PFS and OS of PB-DLBCL were also superior to SB-DLBCL, and the findings were consistent with previous reports in the literature [10]. Additionally, DLBCL has a special type of disease, which not only affects the breast and its regional lymph nodes, but also spreads to the blood. It belongs to phase IV PB-DLBCL, and its prognosis is between PB-DLBCL and SB-DLBCL. Yao Sun et al. conducted a meta-analysis and found that classifying B-DLBCL into in situ (PB-DLBCL Ⅰ E - Ⅱ E) and disseminated (PBD-LBCL Ⅳ E and SBDLBCL) was more effective in reflecting the therapeutic effects of the disease[11].

B-DLBCL is insidious and often presents as a painless breast mass. It needs to be differentiated from benign tumor, breast cancer and metastatic tumor of the breast. Therefore, many B-DLBCL patients will be admitted to hospital with the diagnosis of breast cancer. Over the past 20 years, surgery has been one of the main treatment methods for B-DLBCL, but there is still much controversy over whether surgery can be used as the standard treatment for B-DLBCL[2]. Some studies suggest that B-DLBCL is a systemic disease that should be primarily treated with chemotherapy, while surgery as local treatment cannot effectively reduce the overall tumor burden, improve patient prognosis, and prolong survival[12, 13]. For example, by analyzing 465 patients with B-DLBCL reported in the literature, Jennings, W.C et al found that 156 patients who underwent mastectomy did not achieve a higher OS compared to patients without surgery, furthermore, the analysis yielded that the procedure was associated with a trend toward worse OS (P = 0.055)[12]. Similarly, Ryan, G et al through a retrospective analysis of 204 eligible patients with breast lymphoma, showed that there was no benefit from mastectomy, as opposed to biopsy or lumpectomy only. Importantly, radical breast cancer treatment was even associated with an increased risk of death, HR = 2.4 (95% CI:1.2–4.8; P = 0.03)[13]. Uesato, M et al mentioned in a case study that of 380 patients with primary breast lymphoma documented in Japan, 333 patients (87.6%) underwent surgery and found that tumor removal was necessary, but further axillary lymph node dissection (ALND) was unnecessary and the prognosis was better despite enlargement or metastasis at the axillary lymph nodes[14]. However, Mustafa Ali, M.K. et al found that mastectomy with or without regional lymph node dissection was effective in reducing tumor load and improving PFS and OS through a meta-analysis[15]. The reasons for these differences may be due to the relatively small number of patients included in the study and the different surgical options. In summary, whether surgery can be used as a standard treatment for breast lymphoma remains highly controversial. Many studies have concluded that breast lymphoma as a systemic disease should be treated systemically, such as through chemotherapy. Surgery as a local treatment is not effective in reducing tumor load; however, many findings show the positive aspects of surgery. In our study, 13 patients underwent surgery, of which only 1 patient underwent mastectomy combined with ALND, a ratio consistent with that reported in the above study. Although the results showed that the PFS and OS were higher in the operated patients than in the non-operated patients, there was no statistically significant difference (P > 0.05), probably due to the small sample size in this trial, which needs to be further validated by expanding the sample size.

The current standard chemotherapy regimen for B-DLBCL is CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone) regimen, which is consistent with the chemotherapy regimen used in the patients included in this trial. Rituximab is a chimeric monoclonal antibody against CD20 B-cell antigen that is therapeutic for diffuse large B-cell lymphoma. The study showed that standard chemotherapy regimens combined with rituximab improved the prognosis of B-DLBCL, especially for non-GCB B-DLBCL, eliminating the difference in prognosis between non-GCB and GCB types[16, 17]. According to Coiffier, B et al conducted a randomized trial comparing the efficacy of CHOP chemotherapy plus rituximab with CHOP regimens alone in the treatment of elderly diffuse large B-cell lymphoma in groups, and the results of the study suggested that rituximab significantly improved complete remission rates, prolonged event-free survival and overall survival in elderly patients with diffuse large B-cell lymphoma with no significant increase in clinical toxicity[16]. Consistently, Pfreundschuh, M et al analyzed the efficacy of rituximab in young DLBCL patients by a similar approach and came up with the same results[17]. It is interesting to note that Bouwstra, R et al showed the opposite result with their study that although the addition of rituximab(R) to CHOP chemotherapy regimens improved the prognosis of patients with DLBCL, 40% of patients still failed treatment due to drug resistance[18]. A similar conclusion was reached by Aviles, A N et al, non-GCB genotypes are more common in PB-DLBCL, but the addition of rituximab did not improve the prognosis of primary breast lymphomas with non-GCB phenotypes[19]. The results of this trial were similar to those of Aviles, A N et al, the use of rituximab did not result in improved PFS and OS in patients.

CNS recurrence or metastasis is the most common cause of treatment failure in DLBCL, and extra-nodal DLBCL is more likely to develop CNS metastasis. Methotrexate (MTX) is the most widely used treatment regimen to prevent central nervous system (CNS) metastasis or recurrence in patients with DLBCL. However, Bobillo, S et al examined the effectiveness of the MTX prophylaxis regimen by examining 585 patients newly diagnosed with DLBCL and at high risk of CNS recurrence, of whom 295 (50%) received MTX prophylaxis, the result suggest that although the risk of CNS recurrence at 1 year was lower than in patients who did not receive MTX (2% vs. 7.1%), this prevention effect was not evident over time. This indicates that MTX is not effective in preventing the onset of CNS, but only has the effect of delaying CNS recurrence or metastasis [20, 21]. Therefore, it is urgent to find an optimal regimen that is effective in preventing CNS recurrence and metastasis. The efficacy of rituximab in preventing CNS recurrence or metastasis remains controversial. Villa, D et al divided patients diagnosed with DLBCL into 2 groups, one with the CHOP regimen and the other with the R-CHOP regimen, and assessed the risk of CNS recurrence in patients on both treatment regimens; the results of the multifactorial analysis showed that the use of rituximab significantly reduced the risk of CNS recurrence with statistical significance (p < 0.05), especially in pathologically in patients in complete remission[22]. Consistently, Schmitz, N et al came to a similar conclusion that the use of rituximab reduced the CNS recurrence rate in DLBCL, especially in younger patients with lower IPI scores[23]. On the other hand, Hosein, P. J et al retrospectively collected data from 76 patients with stage I/II (breast and local lymph node involvement) from eight US academic centers, and after a median follow-up of 4.5 years, the analysis showed no survival benefit with rituximab and the odds of extra-nodal progression in the breast or CNS remained high [6, 24]. CAR-T therapy might be effective in preventing CNS relapse [25].

Hu, S et al concluded from a retrospective analysis of 108 patients with PB-DLBCL that although rituximab reduced the five-year cumulative risk, late recurrence in the contralateral breast and CNS was frequent, and radiotherapy combined with rituximab had a complementary effect on preventing recurrence in patients but was poorly effective in preventing CNS recurrence in PB-DLBCL [26]. Although radiotherapy can control local tumor recurrence, it is not valid for improving patients' OS and PFS; In contrast, a meta-analysis of the published literature on the subject showed that receiving radiotherapy in situ or even contralaterally improved patients' OS and PFS[13, 27, 28].

DLBCL can be classified into GCB type and non-GCB type by immunophenotypic detection [29]. Only 14 patients in our study had this staging, and due to incomplete data, we were unable to perform an accurate analysis of the prognostic differences between the two types of B-DLBCL. According to our knowledge of DLBCL, the non-GCB type has a worse prognosis than the GCB type, and the use of rituximab can eliminate this difference. Wilson, W.H. et al found that adding imatinib to the R-CHOP regimen can further improve the survival of patients with non-GCB type [30–32], but whether this conclusion still holds in patients with B-DLBCL needs further investigation.

In future research, on the one hand, it is necessary to validate and promote the currently considered best treatment options, and on the other hand, it is necessary to search for molecular markers that can help diagnosis and suggest prognosis from the perspective of gene expression profiles, so as to improve patient prognosis in a multidimensional manner in terms of early diagnosis and effective treatment.

SB-DLBCL has a worse prognosis than PB-DLBCL, and local surgery combined with standard chemotherapy for CHOP may be the best treatment option for the patients. Further studies on whether the combination of rituximab can further improve the prognosis of the patients are needed after expanding the sample size.

Ethics approval and consent to participate:

All experimental protocols were approved by The Clinical Medical Research Ethics Committee of the Zhejiang cancer hospital and was performed in accordance with the Declaration of Helsinki (Approval number: IRB-2023-589). All methods were carried out in accordance with relevant guidelines and regulations. All subjects obtained informed consent and signed the informed consent form.

Consent for publication: Not applicable

Competing interests: The authors declare no competing interests.

Acknowledgements：Not applicable.

Authors’ contributions：

All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.

Qiu-hui Yang (First author): Conceptualization, methodology, software, survey, form analysis, formulation of manuscripts, production of pictures and tables; Ye-qin Fu：methodology, software, survey; Nin Xu: software, survey; Hong-jian Yang: conceptualization, supervision and writing review. Xi-ping Zhang (Corresponding author): revising the manuscript critically for important intellectual content, writing – the first draft; conceptualization, fund acquisition, resources, supervision, and writing review. All authors reviewed the manuscript. Approval of the version of the manuscript to be published.

Availability of data and materials

The results/data/figures in this manuscript have not been published elsewhere, nor are they under consideration (from you or one of your Contributing Authors) by another publisher. The datasets used and analyzed during the current study available from the corresponding author on reasonable request.

Funding：Natural Science Foundation of Zhejiang Province: Study on the Mechanism of MALAT1 Regulating Lymph Node Metastasis of Three Negative Breast Cancer through CeRNA Mechanism and Its Correlation with Prognosis (No. LBY21H160001).

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No competing interests reported.

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Clinical Characteristics and Prognostic Analysis of 24 Cases with Breast Diffuse Large B-cell Lymphoma

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Abstract

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1 Introduction

2 Cases and Methods

2.1 Cases

2.2 Pathological Diagnosis

2.3 Treatments

2.4 Follow-up Visits

2.5 Statistical Analysis

3 Results

3.1 Clinical Characteristics and Pathological Typing

3.2 Therapeutic Regimes

3.3 Prognostic Analysis

4 Discussion

5 Conclusion

Declarations

References

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