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Primary breast lymphoma

Cancer Treatment Reviews

Abstract

Primary breast lymphoma is a rare form of extranodal lymphoma, defined by the presence of a primary lesion within the breast with or without regional nodal involvement but no other extra-mammary sites of involvement. It comprises diverse histologic subtypes, but diffuse large B-cell lymphoma is the most common. In this review, we describe in detail the clinical features, diagnosis and staging, pathogenesis, risk factors and therapy of primary breast diffuse large B-cell lymphoma. We consider choice and number of cycles of chemotherapy, the indications for radiotherapy and discuss the need for central nervous system prophylaxis. We also provide a brief overview of the less commonly encountered histologic subtypes including marginal zone, follicular, Burkitt and breast implant associated anaplastic large cell lymphoma. We conclude with a suggested treatment approach and potential areas of future research.

Keywords: Primary breast lymphoma, Breast neoplasms, Non-Hodgkin lymphoma, Review article, Extranodal lymphoma.

Introduction

Primary breast lymphoma (PBL) is a rare but distinct extranodal lymphoma subtype, comprising 0.5% of breast malignancies, around 1% of all non-Hodgkin lymphoma (NHL) and <3% of extranodal lymphomas [1], [2], [3], [4], [5], and [6]. Over 98% of cases occur in women [2], [3], [4], [5], [7], [8], [9], and [10]; the most common histology is diffuse large B-cell lymphoma (DLBCL). The case definition proposed by Wiseman and Liao, modified by Hugh et al. requires the presence breast tissue in close proximity with lymphoma, no antecedent diagnosis of lymphoma and no extramammary disease other than ipsilateral axillary nodes [11] and [12]. A strong case can be made to also include patients with involvement of regional (supraclavicular and internal mammary) nodes, and we use this slightly broader definition throughout this review. Patients with bilateral breast involvement without evidence of distant disease beyond regional nodal involvement should also be included. Secondary breast lymphoma is defined by the presence of systemic lymphoma with concurrent or subsequent involvement of the breast. In practice it is often difficult to distinguish between primary breast involvement with secondary dissemination and primary involvement at another site with secondary breast involvement. Although this review will mainly focus on primary breast DLBCL (PB-DLBCL), an overview of rarer histologies will be presented.

Clinical features

The median age at diagnosis in Western countries 62–64 years, however the age range is broad [2], [3], [4], and [9]. In East Asian countries the median age is lower (45–53 years) [8], [10], [13], [14], and [15], a finding which (as with breast carcinoma) likely reflects differences in demographics rather than biology [16] . PBL almost exclusively affects women – a handful of male cases have been reported; although data are limited, outcomes appear similar [4], [17], [18], [19], [20], and [21]. Clinically, PBL is difficult to distinguish from breast carcinoma as both typically present with a painless breast mass [2], [9], and [22]. The right breast is involved slightly more frequently for reasons that are unknown [2], [4], [8], [22], and [23]. Constitutional symptoms are uncommon, reported in 4% of patients and usually indicative of disseminated disease [2], [4], [8], [9], [10], and [22]. Cutaneous manifestations, nipple retraction and discharge are rare [6] and [24]. The median tumor diameter is 4 cm, although masses of up to 20 cm have been reported [4] .

Diagnosis and staging

Although up to 20% of patients are diagnosed following detection of a mass by screening mammography [22] and [25]. Sabaté et al. noted differences between the mammographic appearance of PBL compared with breast carcinoma, proposing size (4–5 cm in lymphoma, 2–3 cm carcinoma) and the absence of spiculation, calcification and architectural distortion in the surrounding tissue as distinguishing characteristics [24] . The same study found patients with PB-DLBCL had diffuse opacity, whilst those with low-grade histology a nodular pattern [24] . However, no radiologic features are truly diagnostic and biopsy remains mandatory. The sonographic and magnetic resonance imaging (MRI) features are also non-specific and have been reviewed in detail elsewhere [6] . Given the superficial anatomic location of most lesions, when possible without extensive surgery or patient morbidity, excisional biopsy should be performed to facilitate correct diagnosis. When this is not feasible, core biopsy under imaging guidance is an acceptable alternative. Although fine needle aspiration may differentiate carcinoma from lymphoma, it lacks architectural detail necessary to accurately classify subtypes of NHL and thus is insufficient as a diagnostic procedure.

Recommended staging procedures for PB-DLBCL are as for nodal DLBCL and include whole body positron emission tomography with computed tomography (PET-CT) and bone marrow biopsy. Although the contralateral breast should be examined for bilateral involvement, PET-CT should detect contralateral lymphomatous involvement. Ultrasound can be reserved for guiding biopsy of suspicious lesions. Given that the risk of central nervous system (CNS) involvement in PB-DLBCL appears to be higher than nodal DLBCL, we also recommend lumbar puncture for cerebrospinal fluid (CSF) analysis by cytology and flow cytometry (which has greater sensitivity for occult CNS involvement) [26] . MRI of the brain should be performed if neurologic manifestations are present. At diagnosis 70% of patients are stage IE, whilst 30% have regional nodes involved (stage IIE) [2], [4], and [8]. Bilateral breast involvement is present in 4–13% at diagnosis although the cumulative incidence approaches 30% [2], [4], [8], [27], and [28]. The staging of bilateral breast involvement is controversial, with expert opinion divided between allocation to stages IE, IIE and IV. In contrast to primary testicular lymphoma (where patients with bilateral involvement are considered stage IE/IIE due to their similar prognosis [29] , bilateral involvement of the breasts appears to be a feature of aggressive disease with poor prognosis [4] and [28]. We consider bilateral disease stage IIE, as the adverse prognosis can be conveyed using the stage-modified International Prognostic Index (IPI), which substitutes one point for stage II in place of stage III/IV [30] .

Risk factors and etiology

Data concerning the specific risk factors for PBL are scarce. A number of investigators have observed concurrent lesions with the morphologic features of both marginal zone lymphoma (MZL) and DLBCL in the same biopsy specimen, suggesting histologic transformation from low-grade lymphoma is responsible for at least some cases of PBL [4] and [31]. Niitsu et al. found cytogenetic evidence of 18q21/BCL2 translocations in three patients with germinal center B-cell phenotype, suggesting that some cases of PB-DLBCL probably arise from follicular lymphoma [32] .

Role of estrogen

The nearly exclusive incidence in females suggests a role for sex hormones in the pathogenesis of PBL. Epidemiological data regarding estrogen as a risk factor for lymphoma are mixed [33], [34], and [35] but a recent large study found a 29% increase in risk of developing NHL (but not specifically PBL) for women treated with unopposed estrogen hormone replacement therapy compared with women never exposed [36] . The role of estrogens on carcinogenesis is complex, but the cellular effects of estrogen depend on the balance of the two isoforms of estrogen receptor (ERα and ERβ) present in the target organ or tissue [37] . ERα predominates in breast, uterus and prostate, and receptor signaling results in cellular proliferation [38] . In contrast ERβ is predominant in ovary, lung, CNS and leukocytes, and stimulation has an anti-proliferative effect [39] . Of relevance to PBL, ERβ is found on lymphoma cell lines [40] and ERβ-selective agonists have demonstrated potent in vitro and in vivo activity against ERβ expressing lymphomas [41] . Activation of ERβ has been shown to inhibit angiogenesis and lymphangiogenesis in vivo [42] . ERα expression by PBL was demonstrated by immunohistochemistry 4/40 (10%) in three older case series [12], [43], and [44]. Furthermore, ERβ expression has been demonstrated on primary human MCL cells [42] . The empiric use of the selective estrogen receptor modulator tamoxifen (an agonist of ERα but not ERβ) as a therapeutic strategy, with one success and one failure [12] and [45]. Analysis of ERβ expression in a larger cohort of patients with PBL appears warranted, given the promising preclinical activity of selective ERβ agonists.

Autoimmune disease

A number of case series have reported high prevalence of antecedent autoimmune diseases such as Hashimoto’s thyroiditis (19–30%) [46] and [47]. Although robust data directly addressing the risk of PBL in such patients are lacking, the increased risk of NHL in connective tissue and autoimmune is well described [48] and [49], suggesting a potential role in lymphomagenesis for patients with PBL.

Pathology

The commonest histologies are DLBCL (56–84% of PBL) [4], [5], [8], [9], [28], and [50], MZL (9–28%) [2], [5], [25], [28], and [51], follicular (10–19%) [2], [9], and [51], and Burkitt lymphoma (<6%) [50], [52], and [53]. Rarer histologies include anaplastic large cell lymphoma [54] , peripheral T-cell lymphoma [55] and [56], small lymphocytic lymphoma [2] and [25], lymphoplasmacytic lymphoma [2] , mantle cell lymphoma [57], [58], and [59] and Hodgkin lymphoma (each < 1%) [5] .

Here we present an overview of the more important rare subtypes, followed by more detailed evaluation of the pathology and clinical aspects of PB-DLBCL.

Marginal zone lymphoma (MZL)

Primary breast MZL (PB-MZL) affects slightly older women, with median age at diagnosis 68 years [51] . No pathophysiologic role for chronic infection has been identified, in contrast to other extranodal sites (e.g. Helicobacter pylori in stomach or Chlamydophila psittaci in ocular adnexal tissue). PB-MZL appears indolent – in the largest retrospective study (from the IELSG, n = 24) the 5-year progression-free survival (PFS) and overall survival (OS) were 56% and 92%, respectively [51] . The excellent OS suggests that although relapses frequently occur, second responses and subsequent disease control are possible. In the companion IELSG paper on PB-DLBCL, 5% of patients had concomitant histologic evidence of MZL, though this appeared not to have prognostic impact [4] and [51]. To our knowledge no prospective studies have been conducted; thus no standard treatment has been defined. Surgery, radiotherapy and chemotherapy have all been used, however surgical resection results in inferior local and distant control to radiotherapy, with no patients relapsing within the irradiated field [51] . The IELSG series did not include rituximab treated patients; also, due to the low number of patients treated with chemotherapy, no conclusion could be reached regarding its impact. Given these findings, extensive surgery should be avoided. Patients with limited-stage disease should receive radiotherapy, with chemo-immunotherapy reserved for patients experiencing symptomatic distant relapse. In this scenario protocols for systemic MZL such as rituximab in combination with either bendamustine (BR) [60] , cyclophosphamide, vincristine and prednisolone (R-CVP) [61] or chlorambucil [62] are all reasonable choices, although no prospective studies specifically in patients with PB-MZL exist.

Follicular lymphoma (FL)

Similar to PB-MZL, primary breast follicular lymphoma (PB-FL) represents a rare entity described in small case series [2], [9], [25], [31], [51], and [63]. The IELSG study of indolent PBL is the largest, including 36 patients with PB-FL in whom median age was 62 years [51] . Treatment included surgery, radiotherapy and chemotherapy either alone or in combination, which in aggregate yielded a 5-year PFS and OS of 49% and 64% respectively – less favorable than PB-MZL [51] . As in PB-MZL, mastectomy was inferior to radiotherapy. No patients receiving breast irradiation relapsed within field – most occurred at distant sites. Eastern Cooperative Oncology Group (ECOG) Performance Status >1 predicted inferior OS but this analysis was limited by sample size. Therefore, we consider that in PB-FL (as in limited stage nodal FL) [64] local radiotherapy should be incorporated into first-line therapy, with no role for extensive surgery. The addition of chemotherapy appeared to reduce relapse risk, though not in a statistically significant manner, possibly due to low numbers [51] . It is tempting given the more aggressive course to incorporate chemo-immunotherapy upfront, although the benefit remains unproven. Patient who experience multifocal distant relapse may be offered a choice of regimens appropriate for nodal FL such as BR, R-CVP or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). Re-treatment with radiotherapy could be considered if the site(s) of relapse can be safely encompassed within a radiotherapy field without undue risks of toxicity.

Mantle cell lymphoma (MCL)

Although MCL frequently involves extranodal sites, involvement of the breast is uncommon. Rare cases have been reported, however evidence of extramammary disease was typically present [57], [58], [59], [65], and [66]. This is unsurprising given the majority of patients have gut and marrow involvement at baseline if sensitive techniques are used [67], [68], and [69]. Furthermore, the limited data regarding outcome in patients with limited stage MCL suggest that their outcomes are similar to patients with advanced stage, with the caveat that radiotherapy may improve PFS [70] and [71]. Thus patients with apparent primary breast MCL should undergo careful staging evaluation if the planned treatment of advanced stage disease differs from limited stage disease. We treat patients with apparent primary breast MCL identically to systemic MCL using chemo-immunotherapy protocols, with consideration for the addition of radiotherapy to the breast (after autologous stem cell transplant if included), if that is a predominant site of disease.

Burkitt lymphoma

Primary Burkitt lymphoma of the breasts is a rare but highly aggressive entity of younger women with poor prognosis often associated with lactation or pregnancy (in which it represents 47% of cases of NHL) [72] . This suggests a possible role for sex hormones in pathogenesis. A recent review examined 28 cases; the median age was 30 years, most were bilateral, occurred during pregnancy or lactation and outcomes were particularly poor with crude survival rates of 14.3% and 30.8% in lactating and pregnant patients respectively [52] . Although no prospective studies exist, we recommend management as systemic Burkitt lymphoma with chemotherapy protocols containing central nervous system (CNS) prophylaxis such as cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide, etoposide and cytarabine (CODOXM-IVAC) [73] . The role of radiotherapy is uncertain given that relapses tend to be systemic and involve distant nodal and extranodal sites such as the CNS.

Breast implant associated anaplastic large cell lymphoma (BIA-ALCL)

Whilst >90% of PBL in the absence of breast implants are of B-cell origin [2], [5], [8], [9], and [28], in the women with implants T-cell phenotype predominates, due to BIA-ALCL [74] . For an excellent recent review of this topic, see Thompson and Prince [75] . This rare but likely under-reported entity can occur following implants for both reconstructive and cosmetic purposes, with many cases arising around textured implants, a recent modification in design that results in greater silicone shedding and possibly increased chronic antigenic stimulation. Cell lines established from primary tumors showed dependence on IL-2 for survival and proliferation, supporting chronic inflammation as a potential pathophysiologic mechanism [76] . By immunohistochemistry, CD30 is strongly positive; ALK1 negative and T-cell lineage and cytotoxic markers are variably present [74] . There are two distinct clinical presentations with disparate clinical behavior: (1) the more common and indolent seroma-type in which fluid containing malignant lymphocytes accumulates between the implant and the surrounding fibrous capsule, (2) the less frequent but more aggressive mass lesion which is usually accompanied by seroma [77] . Miranda et al. recently reported the largest experience of BIA-ALCL, comprising 60 women (42 seroma-type, 18 mass-type), with median age 52 years [54] . The median time from implant insertion to diagnosis of BIA-ALCL was 9 (range 1–32) years and 93% had localized disease (83% stage I, 10% stage II). Capsulectomy was performed in 93% of cases; chemotherapy (mostly CHOP) and radiotherapy were given to 71% and 55% of patients, respectively. Outcomes were favorable, with actuarial 3-year OS 100% and 82% in seroma and mass types, respectively (P = 0.03). No other prognostic factors were identified. Importantly, 16 patients who did not receive chemotherapy (14 seroma-type and 2 mass-type; R. Miranda, personal communication) were alive in CR at last follow up, with one developing local relapse successfully treated with radiotherapy. From the limited available evidence, patients with seroma-type BIA-ALCL may be managed with local treatment, including capsulectomy ± radiotherapy. In contrast, those with a mass lesion, likely benefit from the addition of chemotherapy ± radiotherapy. In the absence of prospective data, we recommend 4–6 cycles of CHOP and radiotherapy to the breast.

Diffuse large B-cell lymphoma (DLBCL)

Activated B-cell (ABC) type comprises 62–77% of PB-DLBCL in studies reporting cell of origin [5], [13], [78], [79], and [80]. Immunohistochemistry findings are consistent with this: one study reported germinal center B-cell marker CD10 positive in 30% whilst ABC-markers BCL6 and MUM1 were positive in 92% and 84% of cases respectively [22] . Cytogenetic data in PB-DLBCL are limited. Kupper-Hommel et al. performed both conventional cytogenetic analysis and fluorescence in situ hybridisation (FISH) in 15 patients with PBL (a mixture of MALT, de novo PB-DLBCL and composite MALT/DLBCL) [81] . Interestingly, they found cases with numeric gains of chromosomes 3 and 18 common to all three histologic presentations. Molecular cytogenetic evidence of t(14;18)(q32q21) involving IGH/MALT1 was present in both DLBCL/MALT and de novo DLBCL. Niitsu et al. using found an abnormal karyotype in 13/18 cases of PB-DLBCL by conventional cytogenetic analysis: three had 18q21/BCL2 translocations with t(14;18)(q32q21) in two and t(12;18)(p13q21) in one patient. Of eight patients with 3q27/BCL6 translocation, t(3;4)(q27q32) was present in three patients and der(3)(q27) in five. Two patients had evidence of 17p deletions [32] . No attempt was made to correlate cytogenetic lesions with outcome in either study, presumably due to small numbers. Recently, of relevance in nodal ABC-type DLBCL, significant advances in understanding of events upstream of the NF-κB pathway have been made. Of potential relevance to PB-DLBCL (which is more commonly ABC-type) the presence of chronic B-cell receptor signaling (through activating mutations in CD79A/B or CARD11) or through constitutive activating mutations in MYD88 might be expected, however in PB-DLBCL no such data have been reported to our knowledge.

Prognostic factors

DLBCL

Identification of robust prognostic factors in rare diseases such as PBL is problematic, as those reported are generally derived from small retrospective series of heterogeneous composition and treatment, subject to bias and inconsistency. In spite of these limitations, some insights can be gleaned ( Table 1 ). The IPI in several studies remains predictive of outcome in PB-DLBCL [4], [5], and [32]. Hosein et al. found stage-modified IPI to predict OS in a patients treated primarily with R-CHOP ( Fig. 1 ). Other investigators have found stage IIE disease to be independently associated with inferior outcome [3], [19], [23], and [82]. Other adverse prognostic markers identified include poor performance status [9] and [25], erythrocyte sedimentation rate > 30 mm/hr [9] , tumor size > 4–5 cm [3], [27], and [32], soluble serum IL2 > 1000U/ml [32] and high tumor microvascular density [82] . Some series have suggested bilateral involvement with DLBCL to be a particularly aggressive entity. The 3-yr PFS and OS of 11 such cases in the IELSG-15 series were 36% and 46% respectively – although numerically inferior, the hazard ratios for progression or death compared with unilateral involvement were 1.6 (P = 0.22) and 1.9 (P = 0.15), respectively [4] . Guo et al. reported bilateral involvement in 3/42 (7%) patients and found it to be a significant adverse predictor of both PFS and OS, largely because all three patients developed CNS relapse [28] .

Table 1 Adverse prognostic factors identified in retrospective series of patients with primary breast lymphoma. Abbreviations: IPI – International Prognostic Index; ECOG – Eastern Cooperative Oncology Group; ESR – erythrocyte sedimentation rate.

Progression free survival Overall survival
IPI (per unit increase [4] or >2 [10] and [28]) IPI (per unit increase [4] or >2 [5] and [28])
Omission of anthracycline [4] or chemoradiation [2] and [5] Omission of anthracycline, [4] radiation [4] or chemoradiation [2] and [4]
Stage IIE (vs. stage IE) [2] and [3] Stage IIE (vs. stage IE) [3] and [19]
<4 Cycles of chemotherapy [10] Received mastectomy [3]
Bilateral involvement of the breasts [28] Tumor size > 4–5 cm [3] and [27]
Tumor size > 5 cm [27] <4 Cycles of chemotherapy [10]
  ESR > 30 mm/hr [9]
  ECOG performance status [9] and [25]
  Bilateral involvement of the breasts [28]
  High microvascular density [81]
  Soluble serum IL-2 > 1000 IU/ml [32]
gr1

Fig. 1 Stage-modified International Prognostic Index predicts overall survival in patients with primary breast DLBCL treated largely with R-CHOP. Reproduced with permission from Hosein et al. [22] .

Patterns of relapse

PB-DLBCL, like primary testicular lymphoma, displays extranodal tropism at relapse [83] . In particular, relapse involved the ipsilateral or contralateral breast in 12–44% of cases [3], [4], [9], and [10]. In the IELSG-15 series, ipsilateral breast relapse occurred in within 3 years of treatment, whilst contralateral relapse occurred up to 13.3 years later [4] . The pathophysiologic mechanism for this tropism is unclear but could include chemokine-mediated migration of lymphoma cells to breast tissue [84] . Other extranodal sites including the bone marrow, lung or pleura, skin, gastrointestinal tract and CNS have all been reported with greater frequency than one would expect for nodal DLBCL [3], [9], [10], [15], and [19].

CNS relapse

The frequency of CNS involvement in PB-DLBCL is difficult to estimate due to the limited size, retrospective nature and heterogeneous treatment of patients in most series. However, in larger series with data, CNS relapse occurred in 5–16% of patients ( Table 2 ). Yhim et al. found higher rates of CNS relapse (3-year cumulative incidence 23.6% vs. 1.4%, P < 0.001) in a matched-pair analysis of PB-DLBCL (n = 25) with limited stage nodal DLBCL uniformly treated with R-CHOP [79] . Similar to CNS relapse in nodal DLBCL, most CNS relapses occurred <2 years following completion of therapy [22] . We conclude CNS relapse risk is increased, but whether this justifies CNS-directed prophylaxis is controversial.

Table 2 CNS relapse in primary breast DLBCL, summarising larger retrospective reporting on CNS relapse.

Study n (DLBCL) Chemotherapy Rituximab (%) Use of CNS prophylaxis Effect of CNS prophylaxis Localization of CNS relapse Rate of CNS relapse (%)
Ryan [4] 204 70% Anthracycline 0 None NA Not reported 5-Year cumulative 5
Hosein [22] 76 72% CHOP 69 12%; mostly IT MTX No impact Leptomeningeal 4/12 (33%) Crude incidence 16
Parenchymal 6/12 (50%)
Both 2/12 (16%)
Jeanerette-Sozzi [3] 57 lowast Any 70%; mostly CHOP-like 0 Not reported NA Not reported Crude incidence 12
Yhim [10] 49 97% Anthracycline based 62 5/49 (10%) IT chemo No relapses in IT group Not reported 5-Year cumulative 12.3
Aviles [87] 96 CHOP-21 0 None NA Not reported Crude incidence 11.4

lowast Only histologic grade reported, this figure includes high and intermediate grade lymphoma. Abbreviations: DLBCL – diffuse large B-cell lymphoma; CNS – central nervous system; NA – not applicable; CHOP – cyclophosphamide, doxorubicin, vincristine, prednisolone.

Risk factors for CNS relapse

Given wide confidence intervals of published estimates, the identification of predictive factors to refine risk and target prophylaxis would be useful. Unfortunately rarity makes this difficult. Potential risk factors suggested by smaller series include bilateral breast involvement [28] and tumor size >5 cm [27] . However, in these studies no formal statistical analysis to show association was performed, and others have failed to replicate these findings. Hosein et al. reported 6/27 (22%) stage IIE patients developed CNS relapse, in comparison with 6/49 (12%) with stage IE; 5/22 (22%) patients with stage-modified IPI 2–4 experience CNS relapse compared with 7/54 (13%) with stage-modified IPI 0–1. These differences were reported not to be significant, but even a CNS relapse risk of 12% warrants consideration of CNS prophylaxis given the dismal outcome. Because of the relatively high event rate even in patients with stage IE or low stage-modified IPI, we recommend in all patients with PB-DLBCL, consideration be given to CNS-directed prophylaxis. This recommendation is stronger if potential high-risk features for CNS involvement are present (stage IIE, stage-modified IPI score > 2, bilateral breast involvement or bulk > 5 cm).

Efficacy of CNS prophylaxis

In most series IT chemotherapy was minimally used, making it difficult to assess impact on CNS relapse. In three series, the handful (<10%) of patients receiving IT chemotherapy did not experience CNS relapse [4], [10], and [27] whilst other studies did not find IT prophylaxis to impact CNS relapse rate [9] and [22]. However, these studies were neither designed nor adequately powered to answer the question. Where localization of CNS relapse has been reported, most involve brain parenchyma [22] and [27], suggesting that that as in nodal DLBCL, the addition of high-dose intravenous (IV) methotrexate or cytarabine may be a more effective prophylactic strategy [85] . We administer IT methotrexate with each cycle of R-CHOP and incorporate two cycles of IV methotrexate (3 g/m [2] adjusted for renal function and age), two weeks apart after the completion of chemo-immunotherapy as this reduces CNS relapse in high-risk patients with nodal DLBCL [86] .

Treatment

The role of surgery

There are robust data that surgical resection results in inferior local control [18] , with multiple series demonstrating treatment including mastectomy associated with higher all-cause and disease-specific mortality [3], [4], and [50]. In a large series managed with surgery alone, the 5-year OS for stage IE and IIE were 40.5% and 20.5% respectively [8] . Therefore, surgical intervention beyond excisional biopsy should be avoided. Patients who undergo surgical excision because of an initial misdiagnosis of PB-DLBCL as breast carcinoma should undergo chemo-immunotherapy followed by radiotherapy as soon as practical after wound healing.

Chemotherapy

Chemotherapy is a key component of therapy, with early series showing improvements in local and distant control for patients in whom chemotherapy was included [2] and [8]. Published experience with chemotherapy focusing on PB-DLBCL is derived mostly from retrospective series with two completed prospective studies [87] and [88]. An ongoing Korean multicenter study is attempting to evaluate R-CHOP Q21 plus IT methotrexate as reference therapy for PB-DLBCL (ClinicalTrials.gov identifier: NCT01448096). In nodal DLBCL, R-CHOP is widely accepted standard of care [89] , and has become routine for PB-DLBCL also. The IELSG-15 study highlighted the importance of including an anthracycline with hazard ratios for PFS 0.4 (95%CI 0.3–0.7) and OS 0.5 (0.3–0.9) ( Fig. 2 ). A summary of the larger series is presented in Table 3 . Series using predominantly CHOP ± R and radiotherapy have reported 5-year PFS and OS ranging from 50% to 70% [2], [4], [22], and [87]. There are data suggesting reducing the number of cycles of chemotherapy compromises outcome. In the pre-rituximab era IELSG-15 study patients receiving >3 cycles (compared with ⩽3) of chemotherapy had improved cause-specific survival (hazard ratio 0.5 (95%CI 0.2–0.9)) [4] . In a more recent study in which 62% of patients received rituximab, Yhim et al. found patients treated with >4 cycles to have superior 5-year PFS (58 v 28%, P < 0.0001) and OS (66 v 19%, P < 0.001) [10] .

gr2

Fig. 2 Combined modality therapy with anthracycline containing chemotherapy and radiotherapy was associated with superior overall survival in the IELSG-15 retrospective series of 204 patients with primary breast DLBCL. Abbreviations: RT – radiotherapy; SC – systemic chemotherapy; S – surgery. Reproduced with permission from Ryan et al. [4] .

Table 3 Treatment and outcome summary of larger recent series of primary breast DLBCL.

Study Year Type n DLBCL (% of series) Chemotherapy Rituximab (%) RT (%) PFS (%) OS (%)
Ryan [4] 2008 Retrospective 204 (100) 70% Anthracycline based 0% 64 5-Year PFS 54 5-Year OS 63
Hosein [22] 2014 Retrospective 76 (100) CHOP 72% 62% 63 5-Year PFS 66 5-Year OS 75
Yhim [10] 2010 Retrospective 49 (100) 97% Anthracycline based 62% 31 5-Year PFS 54 5-Year OS 60
Caon [2] 2012 Retrospective 28 (87 lowast ) CHOP 73% lowast 43% lowast 50 lowast 5-Year ‘distant control’ 70 lowast 5-Year OS 54 lowast
Validire [9] 2008 Retrospective 38 (84) 80% “anthracycline based” 10% 71 5-Year PFS 54 lowastlowast 5-Year OS 61 lowastlowast
Zhao [81] 2011 Retrospective 28 (90) CHOP 74% % not stated 65 5-Year PFS 57 lowastlowast 5-Year OS 71 lowastlowast
Guo [28] 2008 Retrospective 37 (82) CHOP-like 79% 14% 49 5-Year PFS 35 lowastlowast 5-Year OS 50 lowastlowast
Aviles [87] 2005 Prospective 96 RT v CHOP v combined 10-Year PFS 50, 56, 83 10-Year OS 50, 50, 76
Aviles [86] 2007 Prospective 32 R-CEOP Q14 100% 100 3-Year PFS 75 3-Year OS 63

lowast Data includes all aggressive histologies.

lowastlowast Data includes non-DLBCL histologies.

Abbreviations: DLBCL – diffuse large B-cell lymphoma; PFS – progression free survival; OS – overall survival; DFS – disease-free survival; CHOP – cyclophosphamide, doxorubicin, vincristine, prednisolone; CEOP – cyclophosphamide, epirubicin, doxorubicin, vincristine, prednisolone; RT – radiotherapy.

Aviles et al. attempted to improve on CHOP by increasing alkylator dose and adding rituximab in a phase-II study of R-CEOP Q14 (cyclophosphamide 1500 mg/m [2] , epirubicin 100 mg/m2, vincristine 1.2 mg/m2, rituximab 375 mg/m2 D1 prednisolone 100 mg/m2 PO D1-5) with all patients receiving radiation [87] . The patient cohort was young (median age 45 years) but otherwise typical of PB-DLBCL, being mostly stage IE and favorable performance status. The treatment was tolerable but did not improve outcome in a historic comparison with CHOP for 5-year DFS 64% v 60%, P = 0.66) or OS (53% v 52% P = 0.50) [80] and [88] Other studies examining the impact of rituximab are mixed, with several studies showing a non-significant trend toward improvement in PFS and OS [2] and [10] and others no benefit [22] and [32]. Only the study by Zhao et al. showed marginal improvement in 5-year PFS for patients treated with R-CHOP v CHOP (82 v 67%, P = 0.038) [82] . It should be noted that these studies were neither designed nor powered to measure the impact of rituximab. However, a randomized study in PB-DLBCL is unlikely; given R-CHOP is standard of care in nodal DLBCL there is little controversy recommending its use in PB-DLBCL.

Radiotherapy

The primary role of radiotherapy is to consolidate the responses achieved by systemic therapy. In particular, irradiation of the ipsilateral breast (the most common site of first relapse) appears to reduce this risk [4] . The published literature is limited to a small number of retrospective analyses that suggest that improved disease control in the breast translates into an improvement in survival [4] and [88]. The largest retrospective series supporting consolidation radiotherapy was the IELSG-15 study, in which the combination of anthracycline-containing chemotherapy and radiotherapy was associated with improved OS compared to chemotherapy or radiotherapy alone (P = 0.001) [4] . Aviles et al. reported the combination of six cycles of CHOP chemotherapy plus radiotherapy to the ipsilateral breast and regional nodes was also associated with significantly improved outcomes compared to chemotherapy or radiotherapy alone: 10-year event-free survival rates were 83%, 56% and 50%, (P < 0.01); 10-year OS rates were 76%, 50% and 50%, (P < 0.01) [88] . Thus chemo-immunotherapy and consolidation radiotherapy is standard of care for PB-DLBCL.

The optimal volume for consolidation radiotherapy in PB-DLBCL is controversial. Earlier published series of PB-DLBCL described the use of radiotherapy techniques that encompassed the ipsilateral breast at a minimum, and have acknowledged the uncertain benefits of additional irradiation of regional nodes +/− contralateral breast [4], [18], and [90]. This uncertainty is heightened by the evolution of modern functional imaging, improved radiotherapy planning techniques and the addition of molecular-based therapies to the treatment. Extrapolating from nodal DLBCL [91] and [92], the current approach for consolidation radiotherapy is involved site radiotherapy (ISRT) [91], [92], and [93]. This concept was first developed for Hodgkin lymphoma, and has now been applied to DLBCL [94] . The primary difference between ISRT and involved field radiotherapy (IFRT) volumes is that the latter also includes prophylactic radiotherapy to adjacent uninvolved nodes. The principle of ISRT is to restrict the radiotherapy volume to encompass the pre-chemotherapy site(s) of disease, with adequate margins to allow for subclinical disease, physiological movement and set-up variation, whilst also considering post-chemotherapy anatomical changes [94] . Therefore, ISRT relies on the sensitivity of the pre-chemotherapy imaging studies. In PB-DLBCL, we hypothesize the entire ipsilateral breast may potentially harbor subclinical disease, thus we propose that the ISRT volume should include the whole ipsilateral breast plus any additional sites of known pre-chemotherapy disease in the regional nodes or contralateral breast. Elective nodal irradiation of the contralateral breast, axillae or supraclavicular fossae is not routinely included within the ISRT field. However, in the unusual situation that the patient has not been adequately staged with functional and structural imaging prior to the initiation of systemic therapy, then the traditional IFRT is a safer treatment choice for consolidation radiotherapy.

Technically, ISRT volumes tend to be smaller than the traditional IFRT. It is hypothesized that with effective systemic therapy for DLBCL, these smaller radiotherapy volumes will translate into lower risks of radiation-induced side effects, without compromising disease control. A population-based cohort study from British Columbia of 288 patients with limited-stage DLBCL (including PB-DLBCL, but excluding primary DLBCL of the testis or central nervous system) demonstrated the safety of reducing the radiotherapy field size from IFRT, noting a reassuringly low rate of marginal relapse and no detrimental impact on survival [91] . Reducing the radiotherapy field size spares adjacent uninvolved tissues, and extrapolating from radiotherapy planning studies performed in Hodgkin lymphoma, will likely be associated with lower risks of second malignancy and other late effects [95] and [96]. With respect to PB-DLBCL in the era of ISRT, the radiotherapy volume includes the ipsilateral breast [93] , and only includes regional nodal irradiation or contralateral breast irradiation if these sites were known to be previously involved with DLBCL. In this setting, the smaller field size with ISRT (vs. IFRT) reduces the radiation exposure to the contralateral breast, lung, and thyroid gland, and thus the risks of late radiation-induced toxicities and second malignancies in these organs. Modern technological advances in radiotherapy delivery may further reduce the risk of late toxicities; for example, inverse-planning techniques to reduce higher-dose radiation exposure to organs at risk, and breath-holding techniques or respiratory-gating to reduce the cardiac exposure in patients receiving radiotherapy to the left breast.

Treatment recommendation

A suggested approach to treatment for PB-DLBCL is displayed in Fig. 3 . Patients with stage-modified IPI 0–1 and no risk factors should receive 4–6 cycles of anthracycline containing chemotherapy with rituximab. Patients with high-risk disease (defined by stage-modified IPI 2–4, bilateral disease or bulk > 5 cm) should have 6 cycles of anthracycline containing chemotherapy with rituximab. All patients should be considered for CNS-directed prophylaxis; all should receive consolidative ISRT to the ipsilateral breast. Patients with bilateral breast involvement may represent a particularly high risk group, and it would be useful to evaluate the tolerability and efficacy of more intensive chemotherapy regimens such as R-Hyper CVAD (rituximab, hyper-fractionated cyclophosphamide, doxorubicin, vincristine and dexamethasone)/R-MA (rituximab, high dose IV methotrexate, cytarabine) in younger patients without significant comorbidities.

gr3

Fig. 3 Proposed treatment algorithm for patients with primary breast DLBCL. Abbreviations: DLBCL –diffuse large B-cell lymphoma; IPI – International Prognostic Index; R-CHOP Q21 – rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 days; IT – intrathecal; HD IV MTX – high dose intravenous methotrexate; ISRT – involved site radiotherapy.

Relapsed disease

The scarce data available regarding outcomes of patients with PB-DLBCL after relapse suggests prognosis is poor. In the IELSG-15 series the median survival after relapse was 1.0 (95%CI 0.7–2.1) years and 5-year OS 20% [4] . These data are supported by the similarity between PFS and OS curves in most series, implying limited ability to successfully salvage patients. As in other forms of aggressive lymphoma, CNS relapse carries a particularly poor prognosis. The median OS of patients with CNS relapse was 5.0 months in the series from British Columbia [2] . Despite a 54% response rate using high dose IV methotrexate as salvage for CNS relapse, Aviles et al. found all patients subsequently died of progressive lymphoma [88] .

Future directions

The decreasing cost and increasing availability of high throughput technologies such as “next generation” sequencing has resulted in exponential growth in the understanding of genetic alterations in nodal DLBCL. Of particular relevance to PB-DLBCL (which is mostly of ABC-subtype), the recent discovery of oncogenic mutations in genes such as CARD11, CD79B and MYD88 driving constitutive NF-κB activity [97] will likely translate into clinical development of new small molecule inhibitors of pathways such as STAT3 [98] . Inhibition of NF-κB using bortezomib may sensitize ABC-type DLBCL cells to chemotherapy, as R-CHOP with bortezomib had markedly superior ORR and OS in recurrent ABC (compared with GCB) -subtype DLBCL [99] . A prospective study of this combination in PB-DLBCL has appeal. Other potential chemotherapy partners targeting the NF-κB pathway include lenalidomide [100] , ibrutinib [101] , enzastaurin [102] (an inhibitor of PKCβ) and fostamatinib [103] (a SYK inhibitor) which all display promising activity in ABC-type nodal DLBCL. Some of these are being investigated in phase II/III studies in combination with R-CHOP, which will likely have applicability to PB-DLBCL (ClinicalTrials.gov identifiers: RCHOP ± ibrutinib, NCT01855750; R-CHOP + lenalidomide maintenance NCT01122472, R-CHOP ± enzastaurin NCT00451178). Given the preclinical promise, exploration of ERβ agonists in PB-DLBCL appears warranted.

Conclusion

The breast is a rare extranodal site of involvement for lymphoma with particular biological and clinical characteristics. In general, surgery has no role beyond obtaining a histologic diagnosis to guide definitive therapy. For PB-DLBCL, the commonest subtype, anthracycline-containing chemotherapy followed by consolidative ipsilateral breast irradiation is standard of care. Further studies into oncogenic mutations will hopefully assist in the development of more effective agents for the significant minority of patients failing existing treatments.

Conflicts of interest

We declare no conflicts of interest in relation to this article.

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Footnotes

a Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Victoria, Australia

b University of Melbourne, Parkville, Melbourne, Victoria, Australia

c Division of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Victoria, Australia

lowast Corresponding author at: Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, East Melbourne, Victoria 8006, Australia. Tel.: +61 3 9656 1076; fax: +61 3 9656 1408.

1 Tel.: +61 3 9656 1915; fax: +61 3 8678 0636.

2 Tel.: +61 3 9656 1111; fax: +61 3 9656 1408.