Accepted Manuscript

Tumour review

Primary breast lymphoma

Chan Y. Cheah, Belinda A. Campbell, John F. Seymour

PII: S0305-7372(14)00110-8
DOI: http://dx.doi.org/10.1016/j.ctrv.2014.05.010
Reference: YCTRV 1311

To appear in: Cancer Treatment Reviews Cancer Treatment Re-

views

Received Date: 17 March 2014

Revised Date: 22 May 2014
Accepted Date: 26 May 2014

Please cite this article as: Cheah, C.Y., Campbell, B.A., Seymour, J.F., Primary breast lymphoma, Cancer Treatment
Reviews Cancer Treatment Reviews (2014), doi: http://dx.doi.org/10.1016/j.ctrv.2014.05.010

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Cheah et al Primary Breast Lymphoma

Primary breast lymphoma

Chan Y Cheah1,2 Belinda A Campbell2,3 and John F Seymour1,2

1. Department of Haematology, Peter MacCallum Cancer Centre, East

Melbourne, Melbourne, Victoria, Australia
2. University of Melbourne, Parkville, Melbourne, Victoria, Australia
3. Division of Radiation Oncology, Peter MacCallum Cancer Centre, East
Melbourne, Melbourne, Victoria, Australia

main text 5019 words

tables 3
figures 3
header: Primary Breast Lymphoma

keywords: primary breast lymphoma; breast neoplasms; non-Hodgkin lymphoma;

review article; extranodal lymphoma

Prof John F Seymour (correspondence)

Peter MacCallum Cancer Centre
Locked Bag 1, A’Beckett St
East Melbourne, Victoria 8006, Australia
Email: john.seymour@petermac.org
Phone: +61 3 9656 1076
Fax: +61 3 9656 1408

Dr Chan Cheah
Phone: +61 3 9656 1915
Fax: +61 3 8678 0636
Email: chan.cheah@petermac.org

Dr Belinda Campbell
Phone: +61 3 9656 1111
Fax: +61 3 9656 1408
Email: Belinda.campbell@petermac.org

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Cheah et al Primary Breast Lymphoma

Primary Breast Lymphoma

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Cheah et al Primary Breast Lymphoma

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.

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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.1-6 Over 98% of cases occur in women;2-5, 7-
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, 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.2-4, 9 In East Asian countries the median age is lower (45-53 years),8,
10, 13-15
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, 17-21 Clinically, PBL is difficult to distinguish from breast carcinoma as
both typically present with a painless breast mass.2, 9, 22 The right breast is involved
slightly more frequently for reasons that are unknown.2, 4, 8, 22, 23 Constitutional
symptoms are uncommon, reported in 4% of patients and usually indicative of
disseminated disease.2, 4, 8-10, 22 Cutaneous manifestations, nipple retraction and
discharge are rare.6, 24 The median tumor diameter is 4cm, although masses of up to
20cm have been reported.4

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Diagnosis and staging

Although up to 20% of patients are diagnosed following detection of a mass by

screening mammography.22, 25 Sabaté et al noted differences between the
mammographic appearance of PBL compared with breast carcinoma, proposing size
(4-5cm in lymphoma, 2-3cm 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, 8 Bilateral breast involvement
is present in 4-13% at diagnosis although the cumulative incidence approaches
30%.2, 4, 8, 27, 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 prognosis29), bilateral involvement of the breasts appears to
be a feature of aggressive disease with poor prognosis.4, 28 We consider bilateral
disease stage IIE, as the adverse prognosis can be conveyed using the stage-

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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, 31 Niitsu et al found cytogenetic evidence of 18q21/BCL2
translocations in three patients with germinal centre 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 mixed33-35 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 signalling 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 lines40 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 lymphomangiogenesis in vivo.42 ERα expression by PBL was
demonstrated by immunohistochemistry 4/40 (10%) in three older case series.12, 43, 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, 45 Analysis of ERβ expression in a larger cohort of patients with PBL
appears warranted, given the promising preclinical activity of selective ERβ agonists.

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Autoimmune disease

A number of case series have reported high prevalence of antecedent autoimmune

diseases such as Hashimoto’s thyroiditis (19-30%).46, 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, 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, 50 MZL (9-28%),2, 5,
25, 28, 51
follicular (10-19%),2, 9, 51 and Burkitt lymphoma (<6%).50, 52, 53 Rarer histologies
include anaplastic large cell lymphoma,54 peripheral T-cell lymphoma,55, 56 small
lymphocytic lymphoma,2, 25 lymphoplasmacytic lymphoma,2 mantle cell lymphoma57-59
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. H. pylori in stomach or C. 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, 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

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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
chlorambucil62 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, 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.57-59, 65, 66 This is unsurprising given the majority of
patients have gut and marrow involvement at baseline if sensitive techniques are
used.67-69 Furthermore, the limited data regarding outcome in patients with limited

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stage MCL suggest that their outcomes are similar to patients with advanced stage,
with the caveat that radiotherapy may improve PFS.70, 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, 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

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variably present.74 There are two distinct clinical presentations with disparate clinical
behaviour: 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, 78-80 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

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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, 32 Hosein et al found stage-
modified IPI to predict OS in a patients treated primarily with R-CHOP (Figure 1).
Other investigators have found stage IIE disease to be independently associated with
inferior outcome.3, 19, 23, 82 Other adverse prognostic markers identified include poor
performance status,9, 25 erythrocyte sedimentation rate >30mm/hr,9 tumor size >4-
5cm,3, 27, 32 soluble serum IL2 >1000U/ml32 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

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-

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44% of cases.3, 4, 9, 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, 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.

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 involvement28 and tumor size >5cm.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

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present (stage IIE, stage-modified IPI score >2, bilateral breast involvement or bulk
>5cm).

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 relapse4, 10, 27 whilst other studies did not find
IT prophylaxis to impact CNS relapse rate.9, 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, 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 (3g/m2 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, 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, 8 Published experience with chemotherapy focusing on PB-DLBCL is

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derived mostly from retrospective series with two completed prospective studies.87, 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) (Figure 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 50-70%.2, 4, 22, 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

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 1500mg/m2,
epirubicin 100mg/m2, vincristine 1.2mg/m2, rituximab 375mg/m2 D1 prednisolone
100mg/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, 88 Other studies examining the impact of rituximab are
mixed, with several studies showing a non-significant trend toward improvement in
PFS and OS2, 10 and others no benefit.22, 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

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a small number of retrospective analyses that suggest that improved disease control
in the breast translates into an improvement in survival.4, 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, 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, 92 the current
approach for consolidation radiotherapy is involved site radiotherapy (ISRT).91-93
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 hypothesise
the entire ipsilateral breast may potentially harbour 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

15
Cheah et al Primary Breast Lymphoma

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

hypothesised 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, 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 Figure 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 >5cm) 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

16
Cheah et al Primary Breast Lymphoma

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.

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
activity97 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 enzastaurin102 (an inhibitor of PKCβ) and fostamatinib103 (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-

17
Cheah et al Primary Breast Lymphoma

CHOP ± enzastuarin 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.

18
Cheah et al Primary Breast Lymphoma

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Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell
Lymphoma (DLBCL): Interim Results of a Multicenter, Open-Label, Phase 2 Study.
ASH Annual Meeting Abstracts. 2012;120:686.

102. Robertson MJ, Kahl BS, Vose JM, de Vos S, Laughlin M, Flynn PJ, et al. Phase
II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or
refractory diffuse large B-cell lymphoma. J Clin Oncol. 2007;25:1741-6.

103. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A,
et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in
non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578-
85.

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Cheah et al Primary Breast Lymphoma

Figure 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

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Cheah et al Primary Breast Lymphoma

FIGURE 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

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Cheah et al Primary Breast Lymphoma

FIGURE 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.
Cheah et al Primary Breast Lymphoma

Progression free survival Overall survival

IPI (per unit increase4 or >210, 28) IPI (per unit increase4 or >25, 28)
Omission of anthracycline4 or Omission of anthracycline,4 radiation4 or
chemoradiation2, 5 chemoradiation2, 4
Stage IIE (vs stage IE)2, 3 Stage IIE (vs stage IE)3, 19
<4 cycles of chemotherapy10 Received mastectomy3
Bilateral involvement of the breasts28 Tumour size >4-5cm3, 27
Tumour size >5cm27 <4 cycles of chemotherapy10
ESR >30mm/hr9
ECOG performance status9, 25
Bilateral involvement of the breasts28
High microvascular density81
Soluble serum IL-2 >1000IU/ml32
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.

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Cheah et al Primary Breast Lymphoma

use of CNS effect of CNS localisation of rate of CNS

Study n (DLBCL) chemotherapy rituximab
prophylaxis prophylaxis CNS relapse relapse
4
Ryan 5-year cumulative
204 70% anthracycline 0% None NA not reported
5%
22
Hosein leptomeningeal
4/12 (33%)
12%; mostly IT crude incidence
76 72% CHOP 69% no impact parenchymal 6/12
MTX 16%
(50%)
both 2/12 (16%)
Jeanerette- any 70%; mostly crude incidence
3
57* 0% not reported NA not reported
Sozzi CHOP-like 12%
10
Yhim 97% anthracycline 5/49 (10%) IT no relapses in IT 5-year cumulative
49 62% not reported
based chemo group 12.3%
87
Aviles crude incidence
96 CHOP-21 0% None NA not reported
11.4%

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

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 Cheah et al Primary Breast Lymphoma

n DLBCL
Study Year type Chemotherapy Rituximab RT PFS OS
(% of series)
70% anthracycline 5-year PFS
Ryan4 2008 retrospective 204 (100) 0% 64% 5-year OS 63%
based 54%
5-year PFS
Hosein22 2014 retrospective 76 (100) CHOP 72% 62% 63% 5-year OS 75%
66%
97% anthracycline 5-year PFS
Yhim10 2010 retrospective 49 (100) 62% 31% 5-year OS 60%
based 54%
5-year ‘distant 5-year OS
Caon2 2012 retrospective 28 (87*) CHOP 73%* 43%* 50%*
control’ 70%* 54%*
80% “anthracycline 5-year PFS 5-year OS
Validire9 2008 retrospective 38 (84) 10% 71%
based” 54%** 61%**
5-year PFS 5-year OS
Zhao81 2011 retrospective 28 (90) CHOP 74% % not stated 65%
57%** 71%**
5-year PFS 5-year OS
Guo28 2008 retrospective 37 (82) CHOP-like 79% 14% 49%
35%** 50%**
10-year PFS 10-year OS 50,
Aviles87 2005 prospective 96 RT v CHOP v combined
50, 56, 83% 50, 76%
3-year PFS
Aviles86 2007 prospective 32 R-CEOP Q14 100% 100% 3-year OS 63%
75%
Table 3. Treatment and outcome summary of larger recent series of primary breast DLBCL. 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 *data incudes all
aggressive histologies ** data includes non-DLBCL histologies

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Cheah et al Primary Breast Lymphoma

Title: Primary Breast Lymphoam

Authors: Chan Cheah, Belinda Campbell, John Seymour

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

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