Primary Breast Lymphoma in the United States: 1975–2013

Abstract

Background: Primary breast lymphoma (PBL) has gained attention with the description of breast implant–associated anaplastic large cell lymphoma (ALCL). Less is known about PBL incidence, treatment, and survival by lymphoma subtype.

Methods: The Surveillance, Epidemiology, and End Results (SEER) registry database was queried for patients with PBL as first malignancy, with attention to non-Hodgkin Lymphoma PBL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), and ALCL. Incidence was estimated by age and subtype with joinpoint analyses, along with initial local therapy. Five-year relative and overall survival estimates were compared using z and two-sided log-rank tests.

Results: PBL incidence (per 1 000 000 women) increased from 0.66 (1975–1977) to 2.96 (2011–2013) with an annual percentage change (APC) of 5.3% (95% confidence interval [CI] = 3.8% to 6.9%, P < .001) from 1975 to 1999 and no statistically significant change thereafter. Incidence continues to increase for women younger than age 50 years (APC = 2.8%, 95% CI = 1.0% to 4.6%, P = .003) and for ALCL-PBL (APC = 11.8%, 95% CI = 0.2% to 24.9%, P = .047) and MZL-PBL (APC = 2.3%, 95% CI = -0.2% to 4.9%, P = .07), with the latter increasing significantly from 1995 to 2013 (APC = 7.5%, 95% CI = 3.4% to 11.8%, P = .001). Surgery and surgery with radiation declined from 2000 to 2013 as initial local therapy for PBL. Five-year relative survival for PBL improved markedly over four decades and was superior for stage I DLBCL-PBL and stage I follicular PBL than for corresponding systemic presentations.

Conclusions: PBL has increased in incidence over the last four decades and continues to increase for younger women and for some subtypes. The rise in imaging and procedures to the breast might enhance diagnostic sensitivity for PBL. Further study of the etiologies of PBL is needed.

Primary breast lymphoma (PBL) is a rare lymphoma, arising in the breast without evidence of systemic disease. The most common histology is diffuse large B-cell lymphoma (DLBCL), although diverse lymphoma subtypes are represented (1–3). In most series, PBL represents an estimated 1% of non-Hodgkin lymphomas (NHL) and less than 3% of extranodal lymphomas (4–7). By definition, PBL involves the breast and, in more advanced stages, the axilla. Some consider other anatomically close nodal beds, supraclavicular and inframammary, as part of locoregional early-stage disease (4). PBL can present bilaterally, producing debate as to whether to consider this condition localized or metastatic disease (2,8–10). Published series may include what could be primary or secondary breast lymphoma, where in some cases the breast is involved and thought to be the primary site in disease that is disseminated at presentation (3,11).

Lymphoma arising from the breast occurs almost exclusively in women (12), leading some to propose an estrogen-related mechanism for some forms of the disease (4). Smaller series have reported that lymphoma arising from the breast occurs more commonly in the right breast (2,5,10,12). Clinically, PBL can present like breast carcinoma as a painless mass (5,11,12). Diagnosis of PBL by mammogram is less frequent than with breast carcinoma, with 10% to 20% of PBL cases detected by mammogram (11–13). Mammographic images of breast lymphoma lesions are characteristically distinct from those of invasive breast cancer (14,15). Limited literature is available on magnetic resonance imaging and ultrasound findings in PBL (15).

Recent reports have described a new entity in PBL: breast implant–associated anaplastic large-cell lymphoma (ALCL) (16–20). Implant-associated ALCL is localized and appears to occur in two primary forms. The more common effusion presentation often requires only implant removal for long-term disease-free survival (16,21). The less common mass presentation requires multimodal therapy for cure (16,21). Recently, other PBL subtypes have been associated with plastic surgery procedures (22,23).

Contemporary incidence of PBL in a large population-based cohort has not been reported. Use of local therapies over time is also not well understood. In this paper, we estimate the incidence of lymphoma arising in the breast as the first malignant cancer diagnosis in the Surveillance, Epidemiology, and End Results (SEER) database. We also report incidence by lymphoma subtype and initial local therapy for cases diagnosed from 2000 to 2013 and survival for 2000–2012 cases (22–24).

Methods

Patients

Two cohorts of patients with microscopically confirmed lymphoid neoplasms as their first malignancy were created using the SEER database (additional inclusion and exclusion criteria detailed below). Lymphoid neoplasms are classified by SEER as systemic (nodal) or extranodal, based off of information in the forms, records notes, and summary sheets (such as imaging and pathology reports) included in patient medical records (25). For the lymphoid neoplasm to be designated as extranodal by SEER, the lymphoma must be described in the medical records as being extranodal, present only in one organ, or present in one organ and its regional nodes. This study was approved by the University of Iowa Institutional Review Board.

Cohort to Estimate PBL Incidence: SEER 9, 1975–2013

One cohort, created to estimate long-term incidence, included lymphoid neoplasms diagnosed in SEER 9 registries from 1975 to 2013. All male cases and any female cases with unknown age at time of diagnosis were excluded. Women with extranodal lymphoma with breast as the primary site (PBL) and systemic lymphoma presentations, based on International Classification of Diseases for Oncology, Third Edition (ICD-O-3) (26), were included. No stage restrictions were applied because the Ann Arbor staging system was not available until 1983 (Supplementary Figure 1, available online). Age at diagnosis was classified as younger than age 50, age 50 years or older, and all ages.

Cohort to Estimate PBL Incidence, Treatment, and Survival by Subtype: SEER 18, 2000-2013

A second cohort was created to estimate incidence by histologic subtype, use of local therapy, and survival. Data for the SEER 18 registries, covering 28% of the US population in 2010 (27), were selected to allow for subtype analyses while maintaining a consistent population. Cases were eligible if diagnosed from 2000 to 2013 with lymphoid neoplasm. All male cases and any female cases diagnosed on autopsy or death certificate or with unknown age at time of diagnosis, no information on disease laterality, stage III or unilateral stage IV disease (as these were unlikely to be consistent with extranodal disease), or unknown disease stage were excluded (Supplementary Figure 2, available online). The number of cases excluded due to stage and laterality criteria are shown in Supplementary Table 1 (available online).

Covariates, Histology, and Primary Site Definitions for SEER 18 Cohort

Ages at diagnosis were younger than age 50, age 50 years or older, and all ages. PBL laterality categories were left, right, unilateral NOS, and bilateral. First course of local therapy was categorized as no local therapy, surgery (a therapeutic resection) only, radiation only, and both surgery and radiation. Lymphoma histology was categorized based on ICD-O-3 and updated for hematopoietic codes based on World Health Organization classification to identify cases with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), and anaplastic large-cell lymphoma (ALCL). Systemic presentations and extranodal presentations in the breast, stomach, and skin were included.

Statistical Analyses

Incidence was estimated as diagnoses per 1 000 000 women per year (SEER*Stat software, version 8.3.21, Information Management Services, Incorporated, Calverton, MD). Changes in incidence were assessed and fit (Joinpoint Regression Program version 4.2, Information Management Services, Incorporated, Calverton, MD) using log-linear models and annual percentage changes (APCs) estimated for the final, best-fitting model. Differences in trends were also assessed (28). SEER 9 registry data from 1975 to 2013 was used to estimate long-term trends, allowing up to five joinpoints. For PBL among women younger than age 50 years, trends were estimated for 1977 to 2013 because no cases were reported in this group between 1975 and 1976. Incidence by subtype was estimated using SEER 18 data from 2000 to 2013, allowing up to two joinpoints. Similar cohorts of SEER 9 and SEER 13 data with diagnoses from 1995 to 2013 were created for sensitivity analyses.

Survival analyses were conducted using SEER*Stat software, version 8.3.2 (Information Management Services, Incorporated, Calverton, MD) for the SEER18 cohort, diagnosed 2000–2012. Five-year relative survival, cancer survival in the absence of other causes of death, was calculated using the actuarial method and compared across groups with z tests. Kaplan-Meier estimates of overall survival were plotted by subtype and compared across groups using log-rank tests. These analyses were conducted using STATA MP, version 12.0 (StataCorp LP, College Station, TX). Tests were two-sided unless otherwise specified, and a P value of less than .05 was considered statistically significant.

Results

PBL Incidence

PBL incidence increased from 0.66 per 1 000 000 women (hereafter all incidence estimates are per 1 000 000 women) in 1975 to 1977 to 2.96 in 2011 to 2013, with an APC of 5.3% (95% confidence interval [CI] = 3.8% to 6.9%, P < .001, t test (29) from 1975 to 1999 and 1.3% from 1999 to 2013 (95% CI =  -0.7% to 3.3%, P = .20). For women younger than age 50 years, there was a statistically significant increase in PBL incidence from 1977 to 2013, with an APC of 2.8% (95% CI =  1.0% to 4.6%, P = .003) (Figure 1). For women age 50 years or older, the APC for PBL was 5.2% (95% CI =  3.6% to 6.9%, P < .001) from 1975 to 1999 and -0.2% (95% CI =  -2.2% to 1.8%, P = .80) from 1999 to 2013. The incidence of systemic lymphoma presentations for women younger than age 50 years increased at an APC of 1.8% (95% CI =  1.2% to 2.4%, P < .001) from 1975 to 1992 and decreased at an APC of -0.4% (95% CI =  -0.8% to -0.1%, P = .02) from 1992 to 2013. For women age 50 years or older, the APC for systemic lymphoma was 2.5% (95% CI =  1.7% to 3.3%, P < .001) from 1975 to 1987, unchanged from 1987 to 2007, and -4.1% (95% CI =  -5.7% to -2.5%, P < .001) from 2007 to 2013.

Figure 1.

Incidence of lymphoma by age and site, and annual percentage change (APC) trends. Incidence (per 1 000 000 women) in SEER 9 registries, 1975 to 2013. *APCs statistically significantly different than zero at the 5% level, calculated based on a two-sided t test.

PBL Incidence and Presentation by Subtype

Overall, 1034 women in the SEER 18 registry from 2000 to 2013 were diagnosed with PBL (Table 1). The preponderance of PBL was non-Hodgkin B-cell lymphoma, most commonly DLBCL-PBL. Median ages at diagnosis were 67, 66.5, and 67 years, respectively, for DLBCL-PBL, follicular lymphoma-PBL, and marginal zone lymphoma (MZL)–PBL, respectively. By comparison, the median age at diagnosis of ALCL-PBL was 52 years, statistically and clinically significantly younger than for women with other non-Hodgkin PBL (P < .001, Mann-Whitney U test).

Table 1.

Patient and tumor characteristics of primary breast lymphoma diagnosed in SEER 18 registries, 2000–2013

Characteristic	No. (%)	Rate*
Sample size	1034	1.746
Median age, y†	66
Age at diagnosis
Younger than age 50	166 (16.1)	0.280
Age 50 years and older	868 (83.9)	1.466
Histology
Non-Hodgkin lymphoma	1001 (96.8)	1.691
B-cell lymphoma	956 (92.5)	1.615
Diffuse large B-cell lymphoma	409 (39.6)	0.691
Follicular lymphoma	164 (15.9)	0.277
Marginal zone lymphoma	255 (24.7)	0.431
T-cell lymphoma	38 (3.7)	0.064
Anaplastic large-cell lymphoma	22 (2.1)	0.037
Stage
I	784 (75.8)	1.324
II	220 (21.3)	0.372
IV, bilateral	30 (2.9)	0.051
Laterality
Right	483 (46.7)	0.816
Left	490 (47.4)	0.828
Unilateral, NOS	2 (0.2)	0.003
Bilateral	59 (5.7)	0.100

^*Rate per million women. ALCL = anaplastic large-cell lymphoma; DLBCL = diffuse large B-cell lymphoma; MZL = marginal zone lymphoma; NOS = not otherwise specified.

^†Median age by subtype: 67 years (DLBCL), 67 years (MZL), 66.5 years (follicular), 52 years (ALCL).

Presentation with stage I disease occurred more frequently than other disease stages (odds ratio [OR] = 3.14, 95% CI =  2.72 to 3.62, P < .001, z test). From 2000 to 2013, presentation of unilateral disease was balanced between the right and left breasts (49.4% vs 50.6%, P = .82, one-sample t test). Bilateral breast disease, thought to be associated with aggressive disease and a negative prognostic feature (2,9), did not increase statistically significantly in incidence (APC = 3.4%, 95% CI = -1.8% to 9.0%, P = .19, t test). Of the 59 (5.7%) women who presented with bilateral PBL, 18, 11, and 30 were reported as stage I, stage II, and stage IV, respectively.

Among women with non-Hodgkin-PBL B-cell subtypes, DLBCL-PBL and follicular lymphoma-PBL were stable in incidence, whereas T-cell lymphoma-PBL and ALCL-PBL increased (0.04 in 2000–2002 to 0.12 in 2011–2013 and 0.02 in 2000–2002 to 0.08 in 2011–2013, respectively). ALCL-PBL incidence increased from 2000 to 2013 at an APC of 11.8% (95% CI =  0.2% to 24.9%, P = .047). Most of the excess ALCL-PBL occurred in women younger than age 50 years, with an APC of 14.4% (95% CI =  3.1% to 26.9%, P = .02, t test) (Figure 2). Likewise, MZL-PBL increased from 2000 to 2013 with an APC of 2.3% (95% CI =  -0.2% to 4.9%, P = .07). Further examination of the SEER 9 and 13 data from 1995 to 2013 supported an increase in MZL-PBL in women age 50 years or older: APC of 5.0% (95% CI =  1.8% to 8.4%, P = .004) in SEER 9 and APC of 7.5% (95% CI =  3.4% to 11.8%, P = .001) in SEER 13.

Figure 2.

Incidence of primary breast lymphoma by age and subtype, and annual percentage change (APC) trends. Incidence (per 1 000 000 women) in SEER 18 registries, 2000 to 2013. *APCs statistically significantly different than zero at the 5% level, calculated based on a two-sided t test. ALCL = anaplastic large-cell lymphoma; DLBCL = diffuse large B-cell lymphoma; MZL = marginal zone lymphoma.

MZL-PBL and ALCL-PBL Incidence Relative to Systemic and Other Site-Specific Presentations

To evaluate the impact of continued refinement of diagnostic techniques in the diagnosis of MZL-PBL and ALCL-PBL, we also examined the incidence of these histologies at other anatomic sites during the same time period. Although incidence of MZL-PBL tended to increase from 2000 to 2013, systemic presentations of MZL stabilized in 2006, after increasing at an APC of 7.4% (95% CI =  3.8% to 11.0%, P = .001, t test) (Figure 3) from 2000 to 2006. By comparison, incidence of MZL-gastric declined at an APC of -0.6% (95% CI =  -1.4% to 0.1%, P = .08) from 2000 to 2013, a trend statistically significantly different than MZL-PBL (P = .008, one-sided test based on permutation distribution of F-type Joinpoint test statistic). ALCL-PBL also increased steadily from 2000 to 2013, at an APC of 11.8% (95% CI =  0.2% to 24.9%, P = .047, t test). Incidence of systemic presentations of ALCL and cutaneous ALCL decreased during 2000 to 2013 and achieved statistical significance for systemic ALCL (APC = -2.3%, 95% CI =  -4.1% to -0.4%, P = .02), but not cutaneous ALCL (APC = -2.6%, 95% CI =  -9.3% to 4.6%, P = .43).

Figure 3.

Incidence of lymphoma by subtype and site, and annual percentage change (APC) trends. Incidence (per 1 000 000 women) in SEER 18 registries, 2000 to 2013. *APCs statistically significantly different than zero at the 5% level, calculated based on a two-sided t test. ALCL = anaplastic large-cell lymphoma; MZL = marginal zone lymphoma.

PBL Initial Local Therapy

Initial local therapy changed markedly from 2000 to 2013 (Supplementary Figure 3, available online). From 2000 to 2002, surgery or surgery with radiation was delivered to 57.1% of affected women; 22.8% received neither surgery nor radiation. By 2011 to 2013, the proportion of women that did not receive local therapy at diagnosis (presumably treated with only systemic therapy or only observed) increased to 41.1% of new diagnoses. In terms of initial local therapy, radiation alone was delivered to 20.1% of women in 2000 to 2002 and 32.7% in 2011 to 2013.

PBL Five-Year Relative Survival and Overall Survival

Five-year relative survival for PBL improved markedly from 1975 to 2012 (Supplementary Table 2, available online). For cases diagnosed between 1975 and 1984, five-year survival was 45.9% (95% CI =  21.2% to 67.6%) and increased to 90.0% (95% CI =  79.2% to 95.3%) for cases diagnosed between 2005 and 2012 (P < .001, z test). Improvement in survival was also seen for systemic lymphoma, increasing from 55.2% (95% CI =  54.2% to 56.3%) to 76.0% (75.0% to 77.0%) for the same respective time periods (P < .001). Five-year survival tended to be worse for those presenting with bilateral PBL than unilateral PBL (71.3%, 95% CI =  49.7% to 84.69%, vs 87.9%, 95% CI =  83.9% to 91.0%, P = .10) (Supplementary Table 3, available online). Five-year survival also varied among stage I (91.6%, 95% CI =  86.9% to 94.6%; 91.3%, 95% CI =  86.6% to 94.4% for unilateral only) and stage II (75.8%, 95% CI =  66.7% to 82.7%; 75.7%, 95% CI =  66.4% to 82.7% for unilateral only) disease presentations.

Women with stage I–II PBL had overall survival superior to women with stage I–II systemic presentations of the same lymphoma subtype (Figure 4), except for ALCL-PBL where the same trend was seen, although not statistically significant at the 5% level. Very few women presented with limited-stage systemic ALCL. Stratifying by stage revealed that the differences observed were largely driven by the fact that PBL was more likely to be stage I disease and that stage I PBL survival was superior to stage I systemic lymphoma (Table 2).

Figure 4.

Kaplan-Meier survival curves by subtype. Cohort includes stage I–II lymphoma diagnosed in SEER 18 registries, 2000 to 2012. P values from two-sided log-rank test for equality of survivor functions. ALCL = anaplastic large-cell lymphoma; DLBCL = diffuse large B-cell lymphoma; MZL = marginal zone lymphoma.

Table 2.

Five-year relative survival by site and histologic subtype of lymphoma diagnosed in SEER 18 registries, 2000–2012

Histologic subtype and stage	Primary breast lymphoma				Systemic lymphoma				P*
	No. (RS, %)		95% CI		No. (RS, %)		95% CI
All histologies
Stage I	678 (91.3)		86.6 to 94.4		10 409 (85.3)		84.3 to 86.2		<.001
Stage II	185 (75.7)		66.4 to 82.7		12 992 (82.1)		81.2 to 82.9		.52
Stage I–II	863 (87.9)		83.9 to 91.0		23 401 (83.5)		82.9 to 84.1		<.001
Diffuse large B-cell lymphoma
Stage I	258 (82.7)		74.5 to 88.5		2925 (78.4)		76.3 to 80.3		.007
Stage II	95 (67.0)		53.7 to 77.3		3477 (68.8)		66.9 to 70.7		.46
Stage I–II	353 (78.5)		71.7 to 83.8		6402 (73.2)		71.8 to 74.6		<.001
Follicular lymphoma
Stage I	110 (100)		–		3108 (93.8)		91.9 to 95.2		.02
Stage II	22 (96.9)		3.9 to 100		2035 (86.1)		83.8 to 88.1		.13
Stage I–II	132 (100)		–		5143 (90.7)		89.4 to 92.0		.001
Marginal zone lymphoma
Stage I	186 (97.1)		88.0 to 99.3		408 (96.7)		89.2 to 99.0		.54
Stage II	25 (76.2)		40.6 to 92.1		287 (84.1)		76.6 to 89.4		.95
Stage I–II	211 (95.0)		82.5 to 98.6		695 (91.7)		87.1 to 94.7		.07
Anaplastic large-cell lymphoma†
Stage I–II	17 (74.4)		41.3 to 90.6		273 (71.9)		65.4 to 77.4		.76

^*P value from z test comparing survival between primary breast lymphoma and systemic lymphoma. CI = confidence interval; RS = five-year relative survival. Dash indicates the statistic could not be calculated.

^†Data for ALCL suppressed because of small sample size. Five-year relative survival for stage II ALCL-PBL was 100%.

Discussion

Our work is the largest contemporary series describing the presentation, incidence, initial local therapy, and outcomes for women with PBL. In our analyses of data spanning four decades, the overall incidence of PBL increased from 1975 to 2000 and has since stabilized, but continues to increase for women younger than age 50 years. From 2000 to 2013 in the SEER 18 registries, ALCL-PBL saw continued increases in incidence with a trend toward an increase in MZL-PBL, which became statistically significant with a smaller cohort (SEER 9 and 13) but larger time frame of 1995 to 2013. Additionally, initial local therapeutic approaches have changed markedly. The observation of improved five-year survival suggests current therapeutic approaches, likely incorporating newer systemic therapies, have improved survival.

The increase in incidence of ALCL-PBL, observed primarily in younger women, was likely driven by the T-cell implant-associated lymphomas. Implant-associated ALCL appears to remain very rare, with recent reports estimating the risk to be in the range of 1 in 500 000 (24,30), though there is inconsistency in pathologic evaluation of implants (16), which could lead to underestimation of risk. In this study, PBL incidence increased overall for the younger women with only a small portion of this increase due to ALCL-PBL cases. It is interesting to note that the use of cosmetic implants increased 294.8% from 1997 to 2007, fell 21.9% from 2007 to 2009, and remained fairly stable from 2009 to 2015 (31). Still, it remains challenging to tie trends in implant use with overall PBL trends given the variable latency between implant placement and ALCL-PBL, along with the rarity of breast lymphomas (24).

The increase in incidence of MZL-PBL observed from 1995 to 2013 is of unclear etiology. Unlike other extranodal sites of MZL, which are frequently associated with an inflammatory trigger (H. pylori in gastric or C. psittaci in ocular adnexal tissue), no inflammatory stimulus has been described for such disease arising in the breast. One report described a combined case of follicular and MZL-PBL in a patient with a ruptured silicone implant (22). One hypothesis might be that inflammatory agents, perhaps infectious, traumatic, or procedure-related, could be responsible for MZL-PBL or other breast lymphomas. In fact, one series found that 9% of women with DLBCL-PBL had prior benign breast disease, suggesting that a portion of these women had undergone prior invasive procedures to the breast, though latency was not reported (12). The increase in MZL-PBL paralleled the increase in systemic presentations of MZL. Improved recognition of MZL by pathologists could contribute to the increase seen in MZL-PBL; however, a similar trend was not seen for MZL-gastric, which decreased in incidence. It is possible that the advent of wide-spread breast imaging increased sensitivity for this entity, although most PBL is not diagnosed by mammography or other imaging modalities (14,15).

Unlike other series, which suggest a right-sided predisposition for PBL, breast laterality was balanced in our cohort. In previous reports, the right-sided excess became less apparent as the series became larger in size (2,5,10,12). Interestingly, invasive breast cancer has been shown, in several large epidemiologic studies, to have a slight left-sided excess (32,33), possibly attributable to the left breast often being slightly larger than the right (32). We also observed that 6% of women were diagnosed with bilateral PBL, consistent with other reports that showed involvement of both breasts in 1% to 13% of patients (2,5,10,12). By comparison, invasive breast carcinoma is thought to present less frequently with synchronous bilateral disease, 1.3% in a recent large report (34).

From 2000 to 2013, there was no change in the proportions of women presenting with different disease stages. This stands in contrast to invasive adenocarcinoma of the breast, which, because of the widespread adoption of mammographic screening, has seen downward stage migration (35). This finding further suggests that mammography use has not driven the rise in PBL diagnoses.

In our analyses, we included the 30 of 59 women with bilateral PBL who were recorded as having stage IV disease. The International Extranodal Lymphoma Study Group report also considered patients with bilateral breast lymphoma (stage IV_e) to have localized disease (36). These authors reported that 8% of recurrences occurred in the contralateral breast, supporting that some of these lymphomas have a tropism for the breast. Others have reported bilateral primary mucosa-associated lymphoid tissue lymphoma with 18F-FDG PET/CT findings showing active disease involving only the breasts (37), again supporting that exclusive bilateral breast involvement of PBL is a biologic phenomenon. We speculate that the other 29 women with bilateral PBL staged as I (n = 18) or II (n = 11) are more reflective of variable coding practices for multifocal extranodal disease than unique clinical presentations.

The shift in local therapy for PBL, away from surgery and surgery with radiation toward radiation only and neither surgery nor radiation (suggesting systemic therapy or observation) corresponds with the evolution of thought on effective treatment for systemic lymphoma. Multiple studies have established that local surgery alone for PBL leads to inferior overall survival and disease-specific survival (2,6,38), including studies associating more extensive surgery with worse survival (2,6).

Our observed survival trends across both age groups and specific PBL lymphoma subtypes suggest that newer systemic therapies, likely rituximab and possibly others, have realized improvements in control of this disease, although lead-time bias due to improved detection by modern imaging could also be a factor in the improved outcomes. Women who presented with bilateral PBL tended to do worse than their counterparts with stage I_e/II_e disease. If replicated, this finding would be important to the discussion on how to properly stage bilateral PBL. Notably, bilateral testicular lymphoma is considered stage II_e, leading some to argue that stage II_e is appropriate when using the stage-modified International Prognostic Index (IPI) (4,39).

Limitations of our study include those inherent to work with large observational data sets. Although SEER has strict categorization guidelines, some of the women may have been inappropriately grouped; however, the limited number of women excluded with stage III and nonbilateral stage IV disease would support that most of the women were classified correctly. Further, our work did capture the expected rise in ALCL-PBL, which has been attributed to breast implants. To more accurately report survival for PBL only, we excluded women who were diagnosed with PBL as a second or later malignancy; thus, women who received breast implants for reconstruction after breast carcinoma and then developed PBL were excluded from our analyses. As such, our data may underestimate the incidence of PBL. It is possible that some of the lymphoma subtypes were misclassified as SEER does not review pathology centrally and as ICD-O-3 coding rules evolve. Additionally, SEER does not record systemic therapy, so we cannot directly assess the impact of this increasingly important treatment modality. The frequency of central nervous system relapses, an important outcome in aggressive lymphomas, is also not currently available in this data set.

PBL remains a rare form of extranodal lymphoma. The data presented here verify the recent rise in ALCL T-cell lymphoma of the breast, which has been attributed to breast implant use for cosmetic and reconstructive purposes. Concurrently, PBL overall and the MZL subtype of PBL also appear to be presenting more frequently than in earlier eras. Treatments now favor radiation and systemic therapies, and in select cases observation over surgery. Survival trends support that women with this rare disease are often well managed with these newer therapeutic approaches. Future work should focus on confirming these trends and, importantly, on seeking to elucidate any modifiable etiologies.

Funding

This work was supported in part by the University of Iowa Holden Comprehensive Cancer Center Population Research Core, which is supported in part by the National Institutes of Health/National Cancer Institute grant P30 CA086862.

Notes

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors would like to thank Angela Mariotto and Nadia Howlader of the Division of Cancer Control and Population Sciences (DCCPS) for providing a very helpful review of the manuscript, along with Bobbi Jo Matt and Kathleen McKeen of the State Health Registry of Iowa, Iowa Cancer Registry, for clarifying standard of practice regarding identification of extranodal vs systemic lymphoma.