DISCUSSION
PBL, first defined by Wiseman and Liao (1), requires the primary lesion to be within the breast with or without regional nodal involvement but no other extramammary sites of involvement and no antecedent diagnosis of lymphoma. PBL tumors are classified as either Stage I (breast-limited) or stage II (limited to breast and ipsilateral axillary ganglia (2)). Based on the SEER database, the overall incidence of PBL is 1.35/1,000,000 with a significant upward trend from 1975 to 2017 (3). PBS accounts for <0.5 % of breast neoplasms and 2.2% of extranodal lymphomas (4,5) Asynchronous bilateral PBL has only rarely been reported. In this case report, there was a hiatus of 27 years between diagnoses of PBL. To our knowledge, the longest interval between asynchronous PBL was previously 11.5 years (5).
The average age at presentation for PBL is in the fifth and sixth decade of life (6). Most are women, but male PBS has been reported (7). Most PBL presents with a painless, enlarging breast mass and is found more commonly in the right breast compared to the left (8). Most patients do not present with B symptomatology (9,10). Bilateral involvement at presentation occurs in approximately 11% of PBL cases and more commonly affects younger women during pregnancy or in the postpartum period (11). Mammogram and ultrasound are non-specific, usually showing a single ovoid, hyperdense mass with or without adenopathy (12).
B-cell PBLs are more common than T-cell subtype. Pathologically, 50% are DLBCL, followed by follicular lymphoma, and extranodal marginal zone lymphoma (2). Excisional biopsy and core biopsy are the preferred techniques for adequate tissue acquisition. Fine needle aspiration (FNA) is not recommended because although it may differentiate lymphoma from breast carcinoma, the FNA sample lacks architectural detail to accurately classify lymphoma subtypes (13).
The management of PBL has not been standardized; however, most authors recommend diagnostic biopsy followed by chemotherapy and radiotherapy (14). Since DLBCL is the most common histopathological subtype, R-CHOP remains the first-line treatment regimen (15). For patients who undergo initial surgery management, adjuvant chemotherapy and radiation should be recommended to prevent recurrence. Radical mastectomy is not thought to have improved outcomes compared to simple resection (16). Central nervous system (CNS) relapse is increased in PBL (17), occurring in 5-16% of cases (16-20), and usually occurs within two years following completion of therapy (17). Currently, the NCCN guideline V 5.2023 gives a category 2A recommendation for CNS prophylaxis in DLBCL for high-risk patients based on the CNS International Prognostic Index (CNS-IPI) or should be considered for patients with Stage 1E DLBCL of the breast (21), which is what our patient had. Still, the role of CNS prophylaxis remains controversial (13). According to Schmitz et al, the CNS-IPI has low positive predictive value between 10-12% (22). There is no consensus on route of CNS administration. Intravenous methotrexate versus intrathecal methotrexate does not seem to yield significant differences in outcome (23). CNS prophylaxis also has potential for toxicities such as renal impairment, delayed methotrexate clearance, post- lumbar puncture headaches, mucositis, and rarely hematologic toxicities, all of which could lead to delays in therapy (24). In our case, mutual decision was made not to undertake CNS prophylaxis.
There is limited evidence on prognostic factors in PBL. High stage disease (including nodal and/or bilateral breast involvement at presentation), larger tumor size, elevated LDH, poorer performance status, and CNS relapse is associated with worse outcomes (25). The 5-year overall survival rate for PBL with diffuse large B-cell subtype is between 50-60% (20).
Due to the rarity of PBL, a predictive genetic signature is difficult to determine. According to Zhang et al, the presence and frequency of certain high-mutant somatic genes including PIM1, MYD88, DTX1, CD79B, KMT2D, TNFAIP3, and ITKB, do however seem to correlate with age at presentation, pathologic subtype, and have tendency to shorten overall survival and progression free survival in PBL (26). In our case, these somatic genes were not assessed. This appeared to be a germinal center diffuse large B-cell subtype without any unfavorable features noted on IHC or FISH.