Breast implant-associated diffuse large cell B-cell lymphoma (BIA-DLBCL) – a case report and a treatment algorithm

Abstract

Implant-associated lymphomas of the breast are rare. Among breast-implant-associated lymphomas, anaplastic large cell lymphoma (BIA-ALCL) has gained significant attention in recent years and is recognized as a distinct entity. While ALCL is a well-known T-cell lymphoma, there are only a few reports concerning breast-implant-associated B-cell lymphomas. In our report, the lymphoma showed large blasts which were positive for CD20, highly proliferative and associated with Epstein-Barr-Virus. There was no tumor mass present, the cells were seroma associated. BIA-DLCBL has only been known for a few years. They are limited to lymphoma by definition and, unlike DLCBL, BIA-DLCBL is always EBV-positive. A comprehensive evaluation of immunohistochemical markers is crucial for establishing a differential diagnosis between BIA-ALCL and BIA-DLBCL, as overlapping features, particularly CD30 positivity, may lead to misdiagnosis. Other than ALCL, DLCBL typically do not show ALK, CD2, CD3, and other B-cell markers but are positive to CD20, CD5, BCL-2, CD21, CD23, IgD and IgM. This underscores the importance of referring patients to specialized centers to ensure accurate diagnosis and appropriate treatment. The subsequent therapy of BIA-DLCBL should include an en-bloc-resection of the capsule-implant-unit. There is currently no consensus on the optimal therapy for these cases, highlighting the need for further research and expert collaboration

We report on a case of breast-implant-associated diffuse large cell B-cell lymphoma and a diagnostic algorithm based on the available data in the literature.

Introduction

Breast implant-associated (BIA) lymphomas are rare. Among them, BIA-anaplastic large cell lymphoma (BIA-ALCL) is the best characterized T-cell lymphoma and is now recognized as a distinct entity.^1,2 BIA-diffuse large B-cell lymphoma (BIA-DLBCL) is considerably rarer; a review of the literature identified 25 published cases, 22 of which were Epstein-Barr virus (EBV)-positive.3, 4, 5 Ten patients had a history of breast cancer and two had HIV infections. Implants were predominantly textured, with a latency from implantation to lymphoma diagnosis of 7–36 years (mean 9 years). Patients typically presented with breast swelling, seroma, pain, or capsular contracture. CD30-positive BIA-DLBCL can be misdiagnosed as BIA-ALCL, highlighting the importance of thorough immunohistochemical workup.⁵ We present a case of BIA-DLBCL with its diagnostic and therapeutic management.

Case report

A 74-year-old woman presented with severe left breast pain. Her medical history included vascular dementia, diabetes mellitus, arterial hypertension, gait ataxia, and polyneuropathy. No prior EBV infection was documented. She had undergone aesthetic breast augmentation approximately 50 years earlier and implant replacement about 20 years ago; no original records were available. Breast pain began following a car accident in 2022, prompting an ultrasound that revealed left implant rupture. Clinical examination showed bilateral grade 3 ptosis (Regnault) without skin changes, though palpation elicited marked left-sided tenderness.

A replacement-free en-bloc implant removal was performed via the inframammary approach. Intraoperatively, 300 ml of turbid seroma was found on the left side and submitted for histopathology; complete capsule-implant unit resection was carried out. The explanted implants were round, macrotextured McGhan/Allergan 360 mL and structurally intact.

Histology revealed a fibrous capsule with a fibrin-filled implant cavity. Within the fibrin, large blasts were identified that were CD20-positive, highly proliferative, and EBV-positive, establishing the diagnosis of EBV-positive BIA-DLBCL. Postoperative EBV DNA (EBNA1 gene) was 1833 IU/ml. Wound healing was uneventful. CT staging three months postoperatively showed no residual or disseminated disease. The multidisciplinary tumor board recommended follow-up imaging, which the patient and her legal representative declined due to advanced dementia.

Discussion

BIA-DLBCL is a rare but increasingly recognized entity. Unlike DLBCL at other sites, BIA-DLBCL appears to be consistently EBV-positive and is defined by its confinement to the peri‑implant space, often without a discrete tumor mass.^3,4 In our patient, malignant B-cells were found exclusively within the seroma fluid. A broad panel of immunohistochemical markers is described for DLBCL (Table 1).² BIA-DLBCL is characteristically positive for CD20, CD5, BCL-2, CD21, CD23, IgD and IgM negative for T-cell markers such as ALK, CD2, and CD3.^4,5 EBV-positive diffuse large B-cell lymphomas also exhibit positivity for various markers like CD20, CD30, CD79a, MUM1, and PAX-5. CD30 co-expression shared with BIA-ALCL represents the main diagnostic pitfall; careful immunophenotyping is therefore essential to avoid misclassification, and referral to a specialized center is strongly recommended.⁵

Table 1.

Expression profiles of various biomarkers in reported Breast implant associated diffuse large cell B-cell lymphoma cases. This table presents the clinical and molecular characteristics of 25 patients with breast implant-associated diffuse large B-cell lymphoma, including age, site of occurrence, history of prior malignancies, and detailed expression profiles of various cellular and molecular markers. The markers analysed include those associated with B-cell lineage (CD19, CD20, CD79a), T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8), and proliferation markers (Ki-67, Mindbomb E3 Ubiquitin Protein Ligase 1 [MIB-1]).

QUELLE	AGE IN YEARS	TIME TO LYMPHOMA IN YEARS	SIDE	FLUID/ SEROMA	TYP OF IMPLANTS	CARCINOMA IN HISTORY	ALK	KI67 INDEX	EBV	EBER	EBV LMP1	EBV EBNA2 OR EBV EBNA 1	POSITIV FOR	NEGATIV FOR
Q4	46	8	R	+	Allergan Textured	-	-	>90%	+	+	+	+	CD30, CD20, MUM1,PDL1, EMA, BCL6, PAX5, MYC, p53(30%)	ALK, CD10, CD3, CD2, HHV8
Q6	42	7	L	-	Texured		-	50%	+	+			CD79a, CD30, CD20, CD19, MUM1, BLC2, PAX5	CD13, CD10,CD8,CD5,CD4,CD2,MY, BLC6, Cyclin D1, TDT
Q8.1	69	13	R	+	BIOCELL® textured (macrotextured) breast implants
(Allergan style 410MX, 290 g	2011, 8Y Before Lymphoma, Hormon positiv HER2neu neg. /	-	80%		+			CD79, CD45, CD43, CD30, CD20, MUM1, PAX5, MYC	CD138, CD10, CD8, CD4, CD3, CD2, HHV8, Cyclin D1, TDT, AE1/AE3, Granym B, Perforin
Q8.2	53	9	R	+	BIOCELL® textured (macrotextured)
(cohesive silicone gel implant type) (Allergan Style, 410MM,
320 g		-			+			CD43, CD23, C30, CD20, CD19;MUM1 BLC2, PAX5, MYC	CS138, CD10, CD5, CD3, CD2, HHV8
Q9.1	75	27	R	+	bilateral textured Implants	Mamma carcinoma NST	-	70–80%		+	+	+	CD79a, CD30, CD20, MUM1, PDL1, BCL6 PAX5, COPD	ALK, CD10, CD3, CD2, HHV8
Q9.2	45	9	L	+	textured			100%		+	+	+	CD30, CD20, CD19, CD3, MUM1, PDL1, PAX5, HIV	CD10, CD8, CD4, HHV8
Q11.1	62	25	R	+									CD43, CD30	CD10, CD5
Q11.2	69	13	L	+	textured saline implant	left estrogen receptor-positive breast cancer and marginal cell lymphoma in the right axillar node	-						CD45RB, CD30, CD20	CD43, CD10, CD5, CD3
Q11.3	61	21	R	+	saline textured implants			95–100%		-			CD20, CD10, MUM1, MYC, BLC2	CD3
Q12.1	55	15		+	N A					+	+	+	CD79a, CD30,CD20, MUM1, PAX5	CD3, MYC, HHV8, Granzym B, Perforin, p53
Q12.2	59	10		+	N A	Mamma carcinoma				+	+		CD79a, CD30, CD20, MUM1, PAX5, Perforin	CD3, MYC, HHV8, Granzym B, p53
Q12.3	63	20		+	N A	Mamma carcinoma				+	+	+	CD79a, CD30, CD20, CD3, MUM1, Granzym B, Perforin	MYC, PAX5, HHV8, p53
Q13.1	72	8	L		silicone macrotextured
implant (Allergan)	left breast adeneocarcinoma		100%		+	+	+	CD138, CD79a, CD45, CD43, CD30, CD20, CD19,MUM1, PAX5, IRF4, MYC	MYC, BCL6, BLC2, HHV8
Q13.2	61	13	R	+	ilicone
macrotextured
implants (Allergan)	right breast adenocarcinoma		100%		+	-	-	CD79a, CD45, CD30, CD10, CD4, MUM1, BCL6	CD138, HHV8
Q13.3	69	9	R	+	silicone
macrotextured
implant (Allergan)	no		80%		+	+	+	CD79a, CD45, CD30, CD20, CD19, MUM1, BCL2	CD138, HHV8
Q14	70	9	R	+	Allergan macrotextured silicone implant	Mamma carcinoma	-		+	+			CD79a, CD45, CD20, MUM1, PDL1, BCL6, PAX5	CD10, CD8, CD5, CD4, CD3, CD2, HHV8
Q15	51	15	L	+	smooth, round saline-filled implants, second: textured firm cohesive silicone gel implants (Allergan style 510 extra-full projection, full height, volume 560 mL)		-			+			CD79a, CD45, CD30, MUM1, HIV	CD138, CD10, CD5,CD3, CD2
Q16	66	12	R		McGhan, anatomical, textured silicone implants	prophylactic mastectomie	-			+			CD45, CD43, CD30	CD7, CD5, CD3, CD2
Q17	65 (47–71)			-	7/7 textured, 4 silicone 1 saline, Allergan 6, 1 Silimed	4 cosmetic, 2 Mamma carcinoma	0/7	80%		7 7	7 7	7 7	CD79a(7/7), CD45(7/7), CD43(1/2), CD30(6/7), MUM1(7/7), MYC(5/6) BLC6(1/5), PAX5(6/6)	ALK(0/7), CD138(0/5), CD10(0/7), CD8(0/2), CD5(0/5), CD4(0/2), CD3(0/5), HHV8(0/7)
OUR CASE HELIOS EVB	74	20	L	+	textured, McGhan, Allergan, 360cc	cosmetic			+			+	CD20

The presence of viral markers is also shown, with a particular emphasis on Epstein-Barr Virus (EBV) status. This includes the analysis of Epstein-Barr Virus-Encoded RNA (EBER), Epstein-Barr Virus Latent Membrane Protein 1 (LMP1), Epstein-Barr Virus Nuclear Antigen 1&2 (EBNA1&2), and Human Herpesvirus 8 (HHV8). Additionally, oncogenes and tumour suppressors (Myc Proto-Oncogene [MYC], Tumor Protein p53 [p53]), as well as immune checkpoint molecules such as Programmed Death-Ligand 1 (PDL1), are included. Additionally, there are other markers that have been examined including Anaplastic Lymphoma Kinase (ALK), Syndecan-1 (CD138), Leukocyte Common Antigen (CD45), Leukosialin (CD43), Low-Affinity Immunoglobulin E Fc Receptor (CD23), and Ki-1 Antigen (CD30). Further markers include Neprilysin (CD10), Aminopeptidase N (CD13), Epithelial Membrane Antigen (EMA), T-cell Receptor Gamma (TRG), B-cell Lymphoma 6 Protein (BCL6), B-Cell Lymphoma 2 Protein (BCL2), and Paired Box Protein 5 (PAX5), Interferon Regulatory Factor 4 (IRF4), Cyclin D1 Protein (Cyclin D1), Terminal Deoxynucleotidyl Transferase (TDT), Pan-Cytokeratin Markers (AE1/AE3), Granzyme B Protein, and Perforin Protein.

The table aims to demonstrate the utility of these markers in breast implant-associated diffuse large B-cell lymphoma, thereby improving our understanding of the disease's biomarker characteristics.

Abbreviations: ALK: Anaplastic Lymphoma Kinase, CD138: Syndecan-1, CD79a. B-Cell Antigen Receptor Complex-Associated Protein Alpha Chain, CD45: Leukocyte Common Antigen, CD43: Leukosialin, CD23: Low-Affinity Immunoglobulin E Fc Receptor, CD30: Ki-1 Antigen, CD20: B-lymphocyte Antigen CD20, CD19: B-lymphocyte Antigen CD19, CD13: Aminopeptidase N, CD10: Neprilysin, CD8: T-cell Surface Glycoprotein CD8, CD7: T-cell Antigen CD7, CD5: T-cell Surface Glycoprotein CD5, CD4: T-cell Surface Glycoprotein CD4, CD3: T-cell Surface Glycoprotein CD3, CD2: T-cell Surface Glycoprotein CD2, MUM1: Multiple Myeloma Oncogene 1, KI67: Cellular Proliferation Marker, EBV: Epstein-Barr Virus, EBER: Epstein-Barr Virus-Encoded RNA, LMP1: Latent Membrane Protein 1, EBNA2: Epstein-Barr Virus Nuclear Antigen 2, MYC: Myc Proto-Oncogene, IMMUN DISEASE: Immune Disease (General term), PDL1: Programmed Death-Ligand 1, p53: Tumor Protein p53, EMA: Epithelial Membrane Antigen, TRG: T-cell Receptor Gamma, BCL6: B-cell Lymphoma 6 Protein, BCL2: B-cell Lymphoma 2 Protein, PAX5: Paired Box Protein 5, IRF4: Interferon Regulatory Factor 4, HHV8: Human Herpesvirus 8, Cyclin D1: Cyclin D1 Protein, TDT: Terminal Deoxynucleotidyl Transferase, AE1/AE3: Cytokeratin Markers, MIB-1: Mindbomb E3 Ubiquitin Protein Ligase 1 (marker for Ki-67).

A diagnostic algorithm based on current literature is presented in Fig. 1. Following clinical diagnosis of late seroma after implant-based breast surgery, ultrasound-guided biopsy (if a tumor mass is present) and PET-CT/MRI should be performed, alongside bacteriological analysis and testing for CD30 and ALK. Absence of ALK with CD30 positivity warrants further B-cell marker differentiation to confirm BIA-DLBCL.

Fig. 1.

Diagnostic algorithm.

Abbreviations, AE1/AE3: Cytokeratin Markers, ALCAL: anaplastic large cell lymphoma, ALK: Anaplastic Lymphoma Kinase, BCL2: B-cell Lymphoma 2 Protein, BCL6: B-cell Lymphoma 6 Protein, BEACOPP: B- Bleomycine, E-Etoposide, A-Adriamycin, C—Cyclophosphamide, O—Oncovin = Vincristine, P- Procarbazine, P-Prednisone, BIA: breast-implant-associated, CD10: Neprilysin, CD13: Aminopeptidase N, CD138: Syndecan-1, CD19: B-lymphocyte Antigen CD19, CD2: T-cell Surface Glycoprotein CD2, CD20: B-lymphocyte Antigen CD20, CD23: Low-Affinity Immunoglobulin E Fc Receptor, CD3: T-cell Surface Glycoprotein CD3, CD30: Ki-1 Antigen, CD4: T-cell Surface Glycoprotein CD4, CD43: Leukosialin, CD45: Leukocyte Common Antigen, CD5: T-cell Surface Glycoprotein CD5, CD7: T-cell Antigen CD7, CD79a. B-Cell Antigen Receptor Complex-Associated Protein Alpha Chain, CD8: T-cell Surface Glycoprotein CD8, Cyclin D1: Cyclin D1 Protein, DLBCL : diffuse large cell B-cell lymphoma, EBER: Epstein-Barr Virus-Encoded RNA, EBNA2: Epstein-Barr Virus Nuclear Antigen 2, EBV: Epstein-Barr Virus, EMA: Epithelial Membrane Antigen, HHV8: Human Herpesvirus 8, IMMUN DISEASE: Immune Disease (General term), IRF4: Interferon Regulatory Factor 4, KI67: Cellular Proliferation Marker, LMP1: Latent Membrane Protein 1, MIB-1: Mindbomb E3 Ubiquitin Protein Ligase 1 (marker for Ki-67), MUM1: Multiple Myeloma Oncogene 1, MYC: Myc Proto-Oncogene, p53: Tumor Protein p53, PAX5: Paired Box Protein 5, PDL1: Programmed Death-Ligand 1, R-CHOP: R – Rituximab, C – Cyclophosphamide, H – Doxorubicin, O – Vincristine (which used to be called Oncovin), P – prednisolone, TDT: Terminal Deoxynucleotidyl Transferase, TRG: T-cell Receptor Gamma.

As there is no clear treatment recommendation to date due to the rarity of the disease, treatment and follow up is recommended analogous as for BIA-ALCL. By analogy, complete en-bloc resection of the capsule-implant unit is the cornerstone of therapy. For systemic disease or relapse, options include R-CHOP chemotherapy, intrathecal methotrexate, radiation, and autologous stem cell transplantation.³ Follow-up CT at 3 and 6 months postoperatively is reasonable; however, no consensus interval currently exists. All therapeutic decisions must be individualized within a multidisciplinary team.

Conclusion

BIA-DLBCL is a rare entity that must be carefully distinguished from BIA-ALCL through immunohistochemical analysis. Complete en-bloc resection appears curative in localized disease. Given the paucity of data, every new published case can advance understanding of pathogenesis, optimal treatment, and long-term outcomes.

Consent, conflict of interest, funding and ethical approval

Written informed consent was obtained from the patient for publication of this case report. The authors declare that they have no conflicts of interest related to this work. No funding was received. Ethical approval was not required for this case report in accordance with institutional and national guidelines, and the study was conducted in accordance with the principles of the Declaration of Helsinki. Financial Disclosure Statement: None of the authors has a conflict of interest in any of the products, devices, or drugs mentioned in this manuscript.