Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Current Understanding and Recommendations for Management

Abstract

Worldwide, millions of women live with breast implants. Therefore, it is important that physicians be aware of an uncommon but possibly serious complication arising from breast implants: breast implant–associated anaplastic large cell lymphoma (BIA-ALCL). Breast implant–associated anaplastic large-cell lymphoma most commonly presents as a delayed fluid collection around a textured breast implant or as a mass in the capsule surrounding the implant. The exact pathogenesis of the disease remains unclear. The neoplastic cells of BIA-ALCL show strong uniform staining for CD30 and are consistently negative for activin receptor-like kinase 1. Patients with confirmed cases should be referred to a lymphoma specialist or breast medical oncologist for a complete oncologic evaluation before any surgical intervention. For disease confined to the fluid accumulation or capsule, or both, surgical removal of the implant and complete capsulectomy is the preferred treatment. Postoperative chemotherapy or radiation, or both, are not considered necessary for patients with limited-stage disease and are reserved for advanced disease stages. Generally, BIA-ALCL is a local disease that follows an indolent course and has an excellent prognosis. Although complete remission of disease has occurred in patients with BIA-ALCL, median overall survival is reduced. As of March 2018, approximately 529 unique, confirmed BIA-ALCL cases had been reported in 23 countries. To date, 16 patients have died from BIA-ALCL, and all had extracapsular involvement. The aim of this article is to summarize the diagnosis, evaluation, and management of BIA-ALCL, based on established guidelines, for all practitioners who may care for patients with breast implants.

Introduction

Each year, over 450 000 women in the United States have breast implants, either for cosmetic or reconstructive purposes, and this number is likely to increase.¹ Worldwide, millions of women live with breast implants. Therefore, it is important that physicians be aware of the uncommon but possibly serious complications associated with breast implants. Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T-cell lymphoma that was first described in a 1997 case report.² After that report was published, knowledge and awareness of the disease accumulated slowly until 2011, when the US Food and Drug Administration (FDA) released a safety communication detailing what was known about this type of cancer and its association to breast implants.³ This communication prompted interest in the research community, and since 2011, much more has been learned about BIA-ALCL. Numerous reports and guidelines have been released from national and global sources, including the World Health Organization,⁴ National Cancer Institute,⁵ FDA,⁶ National Comprehensive Cancer Network (NCCN), and multiple international government agencies.⁷

Breast implant–associated anaplastic large-cell lymphoma most commonly presents as a delayed fluid collection around a textured implant or as a mass in the fibrous capsule surrounding the implant.^6,8-11 The pathogenesis of the disease remains unclear, but various hypotheses have emerged that link a chronic inflammatory response to the presence of a textured implant, inciting T-cell proliferation and malignant transformation that can lead to lymphoma in a genetically susceptible patient.^12-18 Although much more research is necessary to fully understand the pathogenesis of BIA-ALCL, data that have emerged regarding the histopathology,^19-27 epidemiology,^28-32 imaging assessments,^33,34 and treatment modalities^35,36 have been used to formulate consensus evaluation and management guidelines for the disease.⁸ The aim of this article is to summarize the diagnosis, evaluation, and management of BIA-ALCL, based on established guidelines, for all practitioners who may care for patients with breast implants.

Pathophysiology

The pathophysiology of BIA-ALCL is not fully understood, but current research supports the idea that the evolution of BIA-ALCL is likely a complex process with a multifactorial etiology. Multiple pathways to disease have been proposed, many focusing on the role of chronic inflammation in cancer occurrence and progression. All reported cases of BIA-ALCL have occurred in patients with textured implants,³⁷ which were introduced in the 1970s with polyurethane coating and in the late 1980s with silicone texturing in an attempt to decrease the incidence of capsular contracture.^38,39 The purpose of texturing was to provide a surface upon which native breast tissue could incorporate, thereby minimizing movement of the implant.³⁹ Although there are multiple suppliers of textured implants worldwide, only 3 companies have implants that have been approved for implantation by the FDA: Allergan, Mentor, and Sientra. The 3 manufacturers each use a different texturing process, and each company’s implants have been associated with cases of BIA-ALCL, but most have occurred with Allergan Biocell texturing.^30,39

Recently, researchers have focused their investigations on comparing various surface properties of textured implants versus smooth surfaces and on how the unique microenvironment of textured implants may encourage chronic inflammation and eventual malignant transformation of inflammatory T lymphocytes in a susceptible host. These studies have examined the presence of bacterial biofilm,^12,15,40 repeated micro trauma,^41-43 leakage of silicone particles,¹⁷ and a defective immune response⁴⁴ as initiators of inflammatory reactions that can encourage continual activation of T lymphocytes and eventual clonal transformation. This process is also common for other T-cell lymphomas. Gene expression profiling and next-generation sequencing may help elicit the cause of the disease and clarify how the placement of a textured implant can lead to lymphoma.⁴⁵

Disease Characteristics

Although BIA-ALCL presents in various ways, most patients have a sudden and spontaneous swelling of the breast due to fluid accumulation either around the implant or in the fibrous capsule accompanying the implant (Figure 1).^35,46 Benign fluid accumulation can occur in the immediate postoperative period following implant placement (ie, postoperative seroma) or it may develop secondary to breast trauma. Immediate postoperative seromas are a common complication after breast augmentation and can be caused by various factors including a nonspecific inflammatory reaction, infection, or hematoma.³³ However, if a patient has fluid accumulation in an implant-augmented or reconstructed breast more than 1 year after surgery, BIA-ALCL must be considered. A delayed seroma is not common after placement of a textured implant and is estimated to occur in less than 1% of patients.^47,48 Although BIA-ALCL is not the only possible cause of a delayed fluid accumulation in an implant-augmented or reconstructed breast, it has been found to occur in 9% to 15% of patients with such a finding.⁴⁹ Therefore, BIA-ALCL should be ruled out in any patient who has an implant-associated fluid accumulation occurring more than 1 year after surgery that cannot be explained by trauma or infection.⁵⁰

Figure 1.

A 48-year-old woman 12 years after a bilateral cosmetic augmentation. Periprosthetic fluid had rapidly accumulated in the left breast, and findings of fine-needle aspiration showed large anaplastic cells that expressed confluent CD30 consistent with breast implant-associated anaplastic large-cell lymphoma.

In the setting of BIA-ALCL, the breast may be enlarged, painful, erythematous, or tender, or it may only be swollen (Table 1). Less frequently, patients will have a palpable breast mass. In reported cases of BIA-ALCL, a mass (mean size, 3.5 cm) was present initially in 17% to 31% of cases.^51,52,55 Patients with a mass may also have an accompanying fluid accumulation, but cases have been reported in which a mass was the sole physical examination finding. Patients may also have findings other than a late-developing fluid accumulation or mass, but these findings are rare. These additional findings may include rash and skin lesions,^19,58 capsular contracture,^53,54,59 lymphadenopathy,^56,57 pain, and, even more rarely, symptoms of systemic illness (so-called B-symptoms: fever, night sweats, and weight loss).^60,62 A report have also been published of regional lymph node involvement and no associated breast mass.⁵⁶ Breast implant–associated anaplastic large cell lymphoma has not been confined to women; cases of 3 transgender patients who underwent implant augmentation and subsequently developed BIA-ALCL have been reported.⁶¹

Table 1.

Presenting Signs and Symptoms of BIA-ALCL.

Fluid accumulation 79.3%35,45

Mass 17% to 31%50-52

Lymphadenopathy 17%53,54

Less common symptoms: skin lesions, capsular contracture, “B-symptoms” (fever, night sweats, and weight loss), bilateral disease19,28,53-60,61

Abbreviation: BIA-ALCL, breast implant–associated anaplastic large cell lymphoma.

Breast implant–associated anaplastic large cell lymphoma has been reported in patients who received breast implants for both cosmetic and reconstructive reasons. To date, there does not seem to be a predisposition for BIA-ALCL to develop more commonly in either situation, with roughly half of the reported cases occurring in women who had implants placed for augmentation and half occurring in women after breast reconstruction for a malignant tumor.⁶³ Breast implant–associated anaplastic large cell lymphoma typically occurs 8 to 10 years after implant placement, although reported incidents have ranged from 1 to 32 years after implant placement.^19,55,63 The right and left breast seem to be equally affected, and there have been 8 confirmed cases of bilateral breast involvement.^28,59,64

Confirming the Diagnosis of BIA-ALCL

Imaging

If a patient experiences sudden, late-onset breast swelling (more than 1 year after placement of implants) or has other findings suspicious for BIA-ALCL as described above, ultrasonography should be the first step in evaluation (Figure 2). A periprosthetic fluid accumulation is often the only abnormality found on imaging of patients with BIA-ALCL.^65,66 Adrada et al³³ compared the sensitivity and specificity of various imaging modalities for patients with confirmed BIA-ALCL and found ultrasonography and magnetic resonance imaging to be most effective for detecting a fluid accumulation or mass and differentiating between the 2. The investigators determined that the sensitivity/specificity for detecting a fluid accumulation by ultrasonography and magnetic resonance imaging was 84%/75% and 82%/33%, respectively. Mammography cannot show if an abnormality is fluid filled or solid and thus is not appropriate for evaluating an enlarged breast for fluid accumulation. In addition to its use for detecting fluid accumulation, ultrasonography can also be used to guide fine-needle aspiration of a fluid sample collected for diagnosis. Concern for implant rupture with aspiration should not deter a physician because the implant will likely need to be replaced regardless of the cause of late seroma.

Figure 2.

The same patient from Figure 1 demonstrating preoperative positron emission tomography/computerized tomography scan showing disease confined to the capsule with no associated mass or lymph node metastasis. The patient underwent bilateral implant explantation and total capsulectomies. She did not require any further treatment and is disease-free after 2.5 years.

Diagnostic Specimen Collection

Once it has been established that a suspicious fluid accumulation or mass is present, a fluid or tissue specimen, or both, should be obtained for diagnosis. The amount of fluid present can range from a trace amount up to hundreds of milliliters and is typically viscous and straw colored.⁵⁵ A fine-needle aspiration can be performed to obtain a diagnostic fluid specimen, and ultrasound guidance can be used to avoid injury to the implant. This procedure can be safely performed in a clinic setting or by an interventional radiologist. Similarly, if a suspicious fluid accumulation is encountered during a surgical procedure as much of the fluid as possible should be collected and sent for pathologic evaluation. Freshly aspirated fluid should be submitted as soon as possible, preferably within 24 hours, for both cytologic and flow cytometric evaluations. Thorough evaluation of aspirated fluid by cytology and flow cytometry is essential for the diagnosis of BIA-ALCL, particularly because subsequent surgical specimens may lack detectable lymphoma.⁶⁷ Both cytology and flow cytometry have limitations in the detection of BIA-ALCL; therefore, it is prudent to allocate samples for both. Because BIA-ALCL is easily overlooked and often requires extra steps to identify correctly, the clinical suspicion for this disease should be indicated on the requisition, that is, “rule out BIA-ALCL.” Cytologic evaluation should include smears prepared from a sample concentrated by centrifugation and a cell-block, where a cell pellet is fixed and embedded in paraffin so that sections can be used for histologic and immunohistochemistry studies. Flow cytometry can be used to assist in the identification of neoplastic lymphoid cells, to distinguish them from inflammation, and to evaluate them for the immunophenotypic characteristic of BIA-ALCL.⁶⁸

Removal of the breast implant usually involves excising the surrounding fibrous capsule. The BIA-ALCL arises on the inner surface of the capsule adjacent to the implant and may form a mass lesion protruding from the capsule or may line the inner surface of the capsule without forming a mass. Sections should be taken from mass lesions, along with sampling, to determine the extent of invasion through the capsule and into adjacent tissues. If there is no detectable mass but there is clinical suspicion for BIA-ALCL, the entire capsule should be submitted to evaluate for subtle involvement by BIA-ALCL.^27,69 Any lymph nodes should also be submitted in their entirety for histologic sections in order to identify involvement by lymphoma.⁷⁰

Histopathology

Breast implant–associated anaplastic large cell lymphoma is composed of large pleomorphic cells with moderately abundant pale-staining cytoplasm and multi-lobated or horseshoe-shaped nuclei (Figure 3). Some neoplastic cells may resemble the “hallmark” cells described in systemic anaplastic large cell lymphoma (ALCL), which have kidney-shaped nuclei and paranuclear eosinophilia on hematoxylin–eosin-stained sections.⁷¹ Neoplastic cells can be present individually in aspirated fluid, as small nests within fibrinoid and necrotic material adherent to the inner surface of a capsule or as sheets within a mass lesion.^19,25,72 Often there is an associated inflammatory cell infiltrate, including small lymphocytes, histiocytes, and eosinophils. Sometimes the neoplastic infiltrate is subtle, being present as only a few clustered cells in one of many tissue sections and can be highlighted by CD30 immunohistochemical staining. Lymph node involvement can also be subtle, with neoplastic cells infiltrating in sinusoidal, interfollicular, and perifollicular patterns.⁷⁰ However, detecting lymph node involvement is important for staging, and lymph node involvement may be present even when the tumor is apparently confined to the implant-associated capsule.

Figure 3.

Histopathologic findings in breast implant-associated anaplastic large cell lymphoma. A, The cytologic preparation shows abnormal cells, including multinucleated cells, that are much larger than background lymphocytes (Wright stain). B, Histologic findings from a section of the capsular mass show an abnormal infiltrate of large cells and background eosinophils (hematoxylin–eosin stain). C, An immunohistochemical antibody stain for CD30 shows numerous strongly positive cells.

Distinction of BIA-ALCL from other neoplasms, such as carcinoma and melanoma, and classification as ALCL require immunophenotypic characterization either by immunohistochemistry or flow cytometry studies. The neoplastic cells of BIA-ALCL demonstrate a characteristic immunophenotype, which overlaps that of systemic and cutaneous ALCL. The cells show strong, uniform staining for CD30 and are usually CD43-positive, CD4-positive, positive for cytotoxic markers TIA-1 and granzyme-B, and epithelia membrane antigen–positive.^9,58,68 Transformed, reactive lymphoid cells can also express CD30,^73,74 but BIA-ALCL has more numerous, strongly CD30-positive cells, which have an abnormal appearance and lack expression of other expected lymphoid markers. Although BIA-ALCL is of T-cell lineage, the neoplastic cells are usually negative for CD7 and often lack other pan-T-cell antigens, such as CD2, CD3, and CD5.^23,71 The B-cell markers CD20 and CD79a and the plasma-cell marker CD138 are negative. Unlike a subset of systemic ALCL, BIA-ALCL is consistently Alk-1 negative.⁹ Breast implant–associated anaplastic large cell lymphoma often expresses CD15 and therefore may be confused with classic Hodgkin lymphoma,⁷⁵ particularly when identified in a lymph node. However, in contrast to classic Hodgkin lymphoma, BIA-ALCL has a CD45-positive, Pax-5-negative immunophenotype.⁶⁸

Flow cytometric immunophenotyping can also be used to detect and characterize the neoplastic cells of BIA-ALCL, but this test can be challenging for laboratories unfamiliar with BIA-ALCL. The cells are often larger than lymphoid cells found in reactive processes and other types of lymphoma and may not be included in the evaluation unless the laboratory is alerted to this possibility. In addition, the neoplastic cells often lack expression of many lymphoid markers, and CD30 expression is not usually part of a routine flow cytometric evaluation for lymphoma. However, flow cytometry is a valuable tool for identifying BIA-ALCL, for distinguishing reactive, inflammatory cells, and for identifying an immunophenotype characteristic of BIA-ALCL.⁷⁶

Clonal T-cell receptor gene rearrangement can be identified in most cases of BIA-ALCL, but it is usually not required for diagnosis. When needed, clonal T-cell receptor gene rearrangement can be evaluated in retrospect from archived paraffin-embedded material.

If a diagnosis of BIA-ALCL is confirmed, the case should be reported to the American Society of Plastic Surgeons BIA-ALCL PROFILE registry (Patient Registry and Outcomes For Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology: www.thepsf.org/PROFILE), in accord with specific reporting recommendations from the FDA. The goal of the registry is to acquire reliable patient data to promote and facilitate further research on elucidation of the disease, including (but not limited to) pathogenesis, risk factors, and patient demographic characteristics. If the fluid accumulation or tissue specimen does not contain findings indicative of BIA-ALCL, the patient can be referred to a plastic surgeon for management of the benign findings.

Care Management for Patients With BIA-ALCL

Staging

In 2016, the World Health Organization provisionally classified BIA-ALCL as a peripheral T-cell lymphoma.⁴ Traditionally, the Lugano revision of the Ann Arbor staging system has been used to describe extent of disease in lymphoma, including BIA-ALCL. However, the preferred tumor, lymph node, and metastasis (TNM) staging system has been validated and included in the NCCN guidelines for staging of BIA-ALCL. The Lugano revision to the Ann Arbor staging system includes stage IE for disease limited to the implant capsule and stage IIE for disease limited to the capsule and ipsilateral axillary lymph node(s).⁷⁷ Using this modified staging system, most patients with BIA-ALCL have low-stage disease, with 83% to 96% of patients classified as having stage IE disease.³⁵ Researchers at MD Anderson Cancer Center developed the alternative TNM staging system modeled after the American Joint Committee on Cancer TNM system. With this staging system, BIA-ALCL cases are classified in a broader range of stages including^35,63:

• IA—(35.6%): confined to the fluid or a layer on the luminal side of the capsule

• IB—(11.5%): early capsule infiltration

• IC—(13.8%): cell aggregates or sheets infiltrating the capsule

• IIA—(25.3%): lymphoma infiltrates beyond the capsule

• IIB—(4.6%): involves 1 regional lymph node

• III—(9.2%): multiple regional lymph nodes

• IV—(0% to 9%): spread to other organs/distant sites

It is anticipated that this system will better reflect the range of prognoses of patients with different extents of disease. As evidenced by the diversity in presenting stage, BIA-ALCL can also follow a heterogeneous course, ranging from an indolent nature more akin to a benign or low-grade lymphoproliferative disorder to fulminant disease with high mortality risk. Advanced disease is rare, and in most reported cases, the disease was confined to the breast capsule. However, as noted above, BIA-ALCL can involve adjacent lymph nodes and distant organs. In most cases in which advanced disease developed or death occurred, or both, there was substantial delay in diagnosis or treatment, the treatment was not sufficient, or a mass was present at the time of diagnosis.⁵² Experience described in the literature suggests that the finding of a mass at diagnosis predisposes patients to more advanced disease that typically follows a more aggressive course.^19,75 Some of the poor outcomes related to BIA-ALCL may be explained by the relative rarity and lack of awareness of the disease, which may have kept patients from being offered treatment in keeping with current guidelines.

Treatment

If a diagnosis of BIA-ALCL is confirmed, the patient should be referred to a lymphoma specialist or breast medical oncologist for a complete oncologic evaluation before any surgical intervention. As reflected in NCCN guidelines, a positron emission tomography (PET)/computed tomography (CT) scan can be useful to assess for systemic disease, including extent and location of disease and to develop a plan for surgical treatment. For disease that is confined to the fluid accumulation or capsule, or both, surgical removal of the implant and complete capsulectomy is the necessary and preferred treatment. If a mass is present, magnetic resonance imaging may also be helpful in surgical planning. The mass should be completely removed and surgical margins confirmed to be free of malignant disease. If suspicious lymph nodes are encountered at the time of surgery, an excisional biopsy should be performed. Once completely removed, the capsule should be submitted for pathologic examination to establish extent of lymphoma involvement. Postoperative chemotherapy or radiation, or both, are not considered necessary for limited-stage disease (Lugano IE, NCCN IA, and IIA) because cumulative experience to date suggests that complete remission can be attained via surgical excision in these cases, and chemotherapy does not appear to provide additional therapeutic benefit.¹⁹ Removal of the contralateral implant should be considered, as 4.6% of reported cases of BIA-ALCL have also involved the contralateral breast.⁶³ Currently, no guidelines exist for when, and if, implants should be replaced. Reconstruction in cases of BIA-ALCL has been performed with serial fat grafting, autologous free flaps, and smooth implant reconstruction in both an immediate and delayed reconstruction setting. This controversial topic is the subject requires further study. Reconstruction with a textured implant should be avoided until the pathogenesis of BIA-ALCL is more thoroughly understood to avoid potentially continuing an inflammatory cascade incited by the textured surface, which may have initially led to the development of BIA-ALCL.

Chemotherapy should be considered after the implant and capsule have been removed for patients with disease that has extended beyond the fluid and capsule (Lugano II-IV, NCCN IIB-IV). Most patients with advanced disease have received the conventional CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). This choice is based on standard first-line therapy in systemic ALCL. Brentuximab vedotin, an anti-CD30 antibody conjugated to the cytotoxic drug monomethyl auristatin E, has also been used alone or in combination for patients who have relapses or whose disease is refractory to CHOP as first-line therapy. Current NCCN guidelines support the use of the CHOP regimen or brentuximab vedotin as initial therapy in the treatment of BIA-ALCL when chemotherapy is warranted.

Ideal chemotherapeutic regimens are still under investigation for BIA-ALCL, and data on effectiveness have only been available from case reports and case series. Notably, complete remission has been achieved in patients with visceral disease with use of brentuximab vedotin.⁷⁸ Additionally, the drug has been successful in the neoadjuvant setting for reducing chest wall invasion.⁷⁹

Timely diagnosis, implant and capsule removal, and chemotherapy (when necessary) are essential in the management of BIA-ALCL. National Comprehensive Cancer Network guidelines recommend that local radiation therapy should be reserved for local residual disease that is not amenable to surgery. High-dose chemotherapy with autologous stem-cell rescue has been used for some patients with advanced disease, but long-term results are not currently available.⁷⁵

Follow-Up Care

After completing treatment, patients with BIA-ALCL should be monitored for disease recurrence and any long-term toxicities of therapy. The specifics of care can be determined by the treating team, but at minimum, the patient should be examined every 3 to 6 months for 2 years, as recommended by the NCCN. To monitor for disease recurrence, imaging is recommended every 6 months for 2 years after treatment. The preferred imaging includes either a CT scan with contrast of the chest, abdomen, and pelvis or a PET scan. Following effective initial treatment, 6% to 11% of patients will experience disease recurrence.^9,51,55 Therefore, proper follow-up care and disease surveillance are essential.

Prognosis

Generally, BIA-ALCL is a local disease with an indolent course and an excellent prognosis when the implant and capsule are completely removed surgically. For patients with disease confined to the capsule, remission can be achieved via surgical excision alone. Median overall survival has not been reached for this patient cohort. Alternatively, if a patient begins treatment with extracapsular involvement or has a breast mass, prognosis is negatively impacted. Although complete remission has occurred in these circumstances, median overall survival was reduced to 12 years for these patients.¹⁹ Miranda and colleagues¹⁹ compared the remission rates of BIA-ALCL, specifically data for patients with and without a breast mass. Patients who did not have a mass had a higher rate of disease remission (93%) than those whose disease involved a mass (73%). As of January 2018, approximately 529 unique, confirmed cases of BIA-ALCL had been reported in 23 countries. To date, 16 patients have died from BIA-ALCL, and each had extracapsular involvement.^31,60,80,81 Furthermore, among patients who had advanced disease, many had a substantial delay in either diagnosis or implant removal.

Conclusion

Although rare, BIA-ALCL can develop in patients with breast implants. Physicians who treat patients with implants and the patients themselves must be aware of the potential for BIA-ALCL development. Most patients who have breast augmentation return to their plastic surgeons for follow-up for only 1 year postoperatively. Therefore, all physicians who treat patients with breast implants must be cognizant of the warning signs of BIA-ALCL and the general steps for diagnosis and management.