Key points

Introduction

In 2011, the United States Food and Drug Administration (FDA) published a safety communication stating, “Women with breast implants may have a very small but increased risk of developing anaplastic large cell lymphoma (ALCL) in the scar capsule adjacent to an implant.” This warning was based on case reports dating back to a sentinel case described by Keech and Creech in 1997. The past 18 years have been marked by a transition from a few case reports of a novel periprosthetic T-cell lymphoma to the current understanding and recognition of BI-ALCL. The association of breast implants with a rare cancer of the immune system has created understandable concern among patients, surgeons, and oncologists; therefore, continued investigation is needed to determine which factors play a role in the malignant degeneration of a breast implant capsule. Several evolving concepts have helped define diagnostic tools, therapeutic strategies, and outcomes of BI-ALCL and are the focus of this article.

Introduction

In 2011, the United States Food and Drug Administration (FDA) published a safety communication stating, “Women with breast implants may have a very small but increased risk of developing anaplastic large cell lymphoma (ALCL) in the scar capsule adjacent to an implant.” This warning was based on case reports dating back to a sentinel case described by Keech and Creech in 1997. The past 18 years have been marked by a transition from a few case reports of a novel periprosthetic T-cell lymphoma to the current understanding and recognition of BI-ALCL. The association of breast implants with a rare cancer of the immune system has created understandable concern among patients, surgeons, and oncologists; therefore, continued investigation is needed to determine which factors play a role in the malignant degeneration of a breast implant capsule. Several evolving concepts have helped define diagnostic tools, therapeutic strategies, and outcomes of BI-ALCL and are the focus of this article.

Lymphoma background

Lymphoma is a cancer of the immune system developing from lymphocytes and is the most common malignancy of the blood. Lymphoma broadly includes Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), multiple myeloma, and immunoproliferative diseases. In the United States, Approximately 65,000 cases of NHL were diagnosed in 2010. Stein and colleagues first described ALCL in 1985 as a novel type of NHL characterized by large anaplastic lymphoid cells that express the cell-surface protein CD30. Estimated incidence of T-cell NHL diagnoses in the United States in 2014 was 7000 to 10,000. ALCL represents approximately 2% to 3% of all NHLs and approximately 20% of all T-cell lymphomas.

ALCL was added as a distinct entity to the Kiel classification in 1988 and to the Revised European American Lymphoma Classification in 1994. The World Health Organization (WHO) classification of lymphomas recognized the disease in 2001 and further delineated variants in their updated 2008 classification. NHL prognosis is predicted using the International Prognostic Index (IPI) based on the presence of recognized risk factors, such as the Ann Arbor staging system, age, elevated serum lactate dehydrogenase, performance status, and number of extranodal sites of disease. Clinicopathologic subtypes of ALCL include a spectrum of disease from the more aggressive systemic ALCL down to lymphoproliferative disorders, such as the relatively indolent skin-limited primary cutaneous ALCL (5-year OS >90%–95%) and benign lymphomatoid papulosis. Multiple sites of disease, frequent lymphadenopathy, and metastatic spread characterize systemic ALCL. Systemic ALCL is classified by either the expression or absence of the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor gene translocation. A 2;5 translocation involving the 2p23 and the 5q35 chromosome creates an oncogenic fusion protein of the ALK gene and the nucleophosmin gene. ALK-positive ALCL accounts for approximately 50% to 80% of all ALCLs and occurs most commonly in men (male/female ratio: 6.5:1) under the age of 30 and has a 5-year OS by IPI point value of 0/1: 90%, 2: 68%, 3:33%, and 4/5: 23%. In contrast, ALK-negative ALCL is an immunophenotypically and cytogenetically heterogeneous group and has a 5-year OS by IPI points 0/1: 74%, 2: 62%, 3:31%, and 4/5: 13%. Standard first-line chemotherapy is cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP); and refractory disease is treated with ifosfamide, carboplatin, and etoposide (ICE) or etoposide, methylprednisone, cytarabine, and cisplatin (ESHAP). When treated with chemotherapy, ALK-positive ALCL has a higher 5-year overall survival (OS) rate than systemic ALK-negative ALCL (58% vs 34%, respectively). As a percentage of all T-cell lymphomas, ALK-positive ALCL is more common in North America than Europe or Asia (16.0% vs 6.4% vs 3.2%, respectively). Systemic ALK-negative ALCL is more common in Europe than North America or Asia (9.4% vs 7.8% vs 2.6%, respectively).

Breast implant–associated anaplastic large cell lymphoma: a novel variant

BI-ALCL is distinct from primary breast lymphoma (PBL); PBL, in contrast, is a disease of the breast parenchyma, representing 0.04% to 0.5% of breast cancers and 1% to 2% of all lymphomas. PBL is predominantly a B-cell lymphoma (65%–90%). BI-ALCL is a purely T-cell lymphoma arising either in the effusion or scar capsule surrounding a breast implant. All reported cases of BI-ALCL are ALK negative and express a CD30 cell-surface protein ( Figs. 1 and 2 ). Most cases are diagnosed during implant revision surgery performed for a late-onset (>1 year), persistent seroma and may be associated with symptoms of pain, breast lumps, swelling, or breast asymmetry. The numbers of BI-ALCL cases reported in primary augmentation and reconstruction for breast cancer or prophylaxis are approximately equivalent. BI-ALCL most commonly follows an indolent course with disease regression after adequate surgical ablation alone without systemic therapy, but aggressive exceptions have been reported. No risk factors have been clearly identified for ALCL although many have been theorized, including the presence of a subclinical biofilm, response to particulate from textured implants, a consequence of capsular contracture or repeated capsular trauma (such as with closed capsulotomies), genetic predisposition, or an autoimmune etiology, but these observations have not been confirmed in formal epidemiologic studies. Recent studies have demonstrated a possible pathogenic mechanism of chronic T-cell stimulation with local antigenic drive, ultimately leading to the development of lymphoma. Further research is required to identify modifiable risk factors, susceptible populations, and optimal screening and surveillance modalities.

Hematoxylin-eosin staining of BI-ALCL cells from a malignant effusion demonstrating polymorphic cell shapes with horseshoe-shaped nuclei and nuclear folding (×400 magnification). BI-ALCL cells demonstrate anaplastic large polymorphic cell features, characterized by enlarged horseshoe-shaped nuclei with prominent nucleoli and nuclear folding. Note hematoxylin-eosin staining of BI-ALCL cells at ×400 magnification ( A ). BI-ALCL is characterized by absence of the ALK gene mutation (ALK−) and CD30 staining on immunohistochemistry ( B ).

Scanning electron micrograph at ×300 magnification demonstrating aggregates of lymphoma cells clustered on the surface of a textured silicone implant.

Epidemiology

Since 1997, approximately 91 patients have been reported either in case reports of BI-ALCL or literature reviews ( Fig. 3 ). Reporting has benefitted from formal recognition and wider physician education, which has led to an exponential increase in published cases over the past few years. Reliable epidemiologic data for the incidence and prevalence of BI-ALCL has been difficult to determine for the estimated 10 to 11 million women worldwide with breast implants. The FDA database has received approximately 60 reported cases of ALCL in women with breast implants. de Jong and colleagues reported an individually matched case-control study from the Netherlands’ nationwide pathology database. The pathology database served a total population of approximately 9 million people. The investigators found a positive association for the development of ALCL in women with breast prostheses compared with those without an implant, with an odds ratio of 18.2 (95% CI, 2.1–156.8). Based on these data, the investigators estimated an incidence of 0.1 to 0.3 per 100,000 BI-ALCL cases for women with prostheses per year. Several prior studies failed to show an association between breast augmentation and risk of lymphoma; however, none was able to review such a large patient population or have sufficient follow-up period. These studies underscore the difficulty of determining the incidence and prevalence of a rare and recently recognized clinical entity.

Timeline of published cases of BI-ALCL.

Diagnosis and treatment

Diagnosis of BI-ALCL can be difficult because it remains rare at most medical centers. Two-thirds of BI-ALCL patients present as a malignant effusion associated with the fibrous capsule surrounding an implant occurring on average 9 years after implantation. Any seroma occurring greater than 1 year after implantation not readily explainable by infection or trauma should be considered suspicious for disease ( Fig. 4 ). One-third of patients present with a mass that may indicate a more aggressive clinical course. Beatriz and colleagues reviewed 44 BI-ALCL patients with imaging studies and reported on the sensitivity/specificity for detecting an effusion using ultrasound (84%/75%), CT (55%/83%), MRI (82%/33%), and PET (38%/83%). Additionally, the sensitivity/specificity to detect a BI-ALCL mass was reported for ultrasound (46%/100%), CT (50%/100%), MRI (82%/33%), and PET (64%/88%). The sensitivity of mammography was found inferior for BI-ALCL effusion and mass. Ultrasound is used at the authors’ institution as a screening tool for suspected cases and in combination with PET for confirmed cases to determine extension and for surveillance of disease.

Approach to a patient with a delayed seroma and suspected BI-ALCL. CBC, complete blood cell count.

( Modified from Bengtson B, Brody GS, Brown MH, et al. Managing late periprosthetic fluid collections [seroma] in patients with breast implants: a consensus panel recommendation and review of the literature. Plast Reconstr Surg 2011;128(1):1–7.)

For suspected patients, any aspiration of periprosthetic fluid should be sent to pathology for cytologic evaluation and include a clinical history with the stated intent to “rule out BI-ALCL.” Pathologic evaluation may demonstrate BI-ALCL as individual cells, cell clusters in aggregates, or coherent sheets. Diagnosis by hematoxylin-eosin staining alone can be difficult; however, BI-ALCL demonstrates strong and uniform membranous expression of CD30 immunohistochemistry. Other T-cell antigens are expressed variably, with the most common CD4 (80%–84%), CD43 (80%–88%), CD3 (30%–46%), CD45 (36%), and CD2 (30%). Expression of CD5, CD7, CD8, or CD15 is rare. Ultrasound may help define the extent of a seroma and can be helpful in identifying any associated capsule masses. Clinical examination should include evaluation of regional lymph nodes. Volumes of an effusion can range from 20 to 1000 mL and are typically viscous. The surrounding capsule may be thickened and fibrous or may be completely normal in appearance. If a mass is present, it can protrude into the implant, creating a mass effect distortion on imaging, or the mass may protrude outward into the soft tissue.

Patients with biopsy-proved BI-ALCL must be referred to a lymphoma oncologist. Surgical treatment of BI-ALCL requires complete tumor ablation, which includes removal of the implant, complete removal of any disease mass with negative margins, and total capsulectomy ( Fig. 5 ). Because an implant capsule may drain to multiple regional lymph node basins, there does not seem to be a role for sentinel lymph node biopsy in the treatment of BI-ALCL. Fine-needle aspiration of enlarged lymph nodes can yield a false-negative result and, therefore, excisional biopsies should be performed of any suspicious lymph nodes. A surgical oncologist is strongly recommended because incomplete resection and inadequate local surgical control may subject the patient to the need for adjunctive treatments, such as chemotherapy and radiation therapy, whereas complete resection may be definitive treatment in a majority of cases. Surgery should be performed with strict oncologic technique, including use of specimen orientation sutures, placement of surgical clips within the tumor bed, and use of new instruments if performing a contralateral explantation. At this time, the FDA does not recommend screening or prophylactic implant removal for asymptomatic patients or family members. Although not recommended, several BI-ALCL patients have received implant replacement with a smooth implant after definitive treatment, and these patients are closely monitored for any disease sequelae.

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