16 Breast Implant–Associated Anaplastic Large Cell Lymphoma
Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a rare peripheral T cell lymphoma that can develop after placement of a textured breast implant for either cosmetic or reconstructive purposes. BIA-ALCL most commonly follows an indolent course, with excellent prognosis when treated surgically in early-stage disease. On the other hand, disseminated cancer and deaths from BIA-ALCL have been reported, highlighting the importance of appropriate surveillance, early diagnosis, and prevention of progression to advanced disease through adequate treatment. Most commonly, BIA-ALCL presents approximately one decade after implant placement with capsule-confined disease, seroma, or less frequently as a mass adjacent to the implant. Standardized treatment regimens include surgical intervention with implant removal and total capsulectomy, which is the cornerstone of disease management. This chapter will review the clinical features, diagnosis, treatment, and prognosis of BIA-ALCL.
Approximately 313,735 breast implants were placed in 2018 in the United States for cosmetic or reconstructive purposes, with more than 10 million women having breast implants worldwide. 1 The first case of breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) was reported in 1997. 2 Starting in 2011, the U.S. Food and Drug Administration (FDA) has published safety communications cautioning women with breast implants about the risk of BIA-ALCL. 3 Although BIA-ALCL commonly follows an indolent course and has an excellent prognosis when treated surgically, disseminated cancer and deaths from BIA-ALCL have been reported. 4 BIA-ALCL most commonly presents with localized disease, as a seroma (80%) or mass (40%) adjacent to an implant. Early diagnosis followed by appropriate surgical treatment prevents progression to advanced disease. 5 The purpose of this chapter is to review the clinical features, diagnosis, treatment, and prognosis of BIA-ALCL.
Lymphoma is a cancer of the immune system. Lymphoma develops from B or T lymphocytes, natural killer cells, or plasma cells and includes Hodgkin’s lymphoma (10%), non-Hodgkin’s lymphoma (NHL), multiple myeloma, and immunoproliferative diseases. 6 , 7 It is the most common malignancy of the blood, affecting up to one in 50 in the general population. 8 ALCL is a type of NHL characterized by large anaplastic lymphoid cells that express the cell surface protein CD30, 9 which is a marker for activated T cells, occurring normally on approximately 1–5% of circulating lymphocytes.
Peripheral T cell lymphomas comprise less than 15% of all adult lymphomas. Anaplastic large cell lymphoma (ALCL), a subset of peripheral T cell lymphoma, comprise less than 2% of all lymphomas. The 2016 revisions of the World Health Organization (WHO) classification of lymphoid neoplasms recognize three distinct lymphoma forms of ALCL: anaplastic lymphoma kinase (ALK)-positive systemic ALCL, ALK-negative systemic ALCL, and breast implant–associated ALCL (BIA-ALCL). Primary cutaneous ALCL (PC-ALCL) is recognized as a lymphoproliferative disorder. ALK expression is a result of the t(2;5) translocation involving chromosomes 2p23 and 5q35, creating an oncogenic fusion protein of the ALK gene and nucleophosmin gene. 10 BIA-ALCL does not express the ALK translocation and therefore is ALK-negative in all reported cases.
ALCL subtypes display variable degrees of clinical aggressiveness. Systemic ALCL typically follows a very aggressive course, rapidly evolving when left untreated. Most patients with systemic ALCL present with disseminated stage III or IV disease, commonly with systemic symptoms (B symptoms) and extranodal disease (40–60%). ALK positivity indicates a better prognosis. 11 BIA-ALCL does not express ALK. 12
PC-ALCL tends to be clinically indolent and has excellent prognosis, with disease specific survival rates of 85% at 5–10 years. 13 Systemic spread is uncommon (approximately 5%); however, when present, the prognosis of PC-ALCL appears to be unchanged and favorable. 13 , 14 , 15 BIA-ALCL is classified as a lymphoma by the WHO despite less aggressive behavior. In early-stage disease confined to an effusion, BIA-ALCL is most similar to a lymphoproliferative disorder and likely becomes infiltrative in later stages with increasing mutational burden.
No clear etiology of chronic immune stimulation has been identified in BIA-ALCL. Proposed theories describing the pathogenesis of BIA-ALCL include chronic inflammatory response to particulate matter, presence of subclinical biofilm, induction after mechanical abrasion, and genetic predisposition. Deva, Prince, and colleagues propose a “unifying theory” that four primary factors provide impetus for inflammation, contributing to the malignant degeneration of ALCL: gram-negative bacterial biofilm, high surface area texturing, sufficient time of exposure, and host susceptibility by genetic predisposition.
16.3.1 Bacterial Biofilms and Inflammatory Response
Scientific observations support the biofilm hypothesis that textured implants harbor significantly higher levels of gram-negative bacteria, which correlate with lymphocyte activation. 16 Bizjak et al proposed that in BIA-ALCL, chronic activation of local and systemic immune systems may cause neoplastic transformation. Polyclonal activation of T cells may result in monoclonal T cell expansion in a genetically at-risk host, ultimately leading to lymphoma. 17 In the context of chronic inflammation, host genetic factors influence the likelihood of malignant transformation. 18
Deva and colleagues have shown that bacteria are significantly more likely to attach to textured implants. Textured implants develop a higher load of bacterial biofilm, and once a threshold biofilm is reached on both smooth and textured implants, propensity toward capsular contracture is potentiated. 19 Bacterial biofilm of patients with BIA-ALCL shows a microbiome with a predominance of gram-negative rods and the bacteria Ralstonia pickettii, in contrast to the microbiome in nontumor capsules, which is Staphylococcus spp. predominant. 20 , 21
A link between bacterial biofilm and T cell hyperplasia has been demonstrated in both pigs and humans. Chronic biofilm infection of mammary prosthesis is associated with a T cell–predominant lymphocytic infiltration and bacterial load around an implant. In pigs, increased numbers of T cell–predominant lymphocytes were seen in textured implant capsules compared with smooth implant capsules. 22 Bacteria can be related to capsular contracture. Preliminary studies suggest that BIA-ALCL cells may be derived from Th1/Th17 cells in capsular tissues and seromas. Th1/Th17 are antigen-driven memory T cells, supporting the hypothesis that BIA-ALCL results from chronic bacterial antigen stimulation. BIA-ALCL displays a diffuse CD30 expression on the cell surface. 23 Investigations regarding whether select biomarkers (JunB, SATB1) will identify nonmalignant precursors of BIA-ALCL are pending. 24
Reported cases of BIA-ALCL almost exclusively involve textured implants. 25 As of September 30, 2018, the FDA had received 457 unique medical device reports of BIA-ALCL, with surface characteristics available for 334; of those, 310 (92.8%) were textured implants. Twenty-eight cases of BIA-ALCL following smooth implant reported to the FDA had either minimal or no clinical history and were therefore unreliable. 26 , 27 Out of 173 consecutive BIA-ALCL patients, all patients with known implant characteristics had a history of textured implants. 21
Lista and colleagues reviewed adverse sequelae associated with textured implants including malrotation, capsular contracture, and late seroma and identified no cases of BIA-ALCL in 440 patients reviewed over 9 years, 28 but this sample size was inadequate to evaluate BIA-ALCL appropriately. The proposed incidence of BIA-ALCL ranges from 1 in 1,000 to 1 in 30,000 women with breast implants (see Epidemiology section), necessitating a larger sample population. While not intended to be an epidemiologic study, the prospective CA/CARE Trial reported by McGuire et al represents the largest prospective series ever reported on textured implants. This study revealed six cases of BIA-ALCL in 17,656 women, equating to an incidence of 1 in 2,943 women with textured Biocell breast implants (95% confidence interval: 1,350–8,000). 29
Tribology is the observed effect of friction between two objects. Orthopedic implants have been hypothesized to increase carcinogenicity via tribology. 30 Brody suggests that the etiology of BIA-ALCL is likely multifactorial and that the textured surface may act as the inciting stimulus for BIA-ALCL mutation. 12 No investigation with relation to implants in BIA-ALCL has yet been reported.
16.3.3 Genetic Predisposition
Genetic predisposition may help explain the rarity of this condition. Blombery et al identified acquired activating mutations in JAK1 and STAT3 in two cases of BIA-ALCL, with a germline JAK3 variant as a possible contributor to disease development. The aberrancy in the JAK1/STAT3 pathway supports the inflammatory model of pathogenesis and suggests that similar fundamental driving genetic lesions exist between BIA-ALCL and systemic ALK-negative ALCL despite clinical differences. 18 DiNapoli confirmed that mutations in JAK-STAT pathway genes occur in BIA-ALCL, identified SOCS1 mutation for the first time in this disease, and identified TP53 and DNMT3A mutations as additional somatic events. 31
BIA-ALCL is a rare disease with unknown exact incidence, most commonly presenting one decade after implant placement. The median age of onset of BIA-ALCL is 50 years old. 32 There is a very low absolute risk of developing BIA-ALCL, with a high relative risk in women with textured breast implants compared with the general population. An 18-fold higher rate of developing BIA-ALCL in the setting of breast implants has been reported. 33 Epidemiologic studies that fail to show an association between breast implants and lymphoma are limited by sample size and length of follow-up. 34 , 35 , 36
One hundred thirty-nine case reports of BIA-ALCL were individually reported between 1997 and 2016, with a significant increase in reporting in 2011, reflecting increased physician awareness of the disease after the FDA safety communication. 37 As stated earlier, the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database contains 457 unique reports of BIA-ALCL through September 30, 2018. 27 Worldwide, 573 adverse event reports of BIA-ALCL had been reported to government authorities as of October 17, 2019. 38
Cosmetic and reconstructive implants appear to be equally associated with BIA-ALCL risk. Risk has not been linked to implant type (saline versus silicone). However, BIA-ALCL has been reported almost exclusively with textured implants. 39 Comparing the number of textured implants sold to cases of BIA-ALCL, a lifetime prevalence of 1 in 30,000 is estimated, which is 67.6 times higher than primary ALCL in the general population. 40 In Australia, the Therapeutic Goods Administration estimated a BIA-ALCL disease risk between 1 in 1,000 and 1 in 10,000 women with textured breast implants. 41 The risk discrepancy between the United States and Australia may be due to discrepancy in physician reporting or geographic predisposition, and requires further investigation. Interestingly, the U.S. CA/CARE Trial, the largest published prospective textured implant study to date, reports a BIA-ALCL prevalence within the Australian estimated range (1 in 2,943 women with biocell implants). 29
16.5 Disease Characteristics
Onset of BIA-ALCL ranges from 2 to 28 years after breast implantation, most commonly occurring between 7 and 10 years. Unilateral disease is much more common than bilateral disease, which occurs rarely, in approximately 4.9% of patients. 42
BIA-ALCL initially arises as an effusion adjacent to an implant and then infiltrates into the luminal surface of the scar capsule. 43 Approximately 60–80% of patients present with a seroma surrounding the implant; 17–40% present with a mass. The presence of capsular contracture is both rare (8–10%) and possibly nonspecific for BIA-ALCL. 44
Standardized diagnosis and management guidelines for BIA-ALCL have been developed by the National Comprehensive Cancer Network (NCCN) (Fig. 16‑1). The finding of seroma presenting more than 1 year after placement of breast implants should raise concern and prompt investigation for BIA-ALCL. 45 Physical exam should include inspection and palpation of bilateral breast, axillae, neck and chest wall. The most common presentation of BIA-ALCL is a periprosthetic fluid collection or mass. Other symptoms include breast enlargement, skin rash, capsular contracture, and lymphadenopathy. 46
16.6.2 Imaging and Diagnostic Tests
Ultrasound, the preferred initial imaging modality to investigate BIA-ALCL, can be used to define the extent of a fluid collection (sensitivity 84%, specificity 75%), identify masses (sensitivity 46%, specificity 100%), and evaluate enlarged regional lymph nodes. Magnetic resonance imaging (MRI) or positron emission tomography (PET) can be used if ultrasound is indeterminate. While a small volume of periprosthetic fluid may be normal, seromas should be investigated with fine needle aspiration (FNA). FNA can be performed under ultrasound guidance in a clinic setting or by interventional radiology. Seroma fluid should be aspirated for analysis, along with samples of the capsule and any suspicious masses, and should be sent for cytology. Immunohistochemistry and flow cytometry for T cell markers, specifically CD30 immunohistochemistry, is necessary to establish the diagnosis of BIA-ALCL. 46
Due to the rarity of the disease, communication with the pathologist is imperative and should include explicit directions to rule out BIA-ALCL. Pathologic examination should include cytologic examination of seroma fluid with cell block cytology, flow cytometry, and CD30 immunohistochemistry. Cell block cytology demonstrates anaplastic large cells, and flow cytometry demonstrates a single T cell clonally expanded population. 47 , 48
If lymphoma diagnosis is indeterminate, additional hematopathologist consultation at a center with experience in this disease should be pursued. If the pathology is negative, referral to a plastic surgeon for benign seroma management is suitable. When pathology is positive, referral to a lymphoma oncologist and surgical oncologist with complete workup and staging is indicated.
16.7.1 Staging Tests
Following pathologic confirmation of BIA-ALCL, a multidisciplinary team approach should be used. Routine lab tests include complete blood count (CBC), comprehensive metabolic panel (CMP), lactate dehydrogenase (LDH), hepatitis B, and pregnancy test. PET scan is the preferred modality to evaluate for systemic spread to regional lymph nodes and organ involvement in pathologically confirmed cases. 49 Staging is determined from a combination of imaging and pathologic findings at time of surgery and serves to distinguish localized from disseminated disease.
16.7.2 Staging Systems
The two staging systems used for BIA-ALCL are the Ann Arbor staging system and the MD Anderson (MDA) BIA-ALCL tumor–node–metastasis (TNM) staging system. The Lugano revision to the Ann Arbor staging system is a lymphoma staging, with Stage IE disease limited to a single extranodal site (i.e., breast or capsule) and Stage IIE defining spread to local lymph nodes. 50 Using this system, most patients are classified as having early-stage disease (83–84% Stage IE, 10–16% Stage IIE, versus only 0–7% with Stage IV disease). 40 , 44
The MDA BIA-ALCL TNM staging system is modeled after the American Joint Committee on Cancer (AJCC) TNM system for staging solid tumors (Fig. 16‑2, Table 16‑1). This TNM staging system may be more appropriate for patients who have BIA-ALCL, as this disease is more similar to other solid tumors than other lymphomas. Additionally, the MDA TNM staging system has been shown to be more accurate in predicting overall survival than the Ann Arbor lymphoma staging system. 51
16.8.1 Surgical Treatment
Treatment follows the established standardized guidelines, formulated on best available evidence-based approach by the NCCN. 45 All patients with BIA-ALCL should undergo surgical resection of the implant, total capsulectomy, and resection of any associated masses with negative margins. Oncologic technique should be employed, including specimen orientation, placement of clips in the resection cavity, and use of different instruments on each implant. In cases of bilateral implants, the contralateral implant and capsule should be removed to lessen the risk of recurrence or second contralateral disease. 44 There is no role for sentinel lymph node biopsy, as implants can drain into multiple lymph node basins. Excisional biopsies should be performed for clinically or radiographically enlarged lymph nodes, as 14% of such nodes are pathologically involved. 40
Complete surgical resection provides definitive therapy and is curative in the majority (>85%) of patients. BIA-ALCL has an estimated median overall survival of 13 years after complete surgical excision. Event-free survival was shown to be significantly higher with complete surgery (96%) than with limited surgery (40%) and adjuvant therapy (chemotherapy 76%, radiation 82%).
Optimal management of disseminated, persistent, or recurrent disease is less clear. For patients with localized disease (Ann Arbor stage IE, MDA TNM stage IA–IIA), no adjuvant chemotherapy or radiation is necessary. In patients with unresectable chest wall invasion or regional lymph node involvement (Ann Arbor stage IIE, MDA TNM stage IIB though IV), adjunctive chemotherapy is recommended. 45 Patients who fail surgical therapy alone or who have proven disseminated disease should be managed similarly as de novo ALK-negative systemic ALCL. Anthracycline-based regimens (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) are used as first-line therapy in advanced BIA-ALCL. 45 However, 32% of patients treated with systemic chemotherapy alone experienced disease recurrence, suggesting this treatment may be insufficient. 44
16.8.3 Brentuximab Vedotin
Brentuximab vedotin is an anti-CD30 antibody–drug conjugate with a potential role in the treatment of BIA-ALCL. CD30 is an ideal pharmacologic target, highly expressed on malignant cells with limited expression in normal tissues. Phase I studies using brentuximab vedotin as a primary treatment of systemic ALCL display excellent response and manageable toxicity. 52 , 53 One case report demonstrated complete remission using brentuximab vedotin in the context of refractory disease for the treatment of BIA-ALCL. 54 No recurrences have been reported after treatment with brentuximab. NCCN guidelines allow for the administration of brentuximab vedotin as first-line therapy in place of an anthracycline-based regimen. Further research is needed to delineate its exact role.
In one review of 60 patients, addition of radiation provided no significant benefit compared with surgical treatment alone. 40 There is no evidence to support routine radiation use for BIA-ALCL. Therefore, it is not recommended in cases of complete remission after appropriate surgical treatment. Radiation therapy has been used in locoregionally advanced, unresectable cases and is recommended by the NCCN for local residual or unresectable disease. 55
16.8.5 Treatment Comparison
Treatment with complete surgical excision has shown better overall survival and event-free survival than treatment with partial capsulectomy, systemic chemotherapy, or radiation. 56 One review of 87 patients with BIA-ALCL compared different treatment regimens: surgery alone (40%), surgery and radiation (9%), surgery and chemotherapy (19%), surgery, chemotherapy, and radiation (30%), and chemotherapy alone (2%). Fig. 16‑3 shows the survival curves according to treatment approaches and TNM staging. 44 Fig. 16‑4 and Fig. 16‑5 demonstrate pathologic confirmation and a patient treated with curative surgery, respectively.