ORIGINAL ARTICLE ANZJSurg.com
Variable presentation of anaplastic large-cell lymphoma in patients with breast implants Michelle B. Locke* and Julian Lofts† *Department of Surgery, South Auckland Clinical Campus, Middlemore Hospital, University of Auckland, Auckland, New Zealand and †Private Practice, Auckland, New Zealand
Key words anaplastic, breast implant, large cell, lymphoma, seroma. Correspondence Mr Julian Lofts, Surgeon, Private Practice, 6 St. Vincent Avenue, Remuera, Auckland 1050, New Zealand. Email: [email protected] M. B. Locke MBChB, MD, FRACS (Plast.); J. Lofts MBChB, FRACS (Plast.). Accepted for publication 23 February 2015. doi: 10.1111/ans.13074
Abstract Background: Anaplastic large-cell lymphoma (ALCL) has recently been reported in women with breast implants. The incidence of breast implant-related ALCL is extremely rare and most surgeons would not expect to see this disease in their career. However, the senior author has had three women present to his practice with ALCL over a 2-year period. Methods: The three patients and their presentation were reviewed to establish the presenting complaint in each case of subsequently diagnosed ALCL. Literature was reviewed to establish appropriate treatment protocols for any subsequent patients. Results: The average time between first implant placement and presentation with breast implant-associated ALCL was 13.3 years (range: 10–16 years) and age at presentation was 49 years (range: 45–53 years). Each presentation was somewhat different, being a palpable mass, a painless seroma and a painful seroma. Both patients with seroma underwent ultrasound-guided aspiration of fluid which confirmed ALCL. All patients underwent implant removal and complete capsulectomy. The patient with a mass at presentation initially declined adjuvant treatment but subsequently developed an ALCL-associated seroma and was treated with surgery and post-operative chemotherapy. Conclusion: Patients with breast implant-associated ALCL can present with different clinical signs and symptoms. Late seroma is a relatively common presentation of breast implant-associated ALCL. While firm guidelines for the management of breast implant-related ALCL are lacking, we suggest that any late seroma in the absence of infection should be managed with aspiration and cytological analysis of the fluid.
Introduction Anaplastic large-cell lymphoma (ALCL) was first associated with breast implants in the mid-1990s, with the publication of two articles discussing the occurrence of cutaneous ALCL in the breast skin of four women with breast implants.1,2 Recently, this concern has been increasing with the publication of further cases.3,4 The ‘natural’ rate of ALCL in the breast is extremely low, estimated at about three per 100 million women per year.5 Similarly, ALCL is extremely rare with other types of implantable devices.6 The increasing number of reports of ALCL in the breast in women with breast implants led to the US Food and Drug Administration issuing a white paper on the topic in 2011.7 This was based on only 34 cases in the estimated five to 10 million women with breast implants worldwide. The findings of this paper can be summarized to say that there is uncertainty around the true cause of ALCL in women with breast implants, that © 2015 Royal Australasian College of Surgeons
there is a possible association between ALCL and breast implants and that it is not possible to identify a particular type of implant associated with a higher risk of ALCL. Given the rarity of the diagnosis, it is likely that clinicians will see very few, if any, of these cases during their career. This article aims to highlight the different potential clinical presentations of the disease using a series of three patients who presented to the senior author’s practice over a 2-year period, each with a different presenting complaint. A suggested guideline for the management of suspected breast implant-associated ALCL is presented.
Methods We describe three cases of ALCL associated with breast implants treated by the senior author (JL) within a 2-year period. One patient presented directly to the senior author. Two of the patients initially ANZ J Surg •• (2015) ••–••
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presented to other clinicians and were referred or self-referred to the senior author for treatment.
Case 1 A 49-year-old British woman presented in October 2011 with a small, smooth, firm mobile non-tender lump in a reconstructed breast. She had initially undergone a cosmetic bilateral breast augmentation 10 years prior at age 39. The implants used were McGhan style 410 FM 235 cc anatomical textured cohesive silicone gel (McGhan Medical Corporation, Santa Barbara, CA, USA) placed in a subglandular pocket. She subsequently developed intermediate grade ductal carcinoma in situ (DCIS) in the upper outer quadrant of her right breast. She underwent wide local excision and sentinel lymph node biopsy in February of 2005. Histology showed DCIS with one area of microinvasion. The sentinel node was negative. She progressed to a right skin sparing mastectomy the following month, with immediate breast reconstruction using a pedicled latissimus dorsi flap and McGhan style 410 FF 375 cc anatomical textured cohesive silicone gel implant. Recovery was complicated by an acute, expanding haematoma 9 days post-operatively. She underwent exploration and drainage the same day. Six months later, she underwent replacement of her right breast implant to improve her symmetry. The new implant was McGhan CUI style 120 450 cc round textured cohesive silicone gel implant. Five years later, in November of 2010, she developed sudden, uncomfortable swelling in her reconstructed right breast when training for a marathon. Clinically, she had a Baker grade 3 capsular contracture at this time. Ultrasound scan suggested rupture of the implant and subsequent magnetic resonance imaging showed fluid around the right implant with some infolding but no evidence of rupture. Seven months later, she underwent right implant complete capsulectomy, explantation, drainage of approximately 150 mL of brown serosanguinous fluid assumed to be old haematoma and replacement of the implant with Allergan Inspira TSF 520 cc round textured cohesive gel implant (Allergan, Inc., Santa Barbara, CA, USA). Fresh tissue specimens were sent with a specific request to look for ALCL. Histology and cytology of the explanted tissue were reported normal. In October of 2011, at age 49, 5 months after her last surgery and 10 years after her first breast augmentation, she self-presented to the senior author having noticed a small, smooth, firm, mobile nodule at the 6 o’clock position in her right (reconstructed) breast, just above the inframammary fold. The nodule was excised by her breast surgeon. Histology was consistent with CD30-positive, anaplastic
Locke and Lofts
lymphoma kinase (ALK)-1-negative ALCL. She then underwent staging of her disease. Bone marrow aspirate was negative. Computed tomography (CT) scan of her neck, chest and abdomen showed no focal soft tissue lesions but mild patchy sclerosis in the posterior aspect of her right ilium. Three core biopsies of this area showed no evidence of carcinoma or lymphoma. She was reviewed by the haematology service as well as by the senior author. She was offered explantation, capsulectomy and chemotherapy but she declined any treatment at that time. Five months later, she developed a right breast seroma. Ultrasound-guided needle aspiration of the fluid obtained ALK-1negative ALCL cells. She then underwent right explantation, capsulectomy and excision of previously expanded skin. Postoperative CT scan of the chest, abdomen and pelvis showed low attenuation material within the right chest wall. She therefore underwent four cycles of chemotherapy with cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone (CHOP) in August 2012. She has since been in remission. She still desired breast reconstruction and underwent autologous tissue reconstruction in a delayed fashion with a deep inferior epigastric artery flap in July of 2013. There were no surgical complications and she remains free of disease at time of writing.
Case 2 A 53-year-old New Zealand European woman presented to a breast surgeon with painless right breast swelling in March of 2013, 14 years after undergoing a cosmetic bilateral breast augmentation with McGhan style 410 FM 235 cc anatomical textured cohesive silicone gel placed in a submuscular pocket. She had no history of preceding trauma. Clinically, her right breast was noted to be very hard and tight but not erythematous. An ultrasound scan was arranged which showed periprosthetic fluid. This was treated with oral antibiotics for a month but was not aspirated. She subsequently presented to the senior author in May 2013 to consider replacement of her implants. She was noted to have a grade 3 capsular contracture and the right breast was estimated to be at least 160 g larger than the left (Fig. 1). Ultrasound-guided needle aspiration of the fluid showed very large T-cells and she was diagnosed with CD30-positive CD45-positive, ALK-1-negative ALCL. Staging CT scan of the chest, abdomen and pelvis and positron emission tomography (PET) scan were positive for an ovarian cyst only. She then underwent bilateral explantation and complete capsulectomies. The posterior capsule was densely adherent to the periosteum of the ribs and was tumesced to assist with removal. The
Fig. 1. Case 2: (a) preoperative appearance showing right breast swelling; (b) post-operative appearance following bilateral explantation and capsulectomies.
© 2015 Royal Australasian College of Surgeons
Variable presentation of ALCL
implants were found to be intact. Histology of the capsule did not show any evidence of ALCL; this seemed to be present in the fluid only (Fig. 2). The patient was reviewed at the Regional Lymphoma Conference in July of 2013. Given that there was no evidence of local, regional or distant disease, they recommended observation only and did not offer chemotherapy. She remains free of disease at time of writing. She has since undergone fat grafting to the breast to improve her symmetry.
Case 3 A 45-year-old Argentinian woman presented to a breast surgeon in September of 2013 with a 1 to 2-month history of painful left breast swelling following a trip to Mexico. She had undergone a bilateral breast augmentation 16 years prior, with Silimed style 215 textured round silicone gel implants (Silimed, Inc., Dallas, TX, USA) placed in a subglandular position. She was felt to have grade 3 firmness of the breast and was investigated with a mammogram. This showed fluid around the implant and was suspicious for implant deflation. No fluid was aspirated at this time. She was then referred to the senior author for treatment of implant deflation. An ultrasound scan was arranged, which showed fluid around the implant but no evidence of implant rupture. Ultrasound-guided needle aspiration obtained 50 mL of cloudy yellow fluid. This was sent for cytology, which confirmed abnormal large T-cells and she was diagnosed with CD30-positive CD45-positive, ALK-1-negative ALCL. Staging CT scan of the chest, abdomen and pelvis showed no evidence of
Fig. 2. Case 2: Macroscopic view of capsule upon removal.
Fig. 3. Case 3: (a) Preoperative appearance showing left breast swelling; (b) post-operative appearance following bilateral explantation and capsulectomies.
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enlarged lymph nodes. The scan was positive for fibrocalcific scarring and associated bronchiectasis of the right upper lobe, in keeping with the patient’s disclosure of previous treatment for tuberculosis. The left implant was thought to be ruptured on the imaging. The following month she underwent bilateral explantation and capsulectomies (Fig. 3). The implants were not found to be ruptured. Fluid was found around the left implant; no nodules were seen or felt in the capsules (Fig. 4). Histology confirmed ALCL in the fluid only with no evidence of lymphoma in the capsule itself. She was reviewed by the haematology service. Given that she has no symptoms to suggest systemic lymphoma and no evidence of local, regional or distant disease, they recommended observation only and did not offer chemotherapy. She remains free of disease at time of writing.
Discussion The most common clinical presentation for breast implantassociated ALCL in the literature is unilateral breast swelling because of periprosthetic fluid (effusion or seroma), which presents late, at least 6 months and commonly more than 1 year after surgery.3 Alternatively, it may present as a palpable cutaneous mass or solid mass attached to the implant capsule.4 This is in contrast to primary breast lymphoma, which presents as a palpable mass in 91% of cases in one review of 81 cases over 10 years at a single facility.8 Other presentations of breast implant-associated ALCL include constitutional ‘B’ symptoms such as fever, weight loss and night sweats or general malaise and lethargy.3,9 Of our three patients, presentations were a palpable mobile mass, a painful breast swelling and a painless breast swelling. Our patients were at an average age of 49 years on presentation (range: 45–53 years) and their disease occurred on average 13.3 years after their first implant placement (range: 10–16 years). This is similar to other studies showing an average age of 51 years at diagnosis, occurring approximately 9 years from their initial surgery.3 All our patients are free of disease at follow-up, but the follow-up period is short (2 years or less for all patients). ALCL is a rare subtype of non-Hodgkin’s lymphoma, with a young median age at diagnosis of 34 years and a male predominance of 69%, accounting for 2% of newly diagnosed lymphoma.10 Risk factors for the development of lymphoma include family history, autoimmune disease, immune system deficiency (such as following organ transplantation or human immunodeficiency virus infection) and exposure to radiation or carcinogenic chemicals.11 None of the
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Fig. 4. Case 3: Macroscopic view of capsule upon removal.
Table 1 Staging of lymphoma Stage
Description
Stage 1 Early disease
One group of lymph nodes affected
Stage 2 Locally advanced disease
Two or more groups of lymph nodes affected on the same side of the diaphragm
Stage 3 Advanced disease
Two or more groups of lymph nodes affected on both sides of the diaphragm
Stage 4 Widespread disease
Lymphoma has spread beyond the lymph nodes to other organs
A or B
A = No constitutional symptoms B = Presence of constitutional symptoms
E
Extranodal lymphoma (lymphoma arising outside of the lymph nodes)
patients in this series had any previous history of known risk factors for ALCL. The diagnosis of ALCL is based on the presence of malignant cytology, strong CD30 expression and the exclusion of epithelial malignancy.12 Diagnosis of breast implant-associated ALCL therefore relies on the identification of highly atypical lymphoid cells. These are large, epithelioid and pleiomorphic, with frequent mitoses.13 ‘Hallmark’ cells with eccentric, horseshoe or kidney-shaped nuclei and perinuclear density are often present within the effusion fluid or tissue.14 ALCL is divided into two groups, the first being primary cutaneous ALCL, usually affecting older patients and with excellent prognosis, and the second being systemic nodal ALCL, which is subdivided into ALK-positive and ALK-negative disease. ALK is most commonly overexpressed. Lymphoma prognosis is related to the subtype and stage of the disease, with staging depending on the location and dissemination of the disease (Table 1). Typically, ALK-positive ALCL is correlated with younger age groups and has a more favourable clinical outcome with better 5-year survival than ALK-negative ALCL (5-year survival range 71–100% for ALK-positive compared with 15–45% for ALK-
negative disease).10,15 The ALK-negative group is heterogeneous in clinical outcome but generally has a worse prognosis.15 Primary lymphoma of the breast is even less common than systemic ALCL, accounting for less than 1% of all non-Hodgkin’s lymphoma and less than 1% of all cases of primary breast malignancy.8 Overall, an estimate in population-based studies puts the rate of ALCL at 0.1 per 100 000 women, with or without breast implants.16 Given the infrequent observation of the disease, epidemiological studies to assess the risk of non-Hodgkin’s lymphoma in women with breast implants compared with women without breast implants have not confirmed any association between breast implants and an increased risk of developing ALCL. However, a true association has not been ruled out either.3 In contrast to typical systemic ALCL, breast implant-associated ALCL is commonly ALK-negative. Despite this, the prognosis is generally favourable4,17 although not exclusively, as extranodal disease and death from disease progression have been reported.9,18 Recent literature suggests that cutaneous, solid- or mass-forming ALCL has a worse prognosis than effusion-type disease limited to the seroma fluid or capsule alone. Miranda et al. from the MD Anderson Cancer Centre in the United States recently reviewed the literature to assess the treatment and outcomes of 60 patient with breast implant-associated ALCL between 1997 and 2012.19 Treatment was variable between patients but 93% underwent explantation and capsulectomy, 78% received systemic chemotherapy, 7% received radiotherapy alone and 21% did not receive any adjuvant therapy. The median follow-up in their study was only 2 years but still they were able to show that patients who present with a mass had worse overall survival and progression-free survival, with no difference shown between those who received chemotherapy and those who did not. Most patients (93%) with disease confined to the capsule achieved complete remission compared with only 72% of those who presented with a tumour mass. Therefore, while good outcomes from this disease are commonly recorded, there is mounting evidence of the potential for aggressive clinical behaviour in some cases.20 Current literature seems to support the assessment of the patient for evidence of extranodal spread of the disease to accurately stage the disease but may not support offering adjuvant treatment in Stage 1E disease, when disease is limited to the effusion fluid or capsule.21,22
Evidence for the management of breast implant-associated ALCL While no formal treatment recommendations are in place for breast implant-related ALCL, a multidisciplinary panel of experts was recently convened in the United States to review the issue.21 The panel strongly agreed that aspiration and cytological evaluation of a late seroma around a breast implant should be performed at both the first occurrence and especially in recurrent cases, which is in agreement with other literature.21,23 The team at University of Southern California, led by Dr Brody, have collected 103 cases of breast implant-associated ALCL and reviewed the immunohistochemistry findings for 87 of these cases.22 The lead investigator personally recommends performing a total capsulectomy, facilitated by tumescing the posterior capsule (as we found necessary in case 2), and marking any suspicious or particularly adherent sites for biopsy © 2015 Royal Australasian College of Surgeons
Variable presentation of ALCL
5
Fig. 5. Management of suspected breast implant-associated anaplastic large-cell lymphoma (ALCL).
Suspect ALCL?
Obtain ssue or fluid sample for diagnosis: • Seroma – Ultrasound-guided aspiraon • Mass – Incisional or excisional biopsy Discuss case in advance with pathologist Send sample fresh (not in formalin) Cytology and histology assessment Flow cytometry, cytogenecs, fluorescent in situ hybridizaon if required
Negave
Posive
• • •
Surgery: Explantaon Total capsulectomy +/- Excision of mass
• • •
Roune management. Consider the possibility of a false negave; send further samples if there is significant clinical concern or if any further surgery is undertaken
Staging: Computed tomography scan (chest, abdomen, pelvis) Positron emission tomography scan if required Consider bone marrow aspirate
Refer to haematology/oncology for review and consideraon of adjuvant treatment
by the pathologist, as the tumour may not involve the entire capsule.22 Indeed, Talagas et al. recently discussed the diagnostic challenge that ALCL can pose for pathologists.24 They gave the example of breast implant-associated ALCL which was diagnosed on aspiration of an effusion but stated that repeated biopsies of the capsule showed fibrous tissue only without tumour proliferation. They noted that only meticulous histological examination of the total capsulectomy specimen identified tumour cells as a thin, discontinuous layer along the inner surface of the capsule without capsular invasion. Therefore, communication with the pathologist is vital in making an accurate diagnosis and the likely diagnosis should be clearly indicated when specimens are sent. As there have been several cases of bilateral disease, Dr Brody feels that it is prudent to remove the other implant and capsule also. The expert panel agree with his suggestions for management of the affected breast but are uncertain about the most appropriate management of the contralateral implant.21
Guidelines for management of suspected breast implant-associated ALCL We recommend that any unexplained, late (more than 1 year after surgery) seroma in the absence of infection be aspirated and the fluid sent for cytological evaluation. If ALCL is known or suspected, fluid and any tissue should be sent fresh (not in formalin). This facilitates © 2015 Royal Australasian College of Surgeons
cytological and histological examination, as well as flow cytometry and fluorescent in situ hybridization for cytogenetic analysis (if available) to be performed to assist with the diagnosis. If breast implant-associated ALCL is confirmed, treatment should comprise explantation of the device, total capsulectomy and excision of any mass (if present). Patients should be staged with CT scan of the chest, abdomen and pelvis to assess for the presence of other disease locations. PET scan and bone marrow aspirate may be performed if necessary. All patients should be referred to the appropriate haematology or lymphoma centre for consideration of adjuvant treatment (Fig. 5). The patients in our series were treated in accordance with these guidelines by the senior author. However, in neither case of late seroma presentation was the seroma aspirated by the breast surgeons who were initially caring for the patient. All patients underwent explantation and total capsulectomy. All were staged with CT scans of the chest, abdomen and pelvis. The patient in case 1 also underwent bone marrow aspirate, along with excision of the palpable mass while the patient in case 2 had a PET scan following her CT scan. As the first patient had a tumour mass, she was treated with systemic CHOP chemotherapy, a common chemotherapeutic regime for lymphoma. In cases 2 and 3, the disease was confined to the effusion fluid only so these women were treated surgically with no adjuvant treatment.
6
Conclusions Breast implant-associated ALCL can present with a painful seroma, a painless seroma or a palpable mass. Other possible presentations include constitutional symptoms such as fevers or night sweats, capsular contracture and general malaise. Alternatively, the disease can be an unexpected finding following capsulectomy for cosmetic or other reasons. Surgical treatment comprises explantation, total capsulectomy and excision of any mass. Prognosis is favourable overall, with 100% of patients with effusion-type ALCL and 75% of patients with cutaneous (solid- or mass-forming) ALCL tumours surviving at 5 years post-diagnosis.19 Given that the cutaneous subtype seem to have a worse prognosis, these patients may benefit from systemic chemotherapy. However, if the patient has no symptoms to suggest systemic lymphoma and no evidence of local, regional or metastatic disease (i.e. stage 1E on presentation with complete surgical excision of disease), it may be appropriate to forgo adjuvant treatment. All breast surgeons and physicians working in this field should be mindful of the possible diagnosis. Only by capturing all cases of the disease and sharing the information with the international community will we be able to establish the true incidence and causative factors of breast implant-related ALCL.
References 1. Duvic M, Moore D, Menter A, Vonderheid EC. Cutaneous T-cell lymphoma in association with silicone breast implants. J. Am. Acad. Dermatol. 1995; 32: 939–42. 2. Keech JA Jr, Creech BJ. Anaplastic T-cell lymphoma in proximity to a saline-filled breast implant. Plast. Reconstr. Surg. 1997; 100: 554–5. 3. Jewell M, Spear SL, Largent J, Oefelein MG, Adams WPJ. Anaplastic large T-cell lymphoma and breast implants: a review of the literature. Plast. Reconstr. Surg. 2011; 128: 651–61. 4. Taylor CR, Siddiqi IN, Brody GS. Anaplastic large cell lymphoma occurring in association with breast implants: review of pathologic and immunohistochemical features in 103 cases. Appl. Immunohistochem. Mol. Morphol. 2013; 21: 13–20. 5. Eaves F III, Nahai F. Anaplastic large cell lymphoma and breast implants: FDA report. Aesthet. Surg. J. 2011; 31: 467–8. 6. Kellogg BC, Hiro ME, Payne WG. Implant-associated anaplastic large cell lymphoma: beyond breast prostheses. Ann. Plast. Surg. 2014; 73: 461–4. 7. Center for Devices and Radiological Health USFaDA. Anaplastic Large Cell Lymphoma (ALCL) in Women with Breast Implants: Preliminary FDA Findings and Analysis. [Cited 13 Apr 2014.] Available from URL: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ ImplantsandProsthetics/BreastImplants/ucm239996.htm 8. Domchek SM, Hecht JL, Fleming MD, Pinkus GS, Canellos GP. Lymphomas of the breast: primary and secondary involvement. Cancer 2002; 94: 6–13.
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9. Taylor KO, Webster HR, Prince HM. Anaplastic large cell lymphoma and breast implants: five Australian cases. Plast. Reconstr. Surg. 2012; 129: 610e–7e. 10. Armitage JO, Weisenburger DD. New approach to classifying nonHodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J. Clin. Oncol. 1998; 16: 2780–95. 11. Society AC What are the Risk Factors for Non-Hodgkin Lymphoma? Georgia, USA. [updated 2015; Cited 5 Jan 2015.] Available from URL: http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/ non-hodgkin-lymphoma-risk-factors 12. Falini B, Martelli MP. Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy. Haematologica 2009; 94: 897–900. 13. Xu J, Wei S. Breast implant-associated anaplastic large cell lymphoma: review of a distinct clinicopathologic entity. Arch. Pathol. Lab. Med. 2014; 138: 842–6. 14. Chai SM, Kavangh S, Ooi SS et al. Anaplastic large-cell lymphoma associated with breast implants: a unique entity within the spectrum of peri-implant effusions. Diagn. Cytopathol. 2014; 42: 929–38. 15. ten Berge RL, Oudejans JJ, Ossenkoppele GJ, Meijer CJ. ALK-negative systemic anaplastic large cell lymphoma: differential diagnostic and prognostic aspects – a review. J. Pathol. 2003; 200: 4–15. 16. de Jong D, Vasmel WL, de Boer JP et al. Anaplastic large-cell lymphoma in women with breast implants. JAMA 2008; 300: 2030–5. 17. Kim B, Roth C, Chung KC et al. Anaplastic large cell lymphoma and breast implants: a systematic review. Plast. Reconstr. Surg. 2011; 127: 2141–50. 18. Carty MJ, Pribaz JJ, Antin JH et al. A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast. Reconstr. Surg. 2011; 128: 112e–8e. 19. Miranda RN, Aladily TN, Prince HM et al. Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients. J. Clin. Oncol. 2014; 32: 114–20. 20. Mazzucco AE. Next steps for breast implant – associated anaplastic large-cell lymphoma. J. Clin. Oncol. 2014; 32: 2275–6. 21. Kim B, Roth C, Young VL et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast. Reconstr. Surg. 2011; 128: 629–39. 22. Brody GS. Brief recommendations for dealing with a new case of anaplastic large T-cell lymphoma. Plast. Reconstr. Surg. 2012; 129: 871e–2e. 23. 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: 1–7. 24. Talagas M, Uguen A, Charles-Petillon F et al. Breast implant-associated anaplastic large-cell lymphoma can be a diagnostic challenge for pathologists. Acta Cytol. 2014; 58: 103–7.
© 2015 Royal Australasian College of Surgeons
Variable presentation of anaplastic large-cell lymphoma in patients with breast implants Michelle B. Locke* and Julian Lofts† *Department of Surgery, South Auckland Clinical Campus, Middlemore Hospital, University of Auckland, Auckland, New Zealand and †Private Practice, Auckland, New Zealand
Key words anaplastic, breast implant, large cell, lymphoma, seroma. Correspondence Mr Julian Lofts, Surgeon, Private Practice, 6 St. Vincent Avenue, Remuera, Auckland 1050, New Zealand. Email: [email protected] M. B. Locke MBChB, MD, FRACS (Plast.); J. Lofts MBChB, FRACS (Plast.). Accepted for publication 23 February 2015. doi: 10.1111/ans.13074
Abstract Background: Anaplastic large-cell lymphoma (ALCL) has recently been reported in women with breast implants. The incidence of breast implant-related ALCL is extremely rare and most surgeons would not expect to see this disease in their career. However, the senior author has had three women present to his practice with ALCL over a 2-year period. Methods: The three patients and their presentation were reviewed to establish the presenting complaint in each case of subsequently diagnosed ALCL. Literature was reviewed to establish appropriate treatment protocols for any subsequent patients. Results: The average time between first implant placement and presentation with breast implant-associated ALCL was 13.3 years (range: 10–16 years) and age at presentation was 49 years (range: 45–53 years). Each presentation was somewhat different, being a palpable mass, a painless seroma and a painful seroma. Both patients with seroma underwent ultrasound-guided aspiration of fluid which confirmed ALCL. All patients underwent implant removal and complete capsulectomy. The patient with a mass at presentation initially declined adjuvant treatment but subsequently developed an ALCL-associated seroma and was treated with surgery and post-operative chemotherapy. Conclusion: Patients with breast implant-associated ALCL can present with different clinical signs and symptoms. Late seroma is a relatively common presentation of breast implant-associated ALCL. While firm guidelines for the management of breast implant-related ALCL are lacking, we suggest that any late seroma in the absence of infection should be managed with aspiration and cytological analysis of the fluid.
Introduction Anaplastic large-cell lymphoma (ALCL) was first associated with breast implants in the mid-1990s, with the publication of two articles discussing the occurrence of cutaneous ALCL in the breast skin of four women with breast implants.1,2 Recently, this concern has been increasing with the publication of further cases.3,4 The ‘natural’ rate of ALCL in the breast is extremely low, estimated at about three per 100 million women per year.5 Similarly, ALCL is extremely rare with other types of implantable devices.6 The increasing number of reports of ALCL in the breast in women with breast implants led to the US Food and Drug Administration issuing a white paper on the topic in 2011.7 This was based on only 34 cases in the estimated five to 10 million women with breast implants worldwide. The findings of this paper can be summarized to say that there is uncertainty around the true cause of ALCL in women with breast implants, that © 2015 Royal Australasian College of Surgeons
there is a possible association between ALCL and breast implants and that it is not possible to identify a particular type of implant associated with a higher risk of ALCL. Given the rarity of the diagnosis, it is likely that clinicians will see very few, if any, of these cases during their career. This article aims to highlight the different potential clinical presentations of the disease using a series of three patients who presented to the senior author’s practice over a 2-year period, each with a different presenting complaint. A suggested guideline for the management of suspected breast implant-associated ALCL is presented.
Methods We describe three cases of ALCL associated with breast implants treated by the senior author (JL) within a 2-year period. One patient presented directly to the senior author. Two of the patients initially ANZ J Surg •• (2015) ••–••
2
presented to other clinicians and were referred or self-referred to the senior author for treatment.
Case 1 A 49-year-old British woman presented in October 2011 with a small, smooth, firm mobile non-tender lump in a reconstructed breast. She had initially undergone a cosmetic bilateral breast augmentation 10 years prior at age 39. The implants used were McGhan style 410 FM 235 cc anatomical textured cohesive silicone gel (McGhan Medical Corporation, Santa Barbara, CA, USA) placed in a subglandular pocket. She subsequently developed intermediate grade ductal carcinoma in situ (DCIS) in the upper outer quadrant of her right breast. She underwent wide local excision and sentinel lymph node biopsy in February of 2005. Histology showed DCIS with one area of microinvasion. The sentinel node was negative. She progressed to a right skin sparing mastectomy the following month, with immediate breast reconstruction using a pedicled latissimus dorsi flap and McGhan style 410 FF 375 cc anatomical textured cohesive silicone gel implant. Recovery was complicated by an acute, expanding haematoma 9 days post-operatively. She underwent exploration and drainage the same day. Six months later, she underwent replacement of her right breast implant to improve her symmetry. The new implant was McGhan CUI style 120 450 cc round textured cohesive silicone gel implant. Five years later, in November of 2010, she developed sudden, uncomfortable swelling in her reconstructed right breast when training for a marathon. Clinically, she had a Baker grade 3 capsular contracture at this time. Ultrasound scan suggested rupture of the implant and subsequent magnetic resonance imaging showed fluid around the right implant with some infolding but no evidence of rupture. Seven months later, she underwent right implant complete capsulectomy, explantation, drainage of approximately 150 mL of brown serosanguinous fluid assumed to be old haematoma and replacement of the implant with Allergan Inspira TSF 520 cc round textured cohesive gel implant (Allergan, Inc., Santa Barbara, CA, USA). Fresh tissue specimens were sent with a specific request to look for ALCL. Histology and cytology of the explanted tissue were reported normal. In October of 2011, at age 49, 5 months after her last surgery and 10 years after her first breast augmentation, she self-presented to the senior author having noticed a small, smooth, firm, mobile nodule at the 6 o’clock position in her right (reconstructed) breast, just above the inframammary fold. The nodule was excised by her breast surgeon. Histology was consistent with CD30-positive, anaplastic
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lymphoma kinase (ALK)-1-negative ALCL. She then underwent staging of her disease. Bone marrow aspirate was negative. Computed tomography (CT) scan of her neck, chest and abdomen showed no focal soft tissue lesions but mild patchy sclerosis in the posterior aspect of her right ilium. Three core biopsies of this area showed no evidence of carcinoma or lymphoma. She was reviewed by the haematology service as well as by the senior author. She was offered explantation, capsulectomy and chemotherapy but she declined any treatment at that time. Five months later, she developed a right breast seroma. Ultrasound-guided needle aspiration of the fluid obtained ALK-1negative ALCL cells. She then underwent right explantation, capsulectomy and excision of previously expanded skin. Postoperative CT scan of the chest, abdomen and pelvis showed low attenuation material within the right chest wall. She therefore underwent four cycles of chemotherapy with cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone (CHOP) in August 2012. She has since been in remission. She still desired breast reconstruction and underwent autologous tissue reconstruction in a delayed fashion with a deep inferior epigastric artery flap in July of 2013. There were no surgical complications and she remains free of disease at time of writing.
Case 2 A 53-year-old New Zealand European woman presented to a breast surgeon with painless right breast swelling in March of 2013, 14 years after undergoing a cosmetic bilateral breast augmentation with McGhan style 410 FM 235 cc anatomical textured cohesive silicone gel placed in a submuscular pocket. She had no history of preceding trauma. Clinically, her right breast was noted to be very hard and tight but not erythematous. An ultrasound scan was arranged which showed periprosthetic fluid. This was treated with oral antibiotics for a month but was not aspirated. She subsequently presented to the senior author in May 2013 to consider replacement of her implants. She was noted to have a grade 3 capsular contracture and the right breast was estimated to be at least 160 g larger than the left (Fig. 1). Ultrasound-guided needle aspiration of the fluid showed very large T-cells and she was diagnosed with CD30-positive CD45-positive, ALK-1-negative ALCL. Staging CT scan of the chest, abdomen and pelvis and positron emission tomography (PET) scan were positive for an ovarian cyst only. She then underwent bilateral explantation and complete capsulectomies. The posterior capsule was densely adherent to the periosteum of the ribs and was tumesced to assist with removal. The
Fig. 1. Case 2: (a) preoperative appearance showing right breast swelling; (b) post-operative appearance following bilateral explantation and capsulectomies.
© 2015 Royal Australasian College of Surgeons
Variable presentation of ALCL
implants were found to be intact. Histology of the capsule did not show any evidence of ALCL; this seemed to be present in the fluid only (Fig. 2). The patient was reviewed at the Regional Lymphoma Conference in July of 2013. Given that there was no evidence of local, regional or distant disease, they recommended observation only and did not offer chemotherapy. She remains free of disease at time of writing. She has since undergone fat grafting to the breast to improve her symmetry.
Case 3 A 45-year-old Argentinian woman presented to a breast surgeon in September of 2013 with a 1 to 2-month history of painful left breast swelling following a trip to Mexico. She had undergone a bilateral breast augmentation 16 years prior, with Silimed style 215 textured round silicone gel implants (Silimed, Inc., Dallas, TX, USA) placed in a subglandular position. She was felt to have grade 3 firmness of the breast and was investigated with a mammogram. This showed fluid around the implant and was suspicious for implant deflation. No fluid was aspirated at this time. She was then referred to the senior author for treatment of implant deflation. An ultrasound scan was arranged, which showed fluid around the implant but no evidence of implant rupture. Ultrasound-guided needle aspiration obtained 50 mL of cloudy yellow fluid. This was sent for cytology, which confirmed abnormal large T-cells and she was diagnosed with CD30-positive CD45-positive, ALK-1-negative ALCL. Staging CT scan of the chest, abdomen and pelvis showed no evidence of
Fig. 2. Case 2: Macroscopic view of capsule upon removal.
Fig. 3. Case 3: (a) Preoperative appearance showing left breast swelling; (b) post-operative appearance following bilateral explantation and capsulectomies.
© 2015 Royal Australasian College of Surgeons
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enlarged lymph nodes. The scan was positive for fibrocalcific scarring and associated bronchiectasis of the right upper lobe, in keeping with the patient’s disclosure of previous treatment for tuberculosis. The left implant was thought to be ruptured on the imaging. The following month she underwent bilateral explantation and capsulectomies (Fig. 3). The implants were not found to be ruptured. Fluid was found around the left implant; no nodules were seen or felt in the capsules (Fig. 4). Histology confirmed ALCL in the fluid only with no evidence of lymphoma in the capsule itself. She was reviewed by the haematology service. Given that she has no symptoms to suggest systemic lymphoma and no evidence of local, regional or distant disease, they recommended observation only and did not offer chemotherapy. She remains free of disease at time of writing.
Discussion The most common clinical presentation for breast implantassociated ALCL in the literature is unilateral breast swelling because of periprosthetic fluid (effusion or seroma), which presents late, at least 6 months and commonly more than 1 year after surgery.3 Alternatively, it may present as a palpable cutaneous mass or solid mass attached to the implant capsule.4 This is in contrast to primary breast lymphoma, which presents as a palpable mass in 91% of cases in one review of 81 cases over 10 years at a single facility.8 Other presentations of breast implant-associated ALCL include constitutional ‘B’ symptoms such as fever, weight loss and night sweats or general malaise and lethargy.3,9 Of our three patients, presentations were a palpable mobile mass, a painful breast swelling and a painless breast swelling. Our patients were at an average age of 49 years on presentation (range: 45–53 years) and their disease occurred on average 13.3 years after their first implant placement (range: 10–16 years). This is similar to other studies showing an average age of 51 years at diagnosis, occurring approximately 9 years from their initial surgery.3 All our patients are free of disease at follow-up, but the follow-up period is short (2 years or less for all patients). ALCL is a rare subtype of non-Hodgkin’s lymphoma, with a young median age at diagnosis of 34 years and a male predominance of 69%, accounting for 2% of newly diagnosed lymphoma.10 Risk factors for the development of lymphoma include family history, autoimmune disease, immune system deficiency (such as following organ transplantation or human immunodeficiency virus infection) and exposure to radiation or carcinogenic chemicals.11 None of the
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Fig. 4. Case 3: Macroscopic view of capsule upon removal.
Table 1 Staging of lymphoma Stage
Description
Stage 1 Early disease
One group of lymph nodes affected
Stage 2 Locally advanced disease
Two or more groups of lymph nodes affected on the same side of the diaphragm
Stage 3 Advanced disease
Two or more groups of lymph nodes affected on both sides of the diaphragm
Stage 4 Widespread disease
Lymphoma has spread beyond the lymph nodes to other organs
A or B
A = No constitutional symptoms B = Presence of constitutional symptoms
E
Extranodal lymphoma (lymphoma arising outside of the lymph nodes)
patients in this series had any previous history of known risk factors for ALCL. The diagnosis of ALCL is based on the presence of malignant cytology, strong CD30 expression and the exclusion of epithelial malignancy.12 Diagnosis of breast implant-associated ALCL therefore relies on the identification of highly atypical lymphoid cells. These are large, epithelioid and pleiomorphic, with frequent mitoses.13 ‘Hallmark’ cells with eccentric, horseshoe or kidney-shaped nuclei and perinuclear density are often present within the effusion fluid or tissue.14 ALCL is divided into two groups, the first being primary cutaneous ALCL, usually affecting older patients and with excellent prognosis, and the second being systemic nodal ALCL, which is subdivided into ALK-positive and ALK-negative disease. ALK is most commonly overexpressed. Lymphoma prognosis is related to the subtype and stage of the disease, with staging depending on the location and dissemination of the disease (Table 1). Typically, ALK-positive ALCL is correlated with younger age groups and has a more favourable clinical outcome with better 5-year survival than ALK-negative ALCL (5-year survival range 71–100% for ALK-positive compared with 15–45% for ALK-
negative disease).10,15 The ALK-negative group is heterogeneous in clinical outcome but generally has a worse prognosis.15 Primary lymphoma of the breast is even less common than systemic ALCL, accounting for less than 1% of all non-Hodgkin’s lymphoma and less than 1% of all cases of primary breast malignancy.8 Overall, an estimate in population-based studies puts the rate of ALCL at 0.1 per 100 000 women, with or without breast implants.16 Given the infrequent observation of the disease, epidemiological studies to assess the risk of non-Hodgkin’s lymphoma in women with breast implants compared with women without breast implants have not confirmed any association between breast implants and an increased risk of developing ALCL. However, a true association has not been ruled out either.3 In contrast to typical systemic ALCL, breast implant-associated ALCL is commonly ALK-negative. Despite this, the prognosis is generally favourable4,17 although not exclusively, as extranodal disease and death from disease progression have been reported.9,18 Recent literature suggests that cutaneous, solid- or mass-forming ALCL has a worse prognosis than effusion-type disease limited to the seroma fluid or capsule alone. Miranda et al. from the MD Anderson Cancer Centre in the United States recently reviewed the literature to assess the treatment and outcomes of 60 patient with breast implant-associated ALCL between 1997 and 2012.19 Treatment was variable between patients but 93% underwent explantation and capsulectomy, 78% received systemic chemotherapy, 7% received radiotherapy alone and 21% did not receive any adjuvant therapy. The median follow-up in their study was only 2 years but still they were able to show that patients who present with a mass had worse overall survival and progression-free survival, with no difference shown between those who received chemotherapy and those who did not. Most patients (93%) with disease confined to the capsule achieved complete remission compared with only 72% of those who presented with a tumour mass. Therefore, while good outcomes from this disease are commonly recorded, there is mounting evidence of the potential for aggressive clinical behaviour in some cases.20 Current literature seems to support the assessment of the patient for evidence of extranodal spread of the disease to accurately stage the disease but may not support offering adjuvant treatment in Stage 1E disease, when disease is limited to the effusion fluid or capsule.21,22
Evidence for the management of breast implant-associated ALCL While no formal treatment recommendations are in place for breast implant-related ALCL, a multidisciplinary panel of experts was recently convened in the United States to review the issue.21 The panel strongly agreed that aspiration and cytological evaluation of a late seroma around a breast implant should be performed at both the first occurrence and especially in recurrent cases, which is in agreement with other literature.21,23 The team at University of Southern California, led by Dr Brody, have collected 103 cases of breast implant-associated ALCL and reviewed the immunohistochemistry findings for 87 of these cases.22 The lead investigator personally recommends performing a total capsulectomy, facilitated by tumescing the posterior capsule (as we found necessary in case 2), and marking any suspicious or particularly adherent sites for biopsy © 2015 Royal Australasian College of Surgeons
Variable presentation of ALCL
5
Fig. 5. Management of suspected breast implant-associated anaplastic large-cell lymphoma (ALCL).
Suspect ALCL?
Obtain ssue or fluid sample for diagnosis: • Seroma – Ultrasound-guided aspiraon • Mass – Incisional or excisional biopsy Discuss case in advance with pathologist Send sample fresh (not in formalin) Cytology and histology assessment Flow cytometry, cytogenecs, fluorescent in situ hybridizaon if required
Negave
Posive
• • •
Surgery: Explantaon Total capsulectomy +/- Excision of mass
• • •
Roune management. Consider the possibility of a false negave; send further samples if there is significant clinical concern or if any further surgery is undertaken
Staging: Computed tomography scan (chest, abdomen, pelvis) Positron emission tomography scan if required Consider bone marrow aspirate
Refer to haematology/oncology for review and consideraon of adjuvant treatment
by the pathologist, as the tumour may not involve the entire capsule.22 Indeed, Talagas et al. recently discussed the diagnostic challenge that ALCL can pose for pathologists.24 They gave the example of breast implant-associated ALCL which was diagnosed on aspiration of an effusion but stated that repeated biopsies of the capsule showed fibrous tissue only without tumour proliferation. They noted that only meticulous histological examination of the total capsulectomy specimen identified tumour cells as a thin, discontinuous layer along the inner surface of the capsule without capsular invasion. Therefore, communication with the pathologist is vital in making an accurate diagnosis and the likely diagnosis should be clearly indicated when specimens are sent. As there have been several cases of bilateral disease, Dr Brody feels that it is prudent to remove the other implant and capsule also. The expert panel agree with his suggestions for management of the affected breast but are uncertain about the most appropriate management of the contralateral implant.21
Guidelines for management of suspected breast implant-associated ALCL We recommend that any unexplained, late (more than 1 year after surgery) seroma in the absence of infection be aspirated and the fluid sent for cytological evaluation. If ALCL is known or suspected, fluid and any tissue should be sent fresh (not in formalin). This facilitates © 2015 Royal Australasian College of Surgeons
cytological and histological examination, as well as flow cytometry and fluorescent in situ hybridization for cytogenetic analysis (if available) to be performed to assist with the diagnosis. If breast implant-associated ALCL is confirmed, treatment should comprise explantation of the device, total capsulectomy and excision of any mass (if present). Patients should be staged with CT scan of the chest, abdomen and pelvis to assess for the presence of other disease locations. PET scan and bone marrow aspirate may be performed if necessary. All patients should be referred to the appropriate haematology or lymphoma centre for consideration of adjuvant treatment (Fig. 5). The patients in our series were treated in accordance with these guidelines by the senior author. However, in neither case of late seroma presentation was the seroma aspirated by the breast surgeons who were initially caring for the patient. All patients underwent explantation and total capsulectomy. All were staged with CT scans of the chest, abdomen and pelvis. The patient in case 1 also underwent bone marrow aspirate, along with excision of the palpable mass while the patient in case 2 had a PET scan following her CT scan. As the first patient had a tumour mass, she was treated with systemic CHOP chemotherapy, a common chemotherapeutic regime for lymphoma. In cases 2 and 3, the disease was confined to the effusion fluid only so these women were treated surgically with no adjuvant treatment.
6
Conclusions Breast implant-associated ALCL can present with a painful seroma, a painless seroma or a palpable mass. Other possible presentations include constitutional symptoms such as fevers or night sweats, capsular contracture and general malaise. Alternatively, the disease can be an unexpected finding following capsulectomy for cosmetic or other reasons. Surgical treatment comprises explantation, total capsulectomy and excision of any mass. Prognosis is favourable overall, with 100% of patients with effusion-type ALCL and 75% of patients with cutaneous (solid- or mass-forming) ALCL tumours surviving at 5 years post-diagnosis.19 Given that the cutaneous subtype seem to have a worse prognosis, these patients may benefit from systemic chemotherapy. However, if the patient has no symptoms to suggest systemic lymphoma and no evidence of local, regional or metastatic disease (i.e. stage 1E on presentation with complete surgical excision of disease), it may be appropriate to forgo adjuvant treatment. All breast surgeons and physicians working in this field should be mindful of the possible diagnosis. Only by capturing all cases of the disease and sharing the information with the international community will we be able to establish the true incidence and causative factors of breast implant-related ALCL.
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9. Taylor KO, Webster HR, Prince HM. Anaplastic large cell lymphoma and breast implants: five Australian cases. Plast. Reconstr. Surg. 2012; 129: 610e–7e. 10. Armitage JO, Weisenburger DD. New approach to classifying nonHodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J. Clin. Oncol. 1998; 16: 2780–95. 11. Society AC What are the Risk Factors for Non-Hodgkin Lymphoma? Georgia, USA. [updated 2015; Cited 5 Jan 2015.] Available from URL: http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/ non-hodgkin-lymphoma-risk-factors 12. Falini B, Martelli MP. Anaplastic large cell lymphoma: changes in the World Health Organization classification and perspectives for targeted therapy. Haematologica 2009; 94: 897–900. 13. Xu J, Wei S. Breast implant-associated anaplastic large cell lymphoma: review of a distinct clinicopathologic entity. Arch. Pathol. Lab. Med. 2014; 138: 842–6. 14. Chai SM, Kavangh S, Ooi SS et al. Anaplastic large-cell lymphoma associated with breast implants: a unique entity within the spectrum of peri-implant effusions. Diagn. Cytopathol. 2014; 42: 929–38. 15. ten Berge RL, Oudejans JJ, Ossenkoppele GJ, Meijer CJ. ALK-negative systemic anaplastic large cell lymphoma: differential diagnostic and prognostic aspects – a review. J. Pathol. 2003; 200: 4–15. 16. de Jong D, Vasmel WL, de Boer JP et al. Anaplastic large-cell lymphoma in women with breast implants. JAMA 2008; 300: 2030–5. 17. Kim B, Roth C, Chung KC et al. Anaplastic large cell lymphoma and breast implants: a systematic review. Plast. Reconstr. Surg. 2011; 127: 2141–50. 18. Carty MJ, Pribaz JJ, Antin JH et al. A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast. Reconstr. Surg. 2011; 128: 112e–8e. 19. Miranda RN, Aladily TN, Prince HM et al. Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients. J. Clin. Oncol. 2014; 32: 114–20. 20. Mazzucco AE. Next steps for breast implant – associated anaplastic large-cell lymphoma. J. Clin. Oncol. 2014; 32: 2275–6. 21. Kim B, Roth C, Young VL et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast. Reconstr. Surg. 2011; 128: 629–39. 22. Brody GS. Brief recommendations for dealing with a new case of anaplastic large T-cell lymphoma. Plast. Reconstr. Surg. 2012; 129: 871e–2e. 23. 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: 1–7. 24. Talagas M, Uguen A, Charles-Petillon F et al. Breast implant-associated anaplastic large-cell lymphoma can be a diagnostic challenge for pathologists. Acta Cytol. 2014; 58: 103–7.
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