Advanced Disease Case Examples
- Lymph node involvement: A 51-year-old woman with BRCA2 mutation underwent prophylactic bilateral skin-sparing mastectomies and immediate reconstruction with tissue expanders and textured silicone implants in 2001. In 2007, she underwent an implant exchange with textured silicone implants. In July 2014, she presented with painful swelling of her left breast. Left breast ultrasound revealed a pericapsular fluid collection, which demonstrated an anaplastic large T-cell lymphoma. She underwent bilateral partial capsulectomy with implant removal in August 2014. For surveillance, a follow-up positron emission tomography/computed tomography (PET-CT) scan was done in December 2014, which showed interval development of left internal mammary lymphadenopathy (LAD). She was treated with 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, and follow-up PET-CT demonstrated resolution of the internal mammary LAD, but interval development of left supraclavicular LAD with malignant cells confirmed by fine-needle aspiration. She then underwent 3 cycles of brentuximab vedotin immune therapy with complete response demonstrated on follow-up PET-CT. She was then treated with an allograft stem cell transplantation and remains disease free for 3 years.
- Bilateral breast involvement: A 72-year-old woman developed left invasive breast cancer and was treated with bilateral mastectomies and bilateral latissimus flaps with textured silicone implants (Figs. 2 and 3). Postoperative course was uneventful until 2014 when she developed acute swelling of the left breast. Fine needle aspiration revealed BIA-ALCL on cytology, flow cytometry, and CD30 immunohistochemistry. Patient underwent left explantation and total capsulectomy with resection of a 5 cm mass invading through the capsule. Patient was disease free until 2016 when she developed right axillary LAD. A right explantation, capsulectomy, and selective lymphadenectomy were performed. Pathology demonstrated BIA-ALCL on the luminal surface of the right implant with reactive, but disease-free lymph nodes. Patient was considered to have 2 separate BIA-ALCL primary diseases (left stage IIA and right stage IC), received no further treatments, and remains disease free for 18 months.
- Death from disease: A 38-year-old woman received bilateral cosmetic breast augmentation with silicone textured implants in 1987. Postoperative course was uneventful until 1996 when she palpated a 4 × 3 cm mass in her left breast. She underwent a fine needle aspiration of the periprosthetic capsular mass and was diagnosed as CD30+ ALK− ALCL. The patient was very adamant that she wanted to retain her implants for appearance reasons and declined ablative surgery against medical advice. She received CHOP chemotherapy followed by regional external beam radiation therapy, however, developed recurrence of disease within 4 months of adjunctive treatment. Disease progressed to central nervous system involvement with meningeal disease, and she expired after an additional 5 months.
BIA-ALCL is an uncommon extranodal T-cell lymphoma associated with textured surface breast prostheses. BIA-ALCL is commonly regarded as having an indolent clinical course, and the majority of patients achieve complete remission with surgery alone. However, there exists a subset of BIA-ALCL patients who display characteristics of advanced disease marked by persistent and recurrent growth which can be refractory to treatment. For the purpose of this study, advanced disease includes those patients with bilateral disease, lymph node or organ involvement (stage IIB-IV), and/or death related to BIA-ALCL. In this study, we reviewed 39 patients with BIA-ALCL with advanced features, including 7 with bilateral disease, 24 with lymph node or organ involvement, and 8 who died from BIA-ALCL. We compared treatment and outcomes to 65 patients with early-stage (stage IA-IC) BIA-ALCL.
With regard to treatment, patients with BIA-ALCL with advanced features had higher rates of limited surgery, chemotherapy, salvage chemotherapy, external beam radiation therapy, and autologous stem cell transplantation when compared with a control group of early-stage BIA-ALCL. The rate of definitive surgery (explantation, total capsulectomy, tumor ablation) was significantly lower in patients with advanced BIA-ALCL (59.3% versus 87.7%, P = 0.002). Additionally, the time to definitive surgery was significantly longer in patients with advanced features (21 versus 8 months, P = 0.028). When evaluated by group, no patients who died of BIA-ALCL underwent definitive surgery, and patients with lymph node involvement and bilateral disease had lower rates of definitive surgery when compared with those without advanced features (62.5% versus 87.7%, and 50% versus 87.7%, respectively). Definitive surgery was also significantly correlated with higher rates of complete remission in patients with advanced BIA-ALCL (78.9% versus 21.1%, P = 0.003).
These data suggest that early definitive surgery plays a significant role in the treatment of BIA-ALCL. A smaller percentage of patients with advanced features were treated with definitive surgery, and the time from diagnosis to definitive surgery in this group was significantly longer. Furthermore, definitive surgery was significantly associated with a higher rate of complete remission in BIA-ALCL patients with advanced features. This suggests that patients who are treated with early definitive surgery are less prone to disease progression and more likely to have better outcomes. This also indicates that patients with advanced BIA-ALCL may have developed more advanced disease as a result of delay in treatment or inadequate therapy such as limited or incomplete surgery.
Outcomes were also significantly different between BIA-ALCL patients with and without advanced features. Patients with advanced features had higher rates of death from ALCL and death from an unrelated disease (22.2% versus 0% and 7.4% versus 0%, respectively) and lower rates of complete remission (70.4% versus 100%). Eight patients died from BIA-ALCL, and of these, 4 patients had lymph node involvement, and 1 patient had lymph node involvement and bilateral disease. When divided into groups, patients with lymph node involvement had higher rates of death related to BIA-ALCL (20.8% versus 0%) and death of an unrelated disease (8.3% versus 0%) and lower rates of complete remission (70.8% versus 100%). This suggests that BIA-ALCL patients with lymph node and organ metastasis are less likely to achieve complete remission and more likely to die from their disease than patients without advanced features; however, definitive conclusions are difficult to make with such a small cohort size with widely varied treatment strategies.
A definitive treatment algorithm for patients with advanced and/or refractory disease has yet to be determined. National Comprehensive Cancer Network guidelines provide the current standard of care which includes surgical management, including implant removal, total capsulectomy, and resection of any associated masses and involved lymph nodes with negative margins. Additional treatment for patients with advanced disease after surgery such as lymph node or organ involvement or unresectable tumor has included standard front-line treatment regimen with a combination anthracycline-based chemotherapy or alternatively with targeted immune therapy with brentuximab vedotin.
The main limitation of this study is small sample size. BIA-ALCL is an uncommon disease entity, and only 644 unique worldwide cases are currently known to our institution. Only 104 cases had detailed clinical history and treatment timeline information sufficient to include in this study, and of those, only 39 patients had advanced BIA-ALCL. As awareness of BIA-ALCL and its presentation in patients with breast prostheses increases, the number of patients identified with disease continues to grow. It is expected this will allow further investigation of these patients, their treatment, and outcomes. It is important to note that the advanced cases presented in this manuscript were centralized from the United States and Brazil. Currently, the relative proportion of advanced BIA-ALCL cases is disparate between countries with stage IIB-IV disease being reported as 18% in Italy, 13.8% in the United States, 9.5% in England, and 3.6% in Australia.8 These observed differences between countries may be secondary to differences in surgeon awareness, physician willingness to report cases, and the underlying medicolegal environment, though this remains speculative. Another potential limitation of this study is the incomplete history provided for some advanced disease patients. The majority of detailed clinical information was obtained about the subjects in this study; however, for certain cases, we were unable to obtain a complete history. For example, of the 39 patients with advanced features, it is unknown if 3 patients had limited surgery, 4 patients had salvage chemotherapy, and 2 patients had autologous stem cell transplantation. Thus, when evaluating patients who received each treatment, only the known number of patients was utilized for each category. Despite this small number of unknowns, we believe this is unlikely to significantly change the data and conclusions.
The data from this retrospective review of advanced disease BIA-ALCL patients suggest that this disease is likely not a distinct clinical entity separate from the more indolent or early-stage BIA-ALCL, but instead represents disease that has progressed. Fewer patients with BIA-ALCL with advanced features were treated with definitive surgery, and there was a significantly longer time from diagnosis to definitive surgery when compared with patients without advanced features. Patients who developed lymph node or organ involvement, bilateral disease, and/or death related to BIA-ALCL may have ultimately suffered from advanced disease as a result of a delay in treatment or incomplete therapy. Currently, we recommend initial treatment with en bloc implant removal, total capsulectomy, and excision of involved lymph nodes and associated masses, with negative margins for all patients with BIA-ALCL (Fig. 1). Definitive surgery has proven to increase the rate of complete remission in patients with BIA-ALCL. Of note, within this study, rapid disease was observed in 5 patients who had limited surgery and partially retained a mass. Disease progressed to a rapidly invasive chest wall mass or organ metastasis within months, suggesting that the BIA-ALCL, while usually indolent, may exhibit hyperprogression, an oncologic phenomenon reflecting a very rapid tumor progression when partially incised. Infiltration of breast ducts was uniquely noted in 2 aggressive cases that ultimately died of their disease. Predictors of hyperprogression are not possible to identify within these limited number of patients. Advanced disease patients support the World Health Organization classification of BIA-ALCL as a lymphoma. Whether early-stage effusion-limited disease will always progress to advanced disease or requires additional mutational degeneration has yet to be determined but is the subject of genetic sequencing analysis.
Advanced disease does not appear to be a unique clinical entity, but rather a progression of BIA-ALCL. BIA-ALCL patients with lymph node, organ involvement, and/or death related to BIA-ALCL likely developed advanced disease as a result of delayed or incomplete treatment. Bilateral disease may represent 2 separate primaries in a genetically susceptible patient rather than metastasis. Early recognition of symptoms and expedited treatment with definitive surgery appear to improve the rate of complete remission in patients with BIA-ALCL. Future randomized controlled trials will be needed to develop a definitive treatment algorithm for patients with advanced disease.
Data analyses were supported in part by the Cancer Center Support Grant (NCI Grant P30 CA016672).
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