What Is a Lymphoproliferative Disorder?

The National Cancer Institute defines an LPD as “a disease in which the cells of the lymphatic system grow excessively.” More specifically, an LPD is characterized by abnormal proliferation of lymphocytes into oligoclonal or monoclonal lymphocytosis, and possibly lymphadenopathy, when normal control mechanisms of lymphocyte proliferation are impaired. When this definition is applied to BIA-ALCL, the disease process can range from benign CD30 ⁺ peri-implant seromas to an invasive and potentially metastatic disease.

History of Breast Implant-Associated Anaplastic Large Cell Lymphoma

Anaplastic large cell lymphoma (ALCL) was first described in 1985 when it was found that atypical tumor cells consistently demonstrated a CD30 antigen; however, it was not until 1998 that ALCL was reported as a distinct entity. The first case report of ALCL and breast implants was first published by Keech and Creech in 1997. They reported a patient who underwent bilateral breast augmentation with McGhan Medical Corporation, Style 168 implants for mammary hypoplasia, and subsequently developed a CD30 ⁺ mass 5 years after the index operation. Since this original report, numerous other publications have noted an association between textured breast implants and ALCL.

As of July 24, 2019, the FDA reports an incidence of BIA-ALCL to range from 1 in 3817 to 1 in 30,000. Of note, although most of these patients have had textured implants, there have been reports of BIA-ALCL in patients with a history of multiple mixed implant types (ie, smooth and textured). However, to date, there has never been a documented pure smooth-only case of BIA-ALCL in any global registry or publication.

Is Breast Implant-Associated Anaplastic Large Cell Lymphoma a Lymphoproliferative Disorder?

Kadin and colleagues noted that BIA-ALCL is characterized by (1) an indolent localized (in situ) disease in approximately 80% of reported cases; (2) a requirement for external cytokine stimulation for cell survival; (3) CD30 ⁺ cells in some clinically benign seromas/capsules; (4) undetected T-cell clonality in some cases; (5) JAK/STAT mutations in only a minority of cases; and (6) cure by capsulectomy and implant removal in most cases. The investigators discuss the possibility of BIA-ALCL being reclassified to an LPD citing that BIA-ALCL resembles CD30 ⁺ cutaneous LPD in the following way: (1) ALK ⁻ biomarker; (2) both have CD30 ⁺ anaplastic cells with an aberrant T-cell phenotype; (3) overexpression of the same oncogenes ( JUNB , SATB1pSTAT3 , SOCS3 ) as in lymphomatoid papulosis; (4) frequent apoptosis; (5) can undergo total or partial spontaneous regression as in lymphomatoid papulosis or primary cutaneous ALCL (pcALCL), respectively.

From the clinical standpoint, BIA-ALCL clearly behaves as an LPD given its typically indolent course, high cure rate, and low micromort. Similar to pcALCL, which is classified as an LPD, BIA-ALCL and pcALCL have been shown to possess the same identical oncogenes and biomarkers. Although BIA-ALCL was originally classified as a lymphoma by the World Health Organization, members of the subcommittee acknowledge that they did not have extensive information regarding BIA-ALCL at the time of the classification and went with the most conservative classification. With additional clinical experience and data on the disease, experts have contended that BIA-ALCL is probably better classified as an LPD, because most patients fall on the indolent end of the spectrum of disease. It is important to understand the concept that an LPD is a spectrum of disease that ranges from benign/indolent to advanced disease. Similarly, BIA-ALCL exists on a continuum from a benign disease process (ie, CD30 ⁺ benign seroma) to advanced metastatic disease. Furthermore, approximately 10% of seromas are CD30 ⁺ , but nonmalignant, and thought to be part of this disease spectrum, which is typical of an LPD.

What Are the Potential Causes of Breast Implant-Associated Anaplastic Large Cell Lymphoma?

At the center of the BIA-ALCL controversy are textured breast implants. Textured implants with higher surface area and roughness are thought to subject the patient to a larger overall risk for the development of BIA-ALCL. In the updated Australia and New Zealand study, implant-specific risk was increased 23.4 times for Silimed Polyurethane textured implants compared with Biocell textured implants, which remained relatively static at 16.5 times higher when compared with Siltex textured implants. The thought behind the increased incidence of BIA-ALCL with certain textured implants is the degree of “roughness” and increased surface area, which encourages bacterial sequestration and growth leading to high levels of chronic inflammation. Interestingly, many surgeons have the clinical sense that textured implants gave them more stable long-term results over time, and although this is not proven and still debated, the textured surface coupled with proper technique resulted in a relatively controlled capsular modulation that produced a clinically thicker, more stable capsule. The difference from the transformative host responses that the typical microbiome around implants tends to be more gram-positive and anaerobic in this produced a more fibrotic host response, which went overexpressed, is what is called capsular contracture. In the case of BIA-ALCL, the textured device coupled with a gram-negative microbiome elicited a different host transformative response.

Furthermore, Silimed polyurethane textured implants have demonstrated a significantly higher rate of bacterial load and associated T-cell activation in animal models as well as human series of capsular contracture, some of which may be due to the known manufacturing defect of this implant whereby it had delamination and ultimately led to it being removed from the market. ^, The unification theory put forward by the Australian researchers includes the 4 following components in the pathogenesis:

• 1.
  

  Textured device to provide surface area for sequestration of bacteria

  
  
• 2.
  

  Specific microbiome producing high-level chronic inflammation

  
  
• 3.
  

  Genetic predisposition

  
  
• 4.
  

  Time

Of particular interest to BIA-ALCL are the case clusters of the disease noted in the Australian and New Zealand series and other reports across the globe. With almost ubiquitous use of textured implants around the world, the case clusters strongly suggest an infectious origin as the source of the chronic inflammation that induces and propagates the disease as formally alluded to. This observation indicates that although the textured implants play a role and provide an ideal environment for bacteria to grow and adhere, the implants alone are not the sole cause of BIA-ALCL. Indeed, previous work has shown that BIA-ALCL and nontumor capsule samples demonstrate a high yield of mean numbers of bacteria, with a greater proportion of bacteria being gram-negative bacteria . These findings of high levels of a single bacterial species (ie, Ralstonia ) or related gram-negative species, in conjunction with the textured implant’s ability to harbor bacteria, give overwhelming support to the significant role bacteria play in the development of BIA-ALCL. As previously discussed by the senior author, the theorized role that bacteria play in the development of BIA-ALCL is supported by the following ^, :

• 1.
  

  Textured implants grow higher numbers of bacteria with a direct correlation between implants with increased surface area having more bacteria.

  
  
• 2.
  

  T-cell propagation correlates with the bacterial burden in both animal and human studies.

  
  
• 3.
  

  The more textured or “rough” an implant surface is, the higher the numbers of bacteria and higher T-cell activation.

  
  
• 4.
  

  There is a proven biological pathway between bacterial infections to lymphoma in the setting of Helicobacter pylori infection.

As mentioned earlier, there has been no pure smooth-only case of BIA-ALCL, which is consistent with the scientific data. Specifically, sequestration of high loads of specific gram-negative bacteria over a long time means 8 years are required to produce this transformative host response. Obtaining a similar bacterial load and a smooth implant does not provide an environment where these bacteria can hide from the body, and thus, if that load is reached, the authors believe the implant becomes frankly infected and is removed, therefore breaking the chain of events required to produce BIA-ALCL.

Further research and attention should be focused on techniques and decreasing the bacterial burden at the index operation in hopes of preventing the inciting events leading up to BIA-ALCL.

Detection and Treatment of Breast Implant-Associated Anaplastic Large Cell Lymphoma

Early diagnosis of patients with BIA-ALCL is crucial to the treatment and management of the disease. According to the National Cancer Comprehensive Network guidelines, the most common presentation of BIA-ALCL is a large, spontaneous peri-implant fluid collection occurring at least 1 year, but on average 7 to 10 years, after the index operation. In the Australia and New Zealand study, more than 80% of patients of diagnosed BIA-ALCL presented with a peri-implant fluid collection. In addition to a peri-implant fluid collection, 8% to 24% of patients can present with a palpable mass and 4% to 12% of patients can demonstrate lymphadenopathy. Of note, less than 5% of patients exhibit systemic symptoms, including skin rash, fevers, or capsular contracture.

In patients presenting with an enlarged breast and concerned for possible BIA-ALCL, an ultrasound of the breast should be performed for evaluation of fluid collection, breast masses, and enlarged regional lymph nodes. The most common lymph node basins involved are axillary (93%), followed by internal mammary and supraclavicular nodes. Equivocal ultrasound examinations should be followed by an MRI for further evaluation. Once a peri-implant fluid collection is identified, a fine needle aspiration is performed to gather cells for cytologic evaluation and CD30 immunohistochemistry. Of note, CD30 is not pathognomonic for BIA-ALCL, because benign inflammatory cells can express this marker. Thus, diagnosis of BIA-ALCL requires careful clinicopathologic correlation, and surgeons should directly discuss their concern for BIA-ALCL with the pathologist. For staging of ALCL, please refer to Tables 1 and 2 .

Table 1

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