Breast Implant Associated Anaplastic Large Cell Lymphoma(ALCL)

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Important scientific discoveries have always started with an observation. Profound scientific advancements have begun with an observation of a seemingly mundane phenomenon and testing a hypothesis formed from intuition. 

It is significant that several recent studies reported that patients who received breast augmentation surgeries using textured implants experience a higher incidence of ALCL (anaplastic large cell lymphoma). Comparing the properties of the textured shell to the smooth shell and analyzing how they can relate to the pathophysiology of ALCL can help us find important clues for preventing serious complications such as capsular contracture. In Korea, ALCL is not given enough attention and it is important that more plastic surgeons started learning about ALCL.

The first case of breast implant associated ALCL (BIA-ALCL) was reported in 1997 by John A. Keech Jr. He reported a case of anaplastic T-cell lymphoma developing in a 41-year-old woman who received a breast augmentation using saline implants (John A. Keech Jr., ANAPLASTIC T-CELL LYMPHOMA IN PROXIMITY TO A SALINE-FILLED BREAST IMPLANT. Keech, John A. Jr. D.O., F.A.C.O.I. Plastic & Reconstructive Surgery: August 1997 – Volume 100 – Issue 2 – ppg 554-555).

Previous to the above report, a dermatologic study reported three cases of cutaneous T-cell lymphoma in association with silicone breast implants. However, the association was only a conjecture and was not scientifically supported (Duvic, M.,Moore,D., Cutaneous T-cell Lymphoma in Association with Silicone Breast Implants. J. Am. Acad . Dermatol. 32:939,1995).

Keech reported that a small mass was felt in the lateral right breast of a patient who received bilateral breast augmentation with McGhan’s textured shell round type implants 4 years ago. In 1996, the mass grew larger and excisional biopsy confirmed anaplastic large cell lymphoma.

Image 1. ALCL CT image (Source: Keech’s report).
On CT imaging, lymphoma is seen surrounding the right breast implant and scattered axillary lymph nodes can be observed (Image 1). The patient received chemotherapy and achieved complete resolution. Radiation therapy was carried out and complete clinical recovery was achieved. Implants were not removed and did not obstruct chemotherapy or radiation therapy. The aesthetic appearance was not compromised after cancer treatment. However, the association between saline implants and non-hodgkin’s lymphoma could not be clarified with this single case.

At the time of publication of this study, there was a growing concern over a possible association between silicone breast implants and autoimmune diseases and breast cancer in the US. The academia was too preoccupied with in this concern that the rare association between silicone breast implants and ALCL seemed much less important at the time. 

However, other reports of ALCL developing after breast augmentation with silicone implants followed. In 2011, FDA issued an announcement recognizing breast implant associated ALCL. However, the association was not scientifically confirmed. 

International discussions and public interest in this topic grew drastically following FDA’s announcement. Currently, BIA-ALCL is a hot issue in the field of plastic surgery. Many studies called for inclusion of the risk of ALCL in the consent gathering before surgery. However, others have also argued that due to the rarity of ALCL and lack of proven causality, it does not warrant mentioning the risk of ALCL during the consent gathering phase.  

ALCL is a rare condition. However, different studies report a wide range of different rates and such inconsistent reports can be confusing to a clinician. Just how rare is ALCL? And what is the real risk of ALCL in patients who receive breast augmentation using implants?

Etiology of BIA-ALCL

Pittman et al. explained there have been at least 193 cases of BIA ALCL worldwide (Anaplastic Large Cell Lymphoma: Emerging Consent and Management Patterns among American and International Board Certified Plastic Surgeons, Pittman, Troy A.; Fan, Kenneth L.; Rudolph, Megan A. Plastic & Reconstructive Surgery. 138(5):811e-818e, November 2016). Others have reported that there have been 173 cases.

In 2008, de Jong et al. reported that the prevalence of BIA-ALCL is only 1 out of 1 million based on a Dutch database. However, in a more recent study, they reported that the prevalence is one out of 30,000 (de Jong D, Vasmel WL, de Boer JP, et al. Anaplastic large cell lymphoma in women with breast implants. JAMA 2008;300:2030~2035).

Doren et al. examined the data base for ALCL from 1996 to 2015 and found that it occurred only with textured shell implants at the annual incidence of 2.03 out of 1 million. This is 67.6 times higher than the incidence of primary ALCL in normal breasts. The lifetime prevalence was 33 out of 1 million (U.S. Epidemiology of Breast Implant Associated Anaplastic Large Cell Lymphoma: Doren, Erin L. M.D.; Miranda, Roberto N. M.D. Plastic & Reconstructive Surgery: May 2017 – Volume 139 – Issue 5 – p 1042~1050).

Such a large discrepancy in terms of incidence and prevalence of BIA-ALCL in literature is very confusing. However, there is a trend toward later studies reporting higher rates of BIA-ALCL. I wonder if previous studies have failed to recognize important cases. It is possible that with more attention being given to BIA-ALCL recently, more cases are being recognized. Despite the growing interest in BIA-ALCL, its risk may still be underestimated.

Pitman et al. emphasized that BIA-ALCL tends to be underreported and cited a report by Brody et al. on 23.7% of BIA-ALCL being underreported.

Most plastic surgeons are still not mentioning the risk of BIA-ALCL to their patients and it is not included in the informed consent form either.  

FDA announcement

In March 2017, FDA made an announcement on the significantly higher association between ALCL and breast augmentation using textured shell implants as opposed to smooth shell implants. CNN was quick to report this with a very eye-catching headline.



In August 2017, FDA updated the announcement based on collaboration with other agencies and a more extensive literature review.  

WHO recognized BIA-ALCL as a rare T-cell lymphoma occurring after breast implant placement.

FDA received medical device reports of 359 cases, 9 of which ended in death. Only 231 cases included the type of implant used and 203 cases had textured shell implants and 28 smooth shell implants.

Based on the above figures, FDA issued recommendations to health care providers and patients. FDA recommendation to health care providers can be summarized as following; As BIA-ALCL mostly occurred with the textured shell, inform the patients of the benefits and risks of different types of implants before surgery. Suspect BIA-ALCL if late seroma is seen around the implant and refer the patient to an appropriate specialist. For ALCL screening, collect seroma fluid and a piece of the capsule and send to pathology. Diagnostic screening involves cytological testing using wright giemsa stain of the seroma fluid and cell block immunohistochemistry (for verifying CD and ALK markers). Report all confirmed cases to FDA.

FDA recommended against removing implants for fear of this disease without specific problems.

Clinical manifestation and pathophysiology

BIA-ALCL manifests itself as late seroma, a mass attached to the capsule, an infiltrating tumor or regional LN (cutaneous ALCL is excluded).

Gidengil et al. reported that most cases presented seroma (76%) and 48% of cases showed capsule-related symptoms. Most of the cases received chemotherapy and radiation therapy and 11% received stem cell transfer. ALCL recurred in about a quarter of the patients and 9% died (Breast Implant Associated Anaplastic Large Cell Lymphoma: A Systematic Review, Gidengil, Courtney A. M.D., M.P.H.; Predmore, Zachary B.A.; Mattke, Soeren M.D., D.Sc.; van Busum, Kristin M.P.A; Kim, Benjamin M.D., M.Phil., Plastic & Reconstructive Surgery: March 2015 – Volume 135 – Issue 3 – p 713–720).

ALCL is CD30+ NHL and makes up 3% of NHL and 0.5% of all breast cancer cases.

Due to the rarity of the disease, it is hard to verify association with the implant. Therefore, the term BIA-ALCL is used for convenience rather than scientific accuracy. WHO has categorized ALCL as ALK-. Primary cutaneous ALCL has 90% 5-year survival. The 5-year survival rate is 70% with Alk+ and 49% with Alk-.

However, despite being Alk-, BIA-ALCL shares the positive prognosis of cutaneous ALCL. Therefore, BIA-ALCL may be a unique disease category. It is a malignant tumor but has a very favorable prognosis and is definitely curable. 

Etiology

Hu et al. provided a very important finding in their study on ALCL’s association with capsular contracture. They found a bacteria load in both the ALCL specimen and nontumor capsule sample (obtained from a contracture case). Interestingly, staphylococcus spp. was a dominant strain in the nontumor capsule, whereas ralstonia spp. was found in the ALCL specimen (Bacterial Biofilm Infection Detected in Breast Implant-Associated Anaplastic Large-Cell Lymphoma, Hu, Honghua Ph.D.; Johani, Khalid; Almatroudi, Ahmad; Vickery, Karen Ph.D., B.V.Sc, Plastic & Reconstructive Surgery: June 2016 – Volume 137 – Issue 6 – p 1659-1669).

Ralstonia spp. is a pathogenic gram negative bacterium. It is surprising that it was found in the ALCL specimen as it is commonly infected through contaminated medical solutions. Ralstonia spp. is known to cause serious soft tissue or implant related infection. It has intrinsic resistance to current prophylactic antibiotics or aminoglycoside.

The finding that a majority of ALCL cases occurred with textured shell implants is in agreement with the higher biofilm load of textured shell and proportionally higher T-cell hyperplasia.

Hu et al. pointed out that infection with Ralstonia may have caused lymphoma around the implant much like the infection with Helicobacter Pylori is a major cause of gastric marginal zone lymphoma.

That is, there may be two inflammatory pathways. Biofilm of gram positive strains leads to fibrosis and capsular contracture, whereas, gram negative biofilm leads to lymphocyte stimulation and transformation (eventually, lymphoma).

Although these suspicions need be supported by scientific data, they are still meaningful. We may achieve much more advanced knowledge on etiology of capsular contracture and ALCL by extensively studying the human body’s biochemical reactions to microorganisms. What we know so far is there is an association between biofilms and ALCL and different bacterial strains are involved in ALCL and capsular contracture. There is no proof of a causal link between bacteria and ALCL.

Finally, I would like to ask this question; Why was not a single case of BIA-ALCL reported in Korea?

In the US, the textured breast implants were first introduced in the 1980s and widely used in the 1990s. Cases of ALCL started being reported about 10 years later. This timeline makes sense as chronic biofilm infection gradually causes inflammation, immune activation, and subsequent transformation. Although there are no official statistics, it is true that breast augmentation surgeries drastically increased in the mid 2000s in Korea, following MFDS’s approval of cohesive gel (and textured shell implants). Considering the majority of patients were in their 20s and 30s and malignant tumors tend to affect an older age group, the incidence of ALCL may be delayed in Korea by a few years compared to other countries.

Various countries have reported a widely varying rates of BIA-ALCL. For example, there were a much higher number of cases in Australia and New Zealand and a lower number of cases in Europe. So far, no cases have been reported from Korea, Japan and several European countries. However, there is no denying that ALCL is a very important issue around the world. Korea may not be forever unaffected by it. I hope my fellow health care providers become more interested in BIA-ALCL. There needs to be more data and information about the risk of BIA-ALCL associated with textured implants and it should be included in the consent gathering phase prior to surgery. ALCL may be a rare condition with favorable prognosis and it is true there have been no reported cases in Korea. It is, nonetheless, a malignant tumor and all measures should be in place to prevent it. 


The article was published on the D&PS website. 

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