Breast Anaplastic Large Cell Lymphoma Research Articles

Systematic under-ascertainment of anaplastic large cell lymphoma cases in cancer registries: report from a comprehensive cancer center

IntroductionBreast implant-associated anaplastic large cell lymphoma (ALCL) has been rapidly rising in the US and around the world, leading to a mandated “black-box” label on all silicone- and saline-filled implants by the Food and Drug Administration (FDA). Because regulatory decisions in the US and around the world have been influenced primarily by risk estimates derived from cancer registries, it is important to determine their validity in identifying cases of ALCL. MethodWe reviewed all cases of ALCL submitted to the New York State Cancer Registry from a large comprehensive cancer center in New York City from 2007 to 2019. To determine the possibility of misdiagnosis or under-diagnosis of ALCL cases reported to cancer registries, we accessed the sensitivity and specificity of the ICD-O-3 codes 9714 (ALCL) and 9702 (Mature T-cell lymphoma, not otherwise specified [T-NOS]) to identify pathologically-proven ALCL. ResultsWe reviewed 2286,164 pathology reports from 47,466 unique patients with primary cancers. Twenty-eight cases of histologically-proven ALCL were identified. The sensitivity and specificity of the ICD-O-3 code 9714 (ALCL) were 82% and 100%, respectively. The sensitivity of the combined codes 9714/9702 (ALCL/T-NOS) was 96% and the specificity was 44%. ConclusionPrevious epidemiological studies that influenced regulatory decisions by the FDA may have systematically underestimated the risk of ALCL by at least 20%. We encourage updated global risk estimates of breast ALCL using methods that ensure adequate case ascertainment.

Erythematous, telangiectatic nodule within the melomental fold

Erythematous, telangiectatic nodule within the melomental fold

Risk of Anaplastic Large Cell Lymphoma After Post-Mastectomy Implant-Reconstruction for Breast Cancer

Approximately one in eight women in the United States is diagnosed with breast cancer and eligible for mastectomy with implant reconstruction. Although it has been suggested that patients with breast cancer or those who are at high risk for breast cancer may have an increased risk of anaplastic large cell lymphoma (ALCL) after breast implantation, no studies have explored the association in this population. Our objective was to determine the relative and absolute risks of breast ALCL after post-mastectomy implant reconstruction for breast cancer compared with the general population.This population-based study obtained incidence data on breast ALCL in the general population from the Surveillance, Epidemiology, and End Results (SEER) program from 2000 - 2017. Patients who underwent post-mastectomy implant reconstruction for primary breast cancer from 2000 - 2016 were identified and followed through 2017. Because breast implant-associated ALCL has been documented as early as 2 months after implantation, patients with less than two months of follow-up were excluded. Observed-to-expected ratios for breast ALCL were derived from multiple primary - standardized incidence ratios in the study population versus the general U.S. population after adjusting for age, sex, race, anatomical site, and year of diagnosis. For external validation, we compared the number of cases of breast ALCL diagnosed in SEER with the estimated number of FDA-reported cases over a similar time period.The incidence rate of breast ALCL in the general U.S. female population was 0.08 - 0.12 per 1,000,000 persons per year and was rising. 52,882 women were identified that received post-mastectomy implant reconstruction for primary breast cancer and were followed for a median of 69 months, including 10,979 patients with follow-up time greater than or equal to 10 years (range 2 - 215 months). After adjusting for demographical characteristics of the cohort, the expected incidence rate of breast ALCL was 0.25 - 0.34 per 1,000,000 persons per year versus an observed rate of 5.8 - 8.7 per 1,000,000 persons per year (standardized incidence ratio 23.4 [95% confidence interval 2.8 - 84.7]). These findings corresponded well with FDA-reported cases; 353 SEER versus 333 FDA cases, respectively.Although breast cancer patients who receive post-mastectomy implant reconstruction are at increased risk of breast ALCL, the absolute risk remains extremely low. Furthermore, the risk does not appear to be increased compared to patients that receive implantation (for cosmesis or reconstruction) in previously reported literature.

Incidence of Anaplastic Large Cell Lymphoma and Breast-Implant-Associated Lymphoma-An Analysis of a Certified Tumor Registry over 17 Years.

Background: Breast-implant-associated anaplastic large cell lymphoma (BI-ALCL) and primary breast ALCL are rare extranodal manifestations of non-Hodgkin lymphoma. The rarity of both diseases, along with unreleased sales data on breast implants and constant updates of classification systems impede the calculation of an exact incidence. Methods: The database of the Tumor Center Regensburg in Bavaria was searched for patients with CD30-positive and ALK-negative anaplastic large cell lymphoma between 2002 and 2018. These lymphomas were identified by the ICD-O-3 morphology code “97023” and were cross-checked by searching the diagnosis by name the and ICD-10 code C84.7. Furthermore, we tried to calculate the incidence rates and corresponding 95% confidence intervals, standardized to 1,000,000 implant years of breast-implant-associated anaplastic large cell lymphoma and primary breast anaplastic large cell lymphoma. Results: Twelve ALK-negative and CD30-positive anaplastic large cell lymphomas were identified out of 170,405 malignancies. No case was found within the breast tissue and none of the patients had a previous history of breast implant placement. In five cases, lymph node involvement in close proximity to the breast was observed. Conclusion: We found a low incidence of anaplastic large cell lymphoma and no association to breast implants in these patients. A review of the current literature revealed inconsistent use of classification systems for anaplastic large cell lymphomas and potential overestimation of cases.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has recently been recognised, and so far approximately 200 cases have been described worldwide. From a histopathological and molecular perspective, it does not differ from classical breast anaplastic large cell lymphoma without ALK kinase expression. However, it has a different clinical course and prognosis, with a five-year survival rate about 92% as compared to 20–50% in patients with the classic form. A 60-year-old female patient had undergone bilateral mastectomy at the age of 45 years due to fibrocystic mastopathy and frequent breast cancer in her family history. Her implants were changed twice due to rupture. In 2018 the patient noticed a growing swelling of the right breast and fluid accumulation in the implant pouch; in September 2018 both implants were removed together, with the pouch also thoroughly removed during the procedure, and other PolyTech implants were inserted. Histological examination revealed the following: breast implant-associated anaplastic large cell lymphoma, immunophenotype: CD30+, ALK–, CD68, PGM–, CKAE1/AE3–, Ki 67 in 90% of cell nuclei. The patient was in very good general condition and without abnormalities in haematological tests. In PET-CT with 18F-FDG (13/12/2018), areas of slightly increased 18F-FDG activity were found in the vicinity of the implants on the right side (SUV max = 1.9) and on the left side (SUV max = 2.3), in addition to left axillary lymph node 12 × 7 × 8 mm (SUV max = 2.0). The patient did not decide to go ahead with the proposed removal of the implants, and a suspicious node was taken for examination — no cancer architecture was found. A control PET-CT test was performed after four months, the result of which was comparable to the previous one. The patient is under observation.

Anaplastic Large Cell Lymphoma of the Breast: Incidence, Patterns of Care, and Outcome in the US Population

Background:Anaplastic large cell lymphoma (ALCL) of the breast is a recently described clinicopathologic entity, almost always associated with breast implants, and does not overexpress the anaplastic lymphoma kinase (ALK) protein. Using the two largest US cancer databases, we describe its incidence, patterns of care, and clinical outcome.Methods:Incidence rate was calculated using 2000-2011 data from the Surveillance, Epidemiology, and End Results (SEER) Program and age-adjusted to the US 2000 standard population. For patient level data, we used the National Cancer Data Base (NCDB) Participant User File. We included all adult patients diagnosed from 1998-2011 with ALCL (ICD-O-3: 99714) who had breast as the primary site.Results:The incidence of breast ALCL was 0.001 per million. We identified 61 cases from NCDB. All of the patients were females and they were predominantly White (88.5%). The median age at diagnosis was 64 years (range, 18-90). The stage distribution was I (45.9%), II (21.3%), III (0%), IV (9.8%), and unknown (21.3%). The pattern of initial treatment was surgery alone (13.1%), chemotherapy alone (32.7%), chemotherapy and radiation (19.7%), surgery and chemotherapy (4.9%), surgery and radiation (4.9%), and tri-modality treatment (13.1%). In 7 patients (11.5%), no treatment was given. Two patients (1.6%) received stem cell transplant (1 autologous, 1 allogeneic) as part of initial treatment, one after chemotherapy and another one after surgery and chemotherapy. Overall survival data was available for patients diagnosed in 1998-2006 (29 patients). The median overall survival was 149.8 months (range, 2.6-157.9).Conclusions:ALCL of the breast is very rare. It presents mainly as early stage disease with very good prognosis. The patterns of care varied, although most patients received chemotherapy as part of the initial treatment.Table 1Treatment type receivedFrequencyPercentCumulative FrequencyCumulative PercentChemo only2032.792032.79Surgery only813.112845.90Chemo, Radiation, No surgery1219.674065.57Chemo, Surgery, No radiation34.924370.49Radiation, Surgery, No Chemo34.924675.41All three combined813.115488.52Nothing711.4861100.00 DisclosuresParsons:Celgene: Speakers Bureau.

Breast implant-associated anaplastic large cell lymphoma: review of a distinct clinicopathologic entity.

Primary breast anaplastic large cell lymphoma (ALCL) is rare but is more commonly seen in patients with implants; fewer than 50 cases of breast implant-associated ALCL have been reported in the English language literature. Breast implant-associated ALCL is not a disease of the breast parenchyma, but instead is a disease of the fibrous capsule surrounding the implant. The patients usually present with an effusion around the implant and, rarely, with a solid mass. Morphologically, the neoplastic cells are large, epithelioid, and pleomorphic, with abundant cytoplasm, vesicular irregular nuclei, and frequent mitoses. Occasional "hallmark" cells may be present. The lesional cells typically show strong and diffuse immunoreactivity for CD30 and often express T-cell markers, cytotoxic-associated antigens, and epithelial membrane antigen. Almost all reported cases are negative for anaplastic lymphoma kinase. Molecular genetic analyses have demonstrated T-cell receptor gene rearrangements. The differential diagnosis essentially includes poorly differentiated carcinoma, other lymphomas, and chronic inflammation. Once a diagnosis of lymphoma is established, it is important to exclude systemic anaplastic lymphoma kinase-negative ALCL involving the breast, primary cutaneous ALCL, and other CD30(+) lymphoproliferative disorders. The patients with effusion-associated ALCL often have an indolent course and excellent prognosis, responding well to excision of the fibrous capsule around the implant (capsulectomy) and implant removal. In contrast, patients who present with a distinct mass may have a more aggressive course and poor prognosis, requiring chemotherapy and/or radiation therapy.

Anaplastic large cell lymphoma associated with breast prostheses

Background In 2011 the Therapeutic Goods Administration (TGA) released a summary report 1 in response to concerns from the US Food and Drug Administration (FDA) review of anaplastic large cell lymphoma (ALCL) associated with breast prostheses. 2 The TGA has received notification of six cases 3 of ALCL associated with breast implants in the Australian population. However the rarity of breast ALCL in the setting of breast implants as well as the background population makes the association controversial. In excess of 30 cases of ALCL associated with breast implants have been published worldwide. 4 Both silicone and saline filled implants have been associated with this disease. 5 Case report We present the histopathological findings in a case of ALCL seen in our institution, including cytological, pathological and immunohistochemical findings. This 33-year-old woman presented with recurrent peri-prosthetic seroma. This case is compared and added to the current literature which is reviewed. Discussion While there is majority agreement of an increase association with breast implant and ALCL the causation in still debated. While it may be premature to include this in the consent process for breast implantation, the available evidence does not support the removal of non-complicated breast implants. Fluid accumulating around an implant more than 6 months after surgery should be sent for cytological evaluation. 6

Risk of lymphoma in women with breast implants

Large studies suggest that the overall rate of lymphoma in women with breast implants is no greater than in the general population; clinical reports suggest an association between breast implants and the rare non-Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL). Observed cases of lymphoma reported in Allergan-sponsored breast implant clinical studies were compared with expected cases on the basis of the incidence of lymphoma among women in the National Cancer Institute's Surveillance Epidemiology and End Results program, using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). In clinical studies, there were 28 observed cases of lymphoma among 89 382 patients and 204 682 person-years of follow-up compared with 43 expected cases [SIR: 28/43=0.65 (95% CI: 0.43-0.94), P=0.02]. SIRs were calculated stratifying by baseline cancer history: women without prior cancer [SIR: 17/24=0.70 (95% CI: 0.41-1.13), P=0.17] and women with prior cancer [SIR: 11/14=0.79 (95% CI: 0.39-1.41), P=0.52]. SIRs were calculated by implant shell type: textured shell implants [SIR: 16/23=0.70 (95% CI: 0.40-1.13), P=0.16] and smooth shell implants [SIR: 12/19=0.63 (95% CI: 0.33-1.10), P=0.12]. Surveillance Epidemiology and End Results reported 12 cases of primary breast ALCL in women between 1996 and 2007 without a history of cancer, for an average annual incidence of 4.28 (95% CI: 3.51-5.05)/100 million women in the US - these women may or may not have breast implants. In clinical studies, three ALCL cases were reported in women with breast implants and a history of breast cancer, yielding a crude incidence rate of 1.46 (95% CI: 0.30-4.3)/100 000 person-years. Large clinical studies, based on over 200 000 person-years of follow-up, suggest no evidence of an increased risk of lymphoma among women who have received breast implants.

What about the Informed Consent for Breast Implantation?

Sir:FigureWe read with great interest the article about results obtained by Kim et al.1 from a structured expert consultation process concerning the presumed association between anaplastic large cell lymphoma (ALCL) and breast implants. We congratulate the authors for the exhaustive description through which this dramatically important argument is faced. Basing the investigation on the evidence of the reported cases in the literature,2–4 several aspects of this new clinical entity have been evaluated, including evidence for the association, its clinical significance, and a potential biological model.1 Although some issues regarding ALCL in women with breast implants remain unclear, panelists' conclusions were consistent with a positive association between breast implants and ALCL development but likely underestimated the true number of cases.1 However, anaplastic lymphoma kinase–negative ALCL arising around breast implants should be considered as a clinically indolent disease with a favorable prognosis distinct from the systemic counterpart.1 Furthermore, the panelists set recommendations addressing diagnosis (i.e., aspiration and cytologic analysis of recurrent, clinically evident seroma occurring ≥6 months after breast implantation) and management (i.e., removal of the involved implant and capsule to avoid recurrences and strict evaluation for other sites of disease) of implant-related ALCLs.1 Finally, given that ALCL developing around breast prostheses seems to behave as an indolent disease, Kim et al.1 concluded by suggesting that treatment should focus on local therapies, with aggressive systemic chemotherapy and radiation therapy likely being unnecessary, especially in early-stage cases when the mode of presentation are symptoms and signs linked to or within the fibrous capsule (e.g., seroma, effusion, capsular contracture). Within this context, how should physicians approach patients who require breast implantation? Does informed consent need to include information concerning the possibility of development of implant-related ALCL? Is the classic form, which follows, still ethical and legal? “Currently, medical investigations have not demonstrated any increased risk of breast disease or breast cancer in women who have breast implant surgery for either cosmetic or reconstructive purposes. If they occur, breast diseases develop independently of breast implants. It is recommended that all women perform periodic self examination of their breasts, have mammography according to American Cancer Society guidelines, and seek professional care should they notice a breast lump.” There already have been several criticisms of delay in identifying and downplaying the significance of recent evidence regarding the risks of breast implant–related cancer when speaking to female patients during a recent members-only webinar posted on the American Society of Plastic Surgeons and American Society for Aesthetic Plastic Surgery Web sites.4–6 How should surgeons face this situation? As articles presenting evidence of a possible association between ALCL and implants have now been published and a U.S. Food and Drug Administration alert raised, how could new cases of peri-implant ALCL be justified by physicians to patients who will receive prostheses starting in 2011 without any mention of this risk in the informed consent? Further reports by independent groups should benefit from the dedicated breast implant registry7 that has been recently created. Current U.S. Food and Drug Administration and plastic surgery society1,7–9 guidelines in the United States and those of the European Commission in Europe, further investigations by independent groups, and increased awareness by physicians should lead to earlier diagnoses and proper treatment of implant-related breast ALCLs. Until a connection between breast devices and ALCL is confirmed, breast implants remain safe and effective. In the meantime, although it is actually and realistically estimated that the potential risk of women with breast implants developing ALCL is extremely low (De Jong and colleagues calculated that an incidence of ALCL in the breast would vary between 0.1 and 0.3 per 100,000 women with prostheses per year, which is five cases in 1.7 to 5.1 million person-years10), patients should be aware of this rare complication that should appear in the informed consent for both cosmetic and reconstructive breast implantation. Davide Lazzeri, M.D. Plastic and Reconstructive Surgery Unit Tommaso Agostini, M.D. Burn Center Unit, Hospital of Pisa, Pisa, Italy DISCLOSURE There are no financial conflicts of interest to report in association with the contents of this communication.

Risk of lymphoma in women with breast implants: Analysis of clinical studies.

1588 Background: Large studies suggest the overall rate of lymphoma in women with breast implants is no greater than in the general population although recent clinical reports suggest a potential association between breast implants and the rare non-Hodgkin lymphoma: anaplastic large cell lymphoma (ALCL) of the breast. Methods: Observed cases of lymphoma reported in Allergan-sponsored breast implant clinical studies were compared to the numbers of cases expected based on incidence rates of lymphoma among women in the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program, using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). Results: In these clinical studies, a combined total of 28 observed cases of lymphoma were reported among 89,382 patients with 204,682 person-years of follow-up compared with 43 expected cases [SIR==0·65 (95% CI: 0·43-0·94) P==0·02]. SIRs were calculated stratifying by baseline cancer history: the risk was not significantly elevated either among women without a prior history of cancer [SIR ==0·70 (95% CI: 0·41-1·13) P==0·17], or women with a prior cancer history [SIR==0·79 (95% CI: 0·39-1·41) P==0·52]. SIRs were calculated by implant shell type and, again, there was no evidence of an increased risk either for textured shell implants [SIR==0·70 (95% CI: 0·40-1·13) P==0·16] or smooth shell implants [SIR==0·63 (95% CI: 0·33-1·10) P==0·12]. SEER reported 12 cases of primary breast ALCL in women between 1996-2007 without a previous history of cancer, producing an average annual incidence of 4·28 (95% CI: 3·51-5·05) per 100 million women in the United States – these women may or may not have had breast implants. In clinical studies, three ALCL cases were reported in women with breast implants and a history of breast cancer, yielding a crude incidence rate of 1·46 (95% CI: 0·30-4·3) per 100,000 patient-years. Conclusions: Large, carefully conducted clinical studies, based on over 89,000 subjects with over 200,000 person-years of follow-up, suggest no evidence of an increased risk of lymphoma among women who have received breast implants.

Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity

An increasing number of cases of primary breast anaplastic large cell lymphoma (ALCL) associated with silicone and saline breast implants are being recognised, particularly in association with textured implants. In this article, we review the available literature and show that: 1. There is increasing evidence of an etiological link between implants and this type of lymphoma. 2. There is a distinct clinical presentation, most often with peri-implant effusion or with other implant-related symptoms, rather than with a mass lesion. 3. Despite cytological features identical to systemic ALK-1 negative anaplastic large cell lymphoma, the disease course of this entity is indolent, with most patients alive and disease free. Given the distinct mode of presentation and markedly different clinical course, we feel that seroma-associated anaplastic large cell lymphoma merits a separate category in the WHO classificaton.