BIA-ALCL diagnosis on CytoLyt fixed ThinPrep,cell block and immunohistochemistry

Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) is an emergent rare T cell non-Hodgkin lymphoma arising in association with a breast implant, particularly textured ones. Recent guidelines list cytopathological examination as the first essential step for diagnosis, routinely followed by CD30 immunohistochemistry (IHC) and flow cytometry (FC) for a T cell clone. The majority of BIA-ALCL literature regarding cytopathological evaluation describes morphology based on various preparation methods limited to cytospins and smears with the exception of at least one case report detailing cytomorphological and IHC findings on ThinPrep. This case report details initial diagnosis of BIA-ALCL rendered with CytoLyt prepared ThinPrep and cell block, including the specific antibodies used for IHC. The ThinPrep slide showed numerous singly dispersed large, atypical cells with abundant cytoplasm containing irregular nuclei with dispersed chromatin and prominent nucleoli in a background of macrophages, inflammatory cells and granular debris. TIA-1 and CD30 along with other T-cell markers, including specific antibodies, remains immunoreactive in tissue collected in CytoLyt solution. Cell size reduction, artifactual lymphoid cell aggregation and prominent nucleoli in benign and reactive conditions are among other ThinPrep cellular alterations pathologists should bear in mind.     

Silicone implant and primary breast ALK1-negative anaplastic large cell lymphoma,fact or fiction?

The safety of silicone-based implant for mammoplasty has been debated for decades. A series of anecdotal case reports and a recent epidemiological case-control study have suggested a possible association between silicone implant and the development of primary breast ALK1-negative anaplastic large cell lymphoma (ALCL), a rare type of peripheral T-cell lymphoma. In this report, we describe an additional case of primary breast ALK1-negative ALCL in the fibrous capsule and cystic fluid of silicone breast implant in a 58 year old woman who underwent breast reconstructive surgery after lumpectomy for her infiltrating breast adenocarcinoma. Morphologically and immunohistochemically, the lymphoma cells may be confused with recurrent infiltrating breast adenocarcinoma or other non-hematolymphoid malignancies. Molecular studies were needed to determine T-lineage differentiation of the malignant lymphoma cells. We will also review the case reports and case series published in the English literature and discuss our current understanding of silicone implant in primary breast ALK1-negative ALCL.     

A case of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)

Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) is a recognized but rare complication of breast implantation. This condition occurs with textured implants and on average, presents around 10 years post insertion. We report a case of BIA-ALCL and describe the histological and cytological examination findings. Furthermore, we discuss the condition in more detail, how this disease may be staged and the requirement for central registration.     

Cytological features of breast implant‐associated anaplastic large cell lymphoma in pleural effusion

Breast implant‐associated anaplastic large cell lymphoma (BIA‐ALCL) is a very rare CD30‐positive ALK‐negative T‐cell non‐Hodgkin lymphoma included as a provisional entity in the 2017 WHO classification of lymphoid neoplasms. BIA‐ALCL arises as proliferating cells over the surface of the implant. It is generally an indolent disease if confined within the fibrous capsule. In contrast, mass and/or infiltration beyond the capsule is much more aggressive. This report describes a case of infiltrative BIA‐ALCL with massive pleural effusion containing hallmark BIA‐ALCL cells showing the characteristic morphologic appearance of high‐grade anaplastic lymphoma, CD30‐positive but ALK‐negative with variable staining for T‐cell antigens. Detailed cytological features of BIA‐ALCL in pleural fluid are described along with the results of a literature search performed for BIA‐ALCL cases with pleural effusion. This report expands the spectrum of BIA‐ALCL pathology to include chest wall involvement and pleural effusion.     

Histological analysis of silicone breast implant capsules and correlation with capsular contracture

BACKGROUND: A study was undertaken to investigate long-term histological changes in the environment of breast implants and their correlation with complains at the time of capsular contracture defined by the Baker score. METHOD: The collagenous capsules of 53 silicone breast implants from 43 patients (23 smooth and 30 textured devices) were evaluated histologically for capsular thickness, the presence of histiocytes, the amount of silicone and calcification in the capsule, and the presence of synovial-like metaplasia of the inner surface of the capsule with light microscopy and polarised light. All parameters were correlated with the Baker score. RESULTS: A significantly higher degree of the Baker score was found with increasing patient age (p<0.001), implant duration (p<0.02), and capsular thickness (p<0.009). A trend towards greater capsular thickness was documented in patients who had a breast augmentation for cosmetic reasons. Synovial-like metaplasia was seen in 28 capsules (52.8%). The highest incidence was found in textured implants with a duration of less than 5 years. Histiocytic inflammation was more common in patients with clinical symptoms (p<0.001) and around subglandular implants (p<0.096). CONCLUSIONS: The histological findings of breast capsules were related to: the nature of the device surface (smooth versus textured), implant duration, and the degree of capsular contracture. Capsular contracture (Baker score of 3 or 4) was related to implant duration, capsule thickness, patient age, and inflammation.     

Cytological Diagnosis of Bilateral Breast Implant‐Associated Lymphoma of the ALK‐Negative Anaplastic Large‐Cell Type. Clinical Implications of Peri‐Implant Breast Seroma Cytological Reporting

The cytological examination of peri‐prosthetic breast effusions allowed the diagnosis of bilateral breast‐implant ALK‐negative anaplastic large cell lymphoma (BI‐ALCL) in the case reported. Ten years after reconstructive surgery with bilateral breast implants, a large unilateral seroma developed and was cytologically analyzed. The presence of CD30 and CD4‐positive large‐sized atypical lymphoid cells exhibiting horseshoe‐shaped nuclei and a brisk mitotic activity rendered the diagnosis of BI‐ALCL. Similar cells were seen in the peri‐prosthetic fluid intraoperatively collected from the contralateral breast. Although initial histological analysis of the capsulectomy specimens showed unilateral tumor, the cytological findings prompted a more thorough tissue sampling, resulting in the diagnosis of bilateral disease. BI‐ALCL usually follows an indolent clinical course; however, there are reported cases with an aggressive behavior. While the presence of bilateral disease is a putative risk factor for a bad prognosis, the small number of cases reported precludes a definitive assessment of this risk. Since most BI‐ALCL present with late seromas, cytologic analysis of these effusions in women with breast implants should be mandatory. Cytology is a safe tool for diagnosis and follow‐up of patients with breast implant‐related late seromas, sometimes proven more sensitive than histological analysis. Complete bilateral capsulectomy and a detailed histological analysis should follow a cytological diagnosis of BI‐ALCL in a breast effusion in order to avoid false negative diagnoses. Our case constitutes the first published report of a bilateral BI‐ALCL diagnosed by cytology. Diagn. Cytopathol. 2016;44:623–627. © 2016 Wiley Periodicals, Inc.     

Breast implant-associated anaplastic large-cell lymphoma: A series of two case reports diagnosed by cytopathology

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare T-cell lymphoma with a good prognosis. It occurs in association with textured breast implants. Its most common presentation is a late-onset peri-implant effusion. We present two cases of BIA-ALCL diagnosed by cytopathological examination of the fluid collection and describe the cytopathologic findings. Both patients were disease free after implant removal. This report highlights the contribution of the cytopathologic analysis to early diagnosis and definite treatment of BIA-ALCL.     

B-cell lymphomas associated with breast implants: Report of three cases and review of the literature

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation.     

Phenotype of lymphocytes associated with the inflammatory reaction to silicone gel breast implants.

The tissue response to silicone gel breast implants typically includes an inflammatory infiltrate that consists of macrophages, foreign body-type giant cells, and a variable number of lymphocytes and plasma cells. The phenotype of the lymphocytic component was investigated with three-color flow cytometry. Lymphocytes were obtained by collecting fluid from the space between the implant and the fibrous capsule or by washing cells from the fibrous capsule at the time of implant removal with total capsulectomy. Eighty-nine percent of the implant-associated lymphocytes were T cells. Twenty-five percent of the CD3+ T cells coexpressed HLA-DR compared with only 7.9% of matched peripheral blood lymphocytes. Sixty-eight percent of the implant-associated T cells coexpressed CD4 and CD29, while only 3% of the T cells coexpressed CD4 and CD45RO. The expression of HLA-DR and the predominance of CD29+ CD4+ T cells indicate that there is immune activation with the potential for stimulating antigen-specific antibody production. The role of silicone gel breast implants in immune activation and its clinical significance require further investigation.     

Do biomaterials cause implant-associated mesenchymal tumors of the breast? Analysis of 8 new cases and review of the literature

Implant-associated mesenchymal tumors (IAMT) of the breast are rare, and most are fibromatoses. There has been no systematic analysis of IAMT to determine their full histologic spectrum, whether there is an association with implant type or rupture, and if evidence supports a causal or fortuitous relationship between tumor and implant. We, therefore, analyzed all mesenchymal tumors associated with breast implants from our soft tissue consultation database spanning a period from 1989 to 2005. Information regarding location, type, and integrity of implant and its temporal relationship to tumor was recorded. Eight IAMT were identified exclusively in female patients (ages 28-64 years; median, 38 years), all of whom presented with a palpable mass. Tumors developed after placement of either a silicone (n = 7) or saline (n = 1) implant (median, 2 years; range, 1.8-10 years), which was usually inserted for cosmetic purposes (n = 7). All tumors arose in or around the capsule of a grossly intact implant, and in one case, the tumor was confined exclusively to the implant capsule. In patients with silicone implants, silicone granulomas were identified within the capsule and associated neoplasm despite the integrity of the implant. Six cases were fibromatoses; one was a pleomorphic undifferentiated sarcoma; and one was a fibrosarcoma. None of the patients with fibromatosis was known to have familial adenomatous polyposis (FAP) or Gardner syndrome, although one had Poland syndrome (aplasia of the thorax). One patient with a sarcoma had received radiation 10 years previously for breast carcinoma. Six patients were treated with local excision, one with a wide excision, and one patient with fibromatosis was treated with medical therapy. Median follow-up was 3.2 years (range, 16-92 months). One of the 5 patients with fibromatosis developed 2 recurrences. Neither of the 2 patients with sarcomas has developed metastasis. No patient has died of disease. We conclude that IAMT comprise 2 distinct groups—fibromatosis and sarcoma. Surgical trauma, perhaps occurring in patients with a predisposition to develop desmoid tumors, could account for fibromatosis in this setting. The causal relationship between implants and sarcomas is difficult to assess given the rarity of these tumors and that some may be radiation induced. However, at present, there is insufficient evidence to claim that they are biomaterial related.     

Pathology and genetics of anaplastic large cell lymphoma

Anaplastic large cell lymphomas are a rare subtype of peripheral/mature T-cell lymphomas which are clinically, pathologically and genetically heterogeneous. Both ALK-positive (ALK+) and ALK-negative (ALK-) ALCL are composed of large lymphoid cells with abundant cytoplasm and pleomorphic features with horseshoe-shaped and reniform nuclei. ALK+ ALCL were considered as a definite entity in the 2008 World Health Organization classification of hematopoietic and lymphoid tissues. ALK-ALCL was included as a provisional entity in the WHO 2008 edition and in the most recent 2017 edition, it is now considered a distinct entity that includes cytogenetic subsets that appear to have prognostic implications (e.g. 6p25 rearrangements at IRF4/DUSP22 locus). ALK+ ALCLs are distinct in epidemiology and pathogenetic origin and should be distinguished from ALK-ALCL, cutaneous ALCL and breast implant associated ALCL which have distinct clinical course and pathogenetic features. Breast implant-associated ALCL is now recognized as a new provisional entity distinct from other ALK-ALCL; notably that it is a noninvasive disease associated with excellent outcome. In this article, we will provide an overview of the salient themes relevant to the pathology and genetic mechanisms in ALCL.     

Cellular and molecular composition of fibrous capsules formed around silicone breast implants with special focus on local immune reactions

During the past 30 years, much debate has centered around side effects of silicone breast implants. Meta-analyses rejected the presumed relationship between silicone breast implants and connective tissues diseases but, in seeming contradiction, case reports about connective tissue diseases and rheumatoid symptoms continue to be published. We analyzed the cellular and molecular composition of fibrous capsules removed from patients at various times after surgery for diagnostic purposes (breast cancer relapse) or to relieve painful constrictive fibrosis. Frozen sections of capsule tissue were immunohistochemically stained for subsets of lymphocytes, macrophages, dendritic cells, fibroblasts, smooth muscle cells, for collagenous and non-collagenous extracellular matrix proteins, for heat shock protein 60 (HSP60) and for adhesion molecules. Massive deposition of fibronectin and tenascin was observed adjacent to the implant surface. The capsule/silicone implant contact zone was consistently characterized by a palisade-like single or multilayered cell accumulation consisting of HSP60+ macrophages and HSP60+ fibroblasts. Mononuclear cell infiltrates consisting of activated CD4+ T-cells, expressing CD25 and CD45RO, as well as macrophages were detected beneath the contact zone as well as perivascularly. Importantly, many Langerhans-cell like dendritic cells (DCs) were found with a predilection at the frontier layer zone abutting the silicone implant. Also, at this site, massive expression of ICAM-1, but not VCAM-1 or ELAM-1 emerged. Endothelial cells of the intracapsular neovasculature were P-Selectin+. Our results show that silicone induces a strong local T-cell immune response and future studies will determine the specificity and function of these T-lymphocytes.     

Silicone gel-filled breast and testicular implant capsules: a histologic and immunophenotypic study.

The immunophenotypic characteristics of silicone gel-filled breast and testicular implant capsules have not been well described. Therefore, we studied 17 paraffin-embedded tissue sections from 9 breast implant patients and 1 testicular implant patient to assess the type and extent of inflammatory responses present. Immunohistochemical analyses were performed on paraffin-embedded tissue sections for expression of CD20, CD45RO, betaF1, CD68, CD44, kappa and A immunoglobulin light chains, and bcl-XL (a member of the bcl-2 family of proteins involved in apoptosis). The most common histologic features included prominent T-cell and foamy macrophage reactions with foreign body giant cells and granulomas in a dense fibrovascular connective tissue. Foci of polyclonal plasma cells and acute inflammatory cells were variably present. In one case, there was reactive germinal center formation, a novel finding. A "pseudosynovium" at the implant capsule interface was present in the majority of cases as previously described; it showed reactivity with CD68. Thin strands of highly refractile, nonpolarizable material, consistent with silicone, were regularly noted in intra- and extracellular locations. The immunohistochemical results included reactivity of the majority of lymphocytes with CD45RO and/or betaF1 (confirming an anamnestic reactive T-cell phenotype), and reactivity of the macrophages, giant cells, and "pseudosynovium" with the macrophage/histiocyte marker, CD68. The reactive germinal centers were positive for CD20. Reactivity for CD44, an activation and intracellular adhesion marker, was frequently observed in the foamy macrophages and foreign body giant cells and has not been previously reported. The plasma cells demonstrated polyclonal immunoglobulin light-chain reactivity, consistent with a reactive process. These findings suggest that silicone implants induce chronic inflammatory responses in many adjacent capsules, which consist of anamnestically responding T cells, reactive B-lymphocytes, and macrophages.     

Primary anaplastic large cell lymphoma in the dura of the brain: case report and prediction of a favorable prognosis

Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma composed of CD30-positive lymphoid cells. ALCL arising in the dura matter of the brain is even more infrequent, in which only one case has been reported worldwide so far. We report a case of a 30-year-old immunocompetent male with a dura-based mass, radiographically consistent with meningioma. However, the excised mass via a left parieto-occipital craniotomy was composed of large, pleomorphic lymphoid cells to be immunopositive for CD3, CD30, anaplastic lymphoma kinase protein-1 (ALK-1) and epithelial membrane antigen (EMA), and immunonegative for CD20, CD15 and CD68. Multiple ALK gene fusion signals in the ALK locus were detected by fluorescence in situ hybridization (FISH) analysis. The patient was treated with CHOP chemotherapy and intrathecal methotrexate along with brain radiation therapy, which resulted in a complete remission. In an analysis of 25 previously reported primary CNS ALCLs, ALK-1 positivity was shown to be prevalent in younger age, as ALCL occurs outside the brain. Patient less than 23 years, ALK-1 positivity and unifocal tumor may be associated with a better prognosis. However, sex, dural or leptomeningeal involvement, immune status, and tumor necrosis do not appear to have any influence on survival.     

Anaplastic large‐cell lymphoma associated with breast implants: A unique entity within the spectrum of peri‐implant effusions

Anaplastic large‐cell lymphoma (ALCL) is a rare and newly described complication associated with breast implants. Patients often present with a peri‐implant effusion, which is amenable to fine‐needle aspiration. The laboratory handling of peri‐implant effusions for cytology and ancillary studies is as crucial as recognizing the characteristic cytology of ALCL. All cases of peri‐implant effusions were retrieved from the PathWest database between January 2003 and May 2013, yielding four cases of breast implant‐associated ALCL and six benign samples. The cytological features were evaluated and information from ancillary studies collated. Clinical and follow‐up histology was available in all cases. All ALCL cases contained highly atypical lymphoid cells including ‘hallmark' cells. In contrast, benign peri‐implant effusions showed a mixture of inflammatory cells, being either neutrophil‐rich (three cases) or lymphocyte‐rich (three cases). A CD30 positive, ALK1 negative immunophenotype was demonstrated in all cases on cell block immunohistochemistry. Flow cytometry and T‐cell receptor clonality studies confirmed aberrant T‐cell immunophenotype in four of four and clonally rearranged T‐cell receptor antigens in three of three cases. ALCL was identified in three of four subsequent capsulectomies. Staging confirmed disease limited to the capsular tissue or peri‐implant effusion in all cases. None of the six patients with benign peri‐implant effusions developed lymphoma during follow‐up. Cases of ALCL accounted for 40% of peri‐implant effusions received over a 10‐year period, indicating the rarity of these samples and the high likelihood of malignancy. Awareness of this entity and its presentation should allow for appropriate triage of these specimens and definitive diagnosis on effusion specimens. Diagn. Cytopathol. 2014;42:929–938. © 2014 Wiley Periodicals, Inc.     

Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology.

Anaplastic large cell lymphoma (ALCL) is a paradigm for the process used to define new disease entities, and provides a model that is applicable to all areas of pathology. ALCL was first recognized based on characteristic histologic features (sinusoidal invasion) and a distinctive immunophenotype (CD30+). However, neither sinusoidal invasion nor CD30-positivity proved to be entirely specific. Subsequently, a characteristic cytogenetic abnormality was identified, the t(2;5), that led to identification of the genes involved in the translocation (NPM/ALK) and insights into the pathogenesis. Generation of monoclonal antibodies to the aberrantly expressed anaplastic large cell lymphoma kinase (ALK) such as ALK-1 can be used diagnostically, and have led to improved definition of the diagnostic entity with important clinical and prognostic implications. These studies also have clarified the relationship of ALCL to Hodgkin's disease, another lymphoid malignancy associated with CD30 expression. We have learned that the ultimate histologic spectrum of ALCL is both narrower and broader than originally believed. The small cell and lymphohistiocytic variants of ALCL are ALK-positive, and are an accepted part of the disease entity, although the neoplastic cells may appear neither large nor anaplastic. Conversely, most cases of Hodgkin's-like ALCL have proved to be more closely related to true Hodgkin's disease, and are unrelated to ALCL.     

Influence of local complications on capsule formation around model implants in a rat model

We studied the capsule formation around various filled breast implants and other related changes in distant organs (e.g., liver, spleen, lymph nodes) in a rat model 3 and 6 months after implantation. Model implants, one per rat, (filled with saline, n = 19; silicone, n = 14; cohesive silicone, n = 17; and hydrogel, n = 19) were implanted subcutaneous in the lower back of rats. The animals were sacrificed regularly after 3 and 6 months of implantation or when wound defects occurred. The capsules and organs were examined histologically, and immunohistology of the capsules was performed. A monoclonal antibody specific for AIF-1 (allograft inflammatory factor 1) was used to detect activated macrophages. Wound defects occurred most frequently after implantation of saline and hydrogel implants. Increased capsule thickness was associated with increased grade of inflammation, fibrosis, and the type of implant filling. There was a significant positive correlation between capsule thickness, presence of chronic inflammation, and AIF-1-positive macrophages (p < 0.0001), indicating that inflammation plays an important role in capsule formation. Remarkably, saline and silicone implants (in absence of local complications) cause only a blande slight fibrosis in capsules after 6 months of implantation, whereas capsules around cohesive silicone implants exhibited a more severe fibrosis with an increased capsule thickness. Most importantly, hydrogel seems to be most potent to induce an inflammatory infiltrate with AIF-1 expressing macrophages at the implantation site, independent of implantation time, and capsules also produced a significant increase in thickness after 6 months.     

An unusual self-limited clonal Mott cell proliferation with lymphoplasmacytic lymphoma-like features in a child with the Wiskott–Aldrich syndrome and Von Recklinghausen's neurofibromatosis

Patients with the Wiskott–Aldrich syndrome are at high risk for development of lymphomas, which are predominantly extranodal and of the immunoblastic type. We present a case of a self-limited lymphoproliferation with features of lymphoplasmacytic lymphoma arising in a patient with the Wiskott–Aldrich syndrome. The patient also had stigmata of von Recklinghausen's neurofibromatosis. The tumor was composed of CD138+, IgGκ+, CD20−, PAX-5− Mott cells and CD5−, CD10−, CD19+, CD20+, CD43− small lymphoid B-cells that partially expressed CD23.     

A study of the aging of silicone breast implants using 29Si, 1H relaxation and DSC measurements

In this study 26 previously implanted silicone breast implants from the same manufacturer (Dow Corning) were investigated with two different analytical methods to characterize potential aging processes such as migration of monomer material from the gel and shell to local and distant sites, chemical alterations of the polymer, and infiltration of body compounds such as lipids. (1)H and (29)Si NMR relaxation measurements (spin-lattice, T1, and spin-spin, T2, relaxation times) were used to study the molecular dynamics of polysiloxane chains, both in gels and in shells. In addition, changes in physical properties were monitored by differential scanning calorimetry (DSC). The results of these measurements indicate that NMR relaxation times are influenced by implant generation, implantation time, shell texture and implant status. (1)H T2 values of shells and gels show a tendency to increase with increasing implantation time, indicating higher mobility and possible disintegration of the polymer network of older implants. Furthermore, the data suggest that aging also involves the migration of low cyclic molecular weight (LMW) silicone and linear chain polymer material from the gels into the shells. The high "bleeding" rate of second-generation (G2) implants (implantation period around 1973-1985), exhibiting thin shells is reflected in reduced relaxation times of these devices, most likely due to a loss of low molecular weight fractions from the gels. Moreover, "gel bleeding" also influences the melting behavior observed in DSC studies. Increased shell rigidity (high Tm and Tg) tends to be correlated with longer (29)Si relaxation times of the corresponding gels, suggesting a reduced transfer of LMW silicones and linear chain polymer from the gel to the shell and to the outside. Remarkably, textured implants seem to be less susceptible to degradation processes than implants with thin shells.