BIA-ALCL and BIA-SCC: Updates on Clinical Features and Genetic Mutations for Latest Recommendations.

Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) and Breast Implant-Associated Squamous Cell Carcinoma (BIA-SCC) are emerging neoplastic complications related to breast implants. While BIA-ALCL is often linked to macrotextured implants, current evidence does not suggest an implant-type association for BIA-SCC. Chronic inflammation and genetics have been hypothesized as key pathogenetic players, although for both conditions, the exact mechanisms and specific risks related to breast implants are yet to be established. While the genetic alterations in BIA-SCC are still unknown, JAK-STAT pathway activation has been outlined as a dominant signature of BIA-ALCL. Recent genetic investigation has uncovered various molecular players, including MEK-ERK, PI3K/AKT, CDK4-6, and PDL1. The clinical presentation of BIA-ALCL and BIA-SCC overlaps, including most commonly late seroma and breast swelling, warranting ultrasound and cytological examinations, which are the first recommended steps as part of the diagnostic work-up. While the role of mammography is still limited, MRI and CT-PET are recommended according to the clinical presentation and for disease staging. To date, the mainstay of treatment for BIA-ALCL and BIA-SCC is implant removal with en-bloc capsulectomy. Chemotherapy and radiation therapy have also been used for advanced-stage BIA-ALCL and BIA-SCC. In-depth characterization of the tumor genetics is key for the development of novel therapeutic strategies, especially for advanced stage BIA-ALCL and BIA-SCC, which show a more aggressive course and poor prognosis.

Peripheral T-cell lymphomas expressing CD30 and CD15 expand the spectrum of anaplastic large cell lymphoma, ALK-negative.

Peripheral T-cell lymphomas (PTCL) are morphologically and biologically heterogeneous and a subset expresses CD30, including anaplastic large cell lymphomas (ALCL) and a minority of PTCL, not otherwise specified (PTCL, NOS). ALCL with ALK translocations (ALCL, ALK+) are readily identified by routine diagnostic methods, but differentiating ALCL without ALK translocation (ALCL, ALK-) and PTCL, NOS expressing CD30 (PTCL CD30+) can be challenging. Furthermore, rare PTCL co-express CD30 and CD15 (PTCL CD30+CD15+); some resemble ALCL, ALK- while others resemble classic Hodgkin lymphoma. To explore the relationship between PTCL CD30+CD15+ and ALCL, ALK-, we analysed 19 cases of PTCL with CD30 expression, previously diagnosed as ALCL, ALK- (nine cases) and PTCL CD30+CD15+ (10 cases) for DUSP22/IRF4 rearrangements, coding RNA expression and selected transcriptome analysis using the NanoString nCounter gene expression analysis platform. Unsupervised clustering showed no clear segregation between ALCL, ALK- and PTCL CD30+CD15+. Three cases previously classified as PTCL CD30+CD15+ showed DUSP22/IRF4 rearrangements, favouring a diagnosis of ALCL, ALK-. Our results suggest that cases previously designated PTCL CD30+CD15+, likely fall within the spectrum of ALCL, ALK-; additionally, a subset of ALCL, ALK- with DUSP22/IRF4 rearrangement expresses CD15, consistent with previous reports and expands the immunophenotypic spectrum of this lymphoma subgroup.

Primary cutaneous anaplastic large-cell lymphoma resembling infratemporal space infection: a case report.

BACKGROUND: Primary cutaneous anaplastic large-cell lymphoma (PC-ALCL) is a rare T-cell lymphoma belonging to the CD30 + T-cell lymphoproliferative disorders. The case of PC-ALCL in the temporal region is exceedingly rare. Herein, we report a case of PC-ALCL involving the temporal region mimicking infratemporal space infection. CASE PRESENTATION: A 78-year-old woman presented to maxillofacial surgery service with a 6-month history of swelling and pain in the left side of her face. Laboratory investigations found an elevated C-reactive protein (CRP). Imaging findings showed enlarged lymph nodes and extensive thickening of subcutaneous tissue of the left temples. Based on these findings, the infratemporal space infection was suspected initially. The patient underwent incision and drainage, and we unexpectedly found no pus in the lesion area. Incisional biopsy showed necrosis and extensive involvement of the left temples by a diffuse infiltrate containing large, atypical cells. The tumor cells were positive for CD30, CD3, Ki67. They were negative for ALK (SP8), CD5, CD8, CD20 and PAX5. After considering these findings, a diagnosis of PC-ALCL was rendered. The patient was admitted to the lymphoma department for systemic chemotherapy and no relapse occurred during a follow-up period of six months. CONCLUSIONS: This report suggests that if there are suspicious intraoperative manifestations, carrying out a biopsy simultaneously, using Hematoxylin and eosin (HE) staining, and a comprehensive Immunohistochemistry (IHC) panel are essential to diagnosing PC-ALCL to prevent misdiagnosis.

[Successful bridging therapy with alectinib prior to allogeneic stem cell transplantation for refractory ALK-positive anaplastic large cell lymphoma].

Although alectinib is effective for relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL) and has a favorable safety profile, its role as a bridging therapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the role of allo-HSCT itself in this setting are unknown. A 35-year-old man with ALK-positive ALCL experienced relapse after first-line therapy with CHOP. Brentuximab vedotin led to partial response and high-dose chemotherapy combined with autologous HSCT was performed. However, disease progressed 15 months after transplantation, and alectinib was initiated. Complete response (CR) was achieved after three months of treatment, and alectinib was continued for 5 months. After cessation of alectinib, allogeneic bone marrow transplantation from an HLA 1-locus mismatched unrelated donor was performed after conditioning with fludarabine, busulfan, and total body irradiation. GVHD prophylaxis consisted of tacrolimus and short-term methotrexate. The post-transplant course was unremarkable except for grade I acute GVHD. The lymphoma has not recurred for 2 years after allo-HSCT without resuming alectinib. The clinical course of our case suggests that alectinib bridging therapy and allo-HSCT are effective in relapsed/refractory ALK-positive ALCL.

From Case Reports to Molecular Insight: Examining the Outcomes and Underlying Mechanisms of Squamous Cell Carcinoma in Breast Implant Patients-A Systematic Review.

There is extensive coverage in the existing literature on implant-associated lymphomas like anaplastic large-cell lymphoma, but breast implant-associated squamous cell carcinoma (BIA-SCC) has received limited scholarly attention since its first case in 1992. Thus, this study aims to conduct a qualitative synthesis focused on the underexplored association between breast implants and BIA-SCC. A systematic review was conducted utilizing the PubMed, Web of Science, and Cochrane databases to identify all currently reported cases of BIA-SCC. Additionally, a literature review was performed to identify potential biochemical mechanisms that could lead to BIA-SCC. Studies were vetted for quality using the NIH quality assessment tool. From an initial pool of 246 papers, 11 met the quality criteria for inclusion, examining a total of 14 patients aged between 40 and 81 years. BIA-SCC was found in a diverse range of implants, including those with smooth and textured surfaces, as well as those filled with saline and silicone. The condition notably manifested a proclivity for aggressive clinical progression, as evidenced by a mortality rate approximating 21.4% within a post-diagnostic interval of six months. Our literature review reveals that chronic inflammation, driven by various external factors such as pathogens and implants, can initiate carcinogenesis through epigenetic modifications and immune system alterations. This includes effects from exosomes and macrophage polarization, showcasing potential pathways for the pathogenesis of BIA-SCC. The study highlights the pressing need for further investigation into BIA-SCC, a subject hitherto inadequately addressed in the academic sphere. This necessitates the urgency for early screening and intervention to improve postoperative outcomes. While the review is confined by its reliance on case reports and series, it serves as a valuable reference for future research endeavors.

Flow Cytometry Analysis in Breast Implant-Associated Anaplastic Large Cell Lymphoma: Three Case Reports.

Breast Implant-Associated-Anaplastic Large Cell Lymphoma (BIA-ALCL) is a rare T-cell non-Hodgkin lymphoma associated with breast prosthetic implants and represents a diagnostic challenge. The National Comprehensive Cancer Network (NCCN) guidelines, updated in 2024, recommend for diagnosis an integrated work-up that should include cell morphology, CD30 immunohistochemistry (IHC), and flow cytometry (FCM). CD30 IHC, although the test of choice for BIA-ALCL diagnosis, is not pathognomonic, and this supports the recommendation to apply a multidisciplinary approach. A close collaboration between pathologists and laboratory professionals allowed the diagnosis of three BIA-ALCLs, presented as case reports, within a series of 35 patients subjected to periprosthetic effusions aspiration from 2018 to 2023. In one case, rare neoplastic cells were identified by FCM, and this result was essential in leading the anatomopathological picture as indicative of this neoplasm. In fact, the distinction between a lymphomatous infiltrate from reactive cells may be very complex in the cytopathology and IHC setting when neoplastic cells are rare. On the other hand, one limitation of FCM analysis is the need for fresh samples. In this study, we provide evidence that a dedicated fixative allows the maintenance of an unaltered CD30 expression on the cell surface for up to 72 h.

STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

The Spectrum of Non-neoplastic Changes Associated With Breast Implants: Histopathology, Imaging, and Clinical Significance.

Breast implant-associated anaplastic large cell lymphoma has been recognized as a distinct entity in the World Health Organization classification of hematolymphoid neoplasms. These neoplasms are causally related to textured implants that were used worldwide until recently. Consequently, there is an increased demand for processing periprosthetic capsules, adding new challenges for surgeons, clinicians, and pathologists. In the literature, the focus has been on breast implant-associated anaplastic large cell lymphoma; however, benign complications related to the placement of breast implants occur in up to 20% to 30% of patients. Imaging studies are helpful in assessing patients with breast implants for evidence of implant rupture, changes in tissues surrounding the implants, or regional lymphadenopathy related to breast implants, but pathologic examination is often required. In this review, we couple our experience with a review of the literature to describe a range of benign lesions associated with breast implants that can be associated with different clinical presentations or pathogenesis and that may require different diagnostic approaches. We illustrate the spectrum of the most common of these benign disorders, highlighting their clinical, imaging, gross, and microscopic features. Finally, we propose a systematic approach for the diagnosis and handling of breast implant specimens in general.

Anaplastic large cell lymphoma with ALK::ATIC fusion mimicking a histiocytic sarcoma debuting as an anterior thoracic soft tissue tumor with exceptional clinicopathological, morphological and molecular features.

A 56-year-old woman debuted with a palpable painless mass in the anterior thorax wall at the level of the second and third right parasternal intercostal space, which progressively increased in size over 5 months accompanied by localized skin rash, mild dyspnea and chest pain when changing position. Imaging studies showed a soft tissue mass measuring 75 × 62 mm and a density of 34 Hounsfield Units that had caused the lysis of the costal arches and grew expansively towards the anterior mediastinum, without identifying mediastinal adenopathies only by this imaging method. Core biopsy was performed, which was initially diagnosed as histiocytic sarcoma (HS); however, when the diagnostic panel was expanded to include molecular and NGS studies, the final diagnosis was anaplastic large cell lymphoma with ALK::ATIC fusion. Here, we report a very rare neoplasm with unusual clinical presentation, histopathology and molecular features.

Primary anaplastic large cell lymphoma arising from central nervous system.

A 22-year-old man presented at the emergency department with progressive headache, vomiting and horizontal diplopia over 2-month period. He also developed blurred vision in his left eye. He complained of loss of appetite for the past 2 months, resulting in a 5-kg weight loss. Examination upon arrival revealed papilledema and bilateral abducens nerve palsy. Motor and sensory functions were intact. Magnetic resonance imaging (MRI) of the brain revealed multiple extra-axial nodular enhancing lesions with size of 5-10 mm mainly along with both sides of falx cerebri and vasogenic brain oedema (Fig. 1). Stereotactic brain biopsy was performed to obtain tissue diagnosis. Histologic examination revealed brain infiltration by few atypical cells hidden amongst abundant and mixed population of inflammatory cells including lymphocytes and histiocytes. The atypical cells are large cells with horseshoe nuclei (red arrow; Fig. 2A ×100 and Fig. 2B ×400). Immunohistochemistry showed strong, uniform CD30 expression (Fig. 2C ×400) and cytoplasmic ALK staining (Fig. 2D ×400), as well as for CD3 (Fig. 2E ×400) and CD68 (Fig. 2F ×400). B-cell markers (CD20) were negative (Fig. 2G ×400).

Anaplastic large cell lymphoma presenting as a mass in the uterine cervix: a case report.

T-cell lymphoma is an extremely rare form of malignancy in the female genital tract. Most of the reported cases of lymphoma are B-cell lymphomas. A few cases of primary T-cell lymphomas involving the vagina or the vulva have been reported. We are reporting the first case of anaplastic large cell lymphoma (ALCL) presenting as a uterine cervical mass. The patient is a 24-year-old female who presented to the emergency room with a history of menorrhagia, night sweats and 40-pound weight loss. The diagnosis of ALCL was confirmed through immunohistochemical studies with strong CD30 and ALK expression. Fluorescent hybridization showed a rearrangement of the anaplastic lymphoma kinase (ALK) gene. Since ALCL may have a variable expression of T-cell antigens, the diagnosis may easily be missed when CD45 and/or CD3 is negative, and screening epithelial stains for carcinoma (e.g., p63 and EMA) are positive. CD30 must be performed to raise the consideration of ALCL when reniform nuclei are observed.

Breast implant surface topography triggers a chronic-like inflammatory response.

Breast implants are extensively employed for both reconstructive and esthetic purposes. However, the safety of breast implants with textured surfaces has been questioned, owing to a potential correlation with anaplastic large-cell lymphoma and the recurrence of breast cancer. This study investigates the immune response elicited by different prosthetic surfaces, focusing on the comparison between macrotextured and microtextured breast implants. Through the analysis of intraoperatively harvested periprosthetic fluids and cell culture experiments on surface replicas, we demonstrate that macrotextured surfaces elicit a more pronounced chronic-like activation of leucocytes and an increased release of inflammatory cytokines, in contrast to microtextured surfaces. In addition, in vitro fluorescent imaging of leucocytes revealed an accumulation of lymphocytes within the cavities of the macrotextured surfaces, indicating that the physical entrapment of these cells may contribute to their activation. These findings suggest that the topography of implant surfaces plays a significant role in promoting a chronic-like inflammatory environment, which could be a contributing factor in the development of lymphomas associated with a wide range of implantable devices.

Role of flow cytometric immunophenotyping in the diagnosis of breast implant-associated anaplastic large cell lymphoma: A 6-year, single-institution experience.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon mature T-cell neoplasm occurring in patients with textured breast implants, typically after 7-10 years of exposure. Although cytopathologic or histopathologic assessment is considered the gold standard diagnostic method for BIA-ALCL, flow cytometry (FC)-based immunophenotyping is recommended as an adjunct test. However, the diagnostic efficacy of FC is not well reported. We reviewed 290 FC tests from breast implant pericapsular fluid and capsule tissue from 182 patients, including 16 patients with BIA-ALCL over a 6-year period, calculating diagnostic rates and test efficacy. FC showed an overall sensitivity of 75.9%, specificity of 100%, and negative and positive predictive values of 95.4% and 100%, respectively. Blinded expert review of false-negative cases identified diagnostic pitfalls, improving sensitivity to 96.6%. Fluid samples had better rates of adequate samples for FC testing compared with tissue samples. Paired with FC testing of operating room (OR)-acquired fluid samples, capsulectomy FC specimens added no diagnostic value in patients with concurrent fluid samples; no cases had positive capsule FC with negative fluid FC. Fluid samples are adequate for FC testing more often than tissue. Capsule tissue FC specimens do not improve FC efficacy when paired with OR-acquired fluid FC samples and are often inadequate samples. FC is 100% specific for BIA-ALCL and can serve as a confirmatory test but should not be the sole diagnostic method. Awareness of sample-specific diagnostic pitfalls greatly improves the sensitivity of BIA-ALCL testing by FC.

Case report: The utilization of crizotinib and brentuximab vedotin as a bridge to autologous stem cell transplantation and followed by CD30-directed CAR-T cell therapy in relapsed/refractory ALK+ ALCL.

Background: Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. The prognosis of patients with relapsed or refractory ALCL following first-line chemotherapy is extremely poor. NCCN guidelines recommend intensified chemotherapy with or without ASCT consolidation for r/r ALCL, however, this is not an effective treatment for all ALK+ALCL. Case report: Herein, we report a patient with relapsed/refractory ALK+ ALCL who received crizotinib and brentuximab vedotin as bridging therapy, followed by autologous stem cell transplantation and sequential anti-CD30 CAR T cell therapy. Conclusion: The patient achieved complete remission and long-term disease-free survival of months and continues to be followed up. The combination therapy model in this case may provide guidance for the management of relapsed/refractory ALK+ ALCL, and further prospective trials are needed to confirm its effectiveness.

Loss of or decrease in CD30 expression in four patients with anaplastic large cell lymphoma after brentuximab vedotin-containing therapy.

Brentuximab vedotin (BV), CD30 specific antibody drug conjugate, has been used to treat anaplastic large cell lymphoma (ALCL) and classic Hodgkin lymphoma (CHL); it is also used in the treatment of other CD30-positive peripheral T-cell lymphomas. We aimed to investigate the incidence and clinicopathological characteristics of patients with ALCL or CHL with loss of or decrease in CD30 expression after BV-containing therapy. Twelve and nine patients with refractory/relapsed CHL and ALCL, respectively, were analyzed after receiving BV-containing therapy. In four ALCL patients (44%), CD30 expression was lost/decreased in re-biopsy materials, including one with complete loss and three with a reduction of less than 20%. All 12 CHL patients showed consistent CD30 expression levels after BV treatment. Compared with five ALCL patients with consistent CD30 expression, four ALCL patients with a loss of/decrease in CD30 expression received a higher cumulative dose of BV (P = 0.014) and revealed a lower intensity of CD30 expression in initial biopsy materials (P = 0.017). The subtypes of ALCL (ALK positive, ALK negative, and primary cutaneous) were not related to the loss of/decrease in CD30 expression. In conclusion, 44% of ALCL patients, regardless of histological subtypes, showed a loss of/decrease in CD30 expression after receiving BV-containing therapy, but this phenomenon was not observed in CHL patients. A higher cumulative dose of BV and a lower amount of CD30 antigen in tumor cells in the initial biopsy materials might be predictors of a loss of/decrease in CD30 expression in ALCL patients.

EBV-positive Nodal T-Cell and NK-Cell Lymphoma: A Study of 26 Cases Including a Subset With Strong CD30 Expression Mimicking Anaplastic Large Cell Lymphoma.

Epstein-Barr virus (EBV)-positive nodal T-cell and NK-cell lymphoma is a rare neoplasm of cytotoxic T-cell or NK-cell lineage. Here, we report 26 cases affecting 14 men and 12 women with a median age of 52 years. All patients presented with disease involving multiple lymph nodes, and 20 of 22 (91%) fully staged patients had advanced Ann Arbor stage disease. Spleen, liver, and bone marrow were involved in 70%, 50%, and 52% of cases, respectively. These patients had a dismal prognosis with a median survival of 30 days. Histologically, lymph nodes were replaced by lymphoma in a diffuse pattern. Lymphoma cells were variable in size and large cell morphology was seen in 62% of cases. The neoplastic cells were CD4-/CD8- in 14 (54%) cases and CD4-/CD8+ in 12 (46%) cases. CD56 was positive in 14 (54%) cases. CD30 was positive in 20 (77%) cases; a strong and diffuse pattern was observed in 14 (54%) cases, mimicking, in part, anaplastic large cell lymphoma (ALCL). CD30 expression was associated with younger age and large cell morphology. In summary, EBV+ nodal T-cell and NK-cell lymphoma is an aggressive disease with a poor prognosis. These neoplasms are heterogeneous at the morphologic and immunophenotypic levels. Diffuse and strong expression of CD30 could potentially lead to a misdiagnosis of ALCL if EBV evaluation is not performed. Distinguishing between EBV+ nodal T-cell and NK-cell lymphoma from ALCL is important because treatment strategy and prognosis differ. CD30 expression offers a potential therapeutic target for patients with this aggressive disease.

Variant ALK-fusion positive anaplastic large cell lymphoma (ALCL): A population-based paediatric study of the NHL-BFM study group.

Frequency, distribution and prognostic meaning of ALK-partner genes other than NPM1 in ALK-positive anaplastic large-cell lymphoma (ALCL) are unknown. Forty-nine of 316 ALCL diagnosed in the NHL-BFM study group showed no nuclear ALK expression suggestive of a variant ALK-partner; 41 were analysed by genomic capture high-throughput sequencing or specific RT-PCRs. NPM1::ALK was detected in 13 cases. Among the 28 patients with a non-NPM1::ALK-fusion partner, ATIC (n = 8; 29%) and TPM3 (n = 9; 32%) were the most common. Five of eight patients with ATIC::ALK-positive ALCL relapsed, none of nine with TPM3::ALK. Variant ALK-partners are rare and potentially associated with different prognoses.