Anaplastic large-cell lymphoma

Anaplastic large-cell lymphoma (ALCL) is a rare subtype of non-Hodgkin lymphoma characterized by the proliferation of large, abnormal T-cells or null lymphocytes that express the CD30 antigen on their surface.^[1][2] It is classified into systemic ALCL (which can be ALK-positive or ALK-negative), primary cutaneous ALCL (confined to the skin), and breast implant-associated ALCL (BIA-ALCL), with the ALK status reflecting the presence of anaplastic lymphoma kinase gene rearrangements that drive oncogenesis.^[1][3] This aggressive malignancy accounts for approximately 2% of all non-Hodgkin lymphomas in adults and up to 30% in children, predominantly affecting males and varying in presentation from localized skin lesions to widespread systemic involvement.^[2][4] Systemic ALCL, the most common form, often presents with B symptoms such as fever, night sweats, and weight loss, alongside lymphadenopathy and extranodal sites like skin, bone, or soft tissue.^[1][2] ALK-positive cases, typically seen in younger patients (median age around 24 years), arise from the t(2;5)(p23;q35) chromosomal translocation resulting in the NPM-ALK fusion protein, which activates pathways like JAK/STAT and PI3K/AKT to promote cell survival and proliferation.^[3] In contrast, ALK-negative systemic ALCL affects older adults (median age 61 years) and involves alternative genetic alterations, such as DUSP22 rearrangements or TP53 mutations, leading to a more heterogeneous and often poorer prognosis.^[2][3] Primary cutaneous ALCL manifests as solitary or multifocal reddish-brown nodules on the skin and has an indolent course, with about 25% of cases showing spontaneous regression and a 5-year survival rate exceeding 90%.^[1][2] BIA-ALCL, a distinct entity linked to textured breast implants, usually develops 7-10 years post-implantation as a seroma or capsule mass, driven by chronic inflammation and STAT3 mutations, and is curable in over 90% of noninvasive cases through implant removal.^[1][2] Diagnosis across subtypes relies on excisional biopsy with immunohistochemistry confirming CD30 positivity and ALK status, supplemented by imaging (PET/CT) and staging to guide therapy.^[4][2] Treatment strategies are subtype-specific: ALK-positive systemic ALCL responds well to multi-agent chemotherapy like CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with or without brentuximab vedotin, achieving 5-year survival rates of 70-90%, while relapsed cases may require stem cell transplantation.^[1][2] For ALK-negative disease, outcomes are inferior (5-year survival 15-45%), often necessitating intensified regimens or targeted therapies against CD30 or JAK/STAT pathways.^[2][3] Cutaneous and BIA-ALCL typically require localized interventions like surgery or radiation, with systemic therapy reserved for advanced disease.^[1] Overall, early detection and ALK stratification significantly improve prognosis in this T-cell lymphoma.^[4][2]

Overview

Definition and classification

Anaplastic large-cell lymphoma (ALCL) is a mature peripheral T-cell lymphoma defined by the proliferation of large pleomorphic lymphoid cells that uniformly express the activation marker CD30 and frequently display anaplastic morphology, including hallmark cells with eccentric, horseshoe- or kidney-shaped nuclei, abundant cytoplasm, and prominent Golgi apparatus.^[5] These cells often show defective expression of T-cell lineage markers, contributing to the diagnostic challenge, but the strong membranous and paranuclear CD30 positivity remains a hallmark feature.^[6] In the fifth edition of the World Health Organization (WHO) classification of haematolymphoid tumours (2022), ALCL is recognized as a distinct entity within mature T- and NK-cell neoplasms, encompassing four principal subtypes: systemic ALK-positive ALCL, systemic ALK-negative ALCL, primary cutaneous ALCL, and breast implant-associated ALCL.^[6] ALK protein expression, resulting from underlying genetic rearrangements, serves as a primary classifier that stratifies the systemic subtypes and correlates with differences in pathogenesis and outcome.^[6] Primary cutaneous ALCL is categorized separately under cutaneous T-cell lymphomas due to its localized presentation and indolent behavior, while breast implant-associated ALCL represents a unique subtype linked to chronic inflammation around textured breast implants.^[6] ALCL must be differentiated from other CD30-positive lymphoproliferative disorders, such as classical Hodgkin lymphoma, which features B-cell-derived Reed-Sternberg cells in a reactive inflammatory background rather than the diffuse anaplastic T-cell infiltrate typical of ALCL.^[7] It is also distinguished from other peripheral T-cell lymphomas by its cohesive growth pattern, sinusoidal infiltration in lymph nodes, and consistent strong CD30 expression across nearly all tumor cells, which exceeds the focal or weak CD30 positivity seen in most non-ALCL peripheral T-cell lymphomas.^[6] The diagnostic criteria emphasize the combination of anaplastic cytomorphology and uniform CD30 immunoreactivity, confirmed by immunohistochemistry and exclusion of alternative entities. ALCL is generally considered an aggressive neoplasm, particularly in systemic forms, though prognosis varies widely by subtype, with ALK-positive cases showing more favorable outcomes than ALK-negative counterparts.^[6]

Epidemiology

Anaplastic large-cell lymphoma (ALCL) is a rare subtype of non-Hodgkin lymphoma, accounting for approximately 2-3% of cases in adults and 10-30% in children. The annual incidence is estimated at 0.1-0.3 cases per 100,000 population globally, with primary systemic ALCL representing the majority of diagnoses.^[2][8][9] Demographic patterns differ significantly between subtypes. ALK-positive ALCL predominantly affects children and young adults, with a median age at diagnosis of 12-25 years and a male-to-female ratio of approximately 2:1 to 3:1. In contrast, ALK-negative ALCL occurs primarily in older adults, with a median age exceeding 60 years and less pronounced sex differences. Approximately 90-95% of pediatric systemic ALCL diagnoses are ALK-positive.^{[2][9][10][11]} Geographic variations show higher reported incidence in Western countries, such as the United States and Europe, potentially due to advanced diagnostic capabilities, while underdiagnosis is common in low-resource settings. Ethnic disparities indicate slightly higher rates of systemic ALCL in Caucasians compared to Asians, who exhibit lower incidence. For breast implant-associated ALCL (BIA-ALCL), emerging 2025 data reveal higher incidence among non-Hispanic White and Hispanic women.^[12][13][14] Risk factors include immunosuppression, such as in HIV infection or post-solid organ transplantation, which elevates ALCL risk. A specific association exists with textured breast implants for BIA-ALCL, with an incidence of 1:3,000 to 1:30,000 implantations. Recent trends through 2025 show stable rates for systemic ALCL but increasing BIA-ALCL cases, attributed to heightened awareness and historical implant usage.^{[15][16][17][18][14]}

History

Anaplastic large-cell lymphoma (ALCL) was initially described in 1985 by Harald Stein and colleagues as a distinct subtype of large-cell lymphoma characterized by strong expression of the Ki-1 antigen (later identified as CD30), a marker previously associated with Reed-Sternberg cells in Hodgkin lymphoma.^[19] This recognition highlighted a group of aggressive non-Hodgkin lymphomas with pleomorphic lymphoid cells expressing this activation antigen, initially termed "Ki-1 lymphoma," distinguishing them from other large-cell neoplasms based on immunophenotypic features.^[19] In 1988, further histopathological analysis emphasized the anaplastic morphology of these tumors, featuring hallmark cells with eccentric, kidney-shaped nuclei and abundant cytoplasm, leading to their formal inclusion as a distinct entity in the revised Kiel classification and clear differentiation from Hodgkin lymphoma despite shared CD30 expression.^[2] This morphological characterization was crucial for avoiding misdiagnosis as carcinoma or histiocytic disorders, solidifying ALCL's identity as a peripheral T-cell lymphoma.^[20] The 1990s marked a pivotal advancement with the discovery of the t(2;5)(p23;q35) chromosomal translocation in 1994, fusing the nucleophosmin gene (NPM1) on chromosome 5q35 to the anaplastic lymphoma kinase gene (ALK) on 2p23, resulting in the oncogenic NPM-ALK fusion protein.^[21] This molecular finding enabled the subclassification of ALCL into ALK-positive (ALK+) and ALK-negative (ALK-) subtypes, with ALK+ cases showing constitutive tyrosine kinase activation driving lymphomagenesis and better prognosis. The Revised European-American Lymphoma (REAL) classification in 1994 formally incorporated ALCL as a specific category of mature T-cell neoplasm, emphasizing its cytogenetic and immunophenotypic hallmarks.^[22] Subsequent World Health Organization (WHO) classifications refined ALCL's nosology: the 2001 edition integrated ALK status into diagnostic criteria; the 2008 update expanded on genetic heterogeneity; and the 2016 revision provisionally recognized breast implant-associated ALCL (BIA-ALCL) as a unique subtype linked to textured implants.^[6] Key regulatory milestones included the 2011 FDA alert on the emerging association between breast implants and ALCL, prompting increased surveillance and reporting of BIA-ALCL cases.^[23] The 2022 WHO 5th edition formalized four ALCL subtypes—systemic ALK+, systemic ALK-, BIA-ALCL, and primary cutaneous ALCL—based on clinicopathologic and molecular distinctions.^[6] Recent 2024-2025 studies have further elucidated molecular heterogeneity in ALK- cases, identifying recurrent alterations in DUSP22, TP53, and JAK/STAT pathways that influence prognosis and therapeutic targeting.^[24] Therapeutic milestones paralleled these discoveries: in the 1990s, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) emerged as the standard first-line regimen for systemic ALCL, achieving complete remission rates of 70-90% in ALK+ cases due to their chemosensitivity.^[25] In 2011, the FDA approved brentuximab vedotin, an anti-CD30 antibody-drug conjugate, for relapsed or refractory systemic ALCL, demonstrating objective response rates over 80% and extending progression-free survival in pivotal trials.

Pathogenesis

Histopathological features

Anaplastic large cell lymphoma (ALCL) is characterized by the presence of hallmark cells, which are large lymphoid cells featuring eccentric, horseshoe- or kidney-shaped nuclei with chromatin-poor regions, multiple small nucleoli, and abundant pale to basophilic cytoplasm.^[5][26] These cells often exhibit a prominent Golgi zone and may appear multinucleated or form wreath-like nuclear configurations.^[5][27] In lymph nodes, the neoplastic cells typically show preferential paracortical involvement with prominent intrasinusoidal dissemination, while extranodal sites often display cohesive sheets, clusters, or perivascular rosettes of tumor cells.^[5][26] Architectural effacement can be variable, with diffuse growth patterns predominating in fully involved tissues, sometimes accompanied by fibrosis or necrosis.^[5][27] The immunophenotype of ALCL is defined by uniform, strong positivity for CD30, manifesting as intense membrane and paranuclear (Golgi zone) staining in the neoplastic cells.^[5][26] Most cases express T-cell antigens aberrantly, with frequent loss of pan-T-cell markers such as CD3, CD5, and CD7, while cytotoxic granule proteins (e.g., TIA-1, granzyme B, perforin) are commonly positive; epithelial membrane antigen (EMA) is expressed in the majority of cases.^[5][27] ALK protein staining varies by subtype, showing nuclear and cytoplasmic localization in ALK-positive cases.^[26] Several cytological variants exist, including the classic (common) type with sheets of hallmark cells; the small cell variant, featuring a predominance of small- to medium-sized cells with clear cytoplasm and perivascular clustering of larger cells; the lymphohistiocytic variant, where tumor cells are obscured by abundant reactive histiocytes; and the rare sarcomatoid variant with spindle-shaped cells.^[5][26][27] A Hodgkin-like variant, characterized by Reed-Sternberg-like cells in a mixed inflammatory background, has been reclassified in some systems.^[26] Extracellular features include occasional eosinophilic material, variable inflammatory infiltrates with histiocytes, and rare eosinophils or neutrophils, but granulomatous reactions are absent.^[5][26] Distinction from mimics relies on specific staining patterns: unlike classical Hodgkin lymphoma, ALCL lacks CD15 and PAX5 expression while showing strong CD30 and often ALK positivity; cytokeratin negativity helps differentiate from carcinomas, and the absence of uniform myeloid markers excludes myeloid neoplasms.^[5][26][27]

Molecular mechanisms

Anaplastic large-cell lymphoma (ALCL) is defined by strong expression of CD30, a TNF receptor superfamily member whose gene is upregulated by oncogenic drivers such as NPM-ALK fusions in ALK-positive cases. However, ligation of CD30 in ALCL cells recruits TRAF1 and TRAF2, activating NF-κB and JAK/STAT pathways that ultimately induce cell cycle arrest and apoptosis, rather than promoting survival.^[28][29] This counterintuitive pro-apoptotic role may contribute to immune evasion in the tumor microenvironment. The primary oncogenic signaling in ALCL arises from subtype-specific genetic alterations that constitutively activate pathways like JAK/STAT, NF-κB, and PI3K/AKT, independent of CD30 stimulation.^[30] In ALK-positive ALCL, the t(2;5) translocation generates the NPM-ALK fusion protein, which dimerizes and autophosphorylates to activate downstream effectors including STAT3, promoting proliferation and survival. ALK-negative cases often harbor alternative rearrangements such as DUSP22 (approximately 30%) or TP63 (8%), or mutations in JAK1/STAT3 (around 25-30%), leading to similar pathway dysregulation but with greater heterogeneity.^[30][31] Genomic instability is a defining feature of ALCL, marked by a high proliferation index often exceeding 70% as measured by Ki-67 expression, reflecting rapid cell division and aggressive behavior.^[32] Frequent copy number variations contribute to this instability, including gains on chromosome 2p (encompassing immune regulatory loci) and losses on 6q (affecting tumor suppressor regions), which collectively amplify oncogenic potential and disrupt genomic integrity. Epigenetic dysregulation further impairs T-cell maturation in ALCL, with aberrant DNA hypermethylation silencing differentiation genes such as CD3ε and GATA3 through STAT3-mediated upregulation of DNA methyltransferase 1 (DNMT1).^[33] These alterations, alongside histone deacetylase activity repressing pro-apoptotic loci like BIM, lock cells in an immature, oncogenic state.^[34] The tumor microenvironment in ALCL supports pathogenesis via interactions with tumor-associated macrophages, which secrete immunosuppressive cytokines and polarize toward an M2 phenotype to evade immune surveillance. Cytokine release, including IL-9 in autocrine and paracrine loops, activates JAK3-STAT signaling to bolster tumor cell survival and recruitment of regulatory T cells. Common somatic mutations in ALCL include gain-of-function alterations in STAT3 and STAT5B, occurring in up to 25-30% of cases (primarily ALK-negative) and driving persistent kinase activation in advanced disease; TP53 mutations, present in approximately 10-15% of tumors, correlate with therapy resistance; and MYC amplifications, which enhance glycolytic metabolism and proliferation.^[35][36] The overarching pathogenic model in ALCL centers on dysregulated kinase signaling, where aberrant activation of JAK/STAT, NF-κB, and PI3K/AKT pathways—driven by fusions or mutations—converges to promote uncontrolled survival, inhibit apoptosis through BCL-xL and survivin upregulation, and sustain a permissive microenvironment for clonal expansion. This model underscores the shared reliance on kinase-driven oncogenesis across ALCL variants.^[30]

Systemic ALK-positive anaplastic large-cell lymphoma

Signs and symptoms

Systemic ALK-positive anaplastic large-cell lymphoma (ALCL) most commonly presents with painless lymphadenopathy in the cervical, axillary, or inguinal regions.^[37][38] B symptoms, including fever, night sweats, and unintentional weight loss, occur in approximately 30-50% of cases.^[16] Extranodal involvement is frequent, affecting sites such as skin (10-20%), bone, soft tissue, lung, or liver, and may cause localized symptoms like rash, pain, or respiratory issues.^[39] This subtype predominantly affects children and young adults (median age 12-24 years), with a male predominance (ratio 2-3:1).^[1][2]

Diagnosis

Diagnosis of systemic ALK-positive ALCL requires histopathological examination of an excisional biopsy from an affected lymph node or extranodal site, revealing large anaplastic lymphoid cells with "hallmark" horseshoe-shaped nuclei.^[9] Immunohistochemistry confirms CD30 positivity in all cases and ALK protein expression in the cytoplasm and nucleus, distinguishing it from ALK-negative variants.^[40][2] Additional markers include EMA positivity and variable T-cell antigen expression (e.g., CD3, CD5).^[41] Staging involves PET/CT imaging to assess disease extent, bone marrow biopsy to evaluate involvement (positive in 10-20%), and laboratory tests including LDH levels.^[9] The Ann Arbor staging system is used, with advanced stage (III-IV) common at presentation (60-70%).^[2] Molecular studies, such as FISH or PCR for ALK rearrangements, confirm the diagnosis and exclude mimics like Hodgkin lymphoma or other CD30+ lymphomas.^[42]

Genetic and molecular abnormalities

Systemic ALK-positive ALCL is defined by chromosomal translocations involving the ALK gene on chromosome 2p23, most commonly t(2;5)(p23;q35) resulting in the nucleophosmin-ALK (NPM1-ALK) fusion protein in 75-85% of cases.^[31][43] Less frequent variants include TPM3-ALK, TFG-ALK, and ATIC-ALK fusions.^[30] The NPM-ALK oncoprotein exhibits constitutive tyrosine kinase activity, activating downstream pathways such as JAK/STAT3, PI3K/AKT, and MAPK/ERK, promoting cell proliferation, survival, and resistance to apoptosis.^[10] These alterations drive lymphomagenesis from activated T-cells, with additional genomic instability including MYC amplifications or TP53 mutations in some cases.^[44] Unlike ALK-negative ALCL, DUSP22 rearrangements are absent, and the molecular profile correlates with the favorable prognosis.^[31] Targeted sequencing can identify these fusions for diagnostic confirmation.^[45]

Treatment and prognosis

The standard first-line treatment for systemic ALK-positive anaplastic large-cell lymphoma (ALCL) in adults is multiagent chemotherapy, with brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone (BV-CHP) established as the preferred regimen based on the phase 3 ECHELON-2 trial, which demonstrated superior efficacy over traditional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).^[46] For younger patients (typically under 60 years) with good performance status, intensified regimens such as CHOP plus etoposide (CHOEP) may be considered, particularly in limited-stage disease, though BV-CHP remains the category 1 recommendation in NCCN guidelines due to its improved progression-free survival.^[46] Radiation therapy is generally reserved for localized bulky disease or consolidation in select cases, while consolidative autologous stem cell transplantation is not routinely recommended for patients achieving complete remission after frontline therapy.^[47] In the ECHELON-2 subgroup analysis of ALK-positive ALCL patients, BV-CHP achieved a 5-year progression-free survival rate of 87% compared to 67% with CHOP, with a complete response rate of approximately 85% across both arms but sustained benefit favoring the BV-CHP group (hazard ratio 0.40; 95% CI, 0.17–0.98).^[47] For relapsed or refractory disease, salvage options include platinum-based chemotherapy (e.g., ifosfamide, carboplatin, etoposide [ICE]) followed by autologous or allogeneic stem cell transplantation, with high response rates to brentuximab vedotin monotherapy (about 86% overall response) in CD30-positive cases.^[46] ALK tyrosine kinase inhibitors, such as crizotinib or alectinib, show promise in relapsed settings, particularly for ALK fusion-driven disease, with ongoing trials evaluating their role in frontline integration for adults.^[46] Prognosis for systemic ALK-positive ALCL is favorable compared to other peripheral T-cell lymphomas, with 5-year overall survival rates ranging from 70% to 90%, driven by high complete response rates (up to 90%) and the disease's responsiveness to chemotherapy in younger patients (median age ~35 years).^[46] Limited-stage disease and absence of high-risk features (e.g., elevated LDH or extranodal involvement) further improve outcomes, with relapse-free survival around 60% at 5 years; however, advanced-stage or relapsed cases have lower 5-year progression-free survival (~43–69%), underscoring the need for early intervention.^[46] Long-term survival exceeds 10 years in most cured patients, with BV-CHP reducing relapse risk and enhancing durable remissions.^[47]

Systemic ALK-negative anaplastic large-cell lymphoma

Signs and symptoms

Systemic ALK-negative anaplastic large-cell lymphoma (ALCL) primarily affects adults, with a median age at diagnosis of 60-65 years and a male predominance (male-to-female ratio approximately 1.5:1). It accounts for 2-8% of adult non-Hodgkin lymphomas and 10-30% of T-cell lymphomas. Patients typically present with advanced-stage disease (stage III-IV in about 70% of cases), including peripheral and abdominal lymphadenopathy. B symptoms—fever, night sweats, and unintentional weight loss—occur in 50-75% of cases, with fever being the most common. Extranodal involvement is frequent (up to 60%), commonly affecting the skin (20%), bone (15-17%), soft tissue, lung, and liver, leading to symptoms such as rash, pain, or organ-specific dysfunction. Unlike ALK-positive ALCL, presentations in children are rare, and the disease shows more heterogeneous and aggressive features.^[2][48]

Diagnosis

Diagnosis requires excisional biopsy of an affected lymph node or extranodal site, revealing sheets of large anaplastic lymphoid cells, including characteristic "hallmark" cells with kidney-shaped nuclei. Immunohistochemistry is essential, showing strong, uniform CD30 positivity (membrananous and Golgi zone) in nearly all cases, with ALK negativity distinguishing it from ALK-positive ALCL. T-cell markers are variably expressed (e.g., CD2 positive, CD3 and CD5 often lost), along with frequent expression of EMA, CD43, and cytotoxic granule proteins (granzyme B, perforin, TIA-1). B-cell markers (e.g., CD20, PAX5) and EBV are negative. Molecular studies confirm T-cell receptor (TCR) gene rearrangements, supporting clonality. Staging involves PET/CT imaging, bone marrow biopsy, and the Ann Arbor system with International Prognostic Index (IPI) assessment; about 8% have bone marrow involvement. Differential diagnosis includes other CD30+ lymphomas (e.g., classical Hodgkin lymphoma, other peripheral T-cell lymphomas), requiring multidisciplinary review.^[2][48][49]

Genetic and molecular abnormalities

Systemic ALK-negative ALCL lacks the NPM1-ALK fusion gene translocation t(2;5)(p23;q35) characteristic of ALK-positive cases. Instead, it is genetically heterogeneous, with three main molecular subtypes identified by fluorescence in situ hybridization (FISH): DUSP22 rearrangements (approximately 30% of cases, associated with better prognosis), TP63 rearrangements (about 8%, linked to aggressive disease and poor outcomes), and triple-negative cases (62%, lacking these rearrangements and showing intermediate to poor prognosis). These rearrangements are mutually exclusive. Additional abnormalities include TP53 mutations (30%), activating mutations in STAT3 (20-30%) leading to JAK/STAT pathway dysregulation, and epigenetic alterations in TET2 and DNMT3A. Copy number variations are common, such as gains at 9p24.1 (JAK2 and PD-L1/PD-L2 loci, promoting immune evasion) and losses at 6q. Gene expression profiles differ from ALK-positive ALCL and other T-cell lymphomas, with overexpression of genes like IL21, IL22, and CNTFR. Chronic antigen stimulation may contribute to pathogenesis, though less defined than in ALK-positive disease. Targeted next-generation sequencing and FISH are used diagnostically to identify subtypes.^[48][49][2]

Treatment and prognosis

First-line treatment for systemic ALK-negative ALCL typically involves multi-agent chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOEP (CHOP plus etoposide), achieving complete response rates of 60-80%. The addition of brentuximab vedotin (BV) to CHP (omitting vincristine to reduce neuropathy) is increasingly used based on peripheral T-cell lymphoma trials, though specific data for ALK-negative ALCL are limited. Radiation therapy may be added for bulky or localized disease, while consolidative autologous stem cell transplantation (ASCT) is considered for high-risk patients in first complete remission. For relapsed or refractory cases, salvage regimens (e.g., ICE: ifosfamide, carboplatin, etoposide), BV monotherapy (response rate ~80%), or allogeneic transplantation are options; targeted therapies against CD30 or JAK/STAT pathways (e.g., JAK inhibitors) are under investigation.^[48][2] Prognosis is inferior to ALK-positive ALCL, with 5-year overall survival (OS) rates of 30-50% and progression-free survival (PFS) of 40-45%. Subtype impacts outcomes: DUSP22-rearranged cases have 5-year OS of 80-90%, TP63-rearranged <20%, and triple-negative ~40%. Adverse factors include age >60 years, elevated LDH, stage III-IV, and IPI score ≥3. As of 2024, intensified anthracycline-etoposide regimens show improved OS (5-year 44%), but relapse remains common, highlighting the need for novel therapies. Early genetic subtyping aids risk stratification.^[49][2][48]

Primary cutaneous anaplastic large-cell lymphoma

Signs and symptoms

Primary cutaneous anaplastic large-cell lymphoma (pcALCL) typically presents as solitary or localized reddish-brown nodules or tumors greater than 2 cm in diameter, often on the trunk, limbs, face, buttocks, or arms.^[1][2] Lesions may ulcerate or form plaques, and approximately 25% of cases exhibit spontaneous regression without treatment.^[2] Systemic B symptoms such as fever, night sweats, or weight loss are uncommon unless there is extracutaneous involvement.^[50] pcALCL accounts for about 8-9% of all cutaneous T-cell lymphomas, with an incidence rate of approximately 0.1-0.12 per million people in the United States, showing stability as of 2024.^[2][51] It predominantly affects adults with a median age at diagnosis of 60 years and a male-to-female ratio of about 3:2.^[2][52] Multifocal involvement occurs in around 20% of cases, but dissemination to internal organs is rare at presentation.^[1]

Diagnosis

Diagnosis of pcALCL requires clinicopathologic correlation, beginning with a high index of suspicion for persistent skin nodules in adults. An excisional or incisional biopsy is essential, revealing a dense, diffuse infiltrate of large anaplastic lymphoid cells in the dermis, often with nonepidermotropic growth and possible ulceration.^[50][2] Immunohistochemistry confirms CD30 positivity in greater than 75% of tumor cells, with typical ALK negativity to distinguish it from systemic ALK-positive ALCL. Additional markers include CD4 positivity, EMA negativity, and frequent expression of cytotoxic proteins like TIA-1 or granzyme B.^[2] T-cell receptor gene rearrangement studies demonstrate clonality, supporting the lymphoproliferative nature.^[50] To exclude systemic involvement, staging includes physical examination, blood tests, and imaging such as PET/CT or CT scans of the chest, abdomen, and pelvis. Bone marrow biopsy is not routinely required unless extracutaneous disease is suspected. The 2018 WHO-EORTC classification emphasizes ruling out secondary cutaneous involvement from systemic ALCL.^[53] Differential diagnosis includes lymphomatoid papulosis, transformed mycosis fungoides, and reactive conditions, often necessitating multidisciplinary review.^[50]

Genetic and molecular abnormalities

pcALCL is characterized by ALK negativity in the vast majority of cases, lacking the NPM-ALK fusion seen in systemic ALK-positive ALCL. Instead, approximately 20-30% harbor DUSP22 gene rearrangements at 6p25.3, which are associated with an indolent course and favorable prognosis.^[54][55] Other molecular alterations include IRF4 translocations (often with IGH) in up to 25% of cases, particularly in younger patients, leading to IRF4 overexpression. Activating mutations in the NF-κB pathway and JAK/STAT signaling are common, promoting T-cell survival and proliferation.^[54][50] Genomic studies reveal a low somatic mutation burden, with recurrent changes in epigenetic regulators and copy number variations, but without the TP63 rearrangements typical of some systemic ALCL subtypes.^[56] These abnormalities underscore pcALCL's distinction as a primary cutaneous entity, potentially driven by chronic antigenic stimulation in the skin microenvironment, though no unifying genetic event has been identified. Targeted next-generation sequencing can detect these features, aiding in subclassification and prognosis assessment.^[54]

Treatment and prognosis

Treatment for pcALCL is tailored to disease extent and favors localized approaches due to its indolent nature. For solitary or localized lesions, surgical excision or radiation therapy achieves remission in about 95% of cases.^[2][57] Multifocal cutaneous disease is managed with low-dose methotrexate (10-25 mg weekly), psoralen plus ultraviolet A (PUVA) therapy, or localized radiation, with response rates exceeding 80%.^[57] Brentuximab vedotin, a CD30-targeted antibody-drug conjugate, is effective for recurrent or refractory multifocal disease, often used off-label or in clinical trials.^[2] Systemic chemotherapy (e.g., CHOP) is reserved for extracutaneous spread, which occurs in less than 10% of cases.^[50] Prognosis is excellent, with 5-year disease-specific survival rates of 85-95% and 10-year overall survival around 90%, even with regional lymph node involvement.^[50][57] Cutaneous relapses are common (up to 40% within 5 years) but respond well to retreatment. Adverse factors include multifocal limb disease, extracutaneous dissemination, or transformation to systemic ALCL, reducing 5-year survival to about 50%. Early detection and DUSP22 rearrangement positivity correlate with better outcomes. As of 2025, no major shifts in management guidelines have been reported.^[2][54]

Breast implant-associated anaplastic large-cell lymphoma

Signs and symptoms

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare type of non-Hodgkin lymphoma, a cancer of the immune system and not a form of breast cancer, that arises in the fibrous scar tissue (capsule) surrounding textured breast implants.^[58][59] It typically presents with late-onset periprosthetic seroma, characterized by fluid accumulation around the breast implant occurring 3-14 years after implantation, often accompanied by breast swelling and pain.^[60] This seroma is a hallmark feature, frequently leading to unilateral breast enlargement without signs of infection.^[58] Mass effects from the disease include capsular contracture, breast asymmetry, and palpable lumps, with skin manifestations such as erythema or ulceration observed in approximately 15% of cases.^[60] Systemic symptoms, known as B symptoms (fever, night sweats, weight loss), are rare, occurring in less than 10% of patients, while axillary lymph node involvement may appear in advanced stages (II-III).^[60] BIA-ALCL exclusively affects women with breast implants, with a higher incidence associated with textured implants compared to smooth ones, and a median age at diagnosis of 50 years.^[60][58] The disease progression is often indolent and localized, remaining confined to the implant capsule in about 80% of cases, where effusion cytology plays a key role in confirming the diagnosis.^[60] Following FDA warnings and the 2019-2021 recall of certain textured implants, such as Allergan's Natrelle Biocell line, there has been an increase in reported cases due to heightened awareness, with over 1,600 cases documented worldwide as of mid-2025.^[23][18]

Diagnosis

The diagnosis of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) begins with clinical suspicion in patients with breast implants presenting with persistent swelling, pain, or asymmetry more than one year post-implantation, often due to periprosthetic fluid collections or masses. Initial evaluation typically involves imaging with ultrasound or MRI to detect fluid accumulations, masses, or implant integrity issues, followed by ultrasound-guided fine-needle aspiration of any effusion for cytologic analysis.^[61] Pathologic confirmation requires examination of aspirated fluid or capsule biopsy, revealing anaplastic large lymphoid cells that are CD30-positive and ALK-negative, distinguishing BIA-ALCL from other lymphomas. Cytology of the effusion often shows these hallmark anaplastic cells admixed with CD68-positive macrophages, while immunohistochemistry further supports the diagnosis by confirming strong uniform CD30 expression and negativity for PAX5 to exclude Hodgkin lymphoma.^[61] Staging employs PET-CT to assess for lymph node or distant involvement, alongside evaluation of implant integrity and capsular invasion, using a TNM system where T1 indicates confined effusion and higher stages reflect deeper or systemic spread. Diagnostic criteria, as outlined in the 2019 NCCN consensus guidelines and MD Anderson recommendations, mandate the presence of effusion with cytologic evidence of CD30+ anaplastic cells for confirmation, often supplemented by T-cell receptor gene rearrangement studies.^[62] Common pitfalls include mistaking atypical reactive cells in benign seromas for malignancy, necessitating multidisciplinary input from oncology, plastic surgery, and pathology to ensure accurate interpretation and avoid unnecessary interventions. Anaplastic histology in BIA-ALCL mirrors systemic forms but is localized to the implant site in early cases.^[61]

Genetic and molecular abnormalities

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) exhibits a distinct genomic profile characterized by ALK negativity, distinguishing it from ALK-positive systemic cases, alongside a low somatic mutation burden typically involving fewer than 10 nonsynonymous mutations per megabase.^[63][64] The hallmark molecular abnormality in BIA-ALCL is constitutive activation of the JAK/STAT signaling pathway, most commonly driven by activating mutations in STAT3, reported in 20-30% of cases, which promote uncontrolled T-cell proliferation and survival.^[63][64] Additional pathway alterations include mutations in JAK1 (approximately 7% of cases) and epigenetic regulators such as DNMT3A and TP53, contributing to oncogenesis without the high mutational heterogeneity seen in other peripheral T-cell lymphomas.^[63][65] Unlike systemic ALK-negative ALCL, DUSP22 and TP63 rearrangements are absent in BIA-ALCL, underscoring its unique molecular subclass.^[63][64] Copy number variations (CNVs) play a significant role, with recurrent gains at chromosome 9p24.1 encompassing the PD-L1 (CD274) and PD-L2 loci in roughly 33-40% of cases, resulting in PD-L1 overexpression that enables immune evasion and positions these tumors as candidates for PD-1/PD-L1 checkpoint inhibitors.^[66][67] Other CNVs include losses at 20q (characteristic and frequent) and occasional deletions at 8p, though the latter are less consistently reported in BIA-ALCL compared to broader ALK-negative subtypes.^[68] Epigenetic modifications, potentially induced by prolonged antigen exposure from implant-associated biofilms, further modulate gene expression and tumor microenvironment interactions.^[65] Pathogenic models center on chronic inflammation triggered by bacterial biofilms adhering to textured implant surfaces, with Ralstonia pickettii identified as a predominant species in capsular fluid, fostering persistent T-cell receptor stimulation and lymphomagenesis over years.^[69][70] This antigen-driven process contrasts with sporadic genetic events in non-implant-associated ALCL, emphasizing environmental cofactors in BIA-ALCL transformation.^[71][67] Diagnostically, targeted next-generation sequencing (NGS) panels for STAT3 mutations and fluorescence in situ hybridization or array-based detection of CD274 amplification aid in confirming BIA-ALCL, particularly in effusion or capsular specimens where histopathological features may overlap with reactive processes.^[64][66] These molecular assays, combined with assessment of phosphorylated STAT3 expression, enhance specificity beyond CD30 immunohistochemistry alone.^[63]

Treatment and prognosis

Treatment for breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is guided by disease stage and primarily involves complete surgical removal of the implant and surrounding fibrous capsule (en-bloc capsulectomy), as recommended by the 2019 National Comprehensive Cancer Network (NCCN) consensus guidelines and updated 2024 European Association of Plastic Surgeons (EURAPS) expert consensus.^[72][73] For localized disease (stage I, confined to effusion or capsule), surgery alone is curative in over 90% of cases, with total capsulectomy preferred over partial to minimize recurrence risk.^[18][59] In cases with mass or capsular invasion (stage II), complete oncologic resection of the tumor mass is essential, often followed by implant removal on the contralateral side if textured.^[74] For advanced disease (stages III-IV, with lymph node or distant involvement), multidisciplinary management includes surgery plus systemic therapy such as chemotherapy (e.g., CHOP regimen) or radiation, particularly for incomplete resection or high-risk features; brentuximab vedotin may be considered for CD30-positive relapsed cases.^[73][75] Patients are advised to wait at least two years post-treatment before considering new implants.^[59] Prognosis is excellent for early-stage BIA-ALCL, with 5-year overall survival exceeding 90% and 93% disease-free at three years following complete surgical excision; advanced cases have lower rates (around 50-70% 5-year survival) but still outperform many T-cell lymphomas due to the indolent nature and responsiveness to localized therapy.^[18][59][75] Relapse is rare after curative surgery, with long-term follow-up every 3-6 months recommended for the first two years.^[74]