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Breast implant-associated anaplastic large cell lymphoma (ALCL) is a distinctive type of T-cell lymphoma that arises around textured-surface breast implants. In a subset of patients, this disease can involve surrounding tissues, spread to regional lymph nodes, and rarely metastasize to distant sites. The aim of this study was to assess sequential pathologic specimens from patients with breast implant-associated ALCL to better understand the natural history of early-stage disease. To achieve this goal, we searched our files for patients who had breast implant-associated ALCL and who had undergone earlier surgical intervention with assessment of biopsy or cytologic specimens. We then focused on the patient subset in whom a definitive diagnosis was not established, and patients did not receive current standard-of-care therapy at that time. We identified a study group of ten patients with breast implant-associated ALCL in whom pathologic specimens were collected 0.5 to 4 years before a definitive diagnosis was established. A comparison of these serial biopsy specimens showed persistent disease without change in pathologic stage in three patients, progression in five patients, and persistence versus progression in two patients. Eventually, six patients underwent implant removal with complete capsulectomy and four underwent partial capsulectomy. Seven patients also received chemotherapy because of invasive disease, three of whom also received radiation therapy, two brentuximab vedotin after chemotherapy failure, and one allogeneic stem cell transplant. Eight patients achieved complete remission and two had partial remission after definitive therapy. At time of last follow-up, six patients were alive without disease, one had evidence of disease, one died of disease, and two patients died of unrelated cancers. In summary, this analysis of sequential specimens from patients with breast implant-associated ALCL suggests these neoplasms persist or progress over time if not treated with standard-of-care therapy.

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.

Anaplastic large cell lymphomas (ALCL) are mature T-cell neoplasms, approximately half of which harbor rearrangements of theALKgene that confer a good prognosis. Recent studies have demonstrated that a significant proportion of ALK-negative ALCLs demonstrate rearrangements of theIRF4/DUSP22locus that also are typically associated with a favorable prognosis. ALCL with primary involvement of the central nervous system (CNS) is extremely rare. We report what may be the first case of ALK-negative ALCL withIRF4/DUSP22rearrangement involving the brain in a 55-year-old man. Magnetic resonance imaging demonstrated signal abnormalities in the periventricular region, corpus callosum and cingulate gyrus. Biopsy revealed a diffuse parenchymal and angiocentric infiltrate of CD30-positive cells that showedIRF4/DUSP22rearrangement by fluorescence in situ hybridization. We also review the clinical and pathologic features of primary CNS ALK-negative ALCLs in the literature and highlight the need for awareness of this entity to optimize appropriate management.

INTRODUCTION The combination of cytology and multiparametric flow cytometry (MFC) may be useful in the diagnosis of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and may be a practical way to differentiate lymphoma from benign and reactive seromas. Although the Brazilian breast implant market is the second largest in the world, with several manufacturers and the almost exclusive use of textured implants, the occurrence of BIA-ALCL in Brazil is underreported. METHODS One hundred seventeen sequential collections of suspicious periprosthetic fluid (PF) from 105 Brazilian patients registered between March/2018 and March/2021 were evaluated by routine cytomorphology and flow cytometry. The combination of CD30, HLA-DR, and CD25 was used together with T and B lymphocyte and monocyte evaluation. The PF samples were divided into positive, acute reactive (neutrophilic exudate), or chronic reactive (macrophage or lymphocyte rich), and unavailable samples. RESULTS Nine BIA-ALCL positive cases (7.7%) were identified, with typical morphology and increased FSC/SSC dispersion, bright expression of CD30, CD25 and HLA-DR, and absence or weakness of T-cell antigens (CD3, CD8, CD4, CD5, and CD7). Reactive samples were acute (n = 18, 15.4%) and chronic (n = 70, 59.8%). Twenty samples were excluded. The mean age of BIA-ALCL patients was 50 years (31-57 years) and 35 years in reactive patients (20-69 years). CONCLUSION Use of MFC with a comprehensive antibody panel consisting of CD30 in conjunction with CD25 and HLA-DR can discriminate anaplastic cells of BIA-ALCL from lymphoid or neutrophilic reactive cells and should be considered in the initial evaluation of seroma.

An 81-year-old male presented with a rapidly growing cheek nodule. Biopsy revealed a dermal infiltrate of large atypical cells, some exhibiting a horseshoe-shaped nucleus. Immunohistochemistry revealed positivity for CD4, CD3, CD45, and CD30 (>95%). Melanocytic markers, cytotoxic markers, CD20, CD56, ALK1, synaptophysin, CD1a, and ETS-related gene (ERG) were negative. Notably, there was weak but diffuse expression of pan-cytokeratin (AE1/AE3) and Oscar keratin. There was also a weak expression of epithelial membrane antigen (EMA). CAM 5.2, p40, and IRF4/DUSP22 rearrangement were negative. Further staging revealed skin-limited disease. A diagnosis of primary cutaneous anaplastic large-cell lymphoma (PC-ALCL) was rendered. We present a rare case of cytokeratin positive PC-ALCL, a finding never reported in the literature. Both PC-ALCL and systemic ALCL (S-ALCL) evoke a broad differential. CD45, EMA, and cytokeratin stains help differentiate from metastatic carcinomas. There have been rare prior reports of cytokeratin expression in S-ALCL, which tend to stain with an unusual cytoplasmic and membranous pattern like our case, have variable co-expression of EMA, and null T-cell phenotypes. These show the significant diagnostic challenges that can arise in differentiating ALCL from metastatic or primary skin carcinomas. Awareness, careful attention to morphology (e.g., hallmark cells), and considering routine CD30 can help lead the pathologist to the correct diagnosis.

The DUSP22-IRF4 gene rearrangement results in downregulation of DUSP22, a presumed tumor suppressor in T-cell lymphomagenesis. It has been described in some cases of primary cutaneous and systemic anaplastic large-cell lymphoma, lymphomatoid papulosis, and transformed mycosis fungoides. Here we describe two patients with clinical lesions resembling patch/plaque mycosis fungoides that did not meet WHO criteria for large-cell transformation on histopathology yet showed a DUSP22 translocation. One patient who had a history of systemic anaplastic large-cell lymphoma with DUSP22 translocation presented with cutaneous involvement by his systemic lymphoma along with lymphomatoid papulosis and mycosis-fungoides-like lesions, all showing an identical immunophenotype and T-cell clone. These cases expand the spectrum of DUSP22-rearranged lymphomas to include mycosis-fungoides-like presentations without large-cell transformation.

Primary cutaneous anaplastic large-cell lymphoma (pC-ALCL) is distinguished from systemic anaplastic large-cell lymphoma (S-ALCL) with cutaneous involvement. Although pC-ALCL is a unique entity with different genetics, clinical characteristics, and prognosis, its causes are unknown. Herein, we report the case of a Chinese woman with a 4-month history of a gradually enlarged ulcerative mass in her right forearm following an unidentified insect bite. Biopsy revealed an extensive infiltrate with patches of large anaplastic lymphoid cells. These cells were immunohistochemically positive for CD45, CD30, and TIA-1 and negative for CD2, CD3, CD4, CD5, CD20, CD7, CD8, and ALK-1. DUSP22-IRF4 rearrangement was detected; on the other hand, TP63 rearrangement was not observed by fluorescence in situ hybridization (FISH). No Epstein-Barr virus-encoded small RNAs (EBERs) were detected by ISH. Rearrangement of monoclonal TCR gene was found using BIOMED-2 polymerase chain reaction. No abnormality was found on the subsequent positron emission tomography-computed tomography (PET-CT) scan. After five cycles of cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP) chemotherapy, the patient achieved complete remission. This is the first report of a unique pC-ALCL with DUSP22-IRF4 rearrangement following an insect bite other than S-ALCL involving the skin.

BACKGROUND: Astrocytic tumors are the most common primary brain tumors. Glioblastoma is the most common astrocytic tumor representing the highest World Health Organization (WHO) grade (WHO grade IV) with poor prognosis and short survival time. Anaplastic lymphoma kinase (ALK) has a role in embryonic central nervous system development. ALK receptor is thought to contribute to nervous system function, repair, and metabolic homeostasis and is expressed in high-grade tumors like anaplastic large cell lymphoma that makes it a potential target for therapeutic intervention. AIM: This work aimed to examine the immunohistochemical expression of ALK in astrocytic tumors and its correlation with age, sex, clinical presentation, location, laterality, recurrence, and WHO grade to implicate possible therapeutic potential. METHODS: This retrospective study was conducted on sixty cases of archived, formalin-fixed, paraffin-embedded tissue blocks that included different subtypes and grades of astrocytic tumors. Immunohistochemistry using ALK monoclonal antibody was performed using a standard avidin-biotin-peroxidase system. RESULTS: Of the sixty cases, 57 (95%) cases were negative for ALK, while three (5%) cases are positive for ALK; all showed the strong intensity of expression. No statistically significant association was found between ALK expression and astrocytic tumors in addition to other clinical variables of the studied tumors. CONCLUSIONS: Most cases of astrocytic tumors showed negative ALK expression apart from three positive cases seen in higher WHO grades, especially gliosarcoma. The high number of negative cases for ALK in our study group suggests that ALK expression is not associated with a prognostic significance toward astrocytic tumors whatever its grade.

Anaplastic large cell lymphoma (ALCL) is a histological subtype of non-Hodgkin lymphoma, largely characterized by anaplastic lymphoma kinase (ALK) positivity, resulting from the chromosomal translocation t(2;5). We report a pediatric case of ALK-positive ALCL with primary concomitant involvement of bone and central nervous system (CNS); thereafter, a literature review about pediatric primary bone and primary CNS ALCL was conducted. According to the analyzed data, our case is unique because it is characterized by the contemporary involvement of the spine and CNS. During and after chemotherapy, our patient was monitored by detecting minimal residual disease (MRD) through the analysis of fusion transcript nucleophosmin-ALK. MRD assessment, not only in bone marrow but also in peripheral blood, seems to be a very powerful tool for predicting the prognosis of pediatric ALCL patients, as already described in the literature. Moreover, as shown in our case, it could be used during the follow-up for early recognition of relapse.

After acute leukemia and brain and central nervous system tumors, mature lymphomas represent the third most common cancer in pediatric patients. Non-Hodgkin lymphoma accounts for approximately 60% of lymphoma diagnoses in children, with the remainder representing Hodgkin lymphoma. Among non-Hodgkin lymphomas in pediatric patients, aggressive lymphomas, such as Burkitt lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma, predominate. This article summarizes the epidemiologic, histopathologic, and molecular features of selected mature systemic B-cell and T-cell lymphomas encountered in this age group.

Lymphoproliferative disorders comprise 50% to 60% of all mediastinal malignancies in both children and adults. Primary mediastinal involvement is rare (∼5%), whereas secondary mediastinal involvement by systemic disease is more common (10% to 25%). Primary mediastinal disease is defined as involvement by a lymphoproliferative disorder of mediastinal lymph nodes, the thymus, and/or extranodal mediastinal organs without evidence of systemic disease at presentation. In this review, the clinical, radiologic, histopathologic, immunohistochemical, and genetic features of some of the most characteristic mediastinal lymphoproliferative disorders are presented. The entities discussed here include: classic Hodgkin lymphoma with emphasis on nodular sclerosis and mixed cellularity types, and non-Hodgkin lymphomas, including primary mediastinal (thymic) large B-cell lymphoma, mediastinal gray zone lymphoma, mediastinal diffuse large B-cell lymphoma, thymic marginal zone lymphoma, mediastinal plasmacytoma, T-lymphoblastic lymphoma, and anaplastic large cell lymphoma. Although not a malignant process, hyaline vascular Castleman disease is also discussed here as this disorder commonly involves the mediastinum. Despite multiple advances in hematopathology in recent decades, the day-to-day diagnosis of these lesions still requires a morphologic approach and a proper selection of immunohistochemical markers. For this reason, it is crucial for general pathologists to be familiar with these entities and their particular clinicoradiologic presentation.

CD30 lymphocyte activation antigen and phosphorylated STAT3 (pSTAT3) are consistent markers of tumor cells in breast implant–associated anaplastic large cell lymphoma (BIA-ALCL). We present a case of BIA-ALCL in a breast implant capsule containing clustered tumor cells expressing CD30, pSTAT3, pSTAT6, interleukin 9, and granzyme B tumor cell biomarkers. Remarkably, the contralateral breast contained many scattered large, atypical CD30+ cells surrounded by inflammatory cells, raising a suspicion of bilateral BIA-ALCL, known to occur in some patients. To clarify the diagnosis, immunohistochemistry and multilabel immunofluorescence were performed. Unlike the tumor cells, the atypical CD30+ cells of the contralateral breast lacked pSTAT3, pSTAT6, interleukin 9, and granzyme B, eliminating a diagnosis of bilateral BIA-ALCL. This case highlights the importance of interpreting CD30 staining in the context of other tumor cell biomarkers and histopathology to avoid an incorrect diagnosis of BIA-ALCL. We believe the findings also suggest the possibility of CD30 expression as an early event in the multistep pathogenesis of BIA-ALCL.Level of Evidence: 5

ObjectivesThis review describes our approach to the diagnosis of all 4 anaplastic large cell lymphoma (ALCL) entities.MethodsALCLs are a group of CD30-positive mature T-cell lymphomas with similar morphologic and phenotypic characteristics but variable clinical and genetic features. They include systemic ALK-positive ALCL, systemic ALK-negative ALCL, primary cutaneous ALCL, and the recently described provisional entity breast implant–associated ALCL.ResultsIn cases with classic features, the diagnosis of ALCL is often straightforward. However, variant histology, the importance of clinical history, and multiple antigenic aberrancies all present challenges to accurate diagnosis and subclassification.ConclusionsA systematic approach to the diagnosis of ALCL and awareness of potential mimics are critical to avoid misdiagnosis. It is also crucial to correctly identify localized forms of ALCL to avoid classification as systemic ALCL and subsequent overtreatment.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon lymphoproliferative disorder, mainly associated with textured implants. The average time from the breast implants to the development of BIA-ALCL is about 7 to 10 years, and the median age at the time of diagnosis is in the mid-50s. The exact incidence and prevalence of BIA-ALCL are not known. The pathogenesis of BIA-ALCL remains unclear. Different theories have been postulated, including immune response to textured implants, subclinical bacterial infection, and genetic predisposition. However, none of those theories have yet been proven to be causal in the pathogenesis of BIA-ALCL. BIA-ALCL is histologically similar to but clinically distinct from other CD30-positive T-cell lymphomas such as anaplastic lymphoma kinase-positive, anaplastic lymphoma kinase-negative, and primary cutaneous ALCL. The revised World Health Organization classification of lymphoid neoplasm in 2016 recognized BIA-ALCL as a provisional entity. Suspected cases need proper evaluation and workup to confirm the diagnosis. Surgical resection should be considered for all the cases. However, adjuvant radiotherapy and anthracycline-based chemotherapy are warranted for locally advanced and advanced cases.

The sarcomatoid variant of anaplastic large cell lymphoma is an extremely rare histologic pattern of anaplastic large cell lymphoma that consists of spindle-shaped neoplastic cells and is easily misdiagnosed as a soft tissue sarcoma. We report a case of the sarcomatoid variant of anaplastic large cell lymphoma that was initially diagnosed as an inflammatory myofibroblastic tumor in our hospital and as liposarcoma after consultation. This article analyzed the features of this entity by reviewing the literature. Only 15 cases have been reported, most of which were misdiagnosed as sarcoma, sarcomatoid carcinoma, or inflammatory myofibroblastic tumor. Most of the reported cases showed a myxoid stroma, with a variable number of inflammatory cells. The hallmark cells usually can be found by careful evaluation of the slides. Immunohistochemistry including CD30, EMA, and ALK are the most useful for diagnosis. Most are III or IV stage, and have a good prognosis after chemotherapy.

Anaplastic large cell lymphomas (ALCLs) are a group of CD30 positive T-cell non-Hodgkin lymphomas, accounting for only 3% of all non-Hodgkin lymphomas. As per the 2017 World Health Organization updated classification, there are four variants of ALCL: anaplastic lymphoma kinase (ALK) positive, ALK negative, primary cutaneous, and breast-implant associated. The different variants of ALCL share overlapping clinical presentations and pathologic features, creating a diagnostic challenge. A 71-year-old woman with a past history of T-cell lymphoma presented with a progressively growing nodule on her back for approximately 3 months. Physical exam demonstrated a 8.0 x 8.0 cm pink nodular indurated plaque located on her left upper back. A punch biopsy of the lesion revealed medium to large mononuclear cells with nuclear pleomorphism, hyperchromasia, and scattered mitotic figures. Immunohistochemistry demonstrated cells that were positive for CD30 and negative for ALK. Based on clinical and histopathologic findings, a diagnosis of ALCL was rendered. Differential diagnosis included primary cutaneous ALCL and cutaneous involvement by systemic ALK(-) ALCL. This case demonstrates the importance of clinicopathologic correlation in diagnosing ALCL and guiding therapy.

Non-Hodgkin’s lymphoma of the breast is extremely rare. Most of these lymphomas are type B, including large B cell diffuse lymphoma, extra-nodal marginal lymphoma, follicular lymphoma, primary effusion lymphoma and lympho-plasma-cytic lymphoma. BIA-ALCL is negative anaplastic lymphoma kinase (ALK) and is characterized by cells with horseshoe-shaped eccentric nuclei called “hallmark cells”. Unlike other types of ALCL, BIA-ALCL rarely invades your breast in depth. By contrast, non-Hodgkin’s T-cell lymphoma (NHL) found in breasts without implants is mostly B cell lymphoma. Due to the increasing number of cases and the fact that the first case also appeared in Romania, we consider it advisable to take information and prevention measures as well as to adopt a treatment protocol in our country. The present paper aims at adopting a unitary diagnosis and treatment protocol for all plastic surgeons. We also consider it advisable to inform patients before surgery on risk. Through this paper we want to propose a national protocol to follow and also to argue its choice.

BackgroundAnaplastic large cell lymphoma (ALCL) with uniform CD56 expression is a rare condition, that has been described in limited literature, and its clinicopathological features have not yet been well illustrated. The aim of our study was to fully investigate the clinical, histological, immunohistochemical and molecular features of CD56+ ALCL.MethodsThe clinical and histological characteristics of CD56+ ALCL cases were retrospectively evaluated. The immunohistochemical phenotype, status of Epstein-Barr virus (EBV) and T-cell receptor (TCR) gene rearrangement were examined. Overall survival was also analyzed.ResultsEighteen (5.8%) cases with diffuse CD56 expression were identified out of 313 archived ALCL cases with CD56 test. CD56 expression was significantly higher in ALK+ systemic ALCLs (sALCLs) (13/64, 20.3%) than in ALK- sALCLs (3/101, 3.0%) (p p p = 0.038). Eleven (84.6%) cases presented with stage I-II diseases, which was significantly more than their CD56- ALK+ counterparts (45.5%) (p = 0.015). Histologically, 2 ALK+ cases were of small cell variant and all the others displayed characteristic morphology of classic ALCL. Regarding the immunophenotype, both CD30 and CD56 were diffusely positive in all cases. CD3, CD43, anaplastic lymphoma kinase-1 (ALK1), TIA-1, EMA expression was observed in 30.8% (4/13), 90.9% (10/11), 100% (13/13), 100% (9/9), and 80.0% (8/10) cases, respectively. EBV infection was consistently absent. Monoclonal TCR gene rearrangement was found in 100% (5/5) of investigated ALK+ cases. Chemotherapy with a CHOP regimen was most frequently employed. The 3-year overall survival (OS) rate for CD56+ ALK+ patients was 92.0%, compared with 73.0% for their CD56- counterparts, but there was no significant difference in OS between the two groups (p = 0.264).ConclusionsUniform CD56 expression is an unexpected condition in ALCL. Of ALK+ ALCLs, CD56 expression correlated with a high frequency of early stage and an extranodal predominance. It is of great importance to raise awareness of this condition and familiarity with its characteristic features to avoid diagnostic and therapeutic pitfalls. Further investigations are warranted for a better understanding of this unusual phenotype and the significance of CD56 expression in ALCL.

Lymphomas presenting and mimicking soft-tissue masses are important to recognize, to avoid unnecessary treatment delays or extensive surgery. We describe a case of primary anaplastic large cell lymphoma (ALCL) arising from a deep skeletal muscle in a middle-aged male. He presented with a two-month history of swelling of his right thigh and mild fever, which led to a diagnosis of abscess formation. Antibiotics were prescribed for two weeks, with little improvement of symptoms. Subsequently, an exploratory surgery, with excision of the mass, demonstrated a ALCL of the psoas muscle, ALK-1 positive.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)—a new category of anaplastic large cell lymphoma associated with textured breast implants—has a distinct variation in incidence and is especially rare in Asia. We report the first case of BIA-ALCL in Korea and present its histological and genetic characteristics. A 44-year-old female patient presented with a typical clinical course and symptoms, including breast augmentation with textured breast implants, late-onset peri-implant effusion, and CD30+ALK− histology, followed by bilateral implant removal and total capsulectomy. For histological analysis, we performed immunohistochemistry of the bilateral breast capsules. For transcriptome analysis, we identified highly upregulated gene sets employing RNA-sequencing and characterized the lymphoma immune cell components. In the lymphoma-associated capsule, CD30+ cells infiltrated not only the lymphoma lesion but also the peritumoral lesion. The morphologies of the myofibroblasts and vessels in the peritumoral lesion were similar to those in the tumoral lesion. We observed strong activation of the JAK/STAT3 pathway and expression of programmed death ligand-1 in the lymphoma. Unlike the molecular profiles of BIA-ALCL samples from Caucasian patients—all of which contained activated CD4+ T cells—the Asian patient’s profile was characterized by more abundant CD8+ T cells. This study contributes to a better understanding of the pathogenesis and molecular mechanisms of BIA-ALCL in Asian patients that will ultimately facilitate the development of clinical therapies. Level of Evidence: 5

Primary cutaneous anaplastic large-cell lymphoma and breast implant-associated ALCL (BIA-ALCL) are rare subtypes of anaplastic lymphoma kinase (ALK)-negative ALCLs originating from skin and breast implants, respectively. Herein, we report a unique case of cutaneous ALK-negative ALCL occurring in the skin of left medial breast from a patient with multiple rounds of bilateral breast implants and a history of breast carcinoma. The lymphoma cells are entirely confined to the lymphatic channels in the dermis, and the patient has no other areas of skin abnormality, no lymphadenopathy, peri-implant fluid accumulation, or masses from the bilateral capsules of implants. The differential diagnosis and its relationship with breast implants are further explored.

Introduction: Non-Hodgkin lymphomas (NHL) comprise a wide variety of neoplasms and are subdivided into two main categories of low grade and high grade lymphomas. The major subtypes among T cell lymphomas are Peripheral T cell lymphomas – Not otherwise specified, Anaplastic Large cell lymphoma, ALK positive, Angioimmunoblastic T-cell lymphoma, T lymphoblastic leukemia/lymphoma and Extranodal NK/T cell lymphoma, nasal type. In this study, the histomorphological diagnostic features and the adjunct immunohistochemical expression of various markers are studied in a tertiary care centre in South India. Materials and Methods: Patients with lymphadenopathy over a period of two years were included in the study. Lymph nodes excised from these patients were routinely processed and examined. After initial examination with H&E stain, appropriate special stains like Reticulin stain, Periodic Acid Schiff stain and Ziehl-Neelsen stains are performed along with the specific Immunohistochemical markers. Results: A total of 30 cases were classified as Non-Hodgkin Lymphoma, high grade, T cell type. Peripheral T cell lymphomas-NOS is found to be the most common tumors accounting for 40% of all high grade T cell NHLs. The next common tumor was Anaplastic Large Cell Lymphoma, ALK positive with 36% of cases. T lymphoblastic leukemia/lymphoma accounted for 10% of cases and the rest of the cases were reported as Angioimmunoblastic T-cell lymphoma (7%) and Extranodal NK/T cell lymphoma, nasal type (7%). Conclusion: Appropriate use of immunohistochemistry aids in the sub-classification of lymphomas according to the recommendations of WHO 2008. But, further molecular studies should be performed for confirmation of the subtyping done by immunohistochemistry. Keywords: High grade lymphoma, Anaplastic large cell lymphoma, Peripheral T cell lymphoma.

Anaplastic large cell lymphomas are an aggressive subtype of peripheral T-cell lymphomas that can manifest with a variety of symptoms. Our case highlights the importance of prompt tissue sampling, especially if an associated hemophagocytic lymphohistiocytosis is detected and no clinical improvement is observed upon glucocorticoid treatment.

Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is an uncommon peripheral T cell lymphoma usually presenting as a delayed peri-implant effusion. Chronic inflammation elicited by the implant has been implicated in its pathogenesis. Infection or implant rupture may also be responsible for late seromas. Cytomorphological examination coupled with CD30 immunostaining and eventual T-cell clonality assessment are essential for BI-ALCL diagnosis. However, some benign effusions may also contain an oligo/monoclonal expansion of CD30 + cells that can make the diagnosis challenging. Since cytokines are key mediators of inflammation, we applied a multiplexed immuno-based assay to BI-ALCL seromas and to different types of reactive seromas to look for a potential diagnostic BI-ALCL-associated cytokine profile. We found that BI-ALCL is characterized by a Th2-type cytokine milieu associated with significant high levels of IL-10, IL-13 and Eotaxin which discriminate BI-ALCL from all types of reactive seroma. Moreover, we found a cutoff of IL10/IL-6 ratio of 0.104 is associated with specificity of 100% and sensitivity of 83% in recognizing BI-ALCL effusions. This study identifies promising biomarkers for initial screening of late seromas that can facilitate early diagnosis of BI-ALCL. Electronic supplementary material The online version of this article (10.1007/s00262-020-02778-3) contains supplementary material, which is available to authorized users.

While the lung is frequently involved by systemic lymphoma, primary pulmonary lymphoma accounts for less than 1% of all extranodal ymphomas. In particular, T-cell lymphoma is very rare in the lung, as a primary or secondary lesion. Patients with pulmonary T-cell lymphoma usually present with cough, dyspnea, pain, fever, recurrent infections, and hemoptysis. Typical radiologic features include pulmonary nodules, consolidation, solid pulmonary opacities, cystic changes, hilar adenopathy, and pleural effusions. Patients with these clinical and radiologic findings are frequently presumed to have pneumonia and initially treated with empirical antibiotics. Therefore, CT-guided needle biopsy, bronchoscopic examination, or even wedge biopsy should be considered when clinical symptoms show deterioration despite adequate antibiotic therapy. Precise pathologic diagnosis and molecular characterization are recommended in all cases, following the World Health Organization (WHO) classification. Principles of treatment typically vary with the different histologic types of T-cell lymphoma.

Non-cutaneous extranodal NK/T cell lymphoproliferations constitute a heterogenous group of rare neoplasms, occurring primarily in the gastro-intestinal tract, nasal area, spleen and liver. Besides primarily extranodal NK/T-cell lymphoma entities – i.e. extranodal NK/T-cell lymphoma, hepatosplenic T-cell lymphoma, primary intestinal T-cell lymphomas and NK/T-cell lymphoproliferations of the gastrointestinal tract, and breast implant-associated anaplastic large cell lymphoma – extranodal tissues may also be involved by T-cell leukemias, or other entities usually presenting as nodal diseases. Primary extranodal entities are characterized by distinct clinical and pathologic features, implying variable prognosis, ranging from indolent to highly aggressive. Here, we will review the clinico-pathologic features of the pertinent entities including the recent advances in their molecular and genetic characterization, with an emphasis on those newly recognized, and highlight the diagnostic criteria helpful to sort out the distinction with potential mimickers.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare type of non-Hodgkin T-cell lymphoma, recently defined in the 2016 World Health Organization (WHO) classification of lymphoid neoplasms. It occurs more commonly when textured implants are used and appears clinically as a late seroma. Cytologically, these lesions are composed of large atypical cells with pleomorphic nucleus and an immunophenotype positive for T cell markers and CD30, and negative for ALK1. We report a 56-years-old woman with breast implants who developed a periprosthetic seroma three years after surgery. A fine needle aspiration of the lesion was carried out. Cytology and the immunocytochemical study revealed cells compatible with BIA-ALCL. The flow cytometric study was negative. Excisional biopsy of the capsule was performed, observing that the neoplastic cells were confined to the inner surface of the capsule. Imaging studies did not find evidence of disseminated disease. The present case demonstrates the importance of the study of any late periprosthetic effusion, which can be performed using fine needle aspiration.

Background Primary central nervous system lymphoma (PCNSL) occurs frequently in a deep intraparenchymal location. It rarely occurs in the meninges, and bone invasion is uncommon. Case Description A 12-year-old boy was admitted to our hospital with a history of headache and seizures. Magnetic resonance imaging showed a 4-cm-sized dural-based mass with osteolytic bone change. Craniotomy and tumor removal were performed. Operative findings showed a dural-based hard tumor, including necrosis and hemorrhage, and the skull was focally destroyed by tumor cells. The tumor was completely removed. Pathologically, large atypical cells with pleomorphic nuclei and frequent mitoses were found. The tumor cells were immune-positive for CD30, epithelial cell antigen, and anaplastic lymphoma kinase. The final diagnosis was anaplastic lymphoma kinase–positive anaplastic large cell lymphoma (ALCL). There was no evidence of systemic cancer. The boy underwent chemotherapy following the Non-Hodgkin Lymphoma-Berlin-Frankfurt-Munster protocol. There was no recurrence after a 16-month chemotherapy-off period. Conclusions ALCL is not a common type of PCNSL, and central nervous system ALCL frequently involves the dura and meninges compared with PCNSL in general. However, osteolytic bone lesions are rarely seen in ALCL. This case thus represents a rare case of dural-based ALCL with bone invasion.

We report a case of a 45-year-old female who developed an ALK-positive anaplastic large cell lymphoma (ALCL) 9 years after renal transplant. The patient underwent a cadaveric renal transplant for diabetic nephropathy, and presented 9 years later with fever and multiorgan dysfunction. The initial CT scans showed multiple enlarged supra- and infradiaphrgamatic lymph nodes. A CT-guided core needle biopsy of a retroperitoneal lymph node revealed ALK positive ALCL. She received six cycles of cyclophosphamide, adriamycin, vincristine, etoposide, and prednisone, and has been in remission for over 3 years. Monomorphic T-cell posttransplant lymphoproliferative disorder (PTLD) is an established but rare entity of PTLD and generally carries poor prognosis. This is a case report of a late PTLD with pathology reporting an aggressive T-cell lymphoma that has been successfully treated with multiagent chemotherapy.

Anaplastic large cell lymphoma (ALCL) is a non-Hodgkin lymphoma of T-cell or null-cell lineage with variable cytomorphology. We report two rare ALCL cases with carcinomatous and sarcomatous patterns, respectively, in fine needle aspiration (FNA) cytology and histopathology. The first case was a 56-year-old man with enlarged left inguinal lymph node. FNA smears showed a malignant small round cell tumor with nuclear molding. In addition, there were large bi-nucleated and multinucleated cells with wreath-like arrangement of nuclei. ALCL and small cell (neuroendocrine) carcinoma were the possibilities considered. Immunocytochemical studies on FNA smears showed positive reaction for leukocyte common antigen (LCA) and negative results for cytokeratin (CK) and chromogranin. Histopathological examination of the lymph node showed features of ALCL with following immunohistochemical staining results: LCA+, CD30+, CD45RO+, CD20-, CD3+ (weak), and Alk1-. During review of sections, areas resembling a small cell anaplastic carcinoma were observed. The second case was a 24-year-old woman with right cervical lymphadenopathy. FNA smears showed an ALCL with highly atypical large cells including bi-nucleated and donut shaped cells, which were positive for CD30, EMA, and Alk-1 protein, and negative for CD20, CD3, and CK. Histopathological examination corroborated the cytodiagnosis of ALCL, and with positive immunohistochemical staining for CD30, EMA, Alk-1 protein+, BCL6+, and Ki67+ (40% cells) and negative results for CD20, CD10, CD3, CD5, CD15, BCl2, CD79a, and CD68. Sarcomatous components were noticed during review of cytologic and histopathological specimen. Awareness about these unusual cytomorphological patterns in ALCL may be of help in proper diagnosis of this neoplasm.

Background Primary central nervous system (CNS) anaplastic large cell lymphoma (ALCL) is an uncommon type of brain tumor, usually treated with a regimen that includes high-dose methotrexate (MTX). Only a few cases of primary CNS anaplastic lymphoma kinase (ALK)–positive ALCL have been reported so far, with no reported cases of a small cell variant. Case Description A 26-year-old man presenting with headache and visual field impairment was found to have a supratentorial mass mimicking meningioma. Craniotomy was performed for tumor resection, and postoperative histologic examination revealed atypical cells that were nonenlarged lymphocytes with irregularly shaped and enlarged nuclei; these cells were cluster of differentiation 30 and ALK-positive, leading to the diagnosis of a small cell variant of ALK-positive ALCL. In this case, the tumor exhibited an aggressive behavior with MTX resistance with metastases in the pelvis but responded well to cytarabine and etoposide (CYVE). Conclusions In general, CNS ALK-positive ALCL responds well to MTX, but small cell variants show aggressive behavior and may be resistant to MTX. For small cell variants of ALCL that are resistant to MTX therapy, as in this case, CYVE therapy may be an effective treatment.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare, non-Hodgkin lymphoma which arises within the capsules of breast implants. These particular tumours have expression of CD30 and are negative for Anaplastic Lymphoma Kinase (ALK). Here, we report a case of BIA-ALCL in a 48-year-old woman post breast reconstruction. This case report is aimed at raising awareness and education on the significance of considering the development of BIA-ALCL in cases where cytology is negative and helping better understand this disease process.

Germinotropic lymphoproliferative disorder (GLPD) is a poorly characterized lymphoproliferative entity, recently included in the World Health Organization classification of hematolymphoid neoplasms. The histological pattern of this disease comprises monotypic plasmablasts that involve the germinal centers of the lymphoid follicles (germinotrophism), forming confluent aggregates positive for both human herpes virus type 8 (HHV8) and Epstein-Barr virus. Currently, after 17 years of its first description, only 18 cases have been reported. In this article, we describe a case of a GLPD presenting in an immunocompetent 79-year-old woman with localized axillary lymphadenopathy, showing a prominent sinusoidal growth pattern, with no evidence of germinotrophism or extrasinusoidal spread. Stinking pleomorphism in tumor cells was also noted. An extension study has not revealed involvement of other groups of lymph nodes or extralymphoid sites. The patient is alive and has shown no relapse after 8 years follow-up (the longest follow-up reported period for this entity). This previously unrecognized pure sinusoidal growth pattern along with the striking pleomorphism in neoplastic cells closely mimics the appearance of an anaplastic large cell lymphoma. GLPD is not usually considered in such a setting, but it should be included in the differential diagnosis of sinusoidal proliferations. Our findings contribute to the expansion of the morphological spectrum of HHV8-associated lymphoproliferative lesions and aids in the characterization of the very infrequent GLPD entity.

Breast implant anaplastic large cell lymphoma is an entity recently recognized by the World Health Organization. The tumor arises around textured-surface breast implants and is usually confined to the surrounding fibrous capsule. Currently, there are no recommendations for handling and sampling of capsules from patients with suspected breast implant anaplastic large cell lymphoma without a grossly identifiable tumor. We analyzed complete capsulectomies without distinct gross lesions from patients with breast implant anaplastic large cell lymphoma. The gross appearance of the capsules as well as the presence, extent and depth of tumor cells on the luminal side and number of sections involved by lymphoma were determined by review of routine stains and CD30 immunohistochemistry. We then used a mathematical model that included the extent of tumor cells and number of positive sections to calculate the minimum number of sections required to identify 95% of randomly distributed lesions. We identified 50 patients with breast implant anaplastic large cell lymphoma who had complete capsulectomies. The implants were textured in all 32 (100%) cases with available information. Anaplastic large cell lymphoma was found in 44/50 (88%) capsules; no tumor was found in six (12%) patients who had lymphoma cells only in the effusion. The median number of sections reviewed was 20 (range, 2–240), the median percentage of sections involved by tumor was 6% (range, 0–90%), and the median percentage of sections involved by lymphoma was 10% (range, 0–90%). Invasion deep into or through the capsule was identified in 18/50 (36%) patients. In patients with breast implant anaplastic large cell lymphoma without a grossly identifiable tumor we identified a spectrum of involvement and we propose a protocol for handling, sampling and reporting these cases. The number of sections to exclude the presence of lymphoma with more than 95% certainty was supported by a mathematic rationale.

The programmed cell death 1 (PD-1) pathway is a recently recognized mechanism of tumor immune evasion. In this study, programmed cell death ligand 1 (PD-L1) expression was evaluated in 95 patients with systemic anaplastic large cell lymphoma: 45 ALK+ and 50 ALK-. ALK+ anaplastic large cell lymphoma was more often positive for PD-L1 than ALK- anaplastic large cell lymphoma (76% vs 42%, p = 0.002). ALK- anaplastic large cell lymphoma showed a strong correlation between PD-L1 expression and STAT3 activation (measured by pSTAT3Tyr705) (r = 0.8, p 0.05). Negative ALK status and high IPI score (≥3) were associated with shorter overall survival (p = 0.009 and p = 0.0005, respectively). Overall survival was not different between patients with PD-L1+ vs PD-L1- anaplastic large cell lymphoma (p = 0.44), regardless of ALK status and International Prognostic Index (IPI) score. We conclude that PD-L1 expression is more common in ALK+ anaplastic large cell lymphoma than ALK- anaplastic large cell lymphoma. In ALK- anaplastic large cell lymphoma, PD-L1 is strongly correlated with STAT3 activation and is associated with more frequent EMA and less frequent CD2 expression. PD-L1 has no prognostic significance in predicting the outcome of patients with systemic anaplastic large cell lymphoma, regardless of ALK status. PD-L1 expression on the anaplastic large cell lymphoma cells suggests these patients as potential candidates for PD-1 blockade immunotherapy.

Delayed onset breast implant-associated reactions range widely in symptomatology and underlying etiology. With increasing reports of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), findings such as unilateral breast swelling, capsular thickening, and peri-implant fluid raise concern. Synovial metaplasia is a benign histologic finding commonly associated with implant capsules and can be an unusual cause of such symptoms. Though the clinical significance of synovial metaplasia is unknown, it is important to consider this entity in the differential diagnosis for delayed onset breast symptoms, with signs otherwise concerning for BIA-ALCL or infection.

T- and NK-cell lymphoproliferative disorders of the gastrointestinal (GI) tract are uncommon, but are important to recognise as there may be morphological and immunophenotypic overlap between lymphoid lesions with vastly different clinical outcomes. Recent data have led to the reclassification of some lymphomas and inclusion of new entities in the 2016 revision of World Health Organization (WHO) classification of lymphoid neoplasms. It has become clear that enteropathy associated T-cell lymphoma (EATL), formerly thought to be composed of two subtypes known as type I and type II, are distinct entities. Type I EATL is now simply classified as EATL; it is strongly associated with coeliac disease and occurs mainly in Western populations. Type II EATL has been renamed monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL); it shows no definite association with coeliac disease and occurs worldwide with a predominance in Asian populations. There is also a group of aggressive intestinal T-cell lymphomas which do not meet criteria for EATL, MEITL, extranodal NK/T-cell lymphoma of nasal type or anaplastic large cell lymphoma. These neoplasms are now designated intestinal T-cell lymphoma, not otherwise specified. Indolent T-cell lymphoproliferative disorder of the GI tract has been included as a provisional entity in the most recent WHO classification. It is a clonal T-cell lymphoproliferative disorder (CD4+ or CD8+) with an indolent clinical course. Finally, benign NK-cell proliferations of the GI tract, variably designated 'NK-cell enteropathy' and 'lymphomatoid gastropathy' have also been recognised in the last two decades but have not been included in the WHO classification as their neoplastic nature is not established. This review covers the aforementioned lymphoid proliferations, emphasising their salient clinicopathological features and genetic abnormalities. It also provides practical insights into resolving difficult differential diagnoses in daily surgical pathology practice.

Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described "immune sanctuary" sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant-associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.

Primary anaplastic large cell lymphoma of the trachea is a very rare tumor. Diagnosis is often missed for a long time because the presentation often resembles that of obstructive airway disease. A 24-year-old non-smoker male presented at an outpatient clinic complaining of gradual development of stridor and shortness of breath over a recent period of four weeks. Imaging workup revealed a large lobulated, soft tissue, mildly enhancing, eccentrically placed intraluminal proximal tracheal mass, which showed extension outside of the tracheal lumen in the peritracheal fat. The patient underwent surgery. A biopsy of the resected mass reported anaplastic large cell lymphoma. Post-operation, the patient underwent chemotherapy consisting of four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone). Follow-up imaging showed non-visualization of the mass. Primary lymphoma (anaplastic large cell lymphoma, which is a rare type of non-Hodgkin’s lymphoma) of the trachea is a rare tumor. Early curative resection with post-operative chemotherapy has a favorable outcome, as in our case.

Background: Lymphoma, both Hodgkin and non-Hodgkin, is one of the most common malignancies, with a distinct subtype distribution throughout the world. Methods: A total of 453 lymphoma cases, identified retrospectively from January 2000 to October 2011, were studied to identify the subtype distribution of lymphoma in our center, located in southern Iran, according to the latest WHO classification. Results: The most common sites of involvement of all lymphomas were extranodal (59.16%). The highest frequency of extranodal sites in all lymphoid neoplasms were associated with diffuse large B-cell lymphoma (22.95%) and classical Hodgkin lymphoma (10.15%). Of 453 cases, 23 (5.32%) were T and natural killer cell neoplasms, of which the most common subtypes were T-cell large granular lymphocytic leukemia and anaplastic large cell lymphoma. Conclusion: This study indicated that the subtype distribution of lymphoma (except for the higher prevalence of diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma and lower rate of follicular lymphoma) in this part of Iran is similar to that in the Middle Eastern countries. Mature B-cell neoplasms are less frequent compared with both western and far east Asian countries.