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.

UBTF tandem duplications in pediatric myelodysplastic syndrome and acute myeloid leukemia: implications for clinical screening and diagnosis.

Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor (UBTF). These alterations, which account for ~4.3% of AMLs in childhood and about 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features of UBTF-TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 of UBTF. We demonstrate that UBTF-TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm that UBTF-TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition of FLT3 or WT1 mutations is associated with more stem celllike programs. Lastly, we report rare duplications within exon 9 of UBTF that phenocopy exon 13 duplications, expanding the spectrum of UBTF alterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS with UBTF-TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.

UBTF Tandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis.

Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor (UBTF). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features of UBTF-TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 of UBTF. We demonstrate that UBTF-TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm that UBTF-TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition of FLT3 or WT1 mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 of UBTF that phenocopy exon 13 duplications, expanding the spectrum of UBTF alterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS with UBTF-TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.

The Clinicopathologic Features and Molecular Signatures of Blastoid High-Grade B Cell Lymphoma, Not Otherwise Specified.

A small subset of high-grade B-cell lymphoma (HGBL) with blastoid morphology remains poorly understood. We assessed 55 cases of blastoid HGBL, not otherwise specified (NOS) and compared their clinicopathologic characteristics with those of 81 non-blastoid HGBL-NOS and 62 blastoid HGBL with MYC and BCL2, with or without BCL6 rearrangements (double/triple-hit lymphoma [D/THL]). Patients with blastoid HGBL-NOS showed similar clinicopathologic features to patients with blastoid D/THLs and non-blastoid HGBL-NOS, except more frequently with a history of low-grade B-cell lymphoma, bone marrow involvement, and BCL2 rearrangement (P < .05) compared to the latter. MYC rearrangement (MYC-R), detected in 40% of blastoid HGBL-NOS, was associated with aggressive clinicopathologic features and poorer overall survival, even worse than that of blastoid D/THL (P < .05). Transcriptome profiling revealed a distinct gene expression pattern with differentially expressed genes enriched in MYC and P53-targeted genes in MYC-R blastoid HGBL-NOS. Fifty-two percent of blastoid HGBL-NOS had a double hit-like signature, similar to non-blastoid HGBL-NOS (P = .73). The overall survival of the blastoid HGBL-NOS group was similar to that of the blastoid D/THL group but appeared poorer than that of its non-blastoid counterparts (P = .07). Taken together, blastoid HGBL-NOS is an aggressive B-cell lymphoma that shares overlapping clinicopathologic and genetic features with non-blastoid HGBL-NOS. MYC-R in patients with blastoid HGBL-NOS identifies a highly aggressive subgroup with distinct aggressive clinicopathologic features, unique molecular signatures, and a dismal clinical outcome.

CBFA2T3::GLIS2-positive acute leukemia with RAM and mixed T/megakaryocytic phenotype.

Herein, we present a rare case of acute myeloid leukemia (AML) with CBFA2T3-rearrangement and the expression of megakaryocytic and lymphoid markers, highlighting the need for a high suspicion index in differential diagnosis and applying adequate workup to avoid misdiagnosing this entity. CBFA2T3::GLIS2-positive AML is primarily found in infants with non-down syndrome acute megakaryoblastic leukemia (non-DSAMKL). Flow cytometry immunophenotyping plays an important role in recognizing the unique immunophenotype of bright CD56 expression with dim/negative expression of HLA-DR, CD38, and CD45 termed the RAM immunophenotype in this entity. Still, CBFA2T3::GLIS2-positive acute leukemia with T/megakaryocytic markers could be misdiagnosed as T-lymphoblastic leukemia/lymphoma, early T-cell precursor acute lymphoblastic leukemia/lymphoma, NK lymphoblastic leukemia, AML with minimal differentiation, or AML with myelodysplasia-related changes.

Blastoid and Pleomorphic Mantle Cell Lymphoma Demonstrate Distinct Clinicopathologic and Genetic Features.

The blastoid (B) and pleomorphic (P) variants of mantle cell lymphoma (MCL) are associated with aggressive clinical behavior. In this study, we collected 102 cases of B-MCL and P-MCL from untreated patients. We reviewed clinical data, analyzed morphologic features using an image analysis tool (ImageJ) and we assessed mutational and gene expression profiles. The chromatin pattern of lymphoma cells was assessed quantitatively by the pixel value. Cases of B-MCL showed a greater median pixel value with lower variation compared with P-MCL, indicating a homogeneously euchromatin-rich pattern in B-MCL. In addition, the Feret diameter of the nuclei was significantly smaller (median 6.92 vs. 8.49 µm per nucleus, P <0.001) and had a lesser degree of variation in B-MCL compared with P-MCL, indicating that B-MCL cells have smaller cells with a more monomorphic appearance. B-MCL showed a significantly higher median Ki-67 proliferation rate (60% vs. 40%, P =0.003), and affected patients had poorer overall survival compared with those with P-MCL (median overall survival: 3.1 vs. 8.8 y, respectively, P =0.038). NOTCH1 mutation was significantly more frequent in B-MCL compared with P-MCL (33% and 0%, respectively, P =0.004). Gene expression profiling showed 14 genes overexpressed in B-MCL cases and gene set enrichment assay for the overexpressed genes showed significant enrichment in the cell cycle and mitotic transition pathways. We also report a subset of MCL cases that has blastoid chromatin but a higher degree of pleomorphism in nuclear size and shape, designated here as hybrid MCL. Hybrid MCL cases had a similar Ki-67 proliferation rate, mutation profile, and clinical outcome to B-MCL and distinct from P-MCL. In summary, these data suggest biological differences between B-MCL and P-MCL cases justifying their separate designation when possible.

Blastoid B-Cell Neoplasms: Diagnostic Challenges and Solutions.

Blastoid B-cell neoplasms mainly include B-lymphoblastic leukemia/lymphoma (B-ALL), blastoid mantle cell lymphoma, and high-grade B-cell lymphoma with blastoid morphologic features (blastoid HGBL). Distinguishing blastoid HGBL from B-ALL can be challenging and we previously developed six-point flow cytometry-focused and three-point immunohistochemistry-focused scoring systems to aid in differential diagnosis. However, the six-point scoring system was derived from bone marrow cases and occasional cases may have a misleading score using either system. In this study, we assessed 121 cases of blastoid-HGBL (37 BM and 84 extramedullary) to validate the six-point scoring system in all tissue types and to further compare the two scoring systems. Compared with 47 B-ALL cases enriched for CD34-negative neoplasm, the 121 blastoid-HGBL cases showed distinctive pathologic features. The six-point scoring system showed a sensitivity of 100%. A comparison of the two scoring systems in blastoid HGBL (n = 64) and B-ALL (n = 37) showed a concordance score rate of 88%. Thirteen cases showed misleading scores, including five HGBL and eight B-ALL, and the diagnosis was further validated by gene transcriptome profiling. Twelve of thirteen cases had discordant scores between the two scoring systems. Simultaneous employment of both scoring systems improved the accuracy of classification of blastoid B-cell neoplasms to 99%. In conclusion, the previously defined six-point scoring system showed an excellent performance regardless of the tissue origin. Using both scoring systems together improves the accuracy of classification of blastoid B-cell neoplasms. Cases with discordant scores between the two scoring systems were extremely challenging neoplasms and classification required correlation with all available clinical and genetic features.

High-grade B-cell lymphoma (HGBL)-NOS is clinicopathologically and genetically more similar to DLBCL/HGBL-DH than DLBCL.

High-grade B-cell lymphoma, not otherwise specified (HGBL-NOS) is rare and data focused on these neoplasms is lacking. We studied the clinicopathologic and genetic features of 136 HGBL-NOS patients and compared them to patients with DLBCL/HGBL-DH (n = 224, defined by 5th Edition WHO) and DLBCL (n = 217). HGBL-NOS patients had clinical features similar to DLBCL/HGBL-DH patients. MYC rearrangement (MYC-R) was present in 43% of HGBL-NOS. With induction regimen similar to DLBCL/HGBL-DH patients, HGBL-NOS patients had a median overall survival (OS) of 28.9 months, similar to DLBCL/HGBL-DH (p = 0.48) but inferior to DLBCL patients (p = 0.03). R-EPOCH induction was associated with improved OS compared with R-CHOP. MYC-R, history of lymphoma, and high IPI were independent adverse prognostic factors in HGBL-NOS patients. Whole transcriptome profiling performed on a subset of HGBL-NOS cases showed a profile more similar to DLBCL/HGBL-DH than to DLBCL; 53% of HGBL-NOS had a DH-like signature (DH-like-Sig) and were enriched for MYC-R. DH-like-Sig+ HGBL-NOS patients had a poorer OS than DH-like-Sig-negative patients (p = 0.04). In conclusion, HGBL-NOS has clinicopathologic features and a gene expression profile more similar to DLBCL/HGBL-DH than to DLBCL. Cases of HGBL-NOS frequently carry MYC-R and have a DH-like-Sig+. R-EPOCH induction in HGBL-NOS appears associated with improved OS compared with standard R-CHOP.

Engineering naturally occurring CD7- T cells for the immunotherapy of hematological malignancies.

Chimeric antigen receptor (CAR) T-cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7- T cells to generate CD7-CAR (CD7-CARCD7-) T cells. CD7-CARCD7- T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7- T cells for the immunotherapy of CD19+ hematological malignancies. Direct comparison of nonselected (bulk) CD19-CAR and CD19-CARCD7- T cells revealed that CD19-CARCD7- T cells had enhanced antitumor activity compared with their bulk counterparts in vitro and in vivo. Lastly, to gain insight into the behavior of CD19-CAR T cells with low levels of CD7 gene expression (CD7lo) in humans, we mined single-cell gene and T-cell receptor (TCR) expression data sets from our institutional CD19-CAR T-cell clinical study. CD19-CARCD7lo T cells were present in the initial CD19-CAR T-cell product and could be detected postinfusion. Intriguingly, the only functional CD4+ CD19-CAR T-cell cluster observed postinfusion exhibited CD7lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7lo T cells than nonresponders (NCT03573700). Thus, CARCD7- T cells have favorable biological characteristics and may present a promising T-cell subset for adoptive cell therapy of T-ALL and other hematological malignancies.

Bone marrow clonal hematopoiesis is highly prevalent in blastic plasmacytoid dendritic cell neoplasm and frequently sharing a clonal origin in elderly patients.

Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are reported in up to 20% patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), where a shared clonal origin is shown in individual case studies. In this study, we performed targeted next generating sequencing on multiple bone marrow (BM), skin or sorted cells from 51 BPDCN patients (68.7 years,14.4-84.7), and detected mutations in BM hematopoietic cells in 65% (30/46) and BPDCN in 100% (27/27), both components showing similar high frequencies of TET2 (60% versus 58%) and ASXL1 (33% versus 40%). Of 24 patients with paired mutation data, 13(54%) had shared mutations, with TET2(77%), ASXL1(37%) and ZRSR2(22%) the most commonly shared, and NRAS the most gained mutation in BPDCN(9/24, 38%). Karyotypic abnormalities were detected in 19/29(66%) BPDCN but only in 1/49 BM hematopoietic cells, providing additional evidence of clonal evolution. BM clonal hematopoiesis (CH) was associated with an older age (p < 0.001), being confounding factors in multivariate analysis; whereas <10% BM BPDCN infiltrate and stem cell transplant were associated with favorable outcomes. This study is the first to report a high prevalence of BM CH in BPDCN patients beyond an associated diagnosis of MDS/CMML, and demonstrates a frequent clonal relationship in elderly, findings contributing to the understanding of BPDCN clonal origin.

Small cell/lymphohistiocytic morphology is associated with peripheral blood involvement, CD8 positivity and retained T-cell antigens, but not outcome in adults with ALK+ anaplastic large cell lymphoma.

Several morphologic variants of ALK+ anaplastic large cell lymphoma (ALCL) are recognized. The small cell (SC) and lymphohistiocytic (LH) variants are reported to be associated with poorer outcome in children with ALK + ALCL. In this study of 102 adults with ALK + ALCL, there were 18 (18%) cases of SC and/or LH variants. Patients with SC/LH ALK + ALCL more often had peripheral blood involvement than patients with non-SC/LH neoplasms (60% vs 0%, p = 0.02). There were no other significant differences in clinical features between patients with SC/LH versus non-SC/LH ALK + ALCL. Compared with non-SC/LH cases of ALK + ALCL, neoplasms with SC/LH features were more often positive for CD2 (92% vs. 36%, p = 0.0007), CD3 (81% vs. 15%, p = 0.0001), CD7 (80% vs. 37%, p = 0.03), and CD8 (54% vs. 7%, p = 0.0006). There were no other significant differences in the immunophenotype between SC/LH and non-SC/LH ALK + ALCL cases. The initial chemotherapy regimens and the response rates were similar between patients with ALK + ALCL with SC/LH patterns versus those with non-SC/LH patterns. After a median follow-up of 30.8 months (range, 0.3-208 months), patients with high (>3) International Prognostic Index (IPI) scores had significantly shorter overall survival than patients with low (<3) IPI scores (p = 0.003). However, there was no significant difference in overall or progression-free survival between patients with SC/LH versus non-SC/LH ALK + ALCL (p = 0.99 and p = 0.94, respectively). We conclude that, in adults with ALK + ALCL, SC and LH variants are associated with peripheral blood involvement and a CD8 + immunophenotype with retention of T-cell markers (CD2, CD3, and CD7). However, in contrast with children with ALK + ALCL, SC and LH variants appear to have no impact on prognosis in adults with ALK + ALCL.

Blastoid high-grade B-cell lymphoma initially presenting in bone marrow: a diagnostic challenge.

The 2016 WHO classification introduced the category of high-grade B-cell lymphoma (HGBL), which includes one poorly understood subset, blastoid-HGBL. Establishing the diagnosis and distinguishing blastoid-HGBL from B-acute lymphoblastic leukemia (B-ALL) in bone marrow can be challenging. We assessed 31 cases of blastoid-HGBL diagnosed initially in bone marrow and compared this group to 36 cases of B-ALL using immunophenotyping, fluorescence in situ hybridization, and targeted next generation sequencing analysis. The 31 blastoid-HGBL cases included 14 HGBL with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma, DHL), 13 HGBL, not otherwise specified (NOS), and four cases with TdT expression that were difficult to classify. Compared with B-ALL, blastoid-HGBL cases more often showed increased intensity/bright expression of CD20, CD38, CD45, BCL-6, and MYC, and less frequent bright expression of CD10 and TdT. Cases of blastoid-HGBL also more frequently had MYC rearrangement, a complex karyotype and TP53 mutation (p < 0.01). With the exception of CD34, no other single factor, including TdT, was sensitive or adequately specific to distinguish blastoid-HGBL from B-ALL. We developed a scoring system using six distinctive features between 16 cases of unequivocal blastoid HGBL and 22 cases of CD34-positive B-ALL, with a score of ≥3 defining blastoid-HGBL. The system was further validated by using 15 cases of surface light chain negative, and/or CD45 dim to negative blastoid-HGBL and 14 cases of CD34-negative B-ALL. The sensitivity, specificity, positive, and negative predictive value of this scoring system were 100%, 94%, 94%, and 100%, respectively. Using this system, the four cases with TdT expression were all classified as blastoid-HGBL: three were DHL and one was HGBL-NOS. In conclusion, blastoid-HGBL shows distinctive immunophenotypic, cytogenetic, and molecular features as compared with B-ALL. The proposed scoring system can be helpful for the classification of diagnostically challenging blastoid lymphoid tumors presenting initially in the bone marrow.

Mantle cell lymphoma with chronic lymphocytic leukemia-like features: a diagnostic mimic and pitfall.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by t(11;14) (q13;q32) and cyclin D1 overexpression in >95% of cases. Classic MCL cases are composed of a monotonous population of small- to medium-sized lymphocytes with irregular nuclear contours that are positive for cyclin D1 and SOX11 and negative for CD23 and CD200. By contrast, occasional MCL cases express CD23 and CD200 but lack SOX11 and morphologically and immunophenotypically resemble chronic lymphocytic leukemia (CLL), termed as CLL-like MCL in this study. These neoplasms pose a diagnostic challenge and are easy to be diagnosed as CLL in daily practice. We studied 14 cases of CLL-like MCL to define their clinicopathologic features and compared them with 33 traditional CLL cases. There were 8 men and 6 women with a median age of 62 years (range, 44-80). Compared with CLL, patients with CLL-like MCL have lower levels of peripheral blood and bone marrow involvement and more frequently had mutated IGHV. Immunophenotypically, CLL-like MCL often showed moderate to bright expression of B-cell antigens and surface immunoglobulin light chain, dim and partial expression of CD23 and CD200, infrequent CD43 positivity, and lack of LEF1. The overall survival of patients with CLL-like MCL was similar to that of CLL patients. In conclusion, CD23+, CD200+, and SOX11-negative MCL closely resemble CLL, both clinically and pathologically, including a similar indolent clinical course. They may pose a diagnostic challenge. However, patients with CLL-like MCL also have distinctive immunophenotypic features that are useful to distinguish these neoplasms from CLL.

Value and pitfalls of assessing bone marrow morphologic findings to predict response in patients with myelofibrosis who undergo hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with myelofibrosis (MF). Bone marrow (BM) morphologic evaluation of myelofibrosis following allo-HSCT is known to be challenging in this context because resolution of morphologic changes is a gradual process. PATIENTS AND METHODS: We compared BM samples of patients with myelofibrosis who underwent first allo-HSCT and achieved molecular remission by day 100 with BM samples of patients who continued to have persistent molecular evidence of disease following allo-HSCT. RESULTS: The study group included 29 patients: 17 primary MF, 7 post-polycythemia vera (PV) MF, and 5 post-essential thrombocythemia (ET) MF. In this cohort there were 18 JAK2 p.V617F, 8 CALR; 1 MPL, and 2 patients had concurrent JAK2 p.V617F and MPL mutations. The control group included 5 patients with primary MF, one with post-PV MF, one with post-ET MF (5 JAK2 p.V617F; 2 CALR). Following allo-HSCT, both groups showed reduction in BM cellularity and number of megakaryocytes. The study cohort also less commonly had dense megakaryocyte clusters and endosteal located megakaryocytes and showed less fibrosis. There was no statistical difference in BM cellularity, presence of erythroid islands, degree of osteosclerosis, or megakaryocyte number, size, nuclear lobation, presence of clusters or intrasinusoidal location. CONCLUSIONS: Following allo-HSCT at 100 days, morphologic evaluation of BM in patients with MF cannot reliably predict persistence versus clearance of molecular evidence of MF. Disappearance of BM MF, dense megakaryocyte clusters, and endosteal localization of megakaryocytes are suggestive of disease response.

Follicular lymphoma: updates for pathologists.

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and originates from germinal center B-cells (centrocytes and centroblasts) of the lymphoid follicle. Tumorigenesis is believed to initiate early in precursor B-cells in the bone marrow (BM) that acquire the t(14;18)(q32;q21). These cells later migrate to lymph nodes to continue their maturation through the germinal center reaction, at which time they acquire additional genetic and epigeneticabnormalities that promote lymphomagenesis. FLs are heterogeneous in terms of their clinicopathologic features. Most FLs are indolent and clinically characterized by peripheral lymphadenopathy with involvement of the spleen, BM, and peripheral blood in a substantial subset of patients, sometimes accompanied by constitutional symptoms and laboratory abnormalities. Diagnosis is established by the histopathologic identification of a B-cell proliferation usually distributed in an at least partially follicular pattern, typically, but not always, in a lymph node biopsy. The B-cell proliferation is biologically of germinal center cell origin, thus shows an expression of germinal center-associated antigens as detected by immunophenotyping. Although many cases of FLs are typical and histopathologic features are straightforward, the biologic and histopathologic variability of FL is wide, and an accurate diagnosis of FL over this disease spectrum requires knowledge of morphologic variants that can mimic other lymphomas, and rarely non-hematologic malignancies, clinically unique variants, and pitfalls in the interpretation of ancillary studies. The overall survival for most patients is prolonged, but relapses are frequent. The treatment landscape in FL now includes the application of immunotherapy and targeted therapy in addition to chemotherapy.

The Leukemic Phase of ALK-Negative Anaplastic Large Cell Lymphoma Is Associated with CD7 Positivity, Complex Karyotype, TP53 Deletion, and a Poor Prognosis.

Patients with anaplastic large cell lymphoma (ALCL) rarely develop a leukemic phase of the disease. The reported leukemic ALCL cases are almost all ALK-positive, which are frequently associated with small cell morphology, t(2;5)(p23;q35), and a poorer prognosis. Rare leukemic ALK-negative ALCL cases have been reported. In the present study, we investigated the clinical and pathologic features and outcomes of nine patients with leukemic ALK-negative ALCL and compared these features with 39 patients without leukemic disease. Compared with the non-leukemic ALK-negative ALCL group, patients with leukemic disease more often had absolute lymphocytosis (50% vs. 0%, p = 0.008), thrombocytopenia (60% vs. 11%, p = 0.03), bone marrow involvement (50% vs. 14%, p = 0.04), and CD7 positivity (71% vs. 19%, p = 0.02). Four of five (80%) patients with leukemic ALK-negative ALCL had a complex karyotype, which was significantly higher than that of the patients in the non-leukemic group. A fluorescence in situ hybridization for TP53 was performed on six leukemic ALK-negative ALCL cases and all (100%) had TP53 deletion. There were no significant differences in the other clinicopathologic features, treatment, and complete remission rates between patients in the leukemic versus non-leukemic group (all p > 0.05). The median follow-up of this cohort was 18 months with a range of 0.3-140 months. Eight of nine (90%) patients with leukemic ALK-negative ALCL died, and their overall survival was significantly shorter than that of the patients with non-leukemic disease (median 15.5 vs. 60 months, p = 0.001). In conclusion, we show that the leukemic phase of ALK-negative ALCL is associated with high-risk biologic features and, in particular, a complex karyotype and TP53 deletion. Compared with the non-leukemic ALK-negative ALCL patients, the patients with a leukemic phase of disease have poorer survival and may require more aggressive treatment.