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.

Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group.

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.

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.

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.

DUSP22 rearrangement is associated with a distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma.

DUSP22 rearrangement (R) has been associated with a favorable outcome in systemic ALK-negative anaplastic large cell lymphoma (ALCL). However, a recent study found that patients with DUSP22-R ALK-negative ALCL have a poorer prognosis than was reported initially. In this study, we compared the clinicopathological features and outcomes of patients with ALKnegative ALCL with DUSP22-R (n=22) versus those without DUSP22-R (DUSP22-NR; n=59). Patients with DUSP22-R ALCL were younger than those with DUSP22-NR neoplasms (P=0.049). DUSP22-R ALK-negative ALCL cases were more often positive for CD15, CD8, and less frequently expressed pSTAT3Tyr705, PD-L1, granzyme B and EMA (all P<0.05). TP63 rearrangement (TP63-R) was detected in three of the 66 (5%) ALK-negative ALCL cases tested and none of these cases carried the DUSP22-R. Overall survival of patients with DUSP22-R ALCL was similar to that of the patients with DUSP22-NR neoplasms regardless of International Prognostic Index score, stage, age, or stem cell transplantation status (all P>0.05), but was significantly shorter than that of the patients with ALK-positive ALCL (median overall survival 53 months vs. undefined, P=0.005). Five-year overall survival rates were 40% for patients with DUSP22-R ALCL versus 82% for patients with ALK-positive ALCL. We conclude that DUSP22-R neoplasms represent a distinctive subset of ALK-negative ALCL. However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at present.

Lymphoplasmacytic lymphoma with IgG or IgA paraprotein: a study of 29 cases including cases that can mimic plasma cell neoplasms.

Lymphoplasmacytic lymphoma (LPL) with IgG or IgA paraprotein is rare and a subset of cases can mimic a plasma cell neoplasm (PCN). We studied 29 such cases to explore their clinicopathological features and the best diagnostic approaches with a focus on bone marrow findings. The cohort included 18 men and 11 women with a median age of 68 years. The median M protein was 3.1 g/dL, IgG in 19 patients (66%), IgA in 9 (31%), and dual IgG/IgA in 1 (3%). All patients had bone marrow involvement with CD138+ plasma cells (PCs) ranging from 1 to 35% (median, 10%). Two patients also had amyloidosis. Immunoglobulin light chain concordant monotypic PCs and monotypic B cells were identified in 96% of cases assessed by flow cytometry. Notably, the neoplastic PCs were consistently positive for CD45 (dim, 100%), CD19 (96%), CD81 (89%), CD27 (83%), rarely and only weakly or partially express CD56 (16%), whereas CD117 was consistently negative. Eleven cases analyzed by fluorescence in situ hybridization were negative for CCND1::IGH and myeloma-related aberrations. MYD88 mutation was detected in 17 of 24 cases (71%), and CXCR4 mutation was identified in 6 of 19 cases (32%), of which 4 had concurrent MYD88 mutation. In conclusion, the results highlight a potential diagnostic pitfall of LPL associated with marked plasmacytic differentiation and an IgG or IgA paraprotein that can resemble a PCN. Useful features in favor of LPL against PCN include the characteristic immunophenotypic profile of the PCs in LPL, absence of CCND1::IGH, and the presence of MYD88 and/or CXCR4 mutations.

Impact of Liver Biopsy Size on Histopathologic Evaluation of Liver Allograft Rejection.

CONTEXT.­: Allograft liver biopsy is the gold standard in assessing transplant recipients for graft dysfunction. The impact of biopsy sample size on the diagnosis of acute cellular rejection (ACR) has not been studied. OBJECTIVE.­: To assess the relationship of biopsy sample length with the diagnosis and determine optimal biopsy sample size in the transplant setting. DESIGN.­: We retrospectively reviewed 68 core biopsies from patients with a history of liver transplant. Each biopsy sample was read, on 5 different occasions with differing lengths, to assess for ACR per Banff criteria. Categorical agreement was calculated from rejection severity. RESULTS.­: The length of biopsy sample strongly correlated with the number of portal tracts. ACR rates increased from 73.5% to 79.4% with increase in length from 1 cm to 2 cm, and moderate rejection increased from 27.9% to 33.82%. At 1.0 and 1.5 cm, no cases of severe rejection were detected; at 2.0 cm, 1 case was detected; and at 3.0 cm, 2 cases were detected. The major error rate was reduced to less than 10% with a length of 2.0 cm, at which length the average number of complete and partial portal triads was 10 and 13, respectively. CONCLUSIONS.­: The likelihood of diagnosing ACR and rejection grade increased substantially with increase in biopsy sample length. This study suggests that a minimum length of 2 cm, 10 complete portal triads, or 13 partial/complete portal triads should be obtained for confident exclusion and grading of ACR.

From the archives of MD Anderson Cancer Center: Intravascular large B-cell lymphoma with numerous circulating lymphoma cells.

Intravascular large B-cell lymphoma (IVLBCL) is a rare, clinically aggressive form of large B-cell lymphoma that is preferentially located within blood vessel lumina. Despite its intravascular location, a leukemic phase of disease seems to be uncommon. After encountering a patient with IVLBCL with numerous circulating lymphoma cells, we reviewed the literature and identified 6 patients with IVLBCL who had numerous circulating lymphoma cells (defined by ≥10% lymphoma cells in peripheral blood). The percentage of circulating lymphoma cells in this patient cohort was variable, with a median of 36% (range, 14% - 87%), Bone marrow was involved in all 5 patients assessed. Elevation of liver transaminases preferentially affecting aspartate aminotransferase (AST, 3/3, 100%), hepatosplenomegaly (4/5, 80%), thrombocytopenia (100%), CD5 positivity (100%) and monotypic lambda light chain predominance (3/4, 75%) were common features. Conventional cytogenetic analysis performed in 4 patients revealed a complex karyotype with multiple abnormalities particularly deletions and copy number aberrations involving chromosomes 6q and 18. The clinical courses of these patients were highly variable, but overall there was a high mortality rate of 75% with 18-months of follow-up. Due to the rarity of IVLBCL, along with its variable clinical manifestations and subtle pathologic changes, the diagnosis is often delayed which may contribute to the poor outcome of IVLBCL patients. Recognition that this disease can present rarely with a leukemic phase further expands our knowledge of the clinicopathologic spectrum of IVLBC.

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.

SOHO State of the Art Updates and Next Questions: Pathology and Pathogenesis of Nodal Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and often clinically aggressive group of neoplasms derived from mature post-thymic T-lymphocytes. These neoplasms are rare and usually diagnostically challenging. Our understanding of the pathogenesis of PTCL is increasing and this improved knowledge is leading us to better molecular characterization, more objective and accurate diagnostic criteria, more effective risk assessment, and potentially better treatments. The focus of this paper is to present a brief overview of the current pathology criteria and molecular and genetic features of nodal peripheral T-cell lymphomas focusing on distinct genetically and molecularly defined subgroups that are being recognized within each major nodal PTCL category. It is expected that the molecular stratification will improve the diagnosis and will provide novel therapeutic opportunities (biomarker-driven and targeted therapies) that might benefit and change the outcomes of patients with these neoplasms.

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.

Hematogones with light chain restriction: A potential diagnostic pitfall when using flow cytometry analysis to assess bone marrow specimens.

Light-chain restricted hematogones (LCR HGs) detected by flow cytometry analysis can mimic bone marrow involvement by B-cell lymphoma. This phenomenon can present a diagnostic pitfall and negatively impact patient management, as misinterpretation may upgrade disease stage. In this study, we characterized the immunophenotype of LCR HGs with an aim to differentiate them from B-cell lymphoma. We analyzed 24 patients with LCR HGs, 12 (50 %) were kappa light chain restricted and 12 (50 %) were lambda light chain restricted. LCR HGs account for 51 % (range, 1.5%-99%) of B cells, and 0.5 % (range, 0.1%-3.7%) of total cells. In 15 patients in whom multiple specimens were analyzed, 10 (67 %) showed persistent LCR HGs in more than 1 specimen, and the duration of the light chain restriction ranged from 4 months to 2 years. Among 24 patients, 4 (16.6 %) cases were concurrently involved by B-cell lymphoma/myeloma in addition to LCR HGs. With the exception of light chain restriction, LCR HGs showed a similar immunophenotype as normal HGs and had a distinct location on the CD45/Side Scatter (SSC) plot. They were also consistently positive for CD10, CD19, CD38 (bright), CD43, and CD200. CD20 expression showed a spectrum from dim/negative to positive.