High-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is an aggressive mature B-cell neoplasm whose diagnosis remains challenging due to significant morphologic overlap with diffuse large B-cell lymphoma and Burkitt lymphoma, and the absence of defining molecular alterations. Aberrant antigen expression can further complicate diagnoses and may result in lineage ambiguity. We report a unique case of HGBCL-NOS with MYC rearrangement demonstrating aberrant cytoplasmic CD3 and surface CD4 expression, leading to an initial misdiagnosis as a T-cell lymphoma at an outside hospital. A 50-year-old man with a previous diagnosis of peripheral T-cell lymphoma presented to our institution with central nervous system symptoms and a persistent bladder mass. Evaluation by bladder biopsy and cerebrospinal fluid flow cytometry revealed a high-grade B-cell neoplasm with diffuse CD10 and CD79a expression, patchy CD20 positivity, strong PAX5 expression, lambda light-chain restriction, Ki-67 approaching 100
Cutaneous T-cell lymphoma (CTCL) and classic Hodgkin lymphoma (cHL) are distinct lymphoid neoplasms with differing cells of origin and immunophenotypes. Morphological overlap between these entities can pose significant diagnostic challenges, particularly in patients with a concurrent or prior lymphoma diagnosis. A 67-year-old male with a history of cHL and mycosis fungoides/lymphomatoid papulosis presented with new PET-positive right groin lymphadenopathy. Biopsy revealed atypical cells morphologically consistent with Hodgkin/Reed-Sternberg cells. However, clonal T-cell receptor beta gene rearrangement and immunophenotypic findings were inconsistent with cHL, and integration of these results with the patient’s clinical history led to a final diagnosis of nodal involvement by CTCL. CTCL can morphologically mimic cHL, representing a significant diagnostic pitfall. This case underscores the critical role of immunophenotyping, molecular studies, and clinical context in accurately diagnosing complex hematolymphoid neoplasms.
A 57-year-old male from Guinea presented with 6 months of progressive shortness of breath, productive cough, and occasional night sweats. A lung biopsy revealed an angiocentric pulmonary infiltrate of small bland lymphocytes and lymphoepithelial lesions mimicking a MALT lymphoma. The infiltrate expressed CD3, CD56, and Epstein-Barr virus-encoded RNA with little Ki-67 staining. Blood EBV copies were 519 IU/mL. FDG-PET scan showed no uptake outside the thorax. A diagnosis of small-cell variant pulmonary NK/T-cell lymphoma was made. Following asparaginase/cisplatin-based treatment, the patient developed recurrent cough, and nasal biopsy suggested lymphoma relapse. Following transplant conditioning, the patient developed symptoms of fever and cough, with rising blood EBV load. Lymphoma progression was suspected. A flow RNA assay demonstrated a small population of EBER + CD8 + T-cells in blood. NK/T-cell lymphoma usually present with sino-nasal symptoms. The small-cell variant is rare. The diagnosis is challenging when the clinical presentation and cytological features are atypical. POT1 variants have not been reported in ENKTL to our knowledge, but germline variants have been associated with lymphomas. A multicolour EBER hybridisation flow assay can help identify the cellular origin of EBV reactivation.
A 47-year-old man presented with leukocytosis and absolute lymphocytosis. Peripheral blood smear examination revealed atypical lymphoid cells containing striking Auer rod–like cytoplasmic inclusions, creating a strong morphologic impression of acute promyelocytic leukemia. However, flow cytometry demonstrated a mature monoclonal B cell population lacking myeloid differentiation, and bone marrow biopsy established the diagnosis of marginal zone lymphoma. This rare case highlights a major diagnostic pitfall and underscores that Auer rod–like inclusions are not exclusively restricted to myeloid neoplasms.
Lymphoplasmacytic lymphoma (LPL) is a lymphoproliferative neoplasm characterized by small plasmacytic cells infiltrating the bone marrow and is typically associated with IgM paraprotein detection. In rare cases, LPL may undergo histologic transformation (HT) to a more aggressive, large B cell lymphoma, such as diffuse large B-cell lymphoma (DLBCL). HT with cutaneous involvement is exceedingly rare. Here, we report a case of cutaneous involvement by a CD5+ CD10+ large B cell lymphoma in a post-transplant setting, initially attributed to follicular lymphoma but determined to be LPL with additional molecular testing. These findings highlight a potential diagnostic pitfall that was resolved by using molecular techniques in tandem with morphological observations.
Acute leukemias of the myeloid lineage most commonly show myeloid and/or monocytic differentiation. Leukemias with erythroid, megakaryoblastic, and basophilic differentiation are more rare but are well documented. In contrast, acute leukemia showing marked morphologic and immunophenotypic features of eosinophilic differentiation is not a defined entity. When acute leukemias do show a prominent population of cells with eosinophilic differentiation, the eosinophil populations typically show morphologic features of mature eosinophils and the eosinophilic population may be clonally related to the neoplastic cells or may be reactive. In this case report, we describe an unusual case of acute myeloid leukemia evolving from a myelodysplastic neoplasm with low blasts in which the predominant cell population in the peripheral blood and bone marrow were cells with round nuclei and immature chromatin with prominent eosinophilic granules and immunophenotypic features suggestive of maturation arrest at an eosinophilic promyelocyte-like stage. At the time of leukemic transformation, molecular studies showed acquisition of NRAS G13R, NRAS Q61K, and KRAS G12R mutations in addition to the TET2 variants (N582fs and E1357X), del(20q), and 7q- abnormalities detected in the antecedent myelodysplastic neoplasm. No PDGFRA, PDGFRB, FGFR1, JAK2, or FLT3 rearrangements were detected by FISH or in sequencing assays. BCR::ABL1 testing was also negative. Whole-genome sequencing did not detect additional abnormalities to explain the differentiation block. In summary, this is, to our knowledge, the only reported case of an acute leukemia in which the immature cells themselves demonstrate morphologic and immunophenotypic features of eosinophilic promyelocytes.
The transforming acidic coiled-coil containing protein 1 (TACC1) gene is a recognized oncogenic driver in solid tumors through FGFR1::TACC1 fusions, but remains extremely rare in acute myeloid leukemia (AML), with only one prior case of RUNX1::TACC1 reported. Here, we describe the second documented RUNX1::TACC1 fusion AML case, occurring in an 82-year-old male with t(8;21)(p11;q22) translocation. Comprehensive molecular characterization identified four transcript variants by RNA sequencing, including a new RUNX1(E7)::TACC1(E6) isoform and reciprocal TACC1::RUNX1 fusions. Notably, initial FISH analysis misleadingly suggested FGFR1 involvement, underscoring RNA-seq's critical role in accurate rare fusion detection. While the patient showed no response to azacitidine/venetoclax, the limited number of cases precludes definitive conclusions about treatment resistance patterns. These findings expand TACC1's oncogenic spectrum to AML and warrant further investigation to determine whether RUNX1::TACC1 represents a clinically distinct molecular subtype and to elucidate its potential therapeutic vulnerabilities.
Finding an unexpected metastatic lesion in bone marrow biopsy (BMB) performed for a hematological indication can cause diagnostic issues. In a BMB performed in a patient with suspected acute leukemia evolved from a post-essential thrombocythemia myelofibrosis a group of atypical cells with E-cadherin expression was found. After careful morphological evaluation and further immunohistochemical staining, these cells were identified as a melanoma metastasis with E-cadherin expression. E-cadherin immunostain is performed frequently by hematopathologists to highlight erythroid cells but its expression can be found in a number of hematological and non-hematological neoplasms, including melanoma, which should be considered in the differential diagnosis of E-cadherin-expressing neoplasm.
Severe coronavirus disease 2019 (COVID-19) and secondary hemophagocytic lymphohistiocytosis (sHLH) share overlapping pathogenesis, symptoms, and ultimately fatal outcomes unless prompt early interventions are undertaken. The excessive immune response in COVID-19 may increase hemophagocytes in bone marrow aspirate (BMA), which could mimic sHLH. We aimed to assess hemophagocytic cells in the BM of COVID-19 patients with hematological neoplasms and examine their link to sHLH. BMAs from 44 living COVID-19-positive patients with hematological neoplasms were examined, focusing on the presence of hemophagocytic cells. Alongside clinical and laboratory data, patients were classified into two groups according to the HLH-2004 diagnostic criteria: those meeting ≥ 4 criteria (n = 23) and those meeting < 4 criteria (n = 21). BMAs from 44 COVID-19-negative patients with similar hematological malignancies were also analyzed for comparison. Hemophagocytic cells were present in 33/44 (75.0
INTRODUCTION:Beta thalassemia carriers have hereditary anemia marked by ineffective erythropoiesis and hemolysis, leading to considerable variation in red blood cell (RBC) morphology. Automated hematology analyzers equipped with quality flags (Q-flags) can identify abnormal RBC populations. This study evaluates the diagnostic performance of two Q-flags (RBC Agglutination? and Fragments?) in differentiating beta thalassemia from common nutritional anemias. METHODS:This study was conducted on complete blood count (CBC) data from 37 patients with beta thalassemia carriers and 3317 patients with nutritional anemias, including 2780 with iron deficiency anemia, 478 with vitamin B12 deficiency, and 59 with folate deficiency. All data were obtained using Sysmex hematology analyzers. The Shapiro-Wilk test assessed the distribution of data, and group comparisons were performed using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was employed to determine the cutoff values of Q-flag parameters. RESULTS:Patients with beta thalassemia demonstrated significantly lower values for Q-flag (RBC Agglutination?) and significantly higher values for Q-flag (Fragments?) compared to those with nutritional anemias. The median (interquartile range) for Q-flag (RBC Agglutination?) was 40.0 (40.0-50.0), and for Q-flag (Fragments?) it was 40.0 (20.0-60.0). Significant differences were also noted in routinely reported hematological indices such as MCV, MCH, MCHC, and MicroR%. ROC analysis revealed that cutoff value of 60.0 for Q-flag (RBC Agglutination?) and 20.0 for Q-flag (Fragments?) had reasonable sensitivity and specificity for distinguishing beta thalassemia from nutritional anemias. CONCLUSION:There is a possibility that both Q-flags demonstrate strong discriminatory ability for beta thalassemia carriers in comparison to nutritional anemias and serve as useful screening tools within routine hematology workflows.
OBJECTIVES:We report two rare cases of intrahepatic splenosis in patients with distant histories of abdominal trauma and highlight the diagnostic challenges splenosis can pose for clinicians, radiologists, and pathologists. METHODS:Pathologic and clinical data for the patients were obtained from our institutional and referral records. RESULTS:Patient 1 is a 44-year-old male with a history of heavy alcohol use who presented with chest pain. Imaging study revealed alcoholic steatosis and multiple liver lesions. Patient 2 is a 53-year-old female with a history of primary biliary cholangitis and chronic liver disease who was found to have multiple hepatic lesions during routine follow-up. Imaging studies in both cases raised concern for both benign and malignant processes. Biopsies demonstrated prominent congested thin-walled vascular structures, scant fibrous stroma, and background lymphocytic infiltrates. Immunohistochemistry (IHC) for ERG, CD31, and CD8 highlighted the endothelial cells of the vascular structures, phenotypically consistent with littoral cells of splenic sinuses. Further review of the clinical history revealed remote traumatic motor vehicle accidents resulting in splenectomy in both patients. After clinical, radiologic, and pathologic correlation, the diagnosis of splenosis was made in both cases. CONCLUSIONS:Our cases highlight the distinctive clinical history and characteristic histologic and immunophenotypic features essential for diagnosing splenosis.
Epstein-Barr virus (EBV)–driven lymphoproliferative disorders (LPDs) are important complications of post-transplant immunosuppression. EBV-positive mucocutaneous ulcer (EBV-MCU) is typically a localized, solitary, sharply circumscribed ulcer with an indolent clinical course, whereas post-transplant lymphoproliferative disorder (PTLD) may be multifocal, disseminated, and life-threatening; however, these entities can overlap histologically on limited gastrointestinal biopsies. We report a 60-year-old woman with autoimmune hepatitis/primary sclerosing cholangitis (PSC) status-post liver transplantation (2017; re-transplant 2019 for recurrent PSC) who presented with diarrheal illness and subsequently developed gastrointestinal bleeding. Imaging showed enterocolitis with periportal/mesenteric lymphadenopathy, and endoscopy demonstrated severe colitis with multiple superficial ulcers, without a mass lesion. Biopsies revealed severe active ileocolitis with ulceration and an atypical EBV-positive B cell proliferation (CD20/PAX5+, MUM1+, variably CD30+, EBV-LMP1+; polytypic light chains). The differential diagnosis included EBV-MCU and PTLD - although the superficial ulcerative pattern and absence of a mass initially raised consideration of EBV-MCU, the presence of multiple ulcers and lack of classic EBV-MCU histologic features favored EBV-positive polymorphic PTLD. Later, a PET-CT demonstrated extensive FDG-avid lymphadenopathy above and below the diaphragm with splenic and adrenal involvement, supporting disseminated EBV-positive PTLD and prompting rituximab-based chemotherapy. This case highlights the practical challenges of classifying EBV-positive ulcerative gastrointestinal lesions on small biopsies and underscores the need for radiologic and clinical correlation and close follow-up when EBV-MCU and PTLD are both plausible.
Crystalline inclusions have been reported in macrophages, plasma cells, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, and rarely in myeloid precursors. The presence of crystalline inclusions in myeloid cells may be a feature of aggressive myeloid neoplasm.
Kikuchi-Fujimoto disease (KFD) is a rare, self-limiting form of necrotizing lymphadenitis that primarily affects young adults and often mimics lymphoma or autoimmune lymphadenitis both clinically and histologically. We report the case of a 28-year-old Caucasian woman with a history of Hashimoto's thyroiditis presenting with progressive cervical lymphadenopathy, fever, weight loss, and myalgia. Laboratory findings showed leukopenia, elevated transaminases, and increased LDH. Imaging revealed bilateral lymphadenopathy and mildly enlarged spleen. Histopathological examination of an excised lymph node demonstrated necrotizing lymphadenitis with crescent-shaped histiocytes, plasmacytoid dendritic cells, and karyorrhectic debris. Immunohistochemistry supported the diagnosis and excluded lymphoma, while electron microscopy did not provide evidence of infection. The patient recovered fully without specific treatment. This case highlights the importance of recognizing the characteristic features of KFD to avoid misdiagnosis and overtreatment. Given its potential association with autoimmune disease and recurrence, clinical follow-up is recommended.
BACKGROUND:Nodal T follicular helper cell lymphoma, angioimmunoblastic type (AITL), is a common peripheral AQ1T-cell lymphoma characterized by recurrent mutations in TET2, IDH2, DNMT3A, and RHOA, with TET2 and DNMT3A mutations frequently arising in early hematopoietic stem and progenitor cells (HSPCs) as clonal hematopoiesis (CH). In addition to its well-established association with secondary myeloid neoplasms, AITL is complicated by secondary B-cell lymphomas in up to 10-23% of cases, often associated with EBV infection. However, the clonal relationship between AITL, CH, and associated B-cell lymphomas remains less well understood. We report a rare case of an elderly male who developed AITL followed by EBV-positive Burkitt lymphoma (BL) three years later. METHODS:Comprehensive histopathologic evaluation, immunohistochemistry, flow cytometry, fluorescence in situ hybridization, and next-generation sequencing were performed on both lymphoma specimens and on a staging bone marrow sample. RESULTS:Molecular analysis revealed a shared TET2 p.Q962* mutation present at high variant allele frequencies in both the AITL and BL, which was also detected at low level in the bone marrow which showed no evidence of neoplasia, consistent with underlying CH. Each lymphoma harbored additional disease-characteristic genetic alterations, including RHOA mutation in AITL and MYC rearrangement with ID3 mutation in BL. CONCLUSION:This case establishes the shared clonal origin between AITL and BL arising in the setting of CH and provides additional biological insight into the development of B-cell lymphoma associated with AITL.
Adult T-cell leukemia/lymphoma (ATLL) is a rare T-cell neoplasm with geographic clustering, associated with human T-lymphotropic virus1 (HTLV-1), an oncoretrovirus. Clinical presentation is variable, and diagnosis can be challenging in atypical cases. We describe a 61-year-old man with aggressive CD4/CD8 double-positive T-cell lymphoma involving lymph nodes and bone marrow with circulating lymphoma cells. HTLV serology was positive, confirmed by western blot. However, due to the unusual presentation and absence of classic features such as hypercalcemia, skin lesions, or “flower” cells (circulating lymphoma cells with marked nuclear lobation), further confirmation was warranted. HTLV-1 bZIP factor (HBZ) in situ hybridization (ISH) was performed to confirm the diagnosis of ATLL. This case underscores the importance of including HTLV-1 serology in the initial workup of T-cell lymphomas and highlights the diagnostic value of HBZ ISH in ambiguous presentations.
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most prevalent leukemia in adults which typically follows an indolent clinical course. However, it has the potential to transform into more aggressive categories, including accelerated CLL or diffuse large B-cell lymphoma (DLBCL), a phenomenon known as Richter transformation. Bruton tyrosine kinase inhibidors (BTKI), such as ibrutinib and zanubrutinib, represent a cornerstone of CLL/SLL treatment by inhibiting B-cell receptor signaling. Temporary discontinuation of these agents are common due to surgical procedures or infections which has been associated with rapid disease progression, producing a pseudo-Richter transformation (P-RT) in tissues. We present a case with CLL/SLL who experienced clinical deterioration following ibrutinib withdrawal, resulting in an explosive disease flare and splenic rupture. The patient improved after BTKI reintroduction, and a P-RT was diagnosed. Nine similar patients were found through PubMed search, and we describe their clinicopathological characteristics.
Clinical expression among children with transfusion-dependent β-thalassemia major varies substantially, and this heterogeneity is not fully explained by HBB mutations alone. We evaluated whether HLA-DQB1 alleles were associated with case status in a pediatric case-control cohort and whether selected alleles correlated with hematologic and hemoglobin fraction profiles among affected children. This single-center case-control study included 45 children with transfusion-dependent β-thalassemia major and 45 age- and sex-matched healthy controls. HLA-DQB1 genotyping was performed using a sequence-specific primer real-time PCR assay. Allele frequencies were compared between groups, and within-patient analyses examined associations with pre-transfusion hemoglobin, reticulocyte counts, and hemoglobin fractions. Multivariable and internal-validation analyses were treated as exploratory because of the modest sample size. DQB1 0601 was more frequent in cases than controls (9.7
Anaplastic large cell lymphoma (ALCL) is contained within a larger category of aggressive mature T-cell lymphomas. Their subclassification relies on the presence or absence of Anaplastic Lymphoma Kinase (ALK) gene fusions and other molecular alterations. Cases in the head and neck and mouth are uncommon. The aim of this manuscript is to describe the clinicopathological and immunohistochemical features of a series of anaplastic large cell lymphoma (ALCL) affecting the oral cavity. Three cases are included in this series, all of them affecting male patients, with a mean age of 27.7 years old. Concomitant involvement of the oral cavity and lymph nodes was known to occur in two cases, while cutaneous lesions were not recorded in any patient. The neoplasms more often presented as solitary or multiple painful swellings in the gingiva. All cases were positive for CD30 expression, and the two cases investigated for CD3 were negative. ALK protein was expressed in two cases, and it was negative in one case. EBER was negative in the two cases investigated. One patient was known to decease despite chemotherapy. In conclusion, oral manifestations of ALCL are very rare and more commonly represent a disseminated disease.
