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1.
EJHaem ; 5(4): 900-904, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39157608

ABSTRACT

In the current WHO classification, a T-cell prolymphocytic leukemia (T-PLL) diagnosis requires lymphocytosis of >5 × 109/L, evidence of monoclonality, and TCL1A or MTCP1 rearrangement. However, the 2019 consensus document suggested that in the absence of rearrangement of TCL1-family, the presence of abnormalities involving chromosome 11 (11q22.3; ATM), chromosome 8 (idic(8)(p11), t(8;8), trisomy 8q), 5, 12, 13, 22, or a complex karyotype, as well as involvement specific sites (e.g., splenomegaly, effusions) would suffice for a diagnosis of T-PLL. We present a patient diagnosed with T-PLL with MTCP1 rearrangement who was successfully treated with alemtuzumab followed by consolidative allogeneic unrelated donor stem cell transplantation. Eight years later, the patient presented with inguinal lymphadenopathy with features more akin to peripheral T-cell lymphoma, NOS (PTCL, NOS) of the GATA3 subtype, and there was no evidence of peripheral blood involvement. However, the lymphoma cells were clonally related to those at presentation. Currently, literature on T-PLL-like cases lacking the rearrangement of TCL1A is limited, and the possibility of whether a proportion of such cases could represent PTCL, NOS (with leukemic involvement) needs consideration.

2.
Clin Lab Med ; 43(4): 597-606, 2023 12.
Article in English | MEDLINE | ID: mdl-37865505

ABSTRACT

Myelodysplastic neoplasm with low blasts and SF3B1 mutation (MDS-LB-SF3B1) has undergone significant classification changes in the past year with the publication of the 5th edition of the World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues and the International Consensus Classification. This article reviews the basic biology of SF3B1, iron metabolism, and dysfunction that leads to the formation of ring sideroblasts. It highlights neoplastic and non-neoplastic considerations to the differential diagnoses. Finally, a review on the evolution of the prognostic scoring system and treatment regimens that are available to patients with a diagnosis of MDS is presented.


Subject(s)
Myelodysplastic Syndromes , Neoplasms , Humans , RNA Splicing Factors/genetics , Prognosis , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Mutation , Phosphoproteins/genetics
3.
Clin Lab Med ; 43(3): 427-444, 2023 09.
Article in English | MEDLINE | ID: mdl-37481321

ABSTRACT

Classic Hodgkin lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and T cell/histiocyte-rich large B cell lymphoma form a unique set of lymphomas with similar morphologic growth patterns (occasional neoplastic cells within a prominent cellular cell background) that are pathobiologically related. Distinguishing these entities has been historically difficult by flow cytometry; however, our laboratory has developed antibody-fluorochrome combinations capable of immunophenotyping these lymphomas. Additionally, characterization of the background reactive lymphocytes can aid in narrowing the differential diagnosis. This review summarizes the immunophenotypic features and insights of the neoplastic and reactive populations found in this unique group of lymphomas.


Subject(s)
Hodgkin Disease , Lymphoma, Follicular , Lymphoma, Large B-Cell, Diffuse , Humans , Hodgkin Disease/diagnosis , Hodgkin Disease/pathology , T-Lymphocytes , Lymphoma, Follicular/diagnosis , Lymphoma, Follicular/pathology , Histiocytes/pathology , Flow Cytometry , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphocytes , Immunophenotyping , Diagnosis, Differential
4.
Cancer Cytopathol ; 130(11): 881-890, 2022 11.
Article in English | MEDLINE | ID: mdl-35775861

ABSTRACT

BACKGROUND: ThyroSeq assesses the probability of malignancy (POM) in thyroid fine-needle aspiration cytology specimens diagnosed as atypia of undetermined significance (AUS). The authors investigated whether defined AUS subcategories are associated with specific molecular alterations, the molecular-derived risk of malignancy (MDROM), and the risk of malignancy (ROM). METHODS: Fine-needle aspiration cytology reports of AUS and corresponding results from the ThyroSeq version 3 genomic classifier results were retrieved and subcategorized as follicular cells with either cytologic atypia (FC-C), architectural atypia (FC-A), both cytologic and architectural atypia (FC-CA), or a predominance of Hurthle cells (PHC). The MDROM, ROM, and frequency of molecular alterations by subcategory were computed and analyzed, and p < .05 was considered significant. RESULTS: The final analysis included 541 cases subdivided into 233 with FC-A, 104 with FC-C, 116 with FC-CA, and 88 with PHC. The benign call rate and positive call rate for the AUS category were 72% and 28%, respectively, which varied between AUS subcategories. The MDROM by subcategory was 15.9% FC-A, 20.5% FC-C, 33.8% FC-CA, and 14.4% PHC. Histologic follow-up was available for 155 (28%) AUS cases with a follow-up period ≥12 months. The 95% confidence intervals of the MDROMs overlapped with the ROMs. The highest MDROM and ROM were in the FC-CA subcategory. RAS mutations were present in all subcategories. BRAF V600E mutations and papillary thyroid carcinoma were most frequent in the FC-CA subcategory. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features was significantly more frequent in the FC-C subcategory. CONCLUSIONS: The current results demonstrated that AUS subcategories are associated with specific genetic alterations, the MDROM, and the ROM. Molecular results and an awareness of various cancer probabilities within AUS subcategories can allow for a more tailored management.


Subject(s)
Adenocarcinoma, Follicular , Thyroid Neoplasms , Thyroid Nodule , Humans , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Biopsy, Fine-Needle/methods , Cytodiagnosis/methods , Genomics , Probability , Thyroid Nodule/pathology , Adenocarcinoma, Follicular/diagnosis , Adenocarcinoma, Follicular/genetics , Adenocarcinoma, Follicular/pathology , Retrospective Studies
5.
Leuk Res ; 111: 106733, 2021 12.
Article in English | MEDLINE | ID: mdl-34749168

ABSTRACT

Recent studies demonstrated that MYC epigenetically regulates AML cell survival and differentiation by suppressing IDH1/2-TET2-5hmC signaling and that MYC overexpression is associated with poor survival outcomes in multiple AML patient cohorts. However, the oncogenic roles of MYC in MDS remain to be explored. A total of 41 patients with de novo MDS were retrospectively identified using the Total Cancer Care database at the Moffitt Cancer Center. A total of 61 % of patients had low MYC expression and 39 % of patients had high MYC expression defined as MYC reactivity by immunohistochemical staining in ≥5% of bone marrow (BM) cells at the time of MDS diagnosis. The median MDS-to-AML progression free survival (PFS) was significantly shorter in the high MYC group (median PFS 9.3 vs. 17.7 months, HR = 2.328, p = 0.013). Further, overall survival (OS) was also shorter in the high MYC patients (median OS 19.7 vs. 51.7 months, HR = 2.299, p = 0.053). Multivariate analyses demonstrated that high MYC expression is an independent poor prognostic factor for the MDS-to-AML progression (HR = 2.275, p = 0.046). Our observations indicate that MYC may play a crucial role in MDS transformation to AML and the underlying mechanisms of MYC-driven MDS clonal expansion and leukemic transformation require further investigation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/pathology , Mutation , Myelodysplastic Syndromes/pathology , Neoplasms, Second Primary/pathology , Proto-Oncogene Proteins c-myc/metabolism , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Male , Middle Aged , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Neoplasms, Second Primary/drug therapy , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/metabolism , Prognosis , Proto-Oncogene Proteins c-myc/genetics , Retrospective Studies , Survival Rate , Young Adult
6.
Am J Clin Pathol ; 154(1): 48-56, 2020 06 08.
Article in English | MEDLINE | ID: mdl-32112088

ABSTRACT

OBJECTIVES: To compare the clinical significance of SF3B1/DNMT3A Comutations with SF3B1 or DNMT3A mutation alone in myelodysplastic syndrome (MDS) and clonal cytopenia of undetermined significance (CCUS). METHODS: We identified and compared 31 patients with only DNMT3A mutation, 48 patients with only SF3B1 mutation, and 16 patients with only SF3B1/DNMT3A comutations. RESULTS: SF3B1/DNMT3A comutations were found to be more common in MDS, whereas DNMT3A mutation alone was more common in CCUS. The patients with SF3B1/DNMT3A comutations were less likely to have poor cytogenetics than patients with DNMT3A mutation alone. Patients with SF3B1/DNMT3A comutations showed significantly longer median survival time and better overall survival than patients with DNMT3A mutation alone. CONCLUSIONS: Patients with SF3B1/DNMT3A comutations appear to have better clinical outcomes than patients with isolated DNMT3A mutation. These findings suggest that the favorable prognosis of SF3B1 mutation in is not abrogated by the concurrent presence of a DNMT3A mutation.


Subject(s)
Bone Marrow Diseases/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , Myelodysplastic Syndromes/genetics , Phosphoproteins/genetics , RNA Splicing Factors/genetics , Aged , Bone Marrow Diseases/mortality , DNA Methyltransferase 3A , Female , Humans , Male , Mutation , Myelodysplastic Syndromes/mortality
7.
Hum Pathol ; 97: 80-93, 2020 03.
Article in English | MEDLINE | ID: mdl-31884085

ABSTRACT

Primary gastrointestinal liposarcoma is rare, and information regarding this entity is largely based on single case studies. We report on 8 patients with primary liposarcoma of the gastrointestinal tract and review the pertinent literature. The cohort includes 6 men and 2 women who ranged in age from 51 to 81 years (median 68.5). Two tumors arose in the stomach, 4 in the small intestine, and 2 in the large intestine. Tumors ranged in size from 2.5 to 14.5 cm (median 7 cm), originated in the submucosa or muscularis propria of the intestinal wall, and frequently protruded into the bowel lumen, resulting in mucosal ulceration and luminal obstruction. Six tumors were dedifferentiated liposarcomas, and 2 were well-differentiated liposarcoma. Surgical excision was performed on all tumors except for 1 case of dedifferentiated liposarcoma. On follow-up, 1 patient with dedifferentiated liposarcoma developed a lytic sacral lesion suspicious for metastasis 4 months after resection of the primary, and another underwent marginal resection and presented with recurrence 4 years later, had tumor re-resection, and was considered disease-free at 6 weeks postsurgery. A third patient with dedifferentiated liposarcoma was alive with unknown disease status at 17 months following surgery, and another patient with dedifferentiated liposarcoma was alive without evidence of disease at 30 months following surgery. No follow-up information on the remaining patients is available. Overall, liposarcomas of the intestinal tract are most frequently high-grade dedifferentiated tumors that are biologically aggressive and require surgical excision with widely negative margins to help reduce the risk of local recurrence and dissemination. Important in the differential diagnosis is malignant gastrointestinal stromal tumor. Care must be taken not to misdiagnose one entity for the other because the correct diagnosis carries important therapeutic implications.


Subject(s)
Intestinal Neoplasms/pathology , Liposarcoma/secondary , Stomach Neoplasms/pathology , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Cell Dedifferentiation , Female , Humans , Intestinal Neoplasms/chemistry , Intestinal Neoplasms/diagnostic imaging , Intestinal Neoplasms/surgery , Liposarcoma/chemistry , Liposarcoma/diagnostic imaging , Liposarcoma/surgery , Male , Margins of Excision , Middle Aged , Neoplasm Recurrence, Local , Stomach Neoplasms/chemistry , Stomach Neoplasms/diagnostic imaging , Stomach Neoplasms/surgery , Time Factors , Treatment Outcome , Tumor Burden
8.
J Foot Ankle Surg ; 56(3): 670-673, 2017.
Article in English | MEDLINE | ID: mdl-28268143

ABSTRACT

Bizarre parosteal osteochondromatous proliferation, otherwise known as "Nora's lesion," is a rare benign neoplasm first described by Nora in 1983. The exact etiology of this neoplasm remains unknown, and its presentation in the lower extremity presents a diagnostic challenge, as both clinical and radiologic features cannot fully differentiate it from other neoplasms. We present the case of a 48-year-old female with plantar heel pain secondary to Nora's lesion mimicking plantar fasciitis and periosteal osteosarcoma. Following bone biopsy for histopathologic analysis, the patient's symptoms spontaneously resolved, and she returned to activity with complete resolution of symptoms 18 months post biopsy. Bizarre parosteal osteochondromatous proliferation as an etiology for plantar heel pain has not been previously described in the literature. Although rare, it should be considered in the differential diagnosis for patients presenting with plantar heel pain, especially after failed conservative treatment. Following diagnostic confirmation by histopathology, complete surgical excision is the treatment of choice.


Subject(s)
Bone Neoplasms/diagnosis , Calcaneus/pathology , Heel , Osteochondroma/diagnosis , Pain/etiology , Periosteum/pathology , Biopsy , Calcaneus/diagnostic imaging , Diagnosis, Differential , Fasciitis, Plantar/diagnosis , Female , Humans , Middle Aged , Osteosarcoma/diagnosis
9.
Fetal Pediatr Pathol ; 34(4): 257-70, 2015.
Article in English | MEDLINE | ID: mdl-26111189

ABSTRACT

Limb body wall complex (LBWC) is characterized by multiple severe congenital malformations including an abdominal and/or thoracic wall defect covered by amnion, a short or absent umbilical cord with the placenta almost attached to the anterior fetal wall, intestinal malrotation, scoliosis, and lower extremity anomalies. There is no consensus about the etiology of LBWC and many cases with abnormal facial cleft do not meet the requirements for the true complex. We describe a series of four patients with LBWC and other malformations in an attempt to explain their etiology. There are several reports of fetuses with LBWC and absent gallbladder and one of our patients also had polysplenia. Absent gallbladder and polysplenia are associated with laterality genes including HOX, bFGF, transforming growth factor beta/activins/BMP4, WNT 1-8, and SHH. We postulate that this severe malformation may be due to abnormal genes involved in laterality and caudal development.


Subject(s)
Abdominal Wall/abnormalities , Abnormalities, Multiple/genetics , Body Patterning/genetics , Lower Extremity Deformities, Congenital/genetics , Thoracic Wall/abnormalities , Umbilical Cord/abnormalities , Abnormalities, Multiple/embryology , Abortion, Spontaneous , Adult , Cloaca/abnormalities , Diseases in Twins/genetics , Female , Fetal Death/etiology , Gallbladder/abnormalities , Hernia, Umbilical/embryology , Hernia, Umbilical/genetics , Heterotaxy Syndrome/genetics , Humans , Kyphosis/embryology , Kyphosis/genetics , Lower Extremity Deformities, Congenital/embryology , Male , Pregnancy , Retrospective Studies , Scoliosis/embryology , Scoliosis/genetics , Spine/abnormalities
10.
J Clin Invest ; 124(6): 2378-95, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24762436

ABSTRACT

Cord blood (CB) cells that express CD34 have extensive hematopoietic capacity and rapidly divide ex vivo in the presence of cytokine combinations; however, many of these CB CD34+ cells lose their marrow-repopulating potential. To overcome this decline in function, we treated dividing CB CD34+ cells ex vivo with several histone deacetylase inhibitors (HDACIs). Treatment of CB CD34+ cells with the most active HDACI, valproic acid (VPA), following an initial 16-hour cytokine priming, increased the number of multipotent cells (CD34+CD90+) generated; however, the degree of expansion was substantially greater in the presence of both VPA and cytokines for a full 7 days. Treated CD34+ cells were characterized based on the upregulation of pluripotency genes, increased aldehyde dehydrogenase activity, and enhanced expression of CD90, c-Kit (CD117), integrin α6 (CD49f), and CXCR4 (CD184). Furthermore, siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%. Compared with CB CD34+ cells, VPA-treated CD34+ cells produced a greater number of SCID-repopulating cells and established multilineage hematopoiesis in primary and secondary immune-deficient recipient mice. These data indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts.


Subject(s)
Epigenesis, Genetic , Fetal Blood/cytology , Fetal Blood/metabolism , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Animals , Antigens, CD34/metabolism , Culture Media, Serum-Free , Cytokines/pharmacology , Epigenesis, Genetic/drug effects , Fetal Blood/transplantation , Hematopoiesis/drug effects , Hematopoiesis/genetics , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/drug effects , Heterografts , Histone Deacetylase Inhibitors/pharmacology , Humans , Mice , Mice, SCID , RNA, Small Interfering/genetics , Thy-1 Antigens/metabolism , Valproic Acid/pharmacology
11.
Stem Cell Rev Rep ; 9(3): 303-12, 2013 Jun.
Article in English | MEDLINE | ID: mdl-22628110

ABSTRACT

Epicardial resident stem cells are known to differentiate into cardiomyocytes during cardiac development, amongst other cell types. Whether epicardium-derived progenitor cells (EPDCs) retain this plasticity in the adult heart has been the topic of heated scientific debate. Priming with thymosin beta 4, a peptide which has been suggested to be critical for cardiac development and to have cardio-protective properties, was recently shown to induce differentiation of EPDCs into cardiomyocytes in a small animal model of myocardial infarction. This finding is in stark contrast to another recent study in which thymosin beta 4 treatment following myocardial infarction did not induce cardiomyocyte differentiation of EPDCs. While EPDCs seem to exhibit overall cardio-protective effects on the heart following myocardial infarction, they have not been shown to differentiate into cardiomyocytes in a clinically relevant setting. It will be important to understand why the ability of one therapeutic agent to induce cardiomyocyte differentiation of EPDCs seemingly depends on a single variable, i.e. the time of administration. Furthermore, in light of a recent report, it appears that thymosin beta 4 may be dispensable for cardiac development.


Subject(s)
Cell Differentiation/drug effects , Myocardial Infarction/therapy , Regeneration/drug effects , Thymosin/pharmacology , Heart , Humans , Myocardium/cytology , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Stem Cell Transplantation , Stem Cells/drug effects , Stem Cells/metabolism
12.
Exp Hematol ; 40(7): 564-74, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22381681

ABSTRACT

Drug-induced thrombocytopenia often results from dysregulation of normal megakaryocytopoiesis. In this study, we investigated the mechanisms responsible for thrombocytopenia associated with the use of Panobinostat (LBH589), a histone deacetylase inhibitor with promising anti-cancer activities. The effects of LBH589 were tested on the cellular and molecular aspects of megakaryocytopoiesis by utilizing an ex vivo system in which mature megakaryocytes (MK) and platelets were generated from human primary CD34(+) cells. We demonstrated that LBH589 did not affect MK proliferation or lineage commitment but inhibited MK maturation and platelet formation. Although LBH589 treatment of primary MK resulted in hyperacetylation of histones, it did not interfere with the expression of genes that play important roles during megakaryocytopoiesis. Instead, we found that LBH589 induced post-translational modifications of tubulin, a nonhistone protein that is the major component of the microtubule cytoskeleton. We then demonstrated that LBH589 treatment induced hyperacetylation of tubulin and alteration of microtubule dynamics and organization required for proper MK maturation and platelet formation. This study provides new insights into the mechanisms underlying LBH589-induced thrombocytopenia and provides a rationale for using tubulin as a target for selective histone deacetylase inhibitor therapies to treat thrombocytosis in patients with myeloproliferative neoplasms.


Subject(s)
Blood Platelets/metabolism , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Megakaryocytes/metabolism , Protein Processing, Post-Translational/drug effects , Thrombopoiesis/drug effects , Tubulin/metabolism , Acetylation/drug effects , Blood Platelets/cytology , Cell Proliferation/drug effects , Cells, Cultured , Hematologic Neoplasms/diet therapy , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/pathology , Histone Deacetylase Inhibitors/adverse effects , Humans , Hydroxamic Acids/adverse effects , Indoles , Megakaryocytes/cytology , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/pathology , Panobinostat , Protein Processing, Post-Translational/physiology , Thrombocytopenia/chemically induced , Thrombocytopenia/metabolism , Thrombocytopenia/pathology , Thrombopoiesis/physiology
13.
Blood ; 117(17): 4580-9, 2011 Apr 28.
Article in English | MEDLINE | ID: mdl-21364187

ABSTRACT

The final stages of of megakaryocyte (MK) maturation involve a series of steps, including polyploidization and proplatelet formation. Although these processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton, the mechanisms responsible for regulation of MTs in MKs remain poorly defined. Stathmin is a highly conserved MT-regulatory protein that has been suggested to play a role in MK differentiation of human leukemic cell lines. However, previous studies defining this relationship have reached contradictory conclusions. In this study, we addressed this controversy and investigated the role of stathmin in primary human MKs. To explore the importance of stathmin down-regulation during megakaryocytopoiesis, we used a lentiviral-mediated gene delivery system to prevent physiologic down-regulation of stathmin in primary MKs. We demonstrated that sustained expression of constitutively active stathmin delayed cytoplasmic maturation (ie, glycoprotein GPIb and platelet factor 4 expression) and reduced the ability of MKs to achieve high levels of ploidy. Moreover, platelet production was impaired in MKs in which down-regulation of stathmin expression was prevented. These studies indicate that suppression of stathmin is biologically important for MK maturation and platelet production and support the importance of MT regulation during the final stages of thrombopoiesis.


Subject(s)
Blood Platelets/cytology , Megakaryocytes/physiology , Stathmin/genetics , Thrombopoiesis/physiology , Cells, Cultured , Cytoplasm/physiology , Down-Regulation/physiology , HEK293 Cells , Humans , Lentivirus/genetics , Megakaryocytes/cytology , Microtubules/physiology , Polyploidy , Stathmin/metabolism
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