Publications by authors named "Francisco Vega"

217 Publications

Mantle Cell Lymphoma Involving Tonsils: A Clinicopathologic Study of 83 Cases.

Hum Pathol 2021 Oct 13. Epub 2021 Oct 13.

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address:

We report 83 cases of mantle cell lymphoma (MCL) involving the tonsil as initial manifestation (IM). The median age at the time of tonsillar involvement was 58 years (range, 35 to 79 years). Most (85%) patients presented like acute tonsillitis. Lymphadenopathy (84%) and advanced stage of disease (81%) were frequent. With a median follow-up of 6.1 years (range, 0.5 to 18.4 years), the median overall survival (OS) was 11.3 years for all patients. Cases with classic MCL morphology demonstrated a superior overall survival (median OS: 11.7 years vs. 7.8 years for aggressive morphology, p=0.0361). Approximately 20% of patients had limited stage of disease and they had excellent outcome (median OS: not reached vs. 11.3 years for advanced-stage MCL, p=0.0479). All of the patients were alive after median follow-up of 6.6 years (range: 1 to 16.2 years). There were no differences in relapse free survival in morphology and stage (p>0.05). When tonsils were involved by relapsed MCL, patients less commonly had acute tonsillitis-like symptoms, lymphadenopathy and advanced stage of disease compared to MCL as initial manifestation. Patients in the relapse group had poorer OS compared to patients in the IM group from the time of tonsillar involvement by MCL to the date of death or last follow-up (7.8 vs. 11.7 years, p=0.003). Compared with a group of 93 patients whose initial biopsy specimen was a lymph node, patients whose initial biopsy specimen was tonsil had similar OS (11.7 vs. 8.8 years, p=0.1764). However, patients with tonsillar MCL more commonly had limited stage disease (19% vs. 8%, p=0.0385) and a low risk MIPI score (71% vs. 47%, p=0.0025).
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http://dx.doi.org/10.1016/j.humpath.2021.10.001DOI Listing
October 2021

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.

Mod Pathol 2021 Oct 9. Epub 2021 Oct 9.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.
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http://dx.doi.org/10.1038/s41379-021-00944-1DOI Listing
October 2021

Genetic profiling and biomarkers in peripheral T-cell lymphomas: current role in the diagnostic work-up.

Mod Pathol 2021 Sep 28. Epub 2021 Sep 28.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Peripheral T-cell lymphomas are a heterogeneous, and usually aggressive, group of mature T-cell neoplasms with overlapping clinical, morphologic and immunologic features. A large subset of these neoplasms remains unclassifiable with current diagnostic methods ("not otherwise specified"). Genetic profiling and other molecular tools have emerged as widely applied and transformative technologies for discerning the biology of lymphomas and other hematopoietic neoplasms. Although the application of these technologies to peripheral T-cell lymphomas has lagged behind B-cell lymphomas and other cancers, molecular profiling has provided novel prognostic and diagnostic markers as well as an opportunity to understand the biologic mechanisms involved in the pathogenesis of these neoplasms. Some biomarkers are more prevalent in specific T-cell lymphoma subsets and are being used currently in the diagnosis and/or risk stratification of patients with peripheral T-cell lymphomas. Other biomarkers, while promising, need to be validated in larger clinical studies. In this review, we present a summary of our current understanding of the molecular profiles of the major types of peripheral T-cell lymphoma. We particularly focus on the use of biomarkers, including those that can be detected by conventional immunohistochemical studies and those that contribute to the diagnosis, classification, or risk stratification of these neoplasms.
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http://dx.doi.org/10.1038/s41379-021-00937-0DOI Listing
September 2021

EZH2 expression is associated with inferior overall survival in mantle cell lymphoma.

Mod Pathol 2021 Aug 10. Epub 2021 Aug 10.

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.
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http://dx.doi.org/10.1038/s41379-021-00885-9DOI Listing
August 2021

A triple action CDK4/6-PI3K-BET inhibitor with augmented cancer cell cytotoxicity.

Cell Discov 2020 Jul 28;6(1):49. Epub 2020 Jul 28.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1038/s41421-020-0181-zDOI Listing
July 2020

EBV-positive HIV-associated diffuse large B cell lymphomas are characterized by JAK/STAT (STAT3) pathway mutations and unique clinicopathologic features.

Br J Haematol 2021 Sep 17;194(5):870-878. Epub 2021 Jul 17.

Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.

Even in the era of highly active combination antiretroviral therapy (cART), patients with HIV have a disproportionate risk of developing aggressive lymphomas that are frequently Epstein-Barr virus (EBV)-related. Here, we investigate HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) and compare EBV-positive and EBV-negative cases. HIV-DLBCL were identified from two academic medical centres and characterised by immunohistochemistry, EBV status, fluorescence in situ hybridisation, cell of origin determination by gene expression profiling, and targeted deep sequencing using a custom mutation panel of 334 genes. We also applied the Lymphgen tool to determine the genetic subtype of each case. Thirty HIV-DLBCL were identified, with a median patient age of 46 years and male predominance (5:1). Thirteen cases (48%) were EBV-positive and 14 (52%) EBV-negative. Nine of the 16 tested cases (56%) had MYC rearrangement, three (19%) had BCL6 (two of which were double hit MYC/BCL6) and none had BCL2 rearrangements. Using the Lymphgen tool, half of the cases (15) were classified as other. All HIV-DLBCL showed mutational abnormalities, the most frequent being TP53 (37%), MYC (30%), STAT3 (27%), HIST1H1E (23%), EP300 (20%), TET2 (20%), SOCS1 (17%) and SGK1 (17%). EBV-negative cases were mostly of germinal centre B-cell (GCB) origin (62%), showed more frequent mutations per case (a median of 13·5/case) and significant enrichment of TP53 (57% vs. 15%; P = 0·046), SGK1 (36% vs. 0%; P = 0·04), EP300 (43% vs. 0%; P = 0·02) and histone-modifying gene (e.g. HIST1H1E, HIST1H1D, 79% vs. 31%; P = 0·02) mutations. EBV-positive cases were mostly of non-GCB origin (70%), with fewer mutations per case (median 8/case; P = 0·007), and these tumours were enriched for STAT3 mutations (P = 0·10). EBV-positive cases had a higher frequency of MYC mutations but the difference was not significant (36% vs. 15%; P = 0·38). EBV-association was more frequent in HIV-DLBCLs, arising in patients with lower CD4 counts at diagnosis (median 46·5 vs. 101, P = 0·018). In the era of cART, approximately half of HIV-DLBCL are EBV-related. HIV-DLBCL are enriched for MYC rearrangements, MYC mutations and generally lack BCL2 rearrangements, regardless of EBV status. Among HIV-DLBCL, tumours that are EBV-negative and EBV-positive appear to have important differences, the latter arising in context of lower CD4 count, showing frequent non-GCB origin, lower mutation burden and recurrent STAT3 mutations.
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http://dx.doi.org/10.1111/bjh.17708DOI Listing
September 2021

Epstein-Barr-virus-positive large B-cell lymphoma associated with breast implants: an analysis of eight patients suggesting a possible pathogenetic relationship.

Mod Pathol 2021 Jul 5. Epub 2021 Jul 5.

Department of Myeloma and Lymphoma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.
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http://dx.doi.org/10.1038/s41379-021-00863-1DOI Listing
July 2021

Aggressive Mediastinal Lymphomas.

Semin Diagn Pathol 2021 Jun 16. Epub 2021 Jun 16.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

The mediastinum contains essentially all major intrathoracic organs except for the lungs. A variety of both benign and malignant tumors can involve the mediastinum, of which lymphoma is the most common malignancy. Compared to secondary mediastinal involvement by systemic lymphomas, primary mediastinal lymphomas are less common with several specific entities that are mainly confined to mediastinal lymph nodes, and/or thymus. This review will summarize the clinical, histologic, immunophenotypic and molecular genetic features of the most common and most aggressive primary mediastinal lymphomas as well as provide suggested immunohistochemistry panels and differential diagnoses.
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http://dx.doi.org/10.1053/j.semdp.2021.06.010DOI Listing
June 2021

From the archives of MD Anderson Cancer Center: Concurrent BCR-ABL1 and CRLF2 rearrangements in B-lymphoblast phase of chronic myeloid leukemia.

Ann Diagn Pathol 2021 Aug 5;53:151767. Epub 2021 Jun 5.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.

The t(9;22)(q34;q11.2), also known as the Philadelphia (Ph) chromosome, results in BCR-ABL1 fusion residing on the derivative chromosome 22. This translocation is characteristic of chronic myeloid leukemia, but also can occur in a substantial subset of B acute lymphoblastic leukemia (B-ALL) cases. Ph-like B-ALL has a gene expression profile similar to that of BCR-ABL1 positive/Ph-positive B-ALL, but by definition Ph-like B-ALL does not have the sentinel BCR-ABL1 or the Ph chromosome. About half of Ph-like B-ALL cases carry CRLF2 rearrangements. Rare cases of de novo B-ALL with co-occurrence of BCR-ABL1 and CRLF2 rearrangements have been described. To our knowledge, this is the first report of concurrent BCR-ABL1 and CRLF2 rearrangements in blast phase of chronic myeloid leukemia. In this patient, CRLF2 rearrangement was acquired at the time of disease progression to B-lymphoblast phase of chronic myeloid leukemia. We also review the literature and discuss the distinct clinicopathologic, and genomic characteristics of CRLF2 rearranged B-ALL.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151767DOI Listing
August 2021

Unexpected Primary Extranodal Marginal Zone Lymphoma of Bone in Amputation and Arthroplasty Specimens.

Am J Clin Pathol 2021 Jun 2. Epub 2021 Jun 2.

Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.

Objectives: Amputation due to gangrene and arthroplasty for degenerative joint disease are common orthopedic procedures and are expected to increase as populations age. Histopathologic examination of these specimens can identify unsuspected diseases.

Methods: We reviewed gangrenous amputations and large joint arthroplasty specimens for diagnosis of unexpected lymphoma, January 2014 to January 2020. Pathology and medical records were reviewed to determine diagnosis, treatment, and outcome.

Results: Five cases (0.08%) of unexpected primary extranodal marginal zone lymphoma (MZL) centered in bone were identified in 1,624 amputations for gangrene and 4,163 arthroplasty specimens. The female-to-male distribution was 3:2. Median age was 71 years (range, 62-87). The 3 cases arising in the setting of gangrene involved the first toe phalanges and metatarsals, and the femoral head was involved in all cases of joint disease (2 cases). The bone showed variable (10%-80%) infiltration by dense populations of small lymphoid cells with MZL immunophenotype. One patient died from sepsis 18.5 months after diagnosis; all others are alive with a median follow-up of 27.45 months.

Conclusions: Histopathologic examination of nonneoplastic orthopedic specimens identifies unexpected primary bone extranodal MZL in a small percentage of cases. This neoplasm may be the result of chronic antigenic stimulation in some circumstances.
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http://dx.doi.org/10.1093/ajcp/aqab067DOI Listing
June 2021

Treatment of Miller I Mandibular Gingival Recessions Using PRF vs. Connective Graft.

Int J Dent 2021 8;2021:6616688. Epub 2021 Apr 8.

Grupo de Investigación en Salud Oral, Facultad de Odontología, Posgrado en Periodoncia, Universidad Antonio Nariño, Bogotá, Colombia.

Gingival recession (GR) can cause aesthetic and functional problems. Using connective tissue graft (CTG) and coronally advanced flap (CAF) is considered the technique of choice for treating GR. Considering the morbidity resulting from taking CTG, different alternative biomaterials have been described, including plasma-rich fibrin (PRF) membrane. Studies in lower teeth are few because of the complexity of the factors that can influence obtaining less predictable outcomes. . To compare between CAF + PRF and CAF + CTG in the treatment of lower teeth Miller I gingival recession. . Split-mouth included 26 isolated GR (13 in each side of the mouth). The left side was treated with CAF + PRF and the right side with CAF + CTG. Clinical variables, probing depth (PD), GR, keratinized tissue (KT), vestibular soft tissue thickness (VSTT), and teeth sensitivity (TS), were assessed at the baseline. GR, KT, VSTT, extraoral inflammation (EI), and patient discomfort (PaD) were assessed at 45 days. . Statistically greater VSTT at 45 days was obtained using CAF + CTG ( < 0.05). Less EI and PaD were obtained using CAF + PRF ( < 0.05). No change was observed in GR, KT, and TS values in the intergroup or intragroup comparisons. . Even with the limitations of this study, using PRF and CTG in lower teeth demonstrated an improvement in terms of root coverage, although it was without a total percentage of coverage. Regarding the VSTT, better results were obtained using the CTG + CAF, suggesting eventually long-term stable clinical results. We suggest a combined technique for future investigations.
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http://dx.doi.org/10.1155/2021/6616688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053044PMC
April 2021

Non-Canonical Kinases and Substrates in Cancer Progression.

Authors:
Francisco M Vega

Cancers (Basel) 2021 Apr 1;13(7). Epub 2021 Apr 1.

Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, 41012 Seville, Spain.

Cellular protein kinases remain the target of choice when the intention is to intervene in a particular signaling pathway leading to cancer progression [...].
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http://dx.doi.org/10.3390/cancers13071628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037056PMC
April 2021

Targeted based therapy in nodal T-cell lymphomas.

Leukemia 2021 04 4;35(4):956-967. Epub 2021 Mar 4.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

T-cell lymphomas (TCL) are a group of biologically and clinically heterogenous neoplasms derived from mature T lymphocytes. Recent findings in biology have advanced the classification of these neoplasms; however, clinical investigations based on biologic features have yet to be designed. Two biomarker-driven treatments for TCL are promising: brentuximab vedotin (BV) in combination with chemotherapy or as monotherapy is the standard treatment for newly diagnosed CD30-positive TCL and relapsed/refractory anaplastic large cell lymphoma (ALCL), while ALK inhibitors have induced responses in ALK+ ALCLs. Common genetic alterations in TCL, such as aberrations in PI3K/mTOR, JAK/STAT, and epigenetic regulators are also targetable by pathway inhibitors and HDAC/DNMT inhibitors; however, responses to these treatments as monotherapy are neither satisfactory nor durable, even in patients pre-stratified by several biomarkers. Additional work is needed to extend biology/biomarker-driven treatment in these neoplasms. As T-cell lymphomagenesis is multistep and multifactorial, trials are ongoing to evaluate combination treatments. The focus of this article is to summarize the status and the current role of targeted-based therapy in nodal TCL.
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http://dx.doi.org/10.1038/s41375-021-01191-8DOI Listing
April 2021

Is immunohistochemical expression of GATA3 helpful in the differential diagnosis of transformed mycosis fungoides and primary cutaneous CD30-positive T cell lymphoproliferative disorders?

Virchows Arch 2021 Aug 18;479(2):377-383. Epub 2021 Feb 18.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.
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http://dx.doi.org/10.1007/s00428-021-03056-yDOI Listing
August 2021

The uracil-DNA glycosylase UNG protects the fitness of normal and cancer B cells expressing AID.

NAR Cancer 2020 Sep 27;2(3):zcaa019. Epub 2020 Aug 27.

Institut de Recherches Cliniques de Montréal, 110 Av des Pins Ouest, Montréal, QC H2W 1R7, Canada.

In B lymphocytes, the uracil N-glycosylase (UNG) excises genomic uracils made by activation-induced deaminase (AID), thus underpinning antibody gene diversification and oncogenic chromosomal translocations, but also initiating faithful DNA repair. mice develop B-cell lymphoma (BCL). However, since UNG has anti- and pro-oncogenic activities, its tumor suppressor relevance is unclear. Moreover, how the constant DNA damage and repair caused by the AID and UNG interplay affects B-cell fitness and thereby the dynamics of cell populations is unknown. Here, we show that UNG specifically protects the fitness of germinal center B cells, which express AID, and not of any other B-cell subset, coincident with AID-induced telomere damage activating p53-dependent checkpoints. Consistent with AID expression being detrimental in UNG-deficient B cells, mice develop BCL originating from activated B cells but lose AID expression in the established tumor. Accordingly, we find that UNG is rarely lost in human BCL. The fitness preservation activity of UNG contingent to AID expression was confirmed in a B-cell leukemia model. Hence, UNG, typically considered a tumor suppressor, acquires tumor-enabling activity in cancer cell populations that express AID by protecting cell fitness.
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http://dx.doi.org/10.1093/narcan/zcaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848951PMC
September 2020

Tertiary lymphoid structures with overlapping histopathologic features of cutaneous marginal zone lymphoma during neoadjuvant cemiplimab therapy are associated with antitumor response.

J Cutan Pathol 2021 May 13;48(5):674-679. Epub 2021 Jan 13.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

The development of immune checkpoint inhibitor (ICI) therapy with anti-CTLA-4 and anti-PD-1/L1 monoclonal antibodies has led to a paradigm shift in cancer therapy. ICI neoadjuvant therapy followed by surgery has become the standard of care for several advanced-stage cancers. The pathology associated with ICI therapy is vast and includes neoadjuvant-associated tissue reactions and activation of tertiary lymphoid structures (TLSs) at the site of the tumor bed and off-target immune-related adverse events. TLSs are thought to recapitulate lymph node function and may act as localized immune machinery to mount an antitumor response. B-cell activation in TLSs during neoadjuvant ICI therapy has been correlated with antitumor response. We report a patient with a history of sarcomatoid squamous cell carcinoma treated with neoadjuvant ICI cemiplimab who developed clonal expansion of B-cells in the TLSs of the tumor bed. The TLSs morphologically mimicked a cutaneous marginal zone lymphoma with plasmacytic differentiation. Awareness of clonal expansion of B-cells in TLSs during neoadjuvant ICI therapy is critical to recognize a response to ICI therapy and to avoiding an incorrect diagnosis of low-grade B-cell lymphoma.
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http://dx.doi.org/10.1111/cup.13953DOI Listing
May 2021

Disseminated ALK-positive histiocytosis with fusion in an adult.

Leuk Lymphoma 2021 05 22;62(5):1234-1238. Epub 2020 Dec 22.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1080/10428194.2020.1861273DOI Listing
May 2021

Expression of BCL2 alternative proteins and association with outcome in CLL patients treated with venetoclax.

Leuk Lymphoma 2021 05 17;62(5):1129-1135. Epub 2020 Dec 17.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Venetoclax, a BCL-2 inhibitor, is highly effective for the treatment of patients with chronic lymphocytic leukemia (CLL) and dependence on alternative proteins may result in resistance to BCL-2 inhibition. Patients with CLL treated with venetoclax as monotherapy at MD Anderson Cancer Center between 05/2012 and 01/2016 were included and pretreatment bone marrow was analyzed by immunohistochemistry (IHC) for BCL-W, BCL-XL, BCL2-A1 and MCL-1. Twenty-seven patients were included. BCL-W + and BCL-2A1+ was found in 15% and 7% of the patients, respectively. Both BCL-XL and MCL-1 were negative in all samples. A higher CR and longer PFS rates were observed in patients with BCL-W+ ( = .60,  = .46), BCL-2A1+ ( = .60,  = .29), and either BCL-W + or BCL-2A1+ ( = .33,  = .20), though not statistically significant. Pretreatment IHC expression of BCL-2 alternative proteins does not predict response to venetoclax in CLL, but may be a surrogate for an indolent biology. Sensitive techniques are needed to explore anti-apoptotic pathways.
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http://dx.doi.org/10.1080/10428194.2020.1861278DOI Listing
May 2021

Expression of germinal center cell markers by extranodal marginal zone lymphomas of MALT type within colonized follicles, a diagnostic pitfall with follicular lymphoma.

Leuk Lymphoma 2021 05 7;62(5):1116-1122. Epub 2020 Dec 7.

Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL, USA.

We reviewed 341 consecutive cases of marginal zone lymphoma (MZL) (47) or follicular lymphoma (FL) (294) of which 7 were difficult to distinguish due to perceived coexpression of BCL6 and BCL2 by tumor cells in follicular foci. This stimulated us to develop dual BCL6/BCL2 immunohistochemistry, allowing us to assess coexpression among individual cells. Dual staining confirmed coexpression in 6 of 7 cases, all extranodal MZL (ENMZL) based on overall features and representing 13% of MZL in this series. These findings confirm that MZL cells have plasticity regarding protein expression within the germinal center (GC) microenvironment, an important diagnostic pitfall. Intriguingly, in all MZL expressing BCL6, non-neoplastic GC B cells within colonized follicles showed diminished or absent CD10 expression but preserved BCL6 and high ki67. This finding suggests plasticity of CD10 expression in non-neoplastic GC B cells in the context of colonization by MZL, possibly related to NF-kB dysregulation.
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http://dx.doi.org/10.1080/10428194.2020.1855347DOI Listing
May 2021

Identification of VRK1 as a New Neuroblastoma Tumor Progression Marker Regulating Cell Proliferation.

Cancers (Basel) 2020 Nov 20;12(11). Epub 2020 Nov 20.

Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain.

Neuroblastoma (NB) is one of the most common pediatric cancers and presents a poor survival rate in affected children. Current pretreatment risk assessment relies on a few known molecular parameters, like the amplification of the oncogene MYCN. However, a better molecular knowledge about the aggressive progression of the disease is needed to provide new therapeutical targets and prognostic markers and to improve patients' outcomes. The human protein kinase VRK1 phosphorylates various signaling molecules and transcription factors to regulate cell cycle progression and other processes in physiological and pathological situations. Using neuroblastoma tumor expression data, tissue microarrays from fresh human samples and patient-derived xenografts (PDXs), we have determined that VRK1 kinase expression stratifies patients according to tumor aggressiveness and survival, allowing the identification of patients with worse outcome among intermediate risk. VRK1 associates with cell cycle signaling pathways in NB and its downregulation abrogates cell proliferation in vitro and in vivo. Through the analysis of ChIP-seq and methylation data from NB tumors, we show that VRK1 is a MYCN gene target, however VRK1 correlates with NB aggressiveness independently of MYCN gene amplification, synergizing with the oncogene to drive NB progression. Our study also suggests that VRK1 inhibition may constitute a novel cell-cycle-targeted strategy for anticancer therapy in neuroblastoma.
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http://dx.doi.org/10.3390/cancers12113465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699843PMC
November 2020

MYC expression is associated with older age, common morphology, increased MYC copy number, and poorer prognosis in patients with ALK+ anaplastic large cell lymphoma.

Hum Pathol 2021 02 19;108:22-31. Epub 2020 Nov 19.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

The role of MYC dysregulation has been studied extensively in B-cell lymphomas, but little is known about its significance in T cell lymphomas. This study, for the first time in the literature, assessed the clinicopathologic and prognostic significance of MYC expression in ALK+ anaplastic large cell lymphoma (ALCL) cases. Using ≥50% as the cutoff value for positive MYC expression by immunohistochemistry, 17 of 46 (37%) cases were MYC+. Patients with MYC+ tumors were older (median age, 39 versus 29 years, p = 0.04) and more often showed a common morphologic pattern (100% versus 69%, p = 0.02), when compared with those with MYC-negative tumors. By fluorescence in situ hybridization analysis, 9 of 31 (29%) cases showed increased MYC copy number, and 1 of 31 (3%) case had an MYC rearrangement, and the remaining 21 (68%) cases showed no MYC aberrations. Among the cases with increased MYC copy number, 5 of 8 (62%) cases showed MYC copy gain and/or amplification and 3 of 8 (38%) had polysomy 8. MYC expression was associated with increased MYC copy number (p = 0.01). MYC expression, but not increased MYC copy number, correlated with shorter overall survival (OS) (p = 0.03). In conclusion, MYC expression identified a distinct group of ALK + ALCL patients with more aggressive behavior and shorter OS. Our data suggest that MYC expression is an adverse prognostic factor and may be useful in stratifying or predicting the prognosis of patients with ALK+ ALCL.
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http://dx.doi.org/10.1016/j.humpath.2020.11.002DOI Listing
February 2021

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma with MYC rearrangement.

Br J Haematol 2021 01 20;192(1):e17-e21. Epub 2020 Nov 20.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1111/bjh.17169DOI Listing
January 2021

Optimized Doxorubicin Chemotherapy for Diffuse Large B-cell Lymphoma Exploits Nanocarrier Delivery to Transferrin Receptors.

Cancer Res 2021 02 11;81(3):763-775. Epub 2020 Nov 11.

Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.

New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon-nitride dots (CND) are emerging nanoparticles with excellent stability and distribution and are adaptable to covalent conjugation with multiple substrates. , linking doxorubicin (Dox) and transferrin (TF) to CND (CND-Dox-TF, CDT) was 10-100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer , and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL. SIGNIFICANCE: Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2674DOI Listing
February 2021

Unmasking a T cell lymphoma: Folliculotropic mycosis fungoides with a gamma-delta phenotype.

JAAD Case Rep 2020 Dec 23;6(12):1316-1319. Epub 2020 Sep 23.

Department of Dermatology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1016/j.jdcr.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510555PMC
December 2020

American Registry of Pathology Expert Opinions: Recommendations for the diagnostic workup of mature T cell neoplasms.

Ann Diagn Pathol 2020 Dec 13;49:151623. Epub 2020 Sep 13.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.

The diagnosis of T-cell lymphomas is highly challenging and requires an integrated approach in which clinical, morphologic, immunophenotypic and molecular data are incorporated into the diagnosis. Under the auspices of the American Registry of Pathology, the authors met to discuss this topic with the goal to provide practical and useful recommendations for pathologists when evaluating T-cell lymphomas. In this review, we discuss the diagnostic findings and workup for the various types of nodal T-cell lymphoma including anaplastic large cell lymphoma, nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), and PTCL with a T follicular helper (TFH) phenotype. We review clinicopathologic and immunophenotypic features (including flow cytometry panels) helpful in the differential diagnosis of mature T-cell lymphomas presenting in the peripheral blood and bone marrow, and we discuss some of the more common extranodal-based T-cell lymphomas including extranodal natural killer/T-cell lymphoma of nasal and non-nasal type, gamma delta T cell lymphomas, and aggressive and indolent T- and NK-lymphoproliferative disorders involving the gastrointestinal tract. Mycosis fungoides and most other cutaneous T-cell lymphomas are not the focus of this review, although the differential diagnosis of Sezary syndrome from mycosis fungoides is covered. We do not intend for these recommendations to be anything other than suggestions that will hopefully spur on additional discussion, and perhaps eventually evolve into a consensus approach for the workup of T-cell lymphomas.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151623DOI Listing
December 2020

Pathology and Pathogenesis of T-Cell Lymphoma.

Authors:
Francisco Vega

Clin Lymphoma Myeloma Leuk 2020 09;20 Suppl 1:S89-S93

Department of Hematopathology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas, 77030, US. Electronic address:

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 diagnostic criteria, more effective risk assessment, and potentially to better treatments for these neoplasms.
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http://dx.doi.org/10.1016/S2152-2650(20)30474-2DOI Listing
September 2020
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