Deborah Fuchs

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• Menghani, S. V., Diaz-Hanson, J. P., Heimbigner, A., Wakefield, C., Fuchs, D., Reveles, C. Y., Spier, C., Amaraneni, A., & Kumar, A. (2023). Peripheral T-Cell Lymphoma in a Patient Previously Diagnosed With Sarcoidosis. Journal of hematology, 12(6), 272-276.
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  Sarcoidosis is a multisystem disorder characterized by granulomatous inflammation on histopathological evaluation. Diagnosis of sarcoidosis requires thorough elimination of malignancy and alternative causes of noncaseating granulomatous inflammation. Sarcoidosis and several subtypes of lymphoma have similar clinical presentations and can potentially have similar histopathological findings. Patients with a histopathology-confirmed diagnosis of sarcoidosis are at higher risk of developing malignancies. In this report, we present a case of a 64-year-old male diagnosed with sarcoidosis 2 years before presenting to the emergency department with a 4-month history of generalized weakness, cough, and very high fever. After a thorough workup involving cervical lymph node biopsy and bone marrow biopsy, he was diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Due to the patient's current lymphoma diagnosis and features noted on pathology, a retrospective review of the prior biopsy specimen was performed, finding similar hematopathological features on both initial lymph node biopsy diagnosing sarcoidosis and current biopsies diagnosing lymphoma. Given these findings, our patient likely had early manifestation of PTCL misdiagnosed as sarcoidosis. In summary, lymphoma should be considered in all patients with suspected sarcoidosis, especially those who do not respond to treatment or who present with persistent hematological abnormalities.
• Wu, C., Manchen, P., Edelman, A., Husnain, M., Katsanis, E., Fuchs, D., Stephens, L., & Khurana, S. (2023). Refractory Pure Red Blood Cell Aplasia Secondary to Major ABO-Incompatible Allogeneic Stem Cell Transplantation Successfully Treated With Daratumumab. Journal of hematology, 12(6), 277-282.
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  Pure red cell aplasia (PRCA) is a rare hematologic phenomenon that is usually associated with inherited genetic mutations such as in Diamond-Blackfan anemia. However, due to the emergence of allogenic stem cell transplantation in the treatment of various malignant and non-malignant disorders, the incidence of PRCA has increased. PRCA following hematopoietic stem cell transplant (HSCT) is more commonly seen in the setting of a major ABO-incompatible transplant. Treatment of allo-HSCT induced PRCA can be initially supportive as it takes time for the bone marrow to fully recover. However, prolonged and/or failure of the bone marrow to recover, significantly increases patient's risk of iron overload in the setting of frequent transfusions. Iron deposition can potentially lead to severe life-threatening multiorgan involvement which can be fatal. Therefore, earlier recognition and intervention with immunomodulators in patients who undergo frequent transfusions can be beneficial to mitigate this risk. Here, we present a case with severe transfusion-dependent PRCA following major ABO-incompatible allo-HSCT successfully treated with daratumumab.
• Dagar, M., Starobinska, E., Obert, M., Girard, N., Fuchs, D., Dagar, M., Bilal, J., & Ashoka, A. (2021). A Case of Paraneoplastic Pemphigus with Follicular Dendritic Cell Sarcoma.. The American journal of medicine, 134(8), 980-982. doi:10.1016/j.amjmed.2021.01.028
• Spier, C. M., Otsuji, J., Lai, L., Girard, N., & Fuchs, D. (2021). Sibling donor-derived myeloid sarcoma after hematopoietic stem cell transplant. Human Pathology: Case Reports, 24. doi:10.1016/j.ehpc.2021.200512
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  Abstract Donor-derived myeloid sarcoma (DDMS) is a rare complication which occurs when donor stem cells undergo leukemic transformation. We report here two cases of DDMS following successful allogenic hematopoietic stem cell transplant (allo-HSCT) from HLA-identical, sex-mismatched sibling donors. Both were males in their fourth decade of life and originally diagnosed in 2012 with acute myeloid leukemia (AML) with t(6;11)(q27;q23) and AML with myelodysplasia-related changes (AML-MRC), respectively. They went onto allo-HSCT from their respective haploidentical sisters as donors and achieved complete engraftment in 2014. Both were in remission until 2019 when they were diagnosed with clinical relapse of AML in the setting of DDMS, one presenting in bilateral tibiae and the other in the testis. Verifying donor origin in AML relapse is critical as transformed donor cells may have different genetic alterations and behaviors from initial AML. We reviewed the literature of donor derived myeloid sarcoma and discussed the pathogenesis of this rare late complication of HSCT.
• Russell, S. J., Duran, J., Fuchs, D., & Yeager, A. M. (2019). Atypical CD4/CD8 Lymphocytosis and Prolonged Pancytopenia Associated With Human Herpesvirus 6 Reactivation After Autologous Peripheral Blood Stem Cell Transplantation. Clinical lymphoma, myeloma & leukemia, 19(8), 531-535.
• Adams, T., Fuchs, D., Shadoan, P. K., Johnstone, L., Lau, B. M., McGhan, L., Anwer, F., & Al-Kateb, H. (2018). Unexpected favorable outcome in a patient with high grade B-cell lymphoma with abnormalities of MYC, BCL6 and BCL2 loci. Cancer genetics, 222-223, 25-31.
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  High grade B-cell lymphoma (HGBCL) by WHO 2016 classification requires rearrangements of MYC and BCL2 and/or BCL6, practically covering the so called "double-hit" or "triple hit" lymphomas. We report a case of HGBCL "triple-hit" lymphoma in a 64-year old female. Cytogenetic and fluorescence in situ hybridization (FISH) studies revealed complex karyotype including rearrangement of MYC to a novel, non-IG partner on chromosome 18, and rearrangement of BCL2, BCL6 and IGH as well as ins(3)(q21q27.3q25.1) among other abnormalities. FISH studies showed five copies of MYC and 3-8 copies of BCL2. Gene expression analysis by RNA sequencing showed that MYC, BCL2 and MECOM genes were overexpressed whereas BCL6 was under-expressed. BCL6 was fused to MBNL1 gene due to complex structural rearrangement. MYC was expressed in >70% of cells and BCL2 was diffusely but highly expressed by immunohistochemistry. No pathogenic mutations were identified by sequencing a 26-gene panel including TP53. The patient has unexpectedly been in complete remission for 12 months after diagnosis after intensive chemotherapy including DA-EPOCH regimen despite having HGBCL. The prognostication of HGBCL patients may further be improved by the sub-categorization of these lymphomas on the basis of more detailed genomic markers than merely the WHO 2016 classification.
• Elagib, K. E., Lu, C. H., Mosoyan, G., Khalil, S., Zasadzińska, E., Foltz, D. R., Balogh, P., Gru, A. A., Fuchs, D. A., Rimsza, L. M., Verhoeyen, E., Sansó, M., Fisher, R. P., Iancu-Rubin, C., & Goldfarb, A. N. (2017). Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition. The Journal of Clinical investigation, 127(6), 2365-2377.
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  Hematopoietic transitions that accompany fetal development, such as erythroid globin chain switching, play important roles in normal physiology and disease development. In the megakaryocyte lineage, human fetal progenitors do not execute the adult morphogenesis program of enlargement, polyploidization, and proplatelet formation. Although these defects decline with gestational stage, they remain sufficiently severe at birth to predispose newborns to thrombocytopenia. These defects may also contribute to inferior platelet recovery after cord blood stem cell transplantation and may underlie inefficient platelet production by megakaryocytes derived from pluripotent stem cells. In this study, comparison of neonatal versus adult human progenitors has identified a blockade in the specialized positive transcription elongation factor b (P-TEFb) activation mechanism that is known to drive adult megakaryocyte morphogenesis. This blockade resulted from neonatal-specific expression of an oncofetal RNA-binding protein, IGF2BP3, which prevented the destabilization of the nuclear RNA 7SK, a process normally associated with adult megakaryocytic P-TEFb activation. Knockdown of IGF2BP3 sufficed to confer both phenotypic and molecular features of adult-type cells on neonatal megakaryocytes. Pharmacologic inhibition of IGF2BP3 expression via bromodomain and extraterminal domain (BET) inhibition also elicited adult features in neonatal megakaryocytes. These results identify IGF2BP3 as a human ontogenic master switch that restricts megakaryocyte development by modulating a lineage-specific P-TEFb activation mechanism, revealing potential strategies toward enhancing platelet production.
• Duncan, J., Chen, Y., Fuchs, D., Cantu, C., & Wang, M. (2016). Follicular Lymphoma Presenting Solely as Chronic Follicular Conjunctivitis. Cornea, 35(3), 395-8.
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  Conjunctival lymphoma rarely can have atypical clinical presentations. The authors report a case of conjunctival follicular lymphoma that presented solely as bilateral chronic follicular conjunctivitis. This case underscores that the pathological characteristics of conjunctival follicles can only be determined by histopathologic examination.
• Taverna, J., Nair, A., Yun, S., Paulson, S., Schatz, J. H., Persky, D., Fuchs, D., & Puvvada, S. (2014). A rare presentation of in situ mantle cell lymphoma and follicular lymphoma: a case report and review of the literature. Case reports in hematology, 2014, 145129.
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  A 65-year-old gentleman presented with left groin swelling over the course of two months. Physical exam revealed nontender left inguinal adenopathy, and computed tomography scans detected multiple lymph nodes in the mesenteric, aortocaval, and right common iliac regions. An excisional lymph node biopsy was performed. Pathologic evaluation demonstrated follicular center site which stained positive for PAX5, CD20, CD10, Bcl-2, Bcl-6, and mantle zone cells. These findings demonstrated CCND1 and CD5 positivity, suggesting composite lymphoma comprising follicular lymphoma (FL) with in situ mantle cell lymphoma (MCLIS). FL is known as indolent non-Hodgkin lymphoma; however, the clinical significance of a coexisting MCLIS continues to be elusive, and optimal management of these patients remains largely unknown. This case illustrates the diagnostic and therapeutic challenges of composite lymphomas. This paper also discusses advances in molecular pathogenesis and lymphoma genomics which offer novel insights into these rare diseases.
• Gorlitsky, B. R., Zangeneh, T., Fuchs, D., & Cox, C. (2013). Fifty, febrile, and fatigued: high ferritin as a clue in diagnosis. The American journal of medicine, 126(11), e3-4.
• Fuchs, D. A., McGinn, S. G., Cantu, C. L., Klein, R. R., Sola-Visner, M. C., & Rimsza, L. M. (2012). Developmental differences in megakaryocyte size in infants and children. American journal of clinical pathology, 138(1), 140-5.
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  Developmental differences in megakaryocytes between neonates and adults have been described. However, the age at which megakaryocytes make a transition to an adult phenotype is unknown. Small megakaryocytes are often described as "dysplastic" in the pathology literature. Thus, recognizing the normal features of megakaryocytes at different ages has diagnostic implications. We identified 72 samples from 61 patients, aged 3 days to 80 years, who had negative staging based on bone marrow examination. Megakaryocyte diameters, as highlighted with anti-CD61, were measured. A scatter plot of megakaryocyte size by age revealed a normal distribution of sizes at the youngest ages, with a shift to multiple peaks starting at 24 months indicating that neonates have megakaryocytes of uniform sizes, which diverge into separate clusters of smaller and larger cells beginning at 2 years; this is followed by an overall shift toward larger megakaryocytes at age 4 years. These observations have direct implications for the evaluation of bone marrow megakaryocytes in young children.
• Bartley, A. N., Nelson, C. L., Nelson, D. H., & Fuchs, D. A. (2007). Disseminated extramedullary myeloid tumor of the gallbladder without involvement of the bone marrow. American journal of hematology, 82(1), 65-8.
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  Extramedullary myeloid tumors (myeloid sarcomas) are rare neoplasms that are composed of myeloid precursors. They usually arise concurrently with a diagnosis of acute myeloid leukemia, chronic myeloid leukemia, or other myeloproliferative disorders. They may also indicate relapsing disease in a patient with a prior history of leukemia or myeloproliferative disorder. We present our findings of a 63-year-old female diagnosed with extramedullary myeloid tumor first presenting in the gallbladder. She subsequently developed respiratory failure; pre- and postmortem bone marrow studies were negative for leukemia by morphology, flow cytometry, and karyotypic analysis. However, the myeloid neoplasm was disseminated throughout most of her remaining organs. Immunohistochemical stains of the cells indicated a neoplasm of myelomonocytic derivation (CD4, CD43, CD45, CD68, myeloperoxidase, and lysozyme positive). To our knowledge, this is the first report of an extramedullary myeloid neoplasm of the gallbladder with disseminated disease without involvement of the bone marrow.
• Cohen-Barak, O., Erickson, D. T., Badowski, M. S., Fuchs, D. A., Klassen, C. L., Harris, D. T., & Brilliant, M. H. (2007). Stem cell transplantation demonstrates that Sox6 represses epsilon y globin expression in definitive erythropoiesis of adult mice. Experimental hematology, 35(3), 358-67.
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  Sox6, a member of the Sox transcription factor family, is essential for the silencing of epsilon y globin gene expression in definitive erythropoiesis of mice. Homozygous Sox6-null mice are neonatally lethal, precluding analysis at later stages. We created adult mice that are deficient in Sox6 specifically in hematopoietic tissues by transplanting embryonic liver stem cells from Sox6-deficient mice into lethally irradiated congenic wild-type adult mice. The mice receiving mutant stem cells (mutant engrafted) showed high expression levels of epsilon y in bone marrow, spleen, and circulating blood compared with mice receiving wild-type and heterozygous stem cells (control engrafted). The level of expression of epsilon y in circulating blood was directly correlated with the percentage of successful mutant donor cell engraftment. Additionally, the mutant engrafted adult mice showed an increase in erythroid precursor cells in bone marrow, spleen, and blood. Thus, Sox6 continues to function as a major regulator of epsilon y in adult definitive erythropoiesis and is required for normal erythrocyte maturation. Therefore, Sox6 may provide a novel therapeutic target by reactivating epsilon y in patients with hemoglobinopathies such as sickle cell anemia and beta-thalassemia.
• Ignatz, M., Sola-Visner, M., Rimsza, L. M., Fuchs, D., Shuster, J. J., Li, X., Jotwani, A., Staba, S., Wingard, J. R., Hu, Z., & Slayton, W. B. (2007). Umbilical cord blood produces small megakaryocytes after transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 13(2), 145-50.
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  Delayed platelet engraftment is a major complication of umbilical cord blood (CB) transplantation. Megakaryocytes derived from CB in vitro are smaller than megakaryocytes derived from bone marrow (BM) or mobilized peripheral blood from adults. Small megakaryocyte size may contribute to delayed platelet engraftment. To test whether small size persists after transplantation, we measured megakaryocyte size, concentration, and maturational stage in BM biopsy specimens obtained after transplantation in archived BM samples from patients receiving CB (CB group, n = 10) versus mobilized peripheral blood or BM transplantation (BM group, n = 9). Megakaryocytes in the postengraftment BM samples were significantly smaller in the CB group than in the BM group (median diameter, 16.7 vs 22.0 microm). There were no significant differences in megakaryocyte concentration or maturational stage between the CB and BM groups. For the first time, we demonstrate that the attainment of adult size in CB-derived megakaryocytes is delayed after human CB transplantation.
• Rimsza, L. M., Farinha, P., Fuchs, D. A., Masoudi, H., Connors, J. M., & Gascoyne, R. D. (2007). HLA-DR protein status predicts survival in patients with diffuse large B-cell lymphoma treated on the MACOP-B chemotherapy regimen. Leukemia & lymphoma, 48(3), 542-6.
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  Loss of major histocompatibility class II (MHC class II) molecules on diffuse large B-cell lymphoma (DLBCL) has been associated with poor survival; however, none of these reports analysed a uniformly treated patient cohort. This study was designed to validate one MHC class II antigen, HLA-DR, as a prognostic marker in patients uniformly treated with the MACOP-B regimen. Immunostaining results were correlated with the international prognostic index (IPI) score and overall survival (OS). Of the 97 cases, 82 had interpretable staining. Of these, 52 expressed HLA-DR (median OS, 16.2 years) while 30 were negative (median OS, 4.2 years, P = 0.037). The IPI was also predictive of OS in the study group (P = 0.023). A Cox multivariate model established both IPI (P = 0.031) and HLA-DR (P = 0.04) as independent predictors of OS. This is the first demonstration of the prognostic relevance of HLA-DR in a uniformly treated DLBCL patient group.
• Mahadevan, D., DiMento, J., Croce, K. D., Riley, C., George, B., Fuchs, D., Mathews, T., Wilson, C., & Lobell, M. (2006). Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemia. American journal of hematology, 81(10), 779-86.
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  A Native American-Indian female presenting with anemia and thrombocytosis was diagnosed with myelodysplastic syndrome (MDS, refractory anemia). Over the course of 5 years she developed cytopenias and periods of leukocytosis with normal bone marrow (BM) blast counts, features of an unclassifiable MDS/MPS syndrome. The patient ultimately progressed to acute myelogenous leukemia (AML, FAB M2) and had a normal karyotype throughout her course. The episodes of leukocytosis were associated with infectious complications. Transformation to AML was characterized by a BM blast percentage of 49%. Peripheral blood and BM samples were obtained for serum protein analysis and gene expression profiling (GEP) to elucidate her disease process. An ELISA assay of the serum analyzed approximately 80 cytokines, which demonstrated that hepatocyte growth factor/scatter factor and insulin-like growth factor binding protein 1 were markedly elevated compared to normal. GEP demonstrated a unique "tumor molecular profile," which included overexpression of oncogenes (HOXA9, N-MYC, KOC1), proliferative genes (PAWR, DLG5, AKR1C3), invasion/metastatic genes (FN1, N-CAM-1, ITGB5), pro-angiogenesis genes (c-Kit), and down regulation of tumor suppressor genes (SUI1, BARD1) and anti-apoptotic genes (PGLYRP, SERPINB2, MPO). Hence, a biomics approach has provided insight into elucidating disease mechanisms, molecular prognostic factors, and discovery of novel targets for therapeutic intervention.
• Yi, Z., Cohen-Barak, O., Hagiwara, N., Kingsley, P. D., Fuchs, D. A., Erickson, D. T., Epner, E. M., Palis, J., & Brilliant, M. H. (2006). Sox6 directly silences epsilon globin expression in definitive erythropoiesis. PLoS genetics, 2(2), e14.
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  Sox6 is a member of the Sox transcription factor family that is defined by the conserved high mobility group (HMG) DNA binding domain, first described in the testis determining gene, Sry. Previous studies have suggested that Sox6 plays a role in the development of the central nervous system, cartilage, and muscle. In the Sox6-deficient mouse, p100H, epsilony globin is persistently expressed, and increased numbers of nucleated red cells are present in the fetal circulation. Transfection assays in GM979 (erythroleukemic) cells define a 36-base pair region of the epsilony proximal promoter that is critical for Sox6 mediated repression. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrate that Sox6 acts as a repressor by directly binding to the epsilony promoter. The normal expression of Sox6 in wild-type fetal liver and the ectopic expression of epsilony in p100H homozygous fetal liver demonstrate that Sox6 functions in definitive erythropoiesis. The present study shows that Sox6 is required for silencing of epsilony globin in definitive erythropoiesis and suggests a role for Sox6 in erythroid cell maturation. Thus, Sox6 regulation of epsilony globin might provide a novel therapeutical target in the treatment of hemoglobinopathies such as sickle cell anemia and thalassemia.
• List, A., Kurtin, S., Roe, D. J., Buresh, A., Mahadevan, D., Fuchs, D., Rimsza, L., Heaton, R., Knight, R., & Zeldis, J. B. (2005). Efficacy of lenalidomide in myelodysplastic syndromes. The New England journal of medicine, 352(6), 549-57.
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  Ineffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia caused by ineffective erythropoiesis is difficult. In patients with myelodysplastic syndromes and symptomatic anemia, we evaluated the safety and hematologic activity of lenalidomide, a novel analogue of thalidomide.
• Rimsza, L. M., Sola, M. C., Slayton, W. B., Rimsza, L. M., Perez, J. A., Fuchs, D., Christensen, R. D., & Calhoun, D. A. (2005). Perinatal/Neonatal Case Presentation A Neonate with Severe Thrombocytopenia and Radio-Ulnar Synostosis. Journal of Perinatology, 25(4), 296-296. doi:10.1038/sj.jp.7211286
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  Perinatal/Neonatal Case Presentation A Neonate with Severe Thrombocytopenia and Radio-Ulnar Synostosis
• Rimsza, L. M., Rimsza, L. M., Masoudi, H., Gascoyne, R. D., Fuchs, D. A., Farinha, P., & Connors, J. M. (2004). HLA-DR Protein Status Predicts Survival in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Treated with the MACOP-B Chemotherapy Regimen.. Blood, 104(11), 3273-3273. doi:10.1182/blood.v104.11.3273.3273
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  Background: HLA-DR is one of the MHC Class II antigen presenting molecules. Loss of HLA-DR expression on DLBCL tumor cells has been associated with poor survival in patients on Southwest Oncology Group (SWOG) studies as well as the recent Leukemia and Lymphoma Molecular Profiling project (Rosenwald et al, NEJM 2002). This study was conceived to examine the effect of HLA-DR status on a completely different cohort of patients from a single institution treated uniformly with a single chemotherapy regimen, MACOP-B, in an attempt to validate HLA-DR as an important biomarker in DLBCL. Methods: HLA-DR immunostaining was performed using a tissue microarray block containing two 0.6mm cores of paraffin embedded tissues from 97 patients treated on the MACOP-B regimen (1981–86) at the BC Cancer Agency in Vancouver, Canada (Semin Hematol 1988, suppl 2: 41–6). Only cases of B cell lineage were used. We used the HLA-DR antibody Class II DR, (IgG2b) at a 1:50 dilution (Novocastra, UK) with epitope recovery, on an automated immunostainer (Ventana Benchmark System) using a biotin-avidin-diaminobenzidine-based detection system. Two pathologists (LR and DF) scored all slides for positive or negative results. Results: All patients had advanced-stage disease and were treated uniformly with the MACOP-B chemotherapy regimen. The median follow-up of living patients is 17 years. The IPI was predictive of overall survival (OS) in the study group (p = 0.023). Of the 97 B cell cases, 82 had interpretable staining. The other cases were eliminated for lack of tumor (2), necrotic tissue (1), or lack of internal positive control cells in the tissue core (12). Of the remaining 82 cases, 52 were positive for HLA-DR protein with a median OS of 16.2 years while 30 were negative with a median OS of 4.2 years, (p=0.037, figure below). A Cox multivariate model established both IPI (p = 0.031) and HLA-DR status (p = 0.04) as independent predictors of OS. Discussion: The importance of loss of antigen presenting molecules on cells of DLBCL was a key finding of the previous LLMPP work, and is now further confirmed as impacting OS in a separate set of patients treated uniformly with a different chemotherapy regimen. These findings lend credence to the hypothesis that loss of immunogenicity is of key importance in patient response to treatment and OS and suggest that specific therapies focused on this pathway may benefit patients with DLBCL regardless of their treatment regimen.
• Rimsza, L. M., Roberts, R. A., Miller, T. P., Unger, J. M., LeBlanc, M., Braziel, R. M., Weisenberger, D. D., Chan, W. C., Muller-Hermelink, H. K., Jaffe, E. S., Gascoyne, R. D., Campo, E., Fuchs, D. A., Spier, C. M., Fisher, R. I., Delabie, J., Rosenwald, A., Staudt, L. M., & Grogan, T. M. (2004). Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood, 103(11), 4251-8.
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  The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas (DLBCLs). Four gene expression "signatures" were identified as correlated with patient outcome, including the major histocompatibility complex (MHC) class II genes (eg, HLA-DRA) which correlated with better survival. We further analyzed the effects of HLA-DRA on survival and correlated gene expression with protein status and tumor-infiltrating lymphocytes. The 5-year overall survival was 24% in the lowest 10% of HLA-DRA expression, 37% in the 10% to 25% group, 50% in the 25% to 50% group, and 55% for patients in the highest 50%. Further analysis demonstrated that the hazard ratio of death was a nonlinear function of HLA-DRA expression. Adjustment for the International Prognostic Index did not alter the impact of HLA-DRA on survival. Other MHC class II genes were found to predict survival similarly. Microarray HLA-DRA expression correlated with the presence or absence of human leukocyte antigen-DR (HLA-DR) protein in 20 of 22 cases assessed. Fewer tumor-infiltrating CD8(+) T cells were detected in MHC class II-negative cases compared with positive cases (2.8% versus 11.0%; P =.001), supporting the hypothesis that loss of tumor immunosurveillance has a devastating effect on patient outcome in DLBCL.
• Rimsza, L. M., Wang, M. X., Roberts, R. A., Rimsza, L. M., Mustacich, D. J., Grogan, T. M., Gascoyne, R. D., Fuchs, D. A., Chan, W. C., Braziel, R. M., & Andres, M. W. (2004). Gene Expression Profiling, Frozen and Paraffin Section Immunohistochemistry, and In Situ Hybridization for Determination of Monoclonality in Diffuse Large B-Cell Lymphoma.. Blood, 104(11), 4553-4553. doi:10.1182/blood.v104.11.4553.4553
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  Background: Determining monotypia of surface immunoglobulin (SIg) is often an important step in the diagnosis of B-cell lymphomas. Many competing methods have been developed and are commonly used in clinical practice. The role of gene expression profiling (GEP) in determining light chain restriction is yet to be clarified. The goal of this study was to compare 4 methods by which light chain restriction can be determined: frozen section immunohistochemistry (FS-IHC), paraffin section IHC (PS-IHC), in-situ hybridization (ISH), and GEP. Design: 40 cases of DLBCL, part of a previous GEP study of DLBCL (Rosenwald et al, NEJM 2002), were made into a tissue microarray (TMA). FS-IHC slides, previously stained using by-hand streptavidin and diaminobenzidine, were re-examined for κ:λ restriction. PS-IHC was done on the TMA using the Benchmark system according to manufacturer’s protocols for κ/λ staining (Ventana Medical Systems VMSI, Tucson, AZ). ISH was performed on the TMA with a newly developed sensitive ISH procedure from VMSI which uses a purified streptavidin reagent to reduce background and increase sensitivity. The FS-IHC, PS-IHC, and ISH arrays were reviewed and scored as κ/λ monotypic, SIg-negative or indeterminate by 3 pathologists. The averaged gene expression ratios for microarray elements probing for κ and λ on each case were plotted on a log2 scale. Monoclonality was determined using 2 different GEP criteria: (1) κ-monoclonal if κ:λ expression was >2log2 or λ-monoclonal if expression was λ>κ or (2) κ and λ light chain relative expression on either side of the median. These data from all 4 techniques were used to determine a consensus clonality in which the majority of the results agreed. The results for each technique were then compared to the consensus for that case. Results: 7 Cases had a 4/4 consensus, 9 cases a 3/4, 11 cases a 3/3, 7 cases a 2/3, and 1 case a 2/2. 5 cases were excluded from the study because there was no majority consensus. 19 cases (47.5%) were κ monoclonal, 10 (25%) λ monoclonal, 6 (15%) SIg-negative, and 5 cases (12.5%) indeterminate. Compared to the consensus clonality FS-IHC was accurate in 21/26 (81%), PS-IHC in 28/32 (87%), sensitive ISH in 29/29 (100%) cases. GEP was accurate in 31/35 (89%) cases using either criteria (1) or (2); in 27/35 (77%) using criterion (1) alone, in 28/35 (80%) using criterion (2) alone, and 24/35 (69%) of cases when both criteria (1) and (2) were met. 6 SIg-negative cases failed all GEP criterion, but were considered correctly classified as neitherκ nor λ monoclonal. Discussion: The technique with the highest accuracy compared to consensus was the sensitive ISH assay, in part because samples were eliminated if the mRNA control (polyT probe) staining was suboptimal. GEP was also accurate using either of our criteria. The SIg-negative cases were not classified as either κ or λ monoclonal using any of our criteria. Given the increasing role GEP is likely to play in hematopathology, the application of GEP to B cell clonality may have diganostic utility.
• Sola, M. C., Slayton, W. B., Rimsza, L. M., Perez, J. A., Fuchs, D., Fuch, D., Calhoun, D. A., & Christensen, R. D. (2004). A neonate with severe thrombocytopenia and radio-ulnar synostosis. Journal of perinatology : official journal of the California Perinatal Association, 24(8), 528-30.
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  Bone marrow failure syndromes can be associated with abnormalities of the forearms. We observed a neonate with congenital thrombocytopenia who had bilateral radio-ulnar synostosis and fifth finger clinodactly. We performed an evaluation of the mechanism causing the thrombocytopenia using a combination of direct and indirect measures of thrombopoiesis. These tests indicated decreased platelet production. This entity of congenital hyporegenerative thrombocytopenia with bilateral radio-ulnar synostosis and fifth-finger clinodactly is an uncommon but easily recognizable form of congenital amegakaryocytic thrombocytopenia (CAMT). This entity can be distinguished from the TAR syndrome (thrombocytopenia and absent radii) by the distinctive orthopedic issues, different underlying genetic mutations, and a more worrisome prognosis for CAMT than for TAR.

Presentations

• Hansen Smith, M., Heimbigner, A., Fuchs, D., Perry, C. S., & Reveles, C. (2023, November). From Sarcoidosis to Lymphoma: A Diagnostic Journey to Peripheral T Cell Lymphoma, NOS
  
  Presentation by Mary Hansen Smith, MD. Progress in T- and NK-Cell Lymphomas/LeukemiasSociety for Hematopathology.

Poster Presentations

• Otsuji, J., Girard, N., Perry, C. S., Fuchs, D., & Lai, L. (2020, October/2020). Sibling Donor-Derived Myeloid Sarcoma After Hematopoietic Stem Cell Transplant. CAP20 annual meeting. virtual meeting: College of American Pathologists.
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  Janelle Otsuji, MD (jjotsuji@pathology.arizona.edu); Nicole Girard, MD; Catherine Spier, MD; Deborah Fuchs, MD; Li-Wen Lai, PhD. Department of Pathology, The University of Arizona, Tucson, Arizona.Myeloid sarcoma (MS) occurs in 8% to 20% of post–allogeneic hematopoietic stem cell transplant (allo-HSCT) patients, mostly from recipient's relapsed leukemia. Donor-derived MS (DDMS) is extremely rare. We report 2 cases of DDMS after successful allo-HSCT from human leukocyte antigen (HLA)-identical, sex-mismatched siblings. Donor origin was confirmed by both cytogenetic and molecular chimerism tests. Case 1 was a 50-year-old man with history of KMT2A-rearranged acute myeloid leukemia (AML) presented with bilateral knee soft tissue masses 5 years post–allo-HSCT. Knee biopsy revealed infiltrative large cells with blastic morphology expressing CD4, CD10, CD38, CD33 (dim), subset MPO, while negative for CD117 and CD34 (Table). Interphase fluorescence in situ hybridization (FISH) analysis showed gain of chromosomes 5/6/8/15q/20q/21q and loss of 17q/20q with 95.5% cells showing donor origin. Concurrent bone marrow biopsies showed donor-derived karyotype//46,XX,del(20)(q11.2q13.3)[4]/46,XX[16] versus 46,XY,t(6;11)(q27;q23)[18]/46,XY[2] at diagnosis 8 years prior (Table). Case 2 was a 40-year-old man with history of AML with myelodysplasia-related changes (AML-MRC) presented with a testicular mass 5 years post-HSCT. Orchiectomy yielded a mass of 163 g and 8.7 cm in diameter. Microscopically, there was diffuse effacement of the testis architecture with large cells demonstrating an immature myeloid phenotype CD34+, CD117+, MPO dim subset, and aberrant CD7. FISH analysis showed 100% of cells showing XX donor cells. Concurrent bone marrow biopsies showed 100% normal XX donor cells. Both cases developed DDMS 5 years after allo-HSCT from siblings. Verifying donor origininAML relapseiscriticalas transformed donor cells may have different genetic alterations and behaviors from initial AML. Our case 2 is likely the first testicular sibling-DDMS in the literature.
• Al-kateb, H., Fuchs, D., & Anwer, F. (2017, March). High Grade B-cell Lymphoma with Rearranged MYC to an Unknown Partner on Chromosome 18". American College of Medical Genets and Genomics, Annual Clinical Genetics Meeting. Phoenix, AZ.

Case Studies

• Heimbigner, A., & Fuchs, D. (2022. Drug-induced acanthocytosis(pp --).
• Duran, J., & Fuchs, D. (2017. Macrothrombocytopenia and neutrophils with Döhle-like bodies(pp #00061179).

Other Teaching Materials

• Fuchs, D. (2022. Acquired Thrombophilia for CP Core Curriculum. UA COM.
• Fuchs, D. (2022. Advanced Topics Coagulation interactive teaching session. UA COM.
• Fuchs, D. (2022. Coagulation Unknowns for CP Core Curriculum. UA COM.