A Rare Case of Acquired Fanconi's Syndrome With Monoclonal Gammopathy in an Infant.

BACKGROUND: Monoclonal gammopathies associated with acquired Fanconi's syndrome (AFS) have been reported in the adult population. AFS is characterized by renal dysfunction resulting in proteinuria, aminoaciduria, hypophosphatemia, glucosuria, and hyperchloremic metabolic acidosis. In this case report, we document the clinical and laboratory findings of a preterm infant with features of both AFS and monoclonal gammopathy in the urine. METHODS: Clinical suspicion of AFS prompted the following laboratory studies to be performed: urine protein electrophoresis (UPEP), urine immunofixation, and urine amino acid analysis with high performance liquid chromatography (HPLC). RESULTS: Urine amino acid analysis revealed aminoaciduria. On UPEP, nonselective glomerular proteinuria was seen with a faint band in the gamma region. Urine immunofixation confirmed the presence of a monoclonal IgG lambda component with free monoclonal lambda light chains. CONCLUSION: To the best of our knowledge, this is the first case of pediatric AFS reported with a monoclonal gammopathy and monoclonal free light chains.

Inability to Measure M-Protein With Capillary Zone Electrophoresis (CAPPILLARYS 2) in Tracings With NonDiscernable Peaks.

BACKGROUND: We performed a retrospective study to illustrate the challenges with quantifying monoclonal (M)-protein in the cases of serum protein capillary zone electrophoresis (SPCZE) where no discernable peak is apparent. MATERIALS AND METHODS: We retrospectively reviewed 160 serum immunofixation electrophoresis (SIFE) that were performed at Memorial Hermann Hospital-Texas Medical Center between October 2013 and November 2013 and we identified the positive SIFE results. The corresponding SPCZE of the positive SIFE were retrieved and evaluated for the ability to quantify M-proteins in them. We define the ability to quantify M-protein as the ability for the operator of the SPCZE to identify a discernable peak and to be able to manually gate the area under the peak. RESULTS: Twenty-two cases of SIFE detected a monoclonal immunoglobulin. Of the corresponding 22 SPCZE, we could not quantify the M-protein in 6 (27.3%) of the cases. CONCLUSION: We have shown several cases where we were not able to quantify the M-protein with SPCZE. This poses a challenge in the diagnosis and management of these patients.

How do we manage cardiopulmonary bypass coagulopathy?

BACKGROUND: Patients who undergo cardiopulmonary bypass (CPB) are at risk for coagulopathy. Suboptimal turnaround time (TAT) of laboratory coagulation testing results in empiric administration of blood products to treat massive bleeding. We describe our initiative in establishing the coagulation-based hemotherapy (CBH) service, a clinical pathology consultation service that uses rapid TAT coagulation testing and provides comprehensive assessment of bleeding in patients undergoing CPB. A transfusion algorithm that treats the underlying cause of coagulopathy was developed. STUDY DESIGN AND METHODS: The coagulation testing menu includes all aspects of coagulopathy with close proximity of the laboratory to the operating room to allow for rapid test results. The hemotherapy pathologist monitors laboratory results at several stages in surgery and uses a comprehensive algorithm to monitor a patient's hemostasis. The optimal number and type of blood products are selected when the patient is taken off CPB. RESULTS: The CBH service was consulted for 44 ventricular assist device implants, 30 heart transplants, and 31 other cardiovascular surgeries from May 2012 through November 2013. The TAT for laboratory tests was 15 minutes for complete blood count, antithrombin, and coagulation panel and 30 minutes for VerifyNow and thromboelastography, in comparison to 45 to 60 minutes in normal settings. The transfusion algorithms were used with optimal administration of blood components with preliminary data suggestive of reduced blood product usage and better patient outcomes. CONCLUSION: We described the successful introduction of a novel pathology consultation service that uses a rapid TAT coagulation testing menu with transfusion algorithms for improved management of CPB patients.

High false-positive rate for monoclonal gammopathy using capillary electrophoresis (CAPILLARYS 2) alone.

BACKGROUND: Capillary zone electrophoresis (CZE) is a newer method of performing serum protein electrophoresis and is considered to be faster and more efficient than agarose gel method. We decided to evaluate CZE as an efficient screening tool for monoclonal gammopathies, and we began recommending immunofixation studies in cases with such minor/subtle distortions to avoid missing monoclonal gammopathies. METHODS: We evaluated 163 serum protein agarose gel electrophoresis (SPAGE) samples between October and November 2011, and 447 serum protein CZE (SPCZE) samples between January 2012 to February 2012 and August 2012 to September 2012. RESULTS: Immunofixation studies were recommended in 51 of 163 cases (31.3%) performed by SPAGE, and in 274 of 447 cases (61.3%) performed by SPCZE. While using SPAGE, of the 51 cases recommended for immunofixation (24 were performed to date), six cases (25.0%) were positive for monoclonal gammopathy. In contrast, while using SPCZE, of the 274 cases recommended for immunofixation (118 were performed to date), 18 cases (15.2%) were positive for monoclonal gammopathy. Using the SPCZE method, of these 18 cases, five (27.8%) had minor/subtle distortions without obvious peaks. Our recommendation rate for immunofixation studies has thus almost doubled (61.3% vs. 31.3%) with the adoption of SPCZE. Yet, using SPCZE has not translated to detecting more cases of true monoclonal gammopathies. CONCLUSION: Therefore, we conclude that there is a high false-positive rate for monoclonal gammopathy using CE alone.

The Utility of Thromboelastography in Monitoring Von Willebrand Disease: A Case Report.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. It is primarily attributed to malfunctioning or deficient Von Willebrand factor (VWF). Thromboelastography (TEG) has emerged as a valuable tool for assessing coagulation dynamics and guiding transfusion therapy in bleeding patients. Given this, we present a case study of a 23-year-old pregnant female with a past medical history of type 2B VWD, wherein TEG was employed to optimize disease screening and therapy monitoring while minimizing costs and preventing complications associated with low platelet counts. This case underscores the potential utility of TEG in enhancing the care of VWD patients, particularly in unique critical settings such as pregnancy.

Deep Learning Provides Rapid Screen for Breast Cancer Metastasis with Sentinel Lymph Nodes.

OBJECTIVE: Deep learning has been shown to be useful in detecting breast cancer metastases by analyzing whole slide images (WSI) of sentinel lymph nodes; however, it requires extensive analysis of all the lymph node slides. Our deep learning study attempts to provide a rapid screen for metastasis by analyzing only a small set of image patches to detect changes in tumor environment. METHODS: We designed a convolutional neural network to build a diagnostic model for metastasis detection. We obtained WSIs of Hematoxylin and Eosin-stained slides from 34 cases with equal distribution in positive/negative categories. Two WSIs were selected from each case for a total of 69 WSIs. From each WSI, 40 image patches (100x100 pixels) were obtained to yield 2720 image patches, from which 2160 (79%) were used for training, 240 (9%) for validation, and 320 (12%) for testing. Interobserver variation was also examined among 3 users. RESULTS: The test results showed excellent diagnostic results: accuracy (91.15%), sensitivity (77.92%), and specificity (92.09%). No significant variation in results was observed among the 3 observers. CONCLUSION: This preliminary study provided a proof of concept for conducting a rapid screen for metastasis rather than an exhaustive search for tumors in all fields of all sentinel lymph nodes.

Therapeutic plasmapheresis and red blood cell exchange in a sickle cell trait patient with rhabdomyolysis.

We report a case of a 16-year-old African-American male with sickle cell trait and a past medical history significant for asthma that was transferred to our hospital for management of respiratory failure. On the fourth day of hospitalization, the patient was found to have increased creatine kinase (CK) levels and urine myoglobin levels consistent with rhabdomyolysis. No clear etiology was identified. Aggressive standard hydration and urine alkalization were applied without response. On the sixth day of hospitalization, the patient underwent a 1-1.5 plasma volume therapeutic plasma exchange (TPE) resulting in a transient reduction of serum CK and myoglobin by 50%, which became elevated once again within 4 h. Since his clinical presentation resembles exertional rhabdomyolysis documented in patients with sickle cell trait, RBC exchange was performed. The patient tolerated the procedure without complications. In addition to his improved overall condition, the patient's post-exchange CK and serum myoglobin levels dropped dramatically without rebound. To our knowledge, this case represents the first reported case of TPE followed by RBC exchange in a SCT patient with rhabdomyolysis.

The new LOCI digoxin assay on the Vista 1500 analyzer is virtually free from interferences of herbal supplements hawthorn and ashwagandha (Indian ginseng).

Herbal supplements hawthorn and ashwagandha (Indian ginseng) are indicated for cardiac illnesses and may be taken by patients receiving digoxin therapy. Because both hawthorn and ashwagandha are known to interfere with serum digoxin measurements using certain digoxin immunoassays, we investigated potential interference of these two herbal supplements with the new homogenous sequential chemiluminescent assay for digoxin based on the luminescent oxygen channeling technology (LOCI digoxin) for application on the Dimension and Vista platform. When aliquots of a drug-free serum pool were supplemented with various amounts of hawthorn (three different commercial preparations) or ashwagandha (two different commercial preparations) and apparent digoxin values were measured using LOCI digoxin assay on Dimension Vista 1500 analyzer we observed none-detected values except when aliquots were supplemented with very high amounts of the herbal extracts. When aliquots of a serum digoxin pool (prepared by pooling specimens from patients receiving digoxin) where further supplemented with various amounts of these supplements and digoxin concentrations were remeasured, statistically significant falsely higher digoxin values were observed only in specimens containing very high amounts of these supplements. Such interference may not be clinically significant. We conclude that new LOCI digoxin assay is virtually free from interferences of herbal supplements, hawthorn, and ashwagandha.

Technical Note: Bimodal Negative Interference of Biotin in Roche IL-6 Immunoassay.

OBJECTIVE: Interleukin -6 (IL-6) is an important diagnostic test in COVID-19 patients to determine whether to initiate tocilizumab therapy or mechanical ventilation. We investigated potential interference of biotin in Roche IL-6 assay which utilizes biotinylated antibody. METHODS: We prepared three serum pools from left-over specimens which showed IL-6 values over 40 pg/mL. Then aliquots of each serum pool were further supplemented with various amounts of biotin expected in patients taking biotin supplement and then IL-6 values were measured again using Roche IL-6 assay on the Cobas e411 analyzer. RESULTS: We observed negative interference of biotin in IL-6 assay but interference was bimodal as maximum negative interference was observed with 100 ng/mL biotin but not with 1000 ng/mL. However, no interference was observed in the presence of 25 ng/mL biotin. CONCLUSIONS: Biotin showed negative interference with IL-6 assay.

Pathology Residency Curriculum: Time for a Change?

The current Anatomical and Clinical Pathology residency curriculum, as outlined by the American Board of Pathology (ABP), emphasizes resident exposure to a wide variety of subjects without in-depth training. This has led to a large number of residents pursuing fellowship training. With the demand for further sub-specialization, there is a necessity for the establishment of an updated curriculum that not only encompasses the basic knowledge of pathology but is also focused on training residents in their desired subspecialty.We herein propose a new comprehensive AP/CP residency syllabus. The new curriculum will be divided into two major categories: preliminary and subspecialty training. The curriculum will require residents to undergo basic pathology training within the first two preliminary years, followed by two subspecialty years. In their subspecialty years, each resident will be required to either pick two subjects as majors, each having a duration of one year, or one subject as a major and two subjects as minors, in which case the major will have a one-year duration and the minors will each be six months in length. The proposed curriculum meets the current guidelines of the ABP, reduces the burden of residents to complete multiple fellowships, and allows residents earlier entrance into the workforce.

COVID-19 Cardiac Injury: An Important Cause of COVID-19 Related Morbidityand Mortality.

OBJECTIVE: Although coronavirus disease 2019 (COVID-19) typically presents as a respiratory illness, co-existent cardiovascular symptomatology associated with an elevated serum troponin level has been identified as a risk factor for adverse outcomes. Our study addressed the need to correlate serum cardiovascular biomarkers with tissue pathology based on autopsy. MATERIALS AND METHODS: In 13 patients, we reviewed the clinical history and measurements of serum troponin and other biomarkers and correlated them with autopsy findings. RESULTS: At autopsy, the 13 COVID-19 patients exhibited evidence of diffuse alveolar damage (DAD) and cardiomegaly (heart weights ranged from 380 to 1170 grams). Of the 13 patients, three had elevated troponin I and evidence of severe coronary artery disease (CAD) (cases 4, 5, and 11), while six had elevated troponin I without evidence of severe CAD (cases 1, 3, 6, 7, 8, and 9), and four had no clinical or pathological evidence of CAD. Of note, cases 7 and 9 had significantly elevated troponin I levels (8.84 ng/mL and 4.94 ng/mL, respectively). Several cases showed focal degenerative change or damage of cardiomyocytes. However, none of the cases had evidence of lymphocytic myocarditis. CONCLUSION: Although we observed elevated biomarkers of heart failure in some cases, it was not a consistent finding and did not correlate with evidence of myocarditis. The elevated biomarkers may reflect non-ischemic heart damage as a consequence of COVID-19 infection.

Obesity Is a Risk Factor Associated with H. pylori-negative MALT Lymphoma of Stomach.

OBJECTIVE: More than 90% of gastric mucosa-associated lymphoid tissue (MALT) lymphomas are attributed to Helicobacter pylori infections. However, the pathogenesis of H. pylori-negative MALT lymphomas is controversial, and additional etiologies need to be investigated. MATERIALS: A retrospective study of gastric MALT lymphoma cases over a 15-year period revealed 56 cases. The H. pylori status, clinical information, and body mass index (BMI) data were collected. The results of the urea breath test, serology, stool antigen, and previous biopsy results were documented. RESULTS: The 56 cases had an average height of 166.57 cm (range, 147.3-190.5), weight of 83.98 kg (range 55-153.1), and body mass index (BMI) of 30.34 kg/m2 (range, 17.96-49.77). Twenty-one cases were H. pylori-positive (37.5%), with a mean BMI of 27.36 kg/m2 (range, 17.96-47.25), and BMI>30 kg/m2 in 5 (23.8%) patients. Thirty-five cases were H. pylori-negative, with a mean BMI of 31.90 kg/m2 (range, 18.17-49.77), and 20 (57.1%) having BMI>30 kg/m2. A Fisher's exact test and two-tailed test showed a statistically significant difference between the two groups. CONCLUSION: Obesity leads to a baseline state of chronic inflammation and increased production of pro-inflammatory cytokines that can stimulate the lymphocytes, leading to lymphomatous proliferation. Our study suggests a potential correlation between obesity and the risk of development of primary gastric MALT lymphoma.

Acute myeloid leukemia with mutated NPM1 mimics acute promyelocytic leukemia presentation.

OBJECTIVES: To investigate clinicopathological and molecular features of NPM1-mutated acute myeloid leukemia that presented with infrequent acute promyelocytic leukemia (APL)-like phenotype and clinical presentation. METHODS: Cases with both de novo or secondary Acute Myeloid Leukemia (AML) were retrieved. Data from flow cytometry immunophenotyping, cytogenetics, molecular studies, and clinical presentation were analyzed. RESULTS: Cases presented with abnormal coagulation parameters and low platelets count; four of them showed a DIC index compatible with overt DIC. Two cases showed Auer rods. In all cases, immunophenotypes mimicked APL: blasts expressed CD33, CD13, and cytoplasmic MPO but did not express CD34, HLA-DR, or CD11b. Notably, CD4 expression was observed in all cases. Neither t(15;17) nor PML/RARα gene rearrangement was detected. NPM1 gene mutation was identified in all cases. In four cases, TET2 or IDH2 co-mutations were identified. CONCLUSIONS: Our findings provide additional evidence of association between NPM1-mutated AML with TET2 or IDH2 co-mutations and the APL-like immunophenotype. This AML subset was found to exist in both de novo and secondary AML. High WBC count and blasts with low to moderate side scatter and significant expression of CD4 are observed features that could assist in the differential diagnosis with APL. The occurrence of significant elevated D-dimer levels, or even overt DIC observed at diagnosis in these cases could be relevant for this AML subtype.

Cryptic Acute Promyelocytic Leukemia (APL) Presenting as Seizures in an Adolescent.

There are approximately 800 new cases of acute promyelocytic leukemia (APL) in the United States every year. APL is rarely observed in pediatric populations, and accounts for less than 5-10% of all pediatric cases of acute myeloid leukemia (AML). APL typically presents with symptoms related to the pancytopenia such as fatigue due to anemia, bleeding and bruising secondary to thrombocytopenia, and infections attributed to a lack of functioning leukocytes. The presentation of APL in the central nervous system (CNS) is a rare phenomenon. In addition, APL has a dismal prognosis when found in the CNS. In this case study, we describe a unique presentation of pediatric APL with cryptic insertion of the promyelocytic leukemia (PML)-retinoic acid receptor-alpha (RARA) fusion protein with a surprisingly excellent recovery.

Distortions but not Definitive Peaks by Capillary Serum Protein Electrophoresis Indicate Monoclonal Gammopathy of Undetermined Significance rather than Multiple Myeloma.

OBJECTIVE: Capillary electrophoresis of serum proteins demonstrates occasional distortions. Distortions or peaks in the gamma, beta, and alpha-2 zones may represent monoclonal gammopathy. In this study, we investigated if such distortions are associated with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma. METHODS: Consecutive serum protein electrophoresis results were reviewed and immunofixation studies were recommended on specimens exhibiting distortions or distinct peaks in the gamma, beta or alpha-2 zones. RESULTS AND DISCUSSION: Of the 471 cases, we observed distortions in 101 cases. In the immunofixation studies, 17.8% of cases had a diagnosis of MGUS, but none contained multiple myeloma. CONCLUSIONS: We conclude that distortions in serum capillary electrophoresis may be associated with MGUS, but not multiple myeloma.

Educational Case: Mantle Cell Lymphoma.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

HIV-associated plasmablastic lymphoma in the era of HAART: a single-center experience of 21 patients.

OBJECTIVES: Patients with HIV infection have an increased risk of developing plasmablastic lymphoma (PBL). In this study, we reviewed the clinicopathologic features of PBL in HIV+ patients in the era of HAART from a single health center. DESIGN: Retrospective study. METHODS: The morphologic, immunophenotypic, and clinical features were reviewed in these HIV+ patients with PBL and univariate analysis was employed to determine the survival prognosis. RESULTS: During the interval of 1 January 2008 to 30 December 2018, we identified 95 HIV+ patients with aggressive non-Hodgkin B-cell lymphomas. Among these patients, there were 21 (22%) patients with PBL (19 men and two women; median age: 45 years). Seven patients had PBL at their initial HIV diagnosis and 14 developed PBL after a median interval of 7.7 months of HIV diagnosis. Lymph nodes (n = 10), oral cavity/sinonasal mass (n = 6), and rectal masses (n = 5) were the common involved sites, and five of 15 (33%) had bone marrow involvement. Lymphoma cells were immunoreactive for MUM-1/IRF4 (100%), CD138 (90%), CD45 (63%), CD79a (47%), and CD30 (25%). Proliferation rate assessed by Ki67 was at least 90% in 18 of 20 cases. Eighteen patients received chemotherapy including etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (n = 13) and cyclophosphamide, doxorubicin, vincristine, and prednisone (n = 2). With a median follow-up time of 19 months, nine out of 17 patients died. Bone marrow involvement was associated with a poorer overall survival (median: 4.7 months, P = 0.015). CONCLUSION: PBL is the second most common type of aggressive lymphoma and often presents in lymph nodes of patients with poorly controlled HIV infection. Bone marrow involvement is associated with a poorer outcome.

Howell-Jolly Body-Like Inclusions in Neutrophils of Patients With Myelodysplastic Syndrome: A Novel Correlation.

CONTEXT.­: Howell-Jolly body-like inclusions have been previously associated with patients who are human immunodeficiency virus (HIV) infected, taking antiviral medications, and immunosuppressed. These inclusions appear in neutrophils and resemble Howell-Jolly bodies of normoblasts in abnormal erythropoiesis. In granulocytes, they are thought to represent detached nuclear fragments produced from dysplastic granulopoiesis. To the best of our knowledge, no association of Howell-Jolly body-like inclusions and myelodysplastic syndrome (MDS) has been reported previously. OBJECTIVE.­: To establish an unprecedented correlation of Howell-Jolly body-like inclusions in patients with MDS. DESIGN.­: Eleven bone marrow cases from patients diagnosed with MDS and 20 bone marrow cases with no significant pathologic alterations were retrospectively reviewed. Detailed medical record review was performed to ensure none of the patients had a history of HIV, or was taking immunosuppressants and/or antiviral medications. RESULTS.­: Eight of 11 cases (72%) from the study group show detached intracytoplasmic inclusions in a minority (<5%) of mature neutrophils consistent with Howell-Jolly body-like inclusions. No Howell-Jolly body-like inclusions were identified in the control group. Notably, none of the selected patients had a history of HIV or was taking immunosuppressants and antiviral medications. CONCLUSIONS.­: In review of the literature, Howell-Jolly body-like inclusions seem to correlate with immunosuppression and antiviral therapies with nucleoside analogs. We propose that the formation of Howell-Jolly body-like inclusions is the consequence of dysplasia, and hence its correlation not only with the abovementioned conditions, but also with MDS. The inclusions are, however, seen in only a minority of white cells (<5%), which is probably why they were not brought to practicing pathologists' awareness in the past. This study aims to raise awareness and correlate the presence of Howell-Jolly body-like inclusions in MDS.

Fatal Intracranial Hemorrhage in a Young Pregnant Patient with Acute Promyelocytic Leukemia.

Acute promyelocytic leukemia during pregnancy is associated with a high risk of fetal and obstetrical complications. Although the prognosis of acute promyelocytic leukemia is favorable due to disease-specific drugs, such as all-trans retinoic acid, early death due to fatal intracranial hemorrhage has been observed in some cases. In this study, we present a case of catastrophic intracranial hemorrhage in a young pregnant patient with the finding of leukemic involvement of the placenta. To our knowledge, this is the first confirmed case of acute promyelocytic leukemia involving the placenta. The clinical history, pertinent histological findings, and clinical outcomes will be discussed.

Proteomics Analysis of FLT3-ITD Mutation in Acute Myeloid Leukemia Using Deep Learning Neural Network.

Deep Learning can significantly benefit cancer proteomics and genomics. In this study, we attempted to determine a set of critical proteins that were associated with the FLT3-ITD mutation in newly-diagnosed acute myeloid leukemia patients. A Deep Learning network consisting of autoencoders formed a hierarchical model from which high-level features were extracted without labeled training data. Dimensional reduction reduced the number of critical proteins from 231 to 20. Deep Learning found an excellent correlation between FLT3-ITD mutation with the levels of these 20 critical proteins (accuracy 97%, sensitivity 90%, and specificity 100%). Our Deep Learning network could hone in on 20 proteins with the strongest association with FLT3-ITD. The results of this study allow for a novel approach to determine critical protein pathways in the FLT3-ITD mutation, and provide proof-of-concept for an accurate approach to model big data in cancer proteomics and genomics.