Novel ELANE Mutation Associated with a Clinical Presentation of Cyclic Neutropenia.

OBJECTIVES: Congenital neutropenia, defined by absolute neutrophil count (ANC) 2.5x109/L in infants, includes a variety of genotypic alterations that manifest with chronic immunodeficiency and, as a result, presents in infancy with recurrent infections. The gene that encodes neutrophil elastase, ELANE, has pathological variants yielding two distinct phenotypes: severe congenital neutropenia (SCN) and cyclic neutropenia (CyN). While SCN exhibits persistent pathologic ANC values, CyN exhibits pathologic ANC values in a patterned fashion which can recur in 21-day intervals. Here, we describe a patient with a novel heterozygous ELANE deletion (c.224+(4_19)del16) presenting with clinical features consistent with CyN and a response to first-line therapy of granulocyte colony- stimulating factor.

What's in a Name? The Many Classifications of Acute Myeloid Leukemia with Dysplasia.

OBJECTIVES: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a high-risk subtype of AML that has recently undergone significant reclassification. Proper classification requires the integration of clinical history and diagnostic studies including peripheral blood and bone marrow morphology, flow cytometry, cytogenetic and molecular studies. The latter have significant clinical and prognostic implications. We present a case of a 55-year-old male diagnosed with AML-MRC with a pathogenic variant in TP53 and amplification of KMT2A (MLL) without rearrangement. We discuss presentation, importance of diagnostic testing through multiple modalities, and the changes in classification and diagnostic criteria between the 2017 World Health Organization (WHO) revised 4th edition and the WHO 5th edition and International Consensus Classification (ICC).

Pediatric Myelodysplastic Syndrome with SF3B1 Mutation.

OBJECTIVES: Patients with Fanconi Anemia (FA) have an increased risk of developing myeloid malignancies, which often precede the diagnosis of FA. We describe a patient with non-specific clinical findings diagnosed with myelodysplastic syndrome (MDS) at 17 years of age. A pathogenic SF3B1 alteration was identified and prompted evaluation for a bone marrow failure syndrome. Chromosomal breakage testing demonstrated an increase in breakage and radial formation; a targeted FA molecular panel identified variants of unknown significance in FANCB and FANCM. To date, reports of pediatric patients, with or without a co-morbid diagnosis of FA, diagnosed with MDS with SF3B1 alteration are rare. We describe a patient with FA diagnosed with MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD, WHO revised 4th edition) with an associated SF3B1 alteration and discuss the new classifications of this entity. In addition, as the knowledge around FA grows, so too does the knowledge about genes associated with FA. We present a novel variant of unknown significance in FANCB, to add to the growing body of literature about genetic alterations identified in individuals with a clinical picture most in keeping with FA.

Myelodysplastic Syndrome with Excess Blasts 2 (MDS-EB-2): A Historical Overview and Review of Forthcoming Classifications.

OBJECTIVES: Myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) primarily affects adults older than 50 years and confers a worse prognosis with a higher risk of transformation to acute myeloid leukemia (AML) compared to myelodysplastic syndrome (MDS) and MDS with excess blasts-1 (MDS-EB-1). In ordering diagnostic studies for MDS, cytogenetic and genomic studies are vital as they have significant clinical and prognostic implications for the patient. We present a case of a 71-year-old male diagnosed with MDS-EB-2 with a pathogenic loss-of-function TP53 variant and discuss presentation, pathogenesis, and the importance of thorough diagnostic testing through multiple modalities to accurately diagnose and subtype MDS. In addition, we explore a historical overview of the diagnostic criteria of MDS-EB-2 and how it has changed over time from the World Health Organization (WHO) 4th edition in 2008, the WHO revised 4th edition in 2017, and the upcoming WHO 5th edition and International Consensus Classification (ICC) for 2022.

Multiple Myeloma Detected by Noninvasive Prenatal Testing.

OBJECTIVES: Noninvasive prenatal testing (NIPT) has become a widely used screening method to detect fetal aneuploidies using cell-free fetal DNA (cffDNA) obtained from maternal blood. It is noninvasive, highly sensitive and specific, and can be offered in the first trimester of pregnancy. Though the goal of NIPT is to detect abnormalities in fetal DNA, occasionally abnormalities are detected that are not attributable to the fetus. Tumor DNA is laden with abnormalities and, rarely, NIPT has detected occult malignancy in the mother. Maternal malignancy in pregnancy is relatively uncommon, estimated at 1 in 1,000 pregnant women. We present a case of a 38-year-old woman diagnosed with multiple myeloma after abnormal NIPT testing results.

Noninvasive Prenatal Testing Leading to a Diagnosis of Hodgkin Lymphoma.

OBJECTIVES: Noninvasive prenatal testing (NIPT) is a screening method used to detect the most common fetal aneuploidies using cell-free fetal DNA (cffDNA) obtained from maternal blood. Due to the high sensitivity and specificity, low false positive rate, and use as early as 10-weeks' gestation NIPT has been rapidly integrated into prenatal care. While NIPT is an excellent screening tool, the results can be influenced by many factors including placental mosaicism, maternal aneuploidy or mosaicism, and occult maternal malignancy. The diagnosis and treatment of malignancy during pregnancy present many challenges ranging from the use of imaging techniques to the delivery of optimal therapy, weighing the unique risks to both the mother and the fetus. We present a case of a 30-year-old woman diagnosed with Hodgkin lymphoma after NIPT and outline the challenges in diagnosis and treatment of malignancy occurring during pregnancy.

Mantle Cell Lymphoma Presenting with Cutaneous Lesions: A Rare Manifestation of a Systemic Disease.

OBJECTIVES: Cutaneous lymphoma is a broad term used to describe any type of lymphoma involving the skin. They may be primary, arising in the skin, or secondary, resulting from spread of a systemic lymphoma. Cutaneous involvement of mantle cell lymphoma (MCL) is extremely rare and most often occurs secondarily. To date, less than 100 cases of MCL involving the skin have been described in the English literature. We describe a case of MCL involving the skin as the clinical presentation of disease in a 74-year-old man and highlight the radiographic and pathologic findings, treatment course, and prognosis.

Acute Myeloid Leukemia with Myelodysplasia-Related Changes Presenting as Vitamin B12 Deficiency: A Cautionary Tale.

OBJECTIVES: Acute myeloid leukemia may present with significant dysmyelopoiesis within the peripheral blood smear and bone marrow aspirate. In the setting of Vitamin B12 deficiency, proliferation of a clonal population of malignant cells can become impaired, masking an underlying myelodysplastic or leukemic process. Typically, the cautionary tale warns against diagnosing acute myeloid leukemia before ruling out Vitamin B12 deficiency. Here we describe a patient who initially presented with pancytopenia and Vitamin B12 deficiency who, upon supplementation, developed overt acute myeloid leukemia. This case will highlight the importance of cytogenetic and molecular studies as essential diagnostic tools in patients with unique presentations.

Mantle cell lymphoma presenting with lethal atraumatic splenic rupture.

Mantle cell lymphoma is characterized by t(11;14) with CCND1-IGH fusion and manifests with a spectrum of disease ranging from relatively indolent to aggressive. Here, we present a case of pleomorphic mantle cell lymphoma with three fusion signals that presented with lethal atraumatic splenic rupture. We discuss on the implications of variant CCND1 signal patterns as well as the epidemiology and pathophysiology of atraumatic splenic rupture.

Solving the Puzzle: The Diagnosis of Atypical Chronic Myeloid Leukemia, BCR-ABL1-Negative (aCML).

OBJECTIVES: Atypical chronic myeloid leukemia, BCR-ABL1-negative (aCML), is a rare myelodysplastic/myeloproliferative neoplasm with heterogeneous clinical and genetic features, a high rate of transformation to acute myeloid leukemia (AML), and poor survival rate. The diagnosis of aCML is a diagnosis of exclusion and requires the fulfillment of strict diagnostic criteria. Until recently, there were no distinctive cytogenetic or molecular abnormalities for aCML adding to the diagnostic challenge. We present a case of aCML and highlight the pertinent clinical, morphological, and genetic features required for the diagnosis.

When is surgical resection alone appropriate treatment for pediatric nodular lymphocyte-predominant Hodgkin lymphoma?

The surgeon's role in the management of lymphoma is typically limited to performing biopsies for diagnosis. Most patients with lymphoma are treated with chemotherapy and/or radiation, but in rare cases, lymphoma can be primarily treated with surgery. We present a case of nodular lymphocyte-predominant Hodgkin lymphoma in a 4-year-old child with cervical adenopathy and discuss initial treatment with surgery alone. Surgery as primary treatment avoids the serious long-term sequelae of chemotherapy and radiation, and reserves those options for possible future recurrences; however, this approach should be reserved for patients with limited and low-risk disease. This case report reviews the pros and cons of treating early-stage nodular lymphocyte-predominant Hodgkin lymphoma in a pediatric patient with surgery alone.

Unintended Consequences: Therapy-Related Acute Myeloid Leukemia.

OBJECTIVES: Acute myeloid leukemia (AML) is a group of diseases resulting from a clonal expansion of myeloid precursor cells in the bone marrow. Each subtype harbors characteristic clinical, morphologic, and molecular features. AML is most often de novo and arises from somatic mutations causing unchecked proliferation of myeloblasts, but it may also present as a secondary malignancy, often as the result of prior cytotoxic exposure. Here we present a case of therapy-related AML (t-AML) following chemotherapy exposure found to have a characteristic balanced translocation involving 11q23 and outline a potential mechanism of oncogenesis.

Conventional Cytogenetic Analysis of Hematologic Neoplasms: A 20-Year Review of Proficiency Test Results From the College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee.

CONTEXT.­: One goal of the joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee is to ensure the accurate detection and description of chromosomal abnormalities in both constitutional and neoplastic specimens, including hematologic neoplasms. OBJECTIVE.­: To report a 20-year performance summary (1999-2018) of conventional chromosome challenges focusing on hematologic neoplasms. DESIGN.­: A retrospective review was performed from 1999 through 2018 to identify karyotype challenges specifically addressing hematologic neoplasms. The overall performance of participants was examined to identify potential recurring errors of clinical significance. RESULTS.­: Of 288 total conventional chromosome challenges from 1999-2018, 87 (30.2%) were presented in the context of a hematologic neoplasm, based on the provided clinical history, specimen type, and/or chromosomal abnormalities. For these 87 hematologic neoplasm challenges, 91 individual cases were provided and graded on the basis of abnormality recognition and karyotype nomenclature (ISCN, International System for Human Cytogenomic [previously Cytogenetic] Nomenclature). Of the 91 cases, 89 (97.8%) and 87 (95.6%) exceeded the required 80% consensus for grading of abnormality recognition and correct karyotype nomenclature, respectively. The 2 cases (2 of 91; 2.2%) that failed to meet the 80% consensus for abnormality recognition had complex karyotypes. The 4 cases (4 of 91; 4.4%) that failed to meet the 80% consensus for correct karyotype nomenclature were the result of incorrect abnormality recognition (2 cases), missing brackets in the karyotype (1 case), and incorrect breakpoint designation (1 case). CONCLUSIONS.­: This 20-year review demonstrates clinical cytogenetics laboratories have been and continue to be highly proficient in the detection and description of chromosomal abnormalities associated with hematologic neoplasms.

Mantle cell lymphoma presenting with lethal atraumatic splenic rupture

Mantle cell lymphoma is characterized by t(11;14) with CCND1-IGH fusion and manifests with a spectrum of disease ranging from relatively indolent to aggressive. Here, we present a case of pleomorphic mantle cell lymphoma with three fusion signals that presented with lethal atraumatic splenic rupture. We discuss on the implications of variant CCND1 signal patterns as well as the epidemiology and pathophysiology of atraumatic splenic rupture.

Acute Myeloid Leukemia with t(8;16)(p11.2;p13.3)/ KAT6A-CREBBP in a Patient with an NF1 Germline Mutation and Clinical Presentation Mimicking Acute Promyelocytic Leukemia.

OBJECTIVES: Acute myeloid leukemia (AML) with t(8;16)(p11.2;p13.3)/KAT6A-CREBBP is an uncommon subtype of AML accounting for less than 0.5% of AML cases. AML with t(8;16)/KAT6A-CREBBP has characteristic clinical and pathologic features including disseminated intravascular coagulation (DIC), leukemia cutis, hemophagocytosis, monocytic or myelomonocytic differentiation, is frequently associated with therapy-related AML and has a poor prognosis. We present a classic case of AML with t(8;16)/KAT6A-CREBBP occurring in a patient with both a germline NF1 mutation and recent cytotoxic therapy for embryonal rhabdomyosarcoma.

Educational Case: Cytogenetics.

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.

Acute Myeloid Leukemia with t(6;9)(p23;q34.1); DEK-NUP214: The Pathogenesis and Potential.

OBJECTIVES: Acute myeloid leukemia (AML) is caused by the arrested differentiation and dysregulated proliferation of myeloid precursors. Many AMLs harbor genetic abnormalities which determine the molecular mechanisms of the disease and are associated with distinct clinical and pathological features, prognosis, and targeted therapies. We present a case of acute myeloid leukemia with t(6;9)(p23;q34.1) and review the classic clinical presentations and underlying pathogenesis of the disease.

Noonan Syndrome: Common Molecular Alterations and the Consequences.

OBJECTIVES: Noonan syndrome (NS) is a relatively common autosomal dominant disorder with characteristic features and molecular alterations. The most common recurrent alteration is in the PTPN11 gene, a proto-oncogene that encodes a cytoplasmic receptor tyrosine phosphatase and helps regulate kinase activity and control cell survival and replication. Mutations in this gene can increase the risk for the development of multiple different malignancies, particularly hematopoietic. Here we present a case of NS with a PTPN11 mutation demonstrating the classic presentation of Noonan syndrome as well as the expected clinical follow-up.

Protean Manifestations and Diagnostic Challenges Including Discordance Between Electrodiagnostic-Radiologic Studies in Neurolymphomatosis.

INTRODUCTION: Malignant lymphocytic infiltration of the central nervous system (CNS) and peripheral nervous system (PNS) is diagnostically challenging and informs treatment and prognosis. CASE REPORT: We describe the clinical course of a 49-year-old man with CNS and PNS relapse of mantle cell lymphoma and the diagnostic modalities that enabled the diagnosis of neurolymphomatosis. CONCLUSION: This clinical phenotype reinforces previously reported presentations of neurolymphomatosis and the ability of multimodal diagnostics, when combined with clinical suspicion phenotype, to enable diagnosis of malignant lymphocytic infiltration of the CNS and PNS.