CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Matthew Geller, DO
Elie Traer, MD, PhD
Jennifer Dunlap, MD
November 2015—CAP TODAY and the Association for Molecular Pathology have teamed up to bring molecular case reports to CAP TODAY readers. AMP members write the reports using clinical cases from their own practices that show molecular testing’s important role in diagnosis, prognosis, and treatment. Case report No. 9, which begins here, comes from the Divisions of Hematopathology and Hematology and Medical Oncology and the Knight Cancer Institute, Oregon Health & Science University. If you would like to submit a case report, please send email to the AMP at amp@amp.org. For more information about the AMP and all previously published case reports, visit www.amp.org.
The 2008 World Health Organization diagnostic criteria for chronic myelomonocytic leukemia (CMML) integrate peripheral blood and bone marrow findings, including morphologic and chromosomal abnormalities. Notably, there is no single pathognomonic finding specific to CMML,1,2 and it is important to exclude secondary causes of monocytosis (Fig. 1). Diagnostic difficulty is often encountered in cases in which a technically challenging bone marrow biopsy limits appropriate morphologic evaluation or in cases in which clinical and histologic features do not clearly meet diagnostic criteria.
Fig. 1. WHO diagnostic criteria for CMML
- Persistent peripheral blood monocytosis > 1 × 109/L.
- No Philadelphia chromosome or BCR-ABL1 fusion gene.
- No rearrangements of PDGFRA, PDGFRB, or FGFR1.
- Less than 20 percent blasts (includes promonocytes and monoblasts) in blood and bone marrow.
- Dysplasia in one or more myeloid lineages. If dysplasia is absent or minimal, diagnosis of CMML can be made if other requirements are met and:
- an acquired clonal cytogenetic or molecular genetic abnormality is present;
- monocytosis has persisted for at least three months; and
- all other causes of monocytosis have been excluded.
In CMML, identifying a chromosomal abnormality can make it much easier to reach a diagnosis, particularly in cases where dysplasia is minimal or absent. However, cytogenetic abnormalities detected by metaphase karyotype or fluorescence in situ hybridization are seen in only about 30 percent of cases. Next-generation sequencing technology provides the ability to screen many potentially disease-associated genes for pathogenic mutations and is becoming increasingly important in identifying targeted therapies for patients. Furthermore, depending on the platform, NGS requires relatively little DNA (about 10–250 ng), has a lower limit of detection of about five percent, and can be performed in paraffin-embedded tissue. Here, we discuss the diagnostically challenging case of a man with an ambiguous clinical presentation and bone marrow biopsy whose diagnosis was aided by the use of targeted next-generation sequencing.
Case. The patient is a 65-year-old male with a history of type 2 diabetes mellitus, coronary artery disease, and a monoclonal gammopathy of unknown significance (MGUS) who presented with clinical deterioration including dyspnea, fatigue, abdominal bloating, and lower extremity edema. Over the past year he experienced an 80-pound weight loss with repeated episodes of pleural effusions, ascites, lymphadenopathy, anemia, splenomegaly, and intermittent leukocytosis. These episodes led to several prolonged hospitalizations without a unifying diagnosis. His clinical course was further complicated by a sudden retroperitoneal hemorrhage involving the left renal sack, with subsequent acute renal failure, fever of unknown origin, and failure to thrive.