Educational Case: Small Lymphocytic Lymphoma: Diagnostic Features and Prognosis.

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.

Systemic Iron Deficiency in a Nonhuman Primate Model of Endometriosis.

Endometriosis is characterized by endometrial tissue development outside the uterus. Anemia and iron depletion do not commonly accompany endometriosis in women, despite chronic abdominal inflammation and heavy menstrual bleeding. The objective of this study was to examine iron kinetics associated with endometriosis by using a NHP model, to better understand the underlying mechanism of abnormal hematogram values in women with endometriosis. Hematologic data from 46 macaques with endometriosis were examined for signs of iron depletion. Bone marrow, liver, and serum were used to elucidate whether iron loss or inflammation best explained the hematologic findings. Additional serum markers and intestinal biopsies from NHP with and without endometriosis were evaluated for patterns in iron kinetics across the menstrual cycle and for relative dietary iron-absorbing capacity. Almost half of the NHP with endometriosis were anemic. Overall, NHP had decreased RBC counts, increased MCV, increased percentage of reticulocytes, decreased serum hepcidin, and decreased hepatic and bone marrow iron. Intestinal expression of ferroportin 1, a mediator of iron absorption, was increased, indicating that despite high dietary iron, intestinal iron absorption did not compensate for iron losses. We concluded that use of oral iron supplementation alone does not replenish iron stores in endometriosis. Consequently, iron stores should be evaluated in women with endometriosis, even without overt clinical signs of anemia.

Clinical Utility of Ordered Pathology Blood Smear Reviews - an Overused Resource?

BACKGROUND: Blood smear reviews by pathologists (BSR) are ordered frequently at our institution, take time to evaluate, and result in a written report. Minimal research has been done regarding the amount of novel data reported and its clinical utility. METHODS: Detailed chart review was performed on BSR orders from January 1, 2015 to March 31, 2015 to assess reasons for smear review, if results were mentioned in the chart, if laboratory-driven reviews were already performed, and if novel, clinically influential data was reported. The trends in ordering was also evaluated. RESULTS: A total of 277 reviews were performed and were most commonly ordered to evaluate the presence of malignancy (43%), hemolysis (18%), and anemia (16%). For 130 of the 277 specimens, laboratory-driven smear review was already performed. The BSR smear review findings were not mentioned in the patient chart in 52% of cases. The report provided novel data in 187 cases (68%) which mainly were minor findings such as low levels of red blood cell abnormalities. The novel data appeared to influence clinical decision making in only 3 cases (1%). CONCLUSIONS: Although novel data are often reported, only rarely does it appear to be clinically significant and the information frequently overlaps with information already provided by laboratory-initiated smear reviews. Discussion with, and education of, clinical staff may increase appropriate utilization.

Leukemic Transdifferentiation of Follicular Lymphoma Into an Acute Histiocytic Leukemia in a 52-Year-Old Caucasian Woman.

We report an instructive case of acute myeloid leukemia with histiocytic differentiation (acute histiocytic leukemia) arising in a patient, a 52-year-old woman with a history of follicular lymphoma. The results of genetic studies proved a clonal relationship between the lymphoma and the leukemic cells. To our knowledge, this is the first report of leukemic transdifferentiation of follicular lymphoma into modified base 5-methylcytosine (M(5)c)-like acute histiocytic leukemia and the first reported karyotype on a transdifferentiated neoplasm.

Adequacy of powered vs manual bone marrow biopsy specimens: a retrospective review of sequential marrow aspirates and biopsies in 68 patients.

OBJECTIVES: To evaluate the quality and quantity of the bone marrow aspirates and biopsy specimens obtained with a powered system in comparison with the standard manual method. METHODS: The Pathology Laboratory Information System was reviewed for patients who had previously undergone bone marrow biopsies performed by both the OnControl Bone Marrow System and the manual method. A total of 136 cases (68 patients) were reviewed for adequacy and compared using an unpaired t test. RESULTS: The core biopsy specimens obtained by the OnControl system were significantly longer compared with those obtained by the manual system (16.9 vs 14.4 mm, P = .0036). However, the core biopsy specimens obtained by the manual method had on average more evaluable marrow elements (66% vs 40%, P < .0001), and the manual method was superior in 46 of the 68 cases when the length of evaluable marrow was calculated (9.7 vs 7 mm, P = .0049). CONCLUSIONS: Our findings show that longer core biopsy specimens are obtained by the OnControl Bone Marrow system but that the manual method is still superior when the percentage and length of evaluable bone marrow are analyzed.

Pathology Milestones: Assessing Clinical Competency by Committee.

All Accreditation Council for Graduate Medical Education accredited pathology residency training programs are now required to evaluate residents using the new Pathology Milestones assessment tool. Similar to implementation of the 6 Accreditation Council for Graduate Medical Education competencies a decade ago, there have been challenges in implementation of the new milestones for many residency programs. The pathology department at the University of Iowa has implemented a process that divides the labor of the task in rating residents while also maintaining consistency in the process. The process is described in detail, and some initial trends in milestone evaluation are described and discussed. Our experience indicates that thoughtful implementation of the Pathology Milestones can provide programs with valuable information that can inform curricular changes.

A report on the piloting of a novel computer-based medical case simulation for teaching and formative assessment of diagnostic laboratory testing.

OBJECTIVES: Insufficient attention has been given to how information from computer-based clinical case simulations is presented, collected, and scored. Research is needed on how best to design such simulations to acquire valid performance assessment data that can act as useful feedback for educational applications. This report describes a study of a new simulation format with design features aimed at improving both its formative assessment feedback and educational function. METHODS: Case simulation software (LabCAPS) was developed to target a highly focused and well-defined measurement goal with a response format that allowed objective scoring. Data from an eight-case computer-based performance assessment administered in a pilot study to 13 second-year medical students was analyzed using classical test theory and generalizability analysis. In addition, a similar analysis was conducted on an administration in a less controlled setting, but to a much large sample (n = 143), within a clinical course that utilized two random case subsets from a library of 18 cases. RESULTS: Classical test theory case-level item analysis of the pilot assessment yielded an average case discrimination of 0.37, and all eight cases were positively discriminating (range = 0.11-0.56). Classical test theory coefficient alpha and the decision study showed the eight-case performance assessment to have an observed reliability of σ = G = 0.70. The decision study further demonstrated that a G = 0.80 could be attained with approximately 3 h and 15 min of testing. The less-controlled educational application within a large medical class produced a somewhat lower reliability for eight cases (G = 0.53). Students gave high ratings to the logic of the simulation interface, its educational value, and to the fidelity of the tasks. CONCLUSIONS: LabCAPS software shows the potential to provide formative assessment of medical students' skill at diagnostic test ordering and to provide valid feedback to learners. The perceived fidelity of the performance tasks and the statistical reliability findings support the validity of using the automated scores for formative assessment and learning. LabCAPS cases appear well designed for use as a scored assignment, for stimulating discussions in small group educational settings, for self-assessment, and for independent learning. Extension of the more highly controlled pilot assessment study with a larger sample will be needed to confirm its reliability in other assessment applications.

Expression profiling of transcription factors in B- or T-acute lymphoblastic leukemia/lymphoma and burkitt lymphoma: usefulness of PAX5 immunostaining as pan-Pre-B-cell marker.

The optimal use of transcription factors to determine B-lineage specificity in B-acute lymphoblastic leukemia/lymphoma (B-ALL) has not been fully investigated. We undertook an extensive immunohistochemical study of a panel of B-cell transcription factors in B- and T-ALL and Burkitt lymphoma to evaluate those with the best specificity and sensitivity. Tissue microarrays were constructed from 34 B-ALL, 19 T-ALL, and 30 Burkitt lymphoma samples. All 34 (100%) cases of B-ALL expressed PAX5; 32 (94%), BOB.1; 33 (97%), PU.1; 29 (85%), CD79a; 27 (79%), CD22; 2 (6%), CD20; 9 (26%), OCT-2; and 3 (9%), MUM1. Burkitt lymphoma cases were positive for PAX5 (30/30 [100%]), BOB.1 (27/30 [90%]), PU.1 (23/30 [77%]), CD79a (29/30 [97%]), CD22 (14/30 [47%]), CD20 (30/30 [100%]), OCT-2 (23/30 [77%]), and MUM1 (5/30 [17%]). T-ALLs were only positive for PU.1 (15/19 [79%]) and BOB.1 (12/19 [63%]). PAX5 demonstrated better specificity for B-lineage determination than BOB.1 and PU.1 and better sensitivity than CD79a, CD22, and CD20. These findings suggest that PAX5 has the greatest diagnostic usefulness and lineage determination in B-ALL, especially in cases with an inadequate specimen for flow cytometric analysis.

Bone marrow biopsies in patients 85 years or older.

Increasing numbers of bone marrow aspirates and core biopsies are done in very elderly people; there is little published literature regarding the usefulness of bone marrow biopsies in these patients. We undertook a retrospective review of 119 bone marrow aspirates and biopsies from patients 85 years or older. These procedures were performed for a variety of abnormalities, including unexplained cytopenias; evaluation of a known myelodysplastic syndrome; suspicion or follow-up of plasma cell myeloma, thrombocytosis, or leukocytosis; and suspicion or staging of lymphoma. When staging or follow-up biopsies were excluded, 34 (43%) of 79 yielded specific diagnoses. Follow-up was available for 45 patients, and of these 45, 20 patients received therapy: 17 were treated with an abbreviated or modified regimen, and 12 were treated for leukemia/lymphoma. Therapy failed in all patients. As a result of these biopsies, relatively few patients received more than supportive treatment, suggesting that higher thresholds for biopsy for cytopenias may be indicated.

The usefulness of the aspirate differential count in cases of nonhematologic neoplasia.

A standard bone marrow examination may be done in patients with a known nonhematologic malignancy in order to evaluate the presence or absence of metastatic disease. A 300-cell-count differential of the aspirate is often performed in these cases. However, the clinical utility of the differential count has never been assessed. A retrospective review was performed on 107 bone marrow reports from 86 patients with a documented nonhematologic malignancy to determine the clinical usefulness of the differential counts in this patient population. Two cases out of 107 had clinically relevant findings from the aspirate differential. One patient had an increase in plasma cells (7%) and one had left-shifted granulopoiesis with 19% blasts. In most instances, the performance of an aspirate differential adds little clinically useful information in patients undergoing bone marrow examination for metastatic disease. There are cost savings associated with omitting the routine aspirate differential as either technologist- or pathologist-time in performing the differential is decreased.

Increased blasts mimicking acute leukemia in a patient with polysubstance abuse.

Toxic insult to the bone marrow may result in partial or complete suppression, with or without reactive changes, and probable eventual regeneration of hematopoietic elements. During the regenerative process, increased blasts may be observed. Distinguishing these changes from an acute leukemic process can be difficult. In particular, the diagnosis of hypocellular bone marrow with increased blasts, also known as hypocellular or hypoplastic acute leukemia, presents a diagnostic dilemma for pathologists. We report a case of hypocellular marrow with increased blasts in a 50-year-old man with an extensive history of alcohol and drug abuse in whom chemotherapy was deferred. Recovery of peripheral blood cell counts and reticulocytosis occurred with withdrawal of the offending agents, and he remains alive and well 1 year later.

A phase I and pharmacodynamic study of sequential topotecan and etoposide in patients with relapsed or refractory acute myelogenous and lymphoblastic leukemia.

We designed a pharmacokinetic and pharmacodynamic phase I study of sequential topotecan (2.55-6.3mg/m2) by 72h infusion followed by five daily doses of etoposide for patients with refractory acute leukemia based upon synergistic anti-tumor activity of topoisomerase I and II inhibitors in vitro. Eight of the 29 patients achieved bone marrow aplasia and two patients achieved clinical remission. Common grade 3-4 toxicities included hepatic and gastrointestinal dysfunction, and correlated with increased steady-state plasma topotecan concentration. The predicted up-regulation of topoisomerase II activity by topoisomerase I inhibition was not observed at this dose and schedule and may provide insight into the modest anti-leukemia activity of the regimen.

Detection of factor V leiden and prothrombin gene mutations in patients who died with thrombotic events.

CONTEXT: Individuals with factor V or prothrombin gene mutations are at increased risk for thrombotic events. Furthermore, the risk of recurrent deep venous thrombosis in heterozygous carriers of both factor V Leiden and prothrombin gene mutations is high enough that some investigators suggest lifelong warfarin prophylaxis for these individuals, even with a single spontaneous thrombotic event. OBJECTIVES: To assess the incidence of factor V Leiden and prothrombin gene mutations in an autopsy population and to determine if these tests can prove useful in identification of at-risk family members. DESIGN: We analyzed factor V Leiden and prothrombin gene mutations in 45 patients who died with or of thrombotic events, using archival tissue and multiplex allele-specific polymerase chain reaction amplification. The wild-type factor V gene was amplified in all 45 patients, whereas the wild-type prothrombin gene was amplified in 29 patients. RESULTS: Two patients (4.4%) who died with thrombotic events at the ages of 35 and 92 years were heterozygous for factor V gene mutation. Two additional patients (6.7%), who died with thrombotic events at the ages of 26 and 39 years, were heterozygous for prothrombin gene mutation. Patients homozygous for either factor V or prothrombin gene or simultaneously heterozygous for both genes were not detected in our study. CONCLUSIONS: Our findings suggest that screening the relatives of elderly patients who die with thrombotic events would not be cost-effective because of the low incidence of these mutations in the autopsy population. However, because the incidence of these mutations appeared significantly more frequently among individuals who died at 39 years or younger, testing the relatives of this subset of patients may prove useful for detection of at-risk individuals who would benefit from preventive anticoagulation therapy.

Leukemias resembling acute promyelocytic leukemia, microgranular variant.

Acute promyelocytic leukemia (APL) should be distinguished from other subtypes of acute myeloid leukemia (AML) because of the increased risk of disseminated intravascular coagulation (DIC) and its response to arsenic compounds and retinoids. Some cases of AML seem morphologically similar to the microgranular variant of APL (French-American-British [FAB] AML-M3v) but lack the t(15;17). We evaluated 8 cases of APL-like leukemias for subtle morphologic, cytochemical, immunophenotypic, and cytogenetic differences compared with 5 cases of promyelocytic leukemia/retinoic receptor alpha (PML/RARalpha)-positive APL (FAB AML-M3v). We also evaluated both groups for the presence of DIC. No differences among the groups were noted in blast size, chromatin pattern, nuclear morphologic features, intensity of myeloperoxidase staining, or presence of Auer rods. Immunophenotypes were similar; both types of cases lacked CD34 and HLA-DR and were CD13+ and CD33+. Two cases of APL-like leukemias also were CD56+. DIC was present in 2 patients with M3v. Our study shows that there are no definitive morphologic, cytochemical, or immunophenotypic findings that can distinguish these cases from PML/RARalpha-positive APL.