Lauren B. Smith

Autopsy findings in eight patients with fatal H1N1 influenza.

A novel H1N1 influenza A virus emerged in April 2009, and rapidly reached pandemic proportions. We report a retrospective observational case study of pathologic findings in 8 patients with fatal novel H1N1 infection at the University of Michigan Health Systems (Ann Arbor) compared with 8 age-, sex-, body mass index-, and treatment-matched control subjects. Diffuse alveolar damage (DAD) in acute and organizing phases affected all patients with influenza and was accompanied by acute bronchopneumonia in 6 patients. Organizing DAD with established fibrosis was present in 1 patient with preexisting granulomatous lung disease. Only 50% of control subjects had DAD. Peripheral pulmonary vascular thrombosis occurred in 5 of 8 patients with influenza and 3 of 8 control subjects. Cytophagocytosis was seen in all influenza-related cases. The autopsy findings in our patients with novel H1N1 influenza resemble other influenza virus infections with the exception of prominent thrombosis and hemophagocytosis. The possibility of hemophagocytic syndrome should be investigated in severely ill patients with H1N1 infection.

Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature

Anaplastic large cell lymphoma (ALCL) is an aggressive neoplasm of T- or null cell phenotype and is recognized as a distinct clinicopathologic subtype of non-Hodgkin lymphoma (NHL) in the revised World Health Organization (WHO) classification of hematopoietic neoplasms. It is rarely associated with leukemic phase. Most cases with leukemic involvement are the small cell variant of ALCL. These cases often lack the pleomorphism seen in the common variant of ALCL and may be misdiagnosed. We report a series of three patients who presented with leukemic phase ALCL. The patients included an 11-year-old boy, a 29-year-old man, and a 59-year-old woman. The clinical and pathologic features of these cases are reviewed. The patients in our case series with leukemic phase ALCL exhibited rare clinical features. The patients presented with massive extranodal disease involving cerebrospinal fluid (CSF), liver, spleen, lungs, and bone marrow. CSF involvement was documented morphologically as well as by flow cytometry in two patients. Two of the patients had small cell variant and the third patient had common type ALCL. The neoplastic cells in all three patients were ALK positive; however these patients died within months of diagnosis. Leukemic phase ALCL is rare, and behaves in an aggressive manner. Some, but not all, cases in the literature presenting with peripheral blood involvement had small cell variant ALCL, as seen in two of our cases. The leukemic phase of ALCL should be considered when a T-cell leukemia with unusual morphologic features is encountered.

Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza

BACKGROUND Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. METHODS Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells. RESULTS Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. CONCLUSIONS This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection.

Concomitant BCR-ABL1 translocation and JAK2V617F mutation in three patients with myeloproliferative neoplasms

Chronic myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells, which fall into distinct categories based on a number of characteristics including the presence of the BCR-ABL1 gene fusion (chronic myelogenous leukemia) or the JAK2V617F mutation (polycythemia vera, primary myelofibrosis, and essential thrombocythemia). One of the criteria in the 2008 World Health Organization Classification divides MPN into different categories based on the presence of an underlying genetic abnormality, however the WHO does not currently address the classification of myeloproliferative neoplasms that have more than one genetic abnormality. The coexistence of a JAK2V617F mutation and BCR-ABL1 is rare, and to our knowledge, less than 25 cases have been reported in the literature. Our case series examines the clinical, histopathologic, and genetic features of 3 patients with myeloproliferative neoplasms characterized by concomitant BCR-ABL1 and JAK2V617F. The implications for diagnosis and treatment of patients with concomitant BCR-ABL1 and JAK2V617F are discussed as well as how the BCR-ABL1 and JAK2V617F-positive clones may be related to one another.

Tumor-Absorbed Dose Predicts Progression-Free Survival Following 131I-Tositumomab Radioimmunotherapy

The study aimed at identifying patient-specific dosimetric and nondosimetric factors predicting outcome of non-Hodgkin lymphoma patients after 131I-tositumomab radioimmunotherapy for potential use in treatment planning. Methods: Tumor-absorbed dose measures were estimated for 130 tumors in 39 relapsed or refractory non-Hodgkin lymphoma patients by coupling SPECT/CT imaging with the Dose Planning Method (DPM) Monte Carlo code. Equivalent biologic effect was calculated to assess the biologic effects of nonuniform absorbed dose including the effects of the unlabeled antibody. Evaluated nondosimetric covariates included histology, presence of bulky disease, and prior treatment history. Tumor level outcome was based on volume shrinkage assessed on follow-up CT. Patient level outcome measures were overall response (OR), complete response (CR), and progression-free survival (PFS), determined from clinical assessments that included PET/CT. Results: The estimated mean tumor-absorbed dose had a median value of 275 cGy (range, 94–711 cGy). A high correlation was observed between tracer-predicted and therapy-delivered mean tumor-absorbed doses (P < 0.001; r = 0.85). In univariate tumor-level analysis, tumor shrinkage correlated significantly with almost all of the evaluated dosimetric factors, including equivalent biologic effect. Regression analysis showed that OR, CR, and PFS were associated with the dosimetric factors and equivalent biologic effect. Both mean tumor-absorbed dose (P = 0.025) and equivalent biologic effect (P = 0.035) were significant predictors of PFS whereas none of the nondosimetric covariates were found to be statistically significant factors affecting PFS. The most important finding of the study was that in Kaplan–Meier curves stratified by mean dose, longer PFS was observed in patients receiving mean tumor-absorbed doses greater than 200 cGy than in those receiving 200 cGy or less (median PFS, 13.6 vs. 1.9 mo for the 2 dose groups; log-rank P < 0.0001). Conclusion: A higher mean tumor-absorbed dose was significantly predictive of improved PFS after 131I-tositumomab radioimmunotherapy. Hence tumor-absorbed dose, which can be estimated before therapy, can potentially be used to design radioimmunotherapy protocols to improve efficacy.

How do I allocate blood products at the end of life? An ethical analysis with suggested guidelines.

Blood products are scarce resources requiring prudent and reasoned allocation. The utilization of red blood cells and platelets in terminally ill patients can be complicated and requires guidelines tempered by individualized considerations. Representative cases are discussed in which blood products are requested or utilized by patients at the end of life. Relevant literature is reviewed and ethical issues pertaining to each case are discussed. A practical approach to blood product utilization at the end of life is suggested.

Anaplastic Large Cell Lymphoma: Features Presenting Diagnostic Challenges

Anaplastic large cell lymphoma has histopathologic features that necessitate a broad differential diagnosis. Diagnostic considerations include carcinoma, melanoma, and hematopoietic malignancies, including diffuse large B-cell lymphoma, classical Hodgkin lymphoma, myeloid sarcoma, and peripheral T-cell lymphoma, not otherwise specified. Unusual features can include subtle sinusoidal involvement, histiocytic morphology, cytokeratin expression, CD15 expression, and variant patterns of anaplastic lymphoma kinase expression. Cases with unusual morphologic or immunohistochemical findings will be presented to highlight the complexity encountered in practice.

Systematic evaluation of skeletal mechanical function.

Many genetic and environmental perturbations lead to measurable changes in bone morphology, matrix composition, and matrix organization. Here, straightforward biomechanical methods are described that can be used to determine whether a genetic or environmental perturbation affects bone strength. A systematic method is described for evaluating how bone strength is altered in the context of morphology and tissue‐level mechanical properties, which are determined in large part from matrix composition, matrix organization, and porosity. The methods described include computed tomography, whole‐bone mechanical tests (bending and compression), tissue‐level mechanical tests, and determination of ash content, water content, and bone density. This strategy is intended as a first step toward screening mice for phenotypic effects on bone and establishing the associated biomechanical mechanism by which function has been altered, and can be conducted without a background in engineering. The outcome of these analyses generally provides insight into the next set of experiments required to further connect cellular perturbation with functional change. Curr. Protoc. Mouse Biol. 3:39‐67

Pathology Review of Outside Material: When Does It Help and When Can It Hurt?

PURPOSE Pathology review is performed for patients when care is transferred to a tertiary care center after diagnostic tissue has been obtained. While it has many benefits, this practice can lead to unforeseen difficulties in doctor-patient communication and patient well-being, especially if a diagnosis is overturned or modified years after treatment. The aim of this analysis is to identify clinical situations in which pathology review can result in challenging discussions between patients and oncologists. PATIENTS Representative case scenarios are presented in the subspecialty area of hematopathology. Analysis of the clinical benefits and possible harm to patients, pathologists, and treating oncologists that may ensue from pathology review is performed. RESULTS Pathology review may result in a valuable second opinion and expert subclassification. However, problematic situations may arise with pathology review, especially if the patient has already undergone definitive treatment and is referred to an academic institution in remission. Difficulties can also arise when patients do not understand the limitations of diagnosing disease on small biopsies. The patient may receive a different diagnosis or it may become apparent that the diagnosis could have been made more expeditiously. These discrepancies must be communicated to the patient and may cause confusion and distress. CONCLUSION Pathology review can be beneficial or potentially harmful depending on the clinical situation. Preliminary recommendations are provided for selecting patients for review. Limiting pathology review to certain clinical situations and encouraging patients to get second opinions before initial treatment at local referral centers may be helpful in minimizing reassignment of diagnoses after definitive treatment.

The genetics of interdigitating dendritic cell sarcoma share some changes with Langerhans cell histiocytosis in select cases

Histiocytic disorders have been noted to have evidence of transdifferentiation; examples of cases with combinations of different lineages have been shown. In our index case, we identified interdigitating dendritic cell (IDC) differentiation in a case of Langerhans cell histiocytosis (LCH). Little is currently known about the genetics of IDC sarcoma (IDCS) because they are exceedingly rare. Using array comparative genomic hybridization (aCGH), we evaluated 4 cases of IDCS and compared them with our index case, as well as genetic abnormalities previously found in LCH. Four cases of paraffin-embedded samples of IDCS and 1 case of LCH with IDC differentiation were evaluated using aCGH. Array CGH results showed no abnormalities in a case of LCH with interdigitating cell differentiation. In 3 of 4 cases of IDCS, genetic abnormalities were identified; 1 case had no identifiable abnormalities. Interdigitating dendritic cell sarcoma case 1 had gains of 3q and 13q; IDCS case 2 had trisomy 12; IDCS case 3 had deletions of 7p, 12p, 16p, 18q, 19q, and 22q; and IDCS case 4 had no detectable abnormalities. Our index case, LCH with IDC differentiation, showed no abnormalities by aCGH. A number of LCH cases do not have detectable genetic abnormalities. In contrast, 3 of 4 cases of IDCS evaluated had identifiable abnormalities by aCGH. Furthermore, 2 of these shared abnormalities, albeit of large genetic regions, with published abnormalities seen in LCH. No recurrent abnormalities were identified in the IDCS cases. However, the possibility of a relationship between IDCS and LCH cannot be entirely excluded by these results.