Marian A. Rollins-Raval

An immunohistochemical panel to differentiate metastatic breast carcinoma to skin from primary sweat gland carcinomas with a review of the literature.

CONTEXT Approximately 25% of patients with breast cancer develop cutaneous metastases. Sweat gland carcinomas (SGCs) account for about 0.05% of all cutaneous neoplasms. Cutaneous metastases of breast carcinoma (CMBCs) (especially the ductal type) can be difficult to distinguish from SGCs. Treatment and prognoses for these 2 types of tumors differ radically, making accurate histologic diagnosis crucial. Although a few studies attempt to differentiate these entities employing immunohistochemical (IHC) studies (some of which we review here), to date, no panel of IHC stains exists, to our knowledge, to distinguish these entities. OBJECTIVE To devise a panel of IHC stains to distinguish CMBC from SGC. DESIGN Twelve cases of ductal CMBCs (11 not otherwise specified type, and 1 basal phenotype), 11 cases of SGCs (5 eccrine carcinomas, 3 porocarcinomas, and 3 microcystic adnexal carcinomas), 2 benign sweat gland neoplasm cases, and 2 primary breast cancer cases were retrieved and analyzed with the following IHC panel: mammaglobin, gross cystic disease fluid protein (GCDFP) 15, p63, basal cytokeratins (CK5, CK14, and CK17), androgen receptor, and PAX5. RESULTS The p63 was only weakly expressed in 1 of 12 CMBC cases (8.3%), whereas it was strongly expressed in 10 of 11 SGC cases (90.9%) (P < .001). Basal cytokeratins demonstrated a similar immunoprofile in the SGC group, with 10 of 11 cases (90.9%) expressing all 3 markers, and a variable immunoprofile in the CMBC group with 0% (CK14) (P < .001) to 16.7% (2 of 12 cases; CK5 and CK17) (P < .001) expression. Mammaglobin was expressed in 8 of 12 cases (66.7%) of CMBC. CONCLUSIONS Together, these 5 IHC stains were combined to make a panel that was 100% sensitive and 91% specific in distinguishing between CMBC and SGC.

CD123 immunohistochemical expression in acute myeloid leukemia is associated with underlying FLT3-ITD and NPM1 mutations.

FLT3-ITD and NPM1 mutation testing in acute myeloid leukemia (AML) plays an important role in prognostic risk stratification, especially within the intermediate cytogenetic risk group. Molecular studies require adequate fresh material and are typically performed on a dedicated aspirate specimen, which may not be available in all cases. Prior flow cytometric studies have suggested an association between CD123 overexpression in AML and FLT3-ITD and/or NPM1 mutations; however, the immunohistochemical (IHC) correlate is unknown. We assessed CD123 IHC expression in 157 AML bone marrow biopsies and/or marrow particle preparations, and correlated with the morphologic, immunophenotypic, and cytogenetic features and with the presence of FLT3-ITD and NPM1 mutations. We found that CD123 IHC expression, seen in 40% of AML, occurred across a wide spectrum of 2008 World Health Organization subtypes and was most frequent within the intermediate risk group. As compared with CD123 IHC−AML, CD123 IHC+AML demonstrated higher marrow blast percentages (median 69%), monocytic differentiation (33/63 cases), and CD34 negativity (29/63 cases). Eighty-three percent (25/30) FLT3-ITD-mutated AML were CD123+ (P<0.0001) and 62% (18/29) NPM1-mutated cases were CD123 IHC+ (P=0.0052) with negative predictive values of 95% for FLT3-ITD and 88% for NPM1. CD123 IHC+AML presents with characteristic pathologic features, some of which may be related to underlying FLT3-ITD and/or NPM1 mutations.

Increased numbers of IgG4-positive plasma cells may rarely be seen in lymph nodes of patients without IgG4-related sclerosing disease.

IgG4-related sclerosing disease (IRSD) is a steroid-responsive fibroinflammatory disorder characterized by increased IgG4+ cells. Nodal involvement usually lacks the dense sclerosis seen in extranodal sites, with histologic patterns overlapping with other reactive processes. Twenty-six lymph nodes showing IRSD-related histologic patterns were evaluated for IgG and IgG4 positive cells by immunohistochemistry and correlated with the clinical features. Cases included 7 Castleman disease–like cases (type I pattern), 10 follicular hyperplasia (type II), and 9 plasmacytosis (type III). The mean numbers of IgG4+ cells per high-power field (HPF) were 4.8 (I), 8.4 (II), and 26.6(III), and the mean IgG4/IgG ratios were 0.05 (I), 0.04 (II), and 0.08 (III). Using >50 IgG4+cells/HPF and IgG4/IgG ratio of >0.4 for absolute and relative increases, only 1 case fulfilled both criteria for increased IgG4+ cells, a patient with Hashimoto’s thyroiditis without clinical evidence of IRSD. The results suggest that increased IgG4+ cells may rarely be seen in non-IRSD lymph nodes.

Experience with CellaVision DM96 for peripheral blood differentials in a large multi-center academic hospital system

Context and Aims: Rapid, accurate peripheral blood differentials are essential to maintain standards of patient care. CellaVision DM96 (CellaVision AB, Lund, Sweden) (CV) is an automated digital morphology and informatics system used to locate, pre-classify, store and transmit images of platelets, red and white blood cells to a trained technologist who confirms or edits CV cell classification. We assessed our experience with CV by evaluating sensitivity, specificity, positive predictive value and negative predictive value for CV in three different patient populations. Materials and Methods: We analyzed classification accuracy of CV for white blood cells, erythroblasts, platelets and artefacts over six months for three different university hospitals using CV. Results: CV classified 211,218 events for the adult cancer center; 51,699 events for the adult general hospital; and 8,009 events for the children′s hospital with accuracy of CV being 93%, 87.3% and 95.4% respectively. Sensitivity and positive predictive value were <80% for immature granulocytes (band neutrophil, promyelocyte, myelocyte and metamyelocytes) (differences usually within one stage of maturation). Cell types comprising a lower frequency of the total events, including blasts, showed lower accuracy at some sites. Conclusions: The reduced immature granulocyte classification accuracy may be due in part to the subjectivity in classification of these cells, length of experience with the system and individual expertise of the technologist. Cells with low sensitivity and positive predictive value comprised a minority of the cells and should not significantly affect the technologist re-classification time. CV serves as a clinically useful instrument in performance of peripheral blood differentials.

The value of immunohistochemistry for CD14, CD123, CD33, myeloperoxidase and CD68R in the diagnosis of acute and chronic myelomonocytic leukaemias

Rollins‐Raval M A & Roth C G 
(2012) Histopathology 60, 933–942

Cardiac Injury Is a Common Postmortem Finding in Thrombotic Thrombocytopenic Purpura Patients: Is Empiric Cardiac Monitoring and Protection Needed?

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal disease. Early implementation of therapeutic plasma exchange (TPE) has decreased the mortality rate from >90% to <10%. However, fatalities still occur in these patients. The goal of this study was to characterize the causes of death and related postmortem findings in patients with TTP in the current era of emergent TPE to identify possible areas for improvement in the care of these patients. We analyzed clinical history, laboratory and histopathologic findings, and causes of death of patients with active TTP or TTP in clinical remission autopsied at our institution over 22 years. Of 18 patients, 15 had TTP judged to be a cause of death: it was an underlying cause of death in five cases, intermediate in three, and contributing in seven. The most common immediate causes of death were cardiac arrest and myocardial infarction. The most common TTP‐related findings at autopsy were thrombi/emboli in heart (9), lung (11), brain (3), kidney (7), followed by hemorrhages in heart (7), lung (8), brain (2), kidney (7), and infarcts in heart (5), lung (4), brain (6) and kidney (3). Analysis of the cases with TTP as a cause of death suggests that the mechanism of death is commonly cardiac in origin. Proactive measures to monitor and protect the heart may be beneficial in these patients.

Implementation of a simple electronic transfusion alert system decreases inappropriate ordering of packed red blood cells and plasma in a multi-hospital health care system

BACKGROUND AND OBJECTIVES Prescriber adherence to institutional blood component ordering guidelines can be low. The goal of this study was to decrease red blood cell (RBC) and plasma orders that did not meet institutional transfusion guidelines by using data within the laboratory information system to trigger alerts in the computerized order entry (CPOE) system at the time of order entry. METHODS At 10 hospitals within a regional health care system, discernment rules were created for RBC and plasma orders utilizing transfusion triggers of hemoglobin <8 gm/dl and INR >1.6, respectively, with subsequent alert generation that appears within the CPOE system when a prescriber attempts to order RBCs or plasma on a patient whose antecedent laboratory values do not suggest that a transfusion is indicated. Orders and subsequent alerts were tracked for RBCs and plasma over evaluation periods of 15 and 10 months, respectively, along with the hospital credentials of the ordering health care providers (physician or nurse). RESULTS Alerts triggered which were heeded remained steady and averaged 11.3% for RBCs and 19.6% for plasma over the evaluation periods. Overall, nurses and physicians canceled statistically identical percentages of alerted RBC (10.9% vs. 11.5%; p = 0.78) and plasma (21.3% vs. 18.7%; p = 0.22) orders. CONCLUSIONS Implementing a simple evidence-based transfusion alert system at the time of order entry decreased non-evidence based transfusion orders by both nurse and physician providers.

The number and growth pattern of plasmacytoid dendritic cells vary in different types of reactive lymph nodes: an immunohistochemical study

Plasmacytoid dendritic cells, which play a fundamental role in the innate immune response, are best known for their presence in hyaline-vascular Castleman disease and histiocytic necrotizing lymphadenitis. The relative number and distribution in many reactive entities as detected using more sensitive methods are uncertain, and their diagnostic implications are unknown. Immunohistochemical studies for plasmacytoid dendritic cell-associated markers CD123 and CD2AP were performed on 42 lymph nodes with hyaline-vascular Castleman disease, histiocytic necrotizing lymphadenitis, sarcoidosis, necrotizing granulomatous inflammation, viral infection, dermatopathic lymphadenopathy, autoimmune disease, and a histologic pattern compatible with toxoplasmosis. The overall plasmacytoid dendritic cell numbers and growth patterns (tight aggregates, loose aggregates/clusters, scattered single cells) were assessed. Plasmacytoid dendritic cells were present in all cases and were predominantly distributed in loose aggregates/clusters or singly. They were most numerous in granulomatous inflammation and histiocytic necrotizing lymphadenitis, whereas viral infections showed the fewest overall numbers and a predominant pattern of scattered single cells. Tight aggregates of plasmacytoid dendritic cells were most numerous in hyaline-vascular Castleman disease (100% sensitive, 68% specific). Plasmacytoid dendritic cells are not limited to a small number of reactive lymphadenopathies but are found in many reactive processes, often with a predominant pattern of loose aggregates/clusters and scattered single cells. However, tight aggregates were a characteristic feature of hyaline-vascular Castleman disease, and viral infections typically showed only few scattered cells distributed singly.

ALDH, CA I, and CD2AP: novel, diagnostically useful immunohistochemical markers to identify erythroid precursors in bone marrow biopsy specimens.

Neoplastic erythroid proliferations may represent a diagnostic challenge owing to the difficulty in characterizing immature erythroblasts. Immunohistochemical expression of aldehyde dehydrogenase (ALDH), carbonic anhydrase isoenzyme I (CA I), and CD2-associated protein (CD2AP) was assessed in 66 bone marrow biopsy specimens and compared with glycophorin A and E-cadherin. ALDH, CA I, and CD2AP labeled neoplastic erythroblasts in most acute erythroid leukemias (AELs) and myelodysplasias and highlighted benign erythroid precursors within normal marrows, erythroid hyperplasias, acute lymphoblastic leukemias (ALLs), blastic plasmacytoid dendritic cell neoplasm, and most acute myeloid leukemias (AMLs). In 2 AELs, CD2AP was negative, and 1 AML lacked identifiable ALDH+ erythroid precursors. Immature erythroblasts were strongly ALDH+, weakly CA I+, weakly CD2AP±, E-cadherin±, and weakly glycophorin A±. AML was uncommonly weakly positive for ALDH, CA I, and CD2AP, and lymphoblasts from 1 ALL were weakly ALDH+. ALDH, CA I, and CD2AP are sensitive and relatively specific immunohistochemical markers for the erythroid lineage. ALDH is superior to glycophorin A and E-cadherin in highlighting immature erythroblasts.

Biclonal IgD and IgM Plasma Cell Myeloma: A Report of Two Cases and a Literature Review

Biclonal plasma cell myelomas producing two different isotypes of immunoglobulins are extremely rare entities; to date, the combination of IgD and IgM secretion by a biclonal plasma cell myeloma has not been reported. Bone marrow biopsy immunohistochemical studies in two cases revealed neoplastic plasma cells coexpressing IgD and IgM, but serum protein electrophoresis identified only the IgM monoclonal paraprotein in both cases. Biclonal plasma cell myelomas, while currently not well characterized in terms of their clinical behavior, should be distinguished from B-cell lymphoma with plasmacytic differentiation, given the different therapeutic implications. Both cases reported herein demonstrated chemotherapy-resistant clinical courses.