Showing papers in "American Journal of Clinical Pathology in 2001"

Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas.

Abstract: To facilitate the differential diagnosis of poorly differentiated metastatic carcinomas of unknown primary site, we evaluated p63 and cytokeratin (CK) 5/6 as immunohistochemical markers for squamous cell carcinomas. The study cases were as follows: squamous cell carcinoma of the lungs, head/neck, esophagus, cervix uteri, or anal canal, 73; non-squamous cell carcinomas of various primary sites, 141; and urothelial carcinoma, 20. We also tested 14 malignant mesotheliomas. Immunoreactivity for p63 was as follows: squamous cell carcinomas, 59 (81%); urothelial carcinoma, 14 (70%), most often with diffuse staining patterns; non-squamous cell carcinomas, 20 (14.2%), resulting in a specificity of 0.86 of p63 for squamous cell carcinomas. Coexpression of p63 and CK5/6 had a sensitivity of 0.77 and a specificity of 0.96 for squamous cell carcinomas. Increasing the minimal criterion of positive immunostaining for both markers to more than 50% of immunoreactive tumor cells resulted in a specificity of 0.99, although the sensitivity diminished to 0.66. All malignant mesotheliomas were negative for p63. Our data suggest that positive immunostaining for both p63 and CK5/6 in poorly differentiated metastatic carcinomas is highly predictive of a primary tumor of squamous epithelial origin.

Differential Expression of E-Cadherin in Lobular and Ductal Neoplasms of the Breast and Its Biologic and Diagnostic Implications

Abstract: We studied the pattern of E-cadherin expression in 183 invasive carcinomas (100 ductal, 42 lobular, 41 with mixed ductal and lobular features) and 198 in situ carcinomas (131 ductal, 53 lobular, 14 in situ with ductal and lobular features) by immunohistochemistry. We found a highly significant correlation of E-cadherin membrane expression with the histologic phenotype of the tumors. While moderate to strong membrane expression of E-cadherin was seen in all invasive and in situ ductal carcinomas, 41 of 42 invasive and 50 of 53 in situ lobular carcinomas showed complete loss of expression. All in situ carcinomas diagnosed histologically as showing mixed ductal and lobular features demonstrated complete loss of staining. Invasive carcinomas with ductal and lobular features showed 3 staining patterns: (1) complete or almost complete lack of membrane staining similar to that seen in lobular carcinomas, (2) uniform membrane expression throughout the tumor similar to ductal carcinomas, and (3) focal loss of E-cadherin staining, which correlated well with the histologic impression of focal lobular features. In tumors with histologically equivocal features, immunohistochemical detection of E-cadherin expression can be a useful diagnostic tool for the differentiation of ductal and lobular carcinomas of the breast.

Multiprobe FISH for Enhanced Detection of Bladder Cancer in Voided Urine Specimens and Bladder Washings

Abstract: The aim of this study was to evaluate the UroVysion (Vysis, Downers Grove, IL) fluorescence in situ hybridization (FISH) test for improved detection of bladder cancer in urinary specimens. Three groups of specimens were examined, including voided urine specimens (1) collected before resection of bladder cancer, (2) from cystoscopically negative bladders of patients with previous bladder cancer, and (3) from patients with benign prostatic hyperplasia (controls). FISH positivity was defined as more than 2 urothelial cells with an abnormal signal copy number of at least 1 of the 4 probes. FISH was positive in 1 of 27 control specimens and in 33 (73%) of 45 pTa, 12 (100%) of 12 pT1, and 13 (100%) of 13 pT2-4 tumors. The results were similar in a series of 68 bladder washings. In addition, FISH of voided urine specimens was positive in 5 of 10 patients with negative follow-up cystoscopy results. Subsequent recurrence was found in 4 of these patients but in none of 5 patients with FISH-negative results. Multiprobe FISH markedly improves the sensitivity and specificity of cytology for the detection of bladder cancer in urine specimens.

Absence of CD26 Expression Is a Useful Marker for Diagnosis of T-Cell Lymphoma in Peripheral Blood

Abstract: We report flow cytometric characterization of surface CD26 expression in 271 peripheral blood samples from 154 patients evaluated for the presence of a T-cell lymphoproliferative disorder, primarily mycosis fungoides/Sezary syndrome (MF/SS). The presence of morphologically identifiable tumor cells on peripheral blood smears was the criterion for lymphomatous involvement. In 66 of 69 samples from 28 patients, we identified an abnormal CD26-/dim T-cell population that was distinct from the variable CD26 expression seen in normal peripheral blood T cells. This population was CD26- in 23 patients and weakly CD26+ in 5 patients. CD7 was more variably expressed in MF/SS tumor cells, allowing recognition of a distinct, quantifiable abnormal T-cell population in only 34 of 69 involved samples. An increased CD4/CD8 ratio and lower surface expression of CD4 in tumor cells also helped separate the CD26-/dim atypical population for quantification. In 35 blood samples from other types of T-cell tumors, tumor cells in 10 of 11 morphologically involved cases showed absent/dim CD26. Although capable of detecting abnormalities in most cases of MF/SS, CD7 expression does not provide as clear a separation of the neoplastic population and can be replaced by CD26 staining in routine peripheral blood flow cytometric screening of MF/SS patients.

The proteasome: a new target for novel drug therapies.

Abstract: The proteasome is an enzyme present in all cells, from yeast to human, and has a central role in the proteolytic degradation of the vast majority of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in controlling inflammatory processes, cell cycle regulation, and gene expression. As such, agents that inhibit the proteasome have been shown to be active in numerous animal models of inflammation and cancer. Two proteasome inhibitors are under clinical evaluation. PS-519 is being studied for the treatment of reperfusion injury that occurs following cerebral ischemia and myocardial infarction. The other, PS-341, has recently entered multiple phase 2 clinical trials for the treatment of multiple myeloma, chronic lymphocytic leukemia, and a variety of solid tumors. The proteasome may have an important role in the evolution of HIVrelated disorders including AIDS and inflammatory disorders. Therapeutic strategies using proteasome inhibitors for the treatment of these conditions have now entered preclinical development. The multicatalytic proteasome is the ubiquitous proteinase found in cells throughout the plant and animal kingdoms that is responsible for the degradation of intracellular proteins. 1 Thousands of copies are found in all cells, in both the cytoplasm and the nucleus, and constitute up to 3% of all cellular protein content. Proteasomes serve multiple intracellular functions, including the degradation of damaged proteins and the modulation of many regulatory proteins that affect inflammatory processes, viral shedding, the cell cycle,

Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (Hot tub lung)

Abstract: The clinicopathologic spectrum of infections due to nontuberculous mycobacteria (NTM) includes cavitary disease, opportunistic infection, and nodular disease associated with bronchiectasis. We report a less well-described manifestation of NTM infection: 10 immunocompetent patients without preexisting bronchiectasis had radiographic evidence of diffuse infiltrative lung disease. The most common symptoms were dyspnea, cough, hypoxia, and fever. All 10 patients had used a hot tub. Histologic examination revealed exuberant nonnecrotizing, frequently bronchiolocentric, granulomatous inflammation in all cases. In 1 case, necrotizing granulomas were also noted. The inflammation often was associated with patchy chronic interstitial pneumonia and organization. Cultures revealed NTM in all cases (Mycobacterium avium complex in all but 1 case), but staining for acid-fast bacilli was positive in only 1 case. Four patients received corticosteroids alone for presumed hypersensitivity pneumonia, 4 were treated with antimycobacterial therapy, and 2 received both. All patients demonstrated significant improvement at the time of follow-up. These findings suggest that disease due to NTM may manifest as diffuse infiltrates in immunocompetent adults and that hot tub use may be an important risk factor for this disease pattern.

Qualification of ASCUS. A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage Study.

Abstract: Cytologic detection of high-grade squamous intraepithelial lesions (HSILs) is critical to cervical cancer prevention. Therefore, identifying "equivocal HSIL" (ASCUS [atypical squamous cells of undetermined significance]-H) may be useful. Accordingly, we compared findings associated with "equivocal low-grade SIL" (ASCUS-L), ASCUS-H, and HSIL using data from the ASCUS LSIL (low-grade squamous intraepithelial lesion) Triage Study. The frequency of oncogenic human papillomavirus (HPV) DNA detection and underlying lesions cervical intraepithelial neoplasia (CIN) 2 or worse or CIN 3 or worse in women with ASCUS-H was intermediate between that of ASCUS-L and HSIL. Oncogenic HPV DNA was associated with 85.6% of ASCUS-H ThinPreps and 69.8% of ASCUS-H smears. Histopathologic lesions CIN 2 or worse were associated with 40.5% of ASCUS-H ThinPreps and 27.2% of ASCUS-H smears (mostly CIN 3). Nevertheless, numerically more lesions CIN 2 or worse were preceded by ASCUS-L than by ASCUS-H because ASCUS-L was more common. ASCUS-H is an uncommon interpretation that derives clinical usefulness from its high positive predictive value for lesions CIN 2 or worse.

Study of interlaboratory reliability and reproducibility of estrogen and progesterone receptor assays in Europe. Documentation of poor reliability and identification of insufficient microwave antigen retrieval time as a major contributory element of unreliable assays.

Abstract: Immunohistochemical assays for estrogen receptors (ERs) and progesterone receptors (PRs) have not been surveyed for technical validity. In the present study, the reliability of the immunohistochemical assay for ER and PR was evaluated using data from 105 laboratories participating in external quality assessment (EQA) during a 2-year period. Technical variables associated with reliable immunostaining were analyzed. The efficiency of the antigen retrieval step was identified as the single most important contributory factor influencing the overall reproducibility of the assays. Reliable assays were found in 24 (36%) of 66 laboratories participating in continual EQA, including the majority of centers known to have clinically validated results. Inadequate assay sensitivity, with subsequent weak staining, was the main cause of poor and variable results by laboratories using microwave antigen retrieval; too short a heating time was identified as the principal contributory factor. Extension of the heating time resulted in significant improvement regardless of all other variables in the immunohistochemical protocol. Continual participation in EQA is an effective means for identifying and ameliorating variables that influence the reliability of immunohistochemical assays for predictive markers, thereby assisting in technical validation and standardization.

Precursor B-cell lymphoblastic lymphoma. A study of nine cases lacking blood and bone marrow involvement and review of the literature.

Abstract: We describe 9 cases of precursor B-cell lymphoblastic lymphoma (LYL) without evidence of marrow or blood involvement. Four patients had superficial nodal disease, 2 cutaneous involvement, and 1 each ovarian, retroperitoneal, or tonsillar primary tumor. Six patients had limited disease; 3 patients were stage III. Immunophenotyping revealed a terminal deoxynucleotidyl transferase (TdT)-positive, immature B-cell population with variable expression of CD10, CD20, and CD45. All patients are in complete clinical remission (median follow-up, 14 months). A literature review yielded 105 patients with a diagnosis of precursor B-cell LYL based on less than 25% marrow involvement. Of these, 64% were younger than 18 years. Skin, lymph nodes, and bone were the most common sites of disease. Mediastinal involvement was uncommon. TdT, CD19, CD79a, CD10, and HLA-DR were the most frequently expressed antigens, while CD45 and CD20 were expressed in only two thirds of the cases. Cytogenetic analysis showed additional 21q material as a recurring karyotypic abnormality. At a median follow-up of 26 months, 74% of patients were alive; the median survival was 19 months for patients dying of disease. Comparison with precursor B-cell acute lymphoblastic leukemia showed several overlapping features, although distinct differences were identified.

Microvessel density, vascular endothelial growth factor and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinoma.

Abstract: Assessment of angiogenesis may yield important information for an effective antiangiogenic treatment for hepatocellular carcinoma (HCC) because HCC is characteristically hypervascular. We examined the relationship of microvessel density (MVD), vascular endothelial growth factor (VEGF), and VEGF receptors Flt-1 and Flk-1/KDR in 50 patients with HCC and in 3 hepatoma cell lines. VEGF messenger RNA (mRNA) was overexpressed in 26 tumors (52%), and the 3 VEGF isoforms (121, 165, and 189) were present in high frequencies. Flt-1 mRNA was overexpressed in 34 tumors (68%), with levels significantly increased in HCCs compared with the nontumorous livers. Tumor Flt-1 mRNA significantly correlated with tumor VEGF mRNA levels. Within the group of tumors 8.5 cm or less in diameter, tumors with intrahepatic metastasis in the form of tumor microsatellite formation had significantly higher VEGF mRNA levels. MVD assessed by immunohistochemical analysis with CD34 antibody was inversely related to tumor size. Angiogenesis as assessed by MVD and tumor VEGF expression seems to have a more important role in tumor growth and intrahepatic metastasis in smaller HCCs. The differential up-regulation of Flt-1 suggests that it may have an important role in angiogenesis in HCC.

Is fine-needle aspiration biopsy a practical alternative to open biopsy for the primary diagnosis of sarcoma? Experience with 140 patients.

Abstract: We reviewed the clinicopathologic features of 145 consecutive fine-needle aspiration biopsy (FNAB) specimens from 140 patients without a previous diagnosis of sarcoma. Among 138 adequate specimens, 42 bone sarcomas and 80 soft tissue sarcomas were recognized as sarcomas; histologic subtyping was easier in bone than in soft tissue sarcomas and in pediatric than in adult cases. There was no correlation in accuracy of subtyping in low- vs high-grade sarcomas. FNAB was most accurate for subtyping of skeletal osteosarcoma, pediatric small round cell bone/soft tissue sarcomas, synovial sarcoma, skeletal chondrosarcoma, and adult myxoid soft tissue sarcomas. Although almost always recognized as sarcoma, subtyping of adult pleomorphic soft tissue sarcomas generally was not possible but did not influence therapy; all were considered high-grade sarcomas for treatment purposes. There were 4 misinterpretations of subtype in soft tissue sarcomas; none resulted in a change in therapy. Cytogenetic analysis on aspirated material confirmed t(11;22) in 2 Ewing and t(X;18) in 3 synovial sarcomas. No procedure-related complications occurred. Among bone and soft tissue sarcomas, FNAB was sufficient for initiation of definitive therapy in 87% and 83% of patients, respectively. Most FNAB specimens from bone and soft tissue sarcomas are recognized easily as sarcoma, but subtyping seems more accurate in bone sarcomas. Although histologic subtyping of adult soft tissue sarcomas is often impossible, no influence on initial therapy is usually observed. In contrast, subtyping of pediatric sarcomas by FNAB seems highly accurate and is necessary for appropriate therapy.

Assessment of HER-2/neu status in breast cancer. Automated Cellular Imaging System (ACIS)-assisted quantitation of immunohistochemical assay achieves high accuracy in comparison with fluorescence in situ hybridization assay as the standard.

Abstract: This retrospective study of formalin-fixed infiltrating breast cancer specimens compared manual

Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues.

Abstract: Congenital-infantile fibrosarcoma (CIFS) is a relatively indolent sarcoma that should be distinguished from more aggressive spindle cell sarcomas of childhood. CIFSs have been found to have a novel recurrent reciprocal translocation t(12;15)(p13;q25) resulting in the gene fusion ETV6-NTRK3 (ETS variant gene 6; neurotrophic tyrosine kinase receptor type 3). We studied immunohistochemical expression of NTRK3, and conducted a reverse transcription-polymerase chain reaction (RT-PCR) assay to detect the ETV6-NTRK3 fusion transcripts using archival formalin-fixed paraffin-embedded tissues from 10 CIFSs. Thirty-eight other spindle cell tumors were included as controls. The ETV6-NTRK3 fusion transcripts were identified in 7 (70%) of 10 CIFSs. Nucleotide sequence analysis showed that the fusion occurred between ETV6 exon 5 and NTRK3 exon 13. The 38 control tumors were negative for the fusion transcript. Immunohistochemically, CIFSs consistently expressed NTRK3. But the expression of NTRK3 also was observed in 22 of 38 control tumors. These results show the diagnostic usefulness of RT-PCR methods to detect ETV6-NTRK3 fusion transcripts in archival formalin-fixed paraffin-embedded tissue and the important role of NTRK3 in the development of CIFS, despite its being a protein of little importance in differential diagnosis.

Histopathology of Fibroadenoma of the Breast

Abstract: The aim of this study was to make a thorough inventory of the histologic features of epithelium and stroma within and adjacent to breast fibroadenomas in 396 cases. Breast fibroadenomas seemed to display a wide spectrum of proliferative and nonproliferative histologic changes. Hyperplasia (excluding mild hyperplasia) within the fibroadenoma was found in 32.3% of cases. Carcinoma in situ (CIS; 5 ductal, 3 lobular) was found in 8 fibroadenomas (2.0%) removed from 6 patients, the youngest of whom was 40 years of age. In 3 cases CIS was not confined to the fibroadenoma, but also involved the adjacent parenchyma. No invasive carcinoma was present within this series. Complex histologic features were seen in 40.4% of cases, mostly in relatively older patients (mean age, 35.4 years). Hyperplasia in adjacent tissue was found in 8.8% of cases, usually in older patients (mean age, 45.5 years). Known risk-elevating lesions in and around breast fibroadenomas occur frequently and mostly in patients older than 35 years. These findings may have consequences for the clinical management of a subgroup of patients with fibroadenoma.

Morphologic features suggestive of gluten sensitivity in architecturally normal duodenal biopsy specimens.

Abstract: We studied small bowel biopsy specimens with architecturally normal villi from 78 adult patients with potential gluten sensitivity (GS) and correlated them with outcome to characterize morphologic features that would allow a pathologist to suggest GS. No patient had a previous GS diagnosis. Twelve study patients had GS. The mean number of intraepithelial lymphocytes (IELs) per 20 enterocytes from the tips of 5 random villi was significantly greater in GS than non-GS biopsy samples, but the groups overlapped significantly, making the number diagnostically useful only when markedly increased. Crypt mitoses counts had similar relationships. Twelve patients had an even distribution of IELs along villus sides and over tips (3/66 [5%] non-GS patients, 9/12 [75%] GS patients). Non-GS patients had a decrescendo pattern of IELs along the sides of villi. Architecturally normal small bowel biopsy specimens with an appreciable, continuous, even distribution of IELs along the sides and tips of villi and a mean of 12 or more IELs in the tips of several villi are suggestive of GS. Pathologists should be watchful for these morphologic features in small bowel biopsy specimens to suggest GS.

Chemical typing of amyloid protein contained in formalin-fixed paraffin-embedded biopsy specimens

Abstract: The human amyloidoses represent a heterogeneous group of disorders characterized by the deposition of fibrillar protein in vital organs. Given the fact that at least 20 different molecules can form fibrils, the unambiguous identification of the type of amyloid deposited is critical to the correct diagnosis and treatment of patients with these disorders. Heretofore, this information has been inferred from particular clinical features of the disease, ancillary laboratory tests, and results of immunohistochemical analyses. However, to establish unequivocally the kind of protein that is deposited as amyloid, it is necessary to determine its chemical composition through amino acid sequencing or mass spectroscopy of material extracted from fibrillar deposits. We have developed a micromethod whereby such studies can be performed readily using sections of formalin-fixed, paraffin-embedded biopsy specimens. The ability to identify precisely the nature of the tissue deposits has diagnostic, therapeutic, and prognostic implications for patients with amyloid-associated disorders.

Morphometry confirms the presence of considerable nuclear size overlap between "small cells" and "large cells" in high-grade pulmonary neuroendocrine neoplasms.

Abstract: We morphometrically evaluated 5-μm HE LCNECs, A through F. Morphometry demonstrated considerable nuclear size overlap in high-grade neoplasms. Approximately one third of SCLCs exhibited considerable numbers of neoplastic cells that were larger than 3 normal lymphocytes, while 4 of 12 LCNECs had a predominant number of small cells. Ten tumors exhibited a B histogram with a “borderline” peak TC/L of 3. The rule that a TC/L size ratio larger than 3 helps distinguish “large” from “small” neoplastic cells was confirmed in only 9 of 28 cases. The use of more generic terminology such as “high-grade neuroendocrine carcinoma” or “grade III neuroendocrine carcinoma” for SCLC and LCNEC is discussed.

Mucinous and nonmucinous bronchioloalveolar adenocarcinomas have distinct staining patterns with thyroid transcription factor and cytokeratin 20 antibodies.

Abstract: We studied 14 mucinous and 26 nonmucinous bronchioloalveolar adenocarcinomas (BACs) with thyroid transcription factor (TTF), cytokeratin (CK) 7, CK20, and villin to characterize their staining patterns with these antibodies and identify staining differences between the neoplasms. We also stained 11 mucinous colon adenocarcinomas with the same antibodies to compare their reaction patterns with mucinous BACs. All pulmonary neoplasms were confirmed pulmonary primary BACs. Three (21%) of 14 mucinous neoplasms had weak TTF reactivity in fewer than 25% of neoplastic cell nuclei, and the other 11 (79%) were nonreactive. In contrast, 24 (92%) of 26 nonmucinonus BACs were strongly TTF reactive. Eleven mucinous BACs (79%) had CK20 reactivity in more than 25% of neoplastic cells, whereas only 1 nonmucinous BAC (4%) had reactivity in fewer than 50% of the cells. One mucinous BAC (7%) had villin reactivity in approximately 10% of the neoplastic cells. All mucinous colon adenocarcinomas were diffusely reactive with CK20 and villin. Mucinous and nonmucinous BACs have disparate staining patterns with TTF and CK20. Mucinous BACs are usually TTF nonreactive and CK20 reactive, but nonreactive with villin, which distinguishes them from mucinous colon adenocarcinomas.

Lymphoepithelioma-like carcinoma of the lung with a better prognosis. A clinicopathologic study of 32 cases.

Abstract: The purpose of our study was to clarify the prognosis of lymphoepithelioma-like carcinoma (LELC) of the lung, which is rare. We analyzed the clinicopathologic features of 32 cases of pulmonary LELC and compared the cases with 84 cases of pulmonary non-LELC with available long-term follow-up information. The results show that LELC of the lung as a distinct entity has a better prognosis than non-LELC. We found a significant difference in the survival rates between patients with LELC and patients with non-LELC in stage II and stages III and IV, respectively. Tumor recurrence and necrosis (5% or more of tumor) are associated with a poor prognosis. It seems that the histologic typing (Regaud type and Schmincke type) of pulmonary LELC is of no clinical value.

Neuroendocrine tumors of the genital tract.

Abstract: Neuroendocrine tumors are more common in the female than male genital tract; most are uterine small cell carcinomas or ovarian carcinoids. Primary ovarian carcinoids are divided into insular, trabecular, strumal, and mucinous types; most are benign. Carcinoids metastatic to the ovary are more aggressive; most arise in the gastrointestinal tract. Scattered neuroendocrine cells are seen in a variety of ovarian surface epithelial tumors; sporadic mucinous cystic tumors with neuroendocrine cells have been associated with Zollinger-Ellison syndrome. Frank neuroendocrine carcinomas in the ovary include small cell carcinoma and large cell neuroendocrine carcinoma, each with a poor prognosis and often associated with a conventional surface epithelial tumor Such carcinomas also occur in the endometrium and cervix. Uterine carcinoids are rare if strict criteria are applied. Small cell neuroendocrine carcinomas also occur rarely in the vagina and vulva. Most male genital tract neuroendocrine tumors are prostatic small cell carcinomas or testicular carcinoids. Extragonadal carcinoids of the male genital tract are rare. Testicular carcinoids should be distinguishedfrom metastatic tumors. It is important to distinguish prostatic small cell carcinoma from poorly differentiated adenocarcinoma with small cells. Small cell neuroendocrine carcinomas also occur rarely in the scrotum, penis, and penile urethra.

Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients.

Abstract: The aim of the present study was to describe histologic features of the liver in insulin resistance-associated hepatic iron overload (IR-HIO), defined as the association of metabolic disorders and hepatic iron overload. We included 139 patients in the study on the basis of one or more metabolic disorders and liver iron overload unrelated to usual causes. Liver biopsy specimens were reviewed, and histologic data were compared with those of a previously published, well-defined population with genetic hemochromatosis. Iron overload was characterized by a mixed pattern with iron deposits in hepatocytes and sinusoidal cells. Steatosis was present in 59.7% of patients with inflammation in 32.4% of cases. Periportal fibrosis was found in 67.4% of patients. These patients were older, had higher sinusoidal iron scores, and had a higher prevalence of steatosis and inflammation than patients without fibrosis. Iron overload in IR-HIO was histologically different from that in genetic hemochromatosis.

Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors.

Abstract: To establish whether a combination of morphologic and immunophenotypic criteria could be developed to more precisely define Waldenstrom macroglobulinemia (WM) and prognostic factors, we retrospectively assessed the clinical and laboratory features of 111 cases of WM. Bone marrow infiltration by small lymphocytes was documented in each case; and diffuse, interstitial, nodular, and paratrabecular patterns of infiltration were documented in 58%, 32%, 6%, and 4% of cases, respectively. Ninety percent were characterized by a surface immunoglobulin-positive, CD19+CD20+CD5-CD10-CD23- immunophenotype. The median overall survival from diagnosis was 60 months; univariate analysis revealed the following adverse prognostic factors: older than 60 years, performance status more than 1, platelet count less than 100 x 10(3)/microL (< 100 x 10(9)/L), pancytopenia, and diffuse bone marrow infiltration. Associated median survival was 40, 38, 46, 28, and 59 months, respectively. Multivariate analysis revealed age, performance status, and platelet count as prognostically significant, but stratification of patients according to the International Prognostic Index had limited value. We suggest defining WM by the following criteria: IgM monoclonal gammopathy; bone marrow infiltration by small lymphocytes, plasmacytoid cells, and plasma cells in a diffuse, interstitial, or nodular pattern; and a surface immunoglobulin-positive, CD19+CD20+CD5-CD10-CD23- immunophenotype.

Platelet Counting by the RBC/Platelet Ratio Method: A Reference Method

Abstract: The International Council for Standardization in Haematology (ICSH) and the International Society of Laboratory Hematology (ISLH) recommend the counting of specifically labeled platelets relative to the RBCs with a fluorescence flow cytometer, together with an accurate RBC count determined with a semiautomated, single-channel aperture-impedance counter as a reference method for the enumeration of platelets. Fresh EDTA-anticoagulated venous blood specimens are measured within 4 hours of the draw. The specimen is prediluted (1:20) and the platelets labeled with two monoclonal antibodies specific to a cluster of differentiation common to all platelets. A final 1:1,000 dilution is made and at least 50,000 events with a minimum of 1,000 platelet events are counted with a flow cytometer to determine the RBC/platelet ratio. The platelet count is then calculated from this ratio and the RBC concentration of the original blood specimen.

Elevated expression of caveolin-1 in adenocarcinoma of the colon.

Abstract: Caveolins 1, 2, and 3 are the principal proteins of caveolae, the vesicular invaginations of the plasma membrane. Several reports have suggested that caveolin-1 may have a role in cellular transformation and tumorigenesis. We studied the expression of caveolin-1 and caveolin-2 in normal epithelium, adenoma, and adenocarcinoma of the colon and their possible role in tumorigenesis. Formalin-fixed, paraffin-embedded sections of 41 cases of adenocarcinoma and 13 cases of adenoma of the colon were stained immunohistochemically with anti-caveolin-1 and anti-caveolin-2 antibodies. The expression of caveolin-1 was elevated in the overwhelming majority of the adenocarcinomas, while most normal colonic epithelium and adenomas showed little or no staining. There was significant statistical correlation of the expression of caveolin-1 with adenocarcinoma but not with tumor stage. Expression of caveolin-2 was undetectable in all of the normal colonic glands, adenomas, and carcinomas. We discuss the possible clinical implications of our findings within the context of caveolins and signal transduction.

Interdigitating dendritic cell sarcoma. A report of four cases and review of the literature.

Abstract: To better define the clinical and pathologic features of interdigitating dendritic cell sarcoma (IDCS), we report 4 cases, including the first reported in the tonsil. There were 2 male and 2 female patients (mean age, 70 years). Sites of tumor included 1 case each in the right cervical lymph node, left axillary lymph node, right tonsil, and right inguinal lymph node. Histologically, all showed diffuse effacement of the lymphoid tissue by pleomorphic round to spindled cells with convoluted nuclei and abundant eosinophilic cytoplasm. All were immunoreactive for S-100, CD68, lysozyme, and vimentin. CD45 was positive in 3 cases and CD1a in 1 case. Fascin was positive in 3 cases. Other immunostains, including CD3, CD20, CD21, CD30, actin, cytokeratin, and HMB-45, were negative. Ultrastructurally, the tumor cells were elongated and showed indented nuclei, variable numbers of lysosomes, and interdigitating cytoplasmic processes. Follow-up was available for all cases. One patient died of widespread disease 2 months after diagnosis. One was alive with metastatic lung disease at 12 months. Two patients were disease free at 5 and 9 months.

Inflammation and atherosclerosis: the value of the high-sensitivity C-reactive protein assay as a risk marker.

Abstract: C-reactive protein (CRP) is a prototypic marker of inflammation. Numerous prospective studies in healthy volunteers have confirmed that high-sensitivity CRP (hsCRP) predicts cardiovascular events (CVEs), and hsCRP seems additive to an elevated total cholesterol level and a total/high-density lipoprotein cholesterol ratio in men and women in predicting risk. In smokers and people with metabolic syndrome, hsCRP levels are elevated; in elderly people, there seems to be a relationship between hsCRP and CVEs and mortality. Several properties of CRP make it proatherogenic; however; pending further studies, it should be considered as a risk marker. In people with acute coronary syndromes, hsCRP measurement may be valuable. Elevated levels in the highest quantile seem to predict greater mortality and poorer prognosis in patients with unstable angina and myocardial infarction (MI). While hsCRP is a strong independent predictor of risk of future MI, stroke, peripheral arterial disease, and vascular death, the validity of hsCRP as a risk marker needs to be assessed in all populations. Weight loss, statin drugs, aspirin, and high-dose alpha tocopherol therapy could affect hsCRP. It has its greatest validity as an adjunctive measure in the primary prevention of cardiovascular disease.

Immunophenotypic analysis of peripheral T-cell neoplasms. A multiparameter flow cytometric approach.

Abstract: We retrospectively reviewed multiparameter flow cytometric analyses in 50 peripheral T-cell neoplasms (PTCNs). Results were interpreted within the context of a large cohort of nonneoplastic T-cell populations. All PTCN diagnoses were confirmed with morphologic and/or molecular analysis. Aberrant populations were defined as discrete immunophenotypic clusters exhibiting loss of or increased or diminished expression of T-cell antigens relative to internal immunophenotypically normal T-cell populations. An antigenic pattern was considered abnormal if it exceeded ranges for T-cell subsets in specific anatomic sites or was not normally encountered. Forty-six of 50 and 41 of 50 demonstrated 1 or more and 2 or more aberrations, respectively. The most common abnormally expressed antigen was CD3, followed by CD7, CD5, and CD2. Except for CD7, abnormally dim or bright antigen expression was more common than deletion. Only 3 cases were abnormal solely based on expansion of an otherwise immunophenotypically normal population; the remainder had patterns of antigen expression not seen in nonneoplastic populations. These data indicate that most PTCNs are aberrant by multiparameter flow analysis. However, results must be interpreted within the context of thorough knowledge of the immunophenotypic spectrum of nonneoplastic T cells.

Diagnostic value of tests for reticulated platelets, plasma glycocalicin, and thrombopoietin levels for discriminating between hyperdestructive and hypoplastic thrombocytopenia.

Abstract: We measured reticulated platelets (RPs) and plasma glycocalicin (GC) and thrombopoietin (TPO) levels simultaneously in 107 thrombocytopenic patients to clarify the diagnostic value of these tests for discriminating hyperdestructive from hypoplastic thrombocytopenia. The percentage of RPs and GC index (plasma GC level normalized for the individual platelet count) were markedly elevated in patients with idiopathic thrombocytopenic purpura (ITP) but normal or slightly elevated in patients with aplastic anemia (AA) or chemotherapy-induced thrombocytopenia (ChemoT). For RP percentage for diagnosing hyperdestructive thrombocytopenia the sensitivity and specificity were excellent but were lower for the GC index. Absolute RP counts and plasma GC levels were markedly decreased and plasma TPO levels markedly elevated in patients with AA or ChemoT, but absolute RP counts and plasma GC levels were moderately decreased and plasma TPO levels only slightly elevated in patients with ITP. The sensitivity and specificity of plasma TPO levels for diagnosing hypoplastic thrombocytopenia were excellent. Using the RP percentage and plasma TPO levels in combination improved specificities. Simultaneous measurement of RP percentage and plasma TPO level may help discriminate thrombocytopenia of unknown cause in routine hematologic practice.

Laboratory results. Timeliness as a quality attribute and strategy.

Abstract: Although timeliness of results reporting has not been a major focus in clinical laboratories, there is increasing pressure from clinicians to report results rapidly. Even though there are only sparse data, timeliness in reporting of laboratory results undoubtedly affects clinician and patient satisfaction as well as length of hospital stay. Improving turnaround time (TAT) is a complex task involving education, equipment acquisition, and planning. All the steps from test ordering to results reporting should be monitored and steps taken to improve the processes. Various strategies to improve TAT at each step in the testing process are discussed.

Consultative (expert) second opinions in soft tissue pathology. Analysis of problem-prone diagnostic situations.

Abstract: We reviewed 500 consecutive soft tissue lesions referred for expert consultation to determine types of lesions and/or situations in which major discrepancies occur. Of 266 cases (53.2%) accompanied by a diagnosis, essential agreement with the second opinion was noted in 68%, minor discrepancy in 7%, and major discrepancy in 25%. The 65 major discrepancies were distributed proportionally to the referring sources and could be divided into 4 groups: benign mesenchymal lesions diagnosed as sarcomas (45%), sarcomas diagnosed as benign tumors (23%), nonmesenchymal lesions diagnosed as sarcoma (20%), and major grading discrepancies (12%). Relatively few lesions accounted for a major proportion of major discrepancies. Problematic lesions were lipoma and fasciitis and their variants and desmoplastic-neurotropic melanoma. Needle biopsy specimens were somewhat more likely to be associated with a discrepant opinion. With the exception of nonmesenchymal lesions, the diagnosis for all major discrepant cases could be made on the basis of the H&E-stained slides, suggesting that failure to perform immunostains did not account for discrepancies. Lack of familiarity with rare or unusual lesions is probably more significant in explaining diagnostic discrepancies than is the increasing use of needle biopsy or the failure to perform immunohistochemical analysis.