College of American Pathologists
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  Anatomic Abstracts





October 2010

Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

A study of Epstein Barr virus-positive mucocutaneous ulcer A study of Epstein Barr virus-positive mucocutaneous ulcer

Epstein Barr virus has long been known to be associated with B-cell lymphoproliferative disorder in immunosuppressed patients. Reactive lymphoid hyperplasia associated with the virus has been described in advanced age. The authors, in their practice, encountered lymphoproliferative lesions presenting as isolated cutaneous and mucosal ulcers with positive Epstein Barr virus (EBV). This was encountered in patients on immunosuppressive agents, such as azathioprine (AZA), methotrexate (MTX), and cyclosporin-A (CyA), and in elderly patients. The authors reported on such EBV-positive ulcers in 26 patients—10 males and 16 females—who were a median age of 77 years (range, 42 to 101 years). Nine patients were on the immunosuppressive agents AZA, MTX, or CyA, and 17 had age-related immunosenescence. All of the patients presented with sharply circumscribed, isolated ulcers involving oropharyngeal mucosa (16), skin (six), and the gastrointestinal tract (four). The lesions were characterized histologically by a polymorphous infiltrate with atypical large B cells, often with Hodgkin/Reed-Sternberg cell-like morphology in a background of abundant T cells. The B cells showed strong CD30 and EBER positivity, and some had reduced CD20 expression. CD15 was positive in 43 percent of cases (10 of 23). The pathologic features were identical, regardless of the anatomic site or cause of immunosuppression. Polymerase chain reaction revealed monoclonal immunoglobulin gene rearrangement in 39 percent of cases (seven of 18). Monoclonal T-cell receptor gene rearrangement was found in 38 percent of cases (six of 16), and 31 percent of cases (five of 16) had restricted T-cell patterns. Twenty-five percent of patients (five of 20) received standard chemotherapy or radiotherapy, or both. Forty-five percent (nine of 20) regressed spontaneously with no treatment, and 15 percent (three of 20) had a relapsing and remitting course. Six iatrogenic lesions were available for followup, and all of them responded to reduction of immunosuppression. All of the patients with available followup information (20 of 26) achieved complete remission, with no disease-associated deaths, over a median followup period of 22 months (range, three to 72 months). The authors proposed the EBV-positive mucocutaneous ulcer as a new clinicopathologic entity with infiltrating features resembling Hodgkin lymphoma and a self-limited, indolent course that generally responds well to conservative management.

Dojcinov SD, Venkataraman G, Raffeld M, et al. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010;34(3):405–417.

Correspondence: Dr. Stefan D. Dojcinov at
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Use of cytomorphology and multiparametric flow cytometry for diagnosing NHL Use of cytomorphology and multiparametric flow cytometry for diagnosing NHL

The authors evaluated the validity and accuracy of cytomorphology and multiparametric flow cytometry (C-FCM) for diagnosing oncohematologic disease in 223 consecutive lymph node biopsy specimens from patients with lymphadenopathy, from 2004 to 2007. C-FCM and histopathologic studies were interpreted independently by hematologists and pathologists, respectively. C-FCM detected neoplastic disorders in 133 samples (59.6 percent): 92 non-Hodgkin lymphomas (41.3 percent), 21 Hodgkin lymphomas (9.4 percent), 19 malignant nonhematologic neoplasms (8.5 percent), and one multiple myeloma (0.4 percent). Sensitivity and specificity were 87.25 percent and 95.95 percent, respectively. Positive predictive value and negative predictive value were 97.74 percent and 78.89 percent, respectively. Sensitivity and negative predictive value were 94.79 percent and 96.81 percent upon excluding Hodgkin lymphomas and malignant nonhematologic neoplasms from the analysis. Of the 92 non-Hodgkin lymphomas (NHLs), 89 (97 percent) were categorized according to the 2001 World Health Organization classification of hematolymphoid neoplasms, with a concordance rate of 87 percent. The C-FCM study was significantly faster than the histopathologic study. C-FCM has high sensitivity and specificity, allowing for a valid and reliable diagnosis, especially for NHLs, and enabling the subclassification of NHLs. C-FCM is faster than histopathologic examination, allowing physicians to make therapeutic decisions quickly. However, histopathologic results are needed for the samples for which C-FCM cannot establish a diagnosis.

Colorado M, Cuadrado MA, Insunza A, et al. Simultaneous cytomorphologic and multiparametric flow cytometric analysis on lymph node samples is faster than and as valid as histopathologic study to diagnose most non-Hodgkin lymphomas. Am J Clin Pathol. 2010;133(1):83–91.

Correspondence: Dr. Colorado Araujo at Servicio de Hematología y Hemoterapia, Hospital Universitario Marqués de Valdecilla, Av Valdecilla s/n, Santander, Spain
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Molecular signatures to improve diagnosis in PTCL and prognostication in AITL Molecular signatures to improve diagnosis in PTCL and prognostication in AITL

Peripheral T-cell lymphoma can be difficult to diagnose and classify. The authors performed gene-expression profiling on 144 cases of peripheral T-cell lymphoma (PTCL) and natural killer cell lymphoma. Robust molecular classifiers were constructed for angioimmunoblastic T-cell lym-ph-oma (AITL), anaplastic lymphoma kinase-positive (ALK[+]) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma. PTCL-unclassifiable was molecularly heterogeneous, but the authors were able to identify a molecular subgroup with features of cytotoxic T lymphocytes and a poor survival rate compared with the remaining PTCL-not otherwise specified cases. Many of the pathologic features and substantial components of the molecular signature of AITL are contributed by the follicular dendritic cells, B cells, and other stromal components. The expression of Th17-associated molecules in ALK(+) ALCL was noted and may represent aberrant activation of Th17-cell differentiation by abnormal cytokine secretion. Adult T-cell leukemia/lymphoma has a homogeneous molecular signature demonstrating high expression of human T-lymphotropic virus type 1-induced genes. These classifiers reflect the biology of the tumor cells as well as their microenvironment. The authors also constructed a molecular prognosticator for AITL that appears to be largely related to the microenvironmental signature. The high expression of two immunosuppressive signatures is associated with poor outcome. Oncogenic pathways and tumor-host interactions were also identified. These findings may lead to better therapies and outcomes in the future.

Iqbal J, Weisenburger DD, Greiner TC, et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood. 2010;115(5):1026–1036.

Correspondence: Dr. Wing C. Chan at
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Histopathological tumor regression after neoadjuvant chemotherapy in esophageal adenocarcinomas Histopathological tumor regression after neoadjuvant chemotherapy in esophageal adenocarcinomas

The authors evaluated histomorphological findings in 92 surgical resection specimens of locally advanced esophageal adenocarcinomas after neoadjuvant cisplatin-based chemotherapy. Tumor response to neoadjuvant chemotherapy was determined using a system encompassing three tumor-regression grades. The grades were based on estimating the percentage of residual tumor tissue of the primary tumor site in relation to the macroscopically identifiable pervious tumor bed. The significance of this system was validated by correlating tumor-regression grades with corresponding clinicopathological characteristics and patient survival. Seven patients (seven percent) had complete tumor regression (tumor regression grade 1); 48 patients (52 percent) had subtotal or partial tumor regression (tumor regression grade 2, 1 to 50 percent residual tumor); and 37 patients (40 percent) had minimal or no regression (tumor regression grade 3, more than 50 percent residual tumor). Tumor regression was significantly associated with posttreatment complete tumor resection status (UICC R0 status; P=0.016), tumor category (UICC pT category; P<0.001), and absence of lymph node metastases (P=0.001) or lymphatic invasion (P<0.001). Survival analysis showed significant prognostic relevance of the applied regression system in univariate (P<0.001) and multivariate analyses as a single independent factor (P=0.024). The authors concluded that the effect of preoperative chemotherapy in esophageal adenocarcinomas can be assessed by determining histological tumor regression, which provides highly valuable prognostic information that may even exceed the prognostic impact of the tumor-node-metastasis classification of these tumors. Therefore, they strongly recommend implementing a standardized tumor-regression grading system for pathological reports of esophageal adenocarcinomas treated by neoadjuvant chemotherapy.

Langer R, Ott K, Feith M, et al. Prognostic significance of histopathological tumor regression after neoadjuvant chemotherapy in esophageal adenocarcinomas. Mod Pathol. 2009;22(12):1555–1563.

Correspondence: Dr. R. Langer at
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Analysis of patient misidentification in laboratory medicine Analysis of patient misidentification in laboratory medicine

Mislabeled laboratory specimens can lead to repeat phlebotomy, repeat diagnostic procedures, delay in necessary surgical procedures, and unnecessary surgical procedures. Mislabeling has been estimated to occur at a rate of 0.1 percent for all laboratory and anatomic pathology specimens submitted for evaluation. The authors conducted a study to identify system vulnerabilities in specimen collection, processing, analysis, and reporting associated with patient misidentification involving clinical and anatomic pathology laboratories and blood transfusion services. They performed a qualitative analysis on 227 root-cause anal-ysis reports from the Veterans Health Administration. Content analysis of case reports from March 9, 2000 to March 1, 2008 was facilitated by a natural language processing program. Data were categorized by the three stages of the laboratory test cycle. Patient misidentification accounted for 182 of 253 adverse events, which occurred in all three stages of the test cycle. Among 132 misidentification events occurring in the preanalytic phase were wristbands labeled for the wrong patient applied on admission (n=8) and laboratory tests ordered for the wrong patient by selecting the wrong electronic medical record from a menu of similar names and Social Security numbers (n=31). Furthermore, specimen mislabeling during collection was associated with batching specimens and printed labels (n=35), misinformation produced by manual entry on laboratory forms (n=14), failure of two-source patient identification for clinical laboratory specimens (n=24), and failure of two-person verification of patient identity for blood bank specimens (n=20). For 37 events in the analytic phase, relabeling all specimens with accession numbers was associated with mislabeled specimen containers, tissue cassettes, and microscope slides (n=27). Misidentified microscope slides were associated with a failure of two-pathologist verification for cancer diagnosis (n=4), and incorrect patient transfusions were associated with mislabeled blood products (n=3) and a failure of two-person verification of blood products before such products were released by the blood bank (n=3). For 13 events in the postanalytic phase, results were reported into the wrong patient medical record (n=8), and incompatible blood trans-fusions were associated with failed two-person verification of blood products (n=5). The authors concluded that patient misidentification in the clinical laboratory, anatomic pathology, and blood transfusion processes were due to a limited set of causal factors in all three phases of the test cycle. A focus on these factors will enhance systemic mitigation and prevention strategies.

Dunn EJ, Moga PJ. Patient misidentification in laboratory medicine: a qualitative analysis of 227 root cause analysis reports in the Veterans Health Administration. Arch Pathol Lab Med. 2010;134(2):224–255.

Correspondence: Dr. Edward J. Dunn at
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Endometrial carcinoma during 20-year followup of women with endometrial hyperplasia Endometrial carcinoma during 20-year followup of women with endometrial hyperplasia

The severity of endometrial hyperplasia—simple, complex, or atypical—influences clinical management, but valid estimates of absolute risk of clinical progression to carcinoma are lacking. The authors conducted a case-control study nested in a cohort of 7,947 women from one prepaid health plan who were diagnosed with endometrial hyperplasia between 1970 and 2002 and who remained at risk for at least one year. Patients (n=138) were diagnosed with carcinoma, on average, six years later (range, one to 24 years). Control subjects (n=241) were matched to patients on age at endometrial hyperplasia (EH), date of EH, and duration of followup, and they were counter-matched to patients on severity of EH. The authors independently reviewed the original slides and medical records of the controls and patients. They subsequently combined progression relative risks (atypical versus simple, complex, or disordered proliferative endometrium [that is, equivocal EH]) from the case-control analysis with clinical censoring information—that is, hysterectomy, death, or left the health plan—on all cohort members. This information was used to estimate interval-specific (one to four, five to nine, and 10 to 19 years) and cumulative (through four, nine, and 19 years) progression risks. The authors found that for nonatypical EH, cumulative progression risk increased from 1.2 percent (95 percent confidence interval [CI], 0.6–1.9 percent) through four years, to 1.9 percent (95 percent CI, 1.2–2.6 percent) through nine years, to 4.6 percent (95 percent CI, 3.3–5.8 percent) through 19 years after a diagnosis of EH. For atypical hyperplasia, cumulative risk increased from 8.2 percent (95 percent CI, 1.3–14.6 percent) through four years, to 12.4 percent (95 percent CI, 3–20.8 percent) through nine years, to 27.5 percent (95 percent CI, 8.6–42.5 percent) through 19 years after a diagnosis of atypical hyperplasia. The authors concluded that cumulative 20-year progression risk among women who remain at risk for at least one year is less than five percent for nonatypical EH and 28 percent for atypical hyperplasia.

Lacey JV Jr., Sherman ME, Rush BB, et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol. 2010;28(5):788–792.

Correspondence: Dr. James Lacey at
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Variability in diagnosis of single small atypical foci in prostate biopsies Variability in diagnosis of single small atypical foci in prostate biopsies

Pathologists increasingly are exposed to prostate biopsies with small atypical foci requiring differentiation between adenocarcinoma, atypical small acinar proliferation suspicious for malignancy, and benign findings. The authors studied the level of agreement for such atypical foci among experts in urologic pathology and all-round reference pathologists involved in the European Randomized Screening Study of Prostate Cancer (ERSPC). They retrieved 20 prostate biopsies with small atypical foci, most of which were less than 1 mm. Hematoxylin-and-eosin–stained slides, including 10 immuno-stained slides, were digitalized for virtual microscopy. The lesional area was not marked. Five experts and seven ERSPC pathologists examined the cases. Multirater k statistics were applied to determine agreement and significant differences between the experts and ERSPC pathologists. The k value of the experts (0.39; confidence interval, 0.29–0.49) was significantly higher than that of the ERSPC pathologists (0.21; confidence interval, 0.14–0.27). The five experts reached full agreement for seven of 20 biopsies. The experts and ERSPC pathologists rendered diagnoses ranging from benign to adenocarcinoma on the same biopsy in five and nine biopsies, respectively. Most of these lesions comprised between two and five atypical glands. The experts diagnosed adenocarcinoma (49 percent) more often than the ERSPC pathologists (32 percent). Because agreement was particularly poor for foci comprising fewer than six glands, the authors encourage pathologists to obtain the intercollegial consultation of a specialized pathologist for these lesions before making a diagnosis of carcinoma.

Van der Kwast TH, Evans A, Lockwood G, et al. Variability in diagnostic opinion among pathologists for single small atypical foci in prostate biopsies. Am J Surg Pathol. 2010;34(2):169–177.

Correspondence: Dr. Theodorus H. Van der Kwast at
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Margin assessment in wide local excision specimens for invasive breast carcinoma Margin assessment in wide local excision specimens for invasive breast carcinoma

Standard margin assessment of breast carcinoma surgical specimens uses radial sections perpendicular to the margin. Shave sections assess a larger surface area of the margin than do radial sections. The authors conducted a study to assess the value of additional shave sections of the margin. They used shave and radial sections to assess 471 wide local excision specimens for invasive carcinoma. A total of 179 specimens had positive margins—only radial margins (tumor within 5 mm of the margin) were involved in 76, only shave margins in 45, and both shave and radial margins in 58. Residual carcinoma was found in re-excision specimens (immediate or later) at a rate of 43 percent when the closest distance to the radial margin was 0 to 1 mm, 25 percent at 2 to 4 mm, 18 percent at 5 to 9 mm, and 13 percent at more than 9 mm. Residual carcinoma was found in 44 percent of specimens if any shave section was positive and nine percent if all shaves were negative. Residual carcinoma was found in 32 percent if either radial or shave sections were positive and four percent if neither were positive. The authors concluded that a combination of radial and shave sections appears to be useful in separating patients into groups with high and low risk of residual carcinoma.

Hodi Z, Ellis IO, Elston CW, et al. Comparison of margin assessment by radial and shave sections in wide local excision specimens for invasive carcinoma of the breast. Histopathology. 2010:56;573–580.

Correspondence: A. H. Lee at
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Aggressiveness of interval invasive ductal carcinoma of the breast in postmenopausal women Aggressiveness of interval invasive ductal carcinoma of the breast in postmenopausal women

Whether interval carcinomas differ from screen-detected tumors biologically is subject to debate. The authors conducted a study in which clinicopathological parameters and the expression of well-validated biological markers were compared between ‘true’ interval carcinomas and screen-detected/missed carcinomas. They hypothesized that true interval carcinomas show more aggressive biological behavior. The study group consisted of 92 consecutive postmenopausal women who attended a breast screening program and presented with an invasive ductal carcinoma. All screening mammograms were re-reviewed, and 16 patients were found to have a true interval carcinoma. Seven carcinomas were missed at screening but detected by re-reviewing the screening mammogram. Diagnostic mammograms were used to assess radiological characteristics. Data on patient and tumor characteristics, as well as followup data, were recorded from hospital records. The median followup was 61 months. Immunohistochemistry for estrogen receptor, progesterone receptor, Her2/neu, and p53 was performed on tissue microarray sections. Univariate and multivariate logistic regression analyses were performed. In univariate analysis, true interval carcinomas were significantly larger (odds ratios [OR], 7.2; 95 percent confidence interval [CI], 1.8–28.1) and less frequently positive for estrogen receptor (OR, 0.3; 95 percent CI, 0.1–0.9) and progesterone receptor (OR, 0.3; 95 percent CI, 0.1–1.0). In multivariate analysis, true interval carcinoma was independently associated with larger tumors (OR, 7.0; 95 percent CI, 1.4–36.2). A trend toward estrogen receptor negativity was found (OR, 0.3; 95 percent CI, 0.1–1.1). True interval carcinomas showed a trend toward decreased relapse-free survival (OR, 1.7; 95 percent CI, 0.9–3.1). The authors concluded that although true interval carcinomas were significantly larger than screen-detected/missed interval carcinomas, the ability to observe parameters that determine the difference between true interval carcinomas and screen-detected lesions is challenging.

Van der Vegt B, Wesseling J, Pijnappel RM, et al. Aggressiveness of ‘true’ interval invasive ductal carcinoma of the breast in postmenopausal women. Mod Pathol. 2010:23;629–636.

Correspondence: Dr. G. H. de Bock at
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Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Melissa Kesler, MD, and Rouzan Karabakhtsian, MD, assistant professors of pathology and laboratory medicine, University of Kentucky College of Medicine; and Megan Zhang, MD, visiting fellow, Division of Dermatopathology, University of California, San Francisco.