[Show abstract][Hide abstract] ABSTRACT: To investigate the prevalence of appendiceal pathology in women undergoing surgery for a suspected ovarian neoplasm and the predictive value of intraoperative findings to determine the need for appendectomy at the time of surgery.
Retrospective analysis of patients who underwent oophorectomy and appendectomy during the same surgical procedures at the University of Virginia Health System from 1992 to 2007. Observations were stratified based on the nature (benign, borderline, or malignant) and histology (serous compared with mucinous) of the ovarian neoplasm, frozen compared with final pathological diagnosis, and the gross appearance of the appendix.
Among the 191 patients identified, frozen section was consistent with seven mucinous and 35 serous carcinomas, 16 serous and 33 mucinous borderline tumors, 71 mucinous and serous cystadenomas, and 29 cases of suspected metastatic tumor from a gastrointestinal primary. The highest rates of coexisting appendiceal pathology were associated with serous ovarian cancers (94.4% of grossly abnormal and 35.3% of normal appendices) and ovarian tumors suspected to be of primary gastrointestinal origin (83.3% grossly abnormal and 60.0% normal appendices harbored coexisting mucinous neoplasms). Linear regression analysis revealed that appearance of the appendix and frozen section diagnosis of the ovarian pathology were statistically significant predictors of coexisting appendiceal pathology, but the latter was more important.
The prevalence of coexisting, clinically significant appendiceal pathology is low with a frozen section diagnosis of serous or mucinous cystadenoma. Appendectomy is recommended when frozen section diagnosis is mucinous or serous ovarian carcinoma, borderline tumor or metastatic carcinoma of suspected gastrointestinal origin.
Obstetrics and Gynecology 12/2010; 116(6):1348-53. · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Histopathologic diagnosis of cervical biopsies determines clinical management of patients with an abnormal cervical cancer-screening test yet is prone to poor interobserver reproducibility. Immunohistochemical staining for biomarkers related to the different stages of cervical carcinogenesis may provide objective standards to reduce diagnostic variability of cervical biopsy evaluations but systematic, rigorous evaluations of their potential clinical utility are lacking. To address diagnostic utility of human papillomavirus (HPV) L1, p16(INK4a), and Ki-67 immunohistochemical staining for improving diagnostic accuracy, we conducted a community-based and population-based evaluation using 1455 consecutive cervical biopsies submitted to the Department of Pathology at the University of Virginia during a period of 14 months. Thin-sections of each biopsy from 1451 of 1455 (99.7%) biopsies underwent evaluation of immunohistochemical stains for the 3 biomarkers, masked to the original diagnosis, and the results were compared with an adjudicated, consensus diagnosis by 3 pathologists. p16 immunostaining, using the strongest staining as the cutpoint, was 86.7% sensitive and 82.8% specific for cervical intraepithelial neoplasia (CIN) grade 2 or more severe (CIN2(+)) diagnoses. The performance of p16(INK4a) was more sensitive (P<0.001), less specific (P<0.001), and of similar overall accuracy for CIN2(+) compared with the combined performance of all pathologist reviews in routine clinical diagnostic service (sensitivity=68.9%, specificity=97.2%). Ki-67 immunostaining was also strongly associated with a CIN2(+) diagnosis but its performance at all staining intensities was inferior to p16 immunostaining, and did not increase the accuracy of CIN2(+) diagnosis when combined with p16(INK4a) immunostaining compared with p16(INK4a) immunostaining alone. We found no utility for L1 immunostaining in distinguishing between CIN and non-CIN. In conclusion, with a rigorous evaluation, we found immunohistochemical staining for p16 to be a useful and reliable diagnostic adjunct for distinguishing biopsies with and without CIN2(+).
The American journal of surgical pathology 08/2010; 34(8):1077-87. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Podoplanin, D2-40, is often used for highlighting lymphatics. However, it has been described in a variety of normal and neoplastic tissues. We evaluated the expression of D2-40 in breast, salivary gland, skin, and mucosa, all organs rich in myoepithelial cells and basal cells. This study assessed the utility of using D2-40 to highlight basal/myoepithelial cells and to identify potential pitfalls in misinterpretation of lymphatic invasion. Our results showed that myoepithelial cells in breast and salivary gland and basal cells in prostate consistently demonstrate D2-40 immunoreactivity, but typically less intensely than lymphatics. Cutaneous and mucosal-based basal cells also have D2-40 expression, but often in a patchy, focal manner. In addition, many salivary gland tumors and squamous cell carcinomas had strong D2-40 expression, sometimes making distinction of lymphatics versus tumor edge staining difficult. D2-40 is excellent for assessing lymphatic invasion in breast, prostate, and cervix as long as the pathologist is aware of the expression in myoepithelial cells/basal cells to avoid misinterpretation of ductal carcinoma in situ or normal prostate glands or tumor stroma retraction as tumor lymphatic invasion. Given the patchy positivity in basal cells of skin and mucosa and the reactivity in squamous cell carcinoma, D2-40 was not helpful in assessing for microinvasion of squamous cell carcinoma.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 05/2010; 18(3):226-30. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Protein kinase C-related kinases are regulated by phosphatidylinositol-3-kinase and Rho family GTPases. The isoform PRK1 has been characterized in detail in prostate cancer, but not in other carcinomas. We analyzed our prior microarray data for PRK1 gene expression in 175 carcinomas and evaluated tissue microarrays for protein expression in 251 carcinomas and a comprehensive group of normal tissues. We also used immunoblotting to determine the levels and phosphoactivation status of PRK1, PRK2, and PDK1 in 12 ovarian serous carcinomas, SKOV3 cells, and 3 samples of normal ovarian surface epithelium (OSE). The highest average level of PRK1 messenger RNA was observed in ovarian serous carcinomas compared with all other carcinomas, including those of the prostate, bladder/ureter, breast, colon, stomach/esophagus, kidney, liver, pancreas, and lung (P = .05). By immunohistochemistry, PRK1 was observed in selected normal cells, including epithelium from the gynecologic tract and hematolymphoid elements. All serous ovarian and endometrial endometrioid adenocarcinomas and mesotheliomas were immunoreactive for PRK1. The findings in nonserous ovarian and most carcinomas from the prostate, breast, and pancreas were also positive but less consistently so. In comparison with OSE, the serous carcinomas typically had greater pPRK1/total PRK1 (P = .02) as well as greater pPDK/total PDK (P = .01). The relative phosphorylation status of these 2 kinases correlated within each sample. In summary, PRK1 is present in various malignancies, but especially in serous carcinomas, where the increased activation status of PRK1 and its upstream regulator, PDK, as compared with normal OSE suggests a role in ovarian cancer development or progression.
Human pathology 06/2009; 40(10):1434-40. · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Differentiation of Müllerian serous carcinoma from metastatic breast carcinoma is a challenging and frequent diagnostic dilemma, particularly in the setting of a pelvic mass or peritoneal carcinomatosis. Precise classification is important as it impacts treatment and prognosis. Antibodies exist that assist with this differential but they are often limited by low sensitivity or specificity. This study evaluated the utility of mesothelin and mammaglobin antibodies in differentiating breast carcinoma (particularly those with a papillary morphology) from Müllerian serous carcinomas. Formalin-fixed, paraffin-embedded archival tissue from 21 breast carcinomas (10 micropapillary, 11 usual type ductal carcinomas) and 20 serous carcinomas (12 ovarian and 8 uterine) in addition to 6 cases of metastatic breast cancer to the ovary (5 cases) and cervix (1 case) were evaluated for the pattern and intensity of reactivity to antibodies to mesothelin, mammaglobin, and GCDFP-15. None of the breast carcinomas stained for mesothelin, whereas 8/12 and 3/8 ovarian and uterine serous carcinomas were positive; however, 7 of these had less than 10% positivity. Mammaglobin was negative in all serous carcinomas. When compared with GCDFP-15, mammaglobin was more frequently and diffusely expressed in breast carcinomas (GCDFP-15 positivity in 8/21 and mammaglobin positivity in 14/21). This study indicates that the addition of mammaglobin to immunohistochemical panels is useful in distinguishing metastatic breast carcinoma from a new primary ovarian or uterine malignancy. Mesothelin is extremely specific in this scenario but can be technically challenging to interpret due to the common patchy, focal staining.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 09/2008; 27(4):491-5. · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CDX2 is a member of the caudal-related homeobox gene family that is expressed during the normal development of the intestinal tract. In addition to staining adenocarcinomas of the alimentary system, studies have demonstrated CDX2 positivity in a percentage of ovarian mucinous and endometrioid tumors, carcinoids, and some adenocarcinomas of other sites such as the urinary bladder, prostate, lung, and pancreas. However, CDX2 immunostaining in cervical adenocarcinomas has not been examined in detail with comparison to important clinicopathologic characteristics including histopathologic subtype, tumor stage, and patient follow-up. In this study of 81 invasive cervical adenocarcinomas, 24 of the cases (30%) demonstrated nuclear positivity. Ten of the 15 (67%) endometrioid tumors had positive nuclear staining, compared with 7 of the 33 (21%) endocervical "usual-type" carcinomas, and 7 of the 33 (21%) remaining subtypes (adenosquamous, glassy cell, clear cell, serous, villoglandular, enteric). The frequency of nuclear staining for the endometrioid subtype was significantly different compared with that for the endocervical and other subtypes (P=0.003). Some cases showed granular cytoplasmic staining with or without corresponding nuclear positivity. Positive nuclear or cytoplasmic staining for CDX2 did not correlate with disease stage or patient outcome. Our results indicate that cervical adenocarcinomas can show nuclear immunopositivity for CDX2 even in the absence of overt morphologic features of colorectal differentiation. The frequency and pattern of CDX2 staining in the more common histologic subtypes of cervical adenocarcinoma (endocervical usual-type and endometrioid) is parallel to that which is seen for adenocarcinomas of the upper gastrointestinal tract and pancreaticobiliary system.
The American journal of surgical pathology 09/2008; 32(11):1608-12. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human papillomavirus (HPV) detection is an objective quality assurance benchmark for cervical cytology. There is no comparable metric for cervical biopsies despite biopsies having similar interobserver variability. Because HPV-16 positivity increases with the severity of cervical abnormality, we explored whether HPV-16 detection might be a useful metric for distinguishing a diagnosis of less than cervical intraepithelial neoplasia (CIN) 2 from CIN 2 or worse (representing the clinical threshold for treatment). By using Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion Triage Study data, we compared biopsy diagnoses of the 10 clinical center (CC) pathologists with the quality control (QC) group. Although the percentage of HPV-16 correlated with severity of diagnoses, there was great variability between the rates for each individual CC pathologist. Agreement between individual CC pathologists and the QC group on the percentage of CIN 2 or worse containing HPV-16 correlated weakly with agreement on whether the diagnosis was less than CIN 2 or CIN 2 or worse. Thus the HPV-16 fraction was not found to be broadly useful as a quality assurance metric for biopsy diagnosis in this analysis.
American Journal of Clinical Pathology 08/2008; 130(1):65-70. · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Residents in anatomic pathology are allowed increased diagnostic responsibility including the initial interpretation of intraoperative frozen-section consultations during their years of training. This frozen-section responsibility requires staff faculty backup for diagnostic confirmation and consultation. In this study, we tested a telepathology system using an ultra portable computer with a 4.5-in diagonal screen (scrolled image size of 2.5 x 1.75 in, width x height) and both wireless Local Area Network (LAN) final connection from a DSL and wireless Wide Area Network (WAN) telecommunications. The diagnostic agreement for a chief resident/faculty staff duo using telepathology for 100 consecutive frozen-section cases (50 with wireless LAN final connection and 50 with wireless WAN) with limited clinical information was compared with the original frozen-section diagnosis rendered by other staff pathologists. There was diagnostic agreement for 95 of the 100 cases. For the 5 that were discordant, 2 were deemed to be errors in the original frozen-section diagnosis; 1 was not clinically important; and 2 were believed to have potential clinical implications. For the 2 having potential clinical importance, the absence of knowledge of the gross findings in each case and the preoperative biopsy results for one specimen contributed to the misinterpretation of the frozen sections. The median time between transmission of image(s) from the chief resident to the faculty consultant until diagnosis by the latter was 1 minute 42 seconds for wireless WAN and 51 seconds for the wireless LAN final connection to the display device. We conclude that a telepathology system using an ultra portable computer and wireless telecommunications is useful for frozen-section consultation between an experienced resident and a faculty member in pathology.
Human Pathlogy 10/2007; 38(9):1330-4. · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine if atypical small acinar proliferation (ASAP) represents minimally sampled prostate cancer not fully evaluated on a biopsy or a distinct pathological entity, by examining prostates removed at radical cystectomy, as a finding of ASAP of the prostate on needle-core biopsy is closely associated with the detection of cancer on subsequent biopsy.
In all, 65 consecutive cystoprostatectomy specimens taken from June 1990 to March 2004 had prostatic material reviewed by one genitourinary pathologist (S.E.M.). The presence of high-grade prostatic intraepithelial neoplasia (HGPIN), ASAP, and adenocarcinoma was recorded. Foci of ASAP found in the absence of cancer were assessed with additional sectioning, high-molecular weight keratin (CK903), and alpha-methylacyl coenzyme A racemase (AMACR) immunohistochemistry.
In all, 24 of 65 specimens (37%) had adenocarcinoma. Of the 41 without cancer, 18 (44%) had neither HGPIN nor ASAP, 14 (34%) had HGPIN alone, three (7%) had ASAP alone (four foci), and six had both HGPIN and ASAP (15%). Two foci of ASAP were not present on any further sectioning. The remaining eight foci all lacked CK903 stain, indicating disruption of the basal cell layer. Of these eight, only five were present for the AMACR stain, all of which were positive. Two of these five developed into a lesion considered cancer on further sectioning.
ASAP identified in incidental prostates represented marginally sampled cancer in at least two of 10 foci assessed. The remainder could not be resolved as benign on further evaluation, and remained suspicious for malignancy.
BJU International 05/2007; 99(4):780-5. · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since its description, hyalinizing trabecular adenoma (HTA) of the thyroid has been a controversial entity. Some have considered it a unique entity, some have considered it a variant of papillary carcinoma (PC), and still others have considered it a nonspecific pattern that may be seen with a variety of thyroid lesions. Complicating the matter, studies demonstrating metastases have shown entities that do not appear to be HTAs as originally described, and molecular studies showing changes of PC have used methods that are not specific. This study reviews our experience with thyroid lesions that showed at least some histologic features of HTA and presents the immunohistochemical findings for these lesions using antibodies employed for the diagnosis of PC.
Our files were reviewed for all thyroid resection reports describing lesions with hyalinized or sclerotic stroma and a trabecular architecture within the diagnosis or diagnostic comment. All cases were reviewed and classified as either HTA or as different lesions based upon histologic features. Immunohistochemistry with antibodies to HBME1, CK19 and p63 was performed with all lesions and with a series of controls.
Eighteen thyroid lesions with prominent sclerosis or hyalinization and trabecular architecture were identified. Only 4 of these were found to completely match the histologic and cytologic descriptions of HTA by HE review. The other cases showed histologic features more compatible with other diagnoses including cellular adenomatoid nodule (5), follicular adenoma (4), follicular variant of PC (FVPC) (3), and epithelial neoplasm with features of FVPC (2). All HTAs lacked immunoreactivity for HBME1, CK19 and p63. All cases deemed to be adenomatoid nodules, follicular adenomas and epithelial neoplasms showed no immunoreactivity for HBME1 and CK19 and, of these, only a single AN showed immunoreactivity for p63. Cases deemed to be FVPCs showed diffuse immunoreactivity for HBME1 and CK19 and 1 reacted with antibodies to p63. Of control PCs and other thyroid lesions, reactivity for HBME1, CK19, and p63 was observed in 8/8, 7/7, and 7/8 and 3/27, 7/27, and 7/27 cases, respectively.
A sclerotic or hyalinized stroma with a trabecular growth pattern may be seen in a number of different thyroid lesions and, when seen, is usually a focal feature of a lesion other than HTA. Immunohistochemistry may be of assistance as cases of FVPC with prominent hyalinization and trabeculation will show immunoreactivity for HBME1 and CK19, whereas HTAs and other thyroid lesions with hyalinization and trabeculation will not.
American Journal of Surgical Pathology 11/2006; 30(10):1269-73. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The HE4 (WFDC2) gene encodes a WAP-type four disulphide core domain-containing protein with a presumptive role in natural immunity. Multiple studies have consistently identified upregulation of HE4 gene expression in carcinomas of the ovary; however, the expression in normal and malignant adult tissues has not been examined in detail. Here, we examined the expression of the HE4 gene and protein in a large series of normal and malignant adult tissues by oligonucleotide microarray and tissue microarray, respectively. HE4 gene expression was highest in normal human trachea and salivary gland, and to a lesser extent, lung, prostate, pituitary gland, thyroid, and kidney. In a series of 175 human adult tumors, gene expression was highest in ovarian serous carcinomas. However, adenocarcinomas of the lung, and occasional breast, transitional cell and pancreatic carcinomas had moderate or high levels of HE4 expression. Using tissue microarrays and full tissue sections of normal and 448 neoplastic tissues, HE4 immunoreactivity was found in normal glandular epithelium of the female genital tract and breast, the epididymis and vas deferens, respiratory epithelium, distal renal tubules, colonic mucosa, and salivary glands, consistent with HE4 gene expression. In addition to consistent positivity in ovarian carcinoma, some pulmonary, endometrial, and breast adenocarcinomas, mesotheliomas, and less often, gastrointestinal, renal and transitional cell carcinomas were also positive. Knowledge of the expression patterns of HE4 in our survey is useful for application in histopathologic diagnosis, and should be taken into consideration in future studies that examine the role of HE4 as a serological tumor biomarker or as a target for gene-based therapy.
Modern Pathology 07/2006; 19(6):847-53. · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate the AKT signaling cascade in endometrial cancers and to assess its therapeutic potential.
Western blotting and immunohistochemistry were used to investigate the expression of estrogen receptor, progesterone receptor, HER2, AKT, and 4EBP1 proteins in 27 atrophic endometria, 31 grade 1 and 24 grade 3 endometrioid endometrial cancers, and 19 malignant mixed müllerian tumors. Inhibition of the AKT signaling cascade was investigated in cell lines.
Malignant mixed müllerian tumors and grade 3 endometrioid endometrial cancers demonstrated higher levels of AKT and 4EBP1 activation and hormone receptor loss compared with grade 1 endometrioid endometrial cancers and atrophic samples. HER2 over-expression was identified most often in grade 3 tumors without gene amplification. In endometrial cancer cell-lines, AKT cascade inhibitors decreased cell proliferation by apoptosis and cell cycle arrest.
AKT cascade activation in grade 3 endometrioid endometrial cancers and malignant mixed müllerian tumors is a novel finding. Apoptosis and growth arrest that results from AKT inhibition expose opportunities for therapeutic intervention.
American journal of obstetrics and gynecology 05/2006; 194(4):1119-26; discussion 1126-8. · 3.97 Impact Factor