Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification.

BACKGROUND: In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin. METHODS: We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor (HER2) and DNA topoisomerase II-alpha (TOP2A) gene amplification. RESULTS: Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m(-2) of doxorubicin (HR=1.82 and 3.77; P=0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio. CONCLUSION: We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen.

Desmoplastic small round cell tumor masquerading as advanced ovarian cancer.

Desmoplastic small round cell tumor (DSRCT) is a rare abdominal malignancy usually diagnosed in young adult males. Most patients have widespread disease at presentation, with an organ of origin difficult to ascertain. A 33-year-old female presented to her gynecologist with complaints of suprapubic pressure, abdominal pain, and increased abdominal girth. She had a large intraabdominal tumor on ultrasound, thought to be ovarian cancer. She underwent surgical exploration, which confirmed a malignancy, but the exact etiology was uncertain. Final pathology was consistent with DSRCT. DSRCT is a rare malignancy that can mimic other more commonly seen tumors such as lymphoma and ovarian cancer. When encountering an extensive intraabdominal malignancy of uncertain etiology, DSRCT should be in the differential diagnosis.

Recognition of U1 and U2 small nuclear RNAs can be altered by a 5-amino-acid segment in the U2 small nuclear ribonucleoprotein particle (snRNP) B" protein and through interactions with U2 snRNP-A' protein.

We have investigated the sequence elements influencing RNA recognition in two closely related small nuclear ribonucleoprotein particle (snRNP) proteins, U1 snRNP-A and U2 snRNP-B". A 5-amino-acid segment in the RNA-binding domain of the U2 snRNP-B" protein was found to confer U2 RNA recognition when substituted into the corresponding position in the U1 snRNP-A protein. In addition, B", but not A, was found to require the U2 snRNP-A' protein as an accessory factor for high-affinity binding to U2 RNA. The pentamer segment in B" that conferred U2 RNA recognition was not sufficient to allow the A' enhancement of U2 RNA binding by B", thus implicating other sequences in this protein-protein interaction. Sequence elements involved in these interactions have been localized to variable loops of the RNA-binding domain as determined by nuclear magnetic resonance spectroscopy (D. Hoffman, C.C. Query, B. Golden, S.W. White, and J.D. Keene, Proc. Natl. Acad. Sci. USA, in press). These findings suggest a role for accessory proteins in the formation of RNP complexes and pinpoint amino acid sequences that affect the specificity of RNA recognition in two members of a large family of proteins involved in RNA processing.

A specific 31-nucleotide domain of U1 RNA directly interacts with the 70K small nuclear ribonucleoprotein component.

We have defined the nucleotide sequence of a protein-binding domain within U1 RNA that specifically recognizes and binds both to a U1 small nuclear ribonucleoprotein component (the 70K protein) and to the previously defined RNA-binding domain of the 70K protein. We have investigated direct interactions between purified U1 RNA and 70K protein by reconstitution in vitro. Thirty-one nucleotides of U1 RNA, corresponding to stem-loop I, were required for this interaction. Nucleotides at the 5' end of U1 RNA that are involved in base pairing with the 5' splice site of pre-mRNA were not required for binding. In contrast to other reports, these findings demonstrate that a specific domain of U1 RNA can bind directly to the 70K protein independently of any other snRNP-associated proteins.

Malignant transformation of the human endometrium is associated with overexpression of lactoferrin messenger RNA and protein.

In the mouse uterus, lactoferrin is a major estrogen-inducible uterine secretory protein, and its expression correlates directly with the period of peak epithelial cell proliferation. In this study, we examine the expression of lactoferrin mRNA and protein in human endometrium, endometrial hyperplasias, and adenocarcinomas using immunohistochemistry, Western immunoblotting, and Northern and in situ RNA hybridization techniques. Our results reveal that lactoferrin is expressed in normal cycling endometrium by a restricted number of glandular epithelial cells located deep in the zona basalis. Two thirds (8 of 12) of the endometrial adenocarcinomas examined overexpress lactoferrin. This tumor-associated increase in lactoferrin expression includes an elevation in the mRNA and protein of individual cells and an increase in the number of cells expressing the protein. In comparison, only 1 of the 10 endometrial hyperplasia specimens examined demonstrates an increase in lactoferrin. We also observe distinct cytoplasmic and nuclear immunostaining patterns under different fixation conditions in both normal and malignant epithelial cells, similar to those previously reported in the mouse reproductive tract. Serial sections of malignant specimens show a good correlation between the localization of lactoferrin mRNA and protein in individual epithelial cells by in situ RNA hybridization and immunohistochemistry. Although the degree of lactoferrin expression in the adenocarcinomas did not correlate with the tumor stage, grade, or depth of invasion in these 12 patients, there was a striking inverse correlation between the presence of progesterone receptors and lactoferrin in all 8 lactoferrin-positive adenocarcinomas. In summary, lactoferrin is expressed in a region of normal endometrium known as the zona basalis which is not shed with menstruation and is frequently overexpressed by progesterone receptor-negative cells in endometrial adenocarcinomas.

Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias.

Mutation and deletion of the PTEN tumor suppressor gene occurs in about 40% of endometrial carcinomas. The purpose of this study was to determine whether PTEN mutations also are present in endometrial hyperplasias, which are premalignant precursors of invasive endometrial adenocarcinomas. Genomic DNA from 51 endometrial hyperplasias was extracted from paraffin blocks, and PCR was used to amplify the nine exons of the PTEN gene. These products were screened using single-strand conformation analysis, and variant bands were sequenced. Somatic mutations in the PTEN gene were seen in 10 of 51 cases (20%), and two mutations were found in one case. An identical 4-bp deletion in exon 8 was seen in three cases, and 8 of 11 PTEN mutations predicted truncated protein products. There was no higher frequency of PTEN mutations in endometrial hyperplasias with atypia (6 of 32; 19%) relative to those without atypia (4 of 19; 21%). These data suggest that inactivation of the PTEN tumor suppressor gene is an early event in the development of some endometrial cancers.

M6P/IGF2 receptor: a candidate breast tumor suppressor gene.

The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2r) functions in the activation of TGFbeta, a potent growth inhibitor for most cell types, the degradation of the mitogen, IGF2, and the intracellular trafficking of lysosomal enzymes. We have found its expression to be significantly reduced in both rat and human hepatocellular carcinomas (HCCs) and recently reported loss of heterozygosity (LOH) at this locus with mutations in the remaining allele in human liver tumors. Using the polymerase chain reaction, we utilized two polymorphisms in the 3' untranslated region of M6P/IGF2r to screen breast tumors for LOH. Forty of 62 (65%) patients were informative (heterozygous) and 12/40 (30%) breast tumors had LOH; 5/19 (26%) carcinomas in situ (CIS) and 7/21 (33%) invasive carcinomas. To investigate the early molecular genetic events in breast carcinogenesis, we screened the CIS with LOH for mutations. In 2/5 (40%) of these tumors, missense mutations were found in the remaining allele that gave rise to significant amino acid substitutions. These findings provide evidence that M6P/IGF2r allelic loss is an early event in the etiology of breast cancer, that this gene functions as a tumor suppressor gene in the breast.

Comparison of methods of measuring HER-2 in metastatic breast cancer patients treated with high-dose chemotherapy.

PURPOSE: HER-2 is overexpressed in 20% to 30% of human breast cancer and is associated with poor outcome. Studies suggest an association between HER-2 overexpression and resistance to alkylating agents. To further evaluate this relationship, we assessed the interaction of HER-2, measured by different methods, and outcome after dose intensification with alkylating agents in metastatic breast cancer. PATIENTS AND METHODS: From 1988 to 1995 at Duke University, 425 patients with metastatic breast cancer were enrolled in a study of high-dose alkylating agents (HDC) with autologous cellular support after doxorubicin-based therapy (AFM). HER-2 was measured in serum for shed extracellular domain (ECD) and in tissue by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). RESULTS: HER-2 ECD was positive in 29% (19 of 65) of patients pre-AFM and in 11.7% (34 of 290) pre-HDC. Higher pre-AFM and higher pre-HDC HER-2 ECD predicted worse overall survival (P =.045 and P =.0096, respectively). HER-2 overexpression by IHC and FISH showed no correlation with worse disease-free survival or overall survival. FISH and ECD were highly specific for IHC (97.3% and 97.7% respectively). However, ECD had a low sensitivity for IHC-only 22% of patients with HER-2 in the primary tumor shed ECD into the serum. CONCLUSION: These data suggest that the method of measuring HER-2 is important in predicting clinical outcome. HER2 ECD may identify a poor prognosis subgroup of HER-2-positive tumors. Lack of association of HER2 by IHC/FISH with worse outcome suggests that therapy with AFM and/or HDC therapy may be able to overcome the effect of this prognostic factor or it may not be a prognostic factor in this setting.

Production and characterization of two ependymoma xenografts.

Childhood ependymomas exhibit epidemiologic, anatomic, histologic, and biologic features and distinguish them from other gliomas. Because of their propensity to grow in functionally sensitive regions of the brain, adequate tumor sampling for basic and therapeutic research is limited. We have established xenografts in both subcutaneous and intracranial nude mouse systems (D528 EP-X, D612 EP-X) from the ependymomas of two nonrelated children. Median subcutaneous growth rates (reported in days to grow from 200 mm3 to 1000 mm3) are 82 days for D528 EP-X (n = 10) and 50 days for D612 EP-X (n = 10). D528 EP-X grows intracranially with a median postimplantation survival of 85 days (n = 10); D612 EP produces a median postimplantation survival of 72.5 days (n = 10). Both xenografts grow as well-formed masses with no evidence of infiltration into either brain or subcutaneous tissues. While perivascular pseudopalisading is found in both xenografts, true ependymal rosette formation is absent. Ultrastructurally, neither xenograft exhibits cilia, but both produce abundant intermediate filaments. By light microscopy, the neoplastic cells are immunoreactive for the intermediate filaments glial fibrillary acidic protein, vimentin, and nestin. Karyotypically D528 EP exhibits 46,XX,del(6)(q22q26)/46,XX while D612 EP exhibits 50,XX, +X,t(1;8)(p11;q11),t(1;8)(p11;q11), +1,-4, der(5)t(4;5)(q12;q35), +der(5)t(4;5)(q12;q35),-6, +9, +9,-16, +der(17)t(6;17)(p11;p11), +mar. Restriction fragment length polymorphism studies comparing the primary brain tumor tissue from each patient against multiple passages of the resulting xenografts confirm the origin of both xenografts. These xenografts represent models on which future studies into the oncogenesis, progression and therapy of ependymomas can be performed.

Pre-proglucagon messenger ribonucleic acid: nucleotide and encoded amino acid sequences of the rat pancreatic complementary deoxyribonucleic acid.

Glucagon, a pancreatic peptide hormone of 29 amino acids that regulates carbohydrate, fat, and protein metabolism, is one of a family of structurally similar regulatory peptides which include GH-releasing hormone, vasoactive intestinal peptide, secretin, and gastric inhibitory peptide. The synthesis of glucagon involves its specific proteolytic cleavage from preproglucagon, a large polyprotein precursor. To facilitate analyses of the cellular processing of pre-proglucagon and to begin studies of the regulation of glucagon gene expression in the rat, we have cloned and sequenced two cDNAs derived from rat neonatal pancreas. The cDNAs represent close to the entire transcriptional sequence of the glucagon gene and encode a pre-proglucagon of 180 amino acids. The coding region of pre-proglucagon contains, in addition to the sequence of glucagon, the sequences of two peptide domains that are related in their structures to glucagon. Glucagon and the two glucagon-like peptides are flanked in the precursor by pairs of basic amino acids characteristic of the sites that are cleaved during the posttranslational processing of pro-hormones. Northern blot analyses indicate the presence of a single mRNA of 1400 +/- 100 nucleotides in the rat pancreas, and results of Southern blotting of rat liver genomic DNA are consistent with the existence of a single chromosomal gene. Comparisons of the nucleotide sequence of the rat pre-proglucagon cDNA with those of the two pre-proglucagons of the anglerfish pancreas encoded by two separate genes indicate that the pre-proglucagon genes probably evolved by intragenic duplications of a DNA segment corresponding to the coding sequences of glucagon and the glucagon-like peptides.

Some mullerian inclusion cysts in lymph nodes may sometimes be metastases from serous borderline tumors of the ovary.

Glandular inclusions that appear morphologically benign are occasionally found in lymph nodes as well as in peritoneal and omental biopsies. In patients with gynecologic malignancies, the nature and significance of these mullerian inclusion cysts (MIC) present a diagnostic challenge with regard to whether they are benign and incidental or are related to the coincident tumor for which surgery is being performed. Sixty-two cases of MIC were prospectively identified during a 6-year period. The frequencies were calculated and stratified by lymph node chain distribution, primary tumor site, and primary tumor type. MIC appeared as small cysts lined by a serous (mullerian)-type, cytologically bland, cuboidal to columnar epithelium with a simple architecture. Among 62 women, MIC was found in lymph nodes (27 cases), pelvic peritoneum (19 cases), omentum (16 cases), bowel serosa (9 cases), uterine serosa (8 cases), and parametrial connective tissues (4 cases). Among a set of 417 consecutive cases in which lymphadenectomy was performed, 46 (11%) women had MIC. The MIC involved multiple sites (26 cases in the peritoneum/omentum and 27 in lymph nodes). The primary tumor was in the ovary in 32 of the 46 women with MIC (70%) and of these, 17 were borderline serous (53%). Sixty-two of 6,154 lymph nodes examined contained MIC (1.0%). 3.2% of nodes contained MIC in which the primary tumor arose in the ovary, but only 0.1% with either endometrial or cervical tumors (chi2, p <0.00001). The lymph nodes most often involved by MIC were from para-aortic sites (40%), which reflect the primary drainage route from the ovary. Not uncommonly, neighboring areas in the same lymph node group with MIC disclosed separate foci of obvious metastatic borderline tumor (4 of 10; 40%). In summary, the increased frequency of MIC in lymph nodes sampled for primary ovarian malignancies suggests that MIC in some cases, rather than being benign, incidental inclusions, are more likely bland-appearing forms of metastatic tumor. The preponderance of inclusions occurs with serous ovarian tumors of borderline malignancy, and the inclusions are overrepresented in the lymph nodes that primarily receive drainage from the ovary.

Gastric graft-versus-host disease: a blinded histologic study.

Acute graft-versus-host disease (GvHD) of the upper gastrointestinal (GI) tract is common after allogeneic bone marrow transplantation (BMT). However, diagnosis cannot be made on clinical presentation and endoscopic findings alone, because these are nonspecific, and histologic confirmation is often desirable. The diagnosis of gastric GvHD is often based on subtle findings with considerable potential for variability in interpretation. Evaluation of the reproducibility of diagnosis and recognition of histologic features of gastric GvHD was based on blinded review of 56 gastric biopsies (24 from patients with allogeneic BMT or unrelated umbilical cord blood transplantation and 32 control biopsies from patients who did not undergo BMT, of whom eight had active GI cytomegalovirus [CMV] infection). Histologic criteria for GvHD were apoptosis and gland destruction, sparse inflammatory infiltrate, and granular eosinophilic debris in dilated glands. Seventeen patients (22 biopsies) were judged to have clinical GvHD on the basis of skin or liver involvement and GI symptoms without other known cause. Eighteen of these 22 gastric biopsies were classified as GvHD by at least two of the three pathologists on initial review. Blinded histologic diagnosis of GvHD had a positive predictive value of 69%, a sensitivity of 82%, and specificity of 76%. False-positive results occurred in CMV gastritis, human immunodeficiency virus (HIV) infection, primary immunodeficiency, and after renal transplantation. Of individual features, granular debris in glands was a specific (94% specificity), but insensitive (41% sensitivity) marker for GvHD. Distinction between GvHD and CMV infection can be difficult, and GvHD can be confused with changes seen in HIV infection and other immunodeficiency states.

Villoglandular adenocarcinoma of the endometrium: a clinicopathologic study of 61 cases: a gynecologic oncology group study.

Papillary endometrioid or villoglandular adenocarcinoma (VGA) is a relatively common type of endometrial adenocarcinoma, but studies describing its behavior have yielded conflicting results. Patients with a component of VGA were identified in a review of 819 women entered in a Gynecology Oncology Group Study (Protocol 33) of clinical stages I and II endometrial adenocarcinoma. Cases with coexisting foci of serous or clear cell carcinoma were excluded from further consideration. Of the 61 cases that formed the study sample, there were 24 with pure villoglandular differentiation and 37 who were admixed with typical endometrioid adenocarcinoma (EA). The general clinicopathologic features of patients with pure and mixed VGA are compared with 469 patients with pure EA. The VGAs were better differentiated (grade 1 or 2--97% of VGA versus 74% EA, p = 0.001). but they were not significantly different with respect to median age, depth of invasion, or frequency of nodal spread. Six of the 61 patients with VGA died of their tumor. The disease-specific survival rate at 3 years for VGA is 94% (95% confidence interval: 0.88-0.99) compared with 88% (95% CI: 0.86-0.91) for EA. Two of the patients who died had pure villoglandular tumors and four had mixed villoglandular and endometrioid carcinoma. In view of the frequent admixture of VGA and EA and their generally similar biological characteristics, with a prognosis similar to that of typical EA, we conclude that VGA should be considered a variant of EA.

Endothelial cell and hepatocyte deaths occur by apoptosis after ischemia-reperfusion injury in the rat liver.

BACKGROUND: Ischemic injury of the liver is generally considered to result in necrosis, but it has recently been recognized that mediators of apoptosis are activated during ischemia/reperfusion. This study was designed to characterize the extent and the type of cells within the liver that undergo apoptosis at different periods of ischemia and reperfusion. METHODS: Male Wistar rats were subjected to 30 or 60 min of normothermic ischemia. Liver sections were evaluated at the end of ischemia and at 1, 6, 24, and 72 hr after reperfusion. Apoptosis was determined by DNA fragmentation as evaluated by laddering on gel electrophoresis, in situ staining for apoptotic cells using TdT-mediated dUTP-digoxigenin nick-end labeling (TUNEL), and morphology on electron microscopy. RESULTS: In situ staining of liver biopsy specimens using TUNEL showed significant apoptosis after reperfusion. Sinusoidal endothelial cells (SEC) showed evidence of apoptosis earlier than hepatocytes. For example, at 1 hr of reperfusion after 60 min of ischemia, 22+/-4% of the SEC stained TUNEL positive compared with 2+/-1% of the hepatocytes (P<0.001). With a longer duration of ischemia, a greater number of SEC and hepatocytes became TUNEL positive. An increase in TUNEL-positive cells was also noted with an increasing duration of reperfusion. The presence of apoptotic SEC and hepatocytes was supported by DNA laddering on gel electrophoresis and cell morphology on electron microscopy. Several Kupffer cells were seen containing apoptotic bodies but did not show evidence of apoptosis. Only rare hepatocytes showed features of necrosis after 60 min of ischemia and 6 hr of reperfusion. CONCLUSION: These results suggest that apoptosis of endothelial cells followed by hepatocytes is an important mechanism of cell death after ischemia/reperfusion injury in the liver.

Pathology and pathophysiology of uterine smooth-muscle tumors.

Smooth-muscle tumors of uterine origin encompass a broad family of neoplasms. The leiomyoma, by far the most common of all the neoplasms, generally is hormone sensitive, with rates of growth semiquantitatively related to estrogen and progesterone receptor levels. Several forms of degenerative change can occur in the leiomyoma. The most common is hyaline degeneration, which is important in that it should not be mistaken for the coagulative tumor cell necrosis seen in leiomyosarcoma. Red degeneration (necrobiosis) is a form of degeneration that occurs characteristically but not exclusively in pregnancy, and the process is often the cause of pain and fever. Several forms of treatment have been used medically in the treatment of leiomyoma. Gonadotropin-releasing hormone analogs or agonists or selective arterial embolization with polyvinylformaldehyde particles may lead to substantial degeneration or infarction of the leiomyoma, respectively. Several variants of leiomyoma, the cellular and symplastic leiomyomas, are important to recognize, as they can be misinterpreted as sarcoma. In addition, there are two unusual growth patterns of leiomyoma that are important to recognize. Both the benign metastasizing leiomyoma and disseminated peritoneal leiomyomatosis are found outside the uterus, and neither is malignant. Recent studies offer insights into their origin and hormonal influences. From a diagnostic and therapeutic point of view, the leiomyosarcoma, while rare, is clinically of great import. Coagulative necrosis, cytologic atypia, and mitotic counts are all important in diagnosing the condition.

Genotypic divergence precedes clinical dissemination in a case of synchronous bilateral B-cell malignant lymphoma of the testes.

Malignant lymphoma of the testis occurs bilaterally more often than any other tumor type. We report the case of a 62-year-old man who presented with synchronous, bilateral, testicular malignant lymphomas without clinical or radiologic evidence of extratesticular disease. The patient received no therapy other than bilateral orchiectomy and subsequently developed widespread disease 6 months later. Southern blot DNA analysis was performed on the initial orchiectomy samples for immunoglobulin (Ig) gene rearrangements. These genotypic analyses showed different clonal rearrangements in the Ig heavy chain JH region but identical clonal rearrangements in the Ig light chain C Kappa region. To our knowledge this is the first genotypic demonstration of a common clonal origin in synchronous, bilateral, testicular malignant lymphomas. We interpret these findings as molecular evidence that the patient's malignant lymphoma was already disseminated at initial presentation, although it was clinically undetectable at that time.

Prospective correlation of cervicovaginal cytologic and histologic specimens.

An effective, prospective, computer-guided method of correlation is reported. The mechanism for identification of cases, comparison of diagnoses, and reconciliation of discrepancies are explained. The results are similar to prior, retrospective, correlation studies. The benefits specific to this unique prospective approach include optimal capture of cases for correlation, minimization of errors before diagnoses are released to clinicians and patients, and internal standardization of diagnostic criteria. Three thousand four hundred and four consecutive paired cervicovaginal cytologies and biopsies were accessioned at the Pathology Department of Duke University Medical Center over a 43-month period. Of these, 481 paired cases (14%) had discordant diagnoses, defined as differing more than one degree of dysplasia or as dysplasia or carcinoma identified by only one modality. Additional evaluation reconciled the diagnostic differences in 35 cases. Eighteen initial diagnostic differences arose from cytologic screening errors, 16 from interpretive errors by staff pathologists, and one from superficial initial histologic sections. The remaining 446 discordances were attributed to sampling differences. The cytologic smear contained the diagnostic lesion in 40% of the cases and the biopsy the remainder, emphasizing the utility of pairing these sampling techniques in patients at risk for dysplasia.

Villoglandular adenocarcinoma of the cervix: a case report.

BACKGROUND: Villoglandular adenocarcinoma of the cervix is a rare neoplasm associated with a favorable outcome and has not been described as a complication of pregnancy. CASE: A gravida at 20 weeks' gestation was found to have a bulky stage-IB adenocarcinoma of the cervix. She was delivered at 32 weeks' gestation by cesarean, then a radical hysterectomy and pelvic and periaortic lymphadenectomies were performed. Pathology revealed a deeply invasive, grade 1 villoglandular adenocarcinoma confined to the cervix. The patient remains free of disease at 14 months follow-up. CONCLUSION: Villoglandular adenocarcinoma of the cervix has a favorable prognosis and can be managed conservatively, even when complicated by pregnancy.

Malignant melanoma presenting as a mediastinal mass.

A case of malignant melanoma presenting as a mediastinal mass without an extrathoracic primary is reported. Microscopically the tumor appeared consistent with malignant melanoma, with the presence of focal melanin pigment in large epithelioid cells. Fontana stain confirmed the presence of melanin pigment. Immunohistochemical staining further suggested melanoma, with the tumor cells expressing a HMB45+, S100+ and cytokeratin-phenotype. Electron microscopy showed an abundance of melanosomes confirming the diagnosis of malignant melanoma.