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Author(s): J. Veverka (corresponding author) [1]; B. Farquhar [2]; M. Robinson [3]; P. Thomas [1]; S. Murchie [2]; A. Harch [1]; P. G. Antreasian [4]; S. R. Chesley [4]; J. [...]

From February 13 to May 13, 2000, the near-infrared spectrometer (NIS) instrument on the Near Earth Asteroid Rendezvous (NEAR) spacecraft obtained more than 200,000 spatially resolved 800- to 2500-nm reflectance spectra of the S-type asteroid 433 Eros. An important subset of the spectra was obtained during a unique opportunity on February 13 and 14, when the NEAR spacecraft flew directly through the 0° phase angle point between Eros and the Sun just prior to the orbital insertion maneuver. This low phase flyby (LPF) dataset consists of ∼2000 spectra of the northern hemisphere of Eros, obtained from 1° to 47° phase angle and at spatial resolutions of between 6×12 km to 1.25×2.50 km per spectrum. The spectra were calibrated to radiance factor (I/F, where I=observed radiance and πF=solar input radiance) and then photometrically corrected to normal albedo. The average northern hemisphere spectrum of Eros is similar to the asteroid''s unresolved telescopic spectrum and exhibits absorption features near 1000 nm (Band I) and 2000 nm (Band II) consistent with an orthopyroxene to orthopyroxene+olivine (opx+ol) mixing ratio of approximately 0.38±0.08. The ensemble of NIS LPF spectra falls primarily within the S(IV) to upper S(III) fields of the Gaffey et al. (1993) S-asteroid classification scheme and exhibits Band I and Band II properties similar to those of ordinary chondrite meteorites. While some small spatially coherent spectral variations have been detected, neither the opx/opx+ol) mixing ratio nor other spectral parameters vary spatially by more than ∼1σ across the entire northern hemisphere of the asteroid, suggesting a remarkable homogeneity of the composition and mineralogy of the uppermost regolith. Spectral mixture modeling suggests that the presence of glass and/or a reddening agent like nanophase iron, likely formed from exposure of the regolith to the space environment, is a component of the surface of Eros. Reddening and darkening components could also explain the dissimilarity in overall spectral slope and albedo between Eros and other S(IV) asteroids and ordinary chondrite meteorites. The largest (but still weak) spectral variations across the surface are seen in the depths of Band I and Band II, which are greatest in and around the largest craters and at the 0° longitude “nose” of the asteroid, and in the Band II/Band I area ratio between the large impact craters Psyche and Himeros. These subtle NIS spectral variations are usually associated with albedo and surface slope variations seen in NEAR imaging and topographic data and appear to be related to downslope movement of regolith materials. [Copyright &y& Elsevier]

Background: Although colon carcinomas consisting predominantly of neuroendocrine cells carry a worse prognosis than "routine" colon adenocarcinomas, the clinical significance of scattered neoplastic neuroendocrine cells within a typical colon adenocarcinoma remains controversial. The aim of this study was to document the frequency and clinical significance of neuroendocrine cell expression within a stage-specific group of typical adenocarcinomas of the colon., Methods: Forty-eight patients with resected stage III adenocarcinomas of the colon were selected from our institutional tumor registry. The pathologic specimens from these patients were reviewed and underwent immunohistochemical staining for chromogranin, a sensitive and specific marker of neuroendocrine differentiation. Long-term (> or = 5 years) clinical outcome was compared with the presence of neuroendocrine cell expression., Results: Twenty tumors (41.7%) stained positively for chromogranin. Twenty-two patients (45.8%) had long-term cancer-free survival, although chromogranin positivity did not correlate with this survival., Conclusion: The frequency of scattered neuroendocrine cells within colonic adenocarcinomas is high. This finding does not, however, carry the same adverse prognostic implications for cancer survival as does the presence of true neuroendocrine carcinoma of the colon.

A clear cell variant of primary pulmonary carcinoid tumor is described. The tumor arose in a 53-year-old woman who was incidentally found to have a solitary pulmonary nodule in the left upper lobe during routine chest roentgenography. Histologically, the tumor was composed of predominantly clear to lightly eosinophilic, polygonal cells with bland nuclei arranged in sheets and nests. Nuclear pleomorphism, necrosis, vascular invasion, and mitotic figures were not seen. The tumor cells were negative for oil-red-O and periodic acid-Schiff stains with and without diastase pretreatment on frozen and formalin-fixed sections, respectively. During immunohistochemical evaluation, the tumor cells were focally positive for cytokeratin and diffusely positive for neuron-specific enolase and chromogranin. Electron microscopy performed on paraffin block-retrieved tissue showed the presence of electron-dense, neurosecretory-type granules and variably sized vacuolated areas within the cytoplasm. the nature of which remained unclear. Intracytoplasmic glycogen or lipid were not identified. To our knowledge, this is the first report of pulmonary clear cell carcinoid tumor.

Objective: The goals were to summarize the results of liver transplantation for chronic hepatitis B disease (HBV) at the University of Virginia, correlate pretransplant viral markers with posttransplant hepatitis B immunoglobulin (HBIg) requirements, and identify the relation between viral protein in the liver and clinical reinfection., Summary Background Data: Liver transplantation is an accepted treatment for end-stage liver disease from chronic HBV infection, although lifelong antiviral treatment (with HBIg or antiviral agents) is still necessary. Patients with evidence of active viral replication (detectable serum HBV-DNA or e antigen) at the time of transplant have a higher rate of allograft infection. Whether clinically stable patients receiving HBIg immunoprophylaxis have detectable viral products in their grafts remains unknown., Methods: Forty-four transplants performed for HBV disease at the University of Virginia since March 1990 were reviewed. Most patients underwent aggressive passive immunoprophylaxis with HBIg to maintain serum HBV surface antibody (HBsAb) levels > or =500 IU/l for the first 6 months after the transplant, and > or =150 IU/l thereafter. Patients had viral markers quantified, underwent pharmacokinetic analysis of HBsAb levels to adjust dosing, and were biopsied routinely every 3 to 6 months and when indicated., Results: Forty-four transplants were performed in 39 patients. Actual 1-year and 3-year graft survival was 95% and 81%, respectively, and 1-year and 3-year patient survival was 98% and 96%, respectively. After the adoption of indefinite HBIg prophylaxis, nine grafts became infected (all in recipients positive for HBV e antigen). Three occurred within 8 weeks of transplantation and were associated with a short HBsAb half-life and a wild-type virus. Six occurred >8 months after the transplant, and most of these were associated with viral mutation. Quantification of pretransplant markers was an overall poor predictor of HBIg requirements after the transplant. Immunohistochemistry demonstrated transient low-level expression of core protein in the liver in 23% of patients without serum or clinical evidence of recurrent hepatitis., Conclusions: An excellent outcome is possible after liver transplantation for chronic HBV disease using HBIg dosed by pharmacokinetic parameters. Currently, quantification of pretransplant serum markers of the HBV antigen load does not predict the intensity of posttransplant treatment required for good clinical outcomes. Because HBV is not eradicated from the patient, some form of indefinite antiviral therapy continues to be warranted.

Clear cell tumors of the lower respiratory tract comprise a diverse group of lesions. The prototypical lesion is the benign clear cell tumor or "sugar tumor," a tumor of enigmatic histogenesis, whose name derives from the high glycogen content of the cells. Analogous to the salivary gland lesion of the same name, acinic cell tumors may also occur in the tracheobroncheal tree. The topic of "clear cell carcinoma" is discussed, which in the opinion of the authors does not constitute a distinct tumor entity. A discussion of potential lesion metastatic to the lung with clear cell histology is also presented. Histological details of the various entities are discussed, as well as the significant histochemical, immunohistological, and electron microscopic features; in particular, such findings that are relevant to differential diagnosis are stressed, including the distinction of primary and metastatic lesions.

Gonadoblastomas are composed of nests of neoplastic germ cells and sex cord derivatives surrounded by ovarian-type stroma. These tumors are found almost exclusively in persons with gonadal dysgenesis associated with a Y chromosome or Y chromosome fragment, and accordingly, the Y chromosome has been implicated in gonadoblastoma oncogenesis. To evaluate this association, we used two-color fluorescence in situ hybridization with chromosome-specific probes to determine the distribution of the X and Y chromosomes in the tumor nests and surrounding stromal cells in paraffin tissue sections of three gonadoblastomas in two patients with gonadal dysgenesis and 45,X/46,XY mosaicism. Statistical analysis of the data from the fluorescence in situ hybridization demonstrated that in all three gonadoblastomas, the proportion of nuclei with a Y chromosome signal was significantly higher in the tumor cells than in the nontumoral cells of the surrounding stroma (P<.001). These results suggest that Y chromosome material participates in gonadoblastoma tumorigenesis.

Clear cell neoplasms of the abdominal organs are represented by a variety of epithelial and mesenchymal neoplasms, of varying malignant potential. Several varieties of clear cell carcinomas, including those with tubulopapillary, hepatoid, colloid, or neuroendocrine features, have been described, as well as several benign epithelial neoplasms. These epithelial tumors have been reported in the gastrointestinal hollow viscera, as well as the liver, pancreas, and biliary tract. A second major consideration is the mesenchymal-derived gastrointestinal stromal tumors, which also may feature clear cells, and comprise a spectrum of biological behavior. Miscellaneous lesions include clear cell variants of melanoma and mesothelioma. This review includes histological details of the various entities, as well as important histochemical, immunohistological, and ultrastructural features. Pertinent differential diagnostic points are stressed, including distinction of the primary clear lesions from relevant metastatic neoplasms.

Life arose on an early Earth which was the product to the conditions present, and processes operating, during formation of the solar system. The formation and early state of the solar system are reviewed in order to better understand the nature of the early Earth, and to constrain the conditions present during the origin and early evolution of life on this planet.

Hepatic explant specimens from 171 patients with cirrhosis were examined to determine the incidence of periodic acid-Schiff (PAS)-positive diastase-resistant globules (PDRGs) in end-stage hepatic disease and whether the globules bear a specific relationship to the alpha1-antitrypsin (A1AT) phenotype or to causes of hepatic disease other than A1AT deficiency. PAS-positive diastase-resistant globules were detected in 17 (10%) of the hepatic explant specimens, and the globules in all of these cases were strongly immunoreactive for A1AT. In the 17 patients with PDRGs, the cirrhosis was attributed preoperatively to A1AT deficiency (3 patients), ethanol abuse, viral hepatitis, or both (10 patients), cryptogenic cirrhosis (3 patients), and autoimmune hepatitis (1 patient). The A1AT isoelectric phenotypes classified according to the protease inhibitor (Pi) nomenclature for 16 of these patients were as follows: Pi ZZ (3 patients), Pi SS (1 patient), Pi MZ (8 patients), and Pi MM (4 patients). Because PDRGs were seen in a variety of A1AT phenotypes, serum electrophoretic analysis, not histologic examination, is required for the correct diagnosis of an A1AT abnormality. Furthermore, although PDRGs were seen in a variety of hepatic diseases, the majority of patients with globules had an undetected A1AT abnormality. Accordingly, on identification of hepatocytic PDRGs, the clinician should be alerted to the possibility of an unsuspected A1AT abnormality even in the presence of other causes of hepatic disease.

Chronic hepatitis B is a widespread viral illness with the serious sequelae of cirrhosis and hepatocellular carcinoma. Current therapy with interferon is not universally efficacious, and this has led to the evaluation of other antiviral agents. A recent Phase II trial of the nucleoside analogue, fluoroiodoarabinofuranosyluracil (fialuridine, FIAU) was halted because of the sudden development of severe multisystem toxicity characterized by hepatic failure, lactic acidosis, and pancreatitis, which resulted in the deaths of five patients. We systematically evaluated pre- and post-therapy biopsy, explant, and autopsy specimens from the 15 patients involved in this trial to define the hepatic changes of fialuridine toxicity and to determine whether the degree of pre-existing hepatitis contributed to the severity of toxicity. Severe hepatotoxicity from fialuridine was characterized by hepatomegaly with diffuse, predominantly microvesicular steatosis, hepatocellular glycogen depletion, marked bile ductular proliferation, and cholestasis. Ultrastructural examination revealed intracytoplasmic lipid droplets and marked mitochondrial injury. Patients in whom severe toxicity did not develop mainly showed changes caused by the underlying chronic hepatitis B alone. There was a subtle increase in the amount of microvesicular steatosis in two of six patients with mild or no symptoms of toxicity. The microscopic and ultrastructural pattern of injury and systemic symptoms in patients with fialuridine toxicity are consistent with severe mitochondrial and metabolic derangements. Similar hepatic pathologic findings have been reported rarely for other antiviral nucleoside analogues, which suggests that the mechanisms of toxicity might be related.

Purpose: To determine the computed tomographic (CT), magnetic resonance (MR) imaging, and angiographic findings of papillary endolymphatic sac tumors., Materials and Methods: Clinical and imaging studies in 20 patients (aged 17-65 years) with histopathologically proved papillary endolymphatic sac tumors were retrospectively reviewed. Patients underwent CT (n = 18), MR imaging (n = 15), or angiography (n = 12). CT scans were evaluated for bone erosion and calcification; MR images, for signal intensity, enhancement patterns, and flow voids; and angiograms, for tumoral blood supply., Results: All tumors were destructive and contained calcifications centered in the retrolabyrinthine region at CT. The MR imaging appearance varied with lesion size; 12 of 15 tumors showed increased signal intensity at T1-weighted imaging. The high-signal-intensity area was circumferential in lesions 3 cm or smaller and was scattered throughout the lesion in advanced tumors. Only tumors larger than 2 cm had flow voids. The blood supply arose predominantly from the external carotid artery. Large tumors had additional supply from the internal carotid and posterior circulation., Conclusion: Papillary endolymphatic sac tumors are destructive, hypervascular lesions that arise from the temporal bone retrolabyrinthine region. Increased signal intensity at unenhanced T1-weighted MR imaging is common and may help distinguish these lesions from more common, aggressive temporal bone tumors.

The partial DNA sequence of a putative new herpesvirus has recently been isolated from almost all cases of Kaposi's sarcoma (KS), from a small subset of AIDS-related lymphomas, and from a high proportion of multicentric Castleman's disease. The presence of this KS-associated herpesvirus, which is also known as human herpes virus 8 (KSHV/ HHV8), has not been reported in vascular tumors other than KS. We therefore examined a series of vascular neoplasms of both endothelial and pericyte derivation using polymerase chain reaction to detect a 233-hp segment of the viral DNA. KSHV/HHV8 sequences were found in 7 of 24 (29%) angiosarcomas and 1 of 20 (5%) hemangiomas but not in any hemangiopericytomas (0 of 6). The presence of the virus in angiosarcoma was confirmed by direct sequencing of the polymerase chain reaction product and Southern blotting in one case each. Only one of the affected patients was known to be immunocompromised. By detecting its presence in a significant proportion of angiosarcomas, this study extends the number of tumors associated with KSHV/HHV8, further tightens its association with malignancy, and suggests a tropism of the virus for endothelial cells. The presence of KSHV/HHV8 in angiosarcomas in addition to classical KS also indicates that immunosuppression is not a requisite for viral infection.

Using the polymerase chain reaction (PCR), it has been recently reported that the Epstein-Barr virus (EBV) is present in the majority of Schneiderian sinonasal papillomas (SNP) of the inverted type and may play a role in the pathogenesis of these lesions. The reported prevalence rates of human papillomavirus (HPV) in different types of SNP is also controversial and in need of clarification. Twenty-eight SNP from 27 patients were histologically classified and evaluated for evidence of EBV using PCR and 2 different sensitive and specific in situ hybridization (ISH) procedures for EBER1. Similarly, two methods of ISH were also used for the detection of HPV, using biotinylated DNA probes sensitive for 14 different HPV types as well as more sensitive and specific radioactive RNA probes for HPV types 6, 11, and 16. Polymerase chain reaction was successful in 19 papillomas, including 12 of 19 inverted SNP, 1 of 1 inverted SNP with squamous cell carcinoma, 4 of 5 fungiform SNP, and 2 of 3 oncocytic lesions. Southern blot hybridization of PCR products showed the presence of EBV DNA in two lesions, including one inverted SNP and the single inverted SNP with squamous cell carcinoma. By both DNA- and RNA-mRNA ISH, positivity for EBER was detected in rare stomal lymphocytes but not the overlying epithelium in the inverted SNP with SCC. The remaining cases, including the other inverted SNP positive for EBV by PCR, were completely negative by both ISH techniques. Human papillomavirus was detected by ISH in 1 of 19 (5%) inverted, 1 of 1 (100%) inverted with squamous cancer, 5 of 5 (100%) fungiform, and 0 of 3 (0%) oncocytic SNP. Three SNP contained HPV 6 (all fungiform), three SNP labeled for HPV 11 (two fungiform and the inverted SNP with squamous cancer), and one inverted SNP contained HPV 16. Of the five fungiform SNP, four showed foci of koilocytosis. The results indicate that EBV is not present in sinonasal papillomas. The presence of EBV positive stromal lymphocytes in these lesions may account for a proportion of PCR-positive cases. Oncocytic SNP are unassociated with HPV, whereas inverted SNP contain HPV in a minority of cases. In contrast, fungiform SNP are consistently associated with HPV types 6 and 11 and usually show histologic evidence of viral infection.

Quantitative image cytometry was used to compare 18 parameters relating to ploidy, nuclear area, and chromatin texture to axillary lymph node status, tumor size, and histological grade for 34 infiltrating ductal carcinomas, each of which had been graded independently by each of six surgical pathologists. Zinc formalin-fixed, paraffinembedded tumors were assessed using the Elston and Ellis modification of the Bloom and Richardson histological grading scheme. When axillary lymph node-negative tumors were compared with those involving four or more nodes, % 2 c (diploid) cells, nuclear area, and eight of 12 chromatin texture parameters showed statistically significant differences. Carcinomas < 2 cm had more % 2 c (diploid) cells and fewer % > 4 c (hypertetraploid) cells than larger neoplasms. For tumors having nuclear pleomorphism score two versus those with score three, nuclear area, four of five parameters related to ploidy level, each of five parameters related to run-length matrix features and one of four co-occurrence matrix features showed significant differences. Nearly all of these cytometric parameters also showed significant differences for histological grade and mitotic count, which was strongly correlated with nuclear pleomorphism. In examining the cytometric parameters in relation to the interobserver reproducibility of histological grade and its components, the largest number of statistically significant parameters related to the nonreproducibility of nuclear pleomorphism. The findings indicate that as the grade of infiltrating ductal carcinomas increases, there are fewer % 2 c (diploid) cells and more % > 4 c (hypertetraploid) and % > or = 5 c (polyploid) cells. In addition, the cells of high grade tumors have larger nuclear areas and more small and large dense chromatin clumps, which increase in such number that they tend to join together. When compared with the cytometric parameters, nuclear pleomorphism is the most sensitive component of grade to nonreproducibility.

The deregulation of cyclin D1 (BCL-1, PRAD1, CCND1) protein, normally synthesized in the G1 phase of the cell cycle, has been implicated in the pathogenesis of some malignant neoplasms, including invasive mammary carcinomas. We used rabbit polyclonal antibody 19 to detect cyclin D1 in 55 infiltrating ductal carcinomas and compared the findings to six important clinicopathologic parameters and cyclin D1 gene amplification. Nuclear immunoreactivity of variable intensity for cyclin D1 was present in 35% of the neoplasms, whereas immunoreactivity of normal mammary epithelial nuclei was absent. No significant correlations were observed between immunoreactivity and patient age, axillary lymph node status, estrogen receptors, progesterone receptors, histologic grade, or any of its three components. There was a correlation between cyclin D1 immunostaining and tumor size (P = 0.013). Fourteen of 15 tumors 2 cm or less were negative, whereas 7 of 12 neoplasms larger than 4 cm were immunopositive. Fifteen percent of the invasive carcinomas had cyclin D1 gene amplification. Of these eight tumors, six showed cyclin D1 immunoreactivity (P = 0.017). In this study, cyclin D1 was detected immunohistochemically in approximately one-third of infiltrating ductal carcinomas; approximately one-third of these had detectable cyclin D1 gene amplification. These results further implicate cyclin D1 in breast tumorigenesis and are additional evidence for the role of cell cycle regulatory proteins in invasive mammary carcinoma.

Recent evidence suggests that focal nodular hyperplasia of the liver (FNH) may represent a hyperplastic response to a vascular malformation, but the precise etiology remains unclear. We performed a clonal analysis of ten FNHs from nine patients by patterns of X chromosome inactivation. DNA isolated from paraffin-embedded specimens was subjected to polymerase chain reaction amplification for a highly polymorphic region of the human androgen receptor gene (HUMARA). Predigestion of tumor DNA with the methylation-sensitive, restriction enzyme HpaII allowed for selective amplification of the methylated (inactivated) allele. Of the nine patients analyzed, seven were heterozygous for the HUMARA polymorphism and informative for analysis. One informative patient had two lesions, for a total of eight FNHS. Amplification of lesional DNA after HpaII digestion demonstrated clonality in six of the eight informative cases. Paired tissue samples from different lesional areas were available in four of the six FNHs with evidence of clonality. In three of the four cases, DNA extracted from the two tissue samples showed both evidence of clonality and an identical pattern of X chromosome inactivation. In the remaining case, one sample showed evidence of clonality whereas the other was nonclonal. Three hepatic adenomas from two informative patients were also analyzed for comparative purposes, all of which showed evidence of clonality after HpaII digestion. The current study illustrates that most cases of FNH show a uniform pattern of X chromosome inactivation consistent with clonality.

Amplification of chromosome 11q13 leads to overexpression of a G1 cyclin gene, cyclin D1 (PRAD-1, CCND-1), in many non-cervical human carcinomas. Homology between cyclin D1 and human papillomavirus oncoprotein E7 binding sites for the retinoblastoma tumor-suppressor protein suggests that human papillomavirus oncoproteins cyclin D1, and other cell cycle regulatory proteins may act through a common mechanism in the pathogenesis of human cervical squamous cell carcinoma. We have examined 48 cases of cervical neoplasia by RNA-mRNA in situ hybridization for human papillomavirus mRNA and cyclin D1 mRNA and by immunohistochemistry for cyclin D1 protein expression. Hybridization demonstrated human papillomavirus RNA in all 48 cases with types 6, 16, or 18 in 2, 26, and 20 cases, respectively. Immunohistochemical detection using anti-cyclin D1 rabbit polyclonal antibody 19 demonstrated appropriate cyclin D1 expression at constitutive low levels in normal squamous epithelium and low-grade intraepithelial lesions. Immunohistochemical staining failed to demonstrate significant protein expression in any of the high-grade or invasive lesions. In contrast to the immunohistochemical results, in situ hybridization demonstrated cyclin D1 mRNA overexpression in three of five cases of low-grade squamous intraepithelial lesion, one of eight cases of high-grade squamous intraepithelial lesion, 14 of 18 cases of invasive squamous cell carcinoma, two of five cases of adenocarcinoma in situ, one of seven cases of invasive adenocarcinoma, and two of five cases of small cell undifferentiated carcinoma. Transcriptional activation of cyclin D1 can occur in vivo in human papillomavirus-associated invasive cervical carcinoma, but it does not seem to result in a steady state, increased level of cyclin D1 protein expression. These data indicate a limited role for cyclin D1 protein in the pathogenesis of human papillomavirus-associated invasive cervical squamous carcinoma. They support a model in which human papillomavirus proteins can circumvent cellular requirements for cyclin D1 in human cervical neoplasia.

Granulosa cell tumors with bizarre nuclei (GCT-BN) are rare lesions with a prognosis apparently similar to that of conventional granulosa cell tumors (GCT-NOS). The immunohistochemical features of GCT-BN have not been described, and the exact nature of the bizarre nuclei (BN) is unclear. Thirteen GCT-BN were studied with antibodies to cytokeratin, vimentin, epithelial membrane antigen, muscle-specific actin, alpha smooth muscle actin, desmin, and S-100 protein. Six cases were also examined by fluorescence in situ hybridization for trisomy 12, a nonrandom chromosomal aberration found in a proportion of ovarian sex-cord stromal tumors. Histologically, 12 tumors (86%) contained BN areas interspersed with large areas of GCT-NOS. The remaining tumor contained only microscopic foci of GCT-NOS. Immunohistochemically, the tumors stained for vimentin (13 tumors), S-100 protein (11 tumors), muscle-specific actin (10 tumors), cytokeratin (eight tumors), alpha smooth muscle actin (eight tumors), and desmin (one tumor), but none stained for epithelial membrane antigen. Immunostaining results for the BN and GCT-NOS areas were concordant in eight (73%) of the 11 tumors in which both areas could be independently assessed. The remaining three tumors (27%) showed discordant results for only one of the eight markers used. In five patients, trisomy 12 was detected by fluorescence in situ hybridization in areas of BN but not in areas of GCT-NOS present in the same tumor. Trisomy 12 was also present in another BN tumor in which the foci of GCT-NOS were too small to be evaluated. We conclude that within GCT-BN, areas with BN are immunohistochemically similar to areas of GCT-NOS present in the same tumor. The finding of trisomy 12 in areas with BN but not GCT-NOS in the same tumor, however, suggests that cells with BN represent a genetically distinct clone of tumor cells arising within GCT-NOS.

Chromosome 11q13 amplification has been identified in a subset of head and neck squamous cell carcinomas (H&N SCCs). This region contains several putative oncogenes, including cyclin D1 (PRAD1, CCND1), which encodes for an important cell cycle regulatory protein, and the locus encoding for the drug-detoxifying enzyme glutathione-S-transferase-pi (GST-pi). To determine the relationship of cyclin D1 and GST-pi gene amplification to expression of the encoded proteins, the authors examined 64 H&N SCCs by both Southern blot hybridization and immunohistochemistry, using a recently described, affinity-purified, anticyclin D1 polyclonal antibody no. 19 as well as a polyclonal antibody against GST-pi. Anticyclin D1 antibody no. 19 labeled the tumor cell nuclei in 28 (44%) of the H&N SCCs, whereas cytoplasmic immunoreactivity for GST-pi was noted in 55 (86%) neoplasms. By Southern blot 24 tumors (37.5%) showed twofold to tenfold amplification of 11q13 loci; only two of these were coamplified for GST-pi. Immunopositivity with anticyclin D1 antibody no. 19 but not anti-GST-pi significantly correlated with 11q13 amplification (P < .0001). Of the 28 tumors positive with anticyclin D1 antibody no. 19, however, only 18 (64%) were amplified for 11q13, and six amplified tumors did not react with the no. 19 antibody. A strong trend was noted between anticyclin D1 antibody no. 19 reactivity and a hypopharyngeal primary site (P = .053), but no correlations were observed between immunoreactivity and cytological grade, architectural pattern, pathological stage, and disease-free or overall survival. The inconsistent association of cyclin D1 immunoreactivity with 11q13 amplification indicates that other mechanisms may exist for protein overexpression. Immunoreactivity for the GST-pi protein is prevalent in H&N SCC but is clearly unassociated with amplification. In this series, the presence or extent of cyclin D1 and GST-pi immunoreactivity was of no proven prognostic benefit in H&N SCC.

Glutathione S-transferase pi, a drug-detoxifying isoenzyme of potential prognostic value for subsets of patients with mammary cancer, was studied by immunohistochemistry and Southern blot analysis in 58 infiltrating ductal carcinomas. The results were compared with the findings of six important clinicopathologic parameters. Cytoplasmic immunoreactivity for glutathione S-transferase pi was absent in 40%, 1+ in 26%, 2+ in 15%, and 3+ in 19% of the cases. There were no significant correlations between the level of immunostaining and patient age, tumor size, axillary lymph node status, nuclear pleomorphism, or tubule formation, but there was a trend with mitotic count (P = 0.06). Immunoreactivity was associated with histologic grade (P = 0.02) and inversely correlated with estrogen (P = 0.006) and progesterone (P = 0.02) receptor content. Ten percent of the cases showed modest levels of glutathione S-transferase pi gene amplification, but no significant correlations were observed between glutathione S-transferase pi amplification and any of the clinicopathologic parameters or level of immunostaining. The results indicate that increased immunohistochemical staining for glutathione S-transferase pi occurs in high-grade, estrogen and progesterone receptor-negative neoplasms. As glutathione S-transferase pi gene amplification appears unassociated with immunopositivity, other mechanisms are responsible for the production of this isoenzyme in infiltrating ductal carcinomas.

Objective: To determine the clinical and prognostic significance of chromosome 11q13 amplification in squamous cell carcinoma of the head and neck., Design: Retrospective clinical analysis., Setting: University and private cancer centers., Patients: Fifty-six patients with pathologically confirmed head and neck squamous cell carcinoma whose tumors had been assayed for the presence or absence of chromosome 11q13 amplification., Measurements: The degree of DNA amplification in each tumor was determined using chromosome 11q13 probes for the bcl-1 major translocation cluster, PRAD1/cyclin D1 (CCND1), the fibroblast growth factor gene HST1, EMS1, and glutathione-S-transferase-pi-1. The presence or absence of amplification in each patient was correlated with primary site, tumor stage, nodal status, presence or absence of distant metastasis, disease recurrence, time to recurrence, clinical outcome (disease status), and overall survival., Results: Amplification of chromosome 11q13 was identified in 39% (22/56) of patients. Recurrent or persistent disease was identified in 82% (18/22) of cases with amplification and 50% (14/28) of nonamplified cases (P = .04). Mean time to recurrence was shorter in cases with amplification (6.2 months) than those without amplification (10.1 months) (P = .01). Eighteen patients (82%) with amplification and 10 patients (38%) without amplification died of disease or are alive with disease (P = .001). The mean follow-up period was 15.8 months for patients with amplification and 18.6 months for patients without amplification. Overall survival was significantly diminished in patients with amplification (P = .002). Amplification was not related to nodal status, distant metastases, or initial disease stage., Conclusions: Amplification of chromosome 11q13 loci may be an important biologic marker indicating poor prognosis, independent of clinical stage in head and neck squamous cell carcinoma, and it should be assessed in prospective trials to determine its utility for stratifying treatment and determining prognosis.

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of a variety of lymphoproliferative disorders and several epithelial neoplasms, including undifferentiated nasopharyngeal carcinoma (UNPC; lymphoepithelioma). Lymphoepithelioma-like carcinomas (LEC) are tumors with morphologic features identical to UNPC that occur outside the nasopharynx. To determine whether EBV is associated with LEC, the authors conducted a comprehensive literature review of all pathologically documented LEC reported to date in the English literature. In summary, EBV is associated consistently with LEC from only four anatomic sites: stomach, salivary gland, lung, and thymus. Racial and/or geographic factors influence the association of EBV with LEC in some of these organs. Specifically, the association of EBV with LEC of the salivary gland and lung is restricted to Asian patients, whereas the association of EBV with gastric and thymic LEC is independent of race. The presence or absence of EBV in LEC does not appear to be prognotically important in those cases studies to date.

The interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for invasive breast carcinoma was tested. Six surgical pathologists from four institutions independently evaluated histologic grade and each of its three components for 75 infiltrating ductal carcinomas. The number of slides per case ranged from one to nine (median 3). Pairwise kappa values for agreement ranged from moderate to substantial (0.43-0.74) for histologic grade. Generalized kappa values indicated substantial agreement for tubule formation (0.64), moderate agreement for mitotic count (0.52), and near moderate agreement for nuclear pleomorphism (0.40). Normalizing the mitotic counts per mm2 showed only slight improvement in agreement over the published range of mitotic counts for three different field areas. The results suggest that steps to discriminate between categories for nuclear pleomorphism would likely be of benefit for improving the interobserver reproducibility of histologic grade. Nevertheless, the Nottingham modification of the Bloom and Richardson grading system is recommended as a suitable scheme for evaluating invasive breast carcinomas in the routine clinical setting.

Although cytogenetic data suggest that the t(2;5)-(p23;q35) translocation occurs in many cases of CD30+ lymphomas, the exact frequency of this event is still unknown. To clarify this issue and its epidemiological characteristics, we examined 37 formalin-fixed, paraffin-embedded specimens of CD30+ lymphomas from the United States and Hong Kong by reverse transcriptase-polymerase chain reaction (RT-PCR) for the status of the NPM and ALK genes, which are typically juxtaposed by the t(2;5) translocation. Thirty-four cases were classified as anaplastic large cell lymphomas (ALCL), 2 cases as non-anaplastic large cell lymphomas (LCL), and 1 case as the small cell variant of CD30+ lymphoma. The t(2;5) translocation was detected in 6 cases (16%), including 3 of 18 American patients and 3 of 19 cases from Hong Kong. All cases had a 185-bp NPM RT-PCR product as detected by Southern blot analysis, indicating adequate preservation of mRNA. The 6 positive cases were among 4 of 34 adult lymphomas, as compared with 2 of 3 childhood cases. Five of 17 T-lineage cases were t(2;5)-positive, compared with 1 of 15 B-lineage cases and none of the 5 null-cell or mixed lineage cases. Our results therefore show that t(2;5) occurs at a low frequency among CD30+ lymphomas, at least in our adult-dominated series.

Periurethral polytetrafluoroethylene (Teflon) injections have been reported to be successful for the treatment of urinary incontinence after transurethral resection or radical prostatectomy. However, the use of polytetrafluoroethylene is controversial due to reports of distant migration and granulomatous reaction after periurethral injection. We report on a patient with a history of periurethral polytetrafluoroethylene injection for postoperative stress incontinence in whom bladder outlet obstruction developed and who underwent repeat transurethral resection 9 years later. Pathological examination revealed that the material responsible for the obstruction was almost totally composed of a foreign body giant cell response to the polytetrafluoroethylene implant ("teflonoma").

CD30 (Ki-1)-positive anaplastic large cell lymphoma (CD30+ ALCL) is a morphologically and immunophenotypically distinct subset of non-Hodgkin's lymphoma. Although the presence of Epstein-Barr virus (EBV) has been well documented in a significant proportion of cases of Hodgkin's disease, another CD30+ malignancy, few studies have examined the association of EBV with CD30+ ALCL. These latter studies have produced conflicting findings. To further investigate the existence of a putative association of EBV with CD30+ ALCL, and whether this association, if present, shows geographic variation, we examined 34 formalin-fixed, paraffin-embedded specimens from cases of CD30+ ALCL from the United States and Hong Kong. Immunophenotypically, 15 cases were of B lineage, 15 cases were of T lineage, one case expressed both B- and T-cell markers, and three were of null lineage. A highly sensitive in situ hybridization method was performed with use of an antisense oligonucleotide probe to the EBV-encoded RNA (EBER-1). EBV-RNA was identified in 3 of 14 CD30+ ALCL specimens from Hong Kong patients and in 1 of 20 from the American patients. The EBER-1 signal was present in all or virtually all of the tumor cell nuclei in the three EBV-RNA-positive CD30+ ALCL Hong Kong cases, but was only focally present in the single EBV-positive American case. The latent membrane protein-1 (LMP1) of EBV was identified in only one of the four positive cases, a Hong Kong case. Our results suggest that in contrast to Hodgkin's disease, EBV has no significant association with CD30+ ALCL.

To assess the interobserver reproducibility for the diagnosis of medullary carcinoma of the breast (MC), 53 previously diagnosed MCs were independently assessed by six observers for growth pattern, nuclear grade (NG), inflammation, tumor margin, intraductal component, and glandular features. Tumors were reclassified as MC, atypical MC, or infiltrating ductal carcinoma according to the histopathologic criteria of Ridolfi et al. (Cancer 40:1365, 1977), Wargotz and Silverberg (Hum Pathol 19:1340, 1988), and Pedersen et al. (Br J Cancer 63:591, 1991). NG was the most reproducible parameter, and tumor margin was the least, with consensus agreement by four of six observers for 49 (92%) and 26 (49%) of cases, respectively. Utilizing the histopathologic criteria proposed by Ridolfi et al., Wargotz and Silverberg, and Pedersen et al., consensus diagnoses were achieved in 37 cases (70%), 46 cases (87%), and 51 cases (96%), respectively. A consensus diagnosis of MC in all three systems was unassociated with tumor size, axillary lymph node status or overall survival (median follow-up: 89 mo). The consensus (or better) reclassification of 44/53 (83%), 35/53 (66%), and 27/53 (51%) previously diagnosed MC as atypical MC or infiltrating ductal carcinoma by the criteria of Ridolfi et al., Wargotz and Silverberg, and Pedersen et al., respectively, suggests that MC was previously over-diagnosed. While the scheme of Pedersen et al. is the most reproducible, additional follow-up information is necessary to determine the biological significance of this classification system. To minimize these difficulties in practice, pathologists should carefully adhere to published criteria and indicate the classification system utilized.

The occurrence of an aggressive papillary middle ear/temporal bone tumor (APMET) and a benign adnexal papillary tumor of probable mesonephric origin (APMO) in a patient with von Hippel-Lindau disease (VHL) is reported. Histologically, both tumors were identical to papillary cystadenomas of the epididymis and broad ligament of probable mesonephric derivation. A comprehensive literature review showed that including the current case, seven of 46 (15%) documented cases of APMET and four of four (100%) cases of APMO arose in patients with VHL. Given an estimated minimum birth incidence of 1/36,000, a one-sample test of binomial proportion using the exact method establishes that the association of APMET and APMO with VHL is highly significant (p = 1.4 x 10(-24) and 1 x 10(-18), respectively). The data indicate that APMET and APMO may represent major visceral manifestations of VHL. Accordingly, in the presence of one of these tumors strong consideration should be given to the diagnosis of VHL, given either the presence of another major component of VHL or documentation of VHL in at least one consanguineous relative.

Trisomy 12 is a nonrandom chromosomal abnormality found in a large proportion of ovarian sex cord-stromal tumors (OSCTs), including thecoma-fibromas (TFs) and granulosa cell tumors (GCTs). The prognostic significance of trisomy 12 in these tumors, however, is unknown. A series of 16 OSCTs, obtained from patients with long-term follow-up, was analyzed for the presence of trisomy 12 by interphase fluorescence in situ hybridization on paraffin-embedded sections. Sections of the contralateral nonneoplastic ovary were available in five cases and utilized as controls. Evidence of trisomy 12 was detected in 9 of 10 TFs, and contrary to previous reports, in only one of six GCTs. One TF with trisomy 12 was a malignant variant that resulted in the death of the patient in 5 months, but the remaining TFs with trisomy 12 were cytologically and clinically benign in those with follow-up available. The single GCT with trisomy 12 was a nonaggressive, stage 1 lesion without evidence of recurrence after 264 months, whereas those GCTs without trisomy 12 included one stage 2 tumor and a cytologically atypical GCT with tumor necrosis and an elevated number of mitotic figures. The evidence suggests that the great majority of OSCTs with trisomy 12 is clinically benign, but not all benign OSCTs have trisomy 12. We conclude that the presence of trisomy 12 is of limited prognostic usefulness in OSCTs.

The existence of angiosarcoma of the thyroid gland and its relation to angiomatoid carcinoma have been debated. The authors reviewed eight angiomatoid thyroid neoplasms. Controls consisted of six sarcomatoid thyroid carcinomas without angiomatoid features and an angiosarcoma metastatic to the thyroid gland. All eight angiomatoid neoplasms consisted of epithelioid cells with prominent eosinophilic cytoplasm lining vascularlike spaces. All eight expressed vimentin. Four tumors were predominantly angiosarcomalike neoplasms, based on staining for factor VIII-related antigen (three of four), CD31 (four of four), CD34 (one of four), and Ulex europaeus I lectin (four of four); they lacked epithelial markers other than cytokeratin (two of four). Four tumors were designated as angiomatoid carcinomas, based on staining for multiple epithelial markers: cytokeratin (four of four), epithelial membrane antigen (three of four), thyroglobulin (three of four). Three angiomatoid carcinomas also expressed or labeled with one or more vascular markers: CD34 (one of four), CD31 (two of four), Ulex europaeus I lectin (one of four), factor VIII-related antigen (one of four). The metastatic angiosarcoma to the thyroid gland labeled for factor VIII-related antigen, vimentin, CD31, and with Ulex europaeus I lectin. It did not express CD34. The six sarcomatoid carcinomas without angiomatoid features stained for cytokeratin (four of six), epithelial membrane antigen (one of six), and vimentin (six of six). None labeled for thyroglobulin, factor VIII-related antigen, CD31, CD34, or with Ulex europaeus I lectin. Angiomatoid carcinomas of the thyroid gland exhibit both epithelial and endothelial features. "Angiosarcoma" may represent the extreme in this spectrum of endothelial differentiation. All tumors behaved in a similar clinical fashion characterized by persistent local disease, widespread metastases and poor prognosis.

Undifferentiated carcinoma of the nasopharynx has a well-known association with Epstein-Barr virus (EBV), but only an inconsistent relationship has been identified in undifferentiated carcinomas occurring at other sites. We investigated 22 formalin-fixed, paraffin-embedded cases of sinonasal undifferentiated carcinomas (SNUCs) occurring in Western and Asian patients. A highly sensitive in situ hybridization method was performed using an antisense oligonucleotide probe to the EBER1 gene of EBV. We identified EBV RNA in seven of 11 SNUCs from Asian patients, but in none of the Western SNUC patients (0/11). The EBER1 signal was present in all or virtually all of the tumor cell nuclei in the seven EBV-RNA-positive Asian SNUCs. The latent membrane protein-1 (LMP1) of EBV was not identified in any of the five positive cases tested. Our results suggest that genetic predisposition or environmental/geographical cofactors play an important role in determining the strength of the association of SNUC with EBV.

A B-cell anaplastic large cell lymphoma, confirmed by immunohistochemistry and Southern blot immunoglobulin gene rearrangement analysis, contained neoplastic cells that were immunoreactive for cytokeratin using antibodies CAM 5.2, M20, MAK 6, and KS-B17.2. Bands corresponding to cytokeratin 18 and cytokeratins 18 and 8 were seen on Western blot immunoanalysis using antibodies KS-B17.2 and CAM 5.2. The lymph node also contained cytokeratin-positive extrafollicular fibroblastic reticulum cells. Although it is possible that the presence of cytokeratin in the cells of anaplastic large cell lymphoma represented phagocytosed filaments from the reticulum cells, it is more likely that the cytokeratins were synthesized by the malignant cells. The finding of cytokeratin in anaplastic large cell lymphoma, although infrequent, adds to the confusion in the diagnosis of this pleomorphic neoplasm.

Objective: To establish the frequency and clinicopathologic correlates of 11q13 amplification in head and neck squamous cell carcinoma., Design: Retrospective clinicopathologic analysis., Setting: University and private cancer centers., Patients: Eighty-five patients with pathologically confirmed head and neck squamous cell carcinoma., Measurements: The degree of DNA amplification in each tumor was determined using chromosome 11q13 probes for the bcl-1 major translocation cluster, PRAD1/cyclin D1 (CCND1), the fibroblast growth factor gene HST1, EMS1, and glutathione S transferase, pi-1. The presence or absence of amplification was correlated with anatomic site, tumor stage, cytologic grade, histologic pattern, and mitotic activity., Results: Thirty-one patients (36%) showed a twofold to 10-fold amplification of 11q13 loci compared with the chromosome 11q23 ETS1 control probe. Twenty-nine of these encompassed bcl-1 through EMS1 loci; one sample showed only bcl-1 and PRAD1/cyclin D1 plus HST1 amplification, with another amplified at HST1 and EMS1 with minimal or no bcl-1 and PRAD1/cyclin D1 amplification. Amplification was significantly correlated with high cytologic grade, a diffusely infiltrative growth pattern, and with a hypopharyngeal primary site., Conclusions: Chromosome 11q13 amplification in head and neck squamous cell carcinoma is correlated with an aggressive histologic appearance and hypopharyngeal primary site and should be assessed in prospective clinical trials to determine its utility for treatment stratification and prognosis. Although PRAD1/cyclin D1 and EMS1 have been implicated in the pathogenesis of neoplasms with 11q13 amplification, rare cases with more limited amplicon size suggest that another relevant gene or genes may exist between these loci.

To determine the frequency and clinicopathologic correlates of chromosome 11q13 amplification in breast carcinoma, DNA from 50 invasive tumors was analyzed by Southern blot hybridization using probes for the 11q13 loci bcl-1, PRAD1, hst1, EMS1, and GST-pi, as well as oncogenes c-erbB-2 and c-myc. Sixteen tumors (32%) were amplified for one or more loci. Seven tumors (14%) showed amplification of 11q13 loci; six of these were coamplified with either c-erbB-2 (three), c-myc (two), or both (one). Nine additional tumors (18%) were amplified for c-erbB-2, and three of these were coamplified with c-myc. None showed c-myc amplification alone. Tumors with 11q13 amplification showed equivalent degrees of bcl-1, PRAD1, hst1, and EMS1 amplification, delineating an approximately 800-kb amplicon. GST-pi was inconsistently amplified, evidence that it lies outside the amplicon defined by bcl-1 and EMS1. Amplification of 11q13 was unassociated with patient age, tumor size, axillary lymph node status, hormone receptors, DNA content, histologic grade, mitotic rate, nuclear pleomorphism, or tubule formation. c-myc amplification correlated with the lack of tubule formation (p = 0.04), whereas c-erbB-2 amplification correlated with axillary lymph node positivity (p = 0.04), high histologic grade (p = 0.003), increased nuclear pleomorphism (p = 0.008), and a high mitotic rate (p = 0.02). The frequency of coamplification of 11q13 loci, c-myc, and c-erbB-2 contradicts previous proposals that amplification of these genes occurs in independent subsets of breast carcinoma. Extended clinical followup will be necessary to determine whether 11q13 amplification has prognostic utility in invasive breast cancer.

Fifty-two infiltrating breast carcinomas with medullary features (BCMF) were studied immunohistochemically to determine the immunophenotype of the mononuclear tumor inflammatory cells (MTIC) in formalin-fixed, paraffin-embedded material. The neoplasms were also examined for Epstein-Barr virus (EBV) DNA by the polymerase chain reaction (PCR). BCMF were independently classified as medullary carcinoma (MC) or infiltrating ductal carcinoma (IDC) by six observers according to the criteria of Pedersen et al. DNA from 35 BCMF was successfully amplified using PCR, but all were negative for EBV DNA. These included, by 4/6 consensus diagnosis, 16 MC, 18 IDC, and one BCMF which failed to achieve consensus diagnosis. MTIC were present to a mild degree in 19 BCMF (37%) and to moderate to severe degrees in 33 (63%). MTIC were predominantly (> or = 75%) lymphocytic in 31 BCMF (13 MC, 16 IDC, two without consensus diagnostic agreement), and plasmacytic in 10 (six MC, four IDC); equal proportions of lymphocytes and plasma cells occurred in 11 (six MC, five IDC). Lymphocytic MTIC were mostly CD45RO+/CD3+ T-cells in nearly all cases, and showed a predominant CD3+/CD4+ and CD3+/CD4- immunophenotype in 36% and 64% of cases, respectively. Natural killer cells (CD57+) and histiocytes (MAC 387+) were virtually absent. The number, cell type, and T-cell subsets of the MTIC were unrelated to consensus diagnosis, axillary lymph node status, or overall survival. EBV is unassociated with MC, despite the histologic similarities of MC to EBV-associated lymphoepithelial lesions of other organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Many cases of hemophagocytic syndrome have been associated with viral infections, particularly Epstein-Barr virus (EBV), but the pathogenesis of the syndrome remains unclear. We have examined lymph node, spleen, liver, and bone marrow sections from 12 cases, including four cases of proven or probable infection-related hemophagocytic syndrome (IHPS), three cases of familial hemophagocytic syndrome (FHPS), and five cases of secondary hemophagocytosis associated with T-cell malignant lymphoma (SHPC), for EBV RNA using a sensitive and specific in situ hybridization technique. Epstein-Barr virus RNA was detected in seven of 12 cases (58%), including three cases of IHPS, one case of FHPS, and three cases of SHPC. Numerous EBV-positive cells were detected in two cases of IHPS (in multiple anatomic sites) and in one case of FHPS (in the spleen). Diffuse EBV positivity also was noted within the neoplastic cells of one case of SHPC. Rare to occasional EBV-positive cells were found in multiple sites in another case of IHPS and within admixed, reactive lymphoid cells in two cases of SHPC. The results indicate that numerous EBV-positive cells can be identified in some cases of IHPS, FHPS, and SHPC, suggesting a pathogenetic role for the virus. However, the absence of EBV from a proportion of cases of IHPS and FHPS in this study suggests that other infectious agents also play a role in the pathogenesis of this syndrome.

Ber-EP4 is a recently characterized monoclonal antibody directed against a cell surface glycoprotein that is putatively present on human epithelial cells but lacking on the mesothelium. To investigate the diagnostic efficacy of Ber-EP4 in distinguishing adenocarcinoma from mesothelioma, we studied formalin-fixed, paraffin-embedded sections from well-documented cases of adenocarcinoma (120 cases), adenomatoid tumor (nine cases), and malignant mesothelioma (49 cases). Of the 120 adenocarcinomas, 103 (86%) showed membranous Ber-EP4 positivity, with diffuse reactivity noted in 82 cases and focal staining in 21 cases. Reactivity with Ber-EP4 was also observed in two of nine adenomatoid tumors (22%) and 10 of 49 mesotheliomas (20%). Staining in the mesotheliomas was restricted to epithelioid areas and generally focal. In one mesothelioma, however, Ber-EP4 stained the majority of neoplastic cells. In contrast to previous reports, we conclude that positivity with Ber-EP4 does not exclude the diagnosis of mesothelioma. Nonetheless, most Ber-EP4-positive mesotheliomas exhibit only focal positivity, as opposed to the extensive staining commonly observed in adenocarcinomas. Ber-EP4 has diagnostic utility in the discrimination of mesothelioma from adenocarcinoma, but it is best utilized in an antibody panel that includes other markers of carcinomatous differentiation.