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Bronchoalveolar lavage fluid (BAL) from human lung allografts demonstrates the presence of a multipotent mesenchymal stromal cell population. However, the clinical relevance of this novel cellular component of BAL and its association with bronchiolitis obliterans syndrome (BOS), a disease marked by progressive airflow limitation secondary to fibrotic obliteration of the small airways, remains to be determined.In this study we investigate the association of number of mesenchymal stromal cells in BAL with development of BOS in human lung transplant recipients.Mesenchymal colony-forming units (CFUs) were quantitated in a cohort of 405 BAL samples obtained from 162 lung transplant recipients. Poisson generalized estimating equations were used to determine the predictors of BAL mesenchymal CFU count.Higher CFU counts were noted early post-transplantation; time from transplant to BAL of greater than 3 months predicted 0.4-fold lower CFU counts (P = 0.0001). BOS diagnosis less than or equal to 365 days before BAL was associated with a 2.11-fold higher CFU count (P = 0.02). There were 2.62- and 2.70-fold higher CFU counts noted in the presence of histologic diagnosis of bronchiolitis obliterans (P = 0.05) and organizing pneumonia (0.0003), respectively. In BAL samples obtained from BOS-free patients greater than 6 months post-transplantation (n = 173), higher mesenchymal CFU counts (≥10) significantly predicted BOS onset in both univariate (hazard ratio, 5.61; 95% CI, 3.03-10.38; P0.0001) and multivariate (hazard ratio, 5.02; 95% CI, 2.40-10.51; P0.0001) Cox regression analysis.Measurement of mesenchymal CFUs in the BAL provides predictive information regarding future BOS onset.

The diagnosis and classification of most interstitial lung diseases requires histologic evaluation of lung tissue, obtained by an open lung biopsy to confirm the diagnosis. In addition, it is generally accepted that response to therapy in idiopathic pulmonary fibrosis (IPF) is related to the relative degree of cellularity and fibrosis present. Because only a qualitative assessment of the relative extent and severity of these changes is generally provided, correlation with clinical and physiologic alterations is difficult. This report describes results of a semiquantitative assessment by four pathologists of inflammatory/exudative changes, fibrotic/reparative changes, and airway alterations, in addition to an overall assessment of cellularity and fibrosis in 50 patients with IPF. In 10 randomly selected biopsies examined twice in a blinded fashion, absolute agreement between assessments for a given pathologist varied between 54 and 64% (mean = 57.5%) and in the majority of instances the agreement was greater than would have occurred by chance. There was good agreement for most variables across the four raters on the 101 samples. The mean score for some of the parameters reported by a given rater deviated occasionally from those of the other raters, but no single rater was consistently different from the other raters. A principal component factor analysis revealed that the pathologic features fell into four general groupings: alveolar wall metaplasia, fibrosis, honeycombing, smooth muscle, and vascular changes fell into one group; severity and extent of cellularity in the alveolar wall into a second group; severity and extent of cellularity in the alveolar space into a third group; and interstitial young connective tissue along with granulation tissue in the airways formed the fourth group.(ABSTRACT TRUNCATED AT 250 WORDS)

A 75-year-old woman developed epiphora and a slowly enlarging right medial canthal mass for 1 year. CT revealed a mass with ground-glass radiodensity and hazy borders in the lacrimal sac. At external dacryocystorhinostomy, a tan, gritty, spherical mass was easily removed from the sac lumen. Histopathologic characteristics were typical of fibrous dysplasia. The postoperative course was uneventful.

Paraneoplastic optic neuropathy (PON) is a rare syndrome usually associated with small cell lung carcinoma. In the 27 rigorously reported cases, neurologic manifestations other than visual loss have been present in all but 2. In the single case in which vision improved in response to treatment of the cancer, the collapsin response-mediating protein (CRMP)-5 titer did not change, and the ophthalmic examination was not detailed. We describe a patient with optic neuropathy and vitritis as the only clinical manifestations of PON marked by an extremely high titer of CRMP-5 antibody. Treatment of the underlying small cell lung cancer coincided with resolution of the visual abnormalities and a dramatic decrease in the CRMP-5 titer.

Antigenic characterization of urothelial cells cultured from normal adult ureter was performed. These cells were cultured using a simplified isolation and culture technique and a commercially available serum-free medium. The cells growing in these cultures had epithelioid morphology and normal quantities of DNA. The antigen expression on these cultured normal urothelial cells was evaluated using a panel of monoclonal antibodies: 5G6.4, AN43, URO-5, anti-keratin and anti-blood group antibodies, and 425 (anti-epidermal growth factor receptor). Lower levels of anti-A and AN43 binding on cultured cells were observed than are seen on urothelial cells in sections of normal ureter, while the binding of anti-blood group H, 5G6.4, and URO-5 was unchanged. Binding of anti-epidermal growth factor receptor antibody 425 was improved if the cells were grown in medium lacking epidermal growth factor. These results confirm the urothelial origin of these cultured urothelial cells but indicate that some antigenic differences between cultured normal urothelial cells and urothelial cells in situ in the normal ureter exist. (J. Urol., 144: 1288–1292, 1990)

A 25-year-old woman presented for evaluation of a rapidly enlarging mass of the left bulbar conjunctiva. Debulking biopsy was performed, which led to the diagnosis of myxoid malignant fibrous histiocytoma. The patient underwent left orbital exenteration with clear margins. Histopathology showed involvement of the conjunctiva substantia propria, superior conjunctival fornix, and episclera, as well as extension from the lateral rectus muscle sheath. Immunohistochemical staining was strongly positive for CD68, alpha1-antitrypsin, CD34, and vimentin.

Rationale: Bronchiolitis obliterans syndrome (BOS), defined by loss of lung function, develops in the majority of lung transplant recipients. However, there is a paucity of information on the subsequent course of lung function in these patients. Objectives: To characterize the course of FEV1 over time after development of BOS and to determine the predictors that influence the rate of functional decline of FEV1. Methods: FEV1% predicted (FEV1%pred) trajectories were studied in 111 lung transplant recipients with BOS by multivariate, linear, mixed-effects statistical models. Measurements and Main Results: FEV1%pred varied over time after BOS onset, with the steepest decline typically seen in the first 6 months (12% decline; p < 0.0001). Bilateral lung transplant recipients had significantly higher FEV1%pred at BOS diagnosis (71 vs. 47%; p < 0.0001) and at 24 months after BOS onset (58 vs. 41%; p = 0.0001). Female gender and pretransplant diagnosis of idiopathic pulmonary fibrosis were associated with a steeper decline in FEV1%pred in the first 6 months after BOS diagnosis (p = 0.02 and 0.04, respectively). A fall in FEV1 greater than 20% in the 6 months preceding BOS (termed “rapid onset”) was associated with shorter time to BOS onset (p = 0.01), lower FEV1%pred at BOS onset (p < 0.0001), steeper decline in the first 6 months (p = 0.03), and lower FEV1%pred at 2 years after onset (p = 0.0002). Conclusions: Rapid onset of BOS, female gender, pretransplant diagnosis of idiopathic pulmonary fibrosis, and single-lung transplantation are associated with worse pulmonary function after BOS onset.

The origin and turnover of connective tissue cells in adult human organs, including the lung, are not well understood. Here, studies of cells derived from human lung allografts demonstrate the presence of a multipotent mesenchymal cell population, which is locally resident in the human adult lung and has extended life span in vivo. Examination of plastic-adherent cell populations in bronchoalveolar lavage samples obtained from 76 human lung transplant recipients revealed clonal proliferation of fibroblast-like cells in 62% (106 of 172) of samples. Immunophenotyping of these isolated cells demonstrated expression of vimentin and prolyl-4-hydroxylase, indicating a mesenchymal phenotype. Multiparametric flow cytometric analyses revealed expression of cell-surface proteins, CD73, CD90, and CD105, commonly found on mesenchymal stem cells (MSCs). Hematopoietic lineage markers CD14, CD34, and CD45 were absent. Multipotency of these cells was demonstrated by their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. Cytogenetic analysis of cells from 7 sex-mismatched lung transplant recipients harvested up to 11 years after transplant revealed that 97.2% +/- 2.1% expressed the sex genotype of the donor. The presence of MSCs of donor sex identity in lung allografts even years after transplantation provides what we believe to be the first evidence for connective tissue cell progenitors that reside locally within a postnatal, nonhematopoietic organ.

To report clinical and histopathologic features and biologic behavior of orbital myxomas and angiomyxomas.Noncomparative retrospective case series.Patients with histopathologic diagnoses of orbital myxoma or angiomyxoma.Clinical metadata and features were obtained from the medical record. Neoplasms were studied by routine histopathology, special stains, and immunohistochemistry.Final diagnosis, based on histopathology, special stains, and immunohistochemistry, and clinical course from analysis of metadata and clinical features.Three myxomas and 3 angiomyxomas were identified in 5 males and 1 female. Median age at presentation was 56 years (range, 4-69), with a follow-up ranging from 6 months to 8 years. Two angiomyxomas occurred in children ages 4 and 7 years whose tumors were locally aggressive and recurred. Recurrence also complicated one case of myxoma after incomplete excision. Pathologically, the tumors were poorly circumscribed. Histopathology showed them to be hypocellular, containing stellate and spindled cells in an abundant, loose, myxoid stroma rich in hyaluronic acid. Small blood vessels were rare in myxomas but abundant in angiomyxomas. Tumor cells were frequently immunoreactive for vimentin, CD34, and factor XIIIa.Myxomas rarely involve orbital tissue, and no angiomyxomas of the region have been previously reported. Angiomyxomas in children may be aggressive. Vascularity and bone involvement appear to be important prognostic features for recurrence. Complete resection with a margin of healthy tissue appears to be the treatment of choice. Tumor cell immunopositivity for vimentin, CD34, and factor XIIIa may assist in the histopathologic diagnosis.

A family of high performance, computer oriented multichip module (MCM) products is being developed to provide the building blocks for advanced, high density computer systems. Each MCM is a system level building block that interfaces to other family members through compatible processor and memory busses. By selecting and interconnecting the various MGM blocks, it is possible to configure a variety of high speed, cache coherent, multiprocessing computer designs. The use of multichip modules is necessary to meet system performance and size requirements. This paper focuses on a specific member of the MGM family, a 4M word by 40 bit Dynamic Random Access Memory (DRAM). Special attention is given to product requirements, design methodology, and test strategy. MCM testing is sufficiently complex that test must be an integral part of the complete module design process.

Purpose To evaluate the clinical history, histopathology, and genetics of posterior polymorphous corneal dystrophy (PPMD) in a woman with a prominent retrocorneal membrane. Design Observational case report and genetic analysis of her family, UM:139. Methods Records were reviewed from a case and associated family members. The diagnosis of PPMD was based on clinical examination, immunohistochemical staining, electron microscopy, and screening of genetic markers from regions previously reported to be associated with PPMD. Results Over 17 years, the proband with PPMD had 25 ocular procedures performed for glaucoma, cataract, cornea, retina, and postoperative problems. A prominent retrocorneal membrane grew onto the crystalline lens and intraocular lens (IOL). Histopathology revealed stratified epithelial-like cells on iris from an iridectomy and stratified corneal endothelium on a corneal button. Electron microscopy on the cornea revealed microvilli, tonofilaments, and desmosomes consistent with endothelial transformation, which was confirmed by positive anticytokeratin (CK) AE1/AE3 and CAM 5.2 immunoreactivity. Negative immunoreactivity in epithelium and positive in endothelium with anti-CK 7 supported the diagnosis of PPMD rather than epithelial downgrowth. Multiple relatives were affected with PPMD with apparent autosomal dominant inheritance, but surprisingly, the PPMD, congenital hereditary endothelial dystrophy 1 (CHED1) and CHED2 loci on chromosome 20 and the collagen, type VIII, α-2 (COL8A2) gene were excluded by linkage and haplotype analyses. Conclusions We are unaware of previous PPMD reports describing the unusual feature of a retrocorneal membrane extending onto the crystalline lens and IOL. In addition, this family suggests another PPMD locus.

A 45-year-old woman with a medial canthal mass associated with new-onset epiphora was found to have a darkly pigmented mass arising from the lacrimal sac wall because of intranasal pencil trauma 40 years before. Resection of the graphite-induced granuloma with dacryocystorhinostomy was curative.

A 45-year-old man and a 21-year old man presented with palpable lacrimal gland fossa masses and mechanical ptosis and proptosis, respectively. Computed tomography demonstrated well-circumscribed, partially cystic tumors. Echography in one case showed a well-outlined, predominantly low-reflective lesion with cysts and moderate vascularity detected by Doppler flow and standardized A-scan studies. Histopathology of the excised tumors revealed them to be CD34 antigen-positive hemangiopericytomas, in one case associated with lacrimal gland ductal cysts (dacryops) and with cyst-like spaces containing proteinaceous exudate in the other. No recurrence was found at 14 and 30 months, respectively. Although uncommon, hemangiopericytomas should be included in the differential diagnosis of lacrimal gland tumors. Orbital ultrasound revealing vascularity may be a useful adjunct in this diagnosis. Cystic degeneration or dacryops due to tumor infiltration and compression of lacrimal gland ducts may occur.

Patients with idiopathic interstitial pneumonias (IIPs) can be subdivided into groups based on the histological appearance of lung tissue obtained by surgical biopsy. The quantitative impact of histological diagnosis, baseline factors and response to therapy on survival has not been evaluated. Surgical lung biopsy specimens from 168 patients with suspected IIP were reviewed according to the latest diagnostic criteria. The impact of baseline clinical, physiological, radiographic and histological features on survival was evaluated using Cox regression analysis. The predictive value of honeycombing on high-resolution computed tomography (HRCT) as a surrogate marker for usual interstitial pneumonia (UIP) was examined. The response to therapy and survival of 39 patients treated prospectively with high-dose prednisone was evaluated. The presence of UIP was the most important factor influencing mortality. The risk ratio of mortality when UIP was present was 28.46 (95% confidence interval (CI) 5.5-148.0; p=0.0001) after controlling for patient age, duration of symptoms, radiographic appearance, pulmonary physiology, smoking history and sex. Honeycombing on HRCT indicated the presence of UIP with a sensitivity of 90% and specificity of 86%. Patients with nonspecific interstitial pneumonia were more likely to respond or remain stable (9 of 10) compared to patients with UIP (14 of 29) after treatment with prednisone. Patients remaining stable had the best prognosis. The risk ratio of mortality for stable patients compared to nonresponders was 0.32 (95% CI 0.11-0.93; p=0.04) in all patients and 0.33 (95% CI 0.12-0.96; p=0.04) in patients with UIP. The histological diagnosis of usual interstitial pneumonia is the most important factor determining survival in patients with suspected idiopathic interstitial pneumonia. The presence of honeycombing on high-resolution computed tomography is a good surrogate for usual interstitial pneumonia and could be utilized in patients unable to undergo surgical lung biopsy. Patients with nonspecific interstitial pneumonia are more likely to respond or remain stable following a course of prednisone. Patients remaining stable following prednisone therapy have the best prognosis.

Findings of surgical lung biopsy (SLB) are important in categorizing patients with idiopathic interstitial pneumonia (IIP). We investigated whether histologic variability would be evident in SLB specimens from multiple lobes in patients with IIP. SLBs from 168 patients, 109 of whom had multiple lobes biopsied, were reviewed by three pathologists. A diagnosis was assigned to each lobe. A different diagnosis was found between lobes in 26% of the patients. Patients with usual interstitial pneumonia (UIP) in all lobes were categorized as concordant for UIP (n = 51) and those with UIP in at least one lobe were categorized as discordant for UIP (n = 28). Patients with nonspecific interstitial pneumonia (NSIP) in all lobes were categorized as having fibrotic (n = 25) or cellular NSIP (n = 5). No consistent distribution of lobar histology was noted. Patients concordant for UIP were older (63 +/- 9 [mean +/- SD] yr; p0.05 as compared with all other groups) than those discordant for UIP (57 +/- 12 yr) or with fibrotic NSIP (56 +/- 11 yr) or cellular NSIP (50 +/- 9 yr). Semiquantitative high-resolution computed tomography demonstrated a varied profusion of fibrosis (p0.05 for all group comparisons), with more fibrosis in concordant UIP (2.13 +/- 0.62) than in discordant UIP (1.42 +/- 0.73), fibrotic NSIP (0.83 +/- 0.58), or cellular NSIP (0.44 +/- 0.42). Survival was better for patients with NSIP than for those in both UIP groups (p0.001), although survival in the two UIP groups was comparable (p = 0.16). Lobar histologic variability is frequent in patients with IIP, patients with a histologic pattern of UIP in any lobe should be classified as having UIP.

PURPOSE: To report a case of conjunctival mucoepidermoid carcinoma occurring in a long-standing pterygium in a 33-year-old Cambodian man infected with the human immunodeficiency virus (HIV). METHODS: Review of clinical history and histopathologic findings. RESULTS: A pterygium that was present for 8 years suddenly became highly inflamed and underwent rapid growth. After the initial diagnostic conjunctival and corneal biopsy showed mucoepidermoid carcinoma, subsequent additional deep excisions of the adjacent sclera and cornea were necessary to completely excise the tumor. Cytokeratin and mucicarmine stains were used to confirm the pathologic diagnosis of mucoepidermoid carcinoma. CONCLUSIONS: Unique features of this case include the extremely young age of the patient (perhaps rendered susceptible by his HIV infection), the tumor masquerading as a pterygium, and the use of a hybrid lamellar and full-thickness corneoscleral resection requiring a complementary graft. Seventeen months after the resection, the patient is free of tumor; this was histopathologically confirmed with multiple random conjunctival biopsies.

Fibronectin is a glycoprotein that mediates the attachment of BCG to the murine bladder. To assess the potential role of fibronectin on bladder cancer cells as a specific substrate for BCG binding in man, a semi-quantitative method was employed to evaluate the presence of fibronectin on normal urothelium and bladder cancer. Monoclonal anti-fibronectin binding to normal and malignant urothelial tissues was evaluated by an immunoperoxidase assay. Human tumor cell lines were evaluated with mixed hemadsorption and immunoperoxidase assays. In both systems, immunoreactive fibronectin had low expression on unfixed normal and malignant urothelium. With fixation, immunoreactive fibronectin decreased on supporting stroma and increased in normal and malignant urothelium. Fibronectin distribution did not show tumor specificity either with fixed or unfixed specimens. ( J. Urol., 143: 418–420, 1990 )

To evaluate the role of cytopathology and its different sampling techniques in the diagnosis of Wegener's granulomatosis, we retrospectively reviewed 52 cytologic specimens from 21 patients with an established diagnosis of Wegener's granulomatosis. The smear background, cellular composition, and accompanying reactive changes were evaluated. The majority of the smears were characterized by a bloody background with necrotic debris and extensive acute inflammation. Large sheets of exfoliated reactive pneumocytes and bronchial epithelium were commonly present. Multinucleated giant cells and epithelioid histiocytes were present in 10 and 20 specimens, respectively. Numerous hemosiderin-laden histiocytes were present in variable numbers in most cases and were abundant in 15 cases. Bronchial brush and lavage were the best sampling techniques. Although fine-needle aspiration best demonstrated the granulomas, only 2 of the 6 aspirates were diagnostic. The combination of cytologic findings, negative cultures, and elevated titers of antineutrophil cytoplasmic antibody with a cytoplasmic pattern may serve to establish a presumptive diagnosis of Wegener's granulomatosis.

We report the first example of smooth-muscle proliferations occurring in an allograft lung implanted in a recipient who had end-stage emphysema. Smooth-muscle proliferations were detected 46 months following transplantation in a 53-year-old woman. The lesions involved the airways and were bronchoscopically undetectable. Posttransplant smooth-muscle tumors have been described in liver transplant patients and are thought to be due to Epstein-Barr virus. Evidence of virus infection was not found in the current case.

sema ischaracteristically seen inpatients witha,-antiprotease deficiency. Paraseptal emphy-sema ispoorly understood and possibly relatedtoaging. Inallforms ofemphysema, there isin-creased proteolytic activity because ofthe acti-vation ofprotcolytic enzymes orlack anti-proteascs, resulting indestruction ofalveolartissue.Emphysema affects approximately 1.65mu

The case history is presented of a 50 year old man with a two year history of haemoptysis secondary to an accessory cardiac bronchus.

Robson stage I or II renal carcinomas have a heterogenous clinical outcome. A variety of morphologic features and other parameters have been proposed as prognostically useful. The authors measured the DNA content and PCNA expression of 47 stage I or II renal carcinomas, and assessed the association of these measures with pathologic stage, nuclear grade, and clinical course. Approximately 56% of stage I neoplasms and 40% of stage II neoplasms were diploid. Five of 9 neoplasms in which multiple samples were analyzed manifested both aneuploid and diploid regions. PCNA expression was noted in 20 of 32 stage I neoplasms and 9 of 15 stage II neoplasms, and varied greatly among the neoplasms. Neither ploidy nor PCNA expression is associated with clinical behavior in these data. These results are different from some of those previously reported by others. These discrepancies are likely to be due to differences in methodology and the fact that there were only eight cases of metastatic disease. No single parameter will serve as a completely accurate prognostic indicator. Most individuals with these neoplasms will do well because all of the tumor has been excised.

Epithelioid hemangioma (EH), also known as angiolymphoid hyperplasia with eosinophilia, may affect the eyelids and orbit, mimic idiopathic orbital inflammation, and respond poorly to corticosteroids.1,2 We describe a patient with chronic, bilateral orbital EH unresponsive to corticosteroids. Histopathologic analysis showed lobular vascular proliferations containing plump endothelial cells with surrounding mixed leukocytic infiltrates diagnostic of EH.3 Successful treatment consisted of surgical debulking and intralesional bevacizumab. Periocular EH lesions of 2 additional patients treated by debulking also showed prominent lobular vascular proliferations, highlighting them as the basis of this benign tumor. We conclude that EH is primarily a vascular tumor that can respond to bevacizumab.

We report the first case of recurrent sarcoidosis manifested by clinical symptoms, radiographic abnormalities, and pathologic changes in a patient following sequential double allogeneic lung transplantation. A 40-year-old male patient underwent bilateral allogeneic lung transplantation for end-stage pulmonary sarcoidosis. Thirteen months posttransplantation, he developed fatigue, shortness of breath, and bilateral upper lobe pulmonary infiltrates. Transbronchial biopsy specimens revealed noncaseating granulomata. The patient's symptoms and radiographic abnormalities resolved with an increased dose of oral prednisone.

The cellular receptor for urokinase plasminogen activator (uPA-R) is a monomeric phosphatidylinositol-linked glycoprotein (gp40-65) that may contribute to the invasive capacity of tumor and inflammatory cells by focusing the activity of urokinase (uPA) in converting plasminogen to plasmin, a serine protease capable of degrading extracellular matrix proteins. The further characterization of uPA-R has been facilitated by our recent development of a monoclonal antibody, anti-Mo3f, specific for uPA-R. This mAb bound to uPA-R expressed by phorbol myristate acetate-stimulated U-937 cells and by NIH-3T3 cells permanently transfected with uPA-R cDNA. In competitive binding assays, anti-Mo3f inhibited the binding of fluorescein-conjugated uPA ligand to uPA-R expressed by U-937 cells and uPA-R transfectants; conversely, preexposure of cells to saturating quantities of exogenous uPA partially blocked the subsequent binding of anti-Mo3f mAb to uPA-R. Anti-Mo3f mAb was employed as the capture reagent in an ELISA for the quantitation of soluble forms of uPA-R (derived from U-937 cells and recombinant uPA-R) which had a sensitivity of approximately 4-12 ng/ml. Anti-Mo3f mAb was also applied as a serologic probe for the detection of uPA-R expressed by human tumor tissues. By immunoperoxidase staining, anti-Mo3f demonstrated positive tumor cell staining in 4 of 16 breast and 7 of 31 prostate carcinomas in formalin-fixed, paraffin-embedded specimens. These data indicate that the anti-M03f mAb detects an epitope proximate to or within the ligand binding domain (domain 1) of uPA-R and may be useful as a tool for the serologic detection of uPA-R in soluble form or associated with human tumors.

Multi-drug resistance is a phenomenon by which tumor cells express resistance to a variety of chemically unrelated chemotherapeutic drugs. The classical form of multi-drug resistance is mediated through the expression of P-glycoprotein, which acts as an energy dependent drug efflux pump. P-glycoprotein expression was evaluated in 29 cystectomy specimens from patients with bladder cancer with no prior exposure to chemotherapeutic drugs, and in bladder biopsies from 9 subjects before treatment with intravesical doxorubicin. Furthermore, the strategy of circumvention of P-glycoprotein-mediated resistance using the combination of doxorubicin and verapamil intravesically was tested in 5 patients. P-glycoprotein was expressed in 75% of the cystectomy specimens. In the doxorubicin treated patients no correlation was noted between P-glycoprotein expression on the initial tumors and subsequent response to doxorubicin. The pilot trial of verapamil and doxorubicin was well tolerated but did not suggest increased efficacy of this combination. P-glycoprotein can be expressed on bladder cancer cells without prior chemotherapy. The role of P-glycoprotein mediated multi-drug resistance in bladder cancer treatment failure remains to be defined.

Bladder biopsy samples from 17 interstitial cystitis patients and 20 controls were evaluated for urothelial cell activation using a panel of monoclonal antibodies to HLA-DR, intercellular adhesion molecule 1, interleukin 1 alpha and tumor necrosis factor alpha. Urothelial cells in the majority (13 of 16, 81%) of the biopsies from patients with interstitial cystitis showed increased expression of HLA-DR, while fewer samples were positive for intercellular adhesion molecule 1 (3 of 16, 19%), interleukin 1 alpha (2 of 17, 12%) or tumor necrosis factor alpha (1 of 15, 7%). No urothelial cell expression of intercellular adhesion molecule 1, interleukin 1 alpha or tumor necrosis factor alpha was detected in the controls, and only 1 of 20 control samples contained HLA-DR positive urothelial cells. These results suggest that an unusual type of cellular activation is present in interstitial cystitis. In vitro studies with cultured normal urothelial cells indicated that cells activated with gamma interferon and tumor necrosis factor alpha expressed intercellular adhesion molecule 1 and HLA-DR, although increases in intercellular adhesion molecule 1 expression occurred earlier. Urothelial cells in interstitial cystitis patients may be defective in ability to express intercellular adhesion molecule 1. Alternatively, the differential expression of HLA-DR and intercellular adhesion molecule 1 in interstitial cystitis specimens may represent a functional subset of interstitial cystitis or reflect different stages of the disease. Urothelial cell activation in interstitial cystitis may result in aberrant immune responses and immune activation within the bladder. Because HLA-DR can be detected in paraffin-embedded tissues, evaluation of urothelial cell HLA-DR expression, although not specific for interstitial cystitis, may become a useful tool in the pathological evaluation of biopsy tissues from patients with this disease.

Three cases of an unusual neoplasm of the lung appeared as solitary, peripheral pulmonary nodules in asymptomatic patients. These well-circumscribed neoplasms were composed of distinctive papillae covered by uniform cuboidal to columnar cells; more solid areas often were present. Ciliated cells, epithelial mucin, and necrosis were not observed, and mitotic activity was absent. Terminal tight junctions and microvilli were present in the two cases studied ultrastructurally. One specimen contained lamellar bodies and apical cytoplasmic dense bodies. Another case stained positively for a Clara cell-specific antigen, although surfactant apoprotein was not detected by immunostaining in the three cases. All patients have been free of disease (at 11 to 108 months). Papillary adenoma is an uncommon, apparently benign, and morphologically distinctive neoplasm. The immunohistochemical and ultrastructural findings hint at an origin from type II pneumocytes or Clara cells.

Objective To compare the prevalence of nondiagnostic conjunctival map biopsies in patients with extensive pagetoid sebaceous carcinoma (defined as involvement of 3 or 4 quadrants of the ocular surface) and in patients without extensive pagetoid tumor (defined as involvement of 1 or 2 quadrants of the ocular surface). Methods Retrospective medical record and pathologic specimen review of 20 patients treated for sebaceous carcinoma at a tertiary care center. Biopsies with artifactual loss of or damage to the epithelium were categorized as nondiagnostic. Results One hundred forty-four map biopsies were reviewed, an average of 7.2 (standard deviation [SD], 4.4) biopsies per patient. Sixteen patients had extensive pagetoid tumor, 4 did not. Fifteen percent of biopsies were nondiagnostic. The frequency of nondiagnostic biopsies in patients with and without extensive pagetoid tumor was 37% and 10%, respectively. The odds ratio of nondiagnostic biopsy in the setting of extensive pagetoid tumor was 5.9 (95% confidence interval, 2.3-15.6; P = .004). Six of the sixteen patients (38%) without extensive pagetoid tumor had at least 1 nondiagnostic biopsy, with an average of 1.8 (SD, 1.6) nondiagnostic biopsies per patient (22% of biopsies). Two of the 4 patients (50%) with extensive pagetoid tumor had at least 1 nondiagnostic biopsy, with an average of 5.5 (SD, 3.5) nondiagnostic biopsies per patient (57% of biopsies). Conclusions Nondiagnostic, de-epithelialized conjunctival map biopsies are more common in patients with extensive pagetoid tumor than in those with limited or no pagetoid tumor. Artifactual epithelial loss may result from disruption of epithelial adhesion to the basement membrane by infiltrating tumor cells.

Objective To characterize histopathologic features of leaking mitomycin C–treated blebs and aberrant wound healing that may lead to persistent conjunctival thinning and leakage. Methods Forty mitomycin C–treated filtering blebs excised for persistent leaks from 40 patients were examined histopathologically using hematoxylin-eosin, periodic acid–Schiff, Masson trichrome, and Alcian blue histochemical stains. Results Ninety percent of the leaking blebs contained epithelial-stromal domes with areas of acellular stroma covered by attenuated epithelium. Seventy-five percent of the blebs demonstrated varying degrees of fibrovascular repair growing from the bleb margin, either beneath or interdigitating with the acellular zone. A novel observation in 65% of specimens was Alcian blue–positive myxoid stroma at the interface between the fibrovascular proliferation and the epithelial-stromal dome. The association between the presence of fibrovascular proliferation and Alcian blue–staining myxoid stroma was significant by Fisher exact test ( P = .002). Conclusions A desirable filtration bleb requires a sufficient reparative fibrovascular response to maintain an epithelial-stromal barrier to prevent leakage. Fibroblasts must lay down a continuous collagen-rich fibrous layer, rather than merely myxoid stroma, beneath the conjunctival epithelium to promote bleb stability. Surgical techniques and postsurgical care should aim to attain this desired outcome.

Wegener's granulomatosis (WG) frequently involves the upper respiratory tract, and nasal mucosal biopsy is often initially used to establish the diagnosis. To evaluate the diagnostic efficacy of nasal biopsy in WG, we reviewed the pathologic features of 30 such biopsy specimens from 17 patients with well-documented WG. Active vasculitis (granulomatous or nongranulomatous) was identified in seven of the patients (41%). The presence of extravascular foci of necrosis in lung biopsy samples has recently received attention as a characteristic feature of WG. Similar foci were found in the nasal samples from six of our patients, although vasculitis was absent in the samples from two of them. If extravascular foci of necrosis are regarded as characteristic or even diagnostic of WG, two additional patients in our series could be regarded as having had diagnostic nasal biopsies (nine of 17 patients). Nasal biopsy could thus be considered as diagnostic in 53% of the patients. Samples larger than 5 mm in greatest dimension were more likely to contain diagnostic features than were smaller samples (P = 0.002).

Background Head and neck adenoid cystic carcinoma (ACC) is a malignancy of the salivary and lacrimal glands with a variable growth pattern and propensity for perineural spread. Involvement of the skull base indicates a poor prognosis. Despite surgical resection and adjuvant radiotherapy, tumor recurrence and metastases are common. The urokinase-type plasminogen activator and its receptor (uPAR) have an important role in tumor invasion and metastasis. The expression of uPAR is predictive of poor outcomes in many tumors. This study examines the expression of human uPAR in ACCs involving the skull base. Objectives To determine uPAR expression in ACCs of the skull base by immunohistochemical analysis and compare expression with tumor histologic findings and clinical outcomes. Study Design Analysis of uPAR in archival ACC specimens and a retrospective medical chart review. Setting Multidisciplinary cranial base program at a university medical center with tertiary referral pattern. Results Ten (83%) of 12 tumors stained positive for uPAR. Three of 3 patients who died of ACC and 6 of 6 patients alive with disease expressed uPAR. Only 1 of 3 patients free of disease was uPAR positive. Conclusions In most patients with ACC of the skull base, uPAR was expressed. Its expression seems to be a negative prognostic factor. However, the small study sample limits our observations. Additional study of uPAR expression in ACC at other anatomic sites is required.

We report an unusual example of ovarian neurofibroma in a woman with neurofibromatosis (von Recklinghausen's disease). The neoplasm caused ovarian enlargement which surgically simulated malignant neoplasm. Ovarian neurofibromas are extremely rare and may arise from small myelinated nerves in the ovarian hilum.

The DNA content and nuclear size and shape of 21 Hurthle cell neoplasms of the thyroid were analyzed with a CAS 100RS Image Analyzer (Cell Analysis Systems, Lombard, IL) in order to distinguish between benign and malignant lesions. Neoplasms were considered malignant if documented metastatic disease or pathologic evidence of vascular or capsular invasion was present. Of the ten neoplasms classified as malignant, eight were aneuploid and two were diploid. Nine of the 11 benign neoplasms were diploid, the remaining two neoplasms were aneuploid. Two of the four malignant neoplasms which recurred or metastasized were aneuploid, the other two were diploid. A statistically significant association was found between aneuploidy and tumor invasion (P = 0.007). However, measurement of the percentage of cycling tumor cells as well as nuclear size and shape were not useful in separating benign from malignant neoplasms.