Pleuro-pulmonary endometriosis in baboons (Papio spp.): insights into pathogenesis.

BACKGROUND: Human pleuro-pulmonary endometriosis (PPE) is rare. Recently, we identified several cases of abdominal endometriosis in baboons that developed PPE. MATERIALS AND METHODS: Ten cases of PPE and four of intra-abdominal endometriosis (three simultaneous) were identified at necropsy in baboons (Papio spp.) found dead due to natural causes. The endometriotic lesions were evaluated using immunohistochemistry. RESULTS: The stromal (CD10+) and epithelial cells in intra-abdominal cases were estrogen and progesterone receptor (ER/PR) positive and thyroid transcription factor 1 (TTF-1) negative similar to that seen in humans. In contrast, the PPE cases displayed TTF-1-positive epithelium lining the cystic spaces, while the stroma was ER/PR positive similar to that in abdominal endometriosis. Both lymph nodes and spindle cell rests in lung interstitium contained ER/PR-positive stromal cells. CONCLUSIONS: The lung lesions were different from the abdominal lesions in having a TTF-1-positive lining epithelium. The deep pulmonary interstitial and lymph node endometrial stromal rests probably arrive via lymphatic route. The endometrial stroma is the driving force in PPE upon which the lung-specific epithelium condenses and may require a novel approach to therapy.

Eosinophilic bronchitis-like lesion as the cause of death in a Macaca mulatta: a first case report.

BACKGROUND: Eosinophilic bronchitis is a recently described, relatively benign condition in humans that is characterized by a corticosteroid-responsive chronic cough and sputum eosinophilia without the abnormalities of airway function seen in asthma. The exact cause of this condition is currently unknown, however has been associated with various occupational exposures in humans. It has also been reported to progress to irreversible airway obstruction. This disease has been reported in dogs and horses, but not in non-human primates. METHODS: Gross examination of an otherwise healthy 13-year-old, colony-born Macaca mulatta, which died of severe non-responsive respiratory distress revealed that the lungs were markedly inflated and moist. RESULTS: Hematoxylin and eosin-stained sections from the lungs contained widespread accumulation of eosinophils, sloughed epithelial cells, and mucus centered around bronchioles and adjacent airways. There was no evidence of mast cell infiltration of peribronchiolar smooth muscle, goblet cell hyperplasia, or basement membrane thickening. CONCLUSIONS: This ruled out recurrent episodes as would be expected in asthma, favoring the diagnosis of an eosinophilic bronchitis-like lesion. We report a first case of eosinophilic bronchitis-like features in a M. mulatta.

Segmental disorders of the nephron: histopathological and imaging perspective.

Recent advances in molecular genetics and immunocytochemistry have clarified the cell of origin in many renal disorders. Several renal disorders are thought to involve specific segments of the nephron. Renin-secreting tumours arise from juxtaglomerular cells. Clear cell and papillary renal cell carcinoma (RCC) recapitulate the epithelium of the proximal tubules. Oncocytoma and chromophobe RCC differentiate towards Type A and Type B intercalated cells of the cortical collecting duct, respectively. Medullary collecting ducts are the target sites for the development of autosomal recessive polycystic kidney disease, collecting duct carcinoma and medullary carcinoma. Renal papillae are susceptible to unique changes such as necrosis or papillitis. The purpose of our article is threefold: to illustrate the imaging findings of renal disorders that show segmental involvement of the nephron, to describe proximal and distal nephron disorders and to correlate imaging findings of some entities with histopathological features.

Molecular analysis of synchronous and metachronous tumors of the lung: impact on management and prognosis.

Patients with pulmonary neoplasms have an increased risk for developing a second tumor of the lung, either at the same time or different times. It is important to determine if the second tumor represents an independent primary tumor (ie, a synchronous or a metachronous tumor, depending on whether it is present at the same time or a later time) or recurrence/metastasis, because it will significantly change the management and prognosis. Because the two tumors from the same patient are often morphologically similar, histologic examination alone may not be sufficient to distinguish between the two possibilities. We have attempted to approach this problem by microdissecting malignant cells and comparing patterns of loss of heterozygosity of multiple genes and chromosomal loci between paired tumors. We found that primary tumors of the lung and their metastasis share nearly identical patterns of loss of heterozygosity. In contrast, most synchronous and metachronous tumors as defined by the current arbitrary criteria appeared to be genetically different; therefore, they likely represented independent primary tumors. Rare synchronous tumors had similar genetic profiles, raising the possibility of recurrence/metastasis. Our data suggest that molecular analysis can help fingerprint tumors and has the potential to significantly impact management and prognosis of patients.

Wild-type adenovirus decreases tumor xenograft growth, but despite viral persistence complete tumor responses are rarely achieved--deletion of the viral E1b-19-kD gene increases the viral oncolytic effect.

Strategies to target viral replication to tumor cells hold great promise for the treatment of cancer, but even with replicating adenoviruses complete tumor responses are rarely achieved. To evaluate replicating adenoviral vectors, we have used A549 human lung cancer nude mouse xenografts as a model system. Intratumoral injection of wild-type adenovirus (Ad309) significantly reduced tumor growth from day 14 (p = 0.04) onward; however, tumor volumes reached a plateau at day 50. At 100 days, high levels of titratable virus were present within persistent viable tumors. In contrast to viral injection into established tumors, when tumor cells were infected in vitro with wild-type virus and then mixed with uninfected tumor cells, 1% of infected cells was sufficient to prevent tumor establishment. An E1b-19kD-deleted viral mutant (Ad337) was more efficient than Ad309 in this cell-mixing model. Just 1 cell in 1000 infected with Ad337 prevented tumor growth. However, although better than wild-type virus, Ad337 was unable to eradicate established flank tumors. These data suggest that although replicating adenoviruses exhibit significant oncolytic activity, barriers within the established tumor, such as connective tissue and tumor matrix, may limit the spread of virus. Strategies to enhance viral spread through established tumors are therefore likely to greatly improve the therapeutic efficacy of replicating adenoviruses.

PNET-like features of synovial sarcoma of the lung: a pitfall in the cytologic diagnosis of soft-tissue tumors.

Fine-needle aspiration (FNA) cytology of soft-tissue tumors is evolving. As more experience is gained, we are becoming aware of potential pitfalls. We describe 2 cases of synovial sarcoma of the lung, primary and metastatic, in patients who had FNA biopsy performed on a lung mass. The cytologic smears showed extremely cellular groups of malignant small round cells, intersected by small blood vessels, with numerous loose single cells, in a background of macrophages and mature lymphocytes. The tumors displayed monomorphic cells forming rosettes and displaying occasional mitoses. A diagnosis of neuroendocrine tumor/primitive neuroepithelial tumor (PNET) was suspected. Furthermore, this suspicion was supported by immunohistochemical stains, which showed positivity for a neuroendocrine marker, Leu 7 (case 1), and for a neural marker, CD 99 (O 13 or HBA 71) (both cases); and negativity for cytokeratins (case 1). The resection specimen of case 1 had mostly tightly packed small round cells, with occasional rosettes, similar to the FNA biopsy, and focal areas composed of spindle cells, organized in a focal fibrosarcoma-like and hemangiopericytoma-like pattern. A balanced translocation between chromosomes X and 18, demonstrated by both karyotyping and fluorescent in situ hybridization (FISH), enabled us to make a diagnosis of synovial sarcoma, which was histologically classified as poorly differentiated. Case 2 was a metastatic biphasic synovial sarcoma of the arm, with a prominent epithelial component. Synovial sarcoma, when composed mainly of small round cells on cytologic smears, is a great mimicker of neuroendocrine/PNET tumors, with light microscopic and immunohistochemical overlap. Awareness of this potential pitfall may aid in preventing a misdiagnosis. Its recognition is of major concern, especially for the poorly differentiated variant, because it is associated with a worse prognosis.

Adhesion molecules as prognostic factors in nasopharyngeal carcinoma.

OBJECTIVE/HYPOTHESIS: To identify the significance of molecular markers in determining the risk of recurrence and distant metastases in nasopharyngeal carcinoma. STUDY DESIGN: In this retrospective case study, we evaluated archival nasopharyngeal carcinoma specimens for patterns of expression of E-cadherin, beta-catenin, c-erb-B2, and Ki-67, which have been demonstrated to be important in other tumors. METHODS: Fifty-four cases of nasopharyngeal carcinoma were identified, with a maximum follow-up of 13 years. The histopathological sections were stained using an automated immunohistochemical stainer (NexES, Ventana Medical Systems, Tucson, AZ) for E-cadherin (Zymed Laboratories [San Francisco, CA] and Transduction Laboratories [Lexington, KY] clones), beta-catenin (Zymed), c-erb-B2 (Ventana Medical Systems), and Ki-67 (Novocastra, Burlingame, CA). The numbers of positively staining cells were scored as follows: 0%, 1% to 33%, 34% to 66%, or greater than 67%. RESULTS: E-cadherin (Zymed) stained positively in only one case. The Transduction Laboratories clone demonstrated a spectrum of staining in all cases, from complete to disrupted to no identifiable membranous staining. The staining was consistently absent at the advancing tumor border, regardless of stage. The loss of beta-catenin expression did not correlate with that of E-cadherin or with clinical outcomes. No staining was identified for c-erb-B2. Ki-67 staining was variable and did not correlate with clinical outcomes. CONCLUSIONS: Altered expression or loss of E-cadherin, or both, may result in loss of function, particularly at the infiltrating edge, with resultant loss of cell polarity, cell migration, and eventual metastasis. The interpretation of E-cadherin staining depends on antibody source. In contrast to recent studies, beta-catenin expression is not altered and c-erb-B2 expression not identified, suggesting that these markers are not important in the prognosis of nasopharyngeal carcinoma.

Hut lung. A domestically acquired particulate lung disease.

We report an illustrative case of advanced "hut lung," or domestically acquired particulate lung disease (DAPLD), in a recently emigrated nonsmoking Bangladeshi woman with a history of 171 hour-years of exposure to biomass smoke. She presented with symptoms of chronic cough, dyspnea, and early parenchymal lung disease. High-resolution computed tomography (CT) of the chest demonstrated numerous 2- to 3-mm nodules, sparing the pleural surface. To our knowledge, this is the first such report of CT findings in the literature. Bronchoscopy yielded typical anthracotic plaques and diffuse anthracosis with interstitial inflammation on histopathologic examination of biopsy specimens. DAPLD is potentially the largest environmentally attributable disorder in the world, with an estimated 3 billion people at risk. Caused by the inhalation of particles liberated from the combustion of biomass fuel, DAPLD results in significant morbidity from infancy to adulthood. Clinically, DAPLD manifests a broad range of disorders from chronic bronchitis and dyspnea to advanced interstitial lung disease and malignancy. While a detailed environmental history is essential for making the diagnosis in most individuals, for patients with advanced DAPLD, invasive modalities such as bronchoscopy with transbronchial biopsy and examination of bronchoalveolar lavage fluid help differentiate it from other diseases. Recognition of this syndrome and removal of the patient from the environment is the only treatment. The development of well-controlled interventional trials and the commitment of sufficient resources to educate local populaces and develop alternative fuel sources, stove designs, and ventilation are essential toward reducing the magnitude of DAPLD.

Calretinin staining pattern aids in the differentiation of mesothelioma from adenocarcinoma in serous effusions.

BACKGROUND: The differentiation between malignant mesothelioma and adenocarcinoma based on morphology alone can be a diagnostic challenge. The majority of the available antibodies recognize molecules expressed by adenocarcinoma whereas to the authors' knowledge specific markers for mesothelial cells are lacking. Calretinin, a calcium-binding protein, has been reported to be a selective marker for mesothelioma and largely is absent from adenocarcinoma on histologic material. The results with cytologic preparations have been inconsistent. METHODS: To evaluate the specificity of calretinin in differentiating mesothelioma from adenocarcinoma in cytologic preparations, 21 paraffin embedded cells blocks of serous effusions from 15 patients with metastatic adenocarcinoma and 16 cell blocks from 9 patients with malignant mesothelioma were stained with a monoclonal antibody against calretinin. The immunoreactivity was evaluated blindly by two observers. Positive staining was defined as nuclear and cytoplasmic staining with or without intense membranous decoration. The former resulted in a characteristic "fried egg" appearance. RESULTS: Calretinin staining was positive in all but 2 cases of mesothelioma (14 of 16 cases; 87.5%). The latter contained predominantly spindle-shaped neoplastic mesothelial cells in the cell block preparations. All adenocarcinoma specimens were classified as negative for calretinin staining; 9 (42.9%) lacked any immunoreactivity and 12 (57.1%) showed weak, sparse, coarse, granular cytoplasmic staining without nuclear or membranous staining. Benign reactive mesothelial cells, when observed in association with adenocarcinoma, also showed the characteristic "fried egg" appearance. The difference in the staining pattern of calretinin between cells of mesothelial origin and adenocarcinoma cells was statistically significant. CONCLUSIONS: Calretinin is a useful marker in differentiating mesothelioma of the epithelial type from adenocarcinoma in serous effusions. The "fried-egg" appearance or cytoplasmic and nuclear staining pattern is characteristic of cells of mesothelial origin.

BK virus infection in AIDS.

The BK virus (BKV) belongs to the family of the polyoma group, which contains three species: JC, which is responsible for progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome (AIDS); simian virus 40 (SV40), which is a simian virus of little pathologic significance in humans; and BKV, which is usually not pathogenic and is found in the urine of asymptomatic individuals. Recently BKV has been reported to cause symptomatic infection in renal transplant patients. The authors report a rare case of a 14-year-old boy with AIDS who developed a BKV infection of the lung and kidney that progressed to diffuse alveolar damage and death. The infected type II pneumocytes in the lung and the tubular epithelial cells in the kidney showed large, homogenous purple intranuclear inclusions. The absence of necrosis and destruction made it possible to distinguish BKV infection from herpes simplex. The size of the infected cells and the lack of a halo around the nuclear inclusion helped rule out cytomegalovirus as the cause of infection. Electron microscopy detected the presence of 40-nm intranuclear viral particles compatible with BKV, and in situ hybridization established the diagnosis.

Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice.

The lack of tumor models that can reliably predict for response to anticancer agents remains a major deficiency in the field of experimental cancer therapy. Although heterotransplants of certain human solid tumors can be successfully grown in nude mice, they have never been appropriately explored for prediction of in vivo chemosensitivity to anticancer agents. We determined the tumor response rate and studied the influence of several biological and molecular tumor parameters on the in vivo sensitivity to paclitaxel in a series of heterotransplanted human non-small cell lung cancer (NSCLC) tumors. One hundred consecutive resected NSCLC tumors were heterotransplanted s.c. in nude mice. The in vivo sensitivity to i.v. paclitaxel (60 mg/kg every 3 weeks) was studied in 34 successfully grown heterotransplants. Treatment started when the tumors reached a size of 5 mm in diameter, and strict standard clinical criteria (>50% shrinkage in tumor weight or cross-sectional surface) were used to define tumor response. Baseline multidrug resistance protein (MRP), Her-2/neu, and epidermal growth factor receptor (EGFR) expression, and pre- and posttherapy bax and bcl-2 expression were determined by Western blot analysis. p53 status was determined by sequencing. The overall take rate was 46% (95% confidence interval, 36-56%) and was significantly higher (P < 0.05) for squamous carcinoma tumors (75%) than for adenocarcinoma tumors (30%) and bronchoalveolar tumors (23%). The heterotransplants were morphologically very similar to the original tumors. The response rate to paclitaxel was 21% (95% confidence interval, 9-38%). Baseline tumor parameters associated with response were no Her-2/neu expression (none of the responding tumors expressed Her-2/neu versus 48% of the nonresponding tumors, P = 0.05) and baseline bcl-2 expression (all responding tumors expressed bcl-2 versus only 43% of the nonresponding tumors, P = 0.02). There was a trend toward a higher response rate in bax-positive tumors, and MRP- and EGFR-negative tumors, but it was not statistically significant. The response was independent of baseline p53 status and baseline mitotic index. Responding tumors had a higher bax/bcl-2 ratio 24 h after therapy, but the difference was only marginally significant (2.8 for responding tumors versus 1.1 for nonresponding tumors, P = 0.07). The extent of mitotic arrest at 24 h after therapy was not associated with response. Human NSCLC heterotransplants are morphologically identical to the original tumors and have a response rate to paclitaxel that is equivalent to that reported in Phase II studies in patients with advanced NSCLC treated with single-agent paclitaxel. NSCLC heterotransplants deserve to be explored to evaluate new agents for lung cancer and to predict clinical response on an individual basis in selected groups of patients.

Comparison of molecular changes in cervical intraepithelial neoplasia in HIV-positive and HIV-indeterminate subjects.

OBJECTIVE: HIV infection is associated with an increased incidence of cervical malignancy and its precursor lesions (CIN, cervical intraepithelial neoplasia) compared with the general population. We studied the molecular abnormalities in the development of HIV-associated CIN and compared them with those present in CINs arising in HIV-indeterminate subjects ("sporadic CIN"). METHODS: We investigated the presence of human papilloma virus (HPV) sequences, loss of heterozygosity (LOH), and microsatellite alterations (MAs) at five 3p chromosomal regions using 17 polymorphic markers in precisely microdissected archival tissues from 16 HIV-positive CINs and compared them with those present in 39 sporadic CINs. RESULTS: HPV sequences were detected in 36 of 55 (66%) CIN lesions, and high-risk oncogenic strains (HPV 16 and 18) accounted for 15 of them. No differences in the HPV frequencies were found between HIV-associated and sporadic CINs. Allelic losses at one or more chromosome 3p regions were frequently detected in CIN lesions (49%). The overall frequency of 3p LOH and the frequencies at all individual regions were similar in HIV-associated and sporadic CINs. The frequency of MA present in the HIV-associated CIN cases (0.093) was sixfold greater than in sporadic CINs (0.014; P = 0.0001). At least 1 MA was present in 11 (69%) of 16 HIV-associated vs. 5 of 39 (13%) sporadic CIN (P = 0.0006). Molecular changes were independent of the presence of HPV sequences. CONCLUSION: Chromosome 3p deletions are frequently detected in the precursor lesions of cervical carcinoma (CIN) and there are no differences in the 3p LOH frequencies between HIV-associated and sporadic CIN lesions. Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated CIN. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated neoplasias.

Congenital cystic adenomatoid malformation of the lung (CCAM): evaluation of the cellular components.

Congenital cystic adenomatoid malformation of the lung (CCAM) is a rare congenital lesion whose pathogenesis is not well defined. It is generally accepted that the various types of CCAMs originate at different levels of the tracheobronchial tree. To further define the pathogenesis of CCAM, we evaluated the cellular composition of different CCAM types by immunohistochemistry. Twenty-two CCAMs (17 CCAM type 1, two type 2, one type 3, and two type 4) were collected. The cellular composition was determined using immunohistochemical stains for type I cell-associated antigen (T1 cell-Ag), surfactant proteins and surfactant protein precursors (SP-A, SP-B, proSP-B, and proSP-C), neuroendocrine cells (GRP), Clara cells (UP-1), and the adhesion molecule CD44v6, a glycoprotein thought to be involved in cell-matrix and cell-cell interactions. Eleven fetal lungs also were analyzed to compare cytodifferentiation of the epithelial-lined cysts of the different types of CCAM with the stages of normal lung development. Our results indicate that CCAM is caused by an arrest in lung development, and, on the basis of cytodifferentiation, two major subtypes can be distinguished. One subtype consisting of CCAM types 1, 2, and 3 that shows a bronchiolar type of epithelium and a second subtype, consisting of CCAM type 4, that has an acinar-alveolar type of epithelium. Our findings also suggest that these two subtypes may arise at different stages of the branching of the bronchopulmonary tree, the first at the pseudoglandular stage and the second at the saccular stage.

Primary multifocal tuberculous osteomyelitis with involvement of the ribs.

Two cases of primary multifocal tuberculous osteomyelitis with involvement of the rib cage are presented. The lungs were normal and the appearance of the skeletal lesions did not suggest tuberculosis. These lesions were predominantly lytic, with minimal soft tissue involvement. Tuberculosis should be high in the differential diagnosis of multiple destructive bone lesions, especially in patients from regions where tuberculosis is endemic.

Hemangiopericytoma of the lacrimal sac.

Hemangiopericytoma (HPCT) rarely originates in the lacrimal sac; 7 cases have been reported previously and only 1 contained an ultrastructural study. In this article we report an additional case and review the previous reports. While the initial biopsy specimen showed nonspecific cytologic abnormalities, light and electron microscopic studies on the subsequently excised tumor demonstrated that it had a structure characteristic of HPCT. The onset of lacrimal sac HPCT occurs in a younger age group than that of HPCT of other orbital locations. The tumor may recur locally but, to our knowledge, never has been reported to metastasize from a sac location. The treatment goal is complete surgical excision.

Angular and fibrous particles in lung in relation to silica-induced diseases.

INTRODUCTION: The lung concentration of angular and fibrous particles was measured in cases of lung fibrosis only, in cases of lung fibrosis and lung cancer, and in cases of lung cancer only. These patients worked in different trades (mining, foundries, construction and were not a homogeneous group of exposed workers. MATERIAL AND METHODS: Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique, and analyzed by transmission electron microscopy (TEM) and energy-dispersive spectroscopy (EDS). The quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after extraction from the lung parenchyma. RESULTS: (1) Lung cancer and lung fibrosis cases retained more metal-rich particles (P = 0.02) and more angular particles of all sorts (P = 0.009) than did lung fibrosis cases only, and the differences were statistically significant. (2) However, more quartz was retained in the lungs in lung fibrosis cases than in lung fibrosis or lung cancer cases, but the difference in the concentrations was not statistically significant. (3) More ferruginous bodies were retained in the lungs in lung cancer and lung fibrosis cases than in cases of lung fibrosis only, and the difference in the concentrations was statistically significant (P = 0.02). CONCLUSION: Results obtained from lung tissue must always be interpreted cautiously. However, these results are consistent with the hypothesis that workers in some trades such as foundries were exposed not only to quartz but also to asbestos, ceramic fibers, metal-rich non fibrous particles, and other likely carcinogenic chemicals. The wide range of particle types identified in the lungs of these workers illustrates the complexity of trying to determine disease origins in these work environments. Epidemiology studies have to control for the exposure to these carcinogens as well as for smoking habits.

Transbronchial needle aspiration (TBNA) in patients infected with HIV.

Transbronchial needle aspiration (TBNA) of intrathoracic lymph nodes has been shown to be useful in the diagnosis and staging of bronchogenic carcinoma. With the exception of sarcoidosis, the usefulness of TBNA has not been widely investigated in other clinical settings. We investigated the utility of TBNA with a 19-gauge histology needle in HIV-infected patients with mediastinal and hilar adenopathy at Bellevue Hospital Center. We performed 44 procedures in 41 patients. Adequate lymph node sampling was obtained in 35 of 44 (80%), and diagnostic material was obtained in 23 of 44 (52%) procedures. TBNA was the exclusive means of diagnosis in 13 of 41 (32%) patients. Of the 44 procedures, 23 (52%) were performed in patients with mycobacterial disease, with TBNA providing the diagnosis in 20 of 23 (87%). In these patients, positive TBNA specimens included smears of aspirated materials for acid-fast bacilli in 11, mycobacterial culture in 14, and histology in 15. In other diseases, TBNA diagnosed sarcoidosis with noncaseating granulomata in 2 of 4 patients and non-small cell lung cancer in 1 of 2 patients. TBNA was not helpful in other diseases including Pneumocystis carinii pneumonia, infection with Cryptococcus or Nocardia, bacterial pneumonia, viral pneumonia, and Kaposi's sarcoma. No pulmonary diagnosis was established in five patients. No complications of TBNA occurred. We conclude that TBNA through the flexible bronchoscope is safe and effective in the diagnosis of intrathoracic adenopathy in HIV-infected patients, and is particularly efficacious in the diagnosis of mycobacterial disease. Furthermore, TBNA may provide the only diagnostic specimen in almost one-third of HIV-infected patients, thereby sparing these patients more invasive procedures such as mediastinoscopy.

MIB-1 as a predictor of response in lung allografts with moderate acute cellular rejection.

The major obstacle that long-term lung transplant recipients face is bronchiolitis obliterans. Prior episodes of acute rejection, specifically their frequency, persistence, and severity, are important predictors of bronchiolitis obliterans. Many cells contribute to the damage of acute rejection, and there is no sole cell type that can predict persistent rejection or bronchiolitis obliterans. In this study we evaluated 48 transbronchial biopsy samples from various grades of acute rejection with the proliferation marker MIB-1 and attempted to retrospectively predict response to standard corticosteroid in a subpopulation of nine responders and nine nonresponders, all with grade A3 rejection. We then characterized the proliferating cells by double labeling with MIB-1 and L26, CD3, OPD4, or KP1. Our results indicate that the proliferating cells in acute lung rejection are a heterogeneous pool of T- and B-lymphocytes, T-helper cells, macrophages, endothelial cells, and possibly parenchymal cells, and that MIB-1 is a valuable tool in the evaluation of total cellular activity in this setting. In addition, the overall proliferation rate, defined as the most intense proliferation rate regardless of location in the biopsy, closely matches the grade of acute rejection. Finally, a low lesional proliferation rate, defined as the proliferation rate at the site of perivascular inflammation diagnostic of acute rejection, is an indicator of excellent response to therapy and may have potential clinical importance.

Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects.

CONTEXT: Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population. OBJECTIVE: To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors"). DESIGN: Convenience sample. SUBJECTS: Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. SETTING: University-based medical centers and affiliated hospitals. MAIN OUTCOME MEASURES: Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences. RESULTS: The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas. CONCLUSIONS: Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.