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Lymphangioma is an abnormal collection of lymphatics that are developmentally isolated from the normal lymphatic system. Lymphangioma rarely presents as a solitary pulmonary lesion. We present a case of solitary pulmonary lymphangioma and review the literature on its pathogenesis, clinical features, and radiographic findings.

We present a patient with a pulmonary artery (PA) aneurysm who has none of the documented causes of PA aneurysm but who is pregnant. We believe that this patient represents a case of primary pregnancy-associated PA aneurysm.

Diabetic fibrous mastopathy, an unusual finding in patients with early onset, long-standing insulin dependent diabetes, can present as a palpable mass with mammographic and sonographic findings highly suggestive of breast cancer. These suspicious clinical and imaging findings necessitate a biopsy, which demonstrates characteristic findings of dense, keloid scarring and intralobular lymphocytic infiltrates. We present 2 cases of diabetic fibrous mastopathy with characteristic mammographic, sonographic, and pathologic findings diagnosed with ultrasound guided core needle biopsy and confirmed with surgical excision. In the appropriate clinical setting, a patient with long-standing insulin dependent diabetes with a firm, mobile breast mass and characteristic sonographic findings of a hypoechoic mass with lobulation and marked posterior acoustic shadowing should suggest the possibility of diabetic fibrous mastopathy. Awareness of this entity may obviate the need for surgical excision in patients whose clinical, imaging, and pathologic findings are consistent with diabetic fibrous mastopathy.

Despite the profound therapeutic and prognostic implications of nodal metastases in patients with melanoma, there is no consensus strategy for the optimal detection of metastases in sentinel lymph node biopsies. Traditional microscopic examination may be too crude to detect scattered, individual tumor cells. Conversely, molecular genetic techniques are prone to false-positive results. The authors evaluated the ability of HMB-45 immunohistochemistry to enhance detection of melanoma cells in histologically negative sentinel lymph nodes. Ninety-six sentinel lymph nodes, collected over a 25-month period from 66 consecutive patients with melanoma, were processed routinely and sectioned serially. Slides 1, 3, and 5 were stained with hematoxylin and eosin. HMB-45 staining was performed on an intervening slide in histologically negative nodes. To assess the background incidence of HMB-45-positive cells in lymph nodes draining the skin, the authors stained 244 cervical and axillary lymph nodes from patients without melanoma. Metastases were apparent microscopically in 12 (18%) of the 66 patients with melanoma. Of the remaining 54 patients, four patients (7%) had lymph nodes harboring individual, scattered HMB-45-positive cells. Benign nevocellular aggregates were present in four of the 96 sentinel lymph nodes (4% nodal incidence), but they were HMB-45-negative. The authors did not observe a single HMB-45-positive cell in the 244 lymph nodes from patients without melanoma. Immunohistochemistry appears to represent a specific means of enhancing tumor detection in sentinel lymph nodes from patients with melanoma.

Pulmonary and mediastinal glomus tumors are rare lesions, with four previously reported primary pulmonary cases and three mediastinal cases. The authors report one mediastinal glomus tumor, a locally infiltrative type, and four pulmonary glomus tumors, including the first case of primary pulmonary glomangiosarcoma. These tumors show a variety of clinical and pathologic differences from the more common cutaneous variety, including later age at presentation, larger size, and more frequent atypical/malignant features. Mediastinal and pulmonary glomus tumors both have an average patient age at presentation of 45 years. However, compared with their pulmonary counterparts, mediastinal glomus tumors are less common, more often symptomatic, and are larger (average size, 5.4 cm). Additionally, mediastinal glomus tumors more often demonstrate malignant or atypical features. Pulmonary glomus tumors average 3.3 cm in greatest dimension, with the majority measuring less than 2.5 cm. The pulmonary glomangiosarcoma presented was large, measuring 9.5 cm, and showed increased mitotic count (9 mitoses/10 high-power fields), necrosis, cytologic atypia, and was associated with disseminated disease. Regardless of clinical symptoms, histologic features, and even metastases, the vast majority of all benign and malignant glomus tumors are indolent and cured surgically, with adjuvant therapy needed only for occasional patients with more advanced disease. The four patients with glomus tumors reported are currently alive and free of disease as of last follow up. The patient with the glomangiosarcoma developed widespread metastases and died of disease 68 weeks after initial therapy.

We report a unique case of a minute, occult synovial sarcoma of the lung detected intraoperatively during a pneumothorax repair in a 17-year-old boy. No alternative primary site could be detected upon complete body imaging studies and physical examinations. The diagnosis was confirmed by demonstration of the characteristic SYT/SSX gene fusion by reverse transcriptase polymerase chain reaction (RT-PCR) performed upon RNA extracted from the paraffin block of the biopsy. This case demonstrates the utility of this technique in diagnostic pathology.

Efficient local expression from recombinant adeno-associated virus (rAAV)-cystic fibrosis (CF) transmembrane conductance regulator (CFTR) vectors has been observed in the airways of rabbits and monkeys for up to 6 months following a single bronchoscopic delivery. However, it is likely that repeated administrations of rAAV vectors will be necessary for sustained correction of the CF defect in the airways. The current study was designed to test the feasibility of repeated airway delivery of rAAV vectors in the rabbit lung. After two doses of rAAV-CFTR to the airways, rabbits generated high titers of serum anti-AAV neutralizing antibodies. Rabbits then received a third dose of a rAAV vector containing the green fluorescent protein (GFP) reporter gene packaged in either AAV serotype 2 (AAV2) or serotype 3 (AAV3) capsids. Each dose consisted of 1 ml containing 5 x 10(9) DNase-resistant particles of rAAV vector, having no detectable replication-competent AAV or adenovirus. Three weeks later, GFP expression was observed in airway epithelial cells despite high anti-AAV neutralizing titers at the time of delivery. There was no significant difference in the efficiency of DNA transfer or expression between the rAAV3 and rAAV2 groups. No significant inflammatory responses to either repeated airway exposure to rAAV2-CFTR vectors or to GFP expression were observed. These experiments demonstrate that serum anti-AAV neutralizing antibody titers do not predict airway neutralization in vivo and that repeated airway delivery rAAV allows for safe and effective gene transfer.

Calcification of the fibrous capsule surrounding silicone breast implants is a well-recognized occurrence that increases with time following implantation. These mineralized deposits potentially confound mammographic breast cancer surveillance already made difficult by the obscuring effects of silicone breast implants. The authors performed elemental analysis of silicone breast implant-associated calcifications to define better their chemical composition as related to mammographic and clinical significance. Electron probe microanalysis and infrared spectroscopy revealed all of the calcification deposits to be calcium complexed with tribasic phosphate. No evidence of calcium oxalate, calcium carbonate, silicone, or talc was observed. Caution must be employed in interpreting mammograms in women with silicone breast implants as well as those who have had their silicone breast implants removed. High-density mammographic calcifications indicative of calcium phosphate associated with a silicone breast implant may represent an accepted consequence of implantation or nearby carcinoma. We recommend baseline mammography on women who have had their silicone breast implants removed to prevent unnecessary fine-needle aspiration or tissue biopsy of retained breast capsule calcifications during subsequent routine surveillance for carcinoma.

The mediastinum is the site of a variety of benign and malignant pathological processes in children. While the chest radiograph may be the initial imaging study to suggest an abnormality, spiral or helical CT provides detailed depiction of anatomic relationships and characteristics of the mass, and may increase the likelihood of a successful examination because of shorter scan times. This article will emphasize the important CT features in the evaluation of common and uncommon mediastinal masses in children. Pathologic correlation is presented for greater understanding. In many clinical settings, CT features such as attenuation, enhancement, calcification, anatomic relationships and extent of disease may suggest a specific diagnosis for a mediastinal mass in a child.

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.

Atypical alveolar hyperplasia (AAH) is a potential precursor lesion from which lung adenocarcinomas arise and may be a good target for studying the early events of lung tumorigenesis. We have previously shown that AAHs are neoplastic epithelial proliferations that often harbor activating mutations of the K-ras oncogene. In the current study, we examined a spectrum of AAHs to determine the frequency and timing of p53 alterations in lung tumorigenesis. We analyzed 37 AAHs and their paired overt lung neoplasms for p53 protein accumulation using the monoclonal antibody DO7. DNA sequence analysis of the p53 gene was performed on those cases demonstrating p53 protein accumulation. AAHs were classified as low-grade, high-grade, or AAH-like carcinoma based on cytoarchitectural features. Accumulation of the p53 protein was found in none (0%) of 20 low-grade AAHs, in 1 (9%) of 11 high-grade AAHs, and in three (50%) of six AAH-like carcinomas. There was a statistically significant trend toward p53 accumulation with increasing grade of the AAHs. A missense mutation in exon 7 of the p53 gene was found in 1 AAH-like carcinoma, whereas mutations in exons 5 through 8 could not be detected in the other three AAHs with p53 protein accumulation. Three of the paired overt carcinomas harbored p53 mutations that were not present in the AAHs. Alterations of p53 do not appear to be common events in AAHs, especially when these lesions exhibit low-grade cytoarchitectural features. Alterations of p53, however, are more frequent at the level of AAH-like carcinoma and may be associated with the transition from a benign to a malignant proliferation of pneumocytes.

Peripheral neuroblastic tumors in childhood present unique problems in terms of diagnosis, classification, and histologic determinants of prognosis. The proper specimen handling of these neoplasms requires integration of gross and microscopic pathologic examination along with cytogenetic, immunohistochemical, and electron microscopy studies. The appropriate gross examination and processing of these tumors are described with particular emphasis on ancillary studies. Important special studies such as immunohistochemistry, flow cytometry, and genetic and molecular oncologic investigation are stressed, and the appropriate methods of processing materials for these studies are discussed. The handling of small biopsy specimens, fine-needle aspirates, or both is also addressed. The staging of neuroblastoma varies according to Pediatric Oncology Group and Children's Cancer Study Group systems, and the importance of obtaining appropriate information to satisfy either system is noted. Ancillary information for classification of neuroblastoma and related neoplasms is also presented.

Clinical and pathologic findings are presented of the first reported case in the English-language medical literature of pseudomesotheliomatous adenocarcinoma (PMA) occurring in an HIV-infected patient. PMA is an uncommon variant of peripheral lung cancer which typically occurs in elderly male patients. It mimics a malignant mesothelioma in terms of its clinical presentation and gross and microscopic appearance. The occurrence of this rare tumor in a young HIV-infected patient suggests some association between HIV infection and the development of PMA.

Localized benign pleural mesothelioma is a rare neoplasm representing less than 5% of all pleural tumors. Unlike the malignant diffuse pleural mesothelioma, there is no evidence of a relationship to asbestos exposure. Essentially, the cause of localized benign pleural mesotheliomas remains obscure. We propose that one mechanism of the development of this tumor is prior ionizing radiation to the tumor field. Ionizing radiation is a well-known human oncogen and leads to an increased incidence of benign tumors as well. A 65-year-old woman had a localized benign pleural mesothelioma of her left upper chest 22 years following adjuvant radiation therapy to the left breast and axillary region for a breast carcinoma.

There continues to be confusion as to whether papillary adenocarcinoma (PA) of the lung is a specific histologic entity or simply a variant of bronchioloalveolar carcinoma (BAC). We reviewed our files from 1981 through 1993 for all cases (n = 155) of resected primary lung adenocarcinoma specifically diagnosed as having papillary or bronchioloalveolar features. In addition, a random 10% (n = 67) of all remaining lung adenocarcinomas were reviewed. True PA was diagnosed when > or = 75% of the neoplasm contained papillary structures supported by fibrovascular cores with complicated secondary and tertiary branches. Marked nuclear atypia was present in 100%, and psammoma bodies were seen in 42% of cases. In contrast to BAC, true PA filled and distorted or replaced air spaces in the lung. Thirty-one cases of true PA were found, including 19 men and 12 women (mean age, 64.5 years). The lesions were solitary (n = 27) or multifocal (n = 4) with a mean diameter of 4.1 cm. Forty-five percent of patients had bronchopulmonary lymph node involvement at diagnosis; another 10% had extensive intrapulmonary lymphatic permeation by tumor. Disease-free survival for stage I and II PA was 40% (n = 15) and 25% (n = 8), respectively, at a mean of 3.4 and 3.5 years. Papillary adenocarcinoma of the lung is a distinct clinicopathologic entity with considerably worse morbidity and mortality than BAC.

Gene therapy for cystic fibrosis (CF) would ideally be accomplished with a vector capable of long-term expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in the absence of a host inflammatory response. Recombinant adeno-associated virus (AAV)-CFTR vectors possess these characteristics in rabbits. Because the utility of AAV vectors as gene transfer agents has only been recognized recently, AAV vector-mediated transduction has never been modeled in a primate host, which is an important step before its use in humans. In order to test the safety and biological activity of AAV-CFTR, single doses of AAV-CFTR vector were administered by fiberoptic bronchoscopy to the posterior basal segment of the right lower lobe (RLL) of the lungs of 10 rhesus macaques with four matched vehicle-treated controls. Animals were followed for 10, 21, 90 or 180 days following vector instillation. Vector DNA transfer occurred in bronchial epithelial cells in the RLL of each animal that received vector as assessed by in situ DNA PCR. Vector mRNA was detectable for 180 days after administration as detected by RT-PCR and by RNase protection assay. Safety of vector administration was determined by measurements of pulmonary mechanics, arterial blood gas analysis, chest radiographs, and bronchoalveolar lavage (BAL) fluid analysis including cell count and quantification of inflammatory cytokines. Gross and microscopic pathologic examination were also performed. There was no evidence of inflammation or other toxicity, although vector DNA was found in extrapulmonary organs of some animals. These results indicate that transduction of the primate airway epithelium with the AAV-CFTR mediates long-term CFTR cDNA transfer and is relatively safe.

Atypical alveolar hyperplasia (AAH) is a potential precursor lesion from which lung adenocarcinomas arise and may be a good target for studying the early events of lung tumorigenesis. A common genetic alteration in lung adenocarcinomas is mutational activation of K-ras. To determine the timing of K-ras activation, we evaluated formalin-fixed and paraffin-embedded tissue samples of 41 AAHs and their paired lung neoplasms from 28 patients for codon 12 point mutations of the K-ras oncogene. K-ras codon 12 mutations were detected using PCR followed by allele-specific oligonucleotide hybridization. Mutations were found in 16 (39%) of the 41 AAHs, 8 (42%) of the 18 adenocarcinomas, and none (0%) of the 5 lung neoplasms that were not adenocarcinomas. Of the 18 patients with both an AAH and a synchronous lung adenocarcinoma, 6 had K-ras mutation in the adenocarcinoma but not in the AAH, 6 had mutations in the AAH but not in the adenocarcinoma, 4 did not harbor mutations in either the AAH or the adenocarcinoma, and 2 had mutations in both their AAH and their synchronous adenocarcinoma. In just 1 of the 18 patients was the same K-ras mutation present in the AAHs and adenocarcinoma of the patient. The detection of independent activating point mutations in a cancer-causing gene points to the neoplastic nature of AAH and suggests that glandular neoplasms of the lung arise from a background of field cancerization.

Purpose: Malignant pleural mesothelioma is a rare malignancy with major environmental implications regarding passive asbestos exposure. We have conducted an immunohistochemical and functional study to address three questions: (1) What is the representation of CD44 on tumor cells as detected by immunohistochemistry? (2) Do cultured cell lines derived from malignant pleural mesothelioma tissue express the same CD44 phenotypes as the original tumors, and can they serve as a model for the study of CD44 in mesotheliomas? (3) What is the functional status of the CD44 expressed on mesotheliomas, with regard to hyaluronan anchorage?, Materials and Methods: Thirty-seven samples of pleural mesothelioma were obtained from patients entered on phase I/II protocols conducted in the Surgery Branch of the National Cancer Institute since 1991. The diagnosis was confirmed in all 37 patients by means of a battery of immunohistochemical tests for markers differentiating malignant pleural mesothelioma from adenocarcinoma. Tumor-positive lymph nodes and distant metastases were also examined in six of the patients. Cell lines, established from tumor tissue of six of the patients described above, were used in these experiments. Four (H2596, H2461, H2373, H2452) were derived from primary solid tumors and two (HP-1 and HP-3) were derived from effusions., Results: Immunohistochemical staining with a monoclonal antibody (H4C4) that recognizes a constant region of human CD44 demonstrated that 34 (92%) of the malignant pleural mesotheliomas examined expressed CD44 on 50% to 100% of their cells. The extent of CD44 expression was apparently related to histologic subtype with the highest expression seen in epithelioid mesotheliomas and the least in sarcomatoid tumors. Tumor cell lines established from the primary tumors or effusions of six of the malignant pleural mesothelioma patients showed high expression of the hematopoietic form of CD44. Four of these cell lines exhibited strong attachment to hyaluronan in an in vitro attachment assay, indicating that their CD44 was functional with respect to hyaluronan anchorage. Hyaluronan attachment was specific in that it could be abolished by preincubation with epitope-specific anti-CD44 antibodies or soluble substrate or by hyaluronidase treatment of attachment surfaces., Conclusions: We conclude that CD44 is highly expressed on human mesotheliomas, that cell lines adequately represent tumor expression, and that CD44 mediates association with hyaluronan, a major component of pleural fluid.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) occur in a subset of patients with systemic small vessel vasculitis, including patients with Wegener's granulomatosis, microscopic polyangiitis (microscopic polyarteritis), and Churg-Strauss syndrome. Pulmonary disease appears at some time during the course in many patients with ANCA-associated vasculitis. The histologic features of 25 open lung biopsies and two autopsy cases were studied from 27 patients with ANCA. Patients' ages ranged from 8 to 79 years with a mean of 52.6 years. There were 12 females and 15 males. Autoantibodies were characterized as C-ANCA in 13 patients and as P-ANCA in 14 patients. Anti-proteinase 3 antibodies were documented in 12 of 13 patients with C-ANCA. Anti-myeloperoxidase antibodies were documented in all 14 patients with P-ANCA. Vascular lesions were present in 21 patients (78%) and 11 patients (41%) had bronchial lesions. Capillaritis was the most common vascular lesion (17 patients, 63%), and was found with similar frequency in patients with C-ANCA and those with P-ANCA. Extravascular structures were a common site of tissue injury. Airway lesions including bronchiolitis obliterans organizing pneumonia (4 patients, 19%), necrotizing granulomatous inflammation (4 patients, 15%), and non-granulomatous inflammation (3 patients, 11%) were more commonly associated with patients with C-ANCA. Interstitial lesions were found in 20 patients (74%), and included necrotizing granulomatous inflammation (8 patients, 30%), fibrosis (13 patients, 48%), and chronic inflammation (12 patients, 44%). No histologic lesion were found that were specific for C-ANCA or P-ANCA. This series demonstrates the wide variety of pulmonary lesions found in patients with ANCA-associated pulmonary disease, and shows that extravascular structures are a common site of injury in ANCA-associated vasculitis.

Esthesioneuroblastoma (ENB; olfactory neuroblastoma) is a rare, locally aggressive neoplasm of the sinonasal area and anterior cranial fossa. The histogenesis of the lesion is not clearly delineated, and the broad histological spectrum of ENB has confounded the issue. The location, histological features (neuropil, Homer Wright, and olfactory rosettes), and reported immunocytochemical reactions (neuron-specific enolase (NSE) and chromogranin (CHR) positivity) suggest that ENB may be a neural or neuroendocrine neoplasm derived from the olfactory membrane. Recent demonstration in two of three metastatic putative ENB cell lines of the 11;22 chromosomal translocation, seen in Ewing's sarcoma (ES) of bone and peripheral neuroectodermal tumors (PNET) of bone and soft tissue, has led to the conclusion that ENB may be closely related histogenetically to PNET. The overwhelming majority of cases of ES and PNET express the protein product of MIC-2, a gene located on the pseudoautosomal region of the X and Y chromosomes. This protein can be identified immunocytochemically by antibodies 12E7, HBA71, and ON13. We studied the expression of MIC-2 using the 12E7 antibody as well as multiple neural markers in 18 ENB samples obtained from the files of The Johns Hopkins Hospital. The patients ranged in age from 19 to 90 years (mean, 47.5; median, 47) and included five men and 13 women. None of the 18 specimens reacted with antibody 12E7, but 16 were positive for NSE, nine reacted to synaptophysin (SYN), and 13 showed antibodies to chromogranin (CHR). Our studies agree with the previous suggestions that ENB is a primitive neural tumor but fail to support the hypothesis that it is a member of the PNET family.

Placental transmogrification of the lung was described by Chesney in 1978 as an unusual cystic lesion involving a single pulmonary lobe (3). We studied three additional cases with identical clinical and pathologic features. The patients were a 33-year-old woman and men aged 24 and 27 years. Each patient was first seen with respiratory distress; one had repeated pneumothoraces. Radiographically, an enlarging cystic lesion was present in a lower (two) or middle (one) lobe. The lesion had been present for 10 years in one patient. In two patients, mediastinal shift was noted. Lobectomy was curative in all instances. Grossly there was a uni- or paucilocular cyst lined by papillary structures. Microscopically, the papillae contained proliferating blood vessels, lymphoid nodules, smooth muscle, and fat. Sclerotic foci obliterated the vessels in some areas. The growth pattern and topography resembled those of placental villi. Systematic review of the histologic features in other lungs with marked emphysema revealed a spectrum of similar changes and suggested that the lesion in our patients may be a complication of bulla formation and is most likely the clinico-pathologic analog of the "vanishing lung" syndrome (idiopathic giant bullous emphysema).

Small cell carcinomas (SCCs) and peripheral neuroectodermal tumors (PNETs) are two distinct neoplasms that show considerable histologic, immunohistochemical, and clinical overlap, but differ in their therapies and prognoses. In an attempt to further diagnostically distinguish the two, 33 SSCs were analyzed from both pulmonary and extrapulmonary sites for the MIC2 gene product, a cell surface antigen strongly and reliably expressed in PNETs and Ewing's sarcoma (ES). Two of the 33 SCCs stained positively, but the staining was less intense than that seen with PNET and ES. The remaining 31 tumors did not stain. These data indicate that, in combination with a panel of immunohistochemical stains, analysis of neuroendocrine tumors for MIC2 expression may be useful in distinguishing between small cell carcinomas of both pulmonary and extrapulmonary origins and soft tissue PNETs.

Warthin's tumor previously has been thought to occur much more commonly in men than in women and rarely in African Americans. One hundred thirty-two cases of Warthin's tumor treated at The Johns Hopkins Hospital from 1952 to 1992 were retrospectively reviewed. There were 90 (68%) men and 42 (32%) women, with an overall man-to-woman ratio of 2.2:1. The number and percentage of women with Warthin's tumor increased over each consecutive decade: 1952 to 1962, 5 (21%); 1963 to 1972, 6 (29%); 1973 to 1982, 11 (31%); and 1983 to 1992, 20 (39%). A positive smoking history was found in 88% of the men and in 89% of the women with a Warthin's tumor. Eleven (8%) African Americans and 1 (0.75%) Asian American were diagnosed to have a Warthin's tumor. Also, the incidence of African Americans with a Warthin's tumor increased over each decade: 0 (0%), 1 (4.8%), 2 (5.5%), and 8 (16%). This study's results indicate a progressive increase in the occurrence of this tumor in women and in African Americans and a higher overall incidence in African Americans than previously reported.

Background: Primary lung tumors showing features of salivary gland-type neoplasms are extremely rare., Methods: Eight patients with primary lung neoplasms showing light microscopic and immunohistochemical features of salivary gland-type mixed tumors were studied., Results: The patients were six women and two men, ages 35-69 years (mean, 52.5 years). The tumors ranged from 2 to 16 cm in greatest diameter. In two patients the lesions presented as polypoid endobronchial lesions obstructing the lumen; in another two patients the lesions were found in close proximity or in continuity with a bronchus; in three patients, the lesions presented as peripheral parenchymatous nodules unrelated to a bronchus; and in one patient, the relationship to the bronchus could not be determined. Histologically, the lesions were biphasic, showing admixtures in varying proportions of epithelial elements containing a predominant myoepithelial cell population with a stromal component containing an abundant myxoid or focally chondroid matrix. Immunohistochemical studies showed strong positivity of the cells in the epithelial component with low molecular weight keratins (CAM 5.2), and to a lesser extent with broad spectrum keratin, actin, and vimentin antibodies. The cells also showed variable reactivity in the epithelial and nonepithelial elements with S-100 protein and glial fibrillary acidic protein. Six tumors were grossly and histologically benign; in two patients, the tumors were larger, locally invasive, and showed more atypical histologic features. All patients were treated with surgical excision. On follow-up, of the six patients with histologically benign-appearing tumors, one was alive and well 6 years after surgery; another died 4 years after surgery of a second unrelated malignancy; one died during the immediate postoperative period of myocardial infarction; and three have been lost to follow-up. In the two patients with histologically atypical lesions, the tumors recurred and metastasized after 2 and 3 years, respectively, with one of them leading to death caused by widespread metastases and superior vena cava syndrome., Conclusions: Review of the literature and the findings in the current series indicate that salivary gland-type mixed tumors of the lung may present with a spectrum of histologic features and clinical behavior, ranging from benign to frankly malignant, similar to that observed for their salivary gland counterparts. Size of the lesion at the time of presentation, extent of local infiltration, and degree of mitotic activity appear to be the most reliable prognostic features of these tumors.

The subjects of this study are 445 patients with advanced cervical cancer treated by standardized radiation therapy. Upon entry into one of two Gynecologic Oncology Group (GOG) protocols, original pathologic diagnoses and histologic tumor descriptions for each patient were compared with separate evaluations made by a consensus opinion of two GOG pathologists. A review diagnosis using grade, cell type, and the Stendahl scoring system was then made by the first author (R.J.S.) without knowledge of the prior diagnoses. Of the original pathologists' diagnoses, 21% did not include grade or cell type. There was little agreement among the different pathologists as to the use of either specific grade or cell type. Histologic grade, irrespective of the pathologists making the diagnosis, had no correlation to prognosis. The Reagan and Wentz large-cell keratinizing (LCK) cell type, when applied by the author to tumors with any form of squamous keratinization present, identified a group of patients with a poorer prognosis, although not independently of other prognostic factors. The Stendahl scoring system identified a number of patients with both a poorer and better prognosis. This was statistically significant and independent of other risk factors. A major limitation, however, was the number of patients evaluable because of inadequate biopsy material in 23.6% of the study group.

Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) are small blue cell tumors with no reliable positive diagnostic markers. However, Ewing's sarcoma and PNET recently have been shown to strongly express an antigen determined by the MIC2 gene, whereas other blue cell tumors of childhood for the most part do not. MIC2 analysis therefore offers a distinctive addition to the panel of immunohistochemical stains used to differentiate among small blue cell tumors of childhood, since it represents the first positive marker for Ewing's sarcoma and PNET. This study addresses the reliability of MIC2 analysis using the monoclonal antibody 12E7 on tumors registered in the current Intergroup Ewing's Sarcoma protocol. Of 244 tumors, 221 (91%) showed a diffuse strong membranous pattern. The antibody appears to withstand all the fixation variables inherent in a multi-institutional study. We conclude that MIC2 expression is highly reliable as a positive marker for the Ewing's sarcoma/PNET family of tumors when the results are interpreted in the total context with clinical and pathologic parameters.

Salivary gland anlage tumor (SGAT) is a polypoid lesion of the nasopharynx that presents with respiratory distress at birth or within the first few days or weeks of life. Among our nine cases, there was a male predilection (7M:2F). All tumors were in the midline and attached to the posterior pharyngeal wall by a delicate pedicle. The largest tumor measured 3 cm. A biphasic histologic pattern of squamous nests and duct-like structures at the periphery blended into solid, predominantly mesenchymal-appearing nodules centrally. The surrounding submucosal mantle of epithelial structures was consistently immunoreactive for cytokeratin and epithelial membrane antigen, whereas the stromal-like cells of the central nodules showed variable immunopositivity for cytokeratin, vimentin, and muscle-specific actin. Both components were equally reactive for salivary gland amylase. Ultrastructurally, some of the stromal-like cells had features of myoepithelial cells. The histologic and architectural features of SGAT are similar in some respects to the developing salivary gland. It is proposed that the SGAT is a probable hamartoma of minor salivary gland derivation whose origin in the nasopharynx is potentially life-threatening in an infant.

Background: Point mutations in codon 12 of the K-ras protooncogene occur more frequently in lung adenocarcinomas from smokers (30%) than they do in lung adenocarcinomas from nonsmokers (7%), suggesting that smoking is an important factor in the induction of these mutations. The lack of well defined "early" premalignant or in situ glandular neoplasms of the lung, however, has not permitted direct evaluation of the chronology of ras activation in the development of lung adenocarcinomas. To circumvent the need to evaluate precursor lesions, we examined lung adenocarcinomas from former smokers for point mutations in K-ras., Methods: Mutations in codon 12 of K-ras were detected using polymerase chain reaction amplification and mutation-specific oligonucleotide probes. The types and frequencies of mutations found in adenocarcinomas obtained from 57 former smokers were compared to those found in 27 adenocarcinomas from patients who never smoked and to those found in 27 adenocarcinomas from patients who were current smokers., Results: The overall prevalence of K-ras point mutations in lung adenocarcinomas obtained from former smokers (32%) was not different from that seen in adenocarcinomas from patients who were current smokers (30%, P = 0.83), and was greater than that seen in adenocarcinomas from patients who never smoked (7%, P = 0.015). This pattern was independent of the duration of abstinence from smoking. Furthermore, the predominant type of mutation found in tumors from former smokers was a guanine-to-thymine transversion, the specific type of mutation induced by benzo(a)pyrene, one of the chemical carcinogens found in tobacco smoke., Conclusions: These findings support previous findings that suggest that codon 12 of the K-ras oncogene may be a specific target of the mutagenic activity of tobacco smoke, and suggest that DNA alterations at this site can occur early and irreversibly during the development of adenocarcinomas of the lung.

The CT features of 12 patients with bronchiolitis obliterans organizing pneumonia (BOOP) were reviewed and correlated with clinical history, histologic specimens, and chest radiography. From our series, a spectrum of CT findings of parenchymal lung involvement in BOOP emerged. Focal nodular or mass-like opacities were found in 42% (5 of 12). Areas of consolidation resembling pneumonia were seen in 33% (4 of 12). Peripheral subpleural reticular opacities were identified in 25% (3 of 12). Patchy ground glass infiltrates were seen in 8% (1 of 12). One patient demonstrated a mixed pattern consisting of nodular opacities and areas of pneumonic consolidation. In 4 of the 5 cases demonstrating the nodular form of BOOP either a feeding vessel or bronchus sign could be identified. This feature consisted of a pulmonary vessel leading to a nodular opacity or an air bronchogram entering into a nodular opacity. Correlation of the CT findings of BOOP with histologic specimens showed nodular opacities and areas of consolidation to be associated with classic pathologic features of BOOP including bronchiolar plugs of granulation tissue and surrounding organizing pneumonia. Cases demonstrating peripheral subpleural reticular opacities showed, in addition to pathologic evidence of BOOP, other features such as interstitial disease and fibrosis.

Background: Nineteen patients with Ewing sarcoma of bone, each younger than 3 years of age at the time of initial presentation, are reported. These children represent an unusually young age group for documented Ewing sarcoma and represent 2.6% of all patients registered in the Intergroup Ewing's Sarcoma Study (IESS)., Methods: The diagnosis was made on combined histologic, clinical, and radiographic grounds and was supported by immunohistochemistry in nine patients and electron microscopic study in eight patients. Immunohistochemical studies showed no staining against neuro-specific enolase, chromogranin, or S-100 in any patients, and in only one in nine patients were results of such studies focally positive against Leu-7., Results: The most marked clinical variation between this group of infants and the general IESS patient population was a striking predominance of female patients in the younger age group (P < 0.001). There was a trend toward more rib, pelvis, and proximal long bone tumors in the infants and toddlers. The overall survival rate of the infants was 56%, almost identical to the survival rates of the older children. All of the infants who died of disease did so within 4 years. Extended follow-up as long as 9.9 years has found no late deaths attributable to tumor. The most significant late complications of therapy included cardiotoxicity with cerebral embolization from the heart and a short lower limb secondary to radiation therapy., Conclusions: Ewing sarcoma must be considered in the differential diagnosis of small cell, round cell, and blue cell tumors in bone, even in infants and toddlers.

The authors reviewed the radiographic and computed tomographic (CT) appearances of abnormal air-filled spaces in the lung that develop in response to lung diseases. The major types of these lung diseases include infection, vessel-related or vascular-embolic disorders, bronchiectasis, emphysema, pulmonary fibrosis, adult respiratory distress syndrome and air-block diseases, and unusual disorders of the lung (such as Langerhans cell histiocytosis, Klippel-Trenaunay syndrome, and tracheolaryngeal papillomatosis). After studying the CT scans, conventional radiographs, and medical records of 150 patients with various abnormal air-filled spaces in their lungs and 300 lung specimens and the corresponding high-resolution CT scans, the authors concluded that mechanisms of air-space formation fall into five basic categories: (a) vascular occlusion or ischemic necrosis, (b) dilatation of the bronchi, (c) disruption of the elastic fiber network of the lung, (d) remodeling of the lung architecture and retractile fibrosis, and (e) multifactorial or unknown mechanisms.

Acquired lobar "emphysema" (overinflation) (ALE) is an increasingly recognized complication of advanced bronchopulmonary dysplasia (BPD). To refine current concepts regarding patient management and pathogenesis, we examined clinical and pathological features of six infants with ALE who did not have obstructing intraluminal lesions and who underwent lobectomy after failing nonoperative management. All had severe neonatal respiratory distress and required prolonged ventilatory support (average, 2 months) with peak inspiratory pressures greater than 30 mm Hg and 100% oxygen. ALE developed between 3 weeks and 20 months of age (median, 5 months), with lobar hyperinflation, atelectasis, and mediastinal shift. Selective bronchial intubation provided only transient benefit. Videobronchoscopy demonstrated no intraluminal obstructing lesions in five patients. In one child, ALE became clinically apparent only after laser excision of an endobronchial cicatrix. All infants had bronchomalacia with the involved lobar bronchus being most severely affected. Ventilation-perfusion scans demonstrated severe impairment of both ventilation and perfusion in the involved lobes. The decision to perform lobectomy was based on clinical parameters and failure of non-operative management. After lobectomy, all children dramatically improved. However, only three of six were alive 2 to 3 years later; one infant died of unrelated causes at 6 weeks; and two died of progressive respiratory insufficiency 13 and 24 months postlobectomy. Microscopic evaluation of the lung demonstrated findings of late-stage BPD with peribronchial and interstitial fibrosis, parenchymal overinflation, and alveolar septal disruption.(ABSTRACT TRUNCATED AT 250 WORDS)

The identification of adenovirus in tissue can be difficult. In situ hybridization for adenovirus nucleic acids may aid in the demonstration of adenovirus infections. To develop a probe against adenovirus, a 978 bp fragment of DNA containing the VA-I, VA-II, and a portion of the L-1 regions of the adenovirus type 2 genome was cloned into the SK+ vector. These regions were selected because they are generally conserved among adenoviruses and are abundantly transcribed during the lytic cycle. Sense and antisense tritium or Digoxigenin-labeled riboprobes were generated using in vitro transcription and applied to formalin-fixed paraffin-embedded sections of HeLa cells infected with adenovirus type 2. Extensive in situ hybridization of the antisense riboprobe to HeLa cells with cytopathic changes was found. The number of cells to which the probe hybridized decreased proportionately with dilution of infected with noninfected cells. The control sense riboprobe showed only scattered breakthrough hybridization and in these cells hybridization was mainly located in the nucleus. Northern blot analysis of RNA from infected HeLa cells confirmed the in situ hybridization results. No hybridization was detected when cultured cells infected with herpes simplex virus, Epstein-Barr virus, cytomegalovirus, or human immunodeficiency virus were examined. Specific hybridization was detected in tissues obtained at autopsy from four patients with culture proven adenovirus infection. These observations suggest that this probe is useful in the diagnosis of adenovirus in formalin-fixed paraffin-embedded material.

In a previous study, we found tumor-associated tissue eosinophilia (TATE) to be a favorable prognostic indicator for squamous cell carcinoma of the head and neck (p less than 0.05). The present expanded study was undertaken to confirm this finding. The pathology of 120 head and neck tumors was examined for histologic features suggestive of poor prognosis. Ten descriptive histopathologic variables, including two malignancy grading scales, were correlated with DNA flow cytometric data and clinical outcome. No correlation was found between the malignancy grading scales and DNA flow cytometric data or clinical outcome. The present expanded study confirmed with greater statistical significance (p less than 0.001) that high-grade TATE is a favorable prognostic indicator for head and neck cancer. Furthermore, high-grade TATE was associated with the absence of distant metastasis (p less than 0.05). Using a stepwise logistic regression analysis of the clinicopathologic variables in the study, high-grade TATE was the most influential variable affecting clinical outcome, followed by border, stage, and perineural invasion. We conclude that the grade of TATE is a significant prognostic indicator for head and neck cancer. The significance and possible role of the eosinophil in the tumor-host interaction are discussed.

A total of 59 eligible patients with localized Ewing's sarcoma of the pelvic and sacral bones were entered into a multimodal Intergroup Ewing's Sarcoma Study (IESS-II) (1978 to 1982) and compared with a historical control series of 68 patients entered into an earlier multimodal Intergroup Ewing's Sarcoma Study (IESS-I) (1973 to 1978). High-dose intermittent multiagent chemotherapy (vincristine, cyclophosphamide, Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and dactinomycin) was given to all patients for 6 weeks before and for 70 weeks following local therapy. All patients who had a tumor biopsy or incomplete resection performed received a dose of 55 Gy to the tumor bed. With a median follow-up time of 5.5 years, two of 59 patients (3%) had a local recurrence, five patients (8%) had a local recurrence and metastases, and 17 patients (29%) developed metastases only. There was significant statistical evidence of an advantage in relapse-free survival (RFS) and survival (S) for patients on IESS-II versus IESS-I, P = .006 and P = .002, respectively. At 5 years, the comparison between IESS-II versus IESS-I was 55% versus 23% for RFS and 63% versus 35% for S.

Previous studies compared the diagnostic value of pleural fluid cytology versus pleural biopsy. No direct comparison of the procedures including data from a combination of all diagnostic tests performed on each specimen appears to have been done. A total of 385 patients with concurrent pleural biopsy and fluid examination were identified from 1973 to 1986. Clinical records, histologic and cytologic preparations, and microbiologic and chemical data were reviewed. A total of 109 patients had a final diagnosis of malignancy. Cytology was diagnostic in 71% and "suggestive" in an additional 8%. There were no false-positives but, in two patients with pulmonary infarcts, the effusions were reported as "suspicious." Pleural biopsy was positive in 45%, including three cases with negative cytology. In 71 patients with tuberculosis, the pleural biopsy was diagnostic in 49%. A cytologic picture suggesting the diagnosis was present in 68%. Cultures of the biopsy yielded Mycobacterium tuberculosis in 23% of cases, while pleural fluid was positive in 30%. In six cases, the only confirmatory evidence of tuberculosis was pleural culture. In 205 patients, none of the above procedures provided specific diagnoses. A combination of biopsy and fluid examinations improves the diagnostic sensitivity. Pleural biopsy increases the rate of complications and did lead to fatal hemothorax in two patients. These results support the superiority of pleural fluid examination in the diagnosis of malignancy. In addition, they demonstrate the value of pleural fluid examination in the diagnosis of tuberculosis.

The biological behavior of pleomorphic adenomas (mixed tumors) of salivary gland origin is complex. Tumors with benign histologic features may exhibit recurrence and locally aggressive behavior especially after incomplete excision. A small percentage of pleomorphic adenomas have obvious malignant components in epithelial or in both epithelial and mesenchymal components and can metastasize. There are also rare case reports which appear to document typical pleomorphic adenomas of salivary gland with histologically identical visceral and lymph node metastases. Recently myoepithelial cell proliferation has been identified as a possible predictor of aggressive clinical behavior in otherwise histologically benign pleomorphic adenomas. We report such a parotid gland lesion with local recurrence and retroperitoneal spread. DNA-flow cytometry of cells from the paraffin-embedded primary and metastasis showed similar aneuploid populations. Aneuploidy appeared to reflect the malignant potential of this particular pleomorphic adenoma and suggests that DNA-flow cytometry of salivary gland tumors may yield important prognostic information.

A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).

We studied eight clear cell tumors of the lung (CCTL) to better define their clinical, immunohistochemical, and ultrastructural features, and to clarify their distinction from other neoplasms, particularly metastatic renal cell carcinoma. Patients ranged in age from 31 to 67 years (mean, 51 years). Seven patients had clinically benign, asymptomatic lesions measuring less than 2 cm in diameter that were devoid of necrosis. The eighth patient had a symptomatic, partially necrotic CCTL 4.5 cm in diameter that metastasized to the liver and peritoneum; the patient died of tumor 17 years after diagnosis. Ultrastructural study of seven CCTL showed interdigitating cell processes (all cases), primitive cell junctions (five of seven cases), intracytoplasmic glycogen (all cases), and rare dense core granules (two of seven cases). Immunohistochemically, paraffin-embedded sections from all eight CCTL were negative for cytokeratin (CK), epithelial membrane antigen (EMA), chromogranin, and vimentin. Focal staining was seen for S-100 protein (three of eight cases), neuron-specific enolase (three cases), synaptophysin (one case), and Leu 7 (one case). Although these findings suggest that at least some CCTL exhibit neuroendocrine differentiation, the tumor's histogenesis remains uncertain. Of more practical importance, the combined absence of CK, EMA, and vimentin in formalin-fixed, paraffin-embedded CCTL virtually precludes confusion with renal cell carcinoma. Although traditionally considered benign, CCTL larger than 2 cm that are symptomatic, and focally necrotic should be regarded as potentially malignant neoplasms.