Well-differentiated papillary mesothelioma.

Well-differentiated papillary mesothelioma is an unusual variant of epithelial mesothelioma considered to be of low malignant potential. The majority of previously reported cases developed in the peritoneum of young women without a history of asbestos exposure. The authors report 14 cases of well-differentiated papillary mesothelioma, seven of which originated in the pleura, six in the peritoneum, and one in the tunica vaginalis. Eleven of the patients were male and three were female, with an average age at presentation of 58 years (range 32-82 years). Six of the patients had a quantifiable history of asbestos exposure. Of the nine cases with complete follow-up, six had clinically indolent disease, one showed resolution after adjuvant chemotherapy, one pursued an aggressive course, and one died of other causes. These findings indicate that well-differentiated papillary mesothelioma is a rare variant of mesothelioma with a variable clinical prognosis that is etiologically related to asbestos exposure in some cases.

Malignant mesothelioma from neighborhood exposure to anthophyllite asbestos.

BACKGROUND: Anthophyllite asbestos has been reported to cause asbestosis, lung cancer, mesothelioma, and pleural plaques in occupationally exposed workers. Anthophyllite has also been associated with pleural plaques in Finland and Japan among those who live near mines and mills and have neighborhood or environmental exposure. METHODS: We evaluated a 38-year-old patient with pleural mesothelioma who lived, attended school, and delivered newspapers near a manufacturing facility that used exclusively anthophyllite asbestos fiber from ages 8-17 years. He had no work exposure to asbestos. RESULTS: The pleural mesothelioma was an epithelial type with tubulopapillary structures and was treated with an extrapleural pneumonectomy followed by radiation therapy. The malignant cells were positive by immunohistochemistry for cytokeratin but negative for carcinoembryonic antigen, S100, B72.3, and leu M1 antigen. Anthophyllite fibers were > 5 microm in length in lung tissue compared to 3 microm from a general population study. CONCLUSIONS: Anthophyllite asbestos has been associated with neighborhood environmental exposure and pleural plaques; we now report a neighborhood exposure and pleural mesothelioma.

Pulmonary atypical carcinoid: predictors of survival in 106 cases.

Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm(2) of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (P = .003) and a tumor size of 3.5 cm or greater (P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (P =.002), pleomorphism (P = .018), and aerogenous spread (P =.007). Histologically favorable features by univariate analysis were the presence of palisading (P = .008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P = .022) patterns. Female gender showed a trend toward a poorer prognosis (P =.085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (P<.001), a tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012) to be the only negative independent predictors of prognosis and the presence of rosettes (P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (P<.001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven.

Asbestos in extrapulmonary sites: omentum and mesentery.

STUDY OBJECTIVES: Asbestos fibers have not been reported in tissues from the peritoneal cavity. Therefore, omentum, mesentery, and lung tissues from 20 individuals in whom mesothelioma was diagnosed were analyzed for asbestos bodies and asbestos fibers. DESIGN: Tissue was digested and prepared filters were analyzed by light microscopy and analytical transmission electron microscopy. RESULTS: Asbestos bodies were found in the lungs of 18 individuals, mesentery samples from 5, and omentum samples from 2. Uncoated asbestos fibers were found in lungs of 19 patients, 17 of whom had fibers in at least one extrapulmonary site. The most common asbestos in the omentum and mesentery was amosite. Several features of asbestos found in lung influenced the likelihood of amphibole fibers being found in the omentum or mesentery. Lung features included total amphibole fiber burden, length, aspect ratio, and ferruginous body burden. An increased total ferruginous body burden was strongly associated with increased likelihood of detecting amphiboles in the omentum (p < 0. 05). CONCLUSION: Asbestos fibers reach areas in the peritoneal cavity where some mesotheliomas develop. This study suggests their presence can be predicted based on concentrations and characteristics of fiber burdens in lung tissue.

Ultrastructural features of diffuse malignant mesotheliomas.

The distinction of malignant mesothelioma from tumors metastatic to the serosal membranes can often be made based on the results of histochemical or immunohistochemical studies. However, in some cases, these techniques are inadequate to make a firm diagnosis. In these instances, electron microscopic studies with the observation of a constellation of characteristic ultrastructural findings may permit an unequivocal diagnosis of mesothelioma.

Metastatic adenocarcinoma of unknown primary origin.

Adenocarcinomas account for up to 60% of all metastatic neoplasms of unknown primary origin. In general, adenocarcinomas are the most difficult metastatic tumor to accurately identify the primary site. Some metastatic adenocarcinomas have distinctive histological features that allow for their site determination (eg, colonic adenocarcinoma, bronchioloalveolar cell carcinoma), although the majority of metastatic adenocarcinomas have histological features that are not distinctive enough to allow for a specific diagnosis of their origin. For this reason, electron microscopy and immunohistochemistry have been used to help identify the exact type (origin) of metastatic adenocarcinomas. Relatively specific ultrastructural features used to diagnose metastatic adenocarcinomas of unknown primary origin include tubular myelin, intranuclear surfactant apoprotein tubular inclusions, Clara cell granules, uniform short microvilli with filamentous cores and core rootlets, Langerhans cells associated with neoplastic cells, cytoplasmic hyaline globules, lipid droplets, glycogen, and cytoplasmic crystals. Only a few of these ultrastructural features are absolutely specific. Relatively specific immunohistochemical tests used to diagnose metastatic adenocarcinomas of unknown primary origin include prostate-specific antigen, thyroglobulin, estrogen and progesterone receptor proteins, thyroid transcription factor-I, and surfactant apoproteins. Of these, prostate-specific antigen and thyroglobulin are the most specific. The purpose of this article is to discuss the use of electron microscopy and immunohistochemistry in the site-specific diagnosis of metastatic adenocarcinomas of unknown primary origin.

Lack of asbestos contamination of paraffin.

OBJECTIVE: To investigate possible asbestos contamination of paraffin and migration by asbestos fibers during the tissue-embedding process. DESIGN: Three sample categories were included in the study: (1) commercially available paraffin samples; (2) procedural control samples, which were prepared by processing the paraffin through the use of standard solvents and instruments; and (3) samples taken from areas adjacent to embedded tissue and evaluated for migration of asbestos from the tissue into the surrounding paraffin. The analysis of collected material from all samples was performed with analytical transmission electron microscopy. RESULTS: Only one extremely small tremolite fiber was found in any of the commercially available samples of paraffin. No asbestos fibers were found either in the procedural control samples or in the samples taken adjacent to the embedded lung tissue. CONCLUSIONS: First, it was extremely unlikely that any of the commercial paraffin samples would have skewed data due to embedded tissue. Second, the processing and instrumentation was not found to contribute asbestos material to the paraffin during the preparations. Finally, embedded tissue that contained high numbers of fibers, both uncoated fibers and asbestos bodies, did not contribute asbestos to the adjacent paraffin.

Reproducibility of the histologic diagnosis of pneumonia among a panel of four pathologists: analysis of a gold standard.

STUDY OBJECTIVE: To establish a histologic diagnosis of pneumonia by consensus of a panel of pathologists, to test the interobserver and intraobserver variation in the histologic diagnosis of pneumonia, to compare the diagnostic accuracy of diagnosing pneumonia with and without preselected histologic criteria, and to establish more specific histologic criteria for the diagnosis of pneumonia. METHODS: The study group consisted of 39 patients who died after a mean of 14 days of mechanical ventilation. A postmortem open lung biopsy was performed on all patients. The tissue was reviewed independently by four pathologists who categorized the slides from each patient as showing or not showing pneumonia. Interobserver variation was calculated using the kappa statistic. Six months following the initial evaluation, the same slides were resubmitted to one of the pathologists for reevaluation to look for intraobserver error. Finally, the slides were reviewed and categorized by the criteria of Johanson et al into no pneumonia, mild, moderate, or severe bronchopneumonia. A comparison was made of the patients selected as demonstrating histologic pneumonia by each of the examinations. RESULTS: The reliability coefficient (kappa) measuring agreement among the four pathologists was good at 0.916. However, the prevalence of pneumonia as determined by each of the four pathologists varied; pathologist A, 15 of 39 (38%); pathologist B, 12 of 39 (31%); pathologist C, 9 of 39 (23%); and pathologist D, 7 of 39 (18%). Resubmitting the same slides to the same pathologist 6 months later resulted in reclassification of 2 of 39 patients. Using the histologic criteria of Johanson and colleagues, 14 patients were selected as having pneumonia compared with only nine patients selected by consensus of three of four pathologists. CONCLUSIONS: Recognition of histologic pneumonia varies among pathologists. The preselected criteria of Johanson and colleagues detected histologic pneumonia in eight of nine patients picked by consensus of pathologists, but six additional patients classified as "no histologic pneumonia" by the consensus of pathologists were judged to have histologic pneumonia by these criteria. The results established the necessity for standardization of histologic criteria for studies using biopsy as the gold standard for bacterial pneumonia. An atlas showing the criteria used in our selection was developed.

Analysis of asbestos fiber burden in lung tissue from mesothelioma patients.

Mesothelioma is a rare neoplasm that occurs most frequently in individuals with previous asbestos exposure. Differences for risk of development of asbestos-related mesothelioma and lung cancer have been attributed to the various types of asbestos, as well as to the dimension of the inhaled fibers. In the present study, 55 individuals with the pathological diagnosis of mesothelioma were evaluated as to ferruginous body and fiber content in lung tissue. The procedures used in the analysis included tissue digestion and analysis of the collected material for ferruginous bodies by light microscopy and for uncoated fibers by analytical transmission electron microscopy. Forty-six of the samples had ferruginous body concentrations of over 1000/per gram dry weight of lung tissue. The majority of the cores of these ferruginous bodies were amosite. Likewise, the most common uncoated asbestos fiber in the tissue was amosite. Only a small percentage of each type of asbestos would have been visible by light microscopy or even potentially by electron microscopy if the magnification was not sufficient to detect those with thin (< 0.2 micron) diameters. The consistent finding in most of the cases was a considerable presence of asbestos, often of mixed types.

Malignant vascular tumors of the serous membranes mimicking mesothelioma. A report of 14 cases.

Malignant endothelial neoplasms involving the serous membranes are rare, and only a few cases have been documented. We report 14 patients with epithelioid hemangioendothelioma (EHE) or epithelioid angiosarcoma (EA) diffusely involving the pleural, peritoneal, or pericardial cavities, resulting in a picture closely resembling mesothelioma. The mean age at diagnosis was 52 (range, 34-85). The patients included two women and one man with peritoneal tumors, eight men with pleural tumors, and three men with pericardial tumors. A shared histological appearance was a diffuse sheet-like and clustered pattern of tumor growth with variable degrees of vascular differentiation. A tubulopapillary growth pattern, often seen in mesothelioma, was prominent in four cases. Nine cases showed a variable number of spindle cells, some neoplastic, others reactive, focally producing a biphasic growth pattern, further suggesting mesothelioma. Initial interpretations included mesothelioma, adenocarcinoma, and, in one case with prominent spindle-cell components, leiomyosarcoma. Immunohistochemically, strong vimentin staining and negative or weak to moderate cytokeratin staining were observed in all 14 cases. The tumor cells coexpressed at least two of the four endothelial markers used in the study (CD31, CD34, von Willebrand factor, and Ulex europaeus agglutinin-I [UEA-I)]. Detection of abortive vessel formation was facilitated by staining for collagen type IV. Markers of mesothelial, epithelial, muscular, and neuronal differentiation were all negative in the subset of cases studied. As a control group, 39 mesotheliomas and more than 60 adenocarcinomas of various origins were studied using the same antibody panel. This group revealed strong keratin staining, moderate or negative vimentin staining, and no expression of any of the endothelial-lineage markers, with the exception of positive staining for UEA-I in occasional adenocarcinomas. Clinically, these endothelial tumors were highly aggressive; 12 patients presented with disseminated disease, and most died within months of the initial presentation. These findings indicate that, although uncommon, EHE/EA should be included in the differential diagnosis of serous membrane neoplasms with histological and clinical features of malignant mesothelioma. The diagnosis of an endothelial neoplasm can be suspected by the presence of abortive vessel formation and by the strong expression of vimentin, with absent or low-level expression of cytokeratin. The demonstration of immunoreactivity for two or more endothelial-associated markers is essential in confirming the diagnosis.

Mucin-positive epithelial mesotheliomas: a histochemical, immunohistochemical, and ultrastructural comparison with mucin-producing pulmonary adenocarcinomas.

Pathologists routinely use histochemistry, immunohistochemistry, and electron microscopy to differentiate epithelial mesotheliomas from pulmonary adenocarcinomas. Epithelial mesotheliomas are usually mucicarmine-, PAS-diastase, and carcinoembryonic antigen-negative, whereas about 60-75% of pulmonary adenocarcinomas are mucicarmine- and PAS-diastase-positive, and about 90% express polyclonal carcinoembryonic antigen. During a pathologic evaluation of pleural neoplasms between 1975 and 1990, 10 epithelial mesotheliomas were identified that were mucicarmine- and in some instances PAS-diastase-positive (diagnosis of mesothelioma confirmed by ultrastructural examination), with four mesotheliomas focally expressing carcinoembryonic antigen. The mucicarmine, PAS-diastase, and carcinoembryonic antigen staining were usually eradicated or reduced in intensity by pretreatment of the tissue sections with hyaluronidase, suggesting that hyaluronic acid was responsible for the positive mucin reactions. In three cases the epithelial mesotheliomas showed focal regions of mucicarmine, PAS-d-, and Alcian blue-hyaluronidase-resistant staining. In contrast, 10 mucicarmine-, PAS-diastase-, Alcian blue-, and carcinoembryonic antigen-positive pulmonary adenocarcinomas were not affected by hyaluronidase pretreatment of the tissue. Besides the usual ultrastructural features of well- to moderately well-differentiated epithelial mesotheliomas, the mucin-positive epithelial mesotheliomas often showed medium-electron-dense secretory material covering the microvilli, aggregates of medium electron-dense material in association with the microvilli, producing an ultrastructural morphology that has been observed only in epithelial mesotheliomas.

Granulomatous vasculitis.

Vasculitides are classified by the size of the vessel involved and by the nature of the inflammatory process. Pulmonary granulomatous vasculitis encompasses several entities that are in general characterized by granulomatous inflammation, extensive necrosis, and a variegated cellular infiltrate. Wegener's granulomatosis is a prototype of granulomatous vasculitis and is a disease of unknown etiology that often involves the upper respiratory tract, the lower respiratory tract, and the kidneys. Some of the entities initially classified as pulmonary granulomatous vasculitis have subsequently been found to represent other entities; specifically, lymphomas (lymphomatoid granulomatosis) and part of the spectrum of bronchopulmonary aspergillosis (bronchocentric granulomatosis). In addition, it is recognized that certain infectious conditions, specifically the necrotizing inflammatory processes caused by fungi and mycobacteria, can show granulomatous vasculitis and can be confused with Wegener's granulomatosis. The mechanism by which pulmonary granulomatous vasculitis occurs is not well understood, although is thought to have an immunologic basis. A great deal of data has been accumulated concerning antineutrophil cytoplasmic autoantibodies and the role that these antibodies might play in the development of these conditions.

Quantitative comparison of asbestos and talc bodies in an individual with mixed exposure.

Tissue from an individual with a history of exposure to asbestos and other dust was referred for particulate analysis. The digested material was reviewed by light microscopy to establish the numbers of ferruginous bodies per gram of tissue. Typical asbestos bodies were found at levels consistent with occupational exposure. A second type of elongated ferruginous body was formed on a thicker transparent core which suggested the minerals were sheet silicates. The number of ferruginous bodies with nonasbestos cores was over four times the number of asbestos cored ferruginous bodies. Electron microscopy was used to confirm the core composition of both populations and also to establish the levels of uncoated fibers. The nonasbestos ferruginous bodies were predominantly formed on talc.

The pathology of benign and malignant pleural disease.

A wide spectrum of diseases involve the pleura. Many of these occur as complications of other disease processes, such as infectious pneumonitis, although a pleural effusion or a pleuritis also can be the primary manifestation of a disease. The most common primary neoplasm involving the pleura is a mesothelioma. It is of interest because of its causation by asbestos and because of its wide spectrum of histologic variability. Metastatic tumors also frequently involve the pleura but may not necessarily be biopsied. One type of metastatic neoplasm involving the pleura that may be extremely difficult to differentiate from an epithelial mesothelioma is a pseudomesotheliomatous carcinoma. In most instances, malignant neoplasms can be diagnosed accurately and distinguished from one another by ancillary techniques, such as immunohistochemistry and electron microscopy.

Localized inflammatory pulmonary disease in subjects occupationally exposed to asbestos.

In reviewing pathology materials from patients occupationally exposed to asbestos, we identified eight patients with either localized nodules in their lung or unusual pathologic changes. The chest radiographs of six patients showed isolated parenchymal nodules thought to represent primary neoplasms. In three cases, pathologic examination of these nodules showed intraluminal fibrosis and inflammation of the distal airways, a pattern of change frequently referred to as "bronchiolitis obliterans organizing pneumonitis." In each instance, asbestos bodies were present in association with the fibroinflammatory tissue. In one case, the nodule showed a desquamative interstitial pneumonitis type pattern, and asbestos bodies were present admixed with the alveolar macrophages and occasionally within their cytoplasm. In one case, the nodule was composed of nonspecific inflammation and fibrosis with focal bronchiolitis obliterans and frequent asbestos bodies scattered throughout the area of inflammation and fibrosis, and in another case, necrotizing inflammation association with Aspergillus fungal organisms was identified. Granulomatous inflammation was the dominant pulmonary pathologic change in one patient, and the other patient's lung biopsy specimen showed a diffuse lymphocyte-plasma cell interstitial pneumonitis. The cases reported suggest that asbestos may cause localized lesions in the lung that clinically and radiographically are misinterpreted as cancer and that pathologically show inflammation and fibrosis of the distal airways. In addition, our observations suggest that asbestos may cause granulomatous inflammation, a desquamative interstitial type pneumonitis, and a lymphocytic interstitial pneumonitis type pattern. Our conclusions that asbestos may cause these pathologic changes are supported by case reports in the clinical and pathologic literature, clinicopathologic studies, and by experimental studies.

Controversies and uncertainties concerning the pathologic features and pathologic diagnosis of asbestosis.

Asbestos is a fibrous silicate mineral that has been known for decades to cause pulmonary scarring, referred to as asbestosis. The simplest definition of asbestosis is the presence of pulmonary fibrosis as a result of accumulation of airborne asbestos in the lungs. Not infrequently, the terms "asbestos" and "asbestosis" are used incorrectly (interchangeably) by medical personnel, and sometimes pleural fibrosis caused by asbestos is incorrectly referred to as asbestosis. The earliest lesion of asbestosis, as defined by the CAP-NIOSH Committee is peribronchiolar fibrosis, although controversy exists as to how specific this lesion is with respect to causation by asbestos, and whether this lesion progresses to grade 4 asbestosis. In addition, some authorities in the field suggest that the term "asbestosis" be used only for diffuse interstitial fibrosis. The mechanism by which asbestos causes interstitial fibrosis remains poorly understood, and in recent years, pathologic changes such as organizing pneumonitis-bronchiolitis obliterans, and lymphocytic interstitial pneumonitis, have been described in persons occupationally exposed to asbestos, suggesting that the pulmonary lesions caused by asbestos represent a wider spectrum than had previously been appreciated. By defining areas of uncertainty, medical science will eventually clarify areas of disagreement concerning asbestosis which will eventually lead to a better understanding of this disease.

Cutaneous T-cell lymphoma. Evaluation of pretreatment skin biopsy specimens by a panel of pathologists.

BACKGROUND AND DESIGN: Cutaneous T-cell lymphoma (CTCL) frequently presents a difficult diagnostic challenge for the clinician and pathologist. To assess the diagnostic validity of conventional histopathologic findings in CTCL, pretreatment skin biopsy specimens were scored prospectively and independently by a panel of five to seven dermatopathologists and pathologists. Scores were compared with disease outcome. Repeatability of these scores was examined among observers and for the same observer. The study population consisted of 165 subjects, initially referred for suspected mycosis fungoides or Sézary syndrome. Ninety-two patients determined to have CTCL have been followed up for 6.3 +/- 3.5 years (mean +/- SD) and are categorized according to disease outcome: 22 are in complete remission, 35 are in partial remission, three have progressive lymphoma, 15 died of disease, 13 died of other causes, and four were unavailable for follow-up. Seventy-three patients determined not to have CTCL have been followed up for 5.3 +/- 3.2 years without subsequent clinicopathologic evidence of CTCL. These longitudinal data allowed comparisons of the clinical course with the original histologic interpretations. RESULTS: Data showed that the histologic scores rendered by the pathology panel did not correlate with stage of disease and were not an accurate predictor of clinical outcome, because the histologic ratings did not discriminate between patients who eventually had complete remission and those with either progressive lymphoma or who have died of disease. The results also substantiate the low inherent reliability of histopathologic findings in CTCL. Large differences existed among pathologists in scoring the study populations and repeated reading of selected cases by the same panel member resulted in a change of diagnosis 15% of the time. Among the histologic features evaluated, only the presence of mitoses in the infiltrating cells showed a trend toward an unfavorable outcome. CONCLUSION: Pathologic diagnosis in the CTCL disease spectrum should be interpreted with caution and then only in conjunction with the clinical evaluation. As expected, the use of an average value from a panel of readers added a component of stability to the histologic interpretation.

Amphicrine carcinoma of the uterine cervix.

A case of amphicrine carcinoma of the uterine cervix is described in a 27-year-old woman whose initial cervical biopsy specimen showed small cell undifferentiated neuroendocrine carcinoma. Despite an initial complete clinical response to VP-16 and carboplatin, residual tumor was noted in the cervical cone biopsy specimen and she was treated with external-beam irradiation and cesium implants. The neoplasm subsequently metastasized and required additional VP-16 and carboplatin for control. The pathologic features and biologic behavior of this unusual type of neuroendocrine neoplasm are described in this case report.