Small airways diseases.

The histopathology of the small airways is frequently quite subtle, even in cases with clinically severe disease. In the present paper, we will demonstrate some recognizable straightforward pathological changes in the small airways, and also provide a list of clinico-pathological conditions that should be considered when each is encountered. In the second part of the paper, we will briefly overview some general histological patterns of lesions and specific diseases that may involve the small airways. The basic lesions will be subdivided into inflammatory (acute, chronic, granulomatous, with or without necrosis), proliferative (epithelial or mesenchymal), and remodeling reactions. Inflammatory and proliferative reactions may lead to a the third category of remodeling reactions, characterized by a variety of distortions of normal bronchiolar architecture, including occlusion, constriction, dilatation (with or without mucostasis), tortuosity and nodularity. In addition to this schematic distinction, it is important to recognize that these lesions are frequently combined together and evolve with one another. Each of the 3 reaction patterns may be exquisitely bronchiolar, or may extend in the surrounding parenchyma. In this case, it is important to distinguish between lesions that extend from the bronchiole to the parenchyma or vice versa (such as in organizing pneumonia patterns, where the main lesion is in the parenchyma). As most of these lesions are part of a dynamic process, it is important to recognize that a single causative agent may produce distinct pathologic features at different times in the natural history of the disease. In addition, the same clinical disease may result in a variety of pathologic lesions. Accordingly, there may be not always be an unequivocal relationship between the clinical disease/condition and specific histopathologic lesions in the small airways.

My approach to interstitial lung disease using clinical, radiological and histopathological patterns.

The complex world of interstitial lung disease presents nearly insurmountable challenges to the general surgical pathologist faced with a lung biopsy in this setting. The pathology is often inflammatory and always requires clinical and radiological context for a relevant and clinically useful histopathological diagnosis. A pattern-based histopathological approach to interstitial lung disease provides a "map" for the general pathologist to navigate this area successfully, especially so when used with aid of the clinical and radiological patterns of presentation.

Organizing pneumonia and lymphoplasmacytic inflammation predict treatment response in idiopathic pulmonary fibrosis.

AIMS: To identify individual histopathological features within usual interstitial pneumonia pattern that predict responsiveness to immunosuppressive therapy. METHODS AND RESULTS: Fifty-six retrospectively confirmed usual interstitial pneumonia pattern surgical lung biopsy specimens from subjects with idiopathic pulmonary fibrosis treated with corticosteroid and cytotoxic therapy were included. Eleven prospectively defined histopathological features were evaluated by two expert pulmonary pathologists. Regression analysis identified predictors of response to therapy, as defined by the change in percent predicted forced vital capacity over 6 months. Additional end-points were change in dyspnoea score over 6 months, and survival time. Improvement in percent predicted forced vital capacity was associated with lymphoplasmacytic inflammation, while worsening of percent predicted forced vital capacity was associated with the presence of organizing pneumonia and fibroblast foci. Worsening dyspnoea was associated with fibroblast foci. Survival time was associated with age and baseline percent predicted forced vital capacity, but not with any individual histopathological feature. CONCLUSIONS: In pathological usual interstitial pneumonia pattern, the presence of lymphoplasmacytic inflammation predicts responsiveness to immunomodulatory therapy, while airspace organization predicts lack of response.

Assessment of bone biopsy needles for sample size, specimen quality and ease of use.

OBJECTIVE: To assess whether there are significant differences in ease of use and quality of samples among several bone biopsy needles currently available. DESIGN: Eight commonly used, commercially available bone biopsy needles of different gauges were evaluated. Each needle was used to obtain five consecutive samples from a lamb lumbar pedicle. Subjective assessment of ease of needle use, ease of sample removal from the needle and sample quality, before and after fixation, was graded on a 5-point scale. The number of attempts necessary to reach a 1 cm depth was recorded. Each biopsy specimen was measured in the gross state and after fixation. RESULTS: The RADI Bonopty 15 g and Kendall Monoject J-type 11 g needles were rated the easiest to use, while the Parallax Core-Assure 11 g and the Bard Ostycut 16 g were rated the most difficult. Parallax Core-Assure and Kendall Monoject needles had the highest quality specimen in the gross state; Cook Elson/Ackerman 14 g and Bard Ostycut 16 g needles yielded the lowest. The MD Tech without Trap-Lok 11 g needle had the highest quality core after fixation, while the Bard Ostycut 16 g had the lowest. There was a significant difference in pre-fixation sample length between needles (P<0.0001), despite acquiring all cores to a standard 1 cm depth. Core length and width decrease in size by an average of 28% and 42% after fixation. CONCLUSION: Bone biopsy needles vary significantly in performance. Detailed knowledge of the strengths and weaknesses of different needles is important to make an appropriate selection for each individual's practice.

Endometriosis-associated invasive adenocarcinoma involving the rectum in a postmenopausal female: report of a case.

Sampson first reported a case of malignant transformation of endometriosis to adenocarcinoma in 1925. We present a case of such transformation occurring in a postmenopausal female 22 years after total abdominal hysterectomy and bilateral salpingo-oophorectomy. This case demonstrates histologic progression from endometriosis to complex hyperplasia with cytologic atypia, and ultimately to invasive endometrioid adenocarcinoma involving the rectum. Aggressive surgical extirpation of all visible colorectal endometriosis for patients with advanced disease is recommended.

Pathologic approach to pulmonary hemorrhage.

The pathologist's approach to pulmonary hemorrhage is outlined. Most cases fall into those examples of pulmonary hemorrhage caused by localized sites of bleeding, and those examples that fall within the spectrum of diffuse alveolar hemorrhage. The histologic evaluation of pulmonary hemorrhage is outlined including assessment of fresh hemorrhage in alveolar spaces (including exclusion of traumatic hemorrhage related to the procedure) and the presence of hemosiderin and its various causes. The most common causes of diffuse alveolar hemorrhage and clues to their clinically pathologic diagnosis are discussed.

Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung).

The clinicopathologic spectrum of infections due to nontuberculous mycobacteria (NTM) includes cavitary disease, opportunistic infection, and nodular disease associated with bronchiectasis. We report a less well-described manifestation of NTM infection: 10 immunocompetent patients without preexisting bronchiectasis had radiographic evidence of diffuse infiltrative lung disease. The most common symptoms were dyspnea, cough, hypoxia, and fever. All 10 patients had used a hot tub. Histologic examination revealed exuberant nonnecrotizing, frequently bronchiolocentric, granulomatous inflammation in all cases. In 1 case, necrotizing granulomas were also noted. The inflammation often was associated with patchy chronic interstitial pneumonia and organization. Cultures revealed NTM in all cases (Mycobacterium avium complex in all but 1 case), but staining for acid-fast bacilli was positive in only 1 case. Four patients received corticosteroids alone for presumed hypersensitivity pneumonia, 4 were treated with antimycobacterial therapy, and 2 received both. All patients demonstrated significant improvement at the time of follow-up. These findings suggest that disease due to NTM may manifest as diffuse infiltrates in immunocompetent adults and that hot tub use may be an important risk factor for this disease pattern.

Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients.

Pneumonitis is a serious and unpredictable side-effect of treatment with methotrexate (MTX) that may become life-threatening. The clinical and histological features of nine cases of MTX pneumonitis are reported and the literature reviewed. The typical clinical symptoms include progressive shortness of breath and cough, often associated with fever. Hypoxaemia and tachypnoea are always present and crackles are frequently audible. Chest radiography reveals a diffuse interstitial or mixed interstitial and alveolar infiltrate, with a predilection for the lower lung fields. Pulmonary function tests show a restrictive pattern with diminished diffusion capacity. Lung biopsy reveals cellular interstitial infiltrates, granulomas or a diffuse alveolar damage pattern accompanied by perivascular inflammation. These clinical and pathological findings are not specific to MTX pneumonitis and can be seen with other drug-induced lung toxicities. It is important that all patients receiving methotrexate be educated concerning this potential adverse reaction and instructed to contact their physicians should significant new pulmonary symptoms develop while undergoing therapy. If methotrexate pneumonitis is suspected, methotrexate should be discontinued, supportive measures instituted and careful examination for different causes of respiratory distress conducted.

Squamous cell carcinoma of the vulva stage IA: long-term results.

OBJECTIVE: The aim of this study was to evaluate the risk of metastases to lymph nodes and long-term results of radical and modified radical surgery in patients with a T1 squamous cell carcinoma of the vulva and

Myofibroblasts in diffuse alveolar damage of the lung.

The myofibroblast is an ultrastructurally and metabolically distinctive connective tissue cell identified as a key participant in tissue remodeling in human granulation tissue, organ fibrosis, and the fibroblastic host response to malignant neoplasms. In this study of myofibroblasts in human lung diffuse alveolar damage (DAD), we identified 36 autopsy cases in which DAD could be histologically documented. DAD is known to progress from initial injury through an exudative, proliferative, and terminal fibrotic phase. In the exudative phase (16 cases), myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA) are found in the septa and less frequently in hyaline membranes. In the proliferative phase (18 cases), many myofibroblasts in septa, hyaline membranes, and intra-alveolar fibroplasia express alpha-SMA. The alpha-SMA phenotype should be used in additional studies of myofibroblast differentiation, replication, and apoptosis. A better understanding of the biology of this cell type should offer new therapy for patients with DAD.

Estrogen-receptor-related protein p29 in primary nonsmall cell lung carcinoma: pathologic and prognostic correlations.

BACKGROUND: Estrogen-dependent intracellular processes are important in the growth regulation of normal tissue and may play a role in the regulation of malignancies. Utilization of estrogen receptor assays in breast carcinoma is well established, but the role of such evaluation in other cancers largely is unknown. In this study, immunohistochemical expression of estrogen receptor (ER) and the ER-related protein p29 was correlated with survival of patients with nonsmall cell carcinoma of the lung. METHODS: All patients with a tissue diagnosis of primary nonsmall cell bronchogenic carcinoma diagnosed over a 6-year period at the Medical Center Hospital of Vermont were reviewed. Assays for p29 and ER using a streptavidin-biotin immunoperoxidase method were performed on each tumor. Results were correlated with clinical data, including survival. RESULTS: Of 111 tumors examined, 109 (98%) were positive for p29 whereas none of the tumors reacted with ER (ER1D5). The relation between p29 expression and survival time was different for men and women. A statistically significant negative relation for women was observed; this relation was most pronounced in patients with Stage I and II tumors. A positive but not statistically significant relation was observed for men. CONCLUSIONS: The ER-related protein p29 commonly is expressed in nonsmall cell carcinomas of the lung. The relation between p29 and survival time is different for males and females, suggesting the presence of gender specific factors that may influence tumor growth and overall patient survival, especially in patients with early stage lung carcinoma.

Micronodular pneumocyte hyperplasia.

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by mental retardation, seizures, and central nervous system and visceral hamartomas. Pulmonary involvement manifesting as lymphangioleiomyomatosis (LAM) occurs in 1% of patients (all women) with TSC. Micronodular pneumocyte hyperplasia also has been described as a rare pulmonary manifestation of TSC. We report 14 patients with micronodular pneumocyte hyperplasia (MNPH). The patients ranged in age from 23 to 57 years (mean 37.5). There were 12 women and 2 men. Nine of the patients (one man and eight women) had documented clinical manifestations of TSC: seven with LAM, two without LAM (including one man). Of the five patients who did not have TSC, three had LAM and two did not (including one man). Histologically, all 14 cases demonstrated multiple well-demarcated nodules usually measuring up to 8 mm in size, but most were 1-3 mm. The nodules were produced by a proliferation of enlarged cytologically benign type II pneumocytes, with an associated increase in alveolar macrophages and interstitial reticulin. Immunoperoxidase studies showed the type II pneumocytes within lesions to be reactive with antibodies to cytokeratin (four of four), epithelial membrane antigen (EMA) (five of five), and surfactant apoprotein B (8 of 10). HMB-45 was negative in the MNPH lesions in all nine cases studied. Follow-up was available in 9 of 10 living patients and ranged from 1 to 14 years (mean 6 years). Nine patients are alive; six are clinically stable and three have repeated pneumothoraces related to LAM. Four patients have died. None of the deaths were attributable to MNPH. MNPH appears to be a hamartomatous proliferation occurring most frequently in patients with tuberous sclerosis, is separable from and not a manifestation of LAM, has been observed to occur in men, and, like other hamartomas of tuberous sclerosis, does not appear to possess malignant potential.

Silicosis in mice: effects of dose, time, and genetic strain.

Experimental silicosis allows study of the mechanisms of lung injury, inflammation, and fibrosis. Inbred mice are an attractive species in which to study these mechanisms because of recent progress in murine immunology, molecular biology, and genetics. We exposed mice to an aerosol of silica and examined the effects of exposure dose, the evolution of disease features over time, and the variation in responses among four inbred strains. In C3H/HeN mice incremental cumulative exposure doses of cristobalite silica caused increased initial lung dust burden 12 to 16 weeks post-exposure, progressively intense pathological responses, and increased total lung collagen (hydroxyproline). The histopathological changes and total lung collagen increased progressively over time after exposure. We compared the features of silicosis in four strains of inbred mice selected for common use or immunologic reactivity 16 weeks after aerosol inhalation exposure to crystalline cristobalite silica (70 mg/m3, 5 hours/day, 12 days). C3H/HeN mice demonstrated histopathological silicotic lesions and enlarged intrapulmonary lymphoid tissue, and increased lung wet weight, bronchoalveolar lavage (BAL) recovery of macrophages, lymphocytes, and neutrophils, and total lung collagen (hydroxyproline). BALB/c mice developed slight pulmonary lesions; MRL/MpJ mice demonstrated prominent pulmonary infiltrates with lymphocytes; New Zealand Black mice developed extensive alveolar proteinaceous deposits, inflammation, and fibrosis. Our findings demonstrate orderly dose-time-response relationships, and a substantial variation of responses among inbred strains of mice. This model should prove valuable for future experimental interventions into the mechanisms of silicosis.

Osteocalcin and osteonectin immunoreactivity in the diagnosis of osteosarcoma.

Osteosarcomas (OSAs) can be difficult to distinguish histologically from tumors with significantly different biologic potentials and treatment protocols. The correct diagnosis of OSA relies on identification of malignant osteoblasts that are capable of producing neoplastic bone. To determine the use of immunohistochemistry for the diagnosis of OSA, 106 tumors from the Massachusetts General Hospital and the University of Vermont were immunostained with monoclonal antiosteocalcin (OC) and antiosteonectin (ON) antibodies. They included 42 OSAs, 25 non-bone-forming sarcomas, 24 other malignant tumors including lymphomas, carcinomas, and melanomas, and 15 benign bone tumors. Cytoplasmic staining with OC showed 70% sensitivity and 100% specificity, while staining with ON showed 90% sensitivity and 54% specificity for bone-forming tumors, consistently staining cell types other than osteoblasts. Of the OSAs, 83% demonstrated matrix staining with one or both antibodies, whereas dense collagen was negative for both antibodies in all tumors. We conclude that tumor cell cytoplasmic staining with monoclonal OC may be helpful in distinguishing OSAs from other malignancies, and staining of extracellular matrix for OC and ON antibodies concurrently may help distinguish bone matrix from dense collagen.

Diagnostic accuracy of a rural live video telepathology system.

Accuracy of diagnoses rendered using a live video telepathology network was assessed for permanent sections of surgical pathology specimens. To determine accuracy, telepathology diagnoses were compared with those obtained by directly viewing the glass slide using a standard microscope. A total of 294 cases were read via both telepathology and glass slide by attending pathologists at a tertiary care medical center. Overall accuracy was defined as exact concordance between diagnoses. Clinically insignificant differences in diagnoses were excluded to determine clinically significant accuracy. For the 285 cases with complete data, the overall accuracy for telepathology was 0.912 (95% confidence interval [CI], 0.872-0.941), whereas the overall accuracy for glass slide readings was 0.968 (95% CI, 0.939-0.985). This difference is statistically significant (p = 0.009). When focusing on clinically significant discrepancies, where the difference in diagnosis might affect therapeutic decisions, the video accuracy was only slightly less than the glass slide accuracy (0.965 [95% CI, 0.934-0.982] vs. 0.982 [95% CI, 0.957-0.994], respectively), but this difference is not statistically significant (p = 0.302). Most of the cases with clinically significant differences involved lesions with inherently high interobserver variation. Certainty of diagnosis did not differ between video and glass slide readings (p = 0.911), but there was an association between certainty of diagnosis and diagnostic accuracy for video (p = 0.003 for clinically significant accuracies). Based on these findings, we recommend when using this telepathology system that only preliminary diagnoses should be given in the following situations: for diagnostic areas with known high interobserver variability; when the consultant has any degree of uncertainty about the presence or absence of the lesion in question; and when there is insufficient experience using telepathology as a diagnostic medium.

Pathology of lung cancer.

In this review, we focus on a number of developments pertaining to lung cancer diagnosis, entirely restricted to those parameters assessable by light microscopy. A number of discrete areas of interest stand out in 1996 related to the pathology of lung cancer. Aberrant p53 expression continues to be debated as an independent prognostic factor in nonsmall cell carcinoma. Neuroendocrine differentiation may be an independent prognostic factor in nonsmall cell carcinoma and new associations with the protein product of the bcl-2 oncogene have been described. Angiogenesis continues to arise as a predictor of metastatic potential in lung cancer. Finally, we review conceptual aspects of carcinogenesis from atypical adenomatous hyperplasia to bronchioloalveolar carcinoma, in addition to a variety of individual tumor-related issues associated with progression, response to chemotherapy, and survival.

Second opinions in surgical pathology.

When to obtain opinions in anatomic pathology is a complex issue. The authors discuss the cognitive process of morphologic interpretation, the influence of expertise on the need for a second opinion, the role of ego, and the impact of economic factors on the patterns of consultation.