Spinal extension exercises prevent natural progression of kyphosis.

UNLABELLED: The angle of kyphosis increases with age with the most rapid increase occurring between 50 and 60 years. The progression of kyphosis was prevented in women ages 50-59 years who performed extension exercises three times a week for one year. INTRODUCTION: The purpose of this study was to (1) measure the progression of the angle of kyphosis with age and (2) determine whether spinal extension exercises prevent progression of hyperkyphosis in women 50-59 years of age. METHOD: Part 1: Cross-sectional study of changes in posture with age, determined by measuring spinal curves in 250 women 30-79 years of age. Part 2: One-year prospective, descriptive analysis of the effect of extension exercises on posture in women 50-59 years of age. Depth of the cervical curve (CD), area under the thoracic curve (TA), and height were measured using a device developed at Kansas University Medical Center. Changes in CD and TA in women compliant with extension exercises were compared to those in non-compliant women. RESULTS: Kyphosis increases with age in healthy women, with the greatest difference observed between women 50 and 59 years of age. The progression of kyphosis was greater in women who did not perform extension exercises compared to those who performed extension exercises three times per week for 1 year. The difference in change in CD and TA between the two groups was highly significant (CD p = .0001, TA p = .0001). CONCLUSIONS: Kyphosis increases with age in healthy women. In this study the greatest difference in the angle of kyphosis was observed between the fifth and sixth decade. Exercises which strengthen the extensor muscles of the spine can delay the progression of hyperkyphosis in the group included in this study, i.e., women 50-59 years of age.

EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short term survivors (survival <3 years; STS) and long term survivors (survival >3 years; LTS) of MPM. METHODS: 37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, antiapoptosis, angiogenesis and other cellular activities were investigated by tissue microarray (TMA) technology. RESULTS: Epidermal growth factor receptor (EGFR) was expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling was more abundant in STS. Expression of TIE2/Tek, a receptor for tyrosine kinases involved in angiogenesis, was differentially regulated via PDGFR and thus is more important in STS. Antiapoptosis was upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS. CONCLUSION: We have demonstrated that small scale proteomics can be carried out by powerful linkage of TMA, immunohistochemistry and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.

Estrogen and progesterone receptors in bronchogenic carcinoma.

Although the lung is not usually considered a major target organ of sex hormones, epidemiological observations, studies of pulmonary neoplasms in laboratory animals, and investigations of carcinomas derived from other "nontarget" organs suggest that sex hormones may have a role in the pathogenesis of bronchogenic carcinoma. To confirm that estrogen (ER) and progesterone receptors are present in human lung cancers, 19 resected lung cancers were examined for receptors using a prelabeled sucrose gradient method. Three squamous cell carcinomas were positive for ER (greater than 6.9 fmol/mg cytosol protein). Three squamous cell carcinomas, two adenocarcinomas, and one small cell carcinoma were positive for progesterone receptors (greater than 6.9 fmol/mg cytosol protein). One tumor, a squamous cell carcinoma arising in a woman who smoked, had an ER level of 301 fmol/mg, a highly positive level even for breast cancers. These observations may provide a basis for adjuvant hormonal therapy in selected lung cancer patients.

Absence of retinoblastoma protein expression in primary non-small cell lung carcinomas.

Retinoblastoma (RB) protein expression was examined in paraffin and frozen tissue sections of 36 primary non-small cell lung carcinomas (NSCLC) using immunohistochemistry with confirmation by direct Western blotting. A normal RB protein staining pattern was present in 24 and absent in 10 NSCLC. Two additional RB positive primary tumors have major foci in which all tumor cells showed no RB protein staining. Significantly more high-stage (stages III and IV) NSCLC had altered RB protein expression than those with low-stage (stages I and II) tumors (P less than 0.05). The results suggest that absence of the RB expression may be associated with the initiation and/or progression of many NSCLC. This is the first report of successful RB staining in paraffin sections.

Altered retinoblastoma and p53 protein status in non-small cell carcinoma of the lung: potential synergistic effects on prognosis.

Routinely processed pathological specimens from 119 patients with stage I and II adenocarcinomas or squamous cell carcinomas were examined by immunohistochemical analysis for altered retinoblastoma (RB) and/or p53 protein expression. Absent RB nuclear staining (RB-) indicating loss of RB function occurred in 19 (16%) of the cases studied, whereas expression of a putative mutant p53 nuclear protein (p53(+)) was found in 54 (45%) of the tumors. The median survival was 39 versus 12 months for patients with RB+ and RB- tumors, respectively (P = 0.05 by log rank analysis). Similarly, the median survival was 41 months for patients whose tumors had no expression of mutant p53 (p53(-)) compared with 24 months for individuals with p53 (+) tumors (P = 0.01). These differences in survival, however, were not statistically significant by multivariate analysis. Nevertheless, individuals with RB-/p53(+) tumors had a significantly shorter median survival (12 months) than those with RB+/p53(-) tumors (41 months), as determined by both log rank and multivariate analyses (P = 0.005 and 0.03, respectively). In addition, 66 large cell carcinomas from all stages were examined. Again, a more significant difference in survival (48 versus 8 months) was found between patients with RB+/p53(-) versus RB-/p53(+) tumors (P = 0. 006). These results suggest that RB and p53 status might be used synergistically as prognostic factors in a subset of non-small cell lung carcinomas.

Pulmonary blastoma with rhabdomyosarcomatous differentiation: an electron microscopic and immunohistochemical study.

Pulmonary blastoma is a rare lung tumor composed of epithelial and mesenchymal elements; the latter element may show various patterns of differentiation toward mature tissue, such as cartilage, smooth muscle, and bone. Rhabdomyoblastic differentiation in pulmonary blastoma is quite rare; only five such cases have been reported. We report two cases of pulmonary blastoma with rhabdomyoblastic differentiation documented for the first time by electron microscopy and immunohistochemistry including documentation for myoglobin, actin, vimentin and desmin. The diffuse and prominent rhabdomyoblastic differentiation in one case is most unusual.

The separation of benign and malignant mesothelial proliferations.

The separation of benign from malignant mesothelial proliferations has emerged as a major problem in the pathology of the serosal membranes. For both epithelial and spindle cell mesothelial processes, true stromal invasion is the most accurate indicator of malignancy, but stromal invasion is often difficult to assess, especially in small biopsies. In the pleural cavity, deep penetration of a thickened and fibrotic pleura or penetration of mesothelial cells into the fat of the chest wall are good indicators of malignancy; however, superficial entrapment of mesothelial cells and glands by organizing effusions is common in benign reactions and needs to be distinguished from invasion. In the peritoneal cavity, invasion of fat or of organ walls is again the most reliable indicator of malignancy, but entrapment of benign cells in organizing granulation tissue or between fat lobules is frequent and confusing. Proliferations confined to the pleural or peritoneal space, particularly linear arrays of atypical mesothelial cells on the free surface, should not be called malignant in the absence of unequivocal invasion. Cytologic atypia is often not helpful in separating benign from malignant reactions, because benign processes are commonly atypical and mesotheliomas are often deceptively monotonous. Densely packed mesothelial cells within the pleural space are frequent in benign reactions, but densely packed mesothelial cells within the stroma favor a diagnosis of malignancy. Organizing effusions (fibrous pleurisy) typically show zonation with high cellularity and cytologic atypia toward the pleural space and increasing fibrosis with decreasing cellularity and lesser atypia toward the chest wall, whereas sarcomatous (including desmoplastic) mesotheliomas do not demonstrate this type of zonation. Elongated capillaries perpendicular to the pleural surface are seen in organizing effusions but are not a feature of sarcomatous mesotheliomas. The combination of a paucicellular storiform pattern, plus invasion of the stroma (including fat and adjacent tissues), or bland necrosis, overtly sarcomatous foci, or distant metastases, is required for the diagnosis of desmoplastic mesothelioma. Necrosis is usually a sign of malignancy but is occasionally seen in benign mesothelial reactions. Keratin staining is useful in indicating the distribution of mesothelial cells, and particularly in demonstrating penetration of mesothelial cells into the stroma or adjacent structures, but is of no help in separating benign and malignant proliferations because both are keratin-positive. Although both p53 and EMA staining have been proposed as markers of mesothelial malignancy, in our experience they are not helpful for the individual case.

Thymic carcinoma. A clinicopathologic study of 13 cases.

Thymic carcinoma (TCA) is a thymic epithelial neoplasm with obvious cytologic atypia. We studied 13 cases of TCA by light microscopy, immunohistochemistry, and electron microscopy and correlated the findings with clinical features. The patients' mean age was 54.2 years (range 30-74); the male/female ratio was 7/6. Twelve of the 13 patients presented with signs and symptoms caused by compression of mediastinal organs; the other patient was asymptomatic. Paraneoplastic syndromes were never seen. At thoracotomy, 11 tumors invaded or adhered to surrounding structures; the other two were encapsulated. The histologic types include squamous carcinoma including the lymphoepithelioma-like subtype (seven cases), small cell carcinoma (four cases), clear cell carcinoma (one case), and adenosquamous carcinoma (one case). Positive immunoperoxidase studies were as follows: keratin (13 cases), epithelial membrane antigen (EMA) (13 cases), leukocyte common antigen (none), carcinoembryonic antigen (CEA) (five cases), B72.3 (seven cases), Leu 7 (two cases), human placental alkaline phosphatase (none), vimentin (none), and chromogranin (one case). This profile is similar to those of normal thymus and thymoma except for the absence of CEA, B72.3, EMA in normal thymus, and the absence of CEA and B72.3 in thymoma. Electron-microscopic studies performed on eight cases showed glandular and squamous differentiation in one adenosquamous carcinoma, squamous differentiation in five squamous carcinomas, and neuroendocrine differentiation in one small-cell carcinoma. Nine patients died (three due to postoperative complications and six due to recurrences or metastasis at 3-36 months). Four patients (all with squamous carcinoma) were alive without disease at 2-60 months. The clinical and pathologic features were comparable with those of approximately 62 other cases of TCA previously reported. There are a number of well-defined histologic types of TCA that allow the pathologist to make a differential diagnosis of TCA from tumors extending or metastatic to thymus or other primary mediastinal tumors. Although neither asymptomatic presentation nor encapsulation improves the poor prognosis of TCA, the squamous carcinoma subtype is associated with a better outcome than the other subtypes. Based on the electronmicroscopic and immunohistochemical findings, the presence of normal thymic tissue at the periphery of several tumors, and the observation that several TCA arose from preexisting thymomas or thymic cysts, we conclude that TCA is derived from thymic epithelium.

The diagnosis of CMV pneumonitis in lung and heart/lung transplant patients by PCR compared with traditional laboratory criteria.

Polymerase chain reaction (PCR) amplification of CMV DNA recovered from bronchial alveolar lavage (BAL) and peripheral blood samples was compared with tissue culture, cytology, and/or histology for the earlier detection of CMV pneumonitis in 12 recipients of single-lung or heart/lung transplants. In patients with confirmed CMV pneumonitis, cytological evidence of CMV disease in BAL samples was detected 38 +/- 14 days posttransplantation, while tissue culture and PCR-positive results were noted as early as 30 +/- 4.0 days and 18 +/- 4.6 days, respectively. While PCR was positive earlier than culture in a number of cases, culture-positive results were subsequently obtained in each case, consistent with earlier detection of viral replication by PCR as opposed to detection of latent virus. CMV was detected by PCR in 6 of 24 blood samples from patients with confirmed or suspected CMV pneumonitis, while results of all 24 blood samples were negative when assayed by tissue culture. PCR-based testing was more sensitive than traditional tests, allowing detection of viral replication earlier than tissue culture in the posttransplant period. PCR could provide a powerful means of monitoring the immunocompromised patients in whom preemptive therapeutic intervention for CMV disease is desirable.

Lymphocyte subset populations in bronchiolitis obliterans after heart-lung transplantation.

The long-term success of heart-lung transplantation is limited by the development of bronchiolitis obliterans, possibly as a form of chronic lung allograft rejection. In the present study, we have characterized by immunohistochemical staining the lymphocytes infiltrating the lesions of bronchiolitis obliterans in one patient following heart-lung transplantation. The finding that the preponderant cells expressed the CD8 (putative cytotoxic/suppressor) marker lends support to the notion that chronic rejection is at least one mechanism for the development of bronchiolotis obliterans following heart-lung transplantation.

Congenital stenotic arteriopathy with medial dysplasia.

An unusual, uniformly stenotic arteriopathy involving the aorta and its major branches, the pulmonary trunk, and the left and right pulmonary arteries was found in association with a persistent common atrioventricular canal in an otherwise normal stillborn female infant. The uniform arterial thickening was due to hyperplastic medial elastic laminae, which were in an orderly arrangement in the inner two thirds but dysplastic in the outer third of the media of the arteries.

Peripheral biphasic adenocarcinoma of the lung: light microscopic and immunohistochemical findings.

We report two cases of peripheral biphasic adenocarcinoma primary in the lung. To our knowledge, peripheral adenocarcinoma of the lung with a spindle-cell component has not been described previously. Diffuse positive cytokeratin and negative vimentin immunostaining of the spindle-cell components support an epithelial differentiation of the malignant spindle cells. Although study of additional cases is needed, our initial findings suggest that immunohistochemical staining pattern may help distinguish these neoplasms from other biphasic neoplasms primary or secondary to the lung, such as carcinosarcoma or malignant mesothelioma.

p53 immunostaining in the differentiation of reactive processes from malignancy in pleural biopsy specimens.

To determine the utility of positive p53 protein immunostaining as an adjunct in the diagnosis of malignancy in pleural biopsy specimens, we reviewed 73 recently obtained pleural biopsy specimens that represented the typical range of diagnoses encountered in the evaluation of a proliferative pleural process. Immunohistochemistry was performed on paraffin sections of each biopsy specimen using a monoclonal antibody to the p53 suppressor gene product clone BP53-12 (BioGenex, San Ramon, CA) and a standard capillary gap (Microprobe, Fischer Scientific, Pittsburgh, PA) avidin-biotin complex technique with a citrate buffer antigen retrieval solution. Of the pleural biopsy specimens with unequivocal malignancy, 19 of 40 mesotheliomas and nine of 18 metastatic adenocarcinomas were immunopositive for p53 protein. All 13 of the biopsy specimens with reactive mesothelial hyperplasia or organizing pleuritis were negative. Two pleural biopsy specimens, which were interpreted as suspicious but inconclusive for malignancy, were positive for p53 protein and subsequent pathology specimens confirmed the presence of metastatic carcinoma in both of these biopsy specimens. Our findings suggest that p53 protein immunostaining is relatively sensitive and highly specific in differentiating reactive processes from primary or metastatic malignancies in histopathologically equivocal pleural biopsy specimens.

Pulmonary histopathology in cocaine abusers.

Lung histopathology was reviewed from 52 autopsies with positive toxicologic tests for cocaine from the medical examiners' offices in Dallas and Austin, TX. The median patient age was 34.7 years, and the male to female ratio was 2:1. Twelve individuals primarily used the drug intravenously and six primarily smoked it, but in most patients usage history was not known. The most frequent manner of death was accidental, consisting predominantly of cocaine overdoses. Other frequent manners of death included both natural causes and homicides. Subjects with chest trauma were excluded from the study. Twenty-three age-matched control cases with negative cocaine histories and toxicologic tests also were obtained from medical examiner autopsies. Histopathologic findings in the cocaine abuse group included acute hemorrhage, 58% (P = .05); chronic hemorrhage, 40% (P < .01), interstitial pneumonitis/fibrosis, 38% (P < 0.01); congestion, 88% (P < .01); and intra-alveolar edema, 77% (P < .01). These changes were remarkably consistent regardless of locale or method of use. Our findings demonstrate that pulmonary hemorrhage is more frequent than suggested by clinical hemoptysis and that chronic pulmonary diseases such as interstitial fibrosis may develop in long-term users.

Chromosomal aberrations in a series of large-cell neuroendocrine carcinomas: unexpected divergence from small-cell carcinoma of the lung.

Large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are high-grade neuroendocrine tumors of the lung. Despite different morphologic appearances, loss of heterozygosity and oncogene studies on LCNEC to date suggest genetic similarities. We analyzed 13 LCNEC and 5 mixed SCLC/LCNEC tumors by comparative genomic hybridization and subsequently compared our results with previously published data on 32 SCLCs. Comparison with SCLC showed several shared chromosomal aberrations, specifically losses of 3p, 4q, 5q, and 13q and gains of 5p. However, these aberrations are no special feature of neuroendocrine lung tumors but can also be found in other high-grade lung carcinomas. From this point of view, genetic similarities of LCNEC and SCLC are less important than the nonrandom changes that differ between these 2 tumor types. A gain of 3q observed in 66% of all SCLCs was detected only once in the LCNEC group. In contrast to the pure LCNEC, all mixed types with a SCLC component had a gain of 3q. Gains of 6p occurred more frequently in LCNEC. Deletions of 10q, 16q, and 17p were less frequent in LCNEC than in SCLC.

Utility of surfactant protein B precursor and thyroid transcription factor 1 in differentiating adenocarcinoma of the lung from malignant mesothelioma.

Differentiation of malignant mesothelioma from adenocarcinoma, particularly from a lung primary, remains a difficult diagnostic problem. Surfactant protein B precursor (pro-SP-B) and thyroid transcription factor 1 (ITF-1) are expressed selectively in the normal respiratory epithelium and in adenocarcinomas of the lung. In this study, we evaluated the utility of pro-SP-B and ITF-1 in distinguishing pulmonary adenocarcinomas and malignant mesotheliomas. Immunoreactivity for pro-SP-B and TTF-1 was examined in paraffin sections of 370 primary lung carcinomas (208 adenocarcinomas, 101 squamous cell carcinomas, and 61 large cell carcinomas) and 95 malignant mesotheliomas, using a pro-SP-B antiserum and a monoclonal TTF-1 antibody with a biotin-streptavidin detection system. Immunostaining for pro-SP-B was detected in 57% of adenocarcinomas, and 20% of large cell carcinomas. Immunoreactivity for TTF-1 was shown in 76% of adenocarcinomas and 26% of large cell carcinomas. Malignant mesotheliomas and squamous cell carcinomas did not stain with either antibody. The expression of pro-SP-B and TTF-1 in adenocarcinomas of the lung but not in malignant mesotheliomas shows that pro-SP-B and TTF-1 staining is useful in differentiating these neoplasms.

Potential utility of p53 immunopositivity in differentiation of adenocarcinomas from reactive epithelial atypias of the lung.

Reactive atypia of alveolar epithelium occurs in many types of lung injury and may sometimes raise suspicions of adenocarcinoma or bronchioloalveolar carcinoma. To assess whether there is sufficient difference in the frequency of p53 protein immunopositivity in these lesions to provide a practical basis for differentiating malignancy from reactive atypia, we immunostained 110 malignant and inflammatory/fibrotic lung specimens for p53 protein. Paraffin-embedded sections were immunostained with p53 protein antibody (clone BP53-12; BioGenex, San Ramon, CA) and standard capillary gap (Microprobe; Fisher Scientific, Fairlawn, NJ) avidin- biotin complex technique with antigen retrieval solution. Percent of immunopositive cells was semiquantitatively categorized as follows: 0%, less than 1%, 1% to 10%, 10% to 50%, more than 50%. Of reactive atypias, 94% are negative or show p53 immunopositivity in less than 10% of cells. Of p53 positive malignancies, 86% are positive in more than 10% of cells. When p53 immunopositivity occurs in more than 10% of atypical cells, the lesion is usually a malignancy, primarily adenocarcinoma. Most reactive atypias are immunopositive in less than 10% of atypical cells. Important caveats were noted. Rare reactive atypias are p53 immunopositive in greater than 10% of cells. Bronchioloalveolar carcinomas are infrequently p53 immunopositive. Therefore, this approach would be less useful in their differentiation from reactive atypias.

Absence of prognostic significance of bcl-2 immunopositivity in non-small cell lung cancer: analysis of 427 cases.

The bcl-2 gene product inhibits apoptosis and is thought to participate in oncogenesis. Association of bcl-2 immunopositivity with improved prognosis of non-small cell lung cancers (NSCLC) is controversial. Although two studies have reported better survival in bcl-2-immunopositive NSCLCs, a third series has contradicted this finding. The authors studied a relatively larger case series involving 427 patients for whom detailed information on long-term follow-up was available to determine the prognostic significance of bcl-2 expression. The study included 252 adenocarcinomas (AC), 111 squamous cell carcinomas (SCC), and 64 large cell carcinomas (LC). After antigen retrieval, sections were immunostained using a monoclonal anti-bcl-2 antibody (1:60, Clone 124, Dako) and the avidin-biotin complex technique. Staining was scored as positive or negative and also on a semiquantitative scale as 0, low (<10%), moderate (10% to 75%), or extensive (>75%). Bcl-2 immunoreactivity was correlated with survival using the actuarial survival method, Kaplan-Meier method, and log-rank test and was not associated with statistically significant differences in survival for NSCLCs (P = .5537). Differences in survival remained insignificant even after NSCLCs were stratified for cell type, stage, or grade, singly or in combination. Therefore, using this method, bcl-2 immunopositivity does not appear to act as an independent prognostic indicator in NSCLCs.

p53 accumulation in benign breast biopsy specimens.

Several studies of benign breast lesions using methacran-fixed, paraffin-embedded tissues and cytological preparations have suggested that p53 accumulation in these lesions as detected by immunohistochemical (IHC) staining is rare to absent. As a result, several different investigators have suggested that p53 immunoreactivity in breast specimens infers a diagnosis of malignancy or may identify premalignant lesions. We immunostained 271 breast biopsy specimens from 271 patients with the monoclonal anti-p53 antibody BP-53-12 and found positive nuclear staining in seven of 23 malignant lesions (30%) and 39 of 248 benign biopsy specimens (16%). Of the benign lesions, 30% of fibroadenomas, nonpremalignant breast lesions, were positive. Long-term follow-up information was available on 48 patients with benign biopsy specimens and showed that 12% of those positive and 7% of those negative for p53 developed breast carcinoma. This difference was not significant (P > .2). We conclude that (1) p53 immunoreactivity in breast lesions should not be used as exclusive evidence of malignancy and (2) p53 immunoreactivity in benign breast lesions may not identify a subset of patients at increased risk for breast carcinoma.

Differential expression of thyroid transcription factor 1 in small cell lung carcinoma and Merkel cell tumor.

The distinction between metastatic small cell lung carcinoma (SCLC) and Merkel cell tumor is difficult by routine histology, prompting the search for specific markers that could separate these neoplasms. Thyroid transcription factor 1 (TFF-1) is a homeodomain containing transcription factor expressed in the normal airway epithelium. The expression of TTF-1 has also been shown in adenocarcinomas and small cell carcinomas of the lung. However, the utility of TTF-1 to differentiate between SCLC and Merkel cell tumor has not yet been investigated. In this study, paraffin sections of 36 SCLCs and 21 Merkel cell tumors were analyzed for the presence of immunoreactive TTF-1 and cytokeratin 20 (CK20), a marker previously demonstrated in Merkel cell tumors. Monoclonal TTF-1 and CK20 antibodies were used with a biotin-streptavidin detection system. Immunostaining for TTF-1 was observed in 97% of SCLCs and in no Merkel cell tumors. Immunoreactivity for CK20 was demonstrated in 76% of Merkel cell tumors and 3% of SCLCs. These data indicate that TTF-1 is a sensitive (97%) and specific (100%) marker for SCLCs and can be used to differentiate SCLCs from Merkel cell tumors.