Cumulative exposure to CD8+ granzyme Bhi T cells is associated with reduced lung function early after lung transplantation.

Outcomes following lung transplant remain suboptimal. This is attributable to variable posttransplant recovery of lung function, and inconsistent degrees of lung function loss after peak function is reached. Granzyme B is elevated in the blood and bronchoalveolar lavage (BAL) in acute rejection. We hypothesized that persistent exposure to T cells high in granzyme B would negatively correlate with lung function. We investigated cumulative exposure measured as the area-under-the-curve (AUC) of CD8+ T cell granzyme Bhi cells in the first year posttransplant in both BAL and blood in 24 transplant recipients. We assessed the correlation between cumulative 1-year exposure and FEV1 slope. There was a negative correlation between 1-year exposure and FEV1 slope within the first year (r=-0.63; P=.001). This relationship persisted even when adjusted for transplant type, gender, age, rejection, and indication for transplantation. In contrast, no relationship was seen with the 1-year AUC and lung function after 1 year posttransplant. In contrast to the BAL granzyme Bhi levels, granzyme Bhi levels from the blood showed no relationship with lung function. These findings suggest that CD8+ T-cell-driven factors are responsible for early improvements in lung function after transplantation.

Receptor for advanced glycation end products in donor lungs is associated with primary graft dysfunction after lung transplantation.

Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation. We hypothesized that Receptor for Advanced Glycation End-products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation. We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (transbronchial biopsy) from recipients with and without PGD. RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD versus transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/mL increase in donor RAGE level). In addition, RAGE levels remained high for 14 days in those recipients that developed severe graft dysfunction. Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD posttransplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD.

Eosinophilic pulmonary syndrome as a manifestation of GVHD following hematopoietic stem cell transplantation in three patients.

Eosinophilic pulmonary syndrome is an uncommon problem in SCT recipients that can mimic an infectious process. We report the occurrence of eosinophilic pulmonary syndrome in three patients following allogeneic hematopoietic stem cell transplantation (HSCT), and postulate that this entity is part of the clinicopathologic spectrum of pulmonary GVHD. In all three cases, active chronic GVHD of the skin preceded or coincided with the development of pulmonary involvement. Other common features included peripheral blood eosinophilia, diffuse bilateral pulmonary infiltrates and lung biopsies showing pronounced infiltrates of eosinophils involving the small bronchioles. All patients responded promptly to systemic steroid therapy, with improvement of their pulmonary symptoms and the resolution of peripheral blood eosinophilia. Clinicians should be aware that eosinophilic pulmonary syndrome can occur following HSCT, may be associated with other manifestations of chronic GVHD, and generally responds well to corticosteroid therapy.

[Galanin immunoreactivity in a laryngeal paraganglioma: case report and literature review]. / Paraganglioma laringeo. Descrizione di un caso con espressione immunoistochimica di galanina e revisione della letteratura.

The authors describe a case of laryngeal paraganglioma (LP) occurring in a 57-year-old-woman. To date, 70 cases have been described in the literature. It is benign and recurrences are infrequent. The differential diagnosis with typical and atypical carcinoids, hemangiopericytomas, alveolar soft-part sarcomas, medullary thyroid carcinomas, malignant melanomas and metastatic renal cell carcinomas is supported by immunohistochemistry. Moreover, this tumor shows the immunohistochemical expression of galanin, a variably expressed marker of paragangliomas that it is not expressed in carcinoid tumors. Nevertheless, our observations militate against its role as a solitary marker but advocate its use in conjunction with other antibodies for the differential diagnosis of neuroendocrine neoplasms of larynx.

Neuroendocrine lung tumors: grade correlates with proliferation but not angiogenesis.

Angiogenesis has been implicated in the progression of human neoplasia from benign precursor to invasive and metastatic phenotypes. The acquisition of dominant oncogenes in preneoplastic cells in vitro and in vivo has been associated with the increased ability of tumor cells to secrete angiogenic mediators and recruit blood vessels. However, in a subset of benign lesions, high levels of angiogenesis have been found before the conversion to invasive and metastatic phenotypes. In many of these benign lesions, dominant oncogenic pathways are activated first; then as malignant potential is acquired, there is a loss of nuclear tumor suppressor genes, such as p53 and p16. We studied neuroendocrine lung tumors (NLT) ranging from typical and atypical carcinoid tumors to large cell neuroendocrine and small cell carcinomas in order to determine whether angiogenesis (as assessed by mean vessel density) and proliferation rates (as assessed by MIB-1 nuclear immunohistochemical staining) correlate with tumor type. We found that increased rates of proliferation, but not angiogenesis, correlate with tumor type. The association of increased proliferation and tumor type may prove to be clinically useful and shed light on the role of sequential oncogenic alterations in NLT.

Morphometry confirms the presence of considerable nuclear size overlap between "small cells" and "large cells" in high-grade pulmonary neuroendocrine neoplasms.

We morphometrically evaluated 5-micron H&E-stained sections from 28 surgically resected high-grade pulmonary neuroendocrine neoplasms, including 16 small cell lung carcinomas (SCLCs) and 12 large cell neuroendocrine carcinomas (LCNECs). For each case, 200 tumor nuclei and 20 to 100 normal lymphocytes were measured. The frequency distributions of tumor cell/lymphocyte (TC/L) size ratios were plotted in bins ranging from 1 to 6, classified into 6 histogram types with TC/L size ratio peaks ranging from 2 to 6 (A-E) and a histogram with a wide distribution (F). SCLCs fit histograms A through E; LCNECs, A through F. Morphometry demonstrated considerable nuclear size overlap in high-grade neoplasms. Approximately one third of SCLCs exhibited considerable numbers of neoplastic cells that were larger than 3 normal lymphocytes, while 4 of 12 LCNECs had a predominant number of small cells. Ten tumors exhibited a B histogram with a "borderline" peak TC/L of 3. The rule that a TC/L size ratio larger than 3 helps distinguish "large" from "small" neoplastic cells was confirmed in only 9 of 28 cases. The use of more generic terminology such as "high-grade neuroendocrine carcinoma" or "grade III neuroendocrine carcinoma" for SCLC and LCNEC is discussed.

Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study.

BACKGROUND: Neuroendocrine tumors of the thymus are rare, histologically diverse neoplasms with an unpredictable clinical behavior. This study provides a useful clinicopathological classification and determines the relevance of specific prognostic factors. METHODS: Ten neuroendocrine tumors of the thymus were analyzed for specific clinical and pathological features. Prognostic factors of these cases and 71 previously published cases were evaluated by Kaplan-Meier survival curves and Cox multivariate hazard model. RESULTS: There were 7 males and 3 females, with ages ranging from 26 to 77 years. Cases were classified as carcinoid tumor (2), atypical carcinoid tumor (6), and small cell carcinoma (2). An advanced clinical stage was evident in all instances with frequent recurrence (4) and metastases (8), and a short disease-free survival. Overall mortality was 60%. Statistical analysis of current and previously published cases (n = 81 total) revealed that unresectability (p = 0.0001), extent of surgical resection (p = 0.0002), and advanced clinical stage at presentation (p = 0.03) were associated with higher mortality. By multivariate Cox regression analysis, unresectability (p = 0.02) and advanced clinical stage (p = 0.03) were associated with decreased survival. CONCLUSIONS: Neuroendocrine tumors of the thymus can be classified into distinct clinicopathological entities, and specific factors have prognostic relevance.

Flow and image cytometry in thymic neoplasia: correlation with clinical outcome.

OBJECTIVE: To compare nuclear DNA by flow (FCM) and image cytometry (ICM) in thymic neoplasms and to relate results to clinical outcome. STUDY DESIGN: DNA ploidy of 44 thymomas and 6 thymic carcinomas was studied by FCM and ICM of single nuclear suspensions from paraffin blocks. RESULTS: By FCM, 33 thymomas (75%) and one thymic carcinoma (17%) were diploid; 6 thymomas (14%) and 4 thymic carcinomas (67%) were aneuploid. By ICM, 36 thymomas (82%) were diploid; 7 thymomas (16%) and 6 thymic carcinomas (100%) were aneuploid. Mean follow-up in 44 cases was 46.2 months (range, 1-162). Ten patients with persistent/recurrent disease included four with thymic carcinoma, who died of the disease (two aneuploid by both techniques, two aneuploid by ICM with unsatisfactory/diploid FCM). Four had invasive thymoma and recurrence after 13-150 months (two diploid and two aneuploid by both methods), one had diploidy and noninvasive thymoma that recurred at 92 months, and one had an epithelial thymoma that recurred at 144 months (aneuploid by FCM, diploid by ICM). CONCLUSION: The results obtained in this preliminary, retrospective study show a high concordance between FCM and ICM; aneuploidy correlated with poor outcome by both methodologies. While these findings are encouraging, larger numbers of cases will be needed to define the role of FCM and ICM in predicting outcome in thymic tumors.

Predictors of outcome in thymectomy for myasthenia gravis.

BACKGROUND: Factors determining predictability of response to thymectomy for myasthenia gravis (MG) vary in the literature. METHODS: A 25-year retrospective review (1974 to 1999) of all thymectomies performed at a single institution was undertaken. RESULTS: In 113 consecutive thymectomies for MG, women comprised 79% (89 of 113 patients), and mean age was 40+/-15 years. Complications occurred in 14% of patients (16 of 113). In-hospital mortality was 0, but 90-day hospital mortality was 0.88% (1 of 113 patients). Follow-up was obtained in 81% (92 of 113 patients) at a mean of 51+/-59 months postoperatively. Complete remission was achieved in 21% of patients (19 of 92), and marked improvement of MG in 54% (50 of 92), for a total benefit rate of 75%. Fourteen percent (13 of 92) were unchanged, and 11% (10 of 92) were worse. Using univariate analysis, sex, age, and pathology correlated significantly with outcome (p < 0.05): 80% of women (57 of 70) benefited from the procedure, versus 57% of men (12 of 21). Eighty percent (57 of 70) of patients less than 51 years of age were improved or in remission, versus 57% (12 of 22) older than 50. Twenty-three percent (5 of 22) of patients with thymoma deteriorated, versus 7.1% (5 of 70) without thymoma. Sex did not significantly correlate in the multivariate model. CONCLUSIONS: Sex, age, and thymic pathology are potential predictors of outcome in thymectomy for MG, and may shape treatment decisions and target higher-risk patients.

High tumor grade in salivary gland mucoepidermoid carcinomas and loss of expression of transforming growth factor beta receptor type II.

BACKGROUND: Mucoepidermoid carcinoma (MEC) of salivary glands is a malignant, locally aggressive neoplasm with metastatic potential. The clinical course is usually dependent on histology; however, low-grade carcinomas can result in metastases and tumor-related death. Transforming growth factor beta1 (TGF-beta1) is a potent cytokine that affects growth inhibition of various cells and stimulates extracellular matrix production and angiogenesis. Loss of TGF-beta receptor type II (TGF-beta RII) expression has been related to resistance of TGF-beta1-mediated growth control and tumor progression. In this study, we correlate MEC tumor grade with expression of TGF-beta1 and TGF-beta RII. DESIGN: Immunohistochemical staining was performed on 16 MEC specimens for activated forms of TGF-beta1 and TGF-beta RII. The percentage of cells in which staining yielded positive findings for activated TGF-beta1 and TGF-beta RII was correlated with tumor grade. RESULTS: Activated TGF-beta1 was detected in 16 specimens (100%) of MEC and showed strong positive and diffuse staining. Predominately cytoplasmic staining of TGF-beta1 was seen in salivary gland ducts, stroma, and endothelial cells. There was an inverse correlation between tumor grade and loss of expression of TGF-beta RII. All low-grade MEC tumors yielded positive staining results, whereas only one case of intermediate-grade MEC had TGF-beta RII expression. No high-grade MEC showed TGF-beta RII expression. CONCLUSIONS: Loss of expression of TGF-beta RII correlates with tumor grade. The localization of activated TGF-beta1 within neoplastic epithelium, tumor-associated stroma, and endothelium suggests that it might play a role in the stromal proliferation and/or angiogenesis associated with MEC.

Immunolocalization of erythropoietin and erythropoietin receptor in vestibular schwannoma.

Vestibular schwannomas constitute approximately 6% of intracranial tumors. Apart from the association with neurofibromatosis-2 (NF-2), where a defect in chromosome 22 has been identified, the pathogenesis of sporadic vestibular schwannomas is largely unknown. Very few studies have explored the role of neurotrophic growth factors in vestibular schwannoma. The objective of this study is to evaluate for the presence and pattern of EPO and EPO-R expression within vestibular schwannomas. Our hypothesis that erythropoietin (EPO) and erythropoietin receptor (EPO-R) were expressed in vestibular schwannomas was based on a recent report of rapid growth of a vestibular schwannoma in a patient undergoing preoperative EPO treatment. Using immunohistochemistry, we have demonstrated that both EPO and EPO-R are expressed in a majority of these tumors.

Transforming growth factor and neutralizing antibodies in subglottic stenosis.

Transforming growth factor beta 1 (TGF-beta1), which is implicated in the pathogenesis of fibrotic diseases such as interstitial fibrosis, may be associated with subglottic stenosis. To study this hypothesis, we measured TGF-beta1 expression sequentially in 28 rats after posterior cricoid injury, using both standard immunohistochemistry and reverse transcriptase-polymerase chain reaction. In addition, an osmotic pump infused TGF-beta1 in 18 rats, normal saline solution in 9 rats, and neutralizing antibodies in 9 rats. Specimens were stained for fibronectin and procollagen at 1, 7, and 21 days and underwent optical density analysis. In the injured airway, TGF-beta1 expression peaked at 1 day and returned to baseline by 21 days. The TGF-beta1 infusion led to an increase in the expression of extracellular matrix proteins relative to controls. In contrast, neutralizing antibodies led to a decrease in extracellular matrix protein expression. These findings suggest that TGF-beta1 may possibly play a role in the pathogenesis of subglottic stenosis.

The surgical spectrum of pulmonary neuroendocrine neoplasms.

OBJECTIVES: The purpose of this study is to review our experience with the spectrum of neuroendocrine neoplasms of the lung with emphasis on the histopathologic classification and surgical therapy of each class of neoplasm. DESIGN: This retrospective review covers the entire spectrum of neuroendocrine neoplasms of the lung over an 11-year period (January 1985 to December 1995) in a university hospital setting. Only patients who underwent surgical resection were included in this review. PATIENTS: During this period, a total of 77 patients underwent lung resection for the following neuroendocrine neoplasms: typical carcinoid (TC), 50 patients; atypical carcinoid (AC), 5 patients; large cell neuroendocrine carcinoma (LCNEC), 9 patients; mixed large-small cell neuroendocrine carcinoma (LSNEC), 4 patients; or small cell neuroendocrine carcinoma (SCC), 9 patients. There were 37 men (48.1%) and 40 women (51.9%) among the patients, with a mean age of 57.9 years (range, 14 to 87 years). INTERVENTIONS: Primary surgical resection consisted of the following procedures: 52 lobectomies (67.5%); 10 pneumonectomies (13%); 13 limited resections (16.9%); 1 left main bronchus sleeve resection; and 1 carinal resection. Six patients had the following concomitant procedures: pericardiectomy, 2 patients; mediastinoscopy, 1 patient; chest wall resection, 1 patient; stapling blebs, 1 patient; and transdiaphragmatic liver biopsy, 1 patient. Four patients underwent bilobectomies, and two patients underwent multiple wedge resections. RESULTS: The hospital mortality rate was 2.6% (2 of 77 patients), and both patients died of pulmonary failure. Follow-up was obtained in 62 of 77 patients (80.9%) for an average of 38.1 months (range, 2 to 132 months). There were a total of 13 deaths, and 8 were disease-related (LCNEC, 4 deaths; SCC, 2 deaths; LSNEC, 1 death; and AC tumor, 1 death. The mean disease-free intervals for patients with these neoplasms were the following: TC tumor, 41.3 months; AC tumor, 20 months; LCNEC, 20.4 months; LSNEC, 25 months; and SCC, 48 months. The overall 3-year survival rate was 45.2% (28 of 62 patients). CONCLUSION: This report will emphasize the classification, surgical management, and treatment considerations of pulmonary neuroendocrine neoplasms. Despite the poor overall prognosis in high-grade neuroendocrine tumors of the lung, surgery remains a viable adjunct in the early stages of this disease.

In search of the origins of modern surgical pathology.

Pathology is a relatively new specialty in the history of medicine and borrows much from the clinical and basic sciences. The clinicopathologic correlation began with deceased (autopsy) and was later extended to the living (surgical pathology). Although the roots of surgical pathology began during the first half of the 19th century, this distinctive specialty evolved through many subsequent technical and scientific discoveries. This historical review will trace the advances in microscopy, histochemistry, and surgery in the later half of the 19th century and early 20th century that led to the development of modern surgical pathology.

Glomus tumor of the trachea.

Extracutaneous glomus tumors are unusual and their occurrence in the trachea has been recognized with extreme rarity. We present a case of surgically resected glomus tumor of the trachea in a 34-year-old man who presented with hemoptysis and who was initially diagnosed as having a carcinoid tumor.

Immunolocalization of activated transforming growth factor beta1 in juvenile nasopharyngeal angiofibroma.

BACKGROUND: Juvenile nasopharyngeal angiofibroma (JNA) is a histologically benign, locally aggressive neoplasm of the nasopharynx that exclusively affects male adolescents. It is known to be sensitive to androgens, but there are likely intermediary cytokines and/or growth factors that mediate aggressive stromal cell proliferation and angiogenesis. Transforming growth factor beta1 (TGF-beta1) is a polypeptide that is secreted in an inactive form, cleaved to produce an active form, and then deactivated in the tissues. It activates fibroblast proliferation and is known to induce angiogenesis. OBJECTIVES: To evaluate the presence of activated TGF-beta1 within the stroma of JNA specimens and to quantify the percentage of JNA specimens expressing the active growth factor. DESIGN: Immunohistochemical analysis was performed on 19 specimens of JNA using a unique antibody that identifies only the activated form of TGF-beta1. The percentage of cells staining positively for activated TGF-beta1 was determined semiquantitatively by visual methods. RESULTS: Of 19 cases stained, all 19 (100%) showed strong positive staining (2 cases with 33%-66% of cells staining and 17 with 66%-100% of cells staining). Activated TGF-beta1 was identified in stromal cell nuclei and cytoplasm and in the endothelium of the capillaries within all specimens of JNA. CONCLUSIONS: The localization of activated TGF-beta1 to the fibroblasts and endothelial cells within JNA tumors suggests that TGF-beta1 may play a role in the stromal cell proliferation and angiogenesis associated with JNA. Additional receptor studies and more quantitative methods of analysis are needed to further define the role of TGF-beta1 in the pathogenesis of JNA.

Pancreatic polypeptide hypersecretion associated with a neuroendocrine carcinoma of the gallbladder.

The authors report a case of a suspected pure pancreatic polypeptide-secreting neuroendocrine carcinoma of the gallbladder. The tumor was initially interpreted as an adenocarcinoma of the gallbladder, but was found to have a neuroendocrine component after review. The pathology supports the view that a primitive epithelial stem cell can express both epithelial and neuroendocrine characteristics and can differentiate into both an adenocarcinoma and a neuroendocrine carcinoma. Upon recurrence, the tumor produced symptoms due to local growth, but eventually metastasized and led to the death of the patient within 4 years. The patient was treated with chemoembolization followed by the long-acting somatostatin analog octreotide acetate. The high serum level of pancreatic polypeptide may have contributed to cholestasis and cholelithiasis. Earlier measurement of serum hormone levels and identification of high pancreatic polypeptide levels may have suggested the presence of residual tumor and led to closer follow-up, imaging studies, and therapy.

Ureteral rhabdomyosarcoma.

Rhabdomyosarcoma is a malignant tumor well known to urologists. These tumors arise from the genitourinary system in 20% to 25% of cases, most commonly from the bladder, prostate, vagina, and paratesticular region. This is the first reported case of a rhabdomyosarcoma arising from the ureter. The radiographic findings and ureteroscopic appearance of this tumor suggested a benign fibroepithelial polyp; however, a ureteroscopic biopsy and subsequent nephroureterectomy revealed an embryonal rhabdomyosarcoma.

Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.

Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), and high-grade categories of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). We studied 200 neuroendocrine lung tumors to critically evaluate the Arrigoni histologic criteria for AC using statistical analysis to delimit more rigorously an intermediate survival for AC between TC and the high-grade tumors of LCNEC and SCLC. Histologic features that might predict prognosis were used for Kaplan-Meier and Cox proportional hazards survival analysis, and an optimal mitotic range for AC was calculated. The optimal mitotic range for AC was 2 to 10 mitoses per 2 mm2 of viable tumor (10 high-power fields). Based on this finding, we collapsed mitoses into three categories (< 2; 2-10; > or = 11) and performed Cox multivariate analysis for all 200 neuroendocrine tumors. Mitotic counts were the only independent predictor of prognosis. Based on this analysis, we propose that AC be defined as a tumor with neuroendocrine morphology, mitotic counts between 2-10 per 2 mm2 of viable tumor (10 high-power fields), or coagulative necrosis. Using these criteria, the 200 neuroendocrine tumors were classified as 51 TC, 62 AC, 37 LCNEC, and 50 SCLC. The 5- and 10-year survival was 87% and 87% for TC, 56% and 35% for AC, 27% and 9% for LCNEC, and 9% and 5% for SCLC, respectively. After stratification for stage, survival for AC was significantly worse than for TC (p < 0.001); for LCNEC and SCLC it was significantly worse than for AC; but the survival for LCNEC was no different than that for SCLC.