Lymph node pathology in pulmonary veno-occlusive disease and pulmonary capillary heamangiomatosis.

To assess the histological bases of lymphadenomegaly, which has been reported as a frequent radiological finding in pulmonary veno-occlusive disease (PVOD), we have reviewed pulmonary and mediastinal lymph nodes resected during lung transplantations in 19 patients suffering from PVOD and related pulmonary capillary haemangiomatosis (PCH). Lymphatic congestion was common and was often obvious in subsegmental and segmental lymph nodes. Vascular transformation of the sinuses, intra-sinusal haemorrhage with erythrophagocytosis and lymphoid follicular hyperplasia were frequent especially in lobar, hilar and mediastinal lymph nodes. These lesions were very significantly less frequent in 33 cases of pulmonary hypertension unrelated to PVOD. Due to their thoracic location, these non-specific lesions could simulate other diagnoses such as Castleman disease or lymphangioleiomyomatosis. However, in the setting of pulmonary hypertension, they should suggest PVOD and PCH. They are probably secondary to venous congestion, veno-lymphatic shunts and angiogenetic factors associated with these diseases.

Heart tumors in children and adults: clinicopathological study of 59 patients from a surgical center.

BACKGROUND: Heart tumors are rare lesions with variegated histological types. Their clinicopathological features could be more comprehensively categorized. METHODS: This is a 19-year retrospective study of 17 infants/toddlers (<2 years of age) and 42 patients aged between 14 and 79 years (mean = 51.5) in a surgical center. RESULTS: Congenital tumors (n = 17; 29%), including rhabdomyomas (n = 9), ventricular fibromas (n = 6), and hemangiomas (n = 1), required surgery mainly because of mass effect. Familial myofibromatosis was the only embolic congenital lesion. Acquired benign tumors (n = 28; 47%) included myxomas (n = 21), fibroelastomas (n = 3), myofibroblastic inflammatory tumors (n = 2), and lipomas (n = 2). Eight (29%) were revealed by systemic embolization. These benign noncongenital tumors were all treated by complete resection, except for an incompletely resected lipoma of the mitral valve. Postoperative arrhythmia (n = 1) and pericardial effusion (n = 3) were the only complications. Primary sarcomas (n = 8; 14%) were mostly vascular tumors (five of eight), and patients with high-grade tumors had a mean survival of 15 months (n = 5). Cardiac metastases (n = 6; 10%) were from carcinomas (n = 3) or sarcomas (n = 3); apart from a necrotic metastasis, all patients died (mean survival of 6 months). CONCLUSIONS: This study shows that, regardless of patients' age, heart tumors can be classified as: (a) congenital lesions, which are spontaneously nonprogressive or regressive lesions possibly requiring surgery mainly because of mass effect; (b) acquired benign tumors, which are lesions requiring surgery often because of embolization risk; and (c) primary and secondary malignant tumors, which are lesions with globally poor prognosis but with some indications for resection.

[Pulmonary fibrosis in Hermansky-Pudlak syndrome is not fully usual]. / La fibrose pulmonaire du syndrome de Hermansky Pudlak n'est pas totalement commune.

A 55-year-old female patient with Hermansky-Pudlak syndrome (albinism, thrombopathia and ceroid accumulation) underwent a single lung transplantation for pulmonary fibrosis. Examination of explanted lung showed usual interstitial pneumonia pattern associated with two unusual lesions: presence of numerous macrophages containing ceroid pigments within fibrosis and characteristic foamy swelling of pneumocytes. This later lesion, which has only been recently described, seems related to the mechanism of the disease by defect of surfactant secretion. This lesion allows the histological individualization of pulmonary fibrosis associated with Hermansky-Pudlak syndrome from idiopathic usual interstitial pneumonia.

Cholinesterase activity in human pulmonary arteries and veins: correlation with mRNA levels.

Isolated intact human pulmonary arteries and veins were used to determine the acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) activities in the absence or presence of two selective cholinesterase (ChE) inhibitors, iso-OMPA or BW284c51, respectively. These results were compared with the mRNA levels for each enzyme in human pulmonary vessels. Total ChE activities measured in presence of acetylthiocholine (ACTI, 1 mM) in intact vascular preparations were 45+/-04 and 114+/-07 mU/g tissue in human pulmonary arteries (n=14) and veins (n=14), respectively. These activities were completely abolished in presence of 10 microM neostigmine. In both types of vessels AChE and BChE activities were observed. These activities were at least 2-fold higher in human pulmonary veins when compared with arteries and were correlated with the accumulation of the corresponding transcripts (n=8). In each type of vessel, similar total ChE activities were detected in homogenized and intact preparations, while in human bronchial preparations this activity was 5-fold higher in homogenates than in intact preparations. Together these results provide evidence that the ChE activities in human pulmonary vessels may be extracellular and that the higher activity measured in veins as compared to arteries was associated with the differential accumulation of the corresponding transcripts.

Identification of genes associated with the corticotroph phenotype in bronchial carcinoid tumors.

The proopiomelanocortin (POMC) gene is occasionally expressed in nonpituitary tumors leading to Cushing's syndrome. Bronchial carcinoid tumors, one of the most frequent source for ectopic ACTH secretion, often display numerous features of the corticotroph phenotype. To identify new markers of corticotroph differentiation in these tumors, we compared the pattern of gene expression in ACTH-secreting (ACTH+) and nonsecreting (ACTH-) bronchial carcinoids by differential display/RT-PCR. Using groups of ACTH+ and ACTH- tumors, we initially selected approximately 300 differentially expressed genes. Fifteen were considered differentially expressed after further characterization by RT-PCR on a larger series of 8 ACTH+ and 12 ACTH- bronchial carcinoids; 11 were restricted to--or overexpressed in--ACTH+ and four in ACTH- tumors. In ACTH+, beside the expected POMC gene, we identified cFos, and KIAA1775, a large expressed sequence tag encoding a putative protocadherin-related protein. On the other hand, the tetraspanin TM4SF5 gene was specifically expressed in ACTH-. Dot blot analysis confirmed the specific expression of KIAA1775 in ACTH+ bronchial carcinoids. However, the expression of most of the differential genes, including KIAA1775, was detected by RT-PCR in pituitary or lung tumors, whether secreting ACTH or not, excepted for TM4SF5, which was only detected in some nonendocrine lung tumors. Our results show that corticotroph differentiation of bronchial carcinoid tumors is accompanied by induction and repression of specific genes. The nature of some of these genes, identified here, underlines the importance of cell-cell or cell-extracellular matrix interactions in the establishment of neoplastic corticotroph phenotype. These genes should help to better characterize ACTH+ bronchial carcinoids as well as other bronchial carcinoid subtypes.

Endocardial location of familial myofibromatosis revealed by cerebral embolization: cardiac counterpart of the frequent intravascular growth of the disease?

Myofibromatosis is a rare infantile benign neoplasia, which may involve the heart in the rare and usually fatal generalized form of the disease. Diagnosis of endocardial myofibromas was made on two surgically excised lesions of the mitral valve that were reveled by a cerebral embolization in a 12-month-old female infant. Surprisingly, the patient had no other obvious lesion of myofibromatosis. However, her father had a histologically proven neonatal history of myofibromatosis. This case confirms the likely autosomal dominant mode of inheritance of myofibromatosis. It highlights the embolization risk of the previously unreported endocardial location. We suggest that these clinically isolated non-invasive endocardial myofibromas did not represent a true visceral form of myofibromatosis. They were, rather, similar to the frequent intravascular growth of the disease.

Induction of pulmonary angiogenesis by adenoviral-mediated gene transfer of vascular endothelial growth factor.

BACKGROUND: We hypothesized that gene transfer of vascular endothelial growth factor (VEGF) mediated by an adenovirus vector might induce pulmonary artery angiogenesis in a lamb model of pulmonary artery hypoplasia. METHODS: Thirteen fetal lambs had left pulmonary artery banding at 106 days of gestation. Following birth, 3 groups were divided: VEGF group (n = 5) and beta-GAL group (n = 4) received an adenoviral vector encoding respectively for human VEGF165 and for galactosidase A. A control group (n = 4) had neither gene nor virus. Viral suspensions were selectively instilled in the left bronchus 6.5 days after birth. Five nonoperated lambs constituted the normal group. Euthanasia was performed at 30 days of age. Gene transfer was confirmed by blue coloration of left lung obtained with Xgal solution in an additional experiment. Histomorphometric evaluation was performed. All groups were compared with ANOVA test and paired test was used to compare right and left lung in each animal. RESULTS: Left lung was similarly hypoplastic in all operated lambs. Left pulmonary artery hypoplasia present in all operated groups was significantly less pronounced in VEGF group. The number of pleural arteries was similarly increased in left lung of all operated lambs. Left lung arterial density was higher in VEGF group than in all other groups. The percentage of parenchyma of left lung was lower in beta-GAL group than in all others, partially returned to normal in VEGF group. CONCLUSIONS: In this model, transbronchial VEGF gene transfer induces pulmonary angiogenesis, proximal pulmonary artery growth and contributes to lung parenchyma recovery.

Solitary fibrous tumors of the pleura: clinical characteristics, surgical treatment and outcome.

OBJECTIVE: The aim of this paper is to study clinical characteristics, surgical treatment and outcome of patients with solitary fibrous tumor of the pleura operated in our institutions in a 20-year period. METHODS: Clinical records of all patients operated for solitary fibrous tumors of the pleura between 1981 and 2000 were reviewed retrospectively. Tumors were classified as malignant in the presence of at least one of the following criteria: (1) high mitotic activity; (2) high cellularity with crowding and overlapping of nuclei; (3) presence of necrosis; (4) pleomorphism; otherwise they were considered as benign. RESULTS: Sixty patients (mean age 55 years) were operated in this period. None had asbestos exposure. Symptoms were present in 31 cases. Surgical approaches included thoracotomy (n=53), video-assisted thoracoscopy (n=6), and median sternotomy (n=1). Tumors originated from visceral pleura in 48 cases, from parietal, mediastinal or diaphragmatic pleura in seven, two and three cases, respectively; their mean diameter was 8.5 cm. Tumors could be resected with their implantation basis in 49 patients. In the remaining 11, extended resections were performed, including lung parenchyma (lobectomy, n=4, pneumonectomy, n=2), osteomuscular chest wall structures (n=2), diaphragm (n=2), and pericardium (n=1). Two postoperative deaths (due to myocardial infarction and pulmonary embolism, respectively) occurred. Tumors were pathologically benign in 38 cases and malignant in 22 cases. Mean follow-up was 88 months. Resection was complete in all the patients with benign tumors and no recurrence occurred. Resection was considered as complete in 21/22 malignant tumors. Local recurrence was observed in two cases. Both could be successfully managed by iterative exeresis (no extended resection had been initially performed). Metastatic disease (responsible for patient's death) was observed following the only incomplete resection. Actuarial 5- and 10-year survival rates were 97% for benign tumors and 89% for malignant ones. CONCLUSIONS: Surgical resection provided cure in all the patients with benign tumors. As insufficiency of exeresis is associated with all recurrences in malignant tumors, completeness of resection is in our experience the best prognostic factor in these forms.

[Thymoma with epithelial micronodules and lymphoid hyperplasia: six cases of a rare and equivocal subtype]. / Thymome avec micronodules épithéliaux et hyperplasie lymphoïde: à propos de six cas d'un sous-type rare équivoque

Thymomas with the characteristic pattern of small epithelial nodules separated by an abundant lymphoid tissue have been recently described with divergent interpretations. These thymomas are not specified in currently used classification systems. We present six such thymomas, including three that represented 1.38% of a series of 217 consecutive cases. These thymomas were totally encapsulated (Masaoka stage I, n=1) or minimally invasive (stage II, n=5). The epithelial cells of the nodules were oval and bland-appearing. In one case, these cells formed rosettes. Cysts, that were present in four cases, showed a strong linear expression of EMA and were associated with foci of glandular differentiation. The lymphoid tissue was composed of large immature (CD1a and CD99-positive) T-cell areas (with epithelial cells restricted to small foci of residual thymus) and of B-cell (CD20-positive) areas with germinal centers. Mature T-cells were also present. Furthermore, one case, associated with myasthenia gravis, had an important WHO type B2 (cortical) component. Such a combined case has not been previously reported. Our study demonstrates that so-called micronodular thymomas are rare, usually have clinical and pathological features of WHO type A (medullary) thymomas, and that the lymphoid component is hyperplastic corresponding to both immature T-cell lymphoid tissue and B-cell lymphoid hyperplasia with germinal centers.

Association of HLA-A in autoimmune myasthenia gravis with thymoma.

We investigated an association of the HLA-A locus in 78 French Caucasian patients with autoimmune myasthenia gravis (MG) and thymic epithelial tumours. The largest effect was a protection associated with HLA-A02 in MG patients with a B2 type thymoma (OR=0.323, 95% CI: 0.113-0.756, P=0.00041). The frequency of HLA-A25 was also increased in the whole group of patients (OR=3.62, 95% CI: 1.62-7.08, P=0.0041). Our findings emphasise the interest of the histological classification in the genetic study of thymomas.

Cysts of the posterior mediastinum showing müllerian differentiation (Hattori's cysts).

Cysts of probable müllerian origin have recently been recognized in the mediastinum by Hattori (Virchows Arch. 2005;446:82-84; Chest. 2005;128:3388-3390). In a retrospective study, we found 9 such cases, accounting for 5.5% of a series of 163 consecutive mediastinal nonneoplastic cysts operated in our institution. These cysts occurred in 9 women aged 40 to 58 years (mean, 50.6 years). These women often had overweight (n=4) or various gynecologic history (n=5). Cysts were paravertebral (n=8) or prevertebral (n=1). They were initially classified as bronchogenic or unspecified benign serous cysts. Their diameter measured 1.3 to 5 cm. Their thin wall contained smooth muscle. They were lined by a simple cylindrical or cuboidal, nonmucinous, and often ciliated epithelium resembling uterine tubal epithelium. This epithelium expressed cytokeratin 7, epithelial membrane antigen and estrogen and progesterone receptors. It was negative for cytokeratin 5/6. In the same series, there were 66 bronchogenic cysts, 6 being paravertebral. In conclusion, cysts with müllerian differentiation account for a small proportion of mediastinal cysts and have a usual but nonspecific paravertebral location.

Paraganglioma with ganglioneuromatous component located in the posterior mediastinum.

A 4-cm paravertebral mediastinal tumor was resected in a 70-year-old male patient treated for hypertension. The tumor displayed both paraganglioma and ganglioneuroma areas that were in equal proportion and often merged one into the other. Paraganglioma areas contained synaptophysin and chromogranin-positive chief cells and PS100-positive sustentacular cells. Ganglioneuroma areas contained neurofilament-positive mature ganglion cells and PS100-positive Schwann cells. Such pheochromocytoma-ganglioneuroma has not been previously reported in the mediastinum and appears as the adrenal and aorticosympathetic counterpart of gangliocytic paraganglioma described in other anatomic sites.

Chest wall resection for invasive lung carcinoma, soft tissue sarcoma, and other types of malignancy. Pathologic aspects in a series of 107 patients.

With improvements in surgical techniques for resection and reconstruction of the chest wall, pathologists are confronted with complicated surgical specimens. There are no currently available guidelines specifically dedicated to the handling of these specimens. Extended resections of lung carcinoma chest wall invasions may change the clinical value of some TNM subsets. We reviewed a series of 107 consecutive malignant tumors involving the chest wall and resected in our institution during a 3-year period. The 107 patients included 39 females and 68 males aged 6 to 80 years (mean, 53 years). Ninety-eight cases (92%) were en bloc resection. There were 55 invasions by lung carcinomas including 19 Pancoast tumors. With the current TNM classification, five lung carcinomas, treated with vertebral body resection because of vertebral foramina invasion, were T3. Four lung carcinomas were N3 or M1 only because of supraclavicular or chest wall lymph node invasion. Other tumors included 20 primary soft-tissue tumors, 13 primary skeletal tumors, 12 metastases, four local invasions by breast tumors, and three miscellaneous lesions. Resected structures included one to six ribs (mean, 2.6; n = 89), thoracic inlet (n = 24), three or four vertebral bodies (n = 13), sternum (n = 17), clavicles (n = 15), shoulder blade (n = 4), upper limb (n = 2), skin (n = 29), lung (n = 64), diaphragm (n = 2), and mediastinum (n = 2). Ten cases were incomplete resections including five because of vertebral body or vertebral foramina tumor invasion. The study of surgical specimens resulting from resection of malignant tumors of the chest wall is complicated because of the variety of both tumor histologic types and involved anatomic structures. Specimen radiograms have a great informative value. Assessment of surgical margins, especially vertebral foramina, is imperative. In lung carcinomas invading the chest wall, we suggest that vertebral foramina invasion could be classified T4 and that the prognostic value of chest wall lymph nodes isolated invasions should be assessed for a possible N1 classification.

Prevention of gram-negative translocation reduces the severity of hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations and an increased alveoloarterial oxygen difference (AaPO(2)). These abnormalities are related to augmented pulmonary nitric oxide (NO) production, dependent primarily on increases in the expression and activity of inducible NO-synthase (iNOS) within pulmonary intravascular macrophages and, to a lesser extent, of endothelial NOS (eNOS). Production of iNOS by pulmonary intravascular macrophages might be related to translocated gut bacteria present in the pulmonary circulation. To test this hypothesis, we determined whether macrophage sequestration, lung iNOS expression and activity, and HPS severity were decreased after norfloxacin was given for 5 weeks to prevent Gram-negative bacterial translocation in rats with common bile duct ligation-induced cirrhosis. Norfloxacin decreased the incidence of Gram-negative translocation from 70 to 0% and the percentage of pulmonary microvessels containing more than 10 macrophages from 52 +/- 7 to 21 +/- 8% (p < 0.01). AaPO(2) and cerebral uptake of intravenous (99m)Tc-labeled albumin macroaggregates (reflecting intrapulmonary vascular dilatations) were intermediate to those of untreated cirrhotic and sham-operated rats. The activity and expression of lung iNOS, but not eNOS, were reduced to normal. Norfloxacin may reduce HPS severity by inhibiting Gram-negative bacterial translocation, thereby decreasing NO production by pulmonary intravascular macrophages. Bacterial translocation may be the key to the pathogenesis of HPS.