Diagnosis and prognosis of neuroendocrine tumours of the lung by means of high resolution image analysis.

Neuroendocrine tumours (NET) of the lung are divided in subtypes with different malignant potential. The first is the benign or low-grade malignant tumours, well-differentiated, called typical carcinoids (TC) and the second is the high-grade malignant tumours, poorly differentiated of small (SCLC) or large cell type (LCLC). Between these tumour types lies the well-differentiated carcinoma with a lower grade of malignancy (WDNEC). In clinical routine it is very important with regard to prognosis to distinguish patients with low malignant potential from those with higher ones. In this study 32 cases of SCLC, 13 of WDNEC and 14 of TC with a follow-up time up to 7 years were collected. Sections 4 microm thick from paraffin embedded tissue were Feulgen stained. By means of high resolution image analysis 100 nuclei per case were randomly gathered to extract morphometric, densitometric and textural quantitative features. To investigate the ploidy status of the tumour the corrected DNA distribution was calculated. Stepwise linear discriminant analysis to differentiate the classes and Cox regression analysis for the survival time analysis were applied. Using chromatin textural and morphometric features in two two-class discriminations, 11 of the 14 TC cases and 8 of the 13 WDNEC cases were correctly classified and 11/13 WDNEC cases and 28/32 SCLC cases, respectively. The WDNEC cases are more similar in chromatin structure to TC than to SCLC. For the survival analysis, only chromatin features were selected to differentiate patients with better and worse prognosis independent of staging and tumour type.

Imaging of lung cancer with fluorine-18 fluorodeoxyglucose: comparison of a dual-head gamma camera in coincidence mode with a full-ring positron emission tomography system.

Dual-head gamma cameras operated in coincidence mode are a new approach for tumour imaging using fluorine-18 fluorodeoxyglucose (FDG). The aim of this study was to assess the diagnostic accuracy of such a camera system in comparison with a full-ring positron emission tomography (PET) system in patients with lung cancer. Twenty-seven patients (1 female, 26 males, age 62+/-9 years) with lung cancer or indeterminate pulmonary nodules were studied on the same day with a full-ring PET scanner (Siemens ECAT EXACT) and a coincidence gamma camera system (ADAC Vertex MCD). Sixty minutes after injection of 185-370 MBq FDG, a scan of the chest was performed with the full-ring system. Approximately 2 h p.i., the coincidence camera study was performed. Coincidence gamma camera (CGC) and PET images with (PETac) and without attenuation correction (PETnac) were analysed independently by two blinded observers. In addition, FDG uptake in primary tumours and involved lymph nodes was quantified relative to normal contralateral lung (T/L ratios). All primary tumours were histologically proven. The lymph node status was histologically determined in 23 patients. In four patients, no lymph node sampling was performed because of extensive disease or concurrent illnesses. In the 27 patients, 25 primary lung cancers and two metastatic lesions were histologically diagnosed. The number of coincidences per centimetre axial field of view was 3.33+/-0. 93x10(5) for the CGC and 1.09+/-0.36x10(6) for the dedicated PET system. All primary tumours (size: 4.6+/-2.6 cm) were correctly identified in the CGC and dedicated PET studies. T/L ratios were 4. 7+/-2.5 for CGC and 6.9+/-2.8 for PETnac (P <0.001). Histopathological evaluation revealed lymph node metastases in 11 of 88 sampled lymph node stations (size: 2.3+/-1.0 cm). All lymph node metastases were identified in the PETac studies, while PETnac detected 10/11 and CGC 8/11. For positive lymph nodes that were visible in CGC and PETnac studies, T/L ratios were 3.7+/-2.3 for CGC and 6.6+/-3.1 for PETnac (P=0.02). The diameters of false-negative lymph nodes in the CGC studies were 0.75, 1.5 and 2 cm. False-positive FDG uptake in lymph nodes was found in two patients with all three imaging methods. For all lesions combined, T/L ratios in CGC relative to PETnac studies decreased significantly with decreasing lesion size (r=0.62; P<0.001). In conclusion, compared with a full-ring PET system the sensitivity of CGC imaging for detection of lung cancer is limited by a lower image contrast which deteriorates with decreasing lesion size. Nevertheless, the ability of CGC imaging to detect pulmonary lesions with a diameter of at least 2 cm appears to be similar to that of a full-ring system. Both systems provide a similar specificity for the evaluation of lymph node involvement.

Controlled prospective study of positron emission tomography using the glucose analogue [18f]fluorodeoxyglucose in the evaluation of pulmonary nodules.

BACKGROUND: Positron emission tomography (PET) is a new imaging technique which, by measuring focal metabolic activities, can make a qualitative statement (benign or malignant) about a tumour. PET has been described in many studies to provide a high diagnostic accuracy for the evaluation of pulmonary coin lesions. However, these studies were not always supported by histological confirmation of the results. In a controlled prospective study, it was investigated whether the diagnostic accuracy of PET is sufficiently high to allow omission of diagnostic thoracotomy or thoracoscopy in the case of a negative finding. METHODS: A PET scan was carried out before operation using [18F]fluorodeoxyglucose (FDG) in 50 patients with pulmonary coin lesions (diameter 30 mm or less). All of these lesions were completely removed thoracoscopically or by a formal thoracotomy and were examined histologically. Using the histology results, the diagnostic accuracy of the PET procedure with regard to a benign or malignant diagnosis was evaluated and compared with that of computed tomography (CT). Results From a total of 54 coin lesions (four of the 50 patients had two lesions) there were 31 malignant (19 primary bronchial carcinomas, 12 metastases) and 23 benign diagnoses. With the PET procedure 28 of 31 malignant and 19 of 23 benign lesions were classified correctly (sensitivity 90 per cent, specificity 83 per cent). False negatives included two bronchial carcinomas and one metastasis. CT had a sensitivity of 100 per cent and specificity of 52 per cent. CONCLUSION: FDG PET cannot generally be considered as a replacement for diagnostic thoracoscopy or thoracotomy at the present time. However, by combining FDG PET with radiological follow-up, clinical applications may evolve in patients at low risk for a malignant tumour or at high risk for surgical complications.

Typical and atypical carcinoid tumors of the lung are characterized by 11q deletions as detected by comparative genomic hybridization.

Neuroendocrine tumors of the lung represent a wide spectrum of phenotypically distinct entities with different biological characteristics such as typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC). The histogenetic relationships between TC, AC, LCNEC, and SCLC are still unclear. This study was carried out to provide cytogenetic data about pulmonary neuroendocrine tumors and to evaluate their characteristic alterations and histogenetic relations for an improved understanding of the mechanisms of tumor development. Twenty-nine paraffin-embedded tumor samples of TC (n = 17), AC (n = 6), LCNEC (n = 3), and SCLC (n = 3) were selected for isolation of tumor DNA and subsequent comparative genomic hybridization (CGH) analysis. To confirm the comparative genomic hybridization results for characteristic chromosomal imbalances, selected cases were additionally investigated by loss of heterozygosity analysis. For statistical evaluation, we also used comparative genomic hybridization data from 45 published SCLC cases. DNA underrepresentations of 11q were the most frequent findings in TC (8 of 17) and AC (4 of 6), whereas these aberrations were rare in LCNEC (1 of 3) and SCLC (0 of 3). Furthermore, AC showed DNA underrepresentation of 10q (3 of 6) and 13q (3 of 6). In contrast, SCLC and LCNEC were characterized by a different pattern of DNA losses (3p-, 4q-, 5q-, 13q-, and 15q-) and gains (5p+, 17p+, and +20). Statistical analysis revealed significantly different occurrences of 11q deletions in TC/AC versus SCLC (45 published cases of SCLC and our 3 cases; P = 0.002; Fisher's exact test). Thus, TC and AC display frequent loss of 11q material including the MEN1 gene locus, which represents a characteristic genetic alteration in these tumors. Losses of 10q and 13q sequences allow a further cytogenetic differentiation between TC and AC. These additional changes might be responsible for the more aggressive behavior of AC. Three cases of LCNEC, the first to be analyzed by comparative genomic hybridization, exhibited similar complex abnormal patterns (4q-, 5q-, 10q-, 13q-, 15q-) to those of SCLC. Although neuroendocrine tumors of the lung share common phenotypic features, suggesting a genotypic relationship, they differ remarkably in their cytogenetic characteristics, highlighting an early fundamental molecular divergence during the development of these tumors.

[Diagnosis of bronchial carcinoma]. / Diagnostik des Bronchialkarzinoms.

In addition to conventional chest X-rays in AP and lateral projection, computed tomography of the chest, upper abdomen, and head, precutaneous ultrasonography of the abdomen, and bone scintigraphy represent the standard procedures for the primary diagnosis and staging of bronchial carcinoma. Magnetic resonance imaging should be reserved for special situations and patients with allergy to i.v. contrast medium. The clinical value of positron emission tomography (PET) primarily with respect to lymph-node staging is currently being evaluated in ongoing studies. Due to the high sensitivity of the listed staging modalities in combination with rather low specificity, there is a general tendency towards "over staging", which carries certain risk particularly for potentially operable patients. Consequently the criteria which indicate inoperability (T3, T4, N2, N3 and, in individual cases, M1) have to be confirmed histologically by biopsy employing interventional techniques or even by explorative thoracotomy before definite therapeutic decisions are made.

Pulmonary nodule caused by an alveolar adenoma of the lung.

Alveolar adenomas of the lung may be a rare cause of solitary coin lesions on chest radiographs. We report a case of this neoplasm, describe its morphological and immunohistochemical characteristics and give further evidence that alveolar adenomas of the lung represent a benign proliferation of both the alveolar epithelium and the septal mesenchyme.

Prognostic importance of histomorphologic subclassification for epithelial thymic tumors.

BACKGROUND: The prognostic importance of various clinical variables (age, sex, association with myasthenia gravis), staging according to Masaoka, histologic type according to the Marino/Kirchner/Müller-Hermelink (MKM-H) classification, and residual tumor category (R category) was evaluated in a retrospective analysis. METHODS: Eighty-two patients with epithelial thymic tumors (ETTs) treated in the period 1969-1993 were evaluated, and archived specimens were histologically reclassified according to the classification of MKM-H. RESULTS: Age, sex, and association with myasthenia gravis were of no prognostic importance. The R category is of significant prognostic importance, with 5- and 10-year survival rates of 93.6% and 87.3%, respectively, for R0 resections compared with 0% at 5 years for R1 and R2 resections (p < 0.001). Staging (Masaoka) proved to be a prognostic factor (5-/10-year survival: stage I, 100%/90.9%; II, 95%/88.2%; III, 55.9%/46.6%; and IV, 10.8%/ 10.8%; p < 0.001). Histologic typing according to MKM-H is also of significant prognostic importance (5/10 year survival: thymomas: medullary, 100%/100%; mixed, 100%/100%, predominantly cortical, 68.6%/68.6%; cortical, 65.8%/65.8%; thymic carcinomas: well-differentiated type, 62.3%/44.5%; thymic carcinomas other than well-differentiated type, 33.6%/26.9%; p < 0.001). Multivariate analysis demonstrated that staging (p < 0.001), R category (p < 0.026), and MKM-H classification (p < 0.028) have an independent impact on survival. CONCLUSIONS: Staging (Masaoka), R category, and histologic classification (MKM-H) are important independent prognostic factors for patients with epithelial thymic tumors. Complete (R0) surgical resections should be the ultimate goal in the clinical management of patients with epithelial thymic tumors.

Prognostic value of MIB-1 in neuroendocrine tumours of the lung.

The spectrum of neuroendocrine lung tumours ranges from highly aggressive small cell carcinomas (SCLC) to carcinoid tumours (CD) of low malignant potential. Between these two extremes, the 'well-differentiated neuroendocrine carcinomas' (WDNEC) form a transitional group with uncertain biological behaviour. This study investigated the prognostic value of the proliferation marker MIB-1 (paraffin Ki-67) in 59 neuroendocrine lung tumours (32 SCLC, 13 WDNEC, 14 CD) by immunostaining of routinely processed paraffin sections. Morphometric evaluation was done by semi-automatic image analysis. The results were compared with survival data (mean follow-up: 42 months). The proliferation rates of the tumours as determined by MIB-1 immunoreactivity (MIB-1-PR) were significantly different between the tumour types (SCLC > WDNEC > CD) and showed a strong inverse correlation with survival time. In CD, the percentage of MIB-1-labelled nuclei never exceeded 1.1 per cent; higher values would therefore favour the diagnosis of WDNEC over that of CD. Among WDNEC, MIB-1 was able to differentiate a subgroup with excellent prognosis (MIB-1-PR: 0.3-3.4 per cent) from another subgroup with a death rate of 50 per cent (MIB-1-PR: 7.3-20.3 per cent). Within each tumour type, all patients without distant metastases at diagnosis survived when MIB-1-PR was < or = 9.4 per cent, suggesting a potential threshold for prognosis. Although the status of metastases are complementary prognostic indicators and are best used in combination to characterize the biological behaviour of neuroendocrine lung tumours.

Combined amyloidosis of the upper and lower respiratory tract.

Pulmonary and laryngeal manifestations of localized and organ-limited amyloidosis are sometimes seen, although pulmonary and laryngeotracheal amyloidosis are not always associated. Diagnosis can only be established histologically by the characteristic green birefringence in polarized light after Congo red staining and by immunohistochemical techniques. We describe the case of a 77-year-old woman who presented with hoarseness and an unproductive cough due to extensive amyloid deposits in both the upper and lower respiratory tract, immunohistochemically proven as the A lambda-type.

Prognostic value of nucleolar organizer regions in neuroendocrine tumours of the lung.

The value of the number and size of the nucleolar organizer regions (NORs) as prognostic indicators in human neuroendocrine lung tumours was evaluated in a quantitative study of 57 cases, including 33 small cell carcinomas (SCLCs), 9 well-differentiated neuroendocrine carcinomas (WDNECs) and 15 "classic" carcinoids. NORs were visualized on paraffin sections by an argyrophilic technique (AgNOR) and measured by automatic image analysis. In each case, the mean number and area of AgNORs were evaluated; the results were compared with clinical follow-up and survival. AgNOR values for both number and area were significantly higher in SCLCs than in WDNECs and carcinoids. WDNECs had insignificantly higher AgNOR values than carcinoids. Among SCLCs, AgNOR values of the oat cell subtype and the intermediate cell subtype did not differ significantly. Regardless of the histological tumour type, AgNOR values strongly correlated with prognosis, with more and larger AgNORs indicating a more progressive clinical course. In the present study we demonstrate for the first time that the biological behaviour of neuroendocrine lung tumours is correlated with the number and size of AgNORs. Thus the measurement of AgNORs may serve as an additional prognostic indicator in these neoplasms, particularly in the separation of SCLCs from WDNECs with a more favourable prognosis.

[Actuarial survival and prognostic factors of bronchial cancer]. / Uberlebenswahrscheinlichkeit und prognostische Faktoren des Bronchialkarzinoms.

A total of 1325 patients with bronchogenic carcinoma who were treated at the surgical clinic of the Technical University of Munich between 1981 and 1991 were enrolled in a prospective follow-up study. The 5-year actuarial survival rate of 605 patients with squamous cell carcinoma was 28.2%, of 288 patients with adenocarcinoma 38.0%, of 219 patients with small cell carcinoma 15.4%, of 74 patients with giant cell carcinoma 19.0%, and of 139 patients with other histologic findings 27.8%. In all, 680 patients (51.4%) underwent surgery. Diagnostic thoracotomy without resection was performed in 6.2% of cases. Lethality within 30 days was 1% for lobectomy, 7.3% for bilobectomy, and 7.7% for pneumonectomy including extended resections. The 5-year survival rates among the operated patients were 64.8% for T1N0M0 tumours, 49.4% for T2N0M0, 46.1% for T1N1M0, 43.4% for T2N1M0, 23.8% for T3 and 11.7% for T4. T1N0M0 adenocarcinoma was associated with a better prognosis than squamous cell carcinoma of the same early stage, with a 5-year survival rate of 82.2% vs 55.9%. The prognosis of patients with T3N2 was worse than that of patients with a T3-4 primary tumour but only N0-1 lymph node involvement (5-year survival rate 18.1% vs 31.7%). Stepwise logistic regression analysis identified tumour stage, therapy, and histologic result as the factors with the greatest impact on the prognosis. Adjuvant radiation after resection in patients with T2-3 adenocarcinoma or squamous cell carcinoma improved the prognosis by one tumour stage compared with patients who only underwent surgery. In conclusion, surgical therapy of bronchogenic carcinoma offers favourable survival rates with acceptable risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Multimodal therapy of small cell lung cancer in TNM stages I through IIIa.

Since 1977, Innsbruck University Hospital has been employing a multimodal therapy concept for small cell bronchial carcinomas in stages I to IIIa. This concept includes all three treatment forms effective in this tumor, namely, chemotherapy, surgery, and radiotherapy. The therapy scheme is stage-dependent and begins in stages T1-3 N0-1 with lung resection and in stage N2 with chemotherapy. To date, 45 patients have been included in a prospective, nonrandomized (phase II) trial: 7 in TNM stage I, 11 in stage II, and 27 in stage IIIa (6 T3 and 21 N2). The actuarial 5-year survival rate of the entire group (including therapy-related lethality, early recurrences, and protocol violations) is 36%; it is 57% for those in stage I, 28% for those in stage II, and 34% for those in stage IIIa. Median survival time is 18 months. Patients with completed multimodal treatment have a 5-year survival rate of 56% regardless of disease stage. Three patients died of tumor-unrelated causes after 47, 52, and 54 months.

Simultaneous pneumonectomy and esophagectomy for bronchial carcinoma.

Two cases of bronchial carcinoma with oesophageal involvement are presented. Both were treated by simultaneous pneumonectomy and oesophagectomy. The postoperative course of each patient was complicated by secondary infection of the pneumonectomy space. One patient expired from a recurrent intratracheal tumour on the 83rd postoperative day and the other remains tumour free 3 years after treatment. As few therapeutic alternatives exist for non small cell bronchial carcinoma, primary radical surgical treatment should be considered, even in advanced cases where the tumour invades the oesophagus.

[Pericardial tamponade following extraction of a pacemaker electrode]. / Herzbeuteltamponade nach Extraktion einer Schrittmacherelektrode.

A case of pericardial tamponade in a male patient secondary to the removal of an epicardial pacemaker wire is reported, resulting in rapid circulatory deterioration. Sternotomy with subsequent pericardectomy immediately relieved the compression of the heart. The postoperative period was complicated by a cerebral infarction on the third postoperative day, probably caused by cardiac embolism while the role of intraoperative hypotension is uncertain.

A mediastinal tumor simulated by a sacculated aneurysm of the azygos vein.

A rare case of a true idiopathic aneurysm of the azygos vein is reported. A 54 year old female with signs of obstruction of the superior caval vein was submitted to a chest X-ray-examination. It showed a giant mass in the right chest with a diameter of 12 cm. Mediastinal phlebography, CT and NMR-scans of the thorax yielded an aneurysmatic tumor, which seemed to originate from the superior caval vein near to the right atrium. With the clinical diagnosis of an aneurysm of the superior caval vein a right thoracotomy was carried out. Intraoperatively we found a sacculated aneurysm of the azygos vein near to the superior caval vein. Despite of extensive, clinical and radiographic investigations no cause for the aneurysm could be detected. This is one of the very rare cases of congenital aneurysm of the azygos vein.

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks.

Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activity in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m2 and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m2. At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m2 consisted of ocular symptoms ('light flashes') accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m2/1 hour was considered the MTD. There were four deaths on study, all considered disease-related. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center. The recommended dose for phase II trials derived from our results is 12,550 mg/m2/2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)