Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is defined as a poorly differentiated and high-grade neuroendocrine tumor that is morphologically and biologically between atypical carcinoid and small cell lung carcinoma (SCLC). During a survey concerning bcl-2 protein expression in the subtypes of lung cancer, we noticed that two previously diagnosed non-SCLCs met the criteria for LCNEC. Because LCNEC is a newly recognized clinicopathologic entity and because all reported cases have been retrieved from the so-called "neuroendocrine tumor file," we suspected that LCNEC had been underdiagnosed. In the present study, we histologically reviewed 766 surgically resected lung cancers and were able to diagnose 22 (2.87%) LCNECs with the neuroendocrine features subsequently confirmed by immunostaining for multiple neuroendocrine markers. Each case stained positively for at least three general neuroendocrine markers, and 12 (54.5%) also were positive for neuroendocrine hormones. Histologically, most LCNECs showed a marked decrease in or a loss of organoid architecture and could be mistaken for poorly differentiated adenocarcinoma or squamous cell carcinoma. Because our LCNECs are the first to be identified by retrospective review of routinely diagnosed lung cancers, and 18 had been classified as non-SCLC, they may represent cases relatively difficult to diagnose. The present study shows that the most difficult diagnostic factor of LCNEC is the recognition of its light microscopic neuroendocrine features, and LCNEC must be distinguished not only from atypical carcinoid or SCLC, but also from common non-SCLC. Histologically, when an organoid architecture is subtle or absent, the rosettelike structure becomes the best marker for the recognition of neuroendocrine differentiation. Clinically, the prognosis for our LCNECs was significantly worse than that for stage-comparable non-SCLCs (p = 0.046).

Clinicopathologic significance of telomerase activity and hTERT mRNA expression in non-small cell lung cancer.

Telomerase has been reported to be a novel diagnostic marker for malignant diseases and has been recently proven to be composed of three main components, hTR (human telomerase RNA component), TP1 (telomerase-associated protein 1) and hTERT (human telomerase reverse transcriptase), the last of which plays a key role in telomerase activation. In the present study, quantitative levels of telomerase activity and hTERT gene mRNA (hTERT) expression were analyzed in cancerous and non-cancerous lung tissues of 62 lung cancer patients by telomeric repeat amplification protocol and reverse transcription-PCR, respectively. The telomerase expression levels of each group of tissue samples were compared with clinicopathologic variables. Telomerase activity and hTERT were detected in cancerous tissues (75.8 and 75.8%, respectively), while these parameters were not observed in any non-cancerous tissues. In quantitative assessment of telomerase expression, both telomerase activity and hTERT were significantly correlated with lymph node metastasis (N0 vs. N1+2, P<0.05). Telomerase activity also correlated with tumor cell differentiation and stage classification (P<0.05), but did not correlate with other clinicopathologic variables. The disease-free survival in patients with lung cancer demonstrated that patients with hTERT-positive tumor survived for a significantly shorter period than those with hTERT-negative tumor (P=0.0334). Since hTERT levels are correlated with N factor which represents the true aggressiveness of patients' disease concerning the evaluation of clinical outcome, hTERT was found to be one of the important markers revealing biological malignant potentials for lung cancer.

[Extended operation for lung cancer: concomitant resection of the heart or the great vessels with the lung].

We have analysed our experience in 43 patients with lung cancer invading the heart or great vessels who underwent surgical resection of the invaded portion of the mediastinal organs as well as the primary tumor, and have reviewed the literature on the subject of the extended operation for lung cancer invading the heart or great vessels. Among our experience of those 43 patients, a single mediastinal organ was resected in 32 patients (the left atrium in 20, the main pulmonary artery in 7, superior vena cava in 3 and the adventitia of the aorta in 2), and more than two mediastinal organ were resected in 11 patients (the main pulmonary artery and the other in 8, and the left atrium and esophagus or trachea in 3). There were 34 squamous cell carcinomas, 4 adenocarcinomas, 3 large cell carcinomas and 3 other cell types. Pathology disclosed 6 patients had pT 3 tumor (Group 1, 24 patients had pT 4 tumor that had invaded to a single mediastinal organ (Group 2) and 11 patients had pT 4 tumor that had invaded to more than two mediastinal organs (Group 3). The 5 year survival rate in patients of Group 1, 2 and 3 were 80%, 32.2% and 0%, respectively. There were statistical differences among the survivals of those three groups. We conclude that extended resection for lung cancer invading the heart or great vessels is justified if the invasion is limited to a single mediastinal organ. Several problems on such extended resection were discussed.

[Clinicopathological study of early peripheral adenocarcinoma of the lung].

Fifty surgically resected small peripheral adenocarcinomas measuring 20 mm or less in greatest diameter were reviewed according to Noguchi classification (1995). Type A (localized bronchioloalveolar carcinoma: LBAC) and type B (LBAC with foci of structural collapse of alveoli) showed no lymph node metastasis and in these two types, 5-year survival was 100%. Histologic types A and B in Noguchi classification are thought to be early peripheral adenocarcinoma. By further evaluation of preoperative imaging diagnosis, operative procedure and pathological study patients with early peripheral adenocarcinoma would be able to become candidates for limited surgery (segmentectomy or partial resection).

[Pleuropneumonectomy with combined resection of diaphragma, superior vena cava, and pericardium, for invasive thymoma with pleural dissemination].

A 63-year-old female was admitted to our hospital with chief complaint of exertional dyspnea. Right massive pleural effusion was found. After chest drainage was performed, chest CT scan and MRI showed several masses in the anterior mediastinum and on the diaphragma. Mesothelioma was suspected for needle biopsy. Pleuropneumonectomy with combined resection of diaphragma, superior vena cava and pericardium was performed. Histologically, the Tumor was mixed thymoma. She is well and alive for three years after operation. Pleuropneumonectomy may be a choice of effective treatments for invasive thymoma with pleural dissemination.

[A case of pneumothorax which was operated with the axillary longitudinal small incision].

A pneumothorax usually occurs in young men. From the cosmetic point of view, the size of the skin incision should be considered to be minimal if surgery is applied for young pneumothorax patients. We reported a case of pneumothorax which was operated with a small longitudinal axillary skin incision, the size of which was 3.5 cm long. The patient was a 18-year-old high school student. He was admitted to our hospital with the diagnosis of spontaneous pneumothorax. His chest X-ray showed a moderate collapse of his left lung and bullae in his left apex. Tube drainage was performed and the collapsed lung re-expanded completely. Chest CT scan demonstrated that he had bullae in the apex of his left lung. No other lesions were found in the other part of both lungs. Surgery was indicated socially. Bullectomy was successfully performed with a small (3.5 cm) longitudinal axillary skin incision. We recommend this skin incision for young patients with pneumothorax if the chest CT scan confirms that the bullae or blebs are localized to the apex of superior segment of the lower lobe.

[A case of metachronous multiple primary lung cancers coexistent with atypical adenomatous hyperplasia].

A seventy-year-old woman was admitted for an abnormal chest shadow on a routine radiograph. She had undergone left upper lobectomy with mediastinal lymph node resection (R2a) for lung cancer (stage I), eight years before. We diagnosed this cancer as well differentiated papillary adenocarcinoma, and it coexisted with a focus of atypical adenomatous hyperplasia (AAH) in the resected material. We had been following up this patient with chest radiography, CT scanning, and tumor marker tests, but eight years after her first operation, we found a small nodular lesion in the left upper field (S6). This nodule was not diagnosed with fiberoptic bronchoscopy. Because we could not exclude primary lung cancer or intrapulmonary metastasis (eight years ago), we performed partial lung resection on the left S6 nodule. Histopathologically, the diagnosis was well differentiated papillary adenocarcinoma of the lung, coexisting with a small hyperplastic focus in the resected material. It was very difficult to diagnose whether these two cancers were metachronous multiple primary lung cancers, or one primary and its intrapulmonary metastasis. In a retrospective study, an immunohistochemical examination employing Ki-67, PCNA, p 27 and p 53 was performed in order to differentiate between metachronous multiple primary lung cancer and intrapulmonary metastasis. But we found AAH in the same resected lung eight years ago, and suggested the possibility that another small, atypical focus had developed into a malignancy. We report a case of metachronous multiple primary lung cancers and review the relevant literature.

[Case report of surgically treated dumbbell-type schwannoma arising in the right brachial plexus with von Recklinghausen disease].

We encountered a patient with dumbbell-type schwannoma arising in the right brachial plexus with von Recklinghausen disease. The patient was a 9-year-old girl. An abnormal shadow was detected high in the thoracic cavity by thoracic radiography. Thoracic CT and MRI demonstrated at the apex of the thoracic cavity a tumor measuring 9.0 x 6.0 cm, which was diagnosed as a dumbbell-type neurogenic tumor derived from the brachial plexus. Most cases of such tumors growing inside and outside the spinal cavity have reportedly been treated in a single surgical procedure. However, since the tumor in this patient was large, the intrathoracic portion was removed first in order to minimize the magnitude of the surgical invasion. The residual intraspinal tumor was removed during subsequent surgery. No neurological problems were observed after surgery. Patients with dumbbell-type schwannomas arising in the right brachial plexus appear to be very rare, and this patient was considered noteworthy.

[Legionnaires' disease with mediastinal lymph nodes swelling, diagnosed by open lung biopsy--a case report].

Legionnaires' disease in a 37-year-old male who had had silicosis was reported. He was admitted because of dyspnea. The chest X-ray film and CT scan showed infiltrative shadow and swelling of mediastinal lymph nodes. Open lung biopsy was done and Legionella pneumohila was detected. REP and EM were started and infiltrative shadow of X-ray was disappeared. Pleuro-pneumonectomy and thoracoplasty were performed because of hemoptysis and postoperative empyema. The patient is now well.

[Combined resection of the aortic wall using extracorporeal circulation in lung cancer patients].

Two cases of lung cancer performed combined resection of the aortic wall using extracorporeal circulation were discussed in this paper. One was 59-year old male and another was 63-year old male. Both had squamous cell carcinoma of the left upper lobe. CAT scan suggested the tumor invaded into the aortic wall, main pulmonary artery and left atrium in either patients. For the first case, separated perfusion to the upper half and lower half of his body, and for the second case, perfusion only to the lower half of the body were employed to resect and repair the aortic wall, using Dacron patch. For the first case, the left main pulmonary artery and the left atrial wall were resected in advance under the regular extracorporeal circulation. The first case died of the recurrence of the tumor 1 year and 7 months post-operatively, resulting the hemorrhage into the thoracic cavity. The second case died of empyema resulting massive hemorrhage from the anastomotic site of the patch 3 months post operatively. We think some managements such as the coverage of the synthetic graft with the omentum would be needed.

The significance of frequent and independent p53 and bcl-2 expression in large-cell neuroendocrine carcinomas of the lung.

Both p53 and bcl-2 genes are involved in regulating cell death. Reports, however, concerning the relationship between p53 and bcl-2 expression are contradictory. Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a newly recognized clinicopathologic entity. p53 mutation and bcl-2 overexpression are frequent in small-cell lung carcinoma (SCLC), and we observed a close correlation between bcl-2 expression and cellular neuroendocrine (NE) differentiation in non-SCLC, so we speculated that LCNEC, an NE tumor closely related to SCLC, would exhibit high incidence of both p53 alteration and bcl-2 expression. Immunohistochemical expression of p53 and bcl-2 was evaluated on consecutive sections of 26 LCNECs, including 4 combined LCNECs. p53 accumulation and diffuse bcl-2 staining were observed in 18 (69.2%) of 26 and 24 (92.3%) of 26 LCNECs, respectively, but their immunoreactivities showed no fixed distribution relevance on consecutive sections in individual tumors. Statistical analyses yielded no relationship between p53 and bcl-2 expression (P = .47). In all of the four combined LCNECs, p53 was identically either positive or negative in both tumor cell populations with and without NE differentiation. bcl-2 immunoreactivity was observed only for the tumor cells with NE phenotype in three of the four combined LCNECs and was diffuse among the NE tumor cells but geographic in distribution among the non-NE tumor cells of the remaining one combined LCNEC. Thus, our present findings suggest that p53 and bcl-2 are expressed independently and might have distinct expression significance in LCNECs. A high incidence of p53 expression in LCNECs and equal p53 expression profiles in NE and non-NE tumor cell populations of combined LCNECs suggest that p53 alteration is primarily involved in the tumorigenesis of LCNEC. On the other hand, frequent bcl-2 expression in pure LCNECs and selective bcl-2 expression in tumor cells with NE phenotype in combined LCNECs are suggestive of a role for bcl-2 in regulating cellular NE differentiation.

[A case of pulmonary mucormycosis accompanied by lymphocytic leukemia successfully treated by pulmonary lobectomy].

A 51 years old man with acute lymphocytic leukemia who was treated with antileukemic chemotherapy, developed sepsis and pneumonia. Secondary infection with Mucor intervened with abscess formation cured by lobectomy. The patient is doing well without evidence of recurrence, and treated successfully with anti-leukemic chemotherapy. Surgical treatment offers the last chance of survival in similar cases.

[Chronic hemorrhagic empyema developed in thirty three years after the right pneumonectomy--a case report].

A 55-year-old man was admitted because of exertional dyspnea. He had the right pneumonectomy thirty three years ago. Chest X-ray showed the mediastinal shift to the left. And chest CT scan showed right intrathoracic mass. The bloody pleural effusion was aspirated (Hb 9.4 g/dl) and its examination revealed Staphylococcus epidermidis. We resected the empyema cavity. During the operation, massive bleeding was experienced (total 23200 ml). Pathologically, micro blood vessels were marked in the organized hematomas and the pleura. Chronic hemorrhagic empyema is a specific type of chronic empyemas and it is dangerous to remove of the hematomas because of massive bleeding.

Pulmonary blastoma. Comparison between its epithelial components and fetal bronchial epithelium.

Three cases of pulmonary blastoma exhibiting biphasic epithelial and stromal patterns, and a case of fetal lung-type adenocarcinoma, were examined by immunohistochemistry and electron microscopy (EM) and compared with fetal bronchial epithelium in order to explore the multidirectional differentiation of their epithelial components. The glandular cells of all four tumors resembled fetal bronchial epithelial cells in the pseudoglandular stage. Neuroendocrine (NE) cells were also present; they were argyrophilic and expressed pan-NE markers, neurosecretory granules and peptide hormones. The neural cell adhesion molecule (NCAM) was strongly expressed on the cell membranes of glandular cells, as in the case of proximal bronchial epithelial cells at the pseudoglandular stage in fetal lung. Sialosylated Lewis X was also expressed, indicating that the epithelial cells were possibly of endodermal origin. Two of the four cases showed considerable immunoreactivity for alpha-fetoprotein (AFP). The epithelial cells of pulmonary blastomas may occasionally de-differentiate into cells functionally resembling fetal hepatic, foregut and yolk sac cells expressing AFP. Tumor examination by immunohistochemistry and EM suggested that the glandular cells of the tumors may differentiate to some extent like those of fetal large bronchi at the pseudoglandular stage, but there was concordance and discordance in the expression of neuroendocrine and oncofetal markers between blastomatous tumors and fetal bronchial epithelium.