Large Cell Undifferentiated Carcinoma Research Articles

Long-term survival after brain metastasis from lung cancer

A case is reported of prolonged survival after lobectomy for large cell undifferentiated carcinoma of the lung and resection of metastatic carcinoma of the brain. The patient had survived 11 years 5 months after lung resection and 10 years 4 months after excision of brain metastasis. A review of the reports of another 12 patients who survived 5 years or longer after craniotomy, shows that the surgical excision of a single metastatic lesion of the brain with or without postoperative irradiation offers the best hope for prolonged survival.

Immunodetection of neuron‐specific enolase and keratin in cytological preparations as an aid in the differential diagnosis of lung cancer

The results of neuron-specific enolase (NSE) and keratin immunodetection in cytological specimens of sputum secured from 41 patients with lung cancer are presented. All 19 cases of small-cell carcinoma showed intense immunoreactivity for NSE. No such immunoreactivity was found in 21 of 22 cases of non-small-cell carcinoma. The single positive result was from a case of large-cell undifferentiated carcinoma. All 10 cases of squamous-cell carcinoma showed immunoreactivity for keratin. The 19 cases of small-cell carcinoma showed no such reactivity. Our findings indicate that immunostaining for NSE and keratin is a valuable aid when a definite diagnosis of small-cell carcinoma of the lung can not be made on the basis of conventional cytologic features.

Multiple primary neoplasia of the head and neck and lung. The changing histopathology.

The authors reviewed 1373 consecutive cases of patients with oral head and neck cancer or lung cancer and identified 25 patients with multiple primary neoplasia (MPN). All 25 MPN cases had squamous carcinoma of the head and neck; however, only 40% (N = 10) had squamous carcinoma of the lung. The histologic types of non-squamous lung carcinoma were: adenocarcinoma 36% (N = 9), small cell carcinoma 20% (N = 5), and large cell undifferentiated carcinoma 4% (N = 1). Of 927 cases of MPN of the head and neck and lung reported in the English language literature, only 100 cases (10.78%) demonstrated a histologic discrepancy between the primary tumors. Recent reports demonstrate a histologic shift toward non-squamous lung carcinoma in MPN that is similar to our data, and that corresponds to the increase in non-squamous carcinomas recently seen in lung cancer in general. Possible implications of these findings are discussed.

Dose-Tumor Response and Survival Studies in Radiation Therapy of Non-Small Cell Lung Cancer: Radiotherapy in Lung Cancer

Radiation therapy is the current standard treatment for patients with unresectable non-oat cell carcinoma of the lung or for patients who are inoperable for medical reasons. Many studies have been previously published utilizing different doses and schedules of radiation therapy.1 The Radiation Therapy Oncology Group (RTOG) in 1973 began two randomized studies to determine the most effective and well tolerated doses of irradiation and fractionation schedules in patients with advanced, unresectable or earlier stage medically inoperable non-oat cell carcinoma of the lung (epidermoid carcinoma, adenocarcinoma, large cell undifferentiated carcinoma).

The response of atelectasis from lung cancer to radiation therapy

Between January 1981 and June 1983, 33 newly diagnosed patients with lung cancer presented with radiological findings of atelectasis. These patients were treated by primary radiation therapy, with doses ranging from 1200 to 6000 cGy. The response of atelectasis to radiation therapy was established on the basis of follow-up chest roentgenograms. Of the 28 patients with non-small cell carcinoma of lung, there were 17 (61%) who had improvement of the atelactasis. Among these, 13 patients were treated with doses ranging from 5000 to 6000 cGy in 5 to 8 weeks; 9 of these (70%) responded. By histological subtype, the numbers, though small, show that three of eight patients with adenocarcinoma responded, as compared to 2 out of 4 with large cell undifferentiated carcinoma and 12 of 16 patients with squamous cell carcinoma. In patients treated by more than 5000 cGy, four of eight (50%) patients with squamous cell carcinoma had a complete response and three (37.5%) had a partial relief of atelectasis, for a total response of 87.5%. The study indicates the importance of radiation therapy in the management of atelectasis caused by primary lung cancer.

Prospective evaluation of mediastinoscopy for assessment of carcinoma of the lung

Between 1979 and 1984, mediastinoscopy was performed on 1,000 of the 1,500 patients admitted to the Thoracic Surgical Service of the Toronto General Hospital with the diagnosis of carcinoma of the lung. In 144 cases, concomitant anterior mediastinoscopy was also performed. Abnormal mediastinal nodes were found in 296 (29.6%). The overall complication rate was 2.3%, with no deaths. Mediastinoscopy revealed diseased nodes in 24% of patients with squamous cell carcinoma, 29% with adenocarcinoma, 54% with small cell undifferentiated carcinoma, 31% with large cell undifferentiated carcinoma, and 12% with bronchoalveolar carcinoma. Abnormal mediastinal nodes were found with equal frequency in right- and left-sided tumors and occurred in 31% of tumors in the main bronchus, 25% of upper lobe tumors, and 17% of lower lobe tumors. Of the 704 patients having negative results of mediastinoscopy, 590 were subjected to thoracotomy. Ninety-three percent underwent resection (85% curative, 7% palliative) and 7% had unresectable tumors. Of the resections, 20% were pneumonectomies. At thoracotomy, 52 of the 590 patients with negative mediastinoscopic results were found to have abnormal mediastinal nodes. Sixty-two of the 296 patients with positive results of mediastinoscopy were selected for thoracotomy. Eighty-six percent had resectable lesions (67% curative, 18% palliative) and 14% unresectable. The pneumonectomy rate in this group was 35%. These current data support our previous opinion that routine mediastinoscopy can be done with negligible morbidity and provides essential information for the classification and management of cancer of the lung.

Lung carcinoma by histologic type in coal miners

Histologic types of lung carcinoma were studied in 171 coal miners in the National Coal Workers' Autopsy Study. These miners had an average underground mining tenure of 29 +/- 14 years and an average smoking history of 31 +/- 23 pack-years. The proportion of carcinomas by cell type were: squamous cell carcinoma, 30%; adenocarcinoma, 27%; small-cell undifferentiated carcinoma, 26%; large-cell undifferentiated carcinoma, 9%; and other carcinomas, 8%. More tumors were observed in the right lung and in the upper lobes of both lungs than in the left lung and in the lower lobes of both lungs, respectively. The majority of the tumors were centered on cartilaginous airways (81%) as compared with the peripheral regions of the lung (19%). Squamous cell carcinomas predominated in the older miners and in larger airways. Adenocarcinomas were more common in the peripheral lung. No significant interaction was demonstrated between cell type and years of underground mining. The data indicate that lung carcinoma in coal miners differs little in its pathologic features from men in the general population who smoke cigarettes. No effect of coal mine dust exposure on lung carcinoma histogenesis was demonstrated.

Large cell neuroendocrine tumors of the lung. Clinical significance and histopathologic definition.

Twenty-five cases of neuroendocrine tumors of lung, including bronchial carcinoids (eight), malignant (atypical) carcinoids (nine), and large cell undifferentiated carcinomas (LCAC) with neuroendocrine differentiation (eight) were analyzed. All carcinoids (BC) could be diagnosed by light microscopy; all patients with these tumors are alive without disease. Five of nine malignant carcinoids (MC) could be recognized histologically; four of nine were called LCAC and required electron microscopy for diagnosis. Survival correlated best with stage of diagnosis. High-grade neuroendocrine carcinomas (LCAC-NE) required electron microscopy for their diagnosis. Seven were LCAC histologically; one was diagnosed as malignant carcinoid (MC). Such tumors resemble small cell anaplastic carcinomas ultrastructurally and behaviorally. All eight patients with such high-grade tumors died of their disease; three of eight had no nodal metastases at the time of resection. This experience suggests it is clinically important to distinguish neuroendocrine neoplasms since behavior is predictable on the basis of morphology.

Application of monoclonal antibody 44-3A6 in the cytodiagnosis and classification of pulmonary carcinomas.

Thirty-five pulmonary carcinomas were studied retrospectively with monoclonal antibody (MCA) 44-3A6 raised against a human adenocarcinoma cell line. The antibody was applied to cytologic smears of bronchial brushings originally stained with the Papanicolau method, and to conventional tissue sections. Ten of 12 adenocarcinomas (ADC) immunostained strongly in sections and smears, as did five of seven large-cell "undifferentiated" carcinomas (LCUC). Eight neuroendocrine carcinomas (NEC) and eight squamous-cell carcinomas (SCC) were negative, except for rare weakly positive foci. We conclude that MCA 44-3A6 can be effectively applied on cytologic smears, and that it could be valuable in the precise classification of pulmonary carcinomas. The immunoreactivity of the ADC and SCC was predictable. Positive immunostaining in some LCUC confirms that these constitute a heterogeneus tumor class that includes cases that are phenotypically ADC despite the absence of obvious glands. Occasional immunostaining in NEC suggests focal exocrine differentiation as previously noted by electron microscopy.

Phagocytic activity of alveolar macrophages in patients with bronchogenic carcinoma.

Human bronchoalveolar cells were obtained by lavage during diagnostic fiberoptic bronchoscopy of 21 patients suspected of having lung malignancies. Of these patients 11 were diagnosed as having primary lung cancer (Group I) and included individuals with squamous cell carcinoma, adenocarcinoma, undifferentiated large and oat cell carcinoma at varying locations and TNM stages, 4 patients demonstrated nonprimary metastatic carcinoma (Group II), and 6 patients did not reveal detectable tumors by bronchoscopy or follow-up (Group III) and were included as study controls. We examined the ability of pulmonary alveolar macrophages (PAMs) lavaged from patients in each of the three study groups to phagocytose opsonized sheep red blood cells. Phagocytic activity varied among patients in the same and different study groups; however, no significant differences were observed in the phagocytic or tumoristatic activities of PAMs recovered from tumor-bearing and nontumor-bearing lung regions of the same patient. Moreover, lavage fluids collected from tumor-bearing regions did not suppress the phagocytic activity of PAMs collected from control lungs nor lung regions contralateral to the tumor-bearing lung. The data do not support the view that bronchial neoplasms or their secreted products suppress phagocytic functions of alveolar macrophages.

The malignant pleural effusion. A review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients.

This study reports the cytopathologic diagnoses rendered on all malignant pleural effusions received and processed over a period of 14 years. Specimens of fluid from various body sites (25,464) were examined. Of these, 5888 (23%) were specimens of pleural effusions. Five hundred eighty-four specimens (9.9% of total pleural fluid specimens) taken from 472 patients were diagnosed as containing cancer cells. Of the malignant pleural effusions, 75.7% were classified as carcinomatous in type. Adenocarcinomas comprised 47.4% of the 584 specimens. The groups of large cell undifferentiated carcinoma and lymphoma/leukemia approximated one another in being the second most common cancer groups (14.3% and 15.0%, respectively). For both males and females, the frequency of organ site or primary tumor type was lung (35.6%), lymphoma/leukemia (15.9%), breast (14.8%), female genital tract (8.1%), and gastrointestinal tract (5.9%). Among male patients, the order of frequency was lung (49.1%), lymphoma/leukemia (21.1%), gastrointestinal tract (7.0%), genitourinary tract (6.0%), and malignant melanoma (1.4%). In female patients, the order of frequency was breast (37.4%), female genital tract (usually ovary) (20.3%), lung (15.0%), lymphoma/leukemia (8.0%), and gastrointestinal tract (4.3%). In 48 patients (10.2%) the primary site of neoplasm was never determined. In 90.5% of patients a cytopathologic diagnosis conclusive for cancer was obtained on the first specimen of fluid. There were no false positive diagnoses.

Ovarian metastases from cancer of the lung: Problems in interpretation—A report of seven cases

Seven women, 26 to 66 (average 42) years of age, from whom ovarian tumors were removed before (three cases), synchronously with (three cases), or less than 1 year after (one case) the discovery of a pulmonary neoplasm are the subjects of this report. The ovarian tumor was unilateral in six cases and bilateral in one case and was unassociated with intraabdominal spread. The lung tumors, which were similar to the ovarian tumors on microscopic examination, were central in six cases and peripheral in one; three of them were small cell undifferentiated carcinomas, two large cell undifferentiated carcinomas, one a poorly differentiated adenocarcinoma, and one an atypical spindle cell carcinoid tumor. In each case the question of the primary site of the tumor had been raised clinically. The histological similarity of the ovarian and pulmonary tumors in all the cases to well-recognized forms of pulmonary neoplasia as well as additional clinical and pathological features of the cases led to an interpretation of a pulmonary origin of the tumors in all the cases.

Neuroendocrine neoplasms of the bronchopulmonary tract: A classification of the spectrum of carcinoid to small cell carcinoma and intervening variants

Eighty-one primary pulmonary neuroendocrine neoplasms were assessed by the classification of Gould and associates. The neuroendocrine features of these tumors were studied by a combination of conventional light microscopy, electron microscopy, and immunohistochemical staining for hormonal substances and neuron-specific enolase. In each case, clinical follow-up was obtained to test the prognostic value of this new pathological classification. This study indicated that bronchial carcinoids are very low-grade neuroendocrine neoplasms that are locally invasive and only occasionally metastasize late in their course. Well-differentiated neuroendocrine carcinomas are relatively low-grade carcinomas that either present with or subsequently develop nodal or distant metastases in 73% of patients. Intermediate cell neuroendocrine carcinomas are highly aggressive tumors often mistakenly called "large cell undifferentiated carcinoma." Their clinical course is comparable to that of small cell neuroendocrine carcinomas, which has a mean survival of 9 months. The different clinical courses of these tumors demonstrate the predictive value of the proposed classification. It appears particularly valuable to identify well-differentiated neuroendocrine carcinoma as a low-grade carcinoma, distinct from true bronchial carcinoids. This classification may resolve some discrepancies regarding the therapy for and prognosis of "carcinoids" and their presumed variants.

Supplementary tissue-core histology from fine-needle transthoracic aspiration biopsy.

Biopsies of 150 consecutive suspected lung cancers were performed with fine needles having circumferentially beveled tips that produced cytology and tiny tissue cores suitable for histology. Visible tissue cores were aspirated in 92% (n = 138) and histologic diagnoses were obtained in 72% (n = 108). There were 118 (79%) proven malignant and 27 (18%) proven benign lesions. Sensitivity and specificity of cancer diagnoses were 97% and 100%, respectively. Biopsy histology was the only positive cancer specimen in two biopsies (1.7%). Biopsy cytology was the only positive cancer specimen in 20 cases (17.2%). Biopsy cytology and histology agreed with the proven cell type in 71.8% and 78.6% of cancers, respectively. As expected, when large-cell undifferentiated carcinoma was regarded as a nonspecific cell type consistent with either poorly differentiated adenocarcinoma or poorly differentiated epidermoid carcinoma, biopsy-cell-type accuracy increased greatly. Specific benign diagnoses were obtained in 44% of the 27 biopsies of proven benign lesions: cytology (four), core histology (five), and bacteriology (nine). Simple and complicated pneumothorax occurred in 10% and 4% of biopsies, respectively. It was concluded that biopsy with fine, circumferentially beveled needles can produce useful histology to supplement biopsy cytology.

Prognostic factors in surgically resected limited-stage, nonsmall cell carcinoma of the lung.

The gross pathological, microscopic, and clinical features of 173 Stage I and Stage II primary nonsmall cell carcinomas resected for cure by segmental resection, lobectomy, or pneumonectomy at the Johns Hopkins Hospital were analyzed to determine which provided useful independent prognostic information. The tumors studied included 79 squamous carcinomas (56%); 74 adenocarcinomas (44%), including 15 undifferentiated tumors which contained intracellular mucin; 18 large-cell undifferentiated carcinomas (10%); one giant cell carcinoma (less than 1%); and one adenosquamous carcinoma (less than 1%). Clinical features evaluated for each case included age, sex, race, and history of previous or subsequent malignancy; and pathologic features evaluated included tumor size, lymph node metastases, tumor location, cellular anaplasia, desmoplastic response, inflammatory response, preexisting scar, tumor necrosis, and degree of tumor differentiation. Multivariate analysis using the Cox life table regression model indicated that five features had a significant (p less than 0.05) independent association with subsequent death due to the tumor, and that the final set was highly significant (p = 0.001). These features were the following: large-cell undifferentiated histology, lymph node metastases expressed as N classification, tumor size expressed as T classification, tumor giant cells in any histologic type, and absent or minimal plasma cell infiltration. No additional prognostic information was obtained from any of the other features analyzed.

Cis-platinum (DDP) and VP 16-213 (etoposide) combination chemotherapy for advanced non-small cell lung cancer. A phase II clinical trial

Forty-six patients with non-small cell lung cancer were treated with a combination of cis-platinum, 90 mg/m 2 i.v. on day 1 and VP 16-213, 100 mg/m 2 i.v. on days 1, 3 and 5. The overall remission rate was 22%, with a median duration of 7 months. Squamous cell and large cell undifferentiated carcinomas responded in 27 and 22% of patients, and seven patients with adenocarcinoma did not respond to chemotherapy. Survival was 7 months for all patients, 11.5 months for responders (7–27+), 8.5 months for patients with stable disease (3–27+) and 5 months for progressive tumours (1–9). Prognosis was adversely influenced by a performance status of less than 80%, a weight loss of more than 10 kg during the last 3 months before start of treatment and a radiologically demonstrable ‘major’ atelectasis (collapse of at least once superior or inferior lobe of the lung). Only one out of 31 patients with one or more poor prognostic factors came into remission. In contrast, nine out of 15 patients without poor prognostic factors showed objective tumour regression (60% remission rate). Stage and age did not affect the results. Haemotologic and renal toxicity were mild, but poor subjective tolerance (nausea, vomiting, loss of appetite) was prominent.

The biological implications of bronchial tumors

Seventy-six consecutively resected primary pulmonary tumors were assessed first by routine light microscopy and subsequently by electron microscopy and immunohistochemical staining techniques to precisely identify features of differentiation. In 66% of the cases, this assessment provided information that modified or revised the histologic diagnosis provided by light microscopy alone. The following conclusions were reached: (1) The term "large cell undifferentiated carcinoma" has been applied to a heterogenous group of tumors, most of which have ultrastructural and immunohistochemical features of differentiation not identifiable by routine light microscopy. (2) Forty percent of the tumors previously called "large cell undifferentiated carcinoma" have predominantly neuroendocrine differentiation and appear to have a clinical course comparable to that of small cell neuroendocrine carcinoma. (3) The majority of pulmonary carcinomas (especially those previously called "poorly differentiated" or "undifferentiated") may simultaneously demonstrate more than one pattern of differentiation when studied by electron microscopy and immunohistochemistry. (4) The frequency of neuroendocrine neoplasms of the lung, as determined by these and previous studies, is considerably greater than suspected on the basis of light microscopic studies alone. These comprise a clinical and morphologic spectrum ranging from bronchial carcinoid to small cell carcinoma, all of which have immunohistochemically demonstrable hormone production, although paraneoplastic hormonal syndromes are manifested in only a small minority of cases.

Results of drug therapy of inoperable non-small cell lung carcinoma with VP 16-213 (Etoposide) and cis-platin. A phase II study

Forty-six patients with non-small cell lung cancer were treated with a combination of cis-platinum 90 mg/m2 i.v., day 1 and VP 16-213 100 mg/m2 i.v. on days 1, 3 and 5. The overall remission rate was 22% (10 out of 46 patients) with a median remission duration of 7 months. Squamous cell and large cell undifferentiated carcinomas responded to the chemotherapy with a remission rate of 27% (7 out of 26 patients) and 22% (3 out of 13 patients). Seven patients with adeno-carcinoma did not respond to chemotherapy. The overall survival was 7 months (1-27+). The survival time for patients entering remission was 11.5 months (7-27+), for those with stable disease 8.5 months (3-27+), and for patients with progressive disease 5 months (1-9). Performance status of less than 80%, a weight loss of more than 10.0 kg in the last three months before starting treatment and a "major" atelectasis (collapse of at least one superior or inferior lobe) adversely influenced prognosis. Only 1 out of 31 patients with one or more poor prognostic factors came into remission. In contrast, 9 out of 15 patients (60%) without poor prognostic factors had a remission. Stage, limited versus extensive disease, and age did not affect the results. Hematologic and renal toxicity of the combination were mild, but poor subjective tolerance (nausea, vomiting, loss of appetite) was prominent.

Prostaglandins and human lung carcinomas.

Lung primary carcinomas and normal tissue from 136 patients have been extracted for prostaglandins, and the findings examined in relation to histology. In most cases, tumours yielded more prostaglandin-like material (PG-lm), as judged by bioassay, than did normal tissue from the same lungs. Amounts varied with tumour types, in the following ascending order: small-cell carcinomas, large-cell undifferentiated carcinomas, well-differentiated squamous carcinomas, poorly-differentiated adenocarcinomas, poorly differentiated squamous carcinomas, and well-differentiated adenocarcinomas. Tumour PG-lm was highest when necrosis or the neutrophil content of the tumours were moderate, whereas PG-lm from normal lung tissue correlated with the number of macrophages. Chromatography indicated the presence of various prostaglandins, in agreement with our recent findings using gas chromatography--mass spectrometry.

Influence of histologic type on survival after curative resection for undifferentiated lung cancer

Undifferentiated carcinoma of the lung carries a worse prognosis overall than other cell type, but it is unclear whether these tumors represent a homogeneous group with uniformly poor survival. This study identifies certain histologic subtypes of large cell and small cell undifferentiated carcinoma which have a better prognosis after curative resection than other similarly treated undifferentiated carcinomas. From 1947 through 1975, a total of 2,352 patients with lung cancer were admitted to one hospital. Follow-up to death was available in 98%. Pathological material was reviewed from 1,979 cases by a team of three pathologists during a single 6 month period without knowledge of clinical outcome. Curative resection was carried out in 632, with 170 (27%) 5 year survivors. Small cell cancer occurred in 481 patients and nine (1.6%) survived 5 years. Curative resections were performed in 34 with polygonal small cell carcinoma, 20 with normal lymph nodes and 14 with diseased lymph nodes. Seven survived 5 years (21%), six of 20 with normal and one of 14 with diseases lymph nodes. Eleven with nonpolygonal small cell carcinoma (eight oat cell, three fusiform) (five normal, six diseases nodes) underwent curative resection, with no survivors. Large cell carcinoma occurred in 151 and 19 survived 5 years. Curative resection was performed in 24 having large cell carcinoma with stratification (16 normal, eight diseased nodes), and 12 (50%) survived 5 years. In 26 with nonstratified large cell carcinoma undergoing curative resection (18 normal, eight diseases nodes); six (23%) survived 5 years (chi 2 = 4.06 p less than 0.05). Thus patients with resectable polygonal small cell carcinoma appear to have a better prognosis than those with nonpolygonal small cell carcinoma, and their prognosis approaches that of all patients with resectable lung cancer. Patients having resectable large cell carcinoma with stratification have a significantly better prognosis than those with nonstratified large cell carcinoma. Patients with these subtypes should therefore not be denied an attempt at curative resection because of the diagnosis of undifferentiated lung cancer.