Large Cell Undifferentiated Carcinoma Research Articles

1109 Detection of human papillomavirus DNA in primary lung carcinoma by nested polymerase chain reaction

Human papillomaviruses (HPV) have been implicated in the pathogenesis of human squamous cell carcinoma, especially of cervical carcinomas. In two previous studies concerning squamous cell carcinomas of the lung, DNA to HPV subtypes 6/11/16/18 (and 31/33/35 for one study) was detected by <i>in situ</i> hybridization in 7 to 30% ofthe cases. A series of 31 frozen biopsies of lung carcinomas were examined for the presence of HPV DNA by nested polymerase chain reaction (PCR). Primers for the two PCR were type-specific primers (6/11–16 and 18; kit Amplicis HPV^*) for the transforming region of HPV. HPV DNA is found in two of 18 cases of squamous cell carcinoma (11%), in one of 4 cases of adenocarcinoma, and in two of 7 cases of neuro-endocrin cancers. No case of the two large cell undifferentiated carcinomas was positive. There were three cases of HPV 6/11, one case of HPV 16, and one sample positive for HPV 6/II and HPV 18. No morphologic changes consistent with HPV lesions were seen, and squamous metaplasia was observed only in squamous cell carcinomas. The frequency of 11% among the squamous cell carcinomas is near those found by previous studies, whereas PCR is theoretically more sensitive than <i>in situ</i> hybridization. HPVs have never been detected in adenocarcinomas or neuroendocrin tumors, and this has to be confirmed by studies of many more cases. So HPV might playa role as promoter in carcinogenesis of any types of lung carcinoma, although at a low frequency.

The value of PE‐10, a monoclonal antibody against pulmonary surfactant, in distinguishing primary and metastatic lung tumours

A new monoclonal antibody (PE-10) raised against components of pulmonary surfactant has been assessed for its ability to distinguish primary from secondary carcinomas in the lung. We applied this antibody to a series of 107 primary lung carcinomas, 40 adenocarcinomas of other sites, and 26 cases of adenocarcinoma metastatic to lung and pleura. Of the primary lung carcinomas, all the non-mucinous bronchiolo-alveolar carcinomas were positive whereas all the mucinous cases were negative; 60% of other types of adenocarcinoma were positive and 10% of large cell undifferentiated carcinomas, 20% of small cell carcinomas and 40% of atypical carcinoids also showed focal positivity. Squamous cell carcinomas were all negative. Adenocarcinomas of the breast, kidney, large bowel and ovaries were all negative, as were all 26 cases of adenocarcinoma metastatic to the lung and pleura. We conclude that this antibody is highly specific and moderately sensitive for primary tumours of the lung.

Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma: Holmes EC. 10833 LeConte Ave, Los Angeles, CA 90024. Chest 1994;106: Suppl:293S–296S

Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma: Holmes EC. 10833 LeConte Ave, Los Angeles, CA 90024. Chest 1994;106: Suppl:293S–296S

Phase II trial of carboplatin in combination with etoposide in locally advanced large cell carcinoma and adenocarcinoma of the lung

A total of 18 patients with locally advanced (Stage III) adenocarcinoma and large cell undifferentiated carcinoma of the lung, previously untreated, were enrolled in a Phase II trial. Treatment consisted of carboplatin 325 mg/m 2, day 1 and etoposide 100 mg/m 2 on days 2 and 3. All patients were evaluable for response. Of these, one patient had a partial response (5.5%; confidence interval 0–24%). Toxicity comprised mainly leukopenia and anaemia. Other toxicities were mild. This Phase II study evidenced a poor response rate for these regimes on adenocarcinoma and large cell undifferentiated carcinoma of the lung.

An Immunohistochemical Study with Ultrastructural Correlations

To determine the specificity of immunostaining in the diagnosis of pulmonary neuroendocrine carcinomas, we studied 66 ultrastructurally characterized lung cancers with a panel of markers considered to be selective for neuroendocrine tumors (neuron-specific enolase, chromogranin A, Leu 7, synaptophysin) and B72.3, which is reported to be selective for non-small-cell carcinomas. Neuroendocrine tumors studied included 13 small-cell carcinomas, four low-grade neuroendocrine carcinomas, and two large-cell carcinomas with neuroendocrine differentiation. Non-neuroendocrine tumors included 26 adenocarcinomas, 10 squamous cell carcinomas, and 11 large-cell undifferentiated carcinomas. The following percentages of neuroendocrine carcinomas showing immunoreactivity for the various "neuroendocrine markers" were found: synaptophysin, 100%; neuron-specific enolase, 74%; chromogranin A, 37%; and Leu 7, 5%. However, carcinomas without morphologic features of neuroendocrine differentiation showed the following immunoreactivity: synaptophysin, 62%; neuron-specific enolase, 60%; chromogranin A, 17%; and Leu 7, 9%. B72.3 immunostaining was seen in 81% of the carcinomas without neuroendocrine features and in 31% of the small-cell carcinomas. We conclude that many of the commercially available antibodies used as neuroendocrine markers are nonspecific in the diagnosis of pulmonary neuroendocrine carcinomas.

Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma

Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma

Surgical Adjuvant Therapy for Stage II and Stage III Adenocarcinoma and Large Cell Undifferentiated Carcinoma

The Lung Cancer Study Group (LCSG) randomized 141 patients with resected stage II and III adenocarcinoma and large cell undifferentiated carcinoma to receive postoperative combined chemotherapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy or bacillus Calmette-Guerin (BCG) and levamisole immunotherapy. Careful intraoperative staging was performed on all patients. Before randomization, patients were stratified by stage, weight loss, cardiac arrhythmia, and institution. Prognostic variables such as stage, age, weight loss, and nodal involvement were equally distributed between the two groups. Disease-free survival was significantly prolonged in the group receiving chemotherapy. There was no evidence of a deleterious effect of the immunotherapy. This study indicates that postoperative CAP chemotherapy is effective in prolonging disease-free survival in these patients.

Bronchogenic carcinoma: radiologic-pathologic correlation.

Bronchogenic carcinoma is the leading cause of death from cancer in men and women in the United States. Although the cause of this malignancy is probably multifactorial, approximately 85% of lung cancer deaths are attributable to cigarette smoking. Patients may present with symptoms of airway obstruction caused by central tumors, symptoms related to direct tumor invasion of surrounding structures, or symptoms produced by distant metastases. There are four major cell types: adenocarcinoma, squamous cell carcinoma, undifferentiated large cell carcinoma, and small cell carcinoma. Adenocarcinoma and undifferentiated large cell carcinoma are generally peripheral lesions manifesting as solitary nodules or masses, whereas squamous cell carcinoma and small cell carcinoma are typically central and may manifest as hilar masses, atelectasis, or pneumonia. The prognosis for patients with bronchogenic carcinoma is poor, with an overall 5-year survival of 10%-15%. In general, patients with squamous cell carcinoma have the best prognosis, those with adenocarcinoma and undifferentiated large cell carcinoma have an intermediate prognosis, and those with small cell carcinoma have the worst prognosis.

Flow Cytometric Analysis and Cytokeratin Typing of Human Lung Tumors: A Preliminary Study

In the current study a comparative analysis of keratin typing and DNA content was carried out in human lung tumors from transthoracic fine needle aspiration biopsies (TFNAB) (18 patients) or from surgically resected tumor tissues (14 patients). According to the cytologic and histologic features, 2 of the 32 tumors were diagnosed as benign tumors, 11 as squamous cell carcinomas, 12 as adenocarcinomas, and 7 as undifferentiated large cell carcinomas. Two cases in the adenocarcinoma and one in the undifferentiated large cell carcinoma groups were pulmonary metastasis or second primary tumors. Malignant cells of tumors which reacted positively with KK8.60 anticytokeratin polypeptides No. 10 and 11 (and hence contain keratinizing cells) displayed diploid DNA content in a flow cytometric assay regardless of their cytologic or histologic appearance. In contrast, all tumors which lacked such positive cells (most of which were defined as adenocarcinomas and undifferentiated tumors) were hyperdiploid. The close correlation between high DNA content and both malignancy and the absence of advanced squamous differentiation (keratinization) suggests that such combined analysis may provide new tools for the cytologic diagnosis and prognosis of lung cancers.

Prognostic significance of tissue polypeptide-specific antigen (TPS) in patients with advanced non-small cell lung cancer

In this study, we evaluated the prognostic value of the tumour marker, tissue polypeptide-specific antigen (TPS), in 203 patients with non-small cell lung cancer (NSCLC), and related this to several other known prognostic factors. TPS was significantly correlated with lactate dehydrogenase (LDH), γ-glutamyltranspeptidase and alkaline phosphatase, and the median level of TPS in patients with stage 4 disease was significantly higher as compared to stage 3A and 3B disease. In the univariate analysis, performance status, stage of disease, LDH, alkaline phosphatase, a histology of undifferentiated large cell carcinoma and TPS all had a statistically significant association with survival. Multivariate analysis showed that stage of disease, performance status, histology and TPS were the most important prognostic factors. TPS has prognostic significance for survival in patients with advanced NSCLC, independent from performance status and stage of disease.

CYFRA 21-1, a sensitive and specific new tumour marker for squamous cell lung cancer. Report of the first European multicentre evaluation

The present study was designed to determine whether CYFRA 21-1, measuring cytokeratin 19, could be a specific and sensitive tumour marker for non-small cell lung cancer (NSCLC). Serum measurements were made at diagnosis in 2250 patient samples by an immunoradiometric “sandwich type” assay, using two cytokeratin 19 specific monoclonal antibodies. Among healthy individuals ( n = 711) and patients with benign lung disease ( n = 546), 95 percentiles were 1.2 and 2.95 ng/ml, respectively. Cumulative distribution analysis curves were established. From these data, 3.3 ng/ml gave 96% specificity. Using this cutoff, the sensitivity for small cell lung cancer was 16% ( n = 74) compared to 41% for NSCLC ( n = 547). In histological sub-groups, sensitivity was 57% for squamous cell lung cancer, 34% for undifferentiated large cell carcinoma and 27% for adenocarcinoma. the level of CYFRA 21-1 was correlated with tumour size and UICC stage. In squamous cell lung cancer, the sensitivity of the squamous cell carcinoma marker was 30%, 25% for carcinoembryonic antigen and 46% for tissue polypeptide antigen, using the same series of samples and cutoffs defined at 96% specificity. In conclusion, CYFRA 21-1 is a sensitive tumour marker for NSCLC, especially squamous cell lung cancer.

Neuroendocrine differentiation as a prognostic factor in non-small cell lung cancer

The prognostic value of clinical and pathological factors in 97 patients with non-small cell lung cancer (NSCLC), were analyzed through immunohistochemical methods. The impact on response rate and survival of age, Karnofsky performance status (PS), sex, NSCLC subtype and grade, extent of disease, objective chemotherapy response, LDH values, metastatic sites involved and immunohistochemical markers of neuroendocrine differentiation (neuron specific enolase (NSE), synaptophysin (Sy 38), chromogranin (Chr A) and Leu-7) were analyzed. Median age was 61 years and seven patients were women. Histologically, 58 had squamous cell carcinoma, 28 adenocarcinoma and 11 large cell undifferentiated carcinoma. One patient had Stage II, 35 Stage IIIa, 19 Stage IIIb and 42 Stage IV. Six patients achieved complete response, 18 partial response, 34 stable disease and 39 progressive disease. NSE was negative in 54.3% of cases as was Sy 38 (77.4%), Chr A (97.8%) and Leu-7 (95.8%). We have found correlation between neuroendocrine differentiation and absence of P-Glycoprotein expression; patients included in this subset had a higher response rate but no evidence of longer survival. The univariate analysis showed that four parameters had significant adverse effect on survival: non-responders, poor PS, abnormal LDH value and absence of NSE expression. Multivariate analysis showed that the best combination of independent prognostic factors in predicting survival was: PS and NSE expression by immunohistochemical methods.

Differentiation of single solid lesions in the lungs by means of single-photon emission tomography with technetium-99m methoxyisobutylisonitrile.

The value of technetium-99m methoxyisobutylisonitrile (MIBI) single-photon emission tomography (SPET) of the chest in differentiating lung carcinomas of various histological types and benign lesions was assessed in 54 patients (47 males and 7 females aged 19-77 years) with single solid lung masses. Chest radiography had indicated that 46 of the lesions were malignant (8 small cell carcinomas, 14 epidermoid carcinomas, 18 adenocarcinomas and 6 undifferentiated large cell carcinomas) and eight, benign. Ten, volunteers who also agreed to undergo 99mTc-MIBI SPET of the chest served as a control group. The results showed that only 65% (30/46) of the lung malignancies were detected by 99mTc-MIBI SPECT, including 63% (5/8) of the small cell carcinomas, 64% (9/14) of the epidermoid carcinomas, 72% (13/18) of the adenocarcinomas and 50% (3/6) of the undifferentiated large cell carcinomas. However, 75% (6/8) of the benign lesions were also detected. The diagnostic sensitivity, specificity and accuracy in differentiating malignant and benign lesions were 65%, 57% and 70%, respectively. We conclude that 99mTc-MIBI is of limited use in the differentiation of single solid lesions in the lungs.

Neuroendocrine characteristics in bronchogenic adenocarcinoma and its clinical relevance

For many years there has been a considerable clinical and scientific interest in the classification of malignant lung tumors. From a histopathologic point of view the World Health Organization (WHO) has put effort into the morphologic subtyping of malignant lung tumors and more than 90% of the tumors fall into the four main groups: squamous cell carcinoma, small cell carcinoma (SCLC), large cell undifferentiated carcinoma and adenocarcinoma [ 11. Small cell carcinoma and squamous cell carcinoma have been considered as smoking related and have been considered as the most common cell types. However, the picture has now changed especially in US with an absolute and relative increase in the incidence of adenocarcinoma [2,3]. The reason for this is still not quite clear. From a therapeutic point of view the classification into “small cell carcinoma” (SCLC) and “nonsmall cell carcinoma” (NSCLC) has for many years been sufficient for clinicians because of the chemosensitivity of the SCLC-tumors and the potential for therapeutic success in contrast to the clinical experience with the NSCLC. While therapeutic progress has been limited in the last decade, the biologic understanding of lung tumors has evolved considerably. The histogenetic relationship between the histologic types has been put into a new perspective by the recognition of expression of neuroendocrine markers. Bronchial carcinoids and small cell lung cancer together with other tumors of the diffuse neuroendocrine system have been characterized by the presence of neuroendocrine markers, i.e. dense core granules, high levels of the key amine handling enzyme L-dopadecarboxylase and production of various hormones and neuropeptides [4-6]. These features are shared by their putative progenitors, pulmonary endocrine cells. At the same time morphologic variations and especially mixed histologies were recognized by the pathologists [I. Furthermore, by the establishment of numerous lung cancer cell lines it was noted that even within one main histologic type there were different clones with different biologic

Postoperative Chemotherapy for Non-Small-Cell Lung Cancer

The Lung Cancer Study Group has performed a number of postoperative adjuvant trials in patients with resectable non-small-cell lung cancer (NSCLC). Adjuvant cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy was compared with immunotherapy in the treatment of 130 patients with stage II or III adenocarcinoma or large cell undifferentiated carcinoma. Careful intraoperative staging was performed in all patients. Disease-free interval was significantly prolonged in the chemotherapy group (p = 0.032). After 7.5 years of follow-up, the difference in time to recurrence and cancer deaths remains statistically significant. Another study compared CAP chemotherapy plus radiotherapy with radiotherapy alone in advanced stages II and III resected NSCLC. Again, the chemotherapy arm had significantly increased disease-free survival. In a third study, patients with high-risk stage I NSCLC were randomized after surgery to CAP chemotherapy or observation. In this study there was no difference in recurrence-free survival or overall survival.

Primary lung cancer in young patients: A study of 82 surgically treated patients

The aim of this study was to evaluate the prognosis for surgically treated young patients with primary lung cancer, a prognosis generally considered to be very poor. Eighty-two patients less than 40 years of age were operated on at Marie-Lannelongue Hospital between 1982 and 1990. There were 72 male and 10 female patients. Ten patients (12%) had never smoked, whereas 48 patients (59%) had smoked for more than 20 pack-years. The lung cancer was asymptomatic in 27 patients (33%) and symptomatic in the others. Adenocarcinoma was found in 42% of the patients, epidermoid carcinoma in 28%, mixed cell carcinoma in 16%, small cell carcinoma in 8.5%, and undifferentiated large cell carcinoma in 6%. Among the 69 resected tumors, 22 were stage I, ten were stage II, 32 were stage IIIa, and five were stage IIIb. The resection was considered complete and curative in 56 patients (68%) and noncurative in 26 (32%) either because of an incomplete resection (12 in stage IIIa; 1 in stage IIIb) or because of an exploratory thoracotomy only (13). The overall actuarial 5-year survival rate was 41%, and the actuarial 5-year survival for patients who had a complete resection was 56%. The actuarial 5-year survival rates were as follows: patients in stage I, 70%; stage II, 54%; stage IIIa, 28%; stage IIIb, 0%; and patients having exploratory thoracotomy only, 18%. These survival rates are similar to those of patients older than 40 years with similar stages of disease. In this study, survival had no significant dependence on sex, age (less than versus greater than 30 years), smoker versus nonsmoker status, or histological tumor type. It was dependent mainly on the extent of the disease.

Occurrence of human papillomavirus DNA in primary lung neoplasms.

The occurrence of human papillomavirus (HPV) DNA in primary lung carcinomas and in squamous metaplasia of the bronchus was studied using in situ hybridization techniques and commercially available biotinylated DNA probes to HPV subtypes 6/11, 16/18, and 31/33/35. The authors found HPV DNA in six of 20 cases of squamous cell carcinoma and one of six cases of large cell undifferentiated carcinoma. There were two cases each of the 6/11 serotypes and the 16/18 serotypes and three cases of the 31/33/35 serotypes. Infected cells of the squamous carcinomas uniformly showed koilocytosis. No case of adenocarcinoma, bronchioloalveolar carcinoma, or small cell carcinoma was positive (of 32 cases). Areas of squamous metaplasia in infected tumors showed similar HPV DNA expression in 15% of cases, especially in those with condylomatous atypia. In 5.8% of random bronchial biopsies of squamous metaplasia, HPV DNA was identified. The relationship of HPV infection to the development of upper and lower respiratory tract carcinomas is discussed.

Secondary screening system for preclinical testing of human lung cancer therapies.

The National Cancer Institute has instituted a primary screening system for testing new agents against cultured cancer cell lines. The purpose of this study was to determine the feasibility of using a nude rat orthotopic (organ-specific) human lung cancer model system as an in vivo secondary screen for general evaluation of new anticancer agents and therapies active against lung cancer. To make this determination, we tested whether this system allows measurement of uptake and tumoricidal activity of anticancer therapies. Tumor-bearing lungs from 53 Rowett nude rats with orthotopically implanted human large-cell undifferentiated lung carcinoma (NCI-H460) were perfused ex vivo for 1 hour with or without each of two anticancer modalities. Lungs were perfused with blood-free perfusate alone (untreated control), perfusate with 100 micrograms/mL doxorubicin (treated positive control), or perfusate with lymphokine-activated killer cells plus human recombinant interleukin-2 (LAK/rIL-2). Weight gain during perfusion was the criterion used to quantitate lung injury. Treatment efficacy was measured by clonogenic assay after enzymatic disaggregation of the perfused tumors. Doxorubicin levels in the tumor and in the uninvolved lung were measured by high-performance liquid chromatography. Both treatment groups showed only slight increases in lung weight compared with that in the untreated control group, suggesting good lung tolerance of the procedure. Lung and tumor levels of doxorubicin were 320 +/- 21 ng/mg of tissue and 32 +/- 5 ng/mg of tissue (means +/- SE), respectively. Clonogenic assay demonstrated a fivefold to 10-fold reduction in the surviving fraction of tumor cells with doxorubicin but no change with LAK/rIL-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Granulocyte Colony-Stimulating Factor-Producing Large Cell Undifferentiated Carcinoma of the Lung.

We report a case of granulocyte colony-stimulating factor (G-CSF) producing lung cancer. A 38-year-old Japanese woman had a large cell undifferentiated carcinoma of the left lung with severe granulocytosis without any evidence of infection. A specimen was taken from a metastatic cervical lymph node and a tumor cell line was established. The culture supernatant of the line as well as patient's serum exhibited a high level of G-CSF by sandwich enzyme immunoassay. Immunohistochemical analysis demonstrated that tumor cells from transplanted nude mice were stained granularly in the cytoplasma by anti-human G-CSF monoclonal antibody, 4A6.

Accuracy of bronchial aspiration cytology in typing operable (stage I-II) pulmonary carcinomas.

The accuracy of bronchial aspiration cytology in typing resectable (stage I-II) lung cancer has been investigated in 100 cases, comparing preoperative cytologic features with pulmonary tumor histology seen at surgery. The accuracy has been 100% for small-cell carcinoma (two cases), 98.8% for squamous-cell carcinoma (86 cases), and 91.6% for adenocarcinoma (12 cases). The overall accuracy rate has been 98%. No case of undifferentiated large-cell carcinoma has been identified. It is suggested that the high accuracy in cytologic typing of operable lung cancer is basically related to adequate preservation of differentiation features, thus allowing for correct identification of most non-small-cell carcinoma. Moreover, the absence in this study of any large-cell carcinoma, compared with its frequency in advanced stage series, would indicate that such a histotype reflects excessive dedifferentiation of an original squamous or glandular form.