[Surgical treatment for small cell lung cancer].

Results of surgical treatment for small cell lung cancer were reviewed to confirm the role of surgery. Most of the surgical therapy was performed with post or pre-operative chemotherapy. Clinical staging of small cell lung cancer treated by chemotherapy and/or radiotherapy has not been classified according to the TNM staging system, which made it difficult to compare the results of surgical treatment with non-surgical treatment in detail. Results of surgical treatment for small cell lung cancer according to the TNM staging system reported in 1990's were as follows. For stage I diseases, nearly all the patients underwent complete resection followed by standard chemotherapy. Five-year survival rates were over 50% in most of the reports. Surgical resection followed by chemotherapy is the standard therapy for stage I diseases. For stage II diseases, the greater part of patients were treated by complete resection followed by chemotherapy, which resulted in five-year survival rates of 28-35%. Nationwide statistics on surgical resection for small cell lung cancer in Japan revealed that the stage I and II diseases are actually resected, and the five-year survival rate reached 37%. Thus, surgery followed by chemotherapy for stage II diseases is becoming the standard therapy. For stage IIIA diseases, surgical resection after chemotherapy followed by chemotherapy and/or radiotherapy has been tried investigationally. The five-year survival rates of 16-48% in these patients suggests the increasing role of surgery for these patients.

[Detection of human papillomavirus type 16, 18 and 33 DNA in stage I (pT1N0M0) squamous cell carcinoma of the lung by polymerase chain reaction].

Human papillomavirus (HPV) has been considered one of the important factors of malignant change. To investigate the occurrence of HPV DNA in primary squamous cell carcinoma of the lung, we tried to detect HPV DNA by polymerase chain reaction (PCR). Formalin-fixed paraffin-embedded tissue specimens from 8 cases of stage I (pT1N0M0) squamous cell carcinoma of the lung were examined for the presence of human papillomavirus DNA (type 16, 18 and 33) by polymerase chain reaction. DNA was extracted from double 5 microns sections of each specimen by deparaffinization and proteinase K digestion. Using the primers described previously by Shimada et al, target DNA sequences were selectively amplified through 40 cycles of 94 degrees C for 1 min, 55 degrees C for 2 min, and 72 degrees C for 2 min. When stained band was unclear, second PCR was conducted using product of first PCR as template of second PCR. Human papillomavirus type 18 was present in 1 case (12.5%) in contrast that type 16 and 33 were not detected in these cases.

[Results of surgical treatment of intrathoracic recurrence after complete resection of non-small cell lung cancer: clinical significance of subsequent lesion in lung parenchyma].

Results of surgical treatment for 33 intrathoracic recurrence after complete resection of non-small cell lung cancer were analyzed. Prognosis of the second surgical treatment were favorable in patients with subsequent cancer with in situ component and solitary lesion in lung parenchyma. Retrospective study of 53 patients who recurred and were thoroughly followed up their clinical course until lung cancer death revealed that the solitary one tends to be confined to the intrathoracic location, and the multiple one did not confined to the intrathoracic location but also extended to the extrathoracic distant metastasis or to the supraclavicular lymph nodes.

Tumor doubling time and prognostic assessment of patients with primary lung cancer.

BACKGROUND: Relationships between tumor doubling time (DT) and other prognostic factors and the risk of death related to these factors are not yet fully understood. METHODS: Tumor doubling time of primary lung carcinomas of 174 patients, detected in a limited number of local municipalities during a limited period, was calculated using the Schwartz formula. Survival rate of the 174 patients was compared with reference to categories of prognostic factors (univariate analyses) and significant factors affecting survival were identified by multivariate analyses using the Cox proportional hazard model. RESULTS: Tumor doubling time had a log normal distribution. There was a significant difference in mean DT in relation to sex, smoking history, presence of symptoms, cell type, primary tumor factor, and stage. Univariate analyses showed a significant difference in survival in relation to DT, age, sex, method of tumor detection, smoking history, symptoms, therapy, cell type, primary tumor (T) factor, regional lymph node (N) factor, distant metastasis (M) factor, and stage. Multivariate analyses using the Cox's proportional hazard model in a stepwise fashion identified a final set of five significant variables: N factor (P = 0.0001); therapy (P = 0.0016); M factor (P = 0.0017); T factor (P = 0.0018), and DT (P = 0.0152). CONCLUSIONS: Tumor doubling time was an independent and significant prognostic factor for lung cancer patients.

Multicentricity in resected occult bronchogenic squamous cell carcinoma.

The frequency and the treatment of multicentricity in 127 patients with resected roentgenographically occult bronchogenic squamous cell carcinoma were studied. The cumulative rate and the incidence of postoperative metachronous multiple primary lung cancer were 0.11 at 5 years after initial operation and 0.022 per patient-year, respectively. The cumulative rate and the incidence of second primary lung cancer, which includes synchronous and subsequent metachronous cancer in patients with initial lung cancer, were 0.17 at 5 years after the initial operation and 0.041 per patient-year, respectively. The cumulative rate and the incidence of third primary lung cancer in patients with second primary lung cancer were 0.47 at 5 years, which was significantly higher (p = 0.05) than that of second primary lung cancer, and 0.11 per patient-year, respectively. In all 12 patients with synchronous multiple primary lung cancer, no recurrence was observed after treatment, but 3 had subsequent multiple primary lung cancer. Among the 13 patients with postoperative metachronous multiple primary lung cancer, recurrence was observed in 1 of the 6 patients who underwent resection and in 2 of the 4 patients treated with laser or radiation therapy or both. The overall survival rate at 5 years after initial operation in patients with solitary and those with multicentric occult bronchogenic squamous cell carcinomas was 0.90 and 0.59, respectively.

Localization of double, roentgenographically occult lung cancer. Cytologic findings from selective brushing of all segmental and subsegmental bronchi.

Using selective brushing of all segmental and subsegmental bronchi, six patients were diagnosed as having synchronous, double, roentgenographically occult lung cancers. Experienced bronchoscopists failed to detect four "second cancer" lesions in six patients. The appearance of atypical cells as shown by cytologic examination indicated the probability of the presence of cancer in the examined bronchus. Single cancer cells or tiny clusters of cells with orangeophilic cytoplasm can appear in specimens obtained from all bronchi, and such cells should not be considered to have originated in the bronchi under examination. Medium-sized or large clusters of cancer cells without degeneration and with basophilic cytoplasm appear only in specimens obtained from bronchi in which a cancer lesion exists, and thus they should be considered to have originated in the bronchi under examination. Cancer cells with orangeophilic cytoplasm in clusters should be considered to have originated in unknown locations. To determine the origin of such cells, one must compare the specimens with those obtained from other segmental and subsegmental bronchi. Our findings suggest that selective brushing of all segmental and subsegmental bronchi is a useful method of detecting unrecognizable second cancers and that the method should be employed for all patients with positive sputum cytology.

[Flow cytometric analysis of nuclear DNA content of lung cancer--correlation between nuclear DNA content and tumor doubling time].

A total of 65 resected cases with primary lung cancer were examined on correlation between nuclear DNA content by flow cytometry and other prognostic factors, including tumor doubling time (DT). 1) DNA diploidy was found in 18 cases (28%) and DNA aneuploidy in 47 cases (72%). Percent aneuploidy was 79.5% in cases with adenocarcinoma, which tended to be higher than that in cases with squamous cell carcinoma (57.1%). 2) Percent aneuploidy in cases with advanced carcinomas tended to be higher than that in cases with earlier carcinomas, and percent aneuploidy in cases with rapid growing carcinomas tended to be higher than that in cases with slow growing carcinomas. 3) The geometric mean of DT of DNA aneuploid tumor was 130.0 day, which tended to be shorter than that of DNA diploid tumor (171.9 days), but the difference was not significant. There was not a significant correlation between DT and DNA Index. 4) The five-year survival rate of 47 patients with DNA aneuploid tumor was 45%, which was significantly lower than that of 18 patients with DNA diploid tumor (78%).

[Assessment of nucleolar organizer regions (Ag-NORs) in primary lung cancer--correlation between Ag-NORs and tumor doubling time].

A total of 86 resected cases with primary lung cancer were examined on relationships between argyrophil nucleolar organizer regions (Ag-NORs) and other prognostic factors and correlation between Ag-NORs and tumor doubling time (DT). Survival rates were compared between patients with low Ag-NOR counts and patients with high Ag-NOR counts. 1) After logarithmic conversion of mean Ag-NOR counts in lung cancer, a small skewness (0.00486) and a small kurtosis (-0.7859) showed a normal distribution. Mean Ag-NOR counts was found to have a log-normal distribution. 2) There was a significantly inverse correlation between mean Ag-NOR counts and DT (correlation coefficient -0.705, p < 0.001). By plotting log (DT) on X axis and log (Ag-NORs) on Y axis, a formula representing a linear correlation was obtained: Y = 1.17-0.312 X, correlation coefficient -0.886. 3) The five-year survival rate (35%) of 46 patients with mean Ag-NOR counts which were more than or equal to 3.0 significantly lower than that (74%) of 40 patients with mean Ag-NOR counts of less than 3.0.

[Incidence of nodal involvement of #12u nodes (lymph nodes around the upper lobe bronchus) in cases with right middle lobe, right lower lobe, and left lower lobe carcinoma].

#12u nodes are peribronchial lymph nodes around the upper lobe bronchus which should not be routinely dissected in cases with middle lobe carcinoma or lower lobe carcinoma. In this paper, #12u were examined histologically in 152 lung cancer cases. As a results, 14 of 152 (9.2%) had nodal diseases in #12 nodes. #12u nodes were involved in 3 of 30 N1 diseases (10%), and in 11 of 35 N2 diseases (31.4%). There was a case which had no nodal involvement except for #12u node. And in three cases, we found only one nodal metastasis except for #12u nodes. If we did not dissect #12u nodes, these cases will be relapse in near future. Thus, for curative operation, #12u nodes should be dissected as a standard operation.

Clinicopathological analysis of 19 cases of isolated carcinoma in situ of the bronchus.

Nineteen cases of isolated squamous cell carcinoma in situ (CIS) of the bronchus were described clinicopathologically from among 149 male heavy smokers with roentgenographically occult lung cancer discovered mainly by mass screening performed from 1982 to 1991. All 19 patients had positive sputum cytology tests and negative chest x-ray films and underwent lobectomy (except one who had segmentectomy because of poor lung function). Prior to operation, localization was accomplished by one to eight bronchoscopies using repetitive brush cytology and biopsy. Five cases were bronchoscopically invisible. Polypoid protuberance was noted in three cases, micronodular swelling in three, thickening of spur in five, and mucosal granularity in three. Histology by serial block sectioning showed that there was no nodal involvement in any cases; the maximum length or diameter was 12 mm. Thirteen tumors were < or = 4 mm, four of which were confined to the spur where they occurred. Follow-up data showed a favorable prognosis. Segmentectomy or sleeve resection of bronchus without mediastinal lymph node dissection may be adequate for CIS.

Relation between bronchoscopic findings and tumor size of roentgenographically occult bronchogenic squamous cell carcinoma.

A total of 105 lesions in 98 patients with roentgenographically occult bronchogenic squamous cell carcinoma were examined. The relationship of bronchoscopic findings to the depth of invasion into the bronchial wall and the length of longitudinal extension along the bronchus was documented. From viewpoints of the degree of difficulty of bronchoscopic detection and with reference to the height of the lesions, the bronchoscopic findings were classified into three categories: remarkable, minute, and hidden. Of the 105 lesions, 55 (52%) were remarkable, 27 (26%) were minute, and the remaining 23 (22%) were hidden. Of the 23 hidden lesions, 12 were within and 11 were beyond the range of endoscopic visibility. The maximal depth of bronchial invasion (mean +/- standard error) was 3.07 +/- 0.40 mm in the category designated remarkable and 1.62 +/- 0.47 mm in the category designated minute. The depth was 0.93 +/- 0.36 mm in the hidden lesions within the range of endoscopic visibility and 0.78 +/- 0.21 mm in the hidden lesions beyond the range of endoscopic visibility. The maximal length of longitudinal extension along the bronchus was 19.6 +/- 1.5 mm in the remarkable lesions, 9.9 +/- 1.4 mm in the minute lesions, 5.5 +/- 1.0 mm in the hidden lesions within the range of endoscopic visibility, and 8.6 +/- 2.1 mm in the hidden lesions beyond the range of endoscopic visibility. It is useful for predicting the depth of invasion to classify bronchoscopic findings into these three categories for the study of roentgenographically occult bronchogenic squamous cell carcinomas.

Diagnostic value of differential brushing of all branches of the bronchi in patients with sputum positive or suspected positive for lung cancer.

In roentgenographically occult lung cancer, it is often difficult to determine the location of the tumor despite the existence of cancer. This complicates diagnosis and points to a need for a more systematic method of examination. Differential brushing was performed on all the respective segmental bronchi in both lungs of 196 patients with positive or suspected positive indications of lung cancer as revealed by sputum cytology. Fifty-nine borderline lesions in 43 cases and 107 lung cancer lesions in 95 cases were diagnosed. Localization was possible in 70.4% of the cases. The diagnosis of borderline lesions was also possible. At the first examination, the rate of localization, as compared with that in the historical control group, improved from 64.1% to 95.8%, and, in particular, an improvement from 0% to 86.2% was noted in those cases in which abnormal bronchoscopic findings were not observed. Concurrent multiple primary cancer was also diagnosed in 12.6% of lung cancer cases before treatment. With this method, cytologic findings in sputum and in specimens obtained by brushing and histologic findings of resected lung can be compared in an integrated manner, and henceforth more accurate diagnostic criteria can be established.

[Resected roentgenographically occult bronchogenic squamous cell carcinoma tumor size, survival and recurrence].

The relationship between tumor size and nodal involvement of resected roentgenographically occult squamous cell carcinoma in 127 cases was documented. Survival and recurrent patterns were analyzed. Intrabronchial invasion was observed in 103 cases and extrabronchial invasion in 24 cases. One hundred and nineteen cases (94%) had N0 diseases, six (5%) N1 diseases and two (2%) N2 diseases. One hundred and one cases were in early stage and 26 in non-early stage. Nodal involvement was observed in two (2%) of the 103 cases with intrabronchial invasion and in six (25%) of the 24 cases with extrabronchial invasion. Nodal involvement was noted in none (0%) of 55 cases in whom longitudinal extension of tumors was within 10mm, but was noted in four (9%) of 46 cases in whom it was 11 to 20mm and in four (15%) of 26 cases in whom it was 21 to 55mm. Death from primary lung cancer occurred in three (12%) of the non-early cases, but in none (0%) of the early cases. Death from multiple metachronous lung cancer occurred in one (4%) of the non-early cases and in three (3%) of the early cases. Nodal and extrabronchial involvement reduced survival. Recurrence often involved hilar, mediastinal, supraclavicular nodes, and surgical margin of bronchus.

Lesions preceding squamous cell carcinoma of the bronchus and multicentricity of canceration--serial slicing of minute lung cancers smaller than 1 mm.

A total of ten minute squamous cell carcinomas smaller than 1 mm were found in surgical lung specimens from 108 patients who had roentgenographically occult lung cancer. These minute lesions were detected by submitting, in all the 108 specimens, the whole bronchial tree to 2-mm-thick sequential transverse slicing which was then followed by microscopic examination of each slice on an H-E stained section. When a focus of minute carcinoma was found, the slice was further serially sectioned to study whether there were such carcinoma-related lesions as dysplasia or other atypical changes of epithelia, and when there were, the spatial relation of these with the carcinoma. It was demonstrated that all the minute carcinomas were closely associated with either dysplasia or what we call "basal cells with marked atypia", cells with markedly enlarged nuclei arranged in linear fashion on the basement membrane. The contiguity of these changes with minute carcinoma strongly suggested that they are lesions preceding overt carcinoma. Also, there were some minute foci of carcinoma, which, though not involving the entire epithelial thickness, proved to have already begun microinvasion.

Cytologic assessment of peroperative pleural effusion and prognosis in lung cancer patients who underwent resection.

Twenty-five of 108 lung cancer patients who underwent resection had cytologically positive pleural effusions. The rate at which cancer cells were detected was not related to the amount of the effusion. Almost one third of patients with cancer cells in effusion were alive at the end of the third postoperative year, provided that the pleura itself was free of metastasis at the time of operation. Correlation of the cytologically positive rate of pleural effusion (Y) with the degree of pleural metastasis (X1), the degree of pleural involvement (X2), or the degree of nodal involvement (X3) was analyzed using the Hayashi's quantification method type I. The multiple correlation coefficient was 0.843. Partial correlation coefficients of X1, X2, and X3 were 0.733, 0.446, and 0.653, respectively. Pleural metastasis had the strongest effect on the cytologically positive rate of pleural effusion.

[Experience of Nd-YAG laser treatment in roentogenographically occult bronchogenic squamous cell carcinoma].

Out of 201 patients with roentogenographically occult bronchogenic squamous cell carcinoma, 165 lesions underwent surgical operations, while 41 lesions underwent non-invasive therapy. The 5-year survival rate including all causes of death, was significantly higher in the surgical operation group than that in the non-invasive therapy group (83% vs 43%). Among 14 cases who received Nd-YAG laser treatment, one case died but 4 cases are alive bearing cancer. Since time span of follow-up period is short, it is hard to say that the prognosis of the Nd-YAG laser therapy in fair. Nd-YAG laser treatments were effective for cancers which did not invade beyond bronchial cartilage. From the bronchoscopic examinations and studies with resected lungs, we suggest that Nd-YAG laser treatments may be effective when cancer is extended within 10 mm wide and has only a slight findings in bronchoscopy.

[T4 advanced lung cancer: results of surgical treatment and indications of surgical resection].

A total of 1,289 patients with primary lung cancer were surgically treated at our hospital from January 1953 to December 1985. Surgical treatment for T4 lung cancer was studied in 93 patients who had pulmonary resections. The relationships between histologic type, stage, method of resection, curability, nodal involvement, pleural involvement, site of invasion, pleural metastasis, pleural effusion, combination therapy, and the survival rate were analyzed. The survival rate of 93 patients with T4 lung cancer was 17% at 3 years and 7% at 5 years. Three-year survival rate of 39 patients with adenocarcinoma, 34 patients with squamous cell carcinoma, and 9 patients with large cell carcinoma was 7%, 23%, and 14%, respectively. Two-year survival rate of 6 patients with small cell carcinoma was 17%. Four-year survival rate of 14 patients who had complete resection was 33%. On the other hand, four-year survival rate of 77 patients who had incomplete resection was 7%. Three-year survival rate of 6 patients with N0 disease, and 19 patients with N1 disease, 46 patients with N2 disease, and 22 patients with NX disease was 40%, 39%, 0%, and 15%, respectively. Two patients, who had partial resection of the left atrium because carcinoma made an invasion upon it, had survived more than 5 years. All patients with esophageal invasion or tracheal invasion had died within a year. Indications of surgical resection for patients with T4 lung cancer should be limited to patients with N0 and N1 disease. Radical pulmonary resection can be performed in patients who are expected to have complete resection.

[A study of lung cancer with presence of pleural effusion at the time of thoracotomy--cytologic evaluation of a relatively small amount of pleural effusion and prognosis after removal].

The cytologic evaluation of a relatively small amount of pleural effusion in lung cancer at the time of thoracotomy has not been previously considered, and prognosis after removal has not been clarified. In order to clarify these points, 99 cases of removed lung cancer with presence of pleural effusion at the time of thoracotomy were examined following cytology. Our study was conducted with regard to the amount and nature of pleural effusion, pleural effusion cytology, tumor development and its relation to prognosis. On the basis of this study a formula was developed relating the occurrence rate of cytologically positive pleural effusion with the development of tumor employing multivariate analysis, specifically the multiple regression analysis. 21% of these cases showed cytologically positive pleural effusion, indicating an absence of its correlation to the amount of pleural effusion; the conducting of cytology regardless of the amount of pleural effusion was found to be significant in determining the precise stage. The occurrence rate of cytologically positive squamous cell carcinoma was significantly few compared with those in other cell types. Regarding the pleural effusion of a relatively small amount, the prognosis after removal showed a relatively high three-year survival rate of 32% for those cases with negative pleural metastasis despite the positive showing of pleural effusion cytology, indicating the viability of surgery. From the occurrence rate of cytologically positive pleural effusion (Y) and the degree of pleural metastasis (X1)/the degree of pleural invasion (X2)/the degree of lymph nodes metastasis (X3), the following formula was obtained employing multiple regression analysis: Y = 0.344X1 + 0.050X2 + 0.034X3 + 0.075 (proportion 0.840).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of lymph node metastasis to primary tumor size and microscopic appearance of roentgenographically occult lung cancer.

We investigated the relationship of lymph node metastasis to primary tumor size and microscopic appearance in 92 resected specimens obtained from patients with roentgenographically occult lung cancer (ROLC) located at a site along the airway between the main bronchus and the sub-subsegmental bronchi. Most of the patients were discovered by mass screening. All were treated surgically after bronchoscopic localization of cancer. The bronchial tree of the resected specimens was serial-sectioned into 2-mm thick blocks from the margin of resection to the sub-subsegmental bronchi. Bronchial wall invasion was noted in some blocks of all the specimens. The length of longitudinal extension (LLE) was defined as the product of the thickness and the number of consecutive blocks involved, counting from the most proximal to the most distal block. LLE was used as primary tumor size. Hilar and mediastinal lymph nodes were examined in 84 patients who underwent lymph node dissection. No nodal involvement was found in 59 cancers with LLE of less than 20 mm. Of 25 cancers with LLE of 20 mm or more, six showed nodal involvement. Eleven in situ carcinomas and four cancers of the "suspicious for invasion" type showed no lymph node metastasis. We contend that no lymph node dissection is required when pulmonary resection is performed for patients with ROLC if it is in situ carcinoma, if it is of the "suspicious for invasion" type, or if the LLE is smaller than 20 mm.