Comparison between preoperative versus intraoperative injection of technetium-99 m neomannosyl human serum albumin for sentinel lymph node identification in early stage lung cancer.

PURPOSE: We aimed to evaluate the results of sentinel lymph node mapping according to injection time (preoperative vs. intraoperative) of technetium-99m neomannosyl human serum albumin (99mTc-MSA) in patients with lung cancer. METHODS: Data of 82 patients (55 men; mean age 62.9±9.3 years) who were candidates for lobectomy with mediastinal lymph node dissection for clinical stage I non-small cell lung cancer were retrospectively reviewed. (99m)Tc-MSA was administered at the peritumoral region under chest computed tomographic guidance, 1 to 2 h before surgery (preoperation group, n=48) or soon after thoracotomy (intraoperation group, n=34). RESULTS: Patients' demographic data, except type of operation, did not differ between the two groups. Sentinel lymph nodes were detected in 46 patients (95.8%) in the preoperation group and 33 patients (97.1%) in the intraoperation group (P=.243). The mean number of sentinel nodes per patient was 2.1 in the preoperation group and 2.6 in the intraoperation group (P=.068). No falsely negative sentinel nodes were detected in any of the 17 patients with N1 or N2 disease (0%) in either group. Administration of the intraoperative injection could save additional cost (US$607) and time (70 min) in each patient. CONCLUSIONS: Sentinel node identification using 99mTc-MSA appears to provide similar excellent results in both preoperative and intraoperative injection. Therefore, intraoperative injection of 99mTc-MSA may be preferred as a result of lower cost and less waste of time.

Deregulated expression of hnRNP A/B proteins in human non-small cell lung cancer: parallel assessment of protein and mRNA levels in paired tumour/non-tumour tissues.

BACKGROUND: Heterogeneous nuclear ribonucleoproteins (hnRNPs) of the A/B type (hnRNP A1, A2/B1, A3) are highly related multifunctional proteins participating in alternative splicing by antagonising other splicing factors, notably ASF/SF2. The altered expression pattern of hnRNP A2/B1 and/or splicing variant B1 alone in human lung cancer and their potential to serve as molecular markers for early diagnosis remain issues of intense investigation. The main objective of the present study was to use paired tumour/non-tumour biopsies from patients with non-small cell lung cancer (NSCLC) to investigate the expression profiles of hnRNP A1, A2/B1 and A3 in conjunction with ASF/SF2. METHODS: We combined western blotting of tissue homogenates with immunohistochemical examination of fixed tissue sections and quantification of mRNA expression levels in tumour versus adjacent normal-looking areas of the lung in the same patient. RESULTS: Our study, in addition to clear evidence of mostly uncoupled deregulation of hnRNPs A/B, has revealed hnRNP A1 to be the most deregulated protein with a high frequency of over-expression (76%), followed by A3 (52%) and A2/B1 (43%). Moreover, direct comparison of protein/mRNA levels showed a lack of correlation in the case of hnRNP A1 (as well as of ASF/SF2), but not of A2/B1, suggesting that different mechanisms underlie their deregulation. CONCLUSION: Our results provide strong evidence for the up-regulation of hnRNP A/B in NSCLC, and they support the existence of distinct mechanisms responsible for their deregulated expression.

Pilot study of gefitinib and fulvestrant in the treatment of post-menopausal women with advanced non-small cell lung cancer.

INTRODUCTION: Estrogen receptor beta (ERbeta) has been detected in non-small cell lung cancer (NSCLC) cell lines and tumor specimens. The ER down-regulator, fulvestrant, blocked estradiol-stimulation of tumor growth and gene transcription in NSCLC preclinical models and showed additive effects with the epidermal growth factor receptor (EGFR) inhibitor gefitinib. The safety and tolerability of combination therapy with the EGFR inhibitor, gefitinib, and fulvestrant was explored. METHODS: Post-menopausal women with advanced NSCLC received gefitinib 250 mg po daily and fulvestrant 250 mg IM monthly. RESULTS: Twenty-two patients were enrolled. Eight patients had adenocarcinoma, six NSCLC-NOS, four squamous cell, and four BAC. Seven patients were never-smokers. Eight patients received > or =2 lines of prior chemotherapy, six received one prior chemotherapy, and eight were treatment-naïve. One patient experienced grade 4 dyspnea possibly related to treatment; all other grade 3/4 toxicities were unrelated to treatment. Twenty patients were evaluable for response: three partial responses (PRs) were confirmed (response rate of 15%, 95% CI: 5-36%). The median progression-free survival (PFS), overall survival (OS), and estimated 1-year OS were 12 weeks (3-112 weeks), 38.5 weeks (7-135 weeks), and 41% (95% CI: 20-62%), respectively. Survival outcomes did not differ by prior lines of therapy. A subset analysis revealed that OS in the eight patients whose tumors exhibited at least 60% ERbeta nuclear IHC staining measured 65.5 weeks, while that of the five patients with ERbeta staining of less than 60% was 21 weeks. One patient with bronchioalveolar carcinoma (BAC) and a PR had an EGFR L858R mutation in exon 21. There was no correlation between ERbeta IHC expression and histology or smoking history. CONCLUSIONS: Combination therapy with gefitinib and fulvestrant in this population was well tolerated and demonstrated disease activity.

Surgical resection and long-term survival for octogenarians who undergo surgery for non-small-cell lung cancer.

PURPOSE: An increasing proportion of newly diagnosed non-small-cell lung cancer (NSCLC) patients are octogenarians. It has been questioned whether older patients benefit from surgical resection of lung cancer to the same extent as younger patients. PATIENTS AND METHODS: We conducted a single-institution, retrospective analysis of patients newly diagnosed with NSCLC from 2000-2006, who underwent surgical resection of their lung cancer in Hoag Hospital. We compared resection and survival rates for patients who were age 80 years or older to younger cohorts and determined their stage distribution, rates of surgery, and actuarial survival by age-defined cohort. Of 1293 total patients, 17.2% were age 80 years or older; 36.1%, age 70-79 years; 29.2%, age 60-69 years; 12.9%, age 50-59 years; and 4.6%, under age 50. Of these patients, 482 underwent surgical resection. Surgical procedures included 400 lobectomies, 23 pneumonectomies, and 59 wedge resections. RESULTS: The proportion of patients who had local disease at diagnosis was higher for octogenarians compared with younger patients (33.6% vs. 26.6%; P = .021), but the resection rate for octogenarians was lower (64% vs. 83%; P = .0003). For patients determined to have local- or regional-stage disease, resection rates were 52% versus 67.9% (P = .0007). However, survival curves for patients who underwent surgical resection were similar for all five cohorts with 5-year survival rates of 62%, 53%, 63%, 63%, and 79% from oldest to youngest. CONCLUSION: Non-small-cell lung cancer patients < 80 years of age were less likely to undergo potentially curative surgery, but survival for octogenarians who did undergo surgical resection was comparable to younger age groups. Such patients should not be denied potentially curative surgery simply because of age.

DNA repair gene polymorphisms predict favorable clinical outcome in advanced non-small-cell lung cancer.

BACKGROUND: Genetic polymorphisms of genes involved in DNA repair and glutathione metabolic pathways may affect patients' response to platinum-based chemotherapy. We retrospectively assessed whether single nucleotide polymorphisms (SNP) of DNA-repair genes ERCC1, XPD, XRCC1 and glutathione S-transferase genes GSTP1, GSTT1 and GSTM1 predict overall survival (OS), response and toxicity in 119 non-small-cell lung cancer (NSCLC) patients treated with platinum-based regimens as first- or second-line chemotherapy. PATIENTS AND METHODS: Patients' genotypes were determined by PCR-RFLP and sequencing approaches. RESULTS: ERCC1 (Asn118Asn) genotype was significantly associated with response to treatment. Patients with either one or two C alleles (C/C, C/T) at Asn118Asn were more likely to respond to platinum-based chemotherapy compared with those without the C allele (Odds ratio, 0.10; 95% CI, 0.013-0.828; P = .033, by binary logistic regression). There was a significant association between the ERCC1 C8092A polymorphism and OS (P = .009, by log-rank test), with median survival times of 9.8 (C/C) and 14.1 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with an improved outcome. Cox's multivariate analysis suggested that the joint effect of ERCC1 polymorphic variants (C8092A and N118N) (0 vs. 2, hazard ratio 2.5; 95% CI, 1.26-4.96; P = .009) as well as the XRCC1 N399Q polymorphism (AA vs. GA/GG, hazard ratio 3.1; 95% CI, 1.4-6.8; P = .005) were independent prognostic factors for OS in advanced NSCLC patients treated with platinum-based chemotherapy. CONCLUSION: These findings support the notion that assessment of genetic variations of ERCC1 and XRCC1 could facilitate therapeutic decisions for individualized therapy in advanced NSCLC.

Apparent alveolar bronchiolar tumors arising in the mediastinum of F344 rats.

Rare tumors were observed in chronic studies in F-344 rats that were purely or largely free in the mediastinal cavity, yet had the histological architecture of alveolar bronchiolar tumors. They had originally been diagnosed as either pulmonary alveolar bronchiolar tumors, mediastinal mesotheliomas, or thymomas. The authors described these tumors, estimated the fraction of thoracic tumors that they represented, and carried out a preliminary immunohistochemical investigation of whether they were of pulmonary or mesothelial origin. Sections of 715 thoracic tumors originally diagnosed as alveolar bronchiolar tumors, mesotheliomas, or thymomas from control or treated F-344 rats in NTP two-year studies were reviewed. Thirty (4%) were found to be purely or largely mediastinal, yet to have an alveolar bronchiolar histological pattern. A subset of these tumors and some typical intrapulmonary alveolar bronchiolar carcinomas and pleural mesotheliomas were immunostained for Clara cell secretory protein (CCSP), beta-tubulin IV, and Wilm's tumor 1 susceptibility gene products (WT1). The tumors with the histological architecture of alveolar bronchiolar tumors immunostained positive for CCSP and negative for WT1, implying they might have been of alveolar bronchiolar origin, despite their predominantly mediastinal location, although more certain identification would require the use of a larger panel of antibodies.

Increased cytoplasmic S100A6 expression is associated with pulmonary adenocarcinoma progression.

S100A6 is a calcium-binding protein implicated in many cellular processes and frequently upregulated in cancer. Recently it was reported that S100A6 is one of the genes having higher expression in adenocarcinoma mixed subtype with a bronchioloalveolar carcinoma (BAC) component than in pure BAC. To clarify the association of S100A6 expression with stepwise progression of lung adenocarcinoma, S100A6 protein expression was examined on immunohistochemistry in 92 formalin-fixed and paraffin-embedded lung adenocarcinomas. Both the nucleus and cytoplasm of the tumor cells were stained, and the nuclear and cytoplasmic expression of S100A6 was assessed individually. In addition, six frozen surgical specimens were selected, and the expression of S100A6 was confirmed on western blotting. As a result, although it was not possible to detect any significant correlation between nuclear S100A6 immunoreactivity and tumor progression, advanced adenocarcinoma had significantly higher cytoplasmic S100A6 expression than non-invasive lesions or normal lung tissue (P < 0.05). Moreover, the BAC component tended to have weaker staining than any of the other components. These findings indicate that S100A6 may be associated with the stepwise progression and/or invasion of lung adenocarcinoma, especially BAC-type adenocarcinoma. The present results suggest the utility of S100A6 immunohistochemistry as a marker for estimation of malignancy in adenocarcinoma with a BAC component.

[A case of non-small cell lung carcinoma dying of acute respiratory failure due to aerogenous metastasis].

A 63-year-old man was admitted to our hospital, because of exacerbation of backache and erythema. At the time of admission the chest X-ray film showed infiltrative shadows in the left middle and lower lung fields. Our investigation revealed primary mucinous type bronchioloalveolar carcinoma in the left lung (cT4N2M1 Stage IV). Radiotherapy (C7-Th2, L3-L5. Total 30 Gy/10 fr) was administered to relieve his pain. After radiotherapy, he developed respiratory failure, fever, and infiltrative shadow in his chest X-ray. Antibiotic therapy improved his symptoms, laboratory findings and radiological abnormal findings. We suspected complication with nosocomial infection. However the ground-glass appearance appeared in the right lung a few days later. Although antibiotics and steroids were administered, he died of respiratory failure in 6 days. Necropsy findings revealed bronchioloalveolar carcinoma in the right lung suggesting aerogenous metastasis. Considering these facts together, we diagnosed non-small cell lung carcinoma dying of acute respiratory failure due to aerogenous metastasis.

Bronchoalveolar carcinoma of lung masquerading as iodine avid metastasis in a patient with minimally invasive follicular carcinoma of thyroid.

A 52-year-old man with follicular thyroid carcinoma was administered 182 mCi of radioiodine (I-131) a month after total thyroidectomy. Post-therapy scan revealed diffuse uptake of radioiodine in the apical left lung. CT-guided biopsy of this mass revealed mucinous bronchoalveolar carcinoma. Immunohistochemistry for thyroglobulin was negative. An FDG PET scan showed avid uptake in the lung mass. Surgery was ruled out, so he was given chemotherapy, without benefit. The lesion continued to show I-131 uptake even while on daily T3 substitution, suggesting that the mass was thyroid stimulating hormone-independent. Because the mass showed I-131 uptake and chemotherapy was not beneficial, it was decided to treat with I-131. He was continued on T3 substitution therapy and was given 209 mCi of I-131. Follow-up CT scan a few weeks later reported a 1-cm all round reduction of the mass. I-131 scan showed avid tracer uptake in the mass. This case suggests the possibility of this therapeutic option in nonthyroidal tumors that may concentrate radioiodine.

Bronchoalveolar carcinoma as an unsuspected cause for worsening shortness of breath in a patient with metastatic breast cancer.

A 70-year-old woman with lung metastases from a breast cancer presented with worsening cough and dyspnoea. She recently had a pleurodesis for a malignant pleural effusion. Chest CT scans demonstrated various radiological changes leading to diagnostic challenges. Differential diagnoses included empyema, pleural disease progression, pulmonary oedema, pneumonitis, lymphangitis and atypical infections. She deteriorated despite a multimodality treatment strategy. Postmortem examination confirmed that lung changes were consistent with a bronchoalveolar carcinoma unrelated to the known metastatic breast cancer. The eventual knowledge of this diagnosis was reassuring to the treating medical team and a comfort to the relatives who witnessed the lack of response to standard treatment.

A phase II study of single-agent oral vinorelbine in patients with pretreated advanced non-small-cell lung cancer.

PURPOSE: Intravenous vinorelbine has demonstrated its efficacy and tolerability in advanced non-small-cell lung cancer (NSCLC). An oral formulation of vinorelbine has been developed, and a number of phase II studies have shown its activity in chemotherapy-naive NSCLC, even in elderly patients, but no study has been performed to test activity and toxicity of oral vinorelbine in pretreated patients. The aims of our study were to investigate the activity and toxicity of oral vinorelbine in patients with NSCLC as salvage treatment. PATIENTS AND METHODS: Twenty pretreated patients with locally advanced (n = 6) and metastatic (n = 14) NSCLC entered the study. The schedule was oral vinorelbine 60 mg/m(2) once a week until progression or development of unacceptable toxicity. Median age was 70 years (range, 49-84 years). RESULTS: Seventeen patients were evaluable for response and all for toxicity. A median of 9 cycles were administered (range, 2-21 cycles). No objective responses were reported, 5 patients experienced stable disease, and 12 patients had progressive disease. Median time to progression was 2 months (range, 1-6 months), and median survival was 4 months (range, 1-13 months). Treatment was well tolerated, with grade 4 neutropenia in 1 patient (heavily pretreated); grade 2 diarrhea in 2 patients; asthenia in 2 patients; and abdominal pain in 1 patient. CONCLUSION: Oral vinorelbine 60 mg/m(2) once a week is a very safe schedule in heavily pretreated locally advanced and metastatic NSCLC; however, at this dose, the drug is inactive. Other phase II studies with oral vinorelbine 80 mg/m(2) weekly are warranted.

Phase I Results from a Study of Crizotinib in Combination with Erlotinib in Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer.

INTRODUCTION: This phase I trial was conducted to determine the safety, maximum tolerated dose (MTD)/recommended phase II dose, and efficacy of crizotinib plus erlotinib in patients with advanced NSCLC. METHODS: Patients with NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 after failure of one or two prior chemotherapy regimens were eligible. Erlotinib, 100 mg, was given continuously once daily starting between day -14 and -7; crizotinib, 200 mg twice daily (dose level 1) or 150 mg twice daily (dose level -1), was added continuously beginning on day 1 of treatment cycle 1. Potential pharmacokinetic interactions between crizotinib and erlotinib were evaluated. RESULTS: Twenty-seven patients received treatment; 26 received crizotinib plus erlotinib. Frequent adverse events were diarrhea, rash, decreased appetite, and fatigue. Dose-limiting toxicities were dehydration, diarrhea, dry eye, dysphagia, dyspepsia, esophagitis and vomiting. The MTD was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily. Crizotinib increased the erlotinib area under the concentration-time curve 1.5-fold (dose level -1) and 1.8-fold (dose level 1). The plasma level of crizotinib appeared to be unaffected by coadministration of erlotinib. Two patients whose tumors harbored activating EGFR mutations achieved confirmed partial responses, one at each crizotinib dose level. CONCLUSIONS: The MTD of the combination of crizotinib and erlotinib in patients with advanced NSCLC was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily, which is less than the approved dose of either agent. The phase II portion of the study was not initiated.

[Clinicopathologic characteristics of metastatic carcinomas to spleen].

OBJECTIVE: To study the clinicopathologic characteristics of metastatic carcinomas to the spleen. METHODS: Sixteen cases of metastatic carcinoma to the spleen were retrieved from archival clinical, surgical pathology and autopsy records. The demographic data (including sex and age of patients), clinical symptoms, primary sites, tumor histologic types, gross appearance of spleen and growth patterns within the spleen were analyzed. RESULTS: Among the 16 patients studied, 12 were males and 4 were females. The male predilection was obvious. The age ranged from 48 to 90 years, the median age 66.5 years. Major clinical symptoms included discomfort in the left upper quadrant, pain, emaciation and loss of appetite. Splenomegaly was noted in some patients and computerized tomography could show space-occupying lesions in the spleen. In general, lung was the most common primary site for splenic metastasis and accounted for 43.8% of all cases (7/16). In male patients, primary lung tumor was found in 50.0% cases (6/12). On the other hand, primary ovarian tumor was commonly seen in females (2/4). Histologically, undifferentiated carcinoma of lung was frequently encountered (25.0%, 4/16), including 3 cases of small cell undifferentiated carcinoma and 1 case of large cell undifferentiated carcinoma. Other histologic tumor types included bronchioloalveolar carcinoma (2 cases), colonic adenocarcinoma (2 cases), ovarian serous papillary adenocarcinoma (2 cases), and prostatic adenocarcinoma (2 cases). The commonest histologic tumor type found in male patients was pulmonary undifferentiated carcinoma. The growth patterns of metastatic carcinoma in spleen included nodular, diffuse and multinodular. Most cases presented as a single splenic nodule. Sometimes, tumors with high metastatic potential (5/16) showed diffuse and multinodular growth patterns. Examples of these tumors included small cell undifferentiated carcinoma (3 cases), pulmonary adenocarcinoma (1 case) and prostatic adenocarcinoma (1 case). CONCLUSIONS: Metastatic carcinoma to the spleen is rare. Understanding of the clinicopathologic characteristics is helpful in guiding clinical management and pathologic diagnosis.

Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappaB.

To investigate the role of the transcription factor nuclear factor kappaB (NFkappaB) in tumor metastasis, we generated a murine lung alveolar carcinoma cell line (Line 1) defective in NFkappaB-signaling by retroviral delivery of a dominant negative inhibitor of NFkappaB. The NFkappaB signal blockade resulted in the down-regulation of prometastatic matrix metalloproteinase 9, a urokinase-like plasminogen activator, and heparanase and reciprocal up-regulation of antimetastatic tissue inhibitors of matrix metalloproteinases 1 and 2 and plasminogen activator inhibitor 2. NFkappaB signal blockade did not affect tumor cell proliferation in vitro or in vivo but prevented intravasation of tumor cells in an in vivo chick chorioallantoic membrane model of metastasis as well as spontaneous metastasis in a murine model. These findings suggest that NFkappaB plays a central and specific role in the regulation of tumor metastasis and may be an important therapeutic target for development of antimetastatic cancer treatments.

[Prognosis of patients after resection for lung cancer with intrapulmonary metastasis in different lobes].

BACKGROUND: The prognosis of lung cancer patients with intrapulmonary metastasis in different lobes (pm2) is poor. However, some patients achieve long-term survival. We retrospectively investigated the prognosis of resected primary lung cancer patients with pm2. METHOD: Among 845 patients with primary lung cancer who underwent complete resection from 1984 to 2003, 14 cases that had lung cancer with pm2 were evaluated about prognostic factors. RESULTS: The overall 5-year survival rate was 9.5%. The analysis of survival curve based on clinicopathological factors (surgical procedure, histology, tumor size, lymph nodal metastasis, pleural invasion, pleural dissemination and number of pm2) revealed that bronchioloalveolar carcinoma (BAC), the absence of pleural invasion and the absence of pleural dissemination are better prognostic factors. CONCLUSION: Lung cancer patients with pm2 whose lesions show BAC histology, the absence of pleural invasion or pleural dissemination may achieve long-term survival and could be candidates for surgical treatment.

[Bronchioloalveolar carcinoma]. / Rak oskrzelikowo-pecherzykowy.

Bronchioloalveolar carcinoma (BALC) is a sub-type of adenocarcinoma, accounting for 3-5% of all lung cancer cases. It is characterized by peripheral location in lung parenchyma, without visible changes in main bronchi and tumor spread occurs along the walls of the peripheral airspaces without destruction of the pulmonary interstitium. Their carcinomas were classified into three clinicopathologic types: nodular or tumoral, pneumonic, and diffuse types. The disease may take an asymptomatic form for several months or even years. This form of cancer spreads by way of air tracts creating multiple changes in lungs. Metastases to lymph nodes and other organs occur rarely. It is difficult to provide a correct diagnosis. The complete surgical resection of localized BAL C offers the best chances of long-term survival. Patient prognosis is usually more positive than in other histological types, since the disease is frequently diagnosed at its early development stages.

Immunohistochemically detected micrometastases in peribronchial and mediastinal lymph nodes from patients with T1, N0, M0 pulmonary adenocarcinomas.

The T1, N0, M0 subset of stage I lung adenocarcinoma is a tumor that has a 5-year disease-free survival rate of 66% to 85%. To date, there has not been a rigorous immunohistochemically detected lymph node micrometastasis study composed of patients with identical stage and type of tumors, and in which standard histologic features were incorporated into multivariate analyses. We immunohistochemically examined the peribronchial and mediastinal lymph nodes from 80 consecutively accrued patients with T1, N0, M0 adenocarcinomas and bronchioloalveolar carcinomas unselected for distant metastasis, and an additional 39 patients with similar stage and type neoplasms who were selected for their development of metastases to evaluate the prevalence of micrometastases, their association with distant metastases, and their relationship with other pathologic prognostic features. All slides were stained with keratin AE1/3. Micrometastases were confirmed with Ber-Ep4. Three immunohistochemically detected lymph node micrometastases were identified in three of 80 consecutively accrued patients (4%). These three positive stains constituted 0.5% of the 573 stains required to immunohistochemically screen all of the lymph node blocks from these patients. Among the 39 patients who were selected because they developed distant metastases, three immunohistochemically detected lymph node micrometastases from three patients were identified, which constituted 8% of patients in this group and 1% of the 280 stains required to screen all of these patients' lymph nodes. Small vessel invasion, maximum tumor dimension, and immunohistochemically detected lymph node micrometastases were independently associated with metastases on multivariate analysis. Among patients who developed metastases, there was no significant difference in the disease-free survival rate between those with and those without immunohistochemically detected lymph node micrometastases. Given the low sensitivity in terms of the number of immunohistochemical stains performed, and the prognostic significance of standard histologic features, the use of immunohistochemical screening lymph nodes from all patients with T1, N0, M0 adenocarcinomas is questionable.

Lung adenocarcinoma with mixed bronchioloalveolar and invasive components: clinicopathological features, subclassification by extent of invasive foci, and immunohistochemical characterization.

A significant proportion of small lung adenocarcinomas consists of two components: bronchioloalveolar carcinoma (BAC) and invasive carcinoma. The purpose of this study was to compare their clinicopathologic features with those of BAC and those of invasive cancer without BAC, and to define "early invasive" lesions based on the extent of invasive foci. We reviewed 484 lesions of resected lung adenocarcinoma and classified them into three groups according to tumor growth pattern: group 1 (n = 102, BAC), group 2 (n = 216, adenocarcinoma consisting of BAC and invasive carcinoma), and group 3 (n = 166, invasive adenocarcinoma without BAC component). Group 2 was further subdivided according to the extent of the invasive area: group 2a (n = 54), BAC with invasive foci 5 mm. These groups were compared with regard to their clinicopathologic features, expression of Ki-67 and p53, and expression of laminin-5, a putative marker for tumor invasion. The positivity rates of vascular, lymphatic, and pleural invasion in each group were as follows: 0%, 0%, and 0% in group 1; 5.5%, 14.8%, and 1.9% in group 2a; 45.7%, 41.4%, and 25.9% in group 2b; and 84.9%, 61.4%, and 60.8% in group 3. Notably, no lymph node metastasis occurred in either group 2a or group 1, but it was observed in 24.1% of group 2b and 47.0% of group 3. The mean Ki-67 labeling index, the frequency of p53 overexpression, and the frequency of laminin-5 overexpression increased from group 1 (11%, 4%, and 0%) to group 2a (16%, 20%, and 7%) to group 2b (24%, 41%, and 23%) to group 3 (35%, 38%, and 38%). In contrast, no clear differences were observed when lesions were subdivided according to size. Based on the distribution pattern of Ki-67-positive tumor cells, lesions were classified into two groups: marginal type (63%) and nonmarginal type (37%). The latter showed a significantly higher labeling index than the former. Moreover, the proportion of the marginal type clearly decreased from group 1 (85%) and group 2a (87%) to group 2b (55%) to group 3 (19%). Group 2 lesions showed characteristics intermediate between the BAC and invasive adenocarcinoma. According to the extent of the invasive area, we were able to define a subgroup of mixed-type adenocarcinomas (group 2a) that could be regarded as early invasive cancer because they showed low rates of vascular, lymphatic, and pleural invasion, and no nodal involvement.

Metastatic bronchioloalveolar carcinoma and metastatic adenocarcinoma of the lung: comparison of clinical manifestations, chemotherapeutic responses, and prognosis.

Between 1975 and 1985, 25 patients with metastatic bronchioloalveolar carcinoma and 223 patients with metastatic adenocarcinoma of the lung received experimental cisplatin-based chemotherapy at the Mayo Clinic. The chemotherapeutic response rates were 32% and 33%, respectively. The median times to progression of disease were identical (3 months in both groups). The median survival times were 4 months and 6 months, respectively. Metastatic bronchioloalveolar carcinoma is an aggressive disease that is associated with a poor prognosis, similar to metastatic adenocarcinoma of the lung.