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Ann Thorac Surg 1996;61:1470-1476
© 1996 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Angiogenesis and Molecular Biologic Substaging in Patients With Stage I Non-Small Cell Lung Cancer

Lung Cancer Research Laboratory, Thoracic Oncology Program at the Dana Farber Cancer Institute and the Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. Although complete surgical resection remains the primary treatment for localized stage I non-small cell lung cancer, the cancer recurrence rate is 25% to 40%. If one could identify a subset of patients using molecular factors that contribute to tumor aggressiveness, one might improve prognosis in this group with additional treatment. High expression of angiogenesis factor viii has been associated with the presence of nodal metastases in breast cancer; here we examined its relation to survival with non-small cell lung cancer.

Methods. We examined angiogenesis using immunohistochemistry on paraffin blocks of tumor from 275 consecutive patients with stage I non-small cell lung cancer, more than 68 months of follow-up, and a 64% 5-year survival. Angiogenesis was calculated from the microvessel number per ten 200x microscope fields measured at the tumor periphery, in the center, and in the area of highest concentration.

Results. Measurements in the central area were inconsistent due to prominent necrosis. However, microvessel number recorded at the periphery and at the ``hottest'' area correlated well (r<sup>2</sup> = 0.952; p = 0.001), and a significant survival advantage was noted for low-level expression at both areas (peripheral, p = 0.046; ``hottest'', p = 0.006). Multivariate survival analysis using angiogenesis, protooncogene erbB-2, tumor suppressor gene p53, and the proliferation marker KI-67 defined angiogenesis as the most significant prognostic factor in stage I lung cancer.

Conclusions. This molecular biologic substaging system including angiogenesis for stage I non-small cell lung cancer is independent of routine histopathologic factors and revealed an additive adverse effect with expression of several biologic markers (5-year survival: no marker [n = 51] 81%, 1 marker [n = 82] 71%, 2 markers [n = 84] 54%, and 3 to 4 markers [n = 58] 49%; p = 0.0001).

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
See also page 1476.

The most common cause of cancer mortality in women and men in the United States is non-small cell lung cancer (NSCLC). Unfortunately, the overall survival continues to be less than 15% at 5 years [1]. The subset of patients with a more optimistic outlook are those with pathologic stage I disease (T1-2 N0) [2]. These patients make up approximately 25% to 30% of those with NSCLC, but they have experienced a cancer recurrence rate of 25% to 50% in several retrospective series [2, 3]. If one could identify the subset of stage I patients likely to have recurrence and die of NSCLC, one might affect survival with adjuvant therapy.

Several histopathologic factors have been identified that have independent prognostic significance, including T size, mitotic rate, visceral pleural invasion, and vascular invasion [3–8]. Unfortunately these are relatively crude measures of the biologic aggressiveness of the primary cancer. Recent advances in molecular biology have made the analysis of molecular genetic factors simple, economical, and widely applicable. These factors can be divided into categories according to action: tumor suppressor genes, protooncogenes, markers of metastatic propensity, and proliferation markers [9]. We have previously described the expression of protooncogene erbB-2 (Her2/neu) and tumor suppressor gene p53 in NSCLC [10, 11]. Therefore, the purpose of this project was to evaluate another marker of metastatic propensity (angiogenesis) to determine if a molecular biologic substaging system could be constructed that would be irrespective of traditional histopathologic factors. Patients in this project were limited to those with pathologic stage I disease to eliminate the confounding influence of positive lymph nodes or distant metastases.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Population
The population consisted of 275 consecutive patients treated at a single institution from 1980 until 1988 who had at least two archived paraffin-embedded blocks of tumor and normal lung available for analysis. For inclusion, the cell type had to be adenocarcinoma (either papillary, acinar, or bronchioalveolar), large cell undifferentiated carcinoma, or squamous cell carcinoma. No patient was included with an unclear or mixed histology (eg, adenosquamous), and the original histopathology was reviewed to verify negative hilar and mediastinal nodes (T1-2 N0).

The mean age of the patients was 63 ± 9 years (range, 34 to 82 years). There were 177 men (64%) and 98 women (36%) (Table 1). All patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and normal abdominal computed tomograms and radionuclide bone scans. If any mediastinal adenopathy greater than 1 cm was visualized on computed tomogram, operative sampling was performed to verify stage I. Operative resection included hilar lymph nodes (lobectomy, n = 182; pneumonectomy, n = 21; segmental or stapled wedge resection, n = 72). Histologic types were 137 adenocarcinoma, 98 squamous, and 40 large cell undifferentiated tumors. The mean tumor size was 3.2 ± 1.8 cm (range, 1.0 to 13.0 cm).

Immunohistochemistry
Immunohistochemical analyses were performed on two paraffin blocks of resected lung tissue per patient obtained via an approved Human Subjects Review Committee protocol. Details of the technique have been described previously for a protooncogene erbB-2 (HER-2/neu) and a tumor suppressor gene p53 [10, 11]. Briefly, after paraffin microtome sectioning (4 to 6 µm), slide labeling, and deparaffinization with xylene and EtOH, antigen retrieval was completed after microwaving and phosphate-buffered NaCl washing. The sections were incubated with the primary monoclonal or polyclonal antibody or control antibody: for angiogenesis factor viii, mouse polyclonal antibody to factor viii (Dako Polyclonal, Santa Barbara, CA); for proliferation antigen KI-67, mouse monoclonal antibody to 67-kD nuclear antigen (Dakopatts, Glostrup, Denmark); for tumor supressor gene p53, mouse monoclonal antibody (PAb 1801; Oncogene Science, Mineola, NY); and for protooncogene erbB-2, rabbit polyclonal antibody to p185^neu (PAB₂; Triton Biosciences, Alameda, CA). A second incubation included the secondary antibody (either goat anti-mouse immunoglobulin G or goat anti-rabbit immunoglobulin G), followed by development with the Elite Universal Kit (Vector Labs, Burlingame, CA) and diaminobenzidine-H₂O₂ and counterstaining with methyl green.

Slide Evaluation
All immunohistochemical data were recorded without knowledge of patient outcome. The angiogenesis technique for breast cancer designed by a collaborating laboratory at the Boston Children's Hospital (Dr Judah Folkman) was used for the slide evaluation in NSCLC [12]. Angiogenesis measured with factor viii immunostaining of microvessels was recorded as the number of microvessels per ten 200x microscope fields. For completeness, measurements were recorded at the center, the periphery, and the 200x microscope field with the highest microvessel number, the ``hottest'' area.

The proliferation index (percentage of malignant cells with nuclear staining with KI-67) was determined by static image cytometry using a CAS 200 Image Analysis system (Becton-Dickinson, San Jose, CA). Ten consecutive high-powered fields were analyzed and compared with a background established with the control immunoglobulin G. This technique has been validated in NSCLC by our laboratory and others [10, 13].

The slide analysis of erbB-2 and p53 have been described in previous reports from our laboratory [10, 11].

Statistical Analysis
Overall cancer-specific survival was defined as the period from the date of operation to the date of cancer death. An observation was censored at the last follow-up if the patient was alive or the patient had died of a cause other than NSCLC. The Kaplan-Meier product-limit estimator [14] was used to estimate cancer-specific survival curves for subgroups of patients with stage I NSCLC as defined by the following variables: tumor size (T1 for tumors 3 cm/T2 for tumors >3 cm), visceral pleural invasion, high mitotic rate (15 or more mitotic figures per ten 200x microscope fields), and the presence of vascular invasion into the pulmonary arteries or veins.

Immunohistochemical variables included presence of high-level immunostaining for erbB-2 and p53 (2+ or 3+ on a scale of 0 to 3+), the KI-67 proliferation index (1 to 100% nuclear staining), and the angiogenesis microvessel number. The microvessel number per 200x microscope field was recorded at the periphery, center, and the hottest area. The log-rank test was used to compare these subgroups with respect to cancer-specific survival [15]. The joint effect of covariables that were significant at the 0.25 level in univariate analysis were examined using stepwise Cox regression [16, 17]. The 0.10 level of significance was used for entering or removing a covariable from this model.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
The actual 5-year survival was 64%, whereas actuarial 10-year survival was 59% for the entire population of 275 patients (Fig 1). Data from routine histopathologic variables revealed a significant univariate association with decreased survival for pulmonary vascular invasion, T2 size, visceral pleural invasion, 15 or more mitoses per 200x microscope field, and poor or undifferentiated tumors (Table 2). No difference was noted for cell type (adenocarcinoma, large cell, or squamous). The Cox proportional hazards regression multivariate analysis defined pulmonary vascular invasion, T2 size, and visceral pleural invasion as independent negative prognostic factors (Table 3).

View larger version (11K): [in this window] [in a new window]   Fig 1. . In Figures 1 through 4, Kaplan-Meier survival estimates are displayed for the population of patients with stage I non-small cell lung cancer. This figure shows overall survival for the entire population (n = 275). Vertical tic marks denote censored observations at last follow-up.

Univariate survival analyses defined a significant association with decreased survival for increasing angiogenesis score by either peripheral or hottest area. In fact, the actual 5-year survival for patients with hottest area scores of 4 or less or scores greater than 4 were 69% and 56% (p = 0.006), and the 5-year survival for peripheral area scores of 25 or less or scores more than 25 were 66% and 54% (p = 0.046) (Fig 2).

View larger version (23K): [in this window] [in a new window]   Fig 2. . Kaplan-Meier survival estimates stratified by expression of angiogenesis measured in the periphery of the tumor (A) and at the hottest area (B). Numbers denote censored observations at last follow-up.

View larger version (16K): [in this window] [in a new window]   Fig 3. . Kaplan-Meier survival estimates stratified by KI-67 proliferation index. Numbers denote censored observations at last follow-up. (0 = KI-67 proliferation index 7%; 1 = KI-67 proliferation index >7%.)

Cox proportional hazards regression analysis was used to define the molecular biologic markers with independent predictive value with respect to survival. Factors included in the model were hottest area angiogenesis greater than 4, a KI-67 proliferation index greater than 7%, high-level expression of protooncogene erbB-2, and expression of tumor suppressor gene p53. Angiogenesis was the most significant independent prognostic factor in stage I NSCLC (Table 5). A separate analysis created a molecular biologic substaging. Each of these molecular biologic factors was scored as present or absent in each patient to create a cumulative index (range, 0 [none expressed] to 4 [all expressed]). Figure 4 demonstrates this molecular biologic substaging, which is based on an additive decrement in survival exhibited with increasing number of markers expressed for the entire population (n = 275; p = 0.0001) and for those patients with a T1 lesion (n = 164; p = 0.002).

View larger version (31K): [in this window] [in a new window]   Fig 4. . Molecular biologic substaging for pathologic stage I is demonstrated for expression of four molecular tumor markers: hottest area angiogenesis greater than 4, proliferation marker KI-67 greater than 7%, expression of protooncogene erbB-2, and expression of tumor suppressor gene p53. (A) Each patient (n = 275) was ranked from 0 to 4 by the number of the markers expressed, and a significant decrement in survival was observed for increasing number of markers expressed. Numbers denote censored observations at last follow-up. (B) This curve demonstrates a similar survival analysis for the 164 patients with T1 lesions (3 cm in diameter).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

The goals of this project were to use this patient population to evaluate angiogenesis in relation to survival and to evaluate the utility of molecular biologic factors in prognostic substaging of stage I NSCLC patients independent of routine histopathology. We and others have demonstrated that vascular invasion of the pulmonary vessels is an independent negative prognostic factor [3, 4, 7]. Unfortunately, histologic evidence of blood vessel invasion is a crude marker of the metastatic propensity of a tumor and is only observed in a minority of patients (33 of 275; 12%). In the present study, a more direct measurement of angiogenesis was used, involving immunostaining for factor viii, allowing the number of microvessels present in a tumor to be calculated. Weidner and associates [12] from the laboratory of Dr Judah Folkman have shown that the hottest area microvessel number correlated with the risk of recurrence and death in breast cancer. Macchiarini and colleagues [18], using a similar technique, observed an increased rate of distant metastases for a high microvessel count in a small population of patients with NSCLC. In the present study we evaluated measurements recorded in various locations within a tumor in NSCLC with respect to prognosis in stage I NSCLC. Unfortunately, angiogenesis data acquired in the center of the tumors in our study of 275 patients were inconsistent due to the significant presence of central necrosis. However, we observed that angiogenesis data (microvessel number) were consistent field-to-field when measured in the periphery or at the area of highest microvessel concentration. These values were predictive of long-term cancer-specific survival, and were also the most significant multivariate molecular biologic factor out of our series of four (angiogenesis, proliferation marker KI-67, protooncogene erbB-2, and tumor suppressor gene p53). The only histopathologic factor that could be associated with angiogenesis was pulmonary vascular invasion. A Cox proportional hazards model that included vascular invasion (n = 33) and angiogenesis greater than 4 (n = 135) still had significant independent predictive power (p < 0.01) for both factors, demonstrating the importance of a vascular invasion-related factor that can be measured in every tumor.

The second molecular biologic marker evaluated in this project was the tumor proliferation marker KI-67, a nonhistone nuclear protein that is expressed in cells that are near mitosis (cell phases late G₁, G₂, S, and M). We and others have previously demonstrated an association with a higher level of expression and decreased survival in NSCLC [10, 13]. As would be predicted, the presence of 15 or more mitotic figures by light microscopy was associated with a high KI-67 proliferation index. However, like pulmonary vascular invasion, these mitoses are infrequently observed in NSCLC, so a proliferation factor (KI-67) that can be measured in all tumors is advantageous.

Data from this large number of stage I NSCLC patients verified a significant univariate and Cox proportional hazards multivariate association between decreased survival and high-level expression of protooncogene erbB-2 and tumor suppressor gene p53. Several reports have previously observed this to be true for a smaller number of patients [10, 19, 20].

To create a molecular biologic substaging, we chose four distinct types of molecular markers. Each was associated with survival in stage I NSCLC before placement in the multivariate model (see Tables 4, 5). The factors included a protooncogene (erbB-2), a tumor suppressor gene (p53), a proliferation marker (KI-67), and a marker of metastatic propensity (angiogenesis factor viii). Each of these factors apparently contributes to oncogenesis in a distinct manner, so there was a reasonable assumption that they would each have an independent predictive value with respect to prognosis. In fact, angiogenesis, p53, and erbB-2 were independent prognostic factors. Although a low-level association exists between high-level expression of KI-67 and p53 expression [10], Figure 4A demonstrates a decrease in survival with an increasing number of factors expressed by patients in this population. An 81% 5-year survival for the 51 patients expressing no marker is noteworthy, because this analysis did not include tumor size, mitotic index, vascular invasion, differentiation, or visceral pleural invasion. However, when the same analysis was undertaken for the 164 patients with tumors 3 cm or less in diameter (T1), a group of patients generally considered to be at ``low risk'' (with 70% 5-year survival), a similar result was obtained (see Fig 4B). Significantly, patients with a T1 lesion and expressing three to four markers had a 5-year survival of 52%.

In addition to an increased prognostic value, there are a number of practical advantages to using molecular markers relative to routine histopathology. For example, although the presence of pulmonary vascular invasion is an important prognostic indicator, it could only be observed in 33 patients, whereas a measurement of angiogenesis immunostaining was obtained in all 275 patients. Immunohistochemical techniques are easy to perform, reproducible, moderately inexpensive, and presently available at most hospitals. The present results suggest that the measurement of tissue molecular markers more directly assesses the aggressiveness of a tumor compared with standard histopathologic examinations. The predictive value of this substaging system should improve with the addition of new biologic markers, allowing it to be validated in a future prospective, multiinstitutional trial of adjuvant therapy for high-risk stage I NSCLC patients.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Presented at the Forty-second Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9–11, 1995.

Address reprint requests to Dr Harpole, Division of Thoracic Surgery, Duke University Medical Center, PO Box 3617, Durham, NC 27710.

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