Growth Patterns and Angiogenesis in Primary Lung Cancer

Bronchiolo-alveolar lung adenocarcinomas have a typical "lepidic" growth pattern: Tumor cells replace the normal pneumocytes, thereby preserving the stromal component of the alveolar wall and coopting the capillary blood vessels. The structure of the lung parenchyma remains intact, which probably explains the growth of satellite lesions in the lung due to transportation of tumor cells by airflow. This nonan-giogenic growth has been shown to be present in more common types of nonsmall-cell lung carcinomas (NSCLC) and in lung metastases [3]. In 16 percent of 500 NSCLC, the tumors were growing without parenchymal destruction and without the formation of desmoplastic stroma. In this "alveolar" growth pattern, tumor cells were filling the alveoli as solid nests. The only blood vessels present were those in the preserved alveolar septa. The coopted blood vessels did not express the integrin alpha-v-beta-3 necessary for angiogen-esis. In another study, outcome of 283 patients with operable NSCLC was studied and linked to the growth pattern of the lung tumors (Sardari Nia P. et al., 2004). Whereas the majority of the patients had a tumor with associated desmo-plasia and angiogenesis in which the alveolar architecture of the lung was not preserved, 18 percent of the patients had a NSCLC with an alveolar, nonangiogenic growth at the tumor-lung interface. The alveolar growth pattern was not associated with a specific histiotype (30% adenocarcinoma, 40% squamous cell carcinoma, and 30% large cell carcinoma and other types). In univariate analysis, T-stage, N-stage, and growth pattern predicted overall and disease-free survival. Multiple logistic regression showed that TN-stage and growth pattern were independent prognostic factors. Hazard ratios for the alveolar growth pattern were 2.0 (95% confidence interval: 1.3 to 3.2) for overall survival and 2.4 (95% confidence interval: 1.5 to 3.8) for disease-free survival, if compared to NSCLC with associated desmoplasia and angiogenesis. When stage I tumors were analyzed separately (174 patients), growth pattern retained its independent prognostic value. This confirms the study of Pastorino et al. [8], which described 137 pT1N0 patients. Both a nonangio-genic type of vascular pattern and epidermal growth factor receptor expression were associated with a poorer survival rate.

Assessing the growth pattern in primary NSCLC is potentially important since it can predict prognosis, but probably also the response to different treatment modalities. The growth pattern is indeed an integrative parameter containing information of the relationship between tumor cells and stromal cells. Surgical pathologists can easily determine the growth pattern on a standard hematoxylin-eosin stained tissue section and integrate it in the pathology report. Another consequence of the growth patterns of lung carcinomas is that the prognostic value of microvessel density in NSCLC can only be investigated within the subgroup of angiogenic tumors.

Table II Comparison of Glandular Differentiation, Fibrin Deposition, CAIX Expression, and the Macrophage Content of Breast Cancer and Colorectal

Cancer Liver Metastases.

Breast

Colorectal

Glandular differentiation:

(n = 45)

(n = 28)

1

1 (3%)

21 (75%)

2

8 (17%)

5 (18%)

3

36 (80%)

2 (7%)

p < 0.0001

Fibrin, central:

(n = 37)

(n = 24)

0

16 (43%)

6 (25%)

1

10 (27%)

4 (17%)

2

2 (6%)

4 (17%)

3

9 (24%)

10 (41%)

p = 0.15

Fibrin, interface:

(n = 38)

(n = 25)

0

30 (79%)

11 (44%)

1

6 (15%)

10 (40%)

2

1 (3%)

1 (4%)

3

1 (3%)

3 (12%)

p = 0.037

CAIX, central:

(n = 44)

(n = 24)

Absent

32 (73%)

1 (4%)

Present

12 (27%)

23 (96%)

p < 0.0001

CA IX, interface:

(n = 45)

(n = 24)

Absent

38 (84%)

11 (46%)

Present

7 (16%)

13 (54%)

p = 0.002

Global CA IX score:

14.4 ± 8.6 (0)

74.5 ± 14.9 (52.5)

p < 0.0001

Macrophage count:

4.57 ± 0.28 (4.25)

8.25 ± 0.60 (7.50)

p < 0.0001

Differences in categorical variables are validated by two-tail Fisher's exact testing. Continuous variables are expressed as mean ± standard error (median). Differences are validated by Wilcoxon testing.

Glandular differentiation score: 1, > 75% tubule formation; 2, 10-75% tubule formation; 3, < 10% tubule formation.

Fibrin deposition: Detected immunohistochemically with NYB.T2G1monoclonal antibody. 0, No staining; 1, minimal staining; 2, moderate staining; 3, extensive staining.

Global CAIX score: Carbonic anhydrase IX is an endogenous marker of hypoxia. Its expression is semiquantita-tively scored as the product of the percentage of immunostained cells with an immunostaining intensity score ranging from 0 (no staining) to 3 (strong staining).

CA IX: absent, no immunostaining; present, immunostaining in any percentage of tumor cells.

Macrophage count: the relative area occupied by CD68 immunostained macrophages, quantified with the Chalkley morphometric point counting method.

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