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Angiogenesis in Pituitary Adenomas and the Normal Pituitary Gland

Departments of Endocrinology (H.E.T., J.A.H.W.) and Neuropathology (Z.N., M.M.E.), Radcliffe Infirmary; Department of Pharmacology, University of Oxford (Z.N.); and Departments of Cellular Science (K.C.G.) and Molecular Angiogenesis Group (A.L.H.), Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom OX2 6HE

Address all correspondence and requests for reprints to: Prof. J. A. H. Wass, Department of Endocrinology, Radcliffe Infirmary, Woodstock Road, Oxford, United Kingdom OX2 6HE.

	Abstract

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Angiogenesis is essential for tumor growth beyond a few millimeters in diameter, and the intratumoral microvessel count that represents a measure of angiogenesis has been correlated with tumor behavior in a variety of different tumor types. To date no systematic study has assessed pituitary tumors of different secretory types, correlating vascular count with tumor size. The vascular densities of pituitary tumors and normal anterior pituitary were therefore assessed by counting vessels labeled using the vascular markers CD31 and ulex europaeus agglutinin I. One hundred and twelve surgically removed pituitary adenomas (30 GH-secreting, 25 prolactinomas, 15 ACTH-secreting, and 42 nonfunctioning tumors) were compared with 13 specimens of normal anterior pituitary gland. The vascular counts in the normal anterior pituitary gland were significantly higher (P < 0.05) than those in the tumors using both CD31 and ulex europaeus agglutinin I. In addition, microprolactinomas were significantly less vascular (P < 0.05) than macroprolactinomas, although there was no such difference between vascular densities of microadenomas and macroadenomas producing GH. ACTH-secreting tumors were, like microprolactinomas, of much lower vascular density than the normal pituitary and other secreting and nonsecreting tumor types. In marked contrast to other tumors, pituitary adenomas are less vascular than the normal pituitary gland, suggesting that there may be inhibitors of angiogenesis that play an important role in the behavior of these tumors.

	Introduction

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ANGIOGENESIS IS the process of development of new vessels from existing blood vessels and is crucial for embryo development, wound healing, and the female reproductive cycle. However, angiogenesis has also been shown to be required for tumor growth and metastasis (1). On the basis of experiments showing that tumors implanted into isolated perfused organs failed to develop, whereas the same tumors implanted within 6 mm of blood vessels induced angiogenesis, grew, and metastasized (2, 3), Folkman proposed that solid tumors are dependent on angiogenesis for growth beyond a few millimeters in size, and that an increase in tumor diameter required a corresponding increase in vascularization (4). In many human tumors, including breast, bladder, and stomach, angiogenesis assessed by vascular counts, correlates with development of metastasis (5), poor prognosis (6), and poor survival (7, 8).

It was reported by Schechter in 1972 that the parenchyma of pituitary tumors appeared less vascularized than autopsy specimens of normal tissue (9). Jugenburg and colleagues used immunostaining for factor 8-related antigen to assess vascular density in a group of pituitary adenomas and carcinomas (10). They showed that pituitary adenomas had lower vascular densities compared to nontumorous pituitary, but the relationship to tumor size was not studied, and vascular hot spots were not positively identified for counting. It has been suggested that as the most angiogenic tumor clones will determine tumor behavior, the area of the highest microvessel count (hot spot) should be positively identified when assessing vascular density (5, 11, 12). Using factor 8-related antigen in 22 pituitary adenomas, the highest vascular counts occurred in FSH-expressing adenomas, and the lowest were found in GH-secreting tumors (13). There was no comparison of vascular density with tumor size or normal pituitary tissue.

The object of this study was to assess the vascular densities of a large number of carefully characterized pituitary tumors of different secretory types and compare them with those of normal pituitary, using two different endothelial markers and assessing vessel hot spots (14, 15). In addition, we compared vascular density of macroadenomas and microadenomas to determine whether angiogenesis may play a role in determining pituitary tumor size.

	Materials and Methods

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Specimen collection

One hundred and twelve surgically removed pituitary adenomas were investigated. There were 30 GH-secreting tumors [22 macroadenomas (>1 cm in diameter) and 8 microadenomas (<1 cm in diameter)], 6 microprolactinomas, 19 macroprolactinomas, 15 ACTH-secreting tumors (Cushing’s disease), and 42 nonfunctioning pituitary adenomas (28 gonadotropin-positive and 14 negative on immunostaining). Thirteen specimens of normal anterior pituitary gland obtained during surgery for pituitary tumor (12) and at autopsy (1) were also studied. The tissue has been fixed in 4% buffered formalin, dehydrated, and embedded in paraffin. Histological examination and immunohistochemistry for anterior pituitary hormones had been performed previously and together with the clinical, biological, and radiological data were used to fully characterize each tumor type.

Immunohistochemistry for CD31 and ulex europaeus agglutinin I (UEAI)

The streptavidin-biotin-peroxidase complex technique was used for CD31, and the alkaline phosphatase/antialkaline phosphatase method was used for UEAI.

Four-micron sections were mounted on aptes (3-aminopropyl triethoxy silane; Sigma, St. Louis, MO)-coated slides, dewaxed, and rehydrated. Endogenous peroxidase activity was blocked using 3% hydrogen peroxide for CD31 cases. Sections for CD31 staining were pretreated using 0.1% trypsin at 37 C for 15 min followed by microwave pretreatment in sodium citrate buffer, pH 6. Slides for staining with UEAI did not require pretreatment. Nonspecific primary antibody binding was blocked using FCS at a dilution of 1:20. The primary antibodies were applied for 60 min at room temperature. For CD31, the DAKO Corp. antibody (Carpinteria, CA) was applied at a dilution of 1:20. The biotinylated UEAI (Vector Laboratories, Inc., Burlingame, CA) was used at a dilution of 1:200. After three washes in phosphate-buffered saline, biotinylated secondary antibody (Insight Biotechnology, Wembley, Middlesex, UK) was applied at a 1:200 dilution for 30 min at room temperature, followed by washes and then application of the appropriate avidin-biotin-peroxidase complex. The horseradish peroxidase-streptavidin complex (DAKO Corp.) was applied at 1:400 dilution for 30 min. The alkaline phosphatase/antialkaline phosphatase complex (Vector Laboratories, Inc.) was applied to the UEAI cases for 30 min, followed by washes. Color development was performed with metal-enhanced diaminobenzidine (Pierce Chemical Co., Rockford, IL) applied for 15 min to the CD31 cases and with fast red substrate applied for 20 min to the UEAI cases. The slides were lightly counterstained with hematoxylin. Negative controls were performed where FCS replaced the primary antibody.

Assessment of vascular density

Vascular density was assessed blindly by 1 examiner without prior knowledge of tumor type or size. The Chalkley point technique was used (14). The most vascular area of the tumor section was identified at low power as the hot spot. A 25-point Chalkley eyepiece graticule was orientated so that the maximum number of points was on or within areas of highlighted vessels at x250. The mean of the counts for the 3 most vascular areas was recorded. An overall subjective semiquantitative grading system was also used (1 and 2, low and low moderate vascular density; 3 and 4, high and very high vascular density). The counts and grades were made by a single observer (H.E.T.), and 20% were checked by a second blinded observer (K.C.G.), with 100% concordance for grading into low and high vascular densities.

Statistical analysis

The Statgraphics software package (Manugistics, Rockville, MD) was used. ANOVA was used for categorical data analysis and regression analysis for continuous variables. Statistical analysis using the method described by Landis and Koch was used to assess intra-rater reliability on sections counted and graded by the same observer on different occasions (16).

	Results

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Comparison of different vascular markers

Assessments of vascular density using mean Chalkley count and grade were highly correlated (Spearman rank correlation CD31 mean and grade, r = 0.8; UEAI mean and grade, r = 0.9). Vascular densities measured using the two different endothelial markers were different. UEAI consistently stained more vessels than CD31. Despite these differences, there was good correlation between the two markers (CD31 mean and UEA1 mean: r² = 21.8%; P = 0.0002; CD31 grade and UEAI grade: r² = 25.3%; P = 0.0000). The intra-rater tests for vascular count and vascular grade both gave values of 0.6, indicating substantial agreement ( values, 0.6–0.8) between assessments made on different occasions by the same observer.

Vascular counts

Vascular counts in normal anterior pituitary were 7.1 ± 1.1 with CD31, and 10.3 ± 1.3 using UEAI. Vascular counts in tumors were significantly lower than those in normal tissue (Table 1). The semiquantitative vascular grades in normal pituitary tissue were 3.8 ± 0.4 (±SD) with CD31 and 3.9 ± 0.3 with UEAI. Vascular grades in tumors were also significantly lower than those in normal tissue (Table 1 and Fig. 1, a and b). Macroprolactinomas were the most vascular tumor, significantly more vascular than functionless macroadenomas (P < 0.05). Microprolactinomas and ACTH-secreting tumors were the least vascular (P < 0.05).

View larger version (12K): [in this window] [in a new window]   Figure 1. Comparison of vascular density between normal pituitary and different tumor types. a, Vascular density as measured by CD31 expression. B, Vascular density as measured by UEA1 staining. Normal, Normal anterior pituitary gland; Acro, GH-secreting tumors; NFA, nonfunctioning tumors; MacPRL, macroprolactinomas; MicPRL, microprolactinomas; Cushing’s, ACTH-secreting tumors. The asterisk indicates mean values; error bars indicate the SEM.

Microprolactinomas were significantly less vascular than macroprolactinomas (Fig. 2), but there was no relationship between vascular count and tumor size when GH-secreting tumors were compared (Table 1). Bromocriptine treatment of patients (n = 14) with macroprolactinomas before surgery was not related to the vascular density of the tumors. All patients with microprolactinomas had received bromocriptine, but were resistant or intolerant.

View larger version (9K): [in this window] [in a new window]   Figure 2. Comparison of vascular density between macroprolactinomas and microprolactinomas. Vascular density was measured by CD31 expression. Macro, Macroprolactinomas; Micro, microprolactinomas. The asterisk indicates mean values; error bars indicate the SEM.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Our results show for the first time that different pituitary tumors vary in the relationship between size and vascular density. There is no difference in vascular density between GH-secreting macroadenomas and microadenomas, but microprolactinomas are significantly less vascular than macroprolactinomas. This fits with the clinical observation that microprolactinomas rarely progress in size and are a distinct clinical entity from macroprolactinomas, which may grow to a considerable size, suggesting that they are not part of the same pathological process (27). Macroprolactinomas have been shown to have higher labeling indexes (as a measurement of proliferation) than microprolactinomas, measured using Ki-67 and proliferating cell nuclear antigen (27). In contrast to macroprolactinomas, up to one third of patients with microprolactinomas will show spontaneous remission (28). In contrast, different size GH-secreting tumors are clinically part of the same spectrum of disease.

Vascular counts determined using immunostaining for CD31 and UEAI were clearly related, but the counts using UEAI were higher than those using CD31. In addition, a proportion of tumors did not stain with CD31 (possibly due to differences in fixation), and UEAI was occasionally not assessable because of extensive Golgi staining (29).

Unlike other sites of tumor formation, the anterior pituitary has a dual blood supply; the hypothalamo-pituitary portal supply is the main source, carrying blood from the median eminence with hypothalamic releasing and inhibitory factors, but there is an additional direct arterial supply from the loral and capsular arteries (30). The source of the blood vessels supplying the tumors is unclear, although there are several reports suggesting that a direct arterial supply may develop or perhaps predispose to pituitary tumor development (31). An angiographic study demonstrated tumor vessels that arose directly from the arterial system (32), and an autopsy study of 22 microadenomas showed that 66% of the tumors had a direct extraportal arterial blood supply (33). An animal model of estrogen-induced lactotroph hyperplasia and tumorigenesis in rats demonstrated the development of a direct arterial blood supply (34, 35) that was inhibited by bromocriptine (36). The tumor vasculature detected in our study may therefore represent a completely or partially de novo blood supply from the extraportal system. Thus, although the tumors are less vascular overall, they may have induced new vessel development from the systemic circulation, altering oxygen delivery and escaping hypothalamic influences on hormone production. Further work is required to differentiate the source of the tumoral blood vessels in the different tumor types compared with the mainly portal supply to the normal anterior pituitary gland.

The novel findings that pituitary adenomas are less vascular than normal anterior pituitary tissue, and that, depending on tumor type, size is related to vascular density suggest that these tumors may provide useful information regarding endogenous inhibitors of angiogenesis and their role in determining overall angiogenic phenotype and the resulting tumor behavior.

Received September 2, 1999.

Revised November 23, 1999.

Accepted December 4, 1999.

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Top Abstract Introduction Materials and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Turner, H. E. Articles by Wass, J. A. H. Search for Related Content PubMed PubMed Citation Articles by Turner, H. E. Articles by Wass, J. A. H.