Histologic and immunohistochemical study of clinically non-functioning pituitary adenomas

Seventy-five clinically non-functioning pituitary adenomas were characterized in terms of their histologic and immunohistochemical features. Fourteen adenomas (18.7%) were positive for hormones other than gonadotropins. These included two somatotroph adenomas, three lactotroph adenomas, four thyrotroph adenomas, four corticotroph adenomas and one unusual plurihormonal adenoma. Fifty-five adenomas (73.3%) were exclusively positive for one or more gonadotropin subunits (β-follicle stimulating hormone, p-luteinizing hormone, and α-subunit of glycoprotein hormones), but negative for other hormones such as growth hormone and β-thyrotropin. Histologically, a papillary arrangement along the capillary was most characteristically observed in the gonadotropin-positive adenomas. Five of six adenomas negative for any pituitary hormones exhibited the typical papillary structure. Thus, approximately 80% of clinically non-functioning adenomas constituted a single tumor group that shared the common histologic features of gonadotroph adenomas. These findings suggest that nearly all tumor types of clinically non-functioning adenomas can be diagnosed solely by light microscopy in combination with immunohistochemistry, and that the vast majority of them may be gonadotroph adenomas.     

Human pituitary gonadotroph adenomas: Relationship between gonadotropin immunoreactivity and clinicopathologic findings

Clinically nonfunctioning pituitary adenomas are generally seen in middle-aged and older patients, and most of them may be gonadotropin-immunoreactive adenomas, that is, gonadotroph adenomas. Our aim was to clarify the relationships between the gonadotropin immunoreactivity, patient age, sex, and microscopic features in 68 gonadotroph adenomas with special reference to either gonadotropin-immunonegative or intensively immunopositive adenomas. There were 68 patients with gonadotroph adenomas (mean age 54.7 yr) in the study, including 39 men (mean age, 52.8 yr) and 29 women (mean age, 57.4 yr). The adenomas were diagnosed on the basis of immunoreactivity for gonadotropins (β-subunit of follicle-stimulating hormone: β-FSH; β-subunit of luteinizing hormone: β-LH; and the α-subunit of the pituitary glycoprotein hormone: α-SU) by the avidin-biotin peroxidase complex (ABC) method or by the characteristic histological feature of a perivascular or pseudorosette pattern, that is, the cells aligned polarity directed toward the capillaries. Fifty-four adenomas (79%) were positive for one or more gonadotropin subunits and β-FSH was the most common subunit encountered (47/68, 69%). In men β-FSH immunoreactivity was similar among all age groups, whereas in women, it was significantly less frequent in patients who were 50 yr or older, compared to younger patients. Gonadotropin-immunonegative adenomas were seen in 4 men (mean age, 46.8 yr) and 10 women (mean age, 61.5 yr). Among the 22 women aged 50 or over, β-FSH was negative in 12 tumors (55%), whereas in men of the same age group, it was negative in 3 of 26 tumors (12%). The reason for this reduced frequency is not clear, but the postmenopausal state and associated changes in the systemic endocrine state may play a role. Adenomas that were intensively positive for β-FSH showed an unusual morphology other than the characteristic perivascular pattern, regardless of the patients' age and sex; the tumor cells had abundant vacuolated cytoplasms and were arranged in a sheet-like pattern. Electron microscopically, these cells with abundant cytoplasm had well-developed Golgi complexes, suggesting an enhanced activity of gonadotropin synthesis, and these adenomas seem to be endocrinologically, if not clinically, functioning. The results indicate that gonadotroph adenomas may vary from functioning adenomas with intense immunoreactivity and unusual histology to immunonegative and less functioning adenomas, which are more frequent in women 50 yr or older.     

Expression of vascular endothelial growth factor in normal pituitary cells and pituitary adenomas producing adrenocorticotropic hormone

Vascular endothelial growth factor (VEGF) induces endothelial cell proliferation and an increase in capillary permeability. Because the anterior pituitary gland and pituitary adenomas are highly vascular, expression of VEGF was examined immunohistochemically. Some normal pituitary cells stained positively for VEGF, and restaining for ACTH, prolactin, TSH, LH, FSH, and S-100 protein after VEGF staining revealed that almost all cells staining positively for ACTH also stained for VEGF. Only adenomas staining positively for ACTH stained for VEGF. These results suggest that VEGF is produced by normal pituitary cells and adenomas producing ACTH.     

Pituitary Hormones and Contact Sensitivity in Rats

Hypophysectomized (Hypo-X) rats do not develop contact sensitivity to dinitrochlorobenzene (DNCB). Daily treatment with prolactin or growth hormone completely restores the DNCB-reactivity of Hypo-X animals. Treatment of such animals with ACTH, FSH, LH, TSH or HCG has no restoring potential. Treatment with ACTH in addition to prolactin or growth hormone antagonizes restoration of Hypo-X rats. These experiments indicate that the pituitary gland has the potential of regulating contact sensitivity.     

神经生长因子受体在垂体腺瘤中的表达

目的：探讨两种神经生长因子（ＮＧＦ）受体（ＴｒＫＡ和ｇｐ７５）在各类垂体腺瘤中的表达。方法：采用免疫细胞化学ＳＡＢＣ法,检测了４４例经病理证实的垂体腺瘤中两种ＮＧＦ受体的表达情况。结果：ＴｒＫＡ在垂体ＰＲＬ分沁腺瘤中的过度表达率６９．２％,而在其它类型垂体腺瘤中的过度表达率为１９．４％,两者比较差异有非常显著性（Ｐ〈０．００５）。ｇｐ７５在垂体ＰＲＬ分泌腺瘤中的过度表达率在４６．２％,而在其它类型     

混合性节细胞瘤/垂体腺瘤4例临床病理观察

目的探讨混合性节细胞瘤／垂体腺瘤发生机制、临床病理特征、诊断及鉴别诊断。方法复习4例混合性节细胞瘤／垂体腺瘤患者的临床资料，并对其进行组织学观察和免疫组化（EnVision—plus法）标记。结果4例混合性节细胞瘤／垂体腺瘤患者均为女性，年龄10～35岁，平均26．5岁。临床上3例表现内分泌症状，1例有癫痫症状。组织学上肿瘤由两种不同成分组成，一种结构主要由较多神经节细胞组成，节细胞体积大，可见圆形的尼氏小体，核大，核仁突出，免疫组化标记瘤细胞表达CgA、Syn、S-100蛋白，不表达GFAP；另一部分腺瘤细胞大小形态较一致，圆形或卵圆形，胞质丰富，嗜酸性或空淡，间质血窦丰富，瘤细胞表达GH和PRL。结论混合性节细胞瘤／垂体腺瘤是蝶鞍区极少见的肿瘤，好发于青年女性，常合并肢端肥大症。该瘤的诊断主要依靠组织病理学，并辅以免疫组化标记。治疗主要采用单纯手术切除，预后较好。     

Pituitary Adenomas Producing Growth Hormone,Prolactin, and One or More Glycoprotein Hormones: A Histologic,Immunohistochemical, and Ultrastructural Study of Four Surgically Removed Tumors

The morphologic features of four pituitary adenomas, removed from 2 men and 2 women between 31 and 62 years of age, are reported. The tumors contained growth hormone (GH), prolactin (PRL), and one or more glycoprotein hormones–usually thyrotropin (TSH). Three tumors were associated with acromegaly and one with hyperprolactinemia. Hyperthyroidism was not evident in any of the patients. In the tumors of acromegalic subjects, GH-containing cells were the most numerous, whereas PRL cells were dominant in the adenoma accompanied by hyperprolactinemia. Electron microscopy revealed plurimorphous tumors comprised of various proportions of morphologically different cell types: densely granulated GH cells, TSH-like cells, and the less common mammosomatotrophs and PRL cells. It is suggested that pituitary adenomas producing GH, PRL, and glycoprotein hormones derive from the same precursor; their immunocytochemical profile, fine structural appearance, and endocrine function may depend on the degree and direction of the cellular differentiation.     

Pituitary Adenomas Producing Growth Hormone, Prolactin, and One or More Glycoprotein Hormones: A Histologic, Immunohistochemical, and Ultrastructural Study of Four Surgically Removed Tumors

The morphologic features of four pituitary adenomas, removed from 2 men and 2 women between 31 and 62 years of age, are reported. The tumors contained growth hormone (GH), prolactin (PRL), and one or more glycoprotein hormones-usually thyrotropin (TSH). Three tumors were associated with acromegaly and one with hyperprolactinemia. Hyperthyroidism was not evident in any of the patients. In the tumors of acromegalic subjects, GH-containing cells were the most numerous, whereas PRL cells were dominant in the adenoma accompanied by hyperprolactinemia. Electron microscopy revealed plurimorphous tumors comprised of various proportions of morphologically different cell types: densely granulated GH cells, TSH-like cells, and the less common mammosomatotrophs and PRL cells. It is suggested that pituitary adenomas producing GH, PRL, and glycoprotein hormones derive from the same precursor; their immunocytochemical profile, fine structural appearance, and endocrine function may depend on the degree and direction of the cellular differentiation.     

Morphometric Evidence of Sexual Dimorphism in the infrastructure of Gonadotroph Adenomas of the Human Pituitary

Gonadotroph adenomas resected from the pituitaries of 8 males and 8 females were studied by transmission electron microscopy and morphometry in order to establish whether they exhibit sexual dimorphism. Random photographs were taken and the following parameters compared: (1) cellular volume, (2) nuclear volume, (3) cytoplasmic to nuclear ratio, (4) volume density of endoplasmic reticulum, (5) volume density of Golgi bodies, (6) volume density of mitochondria, (7) volume density of secretory granules, (8) volume density of lysosomes, (9) diameter of secretory granules, (10) surface to volume ratio of secretory granules, (11) surface to volume ratio of Golgi bodies, (1 2) surface to volume ratio of nuclei, (13) surface to volume ratio of cells.

The results showed that gonadotroph adenomas of males differed significantly from those of females in cell size, cell shape, and electron microscopic features of Golgi apparatus. It remains to be established whether differences in the morphology of nonneoplastic gonadotrophs of males and females can explain the development of morphologically distinct adenoma cells between the sexes.     

Immunocytochemical analysis of the synaptic proteins SNAP-25 and Rab3A in human pituitary adenomas. Overexpression of SNAP-25 in the mammosomatotroph lineages

SNAP-25 and Rab3A were originally identified as synaptic proteins involved in neuronal membrane traffic. Recently, both proteins have been detected in several mammalian endocrine cell types and have been proposed as essential components of the exocytotic pathway in neuroendocrine cells. In this study, the expression of SNAP-25 and Rab3A was analysed in biopsied human anterior pituitary tumours (21 cases) by immunocytochemical methods. No differences in Rab3A immunoreactivity were observed between tumour and normal pituitary cells. Strong SNAP-25 immunoreactivity was detected in tumour cells of prolactinomas (n=3). Several growth hormone (GH)/prolactin (PRL) tumours also displayed intense SNAP-25 immunolabelling (n=3), whereas the remaining GH-secreting adenomas (n=4) exhibited moderate to weak SNAP-25 immunoreactivity. In contrast, SNAP-25 near-background immunostaining was observed in tumour cells of adrenocorticotrophic hormone (ACTH)-secreting tumours (n=4) and non-secreting tumours (n=7), as well as in normal pituitary cells. Since SNAP-25 and Rab3A have been shown to be involved in exocytotic events in rodent endocrine cells, overexpression of SNAP-25 protein in PRL and GH/PRL tumour cells might be implicated in the mechanism of exocytosis of the neoplastic human mammosomatotroph lineages. © 1997 John Wiley & Sons, Ltd.     

Correlation between tumor vascularity and clinical findings in patients with pituitary adenomas

Angiogenesis generally plays an essential role in tumor growth and metastasis, and also influences the response to treatment in human malignant solid tumors. Even in nonmalignant tumors, angiogenesis is essential for tumor growth and invasion. In order to define the relationship between tumor vascularity and the clinical course in patients with pituitary adenomas, we quantified the vascularity in 47 pituitary adenomas and in 6 normal anterior pituitary glands obtained at autopsy using a computed image-analyzing system. We estimated two parameters, the vascular number and the area as the vascularity. Additionally, we calculated mean individual vessel size using the above two parameters. The relationships of tumor vascularity to clinical, endocrinological and histological findings was assessed. Factors considered included patient age and gender, preoperative medication, histological type, concentration of each hypersecreted pituitary hormone, maximum tumor size, cavernous sinus invasion, intratumoral hemorrhage, and immunohistological results of localization of vascular endothelial growth factor (VEGF). Vascularity was significantly higher in normal glands than in pituitary adenomas. However, there were no significant correlations between tumor vascularity and other clinical, endocrinological, or histological parameters, suggesting that increased angiogenesis is not essential for pituitary adenoma growth or invasiveness.     

16例伴生长激素缺乏的多种垂体激素缺乏患者的临床特点及生长激素治疗效果分析

目的探讨伴生长激素缺乏(GHD)的多种垂体激素缺乏症(MPHD)患者的临床特点以及生长激素(GH)治疗效果。方法回顾性分析16例伴有生长激素缺乏的多种垂体激素缺乏患者的临床资料。结果本研究纳入了16例MPHD的患者,其中伴甲状腺功能减退症9例、伴低促性腺激素性性腺功能低减13例和伴肾上腺皮质功能减退6例。臀位、足先露和难产等不良生产史患者10例。骨龄(11.0±3.5)岁,明显落后实际年龄。L-Dopa-GH激发试验GH峰值为(0.14±0.17)ng/m L,GH治疗平均剂量(0.11±0.02)IU/kg。治疗后IGF-1水平及生长速度均明显增加。结论排除下丘脑、垂体占位等病变后,伴GH缺乏的MPHD患者在纠正其他轴系激素缺乏后,使用GH治疗可明显改善身高,并且无严重不良事件发生。     

Immunohistochemical analysis of p27 (Kip1) in human pituitary glands and in various types of pituitary adenomas

p27 (Kip1) plays regulatory roles in the cell cycle by inhibiting the activity of cyclin dependent kinases (CDKs). This immunohistochemical study is aimed at elucidating the expression of p27 in human pituitary and in various types of pituitary adenomas in order to clarify its role in the regulation of proliferation. Sixteen normal pituitary glands and 179 human pituitary adenomas were used for immunohistochemical studies. The tissues were fixed in 10% formalin and embedded in paraffin. Indirect peroxidase method was performed after heat-induced antigen retrieval using a monoclonal antibody against p27 protein. p27 protein was expressed in the nuclei of all 16 normal human pituitary glands. p27 protein was also expressed in 128 of 179 cases of pituitary adenomas (71.5%). A marked decrease of p27 expression was noted in ACTH-secreting adenomas, 8/20 (40.0%), compared with other types of pituitary adenomas—GH-secreting adenomas, 35/46 (76.1%); PRL-secreting adenomas, 22/33 (66.7%); TSH-secreting adenomas, 8/11 (72.7%); and nonfunctioning adenomas, 55/69 (79.7%). These results suggest that p27 may play some role in the regulation of proliferation in all types of pituitary adenomas. The lower levels of p27 in ACTH-secreting adenoma is of particular interest with respect to the intermediate lobe-derived pituitary tumor developed in p27 knockout mice.     

The genotypic-phenotypic approach redefines the prognostic evaluation of lung neuroendocrine neoplasms

Lung neuroendocrine neoplasms are heterogeneous in terms of morphological features and clinical behavior. The four-tired WHO classification scheme, together with TNM stage, are currently the most effective prognostic indicators and, to date, they define the clinical management and therapeutic strategies in these neoplasms. However, in the last decade novel information on the phenotypical characteristics and molecular background of these tumors resulted in the proposal of novel biomarkers indicative of biological or clinical behavior. Although most of them are strongly histotype-dependent, some others have been proposed to be significantly associated to tumor characteristics also within individual tumor groups, and are therefore potential additional and complementary tools, with special reference to the carcinoid patients group whose prognostic prediction is still very uneffective. Indeed, these candidate biomarkers are still to be integrated in a multimodal approach and are in the vast majority of cases not validated in independent or prospective series and have been analyzed, with special reference to the molecular ones, on relatively small case series. Once the characterization of these tumors will be further refined, the clinical impact of these information will be strongly determined by their potentiality to be integrated with the current classification, and the tight collaboration between those who are active in this subject (diagnostic pathologists, molecular pathologists/biologists, clinicians) is necessary for a validation in the clinical practice.     

大鼠实验性腹膜炎自愈过程中腺垂体ACTH细胞和TSH细胞的免疫细胞化学研究

用成年雄性Ｗｉｓｔａｒ大鼠７０只，分为实验组和对照组。实验组大鼠在无菌条件下腹腔注射松节油（０．６５ｍｌ／ｋｇ），造成急性非特异性腹膜炎。对照组未经任何处理。分别于注射后１ｄ、２ｄ、３ｄ、５ｄ、７ｄ、１０ｄ取腹水，做瑞氏－姬姆萨染色，取脑垂体做ＡＣＴＨ细胞和ＴＳＨ细胞免疫细胞化学染色。注射后１ｄ，腹水内中性粒细胞百分比明显增高；注射后２ｄ、３ｄ、５ｄ逐渐恢复；７～１０ｄ时，基本恢复正常。脑垂体ＡＣＴＨ细胞和ＴＳＨ细胞的免疫细胞化学反应结果，以积分法表示。统计结果表明，注射后１ｄ、２ｄ、３ｄ、５ｄＡＣＴＨ细胞和ＴＳＨ细胞的积分明显高于对照（Ｐ＜０．０１），注射后３ｄ积分最高，注射后７ｄ，实验组ＡＣＴＨ细胞的积分恢复到正常水平（Ｐ＞０．０５）。ＴＳＨ细胞于注射后１０ｄ恢复（Ｐ＞０．０５）。结果表明，腹膜炎早期ＡＣＴＨ细胞和ＴＳＨ细胞的分泌活动即增强；并于注射后３ｄ达高峰。当腹膜炎恢复时，这些细胞的功能也恢复正常。本研究说明，在大鼠实验性腹膜炎自愈过程中，腺垂体ＡＣＴＨ细胞和ＴＳＨ细胞也参与了内分泌调节。