Plurihormonal pituitary adenomas: immunostaining of all pituitary hormones is mandatory for correct classification

AIMS: We studied the clinicopathological characteristics of plurihormonal pituitary adenomas. METHODS AND RESULTS: The study material included 167 plurihormonal adenomas, which consisted of 31% of the surgically removed pituitary adenomas that we collected during a 12-year period. The mean age of patients with plurihormonal adenoma was 45.7 years (range 13-75 years). There were 86 men and 81 women. All tumours were fully classified by immunohistochemical staining for seven pituitary hormones or subunits. Thirty immunohistochemical subtypes of plurihormonal adenomas were recognized. Hormonal symptoms were present in 70% of patients, while serum hormonal levels were increased in 89% of patients. Most patients had symptoms related to only one of the hormones and only 7% of patients had symptoms related to two hormones. The most common hormonal symptom was acromegaly (50%); symptoms related to hyperprolactinaemia ranked second (20%). Double immunostaining of all the possible combinations of the hormones was performed in 30 selected tumours, and they all showed mixtures of hormones in individual adenoma cells in any hormonal combinations studied. The latter finding supported the view that plurihormonal adenomas are monomorphous adenomas. CONCLUSIONS: Plurihormonal adenomas are common pituitary adenomas. Immunohistochemical staining of all pituitary hormones is mandatory for correct classification.     

Plurihormonal adenomas. Analysis of 62 cases

This paper deals with the cytological features of pituitary plurihormonal adenomas based on 62 cases examined by histology, immunohistochemistry, ultrastructural study and post-embedding immunogold electron microscopy, including double labeling. In GH-cell containing adenomas, there were 9 adenomas consisting of exclusively GH and PRL cells. The other 39 adenomas contained other hormones as well as GH and PRL. Other nine combinations of pituitary hormones or alpha-subunit were observed. Special emphasis was laid on the fact that a greater part of GH-producing adenomas (74% by immunostain) were PRL-producing, although the ratio of GH-cells to PRL-cells widely varied from case to case. Concerning the double labeling study on mixed GH-PRL secreting adenomas, we recognized the existence of secretory granules containing GH only, those containing PRL only, those containing both GH and PRL and those containing neither.     

Alpha-subunit-producing pituitary adenomas

Summary Immunohistological techniques demonstrate the alpha-subunit of glycoprotein hormones in the majority of endocrine-inactive, undifferentiated pituitary adenomas and pituitary oncocytomas. In about one-fifth of endocrine-active adenomas, the alpha-subunit is produced in combination with either adrenocorticotropic hormone or prolactin, and it is found in combination with growth hormone in about half of those adenomas causing acromegaly.Pure alpha-subunit-producing, endocrine-inactive adenomas characteristically have small secretory granules that are destroyed by direct osmium fixation, but are well preserved after prefixation with glutaraldehyde. As only a few atypical prolactinomas show similar secretory granules, and as they display a positive reaction for the alpha-subunit only exceptionally, this ultrastructural feature can serve as a guide to differentiate such adenomas.     

Heterogeneous pituitary adenomas

Summary The combined use of several histological procedures (i.e. conventional light microscopy, immunohistochemistry and electron microscopy) among 45 unselected pituitary adenomas demonstrated the existence of 9 tumors (20%) containing several identifiable adenohypophy seal cell types. Thecellular associations were between 2 or 3 identifiable cell types. Mammosomatotrophic tumors were the most frequent but not the only mixed type (somatomammocorticotrophic, somatocorticotrophic tumors were also found). The cellular components varied in size but the cells appeared randomly distributed in the tumors. In all the adenomas there was an unidentified cell component (no reactivity with antisera used) varying from sparse to numerous elements. On adjacent sections the adenomatous cells reacted with a single specific antiserum, but in two cases the immunohistochemistry on contiguous paraffin embedded sections did not confirm this with certainty. These results confirm those of others and a new term is purposed to designate these tumors: heterogeneous pituitary adenomas. According to the nature and the proportions of the cell components the heterogeneous adenomas were subdivided into two groups: a group A which comprised adenomas formed by a major identifiable cellular type associated with one or two other less frequent cell types, and a group B formed by a predominant unidentifiable (no reactivity with immunochemical stainings) cell type associated with one or two other identified cell types. The present morphofunctional classifications of pituitary adenomas should be modified to include homogeneous adenomas with a single cell type and heterogeneous adenomas with several cell types.     

Invasive giant pituitary adenomas

7 cases of pituitary adenomas with the pronounced signs of invasive growth, confirmed by MRI, clinical and intraoperative observations. Invasive growth of adenomas was related to neither the structure of the tumor, the degree of anaplasia, or the nature of a generated hormone.     

Invasiveness of pituitary adenomas

528 biopsies from 396 pituitary adenomas were re-examined by light microscopy and checked for invasion of neighbouring tissues. The overall invasion rate was 41.9%. Highly differentiated ACTH-cell adenomas were invasive in 24.1%, undifferentiated mucoid-cell adenomas in 66.7%. The histological type of invasion was influenced by the adenoma type and by the invaded tissue. There was no obvious correlation between the adenoma type and the invaded tissue.     

Pure alpha-secreting pituitary adenomas

Isolated hypersecretion of the alpha subunit of the glycoprotein hormones occurred in two men with previously diagnosed "nonfunctioning chromophobe adenomas." The alpha hypersecretion was unresponsive to hypothalamic releasing hormone, thyroid hormone, and sex-steroid hormones. After trans-sphenoidal surgery and conventional pituitary irradiation, alpha secretion was decreased. Increased quantities of immunologically active and biologically inactive luteinizing hormone (LH) material were detected in serum and in tumor homogenate. Immunologic and gel-chromatographic studies determined that only the alpha subunit was present and that it was cross-reacting in the LH immunoassay. These studies suggest that the alpha subunit may be a useful marker of pituitary tumors, particularly in patients without clinical evidence of hormonal hypersecretion.     

Amyloid in pituitary adenomas

71 surgically removed pituitary adenomas with amyloid deposits were studied by light microscopical and immunohistological means. In none of the adenomas was there a predominance of amyloid deposits. There were no correlations between the extent or pattern of the deposits with either age, immunohistological hormone content or localization. Our results do not support either of the theories about the origin of amyloid--whether mesenchymal or produced by adenoma cells--in pituitary adenomas.     

垂体腺瘤的功能分类研究

Pituitary adenomas might be classified into different groups according to different variety of hormone produced. 225 surgical specimens were labeled with anti- sera of GH, PRL, ACTH, TSH, FSH, and LH, via immunohistochemical technique (ABC method). Data indicated that 100 out of the 225 (44.5%) were monohormonal adenomas, including 24 GH, 39 PRL, 1 FSH and 9 LH, 77 (34.2%) were multi- hormonal adenomas, including 28 positive for 2 hormones, 30 positive for 3 hormones, 19 positive for 4 or more different hormones, and the remaining 48 (21.3%) were nonfunctional adenomas. In comparison with Kovacs series, factors which might participate in the mechanism of developing monohormonal or multi- hormonal adenomas are discussed.     

Clinicopathological correlations in pituitary adenomas

Pituitary adenomas are common neuroendocrine neoplasms arising from adenohypophysial cells. Recent progress in our understanding of pituitary tumorigenesis as well as pathways involved in molecular cytodifferentiation of the adenohypophysis has impacted on the classification of pituitary adenomas. The detailed comprehensive classification of pituitary adenomas is now well recognized to reflect specific clinical features and genetic changes that predict targeted treatments, as well as prognostic information for patients with pituitary adenomas. Therefore, the clinical responsibility of pathologists is not only limited to the distinction of pituitary adenomas from other sellar lesions, but also to provide a comprehensive subtype classification using appropriate ancillary tools. In this article, we highlight an approach to clinical diagnosis and pitfalls in the classification of these common neoplasms.     

CD markers in pituitary adenomas

Immunostaining of CD markers in normal pituitary cells has been reported, but a study of these markers in pituitary adenomas has not been done. The expression of CD 3, CD 8, CD 15, CD 20, CD 30, CD 43, CD 45R0, CD 45 R, CD 79 α, and VS-38c was investigated in a collection of 65 pituitary adenomas of various types. CD 3 was present in 75%, CD 8 in 18.5%, CD 15 in 12.3%, CD 20 in 66.1%, CD 30 in 10.8%, CD 43 in 10.8%, CD 45 RO in 72.3%, CD 45 R in 16.9%, CD 79α in 0% and VS-38 c in 44.6%. Densely granulated GH cell adenomas expressed CD 3, CD 20, CD 45 RO, and CD 45 R, but no other markers. Sparsely granulated GH cell adenomas showed CD 3, CD 8, CD 20, CD 43, and CD 45 RO. Mixed GH/prolactin cell adenomas contained CD 3, CD 8, CD 20, CD 30, CD 45RO, CD 45 R, and VS-38c. Mammosomatotroph cell adenomas were positive only for CD 3, CD 8, CD 20, CD 43, and CD 45 RO. Prolactin cell adenomas expressed CD 3, CD 8, and CD 20. ACTH cell adenomas showed CD 3, CD 15, CD 20, CD 30, CD 45 RO, CD 45 R, and VS-38c. TSH cell adenomas contained CD 3, CD 8, CD 15, CD 20, CD 45 RO, and VS-38c. Gonadotroph cell adenomas were positive for CD 3, CD 8, CD 20, CD 45 RO, CD 45 R, and VS-38c. Alpha-subunit-only adenomas expressed CD 3, CD 8, CD 15, CD 20, CD 30, CD 45 RO, and VS-38c. Plurihormonal adenomas contained CD 3, CD 8, CD 20, CD 30, CD 43, CD 45 RO, CD 45 R, and VS-38c. Oncocytic adenomas were positive for all markers except CD 45 RA and CD 79 α. We conclude that the spectra of different adenoma types expressing CD markers varies greatly and that significant correlations do not exist, although noninvasive adenomas appear to express CDs more frequently than invasive adenomas. We have no clear-cut explanations for the various expressions and suggest that it may be a sign of local interactions between the immune system and pituitary adenomas.     

The immunohistochemistry of pituitary adenomas

A great deal of progress has been achieved in recent years in the field of immunohistochemistry of pituitary adenoma. Continued use of more new antisera and monoclonal antibodies against numerous hormones in the adenohypophysis have resulted in new approaches to classification of pituitary adenoma. However, new problems have been discovered, on the other hand, by large-scale studies in recent years. The great number of multihormonal pituitary adenomas and possible change of the immunohistochemically detectable hormone status in cases of recurrent tumours have particularly re-emphasised the need for new thinking about patterns of classification. It would appear somewhat problematic, in this context, to uncritically accept terms, such as ACTH cellular adenoma or GH cellular adenoma. Reference is also made to the distribution pattern of cell and tissue markers in pituitary adenomas. The paper is based on thorough literature screening as well as on experience obtained by the authors from 450 cases of pituitary adenoma of which 260 had been analysed by immunohistochemistry, 131 by morphometry, and 80 by electron microscopy.     

Light bodies in human pituitary adenomas

Summary Light bodies are large cytoplasmic granules originally described in the gonadotrophic cells of the rat pituitary gland. In order to determine whether similar bodies occur in the human anterior pituitary gland, 89 pituitary adenomas and periadenomatous tissue from 20 cases were examined by transmission electron microscopy. Double membrane bound bodies with filamentous internal structure identical to rodent light bodies were identified in 10 hormone-producing adenomas: 5 PRL, 1 PRL-GH, 2 GH, and 2 ACTH-producing tumours. No light bodies were found in the remaining 79 tumours nor in the pituitary cells in periadenomatous tissue from 20 cases. These results show that some human pituitary adenomas may contain light bodies identical to those seen in gonadotrophs of rat pituitary.Abbreviations PRL prolactin - GH growth hormone - ACTH adenocorticotropic hormone - FSH follicle-stimulating hormone - LH luteinizing hormone