Molecular defects in the pathogenesis of pituitary tumours

https://doi.org/10.1016/S0091-3022(03)00012-8Get rights and content

Abstract

The majority of pituitary adenomas are trophically stable and change relatively little in size over many years. A comparatively small proportion behave more aggressively and come to clinical attention through inappropriate hormone secretion or adverse effects on surrounding structures. True malignant behaviour with metastatic spread is very atypical. Pituitary adenomas that come to surgery are predominantly monoclonal in origin and roughly half are aneuploid, indicating either ongoing genetic instability or transition through a period of genetic instability at some time during their development. Few are associated with the classical mechanisms of tumour formation but it is generally believed that the majority harbour quantitative if not qualitative differences in molecular composition compared to the normal pituitary. Despite their prevalence and the ready availability of biopsy material, at the present time, the precise molecular pathogenesis of the majority of pituitary adenomas remains unclear. This review summarizes current thinking.

Introduction

Current understanding of the molecular pathogenesis of pituitary adenomas is based on the concept that transformation of a single cell precedes uncontrolled proliferation and that prior to this event the anterior pituitary consists of a uniformly diploid environment that is polyclonal at the single cell level. The arguments for and against hypothalamic hormone stimulation and intrinsic mutation as exclusive adenoma induction mechanisms and the extent to which local and extrapituitary growth factors contribute to tumour propagation after induction remains open to debate [469]. In general, however, the search for pathogenic mechanisms has tended to focus on the inherent molecular integrity of what are believed to be monoclonal expansions of pituitary cells [19], [43], [104], [195].

Pituitary adenomas are known to be remarkably common in the general population [71], [125], [328], [419]. Their presentation through space occupation, hormone secretion or pituitary failure is relatively infrequent. When they do become overt their behaviour in most cases is remarkably benign and clinical management based around the expectation of a prolonged and stable doubling time rarely requires revision. The efficacy of surgical debulking, if required, is more closely related to the competence of the surgeon than intrinsic trophic activity of the tumour and rapid recurrence after apparently adequate debulking, while familiar, is nevertheless unusual. For this reason the subjective subdivision of pituitary adenomas in molecular and genetic studies into more or less ‘aggressive’ types or even invasive and non-invasive categories based on clinical outcomes alone requires care unless the material analysed is collected at repeat surgery and careful distinction is made between the ongoing rate of growth and the extent of spread at the time of diagnosis and treatment [417], [438], [455], [456].

Pituitary adenomas occasionally appear to stop growing altogether and if silent microadenomas are included, this behaviour, familiar in other endocrine tumours of complex clonal architecture [5], [17], [146], [250], [342] is a feature of the majority [18]. Long-term follow up of hyperprolactinaemic patients indicates that pituitary adenomas may in some cases also resolve of their own accord [56], [217]. Given the typical size of pituitary lesions that spontaneously involute, this phenomenon seems unlikely to be the result of impaired induction of tumour microvasculature with micro-haemorrhagic destruction or asymptomatic infarction [56], [148], [229], [459]. Equally, the prevalence of empty sella in association with previous pituitary adenoma is similar irrespective of whether the tumour had been a microadenoma or macroadenoma [100] rather than higher in macroadenomas as might be expected if vascular supply is being ‘out-paced’ by vigorous parenchymal growth [278]. In these circumstances, despite the presumed persistence of intracellular defects that led to monoclonal expansion in the first place, autonomy of growth is transient and the increased cell mass that resulted is presumably deleted through apoptosis, obscured by transdifferentiation or dispersed by migration of cells into the remaining pituitary tissue. Even when macroprolactinomas reach very large proportions they usually remain sensitive to dopaminergic control and regress in response to pharmacological doses of physiological analogues. Truly malignant, metastatic behaviour of pituitary adenomas, typical of other common malignancies such as those of the lung, colon, or breast, is extremely rare [58], [200], [298], [380]. While this may reflect the relatively small volume of pituitary tissue rather than its isolation from ultraviolet exposure or direct contact with ingested and inhaled carcinogens, the high prevalence of pituitary microadenomas and relatively high prevalence of pituitary adenomas as a proportion of patients requiring surgery for all intracranial neoplasms remains somewhat paradoxical [195].

Pituitary adenomas frequently retain their ability to synthesize and secrete hormone and occasionally acquire new function [464], [491], but like other benign endocrine neoplasms, autonomy of function and growth do not necessarily go together [365]. In addition to the relatively large proportion of endocrinologically inactive pituitary adenomas thought to be derived from the gonadotroph lineage, silent corticotroph adenomas [202], [338], [414], silent somatotroph adenomas [256], [310], [343], and silent thyrotroph adenomas have all been described [513]. When hormone secretion is present, it frequently remains regulated and responsive to normal trophic influences, retaining some of the qualitative if not quantitative characteristics of normal pituitary responses. In addition, although believed to be derived by monoclonal expansion of single abnormal cells, pituitary adenomas are often plurihormonal and many transcribe [281] and translate [271] multiple pituitary hormones in apparent cellular subpopulations. The pattern of hormones represented includes those classically found in the hypothalamus such as GHRH, CRH, TRH, oxytocin, and somatostatin [283], [284], [286], [494], and for unknown reasons, somatotroph adenomas seem particularly susceptible to this seemingly aberrant transcriptional activity.

Two other unusual characteristics of pituitary adenomas, cyclical behaviour [27], [28], [385] and apparent remission after removal of histologically normal pituitary tissue [70], [259] have been noted in corticotroph adenomas. In a review of 57 patients with Cushing’s syndrome and 8 with Nelson’s syndrome, removal of tissue that was histologically indistinguishable from normal pituitary gland in 17 patients nevertheless resulted in a cure in 14 [70]. Although these data may be interpreted merely as artefacts of tissue sampling or histological interpretation, they also suggest that the pituitary adenoma microenvironment is a potent modifier of pituitary adenoma behaviour.

In the pituitary, secretory, synthetic, and trophic responses to a variety of transient but often repeated stimuli are called for throughout life. After each stimulus has passed the assumption is that the pituitary is able to restore its architecture and behaviour to the pre-stimulus state. Persistence of changes, manifesting as a degree of trophic plasticity, may conceivably enable the pituitary to deliver enhanced responses to recurrent stimuli. The same mechanisms, however, may also lead to suboptimal responses [241], [347] and potentially predispose the pituitary to trophic anomalies. In the adult rat pituitary almost undetectably small changes in the relative rates of mitotic and apoptotic activity have substantial effects on cell populations [316], [347], [348], [349]. Imaging and histological studies of gravid and healthy non-gravid young women [4], [83], [126], [217], [449] and of patients with longstanding hypothyroidism [9], [52], [62], [416] and hypoadrenalism [415] indicate that the human pituitary also continually revises its relative proportions of different cell types to meet perceived demands. It is not clear whether trophic activity is confined to an undifferentiated stem cell population, such as that recently identified in rodent brain [301], [395], [435], or whether pituitary cells that were believed to have undergone terminal commitment are able to de-differentiate and contribute further to trophic activity and to new differentiated cellular subtypes [186].

Direct analysis of the prevalence of mitotic figures and apoptotic bodies in human pituitary adenomas has not proven particularly useful as unlike spontaneous rat pituitary adenomas in which mitotic figure prevalence is markedly increased, both events are rare in most human pituitary adenomas [209], [349]. The determination of cell cycle-specific antigen labelling indices for proliferating cell nuclear antigen (PCNA), the anti-apoptotic Bcl-2 subfamily, and the proliferation-associated nuclear antigen Ki-67—detected in many studies using the MIB-1 monoclonal antibody—have also not been found to be sufficiently sensitive and specific to be useful in predicting recurrence rate or invasive behaviour [12], [58], [308], [424], [482], [484]. The observations that ‘clinically significant invasion is more frequent with macroadenomas’ and that ‘tumours identified clinically as more invasive tend to have a higher Ki-67 labelling index’ [58], [105], [212], [309], [424] are to some extent self-fulfiling conclusions derived from the magnitude of previous growth rather than the ongoing rate of expansion, and make no reference to the rate of apoptosis, diagnostic delay or the potential for behaviour to moderate with time. In a rare prospective rather than cross-sectional study, not only was no correlation found between Ki-67 labelling index, maximal tumour diameter and cavernous sinus invasion at diagnosis, but during a mean follow up period of 28.6 months, there was also no association between Ki-67 labelling index and risk of tumour recurrence [296]. A higher proliferation marker index [295], [297] has been inconsistently associated with invasive potential in some pituitary adenoma subtypes, but like many endocrine tumours, histological pleomorphism cannot be correlated with tumour growth characteristics and metastatic potential of pituitary adenomas [366], [398].

Monoclonality is considered compelling evidence able to distinguish a progressive process induced by an intracellular somatic mutation from a reversible or self-limiting trophic response to stromal or environmental signals. As such, clonal status has been embraced as a central guide to the direction and interpretation of research on the pathogenesis of pituitary adenomas. As the clonal architecture of the normal pituitary has not been characterized, however, the results of pituitary clonal analysis still require careful interpretation even if the technical constraints of clonal analysis [337], [493] and other sources of composite error are taken into consideration [278].

The assumption has been that migration and dispersal of cells between assignment of clonality in utero and post-natal life leads to the formation of a mosaic at a single cell level in mature tissues. If so, unless cells of similar identity and clonality spontaneously segregate in differentiated tissue or a polyclonal field spontaneously undergoes differential apoptosis or centrifugal migration leaving a single clone, a monoclonal cellular expansion in a polyclonal field must represent the progeny of a single cell. There is good evidence, however, that migration and dispersal of cells following clonal assignment does not necessarily result in a mosaic at a single cell level under ordinary circumstances, and indeed many normal human tissues are macroscopically monoclonal [91], [115], [336], [351], [378], [427], [474], [479]. If the same is true of the human pituitary it is possible that a purely physiological trophic stimulus affecting a pre-existing clonal patch could lead to the emergence of a truly monoclonal expansion of entirely non-neoplastic origin with benign behavioural characteristics in a polyclonal field [279]. This concept does not conflict with the accepted understanding that malignant tumours in most organ systems are derived from somatic mutation within single cells [207] but reserves the possibility that a truly monoclonal cellular expansion in a polyclonal field need not represent the progeny of a single, trophically disinhibited cell [452].

In published series the majority of pituitary tumours that have been analysed for clonality have been reported to be monoclonal. These consist of 3 out of 3 somatotroph adenomas [194] and one mammosomatotroph adenoma [215], 10 out of 10 endocrinologically inactive adenomas [6], [194], [215], 4 out of 4 prolactinomas [194], and 27 out of 31 corticotroph adenomas [53], [163], [194], [425]. A single ‘mixed plurihormonal adenoma’ examined was found to be polyclonal [194] and in earlier studies based on flow-cytofluorometric techniques for nuclear DNA analysis, biclonal cell lines were isolated from about 10% of pituitary adenomas [14], [15]. In more than half of ‘recurrent’ pituitary tumours in which analysis for loss of heterozygosity was repeated following further surgery, the loci implicated in the original pattern of loss of heterozygosity were heterozygous once again [94], [521]. The explanation that the ‘recurrence’ represents a second entirely independent monoclonal tumour derived from another abnormal clone after complete resection of the first rather than further growth of persistent tumour is not entirely in keeping with clinical experience. Although there are no specific supportive data one way or the other, it is conceivable that many pituitary tumours are initiated as polyclonal or oligoclonal rather than monoclonal events and that selection pressure facing the newly established expansion results in many of the original clones being suppressed and either diluted below detectable levels or eliminated altogether [93], [192], [218], [323], [350].

Clonal interactions, where the survival and dominant proliferative characteristics of one clone are dependent in some way on the presence of one or more others, could also play a part in determining tumour phenotype [7], [51], [319], [509]. This appears to be the case with activating missense mutations of the GNAS1 gene in McCune Albright syndrome where transplantation of a mixture of normal and mutated skeletal progenitor cells into immunocompromised mice reproduces the classical phenotype of fibrous dysplasia whereas implantation of a monoclonal population of mutated skeletal progenitor cells is not viable [51]. The possibility that several clones arise completely independently and asynchronously, while relatively common in mature and senescent rats, seems unlikely in man where concurrent development of more than one pituitary tumour [57], [247], [249], [318], [361], [460] or changes in secretory activity and histological phenotype over time are rare enough to be worthy of reporting [39]. Phenotype is also a surprisingly poor indicator of clonality as tumours that are clearly polyphenotypic may nevertheless be monoclonal [170], [178], [346], [470].

Genetic instability, the classical mechanism of tumour formation, generates mutations in oncogenes and tumour suppressor genes that give rise to self-sufficiency of growth signals, reduced sensitivity to growth inhibitory signals, relative evasion of apoptosis and senescence [187], and the ability not only to induce sustained local angiogenesis [127], [180], [413], [492] but also to induce apoptosis, remodelling or displacement of surrounding tissues that would otherwise obstruct tumour growth. Unlike the gross genetic restructuring characterized by aneuploidy, which tends to be found in tumours without microsatellite instability, mutability at the single nucleotide or nucleotide sequence level appears to be a distinct form of genetic instability in which gross chromosomal integrity is maintained [75]. Whether cancers develop one or the other—instability at the sequence level or chromosomal level—but not usually both [1], [75] or whether chromosomal instability is driven by preceding mutations in growth-controlling oncogenes and tumour suppressor genes [114], [142] is unclear. Defects in nucleotide excision repair [508] and mismatch repair [371], while implicated in colorectal, endometrial, and gastric cancers, occur rarely in other tumours [375] and few of the characteristics of genetic instability at the nucleotide sequence level accord with phenotypic and behavioural characteristics of pituitary adenomas.

At the level of loss of heterozygosity, it seems that no particular chromosomal loci in pituitary adenomas are free of allelic deletions. Given the available reports, the impression that some regions are more involved than others, such as 11 [59], 11q13, 13q12-14, 10q, and 1p [92], 9p, 10, 11, and 13 [138], 1, 3, and 12 [147], 1, 4, 7, and 19 [398] or 7, 9, 12, 20 and X [118], [269], [394], or that there is a direct relationship between the frequency or characteristics of deletions and the aggressiveness of adenoma behaviour, are difficult to support at present. Several studies of chromosomal regions in pituitary adenomas that harbour known tumour suppressors have confirmed loss of heterozygosity but not shown the expected reduction in specific tumour suppressor markers [26], [42], [129], [139], [140], [369], [465].

Gross aneuploidy is reported in sporadic pituitary adenomas at a prevalence of around 50% [14], [16], [147], [398], [466] (Table 1). Identification of aneuploidy in a monoclonal expansion does not necessarily imply that it was responsible for or even present at the time of tumour induction, or that it contributed to tumour propagation [63], [64], [220], [320], [390], [400], [497]. Neither does aneuploidy necessarily signify ongoing genetic instability nor provide information about the rate at which genetic alterations might have occurred [275]. Comparative genomic hybridization [501] has been used to confirm the high rate of gross chromosomal aberrations in a study of 75 adenomas in which 34 were shown to have chromosomal imbalances, mostly affecting entire chromosomes [477]. These chromosomal aberrations were found at similar prevalence in all hormone secretory phenotypes and tended to consist of gains (on X, 19, 12, 7, and 9) rather than losses (on 11, 13, and 10) of genomic material [477]. A further study of 40 primary and 13 recurrent adenomas obtained from 52 patients reported loss or gain of genetic material in 25 involving all chromosomes except 17 and 20 [321] and similar findings of prevalent and widespread aneuploidy in sporadic pituitary adenomas have been confirmed in several other studies [48], [107], [183], [205], [466]. The lack of concordance between the sites and nature of chromosomal involvement and phenotype, and the finding of a similar broad range of chromosomal gains (involving 1, 2, 9, 12, 16, 17, 19, 20, and 22) and losses (on chromosomes 6, 7, and 11) in a patient with Carney complex harbouring a known pathogenic mutation [356], has thus far made it difficult to establish the potential pathogenic significance of aneuploidy.

Section snippets

The p21 family of inhibitors (p21, p27, and p57)

Unbound, p21Cip1, p57Kip2, and p27Kip1 (the Cip/Kip proteins), members of the cyclin-kinase inhibitor family of proteins, directly inhibit the action of the cyclin E/cdk2 complex in inducing progression from G1 into S phase in the cell cycle [433]. Activation of cdk4 or cdk6 by mitogen-stimulated combination with cyclin D1, 2, or 3 sequesters high levels of p21Cip1, p57Kip2, and p27Kip1 proteins, directly disinhibiting a broad range of cyclin–cdk complexes (cyclin E–Cdk2, cyclin A–Cdk2, and

GNAS1

In addition to Gsα, the GNAS1 gene codes for several other transcripts two of which, extra-large s (XLs, derived from the paternal allele) and 55-kDa neuroendocrine secretory protein (NESP55, derived from the maternal allele) are translated in the pituitary [188]. The three proteins share exons 2–13 and have distinct first exons [188]. The association between activation of the gsp oncogene through gain-of-function mutation of the GNAS1 gene on chromosome 20q13 and the development of somatotroph

c-myc, ras, and neu/c-erbB-2

No consistent patterns of amplification or rearrangement of c-myc or several other recognized cellular oncogenes (N-ras, mycLl, mycN, H-ras, bcl1, H-stf1, sea, kraS2, and fos) have been found in 88 pituitary adenomas [59]. The significance of the slight reduction in immunohistochemical c-myc labelling in somatotroph adenomas and slight increase in pituitary adenomas with a higher bromodeoxyuridine labelling index is unclear as there was little correlation between labelling index, which was

FGF- and TGFβ-receptors

The four mammalian FGF receptor (FGFR) genes encode a family of transmembrane tyrosine kinases that through cell- and tissue-specific alternative splicing can generate multiple secretable and cell-bound isoforms, producing tissue- and tumour-specific FGF function that can change with isoform expression during tumour progression. A truncated FGFR-4 has been identified in human pituitary adenomas [2], the effects of which on pituitary adenoma development are currently being investigated in a

Growth factors

The pituitary has long been recognized as a site of synthesis and action of growth factors [106], [167], [393], [480], [527] and potential growth inhibitors [8], [498]. IGF-I and IGF-II, EGF [201], [260], [272], NGF [61], [326], [327], [363], TGF-α [313], TGFβ [8], basic FGF [2], [60], [133], [190], [287], [388], [436], vascular endothelial growth factor (VEGF) [38], [145], [168], [213], mammary cell growth factor [344], adrenal growth factor [409], chondrocyte growth factor, and adipocyte

Summary

An overview of the molecular targets assessed in pituitary adenomas and of qualitative and quantitative molecular abnormalities identified is shown in Table 1. It can be seen that activating GNAS1 mutations are the only known unequivocal association of sporadic pituitary adenomas and menin and germ line PRKAR1A mutations the only associations with familial predisposition to pituitary adenomas. Otherwise, it remains uncertain whether the molecular defects that have been found within the

Concluding remarks

The rate at which molecular defects associated with the pathogenesis of pituitary adenomas have been defined has accelerated appreciably over the last few years. Although there is clear evidence that classical proto-oncogene activation and tumour suppressor mutation are responsible for only a very small proportion of pituitary adenomas, quantitative molecular defects capable of inducing persistently abnormal growth in model systems and human tissues, such as increased expression of PTTG and

References (529)

  • S.A. Abbass et al.

    Altered expression of fibroblast growth factor receptors in human pituitary adenomas

    J. Clin. Endocrinol. Metab.

    (1997)
  • A. Abdollahi et al.

    Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors

    Oncogene

    (1997)
  • M. Abram et al.

    Pituitary tumor syndrome and hyperprolactinemia in peripheral hypothyroidism

    Ann. Endocrinol. (Paris)

    (1992)
  • S. Aeschimann et al.

    Morphological and functional polymorphism within clonal thyroid nodules

    J. Clin. Endocrinol. Metab.

    (1993)
  • J.M. Alexander et al.

    Clinically nonfunctioning pituitary tumors are monoclonal in origin

    J. Clin. Invest

    (1990)
  • P. Alexander

    Do cancers arise from a single transformed cell or is monoclonality of tumours a late event in carcinogenesis?

    Brit. J. Cancer

    (1985)
  • M.G. Alexandrow et al.

    Transforming growth factor β and cell cycle regulation

    Cancer Res.

    (1995)
  • A.M. Alkhani et al.

    Cytology of pituitary thyrotroph hyperplasia in protracted primary hypothyroidism

    Pituitary

    (1999)
  • V. Alvaro et al.

    Invasive human pituitary tumors express a point-mutated α-protein kinase-C

    J. Clin. Endocrinol. Metab.

    (1993)
  • V. Alvaro et al.

    Protein kinase C activity and expression in normal and adenomatous human pituitaries

    Int. J. Cancer

    (1992)
  • A.P. Amar et al.

    Invasive pituitary adenomas: significance of proliferation parameters

    Pituitary

    (1999)
  • R. Amendola et al.

    DR-nm23 gene expression in neuroblastoma cells: relationship to integrin expression, adhesion characteristics, and differentiation

    J. Natl. Cancer Inst.

    (1997)
  • M. Anniko et al.

    Human pituitary tumors with two cell lines

    Arch. Otorhinolaryngol.

    (1983)
  • M. Anniko et al.

    DNA ploidy and cell phase in human pituitary tumors

    Cancer

    (1984)
  • R.L. Apel et al.

    Clonality of thyroid nodules in sporadic goiter

    Diagn. Mol. Pathol.

    (1995)
  • S.L. Asa et al.

    The cytogenesis and pathogenesis of pituitary adenomas

    Endocr. Rev.

    (1998)
  • S.L. Asa et al.

    Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice

    Endocrinolgy

    (1999)
  • S.L. Asa et al.

    Pituitary corticotroph hyperplasia in rats implanted with a medullary thyroid carcinoma cell line transfected with a corticotropin-releasing hormone complementary deoxyribonucleic acid expression vector

    Endocrinology

    (1992)
  • S.L. Asa et al.

    Pituitary mammosomatotroph adenomas develop in old mice transgenic for growth hormone-releasing hormone

    Proc. Soc. Exp. Biol. Med.

    (1990)
  • S.L. Asa et al.

    Pituitary adenomas in mice transgenic for growth hormone-releasing hormone

    Endocrinology

    (1992)
  • S.L. Asa et al.

    Prolactin cells in the human pituitary. A quantitative immunocytochemical analysis

    Arch. Pathol. Lab. Med.

    (1982)
  • S.L. Asa et al.

    A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytomas producing growth hormone-releasing hormone

    J. Clin. Endocrinol. Metab.

    (1984)
  • S.L. Asa et al.

    The MEN-1 gene is rarely down-regulated in pituitary adenomas

    J. Clin. Endocrinol. Metab.

    (1998)
  • A.B. Atkinson et al.

    Cyclical Cushing’s disease: two distinct rhythms in a patient with a basophil adenoma

    J. Clin. Endocrinol. Metab.

    (1985)
  • A.B. Atkinson et al.

    Five cases of cyclical Cushing’s syndrome

    Br. Med. J.

    (1985)
  • G.U. Auer et al.

    The relationship between aneuploidy and p53 overexpression during genesis of colorectal adenocarcinoma

    Virchows. Arch.

    (1994)
  • C.J. Auernhammer et al.

    Interleukin-11 stimulates proopiomelanocortin gene expression and adrenocorticotropin secretion in corticotroph cells: evidence for a redundant cytokine network in the hypothalamo–pituitary–adrenal axis

    Endocrinology

    (1999)
  • A. Baird et al.

    A nonmitogenic pituitary function of fibroblast growth factor: regulation of thyrotropin and prolactin secretion

    Proc. Natl. Acad. Sci. USA

    (1985)
  • S.J. Baker et al.

    Suppression of human colorectal carcinoma cell growth by wild-type p53

    Science

    (1990)
  • S.J. Baker et al.

    p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis

    Cancer Res.

    (1990)
  • A.E. Bale et al.

    Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia Type 1

    Cancer Res.

    (1991)
  • E. Ballare et al.

    Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment

    J. Clin. Endocrinol. Metab.

    (2001)
  • C.M. Bamberger et al.

    Reduced expression levels of the cell-cycle inhibitor p27Kip1 in human pituitary adenomas

    Eur. J. Endocrinol.

    (1999)
  • S.K. Banerjee et al.

    Overexpression of vascular endothelial growth factor164 and its co-receptor neuropilin-1 in estrogen-induced rat pituitary tumors and GH3 rat pituitary tumor cells

    Int. J. Oncol.

    (2000)
  • M. Barausse et al.

    From macroprolactinoma to concomitant ACTH-PRL hypersecretion with Cushing’s disease

    J. Endocrinol. Invest.

    (2000)
  • A. Barlier et al.

    Pronostic and therapeutic consequences of Gsα mutations in somatotroph adenomas

    J. Clin. Endocrinol. Metab.

    (1998)
  • A. Barlier et al.

    Impact of gsp oncogene on the expression of genes coding for Gsalpha, Pit-1, Gi2α, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity

    J. Clin. Endocrinol. Metab.

    (1999)
  • A.S. Bates et al.

    Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker

    J. Clin. Endocrinol. Metab.

    (1997)
  • P. Beck-Peccoz et al.

    Thyrotropin-secreting pituitary tumors

    Endocr. Rev.

    (1996)
  • W.P. Bennett et al.

    p53 Mutation and protein accumulation during multistage human esophageal carcinogenesis

    Cancer Res.

    (1992)
  • Cited by (68)

    • Upregulation of cyclin B1 plays potential roles in the invasiveness of pituitary adenomas

      2017, Journal of Clinical Neuroscience
      Citation Excerpt :

      Because the pituitary comprises of several kinds of cell types responsible for different hormone, the highly heterogeneous pituitary adenoma can contribute to specific hormone hypersecretion and affect the important endocrine functions of the human body by hypothalamus–pituitary–target organ axis systems [2–4]. Pituitary adenoma is usually stable [5] and becomes true malignancy infrequently [2,3,6]. However, its locally aggressive and invasive features always lead to poor prognosis of surgically treated pituitary adenomas [7].

    • Acromegaly

      2015, Endocrinology: Adult and Pediatric
    • Senescence and pre-malignancy: How do tumors progress?

      2011, Seminars in Cancer Biology
      Citation Excerpt :

      Medicine has long recognized the presence of premalignant lesions, with an increased risk (over normal tissue) of progression into invasive cancer. Although some tumors have a negligible risk of malignant transformation (such as uterine leiomyomas [1], thyroid adenomas [2], pituitary adenomas [3,4], lipomas and other benign soft tissue tumors [5]); other lesions have a finite and significant risk of progression into cancer. Lesions such as atypical nevi, large colon adenomas, mammary atypical hyperplasia and carcinoma in situ, prostatic intraepithelial neoplasia, and others, are considered pre-malignant and justify clinical intervention to decrease the risk of development of life-threatening cancer [6–11].

    • Pituitary Masses and Tumors

      2011, Williams Textbook of Endocrinology, Twelfth Edition
    • Pathogenesis of Endocrine Tumors

      2011, Williams Textbook of Endocrinology, Twelfth Edition
    • Pituitary senescence: The evolving role of Pttg

      2010, Molecular and Cellular Endocrinology
    View all citing articles on Scopus
    View full text