Classification Of Pituitary Tumors Research Articles

Pituitary tumors: Changing paradigms in understanding, nomenclature and the newer basis of classification

The pituitary gland is embryologically divided into two main lobes: adenohypophysis (anterior) and neurohypophysis (posterior). Last five decades have witnessed changes in the tumor classifications – anterior pituitary in 2017 and posterior in 2016, based on hormonal immunohistochemistry, molecular profiles, and pituitary specific transcription factors. Few newer entities/terms have been added and at the same time certain terms have been modified/discarded. In this article, relevant anatomy, development, histology, incidence, and clinical manifestations of pituitary tumors evolution of various classification systems and recommended current classification of pituitary tumors; the genetic alterations and the diagnostic implications for today's pathologist have been reviewed in a comprehensive manner.

Both invasiveness and proliferation criteria predict recurrence of non-functioning pituitary macroadenomas after surgery: a retrospective analysis of a monocentric cohort of 120 patients.

Additional robust criteria to predict early postoperative recurrence of non-functioning pituitary macroadenomas (NFMAs) are needed. Recently, a new classification of pituitary tumors has been proposed, which is based on both radiological and histological criteria and allows the grading into 5 groups of different potential aggressiveness. The aim of this study was to use this classification to further characterize predictive factors of recurrence in an independent series of NFMA. 120 patients operated for a NFMA were analyzed retrospectively. For each of them, the invasion of the cavernous and/or sphenoidal sinuses by the tumor was studied on the preoperative MRI and the proliferative character was based on precise histological and immunohistological examination. 26% (n = 31) of the adenomas were proliferative and 57% (n = 68) were invasive. The invasive lesions were larger (P < 0.001) and their removal was complete in only 82% of the cases. The distribution of NFMAs was as follows: 32% grade 1a, 11% (proliferative) grade 1b, 42% (invasive) grade 2a and 15% (proliferative and invasive) grade 2b. Their probability of recurrence at 5 years was 20, 39, 44 and 66%, respectively. A young age, the atypical character and the presence of postoperative residual tumor were all independent risk factors of recurrence (P < 0.025). The new clinicopathological classification proves to be very useful in predicting the risk of recurrence of non-functioning pituitary macroadenomas after a first surgery. In particular, grade 2b lesions showed an overall likelihood of recurrence that was 8.6 times greater than those of grade 1a.

The 2017 World Health Organization classification of tumors of the pituitary gland: a summary.

The 4th edition of the World Health Organization (WHO) classification of endocrine tumors has been recently released. In this new edition, major changes are recommended in several areas of the classification of tumors of the anterior pituitary gland (adenophypophysis). The scope of the present manuscript is to summarize these recommended changes, emphasizing a few significant topics. These changes include the following: (1) a novel approach for classifying pituitary neuroendocrine tumors according to pituitary adenohypophyseal cell lineages; (2) changes to the histological grading of pituitary neuroendocrine tumors with the elimination of the term "atypical adenoma;" and (3) introduction of new entities like the pituitary blastoma and re-definition of old entities like the null-cell adenoma. This new classification is very practical and mostly based on immunohistochemistry for pituitary hormones, pituitary-specific transcription factors, and other immunohistochemical markers commonly used in pathology practice, not requiring routine ultrastructural analysis of the tumors. Evaluation of tumor proliferation potential, by mitotic count and Ki-67 labeling index, and tumor invasion is strongly recommended on individual case basis to identify clinically aggressive adenomas. In addition, the classification offers the treating clinical team information on tumor prognosis by identifying specific variants of adenomas associated with an elevated risk for recurrence. Changes in the classification of non-neuroendocrine tumors are also proposed, in particular those tumors arising in the posterior pituitary including pituicytoma, granular cell tumor of the posterior pituitary, and spindle cell oncocytoma. These changes endorse those previously published in the 2016 WHO classification of CNS tumors. Other tumors arising in the sellar region are also reviewed in detail including craniopharyngiomas, mesenchymal and stromal tumors, germ cell tumors, and hematopoietic tumors. It is hoped that the 2017 WHO classification of pituitary tumors will establish more biologically and clinically uniform groups of tumors, make it possible for practicing pathologists to better diagnose these tumors, and contribute to our understanding of clinical outcomes for patients harboring pituitary tumors.

Overview of the 2017 WHO Classification of Pituitary Tumors.

This review focuses on discussing the main changes on the upcoming fourth edition of the WHO Classification of Tumors of the Pituitary Gland emphasizing histopathological and molecular genetics aspects of pituitary neuroendocrine (i.e., pituitary adenomas) and some of the non-neuroendocrine tumors involving the pituitary gland. Instead of a formal review, we introduced the highlights of the new WHO classification by answering select questions relevant to practising pathologists. The revised classification of pituitary adenomas, in addition to hormone immunohistochemistry, recognizes the role of other immunohistochemical markers including but not limited to pituitary transcription factors. Recognizing this novel approach, the fourth edition of the WHO classification has abandoned the concept of "a hormone-producing pituitary adenoma" and adopted a pituitary adenohypophyseal cell lineage designation of the adenomas with subsequent categorization of histological variants according to hormone content and specific histological and immunohistochemical features. This new classification does not require a routine ultrastructural examination of these tumors. The new definition of the Null cell adenoma requires the demonstration of immunonegativity for pituitary transcription factors and adenohypophyseal hormones Moreover, the term of atypical pituitary adenoma is no longer recommended. In addition to the accurate tumor subtyping, assessment of the tumor proliferative potential by mitotic count and Ki-67 index, and other clinical parameters such as tumor invasion, is strongly recommended in individual cases for consideration of clinically aggressive adenomas. This classification also recognizes some subtypes of pituitary neuroendocrine tumors as "high-risk pituitary adenomas" due to the clinical aggressive behavior; these include the sparsely granulated somatotroph adenoma, the lactotroph adenoma in men, the Crooke's cell adenoma, the silent corticotroph adenoma, and the newly introduced plurihormonal Pit-1-positive adenoma (previously known as silent subtype III pituitary adenoma). An additional novel aspect of the new WHO classification was also the definition of the spectrum of thyroid transcription factor-1 expressing pituitary tumors of the posterior lobe as representing a morphological spectrum of a single nosological entity. These tumors include the pituicytoma, the spindle cell oncocytoma, the granular cell tumor of the neurohypophysis, and the sellar ependymoma.

Clinical Identification of Oncogenic Drivers and Copy-Number Alterations in Pituitary Tumors.

Pituitary tumors are the second most common adult primary brain tumor, with a variable clinical course. Recent work has identified a number of genetic determinants of pituitary tumor subtypes, which may augment traditional histopathologic classification schemes. We sought to determine whether pituitary tumors could be stratified based on objective molecular characteristics using a clinical genomics assay. We performed a retrospective analysis of patients operated on at the Brigham and Women's Hospital from 2012 to 2016 whose pituitary tumors were profiled using multiplexed next-generation sequencing. We analyzed 127 pituitary tumors, including 114 adenomas, 5 craniopharyngiomas, and 8 tumors of other histologies. We observed recurrent BRAFV600E mutations in papillary craniopharyngiomas, CTNNB1 mutations in adamantinomatous craniopharyngiomas, and activating GNAS mutations in growth hormone-secreting adenomas. Furthermore, we validated the presence of two distinct genomic subclasses in adenomas (i.e., those with disrupted or quiet copy-number profiles) and the significant association of disruption with functional hormone status (P < 0.05). We report the clinical implementation of next-generation sequencing of pituitary tumors. We confirmed previously identified molecular subclasses for these tumors and show that routine screening as part of clinical practice is both feasible and informative. This large-scale proof-of-principle study may help to guide future institutional efforts for pituitary tumor classification as well as the incorporation of such techniques into prospective analysis as part of clinical trials.

OS10.1 Genomic landscape of pituitary adenomas

Abstract Introduction: The clinical outcome of pituitary adenomas can be difficult to predict consistently. Methods: We characterized the genomic profile of 150 pituitary adenomas using next-generation sequencing and assessed the correlation between molecular and pathologic characteristics. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent. Results: We observed two classes of pituitary adenomas based on their molecular profile. One class, encompassing one-third of the samples, had widespread genomic disruption with high rates of chromosome arm-level copy-number alterations. The other class tumors exhibited somatic copy-number alterations involving less than 6% of the genome. Levels of genomic disruption correlated with tumor pathology, as 75% of the disrupted subclass were functional adenomas or atypical null-cell adenomas, compared to only 13% of the less disrupted groups. Despite these high rates of genomic disruption, we detected relatively few focal events, which is unusual among highly disrupted cancers. We validated our finding by looking at previously published gene-expression data, and found that the disrupted subtype harbored more variable gene-expression profiles than quiet tumors. We validated these observations from the discovery cohort in an independent cohort of over 100 pituitary adenomas using a targeted clinical sequencing panel, and confirmed that a CLIA-approved assay was able to discriminate between disrupted and non-disrupted tumors. Furthermore, we recapitulated the known patterns of GNAS driver alterations in growth hormone secreting adenomas. Conclusion: Sporadic pituitary adenomas have distinct copy number profiles that associate with hormonal and histologic subtypes and influence gene expression. These results contribute to the growing repertoire of molecular data that have been generated in pituitary tumors, and will guide future efforts of pituitary tumor classification and risk-stratification.

Diagnostic criteria in invasive pituitary adenomas

AbstractPituitary adenomas are benign pituitary primary tumors, the most frequent type of tumor in the pituitary fossa. An important part, around 1/3 of the pituitary adenomas manifests an aggressive behavior, growing faster and invading into parasellar areas (cavernous sinus, neural tissues and bones). Objectives: the first aim of this paper is to review the last findings about invasiveness diagnostic criteria, imagistic and biomarkers, which can be used in the classification of pituitary tumors and also to predict the probability of invasiveness, tumor recurrence and suspicion of malignancy. The second aim is to highlight the morphological and clinic types of invasive pituitary adenomas. Materials and methods: we performed a systematic review and analysis of the published articles, searching PubMed between January 1985 and December 2015. There were selected articles published in English, reviews and abstracts. During the advanced search type in PubMed, combinations of the following keywords were used: “pituitary adenoma”, “invasive”, “aggressive”, “biomarkers”, “classification”, “histological subtypes”, ‘”immunohistochemical markers”. Results: 215 articles were selected, regarding diagnostic, prognostic and therapeutic aspects. There were some histological subtypes of pituitary adenomas known as having an aggressive clinical behavior. Several biomarkers were identified as being associated with the invasive feature: proliferation markers (Ki-67 index, number of mitoses, p53 &amp; p27 expression, microvascularization density, telomerase, topoisomerase 2 Alpha), matrix metalloproteinases, protein kinase C, cyclooxygenase-2, E-cadherin, transcription Factors, genetic alterations (PTTG gene, Galectin-3 protein/ LGALS3 gene), apoptosis markers. Based on their invasion and proliferation characteristics, pituitary tumors are proposed to be classified into five grades (1a, 1b, 2a, 2b, 3), the grade 2b tumor with high risk of recurrence being considered as tumor suspected of malignancy. Conclusions: Using a set of specific biological markers for invasive process, there is hope to establish an early diagnosis and prevention of invasive pituitary adenomas. Due to the fact that aggressive pituitary tumors are generally difficult to manage, unresponsive to therapy, quickly recurrent and associated with poor prognosis, the early diagnosis and the search for new therapeutic approaches is becoming mandatory. Instead of using “invasive” or “aggressive” adenoma, the term “tumor suspected of malignancy” would be used for more accuracy

Histological criteria for atypical pituitary adenomas - data from the German pituitary adenoma registry suggests modifications.

IntroductionThe term atypical pituitary adenoma (APA) was revised in the 2004 World Health Organization (WHO) classification of pituitary tumors. However, two of the four parameters required for the diagnosis of APAs were formulated rather vaguely (i.e., “extensive” nuclear staining for p53; “elevated” mitotic index). Based on a case-control study using a representative cohort of typical pituitary adenomas and APAs selected from the German Pituitary Tumor Registry, we aimed to obtain reliable cut-off values for both p53 and the mitotic index. In addition, we analyzed the impact of all four individual parameters (invasiveness, Ki67-index, p53, mitotic index) on the selectivity for differentiating both adenoma subtypes.MethodsOf the 308 patients included in the study, 98 were diagnosed as APAs (incidence 2.9 %) and 10 patients suffered from a pituitary carcinoma (incidence 0.2 %). As a control group, we selected 200 group matched patients with typical pituitary adenomas (TPAs). Cut-off values were attained using ROC analysis.ResultsWe determined significant threshold values for p53 (≥2 %; AUC: 0.94) and the mitotic index (≥2 mitosis within 10 high power fields; AUC: 0.89). The most reliable individual marker for differentiating TPAs and APAs was a Ki-67-labeling index ≥ 4 % (AUC: 0.98). Using logistic regression analysis (LRA) we were able to show that all four criteria (Ki-67 (p < 0.001); OR 5.2// p53 (p < 0.001); OR 3.1// mitotic index (p < 0.001); OR 2.1// invasiveness (p < 0.001); OR 8.2)) were significant for the group of APAs. Furthermore, we describe the presence of nucleoli as a new favorable parameter for TPAs (p = 0.008; OR: 0.4; CI95 %: 0.18; 0.77).ConclusionsHere we present a proposed rectification of the current WHO classification of pituitary tumors describing an additional marker for TPA and specific threshold values for p53 and the mitotic index. This will greatly help in the reliable diagnosis of APAs and facilitate further studies to ascertain the prognostic relevance of this categorization.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0229-8) contains supplementary material, which is available to authorized users.

In search of a prognostic classification of endocrine pituitary tumors.

Pituitary tumors, the most frequent intracranial tumors, are historically considered benign. However, various pieces of clinical evidence and recent advances in pathological and molecular data suggest the need to consider that these tumors are more than an endocrinological disease despite the low incidence of metastasis. We present here a historical and critical review of the classifications of pituitary tumors, including a new prognostic clinicopathological classification based on tumor size, immunohistological subtype (prolactin (PRL), growth hormone (GH), follicle-stimulating hormone and luteinizing hormone (FSH-LH), adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH)), and five grades, which take into account invasion and proliferation of the tumors. We also present a brief review of the main markers of tumor behavior. We believe that a better classification of these tumors and the identification of prognostic markers will help the clinician to choose the appropriate therapeutic management.

MANAGEMENT OF ENDOCRINE DISEASE: Clinicopathological classification and molecular markers of pituitary tumours for personalized therapeutic strategies

Pituitary tumours, the most frequent intracranial tumour, are historically considered benign. However, various pieces of clinical evidence and recent advances in pathological and molecular analyses suggest the need to consider these tumours as more than an endocrinological disease, despite the low incidence of metastasis. Recently, we proposed a new prognostic clinicopathological classification of these pituitary tumours, according to the tumour size (micro, macro and giant), type (prolactin, GH, FSH/LH, ACTH and TSH) and grade (grade 1a, non-invasive; 1b, non-invasive and proliferative; 2a, invasive; 2b, invasive and proliferative and 3, metastatic). In addition to this classification, numerous molecular prognostic markers have been identified, allowing a better characterisation of tumour behaviour and prognosis. Moreover, clinical and preclinical studies have demonstrated that pituitary tumours could be treated by some chemotherapeutic drugs or new targeted therapies. Our improved classification of these tumours should now allow the identification of prognosis markers and help the clinician to propose personalised therapies to selected patients presenting tumours with a high risk of recurrence.

New classification of pituitary tumours based on the hypopronos database

New classification of pituitary tumours based on the hypopronos database

Aggressive and malignant prolactin pituitary tumors: pathological diagnosis and patient management

According to the World Health Organization classification of pituitary tumors, only tumors with systemic metastasis must be considered as carcinomas. Invasive tumors with multiple recurrences are only classified as aggressive tumors or "atypical adenomas". To illustrate the problems encountered in the pathological diagnosis of pituitary carcinoma and in patient management, we present two male patients operated on for an aggressive prolactin pituitary adenoma with and without metastasis. In case 1, 5 surgeries, 3 irradiations, increased doses of dopamine agonists, and trials of temozolomide and carboplatine-VP16 failed to control tumor progression and the appearance of metastases which lead to death 16 years after onset. In case 2, based on the initial diagnosis of an aggressive-invasive adenoma that was resistant to dopamine agonists, gamma-Knife irradiation was initially performed on the intra-cavernous remnant. Eight years after onset, the remnant remained stabilized and the plasma PRL normalized under dopamine agonist. From these 2 cases alongside other cases found in the literature, we propose that the association of certain clinical signs (male sex, dopamine-resistant hyperprolactinemia), radiological signs (invasive macro or giant tumor on MRI) and histological signs (angiogenesis, Ki-67 > 3%, p53 positive, mitoses >2 per high power field, vascular invasion, up-regulation of genes related to invasion and proliferation, and allelic loss of chromosome 11) might suggest aggressiveness and be suspicious of malignancy before the appearance of metastasis. The early detection of an aggressive phenotype of a prolactin pituitary tumor should permit the earlier establishment of the optimum therapeutic strategy associating surgery and radiotherapy to delay or inhibit metastasis.

The Pathogenesis of Pituitary Tumors

Recently there has been significant progress in our understanding of pituitary development, physiology, and pathology. New information has helped to clarify the classification of pituitary tumors. Epidemiologic analyses have identified a much higher incidence of pituitary tumors than previously thought. We review the pathogenetic factors that have been implicated in pituitary tumorigenesis and the application of novel targeted therapies that underscore the increasingly important role of the pathologist in determining accurate diagnoses and facilitating appropriate treatment of patients with these disorders.

Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry

In 1996, the German Registry of Pituitary Tumors was founded by the Pituitary Section of the German Society of Endocrinology as a reference center for collection and consultant pathohistological studies of pituitary tumors. The experiences of the first 10 years of this registry based on 4122 cases will herein be reported. The data supplement former collections of the years 1970-1995 with 3480 surgically removed tumors or lesions of the pituitary region. The cases were studied using histology, immunostainings and in some cases also molecular pathology or electron microscopy. The adenomas were classified according to the current World Health Organization classification in the version of 2004. From 1996 on 3489 adenomas (84.6%), 5 pituitary carcinomas (0.12%), 133 craniopharyngiomas (3.2%), 39 meningiomas (0.94%), 25 metastases (0.6%), 22 chordomas (0.5%), 115 cystic non-neoplastic lesions (2.8%), and 46 inflammatory lesions (1.1%, 248 other lesions or normal tissue (6.0%)) were collected by us. The adenomas (100%) were classified into densely granulated GH cell adenomas (9.2%), sparsely granulated GH cell adenomas (6.3%), sparsely granulated prolactin (PRL) cell adenomas (8.9%), densely granulated PRL cell adenomas (0.3%), mixed GH/PRL cell adenomas (5.2%), mammosomatotropic adenomas (1.1%), acidophilic stem cell adenomas (0.2%), densely granulated ACTH cell adenomas (7.2%), sparsely granulated ACTH cell adenomas (7.9%), Crooke cell adenomas (0.03%), TSH cell adenomas (1.5%), FSH/LH cell adenomas (24.8%), null cell adenomas (19.3%), null cell adenoma, oncocytic variant (5.8%), and plurihormonal adenomas (1.3%). Following the WHO classification of 2004, the new entity 'atypical adenoma' was found in 12 cases in 2005. Various prognostic parameters and clinical implications are discussed.

Comments on the WHO histological classification of pituitary tumors

I would like to agree, in general, with the view of Drs. Al-Shraim and Asa on the new WHO classification, especially on the necessity of introducing cell lineage. The basic tone of the argument for the new WHO histological classification of pituitary tumors was to try to build a new framework by shifting from the classical classification, which has been mainly based on electron microscopy, to a classification based on light microscopic immunohistochemistry. This was addressed on the background of recently accumulating knowledge on cell lineage of adenohypophysial cells. Nobody doubts that electron microscopic observations can provide essential information about cell nature, although it has been argued that electron microscopy has not been well performed even in sophisticated institutes. That is why each tumor type is primarily described on the basis of immunohistochemical information, such as growth hormone (GH)-producing adenoma, adrenocorticotropic hormone (ACTH)-producing adenoma, and so on. In my view, it seems to be indispensable to show a list of the WHO histological classification of pituitary tumors at the beginning of the chapter. Although a simple list of the WHO classification including typical adenoma, atypical adenoma and carcinoma is shown, it is not sufficient. In other chapters such as those on tumors of thyroid gland, adrenal gland and endocrine pancreas, the comprehensive list is appropriately documented with international classification of diseases (ICD) codes. Remarkably, glucagonoma and VIPoma of the endocrine pancreas, which are much rarer than GH-producing adenoma and ACTH-producing adenoma, are shown in a list with ICD codes. Table 1 may represent such a list of the new classification of pituitary tumors. I am afraid that people may misunderstand that Table 1.01, which shows the incidence of pituitary adenoma types classified by Horvath and Kovacs, indicates the new WHO classification, since this is the only list of pituitary adenoma types shown in the chapter.

The 2004 Who classification of pituitary tumors: comments

The 2004 Who classification of pituitary tumors: comments

The WHO classification of pituitary tumours: a combined neurosurgical and neuropathological view

Ambitious efforts were undertaken to elucidate the molecular pathogenesis of pituitary adenomas, and tumorigenesis has reached a new level of complexity. The identification of specific signalling pathways as well as molecular genetic alterations of tumour suppressor genes and oncogenes led to a novel classification system of pituitary tumours, which is published by the World Health Organization (WHO) in 2004 [2] and now comprehensively reviewed by Mubarak Al-Shraim and Sylvia L. Asa in the current issue of Acta Neuropathologica. From a clinician’s point of view, molecular and histological grading patterns have an increasing impact onto the development of specific treatment strategies but should also address our long-standing bed-side experience. In this respect, the new 2004 WHO classification of pituitary tumours is challenging but requires interpretation. Despite the progress achieved in the pathogenesis of tumours of the sellar region, there is still no reliable marker predicting the biological behaviour of pituitary adenomas, i.e. invasiveness and recurrency. Therefore, diagnostic procedures and surgical or pharmacological treatment options have to follow well-established paradigms:

The 2004 World Health Organization classification of pituitary tumors: What is new?

The classification of pituitary tumors is a dynamic area that changes with advances in cell biology that provide a deeper insight and clearer understanding of cell lineages and pathogenetic mechanisms. The 2004 edition of the World Heath Organization (WHO) text "Histological typing of endocrine tumors" reflects the progress that has been achieved since the previous edition of 2000. Here we review the new information and identify areas of concern for the next effort at classification of pituitary tumors.

The new WHO classification of pituitary tumors: a surgeon’s perspective

The new WHO classification of pituitary tumors: a surgeon’s perspective

Innovations and controversies in the WHO classification of pituitary adenomas

The 2004 edition of the World Heath Organization (WHO) entitled ‘‘Pathology and genetics tumors of endocrine organs,’’ presents a step forward in the classification of pituitary tumors. This classification is mainly based on immunohistochemistry, which has become the gold standard of modern diagnostic approach; electron microscopy remains an important tool in difficult cases. Immunohistochemistry can accurately identify the full spectrum of pituitary hormones produced by adenoma cells, enable more defined configuration of cell morphology and reveal several structural elements and cytoskeleton components, such as cytokeratin filaments and mitochondria. Recognition of these elements, which could previously only be identified by electron microscopy, and application to the current diagnostic approach has facilitated the classification of pituitary adenomas. Immunohistochemistry for b -a nda-subunits of glycoprotein hormones discloses the polar shape of adenoma cells and their attenuated cytoplasmic process, distinct morphological features of ‘‘glycoprotein differentiation’’ of TSH and gonadotroph adenomas [7] (Fig. 1). Antibodies against low molecular weight keratins, particularly keratin 8 reveal fibrous bodies that might be difficult to identify on hematoxylin and eosin sections alone [8]. These structures that are composed of cytokeratin filaments represent a diagnostic key feature, mostly for the sparsely granulated variant of somatotroph adenomas (Fig. 2). In contrast, keratin 8 shows diffuse cytoplasmic distribution in densely granulated somatotroph adenomas. Fibrous bodies in association with mitochondrial gigantism and misplaced exocytosis represent a diagnostic hallmark of the rare type of acidophil stem cell adenoma, whereas small fibrous bodies are also present in mammosomatotroph adeno