Classification Of Pituitary Adenomas Research Articles

Pituitary adenoma…nomen omen?

In 2017, the International Pituitary Pathology Club proposed to rename pituitary adenoma as pituitary neuroendocrine tumors (PitNETs) but since no consensus on this new terminology was obtained the Pituitary Society decided to host on this topic an international multidisciplinary virtual workshop, Pituitary Neoplasm Nomenclature (PANOMEN), to which several Societies participated with the designation of their representatives in the expert panel. Main conclusion of the meeting was that there was not yet a case for adopting the PitNET nomenclature and main recommendation was that the term adenoma is retained. Aim of this Editorial is to comment the outcome of the recently published document of the meeting. Ideally, only the combination of pathological, neuroradiological, and clinical data can define the degree of agressiveness/invasion of a pituitary adenoma and effectively guide treament. This may be classically obtained only with a close multisciplinary collaboration into a PTCOE. It is proposed that improved definition of "invasive" and "aggressive" neoplasms may represent the most clinically effective development in the clinico-neuroradiological-pathological denomination and classification of pituitary adenomas.

The Pituitary Epigenetic Liquid Biopsy for the Peripheral Detection and Classification of Pituitary Adenomas

The Pituitary Epigenetic Liquid Biopsy for the Peripheral Detection and Classification of Pituitary Adenomas

Newer Concepts in the Classification of Pituitary Adenomas.

The classification of tumors of the pituitary gland has seen several changes in recent years. The 4th edition of the World Health Organization Classification of Tumours of Endocrine Organs, published in 2017, saw the introduction of a classification based on cell lineage using immunohistochemistry for both pituitary specific hormones as well as pituitary specific transcription factors. The term "hormone-producing" was thus replaced by "-troph." The other major change was that the entity of "atypical adenoma," which was introduced in the 2004 classification, to identify tumors with a poor prognosis, was removed as it failed to identify aggressive tumors. Instead, assessment of markers of proliferation, clinical parameters, such as invasive status and histological subtypes were recommended to identify tumors with aggressive potential. The diagnostic criteria for pituitary carcinoma, however, remained unchanged and continued to be defined as a tumor of adenohypophyseal cells that metastasize craniospinally or systemically. Null cell adenomas were more clearly defined as tumors that did not show any cell-type differentiation, lacking immunoexpression of hormones as well as transcription factors. Since 2017, the classification has continued to evolve with the identification of aggressive histological variants. There is more recently a proposal to change the terminology from pituitary adenoma to pituitary neuroendocrine tumor (PitNET). This review summarizes the recent advances in the classification of pituitary adenomas.

Pan-genomic classification of pituitary adenomas

Pan-genomic classification of pituitary adenomas

High Expression of Somatostatin Receptors 2A, 3, and 5 in Corticotroph Pituitary Adenoma.

The development of somatostatin analogs for the treatment of pituitary Cushing's disease has been based on somatostatin receptor expression analyses of small cohorts of pituitary adenomas. Additionally, the classification of pituitary adenomas has recently changed. To enable progress with this treatment option, we assessed somatostatin receptors in a large cohort of corticotroph and other pituitary adenomas according to the new WHO classification of endocrine tumors. Paraffin-embedded tumor samples of 88 corticotroph pituitary adenomas and 30 nonadenomatous pituitary biopsies were analyzed after processing into tissue microarrays and immunohistochemical staining for SSTR 1, SSTR2A, SSTR3, SSTR4, and SSTR5. For comparison, 159 other noncorticotroph pituitary adenomas were analyzed. SSTR3 expression was higher in corticotroph adenomas compared to PIT-1-positive, gonadotroph, and nonfunctioning pituitary adenomas (p < 0.0001, p = 0.0280, and p < 0.0001, respectively). This was also the case for the expression of SSTR5 (p = 0.0003, p < 0.0001, and p < 0.0001, respectively). SSTR2A expression was higher compared to gonadotroph and nonfunctioning pituitary adenomas (p = 0.0217 and 0.0126, respectively) while PIT-1-positive adenomas showed even higher SSTR2A expression (p < 0.0001). SSTR2A and SSTR5 were both expressed higher in nonadenomatous pituitary biopsies than in pituitary adenomas (p = 0.0126 and p = 0.0008, respectively). There are marked expression differences of SSTR1-5 as well as changes in expression in recurrent disease that need to be addressed when looking for other possible substances for the treatment of Cushing's disease. SSTR2A, SSTR3, and SSTR5 seem to be most suitable biomarkers for a targeted therapy with somatostatin analogs.

Quantitative immunohistochemical assessment of clinically non-functioning pituitary adenomas

Introduction. Immunohistochemical staining is currently the gold standard of diagnostic and classification of pituitary adenomas. However, there are some discrepancies between immunohistochemical staining results and the clinical picture of pituitary adenomas. Pituitary adenomas with positive immunohistochemical reaction might not cause any endocrinological symptoms or changes in serum pituitary hormone levels. Such a discordance may be caused partly by clinically non-functioning pituitary adenomas (CNFPAs). The aim of our study was to establish the frequency of CNFPAs and identify their histological types using quantitative immunohistochemical assessment. Materials and methods. We enrolled in the study 72 patients with pituitary adenoma, and their medical history was evaluated retrospectively. The immunohistochemical panel of anterior pituitary hormones was introduced in all cases. The immunoreactivity index was calculated manually for each specimen. Results. 36.1% patients of the evaluated group presented as CNFPAs. Among the CNFPA patients we found 38.46% cases with positive immunohistochemical reaction for one or more anterior pituitary lobe hormones. In 23.07% of cases the adenomas were monohormonal, and in 15.38% they were plurihormonal. Conclusions. The morphometric method utilising the immunoexpression index introduced in this study provided a very precise recognition of pituitary adenoma pathology. In the case of CNFPAs the immuno-histochemical staining often reveals a positive reaction also for multiple pituitary hormones. Quantitative assessment limits the subjectivity of the examiner and allows objective results comparison, so it should become a standard in histopathological assessment of pituitary adenomas.

New WHO classification of pituitary adenomas (4th edition): assessment of pituitary transcription factors and the prognostic histological factors.

WHO classification of pituitary adenomas was revised in 2017. The two major and significant changes are discussed. (1) The new classification focuses on adenohypophysial-cell lineage for the designation of adenomas, and thus, assessment of pituitary transcription factors is recommended. Its appropriate use has a complementary role in obtaining an accurate diagnosis, particularly in hormone-negative adenomas. Subclassification of nonfunctioning adenomas was revised accordingly and, consequently, null cell adenomas became quite rare. (2) "Atypical adenoma", a previous category, was eliminated due to the poor reproducibility and predictive value. Assessment of tumor proliferation marker and other clinical parameters such as invasion are recommended to predict aggressiveness. "High-risk adenomas" are those with rapid growth, radiological invasion, and a high Ki-67 proliferation index, whereas some special adenoma subtypes commonly show aggressive behavior.

Clinical Impact of the Current WHO Classification of Pituitary Adenomas.

WHO classifications should be used for comparing the results from different groups of pathologist and clinicians by standardized histopathological methods. Our present report describes the important parameters of pituitary adenoma pathology as demand of the WHO classification for correlation to endocrine data and prognosis. The combination of HE stain based structures with immunostainings for pituitary hormones allows subclassification of adenomas as the best method not only for correlations to clinical hyperfunctions but also for statements to the sensitivity of drug therapies (somatostatin analogs, dopamine agonists). GH-, PRL- and ACTH-secreting pituitary adenomas are further classified based on the size and number of their secretory granules by electron microscopy, or as is mostly the case nowadays by cytokeratin staining pattern, into densely and sparsely granulated. Granulation pattern may be considered for the prediction of treatment response in patients with GH-secreting adenomas, since the sparsely granulated subtype was shown to be less responsive to somatostatin analog treatment. For prognosis, it is important to identify aggressive adenomas by measurements of the Ki-67 index, of the number of mitoses, and of nuclear expression of p53. Among the criteria for atypical adenomas, high Ki-67 labeling index and invasive character are the most important adverse prognostic factors. Promising molecular markers have been identified that might supplement the currently used proliferation parameters. For defining atypical adenomas in a future histopathological classification system, we propose to provide the proliferative potential and the invasive character separately.

Progress in the Diagnosis and Classification of Pituitary Adenomas.

Pituitary adenomas are common neoplasms. Their classification is based upon size, invasion of adjacent structures, sporadic or familial cases, biochemical activity, clinical manifestations, morphological characteristics, response to treatment and recurrence. Although they are considered benign tumors, some of them are difficult to treat due to their tendency to recur despite standardized treatment. Functional tumors present other challenges for normalizing their biochemical activity. Novel approaches for early diagnosis, as well as different perspectives on classification, may help to identify subgroups of patients with similar characteristics, creating opportunities to match each patient with the best personalized treatment option. In this paper, we present the progress in the diagnosis and classification of different subgroups of patients with pituitary tumors that may be managed with specific considerations according to their tumor subtype.

Molecular classification of pituitary adenomas

Molecular classification of pituitary adenomas

Recent advances in the pathology of pituitary adenomas

Abstract Introduction: Pituitary adenomas are the third most common intracranial tumours. The 2004 WHO classification of pituitary adenomas has recommended the use of immunohistochemistry, electron microscopy and molecular techniques along with clinical and morphological evaluation in making a diagnosis. This review examines the subtypes of pituitary adenomas seen using the different diagnostic techniques. Materials and Methods: A comprehensive search of literature as well as an online search of databases was made. Results: The classification and molecular properties of the different subclasses are highlighted in this review. Pituitary adenomas are among the most frequent intracranial tumours and can present with over-expression of the hormones normally produced by the pituitary gland or pressure symptoms from the tumour. Pituitary adenomas are clonal tumours and often show over-expression of tumour suppressor genes which can sometimes be familial. Molecular studies have shown expression of common genes that can be employed to group pituitary adenomas based on their histogenetic origin. These genetic properties can be helpful in delineating those tumours which do not show clear cut lineage. This is particularly useful in the assessment of silent and plurihormonal adenomas. Several subclasses exist and the presentation may be different depending on the particular hormone produced. The prolactinomas are the commonest type followed by the silent adenomas with Gonadotroph and TSH producing adenomas constituting the rare types. Conclusion. Pituitary carcinomas are rare tumours diagnosed only in the presence of metastatic deposits in other tissues.

Pattern of pituitary adenomas in a West African Hospital

Introduction Pituitary adenomas are the third most common intracranial tumours constituting about 15% in most series. Classification of pituitary adenomas is based on immunohistochemical staining properties of the tumours according to the 2007 WHO recommendations. This study was conducted to determine the distribution of the subtypes in a black African population. Materials and methods Fifty-nine archived biopsy samples of cases received over a 13 year period were retrieved. Tissue sections were stained with antibodies for prolactin, growth hormone, ACTH, TSH, FSH and LH. The tumours were classified according to the 2004 WHO classification of pituitary adenomas. Results Females constituted 54% of cases and also had the highest number of cases in all tumour types except gonadotrophs. Null cell adenomas were the most commonly occurring (33.9%) followed by gonadotroph adenomas (32.2%) and mammotrophs were third (18.6%). No thyrotroph adenoma was seen. Three of the adenomas showed plurihormonality with one staining for thyrotroph and corticotroph and two staining for thyrotroph and gonadotroph hormones. Discussion This study showed higher incidence of gonadotroph and null cell adenomas in the population studied. The lower levels of prolactinomas may be explained by medical therapy of patients but could also be due to racial differences.

Protocol for the Examination of Specimens From Patients With Primary Pituitary Tumors

In an effort to improve the diagnosis of pituitary tumors, we propose a synoptic approach to pituitary pathology reporting that will provide clear information to endocrinologists, neurosurgeons, neuropathologists, and surgical pathologists to advance the diagnosis and classification of pituitary adenomas.

Protocol for the Examination of Specimens From Patients With Primary Pituitary Tumors

Abstract In an effort to improve the diagnosis of pituitary tumors, we propose a synoptic approach to pituitary pathology reporting that will provide clear information to endocrinologists, neurosurgeons, neuropathologists, and surgical pathologists to advance the diagnosis and classification of pituitary adenomas.

Atypical pituitary adenomas: incidence, clinical characteristics, and implications

The 2004 WHO classification of pituitary adenomas now includes an "atypical" variant, defined as follows: MIB-1 proliferative index greater than 3%, excessive p53 immunoreactivity, and increased mitotic activity. The authors review the incidence of this atypical histopathological subtype and its correlation with tumor subtype, invasion, and surgical features. The records of 121 consecutive patients who underwent transsphenoidal surgery for pituitary adenomas during an 18-month period were retrospectively reviewed for evidence of atypical adenomas. Eighteen adenomas (15%) met the criteria for atypical lesions; 17 (94%) of the 18 were macroadenomas. On imaging, 15 (83%) demonstrated imaging evidence of surrounding invasion, compared with 45% of typical adenomas (p = 0.004). Atypical tumors occurred in 12 female (67%) and 6 male (33%) patients. Patient age ranged from 16 to 70 years (mean 48 years). Nine patients (50%) had hormonally active tumors, and 9 had nonfunctional lesions. Four (22%) of the 18 patients presented to us with recurrent tumors. Immunohistochemical analysis demonstrated the following tumor subtypes: GH-secreting adenoma with plurihormonal staining (5 patients [28%]); null-cell adenoma (5 patients [28%]); silent ACTH tumor (3 patients [17%]), ACTH-staining tumor with Cushing's disease (2 patients [11%]), prolactinoma (2 patients [11%]), and silent FSH-staining tumor (1 patient [6%]). The MIB-1 labeling index ranged from 3% to 20% (mean 7%). Atypical tumors were identified in 15% of resected pituitary adenomas, and they tended to be aggressive, invasive macroadenomas. More longitudinal follow-up is required to determine whether surgical outcomes, potential for recurrence, or metastasis of atypical adenomas vary significantly from their typical counterparts.

Proliferation markers and cell cycle inhibitors in pituitary adenomas.

Proliferation markers are widely used in general surgical pathology and also in pituitary pathology. They should help for differing aggressive or rapidly growing tumors from those with slower growth, as cellular atypia is not helpful for identifying aggressive adenomas of the pituitary. Only the number of mitoses is important for prognosis. A lot of markers can be used: antibodies for cyclins A, B, D and E, for proliferating cell nuclear antigen, Ki-67/Mib-1, antibodies for the inhibitory proteins p16, p27, p53, and for DNA topoisomerase IIalpha. A marker for apoptosis and its inhibitors may be also important. From our experiences, Mib-1 is the most reliable marker. The recommendation of this marker in the WHO classification of pituitary adenomas is fully justified.

"Honeycomb Golgi" in pituitary adenomas: not a marker of gonadotroph adenomas.

The vacuolar change in Golgi complexes known as "honeycomb Golgi" has been described as the ultrastructural hallmark of a specific tumor that has been called the "female gonadotroph" adenoma of the human pituitary. Recently, a few adenomas presenting with Cushing's disease have been reported to exhibit this feature. To clarify the significance of a "honeycomb Golgi" in the classification of pituitary adenomas, we studied clinically nonfunctioning adenomas with or without "honeycomb Golgi" using immunohistochemistry for adenohypophysial hormones and RT-PCR for the cell-specific transcription factors Tpit that identifies corticotrophs and SF-1 that identifies gonadotrophs. All adenomas were from women. Among 20 adenomas with complete "honeycomb Golgi" change, gonadotrophin subunits were totally immunonegative, but ACTH was positive in a few cells of 12 adenomas. Among eight adenomas with partial vacuolar change of the Golgi complex, five were positive for gonadotrophins and two were positive for ACTH. A subgroup of these lesions were examined by RT-PCR and among eight adenomas with typical "honeycomb Golgi" one case expressed both Tpit and SF-1, probably due to contamination with normal pituitary and another expressed neither Tpit nor SF-1. Of the remaining six cases, Tpit was expressed in two cases and SF-1 in four. These findings indicate that "honeycomb Golgi" change can been seen in corticotroph adenomas as well as gonadotroph adenomas. The reason why this vacuolar change occurs only in females remains to be clarified.

Expression of corticotropin-releasing hormone messenger ribonucleic acid in human pituitary corticotroph adenomas associated with proliferative potential.

Among the factors that promote the growth of human pituitary corticotroph adenomas (hPCAs), the proliferative potential of CRH secreted by hPCAs on these tumors is not well known. In this study, the CRH messenger ribonucleic acid (mRNA) transcripts were demonstrated on paraffin sections using the quantitative in situ hybridization method in 37 of 43 hPCAs, including 17 of 22 microadenomas, 15 of 15 macroadenomas, and 5 of 6 locally invasive adenomas according to Hardy's classification of pituitary adenomas. The more important findings were that CRH mRNA signal intensity in pituitary corticotroph adenoma cells was linearly correlated with Ki-67 tumor growth fractions (r = 0.802; P < 0.0001), and in macroadenoma and locally invasive adenoma cells it was significantly higher than in microadenoma cells (P = 0.035). On the other hand, CRH mRNA transcript accumulation was absent or negligible in 10 normal pituitary glands (P = 0.005). This is the first report of the frequent expression of CRH mRNA localized in human pituitary corticotroph adenoma cells. These results indicate that CRH from a local source of corticotroph adenoma cells not only has autocrine/paracrine functions in corticotroph adenomatous tissue, but also is an important factor associated with a proliferative potential of hPCAs.

分子組織化学的手技に基づく下垂体腺腫の分類(&lt;特集&gt;下垂体)

近年,分子生物学的手法の進歩により,下垂体細胞の機能(ホルモン産生)に関する情報は,個々の細胞レベルにおける遺伝子発現まで明らかにされてきている.それに伴い,下垂体腺腫の分類も臨床情報に加えて詳細な機能情報に対応し得る分類が望まれると思われる.本稿では分子病理学的手法を紹介するとともに,下垂体細胞の機能分化に関与すると考えられる転写因子,核内受容体に関する最近の知見について論述する.さらにこれらの新しい情報を踏まえ,臨床・機能・形態学的知見を盛り込んだ下垂体腺腫の新分類を提示する.この臨床細胞機能分類は2分類より構成され,大分類は臨床的表現を基本にし,機能により7項目に分類し,亜分類として,(1)臨床症状,(2)画像・手術所見,(3)ホルモン産生(免疫組織化学,in situ hybridizationにより検出される),(4)電顕所見を付記する形とした.

Current pathological classification of pituitary adenomas.

A classification of pituitary adenomas basing on detailed structural and immunohistochemical studies is accepted world-wide and is mandatory for each pathologist. Monohormonal (densely or sparsely granulated GH cell adenomas, Prolactin cell adenomas, ACTH cell adenomas. FSH/LH cell adenomas, alpha-subunit-only adenomas), bihormonal (mixed GH/Prolactin cell adenomas, mammosomatotroph cell adenomas, acidophil stem cell adenomas), plurihormonal (GH/Prolactin/Glycoprotein-positive adenomas, other Glycoprotein-positive types) and hormone-negative adenomas (null cell adenomas, oncocytic adenomas) have to be differentiated.