Silent Adenomas Research Articles

THU099 The Challenging Management Of Silent Corticotroph PitNET—From Very Aggressive To Mild Course Of Disease During Long Follow Up

Abstract Disclosure: A. Bogusławska: None. &. Kluczyński: None. A. Hubalewska-Dydejczyk: None. A. Gilis-Januszewska: None. We present a case series of silent corticotroph PitNETs with various clinical outcomes. Case 1. A 33-year-old male admitted to Emergency Department (ED) due to severe headaches and vomiting- giant PitNET (39x33x55 mm) was visualized-debulking transsphenoidal surgery (TSS) was performed. Histopathology results showed silent adenoma subtype 1 (densely granulated), Ki67<1%. Due to rapid progression of PitNET- patient underwent two emergency TSS and stereotactic fractionated radiotherapy. Treatment with temozolomide, pasireotide, cabergoline, radiotherapy was introduced. After 18 months of combined therapy stable disease was observed. Implementation of pasireotide resulted in spectacular decrease of headaches (initially 9-10 to none /10 using NRS). Case 2. A 31-year-old male presented in our clinic due to headaches and bitemporal hemianopsia. In MRI PitNET was found (22x19x23mm) and active Cushing disease (CD) was diagnosed. TSS was performed in 2013. Histopathology results showed corticotroph PitNET with Crook cells. Postoperatively, PitNET progression (17x26x13mm) was observed with no overt CD. In 2022, due to worsening of headaches and vision loss, second TSS was performed. Histopathologists described corticotroph tumor with Crook cells with ATRX mutation of uncertain significance. Pasireotide implementation is planned. Case 3. A 47-yeard-old female was admitted to ED due to severe headache and nausea. In MRI pituitary tumor (20x17x20mm) with local invasion was found. The patient was operated and histopathology showed densely granulated corticotroph PitNET; ACTH(+), GH(+), Ki-67% was 3%, p53<5%, with single Crook cells. In follow-up, progression of PitNET was noted (31x32x30 mm) and the patient underwent proton therapy. Case 4. A 56-yeard old female after three TSS (2012,2017,2018) and craniotomy (2020) due to aggressive corticotroph PitNET with Ki67 <1%. In 2009 a pituitary tumour (9x10x13 mm) was found. Before last craniotomy, the tumour was 24x24x28mm. After neurosurgery, paresis of right III nerve and left hemiparesis occurred. Pasireotide implementation is planned. Case 5. A 70-year old female presented in 2015 with severe headaches/nausea. In MR PitNET (32x24x31mm) was found. The patient underwent TSS and histopathology showed corticotroph PitNET with Ki67<1%. Due to PitNET progression, second TSS and fractionated radiotherapy was performed (2017) however in last MRI (2022), tumor relapse was noted. Case 6/7: A 46-year-old and 50 year-old females were operated due to local symptoms of PitNET. Histopathology revealed silent corticotroph PitNET. In follow-up MRI after one year showed no progression of pituitary tumor. The management of silent corticotroph PitNETs is very challenging and individualized approach is required. Further multicenter studies to understand the pathophysiology and the course of silent corticotroph PitNETs are needed. Presentation: Thursday, June 15, 2023

Integrating Methylome and Transcriptome Signatures Expands the Molecular Classification of the Pituitary Tumors.

To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population. In this retrospective cross-sectional study, clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo. Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs). This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.

The Genomic Landscape of Corticotroph Tumors: From Silent Adenomas to ACTH-Secreting Carcinomas.

Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.

GIANT SILENT CORTICOTROPIC ADENOMA IN AN ADOLESCENT: A CASE REPORT

Pituitary tumors in children and adolescents are dominated by craniopharyngiomas (80-90%) followed by adenomas. Silent pituitary adenomas in children and adolescents are rare represent only 4-6% of all adenomas. We present the case of a silent giant corticotropic adenoma revealed by pituitary tumoral syndrome in an adolescent. This is a 17-year-old patient operated for an invasive interstellar and suprasellar mass of 34x63x42 mm revealed by intense headaches, blindness in the left eye and a significant decrease in visual acuity in the right eye evolving for 1 month in a context of growth retardation for 4 years, without signs of associated pituitary hormonal hypersecretion. immunohistochemistry had concluded to a corticotropic adenoma. control hypothalamic-pituitary MRI showed persistence of the sellar and suprasellar mass of 33x31x34 mm. The patient had been referred for revision surgery. Silent adenomas are rare in childhood and adolescence let alone giant corticotropic silent adenomas. They are associated with significant morbidity due to their location, their mass effect and / or their interference with normal pituitary hormonal functions. Surgical treatment remains the first-line treatment. Long-term follow-up remains essential to detect recurrence and to manage the various pituitary deficits.

Pituitary tumour types in dogs and cats

Pituitary tumours are common in dogs and are being increasingly recognized in cats. Pituitary tumours are usually classified as adenomas and should only be classified as carcinomas when there is evidence of metastatic spread of the tumour, which is rare. Despite the benign nature of most pituitary tumours, they can still compress or invade neighbouring tissues. Pituitary tumours can be functional (hormonally active) or non-functional (hormonally silent). The aim of this review was to provide an overview of the different pituitary tumour types in dogs and cats that have been reported in the literature. In dogs, the most common pituitary tumour type is the corticotroph adenoma, which can cause pituitary-dependent hypercortisolism. In cats, the most common pituitary tumour is the somatotroph adenoma, which can cause hypersomatotropism, and the second-most common is the corticotroph adenoma. A lactotroph adenoma has been described in one dog, while gonadotroph, thyrotroph and null cell adenomas have not been described in dogs or cats. Hormonally silent adenomas are likely underdiagnosed because they do not result in an endocrine syndrome. Tools used to classify pituitary tumours in humans, particularly immunohistochemistry for lineage-specific transcription factors, are likely to be useful to classify canine and feline pituitary tumours of unknown origin. Future studies are required to better understand the full range of pituitary adenoma pathology in dogs and cats and to determine whether certain adenoma subtypes behave more aggressively than others. Currently, the mechanisms that underlie pituitary tumorigenesis in dogs and cats are still largely unknown. A better understanding of the molecular background of these tumours could help to identify improved pituitary-targeted therapeutics.

Deciphering the genetic and epigenetic background of silent and non-silent ACTH adenomas

Deciphering the genetic and epigenetic background of silent and non-silent ACTH adenomas

Clinical Evaluation on Non-Functional Invasive Hypophysis Adenomas

Background
 There are ongoing studies to predetermine non-functional invasive pituitary adenomas which may show aggressive behavior. Our aim is to discuss whether there is a relationship between the immunohistochemical presence of GH, FSH, LH, PRL, ACTH, TSH and their aggressive clinical course in non-functional pituitary adenomas.
 Materials and Methods 
 In this study, we evaluated retrospectively the files of the patients who were diagnosed with thesellar or parasellar tumor in our endocrinology clinic between the years of 2004-2014.The patients were divided into two groups as non-invasive pituitary adenomas and non-functional invasive pituitary adenomas. The immunohistochemical staining characteristics were compared between the two groups.
 Results 
 In this study, we scanned the data of 70 patients who were followed for non-functional sellar or parasellar mass. 47.1% of the patients were female and 52.9% of the patients were male.39 patients had a non-functional pituitary adenoma.The rate of non-functional invasive adenoma was found to be 20.5%. There was a significant relationship between the immunohistochemical positivity of GH, FSH, LH andaggressive behavior of non-functional invasive adenomas. There was no a significant relationship between the immunohistochemicalpositivityof PRL, ACTH, TSH and aggressive behavior of non-functional invasive adenomas.
 Conclusion 
 We found silent GH and gonadotropin adenomas as non-functional aggressive pituitary adenoma. More aggressive treatment and close clinical monitoring should be performed because atypical pituitary adenomas are characterized by invasive growth and aggressive clinical course.

SUN-274 Pituitary Macroadenoma Treated with Peptide Receptor Radionuclide Therapy in a Patient with Common Variable Immunodeficiency - Case Report

Background: Nonfunctional adenomas comprise 25-35% of all pituitary tumors, 70-90% of these are gonadatroph cell adenomas. While ‘silent’ adenoma is the most common type of pituitary macroadenoma. The incidence of silent adenomas is estimated at 22/100000. Common Variable Immune Deficiency (CVID) is the most common primary immune disorder which is associated with neoplasia, mostly of the lymphatic or digestive system. We present probably the first case report of gonadotropinoma in a patient with CVID, treated with PRRT.Clinical Case:A 45-year-old man has been a patient at the Endocrinology Clinic for 12 years. Aged 33 years, he was diagnosed with a common variable immunodeficiency. The human immunoglobulin treatment was included. He also suffered from severe, spreading headaches. MRI of the head was performed. A 45mm tumor was found in the sella turcica, spreading to the sphenoid sinus. The tumor was slipped into the epidural reservois and both cavernous sinuses, causing compression of the internal carotid arteries and compressed the optic chiasm. Laboratory tests were as follows: TSH 2.18uIU/ml, LH 4.26mIU/ml, FSH 9.76 mIU/ml, ACTH 25.88pg/ml, PRL 18.34 ng/ml, HGH 3.9uU/ml, normal plasma and urine osmolality. So, the silent pituitary macroadenoma was diagnosed. Endoscopic transsphenoidal incomplete tumor resection was performed. The operation was complicated by massive parenchymal bleeding. Histopatological examination confirmed presence of pituitary adenoma, and immunohistochemical positive staining also of FSH (+), subunit alpha (+), TSH (+/-). A Ki67 proliferation index was 1%. After 12 months endoscopic reoperation was performed. The extent of operation was larger but not total. After 12 month the tumor mass increased (50x50x45mm). Imaging of somatostatin receptors by SPECT-CT was performed. It showed a heterogeneous radiolabel accumulation in the pituitary tumor. In 2010, 2 doses of 200mCi 90-Y-DOTATATE were administered with good effect. Tumor size was reduced to 20x23x25mm. The patient has had no headache for that time. Since 2011 he has also been treated with octreotide30 mg/month, with good therapy tolerance.Conclusion:This is probably the first description of a 12-year history of complicated but successful treatment of pituitary silent macroadenoma. It was also probably the first use of PRRT in the pituitary tumor with excellent effect. The patient remains in a very good condition, without neurological symptoms and no disorders of pituitary function.

MON-412 Subclinical Cushing's Disease and the Importance of Broad Differential Diagnoses

Introduction: Cushing disease is the most common cause of endogenous Cushing syndrome, and if undiagnosed, carries significant morbidity including diabetes, obesity, infertility, and osteoporosis. Physical exam findings commonly seen include violaceous abdominal striae, supraclavicular fat pads, facial plethora, and proximal muscle weakness. Here, we discuss a case of a rare presentation of Cushing disease in a patient whose chief complaint was fatigue with none of the aforementioned physical manifestations. Case: A 43 year old female with a medical history of multinodular goiter status post hemithyroidectomy presented with persistent fatigue and weight gain over a one year period. Physical exam revealed normal body habitus, no thyroid nodules, no supraclavicular fat pad, abdominal striae, or proximal muscle weakness. Thyroid studies were normal, and despite lifestyle modifications, the patient's symptoms persisted. Laboratory workup revealed elevated midnight salivary cortisol levels, an elevated 24 hour urine free cortisol measurement, and on dexamethasone suppression testing, elevated ACTH levels, confirming Cushing disease. Pituitary MRI was significant for pituitary macroadenoma with cystic changes measuring 1.1x1.9cm and mild compression of the optic chiasm. The patient was transferred for surgical resection, where pathology was consistent with an ACTH-secreting adenoma. Discussion: Subclinical Cushing's disease is defined by an adrenocorticotrophic hormone (ACTH)-induced mild hypercortisolism without typical features of Cushing's disease. In a 2016 cohort study, the prevalence of subclinical and silent corticotroph adenomas was approximately 40%, making it imperative for practitioners to have a broad differential when evaluating patients with non-specific complaints. Additional studies show that clinically silent adenomas (adenomas with normal cortisol secretion and ACTH-immunopositive staining without autonomous ACTH secretion) have the risk of progressing to Cushing's disease, thereby carrying the risk of increased morbidity secondary to the metabolic derangements due to hypercortisolism. Finally, should surgical resection be warranted, the size of the adenoma has been associated not only with the level of difficulty of surgical resection, but also with the risk of recurrence. Ultimately, it behooves the medical community to obtain detailed histories, conduct thorough physical, and maintain broad differentials of rare conditions to allow for better screening.

Morphofunctional features of non-functioning pituitary adenomas

Non-functioning pituitary adenomas (NFPAs) account for about 30% of all pituitary tumors. NFPAs are characterized by the lack of secretory potential or its weak expression insufficient for determination of the blood level of adenohypophyseal tropic hormones and for development of a specific clinical picture. Morphologically, NFPAs are a heterogeneous group of tumors, the classification of which was previously based only on immunoreactivity for pituitary tropic hormones. The WHO revised its Classification of Tumors of Endocrine Organs (4th edition) in 2017. The main changes relate to adenohypophysial-cell lineage for the designation of adenomas into subtypes. The introduction of transcription factor antibodies has become a fundamentally new approach to the classification of NFPAs, which is necessary to recognize less differentiated tumor types. This paper provides information on the new histopathological classification of pituitary adenomas, on the theories of silent adenomas, and on the proliferative and prognostic markers of NFPAs.

The Importance of Immunohistochemical Analysis in Silent Pituitary Adenoma

Pituitary adenoma contributes to 15% of all intracranial neoplasm. It is usually following benign course and some of them are silent (asymptomatic clinically, but hormone-secreting). Silent adenoma usually found incidentally or when the patients show mass effect (neurological deficits). Many of histologically aggressive silent adenoma subtypes are associated with invasiveness, recurrence and progression to clinically functioning adenomas. Aggressive silent adenoma radiologically tends to invade in downward direction, invading bone, sinus cavernosus, parasellar region. The nature of aggressive silent adenoma subtypes is differing in nature compared to benign nature of pituitary adenoma and should be confirmed immunohistochemically to determine the prognosis and anticipate the risk of recurrence or progression. The case illustration show a real case of 46 years old female progressive headache and visual disturbance diagnosed with non-functional pituitary macroadenoma but positive for more than one immunochemistry biomarker (plurihormonal aggressive silent adenoma).

Clinical and Pathological Aspects of Silent Pituitary Adenomas.

ContextSilent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues.Evidence AcquisitionA comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized.Evidence SynthesisThe clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or “whispering” adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification.ConclusionsA concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients.

Inherent Tumor Characteristics That Limit Effective and Safe Resection of Giant Nonfunctioning Pituitary Adenomas.

Surgical treatment of giant pituitary adenomas is sometimes challenging. We present our surgical series of giant nonfunctioning adenomas to shed light on the limitations of effective and safe tumor resection. The preoperative tumor characteristics, surgical approaches, outcome, and histology of giant nonfunctioning adenoma (>40 mm) in 128 consecutive surgical patients are reviewed. The follow-up period ranged from 19 to 113 months (mean 62.2 months). A transsphenoidal approach was used in the treatment of 109 patients and a combined transsphenoidal transcranial approach in 19 patients. A total of 93 patients (72.7%) underwent total resection or subtotal resection apart from the cavernous sinus (CS). The degree of tumor resection, excluding the marked CS invasion, was lower in tumors that were larger (P= 0.0107), showed massive intracranial extension (P= 0.0352), and had an irregular configuration (P= 0.0016). Permanent surgical complications developed in 28 patients (22.0%). Long-term tumor control was achieved in all patients by single surgery, including 43 patients with adjuvant radiotherapy. Most tumors were histologically benign, with a low MIB-1 index (<3.0%) beside a few tumors mainly silent adenomas of pituitary-specific transcription factor lineage. Irrespective of the surgical approach, massive intracranial extension, an irregular configuration, and marked CS invasion are inherent factors that independently limit effective resection. These high-risk tumors require an individualized therapeutic strategy.

The Complementary Role of Transcription Factors in the Accurate Diagnosis of Clinically Nonfunctioning Pituitary Adenomas.

Clinically nonfunctioning pituitary adenomas (NFAs) may be hormonally inactive tumors of differentiated cells, mainly not only gonadotroph adenomas (GAs) but also silent corticotroph adenomas (SCAs) and other differentiated silent adenomas. Recently, the use of transcription factors has been recommended to confirm cytodiffererentiation of these neoplasms. Our objective was to assess the clinical significance of the new classification system using transcription factors. Five hundred sixteen consecutive NFAs were studied retrospectively. They were initially classified based on hormone immunohistochemistry as follows: 119 hormone-negative adenomas (23.1 %), 300 GAs (58.1 %), 51 SCAs (9.9 %), and 46 other silent adenomas. The 119 hormone-negative adenomas were further evaluated for expression of transcription factors including steroidogenic factor-1 (SF-1), estrogen receptor-α (ERα), pituitary-specific transcription factor 1 (Pit-1), and t-box transcription factor (Tpit). One hundred thirteen of 119 (95 %) hormone-negative adenomas showed mutually exclusive lineage-specific differentiation as gonadotrophs (SF-1 positive), corticotrophs (Tpit positive), or somatotrophs/mammosomatotrophs/lactotrophs/thyrotrophs (Pit-1 positive) in 79 cases (66.4 %), 32 cases (26.9 %), and 2 cases, respectively. The 32 ACTH-negative and Tpit-positive adenomas had higher pro-opiomelanocortin mRNA expression levels compared with GAs (P = 0.0001) on quantitative real-time PCR. They showed a female preponderance (P < 0.0001) and were more frequently giant adenomas (P = 0.0028) associated with marked cavernous sinus invasion (P < 0.0001) compared with GAs. These clinical features were identical to those of the 51 ACTH-positive SCAs. Our results justify the complementary role of transcription factors in the precise classification of NFAs that can more accurately characterize biological behavior. Our data suggest that more than one quarter of hormone-negative adenomas are SCAs that share distinct clinicopathological features with ACTH-expressing SCAs.

Biological and radiological exploration and management of non-functioning pituitary adenoma

Non-functioning pituitary adenoma may be totally asymptomatic and discovered “incidentally” during radiological examination for some other indication, or else induce tumoral signs with compression of the optic chiasm and pituitary dysfunction. Non-functioning adenomas are mainly gonadotroph, but may also be “silent”. Treatment strategy depends on initial clinical, biological, ophthalmological and radiological findings. The present French Society of Endocrinology Consensus work-group sought to update the pitfalls associated with hormone assay and outline a hormonal exploration strategy for diagnosis and follow-up, without overlooking the particularities of silent adenoma. We also drew up basic rules for initial exploration and radiological follow-up of both operated and non-operated pituitary adenomas.

New aspects of tumor pathology of the pituitary

Pituitary adenomas have to be studied in detail for structural characteristics, especially regarding the degree of granulation and immunohistochemical hormone expression, such as growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and proliferation markers (e.g. Ki-67 and p53) for correlation to clinical data and assessment of the prognosis. If histological and immunostaining data do not correlate to the patient data, explanations for the discrepancies must be found. All active adenoma types can also be present as inactive, so-called silent adenomas showing the same features. An increased Ki-67 index (> 3%), significant nuclear expression of protein p53 and mitoses are characteristic of atypical adenomas. Up to now the biological relevance of these atypical adenomas, especially their role as preneoplasms for pituitary carcinomas has not been fully elucidated. The only proof of a pituitary carcinoma is the existence of metastases. Extensive local invasion and a greatly increased Ki-67 index are not sufficient for this diagnosis. Craniopharyngiomas have to be classified into adamantinomatous types (intrasellar and suprasellar) and papillary types (only suprasellar). Regressive changes are found in adamantinomatous types only. Strong regression may lead to difficulties in the differential diagnosis of Rathke's cleft cysts with squamous metaplasia. Demonstration of nuclear expression of beta-catenin in these cases enables the diagnosis of craniopharyngioma. Papillary craniopharyngiomas are characterized by BRAF mutations that may be helpful in the differential diagnosis. All pituicytomas of the neurohypophysis, all spindle cell oncocytomas of the anterior pituitary and all granular cell tumors of the posterior pituitary express thyroid transcription factor 1 (TTF-1) and are thought to be variants of a common uniform spindle cell tumor of the pituitary.

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.

Silent (clinically nonfunctioning) pituitary adenomas

Silent, or clinically nonfunctioning, pituitary adenomas can arise from any anterior pituitary cell type. Some are "clinically silent" in that they result in a supranormal serum concentration of the hormonal product of the cell type from which the adenoma arose but do not cause the clinical manifestations typical of excessive levels of that hormone. Others are "totally silent" in that they result in neither hormonal excess nor clinical manifestations. Gonadotroph and null cell adenomas are the most prevalent types and are typically silent. Somatotroph and corticotroph adenomas typically cause clinical syndromes but occasionally are clinically or totally silent. Those that are silent are usually larger and grow more aggressively than those that cause clinical syndromes. Silent adenomas are usually not discovered until they become very large and cause neurologic defects, such as visual impairment, but are also often discovered incidentally when neuroimaging is performed for another reason. Silent adenomas may become, rarely, clinically apparent over time. The diagnosis of a silent pituitary adenoma begins with the detection of a sellar mass by MRI. Biochemical testing can identify the adenoma cell type in those that are clinically silent. Silent adenomas that cause neurologic deficits require transsphenoidal surgery, but those that do not can be followed by MRI. Residual or recurrent disease is treated by radiation therapy, which is usually effective in preventing further growth but results in hormonal deficiencies in about half of patients. Dopamine agonists and somatostatin analogs are usually ineffective, but occasionally have been associated with reduced adenoma size.

Aggressive Silent GH Pituitary Tumor Resistant to Multiple Treatments, Including Temozolomide

Temozolomide (TMZ) has been proposed as a therapeutic option in aggressive pituitary tumors. Among the published cases, GH expressing tumors were rare. We describe a patient with initially benign silent GH adenoma that transformed into an aggressive GH secreting tumor resistant to usual therapy. MGMT expression was high and the MGMT promoter was unmethylated. Before this aggressive course, patient received three cycles of TMZ; no response was observed. Four cases of GH aggressive tumor treated by TMZ have been reported. Response to TMZ was observed in one of these four patients. Predictive factors of failure of TMZ remain unclear.

Correlation Between Histological Subtypes and MRI Findings in Clinically Nonfunctioning Pituitary Adenomas

Clinically nonfunctioning pituitary adenomas (CNFPAs) consist of several histological subtypes, including null cell adenoma (NCA), silent gonadotroph cell adenoma (SGA), silent corticotroph adenoma (SCA), and other silent adenomas (OSA) (i.e., GH, TSH, and prolactin adenomas). To detect possible correlations between MRI findings and the subtypes, we retrospectively studied 390 consecutive patients with CNFPA who underwent surgery between 2008 and 2010. They were classified into three groups: NCA/SGA (313 cases), SCA (39 cases), and OSA (36 cases); in addition there were two unusual cases of plurihormonal adenoma. Three MRI findings were less common in NCA/SGA than in the other groups (P < 0.0001): giant adenoma (>40 mm), marked cavernous sinus invasion (Knosp grade 4), and lobulated configuration of the suprasellar tumor. When these MRI findings were negative in patients older than 40 years old, 91.0% (212/233) were NCA/SGA. These MRI findings were frequently noted despite a low MIB-1 index in SCA. OSA showed a high MIB-1 index and a preponderance in younger patients. In conclusion, although SCA and OSA consisted of only 20% of CNFPAs, their frequency significantly increased when the tumor was large, invasive, and lobulated, and the patient was younger than 40 years old.