Pituitary Neoplasia Research Articles

How to standardize the diagnostic approach to pituitary neuroendocrine tumors.

Pituitary tumors present heterogeneous biochemical, clinico-radiological, and histological features. Although histologically benign, a non-negligible number of cases present an unpredictable aggressive behavior with local invasiveness, partial/complete resistance to treatment and/or recurrence after surgery, and, rarely, metastasize, overall leading to a significant increase of morbidity, and, thus, requiring skilled multidisciplinary management in referral Centers. Histopathological diagnosis is essential to stratify cancer patient risk and uniform follow-up among Centers. Classification of pituitary neoplasia is continuously evolving in relation to the increased knowledge of mechanisms underlying adenohypophyseal cell tumorigenesis, and the attempts of combining clinico-radiological, biochemical, intraoperative, histological, and molecular elements, with the aim of identifying aggressive forms through. An integrated standardized histopathological report has been proposed in 2019 by the European Pituitary Pathology Group, based on the indications of the 2017 WHO classification of pituitary tumors. The last edition of the WHO Classification of Central Nervous System Tumors and of Endocrine and Neuroendocrine Tumors brought substantial novelties: 1) the replacement of the term "adenoma" with "Pituitary Neuroendocrine Tumor" (PitNET), and of "carcinoma" with "metastatic PitNET," and the consequent ICD-11 recoding from benign to malignant disease; and 2) the pivotal role of lineage restricted pituitary transcription factors for histological typing and subtyping. However, this approach does not reflect the spectrum of tumor phenotypes based on hormone secretion, nor include molecular features. Efforts of interdisciplinary groups of pituitary experts should be strongly encouraged to better understand factors involved in PitNETs evolution and, consequently, standardize diagnosis and reporting based on the most recent knowledges, essential to stratify cancer patient risk and uniform follow-up among centers.

ODP309 Ectopic Cushing's Syndrome: Importance of Methodical Approach to Hide and Seek

Abstract Cushing's syndrome (CS) is associated with high morbidity and fivefold excess mortality. Ectopic ACTH syndrome accounts for 20% of CS cases. It is crucial to identify and localize the source of extrapituitary ACTH secretion because surgical resection of the primary, often malignant, tumor has a high probability of cure with complete remission in 80% of cases. A 72-year-old female was admitted to a community hospital for lateral chest pain after a fall. She endorsed progressive weight gain, new HTN, emotional lability and worsening cognition over the prior 6 months. ACTH and cortisol levels were elevated. MRI brain failed to identify a pituitary lesion. CT chest showed multiple rib fractures and anterior mediastinal mass which was biopsied. While awaiting pathology results, IPS sampling attempted but aborted due to pulmonary edema necessitating ICU care. She was transferred to our institution for planned TSR of suspected pituitary adenoma. Examination showed Cushingoid features. Labs showed hypokalemia, high cortisol and high ACTH. MRI pituitary showed normal sella. MRI spine showed multilevel vertebral compression fractures. CT chest showed interval growth of mediastinal mass. A 1 mg dexamethasone suppression test failed to suppress ACTH and cortisol, confirming ACTH dependent hypercortisolism. A high dose 8 mg dexamethasone test failed to suppress ACTH and cortisol, a 10 mcg DDAVP stimulation test showed a flat response, with ACTH and cortisol levels remaining comparable before and after DDAVP injection. Dynamic testing therefore consistent with ectopic ACTH dependent hypercortisolism. Gallium-68 DOTA-TATE PET Scan demonstrated uptake in mediastinal mass suggestive of somatostatin receptor positive neuroendocrine tumor. Biopsy specimens processed at our institution showed cells positive for epithelial markers Cytokeratin and PAX8. Sample showed neuroendocrine differentiation with positive staining for Chromogranin A, synaptophysin and CD 117. Findings consistent with neuroendocrine thymic neoplasm. The patient was started on oral ketoconazole to control hypercortisolism. Surgical resection of tumor was planned with intent to cure CS. Ultimately, due to proximal myopathy and multiple vertebral fractures her performance status was too poor for safe tumor resection. Unfortunately, she died of complications related to CS while attempting preoperative rehabilitation. This case illustrates the importance of a timely, systematic evaluation for ACTH source in ACTH dependent hypercortisolism. Delay in CS diagnosis and localizing correct ACTH source led to missing the window of fitness for curative surgery. If ACTH is elevated, the most common source is pituitary neoplasia, however ectopic ACTH production must be ruled out. Dynamic testing including high dose dexamethasone suppression test, CRH and DDAVP stimulation tests should be used for preliminary localization of ACTH production. IPS sampling is invasive with greater potential for complications, as in the case of our patient. Therefore, it is only indicated if there are conflicting results from different dynamic tests and imaging studies. Presentation: No date and time listed

High Histone Deacetylase 2/3 Expression in Non-Functioning Pituitary Tumors.

Epigenetic modification of chromatin is involved in non-malignant pituitary neoplasia by causing abnormal expression of tumor suppressors and oncogenes. These changes are potentially reversible, suggesting the possibility of targeting tumor cells by restoring the expression of epigenetically silenced tumor suppressors. The role of the histone deacetylase (HDAC) family in pituitary tumorigenesis is not known. We report that HDAC2 and 3, Class I HDAC members, are highly expressed in clinically non-functioning pituitary adenomas (NFPAs) compared to normal pituitary (NP) samples as determined by RT-PCR and immunohistochemical staining (IHC). Treatment of a human NFPA derived folliculostellate cell line, PDFS, with the HDAC3 inhibitor RGFP966 for 96 hours resulted in inhibition of cell proliferation by 70%. Furthermore, the combination of RGFP966 with a methyltransferase/DNMT inhibitor, 5’-aza-2’-deoxycytidine, led to the restoration of the expression of several tumor suppressor genes, including STAT1, P16, PTEN, and the large non-coding RNA tumor suppressor MEG3, in PDFS cells. Our data support the hypothesis that both histone modification and DNA methylation are involved in the pathogenesis of human NFPAs and suggest that targeting HDACs and DNA methylation can be incorporated into future therapies.

Pituitary Carcinoma in a Bitch: Clinical, Tomographic, Histopathological and Immunohistochemistry Findings

Background: Primary pituitary carcinoma is rarely reported in dogs and only few reports describe its malignancy. In veterinary literature, primary pituitary carcinomas correspond up to 2.4% to 3.4% of intracranial neoplasms found in dogs and information regarding its biological behavior is quite limited. In humans, primary pituitary carcinomas represent less than 1.0% of all tumors found in the pituitary gland. The proposed classification for pituitary carcinoma in humans and dogs determines that the tumor must have its origin in adenohypophyseal region and disseminated metastasis by cerebrospinal fluid or systemically to other organs must be observed. In dogs, a few reports have described primary pituitary carcinoma. The goal of this report was to describe clinical, tomographic, histopathological and immunohistochemistry features of a dog with primary pituitary carcinoma with adjacent invasion. Case: A 7-year-old female spayed Golden Retriever dog was assessed by general practice due progressive weight loss, muscular atrophy, lethargy, blindness, head pressing, and hyporexia for 21 days. Computed tomography (CT) showed a cerebral parenchyma with expansive extra-axial base formation, originating from sella turcica topography, measuring about 2.0 centimeter dorsally, displacing the third ventricle, suggesting the diagnosis of pituitary neoplasia. The hormones thyroid-stimulating hormone (TSH) and total thyroxine (T4) as well as stimulation ACTH test were unremarkable. After 7 days, neurological clinical signs progressed and unfortunately the patient died ten days later after hospitalization. A necropsy exam revealed pituitary gland with increased dimensions (2.5 x 2.0 cm). Histopathological findings revealed tumor proliferation in pituitary gland. The neoplasm showed invasion to the nervous parenchyma and metastatic foci between the brain lobes. Immunohistochemistry was positive for keratin and neuron-specific enolase and negative for epithelial membrane antigen, S-100 protein, glial fibrillary acidic protein, estrogen receptor, CD34, chromogranin, somatostatin, and ACTH. The clinical, histopathological and immunohistochemistry findings supported the diagnosis of primary pituitary carcinoma. Discussion: There is lack information regarding pituitary carcinoma prevalence in dogs, and little is known about its pathological and clinical features. The patient showed a shorter survival time (30 days after the onset of clinical signs) for a non-hormonally functional tumor that presented with acute onset of neurological signs due to local effect of an expanding mass, also described in others pituitary carcinoma reports. It was observed a metastatic focus of pituitary neoplasia between cerebral hemispheres, leading us to conclude to be a pituitary carcinoma. Adjacent infiltration was noticed by the presence of neoplasm invasion to the synoptic nervous parenchyma and metastatic foci between the brain lobes as well as the presence of a non-delimited nodular area of neoplastic implantation between the cerebral hemispheres, and optic nerve compromised by neoplasm cells. The data reported here showed that a negative ACTH receptor in neoplasm with 10% Ki-67 proliferation index with no history of clinical signs of pituitary-dependent hyperadrenocorticism (PDH). Pituitary adenocarcinomas are thought to be more often non-secretors. CT findings reveled a pituitary mass of 2.5 cm in vertical height suggesting a pituitary macrotumor although there is lack of description for pituitary carcinomas in veterinary literature. The animal had a fast deterioration of his clinical condition and quickly came to death, suggesting poor biological behavior of the tumor. Keywords: adrenocorticotropic hormone, case report, dog, pituitary tumors.

Multiple endocrine neoplasia type 1 with a frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas:\xa0case report

BackgroundMultiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by pituitary neoplasia, primary hyperparathyroidism and pancreatic endocrine tumor. Here we show a case of MEN1 with a germline frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas.Case presentationA 28-year-old man noticed the decreased visual acuity of both eyes and visited our institution. Since he was diagnosed as visual disturbance and brain computer tomography (CT) showed a mass in the pituitary fossa, he was hospitalized in our institution. Endoscopic trans-sphenoidal hypophysectomy and total parathyroidectomy with auto-transplantation were performed, and a giant cervical lipoma was resected. Furthermore, in genetic search, we found a germline frameshift mutation in MEN1 gene leading to the appearance of a new stop codon.ConclusionsWe should bear in mind that giant skin lipoma and multiple abnormal fatty deposits in the pancreas could be complicated with MEN1.

Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis.

Two novel molecular mechanisms with a driver role in pituitary tumorigenesis have been recently identified. They are (a) mutations in the Ubiquitin-Specific Protease 8 (USP8) gene in corticotroph tumors and (b) overexpression of the HMGA1 and HMGA2 genes in most of the pituitary tumors. Moreover, deregulated expression of the non-coding RNAs has been very frequently observed in this neoplasia. The aim of this review is to better elucidate the role, the mechanisms, and the possible clinical impact of these novel alterations in the development of pituitary neoplasia.

Pathological Findings in the Pituitary Glands of Dogs and Cats.

With the exception of classic functional adenomas in dogs and horses, pituitary lesions are infrequently described in the veterinary literature. Approximately 10% of pituitary glands from asymptomatic humans contain abnormalities, but the equivalent proportion in small animals is unknown. Pituitary glands from 136 dogs and 65 cats collected during routine necropsies were examined to determine the prevalence of pituitary lesions and their histopathological diagnosis. Lesions were characterized in sections stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Gordon and Sweet's and reticulin stains, and immunohistochemistry for adrenocorticotropic hormone (ACTH), growth hormone, melanocyte stimulating hormone-α, and prolactin. Pituitary abnormalities were identified in 36 of 136 (26.4%) dogs and 10 of 65 (15.3%) cats. Cystic changes were the most common lesion, occurring in 18 (13.2%) dogs and 8 (12.3%) cats. Pituitary neoplasia was detected in 14.1% (12/85) of middle-aged and old dogs; 1 (1.5%) cat had pituitary nodular hyperplasia. PAS and reticulin stains helped differentiate ACTH-immunoreactive adenomas from hyperplastic nodules: adenomas contained PAS-positive intracytoplasmic granules and loss of the normal reticulin network. One dog had a pituitary carcinoma with infiltration into the thalamus. Other pituitary abnormalities included secondary metastases (2 dogs) and hypophysitis (4 dogs, 1 cat). In most cases, the lesion appeared to be subclinical and could be considered incidental, whereas clinical manifestations were apparent in only 4 dogs (2.9%) and none of the cats with pituitary lesions. Pituitary abnormalities are common in dogs and cats, and their clinical relevance requires further investigation.

The phenotype of SDHB germline mutation carriers: a nationwide study.

Succinate dehydrogenase B subunit (SDHB) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations. Retrospective descriptive study. Retrospective descriptive study in seven academic centers. We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives. Mean age was 44.8 ± 16.0 years. Median duration of follow-up was 2.6 years (range: 0-36). Sixty persons (30.9%) carried the exon 3 deletion and 46 (23.7%) the c.423 + 1G > A mutation. Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas, 4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas. Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors. At study close, there were 111 (57.2%) unaffected mutation carriers. Statistical analyses showed no significant differences in the number and location of head and neck paragangliomas, sympathetic paragangliomas or pheochromocytomas, nor in the occurrence of metastatic disease or other tumors between carriers of the two founder SDHB mutations (exon 3 deletion vs c.423 + 1G > A). In this nationwide study of disease-affected and unaffected SDHB mutation carriers, we observed a lower rate of metastatic disease and a relatively high number of head and neck paragangliomas compared with previously reported referral-based cohorts.

Findings in Historical Control Harlan RCCHan™: WIST Rats from 104-week Oral Gavage Studies.

Vehicle control Harlan RCCHan™:WIST rats were examined to provide control data for subsequent studies. The rats (180 male and 180 female) were dosed daily via oral gavage with reverse osmosis water for up to 104 weeks. At necropsy, body weights and macroscopic findings were recorded and tissues were collected for histopathology. The mean body weight at terminal sacrifice was 687 g for males and 466 g for females. The overall survival rate was 62% for males and 59% for females. The most common cause of death for males and females found dead or examined following unscheduled euthanasia was pituitary neoplasia with an incidence of 13.9% for males and 18.9% for females. Macroscopic and neoplastic and nonneoplastic microscopic findings are presented by body system.

Stress-reactive rats (high-avoidance female rats) have a shorter lifespan than stress-nonreactive rats (low-avoidance female rats)

Although Hatano high-avoidance and low-avoidance rats (HAA and LAA, respectively) have been selectively bred for good versus poor avoidance learning, HAA rats are known to be more reactive to stress than LAA rats. In this study, HAA and LAA female rats were compared during reproductive aging by observing estrous cycles from 8 to 11 months of age. Furthermore, these rats were allowed to live out their natural lifespans, that is, until 24 months of age, in order to compare their survival and to clarify the relationship between reproductive aging and tumor development. At eight months of age, 2 of 35 HAA rats and 20 of 35 LAA rats had abnormal estrous cycles. The median lifespan of the HAA rats (673 days) was shorter than that of the LAA rats (733 days). The incidence of pituitary neoplasia was higher in the HAA rats than in the LAA rats. These results suggest that HAA female rats (i.e., stress-reactive rats) have a shorter lifespan than LAA female rats (i.e., stress-nonreactive rats) and develop pituitary neoplasia, which was one of the causal factors in their accelerated mortality. However, the onset of an age-matched abnormal cycle did not correspond with their lifespan.

Animal models of pituitary neoplasia

Pituitary neoplasias can occur as part of a complex inherited disorder, or more commonly as sporadic (non-familial) disease. Studies of the molecular and genetic mechanisms causing such pituitary tumours have identified dysregulation of >35 genes, with many revealed by studies in mice, rats and zebrafish. Strategies used to generate these animal models have included gene knockout, gene knockin and transgenic over-expression, as well as chemical mutagenesis and drug induction. These animal models provide an important resource for investigation of tissue-specific tumourigenic mechanisms, and evaluations of novel therapies, illustrated by studies into multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome in which ∼30% of patients develop pituitary adenomas. This review describes animal models of pituitary neoplasia that have been generated, together with some recent advances in gene editing technologies, and an illustration of the use of the Men1 mouse as a pre clinical model for evaluating novel therapies.

Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum.

Mutations in genes encoding the subunits of succinate dehydrogenase (SDH) can lead to pheochromocytoma/paraganglioma formation. However, SDH mutations have also been linked to nonparaganglionic tumors. The objective was to investigate which nonparaganglionic tumors belong to the SDH-associated tumor spectrum. This was a retrospective cohort study. The setting was a tertiary referral center. Patients included all consecutive SDHA/SDHB/SDHC and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center who were affected by non-pheochromocytoma/paraganglioma solid tumors. Main outcome measures were SDHA/SDHB immunohistochemistry, mutation analysis, and loss of heterozygosity analysis of the involved SDH-encoding genes. Twenty-five of 35 tumors (from 26 patients) showed positive staining on SDHB and SDHA immunohistochemistry. Eight tumors showed negative staining for SDHB and positive staining for SDHA: a pancreatic neuroendocrine tumor, a macroprolactinoma, two gastric gastrointestinal stromal tumors, an abdominal ganglioneuroma, and three renal cell carcinomas. With the exception of the abdominal ganglioneuroma, loss of heterozygosity was detected in all tumors. A prolactinoma in a patient with a germline SDHA mutation was the only tumor immunonegative for both SDHA and SDHB. Sanger sequencing of this tumor revealed a somatic mutation (p.D38V) as a likely second hit leading to biallelic inactivation of SDHA. One tumor (breast cancer) showed heterogeneous SDHB staining, positive SDHA staining, and retention of heterozygosity. This study strengthens the etiological association of SDH genes with pituitary neoplasia, renal tumorigenesis, and gastric gastrointestinal stromal tumors. Furthermore, our results indicate that pancreatic neuroendocrine tumor also falls within the SDH-related tumor spectrum.

Mutation analysis of inhibitory guanine nucleotide binding protein alpha (GNAI) loci in young and familial pituitary adenomas.

Pituitary adenomas are neoplasms of the anterior pituitary lobe and account for 15–20% of all intracranial tumors. Although most pituitary tumors are benign they can cause severe symptoms related to tumor size as well as hypopituitarism and/or hypersecretion of one or more pituitary hormones. Most pituitary adenomas are sporadic, but it has been estimated that 5% of patients have a familial background. Germline mutations of the tumor suppressor gene aryl hydrocarbon receptor-interacting protein (AIP) predispose to hereditary pituitary neoplasia. Recently, it has been demonstrated that AIP mutations predispose to pituitary tumorigenesis through defective inhibitory GTP binding protein (Gαi) signaling. This finding prompted us to examine whether germline loss-of-function mutations in inhibitory guanine nucleotide (GTP) binding protein alpha (GNAI) loci are involved in genetic predisposition of pituitary tumors. To our knowledge, this is the first time GNAI genes are sequenced in order to examine the occurrence of inactivating germline mutations. Thus far, only somatic gain-of-function hot-spot mutations have been studied in these loci. Here, we have analyzed the coding regions of GNAI1 , GNAI2, and GNAI3 in a set of young sporadic somatotropinoma patients (n = 32; mean age of diagnosis 32 years) and familial index cases (n = 14), thus in patients with a disease phenotype similar to that observed in AIP mutation carriers. In addition, expression of Gαi proteins was studied in human growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH)-secreting and non-functional pituitary tumors. No pathogenic germline mutations affecting the Gαi proteins were detected. The result suggests that loss-of-function mutations of GNAI loci are rare or nonexistent in familial pituitary adenomas.

Multiple Cerebral Hemorrhagic Foci From Metastases During Temozolomide Treatment in a Patient With Corticotroph Pituitary Carcinoma

Pituitary carcinoma is a rare disorder accounting for 0.1–0.5% of pituitary neoplasia (1, 2), with a poor prognosis despite maximal multimodal standard therapies. Temozolomide has been suggested as effective in treating pituitary carcinomas (3–5). Here, we describe the case of a 58-year-old man with active Cushing’s disease due to a huge pituitary tumor. Repeated adenomectomy failed to control the disease. Histology examination revealed a pituitary adenoma, with positive immunostaining for ACTH and a Ki-67 proliferation index of 10%, whereas Crooke’s cells were absent. Ketoconazole and cabergoline treatment being ineffective, conventional radiotherapy (48.6 Gy) was administered. Five years later, magnetic resonance imaging showed a residual pituitary lesion of 28 16 mm with suprasellar extension. The hormonal evaluation indicated persistent severe hypercortisolism. Bilateral adrenalectomy was then performed. Twelve months later, plasma ACTH levels dramatically increased (up to 1250 pg/mL), and the pituitary neoplasm extended to the clivus and the C2 body (Figure 1A). Liver, vertebral, and meningeal lesions were detected (Figure 1B); biopsies of hepatic lesions confirmed ACTH-positive neuroendocrine metastases. Temozolomide (160 mg/m daily for 5 d) was started. Plasma ACTH levels were unaffected; 27 days later, the patient complained of severe headache, blindness, and rigor nucalis. He was admitted to the intensive care unit where severe thrombocytopenia (18 000/mm), a previously reported adverse event of temozolomide (3), and multiple cerebral hemorrhagic foci from metastases were diagnosed (Figure 1, C and D). He died a few months after discharge. This case report emphasizes the risk of hemorrhages associated with temozolomide and the need for careful management in patients with aggressive pituitary tumors.

Succinate Dehydrogenase Deficiency Is Rare in Pituitary Adenomas

Germline mutations in the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are established as causes of pheochromocytoma/paraganglioma, renal carcinoma, and gastrointestinal stromal tumor. It has recently been suggested that pituitary adenomas may also be a component of this syndrome. We sought to determine the incidence of SDH mutation in pituitary adenomas. We performed screening immunohistochemistry for SDHB and SDHA on all available pituitary adenomas resected at our institution from 1998 to 2012. In those patients with an abnormal pattern of staining, we then performed SDH mutation analysis on DNA extracted from paraffin-embedded tissue, fresh frozen tissue, and peripheral blood. One of 309 adenomas (0.3%) demonstrated an abnormal pattern of staining, a 30 mm prolactin-producing tumor from a 62-year-old man showing loss of staining for both SDHA and SDHB. Examination of paraffin-embedded and frozen tissues confirmed double-hit inactivating somatic SDHA mutations (c.725_736del and c.989_990insTA). Neither of these mutations was present in the germline. We conclude that, although pathogenic SDH mutation may occur in pituitary adenomas and can be identified by immunohistochemistry, it appears to be a very rare event and can occur in the absence of germline mutation. SDH-deficient pituitary adenomas may be larger and more likely to produce prolactin than other pituitary adenomas. Unless suggested by family history and physical examination, it is difficult to justify screening for SDH mutations in pituitary adenomas. Surveillance programs for patients with SDH mutation may be tailored to include the possibility of pituitary neoplasia; however, this is likely to be a low-yield strategy.

Pituitary Null Cell Adenoma in a Domestic Llama (Lama glama)

Pituitary gland neoplasia has been reported rarely in camelids. A 12-year-old neutered male llama (Lama glama) presented with lethargy, inappetence and neurological signs. On physical examination, the llama was mentally dull and exhibited compulsive pacing and circling to the left. Complete blood count and serum biochemistry revealed haemoconcentration, mild hypophosphataemia, hyperglycaemia, hypercreatininaemia and hyperalbuminaemia. Humane destruction was elected due to rapid clinical deterioration and poor prognosis. Post-mortem examination revealed a pituitary macroadenoma and bilateral internal hydrocephalus. Microscopically, the pituitary tumour was composed of neoplastic chromophobic pituitary cells. Ultrastructural studies revealed similar neoplastic cells to those previously described in human null cell adenomas. Immunohistochemically, the neoplastic cells were strongly immunoreactive for neuroendocrine markers (synaptophysin and chromogranin A), but did not exhibit immunoreactivity for epithelial, mesenchymal, neuronal and all major pituitary hormone markers (adrenocorticotropic hormone, follicle stimulating hormone, growth hormone, luteinizing hormone, melanocyte-stimulating hormone, prolactin and thyroid stimulating hormone), consistent with the diagnosis of a pituitary null cell adenoma. This is the first report of pituitary neoplasia in a llama.

Genomic Approaches to Problems in Pituitary Neoplasia

The genetic mutations underlying familial syndromes that include pituitary tumors are rarely noted in the majority of sporadic adenohypophyseal adenomas. In contrast, epigenetic dysregulation is common, resulting in differential expression of cell cycle and apoptosis regulators, adhesion molecules, growth factors, and metabolic determinants of cell function. Here, we discuss the diagnostic and therapeutic implications of these findings as the landscape of pituitary tumor defects unfolds.

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated. Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC. Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression. These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.

FamilialSDHAMutation Associated With Pituitary Adenoma and Pheochromocytoma/Paraganglioma

Reports of the coexistence of pituitary adenomas and pheochromocytoma/paraganglioma are uncommon. Recently germline mutations in 2 of the genes encoding succinate dehydrogenase, SDHC and SDHD, were associated with pituitary tumors. Our aim was to determine whether the development of a pituitary adenoma was associated with SDHA mutation. A 46-year-old female presented with carotid body paraganglioma (proband). Subsequently the proband's son was diagnosed with a nonfunctioning pituitary macroadenoma at age 30 years. An immunohistochemical analysis of the resected paraganglioma and pituitary adenoma revealed the loss of succinate dehydrogenase subunit B and succinate dehydrogenase subunit A (SDHA) expression in both tumors, with the preservation of staining in nonneoplastic tissue. Mutation analysis showed a novel SDHA mutation (c.1873C>T, p.His625Tyr) in the germline of the proband as well as in the proband's son. In the paraganglioma of the proband, in addition to the germline mutation, a somatic mutation was observed (c.1865G>A, p.Trp622*). In the pituitary adenoma of the proband's son, loss of SDHA immunoreactivity was paradoxically accompanied by loss of the mutant allele. This is the first report of a pituitary adenoma arising in the setting of germline SDHA mutation. The loss of SDHA protein expression in both the paraganglioma (proband) and pituitary adenoma (proband's son) argues strongly for a causative role of SDHA mutation. This report further strengthens the link between pituitary neoplasia and germline SDH mutation. Although pituitary adenomas appear rare among patients carrying SDH subunit mutations, they may have been underrecognized due to the low penetrance of disease and lack of systematic surveillance.

Pituitary Stem/Progenitor Cells: Their Enigmatic Roles in Embryogenesis and Pituitary Neoplasia - A Review Article

Although the hypothalamus is the master regulator, it is appropriate terming the pituitary gland as the conductor of endocrine orchestra of the human body. The existence of pituitary stem cells in the adult pituitary gland is supported by such findings as postnatal proliferation, differentiation based on environmental alterations, and development of hormoneproducing cells after specific lesions in the pituitary. Stem cell characteristics, including renewal, proliferation abilities, and the presence of stem cells markers, have been demonstrated in adult pituitary cells from mammals. Research into the capacity of “pituitary stem cells” to differentiate in vitro and in vivo will clarify the regulatory mechanisms of these cells. The characteristics of stem cells include self-renewal capacity, lack of specialization, and pluripotency with the ability to differentiate into different cell phenotypes. Adult pituitary cell lineages might have a pituitary stem cell role and the potential participation of these cells in pituitary tumorigenesis. Inevitably numerous questions remain to be resolved, and future challenges are enormous. Therefore, this review provides a comprehensive overview of the motivating recent developments in the pituitary stem cell exploration. The latest expansion in pituitary stem cell research may commence a stimulating period in the pituitary embryology and pathology