ACTH-producing Pituitary Adenomas Research Articles

Metastatic pituitary tumors: an institutional case series.

Pituitary carcinomas are a rare entity that respond poorly to multimodal therapy. Patients follow a variable disease course that remains ill-defined. We present an institutional case series of patients treated for pituitary carcinomas over a 30-year period from 1992 to 2022. A systematic review was conducted to identify prior case series of patients with pituitary carcinomas. Fourteen patients with a mean age at pituitary carcinoma diagnosis of 52.5 years (standard deviation [SD] 19.4) met inclusion criteria. All 14 patients had tumor subtypes confirmed by immunohistochemistry and hormone testing, with the most common being ACTH-producing pituitary adenomas (n = 12). Patients had a median progression-free survival (PFS) of 1.4 years (range 0.7-10.0) and a median overall survival (OS) of 8.4 years (range 2.3-24.0) from pituitary adenoma diagnosis. Median PFS and OS were 0.6 years (range 0.0-2.2) and 1.5 years (range 0.1-9.6) respectively upon development of metastases. Most patients (n = 12) had locally invasive disease to the cavernous sinus, dorsum sellae dura, or sphenoid sinus prior to metastasis. Common sites of metastasis included the central nervous system, liver, lung, and bone. In a pooled analysis including additional cases from the literature, treatment of metastases with chemotherapy or a combination of radiation therapy and chemotherapy significantly prolonged PFS (p = 0.02), while failing to significantly improve OS (p = 0.14). Pituitary carcinomas are highly recurrent, heterogenous tumors with variable responses to treatment. Multidisciplinary management with an experienced neuro-endocrine and neuro-oncology team is needed given the unrelenting nature of this disease.

LBODP078 Role Of Ire1a-xbp1 Pathway In Rodent Functional Pituitary Tumor Cells.

Abstract Introduction Pituitary tumors (PTs) occur in almost 17% of the population and they represent about 10% of all intracranial tumors. At present, many patients with pituitary tumors suffer from symptoms and complications caused by abnormal hormone production and/or mass effects due to limited treatment options. Therefore, the development of novel therapies is an urgent issue. The inositol requiring enzyme 1a (IRE1a)-X-box binding protein 1 (XBP1) pathway is an important component for the endoplasmic reticulum (ER) stress response. This pathway is activated by immature protein overload in the ER and elimination or repair of such protein can reduce ER stress. This pathway has been reported to regulate cancer cell growth and secretory protein production. The detection of potential XBP1 binding sites in the promoter region of rat GH and mouse POMC similar to those of human genes suggests the involvement of the IRE1a-XBP1 pathway in the production of these hormones and pituitary tumor cell growth. In this study, we aimed to clarify the role of the IRE1a-XBP1 pathway in functional pituitary tumor cells. Methods and Results We conducted in vitro experiments by using rat GH-producing pituitary GH4 cells and mouse ACTH-producing AtT-20 cells as the models of GH- and ACTH-producing pituitary adenomas, respectively. Cell proliferation was measured by WST-8 assay, gene expression levels by qPCR, and protein expression by western blotting, respectively. In GH4 cells, STF08310 (40µM), an IRE1a inhibitor, reduced levels of GH and XBP1 spliced form (XBP1s) mRNA and GH protein with suppressed cell proliferation. In AtT-20 cells, STF08310 (40µM) also suppressed protein expression of proopiomelanocortin (POMC) and cell proliferation. Gene suppression of IRE1a by siRNA and over-expression of XBP1s showed marked reduction and increase of POMC protein, respectively. Conclusion Our findings suggest that the IRE1a-XBP1s pathway would be a possible therapeutic target that has both anti-tumoral and hormone control effects against functional pituitary tumor. Presentation: No date and time listed

PMON102 Utility of the Desmopressin Stimulation Test to Detect Cyclic Cushing's Disease

Abstract Background Arginine-vasopressin stimulates pituitary ACTH secretion after binding to arginine-vasopressin receptor 1B on corticotropes. Desmopressin (DDAVP), which preferentially binds to arginine-vasopressin receptor 2, stimulates the release of ACTH in most patients with pituitary corticotrope adenomas (Cushing's disease, CD), but not in most patients with ectopic ACTH-producing tumors or healthy people. Cyclic CD is characterized by periods of normal or low cortisol and ACTH, interspersed with hypercortisolism. We postulated that the DDAVP stimulation test, with measurement of ACTH and cortisol after a 10 mcg injection of DDAVP, might confirm the presence of an ACTH-producing pituitary adenoma even during periods without hypercortisolemia. Clinical Case A 27-year-old woman was diagnosed with Cushing's disease one year after developing weight gain, striae, intermittent acne, balding, irregular menses, a dorsal fat pad and facial rounding. Pituitary MRI revealed a right-sided 7 mm microadenoma; inferior petrosal sinus sampling confirmed a pituitary source of ACTH. Transsphenoidal resection was performed 6 months later. Histology showed an ACTH-positive adenoma and cortisol levels fell to 33nmol/L (1.2 ug/dL). Ten months later, due to intermittent symptoms, testing confirmed elevated UFC, with midnight cortisol of 565 nmol/L (20.3 ug/dL). Pituitary MRI showed a new right-sided lesion, interpreted as a residual adenoma or postoperative changes. Repeat surgical resection was recommended. She presented to our institution for a second opinion. On evaluation three weeks after recurrent hypercortisolism was confirmed, ACTH was low-normal (11.9 pg/mL, RR 5.0-46.0) and serum cortisol was undetectable. This rapid decrease was thought to signify apoplexy of the remaining adenoma or cyclic Cushing's disease. An MRI excluded apoplexy. However, surgery seemed inappropriate given hypocortisolism. To evaluate for the possibility of cyclic Cushing's disease due to residual adenoma, we performed a DDAVP stimulation test. This showed significant increases in ACTH and cortisol levels from 0 min to a 30-minute peak (ACTH 31.6 to 73.1 pg/mL, 131% increase, nl <50%; cortisol 2.6 to 8.1 mcg/dL [72 - 225 nmol/L], 212% increase, nl <20%). This led to transsphenoidal resection of a right-sided lesion. Cortisol levels were undetectable on post-operative day 3 and pathology showed an ACTH-producing adenoma. One week postoperatively, a repeat DDAVP stimulation test showed an insignificant rise in ACTH, and undetectable cortisol throughout (ACTH 11.1 to 12.4 pg/mL, 12% increase; cortisol <1.0 mcg/dL, 0% increase), which was deemed to indicate successful resection of the residual adenoma. She continues to lose weight and her clinical features of cortisol excess are involuting. Conclusion This case demonstrates how the DDAVP stimulation test can be used to both confirm the presence of ACTH-producing pituitary adenomas and assess the response to surgical resection. It may be particularly useful in the setting of cyclic Cushing's disease when cortisol and ACTH levels are not persistently elevated. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

A method for evaluating the results of brain 18F-FDG PET/CT in the diagnosis of MRI-negative ACTH-producing pituitary adenomas.

A method for evaluating the results of brain 18F-FDG PET/CT in the diagnosis of MRI-negative ACTH-producing pituitary adenomas.

IL-18 expression in clinical human pituitary adenoma.

IL-18 is known as an interferon-inducing factor that belongs to the IL-1 family, and is synthesized as an inactive precursor protein. The present study aims to investigate the expression of IL-18, IL-18R, R and IL-18 binding protein (BP) mRNA in various types of human pituitary tumors, such as adrenocorticotropic hormone (ACTH), growth hormone (GH), prolactin (PRL), thyroid stimulating hormone (TSH)-producing adenomas and non-function adenomas. Pituitary adenoma tissues were obtained during the surgery of 41 patients: nine patients had ACTH-producing pituitary adenomas, nine patients had GH-producing pituitary adenomas, five patients had TSH-producing pituitary adenomas, seven patients had PRL-producing pituitary adenomas, and 11 patients had non-functioning adenomas. The mRNA expression levels of IL-18, IL-18BP, IL-18R and IL-18R were quantified using real-time quantitative PCR. The mRNA expression of IL-18 was significantly higher in ACTH-, GH- and PRL-producing adenomas, when compared to non-function tumors. Similarly, a significantly higher mRNA expression of IL-18BP and IL-18R was observed in ACTH-, GH- and PRL-producing adenomas, when compared with non-functional adenomas. In contrast, no upregulation of IL-18R mRNA was observed in any of the pituitary adenomas. The mRNA levels of IL-18, IL-18BP and IL-18R are significantly elevated in clinical pituitary tumors, such as ACTH-, GH- and PRL-producing adenomas, when compared to non-functional adenomas. These present results suggest the possibility that IL-18 may be involved in the pathogenesis of pituitary adenoma.

Brain 18F-fluorodeoxyglucose PET/CT in localization of MRI-negative ACTH-producing pituitary adenomas

Brain 18F-fluorodeoxyglucose PET/CT in localization of MRI-negative ACTH-producing pituitary adenomas

MON-407 Tumor Control after Radiotherapy and Temozolomide in a Cushing's Disease Patient with Giant Aggressive Pituitary Tumor

Introduction: Typical ACTH-producing pituitary adenomas are benign tumors, microadenomas, successfully treated by neurosurgery. However, 10-20% of Cushing’s disease (CD) patients have macroadenomas, sometimes invasive and aggressive cases with poorer surgical prognosis needing additional approaches. Temozolomide (TMZ), second generation alkylating agent, has been used alone or in combination to other medications/radiotherapy (RTX) for tumor control of aggressive pituitary adenomas and carcinomas. We report one patient with giant aggressive corticotropinoma that presented control tumor with RTX and TMZ after four pituitary surgeries unable to uncontroll tumor growth. Clinical Case: A 18-year-old female patient presented with weight gain, red moon face, supraclavicular fullness, dorsal hump, large purple striae, acanthosis nigricans, secondary amenorrhea, frontotemporal headache, visual impairment and right palpebral ptosis. Hormonal analysis confirmed ACTH-dependent Cushing's syndrome. Pituitary MRI showed the presence of a large selar and suprasellar expansive lesion of 5.2X5.1X4.0 cm with displacement of third ventricle, hypothalamus and lateral ventricles. The patient was submitted to the first neurosurgery (transsphenoidal route) with partial resection. Pathological analyses confirmed pituitary adenoma positive for ACTH, Ki-67 8%, negative p53 and 7 mitoses/10 field of great increase. Subsequent surgery was done by craniotomy with partial resection. Cabergoline 2 mg/week was started but the tumor keeps growing with worsening of visual complaints and increase of cortisol levels. At admission in our center, we planned new surgeries do remove the maximal tumor possible (debulking) and subsequent RTX and TMZ. She was submitted to third surgery by transsphenoidal route and the last surgical procedure by craniotomy. MRI pre-RTX done three months after the 4th surgery showed remnant tumor of 3.5X3.0X3.0 cm. Fractioned stereotaxic radiotherapy was done with linear accelerator in a total of 54 Gy divided in 30 sessions. TMZ was initiated in a dose of 150 m2/day, cycles of five days/month, using for 14 months. Pituitary MRI 3, 6 and 10 months after TMZ showed a small reduction of tumor with increase of intratumor cystic areas. Conclusion: The combined use of TMZ and radiotherapy is an important approach for the treatment of rapidly growing, aggressive pituitary ACTH-secreting tumors resistant to conventional treatment.

MON-330 Cushing Syndrome Secondary to Neuroendocrine Lung Carcinoma: To X-Ray or Not to X-Ray?

Introduction Adrenocorticotropic hormone (ACTH) overproduction leads to hypercortisolism and Cushing syndrome (CS). We describe a rare case of ectopic ACTH secretion (EAS) secondary to a primary lung neuroendocrine tumor (NET). Case description A 30-year-old female presented with fatigue, muscle weakness and poor memory. She had associated weight gain, hair loss and amenorrhea. She had a history of recent microprolactinoma treated with Cabergoline. Vital signs were normal aside from mild hypertension. Physical examination revealed facial acne, posterior neck fullness, hirsutism and abdominal striae. Morning cortisol was 53.6 (4.3-22.4mcg/dl) and ACTH was 147 (0-46pg/ml). A midnight salivary cortisol level was 2.54 (<0.09mcg/dL), urine 24-hour cortisol was 4405 (4-55mcg/24h) and potassium was 3.3 (3.5-4.5mmol/L). Her glycosylated hemoglobin was 6.4% and insulin like growth factor was 163 (53-331 ng/ml). A low-dose 1mg and a high-dose 8mg dexamethasone suppression test failed to suppress cortisol confirming EAS. A review of brain magnetic resonance imaging (MRI) from Vietnam at the time of diagnosis and post treatment did not reveal a microprolactinoma indicating possible misdiagnosis. Given the high clinical suspicion for EAS, a chest x-ray was obtained first which identified two left upper lobe lung masses. As such, inferior petrosal sinus sampling (IPSS) was avoided. A computed tomography guided lung biopsy confirmed well-differentiated NET, staining positive for synaptophysin, chromogranin and pancytokeratin. The Ki-67 proliferation index was low <2%. Positron emission tomography showed hypermetabolic activity within the lung masses, left hilum and mediastinal lymph nodes. Octreotide scan showed increased radiotracer uptake within the lung masses and corresponding lymph nodes. She underwent wedge resection of her left upper lobe and was treated with a steroid taper perioperatively. She required intermittent insulin therapy for hyperglycemia. Post-operatively, her ACTH, blood glucose and cortisol normalized. She remains asymptomatic at 6-month follow up. Conclusion ACTH-producing pituitary adenomas result in most cases of ACTH-dependent CS and 10-15% result from EAS. EAS must be suspected if a pituitary adenoma is not visible on MRI. Challengingly, up to 40% of ACTH-dependent CS from a pituitary source may not have a visualizable adenoma and IPSS is invasive. Although bronchopulmonary NETs are usually non-functional and 1-2% cause CS, studies have shown that pulmonary NETs are up to 4cm in size. As such, we began with a simple chest-xray looking for an ectopic source rather than subjecting our patient to IPSS as guidelines suggest. Hypokalemia can be a clue to EAS causing mineralocorticoid receptor activation. Our diagnosis was made and fortunately a well-differentiated localized tumor with low Ki-67 mitotic index yielded the positive outcome seen in our patient.

How self-perceived disease burden and psychosocial impairment is influenced by coping styles in patients with Cushing's disease

Introduction: Cushing's disease is known to disturb psychosocial well-being and health-related quality of life (HRQoL) for years after treatment and normalization of cortisol levels. As the reasons for long-lasting impairments are yet unclear, we conducted a postal survey on postsurgical after-care, psychosocial impairment and coping strategies in patients after surgical treatment of CD. Methods: A set of self-assessment inventories including questionnaires on depression (Hospital Anxiety and Depression Scale, HADS), HRQoL (Short Form SF-36, Tuebingen Cushing's Disease CD-25) and coping style (Freiburg Questionnaire on Coping with Illness, FKV-LIS) was sent to all patients with CD who had been operated upon ACTH-producing pituitary adenomas at the neurosurgical departments of Erlangen, Tuebingen and Essen during the last years. They also received a self-developed questionnaire on disease duration, treatment, self-perceived disease burden and after-care. For the present analysis the complete Erlangen sample of 101 patients (21 male, 80 female) has been regarded. Results: Patients were questioned on average 6.2 years after diagnosis of CD and were of a mean age of 45.3 years. 5 patients reported elevated cortisol serum levels, 44 normal and 21 too low levels, while 31 patients did not know their current cortisol levels. Psychological HRQol was severely impaired (mental sum score SF-36 > 2 SD below mean) in 28.7% of the patients, while manifest depression (HADS) was present in 11.9% and anxiety (HADS) even in 22.8% of the investigated patients. Interestingly, maladaptive coping (FKV-LIS subscales „depressive coping“ and „minimizing importance“) correlated significantly with more self-assessed present disease burden, severity of depression and anxiety and impaired psychological HRQoL. Conclusion: Even 6 years after diagnosis patients with CD suffer from considerable impairment of psychosocial well-being. Its severity is, however, clearly influenced by the patient's way of dealing with the illness. These results are in line with studies with other patient cohorts with diseases ranging from multiple sclerosis to low back pain. Therefore, it should be considered to add psychological trainings of positive coping styles to the treatment strategy of CD.

The Relevance of ACTH Monitoring during Surgical Management of Cushing's Disease

Introduction: The treatment of choice for ACTH-producing pituitary adenomas is complete removal using a transsphenoidal approach. However, even after gross total removal, high levels of ACTH and cortisol can be occasionally found in the first postoperative days. These hormonal findings could lead to a misdiagnosis of surgical failure with a later cortisol and ACTH drop. We propose an evaluation of intraoperative plasma ACTH and its correlation to hormonal postoperative findings to help improve the prediction of surgical success in patients with ACTH-producing adenomas.

In Brief

The diagnosis of Cushing's syndrome still represents a challenge in clinical endocrinology. Because untreated Cushing's syndrome is associated with significant morbidity and mortality, and because nearly all of the physical and psychologic features are reversible with curative surgical therapy, accurate diagnosis of this endocrine disorder is essential.The source of steroid excess in Cushing's syndrome is classified as either ACTH-dependent or ACTH-independent (adrenal autonomy). The former category is the most frequent (80%) and encompasses ACTH-producing pituitary (Cushing's disease) or ectopic tumors, most commonly bronchial carcinoids. Whereas Cushing's disease is four to sixfold more prevalent in women, ectopic ACTH secretion is more common in men, largely due to the higher incidence of lung cancer in males.41 Cushing's disease accounts for 70% to 80% of ACTH-dependent disease, whereas 15% to 20% is caused by ectopic sources. Adrenal tumors autonomously producing glucocorticoids are found in 20% of patients with Cushing's syndrome, and this group comprises discrete and multiple adrenal lesions, such as adenomas, carcinomas, or micronodular and macronodular hyperplasia.54Although little is known about the pathogenesis of adrenal tumors, the origin of ACTH-producing pituitary adenomas has been investigated extensively. Although the proliferation of ACTH-secreting cells was initially hypothesized to be a possible consequence of stimulation by excess hypothalamic corticotropin-releasing hormone (CRH), the monoclonal origin of most ACTH-producing pituitary tumors strongly argues against this possibility.4 Hence, it is currently believed that the acquisition of a somatic mutation leading to a growth advantage accounts for these corticotroph adenomas, but, unlike the mutations in Gsα-proteins described in many growth hormone-producing adenomas, a specific mutation has not yet been described. Rare cases of ectopic secretion of CRH resulting in the oversecretion of pituitary ACTH have been reported.2The work-up for suspected endogenous glucocorticoid excess is divided into two consecutive steps (Table 1): (1) screening and confirmatory tests for the diagnosis of clinically relevant endogenous glucocorticoid excess, and (2) the localization (differential diagnosis) of the source of hormone excess. A variety of tests have been used for the screening, diagnosis, and localization of Cushing's syndrome, each associated with specific advantages and disadvantages.20 The currently utilized tests are summarized in Table 1.

Diagnosis аnd neurosurgical treatment of Cushing’s disease

The informing of existing diagnostic methods was determined. The optimal algorithm for Cushing’s disease diagnostics was developed. The efficacy of neurosurgical treatment of pituitary adenomas at Cushing’s disease was estimated. 80 clinical cases of Cushing’s disease were analyzed. The adequate approaches to neurosurgical treatment of ACTH-producing pituitary adenomas depending on their size and propensity to invasion were certain.

The 83,557insA variant of the gene coding 11β-hydroxysteroid dehydrogenase type 1 enzyme associates with serum osteocalcin in patients with endogenous Cushing's syndrome

Objective The type 1 and type 2 isoenzymes of the 11β-hydroxysteroid dehydrogenase (HSD11B) play an important role in the prereceptor regulation of glucocorticoid bioavailability and action. The potential importance of gene variants coding HSD11B has not been previously evaluated in patients with endogenous hypercortisolism. The aim of the present study was to explore presumed associations between the 83,557insA variant of the HSD11B1 gene and circulating hormone concentrations, bone turnover and bone mineral density (BMD) in patients with endogenous Cushing's syndrome (CS). Patients and methods Forty one patients with ACTH-producing pituitary adenomas (Cushing's disease—CD), 32 patients with cortisol-producing adrenal tumors (ACS) and 129 healthy control subjects were genotyped for the 83,557insA variant of the HSD11B1 gene using restriction fragment length analysis. BMD was measured by dual-energy X-ray absorptiometry. Serum cortisol, ACTH, osteocalcin (OC) and C-terminal crosslinks (CTX) of human collagen type I (C-telopeptide) were measured by electrochemiluminescence immunoassay. Results No statistically significant differences were found in the allelic frequencies of the 83,557insA polymorphism among patients with CD, ACS and healthy controls. Among all patients with CS, heterozygous carriers of the 83,557insA had significantly higher serum OC as compared to non-carriers. Patients with ACS carrying the 83,557insA variant had higher plasma ACTH concentrations compared to non-carriers. The 83,557insA variant failed to associate with BMD in patients and controls. Conclusions Our present findings indicate that the 83,557insA variant of the HSD11B1 gene may influence serum markers of bone turnover, but not BMD in patients with endogenous Cushing's syndrome.

Possible Relevance between Prohormone Convertase 2 Expression and Tumor Growth in Human Adrenocorticotropin-Producing Pituitary Adenoma

Methods for preoperative diagnosis of prohormone convertase 2 (PC2)-positive ACTH-producing pituitary adenomas (APPAs) have not been established. Also, their characteristics are not evident. This study was designed to understand the meaning of plasma alphaMSH levels and the role of cell proliferation-signaling molecules in PC2-positive APPAs. Nineteen human APPAs (four males and 15 females) were examined for the expression of PC2, phosphorylated ERK1/2, phosphorylated Akt1/2/3 (p-Akt) and receptor tyrosine kinases. alphaMSH was measured in extracted plasma from 17 APPA patients and 30 healthy volunteers. Nine adenomas (47.4%) were immunopositive for PC2 and were large and invasive in nature. In all normal controls and eight PC2-negative cases, plasma alphaMSH was undetectable, whereas in four PC2-positive cases, it was detected at abnormally higher levels. Eight adenomas (42.1%) were immunopositive for both PC2 and p-Akt, and seven others (36.8%) were immunonegative for both, suggesting significant coexpression of PC2 and p-Akt in tumors. Quantitative RT-PCR revealed that PC2 expression is associated with phosphorylation of Akt but not with its gene expression. Most APPAs expressed receptor tyrosine kinases, but membrane-bound receptors could not be identified. Our study suggests that PC2 expression and Akt phosphorylation are related at the molecular level, resulting in a change in cell cycle and an increase in pituitary adenoma size. An elevation of plasma alphaMSH could conjecture the activation of the phosphatidylinositol 3/Akt cascade in PC2-positive APPAs and may become a valuable clinical marker of tumor growth in Cushing's disease.

Facial Metrics in Children with Corticotrophin-Producing Pituitary Adenomas Suggest Abnormalities in Midface Development

Tumors of the hypothalamic-pituitary unit have been linked to genetic syndromes that are associated with midfacial abnormalities. We hypothesized that mutations of genes that affect the development of the face (and consequently of the anterior pituitary) may be present in children with ACTH-producing pituitary adenomas, and if this is true then facial measurements would be different from those predicted by parental features. We studied 20 children with corticotropinomas and a control group and their parents. All facial measurements were expressed according to standard deviation scores. Significant differences were seen between the children with pituitary adenomas and their parents for vertical facial height measures: nasal length (p < 0.001), lower facial height (p < 0.03) and overall facial height (p < 0.01). We conclude that some of the indices of midline craniofacial development, in particular those affecting the vertical axis, are different in children with corticotroph adenomas producing ACTH.

No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.

The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing's disease

✓ Cushing's syndrome can present a complex problem of differential diagnosis. Of cases in which hypercortisolemia results from an adrenocorticotropic hormone (ACTH)–dependent process, approximately 80% are due to a pituitary adenoma (Cushing's disease [CD]), 10% are due to adrenal lesions, and the remaining 10% are secondary to ectopic ACTH secretion. For patients with CD, surgical removal of the pituitary adenoma is the treatment of choice. Thus, localization of the source of ACTH secretion is critical in guiding timely treatment decisions. Inferior petrosal sinus sampling (IPSS) is considered to be the gold standard for confirming the origin of ACTH secretion in patients with Cushing's syndrome. The authors present an overview of IPSS—both the technique and its interpretation—as well as a summary of recent studies. A number of other techniques are discussed including sampling from the cavernous sinus, the jugular vein, and multiple sites to aid the diagnosis and lateralization of ACTH-producing pituitary adenomas. Management is best undertaken by a comprehensive multidisciplinary team taking into account the results of all the biochemical and imaging studies available, to provide the best advice in patient treatment decisions.

The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing's disease

Cushing's syndrome can present a complex problem of differential diagnosis. Of cases in which hypercortisolemia results from an adrenocorticotropic hormone (ACTH)-dependent process, approximately 80% are due to a pituitary adenoma (Cushing's disease [CD]), 10% are due to adrenal lesions, and the remaining 10% are secondary to ectopic ACTH secretion. For patients with CD, surgical removal of the pituitary adenoma is the treatment of choice. Thus, localization of the source of ACTH secretion is critical in guiding timely treatment decisions. Inferior petrosal sinus sampling (IPSS) is considered to be the gold standard for confirming the origin of ACTH secretion in patients with Cushing's syndrome. The authors present an overview of IPSS--both the technique and its interpretation--as well as a summary of recent studies. A number of other techniques are discussed including sampling from the cavernous sinus, the jugular vein, and multiple sites to aid the diagnosis and lateralization of ACTH-producing pituitary adenomas. Management is best undertaken by a comprehensive multidisciplinary team taking into account the results of all the biochemical and imaging studies available, to provide the best advice in patient treatment decisions.

Metallothionein Isoform 3 Gene Is Differentially Expressed in Corticotropin-Producing Pituitary Adenomas

In order to search for candidate genes related to pituitary adenoma aggressiveness, the present investigation was intended to compare the mRNA expression profile from a pool of four nonfunctional pituitary adenomas (NFPA) with a spinal cord metastasis of a nonfunctional pituitary carcinoma (MNFPC). The metallothionein isoform 3 (MT3) gene was differentially expressed in nonfunctional adenomas in comparison to the metastasis of nonfunctional carcinoma. A microarray dataset comprising 19,881 probes was employed for comparing expression profiles of a spinal cord metastasis of a nonfunctional pituitary carcinoma with a pool of four nonfunctional pituitary adenomas. RT-qPCR confirmed the microarray findings and was used to investigate MT3 mRNA gene expression in tumor samples of a series of 52 different pituitary adenoma subtypes comprising 10 corticotropin (ACTH)-producing, 18 growth hormone (GH)-producing, 8 prolactin (PRL)-producing, and 16 nonfunctional adenomas. Microarray data analysis by GeneSifter program unveiled Gene Ontology terms related to zinc ion-binding activity closely related to MT3 function. MT3 mRNA expression was statistically significantly higher in ACTH-producing pituitary adenomas and in nonfunctional pituitary adenomas in comparison to the other pituitary adenoma subtypes. The more abundant expression of this gene in ACTH-producing pituitary adenomas suggests that MT3 could be related to distinct pituitary cell lineage regulating the activity of some transcription factor of importance in hormone production and/or secretion.

Co-localization of Honeycomb Golgi and ACTH Granules in a Giant ACTH-Producing Pituitary Adenoma

We document the co-localization of honeycomb golgi and ACTH-immunopositive granules in giant ACTH-producing pituitary adenoma cells. A 42-yr-old woman presented with Cushing's disease and a giant adenoma that invaded the sphenoid and cavernous sinus. She underwent transsphenoidal surgery followed by radiation therapy. Some of the adenoma cells were ACTH-positive and upon electron-microscopic (EM) study most were found to contain sparse granules and no type-I filaments. In many cells the golgi complex had undergone partial or total vacuolar transformation that resulted in the appearance of honeycomb golgi. Immunohistochemical study of mirror sections of portions containing cells with honeycomb golgi revealed that the cells with honeycomb golgi showed ACTH-immunopositivity. Honeycomb golgi, which was formerly considered a morphological marker of gonadotroph adenomas in females, has previously been identified in large ACTH-producing pituitary adenomas but there has been no direct evidence that individual cells with honeycomb golgi are cells that produce ACTH. Our immunohistochemical documentation of ACTH-immunoreactivity in individual adenoma cells containing honeycomb golgi clearly confirms that honeycomb golgi is not confined only to gonadotroph adenomas in females. Rather, the existence of honeycomb golgi in cells of other adenoma types may be due to their low hormone production and/or to disturbances in the regulation of the exocytotic pathway.