Lost anatomical structure - pharyngeal pituitary gland (Hypophysis pharyngealis or Erdheim pituitary gland): a review and case report

Ectopic pituitary adenomas are defined by the presence of adenomatous pituitary tissue outside the sella and are distinctly separate from the pituitary gland. They are believed to originate from remaining pituitary cells resting along the path of the embryological formation of the pituitary gland. Ectopic pituitary adenomas can be nonfunctioning or secreting, particularly ACTH, GH, and prolactin secreting. The most common site is by far the sphenoid sinus, followed by the cavernous sinus, clivus, nasal cavity, nasopharynx, suprasellar region, and third ventricle. Sphenoid sinus ectopic pituitary adenomas can manifest themselves through a mass effect such as headache and nasal obstruction if large enough, or with symptoms of hormonal excess. Most case reports deal with Cushing disease, and it is accepted today that the sphenoid sinus must be carefully screened if pituitary MRI is negative in the setting of hypercortisolism (Fig. 18.1). Ectopic pituitary adenomas are generally heterogeneous with areas of T1 hypointensity and T2 hyperintensity, and moderate enhancement after contrast administration. Dynamic MRI can help to differentiate ectopic ACTH-secreting from nonfunctioning ectopic adenomas, the time–intensity curve featuring a rapidly enhancing and slow washout pattern in ACTH adenomas. Involvement of adjacent bone is frequent with large ectopic pituitary adenomas. Pituitary adenomas arising from the pituitary stalk are not stricto sensu ectopic adenomas, since the stalk is normally enfolded by an extension of normal anterior pituitary tissue (Fig. 18.2). An empty sella can coexist with an ectopic adenoma (Fig. 18.3). Ectopic pituitary adenomas must be distinguished from pituitary adenomas invading the sphenoid sinus, sometimes through a tiny hole pierced in the sellar floor best detected by CT (Fig. 18.4). Distinction sometimes can be almost impossible before surgery. Careful analysis of case reports of so-called ectopic pituitary adenomas have revealed that some are in fact intrasellar adenomas invading the sphenoid sinus.

Ectopic pituitary adenomas are exceedingly rare entities that are often misdiagnosed. The resulting delay in diagnosis may be particularly concerning in the case of Cushing syndrome caused by an ectopic adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. Although the total resection of ectopic adenomas results in rapid and durable remission, persistent Cushing syndrome is often associated with permanently damaging invasive procedures and significantly higher risk of mortality. The authors report the case of a 48-year-old man with ACTH-dependent Cushing syndrome. On the morning before surgery, his serum cortisol measured 51 μg/dl, his ACTH level was 195.7 pg/ml, and his urinary free cortisol level was 2109 μg/day. Serum cortisol was not suppressed with the administration of high-dose dexamethasone. Imaging showed separate masses in both the sphenoid sinus and the pituitary gland, complicating the diagnostic process and requiring pathological assessment of both masses. No other abnormalities were found on thoracic, abdominal, or pelvic scans. Gross-total resection of both lesions was accomplished via an endoscopic endonasal transsphenoidal approach. Pathology confirmed an ectopic ACTH pituitary adenoma of the sphenoid sinus and a Crooke hyaline change of the pituitary gland. The patient achieved stable hormonal remission without significant postoperative complications, returned to full activity within 3 months, and remained disease free nearly 1 year after tumor resection. In a systematic literature review, the authors identified 41 cases of ectopic ACTH-secreting pituitary adenomas, including 18 arising in the sphenoid sinus without direct involvement of the sella. Including the case described here, the total number of ectopic ACTH pituitary adenomas arising in the sphenoid sinus was 19, and the total number of ectopic ACTH pituitary adenomas without regard to location was 42. For the 19 patients with adenomas found in the sphenoid sinus, ages ranged from 16 to 76 years, and there were 15 women and 4 men. The mean and median diameters of the resected sphenoid masses were 13.9 and 8 mm, respectively, with a range of 3-55 mm. Seven were microadenomas (< 1 cm). Fifteen of the 19 cases reported serum ACTH and morning cortisol levels, the means of which were 106.7 pg/ml and 32.5 μg/dl, respectively. Gross-total tumor resection was achieved in all patients except one, and in all of them durable hormonal remission of Cushing syndrome was achieved (mean follow-up time 20 months). Ectopic pituitary adenomas are rare but important causes of Cushing syndrome and related endocrinopathies, particularly because of the rapid onset and severity of symptoms with atypical presentation. Ectopic pituitary adenomas, especially those in the nasal cavity, nasopharynx, or paranasal sinuses, are easily misidentified. Any patient presenting with signs and symptoms of Cushing syndrome without any obvious pituitary adenoma or other sources of hypercortisolemia should be thoroughly screened for an ectopic adenoma. However, as with the case presented here, the coincident existence of a sellar mass should not preclude the possibility of an ectopic source. There should be a high degree of clinical suspicion for any mass in the general area surrounding the sella when evaluating Cushing syndrome.

Ectopic Sphenoid Sinus Pituitary Adenoma (ESSPA) with Normal Anterior Pituitary Gland: A Clinicopathologic and Immunophenotypic Study of 32 Cases with a Comprehensive Review of the English Literature

The diagnosis of Cushing disease is based on endocrinological pa-rameters, with no single test being specific. In some patients, dynamic thin-slice sellar magnetic resonance imaging fails to detect a pituitary tumor. The purpose of this study is to investigate the role of ectopic pituitary adenoma in this situation. In a retrospective chart review, 5 patients (6%) with ectopic adenomas were identified in 83 consecutive patients undergoing transsphenoidal surgery for adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas by 1 surgeon. In all 5 patients (all female, 32-41years of age), an exclusively extrasellar ACTH-secreting adenoma was excised. Three adenomas were located in the cavernous sinus, 1 in the sphenoid sinus, and 1 in the ethmoidal cells. Histologically, none of the tumors showed signs of aggressiveness. Three of the 5 adenomas specifically expressed somatostatin receptor 5. In 4 patients with Cushing disease, postoperative remission was obtained, with 1 recurrence after 14months. In the patient with Nelson syndrome, ACTH decreased from >800 to <80pg/mL. Three patients underwent previous surgery elsewhere, including 1 hypophysectomy. In this case, the ectopic adenoma (positive for somatostatin receptor 5) in the ethmoidal cells turned out to be positive on gallium 68 DOTATATE positron emission tomography/computed tomography. The incidence of primarily ectopic ACTH-secreting adenomas in this series was 6%. In cases of negative MRI findings, an ectopic ACTH-secreting adenoma should be taken into account. 68 Ga DOTATATE positron emission tomography/computed tomography may identify ectopic pituitary adenomas. Hypophysectomy should always be avoided in primary surgery for CD.

Background: Ectopic pituitary adenomas (EPAs) are exceedingly rare neoplasms, comprising about 0.5% of all pituitary adenomas. These are often misdiagnosed radiologically, while the correct diagnosis requires high index of suspicion on pathology and immunohistochemistry analysis. Clinical Case: 62-year-old female presented to the ED with transient unilateral visual loss. She denied orbital pain, headache, or motor or sensory deficit. Following unremarkable ophthalmology evaluation, initial MRI brain was suggestive of pituitary adenoma. MRI of the pituitary with gadolinium contrast showed nonenhancing focus of about 1.5 cm within the posterior sphenoid sinus adjacent to a normal-appearing pituitary gland. Lab assessment showed no pituitary hormone excess or insufficiency. ENT evaluation with repeat MRI brain with contrast showed a T2 heterogeneously enhancing hyperintense lesion in the clivus measuring 2.1 x 1.9 x 1.3 cm (transverse, AP and CC, respectively) with bony thinning/erosion of the sellar floor, the posterior wall of sphenoid sinus and dorsal clivus. Patient underwent transnasal transsphenoidal resection of the tumor with sample submitted as clival chordoma. Pathology report showed a 3.3 x 2.7 x 0.9 cm tumor with immunohistochemistry positive for ACTH, FSH, synaptophysin, chromogranin, S100 and cytokeratin while staining negative for GH, LH, TSH, prolactin and epithelial membrane antigen (EMA). Reticulin stain showed loss of reticulin network and Ki-67 labeling index was 1%. Neurosurgery and ENT teams confirmed no gross manipulation of the pituitary gland had been performed and findings supported a diagnosis of ectopic pituitary adenoma. On 6-month follow-up patient continued to do well clinically and MRI showed normal-appearing pituitary gland with no residual or recurrent tumor. Conclusion: EPA is a rare entity with about 133 cases described in literature. EPAs are generally benign, however up to 79% are functionally active and more likely than their sellar counterparts to secrete multiple pituitary hormones. EPAs arise from remnants of embryonic pituitary tissue in the migratory part of the Rathke’s pouch during early fetal development. The most common locations for EPA are in the sphenoid sinus, clivus, nasopharynx, cavernous sinus and suprasellar space and these are often misdiagnosed on initial radiology as neuroendocrine tumors, sino-nasal carcinomas, clival chordomas or even fungal infections. It is vital to consider EPA in the differential diagnosis of tumors removed from the mentioned anatomic locations as establishing the correct diagnosis helps to avoid the significant morbidity associated with treatments employed for other tumors. Reference: Riccio, L., Donofrio, C.A., Tomacelli, G. et al. Ectopic GH-secreting pituitary adenoma of the clivus: systematic literature review of a challenging tumour. Pituitary 23, 457-466 (2020)

Ectopic pituitary adenoma: The lost track of ciurea or the right man at wrong place

Ectopic pituitary adenomas usually occur within sphenoid sinus or nasopharynx, and seldom within the clivus. There is only a single reported example of ectopic adenoma with clinical apoplexy, albeit not from clivus. We report a 78-year-old male with known prostate carcinoma admitted with acute onset of blurred vision, suggestive of apoplexy. Work-up revealed unilateral cranial nerve VI palsy and neuroimaging showed a mass confined to the clivus; sellar region was normal. Preoperative considerations included chordoma, chondrosarcoma, or metastatic prostate carcinoma to bone. Resection was via endoscopic transsphenoidal approach to the clivus. An ectopic null cell pituitary adenoma with bland infarction was identified as the cause of the patient's clinical apoplexy. No antecedent precipitating factors for apoplexy were present; specifically the patient had not received leuprolide preoperatively, a known precipitant of pituitary apoplexy in prostate cancer patients who receive drug. We review the literature on ectopic clival pituitary adenomas, apoplexy in ectopic adenomas, and the link between apoplexy and leuprolide usage.

The pharyngeal pituitary gland is a small embryological remnant derived from Rathke's pouch lying in the mucoperiosteum of the nasopharynx and is almost universally present in humans (1, 2). According to the ultrastructural analysis of the pharyngeal pituitary gland, most of the cells are loaded with secretory granules and display all the characteristics of secretory cells (3). Seven hormone-producing cell types have been identified in the pharyngeal pituitary gland of humans by immunocytochemistry (4, 5). It is generally agreed that there is a low probability that the pharyngeal pituitary gland contributes appreciably to the overall secretion of adenohypophyseal hormones because of its anatomical isolation from the hypothalamus and its small size relative to the adenohypophysis. Similarly, it seems that the gland is not responsible for clinical disorders, except for very rare cases in which the gland is the site of a functioning tumor. We report the case of a 43-year-old female patient with Cushing's disease with an adrenocorticotropin (ACTH)-secreting tumor originating from the pharyngeal pituitary gland. Initially she presented with hypertension and diabetes mellitus. Clinically she had the typical features of Cushing's syndrome. Plasma levels of cortisol were elevated with a loss of diurnal variation (0800 h, 1137 nmol/l; 1600 h, 1007 nmol/l). Plasma ACTH was within the normal range (15 pmol/ l). Both low-dose and high-dose dexamethasone suppression tests showed no suppression of plasma or urinary cortisol levels. Abdominal computed tomography (CT) showed a 2 cm nodule in the left adrenal gland, and sellar magnetic resonance imaging (MRI) revealed a normal pituitary gland (Fig. 1A). Under the impression that there was ACTH-dependent macronodular adrenocortical hyperplasia, bilateral adrenalectomy was performed. The patient was fine for a few months, but then plasma ACTH levels increased to 99.6 pmol/l and generalized pigmentation developed. One year after bilateral adrenalectomy a follow-up MRI was performed suspecting Nelson's syndrome. It revealed a 3:8 2:5 cm sized mass in the nasopharynx and a normal intrasellar pituitary gland (Fig. 1B). The mass was removed and histologically proved to be a typical densely granulated ACTH cell adenoma. Immunohistochemistry revealed that the tumor tissue was composed entirely of ACTH-immunoreactive cells. There were no luteinizing hormone-, follicle-stimulating hormone-, thyrotropin-, growth hormone-, prolactinor chorionic gonadotropin-immunoreactive cells in the tumor tissue. On the operation field, the tumor was located at the junction of the nasopharynx and choana. The consistency was soft and somewhat friable like tumors of the pituitary gland. The anterior wall of the sphenoid sinus was partially destroyed by the tumor, but the mucosa and cavity of the sinus were preserved. After the resection of the tumor and postoperative radiation therapy, plasma ACTH was not detected and the patient has now been treated with glucocorticoid substitutive therapy for 4 years. This case is extraordinary in that Cushing's disease was caused by a rapidly growing ACTH-secreting pharyngeal pituitary tumor. Several problems are apparent in the management of this patient. ACTHdependent Cushing's syndrome was initially diagnosed but no corticotropin-releasing hormone test and no search for an ectopic ACTH source was performed (e.g. thoracic CT scan, inferior petrosal sinus sampling). Inferior petrosal sinus sampling might have helped to identify the ACTH source earlier. The other point was that we missed the nasopharyngeal lesion which was clearly visible on the initial MRI (Fig. 1A). This was probably due to unawareness of the possibility that a pharyngeal pituitary tumor could be the source of ACTH excess. Very little is known about functioning tumors of the pharyngeal pituitary gland. Reviewing the literature, there are only few cases of acromegalic patients and one patient with Cushing's disease that originated from a pharyngeal pituitary tumor (6±8). To our knowledge, this is the first case of Cushing's disease due to a pharyngeal pituitary tumor with a more detailed clinical evaluation. In conclusion, in the evaluation of patients with ACTH-dependent Cushing's syndrome, the presence of a functioning pharyngeal pituitary tumor should be kept in mind. ISSN 0804-4643 European Journal of Endocrinology (2001) 144 181±182

Objective To explore clinical and neuroimagine features, as well as the management of rare ectopic pituitary adenoma in clivus. Methods We reported two cases of ectopic pituitary adenoma verified by histology in the clivus region, reviewed the relevant literature briefly, summarized the clinical and neuroimaging features, along with the management of ectopic pituitary adenoma in clivus. Results Ectopic pituitary adenoma in clivus caused symptoms of endocrinopathy and/or neurological dysfunction. Imaging studies showed an occupying lesion in the clivus. Pituitary adenoma was diagnosed in one patient preoperatively, the other was diagnosed as chordoma. The tumors were microsurgically removed through the trans-sphenoidal route. Tumor was radically removed in one patient, and during one-year follow-up, there was no recurrence. The other was partially resected, and suffered postoperative cerebrospinal fluid rhinorrhea and intracranial infection, follow-up of this patient lost finally. Conclusions The patients with ectopic pituitary adenoma in clivus have endocrinopathy or/and neurological dysfunction, and MRI plays a valuable role in the diagnosis. Although extremly rare, ectopic pituitary tumour needs to be considered in case of an occupying lesion in the clivus. Radical resection of tumor can cure the patient. Key words: Ectopic pituitary adenoma; Clivus

Ectopic pituitary adenoma is a condition characterized by the presence of an adenoma originating from extra-sellar pituitary cell residue from the migration of Rathke's pouch. First described in 1909, ectopic pituitary adenoma is a very rare, largely unknown condition with a challenging diagnosis, that requires proving the absence of communication between the extra-sellar mass and the normal pituitary gland (or any of the intra-sellar contents). Here, we describe the case of a 38-year-old female who presented with symptomatic hyperprolactinemia in whom magnetic resonance imaging revealed a space-occupying mass in the sphenoid sinus with an empty sella turcica. Clinical information coupled with magnetic resonance imaging findings raised suspicion for the diagnosis, which was later confirmed through surgery (showing the absence of a breach in the sellar floor dura), and histology. Given the rarity of such cases, management is not standardized; however, most patients reported in the literature, as in our case, have undergone surgical treatment. This case report aims to provide an additional example to the existing literature on this rare condition, especially when it is associated with an empty sella turcica.

Ectopic pituitary adenomas (EPAs) are rare, and the suprasellar cistern seems to be the most common location. At this time, no detailed original classification, diagnosis, or treatment protocols for suprasellar pituitary adenomas (SPAs) have been described. A 19-year-old man showed visual disturbances and lack of libido for 3years, he suffered a sharp decline in vision with only light perception in the last week. Magnetic resonance imaging scans revealed a large suprasellar cystic lesion with a normal pituitary in the sella turcica. Endocrinological findings showed an extremely high prolactin level of 1250ng/mL. Because of the sharp decline in vision, the patient underwent total removal of the suprasellar lesion using a transfrontal interhemispheric approach. The tumor pedicle originated in the lower pituitary stalk without any connection to the anterior pituitary gland in the sella turcica, while the diaphragma sellae was incomplete. Clinical and endocrinological cure criteria were fulfilled and postoperative pathology confirmed a prolactin-secreting pituitary adenoma. Ectopic suprasellar pituitary adenomas (ESPAs) are extremely rare intracranial extracerebral tumors. SPAs can be classified into three types according to their origin and their relationship with surrounding tissue. Only type III is theoretically a true ectopic, based on previous reports. Thus, ESPAs are uncommon compared to other EPAs. Our case is the first reported case of a type IIa 'E'SPA and the first description of this subtype classification until now. The pars tuberalis may be different from the pars distalis, and each subtype of adenohypophyseal cells may have different migration characteristics, which leads to different proportions of each hormone-secreting subtype in SPAs and EPAs. Transsphenoidal surgery is minimally invasive, but transcranial surgery may remain a universal option for the treatment of suprasellar lesions.

Solitary follicular thyroid carcinoma of the skull base and its differentiation from ectopic adenoma — review, use of galectin-3 and report of a new case

Ectopic pituitary adenomas (EPAs) are rare and their association with orthotopic corticotroph hyperplasia has not been published. The case of a 30-year-old woman with clinical and biochemical evidence of Cushing disease (CD) is reported. A magnetic resonance image obtained preoperatively revealed asymmetrical inhomogeneity of the pituitary gland, which was suggestive of localized adenoma. It also showed what was thought to be a small sphenoid polyp. Postoperatively the latter lesion was found to be an ectopic corticotroph adenoma. The pituitary gland, which was free from any tumor, exhibited diffuse unilateral corticotroph hyperplasia. Clinical, radiological, laboratory, and histopathological findings are presented. A review of the literature and a discussion of possible causes of this unique association between the ectopic corticotroph adenoma and the pituitary hyperplasia are provided.

Ectopic pituitary adenomas are defined by the presence of adenomatous pituitary tissue outside the sella and distinctly separate from the pituitary gland. Ectopic ACTH-secreting pituitary adenomas (EAPAs) are a rare cause of Cushing's syndrome. Detecting these radiologically can prove difficult, in part, due to their typically small size and unpredictable anatomical location. In ACTH-dependent Cushing's syndrome, if, despite comprehensive testing, the source of excess ACTH remains occult (including negative work up for ectopic ACTH syndrome) thought should be given to the possibility of the patient harboring an EAPA. In most cases, ectopic ACTH pituitary adenomas within the sphenoid sinus will manifest with symptoms of hormonal excess, have an obvious sphenoid sinus mass on pre-operative imaging and will demonstrate resolution of hypercortisolism after surgical excision if located and removed. Twenty cases of EAPAs have been reported in the literature to date. This paper will review the current literature on all previously reported EAPAs within the sphenoid sinus in addition to the current case.

Objective To evaluate the clinical and laboratory features of 3 cases of ectopic ACTH pituitary adenoma (EAPA). Methods 3 cases of EAPA confirmed by surgery and pathological,examination have been retrospectively investigated in Peking Union Medical College Hospital since 1994.There were 2 female and 1 male patients with age ranging between 17 ～ 22y. The relevant literatures of EAPA were reviewed.Results The level of plasma ACTH was 126 ～ 207 pg/ml.The result of high dose dexamethasone suppression test was not suppressed in 1 case. The localization of EAPA tumor was suprasellar in 2 cases and left cavernous sinus in lcase. The results of inferior petrosal sinus sampling (IPSS) showed the ratio of inferior petrosal sinus (IPS):Peripheral (P) of plasma ACTH was 10.26 for 1 case with suprasellar EAPA and ＜ 2 for the other 1 case with left cavernous sinus EAPA.The pathological examination confirmed the diagnosis of EAPA with positive immunohistochemical staining of ACTH for all 3 cases after operation.The level of plasma ACTH and urine free cortisol decreased obviously after operation.Conclusions EAPA should be considered in the differential diagnosis for all patients with Cushing 's syndrome.The diagnosis and treatment of EAPA tumor are both difficult to carry out.IPSS may be helpful for the diagnosis of EAPA. Key words: Cushing syndrome; Cushing disease; ACTH syndrome, ectopic; Petrosal sinus sampling