Pathology of Crooke Cells in the Human Pituitaries: A Timely Review.

Crooke cell change was first found in the regressed and suppressed corticotroph (adrenocorticotropic hormone-producing) cells, and now is known to occur in pituitary tumors. The tumor cells of this type can be recognized by morphology with immunohistochemistry, and are well known to predict aggressive behavior such as invasion and rare metastases. This is one of the representative neuroendocrine tumors in the pituitary which is now considered to have malignant potential as proposed in the pancreas and gastrointestinal tracts. It is important to emphasize the pituitary tumor pathology such as Crooke cell change for prognostication and appropriate therapies. This review article describes the evolution from the Crooke cells to Crooke cell tumors which is timely along with the Fifth WHO classification 2022 published online.

A case of aggressive pituitary neuroendocrine tumour with extremely rapid progression: possible diagnostic value of TERT promoter methylation.

Most pituitary adenoma/neuroendocrine tumours (PitNET) are histologically benign and grow slowly; however, a subset of these tumours exhibit a more aggressive clinical course characterized by local invasiveness and early recurrence. These high-risk PitNETs often require multiple surgeries and radiation over several years and may eventually acquire carcinomatous characteristics, such as metastasis in some cases. Herein, we report a rare case of PitNET causing oculomotor paresis with extremely rapid recurrence only 3 months after initial surgery, followed by lethal liver metastasis. Preoperative magnetic resonance imaging and intraoperative findings were consistent with typical PitNETs, other than moderate invasion of the cavernous sinus. Pathological examination of the specimen obtained from the initial transsphenoidal surgery revealed increased mitosis and elevated rates of cells positive for Ki-67 and p53. Based on the immunohistochemical assessment for transcription factors and pituitary hormones, the diagnosis was determined to be a silent sparsely granulated corticotroph PitNET with focal malignant transformation. Aggressive features represented by Ki-67 and p53 positivity were more robust in recurrent and metastatic specimens, but hormone immunostaining was decreased. Epigenetic analysis revealed methylation of the telomerase reverse transcriptase (TERT) promoter in the tumour, resulting in TERT upregulation. Despite extensive research, markers for distinguishing extremely aggressive PitNETs have not been determined. Although further analysis is needed, our case demonstrates the possible usefulness of assessing TERT promoter methylation status in the stratification of recurrence risk in extremely high-risk variants of PitNET.

Cathepsin D Inhibits Angiogenesis in Pituitary Neuroendocrine Tumors.

Prolactin and growth hormone can acquire anti-angiogenic properties after undergoing proteolytic cleavage by Cathepsin D and bone morphogenetic protein 1 (BMP-1) into fragments known as vasoinhibins. Little is known about the effect of vasoinhibins on angiogenesis through the involvement of key cleavage enzymes Cathepsin D and BMP-1 in pituitary neuroendocrine tumors (PitNETs, formerly pituitary adenomas). The purpose of this study was to investigate the mechanism of action of Cathepsin D and BMP-1 on angiogenesis in PitNETs compared with that of pro-angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor-2 (FGF2). A total of 43 patients were enrolled in a retrospective analysis and 22 samples were suitable for RNA extraction, including 16 nonfunctional PitNETs and six somatotroph tumors. The mRNA and protein levels of Cathepsin D, BMP-1, VEGF, and FGF2 were compared with those of von Willebrand factor, which was assessed to determine the vascularization of PitNETs. Cathepsin D and FGF2 were significantly correlated with vascularization in PitNETs. Both Cathepsin D and FGF2 are highly involved in angiogenesis in PitNETs, although the effect of Cathepsin D as an anti-angiogenic factor is dominant over that of FGF2 as a pro-angiogenic factor.

FSH-producing macroadenoma associated in a patient with Cushing's disease.

OBJECTIVE AND IMPORTANCE: We encountered a Cushing's disease patient whose surgically removed pituitary macroadenoma was not an ACTH-producing, but rather a gonadotroph adenoma. Cure was obtained only after a tiny microadenoma, overlooked on preoperative studies, was removed by a 2nd operation from a compressed thin normal anterior pituitary gland. CLINICAL PRESENTATION: This 45-year-old woman with Cushing syndrome presented with diabetes mellitus and steroid psychosis. Endocrinological examinations suggested Cushing's disease and MRI disclosed an invasive macroadenoma (22 mm in diameter) with suprasellar extension. INTERVENTION: Despite total removal of the invasive macroadenoma by transsphenoidal surgery, her elevated serum cortisol- and ACTH levels failed to decrease. Histologic study of the surgical specimen disclosed that the tumor was a silent FSH-producing, rather than an ACTH-producing adenoma. Detailed re-evaluation of pre- and postoperative MRI suggested the presence of a 3-mm microadenoma on the left side of a thin compressed normal gland. Venous sampling of the cavernous sinus confirmed this suspicion. In a 2nd operation an ACTH-producing microadenoma was removed from inside the thin remaining compressed normal pituitary gland and endocrinological cure of Cushing's disease was achieved. CONCLUSION: Although double adenomas, being a non-ACTH producing macroadenoma associated with an ACTH producing tiny microadenoma, are extremely rare in patients with Cushing's disease, detailed preoperative MRI evaluation is necessary to avoid missing tiny adenomas hidden in a compressed normal pituitary gland which is the cause of Cushing's disease, especially when a macroadenoma is found in patient with Cushing's disease.

Management of pituitary incidentalomas: according to a survey of pituitary incidentalomas in Japan.

The development of computed tomography (CT) and magnetic resonance imaging (MRI) has resulted in the discovery of unsuspected endocrinologically silent pituitary masses (pituitary incidentalomas). The aim of this study was to clarify the natural history of pituitary incidentalomas in order to establish an appropriate approach to them. Five hundred fifty patients with pituitary incidentalomas were analyzed in this study; 261 patients (47.4%) underwent surgery (surgical group; SG), whereas 289 patients (52.6%) were followed up conservatively (nonsurgical group; NSG) for a mean period of 27.3 months (range, 6-173 months). Clinical and biochemical assessment, CT or MRI of the pituitary, and visual field testing were assessed at baseline and at 6 months and yearly thereafter. A total of 261 tumors in the SG group consisted of 211 (80.8%) nonfunctioning pituitary adenomas and 42 (16.1%) Rathke's cysts. During a follow-up period, of 289 tumors in the NSG group, 209 (72.3%) tumors stayed the same size as before, 35 tumors (12.1 %) increased in size, and 41 tumors (14.2%) decreased in size. The estimated diagnoses of the tumors that increased consist of 28 nonfunctioning pituitary adenomas, 5 Rathke's cyst, and 2 others. The decreased tumors consist of 11 nonfunctioning adenomas, 21 Rathke's cysts, and 3 others. Pituitary incidentalomas usually follow a benign course. We recommend transsphenoidal adenomectomy for a solid mass attached to the optic chiasma estimated to be a pituitary adenoma by MRI. Other patients should be followed up by MRI and biochemical assessment. Especially asymptomatic cystic masses (including Rathke's cleft cysts) could be followed up without surgical intervention because they tend to stay the same size or sometimes be cured spontaneously.

Sellar neuroblastoma mimicking pituitary adenoma.

OBJECTIVE AND IMPORTANCE: Primary intracranial neuroblastomas are rare. They generally arise in the supratentorial parenchyma or paraventricular region. Even more rare are primary sellar neuroblastomas. We present a neuroblastoma that arose in the sellar region and mimicked a non-functioning pituitary adenoma. CLINICAL PRESENTATION: This 33-year-old man presented with bitemporal hemianopsia. MRI showed a sellar mass with suprasellar extension mimicking a pituitary adenoma. INTERVENTION: Because of tumor recurrence and dissemination to the cervical region, he underwent 6 operations and radiosurgery. Detailed histologic examination confirmed the diagnosis of neuroblastoma. Postoperative conventional radiotherapy was effective in reducing the size of the tumor. CONCLUSION: Neuroblastoma should be considered in the differential diagnosis of patients with sellar lesions.

A survey of pituitary incidentaloma in Japan.

OBJECTIVE: The development of computed tomography (CT) and magnetic resonance imaging (MRI) has resulted in the discovery of unsuspected endocrinologically silent pituitary masses (pituitary incidentalomas). The aim of this study was to perform a national survey on pituitary incidentalomas in order to establish an appropriate approach to them. DESIGN AND METHODS: Five hundred and six patients with pituitary incidentalomas were obtained by questionnaire from March 1999 to May 2000 under the auspices of the Ministry of Health, Labor and Welfare in Japan. Two hundred and fifty-eight patients underwent surgery (surgical group), while 248 patients were followed up conservatively for a mean period of 26.9 Months (range 6-173 Months) (non-surgical group). Clinical and biochemical assessment, CT or MRI of the pituitary, and visual field testing by Goldman perimetry were assessed at baseline and 6 Months and Yearly thereafter. RESULTS: Thirty-three patients with pituitary incidentalomas (13.3%) developed tumor enlargement during the mean follow-up period of 45.5 Months. Of 115 estimated non-functioning adenomas, 23 tumors (20.0%) increased during a mean follow-up period of 50.7 Months (range 10-173 Months), while 5 of 94 (5.3%) estimated Rathke's cysts increased in size during follow-up. Pituitary apoplexy occurred in one of 248 patients (0.4%). CONCLUSIONS: Pituitary incidentalomas usually follow a benign course. We recommend transsphenoidal adenectomy for a solid mass attached to the optic chiasma estimated to be a pituitary adenoma by MRI. Other patients should be followed up by MRI every 6 Months for the first 2 Years, and then Yearly.