Development and validation of the disease-specific QOL-CD quality of life questionnaire for patients with Cushing's disease.

OBJECTIVE: Cushing's disease (CD) patients experience a range of debilitating symptoms that impair quality of life (QOL) as assessed using generic measures. These generic measures are inadequate to capture the disease-specific burden of illness. The development of the CD-specific QOL-CD measure of QOL using items generated by CD patients and healthcare professionals will provide a holistic assessment of patient outcomes and efficacy of novel therapies. METHODS: A total of 96 CD patients participated. A list of 177 items (version 1.0) was generated by treated CD patients (n = 9), caregivers (n = 2), healthcare providers (n = 7), and results of a MEDLINE search. Item reduction was performed through content analysis and dual scaling. Patients' rating of importance was incorporated to reduce to a final version of 56 items (version 3.0). Evidence for test-retest reliability was sought through administering the QOL-CD 1 week apart and Cronbach's α of each subscale. Construct validity was assessed through extreme group analysis and comparison with the normal Canadian population. Concurrent validity was sought through comparison with the SF-36, Functional Assessment of Cancer Therapy-Brain (FACT-Br), and Karnofsky Performance Status (KPS). Perioperative testing was conducted on CD patients (n = 25) against nonfunctioning pituitary adenoma controls (n = 25) through pre- and postoperative testing. RESULTS: A total of 96 CD patients (86 females and 10 males; mean age 45.23 ± 14.16 years) participated. The QOL-CD was feasible (mean completion time 15 minutes, with 70% believing accurate capture of QOL), reliable (CD 1 week apart: r = 0.86; control 1 week apart: r = 0.83; Cronbach's α: general health = 0.73, emotional health = 0.85, physical health = 0.78, mental status = 0.82, social well-being = 0.63, medical treatment = 0.54), and valid (extreme group testing p < 0.001; SF-36 and QOL-CD general health: r = 0.56, social well-being: r = 0.21, emotional health: r = 0.61, total score: r = 0.58; FACT-Br and QOL-CD physical health: r = 0.47, social well-being: r = 0.21, emotional health: r = 0.34, total score: r = 0.68; KPS and QOL-CD general health: r = 0.32, total score: r = 0.14). Perioperative testing of CD patients (n = 25) demonstrated improvement in all subscales postoperatively, with a significant difference in emotional health (p < 0.001) and physical health (p < 0.001). CONCLUSIONS: The QOL-CD questionnaire has been developed for patients with CD and has demonstrated evidence for validity and reliability.

Current status on histological classification in Cushing's disease.

INTRODUCTION: Managing Cushing's disease remains a challenge. Surgery is the first option of treatment and it offers a high success rate. Even in cases where biochemical remission is not achieved, it is crucial to obtain surgical tissue for morphological diagnosis because the therapeutic approach can be modified according to the findings. MATERIALS AND METHODS: A literature search was performed using PubMed for information regarding pathology and Cushing's disease. RESULTS: The histopathological features found in the pituitary gland of patients with Cushing's disease are presented. CONCLUSION: Different subtypes of ACTH-producing pituitary tumors are recognized and characterized. The significance of finding a normal pituitary gland with or without Crooke's changes is also discussed.

Endoscopic versus microscopic approach for surgical treatment of acromegaly.

Transsphenoidal surgery in the setting of acromegaly is quite challenging due to increased soft tissue mass, bony overgrowth, and bleeding. There is a debate on the endoscopic versus microscopic approach for these patients. The purpose of our study is to compare the outcomes for acromegaly after transsphenoidal surgery using both techniques. Retrospective review of 65 acromegalic patients who underwent transsphenoidal surgery in our department. Clinical remission was defined as resolution of typical acromegalic symptoms. Radiological resection was defined by volumetric criteria, and biochemical remission was defined as by the 2010 consensus on the criteria for remission of acromegaly. There was no significant difference in age, preoperative endocrine status, percent of macro adenomas, suprasellar, or infrasellar extension between both groups. Patients were assigned to both groups based on our existing referral pattern. Endoscopic approach was performed in 42 patients, while the microscopic approach was performed in 23 patients. No significant difference in remission rates was found between both groups (45.2 vs. 34.7 %, p = 0.40). The endoscopic group, however, had a significantly higher rate of gross total resections (61 vs. 42 %, p = 0.05). There was also a trend towards higher rates of gross total resections when cavernous sinus was present (48 vs. 14.2 %, p = 0.09). Postoperative diabetes insipidus occurred more in microscopic patients (34.7 vs. 17 %, p = 0.05), otherwise there was no significant difference in rates of complications. The median follow-up period was 56.6 months (range 6-156, mean 66.1). There is no significant difference in the rates of biochemical remission between the endoscopic and microscopic techniques. The endoscope technique, however, seems to be superior in achieving gross total resection especially with tumors invading the cavernous sinus.

Impact of technique on cushing disease outcome using strict remission criteria.

BACKGROUND: Cushing disease (CD) constitutes a challenging condition for the pituitary surgeon. Given the variety of factors affecting outcomes in CD, it is uncertain whether the newer endoscopic technique improves the results of surgery. METHODS: A review was conducted of CD cases at our institution between 2000 and 2010. Analysis was done to: determine if surgical technique had an effect on outcome, identify the predictors of outcome and provide details of failed cases. Remission was defined as normal postoperative 24-hour urinary free cortisol (24-h UFC), suppression of morning serum cortisol to <50 nmol/L after 1mg of dexamethasone or being dependent on steroid replacement. RESULTS: Forty-two patients met our inclusion criteria. Average follow-up period was 33 months. There were 15 macroadenomas and 27 microadenomas. Seventeen patients had an endoscopic transsphenoidal surgery and twenty-five patients had a microscopic transsphenoidal procedure. Long-term overall remission was achieved in 26 (62%) patients. There was no significant difference in remission rates between the two techniques (p value 0.757). Patient's subjective symptomatic improvement and drop of morning serum cortisol in the postoperative period to less than 100 nmol/L correlated with long-term remission (p value 0.0031 and 0.0101, respectively) while repeat surgery was the only predictor of the lack of postoperative remission (p value 0.0008). CONCLUSIONS: Revision surgery predicted poor remission rate for CD. Within the power of our study size, there was no difference in outcome between the endoscopic and microscopic approaches. Surgical outcomes should be reviewed in association with remission criteria used in a study.

Outcomes of surgically treated giant pituitary tumours.

OBJECTIVE: To evaluate the outcomes of patients with giant pituitary tumours (GPTs) who underwent a purely binasal endoscopic transsphenoidal surgery (BETS) and compare their outcomes with those achieved through craniotomy and microscopic transsphenoidal surgery (MTS). METHODS: Seventy-two consecutive patients with GPTs (greater than 10 cm3 in volume) who were treated surgically with BETS, craniotomy, or MTS from October 1994 to July 2009 were reviewed for clinical outcomes, degree of tumor resection, recurrence rates, and surgical complications. RESULTS: The BETS group had significantly better mean reduction of tumor volume (91%) than the craniotomy (63%, p = 0.001), and the MTS (63%, p = 0.010) groups. Gross total resection rates were also higher for BETS patients than for craniotomy patients (p = 0.010). Improvements in vision and headaches were noted in 96% and 100% of patients in the BETS group, respectively; these rates were similar to those in the craniotomy and MTS groups. Of the four patients with hormone-secreting tumours in the BETS group, three remained in remission. The median length-of-stay (four days) for the BETS group was shorter (p = 0.010), and surgical complications were less frequent (p = 0.037) and less severe compared to the craniotomy group. There were no differences in the recurrence rates: 79% percent of patients in the BETS group, 69% in the craniotomy group, and 79% in the MTS group were recurrence free at last follow-up (p = 0.829). CONCLUSIONS: Treatment of GPT with BETS offers excellent oncologic and clinical outcomes and can frequently obviate the need for craniotomy in these patients.

Bronchial carcinoid tumors metastatic to the sella turcica and review of the literature.

We review here the literature on neuroendocrine neoplasms metastatic to the pituitary and present an example of the disease. Metastasis of bronchial carcinoid tumors to the sellar region are rare. Herein, we describe the case of a 63-year-old woman who presented with constant cough and headaches. She had previously been operated for carcinoid tumor of the lung. During the preoperative investigation, a CT scan of the head revealed a sellar mass. Six months after a left lower lobectomy, the sellar lesion was removed by transsphenoidal surgery. The two tumors were evaluated by histology, immunohistochemistry and electron microscopy. Both showed identical morphologic features, those of carcinoid tumor. Immunohistochemistry revealed immunoreactivity for the endocrine markers, synaptophysin and chromogranin, as well as CD-56, serotonin, bombesin and vascular endothelial growth factor. The sellar neoplasm showed nuclear immunopositivity for thyroid transcription factor-1, supporting the diagnosis of a metastatic bronchial carcinoid tumor. In conclusion, this is the first report of a serotonin- and bombesin-immunopositive atypical bronchial carcinoid tumor metastatic to the sella.

Folliculo-stellate cells of the human pituitary as adult stem cells: examples of their neoplastic potential.

Two unique, formerly unrecorded sellar neoplasms were observed in two women of 60 and 63 years of age. One lesion consisted of small epithelial cells and the other was a large-cell oncocytic tumor, yet they had the same simple cytoplasmic organization with dominance of polyribosomes and a sprinkle of glycogen. Striking markers shared by the neoplasms: (1) network of typical pituitary follicles, and (2) unexpected similarity to fetal human pituitary tissue at different gestational ages of 6 and 10-12 weeks. The latter showed appreciable endocrine differentiation. The assumed parent cell is the folliculo-stellate cell as pluripotent adult stem cell.

Cushing Disease Presenting as Primary Psychiatric Illness: A Case Report and Literature Review.

We report the case of a woman with long-standing refractory depression and psychotic features who was eventually diagnosed with Cushing disease. After surgical treatment of a pituitary adenoma, she experienced gradual psychiatric recovery and was eventually able to discontinue all psychotropic medication. We review the psychiatric components of Cushing disease, implications of psychiatric illnesses for the treatment and prognosis of Cushing disease, and potential pathophysiological mechanisms linking glucocorticoid excess to psychiatric illness.

Juxtaposition of an ectopic corticotroph adenoma of the sphenoid sinus with orthotopic intrasellar corticotroph hyperplasia in a patient with Cushing disease. Case report.

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.

A double pituitary adenoma presenting as a prolactin-secreting tumor with partial response to medical therapy. Case report.

Double pituitary adenomas are difficult to recognize pre-operatively as only a single mass may be appreciated on imaging. We present herein a giant prolactin-secreting pituitary adenoma in a middle-aged man that had responded partially to dopamine agonist therapy. The excised specimen demonstrated a double adenoma. The prolactin-producing one displayed the expected morphological changes resulting from medical therapy, while the other, a gonadotroph adenoma, did not. The failure of tumor shrinkage can be attributed to the presence of a double adenoma, a previously unreported cause of failure of medical therapy in prolactinoma.

Use of temozolomide in aggressive pituitary tumors: case report.

OBJECTIVE: The management of aggressive pituitary macroadenomas represents a challenge to neurosurgeons. These tumors are very difficult to treat, owing mainly to their invasive nature, thus resulting in incomplete resections and propensity for recurrence. Multiple surgical procedures (transsphenoidal, transcranial, or a combination of both) are the first line management, followed by radiotherapy and chemotherapy. CLINICAL PRESENTATION: Three cases of patients with pituitary adenomas who underwent temozolomide treatment are presented. The first 2 patients had corticotroph macroadenoma of the Crooke's cell variant. Deterioration occurred in both cases despite multiple surgeries and adjuvant therapy. The third patient had a glioblastoma multiforme with an incidental pituitary tumor. INTERVENTION: All 3 patients had temozolomide administered orally on the first 5 days of a 28-day cycle for 12 cycles. Magnetic resonance imaging, endocrinological, and clinical follow-up were performed at monthly intervals. CONCLUSION: The marked improvement in clinical state of the first 2 patients accompanied by radiological evidence of tumor shrinkage in all patients demonstrates the potential use of temozolomide in treating aggressive pituitary macroadenomas. The usefulness of temozolomide in aggressive pituitary adenomas should be studied in larger trials.

Morphologic changes of prolactin-producing pituitary adenomas after short treatment with dopamine agonists.

Treatment of patients with prolactin (PRL)-producing pituitary adenomas with dopamine agonists has proved successful for most cases. Dopamine agonists inhibit PRL secretion, suppress cell proliferation, and may induce apoptosis to adenoma cells. Dopamine agonists induce striking morphologic changes in the majority of treated PRL-producing adenomas. To date, these morphologic effects have been primarily described only after long-term treatment. To the best of our knowledge, no similar studies have investigated apoptotic alterations induced after short-term therapy. The purpose of this report is to describe the morphologic changes seen in PRL-producing adenomas after short-term dopamine agonist treatment. We present two cases of PRL-producing macroadenomas, both from male patients who received treatment with dopamine agonists, the first for 5 and the second for 8 days. In contrast to long-term treatment, no striking reduction of PRL immunoreactivity was noted. Slight stromal fibrosis was noted in case 1, which contained several cells all in late phase of apoptosis. In addition to typical apoptotic cells, numerous "dark" cells representing another common form of cell death were also noted. These novel findings represent characteristic features of short-term dopamine agonist treatment, which are not seen in long-term treatment.

Comparative study of dma content and interphase nucleolar organizer regions in human pituitary adenomas.

DNA content and the number of nucleolar organizer regions (NORs) are claimed to be valuable markers of biological behavior in many tumors. Forty-three human pituitary adenomas removed by surgery were embedded in paraffin and studied by flow cytometry in order to establish DNA index and percentage of cells in different phases of cell cycle. In 31 of these tumors, silver staining showing argyrophilic proteins bound to NORs (AgNORs) was applied. DNA analysis revealed DNA aneuploidy in 32% of the adenomas. The highest number of aneuploid tumors was found in silent corticotroph adenomas (5 of 9), followed by prolactin cell adenomas (3 of 6). The lowest number of aneuploid tumors was noted in null cell adenomas and oncocytomas. The presence of an aneuploid peak could not be correlated with the size of adenomas or with invasiveness. The number of cases with S fraction higher than median was not increased in large or invasive tumors. No close correlation was found between DNA index and AgNOR reading or between S fraction and AgNOR number. These results show that DNA index and AgNOR counting must be interpreted with caution as proliferation markers in pituitary adenomas.

Cushing's Syndrome from an Ectopic Pituitary Adenoma with Peliosis: A Histological, Immunohistochemical, and Ultrastructural Study and Review of the Literature.

Ectopic pituitary adenoma (EPA) is rare and, to the authors' knowledge, its association with peliosis has not yet been described. The case of a 38-yr-old woman with clinical and biochemical evidence of Cushing's syndrome is reported. Magnetic resonance imaging (MRI) disclosed a normal pituitary and a separate mass in the sphenoid sinus. The surgically removed portion of the sellar pituitary contained no adenoma. There was only Crooke's hyaline change in the corticotrophs, indicating exposure to glucocorticoid excess. By histology, the mass in the sphenoid sinus was a congested, chromophobic, partly basophilic, periodic acid-Schiff (PAS)-positive pituitary adenoma composed of pleomorphic, adrenocorticotropic hormone (ACTH)-positive, corticotrophs. There was focal immunopositivity for MIB-1 and proliferating cell nuclear antigen (PCNA). Electron microscopy confirmed the diagnosis of corticotroph adenoma. A striking finding, consistent with the diagnosis of peliosis, was the presence of multiple large blood-filled spaces lacking an endothelial lining. The capillaries were dilated, but often appeared empty and the fenestrated endothelium exhibited discontinuities. The cause of peliosis is obscure. It may be that the venous outflow was impaired in this case leading to capillary dilation, congestion, hyperpermeability, rupture, and accumulation of blood in extravascular spaces.

Basic Fibroblast Growth Factor Expression by Two Prolactin and Thyrotropin-Producing Pituitary Adenomas.

We investigated the expression of basic fibroblast growth factor (bFGF) in an aggressive type of PRL and TSH-producing pituitary adenoma. Immunocytochemistry and electron microscopy were used to characterize the tumors removed from two patients. lmmunoassays were used to measure hormone and bFGF levels in vitro and in vivo. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect bFGF mRNA expression by these tumors. Morphologically, these tumors were characterized by an unusual plurihormonal pattern with expression of PRL and TSH and the ultrastructural characteristics of the silent subtype 3 adenoma; in addition, both adenomas displayed marked interstitial fibrosis. bFGF was measurable in the circulation of these patients ranging from 7.5-20.5 pg/mL (normal < 1 pg/mL). bFGF concentrations were reduced following surgical adenomectomy. bFCF in culture media was present in concentrations of 197-387 pg/24h/10(5) cells. bFGF mRNA expression was identified in both adenomas examined. bFGF levels were unaltered in the culture media and in the serum of patients following GnRH and TRH treatment. In conclusion, the expression of bFGF by these plurihormonal pituitary adenomas suggests the possibility that it may play a role in the development of fibrosis and tumor cell proliferation of this unusual type of pituitary neoplasm.

Plurihormonal Bronchial Carcinoid Associated with Ectopic Cushing's Syndrome.

A 31-year-old woman presented with progressive weight gain, facial acne, round facies, hirsutism, and secondary amenorrhea. Her plasma cortisol, urinary free cortisol, and plasma ACTH were elevated. CT scan of abdomen revealed bilateral diffuse adrenal enlargement. MRI of pituitary failed to identify a lesion. CT scan of chest revealed an 8 mm nodule in the lower lobe of the left lung. The diagnosis of ectopic Cushing's syndrome was made. The lung tumor was surgically removed. The tumor measured up to 1.5 cm in diameter. By light microscopy, a tumor with characteristic features of bronchial carcinoid was noted. Immunostains were positive for neuron-specific enolase, synaptophysin, chromogranin, low-molecular-weight keratin, ACTH, beta endorphin, corticotropin-releasing hormone, bombesin, alpha subunit, and somatostatin. Electron microscopy revealed an endocrine neoplasm. The secretory granules displayed great variation subdividing the endocrine neoplasm. The secretory granules displayed great variation subdividing the cell population into an undetermined number of phenotypes. In situ hybridization demonstrated positivity for pro-opiomelanocortin mRNA in the tumor cells. Postoperatively, plasma cortisol had fallen. The patient remained symptom-free one year later. The case presented here was regarded as a plurihormonal bronchial carcinoid associated with ectopic Cushing's syndrome. This unique plurihormonal bronchial carcinoid tumor produced three hormones, ACTH, CRH, and bombesin, that may have contributed to the patient's ectopic Cushing's syndrome.

Pituitary corticotroph adenoma containing many apoptotic cells: a histologic, immunohistochemical, ultrastructural and molecular study.

Apoptosis regulates cell turnover in normal tissues and occurs during the neoplastic process. Owing to difficulties in recognizing apoptotic cells by histology alone, several complementary approaches have been introduced, which disclosed the presence of cells with typical nuclear and cytoplasmic changes characteristic of apoptosis. Electron microscopy remains the most conclusive method to reveal the structural changes. Identification of caspase cleaved keratin 18 intermediate filament rearrangements can contribute to the identification of early apoptotic changes. The authors present here an unusual case of a pituitary corticotroph adenoma removed surgically from a young woman with Cushing disease. The tumor contained many apoptotic cells identified by histology. In addition, the apoptotic events were investigated using various morphologic techniques, including electron microscopy, the in situ end-labeling technique, and immunohistochemistry to confirm the caspase-cleaved keratin 18 rearrangements.

A Minimally Invasive Approach to the Management of Bronchial Carcinoid Tumors Associated with Ectopic Cushing's Syndrome.

Cushing's Syndrome is usually the result of a pituitary corticotroph or an adrenocortical adenoma. Rarely, an ectopic carcinoid tumor can elaborate sufficient amounts of adrenocorticotropic hormone (ACTH) to result in cortisol excess and Cushing's Syndrome. The diagnosis and management of these unusual neoplasms remains problematic. We describe two cases of Cushing's Syndrome where the diagnosis of ectopic disease was suspected on the basis of inferior petrosal sinus sampling (IPSS). We also describe a minimally invasive thoracoscopic approach to the resection of pulmonary carcinoid tumors. We believe that this technique offers a significant improvement over conventional thoracotomy for the management of potentially compromised patients with Cushing's Syndrome, while still permitting definitive histologic confirmation of the diagnosis.