Brooke Swearingen

Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

OBJECTIVE Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushings syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushings syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushings disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushings disease, and 5) management of ectopic ACTH syndrome, Nelsons syndrome, and special patient populations. EVIDENCE Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS ACTH-dependent Cushings syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushings syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushings disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushings syndrome, early diagnosis and prompt therapy are warranted.

Long-Term Mortality after Transsphenoidal Surgery for Cushing Disease

Survival of patients treated for Cushing disease with current management techniques between 1978 and 1996 was better than the poor survival historically associated with this disorder.

Management of Cushing disease

Cushing disease is caused by a corticotroph tumor of the pituitary gland. Patients with Cushing disease are usually treated with transsphenoidal surgery, as this approach leads to remission in 70–90% of cases and is associated with low morbidity when performed by experienced pituitary gland surgeons. Nonetheless, among patients in postoperative remission, the risk of recurrence of Cushing disease could reach 20–25% at 10 years after surgery. Patients with persistent or recurrent Cushing disease might, therefore, benefit from a second pituitary operation (which leads to remission in 50–70% of cases), radiation therapy to the pituitary gland or bilateral adrenalectomy. Remission after radiation therapy occurs in ∼85% of patients with Cushing disease after a considerable latency period. Interim medical therapy is generally advisable after patients receive radiation therapy because of the long latency period. Bilateral adrenalectomy might be considered in patients who do not improve following transsphenoidal surgery, particularly patients who are very ill and require rapid control of hypercortisolism, or those wishing to avoid the risk of hypopituitarism associated with radiation therapy. Adrenalectomized patients require lifelong adrenal hormone replacement and are at risk of Nelson syndrome. The development of medical therapies with improved efficacy might influence the management of this challenging condition.

CENTRAL NERVOUS SYSTEM NEUROCYTOMA AND NEUROBLASTOMA IN ADULTS-REPORT OF EIGHT CASES

SummaryThe clinical features, pathologic findings and treatment courses of eight adults with central nervous system small-cell neuronal tumors were reviewed. Five patients had central neurocytomas, two patients central nervous system neuroblastomas, and one patient a neurocytoma-like spinal cord tumor. The neurocytomas were intraventricular, moderately cellular tumors with bland nuclei and perinuclear halos. Patients with neurocytoma were treated with surgery, radiation therapy, and/or chemotherapy, and have followed favorable clinical courses. The neuroblastomas were intraparenchymal, hypercellular tumors with necrosis and frequent mitoses. Patients with neuroblastomas were treated with surgery, radiation therapy and chemotherapy, with some clinical response, but overall poor survival. One of the two patients developed extracranial metastasis. The spinal cord tumor had histologic features of neurocytoma, and responded well to biopsy and radiation therapy. The cases are compared with the varieties of small-celled neuronal tumors described in the literature, and pathologic, histogenetic and treatment implications are discussed.

Selective Loss of MEG3 Expression and Intergenic Differentially Methylated Region Hypermethylation in the MEG3/DLK1 Locus in Human Clinically Nonfunctioning Pituitary Adenomas

CONTEXT MEG3 is an imprinted gene encoding a novel noncoding RNA that suppresses tumor cell growth. Although highly expressed in the normal human pituitary, it is unknown which of the normal pituitary cell types and pituitary tumors express MEG3. OBJECTIVES Our objectives were 1) to investigate cell-type- and tumor-type-specific expression of MEG3 in the human pituitary and 2) to investigate whether methylation in the intergenic differentially methylated region (IG-DMR) at the DLK1/MEG3 locus is involved in the loss of MEG3 expression in tumors. DESIGN AND METHODS RT-PCR, quantitative RT-PCR, Northern blot, and a combination of in situ hybridization and immunofluorescence were used to determine the cell-type- and tumor-type-specific MEG3 expression. Bisulfite treatment and PCR sequencing of genomic DNA were used to measure the CpG methylation status in the normal and tumor tissues. Five normal human pituitaries and 17 clinically nonfunctioning, 11 GH-secreting, seven prolactin-secreting, and six ACTH-secreting pituitary adenomas were used. RESULTS All normal human pituitary cell types express MEG3. However, loss of MEG3 expression occurs only in nonfunctioning pituitary adenomas of a gonadotroph origin. All other pituitary tumor phenotypes examined express MEG3. Hypermethylation of the IG-DMR at the DLK1/MEG3 locus is present in nonfunctioning pituitary adenomas. CONCLUSIONS MEG3 is the first human gene identified expressed in multiple normal human pituitary cell types with loss of expression specifically restricted to clinically nonfunctioning pituitary adenomas. The IG-DMR hypermethylation may be an additional mechanism for MEG3 gene silencing in such tumors.

Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas ☆

Pituitary adenomas sometimes progress after surgery and can be locally invasive. Ki-67 and p53 expression are referred to as indicators of aggressive behavior in the World Health Organization Classification of Endocrine Tumors. The real value of these markers including an appropriate threshold for Ki-67 labeling index correlating with tumor progression is controversial. We identified 24 consecutive pituitary adenomas from patients who required surgery for recurrence within 5 years of their first procedure and 31 consecutive adenomas with no evidence of postsurgical progression within 5 years of first surgery. Case selection was based upon availability of complete clinical information, blocks, and slides for study. Immunohistochemistry for Ki-67 revealed that the tumors without progression had a proliferation index of 0.41% +/- 0.01% (mean +/- SEM) (n = 31) (range, 0.08%-1.2%) and the first biopsy from those tumors which progressed had a mean proliferation index of 1.45% +/- 0.09% (mean +/- SEM) (n = 24) (range, 0.1%-10.6%) (P = .01). With the use of ROC analysis, a threshold level of Ki-67 expression greater than 1.3% predicts progression with a high specificity. The group with progression had a higher proportion of nonfunctioning tumors (P < .005, chi(2)). There was no significant difference between the 2 groups with regard to invasion, suprasellar extension, size, tumor type, postoperative radiotherapy, extent of resection, sex, and age. Ki-67 labeling index was an independent predictor of progression (multivariate analysis, P < .011). p53 was positive in 12.5% of cases with surgical progression and in 9.6% of cases without progression, but the difference was not significant (P = .7; chi(2), 0.11).

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND TREATMENT OF ACROMEGALY

ENDOCRINE PRACTICE Vol 10 No. 3 May/June 2004 213 American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice are systematically developed statements to assist health-care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

Changing Patterns in Diagnosis and Therapy of Acromegaly over Two Decades

BACKGROUND The increased morbidity and mortality of acromegaly makes early diagnosis and therapy critical. However, whether the type of medical professional who first diagnoses acromegaly, the major complaint prompting medical attention, or the management paradigms used in the setting of novel medical therapies have changed over time has not been well explored. OBJECTIVES Our objective was to identify the medical professional who first suspected acromegaly and the complaint prompting the diagnosis, and if these have changed. Additional goals were to assess the interval from symptom onset to diagnosis of acromegaly and to compare treatment trends over consecutive decades. DESIGN This was a case-record retrospective study. SETTING The study was performed in a neuroendocrine clinical center at a tertiary care center. SUBJECTS A total of 100 patients (45 men and 55 women) with acromegaly referred from 1985-2005 was included in the study. RESULTS Acral changes (24%) and headaches (20%) were most prevalent presenting symptoms prompting diagnosis. Eighteen percent reported no symptoms of acromegaly at diagnosis. The primary care physician most often initiated the evaluation (44%). Comorbidities were more prevalent in older patients (P = 0.001). The interval between symptom onset and diagnosis decreased, compared with previous reports. Radiation therapy was used less frequently in the decade after 1994 than in the prior (16 vs. 33%; P < 0.05). CONCLUSIONS The primary care doctor plays the major role in diagnosis of acromegaly. The increased use of brain magnetic resonance imaging may contribute to the many incidentally discovered cases and to the shortened time interval to diagnosis. Presumably due to the availability of new medical therapies, the use of radiation therapy has decreased.

Delayed Remission after Transsphenoidal Surgery in Patients with Cushing's Disease

BACKGROUND Transsphenoidal surgery (TSS) is the treatment of choice for Cushings disease (CD). Postoperative hypercortisolemia mandates further therapy. OBJECTIVE The aim of the study was to characterize patients without immediate postoperative remission who have a delayed decrease to normal or low cortisol levels without further therapy. DESIGN AND SETTING A retrospective case series was conducted at three tertiary care centers. PATIENTS AND INTERVENTION We reviewed the records of 620 patients (512 females, 108 males; mean age, 38 +/- 13 yr) who underwent transsphenoidal pituitary surgery for CD between 1982 and 2007. RESULTS Outcomes were classified into the following three groups based upon the postoperative pattern of cortisol testing: group IC (immediate control) included 437 of the 620 patients (70.5%) with hypocortisolism and/or cortisol normalization throughout the postoperative follow-up; group NC (no control) included 148 of 620 patients (23.9%) with persistent hypercortisolism; and group DC (delayed control) included 35 of 620 patients (5.6%) who had early elevated or normal UFC levels and developed a delayed and persistent cortisol decrease after an average of 38 +/- 50 postoperative days. The total rate of recurrence was 13% at a median follow-up time of 66 months after TSS; the cumulative rate of recurrence at 4.5 yr was significantly higher in group DC vs. group IC (43 vs. 14%; P = 0.02). CONCLUSIONS Hormonal assessment in the immediate postoperative period after TSS for CD may be misleading because delayed remission can occur in a subset of patients. Expectant management and retesting may spare some patients from unnecessary further treatment. Optimal timing to determine the need for further therapy after TSS remains to be determined.

PROTON STEREOTACTIC RADIOSURGERY IN MANAGEMENT OF PERSISTENT ACROMEGALY

OBJECTIVE To evaluate the efficacy and safety of proton stereotactic radiosurgery (PSRS) for acromegaly that is refractory to surgical treatment and medication. METHODS From 1992 to 2003, 22 patients were treated at our institution for persistent acromegaly with use of PSRS. All patients had undergone at least one transsphenoidal surgical procedure without biochemical cure. The median treatment dose delivered during PSRS was 20 (range, 15 to 24) cobalt gray equivalents. RESULTS Follow-up was available for all patients at a median of 6.3 (range, 2.5 to 14.2) years after PSRS. A response to PSRS was observed in 21 of 22 patients (95%). A complete response (CR), defined as sustained (> or =3 months) normalization of insulinlike growth factor-I without medical suppression, was attained in 13 patients (59%). Among patients with CR, the median time to CR was 42 (range, 6 to 62) months. No visual complications, seizures, clinical evidence of brain injury, or secondary tumors were noted on regular magnetic resonance imaging scans. One patient had complete pituitary dysfunction before PSRS and was therefore excluded from evaluation for failure. Of the other 21 patients, 8 (38%) had new pituitary deficits. CONCLUSION These results demonstrate that PSRS is effective for persistent acromegaly, with 59% of patients attaining normal insulinlike growth factor-I levels without use of any medication after a median of 6.3 years. Our findings indicate that radiosurgery results in an expeditious biochemical response with low morbidity.