Kamal Thapar

Proliferative Activity and Invasiveness among Pituitary Adenomas and Carcinomas: An Analysis Using the MIB-1 Antibody

Although histologically benign, one-third of all pituitary tumors will be invasive of surrounding structures. In this study, the relationship between the proliferative activity in pituitary adenomas and their invasiveness was investigated. Invasion was defined as gross, operatively or radiologically apparent infiltration of dura or bone. Using the recently developed MIB-1 monoclonal antibody, which recognizes the Ki-67 cell cycle-specific nuclear antigen, the growth fractions of 37 noninvasive adenomas, 33 invasive adenomas, and 7 primary pituitary carcinomas were determined. All tumors were fully classified by histology, immunohistochemistry, and electron microscopy. The mean Ki-67 -derived growth fractions for noninvasive adenomas, invasive adenomas, and pituitary carcinomas were 1.37 +/- 0.15%, 4.66 +/- 0.57%, and 11.91 +/- 3.41%, respectively (mean +/- standard error of the mean). An analysis of variance and then individual pairwise comparisons confirmed significant differences in the mean Ki-67 labeling index between each of the three tumor groups (P < 0.01). The mean growth fraction of hormonally active pituitary adenomas (3.25 +/- 0.26%) was significantly higher than that for nonfunctioning adenomas (2.06 +/- 0.23%) (P = 0.03). Establishing a threshold labeling index of 3% served to distinguish invasive from noninvasive adenomas with 97% specificity and 73% sensitivity and was associated with positive and negative predictive values of 96 and 80%, respectively. Although invasive pituitary tumors exhibited significantly higher growth fractions than did noninvasive tumors, there were individual exceptions, indicating that in a subpopulation of invasive pituitary tumors, factors other than proliferative activity determine invasive potential.

p53 Expression in Pituitary Adenomas and Carcinomas: Correlation with Invasiveness and Tumor Growth Fractions

Although most pituitary tumors are well differentiated, histologically benign neoplasms, their clinical behavior is known to vary greatly. These lesions are relentlessly aggressive in some instances yet biologically indolent in others, but these prognostically relevant differences in behavior are not reflected in their histopathological appearance. As a means of identifying intrinsically aggressive pituitary tumors, we evaluated 70 pituitary adenomas and 7 primary pituitary carcinomas for their expression of the p53 gene product, a nuclear phosphoprotein whose immunohistochemical accumulation has served as an unfavorable prognostic factor for a wide range of human neoplasms. All tumors were fully classified by immunohistochemistry and electron microscopy; adenomas were further stratified on the basis of their invasion status, the latter being defined as gross operatively or radiologically apparent infiltration of dura or bone. Conclusive nuclear immunopositivity for p53 was identified in a total of 12 tumors, all being either invasive adenomas or primary pituitary carcinomas. A clear and highly significant association was evident between p53 expression and tumor behavior, as the proportion of p53-positive cases among noninvasive adenomas, invasive adenomas, and pituitary carcinomas was 0, 15.2, and 100%, respectively (chi 2 = 44.72; degrees of freedom, 2; P << 0.001). A comparison of previously reported growth fraction data with p53 expression indicated that the mean Ki-67-derived growth fraction of p53-positive tumors was significantly higher than that of p53-negative tumors (10.41 +/- 2.20 versus 2.51 +/- 0.28%) (+/- standard error of the mean, two-sample t test for independent samples, P = 0.004). There was no apparent relationship between the functional status of the tumor and p53 expression; positivity was observed among somatotroph, lactotroph, corticotroph, and clinically nonfunctioning pituitary tumors. These data indicate that p53 expression, when conclusively present in pituitary tumors, may be of some diagnostic usefulness as a marker of biologically aggressive behavior.

Pituitary surgery: transsphenoidal approach.

THE TRANSSPHENOIDAL APPROACH for sellar tumors has evolved significantly since it was described initially during the first decade of the 20th century. The approach currently incorporates technological advancements and refinements in patient selection, operative technique, and postoperative care. Although many of these innovations are considered indispensable, the operative technique, as performed by contemporary neurosurgeons, is not standardized. This variability is a reflection of surgeon’s preference, the lessons of experience, and the bias inherent in neurosurgical training. The methods and preferences described herein embody the distillation of an experience gained from 3900 transsphenoidal operations.

Pituitary Surgery for the Management of Acromegaly

Active acromegaly is almost always the result of a benign growth hormone (GH)-secreting adenoma of the pituitary gland. Because the same pituitary stem cell can produce both GH and prolactin (PRL), many acromegalic patients also have hyperprolactinemia. The advantages of surgical excision of pituitary adenomas associated with acromegaly include: (1) prompt decrease in GH; (2) reliable and immediate relief of the mass effect from the tumor (decompression of the optic nerves and chiasm), and (3) the opportunity to obtain tumor tissue for characterization and investigative study. Currently, more than 97% of operations for removal of pituitary tumors associated with acromegaly are done using the transsphenoidal approach rather than craniotomy. Technical advances to make the surgery safer continue to evolve, and include endoscopic approaches, computer-guided image-based intraoperative visualization, and intraoperative magnetic resonance imaging. Criteria for satisfactory remission of acromegaly after surgery are the same as those used for medical management. They include normal insulin-like growth factor (IGF)-I and suppression of GH to undetectable levels (<1.0 ng/ml) during an oral glucose tolerance test (OGTT). Data from a recent series of 86 patients operated upon for acromegaly at the University of Virginia and followed for more than 1 year have been reviewed. In patients receiving surgery as the initial procedure, 67% had a normal IGF-I, and 52% suppressed to <1.0 ng/ml in an OGTT. There was one true recurrence of disease diagnosed 81 months after surgery. Results are best in patients with noninvasive microadenomas. Gamma knife radiosurgery has been a valuable adjunct in those patients who fail to achieve postoperative remission. Pathological evaluation of the tumors revealed that 16% expressed GH only, 25% stained for GH and glycoprotein hormones (follicle stimulating hormone, thyroid hormone, thyroid stimulating hormone, α-subunit), 21% for GH and PRL, and 33% for GH, PRL and glycoprotein hormones. There was one acidophil stem cell tumor and 10% had the mammosomatotroph subtype. This contemporary series was free of mortality or serious complications. One patient had a transient cerebrospinal fluid leak and 3 developed transient SIADH with hyponatremia. Surgical treatment remains an important aspect of the combined management of patients with acromegaly.

Fluoroscopic Frameless Stereotaxy for Transsphenoidal Surgery

OBJECTIVETo assess the value of frameless fluoroscopy-guided stereotactic transsphenoidal surgery using the FluoroNav Virtual Fluoroscopy System (Medtronic Sofamor Danek, Inc., Memphis, TN). METHODSTwenty consecutive patients undergoing transsphenoidal surgery for sellar lesions were assigned to transsphenoidal surgery with or without computer-assisted fluoroscopic image guidance using the FluoroNav system. Prospective data regarding patient age, sex, lesion characteristics, operative time, and treatment cost were obtained. RESULTSAlthough patients in the FluoroNav group were, on average, 17 years younger than the patients in the control group, more patients with recurrent adenomas were treated in the image guidance group. No other significant differences between the groups were found. FluoroNav provided accurate, continuous information regarding the anatomic midline trajectory to the sella turcica as well as anatomic structures (e.g., sella, sphenoid sinus) in the lateral view. No patient required reversion to intraoperative videofluoroscopy. No statistically significant differences were found with regard to preincision setup time, operative time, or cost. FluoroNav allowed procedures to be performed with significantly fewer x-rays being taken. CONCLUSIONFluoroscopic computer-assisted frameless stereotaxy furnishes accurate real-time information with regard to midline structures and operative trajectory. Although it is useful in first-time transseptal transsphenoidal surgery, its primary benefit is realized in recurrent surgery.

Assessment of Mitotic Activity in Pituitary Adenomas and Carcinomas.

Assessment of mitotic activity represents one of the oldest and most routinely used histopathologic methods of evaluating the biological aggressiveness of human tumors. In the case of pituitary tumors, however, the relevance of this approach as a means of gaging tumor behavior remains ill-defined. In this article, the relationship between the mitotic index and biological aggressiveness of pituitary tumors was evaluated in a series of 54 pituitary adenomas and 6 primary pituitary carcinomas. All tumors were fully classified by immunohistochemistry and electron microscopy; adenomas were further stratified on the basis of their invasion status, the latter being defined as gross, operatively, or radiologically apparent infiltration of dura or bone. Mitotic figures were present in 11 tumors, 10 being either invasive adenomas or pituitary carcinomas. A significant association between the presence of mitotic figures and tumor behavior was noted, as evidenced by progressive increments in the proportion of cases expressing mitotic figures in the categories of noninvasive adenoma, invasive adenoma, and pituitary carcinoma (3.9, 21.4, and 66.7%, respectively; Fisher’s exact test, two-tailed,p<0.001). The mitotic index, however, appeared to be a less informative parameter, being extremely low in all cases (mean=0.016%±0.005 [±SEM]). Although the mean mitotic index in pituitary carcinomas (0.09%±0.035) was significantly higher than the mean mitotic index of either noninvasive adenomas (0.002%±0.002) or invasive adenomas (0.013%±0.005), no practical threshold value capable of distinguishing these three groups was evident. Comparison of the mitotic index with Ki-67 derived growth fractions in these tumors revealed a significant but weak linear correlation (r=0.41,p<0.01). These data suggest that when, mitotic figures are present, they do provide some indication of the behavior and invasive potential of pituitary tumors. For routine diagnostic purposes, however, the discriminating power of this parameter is somewhat limited, being superseded by alternative and more informative methods of growth fraction determination such as that provided by the Ki-67 immunolabeling.

Antiproliferative Effect of the Somatostatin Analogue Octreotide on Growth Hormone-Producing Pituitary Tumors: Results of a Multicenter Randomized Trial

OBJECTIVE To determine and quantify the in vivo effects of octreotide on the cell cycle kinetics of growth hormone-producing pituitary adenomas. DESIGN A multicenter randomized trial had been conducted to assess the clinical efficacy of octreotide, and we studied tissue specimens from pituitary macroadenomas in 32 patients with acromegaly from that trial-16 of whom had received 4 months of octreotide therapy before surgical resection and 16 of whom had undergone surgical resection only. MATERIAL AND METHODS All tumors had been fully characterized on the basis of their immunophenotypic profile and their ultrastructural morphologic features. Included were 16 densely and 16 sparsely granulated somatotroph adenomas. In each case, immunostaining for the cell cycle-specific nuclear antigen Ki-67 was performed with use of the MIB-1 antibody. The staining reaction was manually quantified, and a tumor growth fraction was derived in each case. RESULTS The mean growth fraction of tumors exposed to octreotide was suppressed by 83% in comparison with untreated surgical controls (0.011+/-0.004% versus 0.065+/-0.016%, respectively; P = 0.0068). The association between octreotide treatment and lower tumor growth fractions was statistically independent of tumor subtype, being evident among both sparsely and densely granulated somatotroph adenomas. CONCLUSION Octreotide exerts a significant antineoplastic effect on somatotroph adenomas, one readily reflected at the level of the cell cycle. This antiproliferative response provides insight into several clinicopathologic issues surrounding octreotide therapy for these neoplasms.

The Classification and Molecular Biology of Pituitary Adenomas

As illustrated throughout this volume, the contemporary management of pituitary tumors has been the collective product of decades of multidisciplinary contribution. Innovation has been especially brisk during the past two decades in which the introduction of highly sensitive hormone assays, superior resolution imaging technology, trans-sphenoidal microsurgery, receptormediated pharmacotherapy, and focused beam radiotherapy have ushered in a promising new era in the diagnosis and therapy of pituitary tumors. Collectively, these contributions from many disciplines have rendered pituitary tumors eminently treatable, with many patients enjoying long term survival or cure.

Diagnosis and management of pituitary tumors

Pituitary Adenomas: Historic Considerations, Raymond V. Randall, Bernd W. Scheithauer, and Kalman Kovacs. Anatomy of the Pituitary Gland and Sellar Region, Albert L. Rhoton, Jr. Hypothalamic-Pituitary Physiology and Regulation, Miklos I. Goth, Gabor B. Makara, and Ida Gerendai. Epidemiology of Pituitary Tumors, Shozo Yamada. Pathogenesis and Molecular Biology of Pituitary Tumors, Ilan Shimon and Shlomo Melmed. Experimental Models of Pituitary Tumorigenesis, Lucia Stefaneanu. Pathology of Pituitary Adenomas and Pituitary Hyperplasia, Bernd W. Scheithauer, Eva Horvath, Ricardo V. Lloyd, and Kalman Kovacs. Molecular Pathology of Pituitary Tumors, Ricardo V. Lloyd. Diagnosis, Management, and Prognosis of Pituitary Tumoars: General Considerations, Mary Lee Vance. Neuro-Ophthalmologic Evaluation of Pituitary Tumors, Shirley I. Stiver and James A. Sharpe. Imaging of Pituitary Tumors, Derek Emery and Walter Kucharczyk. Positron Emission Tomography in Sellar Tumors: In Vivo Metabolic, Receptor, and Enzyme Characterizaiton, Carin Muhr. Pituitary Surgery, Kamal Thapar and Edward R. Laws, Jr. Medical Therapy of Pituitary Tumors, Mark E. Molitch. Radiation Therapy of Pituitary Tumors: Including Stereotactic Radiosurgery, B. Dawn Moose and Edward G. Shaw. Prolactinomas, Charles F. Abboud and Michael J. Ebersold. Somatotroph Adenomas: Acromegaly and Gigantism, Hans-Jurgen Quabbe and Ursula Plockinger. Corticotroph Adenomas: Cushings Disease and Nelsons Syndrome, Joan C. Lo, J. Blake Tyrrell, and Charles B. Wilson. Thyrotroph Adenomas, Michael Buchfelder and Rudolf Fahlbusch. Clinically Nonfunctioning Pituitary Adenomas, William F. Young, Jr. Pituitary Tumors in Children, Nalin Gupta and James T. Rutka. Invasive Pituitary Adenoma and Pituitary Carcinoma, Peter J. Pernicone and Bernd W. Scheithauer. Sellar Tumors Other Than Adenomas, Paul E. McKeever, Mila Blaivas, and Stephen S. Gebarski. Tumor-like Lesions of the Sellar Region, Wolfgang Saeger. Pituitary Tumors: FuturePerspectives, Gregory M. Miller, Xun Zhang, and Anne Klibanski. Index.

Surgical management of pituitary adenomas

Surgical management of pituitary adenomas continues to be a safe and effective method, suitable for a large number of patients suffering from the effects of these lesions. Frequently surgery is just part of an overall programme that includes medical management and radiation therapy as well. It is important for the physicians and the patients to understand that surgery alone may not be totally successful, but that with careful follow-up and appropriate adjunctive management, patients with pituitary tumours may live normal lives, and may enjoy reversal of the endocrine and visual problems that had been caused by their tumours. Careful study of surgically managed patients has contributed to some of the advances that have occurred in the overall management of pituitary adenomas and in our understanding of their biology, pathophysiology and pathogenesis.