Surgical Management of Pituitary Tumors

Having performed 3000 transsphenoidal procedures during the past 27 years, almost all of them for pituitary adenomas, I have been asked to give a surgical perspective on this small but important aspect of endocrine practice. In preparing this retrospective, I was freed from the customary journalistic format to present a personal perspective on surgical management that may prove helpful to endocrinologists in making decisions about the treatment of patients for whom surgery is a consideration. Transsphenoidal surgery has become an operation with remarkably little morbidity and exceptionally low mortality rates. Hospital stays of 2 days are standard, and selectively patients are being discharged even earlier. Patients whose jobs are not physically demanding can usually return to work within 1 to 2 weeks after surgery. To be sure, complications, both minor and major, occur even in the most experienced hands. As one example postoperative loss of pituitary function, whether categorized as a side effect or a complication, is a serious concern in a patient of any age, but most critically in children and young adults. Considering the benign behavior of most pituitary adenomas, the preservation and possible improvement of anterior pituitary function assumes a priority equal to that of avoiding injury to critical parasellar structures. I subscribe to the principle of specialized care, and if it makes sense for interested internists to acquire special knowledge and experience in endocrinology, it seems reasonable to apply the same rationale to specialization in pituitary surgery. Particularly in neurosurgery practice makes perfect, and I advocate concentrating, rather than diffusing, surgical referrals—not in the sense of creating“ centers”, but by encouraging one of several neurosurgeons in larger communities to become the local expert in pituitary surgery. There is no question about it: such a plan for referrals for pituitary surgery can provide improved outcomes for your patients. Has managed care, including capitated care, complicated the referral process? Unquestionably it has, but I hardly need to remind you that inexpert pituitary surgery can be very expensive, in both the short term and the long term. Care of high quality is rarely cost-ineffective, particularly in the care of children and patients with Cushing’s disease. Endocrinologists have a critical role in the diagnoses, preoperative preparation, and postoperative management of all patients with pituitary adenomas. The short- and long-term followup of every patient treated by surgery is best placed in the hands of an endocrinologist because critical decisions regarding recurrence of endocrine-active adenomas and the subtleties of anterior pituitary insufficiency require continuous monitoring by an expert for optimal outcomes. I am an advocate of immunostaining. At the University of California, San Francisco (UCSF) we do immunostaining routinely on all pituitary adenomas, even though it provides critically important information in only a minority of cases. Without immunostaining, for example, nodular corticotropic hyperplasia might go undetected; and in the case of a large nonsecreting adenoma associated with hyperprolactinemia as a nonspecific effect of the compression and distortion of dopaminergic vascular pathways, the adenoma might be mistaken for a prolactin (PRL)-secreting adenoma and could be managed incorrectly. Only immunostaining differentiates an endocrine-inactive adenoma from a prolactinoma, each of which is managed quite differently. In Table 1 is shown the distribution of tumor cell types in my own series of adenomas. Tumors are classified as either endocrine-active or endocrine-inactive based on their clinical presentation. For several reasons, the distribution of cell types does not reflect the true proportion of cell types in the universe of pituitary adenomas. As this is a series of tumors removed surgically, it does not include recognized but asymptomatic (“incidental” or“ silent”) adenomas, or PRL-secreting adenomas that are managed satisfactorily by medical means and therefore not referred for surgery. Persistent or recurrent adenomas operated on after failed initial surgical procedures are not distinguished in the table, although the relative proportions of tumor types are no different for the secondary than for the primary procedures. Most adenomas of mixed endocrine-active cell types involved PRL and another cell type—either adrenocorticotrophin (ACTH), growth hormone (GH), or thyrotrophin (TSH); and in each instance the tumor was classified according to the other cell type, rather than as a PRL-secreting adenoma. Tumor type for the adenomas in the other categories was determined by the presenting endocrinopathy. Finally, because of an institutional interest in Cushing’s disease and a large pediatric endocrinology group at UCSF, the proportion of ACTH-secreting adenomas in the series, particularly those in children, is misleadingly high. Pituitary adenomas: transsphenoidal resection in 2732 operations (1968–1996) PRL, prolactin; ACTH, adrenocorticotrophin; GH, growth hormone; TSH, thyrotrophin. Pituitary adenomas: transsphenoidal resection in 2732 operations (1968–1996) PRL, prolactin; ACTH, adrenocorticotrophin; GH, growth hormone; TSH, thyrotrophin. Categorized under endocrine-inactive adenomas are those adenomas that were recognized by their clinical presentation as a mass compressing either the anterior pituitary gland or extrasellar structures, presentation only with headache being one characteristic of the latter group. Although immunostaining revealed that many tumors contained one or several cell types, as determined by the presence of secretory granules or their appropriate ultrastructural characteristics, in none was a secretory syndrome associated with the mass effect. In contrast to immunostaining, in my experience routine α-subunit determination has been expensive and valueless in practice. The prolactinoma is the only pituitary adenoma for which medical management in the long term is fully satisfactory, and for that reason the proportion of patients with prolactinomas referred for surgical consultation varies widely in different geographic regions. I assume that the proportion of patients referred for surgical consideration in Northern California represents an approximation of general practice. The referred group in my practice includes patients who have unacceptable side effects caused by medication, patients with dopamine-insensitive adenomas, and those patients who, after becoming informed, for personal reasons select surgical over medical management. In a significant proportion of patients referred to me for surgical consultation, I have advised medical over surgical management based on gender, age, and the probability of a surgical cure—“cure” in the sense of long-term freedom from recurrence. In Table 2 are shown the indications I follow in recommending surgical removal of a microadenoma, and in Table 3 are shown the indications for removal of a macroadenoma. These indications for both small and large adenomas reflect my experience as well as my biases. Based on the basal PRL value and a high-resolution magnetic resonance MR image I can predict the likelihood of a surgical cure. If cure is not possible because of extrasellar spread, almost always on the basis of cavernous sinus invasion, surgery is not advised unless the patient fails to respond to medical management. When there is no likelihood of a surgical cure, surgery has the focused objective of reducing the adenoma’s mass, either to reduce the production of PRL to a level that can be further reduced into a desirable range by a tolerated dose of a dopamine agonist or to relieve symptoms of compression and reduce the bulk of the adenoma before irradiation. Because prolactinomas continue to secrete PRL for several years after being rendered sterile by radiation therapy, irradiation is a poor and much delayed means of treating the hyperprolactinemic syndrome. Surgical indications for prolactin-secreting microadenomas Rarely do microadenomas become symptomatic in the course of pregnancy. However, the microadenoma may expand during pregnancy without symptoms, most patients are still young, the likelihood of cure will never be better, and in my referral area a number of endocrinologists and gynecologists refer patients in this category to consider surgery as an alternative to medical treatment. This is rare, but a microadenoma that originates on the surface of the anterior lobe may extend beyond the sella, and the likelihood of a surgical cure is greater with small tumors if for any reason medical management is rejected because of intolerance or personal choice. Surgical indications for prolactin-secreting microadenomas Rarely do microadenomas become symptomatic in the course of pregnancy. However, the microadenoma may expand during pregnancy without symptoms, most patients are still young, the likelihood of cure will never be better, and in my referral area a number of endocrinologists and gynecologists refer patients in this category to consider surgery as an alternative to medical treatment. This is rare, but a microadenoma that originates on the surface of the anterior lobe may extend beyond the sella, and the likelihood of a surgical cure is greater with small tumors if for any reason medical management is rejected because of intolerance or personal choice. Surgical indications for prolactin-secreting macroadenomas Surgical indications for prolactin-secreting macroadenomas Unless a PRL-secreting adenoma is cystic, partly necrotic, or contains a significant collection of blood, the levels of PRL in the blood accurately reflect the tumor’s size. Furthermore, the preoperative basal PRL value provides an accurate prediction of outcome, the probability of surgical cure having a directly inverse relationship to basal PRL value. An even more accurate prediction of outcome is provided by the immediately postoperative PRL value, obtained 1–2 days after surgery: an unmeasurable (<2 μg/L) value predicts a cure with more than 90% probability, and higher values within the normal range are inversely related to probability of cure (1). Postoperative values even slightly above the upper limit of the normal range indicate incomplete removal of the adenoma. Dopamine agonists, such as Parlodel (Sandoz Pharmaceuticals, Hanover, NJ), inhibit tumor-cell replication in the great majority of prolactinomas, and for that reason patients known or proven to have residual or recurrent adenomas should be treated indefinitely with Parlodel. Often a dose as low as 1.25 mg, taken at bedtime, is sufficient to maintain or restore normal PRL levels and prevent tumor regrowth if the residual volume of adenoma is small or if the adenoma is highly dopamine-sensitive. In all cases involving incompletely removed or recurrent PRL-secreting tumors, long-term administration of a dopamine agonist is the first line of treatment. Irradiation is reserved for those few patients who have adenomas refractory to medical therapy and for the larger number of individuals who cannot tolerate the medication. For almost three decades, the preferred primary treatment for the patient with acromegaly has been surgery. In occasional cases of acromegaly, uncontrolled diabetes, hypertension, or congestive heart failure may counsel against anesthesia, and in such cases preoperative medical preparation, including somatostatin, may be advisable. Still, today (with the exception of such cases) the initial and usually definitive treatment for acromegaly is transsphenoidal surgery. As a general rule, younger patients have larger tumors and higher basal growth hormone (GH) values, whereas older patients with acromegaly are more likely to have smaller tumors and lower, or even normal, random GH values. Technically, surgery for acromegaly is often difficult. Because of the greater distance from the patient’s lip to the sphenoid sinus, a longer speculum is required in many cases. The anesthesiologist must be forewarned of the difficulty often encountered in introducing an endotracheal tube because the enlarged tongue, uvula, and epiglottis of patients with acromegaly and their thickened vocal cords may catch the anesthesiologist unawares, resulting in crisis if pharmacological apnea rapidly produces hypoxia when intubation proves to be difficult. Many patients with acromegaly have chronic sinusitis, and as a consequence the nasal and sinus mucosa is thickened and difficult to manage. However, the surgeon’s biggest concern is the cavernous segment of the carotid artery. Typically, the dolichoectatic artery deviates medially and at times may be found, literally, protruding into the sella and compressing the sellar contents. The size and course of both carotid arteries can be determined exactly on MR coronal images, which is a compelling argument for obtaining an MR image even if doing so requires general anesthesia—the exception being a patient with a cardiac pacemaker. Following selective transsphenoidal adenomectomy, more than 80% of patients with acromegaly have a sustained remission. Incompletely removed adenomas should be treated. Although some patients will do well with medical management using octreotide, most will be treated postoperatively with irradiation. In the short term, Cushing’s disease is the most serious and life-endangering condition caused by any pituitary adenoma; for the surgeon, these tumors present the most difficult challenge of all pituitary adenomas. As I begin each operation for Cushing’s disease, I have to assume that the operation will be difficult from beginning to end, and seldom am I pleasantly surprised by a truly “simple” case. The patient with Cushing’s disease has friable tissue, soft bone, and capillary fragility. Moreover, in many cases, obesity and other factors conspire to produce venous hypertension, a major complicating factor during the transsphenoidal exploration of a normal-size sella surrounded, literally, by a moat of turgid, confluent dural venous sinuses. Neuroanesthesiologists at UCSF have developed a protocol for coping with elevated venous hypertension, and in the majority of cases the venous pressure can be reduced to normal or near-normal levels. However, these pharmacologic maneuvers are not always effective, and maintaining a lowered venous pressure requires sustained effort. In some cases, the surgeon must deal with persistently elevated venous pressure or, very rarely, abandon the procedure altogether. Even after extensive experience, I am wary, even apprehensive, as I prepare to operate on any patient who has Cushing’s disease, and this is especially true if the patient is a young child. In adults with suspected Cushing’s disease, unless MR imaging indicates a tumor larger than 5 mm in diameter, we proceed to preliminary sampling of the cavernous sinuses. This means that the majority of such patients, more than 75%, undergo venous sampling and concurrent cavernous sinus venography. The tumors of Cushing’s disease are tiny, the adenoma having a of than 5 with the likelihood of a MR image in of the normal for preoperative venous sampling in almost all cases. sampling is in surgical to which patients to operate to the and to do in the case of a I have several The cavernous rather than the should be after the is and of both cavernous should be obtained at the same If venous from the sella is obtained values may not be in cavernous sinus should be obtained because a in a cavernous sinus may the presence of an adenoma or larger the of Cushing’s disease, and in experience, the with factor to the value of taken from the cavernous If a patient with no venous a of or removal of the appropriate of the anterior pituitary gland will be in 80% of cases in which is endocrinologists at UCSF are not about venous sampling because children rarely have an of ACTH, venous sampling is difficult in children, and the of morbidity from either local or general is not In I a difficult exploration I a and I a to the adenoma’s a normal I to the of in the of a The of the of venous sampling the need for in under any under the is appropriate in most cases, will be clinical the that one or even slightly of a normal anterior pituitary gland provides normal anterior pituitary The adenoma of Cushing’s disease has is and on and it is often by Because it may be the adenoma can go or can into the of a The adenoma often has a of 2 mm or can the surface of the anterior can be into the can or even within the cavernous sinus, as it in one rarely, it can in the Furthermore, in a small number of cases, Cushing’s disease is the consequence of In none of the other endocrine-active tumors is expert knowledge of the and so The surgical exploration must be and must include the If is after a exploration in an after venous the sella must be the for of the and the pituitary as as possible to the anterior lobe to When is after a exploration in a or who has a venous and a normal venous and who has an the must not be the of the anterior lobe suspected of the I it in the of the anterior lobe that is not to be I have operated on several patients in whom the normal of the anterior lobe been removed based on an of venous Cushing’s disease is not a by one there are recognized cases If the disease is no other tumor is the surgeon’s experience more critical in outcome, and for this reason I that pituitary must experience with tumor types, patients with Cushing’s pediatric an experienced In my these and difficult cases should be in the hands of experienced pituitary the for referral to an surgeon may be because of concern for but a of the long-term of a operation to those from a failed first a compelling argument for referral to an experienced surgeon for even without the of appropriate patient In this category are adenomas that produce no secretory At the of the great majority of cases present with and some of with or without associated Because of the of high-resolution MR a category of and adenomas requires the of a management which I will symptomatic endocrine-inactive adenomas are even when headache is the only presenting of the sellar by all endocrine-inactive macroadenomas have beyond the of an sella the most of extrasellar growth being directly into the the only of growth that removal are into the cavernous sinus or and of the sellar with of tumor into the sphenoid of the the sella from the cavernous sinus, even without into the sinus the tumor unless the is in which case the involved can be large tumor often the dural of the cavernous sinus very without the and unless coronal MR the of the sinus may be rather than The preoperative prediction of into the cavernous sinus may and often For many years, my surgical objective in treating large endocrine-inactive adenomas was of the and with the that irradiation was required to prevent I not a removal of large tumors, very as a from the practice when these tumors were treated by However, as I experience and that it was possible to removal of macroadenomas anterior lobe tissue, I the surgical objective from to In the majority of large adenomas, a surgical the surface of the tumor from the normal structures. and this in the of a large proportion of large tumors can be removed of these adenomas with MR at for the first 2 years and has shown a of recurrence after 5 If tumors that the cavernous sinus are I that as many as of endocrine-inactive adenomas can be by surgery and for this reason the surgeon should go into the operation with rather than as the of anterior pituitary function that before surgery has been an more function that was To from the of the the has been for pituitary Although I have no of the number of patients with pituitary adenomas whom I have the of high-resolution MR images, I that one of patients referred to me with the of pituitary adenoma. some adenomas are rather than adenomas, but if a has a of 1 it should be managed in the same as an adenoma because both the of this size and an whether smaller or larger than 1 have for further The of a pituitary adenoma are it is there is normal anterior pituitary function, including a normal GH to is and the is to the sella the anterior pituitary cell types, are the most to by as a Although GH has a role GH is for the normal of If GH is normal, all other anterior pituitary are almost normal as Because most are and because there is a compelling argument for the presence of should be by before the surgeon assumes that a mixed and mass is an adenoma. of an pituitary adenoma of an pituitary adenoma adenoma or the should be and the patient advised to have by a who for and based on the patient’s age, the size of the and other As a rule, younger patients require more and in that as to in each case. are the indications for surgical The indications in Table 5 are not and a to operate that is appropriate for an may be for an Moreover, an adenoma that has in size within 1 although still should be from an adenoma that has shown but growth over the course of 5 The indications for operation are only to be in with clinical by has for with adenomas has a likely for further in contrast to the and small so often in the the that is 1 or larger in my to have further at some of indications for surgical indications for surgical I have a for pituitary adenomas. Although rarely because of their can have a effect on the quality of and in many cases to secondary caused by endocrine that not only quality but of from patients with acromegaly are and their is Unless treated by either medical or surgical prolactinomas have that are for and as well as The patient with Cushing’s disease rapidly by a range of complications, and a is a consequence of uncontrolled adenomas and pituitary function even though can be by irradiation when the volume of tumor is irradiation of the normal anterior pituitary gland can and often does produce during the past 2 have more than were at any in the but even optimal management of any pituitary adenoma requires in the the and expert of medical and surgical and in many cases a of