The transsphenoidal approach to pituitary tumors represents a fascinating chronicle in surgical history. The result of this evolution and continued refinement of the transsphenoidal approach is that pituitary tumors are now eminently treatable lesions, with long-term and high-quality survival the result. However, the impressive early success rates after transsphenoidal surgery do not equate to durable disease control; indeed, tumor recurrence confronts a significant number of patients, which rises over time. In many cases, it is difficult to distinguish the genuine recurrence of a completely removed tumor from the continued growth of small tumor remnants in a subtotally resected tumor. Although hormone levels are helpful in establishing disease activity and remission status in secretory tumors, imaging is relied upon to assess the residual tumor in nonfunctional tumors. The higher incidence of tumor recurrence than the incidence of new tumors in the general population may suggest that recurrence represents the growth of undetectable tumor remnants from the initial surgery.
Surgery remains central to the management of recurrent pituitary tumors, but the altered anatomical landscape in the reoperated patient can prove challenging to the pituitary surgeon. Although complementary strategies such as pharmacotherapy and radiosurgery are reviewed elsewhere, we review here the surgical principles underlying the management of these frequently difficult recurrences, drawing on the personal experience of the senior author (Edward Laws), which includes more than 5000 transsphenoidal operations.
Several factors have been suggested to predict tumor recurrence. Younger patients are more apt to suffer recurrence, and patients with prior target gland ablation—such as those with Nelson’s syndrome or with thyrotroph adenomas after prior thyroid ablation—may be at greater risk owing to loss of feedback inhibition of target-gland hormones on the pituitary. Tumor invasiveness, size, and proliferative capacity contribute to tumor recurrence. Nearly one third of pituitary adenomas show evidence of local infiltration and invasion, which in compromising the ease of initial resection may lead to eventual recurrence. The inverse relationship between tumor invasiveness and remission has been demonstrated for all adenoma subtypes. Hardy and Wilson attempted to capture the various growth patterns of invasive tumors in a radiological classification system. This radiological classification first differentiates tumors as microadenomas or macroadenomas, with distinction made among microadenomas with abnormal sellar appearance. Macroadenomas causing diffuse enlargement, focal destruction, and extensive destruction of sella are referred to as grade II, grade III, and grade IV tumors, respectively. In this system macroadenomas are further staged according to the degree and direction of extrasellar extension.
Diagnosing the Recurrence of Pituitary Adenomas
The strategy for diagnosing recurrent tumors is similar to that used for diagnosing pituitary tumors in general and entails clarifying an anatomical and, if pertinent, endocrinological diagnosis. Recurrent nonfunctioning tumors will produce symptoms from mass effect, while endocrinologically active tumors will recapitulate the hypersecretory state. Below, we discuss the accepted rates of recurrence for nonfunctioning and hormone-secreting tumors
Visual symptoms and headache constitute the clinical manifestations of nonfunctioning tumors. Symptomatic recurrence develops in relatively few patients, while more clinically subtle recurrences may be detected on routine visual field examinations or serial MRI scans.
Recurrence rates in the literature range from 6% symptomatic recurrence to 21%. In our cohort of 100 patients, radiographic recurrence was documented in 16 patients with a mean follow-up of just more than 6 years; only 6 of these patients were symptomatic.
Recurrent Hormone-Secreting Tumors
Tumor recurrence is usually manifested by clinical hyperprolactinemia rather than frank radiological regrowth. Of 58 women with macroadenomas followed for 10 years, moderate hyperprolactinemia recurred in 43% of patients, while only 2 showed radiographic recurrence. Others have reported recurrent hyperprolactinemia in 17% to 20% of microadenomas and macroadenomas, while other groups report recurrence rates as high as 50% for microadenomas and 80% for macroadenomas after mean remission periods of 4 years and 2.5 years, respectively. From Laws’ series, the recurrence rate of these tumors was 24% at 10 years.
The rate of recurrence for acromegaly depends on the stringency of the criteria with which remission was originally defined and the period of follow-up. Remission criteria vary among groups, with accepted GH levels ranging from 2.5 to 5 ng/mL at baseline and from less than 1 to less than 2.5 ng/mL after oral glucose tolerance testing (OGTT). Recurrence rates in the literature range from 0% to 18%, with mean follow-up periods of 2.9 to 8.9 years. We have used suppression of GH levels to less than 2.5 ng/mL and to less than 1 ng/mL on an OGTT and normalization of IGF-1 levels as remission criteria and have encountered an 8% recurrence rate with more than a 10-year follow-up period.
Corticotroph Adenomas: Cushing’s Disease and Nelson’s Syndrome
The endocrinological criteria for recurrence are the same as for diagnosis at initial presentation: elevated urinary free cortisol; failure to suppress serum cortisol after low-dose dexamethasone administration; and suppression of serum cortisol on high-dose dexamethasone administration. As during the initial work-up, it is important to ensure that cortisol excess is indeed due to pituitary adenoma. Several large studies have reported a recurrence rate of 5% to 27% after initial successful TS surgery. In our experience, most patients recurred within the first few years after successful surgery. The recurrence rate of ACTH-secreting tumors over a 10-year period was 12%.
Nelson’s syndrome, wherein corticotroph adenomas arise following bilateral adrenalectomy, is notoriously intransigent to surgery alone; indeed, Nelson’s adenomas are more invasive than their Cushing’s counterparts. In our series, 25% of patients recurred in 10 years, and repeat transsphenoidal surgery failed to contain growth in this subset of patients.
Therapy for Recurrent Pituitary Tumors
Therapeutic options for pituitary tumors include surgical resection, pharmacotherapy, and radiation therapy (i.e., conventional and stereotactic); pharmacotherapy and radiotherapy are reviewed elsewhere in this volume. The therapeutic goals for recurrent tumors are identical to those in virgin cases and include the following:
Reversing endocrinopathy and restoring normal pituitary function in cases of recurrent hormonally active tumors
Eliminating mass effect and restoring normal neurological function, usually in nonfunctioning tumors
Eliminating or minimizing the possibility of tumor recurrence
Confirming histological diagnosis
These goals apply to clinically active recurrent tumors. Also presenting to the clinician are radiographically present but clinically silent recurrences. These cases are highly individualized, but often a combination of serial imaging and neuro-ophthalmological and endocrine monitoring is warranted. In cases where surgery is considered, a clearly identifiable radiographic anatomical abnormality should be present—except in Cushing’s disease—and a thorough discussion of the increased risk incurred in repeat operations should be undertaken. Furthermore, the surgeon should set realistic expectations as to the success of the repeat operation as nearly 50% of patients undergoing repeat operation will eventually require adjunctive therapy in the form of radiation, medical therapy, or additional surgery.
Choice of Surgical Approach
Approaches to the sellar region can be broadly categorized into three basic groups: transsphenoidal approaches, conventional craniotomy, and alternative skull base approaches. The overwhelming majority of all recurrent pituitary adenomas can be approached through a transsphenoidal approach.
The choice of surgical approach depends on several factors. The most important of these includes the size of the sella, the size and pneumatization of the sphenoid sinus, the position and tortuosity of the carotid arteries, the presence and direction of any intracranial tumor extensions, whether any uncertainty exists about the pathology of the lesion, and whether prior therapy has been administered (i.e., surgery, pharmacological, or radiotherapeutic). Craniotomy may be preferred if the tumor has significant anterior or middle fossa extension or if a tumor with suprasellar extension is suspected to be of sufficiently fibrous consistency as to prevent descent of the lesion inferiorly through the diaphragm.
Occasionally, the configuration of the tumor is such that a single approach, transsphenoidal or transcranial, is insufficient to effect complete tumor removal; in these cases, a combined transcranial-transsphenoidal approach may prove effective. Below, we review the surgical approaches for pituitary tumors, with specific emphasis on transsphenoidal approaches. A singular difference between recurrent and initial operations is the potentially altered anatomy accompanying reoperations. The evolution of endoscopic technology may help in clarifying the altered anatomical landscape in the reoperated patient and is discussed below.
For most pituitary tumors, a transsphenoidal approach is the most appropriate route. Major considerations in the approach to the sella through the sphenoid sinus include entry through the nostril directly (endonasal) or through the nostril via a midline incision under the lip (sublabial) and whether the microscope and/or endoscope is used. In our practice, the endonasal endoscopic approach has become our standard approach in both initial and recurrent cases.
Advantages of the endoscope include the panoramic and angled views that allow the surgeon to obtain a broader anatomical view and may permit one to remove a greater portion of the tumor by direct visualization. The endoscopic approach is also well tolerated, rarely requires nasal packing, and prevents most anterior sinonasal complications. A disadvantage is that current endoscopic technology permits only two-dimensional viewing. Moreover, the surgeon must create enough room not only for the standard operating instruments as used in the microscopic approaches, but also for the endoscope itself. Because more instruments are in place than in the microscopic approach, the exposure must necessarily be larger to accommodate the addition of the endoscope. Below, we review the sequential steps of the transsphenoidal approach.
The patient’s head is supported by a Mayfield headrest with a horseshoe. Because the head is not fixed, gentle lateral movements of the head can be used to optimize intraoperative visualization, especially of the cavernous sinus area. This is not as significant a factor in endoscopic cases, in which the endoscope provides a panoramic view. Fixation of the head may be necessary when certain forms of image guidance are used.
A semirecumbent position is used with the back at a 20-degree angle from the horizontal with the head above the heart. This facilitates venous drainage and decreases venous pressure within the cavernous sinus. The right shoulder is placed at the upper right hand corner of the bed and the patient’s left ear is pointed toward the left shoulder and the bed turned so that the patient’s head remains parallel to the walls of the room. The head may is gently tilted to the right.
Special consideration must be given to the intubation of acromegalic patients who may require awake intubation to safely secure an airway. Perioperative prophylactic antibiotics are routinely employed. We administer steroids only in patients who are adrenally insufficient on preoperative testing. In all others we no longer administer perioperative exogenous steroids. Instead, patients are monitored for clinical symptoms of adrenal insufficiency, and morning serum cortisol levels are drawn on each postoperative day to determine hypothalamic-pituitary-adrenal (HPA) axis reserve. Levels less than 8 μg/dL are considered low and replaced accordingly.
Before and immediately after induction, patients are given oxymetazoline intranasally for nasal decongestion. During positioning, cocaine-soaked patties are placed in both nostrils. The pledgets are allowed to remain in contact with the nasal mucosa for 5 to 10 minutes, during which draping of the patient is completed. The patties are removed after prepping and draping.
In the reoperated patient, the sellar floor may be partially or wholly absent, and autologous graft material—fat and/or fascia—should be considered for reoperations.
Sphenoid Sinus Access and Exposure
The next major consideration in the recurrent trans-sphenoidal procedure is the precise route of entry into the sphenoid sinus. For microscopic approaches, the two basic options are the endonasal approach and the sublabial approach. Selection of one over the other depends on the size of the nostril, the size of the lesion, and the preference of the surgeon. We tend to favor endonasal approaches in most instances, reserving the sublabial incision for pediatric patients or adults with small nostrils in whom the broader corridor afforded by the piriform aperture improves the visualization of the surgical field and the maneuverability of the surgical instruments. The endonasal microscopic approaches include the transseptal submucosal, the septal pushover, and the direct sphenoidotomy. These essentially differ based on the location of the initial incision. With the transseptal submucosal technique, the incision is made just within the nostril posterior to the columella; with the septal pushover it is fashioned at the junction of the bony and cartilaginous septum; and with the direct sphenoidotomy, the incision is made at the junction of the septum and the rostrum of the sphenoid. As the incision is carried farther back, the amount of septal dissection, and therefore nasal complications, necessarily decreases. This decrease in septal dissection does come at the cost of a progressively more narrow and potential off-midline trajectory to the sella. In recurrent cases, we prefer either a septal pushover or direct sphenoidotomy.
Endonasal Microscopic Approaches
In patients who have had previous nasal, septal, or transsphenoidal surgery, we have used an alternative endonasal approach called the endonasal septal pushover technique . The nostril is entered, and an incision is made through the lateral mucous membrane of the nasal septum at the base of the septal insertion onto the maxillary ridge. The incision is carried back to the junction of the cartilaginous and bony septia or back to the face of the sphenoid if this bone has previously been removed. The nasal septum is carefully disarticulated, an opposite-side inferior tunnel is developed, and the septum together with the two layers of attached mucous membrane is reflected laterally to expose the perpendicular plate of the ethmoid and the sphenoid face. This is a rapid method of reaching the sphenoid that we employ commonly, which avoids the difficulty of raising septal mucosal flaps in patients undergoing repeat transsphenoidal surgery.
The most rapid of all endonasal approaches is the direct sphenoidotomy, which is well suited to the reoperated patient in its posterior starting position. In this approach a speculum is inserted directly anterior to the sphenoid rostrum. A sharp incision is made at the attachment of the septum to the sphenoid rostrum and the septum is then reflected laterally, exposing the rostrum of the sphenoid. As there is no submucosal septal dissection, there is rarely a need for nasal packing with its resultant postoperative discomfort. The primary advantages of the septal pushover and direct sphenoidotomy are the rapidity of the approaches and the avoidance of anterior septal dissection and its potential complications. However, these more direct approaches provide a more narrow exposure and an off-midline trajectory.
Sublabial Microscopic Approach
We reserve the sublabial approach for patients with small nasal apertures including pediatric patients and for patients with large tumors with significant extension into the cavernous sinuses and clivus, which may be inadequately visualized through an endonasal approach. After the upper lip is retracted, an incision is made in the buccogingival junction from one canine tooth to the other. Subperiosteal dissection is used to carefully elevate the mucosa from the maxillary ridge and the anterior nasal spine until the inferior border of the piriform aperture is exposed. Two inferior nasal tunnels are created by dissecting the mucosa away from the superior surface of the hard palate. With sharp dissection, a right anterior tunnel is created, and connected with the right inferior tunnels, and the entire right side of the nasal septum is exposed back to the perpendicular plate of the ethmoid. Using firm, blunt dissection along the right side of the base of the nasal septum, the cartilaginous portion of the nasal septum is dislocated and reflected to the left, and a left posterior mucosal tunnel is developed along the left side of the bony septum. At this point, it should be possible to insert the transsphenoidal retractor. After the retractor is in place, the vomer, with its distinctive keel shape, should be visualized. Reoperations in patients who have undergone prior sublabial approaches may be complicated by difficulty raising the mucosal flaps away from the cartilaginous septum, so a septal pushover or direct sphenoidotomy with or without an endoscope may be appropriate.
Whereas the transsphenoidal approach has always been considered minimally invasive, particularly when compared with conventional transcranial approaches, the concept has been redefined in the context of endoscopic approaches to the sella. These approaches use straight and angled endoscopes as the sole visualization tools (i.e., pure endoscopic approach) or as a supplement to the operating microscope (i.e., endoscopic-assisted microscopic approach).
Several endoscopic approaches to the sella are used. The iterations include mononarial or binarial techniques, two-handed approaches with or without the endoscope holder, or three-handed or four-handed approaches without the holder. Some surgeons advocate a unilateral partial middle turbinectomy to improve the maneuverability of instruments. Our bias is to perform a three-handed binarial technique with a partial posterior septectomy without routine middle turbinectomy.
The zero degree endoscope is used for the majority of the exposure and tumor resection. The endoscope is brought within the nostril and the sinonasal anatomy is identified, including the nasal floor and both the inferior and middle turbinates. The middle turbinate is lateralized and the choana and the spheno-ethmoid recess are identified. In primary cases, the sphenoid ostia are identified, and the septum cracked laterally at its insertion on the face of the sphenoid. In reoperated cases, the endoscopic view may assist in identifying midline structures—such as an inferior remnant of the midline sphenoid rostrum—and in delineating layers of scar or tissue.
Cappabianca et al have extolled the virtues of endoscopic assistance in transsphenoidal reoperations, reporting fast entry to the sphenoid and greater ease in navigating a scarred sella when compared with microscopic approaches. Other groups have reported greater difficulty with an endoscopic approach in repeat transsphenoidal surgery, with some reporting CSF leaks in 43%. In our practice, the endoscopic approach has become the preferred method in repeat transsphenoidal surgery owing to speed of entry and to the enhanced views—particularly of scar tissue—afforded by the endoscopic view.