In this study, we present long term data from a large cohort of patients undergoing repeat transsphenoidal surgery for recurrent non-secreting pituitary macroadenomas. Our data suggest that when performed by experienced transsphenoidal surgeons, durable tumor control can be obtained in these frequently locally aggressive tumors with acceptable rates of post-operative morbidity. While it is tempting to refer these patients to radiosurgery in an attempt to save them a second operation [12
], it should be noted that these tumors can change their hormonal and biologic phenotype at the time of recurrence [15
]. Given the good results we have seen with repeat surgery, we feel monotherapy with radiosurgery should be undertaken only in select cases when after endocrinologic work-up, it is certain that the tumor has not become a hormone secreting tumor.
Probably the most interesting finding of our analysis is the relatively low rate of clinically important tumor recurrence/progression (8% at 5 years following the second operation), even though a large number of these patients (35%) had at least some residual tumor left on imaging. A number of these patients with residual disease have been followed well past 10 years, and in a few cases 20 years, without evidence of tumor growth requiring treatment. Also, interesting was the observation that none of the 24 patients in this cohort who made it to 10 years of follow-up without clinically significant tumor growth/regrowth, went onto have a subsequent recurrence. While the number of recurrences in this group was too low to make any definitive conclusions regarding recurrences rates, radiographic gross total resection did not seem to have a protective effect, or at least subtotal resection did not seem to predispose to certain recurrence in this group.
Over one half of these patients presented with visual disturbance, and in this cohort we found that 39% of these patients experienced improved vision with a second surgery. More importantly, no one with normal vision (in whom the indication for surgery is less certain), suffered any appreciable decline in vision. Interestingly, leaving a small amount of residual did not appear to make a difference in long term outcome, as these tumors infrequently recur, and when they do, they seldom make vision worse. While 8% of patients with pre-op visual compromise had post-operative visual worsening, these cases were evenly divided between subtotal and gross total resection, suggesting that the visual decline was not necessarily due to overaggressive attempts to obtain a gross total resection.
Approximately, 35% of patients with pre-operative anterior pituitary dysfunction recovered function after surgery in our series, and no patient’s function worsened. This is important to note, as at repeat transsphenoidal surgery due to scar tissue it can be more difficult to discern clear planes between tumor and normal gland than at the initial surgery, and as such, it wouldn’t be unreasonable to hypothesize that repeat surgery would have a higher rate of hypopituitarism. This does not seem to be the case whether a gross total or subtotal resection is performed, or even if the patient receives external beam radiotherapy. Why this rate seems to be lower than published rates for initial operation is not entirely clear, but perhaps a pseudocapsule of scar tissue around the gland protects the normal tissue at repeat surgery.
While these data and that reported by others demonstrate repeat transsphenoidal surgery can generally be performed with good results and a low amount of major morbidity [1
], the single mortality in this series highlights the potential serious risk of repeat surgery, as typical landmarks and tissue planes helpful in the initial surgery, are not present at repeat surgery, increasing the risk of intrasellar and intracranial bleeding and the attendant complications resulting from these problems. Our complication rates for repeat surgery are slightly higher than those observed for very experienced transsphenoidal surgeons performing initial surgery [3
]. The surgeon and patient must be aware of these risks when weighing the benefits and risks of a repeat entry into the sella.
Rational therapy for recurrent EIA’s involves assessment and application of the cost-risk–benefit balance between treatment, continued observation, and radiation therapy. At time of recurrence, the histologic diagnosis of these tumors has been established, and the primary management goal of these tumors is the prevention of endocrine and visual morbidity related to tumor growth. Given the lack of hormonal hypersecretion for these tumors, the cost-risk–benefit balance largely centers around the issue of tumor control, and necessity of treatment for obtaining tumor control. While our data suggest that repeat surgery is a reasonable and safe option for achieving tumor control, it is certainly not the least invasive or least costly method for achieving this goal. While it is possible that recurrence of tumor implies a persistently growing tumor phenotype, more data regarding the natural history of untreated recurrent EIA’s are needed to determine what fraction, if any, of these tumors plateau in growth, and what fraction continue to regrow. A better understanding of the natural history of recurrent EIA’s is necessary to determine the relative feasibility of observation of recurrent EIA’s, and to determine the indications for repeat transsphenoidal surgery.
In short, we provide long term follow-up data demonstrating that repeat transsphenoidal surgery is a reasonable and effective therapy for large recurrences of endocrine inactive pituitary macroadenomas, which can be performed with good visual and endocrine outcomes, and a low rate of 3rd recurrence, even when followed out over a decade.