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EXTENSIVE CLINICAL EXPERIENCE |
Departments of Neurological Surgery (N.P., D.M.P., J.J., E.R.L.) and Pathology (M.B.L.), Division of Neuropathology, and Department of Medicine (M.L.V.), Division of Endocrinology, University of Virginia, Charlottesville, Virginia 22903
Address all correspondence and requests for reprints to: Nader Pouratian, M.D., Ph.D., Resident, Department of Neurological Surgery, University of Virginia, Box 800212, Charlottesville, Virginia 22903. E-mail: np5k{at}virginia.edu.
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Abstract |
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Setting: This was a retrospective review of patients treated at the University of Virginia Medical Center.
Patients: Of 490 TSS procedures for Cushing’s disease between 1993 and 2004, we identified 111 cases without histological adenoma confirmation.
Main Outcome Measure: Remission and recurrence of Cushing’s disease were measured.
Results: Overall, 50% of these patients achieved remission, a figure lower than for our entire series (79%) and for patients with histological confirmation of an ACTH-staining adenoma (88%) (P < 0.001). Patients with a history of two prior TSS achieved remission less often than patients with a history of fewer TSS (P = 0.026). No other factors influenced remission rates. Although the overall recurrence rate (21%, seven of 33 evaluated) was not different from previously published long-term studies, in three of seven cases of recurrence, early recurrences were noted between 2 and 4 months after remission. In patients who did not achieve remission, the most common and effective treatment options were repeat TSS, 
-knife radiosurgery, and bilateral adrenalectomy.
Conclusion: The lower remission rate in patients without histological evidence of an adenoma is most likely a result of a decreased rate of adenoma extirpation. The incidence of early recurrence may be a unique feature of this patient population; patients without histological confirmation of tumor resection therefore require close and consistent monitoring postoperatively.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although previously described, the significance of this lack of histological confirmation of adenoma after TSS remains unclear. We retrospectively analyzed a series of 111 TSS for Cushing’s disease who did not have an ACTH-staining adenoma to assess the efficacy of TSS in this group of patients, identify factors associated with remission, quantify recurrence rates in patients who achieved remission, describe the postoperative management in patients who did not achieve remission, and propose reasons why an adenoma was not identified histologically.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Between 1993 and 2004, 445 patients were diagnosed with and underwent 490 TSS for Cushing’s disease at the University of Virginia. In accordance with the University of Virginia Human Investigation Committee guidelines, these patients’ records were retrospectively reviewed, identifying 111 cases for which there no histological evidence of an adenoma.
Diagnostic criteria
Hypercortisolism was established in all patients by documenting at least two elevated 24-h urinary free cortisol (UFC) levels. Pituitary dependence was established by a variety of means, including high-dose dexamethasone tests, inferior petrosal sinus sampling (IPSS), magnetic resonance imaging (MRI) evidence of a pituitary adenoma, or a history of prior transsphenoidal adenoma resection with either clinical and biochemical remission or histological evidence of an ACTH staining adenoma.
Surgical procedure
In all cases, a transsphenoidal approach was used for resection of a presumed ACTH-secreting pituitary adenoma. Once the sella was exposed and the dura incised, the entire pituitary gland was carefully explored, regardless of MRI or IPSS findings. All tissue deemed to be abnormal was resected and submitted to pathology. Depending on the patient’s age, history, and severity of disease, hemihypophysectomy (on the side corresponding with either an MRI abnormality or IPSS lateralization), subtotal hypophysectomy, or total hypophysectomy was performed in patients in whom no clearly abnormal tissue could be identified intraoperatively. No filter trap was used on the suction apparatus during surgery.
As reported previously, in many cases at the University of Virginia, we use a strategy of early reoperation (within 15 d of the initial surgery) in patients who were considered surgical failures, particularly in patients in whom an adenomectomy or hemihypohysectomy was performed during the initial surgery (8). Surgical failures were defined as patients whose plasma cortisol levels did not fall to 2 µg/dl or lower within 72 h after surgery.
Specimen handling and histological analysis
All resected tissue was immediately placed on a moist piece of Telfa, bagged, and submitted in its entirety to the neuropathologist within minutes of completing the resection. Specimens were then scraped off the Telfa using a sharp blade, packaged in lens paper, fixed in formalin, and embedded in paraffin for light microscopy.
All specimens were initially evaluated using hematoxylin and eosin (H&E) to identify areas with loss of acinar organization. When a pituitary adenoma was not identified on the initial H&E sections, a Cushing’s panel was ordered, consisting of 30 sequential 5-µm-thick sections through the paraffin block with every third slide stained with H&E. In sections that were suspicious for adenoma, the intervening unstained sections were stained for reticulin and ACTH (immunohistochemical stains). If an adenomatous area was not identified, further Cushing’s panels were ordered until the tissue block was exhausted.
Data collection and analysis
For each patient, we documented patient characteristics (age, gender, duration of Cushing’s symptoms, and comorbidities), preoperative laboratory test results (high-dose dexamethasone tests and IPSS), preoperative imaging results (based on the surgeon’s preoperative impression), intraoperative impressions (whether adenomatous tissue was noted by the surgeon and what type of resection was performed), endocrinological remission, and postoperative follow-up (number and type of further treatments and time to recurrence, if applicable). Remission was defined as requiring corticosteroid replacement postoperatively due to hypocortisolemia and having a documented normal postoperative 24-h UFC.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Diagnosis of Cushing’s disease
Once hypercortisolism was established, four methods were used to confirm a pituitary etiology. Often, more than one method was used in an individual patient. In 59% of cases, a high-dose dexamethasone test was used to determine pituitary dependence. Specifically, 36 patients underwent an 8-mg overnight dexamethasone test with measurement of a serum cortisol the next morning and 29 patients underwent a 48-h (2 mg orally every 6 h) dexamethasone test with measurement of a 24-h UFC after dexamethasone administration. Fifty-eight percent of patients underwent IPSS to establish a pituitary etiology. In 37% of patients, preoperative MRI definitively demonstrated a pituitary adenoma. In 30% of patients, pituitary etiology was based on a history of prior TSS, resulting in clinical remission. Finally, in 23% of patients, a pituitary etiology was based on a history of prior TSS with histological evidence of an ACTH producing adenoma.
Intraoperative findings
In 71% of cases, the primary surgeon (E.R.L) reported having seen either an adenoma (n = 60) or tissue suspicious of an adenoma (n = 19) during surgery. No clearly abnormal tissue was identified in the remaining cases (n = 32). Four types of procedures were described in the operative notes, including adenomectomy (n = 34), hemihypophysectomy (n = 15), subtotal hypophysectomy (n = 34), and total hypophysectomy (n = 28). The procedure performed was significantly associated with whether an adenoma or suspicious tissue was identified intraoperatively (P = 0.002, Kruskal-Wallis nonparametric test of distribution). Whereas an adenomectomy was often performed when an adenoma or suspicious tissue was identified during surgery (accounting for 34 of 79 procedures in which an adenoma or abnormal tissue was identified), an adenomectomy was never performed when abnormal tissue could not be identified. In these cases, a subtotal or total hypophysectomy was the preferred procedure (accounting for 26 of 32 such cases). In all but one case, all resected tissues were immediately delivered to the operating room nurse to be submitted to the neuropathologist. In the one exceptional case, although the adenoma was seen, the tumor was lost in suction. In this case, pathology revealed only Crooke’s hyalinization. An intraoperative cerebrospinal fluid (CSF) leak was present in 58 cases, occurring more often in patients with a history of prior TSS (71%) than in patients undergoing TSS for the first time (39%) (P < 0.001, 
2 test).
Histopathological findings
Four distinct histological patterns were identified. In 69% of cases, the specimen demonstrated normal acinar architecture without evidence of reticulin disruption or Crooke’s hyalinization. Immunohistochemical staining for pituitary hormones revealed a normal distribution of pituitary cell types. In 29% of cases, Crooke’s hyalinization was noted in the pathological specimen. Crooke’s hyalinization is a morphological marker of feedback suppression that indicates the status of normal corticotrophs. Histologically, it consists of accumulation of hyaline material as a concentric whorl in the cytoplasm and shows strong immunoreactivity with cytokeratins. The presence of Crooke’s hyalinization confirms that the patient has raised circulating glucocorticoids (Cushing’s syndrome), but the differential diagnosis includes pituitary adenoma, ectopic ACTH secretion, primary adrenal pathology, or iatrogenic administration of glucocorticoids. The absence of this change may represent a misdiagnosis of Cushing’s syndrome. The specimens otherwise had normal acinar architecture, reticulin network, and pituitary hormone immunohistochemical patterns. In one case, ACTH hyperplasia was identified without evidence of an ACTH adenoma. In two cases, incidental prolactin staining microadenomas were identified.
Outcomes
The remission rate in this series was 50%, a figure lower than for our entire series of 490 operations (79%) and for the subset of patients with histological confirmation of an ACTH-staining adenoma (88%) (2 = 73.4, P < 0.001). Endocrine (biochemical) remission was accompanied by clinical improvement in all patients. Several demographic, historical, diagnostic, imaging, and intraoperative characteristics were investigated to determine whether any were associated with remission (Table 1
). Patients with a history of two prior TSS achieved remission less frequently than patients with a history of one or no prior TSS (P = 0.026, Kruskal-Wallis nonparametric test). Differences in the use of and the results of preoperative diagnostic tests, preoperative MRI findings, intraoperative impressions, type of resection performed, and occurrence of a CSF leak were not associated with different remission rates (Table 1).
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Of 56 patients who achieved remission, 33 were evaluated for recurrence based on having at least 12 months of endocrine follow-up or having documented recurrence within 12 months of the initial procedure. The median, mean, and range of follow-up in this subset of patients were 30, 45, and 4–145 months, respectively. Cushing’s disease recurred in seven of the 33 patients (21%). The median time to recurrence was 29 months (range 2–134 months). Three recurrences were considered early, occurring 2, 3, and 4 months after the operation. Recurrence rates were not related to any factors tested (Table 1
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Postoperative management of patients who did not achieve remission
Records describing additional treatment and management were available in 41 patients who did not achieve remission (Table 2). The most common treatments used were repeat TSS, -knife radiosurgery (GKRS), and bilateral adrenalectomy.
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To assess GKRS efficacy, we evaluated 12 patients who were treated with GKRS and had at least 12 months of follow-up without further intervention (e.g. bilateral adrenalectomy) or who achieved remission within 12 months of treatment. Six achieved and remained in remission at last follow-up (median follow-up after GKRS = 42 months, range 7–75 months). The remaining six patients either underwent bilateral adrenalectomy (n = 4) between 16 and 51 months after GKRS (median=33 months) or continued to be treated with ketoconazole (n = 2). Of the remaining nine patients treated with GKRS, three were treated within 12 months of this analysis, four underwent bilateral adrenalectomy less than 12 months after GKRS, one was lost to follow-up, and one was treated with GKRS for Nelson’s syndrome after bilateral adrenalectomy.
Two patients were treated with fractionated radiotherapy 1 and 7 months after failed TSS. Only one patient had adequate follow-up (>12 months) and had achieved remission.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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TSS is the most effective treatment for Cushing’s disease, providing remission in 59–90% of patients (1, 2, 3, 4, 5, 6, 7). Some reports indicate that histological adenoma confirmation significantly affects remission rates, with remission rates in patients without histological confirmation of tumor resection ranging between 36 and 69% (2, 10, 11). Invitti et al. (10) found remission rates were markedly lower in patients in whom an adenoma could not be identified histologically (36 vs. 75%, P < 0.01). Similarly, several groups have reported that histological confirmation of an adenoma is significantly more likely in patients who achieve remission than in patients with persistent disease (12, 13). Sonino et al. (1) concluded that surgical failure is associated significantly with failure to identify a pituitary adenoma in the surgical specimen. Despite these reports of differences in outcomes related to histological findings, other groups have found indistinguishable remission rates between these two groups (14, 15).
Our current series of 111 patients without histological confirmation suggests that the remission rate in this population is lower than in patients with histological confirmation of a tumor. The lower remission rate is most likely attributable to a decreased rate of adenoma removal in this group. This assertion is supported by several lines of evidence. Residual intrasellar adenoma was histologically confirmed in five patients who underwent repeat TSS. In an additional four patients, repeat TSS resulted in clinical remission (without histopathological evidence of an adenoma), suggesting failure to resect tumor at the time of the initial TSS. The success of postoperative therapies directed at the sella [e.g. fractionated radiotherapy (XRT), GKRS, and repeat TSS] further support the notion that an intrasellar adenoma was not successfully removed during the initial operation. Remission rates are likely lower in patients with a history of prior TSS because of distorted postsurgical sellar anatomy, complicating the operative procedure and making the resection of an adenoma more challenging. Having a history of prior TSS may also indicate a recurrent or persistent adenoma that may have invasive characteristics, making resection and therefore achieving remission more difficult (16).
Recurrence
Recurrence rates for Cushing’s disease range between 0 and 26% (6), with most large studies reporting recurrence rates between 5 and 15% and a median time to recurrence of 33–59 months (2, 5, 6, 7, 17). Although Invitti et al. (10) identified significant differences in remission rates related to the histological confirmation of an adenoma, they reported no significant difference in recurrence rates. Although we previously reported only a 5% recurrence rate at an average follow-up of more than 3 yr (9), our current results indicate a recurrence rate in this population corresponding to the upper range of that reported in the literature. Moreover, the timing of recurrence and incidence of early recurrence (at 2, 3, and 4 months) appears to be a unique feature of these patients. All three patients with early recurrence transiently required corticosteroids postoperatively and had a normal 24-h UFC documented between surgery and recurrence. Early recurrences may be attributed to either incomplete resection of the ACTH adenoma or failure to resect the adenoma but temporarily decrease its secretory status as a result of intraoperative manipulation (9). The incidence and timing of recurrence mandate close monitoring of patients with lack of histological confirmation of a tumor.
Where is the tumor?
There are four reasons for lack of histological confirmation of adenoma resection. First, an ACTH adenoma may have been present and either resected or compromised but not processed for pathological analysis. Examples may include instances when abnormal tissue is reported to be lost in suction (n = 1) or when pituitary gland exploration may cause inadvertent vascular compromise and necrosis of the hypersecreting adenoma. Second, an ACTH adenoma may have been resected, processed for pathological analysis, but not identified by the pathologist on pathological sections. Third, an ACTH adenoma may have been present but not surgically removed secondary to surgical inaccessibility via a transsphenoidal approach, the invasive nature of the tumor, or inadequate exploration of the sellar contents. Fourth, one must consider the possibility of misdiagnosis, that hypercortisolemia is due to an ectopic source of ACTH. Although the diagnosis of pituitary Cushing’s was ascertained by several methods (IPSS, high dose dexamethasone tests, history of prior surgery resulting in remission, history of prior surgery, definitive lesion on MRI), the possibility of ectopic CRH production, an adenoma in the parasellar space, stalk, or dura, and diffuse hyperplasia cannot be excluded. However, diffuse hyperplasia was not identified in the pathological analysis and small samples of dura mater were often included in the surgical specimen, but interpretation is limited by the small sample size.
In patients who achieve remission, the tumor must have been removed or at least sufficiently compromised by the surgical procedure so as to lose function (the first two explanations above). We previously suggested the possibility that manipulation and exploration of the gland could disturb the blood supply of the tumor sufficiently to result in tumor necrosis and remission without resection (9). Alternatively, the tumor may have been removed but lost either during surgery (e.g. in suction) or during the process of submitting it for histological processing (from surgeon to nurse to pathology technician to pathologist). Finally, the specimen could have been processed histologically but not seen by the pathologist on serial sections. In most cases, however, the pathological specimen was analyzed exhaustively, essentially excluding the possibility that an adenoma existed in the tissue block.
In patients who do not achieve remission, the most likely explanation is failure to resect the adenoma, although one must also consider the possibility of misdiagnosis. The preoperative evaluation of those patients who failed to achieve remission after all therapies directed at the sella are detailed in Table 3. Although in individual cases preoperative test results may be interpreted as ambiguous, when considering all patients, preoperative diagnostic test results did not significantly affect remission rates (Table 1), indicating that patients who did not achieve remission did not have significantly different preoperative test results from patients who achieved remission. Moreover, at the University of Virginia, all patients undergo thorough clinical and endocrinological evaluation for Cushing’s disease before being referred for TSS and both the endocrinologists and neurosurgeons are confident in the diagnosis before surgery.
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Assuming that the neurosurgeon and endocrinologist are confident in the diagnosis of Cushing’s disease, in patients who fail to achieve remission after TSS, further interventions directed at the sellar region are warranted. In most series, GKRS results in remission in 50–80% of patients with Cushing’s disease (18, 19, 20, 21). Similarly, we found that GKRS is an effective treatment in 50% of evaluable patients without histological confirmation of adenoma resection. Although not used as often in this series, other treatments including XRT and repeat TSS can also be effective. GKRS, however, offers some advantages over XRT and repeat TSS. Relative to XRT, GKRS allows delivery of highly focused radiation to the sellar region and spares surrounding critical structures. Moreover, GKRS allows treatment of areas that may be inaccessible surgically (e.g. cavernous sinus). When treatment directed at the sella fails, bilateral adrenalectomy is highly effective at controlling hypercortisolemia (22). Because of associated comorbidities with this procedure, this is generally reserved as a final intervention after interventions directed at the sella fail, and pituitary radiation is generally recommended to prevent the development of Nelson’s syndrome.
Conclusions
The significance of lack of histological confirmation of tumor resection after TSS for Cushing’s disease remains controversial. We suggest that these patients have suboptimal remission rates and are more likely to experience early recurrence. Assuming that a rigorous diagnostic workup is completed before performing TSS for Cushing’s disease (which is critical), patients without histological confirmation of tumor resection should be monitored closely to ensure successful and adequate long-term treatment and outcome.
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Footnotes |
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First Published Online June 26, 2007
Abbreviations: CSF, Cerebrospinal fluid; GKRS, -knife radiosurgery; H&E, hematoxylin and eosin; IPSS, inferior petrosal sinus sampling; MRI, magnetic resonance imaging; TSS, transsphenoidal surgery; UFC, urinary free cortisol.
Received January 29, 2007.
Accepted June 15, 2007.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Knife radiosurgery in the treatment of Cushing disease: long-term results. J Neurosurg 97:422–428[Medline]This article has been cited by other articles:
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  C. G. Patil, D. M. Prevedello, S. P. Lad, M. L. Vance, M. O. Thorner, L. Katznelson, and E. R. Laws Jr. Late Recurrences of Cushing's Disease after Initial Successful Transsphenoidal Surgery J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 358 - 362. [Abstract] [Full Text] [PDF]
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