Keywords
magnetic resonance imaging - pituitary - macroadenoma - postoperative
Introduction
Transsphenoidal surgical debulking is important in the initial management of most
pituitary macroadenomas. However, there is evidence of residual tumor postsurgery
in 28 to 70%,[1]
[2]
[3]
[4] and there is subsequent regrowth in 30 to 50% of nonfunctioning pituitary adenomas.[5]
[6]
[7]
Pituitary adenomas may extend laterally into the parasellar region, either by displacement
of the medial wall of the cavernous sinus or by dural penetration and invasion of
the cavernous sinus. Cavernous sinus invasion indicates an aggressive behavior of
the tumor,[8] increases the likelihood of a tumor remnant postsurgery, and reduces the possibility
of endocrinological remission in functioning tumors.[1]
[9]
[10]
Postoperative magnetic resonance imaging (MRI) is used to detect such residual parasellar
tumor.[10]
[11]
[12] It is conventionally performed at 3 to 4 months after tumor excision, so allowing
for the delayed regression of postoperative changes. If a macroscopic tumor remnant
is evident on this imaging, then further radiotherapy or pharmacologic therapy is
usually advocated to decrease its growth potential.[13]
[14]
To anticipate the presence of cavernous sinus invasion, various preoperative MRI features
have been explored for their ability to predict whether lateral extension of tumor
is due to cavernous sinus infiltration rather than displacement. These MRI criteria
have been correlated with the presence of cavernous sinus invasion at surgery[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22] or whether there is dural infiltration on histology.[23] Although this is valuable information, it is the presence of residual parasellar
tumor on postoperative MRI that dictates the subsequent management and prognosis,
rather than evidence of the parasellar invasion itself. Therefore, it is also important
for MRI to be able to predict the likelihood of a radical resection, and a so-called
radiologic cure of this parasellar tumor would be a more appropriate reference standard.
The purpose of this study was to investigate whether preoperative MRI criteria for
parasellar extension could be used to indicate whether a complete resection will be
subsequently evident on imaging. This will allow earlier consideration and patient
discussion concerning the requirement for postoperative radiotherapy or pharmacologic
therapy.
Method
The study was performed at a tertiary neuroscience center with patients managed by
a multidisciplinary team and two experienced pituitary surgeons. The study protocol
was submitted to the institutional review body and considered as a service evaluation.
Consecutive cases with a histologic diagnosis of pituitary adenoma were extracted
from a neuropathology database. Imaging and clinical data were used to select those
patients who had undergone transsphenoidal surgery for pituitary macroadenoma (between
December 2004 and January 2010). The preoperative MRI studies of these patients were
initially reviewed. Subjects were selected who demonstrated potential parasellar extension
on dedicated preoperative pituitary MRI (3-mm coronal and sagittal pre- and postgadolinium
T1-weighted imaging of the pituitary fossa. The preoperative imaging was performed
at a mean of 3.75 months (standard deviation [SD]: 3.5 months) prior to surgery. Those
cases where parasellar extension was not present were excluded. The absence of parasellar
extension was assessed by using MRI criteria,[15]
[21]
[22] which have been shown to have a high negative predictive value for parasellar invasion.
These criteria were (1) depiction of the medial venous compartment; (2) percentage
encasement of the intracavernous internal carotid artery (ICA) by <25%, and (3) no
crossing of the medial intercarotid line ([Fig. 1]). There remained 74 of 354 patients with potential parasellar extension of adenoma
on the preoperative MRI. Appropriate postoperative imaging (3-mm coronal and sagittal
pre- and postgadolinium T1-weighted imaging of the pituitary fossa at 3 months postsurgery)
was only available for 54 of 74 of these patients. It was necessary to exclude a further
5 of 74 patients with bilateral potential parasellar involvement due to reasons of
statistical validity, since it was uncertain whether to consider each side as a different
entity despite being the same patient. The final group for analysis was composed of
49 patients (28 male, 21 female; mean age: 53 years; age range: 23–85 years; SD age:
15 years).
Fig. 1 Gadolinium-enhanced coronal image illustrating criteria used to exclude cases where
parasellar extension was not present. On the left there is depiction of the medial
venous compartment (star), no encasement of the intracavernous internal carotid artery,
and no crossing of the medial intercarotid line (line). On the right there is parasellar
extension of adenoma.
The MRI studies were reviewed by two neuroradiologists (FW and KH), and a consensus
was achieved for each recorded outcome. Preoperative MRI studies were scored for the
presence or absence of the following criteria based on previous references[15]
[ 21]
[ 22]: (1) total encasement of the intracavernous ICA ([Fig. 1]); (2) displacement of the intracavernous ICA by tumor ([Fig. 1]); (3) asymmetry of the right and left cavernous sinuses; (4) nondepiction of the
lateral sulcus venous compartments ([Fig. 2]); (5) nondepiction of the superior venous compartments ([Fig. 2]); (6) nondepiction of the inferolateral venous compartments ([Fig. 2]); (7) nondepiction of the carotid sulcus venous compartment ([Fig. 2]); (8) lateral bulging of the lateral dural wall of the cavernous sinus (convex contour
of the wall) ([Fig. 3]); (9) whether the tumor crossed one of the intercarotid lines (medial, median, or
lateral) according to grade 0 to 3 of the Knosp-Steiner criteria[17] ([Fig. 2]); (10) the perimeter of the intracavernous ICA encased by tumor (divided into twelfths
like a clock face) ([Fig. 3]).
Fig. 2 Gadolinium-enhanced coronal image demonstrating the intercarotid lines and the cavernous
sinus venous compartments. The intercarotid lines (left side) were defined as straight
lines running between the ipsilateral supraclinoid and cavernous limbs of the carotid
artery from their medial edges (medial intercarotid line A), centers (median intercarotid
line B), and lateral edges (lateral intercarotid line C).The venous compartments (right
side) were superior compartment, 1; venous sulcus compartment, 2; inferolateral compartment,
3; and lateral compartment, 4.
Fig. 3 Gadolinium-enhanced coronal image demonstrating the division of the perimeter of
the intracavernous internal carotid artery into twelfths like a clock face, used to
score the degree of encasement. There is also bulging of the lateral wall of the cavernous
sinus (arrow).
The postoperative images were then evaluated for residual disease and classified as
either a complete resection or potential residual tumor by consensus, according to
a priori criteria. A complete resection was recorded if there was a normally enhancing
cavernous sinus ([Fig. 4]) or if only a linear plaque of scar tissue was evident, which markedly differed
in signal and enhancement to the tumor preoperatively. Potential residual tumor was
recorded if (1) there was clear residual parasellar tumor in the same location as
that shown on the preoperative imaging, and with similar signal and enhancement characteristics
([Fig. 5]), or (2) if there was indeterminate abnormal parasellar tissue with signal, enhancement,
or location that differed slightly with the tumor on preoperative MRI ([Fig. 6]).
Fig. 4 Gadolinium-enhanced coronal images (A) pre-resection and (B) 3 months postresection.
A complete resection was recorded because there is normally enhancing cavernous sinus
demonstrated at the site of a preoperative right parasellar tumor.
Fig. 5 Gadolinium-enhanced coronal images (A) pre-resection and (B) 3 months postresection.
Residual parasellar tumor was recorded because there is clear residual left parasellar
tumor in the same location as that shown on the preoperative imaging (arrow), with
similar signal and enhancement characteristics.
Fig. 6 Gadolinium-enhanced coronal images (A) pre-resection and (B) 3 months postresection.
An indeterminate resection was recorded because there is residual tissue that differs
slightly to that on preoperative magnetic resonance imaging (arrow) at the site of
the preoperative left parasellar tumor.
Preoperative MRI criteria and the postoperative MRI findings of complete resection
versus potential residual tumor were compared using the Fisher exact test. The ORs
for potential residual tumor outcomes using each significant criterion were obtained
by logistic regression. A two-sample Wilcoxon rank sum test was performed to assess
the correlation between the degree of intracavernous ICA encasement and complete resection
versus potential residual tumor.
Results
The postoperative images were evaluated as showing a complete resection in 22 cases
and potential residual tumor in 27 cases (of which 3 were indeterminate). [Table 1] shows the correlation between preoperative MRI criteria and the postoperative MRI
findings of complete resection versus potential residual tumor. The criteria that
reached statistical significance using the Fisher exact test (p < 0.05) were the depiction of the inferolateral and lateral compartments of the cavernous
sinus. The percentage of the intracavernous carotid encasement was also significantly
related to the presence of complete resection versus potential residual tumor as evaluated
with a two-sample Mann-Whitney U test (p < 0.0005; z = −3.477). Depiction of the lateral or inferolateral venous compartments and the
percentage of the intracavernous carotid surrounded by tumor (expressed in quarters)
were then used in a logistic regression model. The ORs were 6.1 (95% confidence interval
[CI], 1.28–27.8) for depiction of the lateral venous compartment and 3.4 (95% CI,
0.98–12.0) for each quarter of intracavernous ICA encasement.
Table 1
Fisher exact scores for the preoperative magnetic resonance imaging criteria versus
complete excision/potential residual adenoma
|
Magnetic resonance imaging criteria
|
Fisher exact score
|
|
Total encasement of cavernous carotid
|
0.056
|
|
Displacement of cavernous ICA
|
0.361
|
|
Asymmetry of the cavernous sinuses
|
0.51
|
|
Nondepiction of the superior compartment of the cavernous sinus
|
0.117
|
|
Nondepiction of the carotid sulcus compartment of the cavernous sinus
|
0.182
|
|
Nondepiction of the inferolateral compartment of the cavernous sinus
|
0.001
|
|
Nondepiction of the lateral compartment of the cavernous sinus
|
0.001
|
|
Lateral bulging of the lateral dural venous wall of the cavernous sinus
|
0.228
|
|
Crossing the intercarotid (medial/median/lateral) lines
|
0.188
|
Abbreviation: ICA, internal carotid artery.
The depiction of the lateral venous compartment, inferolateral venous compartment,
and encasement of the intracavernous ICA by <50% demonstrated 0.86/0.62/0.65/0.85,
0.95/0.48/0.6/0.92 and 1.0/0.69/0.63/1.0 sensitivity/specificity/positive predictive
value/negative predictive value for a complete resection on the postoperative MRI.
The high negative predictive values indicate that the adenoma is unlikely to be completely
resected if these MRI features are present preoperatively.
Discussion
Parasellar infiltration by a pituitary adenoma is clinically significant and occurs
in 6 to 10% of cases.[24]
[25] The finding indicates increased tumor aggressiveness and renders the tumor a challenging
surgical target, with the potential for incomplete resection and hence a requirement
for further therapy. Previous studies[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22] focused on the ability of MRI criteria to predict cavernous sinus invasion as assessed
intraoperatively. Using a surgical reference standard may be imperfect, since the
medial wall perforation and exposure of the intracavernous ICA or intracavernous trabeculae
may not be clearly visualized.[21] Moreover, in terms of the resectability, it may not be the presence of parasellar
involvement alone, but rather its extent, which is likely to influence resectability.
We therefore aimed to provide objective MRI-based criteria that could stratify cases
according to whether there would be radical or subtotal removal of parasellar tumor
on postoperative MRI. Although postoperative imaging will still be required, a preoperative
assessment of the likelihood of residual parasellar tumor will allow for earlier consideration
and preoperative patient discussion concerning the need for additional postoperative
therapy.
The assessment of parasellar extension of a macroadenoma is a key part in the evaluation
of the preoperative MRI study. There are few indicators of parasellar involvement,
since clinical features occur late and subsequent examination of both histologic and
molecular tumor markers is inconsistently correlated with parasellar invasion.[17]
[19] Since the medial dural wall of the cavernous sinus is very thin and incomplete,
it is not possible to directly visualize the penetration of the dura on MRI.[26] Hence MRI criteria and scoring systems such as the Knosp criteria[17] have evolved that have been used to predict whether there is infiltration rather
than lateral bulging of adenoma into the cavernous sinus. The most specific MRI features
shown to predict cavernous sinus invasion at surgery are encroachment on specific
venous spaces, encasement of the intracavernous ICA, and crossing of the lateral intercarotid
line (according to the Knosp criteria).[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22] With respect to the venous spaces, it is nondepiction of the lateral venous compartment[22] and carotid sulcus venous compartment,[15] as well as nondepiction of greater than three venous compartments,[22] which have shown high positive predictive values for cavernous sinus invasion. Our
MRI criteria shown to predict residual parasellar tumor on postoperative imaging differ
slightly from those used to predict cavernous sinus invasion at the time of surgery.
Our study also illustrates the importance of the depiction of the venous compartments;
however it was sparing of the most lateral venous spaces (lateral and inferolateral)
that was significantly correlated with a complete excision of tumor on postoperative
MRI. The likelihood of a radical excision increased by more than six when there was
depiction of the normal lateral or inferolateral venous compartments. This finding
is biologically plausible because these lateral compartments are the most distant
from the pituitary fossa and involvement occurs late, suggesting more advanced disease
and a more challenging operation. The degree of intracavernous ICA encasement has
also previously been compared with surgical assessment of cavernous sinus invasion
using differing criteria. Authors have found percentage encroachments of 25%,[18] 45%,[15] 67%,[22] and 100%[16]
[21] to have a high specificity for cavernous sinus invasion. Our data confirm that a
reduction in the intracavernous ICA encasement is helpful in anticipating a complete
removal of any parasellar tumor. A complete excision is 3.4 times more likely on postoperative
imaging with each 25% reduction in the degree of ICA encasement. Tumor extension beyond
the lateral intercarotid line (according to the Knosp criteria) has also proved useful
in predicting parasellar invasion on prior studies.[15]
[16]
[18] However we did not show this MRI criterion to correlate significantly with postoperative
findings of complete excision versus potential residual tumor. Secondary MRI features
such as tentorial enhancement have also been proposed as a feature of cavernous sinus
compromise.[20] However these were not explored in this study.
Only one previous study offers some limited data correlating pre- and postoperative
MRI appearances following resection of parasellar tumor.[1] Ramm-Pettersen et al showed that that the mean Knosp grade (progression of parasellar
tumor laterally across the intercarotid lines) in tumor that was totally excised on
the 3-month postoperative MRI was 3.13 (n = 20); that undergoing subtotal excision was 1.75 (n = 8). Total excision was achieved in all grade 0/1 tumors, 57% of grade 2 tumors,
8% of grade 3 tumors, and none of the grade 4 tumors.
Some methodological issues are worthy of comment. The study outcome was intended to
be pragmatic. We did not confine the study to patients with confirmed cavernous sinus
invasion at surgery, and we included any patient with potential parasellar extension
on the basis of previously defined criteria. Similarly, the postoperative MRI evaluation
grouped those with clear residual parasellar adenoma alongside those demonstrating
indeterminate MRI features. These indeterminate scans were found in three cases. This
is a clinical scenario that confronts the radiologist in routine clinical practice,
when asked to dichotomize cases as complete excision or not, for the purposes of treatment
planning. Some of our indeterminate findings may have been tumor free; however this
would be difficult to confirm without systematic reoperation or long-term follow-up
without treatment. None of these nonfunctioning tumors showed progression of tumor
over 3 years and 4 years on follow-up imaging. Postoperative residual tumor represents
a continuum, and it is difficult to define the size of residuum that would prompt
intervention, rather than monitoring with serial imaging. Our grouping as complete
excision versus potential residual is also justified on the basis of our original
hypothesis, which was to determine which MRI features were important in predicting
a complete resection, rather than predicting residual tumor, on the postoperative
MRI study.
We note that the postoperative MRI assessment required reference to the preoperative
imaging that could potentially introduce an element of bias. However this was unavoidable
considering our a priori MRI criteria for residual tumor assessment. It is also appreciated
that there are likely to be other tumor-related factors that influence the resectability,
such as tumor size and consistency. However it was not considered feasible to control
for such features. Finally, it is not clear whether our results could be extrapolated
to other surgical centers. In particular, differing surgical practices such as the
use of endoscopy or intraoperative MRI[1]
[27] may improve the rates of resection and alter the predictive value of the various
MRI criteria. One study of transsphenoidal surgery aided by intraoperative MRI showed
that only 1 of 9 tumors with likely parasellar extension (Knosp grade 3 and 4 tumors)
were converted from a subtotal to a total resection when comparing the primary resection
with second- and third-look resections,[1] so the preoperative MRI criteria may remain pertinent in this setting.
In conclusion, we have determined MR imaging features to be useful in predicting the
complete removal of the parasellar component of a pituitary adenoma as assessed by
postoperative MRI. These differ slightly from those previously shown to predict cavernous
sinus invasion at the time of surgery. The depiction of the lateral and inferolateral
compartments and decreasing tumor encasement of the intracavernous ICA are associated
with complete resection of parasellar tumor on the postoperative MRI study. In particular,
parasellar adenoma is unlikely to be resected completely if there is encasement of
>50% of the intracavernous ICA or if there is extension to the inferolateral or lateral
venous compartments. Patients with these MR imaging features will need to be counseled
that residual tumor is likely and additional therapy may be required.
