Cavernous sinus invasion: imaging versus clinical outcomes of pituitary adenomas

Pituitary adenomas are one of the most commonly diagnosed brain tumors, constituting approximately 10-15% of all intracranial neoplasms [1]. Despite being considered a benign growth, these tumors can impart an array of clinical side effects and endocrine abnormalities. These include symptoms resulting from mass effect, such as headaches and visual field abnormalities, and hormone dysregulation, including hyperthyroidism, hyperprolactinemia, Cushing disease, acromegaly, infertility, and hypopituitarism [2]. Often classified based on size as a microadenoma (<10mm) or macroadenoma (_­≥10mm), those of larger dimensions often invade into nearby intracranial structures, such as the cavernous sinus. 

The cavernous sinuses are an interconnected network of venous plexuses situated on both sides of the sella turcica and sphenoid sinus. Extension of pituitary adenomas into this region can disrupt the function of any of the structures residing within them. This includes the internal carotid artery and abducens nerve, which are situated medially within the sinuses, as well as the oculomotor, trochlear, ophthalmic, and maxillary nerve, located laterally [3]. Local invasion of tumors into this region increases the difficulty of achieving gross total resection, allowing for residual tumor to cause continued hormone dysregulation, higher rates of tumor recurrence, and the need for continued post-operative medical therapy [4]. 

At this time, MRI is used to delineate the extent of pituitary tumor extension and to classify whether invasion into the cavernous sinus has occurred. The Knosp grading system was specifically designed to categorize the degree of spread into this area, with higher grades associated with larger tumors, higher rates of surgical complications, and decreased biochemical remission after resection [5]. Unfortunately, the use of pre-operative imaging in predicting true CS invasion has shown to be unreliable, even among tumors labeled with higher Knosp grades [6]. While current studies are focused on developing more reliable imaging techniques to predict expansion of tumors into the parasellar space, understanding the factors that may correlate to true CS invasion can be useful in the surgical planning and management of pituitary tumors.

A retrospective review of patients who underwent surgical resection of pituitary adenomas by one neurosurgeon at a single institution was completed between 2018 and 2023. Each patient’s electronic medical record was reviewed to collect relevant demographic information, including age, sex, and body mass index (BMI). Pre-operative MRI scans were read by a neuroradiologist, who documented if there was radiographic evidence of cavernous sinus invasion. The presence or absence of tumor extension into the cavernous sinus was confirmed intra-operatively. Institutional review board approval was obtained prior to study initiation (2018-9379). 

Statistical analysis was completed using means and standard deviations for continuous variables. Cases with and without confirmed cavernous sinus invasion were compared using an independent samples t-test. Categorical variables were summarized using frequencies and compared between the two groups using chi-square or Fisher exact tests. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for MRI reports. Significance was defined as p-value < 0.05. All analyses were performed using SPSS Statistics Version 29.0.0.0 (IBM Corp., Armonk, N.Y., USA).

• Descriptive Statistics 

A total of 47 patients were included in the analysis, consisting of 21 males (44.7%) and 26 females (55.3%) [Table 1]. Average patient age was 55.2 ± 14.7 years (range: 26 to 84 years) and the mean body mass index (BMI) was 32.3 ± 7.2 kg/m². An elevated Ki67 index was identified in 6 patients (12.8%). Mean pituitary tumor dimensions were 3.3 cm (craniocaudal [CC]), 2.6 cm (anterior-posterior [AP]), and 2.9 cm (transverse [TV]). 

Table 1: Descriptive Statistics of Patients 

SD: standard deviation; BMI: body mass index 

• Radiographic versus Operative Findings 

Thirty-three patients had MRI reports suggestive of pituitary tumor invasion into the cavernous sinus, with surgical confirmation of CS invasion occurring in only 3 cases (PPV, 9.1%; P = 0.544) [Table 2]. Out of the 14 cases without radiographic evidence of invasion, all of them were confirmed to lack CS involvement intra-operatively (NPV, 100%, P = 0.544). 

Table 2: CS invasion: Radiographic versus Operative Findings 

CS: cavernous sinus 

Comparative Analysis of Patients with and without Surgically Confirmed CSI 

Analyzing cases with and without verified CS invasion of pituitary tumors revealed that patients with true invasion, as indicated intra-operatively, were significantly younger than patients who did not have lateral tumor growth (P < 0.002) [Table 3]. A statistically significant relationship was also observed between CS invasion and the Ki-67 index of pituitary tumors, with those tumors lacking CS involvement being found to have low levels of Ki-67 expression (P = 0.043). Furthermore, comparing the mean tumor dimensions between cases revealed that pituitary adenomas that did not exhibit lateral expansion into the CS had a significantly greater cranio-caudal dimension compared to tumors with growth into the CS. No significant relationships between cavernous sinus invasion and sex, BMI, eccentric tumor growth, and anterior-posterior or transverse tumor dimensions were observed. 

Table 3: Comparative Analysis of Patients with and without Confirmed CSI 

CSI: cavernous sinus invasion; BMI: body mass index

Despite the benign nature of pituitary adenomas, invasion into the cavernous sinus is a common occurrence, reported in approximately 10% of operative cases [7]. While lateral extension of such tumors can disrupt the function of nearby structures and result in significant clinical consequences such as cranial nerve dysfunction, growth into the parasellar region can increase the risk of operative complications and unfavorable outcomes, such as cerebrospinal fluid leaks, damage to the optic chiasm, cerebrovascular injury, and persistent endocrine dysregulation [3]. Additionally, involvement of the CS has been found to be associated with lower rates of gross total resection and can increase the need for further treatment, including re-resection, radiation therapy, or medical management [4]. Since CS invasion can significantly affect patient outcomes, the ability to recognize true tumor extension or invasion into this area is important for surgical planning and long-term patient management. 

While pre-operative imaging is widely used to quantify tumor size and extent of growth, its use in identifying true cavernous sinus invasion has not always proven to be accurate. Prior studies have focused on developing classification schemes for predicting CS invasion based on MR imaging, with percent of ICA encasement and Knosp grading considered to be potential predictive factors. Cottier et al., for example, reported that ICA encasement of at least 67% was consistently associated with true tumor invasion (100%, PPV), whereas encasement of 25% or less confirmed lack of tumor extension into the CS (100% NPV) [8]. However, given that other studies have reported lower degrees of ICA encasement to be predictive of true invasion, it remains unclear what percent can be accurately used in clinical practice [9]. Other reports have analyzed the utility of the Knosp grading system, widely used in radiographic reports to describe CS invasion, in accurately predicting lateral tumor expansion. However, these results have proven to be variable, as well. While one report identified Knosp grades 3 and 4 to be associated with CSI at a rate of 85% and 100%, respectively, a retrospective review by Fang et. al demonstrated the rates of surgically confirmed CSI to be 37.5%, 54.5%, and 88.9% for grades 3a, 3b, and 4 [8, 10]. In this study, MRI reports suggestive of pituitary tumor invasion into the CS had a low PPV (9.1%) and high NPV (100%), although the relationship between MRI results and surgical findings were not statistically significant. Given that radiographic studies demonstrate greater ability to consistently rule out, rather than confirm true CS invasion, the development of more accurate imaging techniques would be advantageous. 

Aside from the use of imaging reports, identifying other patient factors that may be associated with true CS invasion could prove useful. In this study, younger age was significantly associated with lateral expansion into the cavernous sinus. Among patients with pituitary tumors, younger age has been found to be associated with greater expression of proliferative tumor markers, such as Ki-67 [11]. Given that the average age at diagnosis of pituitary tumors in the United States is approximately 49 years, evidence of increased cavernous sinus invasion among younger patients may be suggestive that such individuals may be harboring more aggressive tumors with increased risk of extension into the parasellar space [12]. Therefore, despite the low specificity of MR imaging, there should remain a higher degree of suspicion for true CS invasion among younger patients where MR imaging is suggestive of such growth. 

Among those cases that demonstrated lack of CS invasion on surgical reports, pituitary tumors were found to be more likely to express a low level of the Ki-67 index marker, a nuclear antigen found to be more strongly expressed in cells exhibiting high rates of cell division and proliferation [13]. Previous reports have suggested a value above 3% to be indicative of tumors having invasive and aggressive characteristics [14]. Therefore, it is unsurprising that in this study a low Ki-67 index level was found among those pituitary adenomas that did not invade into the CS. Interestingly, those tumors that did not invade laterally into the parasellar region were found to be significantly larger in the cranio-caudal direction compared to those tumors that exhibited CS involvement. Since the pituitary gland is bordered inferiorly by the sella turcica of the sphenoid bone and laterally by dura mater, a dense, fibrous layer of connective tissue encasing the CS, pituitary tumors with low invasive potential are more likely to exhibit vertical, rather than horizontal, growth. This vertical pathway between the diaphragma sella and the pituitary infundibulum offers a low resistance pathway, providing a more accessible route for non-aggressive and slow growing tumors. Therefore, while greater vertical growth may not be diagnostic of lack of CS invasion, increasing tumor size in the cranio-caudal direction may be suggestive of a less aggressive and invasive adenoma.

While MR imaging is not always accurate in the diagnosis of true cavernous sinus invasion, the presence of certain clinical characteristics may strengthen the suggestive power of radiographic reports. In this study, younger age was significantly associated with true CS invasion, as confirmed on operative notes. Additionally, a low Ki-67 index and increased vertical tumor growth was found to correspond to tumors with low invasive potential into the lateral parasellar space.

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