Abstract
Purpose
The Knosp grading system classifies the extent of cavernous sinus invasion (CSI) in pituitary adenomas (PAs). Knosp grade is predictive of surgical remission rates and is used in decision-making for the management of these adenomas. This study evaluates the rate and accuracy of Knosp grade reporting of PAs by radiologists.
Methods
This is a retrospective observational study of 100 consecutive patients with pituitary macroadenomas who underwent pituitary MR imaging between March 2023 and March 2025. The rate of CSI reporting in radiologist reports of the scans was determined, and the reported grade was compared with the Knosp grade calculated by the study panel.
Results
Radiologist reports contained a specific comment regarding CSI, or its absence, in 73/100 (73%) of patients. Analysing left and right cavernous sinuses as separate observations, implicit phrasing reporting a specific Knosp grade occurred in 12/200 (6%), and explicit reporting occurred in 10/200 (5%). Analysis of implicit and explicit reporting revealed a statistically significant difference between the reported Knosp grades and study grades (p = 0.02). No significant correlation was found between CSI reporting rates and patients undergoing surgery (p = 0.179), radiotherapy (p = 0.427), or medical therapy (p = 0.127) before or at the time of the MRI.
Conclusion
Despite the integral importance of CSI in pituitary adenoma management decisions as enshrined in international guidelines, the rate and accuracy of Knosp grade reporting are suboptimal. Knosp reporting in MRI reports should be standardised to improve the rate and quality of CSI reporting.
Keywords: Pituitary adenoma, Knosp classification, Cavernous sinus invasion, Pituitary neuroendocrine tumour, Trans-sphenoidal surgery
Introduction
Pituitary adenomas (PAs) are typically histologically benign tumours originating from the pituitary gland which may be subclassified as microadenomas (maximal tumour diameter < 10 mm) or macroadenomas (≥ 10 mm). The cavernous sinuses are complex anatomic structures, with vital neurovascular contents, that lie adjacent to the pituitary gland, and are therefore at risk of direct invasion by pituitary macroadenomas. Cavernous sinus invasion (CSI) by pituitary macroadenomas is known to be a major predictor of long-term prognosis [1, 2]. CSI decreases likelihood of successful surgical resection, predicts tumour recurrence and compromises biochemical remission in hypersecretory PAs [1, 3]. Determination of CSI extent is imperative for pre-operative neurosurgical planning of resections as parasellar growth (i.e., whether invading or displacing the cavernous sinuses) may influence whether complete or partial resection will be safely achievable [3]. In a retrospective study of 228 patients diagnosed with PAs, rate of cure following surgery was dependent on degree of CSI (by Knosp classification), with higher grades decreasing rate of cure [6]. Risk of complications also increased with greater CSI [6]. As CSI is generally clinically elusive, accurate radiological assessment is vital.
Knosp grading is a radiological classification of CSI severity that is accurate in predicting the chance of gross-total PA resection and endocrine remission of hypersecretory PAs [3]. The Knosp classification (Fig. 1), which ranges from Grade 0 (no invasion) to Grade 4 (complete circumferential encasement of the ICA), has proven to be an effective tool for predicting surgical outcomes. These grades are allocated based on preoperative coronal MRI of the brain (Fig. 1).
Fig. 1.
Graphic depicting the boundaries used to determine Knosp Grade in pituitary adenomas. Created using BioRender (Toronto, ON M5V 2J1, Canada)
The Knosp grade is determined by lines drawn through the medial margin, centre and lateral margin of the cavernous and supracavernous ICA segments [9]. Recent studies have suggested refining the classification by adding intermediate grades (i.e., Knosp 3 A and 3B) to better differentiate outcomes between tumours invading the superior (Knosp 3 A) versus inferior (Knosp 3B) compartments of the cavernous sinus [7]. Adenomas defined as Grade 3A exhibit a lower rate of invasiveness of the medial cavernous sinus wall than those defined as Grade 3B [7]. This may be related to the different anatomy of the medial wall of the cavernous sinus, which the tumour displaces rather than invading histologically [8].
This study aimed to examine the quality of Knosp grading of CSI in radiology reports in real-world practice, recognising the critical importance of this radiological finding in PA management decision-making.
Methods
A retrospective observational analysis was conducted on a study cohort consisting of one hundred (n = 100) patients diagnosed with pituitary macroadenomas. The inclusion criteria were as follows: (1) patients diagnosed with pituitary macroadenomas, i.e. the tumour was recorded as size ≥ 10 mm at the time of diagnosis, (2) attendance in the Royal Adelaide Hospital (RAH) Pituitary Multi-Disciplinary Team (MDT) Clinic (new or existing patient), (3) aged 18 years or older, (4) MR images and report were available and within study period (March 31, 2023 to March 31, 2025), and (5) tumour present on the Index MRI. Exclusion criteria were: (1) patients without MR imaging showing the cavernous sinuses and relevant anatomical structures for CSI assessment (e.g., no coronal plane), and (2) inadequate quality of MR imaging.
Ethical approval for this study was granted by the Central Adelaide Local Health Network Human Research Ethics Committee (reference number 20728). Due to the nature of the study as a retrospective audit, a waiver of consent to publication was obtained by the Ethics Committee in line with the National Health and Medical Research Council research guidelines.
The South Australian Pituitary Registry was used to identify patients who attended the RAH Pituitary MDT Clinic. Patients diagnosed with macroadenomas were identified; microadenomas and other lesions were excluded. Brain MRI scans for each patient were reviewed to identify the most recent adequate scan that met the inclusion criteria; this scan was termed the Index MRI. Summary statistics were recorded, such as age at diagnosis, age at Index MRI, clinical diagnosis, non-functioning versus functioning macroadenomas, surgery or radiotherapy pre-Index MRI, tumour-targeted medical therapy at time of Index MRI, and histopathological diagnosis (Tables 1 and 3).
Table 1.
Summary of patient demographics and summary statistics
| Variable | Value (n = 100) |
|---|---|
| Male, number (%) | 54 (54) |
| Age at diagnosis, mean (SD) | 50.32 (18.33) |
| Age at Index MRI, mean (SD) | 55.91 (18.70) |
| Non-functioning adenoma, number (%) | 71 (71) |
| Functioning adenoma, number (%) | 29 (29) |
| Prolactinoma, number (%) | 16 (55) |
| Acromegaly, number (%) | 9 (31) |
| Cushing’s disease, number (%) | 2 (7) |
| Other, number (%) | 2 (7) |
| Surgery prior to Index MRI, number (%) | 32 (32) |
| Radiotherapy prior to Index MRI, number (%) | 8 (8) |
| Tumour-targeted medical therapy at time of Index MRI, number (%) | 12 (12) |
| Index MRI – CSI stated at all1, number (%) | 73 (73) |
| Index MRI – Knosp grade implicitly or explicitly reported either side2, number, (%) | 22 (11) |
| Index MRI – haemorrhage, number (%) | 1 (1) |
| Index MRI – cystic change, number (%) | 14 (14) |
1Any mention of CSI written in the report
2Reports of right and left-sided Knosp Grades taken as individual data points (n=200)
Table 3.
Table showing frequency of histological diagnoses in the cohort, including transcription factors and hormone staining
| Variable | Value |
|---|---|
| Histological report diagnosis (n = 39) | |
| Chromophobe | 4 |
| Chromophobe null cell | 4 |
| Corticotroph adenoma | 1 |
| Gonadotroph adenoma | 10 |
| Growth hormone adenoma | 2 |
| Lactotroph adenoma | 1 |
| Necrotic tissue and inflammatory cells | 1 |
| Null cell | 3 |
| Only cyst material | 1 |
| Pituitary adenoma | 7 |
| Plurihormonal tumour | 1 |
| Somatotroph adenoma | 3 |
| Somatotroph adenoma or acidophilic | 1 |
| Histopathology Diagnosis WHO 2022 | |
| Corticotroph adenoma | 1 |
| Cyst contents | 1 |
| Gonadotroph adenoma | 15 |
| Immature PIT1 lineage tumour | 3 |
| Lactotroph adenoma | 1 |
| Null cell | 1 |
| Null cell or Gonadotroph adenoma | 7 |
| Plurihormonal tumour | 2 |
| Somatotroph adenoma | 6 |
| Thyrotroph adenoma | 1 |
The report corresponding to the Index MRI was reviewed. Any comment regarding CSI was documented, as were specific Knosp grades listed. In the case where the report referenced a previous MRI report mentioning CSI, this was classified as the Index report having defined the CSI. Haemorrhage and cystic changes reported by the radiologist were also documented. Histopathology reports were saved; the reported diagnosis was reviewed using the WHO 2022 classification system using hormone and, when available, transcription factor immunohistochemistry.
The Knosp grades reported in the MRI reports were noted. Few reports listed a specific explicit Knosp grade, with many implying Knosp grade through certain phrasing. Phrases implying specific Knosp grades were identified, such as ‘abutment to ICA’, ‘180-degree encasement’, and ‘extension laterally with encasement’ (Table 2). Correlating Knosp grades for each phrase were confirmed by consensus of pituitary specialists. Ambiguous statements where CSI was mentioned but a specific Knosp grade was not indicated were also identified, such as ‘broad abutment of the ICA’, and ‘mild extension into the CS’ (Table 2).
Table 2.
Phrases used in radiology reports to describe CSI with correlating Knosp grade or Knosp grade range, were applicable
| Phrase | Knosp Grade/Range |
|---|---|
| Slightly more than 180-degree encasement | Knosp 2 |
| Extension beyond the lateral wall of the cavernous segment of ICA | Knosp 3 |
| Beyond lateral margin of ICA | Knosp 3 |
| Encircles the ICA | Knosp 4 |
| Encasement of the ICA | Knosp 4 |
| Abuts/abutment to ICA | Knosp 0–1 |
| Abutment without extension in the CS | Knosp 0–1 |
| No cavernous sinus invasion | Knosp 0–2 |
| No cavernous sinus involvement | Knosp 0–2 |
| 180-degree encasement | Knosp 1–2 |
| Approx. 180-degree encasement of the ICAs | Knosp 1–2 |
| 180-degree partial encasement of the ICA | Knosp 1–2 |
| 180–270 degree contact with the left supraclinoid ICAs and both A1 segments | Knosp 2–3 |
| Contacts ICAs with < 180 degrees of encasement | Knosp 0–1 |
| Less than 180-degree encasement | Knosp 0–1 |
| Contacts but does not encase cavernous ICA | NA |
| Broad abutment of the ICA | NA |
| Lesion within the right CS | NA |
| Extends into left cavernous sinus | NA |
| Broad abutment without encasement | NA |
| Pushing margin into CS | NA |
| Extending to the left CS | NA |
| Abutting the ICA with no encasement | NA |
| Broad contact with the undersurface of the ICA | NA |
| Pituitary tissue at left CS | NA |
| Small volume CSI | NA |
| Lesion within the CS | NA |
| Contact with the ICA | NA |
| Stable degree of right ICA abutment | NA |
| No progressive ICA encasement | NA |
| Approx 120 degrees of contact | NA |
| Stable degree of right ICA abutment | NA |
| Stable appearance of the CS | NA |
| Abutting approx. 50% of the arteries on both sides | NA |
| Cavernous sinuses are unremarkable | NA |
| Contact of pituitary gland with the left CS without invasion | NA |
| Encases the distal left ICA to its bifurcation | NA |
Next, a study panel composed of a neuroradiologist, radiologist and medical graduate determined the Knosp classification grades for the right and left sides of each macroadenoma, independent of any Knosp grade reported in the MRI report. The Knosp grades were determined independently by the medical graduate and the neuroradiologist. The grades were reviewed collaboratively, and the senior neuroradiologist reviewed any cases that were complex or outstanding.
The majority of scans were performed at a single centre, the Royal Adelaide Hospital, which uses a 3 T MRI, with 2.00 mm slice thickness and 0.2 mm gaps. For all studies, T1 sagittal, T1 coronal, and T2 coronal sequences were reviewed and available for optimal visualisation of the cavernous sinuses and coronary arteries. The coronal plane was used in all cases for assessment of CSI invasion.
We next compared the reported grade with our study grade. SPSS Statistics (version 31.0.1.0 (49); IBM Corp., Armonk, NY, USA) and R with ggplot (Wickham H (2016). Springer-Verlag New York. ISBN 978-3-319–24277−4) were used for statistical analysis. A Wilcoxon signed-rank test was used to identify any significant difference between matched data points, with right-sided and left-sided Knosp grades included as separate data points. Chi-square analysis was used to assess for correlation between various factors and CSI reporting rates.
Results
Study cohort
The cohort (n = 100) consisted of 54% male subjects. Specific summary statistics are featured in Table 1. The age at diagnosis ranged from 17 to 85, with a mean of 50 and a standard deviation of 18. The age at the time of the Index scan ranged from 18 to 89, with a mean of 55 and a standard deviation of 19. All patients were diagnosed with a macroadenoma. 71% of the tumours were non-functioning PAs. The remaining cases (29%) were diagnosed with functioning PAs: 9% acromegaly, 2% Cushing’s disease, 16% prolactinomas, one functioning gonadotrophinoma, and one GH/PRL co-secreting adenoma.
12% of patients underwent surgery prior to the date of the Index MRI. 8% of patients received radiotherapy treatment prior to the Index MRI date. Tumour specific medical therapy (bromocriptine, cabergoline, octreotide or pegvisomant) was received in 12% at the time of the Index MRI.
Baseline tumour diameter at the time of diagnosis ranged from 10 to 58 millimetres (mm). The maximal diameter of tumours at the time of the Index MRI was noted by the reporting radiologist in 64% of cases, with a minimum of 5 mm and a maximum of 44 mm. Radiologist reporting of the tumours revealed haemorrhage in one case and cystic change in 14 cases.
Knosp grading
Radiologist reports included a comment regarding CSI, or its absence, in 73/100 (73%) of patients. Eight cases (8/100) exhibited explicit Knosp reporting, with 6 cases being non-functioning PA (n = 6) and 2 cases being prolactinomas (n = 2). When considering left and right cavernous sinuses as separate observations, implicit phrasing reporting a specific Knosp grade was present in 12/200 (6%). Explicit reporting occurred in 10/200 (5%).
Examination of factors such as reporting radiologist, diagnosis, and surgery timing did not reveal any correlation to the frequency of explicit Knosp grade reporting in these eight cases. On two occasions where the Knosp grade was reported explicitly, a range Knosp grading was reported for one side, e.g. ‘Knosp 1 or 2’.
Non-standardised reporting of CSI was prevalent throughout the radiology reports, with various phrases used to describe the degree of CSI (Table 2). Forty-five reports had an implicit Knosp grade range (Table 2). Among these cases, the calculated study grade was within the implicit Knosp grade range in 42 reports (82%).
When comparing the reported grading with our calculated study grade, 13 out of the 22 reported grades matched our calculated study grades (59%). Six out of the 10 explicitly reported Knosp grades matched our calculated study grades (60%). A Wilcoxon signed-rank test revealed a statistically significant difference between the reported Knosp grades and our calculated study Knosp grades (n = 22; p = 0.02), suggesting low accuracy of the reported Knosp grades. The reported Knosp grades were higher (median = 3) compared to the study Knosp grades (median = 2.5), with a moderate effect size (r = 0.35). This difference is demonstrated in Fig. 2.
Fig. 2.
Paired boxplot comparing the reported grade and our study grade. ‘Reported’ grades refer to cases where a specific Knosp grade was implicitly or explicitly reported in the radiology reports. ‘Study’ grades refer to the Knosp Grades calculated in this study for each case
Various factors were analysed against CSI reporting. No significant difference was found between rate of CSI reporting and factors such as whether a patient received surgery prior to the date of Index MRI (p = 0.179), radiotherapy prior to (p = 0.427), or medical therapy at the time of the Index MRI (p = 0.127). The reported diagnosis in the histopathology report was reviewed using the WHO 2022 classification system for this study, using hormone and, when available, transcription factor immunohistochemistry (Table 3).
Discussion
Knosp classification categorically determines the grade of cavernous sinus invasion of PAs. This study aimed to investigate the rate and accuracy of Knosp classification reporting in brain MRI reports; it is the first published study to our knowledge to examine the rate and accuracy of Knosp reporting by radiologists in real-world practice (Fig. 2).
Radiologist reports included any mention of CSI, or its absence, in the majority (73%) of the cohort. Implicit reporting of Knosp grade occurred in only 12/200 (6%) cavernous sinuses, with explicit reporting of Knosp grade occurring in just 5%. Comparison of the reported Knosp grades with study determined Knosp grades revealed concordant grading in 59% of cases, with a statistically significant difference between reported and study grades. This suggests low accuracy of the reported Knosp grades. Furthermore, ambiguous phrasing in 12% of cases resulted in the inability to interpret a Knosp grade. The discrepancies in Knosp grade might indicate that nonspecific phrasing indicating Knosp grade is not a reliable method of determining Knosp grade. Hence, a standardised approach to Knosp reporting should be considered to improve accuracy.
Heterogeneity in the terminology used to report Knosp grade was prevalent. Paraphrasing with an implicit Knosp grade may be sufficient for pituitary subspecialists, who are the same clinicians likely to view the scan images and deduce the Knosp grade independently. Paraphrasing is likely to be more problematic for generalists seeing patients with PAs with less experience of the Knosp classification system and potentially less inclination to review the MR images and perform Knosp grading independently.
Knosp grade is specifically referred to in the 2023 Pituitary Society prolactinoma guidelines recommendations. Petersenn et al. report that Knosp classification is a better predictor of surgical success than the distinction between microprolactinoma and macroprolactinoma, and is also predictive of surgical remission rates [10]. Critically, Knosp grade dictates the place of surgery in the guidelines treatment algorithm, although this has been the subject of ongoing debate [11, 12]. Per the guidelines, surgical resection of well-circumscribed prolactinomas that are Knosp grade 0 or 1 is considered an equal first-line option compared to medical therapy because it has a ‘high chance of cure, is cost-effective and avoids long-term dopamine agonist treatment’ [10]. By contrast, medical therapy is the preferred first-line treatment option in patients with a low chance of surgical remission predicted by Knosp grade ≥ 2 [10].
Knosp grade also features in the 2025 Pituitary Society incidentaloma guidelines recommendations. Fleseriu et al. recommend that standardised MRI reports should include a modified Knosp classification, and that incidental macroadenomas with invasive features such as CSI may require closer imaging intervals. Macroadenomas that are enlarging or invading the cavernous sinus may be considered for surgical intervention [13].
Meta-analysis of several studies has confirmed that Knosp grading is the best objective measure for CSI diagnosis in PAs [4, 5]. Compared to other CSI classifications such as percentage encasement of the internal carotid (PEICA), venous compartment obliteration (VCO) and Fernandez-Miranda classification, Knosp grade of ≥ 1 had the highest sensitivity in a 2021 study assessing 210 cavernous sinuses with comparison to the reference assessment of intraoperative findings and postoperative day 1 MRI [4]. Other parameters with higher specificity, such as PEICA, may be used in tandem with Knosp classification [4]. Several technical factors are important for the diagnosis of CSI. Firstly, MRI is the gold standard for evaluating CSI in PAs, with studies demonstrating 7-Tesla MRI leading to more reliable assessment of CSI, although this technology is not universally available [8]. Secondly, regarding the surgical diagnosis of CSI, endoscopic techniques provide a more accurate assessment of the cavernous sinus over microscopy [5]. Both radiological and surgical techniques for evaluating CSI have been found to be valuable in predicting prognosis of PAs [2].
A potential limitation of this study is the timing of the Index MRI compared to the time of diagnosis. In some cases, the radiologist may have exercised discretion and not referenced minor CS extension due to a lack of clinical relevance. Another limitation of the retrospective case series is that the mean time between diagnosis and index MRI was > 5.5 years, meaning that in many cases the Index MRI was not the scan taken at diagnosis. However, some scans referenced were dated after surgical resection and therefore a recalculation of the Knosp grade is relevant. Larger, multicentre studies are required to better understand the rate and quality of Knosp grading in radiology reports internationally and investigate potential variability in reporting tendencies among other specialists, such as neurosurgeons, ENT surgeons and endocrinologists. These data may then form the basis of prospective trials of standardised CSI reporting and effects on PA management – particularly outside quaternary pituitary centres, noting that multiple international PA management guidelines necessitate knowledge of the presence and degree of CSI to enact correct assessment and management pathways. The implementation of updated guidelines including Knosp Grade reporting for PAs, with additional training for general radiologists, may assist in standardising Knosp reporting by radiologists and improve accuracy.
In conclusion, noting the suboptimal Knosp grade reporting observed in this cohort and given the prominence of Knosp grade in PA management guidelines, we recommend a standardised approach to reporting of Knosp grade.
Author contributions
K.S. wrote the main manuscript text and prepared Tables 1, 2 and 3. J.D. prepared Figure (1). G.B. prepared Figure (2). All authors reviewed the manuscript.
Funding
Open Access funding enabled and organized by CAUL and its Member Institutions. No funding was received to assist with the preparation of this manuscript.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Disclosure statement
The authors declare that they have no competing interests to disclose regarding the content of this article.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Data Availability Statement
No datasets were generated or analysed during the current study.