Abstract
Context
Bilateral inferior petrosal sinus sampling (BIPSS) is widely used to differentially diagnose ectopic ACTH syndrome (EAS) and Cushing’s disease (CD) with pituitary lesions less than 6 mm detected on MRI.
Purpose
This study aimed to investigate the diagnostic accuracy of BIPSS and prognosis of low-lateralization [lateralization ratio of bilateral inferior petrosal sampling (IPS) ≤ 1.4] CD with microadenoma (≤ 6 mm).
Methods
This single-centre retrospective study (2011–2019) included 25 EAS and 179 CD (microadenoma ≤ 6 mm) patients whose diagnoses were confirmed by pathology. All CD patients received two to ten years of follow-up.
Results
According to the multivariable regression results, a false-negative diagnosis at baseline might be associated with a lateralization ratio ≤ 1.4 (adjusted OR = 12.69, 95% CI 4.14–38.86; P < 0.001). CD patients were divided into a low-lateralization group (lateralization ratio ≤ 1.4) and a high-lateralization group (> 1.4). An inferior petrosal sinus-to-peripheral ACTH ratio (IPS: P-ACTH) ≥ 2.0 had a sensitivity of 55.0% (95% CI 39.8%-69.3%) for the low-lateralization group (n = 40), which was lower than the sensitivity of 93.5% (95% CI 88.2%-96.6%) for the high-lateralization group (n = 139) (P < 0.001).
Conclusion
Lower diagnostic accuracy and poorer surgical outcomes were found for the low-lateralization group, with a lesser likelihood of remission and more impaired pituitary function after pituitary surgery.
Clinical trial number
Not applicable.
Keywords: Cushing’s disease, Ectopic ACTH syndrome, Bilateral petrosal sinus sampling, Diagnosis, Prognosis
Introduction
Cushing syndrome (CS) primarily results from excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary adenoma, a condition defined as Cushing disease (CD). CS may also result from ectopic ACTH secretion (EAS), a less frequent aetiology accounting for approximately 10% of cases [1]. These tumours are predominantly neuroendocrine in nature, with common examples including small cell lung cancer (SCLC), bronchial carcinoid tumours, pancreatic neuroendocrine tumours (pNETs), thymic carcinoids or thymomas, and medullary thyroid carcinoma. Accurate differentiation between CD and EAS is crucial for effective treatment. However, the reliability of conventional diagnostic methods, such as the high-dose dexamethasone suppression test (HDDST) and pituitary magnetic resonance imaging (MRI), can be inconsistent [2]. Currently, bilateral inferior petrosal sinus sampling (BIPSS), in which ACTH levels in the pituitary blood are compared with those in peripheral blood, remains the gold standard for definitively excluding ectopic ACTH production [3–5].
The latest expert consensus recommends that all patients with lesions less than 6 mm should undergo IPSS (moderate quality, strong recommendation) [3]. For tumours between 6 and 9 mm, expert opinions vary, but most recommend using IPSS to confirm the diagnosis (moderate quality, discretionary recommendation) [3]. Although there is a noninvasive approach using a combination of three or four tests, specifically CRH and desmopressin stimulation plus MRI (very low quality, discretionary recommendation) [3, 6–12], BIPSS remains an essential diagnostic step for ACTH-dependent CS with MRI-detected lesions ≤ 6 mm.
Despite its high diagnostic accuracy for pituitary localization, the reliability of the BIPSS for tumour lateralization (right or left side) is suboptimal (moderate quality, strong recommendation) [3, 13, 14]. Studies have shown wide variability in lateralization accuracy (42.9% to 100%) [2, 15–18], which may correlate with cavernous sinus venous vascular patterns rather than actual tumour location [19–21]. Consequently, the clinical significance of the BIPSS lateralization ratio requires further study.
Our previous large single-centre study revealed that false-negative BIPSS diagnoses across all tumour sizes in both CD and EAS patients may correlate with low lateralization (lateralization ratio of bilateral IPS ≤ 1.4) [22]. We observed that this ratio might be an inherent feature of CD rather than a reliable predictor of surgical tumour localization. Further analysis suggested that vascular anatomical variations around the pituitary gland could compromise the diagnostic sensitivity of BIPSS in CD patients with low lateralization [23]. On the basis of these findings, we aimed to design a retrospective study to systematically assess the effect of low lateralization on both diagnostic accuracy of BIPSS and postoperative prognosis of CD for patients with MRI-confirmed microadenomas (less than 6 mm).
Methods
Patients
Consecutive patients from 2011 to 2019 who were referred to our hospital [Peking Union Medical College Hospital (PUMCH)] with proven CD or EAS and who successfully underwent BIPSS combined with desmopressin stimulation and whose pituitary MRI indicated a pituitary adenoma lesion ≤ 6 mm or equivocal were included. The aim of including EAS patients was to explore the association between lateralization and the diagnostic accuracy of BIPSS. This study was approved by the Institutional Review Board of PUMCH. Patients signed an informed consent form before information and blood samples were collected and gave approval for the use of their information and samples in future scientific research.
The inclusion criteria were complete biochemical analysis, pituitary dynamic enhanced MRI, BIPSS, transsphenoidal surgery, pathological confirmation and at least two years of follow-up after surgery in our centre. The exclusion criteria were patients who failed to finish BIPSS catheterization, patients whose pituitary lesions were > 6 mm on MRI, or patients whose diagnosis was unclear after transsphenoidal surgery.
Biochemical examinations and tests
Patients with suspected CS underwent a series of examinations. CS was diagnosed on the basis of midnight cortisol level, 24-h urine-free cortisol (24 h UFC) level, and low-dose dexamethasone test (LDDST) results. ACTH level measurements and high-dose dexamethasone tests (HDDSTs) were also conducted for differential diagnoses. These biochemical tests were carried out during hospitalization along with BIPSS.
Pituitary MRI
Pituitary dynamic enhanced MR images were obtained for the patients in the cohort. The maximum dimension of the tumour was measured by MRI. If uneven enhancement of the pituitary stalk or other indirect signs, such as deviation of the pituitary stalk, were detected, the MRI results were interpreted as equivocal, and the maximum dimension was defined as zero.
BIPSS
All BIPSS procedures were conducted before surgery by the same team, following the protocol by Doppman et al. [24]. The specific methods were the same as those in our previous study [23].
Retrograde venography was first used to confirm that the catheter tips were located in the IPS before and after sampling. Then, desmopressin (10 µg) was injected into the peripheral vein. Blood samples were also collected at 3, 5, and 10 min after desmopressin stimulation. All samples were immediately placed on ice for ACTH measurement by chemiluminescence immunoassay (Siemens Immulite).
The cut-off values for the diagnosis of CD were a central-to-peripheral ratio (IPS: P) of plasma ACTH above 2.0 before stimulation and above 3.0 after stimulation. The tumour was predicted to be on the side with the highest ACTH concentration. Tumour lateralization was predicted on the basis of the side with the highest ACTH concentration in the inferior petrosal sinus. A lateralization ratio (defined as a greater left/right or right/left IPS ACTH concentration) > 1.4 was used as a cut-off. Patients with a ratio > 1.4 were classified into the high-lateralization group, and the tumour was predicted to be ipsilateral to the higher ACTH concentration. Those with a ratio ≤ 1.4 were classified into the low-lateralization group [5].
Transsphenoidal surgery and pathology
All CD patients underwent transsphenoidal surgery by an experienced neurosurgery group at the same centre (PUMCH). The diagnosis of CD was confirmed by pathological examinations and by clinical and biochemical remission after surgery. All EAS patients underwent excision (n = 20) or biopsy (n = 5) of the tumour, and the final diagnosis was confirmed pathologically. Therefore, all patients underwent pathological examination as the diagnostic gold standard.
Follow-up after surgery
CD patients were followed up either as outpatients or by telephone after pituitary surgery. Telephone follow-up was designed for distant patients who were located far from this medical centre to obtain the results of the biochemical test from their local medical centre. The follow-up time points were three days after surgery, one month after surgery, three months after surgery, six months after surgery, and one year after surgery. The follow-up of patients in remission and relapse-free states ended on October 1, 2021.
The outcome of interest was the absence of either remission failure or disease relapse following surgery. Event-free survival was defined as the time from surgery in the absence of persistent disease or relapse. Normal hormone values were defined according to the reference ranges established by our hospital’s laboratory. Remission following transsphenoidal surgery was defined as a low morning cortisol concentration (< 2 µg/dl) three days after surgery [25, 26]. The diagnosis of no remission was defined as sustained CD symptoms, blood ACTH level higher than 46 pg/ml, a morning cortisol concentration higher than 22.3 µg/dl and a 24-h UFC concentration higher than 103.5 µg/24 hr after surgery until a second surgery, radiotherapy, and drug therapy. The definition of relapse was the reappearance of CD symptoms, a blood ACTH concentration higher than 46 pg/ml, a morning cortisol concentration higher than 22.3 µg/dl and a 24-h UFC concentration higher than 103.5 µg/24 hr after several months to years. The diagnosis of relapse or no remission was made by an endocrinologist or neurosurgeon at our centre on the basis of symptoms, hormone levels and MRI.
Impaired pituitary function
Impaired pituitary function was diagnosed by endocrinologists at our centre according to the pituitary function workup. The diagnosis was made according to clinical manifestations of hormone deficiency, hormone levels below the normal reference range, and whether hormone replacement therapy was needed. The diagnostic time range was set as six months to one year after surgery.
Secondary adrenal insufficiency was diagnosed if the morning blood cortisol concentration was lower than 3.0 µg/dl or patients needed cortisol replacement therapy. Secondary hypothyroidism was diagnosed if the TSH concentration was lower than 0.380 µIU/ml and the FT4 concentration was normal or lower than 0.81 ng/dl. In male patients, hypogonadotropic hypogonadism was diagnosed by a combination of consistently low serum total testosterone levels (typically below 1.75 ng/ml) and inappropriately normal or low luteinizing hormone (LH) levels (lower than 1.24 U/L) and follicle-stimulating hormone (FSH) levels (lower than 1.27 U/L). This hormonal profile, coupled with clinical symptoms of hypogonadism such as decreased libido, erectile dysfunction, and reduced body hair, confirms the diagnosis. For women in premenopausal period, hypogonadotropic hypogonadism was diagnosed by low serum oestradiol (E2) levels combined with inappropriately normal or low levels of FSH and LH coupled with clinical symptoms such as amenorrhea. Hypoprolactinemia was diagnosed if the prolactin concentration was lower than 2.6 ng/ml for males or lower than 7.2 ng/ml for females younger than 40 years. The growth hormone deficiency was diagnosed if the IGF-1 concentration was lower than 115 ng/ml.
Statistical analysis
For tests with dichotomous outcomes, diagnostic utility was assessed by calculating sensitivity, specificity, and diagnostic consistency with 95% confidence intervals. The correct diagnosis of CD was a true positive diagnosis; a diagnosis of CD misdiagnosed as EAS was a false-negative.
Univariable and multivariable analyses were performed in CD patients to explore the association between low lateralization and false-negative diagnosis in BIPSS before stimulation. In the multivariable analysis, sex, age, BMI, duration of disease and low lateralization were included in Model 1. In Model 2, low lateralization and hormone indicators (morning cortisol level, ACTH level, 24 h UFC level, and HDDST suppression > 50%) were included. In Model 3, low lateralization and the maximum length of the lesion on pituitary MRI were included. In Model 4, the indicators covered in Models 1 to 3 were included.
The Kaplan–Meier method was used to generate survival curves for the low-lateralization and high-lateralization CD groups. The log-rank (Mantel–Cox) test was used to compare survival curves. Postoperative hormonal axis impairment was compared using the chi-square test or t test.
Data were analysed using IBM SPSS Statistics for Mac, version 26.0 (IBM Corp., Armonk, N.Y., USA) and GraphPad Prism version 9.0.0 for Mac (GraphPad Software, San Diego, California, USA). A two-sided P value < 0.05 was considered to indicate statistical significance.
Results
BIPSS combined with desmopressin stimulation was successfully performed in all patients except for one EAS patient with a narrow right IPS for whom samples were collected only from the left IPS. The BIPSS procedure was performed twice in one EAS patient. The EAS patients in this study primarily had neuroendocrine tumours of the lung (17; 68.0%), which were difficult to directly diagnose by imaging, necessitating BIPSS.
The single-centre cohort (2011–2019) included 277 CD patients and 25 EAS patients (26 BIPSS procedures). In accordance with established guidelines and expert consensus [27–29], BIPSS was successfully performed in all patients with CD with a microadenoma (defined as a pituitary lesion ≤ 6 mm on MRI). The number of CD patients with microadenomas in the single-centre cohort was 179 (179 BIPSS) (Table 1).
Table 1.
Clinical characteristics of patients with CD with microadenoma and patients with EAS
| CD with microadenoma (n = 179) | EAS (n = 25) |
P value | |
|---|---|---|---|
| Age (years) (mean ± SD) | 37.3 ± 13.1 | 36.6 ± 14.7 | 0.807 |
| Sex (male) (k/n, %) | 39/179 (22%) | 16/25 (64%) | < 0.001 |
| Duration of disease (months) (median, IQR) | 36(18, 60) | 14(5,29) | 0.002 |
| BMI (mean ± SD) | 26.3 ± 3.8 | 25.6 ± 3.4 | 0.351 |
| Morning cortisol (µg/dl) (median, IQR) | 26.8(20.7, 32.4) | 35.4(27.6, 51.1) | 0.001 |
| ACTH (ng/L) (median, IQR) | 58.6(39.5, 93.5) | 144.0(112.5, 236.5) | < 0.001 |
| 24-hUFC (µg) (median, IQR) | 451.3(229.6, 693.0) | 1708.8(835.2, 3515.1) | < 0.001 |
| HDDST suppression > 50% (k/n, %) | 134/160 (83.8%) | 10/20 (50.0%) | < 0.001 |
| IPS: P before stimulation (median, IQR) | 8.0(4.0, 14.5) | 1.1(1.0, 1.2) | < 0.001 |
| Max IPS: P after stimulation (median, IQR) | 16.8(8.2, 31.0) | 1.3(1.2, 1.6) | < 0.001 |
| Ratio of bilateral IPS before stimulation (median, IQR) | 3.2(1.5, 7.5) | 1.1(1.0, 1.1) | < 0.001 |
| High lateralization (k/n, %) | 139/179 (77.7%) | 0/25(0.0%) | < 0.001 |
| Diagnostic accuracy of predicting tumor lateralization (k/n, %) | 67/139 (48.2%) |
Abbreviations: ACTH: adrenocorticotropic hormone; BMI: body mass index; CD with microadenoma: Cushing’s disease patients with pituitary lesions ≤ 6 mm on MRI; EAS: ectopic adrenocorticotropic hormone syndrome; HDDST: high-dose dexamethasone suppression test; High-lateralization: ratio of bilateral IPS > 1.4; IPS: P: inferior petrosal sinus to peripheral ACTH ratio; IQR: inter quartile range; Ratio of bilateral IPS: maximum of the left/right or right/left inferior petrosal sinus ACTH ratio; SD: standard deviation; 24-h UFC: 24-hour urinary free cortisol
The mean age of CD patients with microadenoma and EAS was 37.3 ± 13.3 years (range 5–69 years). A statistically significant difference in sex distribution was detected, with a greater percentage of males in the EAS group (64%) than in the CD group (22%) (P < 0.001) (Table 1). Significant differences were also found in the ACTH and 24-h UFC levels, which were greater in the EAS group than in the CD group (P < 0.001). The baseline IPS: P ratio was lower in the EAS group than in the CD group, and the poststimulation ratio was lower in the EAS group than in the CD group (P < 0.001). A bilateral IPS ratio > 1.4 (sampling lateralization) was found in 77.7% (139/179) of the patients in the CD group and 0.0% (0/25) of the patients in the EAS group. With the true location of the tumour as observed during surgery serving as the gold standard, the diagnostic consistency for predicting tumour lateralization was 48.2% (67/139).
The sensitivity and specificity of IPS: P > 2 were 84.9% (IQR 79.0%-89.4%) and 100.0% (87.1%-100.0%), respectively, at baseline. After stimulation, the sensitivity and specificity of IPS: P > 3 were 94.4% (IQR 90.0%-96.9%) and 100.0% (IQR 87.1%-100.0%), respectively. However, 15.1% (27/179) of CD cases with microadenoma were misdiagnosed as EAS via BIPSS before stimulation, which was also defined as a false-negative diagnosis.
In the univariable analysis of false-negative BIPSS results, only a bilateral IPS ratio ≤ 1.4 (low lateralization) was found to have a statistically significant association. Among true-positive CD patients (n = 152), low lateralization was present in 14.5% (22/152), whereas among false-negative CD patients (n = 27), it was present in 66.7% (18/27) (OR = 11.82, 95% CI 4.72–29.62; P < 0.001) (Table 2). No statistically significant differences were found in age, sex, disease duration, BMI, morning cortisol level, ACTH level, 24-h UFC level, HDDST suppression > 50%, or MRI-determined pituitary lesion length.
Table 2.
Univariable analysis of BIPSS false-negative diagnosis and potential risk factors in patients with CD with microadenoma (n = 179) using cutoff IPS: P > 2.0 before stimulation
| True-positive CD (n = 152) | False-negative CD (n = 27) | Effect size (95%CI) |
P value | |
|---|---|---|---|---|
| Age(years) (mean ± SD) | 37.7 ± 12.6 | 35.1 ± 15.6 | 2.73(-8.06-2.73) | 0.331 |
| Sex(male) (k/n, %) | 31/152(20.4%) | 8/27(29.6%) | 1.45(0.75–2.81) | 0.284 |
| Duration of disease(months) (median, IQR) | 36(18,60) | 25(12,62) | 6.00(-6.00-19.00) | 0.516 |
| BMI (mean ± SD) | 26.4 ± 3.8 | 25.7 ± 3.8 | 0.79(-2.31-0.80) | 0.341 |
| Morning cortisol(µg/dl) (median, IQR) | 27.4(20.8, 32.2) | 26.4(19.3, 33.6) | 0.21(-3.90-4.77) | 0.769 |
| ACTH (ng/L) (median, IQR) | 60.7(42.2, 95.1) | 54.1(35.5, 75.1) | 7.80(-6.50-22.70) | 0.259 |
| 24-h UFC(µg) (median, IQR) | 451.3(227.6, 717.3) | 540.6(259.2,673.9) | 6.27(-115.73-134.80) | 0.594 |
| HDDST suppression > 50% | 113/136 (83.1%) | 21/24(87.5%) | 1.05 (0.89–1.25) | 0.589 |
| Low-lateralization (k/n, %) | 22/152(14.5%) | 18/27(66.7%) | 11.82(4.72–29.62) | < 0.001 |
| Pituitary lesion length on MRI (mm) (median, IQR) | 3.9(0, 5.0) | 4.0(2.7,5.1) | 0.00(-0.70-0.40) | 0.404 |
Abbreviations: CD with microadenoma: Cushing’s disease patients with pituitary lesions ≤ 6 mm on MRI; ACTH: adrenocorticotropic hormone; BMI: body mass index; HDDST: high-dose dexamethasone suppression test; IPS: P: ratio of the inferior petrosal sinus to the peripheral ACTH concentration; IQR: inter quartile range; Low-lateralization: ratio of bilateral IPS ≤ 1.4; MRI: magnetic resonance imaging; OR: odds ratios; SD: standard deviation; 95%CI: 95% confidence interval; 24-h UFC: 24-h urinary free cortisol
In four models of multivariable regression analysis for BIPSS false-negative diagnosis, low lateralization was associated with significantly higher odds after adjusting for other factors (Table 3). In Model 1, which included baseline clinical characteristics, the adjusted OR for low lateralization was 12.36 (95% CI 4.70–32.52; P < 0.001). In Model 2, which included hormone indicators, the adjusted OR was 11.25 (95% CI 4.03–31.39, P < 0.001). In Model 3, which included imaging examination results, the adjusted OR was 12.13 (95% CI 4.81–30.58; P < 0.001). In Model 4, which included all indicators from Models 1 to 3, the adjusted OR was 12.69 (95% CI 4.14–38.86; P < 0.001). Multivariate analysis revealed a significant association between low lateralization and an increased risk of false-negative BIPSS diagnoses.
Table 3.
Multivariable analysis of the potential association between BIPSS false-negative diagnosis before stimulation and low-lateralization in CD with microadenoma
| Adjusted OR (95%CI) | P value | ||
|---|---|---|---|
| Model 1 | Age(years) | 0.99(0.95–1.02) | 0.479 |
| Sex(male) | 1.73(0.55–5.40) | 0.348 | |
| BMI | 0.91(0.80–1.04) | 0.167 | |
| Duration of disease(months) | 1.00(0.99–1.01) | 0.831 | |
| Low-lateralization | 12.36(4.70-32.52) | < 0.001 | |
| Model 2 | HDDST suppression > 50% | 0.86(0.20–3.82) | 0.846 |
| Morning cortisol(µg/dl) | 1.00(0.95–1.06) | 0.913 | |
| ACTH(ng/L) | 0.99(0.97-1.00) | 0.116 | |
| 24-h UFC(µg) | 1.00(1.00–1.00) | 0.659 | |
| Low-lateralization | 11.25(4.03–31.39) | < 0.001 | |
| Model 3 | Length of lesion on pituitary MRI(mm) | 1.06(0.86–1.32) | 0.591 |
| Low-lateralization | 12.13(4.81–30.58) | < 0.001 | |
| Model 4 | Age(years) | 0.98(0.94–1.02) | 0.300 |
| Sex(male) | 1.89(0.52–6.80) | 0.331 | |
| BMI | 0.88(0.76–1.03) | 0.106 | |
| Duration of disease(months) | 1.00(0.99–1.01) | 0.922 | |
| HDDST suppression > 50% | 0.72(0.15–3.43) | 0.676 | |
| Morning cortisol(µg/dl) | 1.02(0.96–1.08) | 0.528 | |
| ACTH(ng/L) | 0.99(0.97-1.00) | 0.079 | |
| 24-h UFC(µg) | 1.00(1.00–1.00) | 0.550 | |
| Length of lesion on pituitary MRI(mm) | 1.13(0.89–1.44) | 0.314 | |
| Low-lateralization | 12.69(4.14–38.86) | < 0.001 |
Abbreviations: ACTH: adrenocorticotropic hormone; adjusted OR: odds ratios after adjusting for other factors in the model; BMI: body mass index; CD with microadenoma: Cushing’s disease patients with pituitary lesions ≤ 6 mm on MRI; HDDST: high-dose dexamethasone suppression test; Low-lateralization: ratio of bilateral IPS ≤ 1.4; MRI: magnetic resonance imaging; 95%CI: 95% confidence interval; 24-h UFC: 24-h urinary free cortisol
CD patients with microadenomas were divided into a high-lateralization group (n = 139) and a low-lateralization group (n = 40) on the basis of whether their bilateral IPS ratio was greater than 1.4. A comparison of the clinical characteristics of the two groups revealed several significant differences (Table 4). A significant difference in median morning cortisol levels was detected; the median morning cortisol level in the low-lateralization group was 29.3 (IQR 25.0, 36.6), which was significantly greater than that in the high-lateralization group (median of 25.9 (IQR 19.9, 31.9)) (P = 0.012). Similarly, a significant difference was found in the median ACTH concentration; the median ACTH concentration in the low-lateralization group was 74.7 (IQR 50.7, 104.0), which was significantly greater than that in the high-lateralization group [median of 55.3 (IQR 35.5, 88.0)] (P = 0.046). When a cut-off of 2.0 was used for BIPSS diagnosis before stimulation, the sensitivity of the low-lateralization group was significantly lower (55.0%; 95% CI 39.8%–69.3%) than that of the high-lateralization group (93.5%; 95% CI 88.2%–96.6%; P < 0.001). When a cut-off of 3.0 was used after stimulation, the sensitivity of the low-lateralization group was also significantly lower (80.0%; 95% CI 65.2%–89.5%) than that of the high-lateralization group (98.6%; 95% CI 94.9%–99.6%; P < 0.001). The specificity before and after stimulation was 100.0% (95% CI 86.7%–100.0%) in both groups. All CD patients underwent transsphenoidal pituitary tumour surgery. Pathologically verified surgical specimens were obtained from both groups, and no difference was observed in surgical tumour lateralization. DSA revealed that the difference in the bilateral pituitary vascular area was significantly greater in the low-lateralization group than in the high-lateralization group, and the bilateral vascular area ratio was also significantly greater on the low-lateralization side than on the high-lateralization side [23].
Table 4.
Clinical characteristics of CD patients in the high-lateralization group and low-lateralization group
| High-lateralization group (n = 139) | Low-lateralization group (n = 40) | P value | |
|---|---|---|---|
| Age (years) (mean ± SD) | 37.5 ± 12.5 | 36.8 ± 15.0 | 0.780 |
| Sex (male) (k/n, %) | 29/139(20.9%) | 10/40(25%) | 0.577 |
| Duration of disease (months) (median, IQR) | 38(18,67) | 24(12, 60) | 0.173 |
| BMI (mean ± SD) | 26.2 ± 3.5 | 26.7 ± 4.5 | 0.501 |
| Morning cortisol (µg/dl) (median, IQR) | 25.9(19.9, 31.9) | 29.3(25.0, 36.6) | 0.012 |
| ACTH (ng/L) (median, IQR) | 55.3(35.5, 88.0) | 74.7(50.7, 104.0) | 0.046 |
| 24-h UFC (µg) (median, IQR) | 413.0(229.6, 685.9) | 560.8(235.9, 820.2) | 0.213 |
| HDDST suppression > 50% (k/n, %) | 103/123 (83.7%) | 31/37 (83.8%) | 0.995 |
| Length of lesion on pituitary MRI (mm) (median, IQR) | 3.95(0.00,5.03) | 4.00(2.70,5.00) | 0.805 |
| IPS: P before stimulation | 9.3(4.6, 15.9) | 4.1(1.3, 8.5) | < 0.001 |
| Sensitivity of cutoff 2.0(95%CI) | 93.5%(88.2%-96.6%) | 55.0%(39.8%-69.3%) | < 0.001 |
| Specificity of cutoff 2.0(95%CI) | 100.0%(86.7%-100.0%) | 100.0%(86.7%-100.0%) | 1.000 |
| Max IPS: P after stimulation | 21.0(11.1, 36.1) | 8.0(3.7, 16.9) | < 0.001 |
| Sensitivity of cutoff 3.0(95%CI) | 98.6%(94.9%-99.6%) | 80.0%(65.2%,89.5%) | < 0.001 |
| Specificity of cutoff 3.0(95%CI) | 100.0%(86.7%-100.0%) | 100.0%(86.7%-100.0%) | 1.000 |
| Tumor lateralization in pituitary surgery (k/n, %) | |||
| Left | 46/139 (33.1%) | 16/40 (40.0%) | 0.2286 |
| Right | 67/139 (48.2%) | 21/40 (52.5%) | |
| Middle or both | 26/139 (18.7%) | 3/40 (7.5%) |
Abbreviations: ACTH: adrenocorticotropic hormone; BMI: body mass index; CD: Cushing’s disease patients with pituitary lesions ≤ 6 mm on MRI; HDDST: high-dose dexamethasone suppression test; IPS: P: inferior petrosal sinus: peripheral ACTH concentration; High-lateralization: ratio of bilateral IPS > 1.4; IQR: inter quartile range; Low-lateralization: ratio of bilateral IPS ≤ 1.4; MRI: magnetic resonance imaging; >95%CI: 95% confidence interval; 24-h UFC: 24-h urinary free cortisol
Each CD patient (2011–2019) was followed for two to ten years after transsphenoidal surgery. The median follow-up time was 5.7 years for the low-lateralization group and 5.0 years for the high-lateralization group. Survival analysis revealed that the low-lateralization group had a significantly greater risk of relapse or no remission after transsphenoidal surgery (hazard ratio = 3.636, 95% CI 1.456–9.080; P = 0.006) (Fig. 1). A significant difference was found in the no-remission risk, which was 22.5% (9/40) in the low-lateralization group, which was significantly greater than the 4.8% (7/139) in the high-lateralization group (P = 0.002). No significant difference was found in the relapse risk among remission patients, which was 9.7% (3/31) in the low-lateralization group and 7.6% (10/132) in the high-lateralization group (P = 0.7143).
Fig. 1.
Kaplan–Meier analysis of time to remission or relapse-free state of the low-lateralization group and high-lateralization group. The hazard of relapse or nonremission after surgery in the low-lateralization group was higher than that in the high-lateralization group (P = 0.006)
A greater rate of pituitary function axis impairment occurred in the low-lateralization group after transsphenoidal surgery than in the high-lateralization group (Table 5). A significant difference was found in the median number of impaired pituitary functions; the median was 1 (IQR 0, 2) in the low-lateralization group, which was significantly greater than the median of 0 (IQR 0, 1) in the high-lateralization group (P = 0.038). The rate of secondary hypothyroidism was 42.86% (15/35) in the low-lateralization group, which was significantly greater than the 16.00% (20/125) in the high-lateralization group (P = 0.001). Similarly, the rate of hypogonadotropic hypogonadism was 28.13% (9/32) in the low-lateralization group, which was significantly greater than the 11.40% (13/114) in the high-lateralization group (P = 0.019).
Table 5.
Postoperatively impaired pituitary function in the high-lateralization and low-lateralization groups
| High-lateralization (n = 139) |
Low-lateralization (n = 40) |
P value | |
|---|---|---|---|
| Secondary Adrenal Insufficiency (k/n, %) | 26/99(26.26%) | 10/32(31.25%) | 0.583 |
| Secondary Hypothyroidism (k/n, %) | 20/125(16.00%) | 15/35(42.86%) | 0.001 |
| Hypogonadotropic Hypogonadism (k/n, %) | 13/114(11.40%) | 9/32(28.13%) | 0.019 |
| Hypoprolactinemia (k/n, %) | 16/98(16.33%) | 8/29(27.59%) | 0.174 |
| Growth Hormone Deficiency (k/n, %) | 44/103(42.72%) | 12/29(41.38%) | 0.897 |
| Number of Pituitary Axis Deficiencies (median, IQR) | 0(0,1) | 1(0,2) | 0.038 |
Abbreviations: High-lateralization: ratio of bilateral IPS > 1.4; IQR: inter quartile range; Low-lateralization: ratio of bilateral IPS ≤ 1.4
Discussion
In this single-centre retrospective cohort study, we explored the influence of low lateralization on the diagnostic accuracy and surgical outcomes of CD with a microadenoma (less than 6 mm on MRI). Prior research has demonstrated the limited predictive value of the bilateral IPS lateralization ratio for tumour localization in patients with CD [2, 5, 14–18, 30–34]. Our univariable and multivariable analyses revealed that low lateralization might be significantly associated with false-negative diagnoses by BIPSS. With an IPS cut-off of P > 2.0, we observed markedly lower sensitivity in the low-lateralization group [55.0% (39.8%–69.3%), n = 40] than in the high-lateralization group [93.5% (88.2%–96.6%), n = 139] (P < 0.001). Notably, survival analysis revealed a greater risk of no remission after surgery in the low-lateralization group than in the high-lateralization group, and there was greater impairment in pituitary function after surgery in the low-lateralization group. These findings provide a novel perspective on low lateralization by BIPSS, demonstrating that low lateralization not only compromises diagnostic accuracy but also predicts worse prognosis of CD after surgery.
This BIPSS single-centre cohort is one of the largest series in the world, with all included CD and EAS cases confirmed by histopathological diagnosis. To decrease bias regarding surgical technology, all BIPSS procedures were performed by skilled radiologists at the same centre, and the transsphenoidal surgeries were performed by the same team. Each CD underwent comprehensive follow-up ranging from two to ten years through structured telephone interviews or clinical evaluations, ensuring robust outcome assessment.
The association of low-lateralization with low diagnostic accuracy in BIPSS is further elucidated by our study. The mechanism of false-negative diagnosis in BIPSS has been explored in several studies [33, 35–38]. Dating back to the initial cut-off values (2.0 and 3.0) established in 1991, false-negative diagnoses were discussed. Earlier work by Bonelli et al. in 2000 implicated technical factors, anatomical variations, and tumour-specific ACTH secretion patterns as contributors to false-negative diagnoses [31]. Angiographic cross-filling, indicating extensive intercavernous venous connections, significantly affects ACTH gradient dynamics during IPSS and may reduce the specificity of tests for preoperative microadenoma lateralization [39]. Swearingen et al. summarized the characteristics of false-negative diagnoses among 179 CS patients (185 BIPSS), suggesting that false-negative diagnoses might be related to anatomical abnormalities, ACTH dilution by nonpituitary venous blood, incorrect catheter position, tumours located in the sphenoid sinus, cyclical ACTH secretion, and sample processing [36]. Recent AI advances have enabled the development of noninvasive ML algorithms for ACTH-dependent CS diagnosis. Using logistic regression (AUROC = 0.85, accuracy = 86%) on 106 patients (80 CD/26 EAS), key predictors included dexamethasone tests, late-night cortisol, and adenoma size. An accessible clinical interface was created, demonstrating the potential of AI to reduce the number of invasive procedures [40]. However, these studies did not propose a clear indicator associated with an increased risk of false-negative diagnoses. In this study, the adjusted OR of low lateralization was 12.69 (95% CI 4.14–38.86) (P < 0.001) in the multivariable analysis using Model 4 (Table 3). Therefore, low lateralization was reinterpreted as a novel indicator associated with false-negative diagnosis.
Our study further demonstrated that low lateralization is associated with poor prognosis after transsphenoidal surgery. Relapse is a common problem in patients with CD, occurring in approximately 15% of patients. Approximately 50% of relapses occur in the first 50 months after the first surgery [41]. Bochicchio et al. [42] and Chee et al. [43] proposed that identification of the tumour by MRI before surgery indicates remission. Cannavo et al. reported that a lack of sinus cavernous invasion by an adenoma might indicate remission after surgery [44]. Liu et al. reported that the most important predictors for relapse were young age, as well as post-operative blood cortisol levels and postoperative ACTH levels measured during the first seven days after surgery, according to the machine learning algorithms they designed [45]. Several studies have reported that the experience of the surgeon is a main factor influencing remission [46–49]. However, the main indicators of hormone levels are assessed after surgery and do not influence decision-making before surgery. In this study, survival analysis revealed a higher risk of relapse or no remission after surgery in the low-lateralization group (hazard ratio = 3.636, 95% CI 1.456–9.080; P = 0.006) (Fig. 1). The no remission risk of the low-lateralization group was 22.5% (9/40), which was higher than that of the high-lateralization group at 4.8% (7/139) (P = 0.002). Low lateralization before surgery might be reinterpreted as a new indicator for predicting surgical outcomes and might influence decision-making by neurosurgeons before surgery [50].
As it is a reinterpreting indicator associated with both low diagnostic accuracy and poor prognosis, the mechanism of low lateralization needs to be further explored. In high-lateralization patients, ACTH secreted by the pituitary gland might be carried away mainly by the unilateral inferior petrosal vein, producing a high inferior petrosal ACTH gradient. Conversely, in patients with low lateralization, ACTH secreted by the pituitary gland might be distributed through bilateral inferior petrosal veins and even other veins around the pituitary gland. Overall, there is a possibility of anatomical differences between low-lateralization and high-lateralization CD. On the basis of these findings, we propose the anatomical hypothesis shown in Fig. 2.
Fig. 2.
Hypothesis of occult CD (log-lateralization CD with microadenoma under 6 mm). (A) The ACTH secretion orientation might be a one-sided IPS in high-lateralization CD. (B) The ACTH secretion orientation might be two-sided IPS and involve other vessels in low-lateralization CD, which might indicate occult CD, which is difficult to diagnose
In conclusion, this study reinterprets the traditional indicator of low lateralization (a bilateral IPS ratio ≤ 1.4) with regard to its inferior performance in the diagnosis and prognosis of CD with a microadenoma. Clinicians in endocrinology and neurosurgery should pay more attention to the diagnosis and treatment of patients with ACTH-dependent CS with low-lateralization IPS to reduce misdiagnosis and improve prognosis after surgery.
Acknowledgements
None.
Author contributions
X. L., J. L. and D. Z. contributed equally to this work and should be regarded as co-first authors. All authors contributed to the study conception and design. Material preparation, data collection were performed by X. L., J. L., D. Z., X. Z., H. Z., S. C.,L. L., H. P. Analysis was performed by X. L. and Y. Z. The first draft of the manuscript was written by X. L. And all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Peking Union Medical College Hospital Talent Cultivation Program, Category C (UBJ10385).
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Human ethics and consent to participate declarations
This study was approved by the Institutional Review Board of the Peking Union Medical College Hospital. Patients signed informed consent before information and blood samples were collected and approved using their information and samples in future scientific research. Our study adhered to the Declaration of Helsinki.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Xiaohong Lyu, Jiaxuan Liu and Dingyue Zhang are Co-first authors and contributed equally to this work.
Contributor Information
Shi Chen, Email: cs0083@126.com.
Lin Lu, Email: pumchlulin@163.com.
Hui Pan, Email: panhui20111111@163.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.