Cushing’s Syndrome in Pregnancy in Which Laparoscopic Adrenalectomy was Safely Performed by a Retroperitoneal Approach

Posted on October 2, 2023 by MaryO

Abstract

Introduction

Laparoscopic adrenalectomy is the standard treatment for adrenal tumors caused by Cushing’s syndrome. However, few pregnant women have undergone adrenalectomy because of the risk of general anesthesia and surgery.

Case presentation

A 28-year-old woman presented with gradually worsening Cushing’s signs at around 12 weeks of pregnancy. Magnetic resonance imaging displayed a 38-mm left adrenal tumor, which was the cause of the adrenal Cushing’s syndrome. Metyrapone was started, which increased androgen levels. Since the management of Cushing’s syndrome by medication alone is challenging, unilateral laparoscopic adrenalectomy by a retroperitoneal approach was performed at 23 weeks of the pregnancy. No perioperative complications were noted.

Conclusion

Adrenalectomy is considered safe in pregnant women with Cushing’s syndrome. Laparoscopic adrenalectomy by retroperitoneal approach should be chosen and performed between 14 and 30 weeks of pregnancy to prevent mother and fetal complications.

Abbreviations & Acronyms

  • CS
  • Cushing’s syndrome
  • MRI
  • magnetic resonance imaging

Keynote message

We report a rare case of adrenalectomy performed via a retroperitoneal approach for Cushing’s syndrome in a pregnant woman. Cushing’s syndrome may affect the fetus, and surgery can be considered in addition to medical management. Adrenalectomy should be performed in the second trimester of pregnancy. Pneumoperitoneal pressure, position, and surgical approaches must receive careful attention.

Introduction

CS is characterized by excessive cortisol secretion and characteristic symptoms such as full moon-like facial features and central obesity. Premenopausal women with CS rarely become pregnant because excessive glucocorticoid secretion inhibits the synthesis of gonadotropins, leading to impaired ovarian and endometrial function, and causing amenorrhea or oligomenorrhea.1 Furthermore, even when women with CS become pregnant, the incidence of severe complications is high. CS can cause maternal hypertension, diabetes/glucose intolerance, osteopenia/osteoporosis, preeclampsia, pulmonary edema, heart failure, opportunistic infections, and even death. Additionally, CS can potentially cause stillbirth, prematurity, and intrauterine fetal growth restriction.1–6 Therefore, CS must be detected at an early stage in pregnancy; however, CS may go undetected because of the overlapping signs of preeclampsia and/or gestational diabetes.

A cortisol-secreting adrenal tumor is the underlying cause of CS, and laparoscopic adrenalectomy is the standard treatment to it. Medical treatment of CS can include medications that inhibit 11β-hydroxylase, such as metyrapone and osilodrostat, but surgical treatment is considered if the disease is difficult to control with medical treatment. Nonobstetric surgery during pregnancy is performed in 1%–2% of pregnant women.7 Although general anesthesia is relatively safe during pregnancy, the indication for the surgery must be carefully considered because of potential risks such as neurodevelopmental delay, sudden death, etc.

Herein, we present a case of a pregnant woman diagnosed with CS who underwent unilateral laparoscopic adrenalectomy by a retroperitoneal approach without any problems.

Case presentation

The patient was a 28-year-old primiparous woman. Since around 12 weeks of pregnancy, she has experienced facial and lower limb edema; gained 6-kg weight in 1 month; increased facial acne; and experienced subcutaneous bleeding on the forearms, red abdominal dermatitis, proximal muscle weakness, palpitations, insomnia, and decreased vision in eyes. Her symptoms gradually worsened from 14 weeks, and she was referred to our hospital to clarify the cause at 18 weeks of pregnancy.

Adrenal CS was suspected on the basis of her Cushing’s signs, cortisol 25 μg/dL, and adrenocorticotropic hormone <1.5 pg/mL. She had hypokalemia, hypogammaglobulinemia, and liver dysfunction, and her condition was rapidly worsening. Given her pregnant state, she was admitted for intensive testing for the case of CS from 19 weeks of pregnancy. MRI revealed a well-defined 38-mm left adrenal tumor, which was the cause of the adrenal CS (Fig. 1). She was started on metyrapone with 250 mg per day, which increased androgens (0.53–0.69 ng/mL in 1 week). We considered that the management of CS by medication alone would be challenging and performed adrenalectomy during her pregnancy. The dose of metyrapone was increased to 1000 mg per day eventually.

Details are in the caption following the image

Magnetic resonance imaging on admission shows a left adrenal tumor with a long axis of 38 mm (arrowhead). Signal reduction was partially observed on opposed-phase images, leading to diagnosis of cortical adenoma.

She was admitted to the hospital at 23 weeks and 2 days of gestation, and laparoscopic left adrenalectomy was performed via a retroperitoneal approach in the right lateral and jackknife position on the following day (Fig. S1). During the surgery, blood pressure was carefully controlled by an anesthesiologist and the patient’s position and fetal heart rate were monitored by an obstetrician. The operation time, insufflation time, and general anesthesia time were 68, 59, and 123 min, respectively, and the blood loss volume was 75 mL, without any complications. Pathological findings revealed an adrenocortical adenoma. The specimen was positive for one of the nine Weiss criteria (Fig. 2).

Details are in the caption following the image

(a) Intraoperative findings of the retroperitoneal approach. Arrowheads indicate the tumor. (b) Gross appearance of the resected adrenal tumor; a brownish-toned, substantial mass, 60 × 34 × 15 mm in size. (c, d) Hematoxylin–eosin staining showed that nodular lesion with a fibrous capsule, with foci of homogeneous cells with eosinophilic or pale, foamy sporangia and small round nuclei.

Postoperatively, metyrapone was discontinued and both lower leg edema, facial acne, fatigue, and muscle weakness improved. Metyrapone was discontinued after surgery. Hydrocortisone, which had been administered at 150 mg/day during the perioperative period, was reduced every few weeks and was taken at 30 mg/day at delivery. She delivered by cesarean section at 38 weeks and 2 days of gestation, with good outcomes for the mother and her infant. Hydrocortisone was discontinued 15 weeks after delivery.

We showed the changes in cortisol and ACTH from the first visit to postpartum (Fig. 3).

Details are in the caption following the image

The transition of Cortisol and ACTH. Cortisol decreases rapidly after surgery and rises again before delivery. As cortisol improved, ACTH also increased.

Discussion

CS seldom occurs during pregnancy. Symptoms such as weight gain, skin striae, fatigue, and a round face can also occur in normal pregnancies. The dexamethasone suppression test can result in false positives because of ACTH produced by placenta in normal pregnancy. During pregnancy, there is a physiological state of high cortisol levels. The disappearance of diurnal rhythm is a useful indicator for diagnosis of CS in pregnancy because circadian rhythm is maintained in normal pregnancy. Useful diagnostic criteria include urine cortisol levels greater than three times the upper limit of normal, loss of diurnal cortisol rhythm, and presence of adrenal tumors on MRI.

The pharmacologic treatment of endogenous cortisol is complex, and hormonal management is challenging. While the management of the cortisol levels is important, metyrapone is a risk factor for gestational hypertension and may inhibit fetal cortisol production by crossing the placenta.1–6, 8–12

In this case, because androgens were also elevated and drug management was expected to be challenging, the surgery was aggressively considered. Despite the reports of successful adrenalectomy is after 28 weeks of gestation,6, 13, 14 The surgery should be performed by an experienced team between 14 and 30 weeks of pregnancy, that is, after organogenesis phase and before the fetus grows too large.1, 13, 15

A few pregnant women with adrenal CS undergo adrenalectomy. However, the laparoscopic approach is safe, and maternal and fetal complications were higher in women who did not undergo surgery.16 Less postoperative pain, faster wound healing, and faster postoperative recovery are the main advantages of laparoscopic surgery.17

In pregnant women, pneumoperitoneal pressure should be kept <12 mmHg because increased intraabdominal pressure decreases placental blood flow and can cause fetal acidosis due to the absorption of carbon dioxide used for insufflation.

Laparoscopic adrenalectomy can be safely performed through both transperitoneal and retroperitoneal approaches.18 However, in pregnant women, performing the surgery by the retroperitoneal approach in the lateral position is preferable to prevent putting pressure on the fetus during the surgery. The retroperitoneal approach is advantageous, as less pressure is placed on the uterus and adhesions are prevented. After taking the lateral position, the obstetrician is advised to check the position and confirm that the abdomen is not compressed and that the fetal heart rate is normal.

Conclusions

We present a case of a pregnant woman diagnosed with adrenal CS who underwent a unilateral laparoscopic adrenalectomy by a retroperitoneal approach without any problems. Adrenalectomy is a useful treatment when CS is difficult to control despite metyrapone and other medical support.

Author contributions

Nobuyoshi Takeuchi: Conceptualization; methodology; project administration; writing – original draft. Yusuke Imamura: Conceptualization; methodology; supervision; writing – review and editing. Kazuki Ishiwata: Data curation; supervision. Manato Kanesaka: Data curation; supervision. Yusuke Goto: Data curation; supervision. Tomokazu Sazuka: Data curation; supervision. Sawako Suzuki: Data curation; supervision. Hisashi Koide: Data curation; supervision. Shinichi Sakamoto: Data curation; supervision. Tomohiko Ichikawa: Data curation; supervision.

Conflict of interest

The authors declare no conflicts of interest.

Approval of the research protocol by an Institutional Reviewer Board

Not applicable.

Informed consent

Informed consent for the release of the case report and accompanying images has been obtained from the patient.

Registry and the Registration No. of the study/trial

Not applicable.

From https://onlinelibrary.wiley.com/doi/10.1002/iju5.12637

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High-resolution Contrast-enhanced MRI With Three-Dimensional Fast Spin Echo Improved the Diagnostic Performance for Identifying Pituitary Microadenomas In Cushing’s Syndrome

Posted on July 26, 2023 by MaryO

Abstract

Objectives

To assess the diagnostic performance of high-resolution contrast-enhanced MRI (hrMRI) with three-dimensional (3D) fast spin echo (FSE) sequence by comparison with conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI) with 2D FSE sequence for identifying pituitary microadenomas.

Methods

This single-institutional retrospective study included 69 consecutive patients with Cushing’s syndrome who underwent preoperative pituitary MRI, including cMRI, dMRI, and hrMRI, between January 2016 to December 2020. Reference standards were established by using all available imaging, clinical, surgical, and pathological resources. The diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas was independently evaluated by two experienced neuroradiologists. The area under the receiver operating characteristics curves (AUCs) were compared between protocols for each reader by using the DeLong test to assess the diagnostic performance for identifying pituitary microadenomas. The inter-observer agreement was assessed by using the κ analysis.

Results

The diagnostic performance of hrMRI (AUC, 0.95–0.97) was higher than cMRI (AUC, 0.74–0.75; p ≤ .002) and dMRI (AUC, 0.59–0.68; p ≤ .001) for identifying pituitary microadenomas. The sensitivity and specificity of hrMRI were 90–93% and 100%, respectively. There were 78% (18/23) to 82% (14/17) of the patients, who were misdiagnosed on cMRI and dMRI and correctly diagnosed on hrMRI. The inter-observer agreement for identifying pituitary microadenomas was moderate on cMRI (κ = 0.50), moderate on dMRI (κ = 0.57), and almost perfect on hrMRI (κ = 0.91), respectively.

Conclusions

The hrMRI showed higher diagnostic performance than cMRI and dMRI for identifying pituitary microadenomas in patients with Cushing’s syndrome.

Key Points

• The diagnostic performance of hrMRI was higher than cMRI and dMRI for identifying pituitary microadenomas in Cushing’s syndrome.

• About 80% of patients, who were misdiagnosed on cMRI and dMRI, were correctly diagnosed on hrMRI.

• The inter-observer agreement for identifying pituitary microadenomas was almost perfect on hrMRI.

Introduction

Cushing’s syndrome, caused by excessive exposure to glucocorticoids, is associated with considerable morbidity and increased mortality [1]. Cushing’s syndrome has diverse manifestations, including central obesity, moon facies, purple striae, and hypertension [2]. Cushing’s disease, due to adrenocorticotropic hormone (ACTH) hypersecretion from pituitary adenomas, is the most common etiology of ACTH-dependent Cushing’s syndrome [1, 2]. According to the Endocrine Society Clinical Practice Guideline, transsphenoidal surgery is the first-line treatment for Cushing’s disease [3]. The identification of pituitary adenomas on preoperative MRI can significantly increase the postoperative remission rate from 50 to 98% [4]. Therefore, it is critical to identify pituitary adenomas on MRI before surgery.

However, there are considerable challenges in identifying ACTH-secreting pituitary adenomas. This is because about 90% of the tumors are microadenomas (less than 10 mm in size) and the median diameter at surgery is about 5 mm [5, 6]. Conventional contrast-enhanced MRI (cMRI) using a two-dimensional (2D) fast spin echo (FSE) sequence has been routinely used to acquire images with 2- to 3-mm slice thickness, but some microadenomas are difficult to be identified on cMRI, resulting in false negatives reported in up to 50% of patients with Cushing’s disease [7]. Dynamic contrast-enhanced MRI (dMRI) increases the sensitivity of identifying pituitary adenomas to 66% [8], but it also increases false positives at the same time [9, 10]. The 3D spoiled gradient recalled (SPGR) sequence has been introduced in high-resolution contrast-enhanced MRI (hrMRI) to acquire images with 1- to 1.2-mm slice thickness. It is reported that the 3D SPGR sequence is superior to the 2D FSE sequence in the identification of pituitary adenomas with a sensitivity of up to 80% [11,12,13], but it cannot satisfy the clinical needs that about 20% of the lesions are still missed. Therefore, techniques are needed that can help better identify pituitary adenomas, particularly microadenomas. Previously, the 3D FSE sequence was recommended in patients with hyperprolactinemia [14]. Recently, the 3D FSE sequence has developed rapidly and can provide superior image quality with diminished artifacts [15]. Sartoretti et al demonstrated in a very effective fashion that the 3D FSE sequence is a reliable alternative for pituitary imaging in terms of image quality [16]. However, to our knowledge, few studies have investigated the diagnostic performance of 3D FSE sequences for identifying ACTH-secreting pituitary adenomas, particularly microadenomas.

The aim of our study was to assess the diagnostic performance of hrMRI with 3D FSE sequence by comparison with cMRI and dMRI with 2D FSE sequence for identifying ACTH-secreting pituitary microadenomas in patients with Cushing’s syndrome.

Materials and methods

This single-institutional retrospective study was approved by the Institutional Review Board of our hospital. The study was conducted in accordance with the Helsinki Declaration. The informed consent was waived due to the retrospective nature of the study.

Study participants

We retrospectively reviewed the medical records and imaging studies of 186 consecutive patients with ACTH-dependent Cushing’s syndrome, who underwent a combined protocol of cMRI, dMRI, and hrMRI from January 2016 to December 2020. Postoperative patients with Cushing’s disease (n = 97), patients with ectopic ACTH syndrome who underwent pituitary exploration (n = 2), and patients with macroadenomas (n = 5) or lack of pathology (n = 13) were excluded from the study. Finally, 69 patients with ACTH-dependent Cushing’s syndrome were included in the current study (Fig. 1) and the patients included were all surgically confirmed.

Fig. 1
figure 1

Flowchart of patient inclusion/exclusion process and image analysis. ACTH adrenocorticotropic hormone, CD Cushing’s disease, EAS ectopic ACTH syndrome, T1WI T1-weighted imaging, T2WI T2-weighted imaging

MRI protocol

All the patients were imaged on a 3.0 Tesla MR scanner (Discovery MR750w, GE Healthcare) using an 8-channel head coil. The MRI protocol included coronal T2-weighted imaging, coronal T1-weighted imaging, and sagittal T1-weighted imaging before contrast injection. After contrast injection of gadopentetate dimeglumine (Gd-DTPA) at 0.05 mmol/kg (0.1 mL/kg) with a flow rate of 2 mL/s followed by a 10-mL saline solution flush, dMRI and cMRI with 2D FSE sequence were obtained first, and hrMRI with 3D FSE sequence using variable flip angle technique was performed immediately afterward. Detailed acquisition parameters are presented in Table S1.

Image analysis: diagnostic performance

Image interpretation was independently conducted by two experienced neuroradiologists (F.F. and H.Y. with 25 and 16 years of experience in neuroradiology, respectively), who were blinded to patient information. The evaluation order of cMRI, dMRI, and hrMRI sequences was randomized. The identification of pituitary microadenomas on images was scored based on a three-point scale (0 = poor; 1 = fair; 2 = excellent). Scores of 1 or 2 represented the identification of the lesion. Reference standards were established by using all available imaging, clinical, surgical, and pathological resources, with a multidisciplinary team approach.

Image analysis: image quality

Two readers (Z.L. and B.H. with 4 years of experience in radiology, respectively) were asked to assess the image quality of cMRI, dMRI, and hrMRI. Before exposure to images used in the current study, these readers underwent a training session to make sure that they were comparable to the experienced neuroradiologists in terms of image quality assessment. Images were presented in a random order. Image quality was assessed by using a 5-point Likert scale [17], including overall image quality (1 = non-diagnostic; 2 = poor; 3 = fair; 4 = good; 5 = excellent), sharpness (1 = non-diagnostic; 2 = not sharp; 3 = a little sharp; 4 = moderately sharp; 5 = satisfyingly sharp), and structural conspicuity (1 = non-diagnostic; 2 = poor; 3 = fair; 4 = good; 5 = excellent). An example of image quality assessment is shown in Table S2. Final decision was made through a consensus agreement.

The mean signal intensity of pituitary microadenomas, pituitary gland, and noise on cMRI, dMRI, and hrMRI was measured using an operator-defined region of interest. For noise, a 10-mm2 region of interest was placed in the background, and noise was defined as the standard deviation of the signal intensity of the background [17]. For pituitary microadenomas and pituitary gland, the region of interest should include a representative portion of the structure. The mean signal intensity of the pituitary microadenoma was replaced with that of the pituitary gland when no microadenoma was identified. A signal-to-noise ratio (SNR) was defined as the mean signal intensity of the pituitary microadenoma divided by noise. A contrast-to-noise ratio (CNR) was defined as the absolute difference of the mean signal intensity between the normal pituitary gland and pituitary microadenomas divided by noise [17]. Supplementary Fig. 1 shows how to measure the SNR and CNR with the region of interest in a contrast-enhanced pituitary MRI. Supplementary Fig. 2 shows the selection of images for the SNR and CNR calculation.

Statistical analysis

The κ analysis was conducted to assess the inter-observer agreement for identifying pituitary microadenomas. The κ value was interpreted as follows: below 0.20, slight agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, substantial agreement; greater than 0.80, almost perfect agreement.

To assess the diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas, the receiver operating characteristic curves were plotted and the area under curves (AUCs) were compared between MR protocols for each reader by using the DeLong test. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The Mann–Whitney U test was used to evaluate the difference in image quality scores and the Wilcoxon signed-rank test was used to evaluate SNR and CNR measurements between MR protocols. A p value of less than 0.05 was considered statistically significant. Statistical analysis was performed using MedCalc Statistical Software (version 20.0.15; MedCalc Software) and SPSS Statistics (version 22.0; IBM).

Results

Clinical characteristics

A total of 69 patients (median age, 39 years; interquartile range [IQR], 29–54 years; 38 women [55%]) with ACTH-dependent Cushing’s syndrome were included in the study and their clinical characteristics are shown in Table 1. Among the 69 patients, 60 (87%) patients were diagnosed with Cushing’s disease and 9 (13%) were ectopic ACTH syndrome. The median disease course was 36 months (IQR, 12–78 months). The median serum cortisol, ACTH, and 24-h urine free cortisol level before surgery were 33.0 μg/dL (IQR, 25.1–40.1 μg/dL; normal range 4.0–22.3 μg/dL), 77.2 ng/L (IQR, 55.0–124.0 ng/L; normal range 0–46 ng/L), and 422.0 μg (IQR, 325.8–984.6 μg; normal range 12.3–103.5 μg), respectively. The median serum cortisol and 24-h urine free cortisol level after surgery were 3.0 μg/dL (IQR, 1.8–18.4 μg/dL) and 195.6 μg (IQR, 63.5–1240.3 μg), respectively. The median diameter of pituitary microadenomas was 5 mm (IQR, 4–5 mm), ranging from 3 to 9 mm.

Table 1 Clinical characteristics of the patients

Diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas

The inter-observer agreement for identifying pituitary microadenomas by κ statistic between two readers was moderate on cMRI (κ = 0.50), moderate on dMRI (κ = 0.57), and almost perfect on hrMRI (κ = 0.91), respectively.

The diagnostic performance for identifying pituitary microadenomas on cMRI, dMRI, hrMRI, and combined cMRI and dMRI is summarized in Table 2. For reader 1, the diagnostic performance of hrMRI (AUC, 0.95; 95%CI: 0.87, 0.99) was higher than that of cMRI (AUC, 0.75; 95%CI: 0.63, 0.85; p = 0.002), dMRI (AUC, 0.59; 95%CI: 0.47, 0.71; p < 0.001), and combined cMRI and dMRI (AUC, 0.65; 95%CI: 0.53, 0.76; p = 0.001). For reader 2, the diagnostic performance of hrMRI (AUC, 0.97; 95%CI: 0.89, 1.00) was higher than that of cMRI (AUC, 0.74; 95%CI: 0.63, 0.84; p = 0.001), dMRI (AUC, 0.68; 95%CI: 0.56, 0.79; p = 0.001), and combined cMRI and dMRI (AUC, 0.70; 95%CI: 0.58, 0.80; p = 0.003).

Table 2 Diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas

For reader 1, 23 of the 69 patients (33%) were misdiagnosed on both cMRI and dMRI, but 18 of the 23 misdiagnosed patients (78%) were correctly diagnosed on hrMRI. For reader 2, 17 of the 69 patients (25%) were misdiagnosed on both cMRI and dMRI, but 14 of the 17 misdiagnosed patients (82%) were correctly diagnosed on hrMRI.

Figure 2 shows that a 5-mm pituitary microadenoma was identified on preoperative pituitary MRI. The margin of the lesion was fully delineated on hrMRI, but not on cMRI and dMRI. Figure 3 shows that a 3-mm pituitary microadenoma was missed on cMRI, but identified on dMRI and hrMRI. Figure 4 shows that a 5-mm pituitary microadenoma was correctly diagnosed on hrMRI, but missed on cMRI or dMRI. Figure 5 shows that a 4-mm pituitary microadenoma was evident on coronal images as well as reconstructed axial and reconstructed sagittal images on hrMRI.

Fig. 2

figure 2

Images in a 56-year-old man with Cushing’s disease. The 5-mm pituitary microadenoma (arrow) can be identified on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence, but the margin is not fully delineated. The lesion (arrow) is well delineated on (c) coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence. d Intraoperative endoscopic photograph during transsphenoidal surgery after exposure of the sellar floor shows a round pituitary microadenoma (arrow)

Fig. 3

figure 3

Images in a 34-year-old woman with Cushing’s disease. No tumor is identified on (a) coronal contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. The 3-mm pituitary microadenoma (arrow) with delayed enhancement is identified on the left side of the pituitary gland on (b) coronal dynamic contrast-enhanced T1-weighted image obtained with 2D FSE sequence and (c) coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence. d Intraoperative endoscopic photograph during transsphenoidal surgery shows a 3-mm pituitary microadenoma (arrow)

Fig. 4

figure 4

Images in a 43-year-old man with Cushing’s disease. The lesion is missed on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. c Coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence shows a round pituitary microadenoma (arrow) measuring approximately 5 mm with delayed enhancement on the left side of the pituitary gland. d Intraoperative endoscopic photograph for microsurgical resection of the 5-mm pituitary microadenoma (arrow)

Fig. 5

figure 5

Images in a 48-year-old woman with Cushing’s disease. Preoperative high-resolution contrast-enhanced MRI using three-dimensional fast spin echo sequence shows a 4-mm pituitary microadenoma (arrow) with delayed enhancement is well delineated on the left side of the pituitary gland on (a) coronal, (b) reconstructed axial, and (c) reconstructed sagittal contrast-enhanced T1-weighted images. d Intraoperative endoscopic photograph during transsphenoidal surgery after exposure of the sellar floor shows a round pituitary microadenoma (arrow)

Image quality of cMRI, dMRI, and hrMRI

Image quality scores of cMRI, dMRI, and hrMRI are presented in Table 3. Scores for overall image quality, sharpness, and structural conspicuity on hrMRI (overall image quality, 5.0 [IQR, 5.0–5.0]; sharpness, 5.0 [IQR, 4.5–5.0]; structural conspicuity, 5.0 [IQR, 5.0–5.0]) were higher than those on cMRI (overall image quality, 4.0 [IQR, 3.5–4.0]; sharpness, 4.0 [IQR, 3.0–4.0]; structural conspicuity, 4.0 [IQR, 4.0–4.0]; p < 0.001 for all) and dMRI (overall image quality, 4.0 [IQR, 4.0–4.0]; sharpness, 4.0 [IQR, 4.0–4.0]; structural conspicuity, 4.0 [IQR, 4.0–4.5]; p < 0.001 for all).

Table 3 Image quality scores on cMRI, dMRI, and hrMRI

The SNR and CNR measurements are shown in Table 4. The SNR of the pituitary microadenomas on hrMRI (67.5 [IQR, 51.2–92.1]) was lower than that on cMRI (82.3 [IQR, 61.8–127.2], p < 0.001), but higher than that on dMRI (53.9 [IQR, 35.2–72.6], p = 0.001). The CNR on hrMRI (26.2 [IQR, 15.1–41.0]) was higher than that on cMRI (10.6 [IQR, 0–42.6], p = 0.023) and dMRI (11.2 [IQR, 0–29.8], p < 0.001).

Table 4 SNR and CNR on cMRI, dMRI, and hrMRI

Discussion

The identification of pituitary microadenomas is considerably challenging but critical in patients with ACTH-dependent Cushing’s syndrome. Our study demonstrated that hrMRI with 3D FSE sequence had higher diagnostic performance (AUC, 0.95–0.97) than cMRI (AUC, 0.74–0.75; p ≤ 0.002) and dMRI (AUC, 0.59–0.68; p ≤ 0.001) for identifying pituitary microadenomas. To our knowledge, there are no previous studies specifically evaluating the identification of pituitary microadenomas on hrMRI with 3D FSE sequence by comparison with cMRI and dMRI in patients with ACTH-dependent Cushing’s syndrome, and this is the largest study conducted in ACTH-secreting microadenomas with a sensitivity of more than 90%.

Recently, techniques for pituitary evaluation have developed rapidly. Because of false negatives and false positives on cMRI and dMRI using 2D FSE sequence [7, 9, 10], a 3D SPGR sequence was introduced for identifying pituitary adenomas. Previous studies demonstrated that the 3D SPGR sequence performed better than the 2D FSE sequence in the identification of pituitary adenomas with a sensitivity of up to 80% [11,12,13]. In patients with hyperprolactinemia, the 3D FSE sequence was recommended [14] and the 3D FSE sequence has rapidly developed recently with superior image quality [15, 16], suggesting that the 3D FSE sequence may be a reliable alternative for identifying pituitary adenomas. However, to our knowledge, few studies have investigated the diagnostic performance of the 3D FSE sequence for identifying ACTH-secreting pituitary adenomas. To fill the gaps, we conducted the current study and revealed that images obtained with the 3D FSE sequence had higher sensitivity (90–93%) in identifying pituitary microadenomas, than that in previous studies using the 3D SPGR sequence [8, 11,12,13].

There is a trade-off between spatial resolution and image noise. The reduced slice thickness can overcome the partial volume averaging effect, but it is associated with increased image noise [17]. Strikingly, our study showed that hrMRI had higher image quality scores than cMRI and dMRI, in terms of overall image quality, sharpness, and structural conspicuity. The SNR of the pituitary microadenomas on cMRI was slightly higher than that on hrMRI in our study. This is because the SNR was calculated as the mean signal intensity of the pituitary gland (instead of the pituitary microadenoma) divided by noise when no microadenoma was identified, and the mean signal intensity of the pituitary gland is higher than that of the pituitary microadenoma. About 40% of pituitary microadenomas were missed on cMRI, whereas less than 10% of pituitary microadenomas were missed on hrMRI. Given the situation mentioned above, the SNR on hrMRI was lower than that on cMRI. However, the CNR on hrMRI was significantly higher than that on cMRI and dMRI. Therefore, hrMRI in our study can dramatically improve the spatial resolution with high CNR, enabling the better identification of pituitary microadenomas.

The identification of pituitary adenomas on preoperative MRI in patients with ACTH-dependent Cushing’s syndrome could help the differential diagnosis of Cushing’s syndrome and aids surgical resection of lesions. It should be noted that most of the pituitary adenomas in patients with Cushing’s disease are microadenomas [5, 6]. In our study, all the tumors are microadenomas with a median diameter of 5 mm (IQR, 4–5 mm), making the diagnosis more challenging. The sensitivity of identifying pituitary adenomas decreased from 80 to 72% after excluding macroadenomas in a previous study [12], whereas the sensitivity of identifying pituitary microadenomas in our study was 90–93% on hrMRI. In the current study, hrMRI performed better than cMRI, dMRI, and combined cMRI and dMRI, with high AUC (0.95–0.97), high sensitivity (90–93%), and high specificity (100%), superior to previous studies [8, 11,12,13]. The high sensitivity of hrMRI for identifying pituitary adenomas will help surgeons improve the postoperative remission rate [4]. The high specificity of hrMRI will assist clinicians to consider ectopic ACTH syndrome, and then perform imaging to identify ectopic tumors. Besides, the inter-observer agreement for identifying pituitary microadenomas was almost perfect on hrMRI (κ = 0.91), which was moderate on cMRI (κ = 0.50) and dMRI (κ = 0.57). Therefore, hrMRI using the 3D FSE sequence is a potential alternative that can significantly improve the identification of pituitary microadenomas.

Limitations of the study included its retrospective nature and the relatively small sample size in patients with ectopic ACTH syndrome as negative controls. The bias may be introduced in the patient inclusion process. Only those patients who underwent all the cMRI, dMRI, and hrMRI scans were included. In fact, some patients will bypass hrMRI when obvious pituitary adenomas were detected on cMRI and dMRI. These patients were not included in the current study because of lack of hrMRI findings. Given the situation, the sensitivity of identifying pituitary adenomas will be higher with the enrollment of these patients. Besides, the timing of the sequence acquisition after contrast injection is essential [16] and bias may be introduced due to the postcontrast enhancement curve of both the pituitary gland and the microadenoma [14]. In the future, a prospective study with different sequence acquisition orders is needed to minimize possible interference caused by the postcontrast enhancement curve. Moreover, a larger sample size is also needed to verify the diagnostic performance of hrMRI using 3D FSE sequence for identifying pituitary microadenomas and to determine whether it can replace 2D FSE or 3D SPGR sequences for routinely evaluating the pituitary gland.

In conclusion, hrMRI with 3D FSE sequence showed higher diagnostic performance than cMRI and dMRI for identifying pituitary microadenomas in patients with Cushing’s syndrome.

Abbreviations

ACTH:
Adrenocorticotropic hormone
AUC:
Area under the receiver operating characteristics curve
cMRI:
Conventional contrast-enhanced MRI
CNR:
Contrast-to-noise ratio
dMRI:
Dynamic contrast-enhanced MRI
FSE:
Fast spin echo
hrMRI:
High-resolution contrast-enhanced MRI
IQR:
Interquartile range
SNR:
Signal-to-noise ratio
SPGR:
Spoiled gradient re

called

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Acknowledgements

We thank Dr. Kai Sun, Medical Research Center, Peking Union Medical College Hospital, for his guidance on the statistical analysis in this study.

Funding

This study has received funding from the National Natural Science Foundation of China (grant 82071899), the National Key Research and Development Program of China (grants 2016YFC1305901, 2020YFA0804500), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grants 2017-I2M-3–008, 2021-I2M-1–025), the Beijing Natural Science Foundation (grant L182067) and National High Level Hospital Clinical Research Funding (2022-PUMCH-B-067, 2022-PUMCH-B-114).

Author information

Author notes

  1. Zeyu Liu and Bo Hou contributed equally to this work and share first authorship
  2. Hui You and Feng Feng contributed equally to this work and share corresponding authorship

Authors and Affiliations

  1. Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Zeyu Liu, Bo Hou, Hui You, Mingli Li & Feng Feng

  2. Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Lin Lu, Lian Duan & Huijuan Zhu

  3. Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Kan Deng & Yong Yao

  4. State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Yong Yao, Huijuan Zhu & Feng Feng

Corresponding authors

Correspondence to Hui You or Feng Feng.

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Guarantor

The scientific guarantor of this publication is Feng Feng.

Conflict of interest

The authors of this manuscript declare no conflict of interest.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

Written informed consent was waived by the Institutional Review Board.

Ethical approval

Institutional Review Board approval was obtained.

Methodology

• retrospective

• diagnostic or prognostic study

• performed at one institution

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Supplementary Information

Below is the link to the electronic supplementary material.

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Levoketoconazole Treatment in Endogenous Cushing’s Syndrome

Posted on November 9, 2022 by MaryO

Objective: This extended evaluation (EE) of the SONICS study assessed effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing’s syndrome.

Design/Methods: SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at Months 9 and 12 (relative to start of maintenance). For pituitary MRI in patients with Cushing’s disease, a threshold of ≥2 mm denoted change from baseline in largest tumor diameter.

Results: Sixty patients entered EE at Month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At Months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, body mass index, abdominal girth, hirsutism, CushingQoL, and BDI-II scores improved from study baseline at Months 9 and 12. Forty-six patients completed Month 12; 4 (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced ALT or AST >3× ULN, QTcF interval >460 msec, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and Month 12 or follow-up, largest tumor diameter was stable in 27 (87%) patients, decreased in 1, and increased in 3 (largest increase 4 mm).

Conclusion: In the first long-term levoketoconazole study, continued treatment through 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

Read the whole article at https://eje.bioscientifica.com/configurable/content/journals$002feje$002faop$002feje-22-0506$002feje-22-0506.xml?t%3Aac=journals%24002feje%24002faop%24002feje-22-0506%24002feje-22-0506.xml&body=pdf-45566

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MRI-negative Cushing’s Disease

Posted on July 18, 2022 by MaryO

Background

Cushing’s disease (CD) is among the most common etiologies of hypercortisolism. Magnetic resonance imaging (MRI) is often utilized in the diagnosis of CD, however, up to 64% of adrenocorticotropic hormone (ACTH)-producing pituitary microadenomas are undetectable on MRI. We report 15 cases of MRI negative CD who underwent surgical resection utilizing a purely endoscopic endonasal approach.

Methods

Endoscopic endonasal transsphenoidal surgery (EETS) was performed on 134 CD cases by a single surgeon. Fifteen cases met inclusion criteria: no conclusive MRI studies and no previous surgical treatment. Data collected included signs/symptoms, pre- and post-operative hormone levels, and complications resulting from surgical or medical management. Data regarding tumor diameter, location, and tumor residue/recurrence was obtained from both pre- and post-operative MRI. Immunohistochemistry was performed to assess for tumor hormone secretion.

Results

Aside from a statistically significant difference (P = 0.001) in histopathological results between patients with negative and positive MRI, there were no statistically significant difference between these two groups in any other demographic or clinical data point. Inferior petrosal sinus sampling (IPSS) with desmopressin (DDAVP®) administration was performed on the 15 patients with inconclusive MRIs to identify the origin of ACTH hypersecretion via a central/peripheral (C/P) ratio. IPSS in seven, five and three patients showed right, left, and central side lateralization, respectively. With a mean follow-up of 5.5 years, among MRI-negative patients, 14 (93%) and 12 patients (80%) achieved early and long-term remission, respectively. In the MRI-positive cohort, over a mean follow-up of 4.8 years, 113 patients (94.9%) and 102 patients (85.7%) achieved initial and long-term remission, respectively.

Conclusions

Surgical management of MRI-negative/inconclusive Cushing’s disease is challenging scenario requiring a multidisciplinary approach. An experienced neurosurgeon, in collaboration with a dedicated endocrinologist, should identify the most likely location of the adenoma utilizing IPSS findings, followed by careful surgical exploration of the pituitary to identify the adenoma.

Peer Review reports

Introduction

Cushing’s disease (CD) is the most common cause of hypercortisolism [1]. Left untreated, CD can result in multiple complications, most often cardiovascular disease or infection, and has a mortality rate 1.7–4.8-times higher than the general population [2,3,4]. Although MRI is the imaging modality of choice for identifying these tumors, imaging is often inconclusive [5].

Prior studies have shown that adrenocorticotropic hormone (ACTH)-producing pituitary microadenomas are undetectable on MRI in 36–64% of cases [5]. However, the development and widespread utilization of 3-T MRI (3TMRI) has led to much higher tumor detection rates [6, 7]. With a negative predictive value of approximately 19–94% and variable sensitivity and specificity, anywhere from 4 to 54% of MRIs are incorrectly reported, especially in the setting of ACTH-secreting pituitary adenomas [8, 9]. With such variation in radiographic appearance, reliance on imaging for the management of CD patients can cause significant uncertainty for neurosurgeons and endocrinologists alike.

The choice approach in the surgical management of these adenomas is via an endoscopic endonasal transsphenoidal surgery (EETS) [2, 10, 11], resulting in overall post-operative remission rates of 64–93% globally and 50–71% for cases without a conclusive MRI [12,13,14,15]. Inconclusive MRIs pose a significant challenge in the surgical management of CD, with the decision to pursue surgery for MRI-negative CD remaining highly controversial [8, 10, 14, 16]. In this study, we report 15 cases of CD without positive MRIs who underwent adenoma resection via EETS.

Patients, materials and methods

Patients population

Between January 2005 and December 2018, EETS was performed in 134 CD cases by a single surgeon at Loghman hakim and Erfan hospitals. Of those patients, 15 cases met inclusion criteria: inconclusive MRI studies and no prior surgical treatment. The population consisted of 12 women (mean age 32.5 years; range 14–65 years) and 3 men (mean age 35 years; range 22–60 years). Data collected included signs/symptoms, pre- and post-operative hormone levels, and complications resulting from surgical or medical management. Data regarding tumor diameter, location, and tumor residue/recurrence was obtained from both pre- and post-operative MRIs. Immunohistochemistry was performed to assess for tumor hormone secretion.

Ethics approval and consent to participate

All procedures performed in this study involving human participants were in accordance with the ethical standards and approved by the Shahid Beheshti Medical University (SBMU) Ethical Committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Also, a written informed consent was obtained from all subjects (or their parent or legal guardian in the case of children under 16).

Imaging

All patients underwent pre- and post-operative dynamic pituitary MRI via a superconducting 1.5-T scanner. Prior to gadolinium injection, T1-weighted Spin Echo (SE) and T2-weighted turbo SE images, followed by coronal dynamic acquisition (T1-weighted turbo SE), were obtained in the coronal plane using the following protocol: TR/TE, 400/20 ms; 288 · 192 matrix; two excitations; 18 · 18 cm field of view (FOV); 3 mm in thickness with 0.3-mm intersection gap. Afterwards, with simultaneous gadolinium injection, coronal and sagittal T1-weighted SE images were obtained 2 minutes following injection. All images were independently reviewed by both a radiologist and a neurosurgeon.

MRIs studies were categorized into direct and indirect signs of CD. Direct signs consisted of any inhomogeneity found in the pituitary, such as a lesions with diminished enhancement. Indirect signs included pituitary stalk deviation and bulging or erosion of the sellar contour. MRI studies were considered negative (normal) if no direct or indirect signs were identified.

In some cases, small lesions with diameters under 6 mm may be seen on MRI however are not considered indicative of CD due to the high prevalence of incidentalomas in this region. MRIs in which these lesions were present were classified as inconclusive.

Any uncertainty in interpreting the MRIs by any of the reviewers resulted in exclusion of the image from this study.

Pre-operative endocrine examination

All cases were ACTH-dependent Cushing syndrome showing clinical features including weight gain, proximal myopathy, and wide base purple striae. Furthermore, all cases demonstrated laboratory abnormalities consistent with CD, including increased 24-hour urinary free cortisol (UFC) excretion, loss of the cortisol circadian rhythm, high basal ACTH level, failure of low-dose dexamethasone to suppress cortisol secretion in addition to serum suppression or 24-hour UFC after high-dose dexamethasone. Additionally, pre- and post-operative levels of anterior pituitary hormone including prolactin, growth hormone (GH), insulin-like growth factor I (IGF-I), thyroid stimulating hormone (TSH), free/total Triiodothyronine (T3)/ Thyroxine (T4), follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and free/total testosterone (men) or estradiol (premenopausal women) were measured.

The 15 cases of MRI negative CD were diagnosed and categorized according to their endocrine profile in order to distinguish the ACTH-dependent CD from pseudo-cushing syndrome.

Bilateral inferior petrosal sinus sampling (BIPSS)

All 15 cases of MRI-negative ACTH-dependent Cushing’s syndrome underwent bilateral inferior petrosal sinus sampling (BIPSS). To confirm that the elevated ACTH secretion originated from the pituitary, BIPSS was simultaneously performed with central/peripheral (C/P) ACTH gradient measurement, utilizing the calculations described by Oldfield et al. [17].

No significant complications occurred in performing the procedures. A petrosal to peripheral ACTH ratio ≥ 2.0 in the basal state, a peak ratio ≥ 3.0 after desmopressin (DDAVP®) administration, or a normalized IPS:P ratio > 0.8 were considered diagnostic of CD. Additionally, tumor lateralization was specified when the interpetrosal gradient ratio of ACTH was ≥1.4 [18].

Endoscopic Endonasal Transsphenoidal surgical approach

All patients underwent surgery by a single neurosurgeon and otolaryngologist (ENT) with extensive experience in pituitary tumor excision via EETS. Exposure to the sellar floor was provided by an ENT surgeon while drilling of the sella was performed by the neurosurgeon. Extensive drilling of the sellar floor laterally up to the carotid artery bilaterally provided a wide view of the medial wall of the cavernous sinus as well as exposure of the anterior and posterior intercavernous sinuses was performed in all cases. The dura was then opened to expose the pituitary gland. Following tumor identification, adenomectomy was performed with selective removal of a rim of normal pituitary tissue. In cases where a tumor was not visualized on initial exposure of the pituitary, the pituitary gland was explored laterally via a horizontal paramedian incision on the IPSS suggesting side. If a tumor was not visualized at this stage, a vertical paramedian incision was then performed. In some cases, a cream-like substance was drained from the pituitary incision. Although this was suspicious of a tumor and tissue biopsy was obtained, it was not considered a definite tumor diagnosis and thus surgical exploration (EXP) was done in the same manner on the other side of the pituitary. In the scenario where no distinct adenoma was found, both sides of the pituitary gland underwent EXP with emphasis on lateralizing sides distinguished by IPSS. However, we did not rely solely on IPSS lateralization, as whole gland EXP was performed in all cases. Although ACTH secreting pituitary adenomas are the most common cause of Cushing syndrome, pituitary adenomas can also be ectopic, forming outside of the sella turcica with no direct connection to the pituitary gland [19]. After EXP of each side of the gland, ipsilateral periglandular inspection with visualization of the medial wall of the cavernous sinus and diaphragm was performed to identify a potential ectopic microadenoma in the periglandular region. Although the exact origin of ectopic ACTH-producing pituitary adenomas is unclear, they likely emerge from remnants of Rathke’s pouch during its development course [20]. As a result, these tumors can be discovered in the nasopharynx, sphenoid sinus, cavernous sinus, clivus, or suprasellar area [21]. Detecting an adenoma at this stage may prevent further unnecessary EXP of pituitary gland. If a visible tumor was still not detected, a vertical medial incision was made on the pituitary gland adjacent to the pituitary stalk and neurohypophysis. If a tumor could not be reliably identified by extensive EXP of the entire pituitary gland or BIPSS failed to localize a pituitary adenoma, we did not progress to performing incomplete or complete hypophysectomy. Figures 1 and 2, respectively, demonstrate the surgical management algorithm and pituitary incisions for MRI-negative CD.

Fig. 1

figure 1

Eight-step MRI negative Cushing’s disease surgical management

Fig. 2

figure 2

Schematic illustration of 8 steps in endoscopic endonasal approach to MRI inconclusive Cushing’s disease (Resembling half Georgia flag)

If an ectopic ACTH-secreting adenoma is not easily found, permanent destructive or ablative surgeries such as bilateral adrenalectomy and hypophysectomy may be required [20]. Despite the danger of Nelson syndrome, bilateral adrenalectomy remains a feasible option in the management of refractory CD [22, 23].

Histological examination

All intraoperative tissue specimens obtained underwent histological examination by a pathologist. Pituitary specimens were fixed in buffered 10% formalin and embedded in paraffin wax. All specimens were first examined by Hematoxylin and Eosin (H&E) staining to detect regions which had loss of acinar organization. Additionally, reticulin and periodic Acid-Schiff (PAS) staining was implemented for a more accurate histopathologic diagnosis. Immunohistochemistry staining was used to identify cytokeratin and anterior pituitary hormones, including ACTH, in the case of a pituitary adenoma not being detected by H&E staining. The presence of ACTH-secreting cells was examined via immunocytochemistry using specific anti-ACTH antibodies.

Post-operative endocrinologic assessment and follow up

Serum cortisol and ACTH levels were monitored for 2–5 days following surgery. Initial follow-up occurred 2 weeks post-operatively with a subsequent visit occurring 3 months postoperatively, during each visit a complete pituitary hormonal evaluation was performed. This evaluation was repeated every 3 months for up to 2 years and every 6 months after that. An initial postoperative pituitary MRI was typically performed within 3 months after surgery. For patients to be considered to be in initial post-operation remission, a basal plasma cortisol level lower than 140 nmol/L (5 μg/dL) or adequate suppression of plasma cortisol (≤56 nmol/L) (≤1.8 μg/dL) following the 1-mg dexamethasone suppression test was necessary during the first month following surgery. Long term remission was defined as a plasma cortisol lower than 84 nmol/L (3 μg/dL) after a 1-mg dexamethasone suppression test at the final visit. Recurrence was defined as a recurring case of hypercortisolism with insufficient suppression of plasma cortisol (> 140 nmol/L) after a 1-mg dexamethasone suppression test. Clinical criteria for remission included significant symptomatic improvement or resolution without additional therapy (radiotherapy, adrenalectomy). Patients achieving remission had to meet both laboratory and clinical criteria to be classified as such. Glucocorticoids were not given postoperatively except when there was laboratory evidence of hypercortisolism and/or clinical manifestations of glucocorticoid insufficiency. Additionally, 4 to 6 weeks post-operatively, thyroid and gonadal axis function was assessed by measuring free T4, TSH, FSH, and LH levels in addition to end-organ hormones (estradiol in women and testosterone in men).

Statistical analysis

SPSS software (version 26, Chicago, IL) was used to analyze the data. For continuous data, we calculated descriptive statistics, mean and standard deviation (SD), and for categorical variables, frequency and percentages were calculated. The chi-square or Fisher’s exact test was used to analyze categorical data, while the student’s t-test or Mann- Whitney U test was used to analyze continuous variables’ means, depending on the distribution’s normality. Statistical significance was defined by a p value of < 0.05.

Results

Demographic and clinical data of 134 patients with CD who underwent EETS are shown in Table 1. Fifteen (11.2%) of the 134 CD patients who underwent EETS were MRI-negative and 119 patients (88.8%) were MRI positive. The female/male ratio in the MRI-negative group was four to one while this ratio in the MRI-positive cohort was 2.6. With regards to sex distribution, Fisher’s exact test found no statistically significant difference between these two groups (P = 0.565). All patients had clinical manifestation of Cushing’s syndrome including obesity, hirsutism, glucose intolerance, and hypertension. As shown in Table 1, pre-operative ACTH level was 134.02 ± 21.78 ng/l and 151.76 ± 44.17 ng/l in MRI-negative and MRI-positive patients, respectively, and no statistically significant difference was observed between these two groups (P = 0.781). As demonstrated in Table 1, UFC was 462.3 ± 43.98 μg/24 h and 478.4 ± 73.02 in MRI-negative and MRI-positive patients, respectively, and no statistically significant difference was observed between these two groups (P = 0.832).

Table 1 Demographic and clinical data

IPSS with DDAVP® administration was performed on the 15 MRI-negative patients to identify the origin of ACTH hypersecretion via the C/P ratio. Seven patients showed right-sided lateralization and five patients showed left-sided lateralization. In remaining three patients, IPSS did not show an ACTH interpetrosal gradient ratio greater than the cutoff point, which was interpreted as an ACTH hypersecretion with central origin. On EXP, adenomas were found in 2 of the 3 patients, with no adenoma being found in the 3rd. The IPSS results were in concordance with our observations during EXPs in 60% of patients. However, in 13% of patients, no adenoma was detected, and in 26% an adenoma was found on the opposite side of the pituitary where pre-operative IPSS results initially reported a tumor or was suggestive of one being present. In 60% of MRI-negative patients, histological examination demonstrated an adrenocorticotropic pituitary adenoma, but in 40% no adenoma was found after pathological examinations. In MRI-positive patients, positive histology was observed in 112 patients (94.1%), while in 7 patients (5.9%) histopathological studies were negative. Fisher’s exact test revealed that the difference between MRI-negative and MRI-positive patients in terms of histopathological result was statistically significant (P = 0.001).

In all four patients who had discordant IPSS results as well as the patients who had negative or inconclusive findings on EXP, tissue samples were obtained from suspicious sites during EXP and were sent for histopathological examination. Histopathology demonstrated adrenocorticotropic adenoma tissues in 3 of them on the opposite side of the IPSS suggested region, while in 1 of them the histological results were inconclusive. This patient (case 10) achieved initial remission, however she experienced recurrence after 25 months, and similarly to her initial presentation, MRI findings were negative and IPSS suggested right sided lateralization. She underwent revision surgery, and a distinct adenoma was detected on the right side, which was confirmed by histological examination, after which she went into remission following selective adenectomy (Table 2).

Table 2 Presents summary of patients’ demographics, IPSS and surgical exploration results

Among the patients with inconclusive MRI, 14 (93%) achieved initial remission, 12 of which (80%) went on to long term remission with a mean follow up of 5.5 years. Two patients (cases 10 and 11) developed recurrence following initial remission; according to the IPSS suggested side, partial hypophysectomy was performed in both cases however neither was able to achieve remission afterwards. One patient (case 13) was unable to achieve initial remission following the initial surgery and thus required continued medical management. With a mean follow-up of 4.8 years among the 119 patients with positive MRI, 113 patients (94.9%) and 102 patients (85.7%) achieved initial and long-term remission, respectively. There were no statistically significant differences between these two groups in terms of either initial (P = 0.767) or long-term remission (P = 0.457). Among the 102 patients who achieved long-term remission, 12 patients (11.7%) experienced disease recurrence. With regards to recurrence rate, there was no statistically significant difference between patients with either positive or negative MRI (P = 0.542).

In two patients (cases 2 and 6) the adenoma was not found during EXP, however tissue samples obtained from the IPSS suggested side demonstrated adrenocorticotropic pituitary adenoma in both patients on histopathological examination.

Diabetes insipidus (DI) was the most frequent complication associated with CD. Transient DI occurred in seven cases with resolution prior to discharge. There was one case of permanent DI diagnosed in follow-up. Additionally, one patient developed symptomatic adrenal insufficiency requiring glucocorticoid replacement. Two patients developed hypothyroidism requiring hormone replacement. Panhypopituitarism was not seen following the initial surgeries however occurred in one case following revision surgery (partial hypophysectomy) which required hormone replacement therapy. Cerebrospinal fluid (CSF) leak resulting in meningitis was seen in one patient, however no other complications occurred during the post-operative period. None of our patients demonstrated clinical or endocrinological signs of gonadal insufficiency in follow-up aside from the aforementioned case of panhypopituitarism following revision partial hypophysectomy. In the MRI-positive cohort, 51 patients showed transients DI (42.8%), with 4 of the patients (3.4%) experiencing DI till last follow-up. Partial anterior pituitary insufficiency and complete anterior pituitary insufficiency was observed in one (0.8%) and two (1.6%) patients, respectively. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion was observed in 3 patients (2.5%).

Discussion

In this study we present the outcomes of pure endoscopic endonasal surgical treatment of fifteen patients with MRI-negative Cushing’s disease. Due to the arduous nature of treatment in this patient population, we used a precise method of EXP as described above, resulting in initial remission in 93% of patients post-operatively. Based on the work of Bansal et al., patients with a definite adenoma on MRI who underwent microscopic transsphenoidal surgery had a statistically significant greater rate of early remission and lower rates of persistent disease than those with negative/equivocal findings [24]. However, in terms of late remission and recurrence, there was no statistically significant difference between these two groups [24]. Negative/equivocal MRI results and the incidence of macroadenoma, particularly in patients with cavernous sinus invasion, were found to predict poor remission rates [24]. According to some investigations, MRI-negative CD patients had a poorer remission rate [25, 26]. In other studies, however, there was no statistically significant difference in remission between those who had MRI-negative CD and those who had a MRI-positive CD, which is consistent with our result [14, 27,28,29,30,31,32]. Recurrence occurred in 2 patients, while 12 patients showed no clinical or endocrinological signs of recurrence during the mean follow-up of 5 years, and one patient did not go to remission. Aside from one CSF leak leading to meningitis and one case of permanent DI, there were no major surgery related complications. Pituitary CD is a common and potentially lethal condition that, if left untreated, can lead to sequelae such as morbid obesity, hypertension, and diabetes mellitus. Diagnosis and treatment of CD is more challenging than other functional pituitary adenomas. Currently, trans-sphenoidal pituitary EXP is considered the standard of care for CD [33,34,35]. CD is typically diagnosed by endocrinologist through clinical symptoms, and supported by laboratory tests such as the 8 AM blood or saliva cortisol level, 24 hours urinary free cortisol level, low- and high-dose dexamethasone suppression tests, and the corticotropin-releasing hormone (CRH) stimulating test [36,37,38]. When ACTH-dependent CD is diagnosed, or clinical signs and symptoms are highly suggestive of it, MRI imaging of the pituitary is often the next step to identify the causative agent i.e., a pituitary adenoma. With regards to pituitary lesions, MRI is considered the most sensitive imaging modality, however reported sensitivity varies significantly between studies, with reported rates ranging from 22 to 92% [39,40,41].

The rate of MRI-negative microadenomas is reported to be between 36 to 63% [5]. Hofmann et al. reported no identified tumor in 49.3% of 270 MRIs [29]. Yamada et al. reported a lower frequency (17%) of MRI-negative CD in their series [42]. In our series, only 15 out of 134 (11.19%) CD patients were MRI-negative. In general, negative-MRIs could be explained by several factors such as field strength, technique (the correct pulse sequence and parameters), radiologist interpretation errors, or tumor size. Identifying tumors smaller than 3 mm in diameter is difficult in MRIs with 2.5- to 3-mm-thick image sections [29]. Dynamic MRI and 3-TMRI can result in a higher sensitivity in identifying ACTH-secreting microadenomas [6, 7, 43]. In addition, spoiled gradient-recalled echo sequence (SPGR) view can help to increase sensitivity [44]. The relatively low number of negative-MRIs in our study can be attributed to the more extensive review of MRI images, utilization of high-field strength MRI (1.5 T), as well as the implementation of SPGR dynamic studies with 1.5- to 2.0-mm-thick sections, in addition to standard methods. Additionally, assessment of images by experienced pituitary neuroradiologists may have reduced the negative-MRI rate in our series. Although small tumor size is a likely factor in MRI-negative CD, prior studies have reported examples of MRI-negative microadenomas 4-6 mm in size, typically large enough to be easily identified on EXP [42].

If MRI is unable to identify the tumor definitively, the next best step is venous sampling to confirm CD. There are various indication for BIPSS, including patients who have clinical and laboratory findings of CD but normal or inconclusive MRI results [45], cases that do not have a clear hormone test response, or cases where there are inconsistencies between laboratory and imaging results [46]. BIPSS is also recommended by some as standard for any case of confirmed ACTH-dependent Cushing’s syndrome [47, 48]. In our institution, BIPSS is reserved for MRI-negative Cushing’s patients. Newell-Price et al. reviewed 21 studies with 569 total patients, and found that BIPSS with CRH stimulation had a 96% sensitivity and 100% specificity in separating CD from pseudo-Cushing’s states [49]. Most studies report a 90–100% sensitivity and specificity for BIPSS [50,51,52]. In the majority of cases of CD, a pituitary microadenoma can be found eccentric to one side of the pituitary, having venous drainage directly into the ipsilateral inferior petrosal sinus (IPS) [53].

This phenomenon is the basis for utilizing BIPSS as a means of lateralizing ACTH secreting pituitary tumors. There are many instances where EXP fails to detect a pituitary adenoma, despite conformation of pituitary origin of ACTH secretion via BIPSS. Evidence of lateralization prior to surgery can convince the surgeon to perform a guided hemi hypophysectomy. In our series, the accuracy of BIPSS for lateralizing adenomas was 60%, similar to the reported accuracy in the literature of approximately 70% [17]. Inaccurate lateralization from BIPSS has been attributed to asymmetrical venous drainage with shunting of blood toward the dominant side. Thus, BIPSS appears to be a superior diagnostic tool compared to other means of lateralization, and neurosurgeons should be wary of making operative decisions solely from BIPSS data [49].

The standard of care for MRI-negative CD is highly disputed. There is evidence suggesting surgical exploration is more problematic than watchful waiting [8], or that it is not indicated in MRI-negative CD [54]. Many advancements have led to the widespread adoption of transsphenoidal approach during the last three decades, especially the endoscope [31]. Regardless of the width or depth of access, the endoscopic approach allows the surgeon to have a large panoramic view. Many cases in the literature have reported successfully treating functional pituitary tumors via endoscopic surgery [27, 31, 55,56,57,58]. The results suggest that they are on par with, if not superior to, traditional microscopic approaches. When patients were operated on utilizing a microscopic technique assisted by a pre-operative ACTH gradient, the overall rate of partial adenomectomy (partial hypophysectomy) was 30%, including 19% in patients with positive MRIs and 40% in those with negative MRIs [28]. However, endoscopic visualization of pituitary adenomas has allowed for the need for partial adenomectomy to be reduced to less than 2%, limiting the damage to the normal pituitary gland during operation [28]. A recently published meta-analysis demonstrated that although there was no statistically significant differences between EETS and microscopic endonasal transsphenoidal surgery in the sub-analysis with regards to recurrence rate, remission rate, and persistence rate, the recurrence rate in the microscopic endonasal transsphenoidal surgery group was almost three times higher than in the EETS group [11]. As a result, EETS appears to be a possible suggested therapeutic method, while more studies are needed to establish the therapeutic method of choice [59].

In general, pituitary surgery is not advisable in cases of MRI-negative CD where IPSS is not able to prove a central origin of ACTH secretion [42]. However, when IPSS demonstrates central ACTH secretion, surgical intervention has been proposed as a first line treatment in MRI-negative CD [25, 32, 42, 60]. The outcome of surgical intervention in MRI-negative patients is variable in the literature. Some reports indicated lower remission rate in these patients [42, 61], while others have concluded that EXP results in greater complications in this population [8, 15]. Additionally, several studies have shown no significant difference in outcomes of pituitary surgery between MRI-negative and MRI-positive patients [14, 25, 32]. Pivonello et al. found the lack of tumor detection on pre-operative MRI operation to be a negative prognostic factor in surgical management [62]. In the present study, surgery was performed for all MRI-negative Cushing’s patients with positive IPSS results. We achieved 93% initial remission and 80% long term remission rates, comparable to mean remission rates in patients with preoperative identification of tumor, as reported in the literature, ranging from 52.6–100% [62].

Failure to identify an adenoma on EXP or in histologic examination is not uncommon in the surgical management of CD. Intraoperative detection of the adenoma has been shown to be a factor of favorable prognosis [63,64,65]. Similarly, failure to identify an adenoma on histopathology has been found to be a negative prognostic indicator. Specifically, remission rates were significantly lower in cases where no histological tumor identification could be provided [14, 63, 66]. In our study, two cases revealed no adenoma on EXP, however the tissue samples subsequently obtained from the IPSS suggesting side were consistent with pituitary adenoma on histologic examinations. In six cases, a cream-like substance was identified within the pituitary following incision, however histologic examination failed to demonstrate adrenocorticotropic adenoma in any of them. Nonetheless, 5 of the 6 patients went into remission following surgery, potentially due to the small size of tissue samples obtained which in turn made accurate histopathological assessment more difficult [14, 67].

In cases where EXP does not result in localization of an adenoma, surgical decision making becomes complicated. Generally, total hypophysectomy is not advisable due to high rates of endocrine complications as well as failing to provide significantly increased remission rates over partial hypophysectomy [62, 68]. In this scenario, multiple studies have recommended partial hypophysectomy based on IPSS lateralization as the next best step in management [63, 69]. Carr et al. suggested the advantage of 2/3 gland resection on remission rate in MRI-negative CD [60], but as previously discussed, IPSS may incorrectly lateralize adenomas, and thus surgeons should be hesitant when making decisions regarding tumor lateralization based solely on BIPSS data [17, 49]. Moreover, both adenomectomy and hypophysectomy are not without risks and potential complications. Surgical aggressiveness is correlated with increased likelihood of pituitary loss-of-function, supported by literature showing that the larger the amount of resection, the higher the rate of hypopituitarism. It has been reported that patients undergoing adenomectomy, hemi-hypophysectomy, and-total hypophysectomy had mean rates of hypopituitarism of 6.6, 20.2, and 80.2%, respectively [63, 70, 71]. As most CD patients are females of reproductive age, preserving child-bearing capacity is an important consideration, one which results in reluctance to perform hemi-hypophysectomy. In our series, we performed selective adenectomy when distinct adenomas were found, and in the cases where no adenoma was detected, meticulous EXP of pituitary gland bilaterally was performed. Subsequently, if EXP was inconclusive, a vertical median incision was made near the pituitary stalk to explore central part of the gland, which is believed to be the nest for adrenocorticotropic cells. Although an important step in localizing the adenoma, this also likely explains the high rate of postoperative DI in our study. No additional hemi-hypophysectomy was performed during the initial surgery in our study. With this technique, we achieved acceptable results with regards to remission rates, and none of our patients experienced panhypopituitarism in postoperative follow-ups. In one patient where CD recurred 2 years post-operatively, inadequate bony exposure and limited visualization of the medial wall of the right cavernous sinus resulted in failure to identify the adenoma during the initial surgery, further supporting the strategy of creating extensive exposure of the operative field in MRI-negative CD. Another possible reason for recurrence in this patient would be growth of a previously undetected microadenoma.

Conclusion

Surgical treatment of MRI-negative Cushing’s disease is a demanding scenario necessitating multidisciplinary management. An experienced neurosurgeon working in collaboration with an endocrinologist should specify the most likely region of the tumor via IPSS. Additionally, surgical exploration of the pituitary is an invaluable tool in identifying adenomas while reducing the need for aggressive hypophysectomy, thus decreasing the likelihood of complications. Although MRI-negative Cushing’s disease presents significant challenges to neurosurgeons, surgical management remains essential in achieving remission.

Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article.

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Acknowledgments

We are grateful to all those who have helped us to accomplish and fulfil this project.

Funding

None.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Guive Sharifi, Amir Arsalan Amin & Seyed Ali Mousavinejad

  2. Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Guive Sharifi, Amir Arsalan Amin, Nader Akbari Dilmaghani & Seyed Ali Mousavinejad

  3. Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran

    Mohammadmahdi Sabahi

  4. Department of Neurosurgery, Rutgers-New Jersey Medical School, Newark, NJ, USA

    Nikolas B. Echeverry

  5. Department of Otolaryngology, Head and Neck Surgery, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Nader Akbari Dilmaghani

  6. Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Majid Valizadeh

  7. Department of Endocrinology, Loghman Hakim Hospital, Shahid Beheshti Medical University, Tehran, Iran

    Zahra Davoudi

  8. Department of Neurological Surgery, Pauline Braathen Neurological Center, Cleveland Clinic Florida, Weston, Florida, USA

    Badih Adada & Hamid Borghei-Razavi

  9. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Director of Minimally Invasive Cranial and Pituitary Surgery Program, Research Director of Neuroscience Institute, Cleveland Clinic Florida Region, 2950 Cleveland Clinic Blvd. Weston, Cleveland, FL, 33331, USA

    Hamid Borghei-Razavi

Contributions

Guive Sharifi, Mohammadmahdi Sabahi and Amirarsalan Amin have given substantial contributions to the conception and the design of the manuscript, Mohammadmahdi Sabahi, Nikolas B. Echeverry, Nader Akbari Dilmaghani, Ali Mousavi Nejad, and Zahra Davoudi to the acquisition, analysis, and interpretation of the data. All authors have participated in drafting the manuscript. Mohammadmahdi Sabahi, Majid Valizadeh, and Badih Adada revised it critically. Hamid Borghei-Razavi supervised this project. All authors read and approved the final version of the manuscript. All authors contributed equally to the manuscript and read and approved the final version of the manuscript.

Corresponding author

Correspondence to Hamid Borghei-Razavi.

Ethics declarations

Ethics approval and consent to participate

All procedures performed in this study involving human participants were in accordance with the ethical standards and approved by the Shahid Beheshti Medical University (SBMU) Ethical Committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Also, informed consent to participate in this study was obtained from participants included in the (or their parent or legal guardian in the case of children under 16).

Consent for publication

Not applicable.

Competing interests

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

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Sharifi, G., Amin, A.A., Sabahi, M. et al. MRI-negative Cushing’s Disease: Management Strategy and Outcomes in 15 Cases Utilizing a Pure Endoscopic Endonasal Approach. BMC Endocr Disord 22, 154 (2022). https://doi.org/10.1186/s12902-022-01069-5

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Pituitary MRI standard and advanced sequences: Role in the diagnosis and characterization of pituitary adenomas

Posted on December 27, 2021 by MaryO

This article involves discussion on the use of standard and advanced magnetic resonance imaging (MRI) sequences to diagnose and characterize pituitary adenomas (PAs), including MRI characteristics related to treatment response that could assist in presurgical assessment and planning, and red flags that could suggest an alternative diagnosis.

  • Besides PAs, several other lesions may be found in the sellar region, such as meningiomas, craniopharyngiomas and aneurysms.
  • For assessing lesions in the sella turcica, sellar MRI is preferred.
  • With a systematic MRI approach to the pituitary region, generally the obtained information comprises: the size and shape of the PA, the presence of cysts or hemorrhage within the tumor, its link with the optic pathways and surrounding structures, potential cavernous sinus invasion, sphenoid sinus pneumatization type, and differential diagnosis with other sellar lesions.
  • In the majority of cases, standard protocol serves the purpose; but additional information could be obtained by using some advanced techniques (susceptibility imaging, diffusion-weighted imaging, 3D T2-weighted high-resolution sequences, magnetic resonance elastography, perfusion-weighted imaging) and such information may be important for some cases.

Filed under: pituitary, Rare Diseases | Tagged: , | Leave a comment »

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