Bilateral Inferior Petrosal Sinus Sampling: Validity, Diagnostic Accuracy in Lateralization of Pituitary Microadenoma, and Treatment In Eleven Patients with Cushing’s Syndrome – a Single-Center Retrospective Cohort Study

Posted on November 17, 2023 by MaryO

Abstract

Background

This single-center retrospective cohort study aimed to describe the findings and validity of Bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of patients with ACTH-dependent Cushing’s syndrome (CS).

Methods

Eleven patients underwent BIPSS due to equivocal biochemical tests and imaging results. Blood samples were taken from the right inferior petrosal sinus (IPS), left IPS, and a peripheral vein before and after stimulation with desmopressin (DDAVP). ACTH and prolactin levels were measured. The diagnosis was based on the ACTH ratio between the IPS and the peripheral vein. Also, lateralization of pituitary adenoma in patients with Cushing’s disease (CD) was predicted. No significant complications were observed with BIPSS.

Results

Based on the pathology report, eight patients had CD, and three had ectopic ACTH syndrome (EAS). Unstimulated BIPSS resulted in a sensitivity of 87.5%, specificity of 100%, PPV of 100%, NPV of 75%, and accuracy of 91%. Stimulated BIPSS resulted in a sensitivity of 100%, specificity of 100%, PPV of 100%, NPV of 100%, and accuracy of 100%. However, pituitary magnetic resonance imaging (MRI) had a lower diagnostic accuracy (sensitivity:62.5%, specificity:33%, PPV:71%, NPV:25%, accuracy:54%). BIPSS accurately demonstrated pituitary adenoma lateralization in 75% of patients with CD.

Conclusions

This study suggests that BIPSS may be a reliable and low-complication technique in evaluating patients with ACTH-dependent CS who had inconclusive imaging and biochemical test results. The diagnostic accuracy is improved by DDAVP stimulation. Pituitary adenoma lateralization can be predicted with the aid of BIPSS.

Peer Review reports

Introduction

All disorders with manifestations associated with glucocorticoid excess are called Cushing’s syndrome. Exogenous corticosteroids cause most CS cases, and endogenous CS cases are rare [1, 2].

The diagnosis of Cushing’s syndrome may be complicated, particularly in cases with ambiguous clinical findings, atypical presentations, and cyclic hypercortisolemia [3,4,5]. The initial laboratory tests for diagnosis of CS include 24-hour urinary free cortisol (UFC), late-night salivary cortisol, and low-dose dexamethasone suppression test (DST). These tests only represent hypercortisolemia [1, 2].

Once CS is diagnosed, further evaluations are needed to identify the etiology. The first step is to measure the plasma ACTH level. A low plasma ACTH level indicates ACTH-independent CS and a high level suggests ACTH-dependent CS. Normal ACTH can also occur in ACTH-dependent CS. Almost all cases of ACTH-dependent are due to pituitary adenoma (Cushing’s disease) or EAS [1, 2, 6].

Some ectopic sources include neuroendocrine tumors, bronchial carcinoma, and pancreatic carcinoma [7, 8]. Because of the high mortality in tumors associated with EAS, it is essential to differentiate CD from EAS.

To distinguish CD from EAS, a high-dose dexamethasone suppression test (HDDST), corticotropin-releasing hormone (CRH), or DDAVP stimulation tests, or pituitary MRI is recommended [1, 2, 6, 9,10,11,12]. MRI can be equivocal in half of the patients, and only relatively large lesions (> 6 mm) detected on MRI reliably confirm the diagnosis of CD with biochemical confirmation and expected clinical symptoms [9].

Considering the relatively low sensitivity and specificity of non-invasive tests [13, 14] and the high complications of the surgery, it seems reasonable to use a test with high sensitivity and specificity and few complications before resection. BIPSS with CRH or DDAVP stimulation can be helpful for further evaluation [1, 2, 10, 15, 16]. The BIPSS procedure is the same in both stimulation methods. Due to its lower cost, availability, and comparable diagnostic accuracy, using DDAVP instead of CRH for BIPSS is an alternative [17, 18]. BIPSS has been reported to have high sensitivity and specificity and is a safe procedure when performed by experienced interventional radiologists [15, 16, 19, 20].

This case series describes the experience with BIPSS and examines the validity of BIPSS for differentiating CD from EAS in patients with ACTH-dependent CS who had ambiguous or equivocal results in non-invasive tests.

Materials and methods

Patients

This retrospective cohort study included 11 patients with ACTH-dependent CS who underwent BIPSS between 2018 and 2020 in a tertiary care hospital.

Data collection

Well-trained nurses conducted anthropometric measurements, including height and weight. Standing height was measured with a portable stadiometer (rounded to the nearest 0.1 cm). Using a calibrated balance beam scale, this study measured weight in the upright position (rounded to the nearest 0.1 kg). Body mass index (BMI) was calculated by dividing weight (kg) by height squared (m2). Well-trained examiners measured blood pressure (systolic and diastolic) at the left arm in the sitting position after 5 min of rest using a calibrated mercury sphygmomanometer. The blood sample was taken, and fasting blood sugar (FBS), hemoglobin (Hb), potassium (K), and creatinine (Cr) were measured. All research was performed in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants or their legal guardians.

Biochemical tests and imaging

Patients with signs and symptoms of CS underwent screening evaluations, and confirmatory tests were performed using serum cortisol and 24-hour UFC. After confirmation of CS, ACTH was measured using an immunoradiometric assay to categorize patients into ACTH-dependent or independent groups. ACTH test was performed with SIEMENS IMMULITE 2000 device with an analytical sensitivity of 5 pg/ml (1.1 pmol/l) and CV ∼7.5%. HDDST was conducted by administering 2 mg dexamethasone every 6 h for 48 h to all patients, and then serum cortisol and 24-hour UFC were rechecked. A pituitary MRI was performed with sagittal and coronal T1- and T2-weighted images before and after the gadolinium injection.

BIPSS procedure

After biochemical tests and imaging, an experienced interventional radiologist performed bilateral and simultaneous catheterization of the inferior petrosal sinuses. Venography was obtained to evaluate venous anatomy and catheter placement. The retrograde flow of contrast dye into the contralateral cavernous sinuses was used as a marker of adequate sampling. After the correct placement of catheters, blood samples were obtained from each of three ports (peripheral (P), left inferior petrosal sinus (IPS), and right IPS) at -15, -10, -5, and 0 min. The current study used DDAVP for stimulation. After peripheral injection of 10 micrograms of DDAVP, blood samples from these three sites were obtained at + 3, +5, + 10, and + 15 min. Three samples from these sites were also obtained to measure prolactin. Upon collection, BIPSS samples were placed in an ice-water bath. At the end of the procedure, samples were taken to the laboratory, where the plasma was separated and used for immediate measurement of ACTH. Specimens were refrigerated, centrifuged, frozen, and assayed within 24 h.

After the samples were obtained, both femoral sheaths were removed, and manual compression was used to obtain hemostasis before transferring patients to the recovery room. The whole procedure took 1–2 h. Patients underwent strict bed rest for 4 h before discharge on the same day. All BIPSS were performed without significant complications, and only hematoma at the catheterization site was observed in some patients.

BIPSS interpretation

The ratio of IPS ACTH to peripheral ACTH level (IPS/P ACTH) for each side was calculated. Baseline sampling at minute 0 with IPS/P ≥ 2 or stimulated sampling at minute 3 with 1PS/P ≥ 3 is confirmatory for CD [1, 8]. Also, the IPS/P ratio was checked for prolactin level after DDAVP stimulation (stimulated IPS/P prolactin). A stimulated IPS/P prolactin ≥ 1.8 indicates successful catheterization, meaning the catheter is correctly placed in the IPS [21]. For further evaluation, the current study normalized the ACTH to the prolactin level by dividing stimulated IPS/P ACTH into stimulated IPS/P prolactin for each side. A normalized ACTH/prolactin IPS/P ratio ≥ 1.3 supports a pituitary ACTH source (Cushing’s disease), and a normalized ratio ≤ 0.7 an ectopic source (EAS) [22]. The values between 0.7 and 1.3 are equivocal. The inter-sinus ratio was defined as the ratio of the IPS/P ACTH level of one side with the higher level divided by the IPS/P ACTH level of the other side with the lower level, either before or after stimulation. An inter-sinus ratio ≥ 1.4 indicates lateralization to the side with a higher IPS/P ACTH level [23].

Statistical analysis

This analysis used SPSS software version 18 (SPSS, Inc.) to perform analyses. Data were expressed as numbers and percentages. Continuous variables were presented as means (± SD). This study reported the median or range when the data did not follow a normal distribution. The Shapiro-Wilk test was used to test for normality. The nonparametric Mann-Whitney U Test was utilized to compare variables. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the tests were calculated based on standard statistical equations.

Results

Baseline characteristics and clinical manifestations

This retrospective research studied 11 patients with ACTH-dependent CS, including eight females (72.7%) and three (27.3%) males. The median (Q1-Q3) age was 32.0 (22–45) years. The median (Q1-Q3) of BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), FBS, Hb, K, and Cr were 29.2 (24.8–33.3), 130.0 (125–140), 80.0 (80–95), 98.0 (88–103), 13.5 (12.4–13.9), 4.2 (3.9–4.5), and 1.0 (0.9–1.1), respectively. The demographic characteristics of patients are presented in Table 1. The Hb levels were not different in women and men (median 13.35 vs. 13.70, p-value = 0.776). In addition, no statistical difference between patients with a final diagnosis of CD and EAS was detected for Hb levels (Total: median 13.60 vs. 13.2, p-value > 0.05) (Women: median 13.5 vs. 13.2, p-value > 0.05) (Men: median 13.7 vs. 13.25, p-value > 0.05).

Table 1 Demographic characteristics of the studied patients

90% of patients had at least one skin manifestation, such as striae, easy bruising, acne, hyperpigmentation, hirsutism, hair loss, edema, and hypertrichosis. Other symptoms were hypertension (HTN) (81%), reproductive dysfunction (81%), including infertility, oligomenorrhea, loss of libido, weight gain (72%), proximal muscle weakness (45%), and headache (27%) (Table 2).

Table 2 Clinical manifestations of the studied patients

Results of biochemical tests

Biochemical tests results, including basal serum cortisol (median:26 mcg/dl, range:15-54.5 mcg/dl), basal 24-hour UFC (median:670 mcg/dl, range:422–1545 mcg/dl), ACTH (median:58.8 pg/ml, range:25–155 pg/ml), serum cortisol after HDDST (median:14.2 mcg/dl, range:2.63-36.0 mcg/dl), 24-hour UFC after HDDST (median:292 mcg/dl, range:29.5–581 mcg/dl) are presented in Table 3. According to the basal serum cortisol results, eight patients (Cases 1, 3, 5, 7, 8, 9, 10, and 11) had basal serum cortisol levels > 22 mcg/dl, which indicates hypercortisolemia. Other patients (Cases 2, 4, and 6) had basal serum cortisol in the normal range (5–25 mcg/dl) and were considered as false negative results of this test.

Table 3 The results of biochemical tests in the studied patients

All patients had elevated basal 24-hour UFC levels (422–1545 mcg/dl), indicative of hypercortisolemia (Table 3).

There were six patients with elevated peripheral ACTH levels (> 58 pg/ml) (cases 5, 6, 8, 9, 10, and 11). Other patients had ACTH within the normal range (6–58 pg/ml) (cases 1, 2, 3, 4, 7) (Table 3).

None of the patients showed suppression after 1 mg DST. After HDDST, cases 2, 3, 8, and 10 had more than 50% suppression of serum cortisol. In the other six patients, serum cortisol was not suppressed or suppressed by less than 50%. In one patient, serum cortisol levels were not measured (case 1) because the sample was not stored under standard test conditions.

Also, eight patients had more than 50% 24-hour UFC suppression after HDDST (cases 1, 2, 3, 4, 6, 7, 9, and 10). In two patients, 24-hour UFC was suppressed less than 50% (cases 5 and 11), and in one patient (case 8), the 24-hour UFC sample was not tested due to the non-standard condition of the sample.

BIPSS results

BIPSS results before and after stimulation are shown in Table 4. The baseline value (sampling at minute 0) of IPS/P ACTH ≥ 2 confirms CD. According to this ratio, cases 1,3,4,5,6,7, and 8 were diagnosed as CD. The unilateral source for CD was confirmed in cases 1, 3, 7, and 8. BIPPS didn’t demonstrate lateralization in cases 4, 5, and 6.

Table 4 Baseline and stimulated IPS/P ratio for ACTH and Prolactin in the studied patients

The highest IPS/P ACTH ratio was 3 min after the DDAVP injection. A sampling at minute 3 with stimulated IPS/P ACTH ≥ 3 confirms CD. This ratio confirmed CD in cases 1–8 and showed a unilateral source for CD in cases 1, 2, 3, and 7. The ratio didn’t demonstrate lateralization in cases 4, 5, 6, and 8. The stimulated IPS/P prolactin was ≥ 1.8 in all cases.

The variability in the IPS/P ACTH ratio in patients with CD is shown in Fig. 1. The peak of this ratio was 3 min after the DDAVP injection. In patients with EAS, there were no changes before or after the DDAVP stimulation.

Fig. 1

figure 1

Comparison of mean values of IPS/P ACTH in CD (Lt.) and EAS (Rt.). IPS; inferior petrosal sinus; P: peripheral; ACTH: adrenocorticotropic hormone; CD: Cushing’s disease; EAS: ectopic ACTH syndrome; Lt: left; Rt: right

According to the Prolactin-normalized ACTH IPS/P ratios, eight patients (cases 1–8) were diagnosed as CD and three as EAS (cases 9–11). In cases 1, 2, 3, 7, and 8, unilateral sources of CD were confirmed, but in cases 4,5 and 6, bilateral sources were detected (Table 4).

According to the inter-sinus ratio, BIPSS could lateralize the source of ACTH in all patients with CD. The inter-sinus ratio in patients with EAS could not lateralize any pituitary source for ACTH (Table 4).

In five patients with CD and one with EAS, the highest peripheral ACTH level was observed 15 min after stimulation. Two patients with CD and one with EAS had the highest peripheral ACTH level 10 min after stimulation. Only one patient with CD and one with EAS had the highest peripheral ACTH level 5 min after stimulation. No patient had maximum peripheral ACTH levels in the first post-stimulation sample (minute 3).

The larger numerator or smaller denominator produces a higher value in a ratio. In the samples obtained immediately after stimulation, the highest concentration of ACTH was in the IPS, and the lowest was in the peripheral blood. Therefore, as mentioned, the highest post-stimulation value of the IPS/P ACTH ratio was obtained at minute 3.

MRI results

MRI results showed pituitary adenoma in five patients, enhancement in one patient, pituitary mass and lesion in two patients, empty sella in two patients, and possible pituitary adenoma and adrenal mass in one patient (Table 5).

Table 5 Final diagnosis, lateralization, MRI results, and management

Immunohistochemistry (IHC) results

According to the pathology report, eight patients were confirmed as CD (Table 5). The other two patients were EAS (one carcinoid tumor of the lung and one pheochromocytoma). One patient had no documented pathologic source of hypercortisolemia because the patient did not consent to surgery, and the diagnosis of EAS was made based on the results of biochemical tests.

BIPSS vs. MRI results

MRI results showed pituitary adenoma in five patients with CD. MRI and BIPSS showed the adenoma on a similar side in two of them. In the other three patients, MRI showed bilateral adenoma, but BIPSS lateralized the adenoma to one side. One of the other three patients had only left-sided enhancement but no overt adenoma on MRI, whereas BIPSS lateralized the adenoma to the right side. One patient had a low-signal pituitary mass on the right side on MRI, and BIPSS also lateralized to the right. Another patient with a history of transsphenoidal surgery (TSS), diagnosed as recurrent CD, had a partially empty sella. MRI was equivocal, but BIPSS lateralized to the left side.

Among patients with EAS, one with an equivocal BIPSS result had an empty sella on MRI. Two other patients had pituitary lesions on MRI, but BIPSS results were equivocal.

Comparison between BIPSS, MRI, and surgery

Among patients with CD, the final diagnosis based on surgery in three patients was consistent with MRI and BIPSS results and lateralized the adenoma on the same side. In one patient, the surgery result was similar to the MRI findings and showed bilateral adenoma, but BIPSS showed adenoma on the left side. In the patient with equivocal MRI findings and a history of TSS, IHC could not identify ACTH +, although BIPSS lateralized to the left side. In three other patients, surgery results were concordant with BIPSS and lateralized the adenoma on the same side, although MRI showed discordant results.

Validity of BIPSS

Baseline IPS/P ACTH resulted in a sensitivity of 87.5%, specificity of 100%, PPV of 100%, NPV of 75%, and accuracy of 91%. Stimulation with DDAVP improved validity. Both stimulated IPS/P ACTH and normalized ACTH/prolactin IPS/P ratio resulted in a sensitivity of 100%, specificity of 100%, PPV of 100%, NPV of 100%, and accuracy of 100%. BIPSS, either unstimulated or stimulated, had higher validity than MRI, with a sensitivity of 62.5%, specificity of 33%, PPV of 71%, NPV of 25%, and accuracy of 54%. BIPSS accurately predicted pituitary adenoma lateralization in 75% of patients with CD.

Discussion

In this study, BIPSS before stimulation showed a sensitivity of 87.5% and a specificity of 100%. However, BIPSS after stimulation showed a sensitivity of 100% and specificity of 100%. It has been demonstrated that the sensitivity of BIPSS can vary from 88 to 100%, and its specificity from 67 to 100% in the diagnosis of CD [24]. Previous studies have reported sensitivity and specificity of more than 80% and 90% for BIPSS, and the combination of BIPSS with stimulation by CRH or DDAVP improves the sensitivity and specificity to more than 95 and 100%, respectively [15, 19, 25]. Chen et al. suggested the optimal IPS:P cutoff value of 1.4 before and 2.8 after stimulation [20]. Considering these cutoffs, the only patient in this study who was negative for CD before stimulation becomes positive, and the sensitivity before stimulation increases from 87.5 to 100%. The diagnostic accuracy after stimulation remains unchanged. Results of the current study showed that BIPSS is highly valued in final diagnosis, even without stimulation.

In this investigation, the utilization of Prolactin-normalized ACTH IPS/P ratios exhibited a sensitivity and specificity of 100% for the CD diagnosis. This finding aligns with research conducted by Detomas et al., which reported a sensitivity of 96% and specificity of 100% for the normalized ACTH: Prolactin IPS/P ratio [26]. It seems that concurrently assessing prolactin levels may potentially enhance the diagnostic accuracy of BIPSS. However, the current literature is inconsistent. Some studies do not support the use of prolactin to diagnose CD [27].

In all patients, the IPS/P ACTH ratio at minute 15 did not show a considerable difference from this ratio at minute 0. Previous studies have shown that sampling at minute 15 is not helpful for diagnosis [1, 15, 20, 28]. Unlike the IPS/P ACTH ratio, six patients had the highest peripheral ACTH level at minute 15 after stimulation, but no patient had it at minute 3 after stimulation. However, more studies are needed to obtain more precise results, and this study’s sample size was limited.

BIPSS accurately lateralized the adenoma in six patients with CD, but MRI was able to lateralize the adenoma in two patients correctly. BIPSS had higher validity than MRI in differentiating CD from EAS, both with and without stimulation. The current literature is controversial. Colao et al. reported that adenoma could be accurately localized in 65% of patients using IPSS [23]. However, Lefournier et al. showed that the diagnostic accuracy of IPSS in identifying the side of the pituitary adenoma was 57% [28]. Wind et al. showed that the PPV for IPSS to identify the tumor side correctly was 69%. Additionally, MRI was more accurate than IPSS in tumor lateralization [29]. Earlier studies have shown that MRI may show a pituitary lesion, and BIPSS indicates a pituitary adenoma. However, the lesion observed on the MRI is not related to the pituitary adenoma [1, 15, 19, 25, 28]. Also, MRI may show pituitary lesions, while BIPSS indicates EAS.

In the current study, the concordance of IHC results with BIPSS and MRI findings was inconclusive, possibly due to the limited number of patients. However, there is disagreement about the role of pathological study in diagnosis [19, 28].

Eight patients had elevated basal serum cortisol levels in this study (Sensitivity:73%). Instead, all patients had hypercortisolemia according to basal 24-hour UFC results, and no false-negative results were observed (Sensitivity:100%). This study’s findings were consistent with previous studies regarding low sensitivity for basal serum cortisol and high sensitivity for 24-hour UFC as screening tests for hypercortisolemia [6, 30, 31].

After HDDST, basal serum cortisol suppression was observed in three patients with CD (cases 2, 3, and 8) but not in the others with CD. Also, serum cortisol levels were suppressed after HDDST in a patient with EAS who had a lung carcinoid tumor. Arnaldi et al. showed that some carcinoid tumors might be sensitive to HDDST, and suppression of serum cortisol may be observed after this test [1, 32]. After HDDST, six patients with CD had suppressed 24-hour UFC, but one did not show more than 50% suppression. Two patients with EAS had more than 50% 24-hour UFC suppression.

According to the final pathology report, the sensitivity of serum and urine cortisol level tests after HDDST was 43% and 86%, and the specificity was 67% and 33%, respectively. PPV in both was 75%, NPV was 33% and 50%, and accuracy was 50% and 70%, respectively, which shows that these preliminary tests cannot be a good guide for the final diagnosis and subsequent treatment planning. Previous studies showed that more than one biochemical test could improve the accuracy for differentiating between CD and EAS [1, 5, 6, 9, 31]. The current study confirms the importance of using more than one biochemical test for diagnosing hypercortisolemia and diagnosing CD from EAS.

Detomas et al. reported that Hb levels were high in females with CS while they were low in males with CS. Furthermore, there were lower levels of Hb in EAS than in CD in females [33]. In the current study, the Hb levels were not different in women and men. Furthermore, no statistical difference was observed for Hb levels between patients with a final diagnosis of CD and EAS. Hb levels did not contribute to diagnosing ACTH-dependent CS in this analysis.

There were some limitations in this study. First, the sample size was relatively small. Second, it was a retrospective study. Further studies could investigate the BIPSS in a larger sample size and determine the validity of this method in patients with CS.

Conclusions

The current study suggests that BIPSS can be a reliable and low-complication method in evaluating patients with ACTH-dependent CS who had equivocal results in imaging and biochemical tests, even before stimulation. Stimulation with DDAVP increases diagnostic accuracy. BIPSS can be used to predict the lateralization of the pituitary adenoma.

Data Availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

BIPSS:
Bilateral inferior petrosal sinus sampling
ACTH:
Adrenocorticotropic hormone
CS:
Cushing’s syndrome
IPS:
Inferior petrosal sinus
DDAVP:
Desmopressin
CD:
Cushing’s disease
EAS:
Ectopic ACTH syndrome
MRI:
Magnetic resonance imaging
UFC:
Urinary free cortisol
DST:
Dexamethasone suppression test
HDDST:
High-dose dexamethasone suppression test
CRH:
Corticotropin-releasing hormone
BMI:
Body mass index
FBS:
Fasting blood glucose
Hb:
Hemoglobin
Cr:
Creatinine
PPV:
Positive predictive value
NPV:
Negative predictive value
SBP:
Systolic blood pressure
DBP:
Diastolic blood pressure
K:
Potassium
HTN:
Hypertension
IHC:
Immunohistochemistry
TSS:
Transsphenoidal surgery

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Acknowledgements

The authors wish to thank the patients for their participation and kind cooperation.

Funding

The authors did not receive support from any organization for the submitted work.

Author information

Authors and Affiliations

  1. Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Mohammadali Tavakoli Ardakani, Soghra Rabizadeh, Amirhossein Yadegar, Fatemeh Mohammadi, Sahar Karimpour Reyhan, Reihane Qahremani, Alireza Esteghamati & Manouchehr Nakhjavani

  2. Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran

    Hossein Ghanaati

Contributions

MN and MTA and SR: Conception and design of the study. AY and FM and HG: Acquisition of data. MTA and AY and SR: Analysis and interpretation of data. FM and RQ and SK: Drafting the article. MN and AE and AY: Critical revision of the article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Manouchehr Nakhjavani.

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This study was performed in line with the principles of the Declaration of Helsinki. Informed consent was obtained from all participants or their legal guardians. Approval was granted by the Research Ethics Committee of Tehran University of Medical Sciences (Approval number: IR.TUMS.MEDICINE.REC.1398.707).

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In order to publish this study, written informed consent was obtained from each participant. A copy of the written consent form is available for review by the journal editor.

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Ardakani, M.T., Rabizadeh, S., Yadegar, A. et al. Bilateral inferior petrosal sinus sampling: validity, diagnostic accuracy in lateralization of pituitary microadenoma, and treatment in eleven patients with Cushing’s syndrome – a single-center retrospective cohort study. BMC Endocr Disord 23, 232 (2023). https://doi.org/10.1186/s12902-023-01495-z

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Intensity-Modulated Radiotherapy for Cushing’s Disease: Single-Center Experience in 70 Patients

Posted on October 16, 2023 by MaryO

Context: Intensity-modulated radiotherapy (IMRT) is a modern precision radiotherapy technique for the treatment of the pituitary adenoma.

Objective: Aim to investigate the efficacy and toxicity of IMRT in treating Cushing’s Disease (CD).

Methods: 70 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). The outcome of endocrine remission, endocrine recurrence, tumor control and complications were retrieved from medical record.

Results: At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95%CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 22.9%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission.

Conclusion: IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Introduction

Cushing’s disease (CD) is characterized by hypersecretion of adrenocorticotropic hormone (ACTH) from pituitary adenoma. As the state of hypercortisolemia considerably increases morbidity and mortality, normalizing cortisol levels is regarded as the major treatment goal in patients with CD (1). Transsphenoidal selective adenomectomy (TSS) is now established as the first-line treatment of CD. Despite the satisfactory remission rate that can be achieved with TSS (ranging from 59-97%), delayed recurrences have also been reported in up to 50% of patients (2).

The Endocrine Society guidelines suggest a shared decision-making approach in patients who underwent a noncurative surgery or for whom surgery was not possible (3). Second-line therapeutic options include repeat transsphenoidal surgery, medical therapy, radiotherapy and bilateral adrenalectomy. Radiotherapy (RT) is generally used in patients who have failed TSS or have recurrent CD, as well as in progressively growing or invasive corticotroph tumors (3, 4).

Both stereotactic radiosurgery(SRS)and fractionated radiotherapy (FRT) have been used in the treatment of CD. Conventional radiotherapy as one of the technique for FRT has been used with a long experience, but its benefits were hindered by high risk of toxicity, mainly attributed to the harm to healthy surrounding structures (4). Previous studies on conventional RT in treating CD showed high efficacy (tumor control rate of 92-100% and hormonal control rate of 46-89%), but RT-induced hypopituitarism (30-58%) and recurrence (16-21%) were also commonly reported (1, 4–7). Modern precise radiotherapy, especially intensity-modulated radiotherapy (IMRT), can spare the surrounding normal structure better by a more conformal and precise dose distribution (8). However, a large cohort study on long-term efficacy and toxicity of IMRT for CD is still lacking. Therefore, in the current study, we aim to analyze the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) in treating CD. We also investigated the predictors of endocrine remission in aid of further management.

Methods

Patient

We collected 115 cases of Cushing’s disease treated at our center from April 2012 to August 2021. Patients were excluded under the following conditions: (1) follow-up time less than 3 months, (2) lacking evaluation of serum cortisol (F), adrenocorticotropic hormone (ACTH) or 24-hour urinary free cortisol (24hUFC) before or after RT, (3) underwent uni or bilateral adrenalectomy, (4) having received RT at other institutes before admitted to our center. At last, a total of 70 cases were included in this study.

Radiotherapy parameters

RT was administrated by a linear accelerator (6 MV X-ray). Intensity-modulated radiation therapy was applied for all patients. Including fix-filde IMRT (FF-IMRT), volumetric modulated arc therapy (VMAT) or Tomotherapy. We immobilized the patient with an individualized thermoplastic head mask and then conducted a computed tomography (CT) simulation scan at 2- to 3-mm intervals. The target volume and organs at risks (OARs) were delined with a contrast enhanced T1-weighted image (T1WI) magnetic resonance imaging (MRI) fusing with planning CT. The gross tumor volume (GTV) was defined with the lesion visible on MRI or CT. The clinical target volume (CTV) included microscopic disease, especially when the tumor invaded cavernous sinus and surrounding bones. The planning target volume (PTV) was defined as CTV plus a margin of 2- to 3-mm in three dimensions. The prescription dose was defined at 100% isodoseline to cover at least 95% PTV. The maximum dose was limited to less than 54 Gy for the brain stem and optic pathway structures. Radiotherapy was performed once a day and five fractions a week during five to six weeks. The total dose was 45-60 Gy, delivered in 25-30 fractions, with most patients (78.6%) receiving 45-50 Gy in 25 fractions. The fractionated dose was 1.8-2.0 Gy.

Data collection and clinical evaluation

Baseline characteristics were collected at the last outpatient visit before RT, including demographic characteristics, biochemical data, tumor characteristics and details of previous treatments. After RT, endocrine evaluations were performed every 6 months. Endocrine remission was considered when 1 mg dexamethasone suppression test (DST)<1.8 mg/dl. If 1mg DST results were lacking, then 24hUFC within the normal range was used as a remission criterion. Patients who regained elevated hormone levels after achieving remission were considered to have endocrine recurrence. For patients receiving medications that could interfere with the metabolism of cortisol, hormonal evaluation was performed at least 3 months after the cessation of the therapy.

Tumor size was measured on magnetic resonance imaging (MRI) before RT and annually after the completion of RT. Any reduction in or stabilization of tumor size was considered as tumor control. Tumor recurrence was defined as an increase of 2 millimeters in 2 dimensions comparing to MRI before RT, or from invisible tumor to a visible tumor on MRI (9).

Anterior pituitary function was assessed before RT and every 6 months during the follow-up after RT. RT-induced hypopituitarism was defined as the development of new onset hormone deficiency after RT. The diagnostic criteria for growth hormone deficiency (GHD), central hypothyroidism and hypogonadotropic hypogonadism (HH) refer to previous literature (10–12). Panhypopituitarism referred to three or more anterior pituitary hormone deficiencies (13).

Statistical analysis

Statistical analysis was performed with SPSS version 25.0. Longitudinal analysis was performed with Kaplan-Meier method. For time-dependent variable, Log rank test was used for univariate analysis and Cox regression for multivariate analysis. The cut-off of F, ACTH and 24hUFC were defined as their median value. All variants in the univariate analysis were included in the model of multivariate analysis. P value < 0.05 was considered statistically significant. Plot was created with GraphPad Prism version 9.4.

Results

Patient characteristics

Of 70 cases included in the study, the median age was 32 years (range, 11-66 years). 60 (85.7%) were female and 10 (14.3%) were male (F:M= 6:1). The median follow-up time was 36.8 months (range, 3.0-111.0 months). 68 patients received RT as a second-line treatment because of incomplete tumor resection, failure to achieve complete endocrine remission or recurrence postoperative, and 2 were treated with RT alone because of contraindication of surgery. The frequency of surgical treatment was 1 for 42 patients, 2 for 21 and more than 3 for 5. A total of 8 patients received medical treatment before RT. 5 of them used pasireotide, 2 used ketoconazole and 1 used mifepristone. The median ACTH level was 58.7 pg/ml (range 14.9-265 pg/ml), F, 26.2μg/dl (range 11.8-72.6 μg/dl) and 24hUFC, 355.7 μg/24hr (range 53.5-3065 μg/24hr) before RT. Tumor size evaluation was performed in all 70 patients before RT. Among them, 36 patients showed no visible residual tumor identified on MRI and only 5 patients showed tumor size more than 1 cm. Hypopituitarism was found in 31 patients (38.8%) before RT. HH was the most common (21 patients, 26.3%), followed by central hypothyroidism (13 patients, 16.3%) and GHD (9 patients, 11.3%). Panhypopituitarism was found in 4 patients (5.0%). (Table 1).

Table 1
www.frontiersin.orgTable 1 Patient characteristics.

Endocrine remission

Endocrine remission was achieved in 37 of 70 patients during the follow-up. Six of them were evaluated by 1mg DST. The hormonal remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively, gradually increasing with follow-up time (Figure 1). The median time to remission was 24.0 months (95%CI: 14.0-34.0 months). Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission. There was no significant correlation between remission and age, sex, tumor size, the frequency of surgery, medication prior RT. The hormone levels (F, ACTH and 24hUFC prior RT) were divided into high and low groups by the median value, and were also not found to be associated with endocrine remission (Table 2). Since only Ki-67 was significant in the univariate analysis and all other parameters were far from significant, a multivariate analysis was no longer performed.

Figure 1
www.frontiersin.orgFigure 1 Endocrine remission rate during the follow-up after RT.

Table 2
www.frontiersin.orgTable 2 Univariate predictors of endocrine remission.

Endocrine recurrence was found in 5 patients till the last follow-up, with an overall recurrence rate of 13.5% (5/37). The median time to recurrence after reaching endocrine remission was 22.5 months. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively (Figure 2).

Figure 2
www.frontiersin.orgFigure 2 Recurrence free rate after endocrine emission.

Tumor control

A total of 51 patients had repeated MRI examinations before and after treatment. During the follow-up, 20 patients showed reduction and 30 patoents remained stable in tumor size, with a tumor control rate of 98%. Only 1 patient showed enlargement tumor 1 year after RT, with F, ACTH and 24hUFC increase continuously.

Complications

At the last follow-up, 16 patients developed new onset hypopituitarism after RT. The overall incidence of RT-induced hypopituitarism was 22.9%. Hypothyroidism was the most common of hypopituitarism (8 patients), followed by HH (7 patients), adrenal insufficiency (4 patients) and GHD (3 patients). Only 1 patient (1.3%) with systemic lupus erythematosus (SLE) comorbidity complained of progressively worsening visual impairment during the follow up. No cerebrovascular event or radiation associated intracranial malignancy was found in our cohort.

Discussion

Efficacy and radiotherapy techniques

RT has been emerged as an effective second-line treatment for CD for many years. Although conventional fractionated RT has been used for a long experience in patients with CD, study on the modern precise radiotherapy, particularly IMRT, is rare and reports limited evidence on its long-term treatment outcome. IMRT can be implemented in many different techniques, such as fixed-field intensity-modulated radiotherapy (FF-IMRT), volumetric-modulated arc therapy (VMAT) and tomotherapy. Compared with conventional RT, IMRT allows a better target volume conformity while preserves adequate coverage to the target (14, 15). Our study reported that IMRT for CD has an endocrine remission rate of 74.0% at 5 years, with a median time to remission of 24.0 months (95%CI: 14.0-34.0 months). The endocrine remission rate at 5 years was comparable to those reported in previous series of FRT, with a median time to remission within the reported range (4.5-44 months) (9, 16–18) (Table 3). Compared with SRS in treating CD, the endocrine remission rate and median time to remission were also similar. Pivonello et al (19) summarized 36 studies of SRS for CD between 1986 to 2014, the mean endocrine remission rate was 60.8% and the median time to remission was 24.5 months. Tumor control rate was 98% in our cohort, only one patient showed enlargement tumor with elevating hormones. This local control rate was also comparable to that reported in a series of pituitary adenoma treated with FRT (93-100%) and SRS(92-96%) (9, 16–18, 20, 21). Indeed, despite the lack of controlled studies about SRS and FRT in treating CD, many reviews that summarize the biochemical control and tumor contral of both are similar (2, 6, 19).

Table 3
www.frontiersin.orgTable 3 Literature review of FRT and SRS in patients with CD published in recent years.

The overall endocrine recurrence rate in our study was 13.5%, with a median time to recurrence of 22.5 months. We, for the first time, reported the actuarial recurrence free rate at 1, 2, 3 and 5 years in CD patients treated with IMRT. The recurrence free rate at 3 and 5 years was 88.7% in our study. Outcomes were comparable to those reported in patients treated with conventional RT or SRS, with a mean recurrence rate and a median recurrence time of 15.9% (range, 0-62.5%) and 28.1 months, or 12.3% (range, 0-100%) and 33.5 months, according to a review conducted by Pivonello et al (19).

At 2020, we reported the outcomes of pituitary somatotroph adenomas treated with IMRT at our institution (20). Compared with pituitary somatotroph adenomas, CD has a similar 5-year remission rate (74.0% vs 74.3%) but a shorter median time to remission (24.0m vs 36.2m) (Figure 3). The tumor contral rates were similar, at 98% and 99%, respectively. The endocrine recurrence rate was significantly different, with CD being about one-fold higher than the pituitary somatotroph adenoma (13.8% vs 6.1%). This may be due to the majority of microadenomas in CD and that of macroadenomas in pituitary somatotroph adenomas.

Figure 3
www.frontiersin.orgFigure 3 Endocrine remission rate of CD and pituitary somatotroph adenoma.

Predictors of endocrine remission

In the univariate analysis, we found that only Ki-67 index ≥ 3% was correlated with better endocrine remission (p=0.044). Cortisol levels before RT and tumor size were not predictors of endocrine remission. For surgery in treating CD, higher preoperative ACTH level was considered as unfavorable prognostic factor for endocrine remission in a few studies (22, 23). For radiotherapy, some previous studies also have reported a faster endocrine remission in patients with lower serum cortisol level. Minniti et al. reported that hormone level was normalized faster in patients with lower urinary and plasma cortisol level at the time of RT (16). Apaydin also reported that low postoperative cortisol and 1mg DST was a favorable factors for faster remission in patients treated with gamma knife surgery (GKS) and hypofractionated radiotherapy (HFRT), although no significant relationship was found between remission rate and plasma cortisol level prior RT in both studies (9, 16). Castinetti et al. found that initial 24hUFC was a predicative factor of endocrine remission in patients treated with GKS, which was not reported in our cohort treated with IMRT (24). However, the discrepancy between the results can be attributed to various factors, including selection bias of retrospective study, duration of follow-up, endocrine remission criteria and cut-off value.

Tumor size before RT was considered as a significant predictor for endocrine remission in some published series of patients treated with SRS. Jagannathan et al. reported a significant relationship between preoperative tumor volume and endocrine remission in patients with CD treated with GKS (25). However no significant correlation between tumor size and endocrine remission was found in series of patients treated with FRT (5, 9, 16, 17). But our study found no significant correlation between tumor size (visible or no-visible residual tumor on MRI) before RT and endocrine remission. The frequency of surgery before RT was also not found to be associated with endocrine remission in our study, which reached a similar conclusion with some previous studies (9, 17, 18, 26). Abu Dabrh et al. reported a higher remission rate in patients receiving TSS prior RT in their meta-analysis (5). Similar result was also reported in a review on the treatment outcome of GKS in patients with CD, that postoperative GKS was more effective than primary GK (19). However, analysis on this parameter was difficult in our cohort considering the low number of patients who received IMRT as the first-line treatment.

Reports on the effect of medical treatment on endocrine remission have been controversial. Some studies reported a negative effect of medical treatment at the time of SRS on endocrine remission in patients with CD. Castinetti et al. showed a significant higher rate of endocrine remission in patients who were not receiving ketoconazole at the time of GKS, compared to those who were (27). Sheehan et al. also found a significantly shorter time to remission in patients who discontinued ketoconazole at the time of GKS (28). However, no such correlation was found in patients treated with FRT (9, 17). Like previous studies on FRT, we also noted no significant relationship between preradiation use of medication and endocrine remission, but our statistical analysis may be hindered by the low proportion of patients undergoing medical treatment before RT. Moreover, the anticortisolic drugs used in previous studies were mainly ketoconazole or cabergoline, while most of our patient have received pasireotide, whose effect have not been well-studied yet. Further studies are necessary to understand the effect of somatostatin receptor ligands on the outcome of radiotherapy in patients with CD.

Complications

Hypopituitarism is the most common complication secondary to radiotherapy, with the rate of new-onset hypopituitarism ranging widely in previous report. Pivonello et al. reviewed series of CD patients who were treated with conventional RT with a follow-up of at least 5 years (19). The reported mean and median rates of hypopituitarism were 50% and 48.3%, respectively (range, 0-100%). As regards FRT, the overall rate of new-onset hypopituitarism was 22.2-40% at a median follow-up ranging from 29-108 months, with both incidence and severity increasing with longer follow-up (9, 16–19). The incidence of hypopituitarism in our series was 22.9%, which was within the reported range of new onset hypopituitarism after FRT. Lower rate of hypopituitarism after SRS compared to conventional RT has been recognized in previous reviews (2, 6). Our study showed that new onset hypopituitarism was less prevalent after IMRT than after conventional RT. This can be attributed to a higher precision in contouring the target volume and OARs, allowing these modern radiotherapy techniques to provide a better protection to hypothalamus-pituitary axes. In previous studies, potential risk factors for new onset hypopituitarism included suprasellar extension, higher radiation dose to the tumor margin and lower isodose line prescribed (29, 30). Sensitivity of individual hormonal axes to RT varies in different series. In our study, central hypothyroidism was the most common individual axis deficiency, followed by HH, adrenal insufficiency and GHD. This sequence was similar to that reported by Sheehan et al., whose series included 64 CD patients treated with SRS, as well as some other series (29, 31). It is noted in some studies that GHD is the most vulnerable axes (19, 32, 33). Limited number of patients undergoing stimulation test may underestimate the prevalence of GHD in our study and some previous series, and longer follow-up is needed to generate a more accurate, time-dependent rate of new onset hypopituitarism.

In our study, only one patient complained of mild visual impairment, which was comparable to the rate ranging from 0-4.5% in previous series of FRT treating pituitary adenoma (9, 16–18, 26, 32, 34, 35). This patient had concomitant SLE and the associated microangiopathy may render the optic nerve intolerant to radiotherapy. Cranial nerve damage was acknowledged as an uncommon complication, with an estimated risk of vision deterioration below 1% if single radiation dose was no more than 2.0 Gy and total dose no more than 45-50 Gy (2, 36). The actuarial rate of optic neuropathy at 10 years was 0.8% in a series containing 385 patients with pituitary adenoma (37). No patient in our cohort developed cerebrovascular accident or secondary brain tumor. This finding was consistent with the low actuarial prevalence of these complications reported in other published series of FRT. Secondary brain tumor was extremely rare after SRS, with an overall incidence of 6.80 per patients-year, or a cumulative incidence of 0.00045% over 10 years in a multicenter cohort study containing 4905 patients treated with GKS (38). Ecemis et al. reviewed cohort studies of conventional RT in treating pituitary adenoma from 1990 to 2013 and found that 1.42% of patients developed secondary brain tumor, with a latency period of 19.6 years for meningioma, 11 years for glioma and 9 years for astrocytoma (39). As for cerebrovascular accident, Minniti et al. reported two patients (in a total of 40 patients) who had stroke 6 and 8 years after FRT (16). Data was still limited for FRT. Considering the low incidence and long latency period, large, controlled cohort study with long follow-up of FRT is still needed to accurately evaluate these complications.

Limitations

Our study has several limitations. First, not all patients rigorously followed regular follow-up time points, making time-dependent statistical analysis less accurate. In addition, the excessively low number of cases with 1mg DST as the endocrine remission criterion may affect the accuracy of the remission rate.Moreover, a median follow-up time of about 3 years hampered evaluation on some late complications, including cerebrovascular events and secondary brain tumor.

In conclusion, our study revealed that IMRT was a highly effective second-line therapy with low side effect profile for CD patients, and it’s endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Author contributions

1. Conceptualization: FZ and HZ 2. Data curation: XL and ZX. 3. Funding acquisition: FZ. 4. Investigation: XL and ZX 5. Methodology: WW 6. Resources: XL, SS and XH 7. Validation: LL and HZ. 8. Writing – original draft: ZX 9. Writing – review and editing: XL. All authors contributed to the article and approved the submitted version.

Funding

Supported by grants National High Level Hospital Clinical Research Funding (No.2022-PUMCH-B-052) and National Key R&D Program of China, Ministry of Science and Technology of the People’s Republic of China.(Grant No. 2022YFC2407100, 2022YFC2407101).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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Keywords: cushing’s disease, intensity-modulated radiotherapy, radiotherapy, pituitary adenoma, ACTH

Citation: Lian X, Xu Z, Sun S, Wang W, Zhu H, Lu L, Hou X and Zhang F (2023) Intensity-modulated radiotherapy for cushing’s disease: single-center experience in 70 patients. Front. Endocrinol. 14:1241669. doi: 10.3389/fendo.2023.1241669

Received: 17 June 2023; Accepted: 31 August 2023;
Published: 26 September 2023.

Edited by:

Luiz Augusto Casulari, University of Brasilia, Brazil

Reviewed by:

Luiz Eduardo Armondi Wildemberg, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Brazil
Carolina Leães Rech, Federal University of Health Sciences of Porto Alegre, Brazil

Copyright © 2023 Lian, Xu, Sun, Wang, Zhu, Lu, Hou and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Fuquan Zhang, zhangfq@pumch.cn

†These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

From https://www.frontiersin.org/articles/10.3389/fendo.2023.1241669/full

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A Patient With a Bronchial Carcinoid Presents With Cushingoid Symptoms Due To An Atypical and Potentially Dangerous Supplement

Posted on October 11, 2023 by MaryO

Highlights

•

The most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer; however it is a relatively uncommon complication of pulmonary neoplasms.

•

The most common cause of Cushing syndrome is iatrogenic corticosteroid use and it should be considered in all patients regardless of clinical background.

•

Low urine cortisol levels may be associated with exogenous glucocorticoid exposure.

•

Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography.

•

Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products.

Abstract

Background

Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and rarely cause Ectopic ACTH syndrome. Iatrogenic corticosteroid use is the most common cause of Cushing syndrome and should be considered in all patients regardless of clinical background.

Case report

A 59 year old woman with an 11 year history of a 1.5 cm well differentiated bronchial carcinoid, presented with Cushingoid features. Laboratory results were not consistent with an ACTH dependent Cushing Syndrome and exogenous steroids were suspected. The patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain.

Discussion

Ectopic ACTH production is reported in less than 5% of patients with squamous cell lung cancer and 3% of patients with lung or pancreatic (non-MEN1) neuroendocrine tumors. Factitious corticoid exposure is rare and can be evaluated with synthetic corticosteroid serum testing.

Conclusion

Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing.

1. Introduction

Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and can rarely exhibit Cushing syndrome due to ectopic production of adrenocorticotropic hormone (ACTH). However the most common cause of Cushing syndrome is iatrogenic corticosteroid use and should be considered in all patients regardless of clinical background (see Fig. 1, Fig. 2, Fig. 3, Fig. 4).

Fig. 1

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Fig. 1. DOTATATE PET/CT demonstrates a right upper lobe pulmonary nodule with intense uptake.

Fig. 2

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Fig. 2. DOTATATE PET/CT demonstrates intense uptake within a right upper lobe pulmonary nodule, consistent with biopsy-proven carcinoid tumor. There are no distant sites of abnormal uptake to suggest metastatic disease.

Fig. 3

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Fig. 3. Artri Ajo King Supplement (Source: FDA). The label claims that the product contains glucosamine, chondroitin, collagen, vitamin C, curcumin, nettle, omega 3, and methylsulfonylmethane.

Fig. 4

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Fig. 4. Artri King Supplement (Source: FDA).

2. Case report

A 59–year old woman with an 11 year history of a 1.5 cm well-differentiated bronchial carcinoid, presented with 20 lb. weight gain, facial swelling, flushing, lower extremity edema and shortness of breath over 3 months. On exam, the patient was normotensive, centrally obese with mild hirsutism, facial fullness and ruddiness with evidence of a dorsocervical fat pad. Initially there was concern for hormonal activation of her known bronchial carcinoid. Testing resulted in a normal 24-hour urine 5-HIAA (6 mg/d, n < 15 mg/dL), elevated chromogranin A (201 ng/mL, n < 103 ng/mL), normal histamine (<1.5 ng/mL, n < 1.7 ng mL), low-normal 7 AM serum cortisol (5.1 μg/dL, n 3.6–19.3 μg/dL), normal 7 AM ACTH (17 pg/mL, n < 46 pg/mL) and a surprisingly low 24-hr urinary free cortisol (1.8 mcg/hr, n 4.0–50.0 mcg/hr). A late night saliva cortisol was 0.03 mcg/dL (n 3.4–16.8 mcg/dL). Testosterone, IGF-1, glucose and electrolytes were appropriate. An echocardiogram showed an ejection fraction of 60% with no evidence of carcinoid heart disease. A Dotatate PET-CT was obtained to evaluate for progression of the neuro-endocrine tumor and revealed a stable right upper lobe pulmonary nodule with no evidence of metastatic disease. Given low cortisol levels, ectopic Cushing syndrome was excluded and exogenous steroids were suspected, however the patient denied use of oral,inhaled, or injected steroids. A cosyntropin stimulation study yielded a pre-stimulation cortisol 6.2 μg/dL with an adequate post-stimulation cortisol 23.5 μg/dL. At this stage of evaluation, the patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. The notification advised of hidden drug ingredients including dexamethasone, diclofenac, and methocarbamol contained within Artri King Glucosamine supplements not listed on the product label but verified by FDA lab analysis. The FDA had received several adverse event reports including liver toxicity and even death associated with such products. The patient’s symptoms gradually improved after discontinuation of the supplement.

3. Discussion

3.1. Ectopic ACTH syndrome

This patient’s Cushingoid features were initially suspected to be secondary to the known bronchial neuroendocrine tumor. Ectopic ACTH production accounts for about 5–10% of all Cushing Syndrome cases [1]. The most common location of ectopic ACTH is the lungs with pulmonary carcinoid tumors being the most common cause, followed by squamous cell lung cancer [2]. Despite this patient’s history of bronchial carcinoid tumor and positive chromogranin histopathological marker, her laboratory results were not consistent with an ACTH dependent Cushing Syndrome. In fact, Cushing syndrome is a relatively uncommon neuroendocrine neoplasm complication. The prevalence of ectopic ACTH production in patients with lung tumors is rare, at less than 5% in squamous cell lung cancer and about 3% in patients with lung or pancreatic (non-MEN1) neuroendocrine tumors1.

Patients with ACTH dependent Cushing syndrome not suspected to originate from the pituitary, undergo further testing to evaluate for an ectopic ACTH secreting tumor. These tests include conventional imaging of the chest, abdomen and pelvis, as well as functional imaging such as octreotide scans, fluoride 18-fluorodeoxyglucose-positron emission tomography [18F-FDG PET], and gallium-68 DOTATATE positron emission tomography-computed tomography [Dotatate PET-CT] scan [3]. In our literature review, we found that there was insufficient evidence to determine the sensitivity and specificity of nuclear medicine imaging techniques [4,5]. In this case, the patient had no laboratory evidence for ACTH dependent Cushing Syndrome, but given the known bronchial carcinoid tumor, a repeat Dotatate PET-CT scan was obtained which demonstrated no indication of growth or spread of the known bronchial tumor.

3.2. Supplement induced Cushing Syndrome

One of the most remarkable findings in this case was the patient’s low urine cortisol level in the setting of her overt Cushingoid features. In our survey of the literature, we found that low urine cortisol levels were associated with exogenous glucocorticoid use [6,7]. The low urine cortisol levels may be reflective of intermittent glucocorticoid exposure. Indeed, this patient’s Cushingoid features were determined to be secondary to prolonged use of Artri King supplement.

Occult glucocorticoid use is difficult to diagnose even after performing a thorough medication reconciliation as patients may unknowingly consume unregulated doses of glucocorticoids in seemingly harmless supplements and medications. The incidence of supplement induced Cushing Syndrome is currently unknown as supplements are not regularly tested to detect hidden glucocorticoid doses. Additionally, the likelihood of developing supplement induced Cushing syndrome is dependent on dosage and duration of use.

In our literature review we found nine published articles describing supplement induced Cushing Syndrome [[7], [8], [9], [10], [11], [12], [13], [14], [15]], one case report of tainted counterfeit medication causing Cushing Syndrome [16], and two cases of substances with probable glucocorticoid-like activity [17,18]. Of the nine published articles of supplement induced Cushing Syndrome, six were associated with supplements marketed as arthritic joint pain relief products including ArtriKing, Maajun, and AtriVid [[7], [8], [9], [10], [11], [12]]. These products later received government issued warnings in Mexico, Malaysia, and Colombia respectively [[19], [20], [21]].

To our knowledge there have been four published reports of ArtiKing supplement induced Cushing Syndrome [[7], [8], [9], [10]]. The first documented cases were reported in 2021 in Vera Cruz, Mexico; since then the Mexican medical community reported seeing a disproportionate increase in cases of iatrogenic Cushing Syndrome due to these supplements [7]. There have also been three American published articles describing a total of 4 cases of ArtriKing supplement induced Cushing syndrome [[8], [9], [10]]. In January 2022 the FDA issued a warning about Atri Ajo King containing diclofenac, which was not listed in the product label [22]. In April 2022 the FDA expanded its warning, advising consumers to avoid all Artri and Ortiga products after the FDA found these products contained dexamethasone and diclofenac [23]. In October 2022 the FDA issued warning letters to Amazon, Walmart, and Latin Foods market for distributing Artri and Ortiga products [24].

Many supplements are not regulated by the government and may contain hidden ingredients such as glucocorticoids. In these cases further evaluation of suspected products [25], medications [16], and patient serum [26] and urine [6] utilizing techniques such as liquid chromatography may be used to confirm occult glucocorticoid exposure.

This case highlights the importance of educating patients to exercise caution when purchasing health products both online and abroad. Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products.

4. Conclusion

Although the most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer, it is a relatively uncommon complication of pulmonary neoplasms.

Exogenous Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing. Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography. This case report emphasizes the importance of teaching patients to be vigilant and appropriately research their health supplements.

Patient consent

Formal informed consent was obtained from the patient for publication of this case report.

Declaration of competing interest

The authors (Tomas Morales and Shanika Samarasinghe) of this case report declare that they have no financial conflicts of interest. Shanika Samrasinghe is an editorial member of the Journal of Clinical and Translational Endocrinology: Case Reports, and declares that she was not involved in the peer review and editorial decision making process for the publishing of this article.

References

Filed under: Cancer, Cushing's, Rare Diseases | Tagged: , , , , , , , | Leave a comment »

Dexamethasone Suppression for 18F-FDG PET/CT to Localize ACTH-Secreting Pituitary Tumors

Posted on September 26, 2023 by MaryO

Abstract

Background

18Fluorine-Fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) is widely used for diagnosing various malignant tumors and evaluating metabolic activities. Although the usefulness of 18F-FDG PET has been reported in several endocrine diseases, studies on pituitary disease are extremely limited. To evaluate whether dexamethasone (DEX) suppression can improve 18F-FDG PET for the localization of adrenocorticotropic hormone-secreting adenomas in the pituitary gland in Cushing’s disease (CD).

Methods

We included 22 patients with CD who underwent PET imaging before and after DEX administration. We compared the success rates of PET before and after DEX suppression, magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus sampling (BIPSS). We determined the final locations of adenomas based on intraoperative multiple-staged resection and tumor tissue identification using frozen sections. Standardized uptake value (SUV) were analyzed to confirm the change of intensity of adenomas on PET.

Results

Twenty-two patients were included (age at diagnosis: 37 [13–56] years), and most were women (90.91%). Pituitary adenomas compared to normal pituitaries showed increased maximum SUV after DEX suppression but without statistical significance (1.13 versus. 1.21, z=-0.765, P = 0.444). After DEX suppression, the mean and maximum SUV of adenomas showed a positive correlation with nadir cortisol levels in high-dose DEX suppression test (Rho = 0.554, P = 0.007 and Rho = 0.503, P = 0.017, respectively). In reference sites, mean SUV of cerebellum was significantly decreased (7.65 vs. 6.40, P = 0.006*), but those of the thalamus and gray matter was increased after DEX suppression (thalamus, 8.70 vs. 11.20, P = 0.010*; gray matter, 6.25 vs. 7.95, P = 0.010*).

Conclusion

DEX suppression did not improve 18F-FDG PET/CT localization in patients with CD.

Introduction

Cushing’s disease (CD) is a rare endocrine disease that results from chronic exposure to high cortisol levels because of adrenocorticotropic hormone (ACTH)-secreting pituitary tumors and is associated with increased morbidity and mortality. It represents approximately 80% of all cases of endogenous hypercortisolism [1,2,3]. Accurate localization of primary lesions in CD leads to improved remission rates and reduced adverse events following surgery [4, 5]. A biochemical remission rate of 90–100% has been reported when tumors are localized before surgery, but it can decrease to 50–60% when surgery is performed when the location of the tumor is unknown in patients with CD [6,7,8].

Currently, magnetic resonance imaging (MRI) is the gold standard for detecting pituitary adenomas. Nevertheless, modern MRI modalities, including dynamic or volumetric sequences, can reliably detect corticotrophic adenomas in 50–90% cases of CD [9,10,11,12]. This indicates that complementary imaging strategies are required to improve the localization of primary lesions in CD.

One of the most characteristic features of corticotrophic adenomas is a compromised response to negative glucocorticoid feedback, which defines glucocorticoid resistance [13]. ACTH activates the adrenal glands to synthesize and secrete cortisol, which in turn negatively modulates the release of ACTH from the pituitary gland and corticotrophin-releasing hormone (CRH) and vasopressin from the hypothalamus [1]. In CD, a corticotrophic tumor is only partially sensitive to the inhibitory feedback exerted by cortisol, which in turn is not regulating its own production and secretion of ACTH, resulting in both excessive ACTH and cortisol levels. Glucocorticoid resistance is caused by multiple factors including glucocorticoid receptor availability, splice variant expression and affinity, and imbalanced glucocorticoid receptor signaling [14, 15].

Radioactive 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) often demonstrates increased fluorodeoxyglucose (FDG) uptake in nonfunctioning and hormone-secreting pituitary adenomas [16,17,18]. In large observational studies of whole-body 18F-FDG positron emission tomography (PET) scans, incidental sellar 18F-FDG uptake was found in < 1% of cases, and this sign is highly specific for pituitary adenomas [19,20,21]. 18F-FDG PET imaging can detect up to 40% of corticotropinomas, some as small as 3 mm, and the rate of PET detection of corticotropinomas can be increased by CRH stimulation [9, 22].

Here, we evaluated whether DEX suppression could improve the localization of ACTH-secreting adenomas using 18F-FDG PET/CT in patients with CD. The rationale for this is as follows. FDG uptake of corticotrophic adenomas is less suppressed than that of normal pituitary glands after DEX suppression due to glucocorticosteroid resistance.

Materials and methods

Study design and population

In this retrospective cohort study, we enrolled all patients with CD who underwent two rounds of 18F-FDG-PET/CT before and after 8-mg DEX suppression and pituitary MRI before surgery. Total 22 patients were included in this study, of which thirteen had bilateral inferior petrosal sinus sampling (BIPSS) results. All patients were diagnosed with CD by staff of the Department of Endocrinology and/or Neurosurgery at Severance Hospital between 2014 and 2015. The diagnosis of CD was confirmed based on biochemical test results, including the cortisol, 24-hour urine free cortisol (24 h UFC), and serum ACTH levels, overnight dexamethasone suppression test (ON DST) results, and high-dose dexamethasone suppression test (HD DST) results.

Immediate remission was defined as hypocortisolism (serum cortisol level < 1.8 µg/dL) within the first 7 days after surgery. Delayed remission was defined as the achievement of hypocortisolism within 6 months, although immediate remission was not confirmed. If patients showed elevated postoperative cortisol levels and needed additional treatment within 6 months after surgery, we defined them as having persistent disease [23,24,25].

A serum cortisol concentration > 1.8 µg/dL for 8 h in the morning after 1 mg of DEX was given at midnight was considered to be a positive result in the ON DST [26]. Suppression of the serum cortisol level by > 50% for 6 h after 2 mg of DEX was administered for 2 days was defined as the suppression on the HD DST [26]. The final diagnosis was confirmed using surgical pathology and clinical follow-up.

Endocrinological evaluation

All laboratory analyses were performed at the Department of Laboratory Medicine, Severance Hospital. Preoperative cortisol and 24 h UFC were measured by chemiluminescence immunoassay using an automated UniCel DXC880i Synchron analyzer (Beckman Coulter, Pasadena, CA, USA; coefficient of variation [CV] ± 15 nmol/L at < 100 nmol/L and ± 15% at > 100 nmol/L). Preoperative ACTH levels were analyzed by electrochemiluminescence immunoassay using the Roche Cobas 6000 analyzer (Roche Diagnostics GmbH, Mannheim, Germany; CV ± 2.0 pmol/L at < 20 pmol/L and ± 10% at > 20 pmol/L).

The serum cortisol concentration at 8:00 am the following day after 1 mg of DEX was administered at midnight was considered positive on the ON DST. We determined the result as “suppression” by the cortisol level of < 1.8 µg/dL. A serum cortisol level suppressed by > 50% of the original level after 6 hourly administrations of 2 mg of DEX for 48 h was defined as suppression on the HD DST [27].

18F-FDG PET/CT evaluation

PET/CT was performed using a GEADVANCE PET scanner (GE, Milwaukee, WI, USA) after the intravenous injection of 7–9 mCi of 18F-FDG. All patients fasted for at least 6 h before the test. Emission scanning was continued for 15 min (4.25-mm axial spatial resolution, 4.8-mm transaxial spatial resolution). Transmission scans were performed for 8 min using triple Ge-68 rod sources to correct attenuation. Gathered data were reconstructed in a 128 × 128 × 35 matrix with a pixel size of 1.95 × 1.95 × 4.25 mm by means of a filtered back-projection algorithm employing a transaxial 8.5-mm Hanning filter and 8.5-mm axial ramp filter. Two specialists independently interpreted the encoded baseline PET images, and after a two-week period, they interpreted the encoded post DEX suppression PET images. Each specialist was blinded to MRI imaging, clinical characteristics, and surgical outcomes of these subjects. Each was tasked with determining whether the PET image indicated a “negative” or “positive” result for pituitary adenoma and its location on a high-resolution computer screen.

The scan after DEX suppression was performed 24 h after the oral administration of 8 mg of DEX using the same procedures as for the baseline PET/CT scan.

18F-FDG uptake analysis

The Region of interest (ROI) was drawn using MIM software (version 6.5, Software INc., Cleveland, OH, USA) (Fig. 1). PET images were reviewed by experienced by an experienced specialist. The pituitary gland was identified and a circular ROI was drawn. A fixed ROI with a 3-mm diameter was used for all patients. The ROI was placed on the lesion with the highest FDG uptake. If there was no significantly increased FDG uptake, the same sized circular ROI was drawn on the suspected adenoma location. For the normal pituitary gland, the same sized 3 mm ROI was used.

Fig. 1

figure 1

Images of ROI for pituitary adenoma on18F-FDG PET scan

Example of ROI definition in pituitary adenomas of 18F-FDG PET scan of the patients with CD. We draw the fixed circular ROI with a 3-mm diameter for pituitary adenomas (red circle) and normal pituitary gland (green circle)

ROI, Reason of interest; 18F-FDG PET, 18 F-fluorodeoxyglucose positron emission tomography; CD, Cushing disease

The mean standardized uptake value (SUVmean) and maximum SUV (SUVmax) for pituitary adenomas and normal pituitary glands were automatically measured using MIM, version 6.5 (Software Inc., Cleveland, OH, USA). The standardized uptake value (SUV) of the volume of interest was calculated as follows: (decoy-corrected activity (kBq) / volume (mL)) / (injected dose (kBq) / body weight (g)).

SUVmean and SUVmax of pituitary adenomas were divided into the SUVmean of normal pituitary glands for adjustment. We used the ratio of SUVmax to SUVmean to analyze the homogeneity of the pituitary adenomas.

MRI evaluation

All patients underwent pituitary MRI with a 3.0-Tesla scanner (Achieva, Philips Medical Systems, Best, the Netherlands). Imaging protocols included T1-weighted imaging, T2-weighted imaging, and delayed gadolinium-enhanced T1-weighted imaging. The extent, location, and sizes of the pituitary tumors were reviewed based on official records determined by radiologists.

Pituitary tumors were classified based on radiological findings using MRI of the sellar and parasellar regions. Type I refers to tumors < 1 cm in diameter limited to the sella. Type II tumors extend into the suprasellar space, < 1 cm from the diaphragm. Type III includes tumors extending into the suprasellar space > 1 cm from the diaphragm or sphenoid sinus and encroaching on the internal carotid arteries. Lastly, type IV refers to adenomas with obvious invasion into the cavernous sinus, as shown on MRI, and into the medial dural wall of the cavernous sinus, as confirmed during surgery.

BIPSS

Before surgery, BIPSS was performed to confirm the cause of CD and lateralize the tumors. A catheter was placed in patients using a unilateral femoral venous approach and 3 cc of blood was collected from the peripheral (P) and both inferior petrosal sinuses (IPS) [28]. CRH at a dose of 1 µg/kg was administered, and peripheral and petrosal samples were drawn after 5 and 10 min, respectively. The catheters and sheath were removed, and the groin was compressed under pressure until venous hemostasis was achieved.

The IPS:P prolactin ratio was calculated at each time point to confirm the accuracy of the inferior petrosal venous sampling. A value of ≥1.8 was considered successful IPS catheterization. The prolactin-normalized ACTH ratio was calculated by dividing the dominant ACTH IPS:P ratio by the concurrent and ipsilateral IPS:P prolactin ratio. A value of ≥1.3 was considered diagnostic of CD. An intersinus ACTH ratio of ≥1.4 either at baseline or after stimulation was used for lateralization of the pituitary adenoma [29].

Location of the adenoma

The final assignment of the true location of the pituitary adenoma was based on intraoperative multiple stage resection and tumor tissue identification using frozen sections. Surgically identified adenomas were histologically evaluated and stained for ACTH immunoreactivity. In cases of multiple specimens obtained during the procedure, the true location of the adenoma was assigned based on the original site of the specimen containing the adenoma [30].

Statistical analysis

Data are presented as medians (ranges) or numbers (percentages). The baseline characteristics of the patients were compared using Kruskal–Wallis’ test with Dunn’s procedure for nonparametric continuous variables. Categorical variables were compared using Fisher’s exact test. Spearman’s correlation coefficients were used to determine the correlation between FDG uptake and hormone levels. Wilcoxon’s signed-rank test was used to identify changes in the SUV after DEX administration.

The interobserver agreement for image analysis was assessed using κ statistics. κ values were categorized as follows: κ < 0.20 indicated poor agreement, κ of 0.21–0.40 indicated fair agreement, κ of 0.41–0.60 indicated moderate agreement, κ of 0.61–0.80 indicated good agreement, and κ > 0.81 indicated excellent agreement [31].

Statistical significance was set at a two-sided P < 0.05. All statistical analyses were performed using SPSS software (IBM Corp., Armonk, NY, USA).

Results

Patient characteristics

We enrolled all patients with CD who underwent two rounds of the 18F-FDG PET/CT with or without DEX suppression and sellar MRI before transsphenoidal adenectomy (TSA). Twenty-two patients were included (age at diagnosis: 37 [13–56] years), and most were women (90.91%). Patients’ baseline characteristics are shown in Table 1. There were 16 microadenomas and 6 macroadenomas. Immediate remission was achieved in 81.82% of the patients and delayed remission in 13.64%; one patient showed persistent disease after TSA. The median preoperative 24 h UFC, serum ACTH, and cortisol levels were 443.35 (93.00–4452.00) µg/day, 36.16 (6.00–92.00) pg/mL, and 18.55 (6.00–40.00) µg/dL. The size of pituitary adenomas on MRI was 7.85 (2.00–28.00) mm. The Ki-67 index of 47.06% of adenomas ranged from 1 to 2, that of 35.29% was below 1, and that of 17.65% was 2 or higher. Overall, 75.00% of the adenomas were classified as Knosp grade 0, 5.00% as grade 1, 5.00% as grade 3b, and 15.00% as grade 4. In total, 77.27% (17/22) of patients had an ACTH-staining adenoma. Only one patient showed unsuppressed cortisol levels on the HD DST.

Table 1 Patients’ imaging and clinical characteristics

MRI negative but PET positive case

Two patients showed negative MRI results, and one of them showed FDG uptakes on both 18F-FDG PET scans at baseline and after DEX suppression. A 26-year-old man visited our hospital complaining of weight gain and was diagnosed with ACTH-dependent CD. Cortisol secretion was suppressed on the HD DST; however, sellar MRI did not reveal any suspicious lesions. BIPSS revealed a central tumor (central/peripheral ACTH level of 36.25 after CRH stimulation) lateralized to the right side of the pituitary gland. The patient underwent 18F-FDG-PET/CT before and after DEX suppression to identify the primary lesions. Baseline PET/CT showed diffused FDG uptake with an SUVmax of 1.03 at the pituitary fossa but failed to localize the tumor. After DEX treatment, focal FDG uptake with an SUVmax of 1.06 remained at the right side of the pituitary fossa, which resulted in the successful localization of the corticotrophic adenoma. The MRI and PET/CT images of this case are presented in Fig. 2A–C. During TSA, the surgeon identified solid tumor-like tissues on the right side of the pituitary gland and successfully removed them. Results of pathology and ACTH immunohistochemistry were negative, but the patient achieved immediate biochemical remission and CD-related symptoms were relieved after surgery. We followed the patient for 98 months after the surgery and confirmed that he had lived without recurrence.

Fig. 2

figure 2

Images of a corticotroph with negative MRI but positive18 F-FDG PET/CT after DEX suppression

An MRI-negative adenoma was detected on 18F-FDG PET/CT at baseline and after DEX suppression. In this patient, the pituitary adenoma was visible on PET scans at baseline (B) and after DEX suppression (C) at the same location, as confirmed by the surgeon

A. Co-registered baseline 18F-FDG PET/CT and MRI images. Diffuse 18F-FDG uptake is detected in the pituitary fossa with an SUVmean of 0.86 and SUVmax of 1.03, but there was failure to localize the adenoma on baseline 18F-FDG PET/CT.

B. Co-registered 18F-FDG PET/CT and MRI images after DEX suppression. 18F-FDG uptake is not suppressed in the right side of the pituitary gland with an SUVmean of 1.03 and SUVmax of 1.06. 18F-FDG PET/CT after DEX suppression was successful in localizing the right-sided corticotrophic adenoma

C. MRI image. There is no suspicious lesion in the pituitary gland

ACTH, adrenocorticotropic hormone; MRI, magnetic resonance imaging; 18F-FDG, 18 F-fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography; DEX, dexamethasone; SUVmean, mean standardized uptake value; SUVmax, maximum standardized uptake value

Change of 18F-FDG uptake after DEX suppression

We included 18 pituitary adenomas that were successfully localized using PET/CT after DEX suppression, and analyzed the change of SUV for 15 adenomas, excluding outliers with SUV over 2.00. The results are presented in Fig. 3A and B. The SUVmean of adenomas did not changed after DEX suppression compared to normal pituitary glands (SUVmean of adenoma/SUVmean of normal pituitary glands: 1.13 [0.85–1.35] vs. 1.14 [0.87–1.39], z=-1.288, P = 0.198). DEX suppression increased SUVmax of adenomas compared to normal pituitary glands but without statistical significance (SUVmax of adenoma/SUVmean of normal pituitary glands: 1.13 [0.96–1.52] vs. 1.21 [0.97–1.56], z=-0.765, P = 0.444).

Fig. 3

figure 3

Changes in the SUVs of corticotrophs between18F-FDG PET/CT before and after DEX suppression

The SUVmean (A) and SUVmax (B) of corticotrophic adenomas are shown in this pairwise analysis. The SUVmean did not changed after DEX suppression from (z=-1.288, P = 0.198). The SUVmax of the corticotrophic adenoma increased from 1.13 to 1.21 (z=-0.765, P = 0.444). In this analysis, the SUVmean and SUVmax of pituitary adenomas were adjusted using the SUVmean of the normal pituitary gland. Colored plots and bars presented median and interquartile range in this figure. We presented the tumors with size larger than 5 mm and SUV adjusted by normal pituitary>1 for blue line

SUVmean, mean standardized uptake value; SUVmax, maximum standardized uptake value; DEX, dexamethasone; 18F-FDG, 18 F-fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography

In Fig. 3, the blue line indicates change in SUV of adenomas larger than 5 mm with higher FDG uptake than the surrounding pituitary parenchyma. For these adenomas, DEX suppression did not change the SUV (SUVmean of adenoma/SUVmean of normal pituitary glands: 1.31 [1.04–2.52] vs. 1.33 [1.05–2.38], z=-0.784, P = 0.433; SUVmax of adenoma/SUVmean of normal pituitary glands: 1.36 [1.02–2.61] vs. 1.40 [1.03–2.65], z=-1.022, P = 0.307).

The value of SUV increased in 73.33% adenomas, while the SUVmax increased in 66.67% compared with normal pituitary glands after DEX treatment.

Correlation between the hormone level and 18F-FDG uptake

Table 2 shows the results of the Spearman correlation analysis of the SUV with preoperative cortisol, ACTH, and nadir cortisol levels on the HD DST. On the baseline 18F-FDG PET scan, the SUVmax of the adenomas did not show any correlation with the levels of three hormones. The SUVmean of adenomas showed a positive correlation with nadir cortisol levels on the HD DST (P = 0.014) and preoperative ACTH levels, with marginal significance (P = 0.062). After DEX suppression, the SUVmax and SUVmean of adenomas had a positive correlation with moderate degrees of nadir cortisol on the HD DST (SUVmax: Spearman Rho = 503, P = 0.017; SUVmean: Spearman Rho = 0.554, P = 0.007).

Table 2 Correlation between FDG uptakes and hormone levels

FDG uptake of reference sites after DEX suppression

We evaluated the FDG uptake for five types of reference areas (normal pituitary gland, cerebellum, thalamus, white matter, and gray matter) (Table 3). Normal pituitary gland and white matter did not affect the unadjusted SUVmean by DEX suppression (all P >0.05). DEX significantly increased SUVmean of the thalamus and gray matter (thalamus, 8.70 [4.40–22.70] vs. 11.20 [6.40–17.5], P = 0.010*; gray matter, 6.25 [2.50–15.00] vs. 7.95 [5.00–11.90], P = 0.010*). However, SUVmean of the cerebellum significantly decreased after DEX administration (7.65 [4.50–10.80] vs. 6.40 [2.60–12.00], P = 0.006*).

Table 3 The change of FDG uptake for reference sites after DEX suppression in the patients with CD

Qualitative analysis by diagnostic modalities for CD

The qualitative results of localizing pituitary adenomas in CD patients are shown in Table 4 and Fig. 4. Only 13 patients had BIPSS results. The success rates were 90.91% for MRI and 84.62% for BIPSS.

Table 4 Qualitative analysis by diagnostic modalities for CD
Fig. 4

figure 4

Images for corticotroph adenomas that appear different for localization in18F-FDG PET/CT.

9 mm sized adenoma in the left lateral wing of pituitary gland. It was found in the left lateral wing of the pituitary gland, showing an 18F-FDG uptake in the pituitary fossa with an SUVmean of 1.04 and SUVmax of 1.07. However, after DEX suppression, the left side of the pituitary gland did not exhibit suppressed 18F-FDG uptake, with SUVmean 1.05 SUVmax 1.14

(A). Co-registered baseline 18F-FDG PET/CT and MRI images. (B). Co-registered 18F-FDG PET/CT and MRI images after DEX suppression. (C). MRI image

2 mm pituitary adenoma was detected at the left lateral wing, showing diffuse FDG uptake in the pituitary fossa with an SUVmean of 0.86 and SUVmax of 1.04. After DEX suppression, focal FDG uptake was observed, with SUVmean 0.87 and SUVmax 0.98. (D). Co-registered baseline 18F-FDG PET/CT and MRI images. (E). Co-registered 18F-FDG PET/CT and MRI images after DEX suppression. (F). MRI image

In baseline PET scans, the specialists agreed that pituitary adenomas were visible in 17 scans and not visible in 5 scans. They reached a consensus that the tumor was evident in two scans, but there was a discrepancy in their assessments of its location.

After DEX suppression, pituitary adenomas showed positive results in 16 scans and negative results in 5 scans. Specialists disagreed on the presence of pituitary adenomas in one case only.

Interobserver agreement for localizing adenomas was 0.872 (95%CI: 0.711, 1.033) for baseline PET/CT and 0.938 (95%CI: 0.762, 1.056) for post dexamethasone suppression PET/CT, confirming excellent interobserver agreements, and the result was judged reliable. Among the instances where both opinions agreed, there were no lesions that showed differences in visibility between scans before and after DEX administration. This meant that lesions were either consistently visible or invisible in both scenarios.

Discussion

We found that DEX suppression did not improve localization of ACTH-secreting pituitary adenomas using 18F-FDG PET/CT. Further, it did not significantly affect FDG uptakes in adrenocorticotrophic adenomas or normal pituitaries in patients with CD. The decision to administer 8 mg dexamethasone was based on the standard high-dose DST, which is internationally recommended for differentiating between ectopic ACTH secretion and CD [26]. This test involved comparing serum cortisol levels at 8 am before and after a single dose of 8 mg dexamethasone administered at 11 pm. Suppression of the serum cortisol level to less than 50% of the baseline value indicated a diagnosis of CD [32, 33]. Previous studies have reported that the 8-mg DST has a sensitivity of 90%, specificity of 100%, accuracy of 96.8%, positive predictive value of 100%, and negative predictive value of 95.5% [34, 35]. Our use of 8 mg dexamethasone was based on the theory that orally administering dexamethasone at this dose can effectively suppress cortisol levels in ACTH-secreting pituitary tumors.

We expected that FDG uptake by corticotrophic adenomas would not decrease after DEX administration in patients with CD, and this change may improve the ability to discriminate the tumor location from surrounding tissues on 18F-FDG PET. The SUVmax of pituitary adenomas adjusted for the normal pituitary gland increased from 1.13 to 1.21. However, this change was not statistically significant, and the success rate of localizing corticotrophic adenomas using 18F-FDG PET was not significantly improved after DEX suppression. If the FDG uptake of adenomas changed lesser compared to that of surrounding normal tissues after DEX suppression, the tumor could be more easily visualized because of the difference.

In addition, we attempted to evaluate FDG uptakes in other brain areas (cerebellum, thalamus, white matter, and gray matter) according to DEX administration in CD patients. SUVmean of the cerebellum decreased significantly, but that of the thalamus and gray matter increased after DEX suppression. DEX did not change FDG uptake in pituitary adenoma, normal pituitary, or white matter. In a previous study analyzing FDG PET in CD patients, researchers observed varying correlations between FDG uptake and blood cortisol concentration across different brain regions [35, 36]. Nevertheless, the examination did not include an analysis of FDG uptake in the pituitary gland. Additionally, no previous studies have explored the effects of high-dose dexamethasone suppression on brain glucose metabolism in individuals with CD. Further studies are needed to explain the change in FDG uptake after DEX administration in patients with CD.

18F-FDG PET/CT provides information regarding glucose metabolism in the brain in vivo and has been widely used to evaluate brain metabolism in clinical and research settings [37]. Here, the nadir cortisol level on the HD DST correlated with the SUVmean and SUVmax of pituitary adenomas on PET scans after DEX suppression. Cortisol secretion activity is thought to be associated with metabolic activity, and DEX administration altered this. Cortisol levels and FDG uptake in other regions of the brain are correlated in patients with CD, but the correlation between cortisol and FDG uptake in the pituitary glands and/or corticotrophic adenomas themselves has not been discussed [35, 36]. In our study, cortisol levels did not show a correlation with FDG uptake of corticotrophic adenomas, but after DEX suppression FDG uptake showed a correlation with the nadir cortisol level on the HD DST. This indicated that tumors in which cortisol secretion was less suppressed by on the HD DST showed higher FDG uptake than tumors with lower cortisol levels on the HD DST.

Although many studies have analyzed FDG uptake of brain tumors, reference sites defined in each study varied without a uniform standard. Gray matter, white matter, or adjacent tumor tissue was defined as a reference site [38,39,40]. We measured SUVmean of normal pituitary tissues, gray matter, white matter, thalamus, and cerebellum as possible references. We defined the SUVmean of normal pituitary tissues as a reference because the localization of adenomas requires an apparent difference between the adenoma and surrounding tissues.

Use of fixed ROI to measure FDG uptake caused partial volume effect in this study. However, lesions smaller than 5 mm with intense FDG uptake may still show increased FDG uptake, especially in tumors, albeit with lower SUV values compared with the actual values [41]. This study was performed because pituitary adenomas smaller than 5 mm with higher FDG uptake than the surrounding pituitary parenchyma have been observed in routine clinical practice. To control for the partial volume effect, the analysis was performed again for tumors which were larger than 5 mm and had higher FDG uptake than the surrounding pituitary parenchyma, and the results remained unchanged.

PET/CT has been explored as an alternative to or combined with MRI for the localization of corticotrophic adenomas. 18F-FDG PET/CT has a limited role in CD diagnosis, but CRH stimulation can increase its success rate [22, 42]. This study is important for increasing the effectiveness of PET using DEX. In addition, data on DEX effect on brain metabolism in patients with CD will be important for future studies.

Conclusions

DEX suppression did not improve the localization of 18F-FDG PET/CT in patients with CD. This is considered to have sufficient significance in an effort to increase the diagnostic value of 18F-FDG PET/CT.

Data Availability

All datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.

Abbreviations

18F-FDG:
18F-fluorodeoxyglucose
PET/CT:
Positron emission tomography/computed tomography
DEX:
Dexamethasone
MRI:
Magnetic resonance imaging
BIPSS:
Bilateral inferior petrosal sinus sampling
CD:
Cushing’s disease
SUV:
Standardized uptake value
ACTH:
Adrenocorticotropic hormone
CRH:
Corticotrophin-releasing hormone
FDG:
Fluorodeoxyglucose
24hr UFC:
24-hour urine free cortisol
ON DST:
Overnight dexamethasone suppression test
HD DST:
High-dose dexamethasone suppression test
SUVmean :
Mean standardized uptake value
SUVmax :
Maximum standardized uptake value
P:
Peripheral
IPS:
Inferior petrosal sinuses
TSA:
Transsphenoidal adenectomy

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    Acknowledgements

    We would like to thank Editage (www.editage.co.kr) for English language editing.

    Funding

    The study was supported by the “Team Science Award” of Yonsei University College of Medicine (6-2022-0150).

    Author information

    Authors and Affiliations

    1. Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

      Kyungwon Kim, Cheol Ryong Ku & Eun Jig Lee

    2. Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

      Dong Kyu Kim

    3. Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

      Ju Hyung Moon, Eui Hyun Kim & Sun Ho Kim

    Contributions

    Conception and design: EJL, CRK, KK. Acquisition of data: KK, DKK. Analysis and interpretation of data: KK. Drafting the article: KK. Administrative/technical/material support: JHM, EHK, SHK. Study supervision: EJL, CRK. Writing, review, and revision of the manuscript: KK, DKK, SHK, CRK. Final approval of the manuscript: CRK, EJL.

    Corresponding authors

    Correspondence to Cheol Ryong Ku or Eun Jig Lee.

    Ethics declarations

    Ethics approval and consent to participate

    The data were collected under the conditions of regular clinical care with approval from the ethics committee of our hospital, and the requirement for written informed consent was waived owing to its retrospective design (institutional review board number: 2023-0110-001).

    Consent for publication

    Not applicable.

    Competing interests

    The authors declare no conflicts of interest that could be perceived as prejudicing the impartiality of this study.

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    Electronic supplementary material

    Additional file 1 of Dexamethasone suppression for 18F-FDG PET/CT to localize ACTH-secreting pituitary tumors

    Additional file 1

    Below is the link to the electronic supplementary material.

    Cite this article

    Kim, K., Kim, D.K., Moon, J.H. et al. Dexamethasone suppression for 18F-FDG PET/CT to localize ACTH-secreting pituitary tumors. Cancer Imaging 23, 85 (2023). https://doi.org/10.1186/s40644-023-00600-8

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    Keywords

    • 18F-FDG PET/CT
    • ACTH-secreting pituitary tumor
    • Cushing’s disease
    • Dexamethasone suppression
    • High-dose dexamethasone suppression test

    From https://cancerimagingjournal.biomedcentral.com/articles/10.1186/s40644-023-00600-8

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Cushing Syndrome Caused by an Ectopic ACTH-Producing Pituitary Adenoma of the Clivus Region

Posted on July 10, 2023 by MaryO

Abstract

Rationale:

Ectopic ACTH–producing pituitary adenoma (EAPA) of the clivus region is extraordinarily infrequent condition and merely a few reports have been reported to date.

Patient concerns:

The patient was a 53-year-old woman who presented with Cushing-like appearances and a soft tissue mass in the clivus region.

Diagnoses:

The final diagnosis of clivus region EAPA was established by clinical, radiological and histopathological findings.

Interventions:

The patient underwent gross total clivus tumor resection via transsphenoidal endoscopy.

Outcomes:

Half a year after surgery, the patient Cushing-like clinical manifestations improved significantly, and urinary free cortisol and serum adrenocorticotropin (ACTH) returned to normal.

Lessons:

Given the extreme scarcity of these tumors and their unique clinical presentations, it may be possible to misdiagnose and delayed treatment. Accordingly, it is especially crucial to summarize such lesions through our present case and review the literature for their precise diagnosis and the selection of optimal treatment strategies.

1. Introduction

Pituitary adenoma arises from the anterior pituitary cells and is the commonest tumor of the sellar region.[1] It makes up approximately 10% to 15% of all intracranial tumors.[2] Ectopic pituitary adenoma (EPA) is defined as a pituitary adenoma that occurs outside the sellar area and has no direct connection to normal pituitary tissue.[3] The most frequent sites of EPA are the sphenoid sinus and suprasellar region, and much less frequent sites including the clivus region, cavernous sinus, and nasopharynx.[4]

Hypercortisolism and the series of symptoms it leads to is termed Cushing syndrome (CS).[5] CS is classified into adrenocorticotropin (ACTH)-dependent and ACTH-independent CS depending on the cause, accounting for 80% to 85% and 15% to 20% of cases, respectively.[6] Pituitary adenoma accounts for ACTH-dependent CS 75% to 80%, while ectopic ACTH secretion accounts for the remaining 15% to 20%.[7] Ectopic CS is a very rare disorder of CS caused by an ACTH-secreting tumor outside the pituitary or adrenal gland.[8] It has been reported that ectopic ACTH–producing pituitary adenoma (EAPA) can occur in the sphenoid sinus, cavernous sinus, clivus, and suprasellar region,[9] with EAPA in the clivus region being extremely rare, and merely 6 cases have been reported in the English literature (Table 1).[10–15] Furthermore, as summarized in the Table 1, EAPA in the clivus area has unique symptoms, which may lead to misdiagnosis as well as delay in treatment. Therefore, we herein described a case of CS from an EAPA of the clivus region and reviewed relevant literature for the purpose of further understanding this extraordinarily unusual condition.

Table 1 – Literature review of cases of primary clival ectopic ACTH–producing pituitary adenoma (including the current case).

Reference Age (yr)/sex Symptoms Imaging findings Maximum tumor diameter (mm) Preoperative elevated hormone IHC Surgery RT Follow-up (mo) Outcome
Ortiz et al 1975[10] 15/F NA NA NA NA NA Right transfrontal craniotomy, NA Yes NA Symptomatic relief
Anand et al 1993[11] 58/F Anosphrasia, blurred vision, occasional left frontal headache, Routine radiographic evaluation revealed a clival tumor and nasopharyngeal mass with bone erosion. MRI demonstrated a Midline homogeneous mass. 30 ACTH ACTH in a few isolated cells Maxillotomy approach, GTR Yes 12 Symptomatic relief
Pluta et al 1999[12] 20/F Cushing syndrome MRI revealed a hypodense contrast-enhancing lesion. NA ACTH ACTH Transsphenoidal surgery, GTR No 18 Symptomatic relief
Shah et al 2011[13] 64/M Facial paresthesias, myalgias, decreased muscle strength, and fatigue CT imaging showed a clival mass. 21 ACTH ACTH NA, GTR No 7 Symptomatic relief
Aftab et al 2021[14] 62/F Transient unilateral visual loss MRI showed a T2 heterogeneously enhancing hyperintense lesion. 21 No ACTH Transsphenoidal resection, GTR NO 6 Symptomatic relief
Li et al 2023[15] 47/F Bloody nasal discharge, dizziness and headache CT revealed an ill-defined mass eroding the adjacent bone. MRI T1 showed a heterogeneous mass with hypointensity, hyperintensity on T2-weighted images and isointensity on diffusion-weighted images. 58 NA ACTH Transsphenoidal endoscopy, STR Yes 2 Symptomatic relief
Current case 53/F Headache, and dizziness, Cushing syndrome CT demonstrated bone destruction and a soft tissue mass. MRI T1 revealed irregular isointense signal, and MRI T2 showed isointense signal/slightly high signal. 46 ACTH ACTH Transsphenoidal endoscopy, GTR NO 6 Symptomatic relief
ACTH = adrenocorticotropin, CT = computed tomography, GTR = gross total resection, IHC = immunohistochemistry, MRI = magnetic resonance imaging, NA = not available, RT = radiotherapy, STR = subtotal resection.

2. Case presentation

A 53-year-old female presented to endocrinology clinic of our hospital with headache and dizziness for 2 years and aggravated for 1 week. Her past medical history was hypertension, with blood pressure as high as 180/100 mm Hg. Her antihypertensive medications included amlodipine besylate, benazepril hydrochloride, and metoprolol tartrate, and she felt her blood pressure was well controlled. In addition, she suffered a fracture of the thoracic vertebrae 3 month ago; and bilateral rib fractures 1 month ago. Physical examination revealed that the patient presented classical Cushing-like appearances, including moon face and supraclavicular and back fat pads, and centripetal obesity (body mass index, 25.54 kg/m2) with hypertension (blood pressure, 160/85 mm Hg).

Laboratory studies revealed high urinary free cortisol levels at 962.16 µg/24 hours (reference range, 50–437 µg/24 hours) and absence of circadian cortisol rhythm (F [0am] 33.14 µg/dL, F [8am] 33.52 µg/dL, F [4pm] 33.3 µg/dL). ACTH levels were elevated at 90.8 pg/mL (reference range, <46 pg/mL). The patient low-dose dexamethasone suppression test demonstrated the existence of endogenous hypercortisolism. High-dose dexamethasone suppression test results revealed that serum cortisol levels were suppressed by <50%, suggesting the possibility of ectopic ACTH-dependent CS. Serum luteinizing hormone and serum follicle stimulating hormone were at low levels, <0.07 IU/L (reference range, 15.9–54.0 IU/L) and 2.57 IU/L (reference range, 23.0–116.3 IU/L), respectively. Insulin-like growth factor-1, growth hormone (GH), prolactin (PRL), thyroid stimulating hormone, testosterone, progesterone and estradiol test results are all normal. Oral glucose tolerance test showed fasting glucose of 6.3 mmol/L and 2-hour glucose of 18.72 mmol/L; glycosylated hemoglobin (HbA1c) was 7.1%. Serum potassium fluctuated in the range of 3.14 to 3.38 mmol/L (reference range, 3.5–5.5 mmol/L), indicating mild hypokalemia.

High-resolution computed tomography (CT) scan of the sinuses revealed osteolytic bone destruction of the occipital clivus and a soft tissue mass measuring 20 mm × 30 mm × 46 mm (Fig. 1A). The mass filled the bilateral sphenoid sinuses and involved the cavernous sinuses, but the pituitary was normal. Cranial MR scan showed the T1W1 isointense signal and the T2W1 isointense signal/slightly high signal in the sphenoid sinus and saddle area (Fig. 1B–D). Bone density test indicated osteoporosis.

F1
Figure 1.: 

Radiological findings. (A) CT demonstrated bone destruction and a soft tissue mass on the occipital clivus (white arrow). (B) Axial view of the MR T1 revealed irregular isointense signal in the sphenoid sinus and saddle area (white arrow). (C and D) Axial view and sagittal view of the MR T2 showed isointense signal/slightly high signal in the sphenoid sinus and saddle area (black arrow). CT = computed tomography.

Subsequently, the patient underwent gross total clivus tumor resection via transsphenoidal endoscopy. During surgery, the tumor was found to be light red in color with a medium texture, and the tumor tissue protruded into the sphenoidal sinus cavity and eroded the clival area. Histologically, the tumor cells were nested, with interstitially rich blood sinuses and organoid arrangement (Fig. 2A). The tumor cells were relatively uniform in size, with light red cytoplasm, delicate pepper salt-like chromatin, and visible nucleoli (Fig. 2B). In addition, mitosis of tumor cells was extremely rare. Immunohistochemically, the neoplasm cells were diffuse positive for CK (Fig. 2C), CgA (Fig. 2D), ACTH (Fig. 2E), Syn and CAM5.2, with low Ki-67 labeling index (<1%) (Fig. 2F). Simultaneously, all other pituitary hormone markers like GH, thyroid stimulating hormone, PRL, luteinizing hormone, as well as follicle stimulating hormone were negatively expressed. On the basis of these medically historical, clinical, laboratorial, morphologic, and immunohistochemical findings, the final pathological diagnosis of an EAPA was established.

F2
Figure 2.: 

HE and immunohistochemical findings. (A) Histologic sections revealed morphologically homogeneous tumor cells in nests with a prominent and delicate vascularized stroma (H&E, × 200). (B) The tumor cells had fine chromatin with visible nuclei and rare mitoses (H&E, × 400). CK (C), CgA (D) and ACTH (E) immunohistochemically showed diffuse reactivity of the tumor cells (SP × 200). (F) The proliferation index is <1% on Ki-67 staining (SP × 200).

When evaluated 2 months after surgery, her Cushing-like characteristics had well improved, and her blood pressure was normal. Furthermore, her serum cortisol and ACTH returned to the normal levels. Six-month postoperative follow-up revealed that serum cortisol and ACTH were stable at normal levels, and no signs of tumor recurrence were detected on imaging.

3. Discussion

EAPA is defined as an ACTH-secreting ectopic adenoma located outside the ventricles, and has no continuity with the normal intrasellar pituitary gland.[9] ACTH promotes cortisol secretion by stimulating the adrenal cortical fasciculus. The clinical manifestations of hypercortisolism are diverse, and the severity is partly related to the duration of the cortisol increase.[8] Clival tumors are typically uncommon, accounting for 1% of all intracranial tumors. There are many differential diagnoses for clival lesions, including the most common chordoma (40%), meningioma, chondrosarcoma, astrocytoma, craniopharyngioma, germ cell tumors, non-Hodgkin lymphoma, melanoma, metastatic carcinoma, and rarely pituitary adenoma.[16] The commonest clival EPA is a PRL adenoma, followed by null cell adenoma, and the least common are ACTH adenoma and GH adenoma.[2] The clival EAPA is extremely unwonted, and only 6 other cases apart from ours have been reported in literature so far (Table 1).

The average age of the patients with these tumors was 48 years (range, 15–64 years). There was a obvious female predominance with a female-to-male prevalence ratio of 6:1. Only 2 patients (2/6, 33.3%) with reported clinical symptoms, including our patients, presented with overt clinical manifestations of CS. Compression of the mass on adjacent structures (e.g., nerves) may result in anosphrasia, visual impairment, headache, myalgias, decreased muscle strength, dizziness and facial sensory abnormalities. The diagnosis and localization of these tumors relied heavily on radiological imaging. Head MRI was the most basic method used for them detection, for localization adenomas and their invasion of surrounding structures to guide the choice of treatment and surgical options methods. Radiographic characteristics had been reported in 6 patients with EAPA in the clivus region. All of these patients (6/6, 100%) had initial positive findings of sellar MRI (or CT) identifying an ectopic adenoma before surgery. MR T1 was usually a low-intensity or isointense signal, while MR T2 was usually an isointense or slightly higher signal. The maximum diameter of the tumor was reported in 5 cases, with the mean maximum diameter was 35.2 mm (range, 21–55 mm) according to preoperative MRI and intraoperative observations. As summarized in Table 1, 4/5 clival EAPA cases secreted ACTH. Histologically, all cases (6/6, 100%) expressed ACTH scatteredly or diffusely.

The gold standard for the treatment of CS caused by EAPA was the surgical removal of EPA, which was essential to achieve remission and histological confirmation of the disease.[9] The most common method of EAPA resection in the clivus region was transsphenoidal sinus resection (4/6, 66.67%), followed by craniotomy (1/6, 16.67%) and maxillary osteotomy (1/6, 16.67%). Transsphenoidal endoscopic surgery allowed resection of the EAPA and manipulation of neurovascular structures and avoidance of cerebral atrophy, whereas craniotomy allowed full exposure of the suprasellar region, direct visualization or manipulation of the adenoma, and reduced the risk of postoperative CSF leak.[9] Both approaches had their advantages, and there was no consensus on which surgical approach was best for the treatment of EAPA in the slope area.[9] The choice of the best surgical approach was believed to be based on the condition of the adenoma, as well as the general condition of the patient and the experience of the surgeon.[9] As summarized in Table 1, most complete tumor resections were achieved regardless of the method chosen. A minority of patients underwent postoperative radiotherapy (3/7, 42.86%), and most of them had invasion of the surrounding bone tissue. All patients experienced effective postoperative relief of symptoms.

In summary, due to the rarity of this disorder, an accurate preoperative diagnosis of EAPA in the slope area is extremely challenging for the clinician or radiologist. The final precise diagnosis relies on a combination of clinical symptoms, imaging findings, histology and immunohistochemical markers. For this type of tumor, surgery is an effective treatment to relieve the clinical manifestations caused by tumor compression or hormonal secretion. The choice of postoperative adjuvant radiotherapy is mainly based on the presence of invasion of the surrounding bone tissue. Further cases may be necessary to summarize the clinical features of such lesions and to develop optimal treatment strategies.

Acknowledgments

We would like to thank the patient and her family.

Author contributions

Conceptualization: Yutao He.

Data curation: Ziyi Tang.

Formal analysis: Na Tang.

Methodology: Yu Lu, Fangfang Niu, Jiao Ye, Zheng Zhang, Chenghong Fang.

Writing – original draft: Yutao He.

Writing – review & editing: Yutao He, Lei Yao.

Abbreviations:

ACTH
adrenocorticotropin
CS
cushing syndrome
CT
computed tomography
EAPA
ectopic ACTH–producing pituitary adenoma
EPA
ectopic pituitary adenoma
GH
growth hormone
PRL
prolactin

References

[1]. Gittleman H, Ostrom QT, Farah PD, et al. Descriptive epidemiology of pituitary tumors in the United States, 2004-2009. J Neurosurg. 2014;121:527–35.

[2]. Karras CL, Abecassis IJ, Abecassis ZA, et al. Clival ectopic pituitary adenoma mimicking a Chordoma: case report and review of the literature. Case Rep Neurol Med. 2016;2016:8371697.

[3]. Bălaşa AF, Chinezu R, Teleanu DM, et al. Ectopic intracavernous corticotroph microadenoma: case report of an extremely rare pathology. Rom J Morphol Embryol. 2017;58:1447–51.

[4]. Zhu J, Wang Z, Zhang Y, et al. Ectopic pituitary adenomas: clinical features, diagnostic challenges and management. Pituitary. 2020;23:648–64.

[5]. Paleń-Tytko JE, Przybylik-Mazurek EM, Rzepka EJ, et al. Ectopic ACTH syndrome of different origin-diagnostic approach and clinical outcome. experience of one clinical centre. PLoS One. 2020;15:e0242679.

[6]. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281–93.

[7]. Aniszewski JP, Young WF Jr, Thompson GB, et al. Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg. 2001;25:934–40.

[8]. Mohib O, Papleux E, Remmelink M, et al. An ectopic Cushing’s syndrome as a cause of severe refractory hypokalemia in the ICU. Acta Clin Belg. 2021;76:373–8.

[9]. Sun X, Lu L, Feng M, et al. Cushing syndrome caused by ectopic adrenocorticotropic hormone-secreting pituitary adenomas: case report and literature review. World Neurosurg. 2020;142:75–86.

[10]. Ortiz-Suarez H, Erickson DL. Pituitary adenomas of adolescents. J Neurosurg. 1975;43:437–9.

[11]. Anand VK, Osborne CM, Harkey HL. Infiltrative clival pituitary adenoma of ectopic origin. Otolaryngol Head Neck Surg. 1993;108:178–83.

[12]. Pluta RM, Nieman L, Doppman JL, et al. Extrapituitary parasellar microadenoma in Cushing’s disease. J Clin Endocrinol Metab. 1999;84:2912–23.

[13]. Shah R, Schniederjan M, DelGaudio JM, et al. Visual vignette.s Ectopic ACTH-secreting pituitary adenoma. Endocr Pract. 2011;17:966.

[14]. Aftab HB, Gunay C, Dermesropian R, et al. “An Unexpected Pit” – ectopic pituitary adenoma. J Endocr Soc. 2021;5:A557–8.

[15]. Li Y, Zhu JG, Li QQ, et al. Ectopic invasive ACTH-secreting pituitary adenoma mimicking chordoma: a case report and literature review. BMC Neurol. 2023;23:81.

[16]. Wong K, Raisanen J, Taylor SL, et al. Pituitary adenoma as an unsuspected clival tumor. Am J Surg Pathol. 1995;19:900–3.

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Keywords:

clivus region; Cushing; Ectopic ACTH; like appearance; producing pituitary adenoma

From https://journals.lww.com/md-journal/Fulltext/2023/06230/Cushing_syndrome_caused_by_an_ectopic.32.aspx

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