OXFORD
ENDOCRINE SOCIETY
Hepatic embolization for Cushing syndrome from metastatic tumors: a single-center case series
Shuyao Zhang 1D1, Jorge Esteban Mosquera1, Clive Musonza2, Anil K. Pillai2, Jessica Abramowitz D1, , Sasan Mirfakhraee 1D1, Patricio M. Polanco3, Salwan Al Mutar4, Waddah Arafat4, and Oksana Hamidi D 1*
1Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
2Department of Radiology, Division of Vascular & Interventional Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
3Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
*Correspondence: Oksana Hamidi, DO, MSCS, Division of Endocrinology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA. Email: oksana.hamidi@utsouthwestern.edu.
Abstract
Background Cushing syndrome (CS) from metastatic adrenocortical carcinoma (ACC) or neuroendocrine tumors (NETs) presents a therapeutic challenge when surgery is not feasible. Liver-directed embolization, including bland transarterial embolization (TAE) and yttrium-90 (Y-90) radioembolization, may palliate hypercortisolism arising from hormonally active hepatic metastases.
Methods We conducted a retrospective single-center case series of 4 adult patients (≥18 years) with CS and liver-dominant metastatic ACC or NET who underwent hepatic embolization between 2015 and 2025. Inclusion criteria were: (1) confirmed CS based on standard biochemical testing, and (2) receipt of liver-directed embolization (TAE or Y-90) for hypercortisolism. Exclusion criteria were absence of pre- and postembolization hormonal data preventing biochemical assessment. The primary outcome was biochemical response within 14 days (≥50% reduction or normalization of morning cortisol). Secondary outcomes included duration of biochemical control, radiographic response (RECIST 1.1), and adverse events (CTCAE v5.0).
Results Four patients (2 ACC, 2 NET) underwent Y-90 (n = 1) or TAE (n = 3). All achieved significant cortisol; 2/4 normalized cortisol with transient adrenal insufficiency. The Y-90 patient had sustained remission, while 2 TAE patients achieved partial hormonal control enabling tapering of medical therapy. Radiographically, tumor burden stabilized or improved in most treated lesions. Embolization was well tolerated, with only 1 case of post-embolization syndrome and no procedure- related mortality. One patient died from disease progression; 3 remain alive with controlled or improving disease.
Conclusion Hepatic embolization is a viable palliative option for CS due to unresectable liver-dominant metastases, providing meaningful biochemical improvement with acceptable safety and supporting integration into multidisciplinary CS management.
Key Words Cushing syndrome, hepatic embolization, yttrium-90 radioembolization, transarterial embolization, adrenocortical carcinoma, neuroendocrine tumor
Cushing syndrome (CS) caused by ectopic adrenocorticotropin hormone (ACTH) secreting neuroendocrine tumors (NETs) or cortisol-secreting adrenocortical carcinoma (ACC) is a rare but clinically challenging condition, often presenting with severe hypercortisolism and limited treatment options [1, 2]. Treatment goals for patients with CS include tumor control and management of clinical symptoms and impaired quality of life by means of controlling excess cortisol production [3, 4]. Surgical resection is the preferred approach for localized disease. However, some patients present with unresectable metastases or are unsuitable for surgery [2, 5], where outcomes
are unfavorable and medical therapy often fails to adequately achieve hormonal control [6, 7].
Because functional liver-dominant metastases can be the pre- dominant source of cortisol or ACTH production, hepatic trans- catheter arterial embolization (TAE) and yttrium-90 (Y-90) radioembolization have emerged as minimally invasive strat- egies that may reduce tumor perfusion and rapidly improve hor- monal control [8]. The rationale for using hepatic arterial embolization-directed techniques lies in the liver’s unique vascu- lar anatomy. The liver receives ~75% of its blood supply from the portal vein, while malignant liver tumors derive the majority
(~90-100%) of their blood supply from the hepatic artery. This differential allows for selective delivery of particles into the hep- atic artery, where they are preferentially trapped in the hypervas- cular tumor bed while the normal hepatic parenchyma remains protected by its portal venous supply. Tumor-directed ischemia (TAE) or radiation-induced necrosis (Y-90) can therefore provide local tumor control and reduction in tumor burden independent of hormonal status [6, 7]. While these techniques are well- established in hepatocellular carcinoma and metastatic colorec- tal cancer [9, 10], their role in hormonally active tumors, such as those causing CS, remains insufficiently investigated.
We present 4 patients with CS where liver metastases were treated with hepatic embolization for palliative management. This series evaluates the biochemical and radiographic out- comes of embolization and reviews the current literature on its use in CS.
Materials and methods
We conducted a single-center retrospective case series between September 1, 2015 and July 31, 2025 to evaluate the outcomes of liver-directed arterial embolization in patients with CS due to metastatic liver tumors. Only adult patients (age ≥18 years) were eligible for inclusion in this study. An Institutional Review Board approval was waived, and electronic health records were reviewed to identify patients who underwent hepatic em- bolization for ACC or NET. Our objective was to evaluate bio- chemical, radiographic, and safety outcomes.
Inclusion criteria were: (1) a biochemically confirmed diagno- sis of CS [morning cortisol >1.8 µg/dL (50 nmol/L) following over- night 1 mg dexamethasone suppression test, elevated 24-hour urinary free cortisol (UFC), and/or elevated late-night salivary cortisol (LNSC) with ACTH concordance], and (2) liver-directed embolization (Y-90 radioembolization or bland TAE) performed specifically for controlling hypercortisolism. Exclusion criteria in- cluded absence of documented hormonal evaluation before and after embolization, which precluded assessment of biochemical response.
A total of 114 cases of liver-directed embolization for hormo- nally active liver metastases were evaluated at our center. Of these, 4 cases (3.5%) met all eligibility criteria for biochemically confirmed CS with liver-dominant metastatic disease and were included in this case series. The age range of the included pa- tients was 18 to 63 years, with 18 years being the youngest adult participant. We extracted demographics, tumor characteristics, hormonal profiles [UFC, serum cortisol, ACTH, dehydroepian- drosterone sulfate (DHEA-S)], embolization technique parame- ters, and clinical outcomes. Imaging was assessed by RECEIST 1.1 when available. Laboratory results were reviewed to confirm diagnosis and assess treatment response.
Clinical cases
The following 4 cases, summarized in Table 1, illustrate the clin- ical and biochemical outcomes of hepatic embolization in pa- tients with CS. Embolization techniques varied-1 patient received Y-90 radioembolization, while the remaining 3 under- went bland embolization.
Case 1
A 40-year-old man with severe CS secondary to metastatic ACC presented with large, unresectable hepatic metastases. He was initially diagnosed with ACTH-independent CS after identifica- tion of a 6.9 cm heterogeneous right adrenal mass. Robotic lap- aroscopic adrenalectomy was performed at an outside institution, and pathology revealed an oncocytic neoplasm of un- certain malignant potential. He was treated with prednisone 5 mg daily for 4 months, which was subsequently discontinued.
Approximately 1 year following adrenalectomy, the patient de- veloped worsening hyperglycemia accompanied by recurrent Cushingoid features. Two years postoperatively, he presented to our institution with clinical evidence of recurrent CS. Biochemical evaluation revealed elevated 24-UFC of 209 µg/24 hours, reference <45 µg/24 hours (576.84 nmol/24 hours, reference <124.2 nmol/24 hours), LNSC of 0.95 and 0.63 µg/dL, reference <0.1 µg/dL (26.22 nmol/L and 17.39 nmol/L, reference <2.76 nmol/L), and suppressed serum ACTH <5 pg/mL, reference 10 to 60 pg/mL (<1.1 pmol/L, reference 2.2-13.2 pmol/L). Computed tomography (CT) demonstrated an 8.7 cm hepatic le- sion in segment 6 with extension into segment 7 (Fig. 1A). 18-F Fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) showed no evidence of extrahepatic disease.
Despite escalating osilodrostat dose to 6 mg twice daily, hy- percortisolism remained uncontrolled. Surgical resection was at- tempted but aborted intraoperatively due to extensive peritoneal carcinomatosis, highlighting the limited sensitivity of PET imaging for detecting small-volume or miliary peritoneal disease. The patient subsequently underwent Y-90 radioemboli- zation with TheraSpheres Y-90 glass microsphere (Boston Scientific). A total of 159 mCi was delivered to the segmental ar- tery supplying the dominant hepatic lesion.
Fourteen days post-embolization, morning serum cortisol de- creased from a peak of 49.6 ug/dL, reference: 6 to 23 µg/dL (1369 nmol/L, reference: 165.6-634.8 nmol/L) to 6.9 µg/dL (190.4 nmol/L), prompting initiation of hydrocortisone for adrenal insufficiency. Post-embolization CT scan showed a marked reduc- tion of the lesion to 3.0 cm (Fig. 1B). Systemic chemotherapy with cisplatin, doxorubicin, and etoposide was initiated but discontin- ued after the first cycle due to septic shock and acute kidney injury requiring dialysis. Mitotane was trialed but the patient could not tolerate it due to gastrointestinal side effects. The patient was lost to follow-up for nearly 1 year due to loss of insurance.
Upon re-presentation, he reported recurrent Cushingoid symptoms, worsening diabetes, and hypertension. Morning cor- tisol was 19.6 µg/dL (540.96 nmol/L), ACTH remained suppressed <5 pg/mL (<1.1 pmol/L), and UFC was within normal limits at 37.9 µg/24 hours (104.7 nmol/24 hours). Repeat 18F-FDG PET/CT showed post-radioembolization changes in segment 6 and a new 4.4 cm hypermetabolic lesion in segment 5 near the gallbladder fossa (Fig. 1C), along with new suprarenal nodules. The previously treated segment VI liver lesion demonstrated interval decrease in surrounding FDG activity in keeping with re- solving posttreatment change. A second Y-90 treatment was ad- ministered. Post-procedure labs showed UFC 31.9 µg/24 hours (88.0 nmol/24 hours), morning cortisol 11.5 µg/dL (317.4 nmol/L), and ACTH 7 pg/mL (1.54 pmol/L) (Fig. 1D).
At last follow-up, ~32 months after initial Y-90 embolization, the patient remained in biochemical remission. Diabetes was
| Case | 1 | 2 | 3 | 4 |
|---|---|---|---|---|
| Age/sex | 40/M | 49/F | 63/M | 18/F |
| Diagnosis | Metastatic ACC | Metastatic NET | Metastatic NET | Metastatic ACC |
| Peak serum cortisol µg/dL (nmol/L) Ref: < 23 µg/dL, <634.8 nmol/L | 49.6 (1369 nmol/L) | 71.4 (1971.4 nmol/L) | 59 (1628.4 nmol/L) | 25.8 (712.1 nmol/L) |
| Nadir serum cortisol ug/dL (nmol/L) | 6.9 (190.4 nmol/L) | 13.8 (380.9 nmol/L) | 2.2 (60.7 nmol/L) | 8.3 (229.1 nmol/L) |
| ACTH pg/mL (pmol/L) Ref: 10 to 60 pg/mL, 2.2 to 13.2 pmol/L | <5 (1.1 pmol/L) | 190 (41.8 pmol/L) | 158 (34.8 pmol/L) | <5 (1.1 pmol/L) |
| Peak UFC µg/24hours (nmol/24 hours) | 209 (577 nmol/24 hours) | N/A | N/A | 1022 (2821 nmol/24 hours) |
| Ref: < 45 µg/24 hours, <124.2 nmol/24hours | ||||
| Tumor type | Adrenocortical carcinoma | Well-differentiated NET | Well-differentiated NET | Adrenocortical carcinoma |
| Size of initial hepatic metastasis | 8.7 cm | 16 cm | 14.1 cm | 12.4 cm |
| Embolization type | Y-90 radioembolization (2 rounds) Osilodrostat | Bland embolization (2 rounds) Metyrapone, Osilodrostat | Bland embolization | Bland embolization Osilodrostat |
| Systemic therapy prior to embolization | ||||
| Follow-up time, months | 32 | 24 | 1 | 3 |
| Outcome | Biochemical remission; resumed mitotane with hydrocortisone | Biochemical remission; on hydrocortisone for adrenal insufficiency | Deceased; transitioned to hospice passed away 33 days postembolization | and Stable disease; on mitotane with hydrocortisone and osilodrostat |
Abbreviations: ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; NET, neuroendocrine tumor; UFC, urinary free cortisol.
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well-controlled with tirzepatide and insulin. He is currently reat- tempting mitotane monotherapy with hydrocortisone replacement.
Case 2
A 49-year-old woman presented with bilateral lower extremity edema, weight gain of 50 pounds (22.7 kg) over 6 months, and se- vere hypokalemia (serum potassium 2.8 mmol/L; reference: 3.5-5.1 mmol/L). Laboratory evaluation revealed ACTH-dependent CS with markedly elevated serum cortisol at 71.4 ug/dL (1970.6 nmol/L), plasma ACTH 190 pg/mL (41.8 pmol/L), and DHEA-S at 462 µg/dL, reference: 35 to 430 µg/dL (12.5 umol/L; reference: 1.0-11.8 umol/L). Computed tomography of the chest, abdomen, and pelvis demonstrated a 3.4 cm left adrenal nodule and multiple hepatic lesions, the largest measuring 16 cm (Fig. 2A). Given the presence of an adrenal nodule and se- vere hypokalemia, primary aldosteronism was evaluated. Aldosterone was suppressed <4.0 ng/dL (<140 pmol/L) with nonsuppressed renin of 1.0 ng/ml/hour (1 mcg/L/hour), argu- ing against autonomous aldosterone secretion. Liver biopsy re- vealed a grade 2 (G2) well-differentiated NET of unknown primary origin (<1 mitosis per 10 high-power fields, no necrosis, and Ki-67 index of 5-8%).
She was initiated on subcutaneous octreotide, spironolactone, and metyrapone. Despite uptitration of metyrapone to 3000 mg/day in divided doses, hypercortisolism remained poorly controlled. Due
to extensive tumor burden and poor functional status, she was not a candidate for bilateral adrenalectomy or hepatic resection. She sub- sequently underwent 2 sessions of bland embolization targeting the dominant hepatic lesions.
Following the first embolization, serum cortisol declined from 63.9 µg/dL (1762.4 nmol/L) to a nadir of 13.8 µg/dL (381.7 nmol/L) by day 8 but rebounded to 67.3 µg/dL (1856.9 nmol/L) by day 10 (Fig. 2B). After the second embolization, cortisol decreased to 20.8 µg/dL (573.9 nmol/L) on day 1 but rose again to 35.7 µg/dL (986.0 nmol/L) by day 2 (Fig. 2C). Metyrapone was resumed at 500 mg 3 times daily, followed by a transition to osilodrostat to improve hormonal control and reduce pill burden. 18F-FDG PET/ CT showed persistent hepatic metastases with decreased uptake in the most avid lesion and no new extrahepatic disease at 4 months postembolization (Fig. 2D). Ectopic CS remained well- controlled on osilodrostat 1 mg twice daily, which was later dis- continued due to adrenal insufficiency. She is maintained on hydrocortisone replacement.
For management of metastatic NET, she completed 3 of 9 planned cycles of nivolumab and ipilimumab. A follow-up 18F-FDG PET/CT demonstrated increased uptake in several hepatic lesions concerning for progression, and she has since transitioned to FOLFOX chemotherapy. Over the course of follow-up, the adrenal lesion demonstrated radiographic be- havior consistent with metastatic disease rather than a primary adrenal tumor. Despite disease progression, she remains active and has returned to full-time work. At last follow-up approxi- mately 24 months after initial bland embolization, she has
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lost over 100 pounds (45.4 kg), returning to her baseline weight of 164 pounds (74.4 kg). Hypertension is in remission off all anti- hypertensive medications, and hypokalemia has resolved with- out supplementation.
Case 3
A 63-year-old man presented with worsening back pain. Computed tomography of the abdomen and pelvis revealed a 2.8 cm mildly enhancing mass at the pancreatic body/tail junc- tion with peripheral calcifications, innumerable centrally hypoat- tenuating liver lesions (largest measuring 14.1 cm in the right hepatic lobe; Fig. 3A), and spinal metastases. Liver biopsy con- firmed metastatic, well-differentiated, grade 2 NET (Ki67 4.6%), immunohistochemically positive for AE1/AE3, synaptophysin, and chromogranin, and negative for Glypican-3, CK7, and CK20.
Biochemical evaluation was consistent with carcinoid syn- drome: 24-hour urinary 5-hydroxyindoleacetic acid was elevated to 357 mg/24 hours, reference: ≤10.0 mg/24 hours (1867umol/ 24 hours, reference: ≤52.3 umol/24 hours), serum serotonin was 1010 ng/ml, reference: ≤330 ng/ml (5.73 nmol/L, reference: ≤1.87 nmol/L), and chromogranin A was 2380 ng/ml, reference: <93 ng/ml (0.049 nmol/L, reference: < 0.002). The patient was started on continuous octreotide infusion.
Further workup revealed ACTH-dependent CS with random se- rum cortisol of 33 µg/dL (911.5 nmol/L) and ACTH of 158 pg/mL (34.76 pmol/L). Medical therapy was initiated with ketoconazole 200 mg every 8 hours and metyrapone 1500 mg daily in divided
doses. Bilateral adrenalectomy was considered but deemed un- feasible due to poor surgical candidacy.
The patient underwent bland embolization of right hepatic lobe metastases using Embozene microspheres in a stepwise fashion: 100 um (3 vials), 250 um (2 vials), and 400 um (2 vials), until stasis was achieved in the right hepatic artery.
On postembolization day 1, serum cortisol decreased from a peak of 59.0 µg/dL (1629 nmol/L) to 2.2 µg/dL (60.7 nmol/L) (Fig. 3B). Ketoconazole and metyrapone were held, and hydro- cortisone was initiated for adrenal insufficiency. Cortisol levels began to rise, and metyrapone was restarted on day 4. Due to poor oral tolerance, osilodrostat 5 mg twice daily was adminis- tered via nasogastric tube.
The hospital course was complicated by grade 4 hypoxemia re- quiring mechanical ventilation, grade 4 hypotension requiring vasopressor support and opportunistic Pneumocystis jirovecii pneumonia. Postembolization CT showed necrotic changes in right hepatic metastases, but also revealed enlarging left hepatic lesions, an unchanged pancreatic tail mass, and a new 3.1 cm le- sion in the pancreatic head (Fig. 3C).
Given the severity of illness and comorbidities, the patient transitioned to comfort-directed care and passed away on post- embolization day 33.
Case 4
An 18-year-old woman transferred care to our institution follow- ing a diagnosis of metastatic right ACC complicated by severe CS.
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| Author (year) | Primary tumor (size) | Primary tumor resection | Systemic therapy | Embolization technique | No. of hepatic embolizations | Biochemical response | Outcome |
|---|---|---|---|---|---|---|---|
| Doi et al (2003) [17] | Pancreatic NET (5 cm) | Surgical resection of pancreatic NET | Octreotide, metyrapone, interferon-a, adriamycin + dacarbazine streptozotocin + 5-FU | TAE | 5 | Biochemical response for 8 months | Biochemical and radiologic response for 8 months; subsequent tumor progression |
| Lin et al(2012) | Pancreatic | Not resected | Octreotide | TAE | 1 | Į cortisol, improved serum potassium | No long-term follow-up |
| [18] | NET (3.1 cm) | (tumor burden too large) | reported | ||||
| Vaduganathan et al (2015) [19] | Pancreatic NET | Not resected (tumor burden too large) | Metyrapone, octreotide | TAE | 1 | No significant effect on cortisol; bilateral adrenalectomy 10 days later | Died within 4 months due to postoperative complications |
| Zhang, et al (2020) [20] | Pancreatic NET | Not reported | Not reported | TAE | Not reported | Cortisol level returned to normal following TAE | Did not continue treatments with somatostatin analogs and lost to follow-up. Deceased 1 year later. |
| Watanabe et al (2022) [21] | ACC (16 cm) | Adrenalectomy | Mitotane, EDP | TAE | 6 | Not reported | 5 of 8 liver metastases showed complete response; others <2 cm at 8 years |
| Blew et al (2023) | Pancreatic | Modified Whipple | Lanreotide, cabergoline, | TAE | 2 | Persistent hypercortisolism | Į size/enhancement of |
| [22] | NET (5.3 cm) | procedure | metyrapone, sunitinib | (UFC 2479 nmol/24 hours); required additional medical therapy | hepatic metastases; | ||
| nodal progression | |||||||
| Makary et al (2018) [23] | ACC (8.9 cm) | Adrenalectomy | Not reported | Y-90 (ETP) | 2 | Į aldosterone; cortisol not reported | Stable disease; symptom resolution at 12 months |
| Pigg et al (2020) [24] | ACC (12 cm) | Adrenalectomy | Mitotane, etoposide, adriamycin, cisplatin, metyrapone | Y-90 | 2 | Not reported | Stable hepatic disease; symptom-free at 2 years |
| Lu et al (2021) [25] | ACC (15 cm) | Adrenalectomy | Mitotane, ETP | Y-90 | 2 | Adrenal crisis postprocedure; cortisol not recorded | No hepatic recurrence at 23 months |
| Lin et al (2022) [26] | ACC (5.1 cm) | Adrenalectomy | Mitotane, paclitaxel, cisplatin, 5-FU | Y-90 | 2 | Į size of hepatic metastases after Y-90; biochemical response not reported | Complete remission after RFA; disease-free at 16 months |
(continued)
| Outcome Biochemical response No. of hepatic embolizations Embolization technique Systemic therapy Primary tumor resection Primary tumor (size) Author (year) | Stable for 18 months Decrease/stability in hepatic | complications. without serious lesion size for most lesions, biochemical response not reported | NET, neuroendocrine | Initial biochemical evaluation revealed markedly elevated UFC at 1022 µg/24 hours (2820.7 nmol/24 hours), DHEA-S 939 ug/dL (25.45 umol/L), morning cortisol 25.8 µg/dL (712.0 nmol/L), ACTH <5 pg/mL (<1.1 pmol/L), testosterone 106 ng/dL, refer- ence: < 43 ng/dL (3.68 nmol, reference: < 1.49 nmol/L), and androstenedione 2170 ng/dL, reference: 41 to 262 ng/dL |
| platinum-based chemotherapy (context-dependent); | (75.76 nmol/L, reference 1.43-9.15 nmol/L). Cross-sectional imaging (CT and magnetic resonance imaging) demonstrated a 14 x 10 cm heterogeneous, partially calcified right adrenal mass abutting the posterior liver and displacing the right kidney inferiorly. Multiple hepatic metastases were identified, the largest measuring 12.4 x 11.2 cm in segments 7/ 8 (Fig. 4A), along with a 1.3 cm pulmonary nodule in the right lung base concerning for metastatic disease. 18-F FDG PET/CT confirmed metabolic activity in the adrenal mass, hepatic le- sions, and pulmonary nodule. Genetic testing of 85 cancer- related genes was negative. Initial treatment included combination chemotherapy (cis- platin, etoposide, doxorubicin), osilodrostat (maximum toler- ated dose: 6 mg twice daily), and mitotane (2000 mg twice daily), along with hydrocortisone as part of a block-and-replace | |||
| 1 Y-90 Ketoconazole, Not resected (due | octreotide, lanreotide, capecitabine, temozolomide disease) to metastatic | adrenocortical carcinoma; EDP, etoposide, doxorubicin, and cisplatin; ETP, etoposide, mitotane, and/or strategy. Due to radiographic progression, chemotherapy was transitioned to pembrolizumab. Surgical intervention was de- ferred due to high morbidity risk, as determined by multidiscip- linary tumor board review. Interventional radiology performed TAE targeting the right ad- renal, inferior phrenic, and hepatic artery branches using 100 to 300 um microspheres. A second order right inferior phrenic artery was also embolized using a 2 mm x 6 mm fibered coil. The proced- ure was completed without immediate complications. On postembolization day 1, morning cortisol decreased to 8.3 µg/dL (229.08 nmol/L) (Fig. 4B). Osilodrostat and hydrocorti- sone were resumed, while mitotane was temporarily held due to elevated liver enzymes. The patient developed postembolization syndrome, characterized by fever, tachycardia, hypertension, and leukocytosis; infectious workup was negative. She was dis- charged on postembolization day 8. Follow-up CT 1 month later showed stable disease in the pri- mary adrenal tumor and hepatic metastases, with the dominant hepatic lesion measuring 12 x 11.8 cm (Fig. 4C). However, a re- peat scan 2 months postembolization revealed interval enlarge- ment of other hepatic lesions. Currently at 3 months post embolization, the patient contin- ues to have biochemical control with mitotane and osilodrostat and has resumed pembrolizumab. Discussion transarterial embolization; UFC, 24-hour urinary free cortisol; Y-90, yttrium-90 radioembolization. | ||
| Pancreatic Tamhane et al | NET (2023) [27] | Abbreviations: 5-FU, 5-fluorouracil; ACC, tumor; RFA, radiofrequency ablation; TAE, The management of CS due to unresectable hepatic metastases represents a significant clinical challenge, particularly when con- ventional therapies such as surgical resection or medical man- agement are ineffective or not feasible. This case series highlights the potential role of TAE and Y-90 radioembolization as minimally invasive, palliative strategies for controlling hyper- cortisolism and reducing tumor burden in patients with meta- static, hormonally active tumors. Surgical resection of the primary lesion remains the first-line treatment for CS [11]. However, in patients with metastatic dis- ease, such as ACC or ectopic ACTH-producing tumors, surgical op- tions are often limited due to extensive tumor burden at diagnosis | ||
CONFIRM CS AND ESTABLISH LIVER DOMINANCE Biochemical testing (1mg DST, UFC, MNSC) & cross-sectional imaging
INITIAL MEDICAL STABILIZATION Steroidogenesis inhibitors (ketoconazole, metyrapone, osilodrostat)
HEPATIC METASTASECTOMY Hepatic resection feasible
TUMOR BOARD REVIEW Assess surgical feasibility
POOR SURGICAL CANDIDATE Hepatic resection not feasible
SELECT HEPATIC TRANSARTERIAL THERAPY
TAE (BLAND EMBOLIZATION) Focal or rapidly progressive lesion
Y90 EMBOLIZATION Bi-lobar or multifocal disease
POST-PROCEDURE MONITORING AND MANAGEMENT
CORTISOL SURVEILLANCE Days 1, 3-5, 7-14
SAFETY MONITORING Evaluate for adrenal insufficiency, infection or abscess
INTEGRATE SYSTEMIC THERAPY (once stable) (E.g. Mitotane, EDP)
or poor functional status [12]. In these scenarios, where no stand- ardized treatment sequence exists and medical therapy alone is in- sufficient, alternative approaches are urgently needed [5, 6, 11].
Targeted embolization techniques have been increasingly used to treat liver-dominant metastatic tumors with successful radiographic and symptomatic responses [9, 10, 13]. While their use in hormonally active tumors is not well characterized, emer- ging evidence (including the present series) suggests that TAE and Y-90 radioembolization may offer meaningful biochemical and clinical improvements in patients with CS due to hepatic me- tastases [14-16]. A summary of previously reported cases of pal- liative hepatic embolization for hormonally active metastatic tumors, including embolization modality and biochemical out- comes, is provided in Table 2.
TAE works by selectively occluding the arterial supply to hep- atic tumors, inducing ischemic necrosis and reducing both tumor volume and hormonal output [28]. In our series, 2 patients (Cases 2 and 3) with ectopic ACTH syndrome underwent TAE, resulting in rapid biochemical improvement and partial radiographic re- sponse. These findings align with prior reports demonstrating the efficacy of TAE in controlling hormone excess and tumor pro- gression in neuroendocrine liver metastases [17-22].
Y-90 radioembolization offers an alternative approach, deliver- ing localized radiation via microspheres to tumor vasculature. This technique allows for targeted cytotoxicity while sparing sur- rounding hepatic parenchyma [13, 29, 30]. In our series, the patient who underwent Y-90 embolization (Case 1) experienced significant tumor shrinkage and sustained biochemical remission. Y-90 may be particularly advantageous in cases with multifocal or bilobar liver disease, where diffuse hepatic involvement limits the utility of surgical or segmental interventions [23-27].
Both TAE and Y-90 embolization are minimally invasive, re- peatable, and generally well-tolerated, with lower procedural risk compared with surgical resection [9, 31]. These techniques can be performed under local anesthesia and may serve as bridg- ing or adjunctive therapies in patients awaiting systemic treat- ment or experiencing refractory hypercortisolism. While often reserved for refractory cases, the favorable safety profile and bio- chemical responses observed in our series suggest that transar- terial therapies may also be considered earlier in the treatment course for selected patient with liver-dominant metastatic dis- ease. Furthermore, as illustrated by Case 4, locoregional embol- ization can be applied not only to large hepatic metastases but also to metastatic lesions in other organs when anatomically feasible. Integration of these techniques may decrease tumor burden and also facilitate more rapid biochemical stabilization.
Based on our experience and prior reports, we propose a prag- matic pathway: (1) confirm CS with biochemical testing; (2) es- tablish liver dominance by cross-sectional imaging; (3) stabilize with steroidogenesis inhibitors (often block-and-replace); (4) tu- mor board review to assess surgical feasibility; (5) choose TAE for focal, rapidly progressive lesions or Y-90 for bilobar/multifocal disease; (6) monitor cortisol on postprocedure days 1, 3 to 5, and 7 to 14; (7) screen proactively for adrenal insufficiency and infection; (8) integrate systemic therapy once stable (Fig. 5). Despite these promising outcomes, several limitations remain. Tumor revascularization and recurrence are known risks, and hepatic dysfunction may occur, particularly in patients with underlying liver disease [14, 32]. The retrospective nature of this report, with a small number of cases, further limits the gen- eralizability of these findings; thus, the results should be inter- preted with caution. Future multicenter studies are needed to
better characterize patient selection, durability of hormonal con- trol, safety outcomes, and optimal integration of hepatic embol- ization with other therapies. In addition, adrenal insufficiency is also a potential concern in this patient population, underscoring the importance of screening for this condition and initiating prompt glucocorticoid therapy when indicated. Finally, the long- term impact of embolization on survival and quality of life in this population remains unclear. Future prospective studies are needed to refine patient selection, optimize embolization proto- cols, and evaluate the integration of embolization with systemic therapies such as chemotherapy, immunotherapy, or targeted agents. Future studies should also evaluate the long-term endo- crine consequences of repeated hepatic embolization, including the incidence and recovery patterns of adrenal insufficiency, as well as the broader impact on patient-reported quality-of-life outcomes. In addition, prospective collaborative registries or multicenter consortia may help refine optimal patient selection criteria, treatment sequencing with systemic therapies, and standardized monitoring protocols to improve safety and dur- ability of biochemical control.
In conclusion, hepatic TAE and Y-90 radioembolization are ef- fective, minimally invasive options for palliating CS due to liver- dominant metastatic disease. These techniques may serve as additive tools within a multimodal treatment strategy in selected patients with liver-dominant metastatic disease. These liver- directed interventions can provide meaningful biochemical con- trol and tumor reduction when conventional treatments are in- sufficient. Although our findings primarily pertain to hepatic metastases, targeted embolization of extra-hepatic lesions may also offer therapeutic benefit in carefully selected cases.
Funding
This research was partly supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) USA under award 1K23DK142038-01A1 (to O.H). The views expressed are those of the author(s) and not necessarily those of the National Institutes of Health USA.
Disclosure
O.H. reports consulting or advisory board participation with Corcept Therapeutics, Neurocrine Biosciences, Xeris Pharma, Camurus, Crinetics Pharmaceuticals, and Recordati Rare Diseases, Inc. outside the submitted work; occasional education- al speaking engagements with Neurocrine Biosciences, Corcept Therapeutics, and Recordati Rare Diseases, Inc. S.M. reports ad- visory board participation with Crinetics Pharmaceuticals and Camurus. The remaining authors have nothing to disclose.
Data availability
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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