Combined Ovarian and Adrenal Venous Sampling in the Localization of Adrenocorticotropic Hormone-Independent Ectopic Cushing Syndrome

Combined Ovarian and Adrenal Venous Sampling in the Localization of Adrenocorticotropic... Abstract Context Cushing syndrome is rarely caused by the secretion of cortisol from ovarian tumors. In clinical decision-making, it is important to determine whether the ovarian tumor is capable of secreting cortisol. Selective ovarian and adrenal venous sampling is scarcely reported in the localization of ACTH-independent ectopic Cushing syndrome. Case Description We present a case of 40-year-old Chinese woman who had weight gain, hirsutism, hypertension, and menstrual disorder over 6 months. Her physical examination and biochemical assessment revealed adrenocorticotropic hormone-independent Cushing syndrome. Adrenal computed tomography scan indicated no abnormality. A mass of 5.7 cm × 4.2 cm × 3.4 cm was discovered by pelvic ultrasonography. Somatostatin receptor scintigraphy revealed no abnormal radioactivity intake. Combined ovarian and adrenal venous sampling together with a cortisol assay were conducted. Results revealed cortisol concentration of the right-side ovarian vein, left-side ovarian vein, and peripheral vein of 268.60, 29.00, and 35.18 μg/dL, respectively, suggesting a right-side ovarian origin. A right-side salpingo-oophorectomy was performed and the pathological diagnosis revealed ovarian steroid cell tumor, not otherwise specified. The cortisol level was substantially lower after the patient underwent surgery and symptoms of Cushing syndrome disappeared. At 3-year follow-up, the patient remained disease free, and no tumor was observed on pelvic ultrasonogram. Conclusion Combined ovarian and adrenal venous sampling is valuable in the localization of adrenocorticotropic hormone–independent ectopic Cushing syndrome. Adrenocorticotropic hormone (ACTH)–independent Cushing syndrome (CS) is mainly caused by primary adrenal disease. In rare cases, it is attributed to adrenal rest tumors or ovarian tumors that secrete cortisol. In clinical decision-making, to avoid unnecessary exploratory surgery, it is important to determine if the tumor can produce cortisol. Selective venous sampling, together with hormone measurement, were predominantly used in patients with hyperandrogenism and primary hyperaldosteronism (1, 2). However, to our knowledge, this approach has not been reported in the localization of ectopic CS. Herein, we present a rare case of ACTH-independent CS with ovarian origin that was confirmed by combined ovarian and adrenal venous sampling. The patient gave signed informed consent and the study was approved by the Ethics Committee of Peking Union Medical College Hospital. Case Presentation A 40-year-old Chinese woman was referred to our department with a 6-month history of weight gain, hirsutism, hypertension, and menstrual disorder. Her weight was increased by 5 kg within 6 months. Her blood pressure varied between 160/100 mm Hg and 170/110 mm Hg. She had delayed menstrual cycles and decreased menstrual volume, and had no abdominal pain. She denied administration of herbal medication, steroids, or drug supplements. Physical examination revealed typical signs of CS, such as hirsutism, supraclavicular fat pads, and centripetal obesity [Fig. 1(a) and 1(b)]. The body mass index was 25.4 kg/m2 (height, 170 cm; weight, 73.5 kg) with an increased waist circumference of 86 cm and thin limbs. The patient had thin skin but showed no bruises or purple striae. Figure 1. View largeDownload slide Images of a 40-year-old Chinese woman with typical manifestations of Cushing syndrome due to an ovarian cortisol-secreting tumor. The images demonstrate the physical examination findings of (a) full-moon face and (b) buffalo hump. (c) A reconstruction image of an enhanced abdominal and pelvic computed tomography scan shows a tumor originating from the right-side ovary. (d) A cross-sectional image of an enhanced pelvic computed tomography scan showing a mass in the pelvic cavity. Figure 1. View largeDownload slide Images of a 40-year-old Chinese woman with typical manifestations of Cushing syndrome due to an ovarian cortisol-secreting tumor. The images demonstrate the physical examination findings of (a) full-moon face and (b) buffalo hump. (c) A reconstruction image of an enhanced abdominal and pelvic computed tomography scan shows a tumor originating from the right-side ovary. (d) A cross-sectional image of an enhanced pelvic computed tomography scan showing a mass in the pelvic cavity. Laboratory examination revealed basal serum cortisol concentrations of 30.72 μg/dL at 8:00 am (normal, 4.0 to 22.3 μg/24 hours) and 29.15 μg/dL at 12:00 am (normal, <1.8 μg/24 hours), and serum ACTH concentration of <5 pg/mL (normal, 0 to 46 pg/mL). Basal, 24-hour urine-free cortisol (UFC) level was 1753 μg/24 hours (normal, 12.3 to 103.5 μg/24 hours), and was not suppressed by either 2 mg or 8 mg dexamethasone (2081 and 2045 μg/24 hours, respectively). Computed tomography (CT) scan of the adrenal glands demonstrated no nodules or hyperplasia. Diagnosis of primary pigmented nodular adrenocortical disease (PPNAD) was suspected at first because of normal adrenal imaging and an anomalous increase in 24-hour UFC after dexamethasone suppression test. Echocardiography, and thyroid and breast ultrasound examinations were conducted and revealed no abnormalities. We further conducted whole-exome sequencing of the PRKAR1A, PDE11A, and PDE8B genes, which are closely related to PPNAD (3, 4, 5), but no pathogenic mutations were detected. Pelvic ultrasonography revealed a hypoechoic mass arising from the right ovary. It measured 5.7 cm × 4.2 cm × 3.4 cm, and the mass was further confirmed by enhanced CT scan of the abdomen and pelvis [Fig. 1(c) and 1(d)]. The concentration of the tumor marker CA125 (49.3 U/mL; normal range, 0 to 35.0 U/mL) was slightly elevated, whereas α-fetoprotein and carcinoembryonic antigen were within the normal ranges. Somatostatin receptor scintigraphy (SRS) revealed no abnormal radioactivity intake. To confirm the source of cortical overproduction, bilateral ovarian and adrenal venous sampling, together with a cortical hormone assay, were carried out [Fig. 2(a) and 2(b)]. The cortisol concentration from the right-side ovarian vein was six times higher than that of the peripheral vein and no difference was observed between that of the adrenal vein and peripheral vein, suggesting a right-side ovarian origin of hypercortisolism (Table 1). Figure 2. View largeDownload slide (a, b) Venography of bilateral ovarian veins. (c) A tumor originating from the right-side ovary was found during laparoscopic surgery. The tumor was yellowish-brown with papillary surface. (d) Micrograph showing hematoxylin-and-eosin staining with typical microscopic appearance and histology of steroid cell tumor, not otherwise specified. Large polygonal tumor cells with abundant cytoplasm and prominent nucleoli are seen in a nest-like arrangement. Figure 2. View largeDownload slide (a, b) Venography of bilateral ovarian veins. (c) A tumor originating from the right-side ovary was found during laparoscopic surgery. The tumor was yellowish-brown with papillary surface. (d) Micrograph showing hematoxylin-and-eosin staining with typical microscopic appearance and histology of steroid cell tumor, not otherwise specified. Large polygonal tumor cells with abundant cytoplasm and prominent nucleoli are seen in a nest-like arrangement. Table 1. Results of Bilateral Adrenal and Ovarian Venous Sampling   Adrenal Vein  Peripheral Vein  Ovarian Vein  Right  Left  Right  Left  Cortisol, μg/dL  37.31  32.75  35.18  268.60  29.00  Adrenal vein or ovarian vein-to-peripheral vein ratio  1.06  0.93    7.64  0.82    Adrenal Vein  Peripheral Vein  Ovarian Vein  Right  Left  Right  Left  Cortisol, μg/dL  37.31  32.75  35.18  268.60  29.00  Adrenal vein or ovarian vein-to-peripheral vein ratio  1.06  0.93    7.64  0.82  View Large A month after the patient was admitted to our hospital, a laparoscopic salpingo-oophorectomy of the right-side ovary was performed and revealed a neoplasm of 6 cm in diameter. The mass was yellowish-brown with a papillary surface [Fig. 2(c)]. A nodule with a diameter of 0.5 cm was found on the pelvic wall and was removed. Histopathological examination revealed a steroid cell tumor, not otherwise specified (NOS) [Fig. 2(d)]. On the second postoperative day, the serum cortisol level at 8:00 am had declined to 1.28 μg/dL. The patient was prescribed glucocorticoid replacement therapy with 10 mg of prednisone, twice daily, in the morning and at night, and the steroid was gradually withdrawn over 8 months. Clinical features of CS disappeared after 1 year postsurgery; the patient experienced weight loss (from 73.5 to 65 kg) and lower blood pressure (120/76 mm Hg). At 3-year follow-up, no evidence of recurrence was found via ovarian ultrasonography, and the patient had normal blood pressure and menstrual cycles. Discussion We used combined ovarian and adrenal venous sampling in the diagnosis of ACTH-independent ectopic CS in a Chinese patient. Typical manifestations of CS, failure of suppression by dexamethasone suppression test, and undetectable ACTH level confirmed ACTH-independent CS. Although patients with PPNAD typically present with micronodules on bilateral adrenal glands, normal appearance of adrenal glands can be observed, albeit rarely (6). Thus, the diagnosis of PPNAD in this patient was suspected initially. However, severe hypercortisolism was present, with a 24-hour UFC level of 1753 μg, which was inconsistent with typical endocrinal manifestation of PPNAD, and high levels of 24-hour UFC were commonly seen in patients with ectopic CS. Negative whole-exome sequencing of the PRKAR1A, PDE11A, and PDE8B genes provided support for the ectopic source of hypercortisolism rather than adrenal gland origin. Nuclear imaging has been reported to be helpful when conventional imaging is difficult to interpret. Although SRS is commonly used in the localization of neuroendocrine tumors, SRS has been used in the diagnosis of adrenocortical carcinoma (7). In the current study, no radioactive uptake was detected with SRS. Radiocholesterol imaging with 131I-6-beta-iodomethyl-19-norcholesterol (NP-59), a cholesterol precursor of low-density lipoprotein (a component of the corticosteroid synthesis pathway) has been documented in the localization of the responsible tumor in patients with ACTH-independent CS (8). However, because of the unavailability of 131I-6-β-iodomethyl-19-norcholesterol, it was not used in the current study. Imaging with a new adrenocortical specific tracer, 123I-iodometomidate, has been used in adrenocortical carcinoma, and it might serve as an alternative imaging tool to diagnose ectopic ACTH-independent CS (9). Noninvasive imaging technology has provided limited information regarding the responsible tumor in ACTH-independent CS; hence, a method that functionally localizes the tumor is urgently required. Selective venous sampling has been well documented in the localization of various neuroendocrine tumors (10). Ovarian and adrenal catheterization has been used to localize androgen-secreting ovarian and adrenal tumors, revealing a right-to-left ovarian testosterone-ratio >1.44 and correctly identifying 90% of right-sided tumors (1, 2). But the use of venous sampling in localizing ACTH-independent ectopic CS was scarcely reported. We performed combined ovarian and adrenal venous sampling with glucocorticoid hormone assay in localizing the ovarian cortisol-producing tumor in the patient described in this case report. Cortisol concentration of the right-side ovarian vein was higher than that of the peripheral vein and left-side ovarian vein. Nevertheless, the levels of cortisol were roughly equal between the bilateral adrenal vein and peripheral vein, and the right-to-left ovarian cortisol ratio was 9.26, suggesting a right-side ovarian origin. The cutoff value of the ratio needs to be elucidated by expanding the sample size in future studies. Severe hypercortisolism is an endocrine emergency and, if the UFC level is greater than fivefold the normal level, prophylactic treatment is advised; anticoagulation agents are used to prevent deep venous thrombosis and trimethoprim-sulfamethosazole is recommended for prevention of Pneumocystis jirovecii (11). Steroid cell tumors are rare stromal tumors of the ovary that were first defined by Hayes and Scully in 1979; previously, these tumors were categorized as “lipid cell tumors” (12). Steroid cell tumors can produce steroid hormone and are often associated with 56% to 77% of androgenic changes, 6% to 23% of estrogen secretion, and 6% to 10% of CS cases (13). We have summarized in Table 2 the available English-language literature about ectopic ACTH-independent CS with ovarian steroid cell tumor (12, 14–19). In the previous studies in Table 2, exploratory laparotomy was conducted without full certainty of the responsible tumor. Venous sampling enabled us to localize the ovarian source precisely, which was an advantage in formulating subsequent management strategies. Table 2. Summary of English-Language Studies of Ectopic ACTH-Independent Cushing Syndrome Caused by Ovarian Steroid Cell Tumor Patient Number  First Author  Age of Onset, y  Manifestations and Duration  ACTH (pg/mL)  24-h UFC  Size of Ovarian Neoplasm  Pathology  Treatment  Outcome  P1  Marieb (14)  35  Lower abdominal mass, acne, facial hirsutism, weight gain, and edema for 8 mo  28 (20–100)  Not available Plasma cortisol level at 8:00 am: 34 (8–24) μg/dL  Bilateral ovarian masses (size not known) with extensive metastases  Ovarian malignant lipid cell tumor  Hysterectomy and bilateral salpingo-oophorectomy, debulking operation, chemotherapy  Death after 17 mo  P2  Young (12)  48  Virilization, a moon face, prominent supraclavicular fat pads, purple blotches, and hypertension  Undetectable  Not available Plasma cortisol level in the morning: 43 (8–24) μg/dL  Mass on the right ovary with extensive abdominal metastases  Ovarian steroid cell tumor  Surgery and chemotherapy (details not available)  Death after 10 mo  P3  Young (12)  52  Weight gain, purple blotches, edema, a moon face, a prominent hump, and hirsutism for 7 mo  Normal  Not available Urinary cortisol levels: 140–252 (20–90) μg/100 mL  9 cm×7 cm×5 cm mass on the right ovary with extensive omental metastasis  Ovarian steroid cell tumor  Right salpingo-oophorectomy and the omental biopsy  Death after 6 mo  P4  Donovan (15)  66  Abdominal enlargement and leg edema for 3 wk  26 (20–100)  1650 (35–120) μg/24 h  8-cm–diameter mass on the right ovary with bowel, omentum, and liver metastases  Ovarian steroid cell tumor  Surgery plus ketoconazole plus chemotherapy (details not available)  Death after 4 mo  P5  Elhadd (16)  73  Weight gain, hirsutism, and hypertension for 4 mo  <10 (<10)  603 (<300) nmol/24 h  2 cm × 2 cm × 1 cm mass on the left ovary  Ovary lipid cell tumor  Bilateral salpingo-oophorectomy  Recurrence and peritoneal metastases at 12 mo  P6  Yuan (17)  31  Irregular menses and excess hair growth for 3.5 y  16 (0–46)  1024.8 (30–110) μg/24 h  25 cm × 20 cm × 15 cm mass on the left ovary  First operation misdiagnosed with ovarian thecoma, second diagnosis: steroid cell tumor (NOS)  First operation: left oophorectomy; second operation: debulking  Symptoms resolved after the first operation; died of metastases after 16 mo  P7  Sedhom (18)  67  Hirsutism, deepening voice, weight gain, easy bruising, hair thinning, and chest redness for 4 mo  Not known  273 (<45) μg/24 h  9.4 cm × 5.8 cm × 7.9 cm mass on the right ovary with diffuse abdominal metastasis  Ovarian steroid cell tumor  Hysterectomy, bilateral salpingo-oophorectomy, and tumor debulking  Died on postoperative day 24  P8  Chentli (19)  34  Psychiatric signs, diabetes mellitus, lower limb edema, duration unknown  <10 (20–46)  Not available  14.5 cm × 13.7 cm mass on the right ovary with abnormal lymph nodes and hemoperitoneum  Ectopic adrenocortical carcinoma (positive for inhibin-α, melan-A, and SF1)  Ovarian mass resection  Died of pulmonary embolism on second postoperative day  Patient Number  First Author  Age of Onset, y  Manifestations and Duration  ACTH (pg/mL)  24-h UFC  Size of Ovarian Neoplasm  Pathology  Treatment  Outcome  P1  Marieb (14)  35  Lower abdominal mass, acne, facial hirsutism, weight gain, and edema for 8 mo  28 (20–100)  Not available Plasma cortisol level at 8:00 am: 34 (8–24) μg/dL  Bilateral ovarian masses (size not known) with extensive metastases  Ovarian malignant lipid cell tumor  Hysterectomy and bilateral salpingo-oophorectomy, debulking operation, chemotherapy  Death after 17 mo  P2  Young (12)  48  Virilization, a moon face, prominent supraclavicular fat pads, purple blotches, and hypertension  Undetectable  Not available Plasma cortisol level in the morning: 43 (8–24) μg/dL  Mass on the right ovary with extensive abdominal metastases  Ovarian steroid cell tumor  Surgery and chemotherapy (details not available)  Death after 10 mo  P3  Young (12)  52  Weight gain, purple blotches, edema, a moon face, a prominent hump, and hirsutism for 7 mo  Normal  Not available Urinary cortisol levels: 140–252 (20–90) μg/100 mL  9 cm×7 cm×5 cm mass on the right ovary with extensive omental metastasis  Ovarian steroid cell tumor  Right salpingo-oophorectomy and the omental biopsy  Death after 6 mo  P4  Donovan (15)  66  Abdominal enlargement and leg edema for 3 wk  26 (20–100)  1650 (35–120) μg/24 h  8-cm–diameter mass on the right ovary with bowel, omentum, and liver metastases  Ovarian steroid cell tumor  Surgery plus ketoconazole plus chemotherapy (details not available)  Death after 4 mo  P5  Elhadd (16)  73  Weight gain, hirsutism, and hypertension for 4 mo  <10 (<10)  603 (<300) nmol/24 h  2 cm × 2 cm × 1 cm mass on the left ovary  Ovary lipid cell tumor  Bilateral salpingo-oophorectomy  Recurrence and peritoneal metastases at 12 mo  P6  Yuan (17)  31  Irregular menses and excess hair growth for 3.5 y  16 (0–46)  1024.8 (30–110) μg/24 h  25 cm × 20 cm × 15 cm mass on the left ovary  First operation misdiagnosed with ovarian thecoma, second diagnosis: steroid cell tumor (NOS)  First operation: left oophorectomy; second operation: debulking  Symptoms resolved after the first operation; died of metastases after 16 mo  P7  Sedhom (18)  67  Hirsutism, deepening voice, weight gain, easy bruising, hair thinning, and chest redness for 4 mo  Not known  273 (<45) μg/24 h  9.4 cm × 5.8 cm × 7.9 cm mass on the right ovary with diffuse abdominal metastasis  Ovarian steroid cell tumor  Hysterectomy, bilateral salpingo-oophorectomy, and tumor debulking  Died on postoperative day 24  P8  Chentli (19)  34  Psychiatric signs, diabetes mellitus, lower limb edema, duration unknown  <10 (20–46)  Not available  14.5 cm × 13.7 cm mass on the right ovary with abnormal lymph nodes and hemoperitoneum  Ectopic adrenocortical carcinoma (positive for inhibin-α, melan-A, and SF1)  Ovarian mass resection  Died of pulmonary embolism on second postoperative day  Abbreviations: NOS, not otherwise specified; P, patient; SF1, steroidogenic factor 1. View Large Patients with ovarian steroid cell tumors, NOS, usually have a benign clinical course. However, patients who had CS demonstrated rapid progression with extensive metastasis, as shown in Table 2. The average age of the patients in the studies listed in Table 2 was 53 years, ranging from 31 to 73 years old, and the overall survival time was 8 months. Compared with the previous cases, the patient described in our case report had an ovarian mass and a nodule in the pelvic wall. The nodule and the ovarian mass were totally removed, and no recurrence or metastasis was found at 3 years’ follow-up. Differential prognosis might partly be associated with the early-stage localization and thorough removal of the tumor with the help of combined ovarian and adrenal venous sampling. We have reported a rare case of ectopic ACTH-independent CS caused by ovarian steroid cell tumor, NOS. After right-side salpingo-oophorectomy, CS manifestations disappeared, serum cortisol level returned to normal, and the patient remained disease free at 3-year follow up. Abbreviations: ACTH adrenocorticotropic hormone CS Cushing syndrome CT computed tomography NOS not otherwise specified PPNAD primary pigmented nodular adrenocortical disease SRS somatostatin receptor scintigraphy UFC urine-free cortisol. Acknowledgments We thank Dr. Dachun Zhao from the Department of Pathology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, for valuable discussion about the pathology of ovarian steroid cell tumor. Financial Support: The study was supported by grants from the National Key Program of Clinical Science (WBYZ2011-873). Disclosure Summary: The authors have nothing to disclose. References 1. Weiland AJ, Bookstein JJ, Cleary RE, Judd HL. Preoperative localization of virilizing tumors by selective venous sampling. Am J Obstet Gynecol . 1978; 131( 7): 797– 802. Google Scholar CrossRef Search ADS PubMed  2. Bogdanou D, Meyer G, Stuecker AU, Thalhammer A, Hansmann ML, Bojunga J. A rare case of an androgen-producing stromal luteoma of the ovary in a postmenopausal woman, diagnosed by means of selective venous blood sampling. Gynecol Endocrinol . 2016; 32( 9): 704– 708. Google Scholar CrossRef Search ADS PubMed  3. Groussin L, Jullian E, Perlemoine K. Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab . 2002; 87( 9): 4324– 4329. Google Scholar CrossRef Search ADS PubMed  4. Horvath A, Boikos S, Giatzakis C. A genome-wide scan identified mutations in the gene encoding phosphodiesterase 11A4(PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet.  2006; 38( 7): 794– 800. Google Scholar CrossRef Search ADS PubMed  5. Horvath A, Mericq V, Stratakis CA. Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. N Engl J Med . 2008; 358( 7): 750– 752. Google Scholar CrossRef Search ADS PubMed  6. Doppman JL, Travis WD, Nieman L, Miller DL, Chrousos GP, Gomez MT, Cutler GB, Jr, Loriaux DL, Norton JA. Cushing syndrome due to primary pigmented nodular adrenocortical disease: findings at CT and MR imaging. Radiology . 1989; 172( 2): 415– 420. Google Scholar CrossRef Search ADS PubMed  7. Andersen KF, Mellemgaard A, Hendel HW. Multimodality imaging in a patient with adrenocortical carcinoma leading to peptide receptor radionuclide therapy. Clin Nucl Med . 2009; 34( 8): 543– 548. Google Scholar CrossRef Search ADS PubMed  8. Wong KK, Komissarova M, Avram AM. Adrenal cortical imaging with I-131 NP-59 SPECT-CT. Clin Nucl Med . 2010; 35( 11): 865– 869. Google Scholar CrossRef Search ADS PubMed  9. Gaujoux S, Mihai R; Joint Working Group of ESES and ENSAT. European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical management of adrenocortical carcinoma. Br J Surg . 2017; 104( 4): 358– 376. Google Scholar CrossRef Search ADS PubMed  10. Patel C, Matson M. The role of interventional venous sampling in localising neuroendocrine tumours. Curr Opin Endocrinol Diabetes Obes . 2011; 18( 4): 269– 277. Google Scholar CrossRef Search ADS PubMed  11. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A; Endocrine Society. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab . 2015; 100( 8): 2807– 2831. Google Scholar CrossRef Search ADS PubMed  12. Young RH, Scully RE. Ovarian steroid cell tumors associated with Cushing's syndrome: a report of three cases. Int J Gynecol Pathol . 1987; 6( 1): 40– 48. Google Scholar CrossRef Search ADS PubMed  13. Hayes MC, Scully RE. Ovarian steroid cell tumors (not otherwise specified). A clinicopathological analysis of 63 cases. Am J Surg Pathol . 1987; 11( 11): 835– 845. Google Scholar CrossRef Search ADS PubMed  14. Marieb NJ, Spangler S, Kashgarian M, Heimann A, Schwartz ML, Schwartz PE. Cushing’s syndrome secondary to ectopic cortisol production by an ovarian carcinoma. J Clin Endocrinol Metab . 1983; 57( 4): 737– 740. Google Scholar CrossRef Search ADS PubMed  15. Donovan JT, Otis CN, Powell JL, Cathcart HK. Cushing’s syndrome secondary to malignant lipoid cell tumor of the ovary. Gynecol Oncol . 1993; 50( 2): 249– 253. Google Scholar CrossRef Search ADS PubMed  16. Elhadd TA, Connolly V, Cruickshank D, Kelly WF. An ovarian lipid cell tumour causing virilization and Cushing’s syndrome. Clin Endocrinol (Oxf) . 1996; 44( 6): 723– 725. Google Scholar CrossRef Search ADS PubMed  17. Yuan M, Qiu M, Zhu M. Symptomatic Cushing syndrome and hyperandrogenemia revealing steroid cell ovarian neoplasm with late intra-abdominal metastasis. BMC Endocr Disord . 2014; 14( 1): 12. Google Scholar CrossRef Search ADS PubMed  18. Sedhom R, Hu S, Ohri A, Infantino D, Lubitz S. Symptomatic Cushing’s syndrome and hyperandrogenemia in a steroid cell ovarian neoplasm: a case report. J Med Case Reports . 2016; 10( 1): 278. Google Scholar CrossRef Search ADS   19. Chentli F, Terki N, Azzoug S. Ectopic adrenocortical carcinoma located in the ovary. Eur J Endocrinol . 2016; 175( 4): K17– K23. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Combined Ovarian and Adrenal Venous Sampling in the Localization of Adrenocorticotropic Hormone-Independent Ectopic Cushing Syndrome

Loading next page...
 
/lp/ou_press/combined-ovarian-and-adrenal-venous-sampling-in-the-localization-of-39A2uZAyIv
Publisher
Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2017-01977
Publisher site
See Article on Publisher Site

Abstract

Abstract Context Cushing syndrome is rarely caused by the secretion of cortisol from ovarian tumors. In clinical decision-making, it is important to determine whether the ovarian tumor is capable of secreting cortisol. Selective ovarian and adrenal venous sampling is scarcely reported in the localization of ACTH-independent ectopic Cushing syndrome. Case Description We present a case of 40-year-old Chinese woman who had weight gain, hirsutism, hypertension, and menstrual disorder over 6 months. Her physical examination and biochemical assessment revealed adrenocorticotropic hormone-independent Cushing syndrome. Adrenal computed tomography scan indicated no abnormality. A mass of 5.7 cm × 4.2 cm × 3.4 cm was discovered by pelvic ultrasonography. Somatostatin receptor scintigraphy revealed no abnormal radioactivity intake. Combined ovarian and adrenal venous sampling together with a cortisol assay were conducted. Results revealed cortisol concentration of the right-side ovarian vein, left-side ovarian vein, and peripheral vein of 268.60, 29.00, and 35.18 μg/dL, respectively, suggesting a right-side ovarian origin. A right-side salpingo-oophorectomy was performed and the pathological diagnosis revealed ovarian steroid cell tumor, not otherwise specified. The cortisol level was substantially lower after the patient underwent surgery and symptoms of Cushing syndrome disappeared. At 3-year follow-up, the patient remained disease free, and no tumor was observed on pelvic ultrasonogram. Conclusion Combined ovarian and adrenal venous sampling is valuable in the localization of adrenocorticotropic hormone–independent ectopic Cushing syndrome. Adrenocorticotropic hormone (ACTH)–independent Cushing syndrome (CS) is mainly caused by primary adrenal disease. In rare cases, it is attributed to adrenal rest tumors or ovarian tumors that secrete cortisol. In clinical decision-making, to avoid unnecessary exploratory surgery, it is important to determine if the tumor can produce cortisol. Selective venous sampling, together with hormone measurement, were predominantly used in patients with hyperandrogenism and primary hyperaldosteronism (1, 2). However, to our knowledge, this approach has not been reported in the localization of ectopic CS. Herein, we present a rare case of ACTH-independent CS with ovarian origin that was confirmed by combined ovarian and adrenal venous sampling. The patient gave signed informed consent and the study was approved by the Ethics Committee of Peking Union Medical College Hospital. Case Presentation A 40-year-old Chinese woman was referred to our department with a 6-month history of weight gain, hirsutism, hypertension, and menstrual disorder. Her weight was increased by 5 kg within 6 months. Her blood pressure varied between 160/100 mm Hg and 170/110 mm Hg. She had delayed menstrual cycles and decreased menstrual volume, and had no abdominal pain. She denied administration of herbal medication, steroids, or drug supplements. Physical examination revealed typical signs of CS, such as hirsutism, supraclavicular fat pads, and centripetal obesity [Fig. 1(a) and 1(b)]. The body mass index was 25.4 kg/m2 (height, 170 cm; weight, 73.5 kg) with an increased waist circumference of 86 cm and thin limbs. The patient had thin skin but showed no bruises or purple striae. Figure 1. View largeDownload slide Images of a 40-year-old Chinese woman with typical manifestations of Cushing syndrome due to an ovarian cortisol-secreting tumor. The images demonstrate the physical examination findings of (a) full-moon face and (b) buffalo hump. (c) A reconstruction image of an enhanced abdominal and pelvic computed tomography scan shows a tumor originating from the right-side ovary. (d) A cross-sectional image of an enhanced pelvic computed tomography scan showing a mass in the pelvic cavity. Figure 1. View largeDownload slide Images of a 40-year-old Chinese woman with typical manifestations of Cushing syndrome due to an ovarian cortisol-secreting tumor. The images demonstrate the physical examination findings of (a) full-moon face and (b) buffalo hump. (c) A reconstruction image of an enhanced abdominal and pelvic computed tomography scan shows a tumor originating from the right-side ovary. (d) A cross-sectional image of an enhanced pelvic computed tomography scan showing a mass in the pelvic cavity. Laboratory examination revealed basal serum cortisol concentrations of 30.72 μg/dL at 8:00 am (normal, 4.0 to 22.3 μg/24 hours) and 29.15 μg/dL at 12:00 am (normal, <1.8 μg/24 hours), and serum ACTH concentration of <5 pg/mL (normal, 0 to 46 pg/mL). Basal, 24-hour urine-free cortisol (UFC) level was 1753 μg/24 hours (normal, 12.3 to 103.5 μg/24 hours), and was not suppressed by either 2 mg or 8 mg dexamethasone (2081 and 2045 μg/24 hours, respectively). Computed tomography (CT) scan of the adrenal glands demonstrated no nodules or hyperplasia. Diagnosis of primary pigmented nodular adrenocortical disease (PPNAD) was suspected at first because of normal adrenal imaging and an anomalous increase in 24-hour UFC after dexamethasone suppression test. Echocardiography, and thyroid and breast ultrasound examinations were conducted and revealed no abnormalities. We further conducted whole-exome sequencing of the PRKAR1A, PDE11A, and PDE8B genes, which are closely related to PPNAD (3, 4, 5), but no pathogenic mutations were detected. Pelvic ultrasonography revealed a hypoechoic mass arising from the right ovary. It measured 5.7 cm × 4.2 cm × 3.4 cm, and the mass was further confirmed by enhanced CT scan of the abdomen and pelvis [Fig. 1(c) and 1(d)]. The concentration of the tumor marker CA125 (49.3 U/mL; normal range, 0 to 35.0 U/mL) was slightly elevated, whereas α-fetoprotein and carcinoembryonic antigen were within the normal ranges. Somatostatin receptor scintigraphy (SRS) revealed no abnormal radioactivity intake. To confirm the source of cortical overproduction, bilateral ovarian and adrenal venous sampling, together with a cortical hormone assay, were carried out [Fig. 2(a) and 2(b)]. The cortisol concentration from the right-side ovarian vein was six times higher than that of the peripheral vein and no difference was observed between that of the adrenal vein and peripheral vein, suggesting a right-side ovarian origin of hypercortisolism (Table 1). Figure 2. View largeDownload slide (a, b) Venography of bilateral ovarian veins. (c) A tumor originating from the right-side ovary was found during laparoscopic surgery. The tumor was yellowish-brown with papillary surface. (d) Micrograph showing hematoxylin-and-eosin staining with typical microscopic appearance and histology of steroid cell tumor, not otherwise specified. Large polygonal tumor cells with abundant cytoplasm and prominent nucleoli are seen in a nest-like arrangement. Figure 2. View largeDownload slide (a, b) Venography of bilateral ovarian veins. (c) A tumor originating from the right-side ovary was found during laparoscopic surgery. The tumor was yellowish-brown with papillary surface. (d) Micrograph showing hematoxylin-and-eosin staining with typical microscopic appearance and histology of steroid cell tumor, not otherwise specified. Large polygonal tumor cells with abundant cytoplasm and prominent nucleoli are seen in a nest-like arrangement. Table 1. Results of Bilateral Adrenal and Ovarian Venous Sampling   Adrenal Vein  Peripheral Vein  Ovarian Vein  Right  Left  Right  Left  Cortisol, μg/dL  37.31  32.75  35.18  268.60  29.00  Adrenal vein or ovarian vein-to-peripheral vein ratio  1.06  0.93    7.64  0.82    Adrenal Vein  Peripheral Vein  Ovarian Vein  Right  Left  Right  Left  Cortisol, μg/dL  37.31  32.75  35.18  268.60  29.00  Adrenal vein or ovarian vein-to-peripheral vein ratio  1.06  0.93    7.64  0.82  View Large A month after the patient was admitted to our hospital, a laparoscopic salpingo-oophorectomy of the right-side ovary was performed and revealed a neoplasm of 6 cm in diameter. The mass was yellowish-brown with a papillary surface [Fig. 2(c)]. A nodule with a diameter of 0.5 cm was found on the pelvic wall and was removed. Histopathological examination revealed a steroid cell tumor, not otherwise specified (NOS) [Fig. 2(d)]. On the second postoperative day, the serum cortisol level at 8:00 am had declined to 1.28 μg/dL. The patient was prescribed glucocorticoid replacement therapy with 10 mg of prednisone, twice daily, in the morning and at night, and the steroid was gradually withdrawn over 8 months. Clinical features of CS disappeared after 1 year postsurgery; the patient experienced weight loss (from 73.5 to 65 kg) and lower blood pressure (120/76 mm Hg). At 3-year follow-up, no evidence of recurrence was found via ovarian ultrasonography, and the patient had normal blood pressure and menstrual cycles. Discussion We used combined ovarian and adrenal venous sampling in the diagnosis of ACTH-independent ectopic CS in a Chinese patient. Typical manifestations of CS, failure of suppression by dexamethasone suppression test, and undetectable ACTH level confirmed ACTH-independent CS. Although patients with PPNAD typically present with micronodules on bilateral adrenal glands, normal appearance of adrenal glands can be observed, albeit rarely (6). Thus, the diagnosis of PPNAD in this patient was suspected initially. However, severe hypercortisolism was present, with a 24-hour UFC level of 1753 μg, which was inconsistent with typical endocrinal manifestation of PPNAD, and high levels of 24-hour UFC were commonly seen in patients with ectopic CS. Negative whole-exome sequencing of the PRKAR1A, PDE11A, and PDE8B genes provided support for the ectopic source of hypercortisolism rather than adrenal gland origin. Nuclear imaging has been reported to be helpful when conventional imaging is difficult to interpret. Although SRS is commonly used in the localization of neuroendocrine tumors, SRS has been used in the diagnosis of adrenocortical carcinoma (7). In the current study, no radioactive uptake was detected with SRS. Radiocholesterol imaging with 131I-6-beta-iodomethyl-19-norcholesterol (NP-59), a cholesterol precursor of low-density lipoprotein (a component of the corticosteroid synthesis pathway) has been documented in the localization of the responsible tumor in patients with ACTH-independent CS (8). However, because of the unavailability of 131I-6-β-iodomethyl-19-norcholesterol, it was not used in the current study. Imaging with a new adrenocortical specific tracer, 123I-iodometomidate, has been used in adrenocortical carcinoma, and it might serve as an alternative imaging tool to diagnose ectopic ACTH-independent CS (9). Noninvasive imaging technology has provided limited information regarding the responsible tumor in ACTH-independent CS; hence, a method that functionally localizes the tumor is urgently required. Selective venous sampling has been well documented in the localization of various neuroendocrine tumors (10). Ovarian and adrenal catheterization has been used to localize androgen-secreting ovarian and adrenal tumors, revealing a right-to-left ovarian testosterone-ratio >1.44 and correctly identifying 90% of right-sided tumors (1, 2). But the use of venous sampling in localizing ACTH-independent ectopic CS was scarcely reported. We performed combined ovarian and adrenal venous sampling with glucocorticoid hormone assay in localizing the ovarian cortisol-producing tumor in the patient described in this case report. Cortisol concentration of the right-side ovarian vein was higher than that of the peripheral vein and left-side ovarian vein. Nevertheless, the levels of cortisol were roughly equal between the bilateral adrenal vein and peripheral vein, and the right-to-left ovarian cortisol ratio was 9.26, suggesting a right-side ovarian origin. The cutoff value of the ratio needs to be elucidated by expanding the sample size in future studies. Severe hypercortisolism is an endocrine emergency and, if the UFC level is greater than fivefold the normal level, prophylactic treatment is advised; anticoagulation agents are used to prevent deep venous thrombosis and trimethoprim-sulfamethosazole is recommended for prevention of Pneumocystis jirovecii (11). Steroid cell tumors are rare stromal tumors of the ovary that were first defined by Hayes and Scully in 1979; previously, these tumors were categorized as “lipid cell tumors” (12). Steroid cell tumors can produce steroid hormone and are often associated with 56% to 77% of androgenic changes, 6% to 23% of estrogen secretion, and 6% to 10% of CS cases (13). We have summarized in Table 2 the available English-language literature about ectopic ACTH-independent CS with ovarian steroid cell tumor (12, 14–19). In the previous studies in Table 2, exploratory laparotomy was conducted without full certainty of the responsible tumor. Venous sampling enabled us to localize the ovarian source precisely, which was an advantage in formulating subsequent management strategies. Table 2. Summary of English-Language Studies of Ectopic ACTH-Independent Cushing Syndrome Caused by Ovarian Steroid Cell Tumor Patient Number  First Author  Age of Onset, y  Manifestations and Duration  ACTH (pg/mL)  24-h UFC  Size of Ovarian Neoplasm  Pathology  Treatment  Outcome  P1  Marieb (14)  35  Lower abdominal mass, acne, facial hirsutism, weight gain, and edema for 8 mo  28 (20–100)  Not available Plasma cortisol level at 8:00 am: 34 (8–24) μg/dL  Bilateral ovarian masses (size not known) with extensive metastases  Ovarian malignant lipid cell tumor  Hysterectomy and bilateral salpingo-oophorectomy, debulking operation, chemotherapy  Death after 17 mo  P2  Young (12)  48  Virilization, a moon face, prominent supraclavicular fat pads, purple blotches, and hypertension  Undetectable  Not available Plasma cortisol level in the morning: 43 (8–24) μg/dL  Mass on the right ovary with extensive abdominal metastases  Ovarian steroid cell tumor  Surgery and chemotherapy (details not available)  Death after 10 mo  P3  Young (12)  52  Weight gain, purple blotches, edema, a moon face, a prominent hump, and hirsutism for 7 mo  Normal  Not available Urinary cortisol levels: 140–252 (20–90) μg/100 mL  9 cm×7 cm×5 cm mass on the right ovary with extensive omental metastasis  Ovarian steroid cell tumor  Right salpingo-oophorectomy and the omental biopsy  Death after 6 mo  P4  Donovan (15)  66  Abdominal enlargement and leg edema for 3 wk  26 (20–100)  1650 (35–120) μg/24 h  8-cm–diameter mass on the right ovary with bowel, omentum, and liver metastases  Ovarian steroid cell tumor  Surgery plus ketoconazole plus chemotherapy (details not available)  Death after 4 mo  P5  Elhadd (16)  73  Weight gain, hirsutism, and hypertension for 4 mo  <10 (<10)  603 (<300) nmol/24 h  2 cm × 2 cm × 1 cm mass on the left ovary  Ovary lipid cell tumor  Bilateral salpingo-oophorectomy  Recurrence and peritoneal metastases at 12 mo  P6  Yuan (17)  31  Irregular menses and excess hair growth for 3.5 y  16 (0–46)  1024.8 (30–110) μg/24 h  25 cm × 20 cm × 15 cm mass on the left ovary  First operation misdiagnosed with ovarian thecoma, second diagnosis: steroid cell tumor (NOS)  First operation: left oophorectomy; second operation: debulking  Symptoms resolved after the first operation; died of metastases after 16 mo  P7  Sedhom (18)  67  Hirsutism, deepening voice, weight gain, easy bruising, hair thinning, and chest redness for 4 mo  Not known  273 (<45) μg/24 h  9.4 cm × 5.8 cm × 7.9 cm mass on the right ovary with diffuse abdominal metastasis  Ovarian steroid cell tumor  Hysterectomy, bilateral salpingo-oophorectomy, and tumor debulking  Died on postoperative day 24  P8  Chentli (19)  34  Psychiatric signs, diabetes mellitus, lower limb edema, duration unknown  <10 (20–46)  Not available  14.5 cm × 13.7 cm mass on the right ovary with abnormal lymph nodes and hemoperitoneum  Ectopic adrenocortical carcinoma (positive for inhibin-α, melan-A, and SF1)  Ovarian mass resection  Died of pulmonary embolism on second postoperative day  Patient Number  First Author  Age of Onset, y  Manifestations and Duration  ACTH (pg/mL)  24-h UFC  Size of Ovarian Neoplasm  Pathology  Treatment  Outcome  P1  Marieb (14)  35  Lower abdominal mass, acne, facial hirsutism, weight gain, and edema for 8 mo  28 (20–100)  Not available Plasma cortisol level at 8:00 am: 34 (8–24) μg/dL  Bilateral ovarian masses (size not known) with extensive metastases  Ovarian malignant lipid cell tumor  Hysterectomy and bilateral salpingo-oophorectomy, debulking operation, chemotherapy  Death after 17 mo  P2  Young (12)  48  Virilization, a moon face, prominent supraclavicular fat pads, purple blotches, and hypertension  Undetectable  Not available Plasma cortisol level in the morning: 43 (8–24) μg/dL  Mass on the right ovary with extensive abdominal metastases  Ovarian steroid cell tumor  Surgery and chemotherapy (details not available)  Death after 10 mo  P3  Young (12)  52  Weight gain, purple blotches, edema, a moon face, a prominent hump, and hirsutism for 7 mo  Normal  Not available Urinary cortisol levels: 140–252 (20–90) μg/100 mL  9 cm×7 cm×5 cm mass on the right ovary with extensive omental metastasis  Ovarian steroid cell tumor  Right salpingo-oophorectomy and the omental biopsy  Death after 6 mo  P4  Donovan (15)  66  Abdominal enlargement and leg edema for 3 wk  26 (20–100)  1650 (35–120) μg/24 h  8-cm–diameter mass on the right ovary with bowel, omentum, and liver metastases  Ovarian steroid cell tumor  Surgery plus ketoconazole plus chemotherapy (details not available)  Death after 4 mo  P5  Elhadd (16)  73  Weight gain, hirsutism, and hypertension for 4 mo  <10 (<10)  603 (<300) nmol/24 h  2 cm × 2 cm × 1 cm mass on the left ovary  Ovary lipid cell tumor  Bilateral salpingo-oophorectomy  Recurrence and peritoneal metastases at 12 mo  P6  Yuan (17)  31  Irregular menses and excess hair growth for 3.5 y  16 (0–46)  1024.8 (30–110) μg/24 h  25 cm × 20 cm × 15 cm mass on the left ovary  First operation misdiagnosed with ovarian thecoma, second diagnosis: steroid cell tumor (NOS)  First operation: left oophorectomy; second operation: debulking  Symptoms resolved after the first operation; died of metastases after 16 mo  P7  Sedhom (18)  67  Hirsutism, deepening voice, weight gain, easy bruising, hair thinning, and chest redness for 4 mo  Not known  273 (<45) μg/24 h  9.4 cm × 5.8 cm × 7.9 cm mass on the right ovary with diffuse abdominal metastasis  Ovarian steroid cell tumor  Hysterectomy, bilateral salpingo-oophorectomy, and tumor debulking  Died on postoperative day 24  P8  Chentli (19)  34  Psychiatric signs, diabetes mellitus, lower limb edema, duration unknown  <10 (20–46)  Not available  14.5 cm × 13.7 cm mass on the right ovary with abnormal lymph nodes and hemoperitoneum  Ectopic adrenocortical carcinoma (positive for inhibin-α, melan-A, and SF1)  Ovarian mass resection  Died of pulmonary embolism on second postoperative day  Abbreviations: NOS, not otherwise specified; P, patient; SF1, steroidogenic factor 1. View Large Patients with ovarian steroid cell tumors, NOS, usually have a benign clinical course. However, patients who had CS demonstrated rapid progression with extensive metastasis, as shown in Table 2. The average age of the patients in the studies listed in Table 2 was 53 years, ranging from 31 to 73 years old, and the overall survival time was 8 months. Compared with the previous cases, the patient described in our case report had an ovarian mass and a nodule in the pelvic wall. The nodule and the ovarian mass were totally removed, and no recurrence or metastasis was found at 3 years’ follow-up. Differential prognosis might partly be associated with the early-stage localization and thorough removal of the tumor with the help of combined ovarian and adrenal venous sampling. We have reported a rare case of ectopic ACTH-independent CS caused by ovarian steroid cell tumor, NOS. After right-side salpingo-oophorectomy, CS manifestations disappeared, serum cortisol level returned to normal, and the patient remained disease free at 3-year follow up. Abbreviations: ACTH adrenocorticotropic hormone CS Cushing syndrome CT computed tomography NOS not otherwise specified PPNAD primary pigmented nodular adrenocortical disease SRS somatostatin receptor scintigraphy UFC urine-free cortisol. Acknowledgments We thank Dr. Dachun Zhao from the Department of Pathology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, for valuable discussion about the pathology of ovarian steroid cell tumor. Financial Support: The study was supported by grants from the National Key Program of Clinical Science (WBYZ2011-873). Disclosure Summary: The authors have nothing to disclose. References 1. Weiland AJ, Bookstein JJ, Cleary RE, Judd HL. Preoperative localization of virilizing tumors by selective venous sampling. Am J Obstet Gynecol . 1978; 131( 7): 797– 802. Google Scholar CrossRef Search ADS PubMed  2. Bogdanou D, Meyer G, Stuecker AU, Thalhammer A, Hansmann ML, Bojunga J. A rare case of an androgen-producing stromal luteoma of the ovary in a postmenopausal woman, diagnosed by means of selective venous blood sampling. Gynecol Endocrinol . 2016; 32( 9): 704– 708. Google Scholar CrossRef Search ADS PubMed  3. Groussin L, Jullian E, Perlemoine K. Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab . 2002; 87( 9): 4324– 4329. Google Scholar CrossRef Search ADS PubMed  4. Horvath A, Boikos S, Giatzakis C. A genome-wide scan identified mutations in the gene encoding phosphodiesterase 11A4(PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet.  2006; 38( 7): 794– 800. Google Scholar CrossRef Search ADS PubMed  5. Horvath A, Mericq V, Stratakis CA. Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. N Engl J Med . 2008; 358( 7): 750– 752. Google Scholar CrossRef Search ADS PubMed  6. Doppman JL, Travis WD, Nieman L, Miller DL, Chrousos GP, Gomez MT, Cutler GB, Jr, Loriaux DL, Norton JA. Cushing syndrome due to primary pigmented nodular adrenocortical disease: findings at CT and MR imaging. Radiology . 1989; 172( 2): 415– 420. Google Scholar CrossRef Search ADS PubMed  7. Andersen KF, Mellemgaard A, Hendel HW. Multimodality imaging in a patient with adrenocortical carcinoma leading to peptide receptor radionuclide therapy. Clin Nucl Med . 2009; 34( 8): 543– 548. Google Scholar CrossRef Search ADS PubMed  8. Wong KK, Komissarova M, Avram AM. Adrenal cortical imaging with I-131 NP-59 SPECT-CT. Clin Nucl Med . 2010; 35( 11): 865– 869. Google Scholar CrossRef Search ADS PubMed  9. Gaujoux S, Mihai R; Joint Working Group of ESES and ENSAT. European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical management of adrenocortical carcinoma. Br J Surg . 2017; 104( 4): 358– 376. Google Scholar CrossRef Search ADS PubMed  10. Patel C, Matson M. The role of interventional venous sampling in localising neuroendocrine tumours. Curr Opin Endocrinol Diabetes Obes . 2011; 18( 4): 269– 277. Google Scholar CrossRef Search ADS PubMed  11. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A; Endocrine Society. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab . 2015; 100( 8): 2807– 2831. Google Scholar CrossRef Search ADS PubMed  12. Young RH, Scully RE. Ovarian steroid cell tumors associated with Cushing's syndrome: a report of three cases. Int J Gynecol Pathol . 1987; 6( 1): 40– 48. Google Scholar CrossRef Search ADS PubMed  13. Hayes MC, Scully RE. Ovarian steroid cell tumors (not otherwise specified). A clinicopathological analysis of 63 cases. Am J Surg Pathol . 1987; 11( 11): 835– 845. Google Scholar CrossRef Search ADS PubMed  14. Marieb NJ, Spangler S, Kashgarian M, Heimann A, Schwartz ML, Schwartz PE. Cushing’s syndrome secondary to ectopic cortisol production by an ovarian carcinoma. J Clin Endocrinol Metab . 1983; 57( 4): 737– 740. Google Scholar CrossRef Search ADS PubMed  15. Donovan JT, Otis CN, Powell JL, Cathcart HK. Cushing’s syndrome secondary to malignant lipoid cell tumor of the ovary. Gynecol Oncol . 1993; 50( 2): 249– 253. Google Scholar CrossRef Search ADS PubMed  16. Elhadd TA, Connolly V, Cruickshank D, Kelly WF. An ovarian lipid cell tumour causing virilization and Cushing’s syndrome. Clin Endocrinol (Oxf) . 1996; 44( 6): 723– 725. Google Scholar CrossRef Search ADS PubMed  17. Yuan M, Qiu M, Zhu M. Symptomatic Cushing syndrome and hyperandrogenemia revealing steroid cell ovarian neoplasm with late intra-abdominal metastasis. BMC Endocr Disord . 2014; 14( 1): 12. Google Scholar CrossRef Search ADS PubMed  18. Sedhom R, Hu S, Ohri A, Infantino D, Lubitz S. Symptomatic Cushing’s syndrome and hyperandrogenemia in a steroid cell ovarian neoplasm: a case report. J Med Case Reports . 2016; 10( 1): 278. Google Scholar CrossRef Search ADS   19. Chentli F, Terki N, Azzoug S. Ectopic adrenocortical carcinoma located in the ovary. Eur J Endocrinol . 2016; 175( 4): K17– K23. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society

Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Mar 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off