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00019616-200711000-00011ReviewThe EndocrinologistThe Endocrinologist© 2007 Lippincott Williams & Wilkins, Inc.17November 2007 p 341-345Coexistence of Adrenal Cushing Syndrome and Pheochromocytoma in a “Corticomedullary Adenoma”A Case Report and Review of the LiteratureCME Review Article #33Ma, Wen-Ya MD*; Yang, An-Hung MD, PhD†; Chang, Yen-Hwa MD, PhD‡; Lin, Liang-Yu MD§; Lin, Hong-Da MD¶*Attending Physician, Division of Endocrinology and Metabolism, Department of Internal Medicine, Tauyuan Veteran Hospital, Tauyuan, Taiwan; and †Chief, Ultrastructural and Molecular Pathology, Pathology and Laboratory Medicine Department, ‡Attending Urologist, Division of Urology, Department of Surgery, and §Chief Resident and ¶Chief, Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.The authors have disclosed that they have no significant relationships with or financial interests in any commercial company that pertains to this educational activity.Lippincott Continuing Medical Education Institute, Inc. has identified and resolved all faculty conflicts of interest regarding this educational activity.Reprints: Hong-Da Lin, MD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan. E-mail: [email protected] Editor’s Note: This article is the 33rd of 35 that will be published in 2007 for which a total of up to 35 AMA PRA Category 1 Credits™ can be earned. Instructions for how credits can be earned precede the CME Examination at the back of this issue.AbstractMixed pheochromocytoma and adrenal cortical adenoma (corticomedullary adenoma) is extremely rare. We report a 41-year-old woman diagnosed preoperatively with Cushing syndrome of adrenal origin. Nonsuppressible serum cortisol and 24-hour urine free cortisol levels by a standard low-dose dexamethasone suppression test with a low plasma adrenocorticotropic hormone (ACTH) level suggested ACTH-independent Cushing syndrome. Magnetic resonance imaging (MRI) revealed a left adrenal mass about 4 cm in diameter, showing a slightly heterogenous signal drop in chemical shift imaging, suggesting high lipid content in the tumor. The T2-weighted image, however, had a mildly high signal, rather than the typical normal to low signal characteristic of a cortical adenoma. 131I-6β-iodomethyl-norcholesterol (NP-59) scintigraphy revealed early accumulation of radioactivity in the left suprarenal region, suggesting a functioning cortical tumor. The patient underwent left adrenalectomy, but the surgery caused a marked elevation of systolic blood pressure (greater than 200 mm Hg). The suspicion of pheochromocytoma was entertained. Mixed pheochromocytoma and adrenal cortical adenoma (corticomedullary adenoma) were disclosed by immunohistochemical stains and electron microscopic examination. This case is the fifth reported pathologically proven corticomedullary adenoma. We include special image findings that contain characteristics of both cortical and medullary components.Learning ObjectivesRelate this patient’s symptoms, physical signs, and clinical course to the coexistence of pheochromocytoma and Cushing syndrome.Describe how the findings on MR imaging and scintigraphy helped to clarify the clinical picture.Outline the immunohistochemical findings in this rare case of corticomedullary adenoma, and suggest possible mechanisms for its origin and clinical manifestations.The coexistence of pheochromocytoma and Cushing syndrome (CS) is well recognized. It is usually associated with the ectopic production of hormones such as adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH) by the pheochromocytoma cells.1,2 Pheochromocytoma associated with adrenocortical adenoma (adrenal CS) is not uncommon.3–5 However, 1 tumor with both cortical and medullary components, “corticomedullary adenoma,” is rarely encountered in clinical practice.6–8 We present the clinical, biochemical, pathologic, and imaging features of a case with documented adrenal CS, arising from a mixed pheochromocytoma and adrenocortical adenoma. Previously reported cases are reviewed.CASE REPORTA 41-year-old woman presented with the chief complaint of amenorrhea for 6 months and a progressive weight gain of 20 kg. Hypertension and left ventricular hypertrophy were found. Except for an episodic feeling of palpitation and chest distress, she denied any pallor, headache, sweating, or tremor. There was no known family history of hypertension. The patient weighed 75 kg and was 160 cm tall. Blood pressure was 152/108 mm Hg. Pulse rate was 110/min. Physical examination showed a moon face, buffalo hump, truncal obesity, and proximal muscle wasting. Purplish striae were noted over the lower abdomen and the medial proximal region of both arms and thighs. Thinning of the skin and subcutaneous ecchymoses were found in all 4 extremities. She denied the use of glucocorticoids.Blood cell counts and biochemical data were unremarkable, except for hypercholesterolemia (305 mg/dL) and hypertriglyceridemia (222 mg/dL). The serum potassium level was normal (4.0 mg/dL). Serum cortisol levels at 8 am and 10 pm were 21 μg/dL and 31 μg/dL, respectively. Followed a standard low-dose dexamethasone suppression test (LDDST) with 0.5 mg dexamethasone q6 hours for 2 days, the serum cortisol level was 26 μg/dL. Twenty-four-hour urine free cortisol (UFC) was 282 μg/d (normal, <100 μg/d) at baseline and 269 μg/d after LDDST. The plasma ACTH concentration was 7 pg/mL. Other hormone profiles were within normal limits. The biochemical data are summarized in Tables 1 and 2.JOURNAL/endst/04.03/00019616-200711000-00011/table1-11/v/2021-02-17T201839Z/r/image-tiff Hormone ProfilesJOURNAL/endst/04.03/00019616-200711000-00011/table2-11/v/2021-02-17T201839Z/r/image-tiff Evaluation of Cushing SyndromeMagnetic resonance imaging (MRI) discovered a well-defined mass lesion, measuring about 4 × 4 cm, in the left adrenal gland, with isosignal on T1-weighted imaging but with slightly high T2-weighted signal intensity. The heterogenous signal dropped somewhat on the out-of-phase of the T1 chemical shift imaging, implying lipid content within the tumor (Fig. 1). 131I-6β-iodomethyl-norcholesterol (NP-59) scintigraphy revealed early visualization of accumulated radioactivity since day 1 in the left suprarenal area. This suggests a functioning adrenocortical tumor (Fig. 2).JOURNAL/endst/04.03/00019616-200711000-00011/figure1-11/v/2021-02-17T201839Z/r/image-tiff TIWI of MRI revealed a well-defined isosignal mass lesion (arrow), about 4 × 4 cm, in the left adrenal gland (1A). Chemical shift imaging disclosed a mildly heterogenous signal drop in the out phase, indicating lipid component of the tumor (1B). The adrenal lesion showed slightly high signal intensity on the T2WI (1C).JOURNAL/endst/04.03/00019616-200711000-00011/figure2-11/v/2021-02-17T201839Z/r/image-tiff NP-59 scintigraphy after dexamethasone suppression revealed an accumulation of radioactivity in the left suprarenal area (arrow) since day 1 (2A), with increasing intensity till day 4 (2B).The patient underwent a left adrenalectomy. The blood pressure markedly elevated (above 200/118 mm Hg) during the operation and dropped abruptly to 90/60 mm Hg after removal of the tumor. These dramatic features raised the clinical suspicion of pheochromocytoma. Regretfully, the catecholamines or metanephrines of serum or urine were not measured before surgery. Histologic examination revealed a mixed tumor with both pheochromocytoma and adrenocortical adenoma. There were round to polygonal tumor cells arranged in alveolar clusters or cords, which were positive in chromogranin, synaptophysin, melan-A and α-inhibin. The former 2 are the markers for pheochromocytoma and the latter 2 are for corticoadenoma (Fig. 3). Electron microscopic examinations disclosed 2 types of tumor cells admixed in all tumor clusters. One type of tumor cells had abundant mitochondria, well-developed rough endoplasmic reticuli, and aggregation of dense-core granules in cytoplasm, with diameter ranging between 121 nm and 292 nm. The other type contained abundant lipid inclusions and smooth endoplasmic reticuli, without dense-core endosecretory granules. The ultrastructural features suggested a mixture of adrenal medullary neuroendocrine and cortical endocrine tumor (Fig. 4).JOURNAL/endst/04.03/00019616-200711000-00011/figure3-11/v/2021-02-17T201839Z/r/image-tiff Histologic features of the adrenal tumor (H & E, 3A). The immunohistochemical stains showed predominant pheochromocytoma cells, which were positive for chromogranin (3B) and synaptophysin (3C), with scattered cortical cells for melan-A (3D), indicating the existence of mixed corticomedullary cells.JOURNAL/endst/04.03/00019616-200711000-00011/figure4-11/v/2021-02-17T201839Z/r/image-tiff Electron microscopic examinations disclosed 2 types of tumor cells admixed in all tumor clusters. One had abundant mitochondria, well-developed rough endoplasmic reticuli, and aggregation of dense-core granules in cytoplasm, with diameter ranging from 121 nm to 292 nm (A, B). The other contained abundant lipid inclusions and smooth endoplasmic reticuli without dense-core endosecretory granules (C, D).After the tumor resection, the symptoms of “spells” disappeared and blood pressure returned to normal. Glucocorticoid replacement was administered immediately after the operation. Abdominal computed tomography (CT) discovered a retroperitoneal abscess and the culture grew group D Salmonella enteritidis. Antibiotic therapy and adequate abscess drainage resolved the situation. Most features of CS faded gradually.DISCUSSIONCorticomedullary adenoma is extremely rare. To our knowledge, there have been only 4 cases reported.6–8 In 1969, Mathison and Waterhouse6 first reported an adrenal CS detected when hypertension developed during the surgical removal of the adrenal tumor. Both adrenal cortical and medullary tissues were found in the tumor. Akai et al7 reported a case of corticomedullary adenoma that had ipsilateral uptake of both 131I-metaiodobenzylquanidine and 131I-adosteral. The relatively “high” plasma ACTH level (43 pg/mL) in this case was unexplained. Michal and Havlicek8 reported 2 cases of pathology-proven adrenal corticomedullary adenoma. In addition to high plasma cortisol and catecholamine levels, the plasma aldosterone concentrations were also elevated. Details of hormone and image studies were not included in the article. Our patient had a histologically proved adrenal corticomedullary adenoma. Corticoadenoma was supported by a typical signal drop in chemical-shifting MRI.9,10 An intraoperative hypertensive crisis and a high-signal T2WI adrenal MRI feature11 suggested the concomitant existence of a functioning pheochromocytoma. Unfortunately, preoperative biochemical evidence of pheochromocytoma was not available. All reported cases with pathologically proven corticomedullary adenomas are summarized in Table 3.JOURNAL/endst/04.03/00019616-200711000-00011/table3-11/v/2021-02-17T201839Z/r/image-tiff Reported Cases of Pathology-Proven Corticomedullary AdenomaA positive NP-59 scintigraphy can be found in some adrenocortical carcinomas14,15 or in other rare adrenal conditions.16–18 In a study of adrenal incidentalomas, Gross et al19 have never found increased NP-59 uptake in the pheochromocytoma. Kalff et al20 also demonstrated a discordant pattern of NP-59 scintigraphy in a case of pheochromocytoma. We believed that the concordant early visualization of an adrenal mass in the NP-59 scintigraphy of our patient was due to the cortical component within the tumor.All the reported corticomedullary adenomas, including our present case, are unilateral. Ectopic ACTH or CRH production by pheochromocytoma or aberrant expression of gastric inhibitory polypeptide (GIP)21 or interleukin-1 (IL-1) receptors in the adrenal cortical tumors22 cannot explain the ACTH-independent unilateral adrenal corticomedullary adenoma. The rate-limiting step in catecholamine biosynthesis is the conversion of tyrosine to dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydroxylase (TH). Transcription of TH and the copper-containing enzyme dopamine β-hydroxylase (DBH) is stimulated by glucocorticoids. In addition, the expression of phenylethanolamine-N-methyl transferase (PNMT), which converts norepinephrine to epinephrine, is regulated by glucocorticoids. On the other hand, catecholamines may also play a role in the steroidogenesis of the adjacent cortical cells in a paracrine manner.23 One could hypothesize that corticomedullary adenoma is the chronic interaction between excessive glucocorticoids and catecholamines. There is experimental evidence that in humans, however, a chronic increase in cortisol production does not increase TH and/or PNMT activity.24 The pathogenesis of corticomedullary adenoma remains unknown.In summary, we present a rare case of corticomedullary adenoma causing overt clinical symptoms of CS and hypertensive crisis during operation. Histology confirmed a mixture of cortex and medulla-derived cells within 1 tumor mass.REFERENCES1. O’Brien T, Young WF Jr, Davila DG, et al. Cushing’s syndrome associated with ectopic production of corticotrophin-releasing hormone, corticotrophin and vasopressin by a phaeochromocytoma. Clin Endocrinol. 1992;37:460–467.[Context Link][CrossRef][Medline Link]2. White A, Ray DW, Talbot A, et al. Cushing’s syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin. J Clin Endocrinol Metab. 2000;85:4771–4775.[Context Link][Full Text][CrossRef][Medline Link]3. Cope O, Labbe JP, Raker JW, et al. 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Link]912202500019616-200711000-0001100003626_2002_41_95_lockhart_imaging_|00019616-200711000-00011#xpointer(id(citation_FROM_JRF_ID_d5454e688_citationRF_FLOATING))|11065213||ovftdb|SL000036262002419511065213citation_FROM_JRF_ID_d5454e688_citationRF_FLOATING[CrossRef]10.1016%2FS0720-048X%2801%2900444-200019616-200711000-0001100003626_2002_41_95_lockhart_imaging_|00019616-200711000-00011#xpointer(id(citation_FROM_JRF_ID_d5454e688_citationRF_FLOATING))|11065405||ovftdb|SL000036262002419511065405citation_FROM_JRF_ID_d5454e688_citationRF_FLOATING[Medline Link]11809539 Hormone Profiles Evaluation of Cushing Syndrome TIWI of MRI revealed a well-defined isosignal mass lesion (arrow), about 4 × 4 cm, in the left adrenal gland (1A). Chemical shift imaging disclosed a mildly heterogenous signal drop in the out phase, indicating lipid component of the tumor (1B). The adrenal lesion showed slightly high signal intensity on the T2WI (1C). NP-59 scintigraphy after dexamethasone suppression revealed an accumulation of radioactivity in the left suprarenal area (arrow) since day 1 (2A), with increasing intensity till day 4 (2B). Histologic features of the adrenal tumor (H & E, 3A). The immunohistochemical stains showed predominant pheochromocytoma cells, which were positive for chromogranin (3B) and synaptophysin (3C), with scattered cortical cells for melan-A (3D), indicating the existence of mixed corticomedullary cells. Electron microscopic examinations disclosed 2 types of tumor cells admixed in all tumor clusters. One had abundant mitochondria, well-developed rough endoplasmic reticuli, and aggregation of dense-core granules in cytoplasm, with diameter ranging from 121 nm to 292 nm (A, B). The other contained abundant lipid inclusions and smooth endoplasmic reticuli without dense-core endosecretory granules (C, D). Reported Cases of Pathology-Proven Corticomedullary AdenomaCoexistence of Adrenal Cushing Syndrome and Pheochromocytoma in a “Corticomedullary Adenoma”: A Case Report and Review of the LiteratureMa Wen-Ya MD; Yang, An-Hung MD, PhD; Chang, Yen-Hwa MD, PhD; Lin, Liang-Yu MD; Lin, Hong-Da MDCME Review Article #33CME Review Article #33617p 341-345