DOI: 10.1148/radiol.2443041507
(Radiology 2007;244:923-926.)
© RSNA, 2007
Case 121: Familial Adrenocorticotropin-independent Macronodular Adrenal Hyperplasia Causing Cushing Syndrome1
Timothy D. Watson, MD, MPH ,
Shital J. Patel, MBBS and
Peter M. Nardi, MD
1 From the Department of Radiology, Long Island College Hospital, 339 Hicks St, Brooklyn, NY 11201. Received September 1, 2004; revision requested November 10; revision received December 16; accepted January 20, 2005; final version accepted March 2.
Correspondence: Address correspondence to T.D.W. (e-mail: twowatsons1{at}msn.com).
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HISTORY
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A 41-year-old African-American woman with a medical history of poorly controlled hypertension was found unresponsive. She was intubated by paramedics in the field. When she arrived at the emergency department, neurologic examination revealed obtunded mental status with right-sided hemiparesis and diminished peripheral reflexes. Vital signs were remarkable for a blood pressure of 220/170 mm Hg. An unenhanced computed tomographic (CT) scan of the head was obtained, and the patient was admitted to the neurosurgical intensive care unit for further observation. Routine chest radiography performed at admission revealed symmetric but abnormal widening of the superior mediastinum. This finding led us to obtain contrast material–enhanced CT scans of the chest and upper abdomen after intravenous administration of 140 mL of iopromide (Ultravist; Berlex Laboratories, Wayne, NJ). Several years later, this patient's older sister presented with worsening uncontrolled blood pressure. Diagnostic work-up, including intravenous contrast-enhanced CT of the abdomen, was performed in the patient's sister.
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IMAGING FINDINGS
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Unenhanced CT of the head revealed an acute large left basal ganglia and frontal lobe intracerebral hemorrhage with mass effect, left-to-right midline shift, subfalcine herniation, and intraventricular extension into the left lateral ventricle (Fig 1). Admission chest radiography revealed symmetric but abnormal superior mediastinal widening. This finding was confirmed with subsequent contrast-enhanced chest CT (Fig 2), which revealed diffuse fatty infiltration of the mediastinum. This finding was consistent with mediastinal lipomatosis. The upper abdominal portion of this examination revealed incidental findings of bilateral soft-tissue masses in the expected location of the adrenal glands (Fig 3). Several years later, contrast-enhanced CT of the abdomen was ordered as part of the patient's sister's directed work-up for worsening uncontrolled hypertension. This examination revealed similar, albeit more dramatic, findings of large bilateral macronodular soft-tissue adrenal masses (Fig 4).
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Figure 1: Unenhanced transverse CT scan of the head. Large acute left basal ganglia and frontal lobe intracerebral hematoma are visible. There is substantial mass effect obliterating the left lateral ventricle, with left-to-right midline shift and subfalcine herniation (arrowhead). Intraventricular extension of the hemorrhage (arrow) is also visible.
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Figure 2a: (a, b) Sequential transverse contrast-enhanced CT scans of the chest demonstrate uniform and symmetric encasement of the mediastinal structures, with a smoothly contoured hypoattenuating mass (arrowheads). This insinuating mass does not have notable mass effect and demonstrates homogeneous fat attenuation. These findings are characteristic of mediastinal lipomatosis. Aspiration is responsible for the right upper lobe abnormality.
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Figure 2b: (a, b) Sequential transverse contrast-enhanced CT scans of the chest demonstrate uniform and symmetric encasement of the mediastinal structures, with a smoothly contoured hypoattenuating mass (arrowheads). This insinuating mass does not have notable mass effect and demonstrates homogeneous fat attenuation. These findings are characteristic of mediastinal lipomatosis. Aspiration is responsible for the right upper lobe abnormality.
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Figure 3a: (a, b) Selected transverse contrast-enhanced CT scans of the upper abdomen demonstrate bilateral homogeneous soft-tissue attenuation masses (arrowhead) in the expected locations of the adrenal glands.
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Figure 3b: (a, b) Selected transverse contrast-enhanced CT scans of the upper abdomen demonstrate bilateral homogeneous soft-tissue attenuation masses (arrowhead) in the expected locations of the adrenal glands.
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Figure 4: Sequential transverse contrast-enhanced CT scans of the abdomen obtained several years later in the patient's sister demonstrate similar, albeit more dramatic, findings of bilateral macronodular adrenal masses (arrowheads). Note the readily apparent large contour-deforming and homogeneously enhancing nodules characteristic of adrenocorticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH).
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DISCUSSION
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Analysis of this case required linking certain clinical and imaging findings. First, poorly controlled hypertension in a relatively young and otherwise healthy African-American woman with an accelerated hypertensive emergency indicated secondary hypertension (1). The finding of mediastinal lipomatosis, particularly in the setting of secondary hypertension, strongly indicated a diagnosis of Cushing syndrome.
The finding of bilateral adrenal masses argued against iatrogenic causes and indicated an organic adrenal cortical origin of Cushing syndrome. Our arrival at the final diagnosis required us to connect these seemingly independent findings with knowledge of adrenal abnormalities responsible for Cushing syndrome, particularly those that involve both glands.
Iatrogenic steroid intake is the most common cause of Cushing syndrome (2). When one encounters the remaining causes of Cushing syndrome, it is essential to differentiate between ACTH-dependent and ACTH-independent forms. Approximately 80% of patients with Cushing syndrome have ACTH dependence: Of the ACTH-dependent types of Cushing syndrome, 85% are due to an ACTH-secreting pituitary adenoma (ie, Cushing disease), and the remaining 15% are due to ectopically ACTH-secreting tumors (3). In this patient, the clinical biochemical work-up findings were consistent with ACTH-independent hypercortisolism, as will be discussed later, and no pituitary or primary soft-tissue masses were found.
ACTH-independent hypercortisolism is always of adrenocortical origin. There are only a few primary adrenal diseases that cause Cushing syndrome, and they are most commonly (>95%) caused by an adrenal neoplasm (ie, hyperfunctioning adrenocortical adenoma or carcinoma). Primary adrenal processes that affect the glands bilaterally are even rarer and are limited to three clinically and radiologically discrete entities. Primary pigmented nodular adrenal dysplasia is typically seen in younger female patients and is often associated with Carney complex. This disease has a micronodular CT appearance with normal-sized glands; thus, findings in this patient were inconsistent with this diagnosis. Pheochromocytomas, which are frequently bilateral in the setting of multiple endocrine neoplasia II syndrome, commonly occur in patients with hypertension; however, the other stigmata of Cushing syndrome are not encountered unless ACTH is also secreted. Typically, AIMAH is seen in middle-aged patients with equal sex distribution and is currently not a part of any described complex. AIMAH has characteristic imaging findings that include bilaterally enlarged glands with multiple nodules that range in size from 0.1 to 5.5 cm. The findings described in this patient (macronodular bilaterally enlarged adrenal glands in the setting of Cushing syndrome) are most typical of AIMAH (4).
The differential diagnosis of bilaterally enlarged nodular adrenal glands may include bilateral metastatic disease, granulomatous disease, or multinodular adrenal hyperplasia due to chronic stimulation in Cushing disease. Patients with metastatic disease or granulomatous disease do not present with symptoms of Cushing syndrome. They are usually asymptomatic; however, if they are symptomatic, they have hypocortisolism. The smaller nodules encountered in multinodular adrenal hyperplasia, which can be as large as 2 cm, typically can be used to distinguish this process from AIMAH (5).
AIMAH has a characteristic and fairly consistent CT appearance. There is typically marked enlargement of both adrenal glands in association with multiple prominent nodules, the largest of which have been reported to be 5.5 cm (4). The size of the nodules varies, and no cutoff criteria have been described. A case with a CT appearance similar to that of bilateral adrenal hyperplasia has been reported (5); however, typically, macronodules that distort the normal contour of the adrenal glands are the predominant finding. The nodules of AIMAH typically demonstrate soft-tissue attenuation values and usually are homogeneous.
The appearance of AIMAH on magnetic resonance (MR) images is also fairly consistent. The adrenal glands are hypointense to the liver, approximately isointense to muscle on T1-weighted images, and hyperintense to the liver on T2-weighted images. There is characteristic signal dropout on out-of-phase chemical shift MR images, consistent with the lipid-rich composition of the nodules. However, MR imaging does not contribute much more information than that acquired with CT.
Additional imaging may include examination of the pituitary gland to exclude pituitary tumors and ACTH-dependent macronodular adrenal hyperplasia if these entities were not satisfactorily excluded on the basis of biochemical or radiologic findings. Adrenal scintigraphy with NP59 (iodine 131–labeled 6-ß-iodomethyl-19-norcholesterol) has demonstrated bilateral uptake in the majority of reported cases. The presence of unilateral uptake has been used to guide treatment options, including bilateral versus unilateral adrenalectomy (4).
AIMAH is a rare idiopathic cause of Cushing syndrome that was described by Kirschner et al in 1964 in a 40-year-old woman with long-standing Cushing syndrome (6). Approximately 110 cases have been reported since then, and AIMAH is now recognized as a rare but distinct cause of Cushing syndrome that accounts for less than 1% of cases (7). A review of the case series presented in the literature revealed that the mean age of patients who present with symptoms of AIMAH is approximately 49 years and ranges from 32–62 years (8,9). These patients are a decade older than those who present with symptoms of Cushing disease. The incidence of this disease in male patients is almost equal to that in female patients; this is contrary to the female predominance in most other causes of Cushing syndrome, including primary pigmented nodular adrenal dysplasia. Although many earlier case reports have been from Japan, no important racial or geographic factors have been noted.
The clinical presentation of AIMAH is variable and ranges from hypertension to psychiatric changes. Although intracranial hemorrhage has been mentioned as a possible complication, to our knowledge, it has not been reported previously as an initial presentation. The typical biochemical abnormalities associated with AIMAH include failure to suppress cortisol levels after dexamethasone suppression, a low or undetectable level of serum ACTH, and a blunted response to corticotrophin-releasing hormone stimulation.
Familial Cushing syndrome is a rare disease, and most cases are primary pigmented nodular adrenal dysplasia, which has an autosomal dominant inheritance pattern. However, a few cases of familial AIMAH have been reported; thus, there may be a genetic basis for its pathogenesis. Findlay et al (10) reported the occurrence of this disease in a mother and her daughter; to our knowledge, this was the first report of this disease in two generations of a family. In the other case reports, authors described AIMAH in a brother and sister (11), in two brothers (12), in two brothers and a sister (13), and in two sisters (the current case). The overwhelming majority of reported cases appear to be sporadic.
AIMAH demonstrates a characteristic histologic appearance that consists of cord-forming clear cells with nest-forming compact cells. Sasano et al (14) described the presence of a differential enzyme expression within these cells, P450c17 in compact cells and 3 bHSD in clear cells, that led to inefficient cortisol production. This inefficiency may help explain the large number of cells necessary for Cushinoid symptoms to manifest clinically, as evidenced by the characteristic marked enlargement of the adrenal glands caused by the AIMAH at the time of diagnosis. Lieberman et al (8) described the average duration of disease at the time of diagnosis as being approximately 4.3 years. This relatively long latent period provides the radiologist with a theoretically wide window of opportunity to first suggest incidentally discovered bilateral macronodular hyperplasia and AIMAH. This time may facilitate early diagnosis and intervention.
Definitive therapy for AIMAH is surgery. In the current case, histopathologic correlation was not performed, as the patient refused surgery and died 6 months later from complications. The patient's sister underwent bilateral adrenalectomy shortly after her presentation, and findings in histopathologic specimens were consistent with AIMAH. She had an uncomplicated postoperative course and, at the time of last report, was doing well with physiologic doses of steroid replacement.
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FOOTNOTES
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Authors stated no financial relationship to disclose.
| Part one of this case appeared 4 months previously and may contain larger images.
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References
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- Hypertension. In: Goldman L, Ausiello D, eds. Cecil's textbook of internal medicine. 22nd ed. Philadelphia, Pa: Saunders, 2004; 360–361.
- Kirk LF Jr, Hash RB, Katner HP, Jones T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician 2000;62:1119–1127. [Published correction appears in Am Fam Physician 2002;65(3):386.][Medline]
- Soodini G, Rivas S. Cushing syndrome due to adrenocorticotropin-independent macronodular adrenal hyperplasia. Hosp Physician 2004;000:47–52.
- Doppman JL, Chrousos GP, Papanicolaou DA, Stratakis CA, Alexander HR, Nieman LK. Adrenocorticotropin-independent macronodular hyperplasia: an uncommon cause of primary adrenal hypercortisolism. Radiology 2000;216:797–802.[Abstract/Free Full Text]
- Doppman JL, Nieman LK, Travis WD, et al. CT and MR imaging of massive macronodular adrenocortical disease: a rare cause of autonomous primary adrenal hypercortisolism. J Comput Assist Tomogr 1991;15:773–779.[Medline]
- Kirschner MA, Powell RD Jr, Lipsett MB. Cushing's syndrome: nodular cortical hyperplasia of adrenal glands with clinical features suggesting adrenocortical tumor. J Clin Endocrinol Metab 1964;24:947–955.[Abstract/Free Full Text]
- Terzolo M, Boccuzzi A, Ali A, et al. Cushing's syndrome due to ACTH-independent bilateral adrenocortical macronodular hyperplasia. J Endocrinol Invest 1997;20:270–275.[Medline]
- Lieberman SA, Eccleshall TR, Feldman D. ACTH-independent massive bilateral adrenal disease (AIMBAD): a subtype of Cushing's syndrome with major diagnostic and therapeutic implications. Eur J Endocrinol 1994;131:67–73.[Abstract/Free Full Text]
- Rockall AG, Babar SA, Sohaib SA, et al. CT and MR imaging of the adrenal glands in ACTH-independent Cushing syndrome. RadioGraphics 2004;24:435–452.[Abstract/Free Full Text]
- Findlay JC, Sheeler LR, Engeland WC, Aron DC. Familial adrenocorticotropin-independent Cushing syndrome with bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 1993;76:189–191.[Abstract]
- Minami S, Sugihara H, Sato J, et al. ACTH independent Cushing syndrome occurring in siblings. Clin Endocrinol (Oxf) 1996;44:483–488.[CrossRef][Medline]
- Oheda T, Noguchi Y, Morio H, Terano T, Hirai A, Tamura T. Study on steroidogenic activity of ACTH-independent macronodular adrenocortical hyperplasia which occurred in brothers in a cancer family. Folia Endocrinol 1995;71:416.
- Someya T, Koyano H, Ozawa Y. ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) in two brothers and a sister. Folia Endocrinol 1996;72:762.
- Sasano H, Suzuki T, Nagura H. ACTH-independent macronodular adrenocortical hyperplasia: immunohistochemical and in situ hybridization studies of steroidogenic enzymes. Mod Pathol 1994;7:215–219.[Medline]
Congratulations to the 55 individuals and four resident groups that submitted the most likely diagnosis (familial adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing Syndrome) for Diagnosis Please, Case 121. The names and locations of the individuals and resident groups, as submitted, are as follows:
Individual responses
- Hisashi Abe, MD, Suita City, Osaka, Japan
- Erhan Akpinar, Ankara, Turkey
- Hans Bender, MD, Krefeld, Germany
- Eric L. Bressler, MD, Minnetonka, Minn
- Antonio A. Cavalcanti, MD, São Paulo, Brazil
- Peter De Baets, Damme, Belgium
- Mustafa Kemal Demir, MD, Istanbul, Turkey
- Thaworn Dendumrongsup, MD, Songkla, Thailand
- Walter T. Depaulaneto III, MD, Rio de Janeiro, Brazil
- Seyed A. Emamian, MD, PhD, Rockville, Md
- Virginia Fattal Jaef, MD, Rosario, Argentina
- Akira Fujikawa, MD, Setagaya, Tokyo, Japan
- Vidisha V. Ghole, MD, Irving, Tex
- Douglas E. Goodman, MD, Saint Joseph, Mo
- Flavius F. Guglielmo, MD, Basking Ridge, NJ
- Pramod K. Gupta, MD, Plano, Tex
- Alberto C. Iaia, MD, Wilmington, Del
- Waleed M. Ibrahim, MD, Columbus, Ohio
- Masako Kataoka, MD, Cambridge, United Kingdom
- Yasuhiro Kawahara, Nagasaki, Japan
- Rujimas Khumtong, MD, Hat Yai, Songkhla, Thailand
- Richard E. Krauthamer, MD, Rolling Hills, Calif
- Stefanos Lachanis, Athens, Greece
- Myron M. Levitt, MD, Scotch Plains, NJ
- David A. Lisle, MBBS, Brisbane, Australia
- Edward Lubat, MD, Englewood, NJ
- Satoshi Matsushima, MD, Tokyo, Japan
- Waldir H. Maymone, MD, Rio de Janeiro, Brazil
- Nikolaos Michailidis, Thessaloniki, Greece
- Sankar R. Mondal, MD, Nassau, Bahamas
- Tetsuo Nakayama, MD, Osaka, Japan
- Tammam N. Nehme, MD, East Wenatchee, Wash
- Hiroshi Nobusawa, MD, PhD, Ota, Tokyo, Japan
- Klaus Orth, Aachen, Germany
- Ivan Pilate, Brussels, Belgium
- Ilias Primetis, MD, Athens, Greece
- Daniel C. Rappaport, MD, Toronto, Ontario, Canada
- Manoel D. Rocha, MD, São Paulo, Brazil
- Tsutomu Sakamoto, MD, Tokyo, Japan
- Matthew P. Shapiro, MD, Charlottesville, Va
- Hideki Shima, MD, Tokyo, Japan
- Taro Shimono, MD, Osaka, Sayama, Japan
- Subramanian Subramanian, MD, New Delhi, India
- Kouichi Sugiyama, Numazu, Japan
- Norio Takahashi, MD, Fukui, Japan
- Kazuma Terauchi, Fujieda, Shizuoka, Japan
- Ricardo H. Trueba, MD, Buenos Aires, Argentina
- Baris I. Turkbey, MD, Ankara, Turkey
- Herminia Tyminski, MD, Manama, Bahrain
- Hiroyuki Ueda, MD, Kobe, Japan
- Eleni Vafeiadou, Thessaloniki, Greece
- Bonny Varghese, MD, Melbourne, Australia
- Jeffrey H. West, MD, Jacksonville, Fla
- David C. Wilkes, MD, Dallas, Tex
- Joe Yut, Olathe, Kan
Resident group responses
- Diagnostico Medico Radiology Residents, Buenos Aires, Argentina
- Prince of Songkla University Radiology Residents, Hat Yai, Songkla, Thailand
- Santa Casa da Misericórdia do Rio de Janeiro Radiology Residents, Rio de Janeiro, Brazil
- Trakya University School of Medicine Radiology Residents, Edirne, Turkey
TOP
HISTORY
IMAGING FINDINGS
