Primary Adrenocortical Nodular Dysplasia, a Distinct Subtype of Cushing’s Syndrome
Case Report and Review of the Literature
JENNIFER L. LARSEN, M.D. W. J. CATHEY, M.D. WILLIAM D. ODELL, M.D., Ph.D. Salt Lake City, Utah
From the Departments of Internal Medicine and Pathology, University of Utah Medical Center, Salt Lake City, Utah. Dr. Larsen was supported by National Institutes of Health Training Grant 1T32-AM07451-01. Requests for reprints should be addressed to Dr. Jennifer L. Larsen, Universi- ty of Utah Medical Center, Salt Lake City, Utah 84132. Manuscript accepted February 19, 1985.
Non-iatrogenic Cushing’s syndrome has been associated primarily with three entities: (1) pituitary-dependent processes due to pituitary adenomas or microadenomas causing adrenal hyperplasia; (2) pitu- itary-independent primary adrenal causes, predominantly unilateral adenomas, rarely multiple adenomas or adrenal carcinoma; (3) ectop- ic sources of adrenocorticotropic hormone (ACTH) production. Al- though non-neoplastic bilateral adrenal disease generally has been ascribed to extra-adrenal stimulation, a rare cause of Cushing’s syn- drome that involves bilateral adrenal nodule formation independent of pituitary stimulation has been identified. Nodular adrenal diseases represent a confusion of terms in the literature, but one subgroup of Cushing’s syndrome has most frequently-and, perhaps, most appro- priately-been designated primary adrenocortical nodular dysplasia. A case of this unusual entity is presented, and previous case reports pertaining to this confusing area of adrenal hyperfunction are reviewed. The characteristic manifestations that separate this diagnosis from other types of nodular adrenal disease are also discussed. Recognition of this diagnosis, although rare, is important, as bilateral adrenalecto- my is the treatment of choice.
Adrenal hyperfunction associated with adrenal nodularity on pathologic examination is a subject of much confusion in the literature due to the variety of terms used to designate all or some of these cases. Terminolo- gy used in the literature, sometimes interchangeably, includes primary adrenal hyperplasia, micronodular and macronodular types [1-5], mi- cronodular adrenal disease [6], primary adrenocortical microadenomato- sis [7], bilateral adenomatous adrenal hyperplasia [8], and primary adre- nal nodular dysplasia [9, 10]. Closer inspection of these cases shows that the group is not homogeneous. The clinical presentations are varied, the adrenal testing results are not uniform, and the adrenal glands may all demonstrate nodules but otherwise exhibit no single group of identifying characteristics. Past investigators have expressed concern that either these disorders reflect a wide continuum of a single metabolic abnormali- ty, or-more likely-this group of “adenomatous adrenal hyperfunction” can be subdivided into certain distinguishable subgroups with more unifying characteristics.
We present a case report of what has been termed primary adrenocor- tical nodular dysplasia, an uncommon diagnosis with a consistent, if confusing, presentation best treated by bilateral adrenalectomy. This case is of interest also because of a spurious computed tomographic finding that further confused the evaluation. We will also review the literature concerning this diagnosis and distinguish its features from other reported cases of bilateral adrenal nodular disease.
CASE REPORT
The patient was a 15-year-old young man from Madras, India. He was the product of a normal pregnancy and was normal at birth. He was considered short throughout child- hood but had no significant illness during this time. He first received medical attention in India at eight years of age, when weight gain without progression in height and the onset of axillary and pubic hair growth were noted. His bone age at this time was 11 years, the 8 A.M. cortisol value was 16 mg/dl, and 1 and 2 mg overnight dexamethasone sup- pression tests resulted in 8 A.M. serum cortisol values of 19 and 14 mg/dl, respectively. No diagnosis was made, and he received no treatment. He was followed until age 11, while he continued to experience increased body hair growth. At this time, he had normal plasma and urinary cortisol values as well as a normal sella turcica on skull roentgenography, and so a presumptive diagnosis of congenital adrenal hy- perplasia was made. He was treated with 5 mg predniso- lone per day, which was discontinued one month later due to marked skin thinning. He noted no change in either body habitus or hair growth during this time.
At the age of 15 years, he was evaluated at the University of Utah Medical Center. His symptoms at this time included inability to lose weight, abdominal striae formation, acne, severe hirsutism, easy bruis ability, decreased energy, and rough skin. His visual acuity had decreased recently, al- though he denied any field deficit. He had noted a clear left breast discharge for one to two weeks one month before presentation. His school performance had decreased mark- edly over the last one to two years and he had become much less physically active, although he denied specific muscle weakness. His family members had noted personal- ity changes, including social withdrawal occasionally to the point of paranoia. He had no prior history of hypertension or glucose intolerance. He also denied use of alcohol and illicit drugs and was taking no medications at the time of presen- tation. There was no endocrine disease, congenital defect, or hirsutism in the family history.
On physical examination, he was 53 inches tall and weighed 94 pounds. Truncal obesity, moon facies, promi- nent buffalo hump, and supraclavicular fat pads were present. His supine blood pressure was 170/125 mm Hg in the right arm and 160/120 mm Hg in the left without ortho- static change. Pulse was 135 beats per minute at rest. Direct ophthalmoscopy suggested a left lenticular opacity. No visual field deficits were demonstrated. No candidiasis was evident. The thyroid gland was normal in size and consistency. He had no evidence of gynecomastia or expressable breast discharge. Findings on lung and cardiac examination were within normal limits except for the per- sistent resting tachycardia. Abdominal examination showed an obese abdomen with reddish brown striae, 1 cm wide. No organomegaly or palpable masses were present. Geni- tal examination showed a small phallus with 4 by 2 cm firm testes bilaterally. He had an adult male hair distribution over the pubic area as well as in both axillae and over the chest. Results of neurologic examination were entirely normal except for mild lower extremity muscle weakness and very thin arms with decreased muscle mass by inspection. The
| Time (minutes) | Cortisol (mg/dl) |
|---|---|
| 0 | 22.5 |
| 15 | 30.8 |
| 30 | 31.1 |
| 60 | 27.9 |
skin was generally thin with striae evident over the upper arms as well as the abdomen. A few ecchymoses were evident, and minimal facial acne was present.
Roentgenography of the hips and shoulders showed dif- fuse osteoporosis. On the basis of wrist roentgenography, bone age was 16 years. Laboratory values on admission showed a potassium level of 3.4 meq/liter (normal, 3.8 to 5.4), uric acid level of 9.2 mg/dl, random blood sugar level of 160 mg/dl, and normal serum sodium, blood urea nitro- gen, and creatinine levels. The thyroxine value was 10.5 mlU/ml, and triiodothyronine resin uptake was 34 percent. Electrocardiogramawed sinus tachycardia.
Further endocrine testing showed a DHEA sulfate level of 1.95 µg/ml, testosterone level of 429 ng/dl, and serum cortisol levels of 18.6 and 18.4 µg/dl for 8 A.M. and 5 P.M. samples, respectively. Adrenocorticotropic hormone (ACTH) concentrations, measured by sensitive radioimmu- noassay, were less than 10 pg/ml at 8 A.M. The prolactin level was normal at 4.8 ng/ml. According to a Clinical Research Center protocol for Cushing’s syndrome, base- line urinary free cortisol was determined and was 25.4 ug/24 hours/m2; following 1 mg of dexamethasone, the urinary free cortisol value was 122 ug/24 hours/m2, and following 4 mg of dexamethasone, it was 362 ug/24 hours/m2. Serum cortisol values at 8 A.M. following over- night dexamethasone tests of 1 and 4 mg were 25.5 and 35.4 µg/dl, respectively. ACTH stimulation performed after overnight suppression with 4 mg of dexamethasone re- sulted in the values seen in Table I. Seventy-two hours later, overnight administration of 3.0 g of metyrapone re- sulted in an 8 A.M. cortisol value of 10.0 µg/dl with an 11- deoxycortisol value of 13.9 µg/dl and an ACTH value of less than 20 pg/ml. Computed tomographic scanning of the pituitary gland showed no abnormalities, and computed tomographic scanning of the adrenal glands showed bilater- ally small glands with an 8 mm nodule on the left. Indirect ophthalmologic examination demonstrated tilted optic discs bilaterally. These had previously been thought to be cata- racts, but no cataracts were found. Echocardiography showed left ventricular hypertrophy without other anatomic lesions.
Throughout his hospitalization, the patient exhibited per- sistent hypertension, which was treated with propranolol. When the results of the foregoing testing were available, the lack of dexamethasone suppressibility and lack of ACTH stimulation along with the 8 mm nodule seen on computed tomographic scanning of the abdomen led to probable diagnosis of a solitary adrenal adenoma. Thus, a
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3
A
left flank approach was recommended for the presumed curative left adrenalectomy, with one of us (W.D.O.) present at surgery. At time of removal, the left adrenal gland was seen to be small (3.11 g) and contained no large nodule corresponding to the computed tomographic ap- pearance. Instead, the adrenal cortex was studded with black nodules 1 to 2 mm in diameter, which were seen to be separated by areas of atrophic cortex on frozen section examination. A presumptive diagnosis of primary adreno- cortical nodular dysplasia was made. Right adrenalectomy was also recommended and was performed during the same operative period. Following surgery, high-dose opera- tive hydrocortisone therapy was tapered, and the patient was discharged receiving hydrocortisone, 20 mg in the morning and 10 mg at night, with 0.1 mg of fludrocortisone. The hydrocortisone dosage was subsequently tapered to 10 mg twice a day.
On gross pathologic examination, both adrenal glands were dark brown and soft. Weights of the left and right glands were 3.1 and 3.5 g, respectively, with the left gland measuring 3.5 by 1.5 by 1 cm on cross-section and the right 3 by 2 by 1 cm. Both contained numerous dark brown
nodules, 1 to 2 mm in diameter on cut surface, interspersed through the cortex (Figure 1). On microscopic examination, the cortex was normal in thickness and composed mainly of sheets and nodular aggregates of plump, closely packed polyhedral cells with abundant pink cytoplasm. The nuclei were slightly pleomorphic with a fine chromatin pattern and prominent nucleoli. The cytoplasm contained basophilic granular, brown pigment and occasional round eosinophilic inclusions. Atrophic cortical cells filled the space between these nodules in fasciculate and glomeruloid arrangements (Figure 2). Prominent collections of lymphocytes and plas- ma cells lay within cortical and medullary tissue. Pigment granules within the plump epithelial cells of the cortical nodules and in macrophages lying among the lymphoid cells stained bright red with periodic acid-Schiff and acid- fast stains and were thus identified as lipofuschin.
On follow-up, the patient showed increasing energy and muscular strength with normal blood pressure and weight loss over the subsequent six months.
COMMENTS
The term “Cushing’s syndrome” refers to a constellation of abnormalities resulting from hypercortisolism. “Cush- ing’s disease” refers to a pituitary-dependent, ACTH- mediated state of hypercortisollsm usually (80 percent) caused by an ACTH-secreting adenoma. Table Il lists the classification of causes of Cushing’s syndrome. The usual functioning nodule of the adrenal is ACTH-independent, and plasma ACTH concentration is low or undetectable when reliable assays are used. Adrenal hyperplasia is generally believed to be pituitary-dependent, although considerable controversy has arisen as to whether ACTH dependency exists or not in cases termed macronodular adrenal hyperplasia. In recent years, successful treatment of this disorder by yttrium treatment of the pituitary [11] and the documentation of significant amounts of ACTH using reliable assays (compared with previously unreli- able assays) have indicated that this disorder is secondary to pituitary pathology.
The patient described herein presents a rare form of primary adrenal disease producing Cushing’s syndrome that is ACTH-independent. The undetectable plasma ACTH, lack of suppression with high-dose dexametha- sone, and the small adrenal weight with atrophy between nodules all support this. However, the published literature concerning this entity is confusing. Chute et al [12] were the first to report a case of Cushing’s syndrome associ- ated with small pigmented nodules of the adrenal gland, but Ruder et al [6] first suggested that such a condition represented an entity distinct from the usual multi(ma- cro)nodular disease. These latter investigators character- ized the disorder by its unusual pathologic features: “presence of many small nodules containing black or brownish pigment diffusely studding the adrenal cortex.” The variety of terms coined for this lesion-or for nodular adrenal diseases, in general, with which this entity is
frequently grouped-has contributed to the confusion. Semantics aside, many different investigators subclassify the nodular adrenal diseases quite differently. Terms such as micro- versus macro-nodular adrenal disease are used in particular, although there is no established definition of either. Smals et al [4] delineated macronodular disease as nodules more than 0.5 cm, although much larger nodules have been demonstrated in adrenal glands otherwise termed as displaying microscopic hyperplasia. Whether distinctions based on nodular size have any functional significance is not clear. Pituitary imaging and surgery have resulted in the discovery of pituitary disease in the majority of these cases of hyperplasia, whether the adre- nal gland is “micro-” or “macro-” nodular. However, Smals et al [4] have suggested that adrenal glands with larger nodules have usually been present longer and are associated with less clearcut pituitary-dependence, in- cluding less successful outcome with pituitary surgery alone. Micro- and macro-nodular hyperplasia clearly rep- resent hyperplasia, regardless. Another type of “micro- nodular adrenal disease,” as described in this case report, is associated with adrenal atrophy between the nodules, and does not exhibit a spectrum of pathology from micro- nodules to much larger nodules as seen in hyperplastic adrenal disease. Yet this entity has been grouped with all other nodular adrenal conditions by many [3,5].
Thus, as outlined earlier, we agree with Ruder and his co-workers that a small subset of patients with nodular adrenal glands should be set apart for the following rea- sons: (1) the disease is distinct due to both the degree of nodule pigmentation and the cortical atrophy between the nodules as opposed to hyperplasia seen in other nodular disorders; (2) the Cushing’s symptoms are frequently mild enough that a long interval between onset of symptoms and diagnosis is not uncommon; (3) the condition usually presents in a younger age group; and (4) the treatment of this disorder requires bilateral adrenalectomy, as it is functionally independent of the pituitary and has never been associated with pituitary adenomas or microadeno- mas, in contrast to other forms of nodular hyperplasia.
We have reviewed the literature for past case reports that meet the following minimal criteria: (1) Cushing’s syndrome by clinical and laboratory criteria; (2) absence of high-dose dexamethasone suppression, indicating pitu- itary independence; and (3) pigmented nodules with inter- nodular cortical atrophy on pathologic examination of the adrenal glands (Tables III and IV). Due to inadequate pathologic description, some of the cases previously be- lieved to represent this disorder have been excluded. It is because of the third criterion that we favor the term primary adrenocortical nodular dysplasia over previous terms using hyperplasia for this subtype of adrenal nodular disease. Dysplasia strictly means an abnormality of form; unfortunately, as it has been applied to many precancer- ous lesions, it has come to imply a premalignant lesion.
TABLE II Cushing’s Syndrome: Causes
Cushing’s disease (usually pituitary adenoma) Associated with diffuse adrenal hyperplasia Associated with micronodular adrenal hyperplasia Associated with macronodular adrenal hyperplasia Ectopic adrenocorticotropic hormone production Ectopic corticotropic-releasing hormone production Adrenal tumors Single adenoma Multiple adenomas Carcinoma Exogenous steroids “Pseudo” Cushing’s syndrome (alcohol syndrome) Primary adrenocortical nodular dysplasia
There is no evidence that primary adrenocortical nodular dysplasia is a premalignant state. A newer term coined by Shenoy et al [25], bilateral primary pigmented nodular adrenocortical disease, is perhaps more descriptive of the lesion but less specific, as nodular hyperplasia can dis- play pigmented nodules as well.
Altogether, including the present case, 30 patients described in the literature have met our criteria; they ranged from seven days to 29 years old at presentation. The duration of symptoms varied between being present at birth, in some cases involving infants, to 18 years. Two infants have been included who do not completely meet the criteria in that no evidence of internodular atrophy was seen, and a persistent fetal zone was present [2,10]. Whether these cases represent an entirely different cause, as suggested by Shenoy et al [25], or whether the internodular atrophy had not yet developed because they presented as very young infants, cannot be determined. However, both infants demonstrated no evidence of pitu- itary disease and otherwise had pigmented nodules like those in the other reported cases.
All patients treated with bilateral adrenalectomy had resolution of the symptoms and signs of Cushing’s syn- drome. One patient improved after removal of a single adrenal gland; however, the condition recurred during pregnancy two years later [17], although the pregnancy was completed successfully without treatment. The pa- tient returned to “normal” function without surgery, but she continued to have undetectable ACTH and non- suppressible serum cortisol levels despite absence of clinical symptoms at five years’ follow-up. Two more subjects underwent only unilateral adrenalectomy with persistent biochemical abnormalities after surgery [6, 19]. One subject with recurrence four and a half years after single adrenalectomy required a second adrenalectomy, and another patient treated with unilateral adrenalectomy did not improve [7] until the second adrenalectomy was performed. Thus, although the abnormality is bilateral, its
| Reference | Pathologic Diagnosis | Sex/Age | Duration of Symptoms | Osteopenia | Other Features/Outcome |
|---|---|---|---|---|---|
| [12] | F/8 years | 3.5 years | Marked | Died two days after left adrenalectomy; pitu- itary normal at autopsy | |
| [13] | Adrenocortical hyper- plasia | F/13.6 years | 8 months | Present | Died eight months after partial adrenalecto- my of ulcer and pneumonia |
| [14] | F/14 months | 2 months | Absent | First successful bilateral adrenalectomy in infant | |
| [15] | Multinodular adrenal glands | F/15 years | 1 year | Marked | |
| [16] | F/19 years | 3 months | Moderate | ||
| [17] | F/18 years | 1 year | Absent | Pituitary irradiation unsuccessful; relapse two years later following left adrenalecto- my during pregnancy; ACTH suppressed five years later | |
| [8] | Bilateral adenomatous adrenal hyperplasia | F/2 years | 18 years | Marked | Pituitary Irradiation unsuccessful |
| [18] | Nodular adrenal hyper- plasia | M/7 weeks | 6 weeks | Marked | Died 13 weeks after surgery; pituitary nor- mal at autopsy |
| [9] | Primary adrenocortical nodular dysplasia | F/14 years | 3 years | Marked | |
| [19] | M/22 years | 6 months | Present | Testing not normal after surgery | |
| [20] | F/14 years | 4 years | Moderate | ||
| [6] | M/19 years | 2 years | Marked | Left adrenalectomy; no dexamethasone sup- pression after surgery | |
| F/23 years | 12 years | Marked | |||
| [7] | Primary adrenal mi- croadenomatosis | M/18 years | 12 years | Unresolved by pituitary irradiation and left adrenalectomy; history of fibromas and hyperpigmentation | |
| F/28 years | 14 years | Sister of preceding patient; died of cerebral hemorrhage from atrial myxoma; same skin findings | |||
| [21] | Primary bilateral nodu- lar cortical dysplasia | ?/28 years | |||
| ?/29 years | Brother had bilateral adrenalectomy; patho- logic features unknown | ||||
| [22] | Adrenal cortical nodular hyperplasia | M/17 years | 11 years | History of large-cell calcifying Sertoli cell tumor of the testis | |
| M/16 years | Brother of preceding patient; large-cell cal- cifying Sertoli cell tumor of the testis; died of ventricular myxoma; primary adre- nocortical nodular dysplasia at autopsy | ||||
| [2] | Nodular adrenal hyper- plasia | M/10 weeks | At birth | Died five weeks after subtotal adrenalecto- my | |
| F/7 days | At birth | Sister of preceding patient; same congenital anomalies as brother | |||
| [10] | Primary adrenocortical nodular dysplasia | M/6.5 months | 3 months | Mild | |
| M/14.4 years | 5 years | Mild | |||
| [23] | Micronodular adrenal disease | F/17 years | 4 years | ||
| [24] | Pigmented multinodular adrenodysplasia | F/14 years | 3 years | Marked | |
| M/14 years | 3 years | Marked | Nephew of preceding patient | ||
| [25] | Bilateral primary pig- mented nodular adre- nocortical disease | M/12 years M/19 years | |||
| F/21 years | |||||
| Present report | Primary adrenocortical nodular dysplasia | M/15 years | 7 years | Moderate |
| Reference | Plasma ACTH | Dexamethasone Suppression* | ACTH Response | Adrenal Gland Weight (g; left/right) | Nodules | Atrophy | |
|---|---|---|---|---|---|---|---|
| Size (mm) | Pigment | ||||||
| [12] | 4.7/5.3 | 1-5 | Yellow to dark red brown | + | |||
| 13] | 6 + 2.1/2.5 | Gold-brown | + | ||||
| 14] | Low | None | Slightly enlarged | + | |||
| 15] | No | Mild increase | 16.2 total | Green-brown | Focal | ||
| 16] | No | None | 3.2/3.1 | 2-3 | Brown | + | |
| [17] | No | 6 (left) | Brown | + | |||
| [8] | No | Increase after two days | "Normal" | Micro | Brown | + | |
| [18] | No (2 mg) | 4.7/4.3 | - | ||||
| [9] | No | No | 5.5/4 | <2 | Brown | + | |
| 19] | No | Yes | 10 (left) | Micro-2 | Brown-black | Focal | |
| [20] | t | No | No | 5.6/6.7 | 1-5 | Blue | + |
| [6] | No | No | 3.5 (left) | 3 | Dark brown | + | |
| No | Yes | 0.9/3.5 | 2 | Black | + | ||
| [7] | "Mild" | 12.5/8.5 | Gray-yellow-brown | + | |||
| No | 7/5.5 | 1.5 | Gray-yellow-brown | + | |||
| [21] | No | 5-7 each | Yellow and brown | ||||
| No | 5-7 each | Yellow and brown | |||||
| [22] | |||||||
| [2] | No | No | 9 total | Dark brown | - | ||
| [10] | 2.3/2.6 | Micro | + | ||||
| 6.3/2.5 | Micro-6 | Brown | + | ||||
| [23] | No | 8.2/5.3 | Micro-1 | Black and yellow | + | ||
| [24] | No | No | 10.5 total | 1-4 | Brown/yellow-gray | + | |
| No | No | 9.8 total | 1-4 | + | |||
| [25] | Normal | No | 9.2 total | 4 | Green-black | + | |
| Normal | No | 7.0 total | 3 | Brown-black | + | ||
| Normal | No | 4.8 total | 4 | Dark brown | + | ||
| Present | No | No | 3.1/3.5 | 1-2 | Black | + | |
| report | |||||||
* Cortisol suppression with dexamethasone; many early reports did not indicate how much dexamethasone was given.
+ Undetectable in assay used.
symptoms may be mild enough that unilateral adrenalec- tomy can result in improvement.
The infants or children had, in general, a more fulmi- nant course with severe symptoms developing rapidly. Of six cases reported in children eight years or younger, three died postoperatively; however, two had been treat- ed with subtotal adrenalectomy, and the third was man- aged prior to the availability of pharmacologic corticoste- roids [2, 12, 14, 18].
None of the patients described in the literature had pituitary disease as evaluated by sella roentgenography, computed tomographic scanning of the head when it became available, or autopsy in five cases. None of the patients was reported to have had Nelson’s syndrome postoperatively, including one case followed for 21 years [10].
Meador et al [9] were struck by the incidence of osteoporosis on review of this subgroup of patients with adrenal nodular disease. Of the 30 patients described to date, marked osteoporosis was present in nine, osteopo- rosis was noted as present or mild in four, moderate osteoporosis was seen in three, osteoporosis was absent
in two, and the condition was not commented on in regard to 12. Thus, although osteoporosis may be a common finding, it may or may not be a predominant feature in the majority of cases.
Four families with more than one member affected have been described, a brother and sister in two cases, and of two brothers in one case, and an uncle and nephew in another. All were products of non-consanguineous marriages. In three of the families, other congenital ab- normalities were noted. In one report [7], myxomatous fibromas and Peutz-Jeuger type pigmentation were found in one subject, a cardiac myxoma as well as the fibromas and pigmentation were found in the patient’s affected sister, and one other brother died at age four of atrial myxoma without history of adrenal dysfunction. In another report, both brother and sister had unusual facies with hypertelorism, large fontanelles, small heads, and dark skin pigmentation [2]. Their mother was reported to have had five first-trimester miscarriges. One family had two members with primary adrenocortical nodular dysplasia, one found at autopsy at age 16 after death caused by embolic disease from a cardiac myxoma without prior
TABLE V Characteristics of Primary Adrenocortical Nodular Dysplasia
History
Onset in infancy, childhood or adolescence
Generally mild symptoms: obesity, decreased growth, viriliza- tion
Family history may include similar cases
Long interval between onset of symptoms and diagnosis not uncommon
Physical examination: no characteristic findings other than those of Cushing’s syndrome in general
Non-endocrinologic testing Osteoporosis on bone films
Computed tomographic scanning of pituitary shows no abnor- malities
Computed tomographic scanning of adrenal glands may show normal or slightly enlarged glands without evidence of mass
Endocrinologic testing
Moderate cortisol elevation with low ACTH on multiple samples Cortisol not suppressed by high-dose dexamethasone adminis- tration
ACTH stimulation equivocal
Pathologic features Gross Glands often not enlarged, but both involved Often no visible nodularity on gross examination Cortical pigmentation evident on section
Microscopic Small, pigment (lipofuschin) filled nodules Internodular adrenal atrophy
Invasion into pericapsular fat and vascular structures de- scribed
Clinical course
Unilateral adrenalectomy usually does not ameliorate symp- toms
Bilateral adrenalectomy with appropriate steroid replacement results in normal adrenal function
No evidence of premalignant state
No report of subsequent Nelson’s syndrome or hyperpigmenta- tion following surgery
Cushing’s symptoms [22]. Both members also had large- cell calcifying Sertoli cell tumors of the testes, and one other family member had cardiac myxomas resulting in death at age 10. In another case, a brother with past bilateral adrenalectomy was noted, although the patholog- ic features were unknown [21]. Thus, primary adrenocor- tical nodular dysplasia may represent a congenital anom- aly in some cases that can be recessively transmitted, perhaps with traits for other congenital anomalies, such as hyperpigmentation, cutaneous and cardiac myxomas, and large-cell calcifying Sertoli cell tumors of the testes.
Many of the cases were reported prior to the availability of ACTH radioimmunoassay, but very reliable plasma ACTH values can be helpful. Wolfsen and Odell [26] have determined average plasma ACTH concentrations at mul- tiple, carefully adjusted cortisol concentrations to estab- lish the normal ACTH/cortisol dose-response relation-
ship, as well as that in subjects with Cushing’s disease. Although ACTH is seldom elevated above normal in Cush- ing’s disease, it is always at an inappropriate concentra- tion in relation to the cortisol level. Using reliable and sensitive ACTH assays (in patients with functioning pri- mary adrenal nodules), the plasma ACTH concentration is usually less than 10 pg/ml and never above 25 pg/ml in our experience. In Cushing’s disease, ACTH values range from 40 to 150 pg/ml. Patients with Nelson’s syndrome and ectopic ACTH secretion have higher ACTH values, often 7,500 pg/ml [27]. The patient described herein had undetectable ACTH values (less than 10 pg/ml), as did several other patients described in the literature for whom ACTH radioimmunoassay was available.
In addition to low or undetectable ACTH levels, the absence of dexamethasone suppression aids in diagno- sis. However, lack of suppression has also been de- scribed in adrenal nodular hyperplasia caused by pituitary ACTH overproduction, as reported by Smals et al [4] as well as others [1,28,29]. In these cases, ACTH values were inappropriately high for the corresponding cortisol concentration. Likewise, lack of dexamethasone sup- pression can also occur with adrenal adenoma; in this case, ACTH would be expected to be suppressed just as in primary adrenocortical nodular dysplasia. However, computed tomographic scanning of the abdomen and the surgical specimen itself should demonstrate the adeno- ma. The computed tomographic appearance proved to be misleading in our case, however, which may be an even greater problem if the “resolution” of this procedure improves.
Although certain historic and diagnostic clues may lead an investigator to suspect this unusual condition, the pathologic features of the adrenal glands themselves con- firm it. Grossly, the glands may be small to slightly en- larged but never as large as seen with long-standing hyperplasia. The nodules may not be apparent on gross examination, but they usually are visible as focal pigmen- tation on cut section. The nodules have been described as up to 5 mm in size, but they usually are microscopic to 3 mm. The pigment is lipofuschin and has been described as yellow-brown, red-brown, dark blue, grey, brown, or black. Except for the two infants mentioned earlier, atro- phy was universal when detailed pathologic description was included. In one case, pigmented nodules were found in the capsule and pericapsular fat [7]. This has previously been described with hyperplasia as well [30]. In another case, adrenal cells were found in a vascular space [21], and a rest of abnormal adrenal tissue was also found on postmortem examination of the testes in a separate case [13] and suspected in another [22]. However, no evi- dence of metastasis or associated adrenal carcinoma has been described.
The importance of recognizing this diagnosis as a separate condition is to identify the necessity for bilateral
adrenalectomy to cure the Cushingoid symptoms. This is demonstrated by the failure of pituitary irradiation to con- trol the symptoms in three cases [7,8,17], the failure of unilateral adrenalectomy in those cases described previ- ously, the absence of any identified Nelson’s syndrome following adrenalectomy, and the lack of dexamethasone suppressibility indicating adrenal autonomy.
In summary, although a spectrum of nodular adrenal diseases has been identified under a variety of group terms, at least one group deserves separate distinction. As these cases demonstrate associated internodular ad- renocortical atrophy rather than hyperplasia, they are best described by the term primary adrenocortical nodular dysplasia, the characteristics of which are summarized in Table V. Many cases occur in childhood or after a long period of symptoms in adolescence or early adulthood; 28 of 28, for whom duration of symptoms was noted, had onset of symptoms or diagnosis by age 22. On laboratory evaluation, the plasma ACTH value is normal or sup- pressed, and cortisol production is unsuppressible by
high-dose dexamethasone. The computed tomographic appearance of the pituitary should be normal, and com- puted tomographic scanning of the adrenals would be expected to show normal size to mild enlargement, unless the investigator is led astray by a false-positive report of adrenal mass. The adrenal lesion is bilateral and consists of microscopic to 5 mm brown-black pigmented nodules with internodular cortical atrophy. When this lesion is encountered, bilateral adrenalectomy is generally re- quired for control of the Cushing’s symptoms.
ADDENDUM
Since this report was submitted, two more reports have described a dominant inheritance of a complex of myxo- mas, spotty pigmentation, and endocrine overactivity in- cluding primary adrenal nodular dysplasia. Eighteen of the 40 patients reviewed had established pigmented nodular adrenal disease. Of these 18 patients, nine are included in this review [31,32].
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