CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL
Founded by Richard C. Cabot
Nancy Lee Harris, M.D., Editor Jo-Anne O. Shepard, M.D., Associate Editor Sally H. Ebeling, Assistant Editor
Eric S. Rosenberg, M.D., Associate Editor Alice M. Cort, M.D., Associate Editor Christine C. Peters, Assistant Editor
Case 36-2006: A 35-Year-Old Pregnant Woman with New Hypertension
Anne Klibanski, M.D., Antonia E. Stephen, M.D., Michael F. Greene, M.D., Michael A. Blake, M.D., and Chin-Lee Wu, M.D., Ph.D.
PRESENTATION OF CASE
Dr. Andrea L. Utz (Endocrinology): A 35-year-old pregnant woman (gravida 2, para 1) was admitted to this hospital at 19 weeks and 6 days of gestation because of the re- cent onset of hypertension and diabetes.
Three weeks before admission, at a routine prenatal visit, her blood pressure was 150/100 mm Hg. On the same day she saw her primary care physician, who recorded a blood pressure of 172/102 mm Hg. The results of a physical examination were nor- mal. Urinalysis showed glucose (4+). The results of other laboratory tests are shown in Table 1. The next day, the blood pressure was 180/100 mm Hg. The blood glucose level 1 hour after the oral administration of glucose (50 g) was 346 mg per deciliter (19.2 mmol per liter). Treatment with labetalol, glyburide, and potassium supple- ments was initiated. The results of fetal ultrasound examination were normal for the gestational age of the fetus. Three weeks later, despite increasing doses of labetalol, the patient’s blood pressure remained in the range of 180/110 mm Hg and her fast- ing blood glucose level ranged between 140 and 180 mg per deciliter (7.8 and 10.0 mmol per liter); the patient was admitted to the hospital.
The patient had gained 6.8 kg in weight during the pregnancy. She had recently had polyuria and polydipsia and increased facial puffiness; her complexion was chronically ruddy. She did not have headaches, proximal muscle weakness, bruising, flushing, abdominal pain, edema, palpitations, diaphoresis, edema, or changes in vi- sion. Her menses had been regular before pregnancy, and she had had no difficulty conceiving with either this pregnancy or a pregnancy 3 years earlier, during which she had had mild, diet-controlled gestational diabetes. She had been mildly over- weight, with a body-mass index (the weight in kilograms divided by the square of the height in meters) of approximately 25 for several years. She did not smoke, drink alcohol, or use illicit drugs. She was married, with a 2-year-old daughter. Her mother and maternal grandmother had type 2 diabetes mellitus, and many family members had hypertension.
On physical examination, the patient’s weight was 80 kg and height 170 cm, with a body-mass index of 28. The blood pressure was 180/100 mm Hg, and the pulse was 88 beats per minute; other vital signs were normal. Her face was slightly rounded,
From the Neuroendocrine Unit (A.K.), the Department of Surgery (A.E.S.), the Ob- stetrics and Gynecology Service (M.F.G.), and the Departments of Radiology (M.A.B.) and Pathology (C .- L.W.), Massachusetts General Hospital; and the Departments of Medicine (A.K.), Surgery (A.E.S.), Obstet- rics, Gynecology and Reproductive Biology (M.F.G.), Radiology (M.A.B.), and Pathol- ogy (C .- L.W.), Harvard Medical School.
N Engl J Med 2006;355:2237-45.
Copyright @ 2006 Massachusetts Medical Society.
| Variable | Normal Range | Values in Patient |
|---|---|---|
| Sodium (mmol/liter) | 135-145 | 139 |
| Potassium (mmol/liter) | 3.4-4.8 | 2.6 |
| Chloride (mmol/liter) | 100-108 | 99 |
| Carbon dioxide (mmol/liter) | 23.0-31.9 | 31.2 |
| Urea nitrogen (mg/dl) | 8-25 | 8 |
| Creatinine (mg/dl) | 0.6-1.5 | 0.6 |
| Glucose (mg/dl) | 70-110 | 240 |
| Calcium (mg/dl) | 8.5-10.5 | 9.2 |
| Protein (g/dl) | 6.0-8.0 | 6.7 |
| Albumin (g/dl) | 3.1-4.3 | 3.4 |
| Globulin (g/dl) | 2.6-4.1 | 3.3 |
| Alkaline phosphatase (U/liter) | 30-100 | 40 |
| Aspartate aminotransferase (U/liter) | 9-25 | 12 |
| Alanine aminotransferase (U/liter) | 7-30 | 22 |
| Lactate dehydrogenase (U/liter) | 110-210 | 240 |
| Bilirubin (mg/dl) | ||
| Total | 0-1.0 | 0.4 |
| Conjugated | 0-0.4 | 0.1 |
| Urinary total protein (mg/24 hr) | 0-135 | 241 |
| Glycated hemoglobin (%) | 3.80-6.40 | 8.2 |
* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for total and conjugated bilirubin to micro- moles per liter, multiply by 17.1.
there was mild periorbital edema, and her facial complexion was ruddy. Extraocular movements and visual fields were intact. The thyroid was nor- mal in size, with no palpable nodules. There was no increase in supraclavicular or dorsal adipose tissue, hirsutism, or evidence of bruising. The ab- domen was gravid, nontender, and without striae. Proximal muscle strength and reflexes were nor- mal. There was no peripheral edema.
The dose of labetalol was increased to 800 mg three times daily; extended-release nifedipine (30 mg daily) and insulin (66 U per day in divided doses) were added. Both the blood glucose levels and the blood pressure fell, and the patient was discharged on the third hospital day; the results of laboratory tests (Table 2) were pending.
One week later, the patient was seen in the neu-
roendocrine clinic. A repeated 24-hour urinary cortisol measurement showed that the level was 1865 µg. A diagnostic procedure was performed.
DIFFERENTIAL DIAGNOSIS
Dr. Michael F. Greene: When I saw this patient dur- ing her first admission, she had marked hyperten- sion, poorly controlled diabetes mellitus, and hy- pokalemia.
HYPERTENSION IN PREGNANCY
The four hypertensive disorders that are recog- nized during pregnancy are preeclampsia or eclampsia, chronic hypertension (including “es- sential” hypertension and secondary hyperten- sion), preeclampsia or eclampsia superimposed on chronic hypertension, and gestational hyperten- sion. Although this patient had proteinuria, it was not severe enough to warrant a diagnosis of pre- eclampsia; in addition, the onset of preeclampsia would be unlikely this early in the pregnancy. Ges- tational hypertension would also be unlikely this early in pregnancy. Thus, I was left with a probable diagnosis of chronic hypertension.
In a patient with newly diagnosed chronic hy- pertension, the major question is whether it is es- sential hypertension or associated with another condition. A pregnant patient with chronic hyper- tension is at increased risk for superimposed pre- eclampsia, intrauterine growth restriction, abrup- tio placentae, premature birth, and perinatal death. Efforts to control blood pressure with labetalol or methyldopa to reduce the incidence of preeclamp- sia and its associated perinatal morbidity have been disappointing; thus, a search for a second- ary cause in a case such as this is mandatory.1 In this patient, the presence of hypokalemia in- creased my suspicion that the problem was sec- ondary hypertension.
DIABETES IN PREGNANCY
This patient also had carbohydrate intolerance, with glycosuria at 16 weeks and 6 days’ gestation, as well as gestational diabetes (defined as carbohy- drate intolerance of any degree of severity, with an onset or first recognition during pregnancy). The glycated hemoglobin value of 8.2% at 16 weeks and 6 days’ gestation led me to suspect that she had had hyperglycemia for some time before her pregnancy began. The broad definition of ges- tational diabetes includes the coincidental devel-
opment of type 1 during pregnancy as well as the presence of preexisting, undiagnosed type 2. The vast majority of patients who receive a diagnosis of gestational diabetes have a relatively mild de- gree of carbohydrate intolerance that develops late in pregnancy and is associated with the insulin re- sistance of pregnancy. It seemed fairly clear to me that this woman had preexisting, undiagnosed type 2 diabetes. The results of additional labora- tory tests (Table 2) led me to suspect that she had Cushing’s syndrome and to request a consultation with an endocrinologist.
CUSHING’S SYNDROME IN PREGNANCY
Dr. Anne Klibanski: In a case that is suggestive of Cushing’s syndrome, the goals are to confirm the presence of a pathologic excess of endogenous cor- tisol, to determine its source, and to remove the source to prevent illness and death. Both the di- agnosis and management in this case were fur- ther complicated by the patient’s pregnancy. The diagnosis of Cushing’s syndrome in pregnancy is confounded by the normal hormonal and biochem- ical changes of pregnancy; the management is con- founded by the profoundly deleterious effect of hy- percortisolemia on both mother and fetus, the side effects of medications, and the technical prob- lems involved in undertaking surgical resection. The complications of pregnancy2 for women with Cushing’s syndrome include hypertension, dia- betes, preeclampsia, and infection. Fetal complica- tions include prematurity and intrauterine growth retardation.
This patient had no signs or symptoms of Cushing’s syndrome before pregnancy. Consider- ation of the diagnosis of Cushing’s syndrome is typically based on clinical features. However, many features of this disease are similar to those of normal pregnancy, including weight gain, amen- orrhea, striae, fatigue, back pain, mood changes, and plethora. In this patient, clinically significant hypertension and abnormal glucose tolerance were present; although these findings are common in Cushing’s syndrome, they are nonspecific. Objec- tive signs favoring a diagnosis of Cushing’s syn- drome - such as weakness, particularly proximal weakness, spontaneous ecchymoses, and wide striae - were not seen in this case, probably be- cause the development of hypercortisolemia had been rapid. The single finding that appropriately prompted an evaluation of this patient for Cush- ing’s syndrome was unexplained hypokalemia.
| Table 2. Results of Endocrine Tests .* | ||
|---|---|---|
| Variable | Normal Range | On Admission |
| Plasma corticotropin (pg/ml) | 6-76 | 3 |
| Serum aldosterone (ng/dl) | 4-31 | 28.7 |
| Plasma renin activity (ng/ml/hr) | 0.65-5.0 | 11.6 |
| Dehydroepiandrosterone sulfate (ug/dl) | 52-400 | 13 |
| Testosterone (ng/dl) | <86 | 43 |
| Thyrotropin (uU/ml) | 0.4-5.0 | 0.21 |
| Free thyroxine (ng/dl) | 0.9-1.8 | 0.8 |
| 24-hr urinary cortisol (ug/24 hr) | 20-70 | 1302 |
* To convert the values for corticotropin to picomoles per liter, multiply by 0.2202. To convert the values for aldosterone to picomoles per liter, multiply by 27.74. To convert the values for dehydroepiandrosterone sulfate to nano- moles per liter, multiply by 27.21. To convert the values for testosterone to nanomoles per liter, multiply by 0.03467. To convert the values for free thyrox- ine to picomoles per liter, multiply by 12.87.
Detecting Pathologically Excessive Cortisol Production
Confirmation of a pathologic excess of cortisol is based on one or more of three methods: assess- ment of total cortisol production over a 24-hour period with a determination of 24-hour urinary free cortisol, documentation of the loss of normal diurnal variation in cortisol secretion on the basis of a late-night salivary cortisol measurement, and documentation of the loss of feedback inhibition of cortisol on the hypothalamic-pituitary-adre- nal axis with dexamethasone suppression testing. The biochemical diagnosis of hypercortisolemia in pregnancy is complicated by two factors. First, cortisol production rates markedly increase dur- ing pregnancy, so that urinary free cortisol levels in the second and third trimesters may overlap with levels seen in Cushing’s syndrome.3 Second, levels of corticotropin rise despite increasing cor- tisol levels, which is consistent with the occurrence of decreased feedback on corticotropin secretion. Therefore, unless cortisol levels are markedly ele- vated, the results of these tests may be difficult to interpret.
In healthy people, cortisol secretion peaks in early morning and reaches a nadir as midnight approaches; the difference in cortisol secretion between such people and those with Cushing’s syndrome is maximal at approximately 11 p.m.4 However, although this difference provides an ex- cellent screening test for Cushing’s syndrome, normal late-night salivary cortisol levels are not well established during pregnancy.
Low-dose dexamethasone suppression testing can be used to diagnose Cushing’s syndrome de- spite the occurrence of false negative results.5 Dur- ing pregnancy, however, false positive results can occur.6 Possible reasons for false positive results include an estrogen-induced elevation in the cor- tisol-binding globulin; the impaired suppressibil- ity of the hypothalamic-pituitary-adrenal axis; placental production of corticotropin and cortico- tropin-releasing hormone, which is not regulated by negative feedback control; tissue refractoriness to glucocorticoids; and possible antiglucocorticoid effects of progesterone.7
In this case, urinary free cortisol levels that were more than 1000 µg above the upper limit of the normal range during two 24-hour periods in the absence of glucocorticoid therapy clearly es- tablished the diagnosis of Cushing’s syndrome. The hypokalemia reflected the magnitude of this excess cortisol. The normal aldosterone level and elevated plasma renin activity were consistent with pregnancy, ruling out an aldosterone-secreting tu- mor as a cause of hypokalemia.
Determining the Cause of Excess Cortisol Production Once pathologic hypercortisolemia has been iden- tified, the next step is to determine whether the hormone excess is corticotropin-dependent. Cor- ticotropin-independent Cushing’s syndrome is due to an adrenal lesion, whereas the corticotropin- dependent form of the disease can be traced to ei- ther a pituitary or an ectopic source. The most com- mon cause of endogenous Cushing’s syndrome is overproduction of corticotropin by a benign pitu- itary corticotropic tumor. The vast majority of such tumors are microadenomas (<1 cm in diameter); approximately one third are too small to be visu- alized on sensitive high-resolution magnetic res- onance imaging (MRI). Ectopic Cushing’s syn- drome is caused by a neoplasm outside of the pituitary gland that produces corticotropin or, in rare cases, corticotropin-releasing hormone. Many tumors have been reported to cause ectopic Cush- ing’s syndrome, but the most common are pulmo- nary in origin, ranging from carcinoid tumors to bronchogenic carcinomas.
In Cushing’s syndrome caused by excess cor- ticotropin from any source, corticotropin levels are typically in the normal range - which is inappro- priate given the level of cortisol - or they are elevated. In corticotropin-independent Cushing’s syndrome, corticotropin levels should be sup- pressed. In the setting of hypercortisolemia, an
undetectable corticotropin level or a 9 a.m. level below 10 pg per milliliter (2 pmol per liter) with a two-site immunoradiometric assay is considered to be suggestive of corticotropin-independent Cush- ing’s syndrome.8 However, because corticotropin levels may be higher in pregnant women than in nonpregnant women, this measure may be mis- leading. Therefore, unless corticotropin levels are lower than normal, a corticotropin-dependent tu- mor may be erroneously diagnosed. In this case, the corticotropin level of 3 pg per milliliter (0.6 nmol per liter) in the setting of profound hyper- cortisolemia was strongly suggestive of an adre- nal source of Cushing’s syndrome, and it led us to order an adrenal MRI without the administration of contrast material.
Dr. Michael Blake: The abdominal MRI scan re- veals a left adrenal mass, 5.4 by 4.3 by 3.8 cm, with well-defined borders, that is relatively homoge- neous in signal intensity.
There was no decrease in signal between in- phase (echo time, 4.2 msec) (Fig. 1A) and out-of- phase (echo time, 2.1 msec) (Fig. 1B) T1-weight- ed images, which is consistent with the absence of intracellular fat within the mass; if a marked amount of fat had been present, the signals from the fat and water protons in the mass would have been added on the in-phase sequences and would have been canceled out on the out-of-phase se- quences. More than 70% of adenomas are lipid- rich and show marked signal decrease on out- of-phase imaging.9 The mass is not bright on T2-weighted images (Fig. 1C). More than 70% of pheochromocytomas show a bright signal on T2- weighted images.10
In summary, this patient had a large, solid left adrenal mass, without evidence of invasion, but with no specific or characteristic features on MRI studies.
Dr. Klibanski: Although a pituitary tumor is the most common cause of Cushing’s syndrome, an adrenal source accounts for 40 to 50% of the cases in pregnant patients.11,12 Two explanations for this difference have been proposed. First, corticotro- pin-dependent Cushing’s syndrome is typically as- sociated with elevated androgen production, which may cause infertility and thus makes women with this form of the disease less likely to become preg- nant. In contrast, most benign adrenal tumors exclusively produce cortisol; androgen levels are likely to be normal or low, so that fertility may be spared. Second, endocrine tumors may express aberrant receptors for peptide hormones, includ-
Figure 1. Axial MRI of the Left Adrenal Gland.
Panel A shows a very well-circumscribed mass (arrow) in the left adrenal gland with a low, relatively homoge- neous signal intensity on this in-phase T1-weighted im- age (echo time, 4.2 msec) and no evidence of local in- vasion. In Panel B, the out-of-phase T1-weighted image (echo time, 2.1 msec) shows no marked decrease in the signal intensity of the mass (arrow), unlike a typical adenoma. In Panel C, a T2-weighted image shows that the mass (arrow) has only intermediate signal inten- sity, unlike a typical pheochromocytoma. Thus, this large, solid left adrenal mass has no specific or charac- teristic features on MRI.
ing human chorionic gonadotropin receptors,13-15 and the high circulatory levels of human chori- onic gonadotropin during pregnancy may stimu- late production of cortisol in a tumor with aber- rant hormone receptors.
In this patient, rapidly escalating hypertension and insulin-requiring diabetes made surgical cure an immediate goal. If surgery cannot be per- formed in a case such as this, the use of interim medical therapy to block cortisol production should be considered. In this case, metyrapone, a drug that blocks the conversion of 11-deoxycortisol to cortisol, was used briefly while surgery was being scheduled. The use of metyrapone during preg- nancy has been reported in a few cases15-18; how- ever, definitive surgery usually should not be de- layed until the cortisol level is normalized. Other drugs more commonly used to treat hypercorti- solemia, such as ketoconazole, cross the placenta, inhibit progesterone production, and may be both teratogenic and associated with fetal loss.
Dr. Utz: Immediately after the MRI, the patient was readmitted to the hospital at 21 weeks’ ges- tation. The blood pressure was 148/88 mm Hg. Metyrapone (250 mg three times daily) was admin- istered, and the blood pressure gradually normal- ized. The insulin dose was increased to 112 U daily.
Dr. Antonia E. Stephen: Once it was established that the cause of Cushing’s syndrome was a uni- lateral adrenal tumor, the treatment of choice was an adrenal resection. The surgeon had to answer two questions: what was the ideal timing for sur- gery, and what was the best surgical approach?
In pregnant patients with Cushing’s syndrome,19 prompt adrenalectomy, as compared with post- ponement of the surgery until after delivery, re- duces the risk of maternal complications, fetal death, premature birth, and neonatal complica- tions. We therefore recommended immediate sur-
A
B
C
gery. Because of the small size of the adrenal gland, the benign nature of most hormonally pro- ductive tumors, and the location of the adrenal gland, laparoscopic adrenalectomy has become the preferred option for the resection of benign ad- renal tumors. 20-22
Potential risks of laparoscopy during pregnancy include fetal acidosis or decreased uterine blood flow as a result of the carbon dioxide pneumo- peritoneum and the possibility of uterine injury
from trocar placement.23,24 However, several stud- ies have shown that laparoscopy during pregnancy is safe for both the mother and the fetus.25,26 All types of surgery should ideally be performed in the second trimester, since the risk of spontaneous abortion is greatest during the first trimester and the risk of premature labor is greatest during the third trimester.27 Since this patient was in the sec- ond trimester, we performed a laparoscopic adre- nalectomy 6 days after admission.
Because pregnant patients have hypercoagula- bility and pneumoperitoneum during laparoscopy increases lower-extremity venous stasis, we used compression boots during surgery and subcuta- neous heparin postoperatively; before discharge we ordered noninvasive venous studies to rule out deep venous thrombosis. We obtained initial ac- cess to the abdomen by making a small incision and placing the first trocar under direct vision, which is preferred over blind needle placement to avoid injury to the uterus. We monitored the pa- tient with a central venous catheter as well as with an arterial line and fetal ultrasound examinations before and after surgery. Pneumoperitoneum pres- sures were closely monitored and minimized.
During the procedure, the patient was placed in the lateral position on her right side; although this is not the ideal position in pregnancy because the uterus can rest on the inferior vena cava, it was necessary to provide access to the left adrenal tu- mor. Had we encountered reduction in the central venous pressure during the procedure, we would have adjusted the patient’s position to decrease the pressure on the inferior vena cava. We then mobilized the splenic flexure of the colon and the spleen to gain access to the adrenal gland; divided the superior and lateral attachments of the tumor using the Harmonic Scalpel; identified, clipped, and divided the adrenal vein; and removed the adrenal tumor with the use of an impermeable bag through a trocar site.28 The tumor was round, soft, and well circumscribed (Fig. 2A). There were no intraoperative or postoperative complications in the mother or the fetus.
DR. ANNE KLIBANSKI’S DIAGNOSIS
Cushing’s syndrome due to an adrenal cortical tumor.
A
Left lobe of the liver
Spleen
Adrenal tumor
B
C
PATHOLOGICAL DISCUSSION
Dr. Chin-Lee Wu: The adrenal tumor was 5 cm in di- ameter, with a red-to-orange cut surface and focal hemorrhagic areas. On microscopical examination, the tumor cells formed nested and trabecular pat- terns (Fig. 2B). Two types of tumor cells were pres- ent. The first type, composing about half of the tumor, had abundant, lipid-rich, clear cytoplasm, with small nuclei and no mitoses, resembling the cells seen in the zona fasciculata of the normal ad- renal cortex (Fig. 2B). The second type contained abundant eosinophilic cytoplasm, with slightly larger, slightly more pleomorphic nuclei and oc- casional mitotic cells (Fig. 2C).
The differential diagnosis of an adrenal corti- cal tumor includes adrenal cortical adenoma and carcinoma. Grossly, adrenal cortical adenomas are small (median size, 2 cm; median weight, 10 g) and well circumscribed, with a smooth cut surface and no necrosis or hemorrhage.29 Adrenal corti- cal carcinomas are typically large (median size, 14 cm; median weight, 510 g) and have an ill- defined border and a nodular, coarse cut surface with necrosis and hemorrhage.3º This tumor was larger than the median size of an adenoma and had focal hemorrhage but had no gross features of a carcinoma.
Microscopical examination of adrenal cortical carcinomas usually shows atypical mitotic cells, vascular and capsular invasion, and extension into adjacent adipose tissue. Nine histologic features are used to distinguish carcinoma from adenoma: a high mitotic rate (>5 per 50 high-power fields), atypical mitotic cells, venous invasion, and high nuclear grade (Fuhrman grade 3 to 4 on a scale from 1 to 4, with grade 1 indicating the least atypia and grade 4 the most), a small proportion of cells with clear cytoplasm (<25% of the cells), a diffuse growth pattern (more than one third of the tumor), necrosis, sinusoidal invasion, and cap- sular invasion.31 If three or more of these features are present, a diagnosis of adrenal cortical carci- noma is made. Adrenal cortical adenomas have no more than two of these features.31,32 In this case, there was no microscopical evidence of vascular or capsular invasion, a diffuse growth pattern, or atypical mitotic cells; clear cells made up more than 25% of the cells; the nuclear grade was 3; and there were 5 mitotic cells per 50 high-power
fields. Thus, although there is more cytologic atypia than is usually seen, the tumor does not meet the criteria for carcinoma, and the patho- logical diagnosis is adrenal cortical adenoma with atypia. It is important to recognize that neither this nor other proposed systems for distinguish- ing adenoma and carcinoma are infallible33; clini- cal correlation is required.
Although it is clinically important to distin- guish functioning from nonfunctioning adre- nal tumors, it is usually not possible to make this distinction on the basis of the pathological findings.
CLINICAL FOLLOW-UP
Dr. Utz: After the operation, glucocorticoid replace- ment with dexamethasone was begun. Postopera- tive tests showed complete suppression of the lev- els of 24-hour urinary cortisol and morning serum cortisol. The results of thyroid function tests nor- malized. During the next 10 days, the labetalol dose was tapered and discontinued, and blood pressure remained normal. Prednisone (5 mg twice daily) was continued throughout the pregnancy. The patient continued to require insulin and po- tassium supplementation.
Ultrasound monitoring showed that in size, the fetus had dropped from the 45th percentile at 26 weeks to the 5th percentile at 36 weeks. At that time the patient was readmitted to the hospital, and stress-dose hydrocortisone was administered. A 2205-g male infant was delivered by cesarean section, with Apgar scores of 9 at both 1 minute and 5 minutes. The baby’s blood glucose levels were slightly low, but they normalized spontane- ously during the first week of life. His cortico- tropin and corticotropin-stimulated cortisol lev- els were normal.
Five days after delivery, the patient’s morning cortisol level remained low, at 2.4 µg per decili- ter (66.3 nmol per liter); thus, the dose of predni- sone was continued and gradually tapered to 5 mg daily. Blood glucose and potassium levels returned to normal. Although the Cushing’s syndrome had been cured by the operation, adrenal cortical tu- mors are malignant in rare cases, and pathologi- cal identification of a malignant tumor can be difficult; consequently, follow-up studies were con- tinued after delivery to rule out recurrence.
Five months after delivery, a morning cortisol level was 7.2 µg per deciliter (198.6 nmol per liter). Two months later, the morning cortisol level was 22.2 µg per deciliter (612.5 nmol per liter).
Dr. Blake: Computed tomography and MRI of the abdomen showed multiple nodules in the liver, which were consistent with the presence of meta- static carcinoma (Fig. 3A).
A
B
PATHOLOGICAL FOLLOW-UP
Dr. Wu: Fine-needle aspiration and core biopsies of the liver performed with ultrasound guidance showed an adrenal cortical tumor involving liver parenchyma (Fig. 3B); although the histologic fea- tures that are diagnostic of cancer were still not present, the presence of a tumor in the liver is diag- nostic of adrenal cortical carcinoma. This case il- lustrates the difficulty of establishing a patho- logical diagnosis of cancer in patients with adrenal cortical tumors and the need for new molecular diagnostic and prognostic markers. A recent gene expression profile study identified 91 genes, in- cluding the IGF2 gene, that are associated with adrenal cortical carcinoma.34 IGF2 expression is also elevated in adrenal cortical carcinoma on im- munohistologic examination.35 These findings should be further studied to determine their clini- cal usefulness in predicting the malignant poten- tial of adrenal cortical tumors and the outcome of the disease.
Dr. Utz: Subsequent evaluation revealed a 24- hour urinary cortisol level of 825 µg, hypertension, and elevated blood glucose levels. Treatment with mitotane and ketoconazole was initiated, and the 24-hour urinary cortisol level declined to 126 µg. The patient was referred to an oncologist. While she was receiving high-dose mitotane, the tumor progression slowed; however, the high doses caused severe neurologic and gastrointestinal side effects. Because of progressive enlargement of he- patic metastases and elevated urinary cortisol lev- els, chemotherapy with low-dose mitotane, eto- poside, doxorubicin, and cisplatin was recently begun, 9 months after the diagnosis of metastatic disease.
ANATOMICAL DIAGNOSIS
Cushing’s syndrome due to adrenal cortical car- cinoma.
Dr. Klibanski reports receiving consulting fees from Novartis, Johnson & Johnson Pharmaceutical Research and Development, Takeda, Procter & Gamble, Bioenvision, and Tercica and grant support from Pharmacia/Pfizer and Novartis. No other potential conflict of interest relevant to this article was reported.
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