Case 36-2006 — A 35-Year-Old Pregnant Woman with New Hypertension
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《新英格兰医药杂志》
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 recent 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 normal. 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 supplements 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 fasting 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.
Table 1. Results of Serum and Urine Chemical Tests between 16 Weeks 6 Days and 19 Weeks 6 Days.
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 vision. 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 overweight, 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, there was mild periorbital edema, and her facial complexion was ruddy. Extraocular movements and visual fields were intact. The thyroid was normal in size, with no palpable nodules. There was no increase in supraclavicular or dorsal adipose tissue, hirsutism, or evidence of bruising. The abdomen was gravid, nontender, and without striae. Proximal muscle strength and reflexes were normal. 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.
Table 2. Results of Endocrine Tests.
One week later, the patient was seen in the neuroendocrine 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 during her first admission, she had marked hypertension, poorly controlled diabetes mellitus, and hypokalemia.
Hypertension in Pregnancy
The four hypertensive disorders that are recognized during pregnancy are preeclampsia or eclampsia, chronic hypertension (including "essential" hypertension and secondary hypertension), preeclampsia or eclampsia superimposed on chronic hypertension, and gestational hypertension. Although this patient had proteinuria, it was not severe enough to warrant a diagnosis of preeclampsia; in addition, the onset of preeclampsia would be unlikely this early in the pregnancy. Gestational 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 hypertension, the major question is whether it is essential hypertension or associated with another condition. A pregnant patient with chronic hypertension is at increased risk for superimposed preeclampsia, intrauterine growth restriction, abruptio placentae, premature birth, and perinatal death. Efforts to control blood pressure with labetalol or methyldopa to reduce the incidence of preeclampsia and its associated perinatal morbidity have been disappointing; thus, a search for a secondary cause in a case such as this is mandatory.1 In this patient, the presence of hypokalemia increased my suspicion that the problem was secondary 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 carbohydrate 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 gestational diabetes includes the coincidental development 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 degree of carbohydrate intolerance that develops late in pregnancy and is associated with the insulin resistance of pregnancy. It seemed fairly clear to me that this woman had preexisting, undiagnosed type 2 diabetes. The results of additional laboratory 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 cortisol, to determine its source, and to remove the source to prevent illness and death. Both the diagnosis and management in this case were further complicated by the patient's pregnancy. The diagnosis of Cushing's syndrome in pregnancy is confounded by the normal hormonal and biochemical changes of pregnancy; the management is confounded by the profoundly deleterious effect of hypercortisolemia on both mother and fetus, the side effects of medications, and the technical problems involved in undertaking surgical resection. The complications of pregnancy2 for women with Cushing's syndrome include hypertension, diabetes, preeclampsia, and infection. Fetal complications include prematurity and intrauterine growth retardation.
This patient had no signs or symptoms of Cushing's syndrome before pregnancy. Consideration 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, amenorrhea, 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. Objective signs favoring a diagnosis of Cushing's syndrome — such as weakness, particularly proximal weakness, spontaneous ecchymoses, and wide striae — were not seen in this case, probably because the development of hypercortisolemia had been rapid. The single finding that appropriately prompted an evaluation of this patient for Cushing's syndrome was unexplained hypokalemia.
Detecting Pathologically Excessive Cortisol Production
Confirmation of a pathologic excess of cortisol is based on one or more of three methods: assessment 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–adrenal axis with dexamethasone suppression testing. The biochemical diagnosis of hypercortisolemia in pregnancy is complicated by two factors. First, cortisol production rates markedly increase during 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 cortisol levels, which is consistent with the occurrence of decreased feedback on corticotropin secretion. Therefore, unless cortisol levels are markedly elevated, 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 excellent 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 despite the occurrence of false negative results.5 During pregnancy, however, false positive results can occur.6 Possible reasons for false positive results include an estrogen-induced elevation in the cortisol-binding globulin; the impaired suppressibility of the hypothalamic–pituitary–adrenal axis; placental production of corticotropin and corticotropin-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 established 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 tumor as a cause of hypokalemia.
Determining the Cause of Excess Cortisol Production
Once pathologic hypercortisolemia has been identified, the next step is to determine whether the hormone excess is corticotropin-dependent. Corticotropin-independent Cushing's syndrome is due to an adrenal lesion, whereas the corticotropin-dependent form of the disease can be traced to either a pituitary or an ectopic source. The most common cause of endogenous Cushing's syndrome is overproduction of corticotropin by a benign pituitary corticotropic tumor. The vast majority of such tumors are microadenomas (<1 cm in diameter); approximately one third are too small to be visualized on sensitive high-resolution magnetic resonance imaging (MRI). Ectopic Cushing's syndrome 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 Cushing's syndrome, but the most common are pulmonary in origin, ranging from carcinoid tumors to bronchogenic carcinomas.
In Cushing's syndrome caused by excess corticotropin from any source, corticotropin levels are typically in the normal range — which is inappropriate given the level of cortisol — or they are elevated. In corticotropin-independent Cushing's syndrome, corticotropin levels should be suppressed. 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 Cushing's syndrome.8 However, because corticotropin levels may be higher in pregnant women than in nonpregnant women, this measure may be misleading. Therefore, unless corticotropin levels are lower than normal, a corticotropin-dependent tumor 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 hypercortisolemia was strongly suggestive of an adrenal 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 reveals a left adrenal mass, 5.4 by 4.3 by 3.8 cm, with well-defined borders, that is relatively homogeneous in signal intensity.
There was no decrease in signal between in-phase (echo time, 4.2 msec) (Figure 1A) and out-of-phase (echo time, 2.1 msec) (Figure 1B) T1-weighted 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 sequences. 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 (Figure 1C). More than 70% of pheochromocytomas show a bright signal on T2-weighted images.10
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 homogeneous signal intensity on this in-phase T1-weighted image (echo time, 4.2 msec) and no evidence of local invasion. 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 intensity, unlike a typical pheochromocytoma. Thus, this large, solid left adrenal mass has no specific or characteristic features on MRI.
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, corticotropin-dependent Cushing's syndrome is typically associated with elevated androgen production, which may cause infertility and thus makes women with this form of the disease less likely to become pregnant. 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, including human chorionic gonadotropin receptors,13,14,15 and the high circulatory levels of human chorionic gonadotropin during pregnancy may stimulate production of cortisol in a tumor with aberrant hormone receptors.
In this patient, rapidly escalating hypertension and insulin-requiring diabetes made surgical cure an immediate goal. If surgery cannot be performed 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 pregnancy has been reported in a few cases15,16,17,18; however, definitive surgery usually should not be delayed until the cortisol level is normalized. Other drugs more commonly used to treat hypercortisolemia, 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' gestation. The blood pressure was 148/88 mm Hg. Metyrapone (250 mg three times daily) was administered, and the blood pressure gradually normalized. 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 unilateral adrenal tumor, the treatment of choice was an adrenal resection. The surgeon had to answer two questions: what was the ideal timing for surgery, and what was the best surgical approach?
In pregnant patients with Cushing's syndrome,19 prompt adrenalectomy, as compared with postponement of the surgery until after delivery, reduces the risk of maternal complications, fetal death, premature birth, and neonatal complications. We therefore recommended immediate surgery. Because of the small size of the adrenal gland, the benign nature of most hormonally productive tumors, and the location of the adrenal gland, laparoscopic adrenalectomy has become the preferred option for the resection of benign adrenal tumors.20,21,22
Potential risks of laparoscopy during pregnancy include fetal acidosis or decreased uterine blood flow as a result of the carbon dioxide pneumoperitoneum and the possibility of uterine injury from trocar placement.23,24 However, several studies 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 second trimester, we performed a laparoscopic adrenalectomy 6 days after admission.
Because pregnant patients have hypercoagulability and pneumoperitoneum during laparoscopy increases lower-extremity venous stasis, we used compression boots during surgery and subcutaneous heparin postoperatively; before discharge we ordered noninvasive venous studies to rule out deep venous thrombosis. We obtained initial access 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 patient with a central venous catheter as well as with an arterial line and fetal ultrasound examinations before and after surgery. Pneumoperitoneum pressures 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 tumor. 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 (Figure 2A). There were no intraoperative or postoperative complications in the mother or the fetus.
Figure 2. Left Adrenal Tumor.
An intraoperative photograph (Panel A) shows the adrenal tumor (arrow) after mobilization and before removal. The tumor was approximately 5 cm in diameter, was well circumscribed, and did not invade adjacent tissues. On microscopical examination, there was a trabecular and nested pattern (Panel B, hematoxylin and eosin). In addition, two types of tumor cells are present: one type has abundant, lipid-rich, clear cytoplasm, with small nuclei and no mitotic cells, resembling the cells seen in the zona fasciculata of the normal adrenal cortex (Panel B); the other type has abundant eosinophilic cytoplasm and more nuclear atypia, with occasional mitotic cells (Panel C, hematoxylin and eosin).
Dr. Anne Klibanski's Diagnosis
Cushing's syndrome due to an adrenal cortical tumor.
Pathological Discussion
Dr. Chin-Lee Wu: The adrenal tumor was 5 cm in diameter, with a red-to-orange cut surface and focal hemorrhagic areas. On microscopical examination, the tumor cells formed nested and trabecular patterns (Figure 2B). Two types of tumor cells were present. 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 adrenal cortex (Figure 2B). The second type contained abundant eosinophilic cytoplasm, with slightly larger, slightly more pleomorphic nuclei and occasional mitotic cells (Figure 2C).
The differential diagnosis of an adrenal cortical 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 cortical 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.30 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 capsular invasion.31 If three or more of these features are present, a diagnosis of adrenal cortical carcinoma 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 pathological diagnosis is adrenal cortical adenoma with atypia. It is important to recognize that neither this nor other proposed systems for distinguishing adenoma and carcinoma are infallible33; clinical correlation is required.
Although it is clinically important to distinguish functioning from nonfunctioning adrenal 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 replacement with dexamethasone was begun. Postoperative tests showed complete suppression of the levels of 24-hour urinary cortisol and morning serum cortisol. The results of thyroid function tests normalized. 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 potassium 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 spontaneously during the first week of life. His corticotropin and corticotropin-stimulated cortisol levels were normal.
Five days after delivery, the patient's morning cortisol level remained low, at 2.4 μg per deciliter (66.3 nmol per liter); thus, the dose of prednisone 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 tumors are malignant in rare cases, and pathological identification of a malignant tumor can be difficult; consequently, follow-up studies were continued 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 metastatic carcinoma (Figure 3A).
Figure 3. Follow-up MRI and Liver-Biopsy Specimen.
An axial fat-suppressed, T1-weighted image obtained after the intravenous administration of gadolinium (Panel A) shows new hepatic masses (thin arrows), with irregular peripheral enhancement — findings that are consistent with the presence of metastatic disease. A small hematoma in the left adrenalectomy bed is also present (thick arrow). A specimen from an ultrasound-guided biopsy of the liver (Panel B, hematoxylin and eosin) shows nests of tumor with histologic features similar to those of the left adrenal primary tumor. Although cytologic criteria for cancer are still not present, the metastatic tumor itself establishes the diagnosis of adrenal cortical carcinoma.
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 (Figure 3B); although the histologic features that are diagnostic of cancer were still not present, the presence of a tumor in the liver is diagnostic of adrenal cortical carcinoma. This case illustrates the difficulty of establishing a pathological 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, including the IGF2 gene, that are associated with adrenal cortical carcinoma.34 IGF2 expression is also elevated in adrenal cortical carcinoma on immunohistologic examination.35 These findings should be further studied to determine their clinical usefulness in predicting the malignant potential 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 hepatic metastases and elevated urinary cortisol levels, chemotherapy with low-dose mitotane, etoposide, doxorubicin, and cisplatin was recently begun, 9 months after the diagnosis of metastatic disease.
Anatomical Diagnosis
Cushing's syndrome due to adrenal cortical carcinoma.
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.
Source Information
From the Neuroendocrine Unit (A.K.), the Department of Surgery (A.E.S.), the Obstetrics 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.), Obstetrics, Gynecology and Reproductive Biology (M.F.G.), Radiology (M.A.B.), and Pathology (C.-L.W.), Harvard Medical School.
References
Sibai BM, Mabie WC, Shamsa F, Villar MA, Anderson GD. A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am J Obstet Gynecol 1990;162:960-966.
Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing's syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab 2005;90:3077-3083.
Carr BR, Parker CR Jr, Madden JD, MacDonald PC, Porter JC. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 1981;139:416-422.
Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing's syndrome. J Clin Endocrinol Metab 1998;83:2681-2686.
Findling JW, Raff H, Aron DC. The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome. J Clin Endocrinol Metab 2004;89:1222-1226.
Odagiri E, Ishiwatari N, Abe Y, et al. Hypercortisolism and the resistance to dexamethasone suppression during gestation. Endocrinol Jpn 1988;35:685-690.
Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev 2005;26:775-799.
Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2003;88:5593-5602.
Outwater EK, Siegelman ES, Radecki PD, Piccoli CW, Mitchell DG. Distinction between benign and malignant adrenal masses: value of T1-weighted chemical-shift MR imaging. AJR Am J Roentgenol 1995;165:579-583.
Varghese JC, Hahn PF, Papanicolaou N, Mayo-Smith WW, Gaa JA, Lee MJ. MR differentiation of phaeochromocytoma from other adrenal lesions based on qualitative analysis of T2 relaxation times. Clin Radiol 1997;52:603-606.
Buescher MA, McClamrock HD, Adashi EY. Cushing syndrome in pregnancy. Obstet Gynecol 1992;79:130-137.
Pickard J, Jochen AL, Sadur CN, Hofeldt FD. Cushing's syndrome in pregnancy. Obstet Gynecol Surv 1990;45:87-93.
Pabon JE, Li X, Lei ZM, Sanfilippo JS, Yussman MA, Rao CV. Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands. J Clin Endocrinol Metab 1996;81:2397-2400.
Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone-dependent Cushing's syndrome. N Engl J Med 1999;341:1577-1581.
Hána V, Dokoupilová M, Marek J, Plavka R. Recurrent ACTH-independent Cushing's syndrome in multiple pregnancies and its treatment with metyrapone. Clin Endocrinol (Oxf) 2001;54:277-281.
Gormley MJ, Hadden DR, Kennedy TL, Montgomery DA, Murnaghan GA, Sheridan B. Cushing's syndrome in pregnancy -- treatment with metyrapone. Clin Endocrinol (Oxf) 1982;16:283-293.
Close CF, Mann MC, Watt JF, Taylor KG. ACTH-independent Cushing's syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone. Clin Endocrinol (Oxf) 1993;39:375-379.
Connell JM, Cordiner J, Davies DL, Fraser R, Frier BM, McPherson SG. Pregnancy complicated by Cushing's syndrome: potential hazard of metyrapone therapy: case report. Br J Obstet Gynaecol 1985;92:1192-1195.
Pricolo VE, Monchik JM, Prinz RA, DeJong S, Chadwick DA, Lamberton RP. Management of Cushing's syndrome secondary to adrenal adenoma during pregnancy. Surgery 1990;108:1072-1077.
Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing's syndrome and pheochromocytoma. N Engl J Med 1992;327:1033-1033.
Assalia A, Gagner M. Laparoscopic adrenalectomy. Br J Surg 2004;91:1259-1274.
Gonzalez R, Smith CD, McClusky DA III, et al. Laparoscopic approach reduces likelihood of perioperative complications in patients undergoing adrenalectomy. Am Surg 2004;70:668-674.
Soper NJ, Hunter JG, Petrie RH. Laparoscopic cholecystectomy during pregnancy. Surg Endosc 1992;6:115-117.
Hunter JG, Swanstrom L, Thornburg K. Carbon dioxide pneumoperitoneum induces fetal acidosis in a pregnant ewe model. Surg Endosc 1995;9:272-277.
Reedy MB, Kallen B, Kuehl TJ. Laparoscopy during pregnancy: a study of five fetal outcome parameters with use of the Swedish Health Registry. Am J Obstet Gynecol 1997;177:673-679.
Wolf A, Goretzki PE, Rohrborn A, et al. Pheochromocytoma during pregnancy: laparoscopic and conventional surgical treatment of two cases. Exp Clin Endocrinol Diabetes 2004;112:98-101.
SAGES guidelines for laparoscopic surgery during pregnancy. Los Angeles: Society of American Gastrointestinal Endoscopic Surgeons, 2000. (Publication no. 0023.) (Accessed September 20, 2006, at http://www.sages.org/sg_pub23.html.)
Gagner M, Pomp A, Heniford BT, Pharand D, Lacroix A. Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg 1997;226:238-246.
Adrenal cortical adenoma. In: Lack EE. Tumors of the adrenal gland and extra-adrenal paraganglia. 3rd series. Fascicle 19. Washington, DC: Armed Forces Institute of Pathology, 1997:91-122.
Adrenal cortical carcinoma. In: Lack EE. Tumors of the adrenal gland and extra-adrenal paraganglia. 3rd series. Fascicle 19. Washington, DC: Armed Forces Institute of Pathology, 1997:123-52.
Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-169.
Weiss LM, Medeiros IJ, Vickery AL Jr. Pathological features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202-206.
Medeiros LJ, Weiss LM. New developments in the pathologic diagnosis of adrenal cortical neoplasms: a review. Am J Clin Pathol 1992;97:73-83.
Giordano TJ, Thomas DG, Kuick R, et al. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 2003;162:521-531.
Schmitt A, Saremaslani P, Schmid S, et al. IGFII and MIB1 immunohistochemistry is helpful for the differentiation of benign from malignant tumours. Histopathology 2006;49:298-307.(Anne Klibanski, M.D., Ant)
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 recent 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 normal. 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 supplements 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 fasting 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.
Table 1. Results of Serum and Urine Chemical Tests between 16 Weeks 6 Days and 19 Weeks 6 Days.
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 vision. 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 overweight, 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, there was mild periorbital edema, and her facial complexion was ruddy. Extraocular movements and visual fields were intact. The thyroid was normal in size, with no palpable nodules. There was no increase in supraclavicular or dorsal adipose tissue, hirsutism, or evidence of bruising. The abdomen was gravid, nontender, and without striae. Proximal muscle strength and reflexes were normal. 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.
Table 2. Results of Endocrine Tests.
One week later, the patient was seen in the neuroendocrine 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 during her first admission, she had marked hypertension, poorly controlled diabetes mellitus, and hypokalemia.
Hypertension in Pregnancy
The four hypertensive disorders that are recognized during pregnancy are preeclampsia or eclampsia, chronic hypertension (including "essential" hypertension and secondary hypertension), preeclampsia or eclampsia superimposed on chronic hypertension, and gestational hypertension. Although this patient had proteinuria, it was not severe enough to warrant a diagnosis of preeclampsia; in addition, the onset of preeclampsia would be unlikely this early in the pregnancy. Gestational 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 hypertension, the major question is whether it is essential hypertension or associated with another condition. A pregnant patient with chronic hypertension is at increased risk for superimposed preeclampsia, intrauterine growth restriction, abruptio placentae, premature birth, and perinatal death. Efforts to control blood pressure with labetalol or methyldopa to reduce the incidence of preeclampsia and its associated perinatal morbidity have been disappointing; thus, a search for a secondary cause in a case such as this is mandatory.1 In this patient, the presence of hypokalemia increased my suspicion that the problem was secondary 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 carbohydrate 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 gestational diabetes includes the coincidental development 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 degree of carbohydrate intolerance that develops late in pregnancy and is associated with the insulin resistance of pregnancy. It seemed fairly clear to me that this woman had preexisting, undiagnosed type 2 diabetes. The results of additional laboratory 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 cortisol, to determine its source, and to remove the source to prevent illness and death. Both the diagnosis and management in this case were further complicated by the patient's pregnancy. The diagnosis of Cushing's syndrome in pregnancy is confounded by the normal hormonal and biochemical changes of pregnancy; the management is confounded by the profoundly deleterious effect of hypercortisolemia on both mother and fetus, the side effects of medications, and the technical problems involved in undertaking surgical resection. The complications of pregnancy2 for women with Cushing's syndrome include hypertension, diabetes, preeclampsia, and infection. Fetal complications include prematurity and intrauterine growth retardation.
This patient had no signs or symptoms of Cushing's syndrome before pregnancy. Consideration 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, amenorrhea, 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. Objective signs favoring a diagnosis of Cushing's syndrome — such as weakness, particularly proximal weakness, spontaneous ecchymoses, and wide striae — were not seen in this case, probably because the development of hypercortisolemia had been rapid. The single finding that appropriately prompted an evaluation of this patient for Cushing's syndrome was unexplained hypokalemia.
Detecting Pathologically Excessive Cortisol Production
Confirmation of a pathologic excess of cortisol is based on one or more of three methods: assessment 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–adrenal axis with dexamethasone suppression testing. The biochemical diagnosis of hypercortisolemia in pregnancy is complicated by two factors. First, cortisol production rates markedly increase during 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 cortisol levels, which is consistent with the occurrence of decreased feedback on corticotropin secretion. Therefore, unless cortisol levels are markedly elevated, 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 excellent 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 despite the occurrence of false negative results.5 During pregnancy, however, false positive results can occur.6 Possible reasons for false positive results include an estrogen-induced elevation in the cortisol-binding globulin; the impaired suppressibility of the hypothalamic–pituitary–adrenal axis; placental production of corticotropin and corticotropin-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 established 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 tumor as a cause of hypokalemia.
Determining the Cause of Excess Cortisol Production
Once pathologic hypercortisolemia has been identified, the next step is to determine whether the hormone excess is corticotropin-dependent. Corticotropin-independent Cushing's syndrome is due to an adrenal lesion, whereas the corticotropin-dependent form of the disease can be traced to either a pituitary or an ectopic source. The most common cause of endogenous Cushing's syndrome is overproduction of corticotropin by a benign pituitary corticotropic tumor. The vast majority of such tumors are microadenomas (<1 cm in diameter); approximately one third are too small to be visualized on sensitive high-resolution magnetic resonance imaging (MRI). Ectopic Cushing's syndrome 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 Cushing's syndrome, but the most common are pulmonary in origin, ranging from carcinoid tumors to bronchogenic carcinomas.
In Cushing's syndrome caused by excess corticotropin from any source, corticotropin levels are typically in the normal range — which is inappropriate given the level of cortisol — or they are elevated. In corticotropin-independent Cushing's syndrome, corticotropin levels should be suppressed. 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 Cushing's syndrome.8 However, because corticotropin levels may be higher in pregnant women than in nonpregnant women, this measure may be misleading. Therefore, unless corticotropin levels are lower than normal, a corticotropin-dependent tumor 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 hypercortisolemia was strongly suggestive of an adrenal 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 reveals a left adrenal mass, 5.4 by 4.3 by 3.8 cm, with well-defined borders, that is relatively homogeneous in signal intensity.
There was no decrease in signal between in-phase (echo time, 4.2 msec) (Figure 1A) and out-of-phase (echo time, 2.1 msec) (Figure 1B) T1-weighted 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 sequences. 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 (Figure 1C). More than 70% of pheochromocytomas show a bright signal on T2-weighted images.10
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 homogeneous signal intensity on this in-phase T1-weighted image (echo time, 4.2 msec) and no evidence of local invasion. 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 intensity, unlike a typical pheochromocytoma. Thus, this large, solid left adrenal mass has no specific or characteristic features on MRI.
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, corticotropin-dependent Cushing's syndrome is typically associated with elevated androgen production, which may cause infertility and thus makes women with this form of the disease less likely to become pregnant. 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, including human chorionic gonadotropin receptors,13,14,15 and the high circulatory levels of human chorionic gonadotropin during pregnancy may stimulate production of cortisol in a tumor with aberrant hormone receptors.
In this patient, rapidly escalating hypertension and insulin-requiring diabetes made surgical cure an immediate goal. If surgery cannot be performed 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 pregnancy has been reported in a few cases15,16,17,18; however, definitive surgery usually should not be delayed until the cortisol level is normalized. Other drugs more commonly used to treat hypercortisolemia, 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' gestation. The blood pressure was 148/88 mm Hg. Metyrapone (250 mg three times daily) was administered, and the blood pressure gradually normalized. 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 unilateral adrenal tumor, the treatment of choice was an adrenal resection. The surgeon had to answer two questions: what was the ideal timing for surgery, and what was the best surgical approach?
In pregnant patients with Cushing's syndrome,19 prompt adrenalectomy, as compared with postponement of the surgery until after delivery, reduces the risk of maternal complications, fetal death, premature birth, and neonatal complications. We therefore recommended immediate surgery. Because of the small size of the adrenal gland, the benign nature of most hormonally productive tumors, and the location of the adrenal gland, laparoscopic adrenalectomy has become the preferred option for the resection of benign adrenal tumors.20,21,22
Potential risks of laparoscopy during pregnancy include fetal acidosis or decreased uterine blood flow as a result of the carbon dioxide pneumoperitoneum and the possibility of uterine injury from trocar placement.23,24 However, several studies 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 second trimester, we performed a laparoscopic adrenalectomy 6 days after admission.
Because pregnant patients have hypercoagulability and pneumoperitoneum during laparoscopy increases lower-extremity venous stasis, we used compression boots during surgery and subcutaneous heparin postoperatively; before discharge we ordered noninvasive venous studies to rule out deep venous thrombosis. We obtained initial access 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 patient with a central venous catheter as well as with an arterial line and fetal ultrasound examinations before and after surgery. Pneumoperitoneum pressures 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 tumor. 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 (Figure 2A). There were no intraoperative or postoperative complications in the mother or the fetus.
Figure 2. Left Adrenal Tumor.
An intraoperative photograph (Panel A) shows the adrenal tumor (arrow) after mobilization and before removal. The tumor was approximately 5 cm in diameter, was well circumscribed, and did not invade adjacent tissues. On microscopical examination, there was a trabecular and nested pattern (Panel B, hematoxylin and eosin). In addition, two types of tumor cells are present: one type has abundant, lipid-rich, clear cytoplasm, with small nuclei and no mitotic cells, resembling the cells seen in the zona fasciculata of the normal adrenal cortex (Panel B); the other type has abundant eosinophilic cytoplasm and more nuclear atypia, with occasional mitotic cells (Panel C, hematoxylin and eosin).
Dr. Anne Klibanski's Diagnosis
Cushing's syndrome due to an adrenal cortical tumor.
Pathological Discussion
Dr. Chin-Lee Wu: The adrenal tumor was 5 cm in diameter, with a red-to-orange cut surface and focal hemorrhagic areas. On microscopical examination, the tumor cells formed nested and trabecular patterns (Figure 2B). Two types of tumor cells were present. 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 adrenal cortex (Figure 2B). The second type contained abundant eosinophilic cytoplasm, with slightly larger, slightly more pleomorphic nuclei and occasional mitotic cells (Figure 2C).
The differential diagnosis of an adrenal cortical 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 cortical 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.30 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 capsular invasion.31 If three or more of these features are present, a diagnosis of adrenal cortical carcinoma 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 pathological diagnosis is adrenal cortical adenoma with atypia. It is important to recognize that neither this nor other proposed systems for distinguishing adenoma and carcinoma are infallible33; clinical correlation is required.
Although it is clinically important to distinguish functioning from nonfunctioning adrenal 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 replacement with dexamethasone was begun. Postoperative tests showed complete suppression of the levels of 24-hour urinary cortisol and morning serum cortisol. The results of thyroid function tests normalized. 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 potassium 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 spontaneously during the first week of life. His corticotropin and corticotropin-stimulated cortisol levels were normal.
Five days after delivery, the patient's morning cortisol level remained low, at 2.4 μg per deciliter (66.3 nmol per liter); thus, the dose of prednisone 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 tumors are malignant in rare cases, and pathological identification of a malignant tumor can be difficult; consequently, follow-up studies were continued 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 metastatic carcinoma (Figure 3A).
Figure 3. Follow-up MRI and Liver-Biopsy Specimen.
An axial fat-suppressed, T1-weighted image obtained after the intravenous administration of gadolinium (Panel A) shows new hepatic masses (thin arrows), with irregular peripheral enhancement — findings that are consistent with the presence of metastatic disease. A small hematoma in the left adrenalectomy bed is also present (thick arrow). A specimen from an ultrasound-guided biopsy of the liver (Panel B, hematoxylin and eosin) shows nests of tumor with histologic features similar to those of the left adrenal primary tumor. Although cytologic criteria for cancer are still not present, the metastatic tumor itself establishes the diagnosis of adrenal cortical carcinoma.
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 (Figure 3B); although the histologic features that are diagnostic of cancer were still not present, the presence of a tumor in the liver is diagnostic of adrenal cortical carcinoma. This case illustrates the difficulty of establishing a pathological 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, including the IGF2 gene, that are associated with adrenal cortical carcinoma.34 IGF2 expression is also elevated in adrenal cortical carcinoma on immunohistologic examination.35 These findings should be further studied to determine their clinical usefulness in predicting the malignant potential 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 hepatic metastases and elevated urinary cortisol levels, chemotherapy with low-dose mitotane, etoposide, doxorubicin, and cisplatin was recently begun, 9 months after the diagnosis of metastatic disease.
Anatomical Diagnosis
Cushing's syndrome due to adrenal cortical carcinoma.
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.
Source Information
From the Neuroendocrine Unit (A.K.), the Department of Surgery (A.E.S.), the Obstetrics 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.), Obstetrics, Gynecology and Reproductive Biology (M.F.G.), Radiology (M.A.B.), and Pathology (C.-L.W.), Harvard Medical School.
References
Sibai BM, Mabie WC, Shamsa F, Villar MA, Anderson GD. A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am J Obstet Gynecol 1990;162:960-966.
Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing's syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab 2005;90:3077-3083.
Carr BR, Parker CR Jr, Madden JD, MacDonald PC, Porter JC. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 1981;139:416-422.
Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing's syndrome. J Clin Endocrinol Metab 1998;83:2681-2686.
Findling JW, Raff H, Aron DC. The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome. J Clin Endocrinol Metab 2004;89:1222-1226.
Odagiri E, Ishiwatari N, Abe Y, et al. Hypercortisolism and the resistance to dexamethasone suppression during gestation. Endocrinol Jpn 1988;35:685-690.
Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev 2005;26:775-799.
Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2003;88:5593-5602.
Outwater EK, Siegelman ES, Radecki PD, Piccoli CW, Mitchell DG. Distinction between benign and malignant adrenal masses: value of T1-weighted chemical-shift MR imaging. AJR Am J Roentgenol 1995;165:579-583.
Varghese JC, Hahn PF, Papanicolaou N, Mayo-Smith WW, Gaa JA, Lee MJ. MR differentiation of phaeochromocytoma from other adrenal lesions based on qualitative analysis of T2 relaxation times. Clin Radiol 1997;52:603-606.
Buescher MA, McClamrock HD, Adashi EY. Cushing syndrome in pregnancy. Obstet Gynecol 1992;79:130-137.
Pickard J, Jochen AL, Sadur CN, Hofeldt FD. Cushing's syndrome in pregnancy. Obstet Gynecol Surv 1990;45:87-93.
Pabon JE, Li X, Lei ZM, Sanfilippo JS, Yussman MA, Rao CV. Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands. J Clin Endocrinol Metab 1996;81:2397-2400.
Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone-dependent Cushing's syndrome. N Engl J Med 1999;341:1577-1581.
Hána V, Dokoupilová M, Marek J, Plavka R. Recurrent ACTH-independent Cushing's syndrome in multiple pregnancies and its treatment with metyrapone. Clin Endocrinol (Oxf) 2001;54:277-281.
Gormley MJ, Hadden DR, Kennedy TL, Montgomery DA, Murnaghan GA, Sheridan B. Cushing's syndrome in pregnancy -- treatment with metyrapone. Clin Endocrinol (Oxf) 1982;16:283-293.
Close CF, Mann MC, Watt JF, Taylor KG. ACTH-independent Cushing's syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone. Clin Endocrinol (Oxf) 1993;39:375-379.
Connell JM, Cordiner J, Davies DL, Fraser R, Frier BM, McPherson SG. Pregnancy complicated by Cushing's syndrome: potential hazard of metyrapone therapy: case report. Br J Obstet Gynaecol 1985;92:1192-1195.
Pricolo VE, Monchik JM, Prinz RA, DeJong S, Chadwick DA, Lamberton RP. Management of Cushing's syndrome secondary to adrenal adenoma during pregnancy. Surgery 1990;108:1072-1077.
Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing's syndrome and pheochromocytoma. N Engl J Med 1992;327:1033-1033.
Assalia A, Gagner M. Laparoscopic adrenalectomy. Br J Surg 2004;91:1259-1274.
Gonzalez R, Smith CD, McClusky DA III, et al. Laparoscopic approach reduces likelihood of perioperative complications in patients undergoing adrenalectomy. Am Surg 2004;70:668-674.
Soper NJ, Hunter JG, Petrie RH. Laparoscopic cholecystectomy during pregnancy. Surg Endosc 1992;6:115-117.
Hunter JG, Swanstrom L, Thornburg K. Carbon dioxide pneumoperitoneum induces fetal acidosis in a pregnant ewe model. Surg Endosc 1995;9:272-277.
Reedy MB, Kallen B, Kuehl TJ. Laparoscopy during pregnancy: a study of five fetal outcome parameters with use of the Swedish Health Registry. Am J Obstet Gynecol 1997;177:673-679.
Wolf A, Goretzki PE, Rohrborn A, et al. Pheochromocytoma during pregnancy: laparoscopic and conventional surgical treatment of two cases. Exp Clin Endocrinol Diabetes 2004;112:98-101.
SAGES guidelines for laparoscopic surgery during pregnancy. Los Angeles: Society of American Gastrointestinal Endoscopic Surgeons, 2000. (Publication no. 0023.) (Accessed September 20, 2006, at http://www.sages.org/sg_pub23.html.)
Gagner M, Pomp A, Heniford BT, Pharand D, Lacroix A. Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg 1997;226:238-246.
Adrenal cortical adenoma. In: Lack EE. Tumors of the adrenal gland and extra-adrenal paraganglia. 3rd series. Fascicle 19. Washington, DC: Armed Forces Institute of Pathology, 1997:91-122.
Adrenal cortical carcinoma. In: Lack EE. Tumors of the adrenal gland and extra-adrenal paraganglia. 3rd series. Fascicle 19. Washington, DC: Armed Forces Institute of Pathology, 1997:123-52.
Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-169.
Weiss LM, Medeiros IJ, Vickery AL Jr. Pathological features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202-206.
Medeiros LJ, Weiss LM. New developments in the pathologic diagnosis of adrenal cortical neoplasms: a review. Am J Clin Pathol 1992;97:73-83.
Giordano TJ, Thomas DG, Kuick R, et al. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 2003;162:521-531.
Schmitt A, Saremaslani P, Schmid S, et al. IGFII and MIB1 immunohistochemistry is helpful for the differentiation of benign from malignant tumours. Histopathology 2006;49:298-307.(Anne Klibanski, M.D., Ant)