CLINICAL CASE SEMINAR
Collision/Composite Tumors of the Adrenal Gland: A Pitfall of Scintigraphy Imaging and Hormone Assays in the Detection of Adrenal Metastasis
Adeline Thorin-Savouré, Frédérique Tissier-Rible, Laurence Guignat, Anne Pellerin, Xavier Bertagna, Jérome Bertherat, and Hervé Lefebvre
Institut National de la Santé et de la Recherche Médicale U413 (A.T .- S., H.L.), European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), Department of Endocrinology, Diabetology, and Metabolic Diseases, and Department of Pathology (A.P.), Centre Hospitalier Universitaire of Rouen, 76031 Rouen, France; and Department of Pathology (F.T .- R.), Centre Hospitalier Universitaire Cochin, and Department of Endocrinology (L.G., X.B., J.B.), Centre Hospitalier Universitaire Cochin and Institut Cochin, Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique UMR8104, IFR 116, Université Paris V-René Descartes, 75014 Paris, France
Context: In patients with a history of extraadrenal tumor, incidental discovery of an adrenal mass necessitates excluding the possibility of metastatic malignancy. Detection of the malignant tissue is a difficult challenge when metastasis occurs in an adrenal adenoma, forming a collision/composite tumor.
Objective, Design, and Setting: We report two patients with ad- renal collision/composite tumors referred to two French university hospitals.
Patients and Results: Two patients with histories of mammary and sigmoid carcinomas, respectively, presented with adrenal mass dis- covered 8 and 3 yr after surgical removal of the primary tumor. In the two cases, computerized tomographic scan showed that the adrenal tumor contained two components with low and high attenuation val- ues, respectively. Uptake of iodocholesterol by the adrenal tumor in case 1 and elevated plasma ACTH-stimulated 17-hydroxyprogester-
one values in case 2 strongly argued for the diagnosis of primary adrenocortical tumors. Enlargement of the adrenal mass during fol- low-up in case 1 and association of the adrenal lesion with a hepatic mass in case 2 led to adrenalectomy. In both cases, histological ex- amination of the tumor demonstrated the presence of metastatic carcinoma tissue in an adrenocortical adenoma, allowing classifica- tion of the neoplasia as a collision/composite tumor.
Conclusion: These observations show that collision/composite tu- mors of the adrenal gland formed by carcinoma metastasis in benign adenomas are a pitfall of iodocholesterol scintigraphy and/or plasma steroid assays to exclude the diagnosis of adrenal metastasis. Con- versely, computerized tomographic scan is a useful tool for the dis- tinction between the benign and malignant tissues in adrenal colli- sion/composite tumors. (J Clin Endocrinol Metab 90: 4924-4929, 2005)
T HE EXTENSIVE USE of abdominal computerized to- mography (CT) scan has led to a dramatic increase in incidentally discovered adrenal masses also called inciden- talomas (1, 2). Management of adrenal incidentalomas has therefore become a common occurrence in endocrinological practice. One of the major questions addressed to the clini- cian is to exclude the possibility of metastatic malignancy, especially in patients with known extraadrenal primary tu- mor (3). Indeed, patients with no other evidence of metastasis may benefit from surgery of a single metastatic adrenal mass (4). The distinction between benign and metastatic adrenal masses is usually based on imaging and scintigraphic criteria as well as fine-needle aspiration (FNA) biopsy of the tissue
(2,3). On CT scan, a tumor size less than 4 cm and attenuation values lower than 10 HU are considered as valuable indi- cators of benignity (5). Chemical-shift magnetic resonance imaging (MRI) not only helps in the anatomical description of the adrenal mass but also provides important clues for the characterization of the tissue. As a matter of fact, the presence of high amounts of lipids in adenomas causes a loss of signal intensity on chemical-shift MRI contrary to lipid-poor met- astatic lesions, which therefore appear brighter than adre- nocortical adenomas (6).
Radiocholesterol scintigraphy is also an important tool for the diagnosis of metastatic adrenal lesions that present as cold masses, whereas benign adenomas and 14% of primary adrenocortical carcinomas exhibit significant uptake of the tracer (2, 7, 8). Similarly, exclusion of an adrenal metastatic process can be facilitated by the demonstration of high plasma steroid levels, which strongly argues for a primary adrenal lesion (2). Adrenal masses containing low lipid amounts and/or presenting as cold masses at radiocholes- terol scintigraphy warrant further evaluation. After exclu-
Abbreviations: CK7, Cytokeratin 7; CT, computerized tomography; FNA, fine-needle aspiration; MRI, magnetic resonance imaging; 17OH progesterone, 17-hydroxyprogesterone.
JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the en- docrine community.
sion of a possible pheochromocytoma by use of urinary cat- echolamine and metanephrine assays, the diagnosis of adrenal metastasis can be confirmed by percutaneous CT scan-guided FNA biopsy with a sensitivity of about 90% (9). Exceptionally, adrenal metastasis may develop in a benign adenoma forming a collision or composite tumor, i.e. con- sisting in two contiguous but histologically different tissues (10). Endocrinologists must be aware of this possibility be- cause collision/composite tumors may represent a pitfall of imaging, scintigraphy, hormone assays, and FNA in the de- tection of adrenal metastasis. In the present study, we report two cases of benign adrenal adenomas containing metastasis from colonic and mammary primary carcinomas, respectively.
Case Reports
Case 1
A 51-yr-old woman was hospitalized for reevaluation of a right adrenal mass. The patient had a history of bilateral breast carcinoma treated 8 yr before by bilateral tumorec- tomy with axillary lymphadenectomy. Pathological exami- nation revealed a bilateral infiltrative ductal carcinoma of the external upper quadrants measuring 35 mm in diameter on the right (grade II) and 22 mm on the left (grade I). Immu- nohistochemical studies showed that the two tumors were positive for estradiol and progesterone receptors. There was no evidence of metastasis (stage T2NOM0) and plasma CA 15.3 level was normal (18 KU/1; N: 5-30). Surgery was fol- lowed by radiotherapy (cobaltotherapy, 20 Gy) and four courses of farmorubicin and endoxan. The adrenal mass had been discovered 2 yr later, during the follow-up of the ma- lignant disease. It presented as a 3.4-cm well-shaped, ho- mogenous, and low-density (<0 HU) tumor on unenhanced CT scan (Fig. 1A) and was therefore considered as a benign adrenocortical adenoma. Plasma CA 15.3 level remained nor- mal (21 KU/liter), and bone scintigraphy did not show any evidence of metastasis. No endocrine evaluation was per- formed at that time.
Six years later, at the time of referral to our Department of Endocrinology, clinical examination did not show any sign of catecholamine or steroid hormone excess. Arterial blood pres- sure was normal. Hormone assays revealed normal levels of plasma ACTH at 0800 h [10 pg/ml (2.2 pmol/liter); N: 10-80 pg/ml (2.2-17.6 pmol/liter)], cortisol after 1 mg dexametha- sone [1.6 µg/dl (44 nmol/liter); N < 1.8 µg/dl (50 nmol/liter]), 17-hydroxyprogesterone [17OH progesterone; 0.1 ng/ml (0.3 nanomoles per liter); N < 0.2 ng/ml (0.6 nmol/liter)], and urinary free cortisol [28 µg/d (77.3 nmol/d); N: 20-80 µg/d (55-220 nmol/d)] and metanephrines [59 µg/d (299 nmol/d); N < 296 µg/d (1500 nmol/d)]. CT scan reassessment of the adrenal lesion showed moderate mass enlargement (diameter 4.1 cm). In addition, the tumor appeared heterogenous, i.e. containing two distinct components exhibiting spontaneous attenuation values of -0.9 and 45 HU, respectively (Fig. 1B). Immediately after iv contrast, attenuation values rose to 32 and 76 HU (Fig. 1C) and then decreased to 7 and 44 HU, respec- tively, after 10 min (Fig. 1D). Iodocholesterol scintigraphy showed a bilateral adrenal uptake of the tracer predominant on the right gland (Fig. 2). Bone scintigraphy as well as abdominal and thoracic CT scan did not show any sign of metastasis and
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plasma CA 15.3 concentration was normal (12 KU/liter). The increase in mass size as well as heterogeneity of the tissue on CT scan led to surgical removal of the adrenal tumor. Patho- logical examination of the lesion demonstrated the occurrence of malignant tissue in a benign (Weiss score 0) adrenocortical
adenoma (Fig. 3A). Malignant cells were intermingled with benign adrenal adenoma cells. The presence of a fibrous neo- plastic stroma was also noticed (Fig. 3A).
In an attempt to characterize the histological type of the malignant component of the tumor, tissue slices were incu- bated with monoclonal antibodies directed against cytoker- atin 7 (CK7, 1:100, clone OV-TL12/30, Dakopatts, Trappes, France), vimentin (1:300, clone V9, Dakopatts), melan-A (1: 50, clone A103, Dakopatts), inhibin «-subunit (1:50, clone MCA951S, Oxford Bio-Innovation, Upper Heyford, UK), the estrogen receptor-« (1:50, clone 1D5, Dakopatts), and the progesterone receptor (1:75, clone PgR636, Dakopatts). These immunohistochemical studies revealed that the malignant tissue was positive for CK7 and the estrogen and proges- terone receptors (Fig. 3, B-D). In contrast, no immunoreac- tivity was observed in malignant cells after incubation of tumor slices with antibodies directed against vimentin, melan-A (Fig. 3, E and F), and inhibin «-subunit (data not shown). As expected, vimentin and melan-A antibodies in-
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tensely stained the adrenocortical adenoma tissue (Fig. 3, E and F), which was negative for inhibin «-subunit (data not shown). Two months after adrenal surgery, a left-sided breast recurrence of the carcinoma was detected and surgi- cally removed. CT scans and bone scintigraphy did not show any other metastasis. Breast surgery was followed by treat- ment with an aromatase inhibitor (anastrozole, 1 mg/d). Two years later, there was no evidence of recurrence of the breast cancer.
Case 2
A 54-yr-old patient was referred for a right adrenal mass. The patient had a history of arterial hypertension and stage C (Dukes) sigmoid carcinoma treated 3 yr before by surgery and chemotherapy with 5-fluorouracile. Two years before, a CT scan performed during a systematic assessment of the malignant disease had shown a 2-cm nodule located in seg- ment II of the left liver lobe. A percutaneous CT scan-guided biopsy of the lesion did not reveal the presence of any car- cinoma cell. A CT scan performed 18 months later did not show any significant variation of the size of the hepatic nodule but did detect a heterogenous tumor of the right adrenal gland measuring 3 cm in diameter (Fig. 4A).
Six months later, CT scan showed significant enlargement of the hepatic nodule, which reached 4 cm in diameter, whereas the right adrenal mass remained stable (Fig. 4B). On unenhanced CT scan, the attenuation values of the adrenal tumor were 85 HU in the central zone and 7.6 HU at the periphery. Biological evaluation revealed an increase in blood carcinoembryonic antigen level up to 26 µg/liter (N < 5). Plasma ACTH at 0800 h [44 pg/ml (9.7 pmol/liter); N: 10-60 pg/ml (2.2-13.2 pmol/liter)], salivary cortisol after 1 mg dexamethasone [0.06 µg/dl (1.66 nmol/liter); N < 0.1 µg/dl (2.76 nmol/liter)], supine renin [6 pg/ml (0.14 pmol/
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liter]; N: 5-40 pg/ml (0.12-0.95 pmol/liter)], and aldoste- rone levels [56 pg/ml (155 pmol/liter); N: 20-130 pg/ml (55-360 pmol/liter)] were normal. Urinary cortisol [20 µg/d (55 nmol/d); N <90 µg/d (248 nmol/d)] and metanephrine concentrations [45 µg/d (230 nmol/d); N < 345 µg/d (1750 nmol/d)] were not elevated. Plasma 17OH progesterone level was normal in basal conditions [0.9 ng/ml (2.72 nmol/ liter); N < 2.8 ng/ml (8.47 nmol/liter)] but abnormally in- creased after 250 µg iv of cosyntropin [peak value: 28.4 ng/ml (85.9 nmol/liter); N < 10 ng/ml (30.3 nmol/liter)]. There was no other evidence of metastasis.
The patient thus underwent both left hepatectomy and right adrenalectomy. Pathologic examination of the hepatic tissue confirmed the diagnosis of metastatic sigmoid carci- noma. Surprisingly, microscopic examination of the adrenal tissue revealed the presence of a benign adrenocortical ad- enoma (Weiss score 0) containing an independent metastasis of the sigmoid carcinoma (Fig. 5, A-C). ACTH-stimulated 17OH progesterone level returned to normal (1.3 ng/ml) after surgery.
Discussion
Collision and/or composite tumors are unusual entities that represent the coexistence of two distinct tissues, like one benign tissue and one metastatic tissue, in a single tumor mass (11). They can occur in various organs such as lungs, liver, and the genitourinary tract (12-14). Despite the rela- tively high prevalence of both adrenocortical adenoma and adrenal metastasis, collision tumors of the adrenal gland are exceptional. A review of the literature reveals that only four cases of metastasis, i.e. two cases of lung carcinoma, one case of leiomyosarcoma, and one case of melanoma metastasis, have been observed in adrenocortical adenomas (10, 15, 16). We now describe two additional patients with adrenal me- tastasis of sigmoid and breast carcinomas, respectively, oc- curring several years after surgical removal of the primary malignant tumor.
Preoperative diagnosis of adrenal collision tumors is a difficult challenge, adrenal adenomas being frequently ob- served in the general population including patients with histories of primary malignancy (17). However, several im- aging techniques may be of great interest for the discrimi- nation between the benign and malignant components of the tumor mass. For instance, in two previously published cases (10), chemical-shift MRI was able to differentiate the benign lipid-rich tissue, which exhibits a decrease in signal intensity relative to that of the liver on opposed-phase images, from the malignant lipid-poor component, which shows an in- crease in signal intensity. In addition, a recent report suggests that positron emission tomography /CT, which has proven to be an accurate technique for the differentiation of benign vs. malignant adrenal masses (18-20), is a promising approach for the in vivo characterization of adrenal collision tumors (16). Adrenal collision tumors may also be suspected on high resolution CT scan. Adenomatous adrenal tissues usually have attenuation values lower than 10 HU and are generally characterized by rapid washout of iv contrast on enhanced CT scan. Using a 10-min delayed enhanced CT, a threshold value of 50% of the initial enhancement allows to distinguish
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adenoma from carcinoma tissues (21). In patient 1 of the present study, imaging of the adrenals revealed the presence of two adrenal tumor components exhibiting the usual CT characteristics of benign and malignant tissues, respectively. A high-density zone was also observed in the center of the adrenal mass in case 2, suggesting the possibility of a colli- sion tumor. However, the presence of high-density areas in the tumors may correspond to fibrotic degeneration of the adenoma tissue (22, 23) and therefore is not sufficient to establish the diagnosis of adrenal metastasis.
Adrenal radiocholesterol scintigraphy is considered the most accurate noninvasive imaging technique in distinguish- ing benign adrenocortical adenomas from lesions of extraa- drenal origin (8). In case 1, scintigraphy showed an increased tracer uptake in the adrenal mass depicted at CT imaging. Such pattern, usually described as concordant, is consistent with the presence of an adrenocortical adenoma and classi- cally allows to exclude the possibility of a destructive or space-occupying lesion like a metastasis (8). Similarly, the increased 17OH progesterone response to ACTH observed preoperatively in patient 2 indicated that the adrenal mass was a steroid-producing tumor, eliminating the diagnosis of a metastasis of extraadrenal origin and favoring the hypoth- esis of a primary adrenocortical neoplasm. Indeed, it has been well demonstrated that secreting adrenocortical tumors
frequently exhibit a low 21-hydroxylase activity responsible for elevated plasma levels of 17OH progesterone both in basal conditions and after stimulation by ACTH (24-28). The observation that the two tumors also contained metastatic components clearly shows that composite and/or collision tumors are a pitfall of radiocholesterol scintigraphy imaging and/or steroid assays in the exclusion of adrenal metastases due to uptake of the tracer and/or production of steroids by the adenomatous components of the adrenal masses. There- fore, the radiocholesterol scintigraphy imaging pattern as well as the results of plasma steroid assays must be inter- preted with caution in patients with a history of malignant disease when CT scan and/or chemical-shift MRI show the presence of two tumor components exhibiting different at- tenuation values and/or signal intensities.
In this situation, assessment of the diagnosis of adrenal metastasis can benefit from FNA biopsy of the lesion after formal exclusion of a possible pheochromocytoma by cate- cholamine and metanephrine assays. It is then necessary to perform the biopsy under CT scan guidance to ensure that the most suspicious component of the tumor is sampled (10). However, the sensitivity of FNA biopsy to establish the di- agnosis of metastatic disease has never been determined in patients with adrenal collision tumors owing to the rarity of this type of neoplasia. Another option is to surgically remove the adrenal mass as soon as the diagnosis of collision tumor is suspected or when CT scan shows an increase in tumor size during follow-up. In our two cases, enlargement of the ad- renal mass or association of the adrenal lesion with a hepatic mass led to adrenalectomy.
Histological examination of the two tumors showed the presence of a malignant tissue in an adrenocortical adenoma. It was conceivable that the malignant component of each tumor may correspond to primary adrenocortical carcinoma, as previously reported in benign adrenal adenoma (29). In case 1, immunohistochemical studies allowed to exclude this hypothesis for the following reasons: (1) antibodies directed against vimentin, melan-A, and inhibin «-subunit, which are widely expressed in adrenocortical neoplasms (30-35), failed to label malignant cells; and (2) the malignant tissue was positive for CK7, an epithelial carcinoma marker that is clas- sically absent in adrenocortical carcinomas (36). In addition, the observation that malignant cells were positive for CK7 and estrogen and progesterone receptors strongly supported the diagnosis of breast carcinoma metastasis. Although in- frequent, the lack of staining of tumor benign cells by the anti-inhibin «-subunit antibody is consistent with previous findings showing that adrenocortical adenomas do not al- ways express the inhibin «-subunit gene (33). In case 2, the histological presentation of the malignant component of the tumor was typical of a colonic carcinoma metastasis and formally excluded the diagnosis of primary adrenocortical carcinoma. Histological examination of the two tumors also revealed significant intermingling of the two different cell types in case 1 and a sharp demarcation between the ma- lignant and adenomatous components in case 2, allowing to classify the neoplasias as a composite tumor and a collision tumor, respectively. It seems doubtful that the presence of malignant cells may explain the heterogeneity of the tumor at CT scan in case 1. It is more likely that the high attenuation
values measured in part of the tumor were related to the fibrous neoplastic stroma shown by histological examina- tion. In case 2, histological studies proved that the dense central zone of the tumor visualized by CT imaging actually corresponded to the sigmoid carcinoma metastasis.
In conclusion, we have described two cases of collision/ composite tumors of the adrenal gland formed by breast and colonic carcinoma metastasis, respectively, in benign adre- nocortical adenomas. In this unusual situation, iodocholes- terol scintigraphy and/or plasma steroid assays can exclu- sively detect the adenomatous component of the adrenal mass and fail therefore to exclude the diagnosis of adrenal metastasis. Conversely, CT scan and/or MRI are useful tools for the distinction between the benign and malignant com- ponents of the adrenal collision/composite tumors. When a collision tumor is suspected, especially in a patient with known extraadrenal primary malignancy exhibiting no other evidence of metastasis, surgical removal of the adrenal mass seems preferable.
Acknowledgments
We are indebted to Professor P. Legmann and Dr. J. P. Louvel for radiological investigations, Professor A. Laquerrière for her critical re- view of histological data, and Drs. M. A. Dugué and A. Legrand for hormonal assays.
Received December 30, 2004. Accepted May 16, 2005.
Address all correspondence and requests for reprints to: Dr. Hervé Lefebvre, Institut Fédératif de Recherche Multidisciplinaires sur les Pep- tides 23, Institut National de la Santé et de la Recherche Médicale U413, Department of Endocrinology, Hospital of Boisguillaume, Centre Hos- pitalier Universitaire of Rouen, 76031 Rouen cedex, France. E-mail: herve.lefebvre@chu-rouen.fr.
This work was supported by the Conseil Régional de Haute-Nor- mandie, Institut Fédératif de Recherches Multidisciplinaires sur les Pep- tides 23, Institut National de la Santé et de la Recherche Médicale U413, the Centre Hospitalier Universitaire de Rouen, and the Réseau COrtical and MEdullary Tumors (COMETE) (Programme Hospitalier de Recher- che Clinique AOM 95201).
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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.