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Virilizing oncocytic adrenocortical carcinoma: clinical and immunohistochemical studies
Julie Carré, Solange Grunenwald, Delphine Vezzosi, Catherine Mazerolles, Antoine Bennet, Geri Meduri & Philippe Caron
To cite this article: Julie Carré, Solange Grunenwald, Delphine Vezzosi, Catherine Mazerolles, Antoine Bennet, Geri Meduri & Philippe Caron (2016): Virilizing oncocytic adrenocortical carcinoma: clinical and immunohistochemical studies, Gynecological Endocrinology, DOI: 10.3109/09513590.2016.1149811
To link to this article: http://dx.doi.org/10.3109/09513590.2016.1149811
Published online: 07 Mar 2016.
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GYNECOLOGICAL ENDOCRINOLOGY
Gynecol Endocrinol, Early Online: 1-5 c 2016 Taylor & Francis. DOI: 10.3109/09513590.2016.1149811
Taylor & Francis Taylor & Francis Group
ORIGINAL ARTICLE
Virilizing oncocytic adrenocortical carcinoma: clinical and immunohistochemical studies
Julie Carré1, Solange Grunenwald1, Delphine Vezzosi1, Catherine Mazerolles2, Antoine Bennet1, Geri Meduri3, and Philippe Caron1
1Department of Endocrinology and Metabolic Diseases, Pôle Cardio-Vasculaire Et Métabolique, CHU Larrey, Toulouse, France, 2Department of Pathology, IUCT-Oncopole, Toulouse, France, and 3 INSERM UMR 788, Bicêtre, France
Abstract
Context: Oncocytic tumors of the adrenal cortex are rare, mostly nonfunctioning and benign. Setting: Report virilizing oncocytic adrenocortical carcinoma in a 50-year-old woman.
Patient: She presented a recent and progressive virilization syndrome, associated with high blood pressure. Hormonal evaluation showed elevated serum testosterone and delta-4- androstenedione levels, normal urinary free cortisol level and incomplete suppression of cortisol at the 1 mg dexamethasone suppression test. CT scan of the abdomen revealed a 35 mm left adrenal mass.
Intervention: The patient underwent a left adrenalectomy, and the histological study showed a 3 cm oncocytic adrenocortical carcinoma with signs of malignancy.
Results: Immunohistochemical study revealed that tumor cells expressed the steroidogenic enzymes involved into androgen synthesis (3BHSD and P450c17x), P450 aromatase and luteinizing hormone (LH) receptors. Post-operatively, signs of virilization improved rapidly, serum testosterone and delta-4-androstenedione levels returned to normal, as did the dexamethasone suppression test. During follow-up CT-scan and 18-FDG PET/CT showed a right ovary mass, corresponding to a follicular cyst associated with hyperthecosis. The patient is alive with no recurrence 48 months after adrenal surgery.
Conclusion: Oncocytic adrenocortical carcinomas, although extremely rare, should be con- sidered in women with a virilization syndrome. In this woman immunohistochimical studies revealed the presence of steroidogenic enzymes involved into androgen synthesis and aromatization, and LH receptors could be implicated in this pathology.
Keywords
Immunohistochemistry, luteinizing hormone receptors, oncocytic adrenocortical carcin- oma, steroidogenic enzymes, virilization
History
Received 13 September 2015 Revised 27 January 2016
Accepted 30 January 2016 Published online 7 March 2016
Introduction
Oncocytomas are rare neoplasms, most frequently of adenohypo- physis, salivary glands, thyroid, parathyroid and kidney, com- posed by large, eosinophilic, epithelial cells of unknown origin, with a granular cytoplasm corresponding to abnormal accumula- tion of swollen mitochondria. Oncocytomas of the adrenal cortex are rare [1-10]. Most are nonfunctioning and found incidentally during investigations for another indication. We report the case of a 50-year-old woman who presented with a virilization syndrome due to a functional, androgen-secreting oncocytic adrenocortical carcinoma.
Patient
A 50-year-old woman presented with a recent and progressive virilization syndrome, including hirsutism and clitoris hypertro- phy. She had not clinical sign of Cushing’s syndrome, but high
Address for correspondence: Philippe Caron, MD, Department of Endocrinology and Metabolic Diseases, CHU Larrey, 24 Chemin de Pourvouville, TSA 30030, 31059 Toulouse Cedex 9, France. Tel: +33 567771701. Fax: +33 567771672. E-mail caron.p@chu-toulouse.fr
blood pressure with normokaliemia. The patient had previously undergone a total thyroidectomy for benign multinodular goiter and a radical hysterectomy for cervical cancer at the age of 43 years.
Hormonal evaluation showed elevated serum testosterone and delta-4-androstenedione levels (Table 1). The patient had normal urinary free cortisol (47 µg/day, normal range <100 µg/day), but serum cortisol level was 4.5 µg/100 ml at midnight with incom- plete suppression after the 1 mg dexamethasone suppression test (4.8 µg/100 ml, normal range <1.8 µg/100 ml). The ACTH level was at the lower limit of the normal range (15 pg/mL). Serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sul- phate (DHEAS), 17OH-progesterone (17OHP), renin and aldos- terone levels were normal (Table 1). Estradiol level was 53 pg/ml, and luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were 2.10 mIU/ml and 4 mIU/ml, respectively.
Abdominal ultrasonography showed normal ovaries, and a CT scan of the abdomen revealed a 35 mm left adrenal mass with a density of 37 Hounsfield units and a wash-out at 42%.
The patient underwent a left adrenalectomy by laparoscopy. Postoperatively, virilization signs improved and serum testoster- one and delta-4-androstenedione levels returned to normal, as did
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| Testosterone (ng/100 ml) | Delta-4* (ng/100 ml) | DHEAS (µg/100 ml) | 17OHP ** (ng/100 ml) | 17ß-estradiol (pg/ml) | |
|---|---|---|---|---|---|
| Pre-operative | 200 | 1051 | 90 | 260 | 53 |
| Post-operative | 16 | 67 | 132 | 35 | 2 |
| Normal range | 10-85 | 35-180 | 10-235 | 20-330 | follicular phase 10-90 post menopausal <15 |
*Delta-4-androstenedione.
** 17-OH progesterone.
the dexamethasone suppression test. After surgery, the serum cortisol level was low (2.7 µg/100 ml), and the patient received a substitutive hydrocortisone treatment at decreasing dosage during six months. Follow-up of hormonal evaluation and CT scans performed during 48 months after surgery showed no evidence of tumor recurrence.
During clinical follow-up, 26 months after adrenalectomy, the CT scan of the pelvis revealed a 28 x 22 mm2 right ovary lesion, persistent on successive scans, with high uptake on 18F-FDG PET/CT. A bilateral oophorectomy was performed.
Methods
In vivo studies
Serum testosterone, estradiol and 17OH progesterone concentra- tions were measured with a commercial RIA kit from Cisbio (Gif sur Yvette, France). A RIA kit from DSL-Beckmann Coulter® (Fullerton, California) was used to assay delta-4-androstenedione hormone. DHEAS was measured by Elecsys® automated analyzer using a two-site chemiluminescent enzyme immunometric assay (Roche Diagnostics, Mannheim, Germany). In addition, serum concentrations of LH, FSH were assessed by the Centaur automated analyzer (Bayer Corp., Tarrytown, NY).
Immunohistochemical studies
Briefly, 5 um-thick tissue sections were deparaffinised and rehydrated by successive baths of toluene and graded alcohols and subjected to 15 min microwave antigen retrieval in pH 6 citrate buffer. After cooling and 30 min pre-incubation with a blocking serum (DakoCytomation), slides were incubated with the primary antibodies overnight at 4℃ in a humid chamber. Bound immunoglobulins were revealed with a streptavidin-biotin- peroxydase-aminoethylcarbazole kit (LSAB+, DakoCytomation) according to manufacturer’s instructions.
The antibodies directed against the steroidogenic enzymes used were all rabbit polyclonals: an anti-3ßHSD (3-Beta- hydroxysteroid-dehydrogenase), anti-P450c17x(P450c17alpha hydroxylase (OH)) anti-P450 aromatase (Kind gifts, respectively, of Pr Van-Luu, The Laval University, Canada, of Pr S Takemori, Hiroshima University, Japan, of Pr Y Osawa, Michigan University, USA) and were used at the respective dilutions of 1:8000, 1:3000, 1:700. The antibody LHR 29 directed against the LH receptor was utilized at the concentration of 10 µg/ml [11]. The slides were examined with an Axio Imager 2 Research Microscope.
For immunofluorescence confocal microscopy, the sections were incubated overnight at 4 ℃ with primary anti LHR and anti P450c17a antibodies as previously indicated, donkey anti-mouse and anti-rabbit secondary antibodies conjugated, respectively, with Alexa 555 and Alexa 488 fluorochromes were successively used at the concentration of 1/1000. The slides were examined with a Leica TCS SP8 confocal microscope, and the LAS X program was used for image acquisition.
Results
In vivo studies
At diagnosis, the patient had significantly increased serum testosterone and delta-4-androstenedione levels whereas DHEAS and 17OH-progesterone levels were normal. After left adrena- lectomy, serum testosterone and delta-4-androstenedione levels became normal. Serum 17ß estradiol concentration was 53 pg/ml at diagnosis and decreased after removal of the oncocytic adrenocortical carcinoma (2 pg/ml) (Table 1).
On day 5 post-operatively, LH level was in the normal range (5.8 mIU/ml) while FSH level was at the upper value of the normal range (14.3 mIU/ml). Before bilateral oophorectomy (26 months after adrenalectomy), testosterone level was 28 ng/100 ml, and gonadotropin levels were increased (LH =27.6 mIU/ml, FSH 40.9 mIU/ml).
Histological and immunohistological results
The histological study showed a 3 cm oncocytic adrenocortical carcinoma with signs of malignancy (Weiss criteria: 6, Bisceglia score: malignant, Ki 67: 6.8%). The immunohistochemical profile was positive for Melan-A, synaptophysin and calretinin, and thus was typical of adrenocortical carcinoma.
Most tumor cells expressed the steroidogenic enzymes involved into androgen synthesis: 3ßHSD and P450c17a (Figure 1a: A, B). Aromatase expression was also detected (Figure 1a: C), albeit in a lesser number of cells, and some tumor cells also expressed LH receptors (Figure 1a: D). Confocal microscopy studies revealed a colocalization of LH receptors and the P450c17a enzyme in some tumor cells (Figure 1b). The histologic study of the right ovary showed hyperthecosis associated with a follicular cyst.
Discussion
Oncocytic adrenocortical carcinomas are mostly nonfunctioning and discovered incidentally. To our knowledge, only fifteen cases of functional androgen-secreting oncocytic adrenocortical carcin- oma have been reported in English literature [6,12-25] (Table 2). In our middle-aged woman, the high plasma level of testosterone associated with normal DHEAS concentration suggested the presence of ovarian hyperthecosis or androgen-secreting ovarian tumors such as Leydig-Sertoli tumors. However, the pelvic ultrasonography was normal whereas the abdominal CT scan revealed a left adrenal mass. After left adrenalectomy, virilization signs disappeared, serum testosterone and delta-4-androstene- dione levels became normal, and at 4-year follow-up there were no clinical, hormonal or radiologic (CTscan) signs of recurrence.
Expression of steroidogenic enzymes has been rarely char- acterized in androgen-secreting oncocytic tumors. A recently published extensive study of an androgen-secreting adrenocortical oncocytoma from a 34-year old hirsute woman revealed intense expression of 17xOH and 30-hydroxysteroid-deshydrogenase 2
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(a)
A
B
C
D
(b)
P450c17a
LHR
Merge
Merge
indicating tumoral 17OH-progesterone synthesis. This study also revealed that a subpopulation of oncocytic cells could metabolize delta-4-androstenedione into testosterone by 17ß HSD [25]. Furthermore, ACTH-stimulation of tumor cell cultures induced cortisol, delta-4-androstenedione and testosterone secretion. These results and the presence of melanocortin 2 receptor (MC2R) immunoreactivity in clusters of adenoma cells strongly suggested an adrenocortical phenotype of the benign oncocytic
tumor [25]. In our patient, immunohistochemical studies of the oncocytic adrenocortical carcinoma cells showed instead expres- sion of enzymes involved in androgen synthesis (3ßHSD, P450c17x), and with less intensity, of P450 aromatase, involved in estrogen synthesis, thus explaining the clinical symptoms and hormonal profile of the patient. Surprisingly, some oncocytic cells were also immuno-positive for LH receptors (LHR). Thus, our patient presented subclinical Cushing’s syndrome before surgery
| Author and reference | Age | Elevated androgen serum levels | Tumor size | Type |
|---|---|---|---|---|
| Geramizadeh [6] | 43-yr-old female | Testosterone = 1170 ng/dl DHEAS≥ 90 µg/dl | 9 cm | Benign |
| Golkowski [12] | 51-yr-old male | DHEAS =1101.9 µg/dl Cortisol after 1 mg dexamethasone test =5.1µg/dl | 17 cm | Borderline |
| Logasundaram R [13] | 58-yr-old female | Testosterone = 164.3 ng/dl Androstenedione = 446.7 ng/dl DHEAS =176ug/dl | 9 cm | Benign |
| Gumy-Pause F [14] | 12-yr-old female | Testosterone = 43.3 ng/dl Androstenedione = 507 ng/dl | 5 cm | Benign |
| Lim YJ [15] | 14-yr-old female | Testosterone = 500 ng/dl DHEAS =1000µg/dl 17OHP = 56.4 ng/dl | 17.5 cm | Borderline |
| Mwandila M [16] | 19-yr-old female | Testosterone = 345.8 ng/dl DHEAS =362µg/dl | 5 cm | Malignant |
| Surrey LF [17] | 55-yr-old female | Testosterone = 635 ng/dl DHEA = 268µg/dl (normal range15-170µg/dL) | 7 cm | Benign |
| Song W [18] | 11-yr-old female | Testosterone = 1133 ng/dl | 5 cm | Benign |
| Sharma D [19] | 16-yr-old female | Testosterone = 435 ng/dl DHEAS > 1500µg/dl | 12 cm | ? |
| Subbiah S [20] | 3.5-yr-old female | Testosterone = 154.8 ng/dl DHEAS =1000 µg/dl | 2.5 cm | Benign |
| Kolev NY [21] | 9-yr-old female | Testosterone = 749.3 ng/dl DHEAS = 700.3µg/dl | 3.5 cm | Benign |
| Son SH [22] | 53-yr-old female | DHEAS = 872.9 µg/dl 24h urinary cortisol = 722ug/24h | 9.8 cm | Borderline |
| Sahin SB [23] | 23-yr-old female | Testosterone = 420 ng/dl DHEAS =574µg/dl | 2.2 cm | Benign |
| Yordanova G [24] | 9-yr-old female | Testosterone = 513 ng/dl DHEAS =288µg/dl | 2.2 cm | Benign |
| Nomigni NT [25] | 34-yr-old female | Testosterone = 144 ng/dl Androstenedione = 700 ng/dl | 2.6 cm | Benign |
with transient post-operative corticotrope insufficiency compat- ible with an adrenal phenotype of the oncocytic tumor. On the other hand, the steroid profile, the presence of 17xOH and 3BHSD, the aromatase expression, and the presence of LH receptors suggested a gonadal phenotype of the oncocytic carcinoma cells.
The presence of low levels of functional LHR in the adrenal cortex has been previously reported [26], and a significant correlation between elevated postmenopausal LH levels and cortisol or DHEAS secretion has been established [27]. In humans, cases of pregnancy-associated Cushing’s syndrome, secondary to elevated gestational hCG levels [28] and also of LH-dependent Cushing syndrome in postmenopausal women with macronodular adrenal hyperplasia [29,30] have been reported. Also, experimental data seem to support the possible contribution of LHR activation to adrenal tumorigenesis [26,30-33]: trans- genic mice for the murine inhibin alpha subunit promoter develop adrenal tumors expressing highly functional LHR after castration [34]. It has been suggested that LHR might be normally expressed in the mouse adrenal gland at a very low level, and that the elevation of LH levels in castrated animals might transform LHR bearing adrenocortical precursor cells into steroidogenic cells [35] expressing the gonadic-specific transcription factor GATA-4 instead of the adrenal transcription factor GATA-6 [36].
The hypothesis of persistent LHR on adrenal cells is further supported by the common embryological origin of adrenal and gonadal primordial arising from the urogenital ridge. Moreover, both adrenals and gonads share common genes such as P450 aromatase and P450c17a and it is conceivable that in rare cases, a residual expression of LHR could persist in precursor adrenal cells. This subset of progenitor adrenocortical cells, which retain the capacity to respond to gonadotropic stimuli, might proliferate
and eventually become neoplastic under chronic LH exposure. Alternatively, it could be hypothesized that cellular dedifferenti- ation during tumorigenesis, could reactivate the expression of some genes shared by cells of the adrenogonadal primordium but silenced after birth in adrenocortical cells, such as LHR.
The implication of improper activation of LHR in this patient is also supported by the successive onset of hyperthecosis, characterized by high LH levels and LHR activation on interstitial ovarian cells, causing stromal hyperplasia with foci of steroid- secreting luteinized cells [37].
Declaration of interest
The authors have nothing to disclose.
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