Ectopic adrenocortical carcinoma located in the ovary
Farida Chentli1, Nadia Terki2 and Said Azzoug1
1Department and Endocrine and Metabolic Diseases, Bab El Oued Teaching Hospital Algiers, Algiers, Algeria and 2Department of Pathology, Pierre and Marie Curie Centre, Algiers, Algeria
Correspondence should be addressed to F Chentli Email chentli.f@gmail.com
Abstract
Aim: Ovarian corticosteroid-producing tumors are exquisitely rare. Our aim was to describe the first case observed in our practice.
Case history: A 34-year-old female was referred for Cushing’s syndrome (CS) occurring in the postpartum period. Clinical examination showed severe CS with diabetes mellitus, hypertension, and a large mass in the right lower abdomen. Biochemistry demonstrated corticotropin (ACTH)-independent CS (cortisol = 1900 ng/ml (n=50-250), ACTH < 10 pg/mL (n=20-46)) with estradiol and testosterone overproduction.
Investigations: Abdomen CT scan revealed a 14 cm right ovarian mass and small adrenal glands. Surgical exploration found the ovarian tumor with hemoperitoneum and enlarged lymph nodes. Histological study confirmed adrenocortical tumor located in the ovary with a Weiss score >5, associated with peritoneal and lymph node metastases. Immunohistochemical staining was positive for inhibin-a, melan-A, and SF1, demonstrating tissue of adrenal origin. After surgery, plasma glucose level spontaneously returned to normal. However, the patient died on the second post-surgical day due to catastrophic pulmonary embolism.
Conclusion: In this reported case, clinical, hormonal, histological, and immunohistochemical findings confirmed a cortisol and sex hormone-producing ovarian tumor with peritoneal and lymph node metastases, a very rare but important condition to recognize.
European Journal of Endocrinology (2016) 175, K17-K23
Introduction
It is well known that corticotropin (ACTH)-independent Cushing’s syndrome (CS) is rarer than the ACTH- dependent CS (1, 2).
ACTH-independent CS is usually due to benign or malignant tumors located in the adrenal glands (3, 4, 5). However, in exceptional situations, a tumor located far from the adrenal area may synthesize adrenocortical hormones, mimicking perfectly adrenal secretion.
Ectopic tumors secreting cortisol are so rare that they are not discussed in current reviews on adrenocortical tumors in general and even in adrenocortical carcinomas. Among ectopic neoplasms, ovarian tumors secreting cortisol causing overt CS with metastases are exceptional. To the best of our knowledge, there are six reported cases in English literature: five in human beings (6, 7, 8, 9) and
one in a dog (10). Given its rarity, our aim was to describe the first case observed in our practice.
Case report
A 34-year-old female was referred to our unit for CS with psychiatric signs, diabetes mellitus, and lower limb edema occurring 2 months postpartum. Her medical history was unremarkable. During pregnancy, apart from tiredness, the patient denied having any abnormal symptoms. Her baby was delivered at term by Cesarean section weighing 4.3 kg.
Clinical examination showed severe CS with metabolic and androgenic features including facial plethora, bruises, lower limb edema, severe muscular
| Cortisol (ng/ml) | ACTH (pg/mL) | DHEA-S (pg/mL) | 17-OHP (nmol/L) | TT (ng/ml) | E2 (pg/mL) | FSH (U/mL) | LH (U/mL) | PRL (ng/ml) | TSH (μU/mL) | FT4 (pmol/L) |
|---|---|---|---|---|---|---|---|---|---|---|
| Before DXM 1990 After 2 mg DXM = 1840 After 8 mg = 848 | <10 | 548 | 28.8 | 4.5 | 124 | 0.16 | 0.7 | 13 | 0.58 | 13.8 |
| Reference values 50-250 | 20-46 | 50-580 | 0.3-3 | 0.1-1.2 | <50 | 2.8-11 | 1.1-11 | 3-20 | 0.2-4 | 9-20 |
17-OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropin; DHEA-S, dehydroepiandrosterone sulfate; DXM, dexamethasone; E2, estradiol; FSH, follicle-stimulating hormone; FT4, free thyroxin; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone; TT, total testosterone.
atrophy, and hirsutism. She weighed 58 kg, height 159 cm (BMI=27.5 kg/m2), and had an increased abdominal girth of 102cm. Blood pressures varied between 150/90 and 170/100 mmHg. There was a large palpable mass in the right pelvic area. Galactorrhea and skin hyperpigmentation were absent. Hormonal parameters, done through chemiluminescence, confirmed an ACTH- independent CS (Table 1) with high sex hormones (estradiol and testosterone) and 17-OH progesterone. The very high serum cortisol failed to be suppressed by both 2 and 8 mg dexamethasone. Other evaluated hormonal parameters were within the normal range, except for low FSH and LH levels.
Routine analyses showed normal liver and renal function; however, hyperglycemia, mild dyslipidemia, hypokalemia, and a normocytic hypochromic anemia were present (Table 2).
Abdomen ultrasound did not show any adrenal masses. CT scan showed small adrenal glands and a 14cm heterogeneous tumor in the right pelvic area (Fig. 1) with ascites.
Chest x-ray was unremarkable and echocardio- graphy showed an increase in septal size related to systemic hypertension. Work up for distant metastases was negative.
| Plasma parameters | Patient's values | Normal values |
|---|---|---|
| Glucose | 267 | 70-100 mg/dL |
| Triglycerides | 1.61 | ≤1.5g/L |
| HDL cholesterol | 0.36 | ≥0.50 |
| Total cholesterol | 1.95 | ≤2 g/L |
| Sodium | 144 | 135-145 meq/L |
| Potassium | 2.4 | 3.5-5 meq/L |
| Hemoglobin | 6.8 | 11-14g/dL |
| Hematocrit | 21 | 35-45% |
| MCV | 94 | 80-99 fL |
| MCHC | 31 | 33-37 g/dL |
MCHC, mean cell hemoglobin concentration; MCV, mean corpuscular volume or mean cell volume.
In this patient with rapid evolution, lack of skin hyperpigmentation and low plasma ACTH levels suggested ACTH-independent CS. As both adrenals were small in size with no masses, ectopic glucocorticoids production by the large pelvic tumor was suspected.
Tumor markers were normal (CEA: 1.09 ng/ml (n≤10), AFP: 3.8IU/mL (n≤10), and beta HCG: negative), except for Ca 125, which was slightly increased= 52.5IU/mL (n=0.1-35).
At surgery, a malignant process was encountered by a large friable ovarian mass with abnormal lymph nodes and 400mL hemoperitoneum. The patient underwent total resection with immediate normalization of plasma glucose without any treatment, apart from hydrocortisone given for adrenocortical substitution. On the second postoperative day, the patient died of acute pulmonary embolism.
Macroscopic examination showed a brown lobulated mass measuring 14.5x13.7cm located in the ovary. Cut sections were heterogeneous with numerous hemorrhage and large necrotic areas.
Histological examination showed an encapsulated tumor within the ovary, but with some areas that had breached the capsule (Fig. 2).
The pathological tissue composed of cells arranged in an endocrine and trabecular aspect with vascular embolism and large necrotic areas, with nests of cells similar in appearance to different layers of adrenocortical gland (Fig. 2). A large part of tumor cells was pleomorphic: some were polygonal, others had a round shape. Their cytoplasm was finely granular. The nuclei were vesicular and hyperchromatic with abnormal mitotic figures. Spongiocytic aspects, composed of lipid- laden cells (similar to those of the glomerular zone), with prominent and monstrous nuclei were also observed. The Weiss score was >5.
Immunohistochemical staining was positive for inhibin-a, melan-A, and steroidogenic factor 1 (SF1) (Fig. 3). The positivity was discrete for synaptophysin and
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negative for ACTH, CD 99 (cluster of differentiation 99), cytokeratin AE1/AE3, and calretinin.
Lymph node examination demonstrated that one out of three nodes contained abnormal cells similar to those observed in the ovarian tumor. The peritoneal fluid contained pathological cells.
All these features classified the ovarian tumor as ectopic and poorly differentiated (high grade of malignancy) adrenocortical tumor responsible for ACTH- independent CS. The tumor was considered malignant because of lymph node and peritoneal metastases.
Discussion
Primary or eutopic adrenocortical carcinomas are very rare tumors with an incidence of 0.5-2 per million per year (11). Due to their poor prognosis, they are considered the second most aggressive endocrine malignancy behind anaplastic thyroid cancers.
Adrenocortical neoplasms arising in ectopic locations are extremely rare, and those secreting cortisol are even rarer. Their frequency, incidence and follow-up are totally unknown.
Ovarian localization seems to be exceptional, as to the best of our knowledge; fewer than ten cases have been reported so far in the world literature. Their main characteristics and follow-up are summarized in Table 3.
The first well-documented ovarian carcinoma producing cortisol was reported by Marieb in 1987 (6). On the pathological point, this type of tumor was classified as a lipoid cell tumor of the ovary, as ovarian lipoid tumors are commonly associated with androgenic and estrogenic effects and less frequently with other endocrinological abnormalities (8).
In our case, there is no doubt about the overproduction of cortisol by the tumor located in the ovary, as ACTH was very low, the adrenal glands were small and tumor free, and with ectopic adrenal tissue within the ovary. The ectopic adrenal tissue was
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confirmed by immunostaining positivity to inhibin-a, melan-A, SF1, and synaptophysin. Although distant metastases were absent, the large size, histopathological characteristics, and presence of lymph node and peritoneal metastases defined a malignant process. The negativity of tumor markers does not argue at all against malignancy, especially in tumors secreting cortisol, as glucocorticoid excess inhibits tumor markers (12).
Overt or subclinical CS (13) due to ovarian tumor is an exceptional phenomenon. Only two types of ovarian tumors may be responsible for CS: the first group secretes ACTH or an ACTH-like substance generating paraneoplastic CS, where both adrenals are large as stimulated by an ectopic ACTH, and the second group, which is uncommon, synthesizes some or most adrenocortical steroids that inhibit pituitary corticotropin hormone. In this situation, the adrenal glands are usually atrophic and non-functioning as demonstrated by postmortem studies (Table 3).
Most ovarian tumors secreting adrenal hormones reported in the literature are considered benign (14) probably because histological examination is generally unable to give the certainty of malignancy, or because they are published after a short follow-up period.
Searching Pub Med and Google scholar, we found only six malignant intra-ovarian tumors secreting cortisol with proven metastases. Five were described in humans (6, 7, 8, 9), and one in a dog (10). Our case is the sixth human case.
The mechanism of adrenal tumors arising from the ovary is still debated. One theory is that these tumors originate from transformation of the adrenocortical embryonic remnants that broke off during adrenal migration or descent with gonadal cells (15). For the second theory, ectopic adrenal adenomas/carcinomas may result from mutation of ovarian tissue and its steroid enzymes and/or acquisition of aberrant receptors (16) that are stimulated not by ACTH but by LH and/or HCG, especially during pregnancy (which may be the case in our patient). This pathological situation allows the ovary to synthesize adrenal hormones.
For the first theory, adrenal embryonic remnants are well known, as they were demonstrated for the
first time in 1740 by Schelter and then confirmed by Marchand in 1843 (17). Necropsy studies revealed that ectopic adrenal tissue is frequently found in newborns and children, but it is less common in adults. Adrenal aberrant tissue can be situated anywhere, especially in the pathway of the genital tract migration: celiac trunk, ovaries, testes, spermatic cord, and kidneys (18). Although very rare, normal, hyperplastic, or tumorous adrenal tissue has been observed in unusual sites such as pulmonary area, liver, stomach, brain, and spinal cord (19).
Tumors arising from adrenal remnants are usually scarce. They are often benign (20) and non- functioning. They are discovered incidentally, or after surgery for inguinal hernia (21), pathology of the testis or spermatic cord (22), or at autopsy studies. However on occasion, these tumors may be functional (13, 14, 20) and produce glucocorticoids, androgens (19), or mineralocorticoids (23).
Functioning, benign or malignant, ectopic adrenocortical tumors may also arise from the kidneys (24) or near it (17, 18), near the adrenal gland, in the retro-hepatic space (25), in the testis (26), placenta (27), large intestine (28), or in the ovary (7, 8, 9, 10, 13).
The prognosis of ectopic ovarian tumors secreting cortisol seems to be worse in comparison with eutopic tumors, with mean survival of 8 months (0-18) for the six ovarian tumors secreting cortisol (Table 3) vs 31.5 months for eutopic adrenal carcinomas reported by Bilimoria et al. (29). When the tumor appears and/ or overgrows during pregnancy, as in the reported case, the prognosis is the worst. Rapid progression during pregnancy or in the early postpartum period can be explained by an increased sensitivity of ovarian receptors to LH, HCG, or to aberrant, illicit, or inappropriate membrane hormone receptors as postulated for eutopic adrenocortical tumors (16).
The treatment of ectopic adrenocortical carcinoma does not differ from that of eutopic tumors. Surgery is the cornerstone, but mitotane and ketoconazole alone or with metyrapone (30) can be useful as in eutopic disease. Classical or targeted chemotherapy may also be used. However, the results are generally poor because of the
European Journal of Endocrinology
| Cases | Age (years) | Clinical features | Hormones | ACTH | Radiological aspect | Surgery | Pathological examination | Follow-up | Autopsy |
|---|---|---|---|---|---|---|---|---|---|
| Marieb et al. (1983) (6) | 35 | - Cushing's syndrome - Severe hirsutism - Peripheral edema - Amenorrhea - Mass in lower abdomen - Blood | Increased: -Urinary and plasma cortisol - Urinary 17-hydroxysteroids and 17-ketosteroids - Cortisol levels from the venous effluents higher than that in peripheral plasma Low -FSH and LH Increased cortisol Increased - Plasma and urinary cortisol - Urinary 17-ketosteroids and 17-hydroxysteroids | Nl low=28pg/ mL (20-100) Undetectable | Bilateral ovarian tumors No adrenal masses Adrenals normal in size | Bilateral ovarian tumors Implants in the omentum cul-de-sac, and mesentery | Right ovarian carcinoma = 15 cm Left one = 8 cm Extensive metastases Classification: | Steroids' normalization then relapsing Chemotherapy failure Death after 17 | Extensive tumor of the pelvis Extensive abdomen metastases |
| Young et al. (1987) (7) | 48 52 | pressure=150/80mmHg - Cushing's syndrome - Mild virilization - Blood pressure: 180/110 mmHg - Diabetes mellitus | Right adnexal mass | Normal adrenals Ovary replaced by a yellow brown tumor Brown yellow nodules on visceral | Ovarian tumor of the malignant lipid cell group steroid cell (lipid cell) type abdomen metastases | months Normalization of cortisol and blood pressure Relapsing at 3 months | Atrophic adrenal | ||
| - Cushing's syndrome - Hirsutism - High blood pressure for 17 years (170/100) - Diabetes mellitus | Normal | Normal venographic studies of the adrenal glands | and parietal peritoneum greater omentum and diaphragm Large right ovary Extensive metastases to the omentum | Large ovary of 135g (9×7×5cm) with intact external surface Malignant tumor The omental lesions with the same aspect | Chemotherapy failure Death at 10th month Death at 6 months | ||||
| Donovan et al. | 66 | - Abdominal-pelvic mass - Legs edema | Hypokalemia Increased - CA 125 - Plasma and urinary cortisol - DHEA-S - Testosterone - Androstenedione | Normal | 8 cm multi-lobulated right ovarian | Ovarian steroid cell tumor Metastases: the small and large bowels, the omentum, and liver | Ketoconazole and classical | Extensive tumor | |
| (1993) (8) | - Diabetes mellitus Cushing's syndrome + hypertension appeared after surgery | tumor with multiple adherent loops of the small bowel | chemotherapy failure Death at 4 months | arriving to the right lower lung Bilateral adrenal atrophy | |||||
| Elhadd | 73 | - Rapid Cushing's | High: | Low <10 pg/mL | No adrenal masses No ovarian tumor, but venous catheter showed a left ovarian source | Left ovarian tumor Atrophy of right ovary | 2×2×1 cm lipid cell tumor, but no definite evidence of malignancy | No adjuvant treatment - After 12 months: recurrence and peritoneal metastases | |
| et al. (1996) (9) | syndrome | - Plasma and free urinary cortisol - Testosterone - Estradiol - 17-OHP Low: FSH and LH | |||||||
| - Virilism (clitoromegaly + severe hirsutism) - Hypertension 220/120 mmHg | |||||||||
| Our case (2016) | 34 | Cushing's syndrome - Psychiatric problems - Hirsutism - Hypertension - Diabetes mellitus - Legs' edemas - Pelvic mass | High: - Cortisol - Estradiol - Testosterone - 17-OHP | Low <10 pg/mL | No adrenal masses small adrenals Large ovarian tumor Ascites | - Ovarian tumor: - Hemoperitoneum - Lymph nodes | - Ovarian tumor 14× 13 cm - Peritoneum and lymph node metastases | No adjuvant treatment Death day 2 postoperatively due to pulmonary embolism | |
aggressive and poorly differentiated character of ectopic adrenocortical tumors.
The prognosis is poor as death may be caused by metabolic disorders such as severe hypokalemia and ketoacidosis. However, the most threatening causes are metastatic disease and thromboembolism. The later occurs frequently in CS in general (31), and especially in adrenocortical tumors because of the hypercoagulable state due to an increase in pro-coagulant factors (32).
Conclusion
In our observation, ACTH-independent Cushing’s syndrome with small adrenals was suggestive of an ectopic tumor producing glucocorticoids and sex hormones. Abdomen CT scan and surgical exploration revealed an ovarian primary mass with metastatic spread. Histological, immunohistochemical staining, and normalization of glucose metabolism just after ovarian tumor resection support glucocorticoids and other hormone secretion from the ovary.
Although this phenomenon is exceptional, gynecologists, endocrinologists, and pathologists should be aware that ectopic adrenocortical tumors might arise in ovaries. Morphological features combined with immune- phenotype (melan-A, inhibin-a, and synaptophysin) and ultrastructural findings are essential in ruling out other forms of ovarian tumors. High mortality is associated with this disease.
Declaration of interest
The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or profit sector.
Acknowledgements
The authors are grateful to Dr Carmela Caputo for language editing. The authors would like to thank Drs Frederic Tissier, Anne Audebourg and Brigitte Radenen, Department of Pathology, Cochin Hospital and Descartes University (France) for the immunohistochemical study, Drs Khireddine Osmani and Malik Benamara for their help concerning some references, and Dr Yesli Fatma for histological pictures.
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Received 14 March 2016 Revised version received 2 July 2016 Accepted 7 July 2016