Submitted: 10.01.2025
Accepted: 11.02.2025 Early publication date: 13.06.2025
Adrenocortical carcinoma during pregnancy
Marta Klepinowska ®, Elżbieta Sowińska-Przepiera ®, Elżbieta Andrysiak-Mamos (D, Bartosz Kiedrowicz , Karol Sagan, Anhelli Syrenicz
Department of Endocrinology, Metabolic and Internal Diseases, Pomeranian Medical University Hospital No. 1, Szczecin, Poland
Abstract
Introduction: Adrenocortical carcinoma (ACC) is a rare malignant neoplasm. Hypercortisolism and inhibition of gonadotropin secretion usually result in menstrual disorders and secondary amenorrhea. The coincidence of ACC and pregnancy is therefore extremely rare. The signs of hypercortisolism are commonly seen in otherwise healthy pregnancies, which decreases the doctor’s vigilance. We present the diagnostic challenges and current treatment recommendations according to European guidelines from the European Society of En- docrinology (ESE) and European Network for the Study of Adrenal Tumors (ENS@T) 2018 and Polish guidelines 2024.
Material and methods: We conducted an extensive search via MEDLINE using the phrases “Adrenocortical carcinoma”, “ACC”, and “Preg- nancy” without temporal or language restrictions. Only cases with ACC diagnosed during pregnancy were taken into consideration. Ten papers were found, with 12 described cases. We analyzed the management and outcome both for the mother and the child. We also included a case of a woman treated in our department. A 29-year-old woman in the 20th/21st gestation week (GW) presented to us with Cushing’s syndrome symptoms and androgenization. Laboratory tests showed low plasma adrenocorticotropic hormone (ACTH), high cortisol, testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), androstenedione, 24-hour urinary free cortisol (UFC), and hypoka- lemia. In the abdominal magnetic resonance imaging (MRI) there was a mass in the left adrenal gland. An open surgery was performed in the 21st GW with no perioperative complications. The pathology report established the diagnosis of ACC. The tumor board along with the patient decided to defer the adjuvant therapy until the 32nd GW to increase the odds for the fetus to survive. In the 31st GW an urgent caesarian section was performed due to risk of fetal hypoxia. Computed tomography (CT) scan after the delivery showed local recurrence in the tumor bed. The patient was qualified to mitotane therapy and underwent tumor bed radiotherapy followed by chemotherapy, but the treatment did not stop the progression of the disease. She passed away 14 months after the diagnosis.
Conclusions: It is critical to remember about the possibility of ACC occurrence during pregnancy, as well as to know about the differences in hormonal tests in pregnant women such as higher free plasma cortisol, ACTH, UFC, and high rate of false-positive results of low-dose dexamethasone suppression test (LDDST) in comparison to non-pregnant women. Therapeutical options are scarce and pose an ethical dilemma. (Endokrynol Pol 2025; 76 (3): 229-235)
Keywords: adrenocortical carcinoma; pregnancy; hypercortisolism during pregnancy
Introduction
Adrenocortical carcinoma (ACC) is a rare malignant epithelial neoplasm arising from the outermost layer of the adrenal gland. The incidence of ACC is estimated at 0.7 to 2.0 per one million population per year and peaks between 40 and 60 years of age with slight predilection to females [1]. The most common manifestation of ACC is Cushing’s syndrome and androgenization. As a result of hypercortisolism and inhibition of gonadotropin secretion, menstrual disorders and secondary amen- orrhea can be observed. Therefore, the coincidence of ACC and pregnancy is extremely rare. In addition, the signs of hypercortisolism such as hypertension, weight gain, striae, or hyperglycemia are commonly seen in otherwise healthy pregnant women, which decrease the doctor’s vigilance.
Due to its rarity, recommendations regarding the management of ACC during pregnancy are not precise. According to European Society of Endocrinology (ESE) and European Network for the Study of Adrenal Tumors (ENS@T) 2018 guidelines, when ACC is sus- pected during pregnancy, surgery should be scheduled regardless of pregnancy trimester. Non-pregnant women with ACC should be informed about the necessity of using efficient contraception during mitotane treatment (preferably without estrogens). After 3 to 12 months of mitotane withdrawal, the serum mitotane level should be established. Conception can be considered when the serum mitotane level is not detected. If a patient conceives during mitotane therapy and wishes to con- tinue pregnancy, the mitotane should be withheld [1].
In ACC, significant morbidity and mortality for the mother and fetus are observed [2]. The most
☒ Elżbieta Sowińska-Przepiera, Department of Endocrinology, Metabolic and Internal Diseases, Pomeranian Medical University Hospital No. 1, Szczecin, Poland, ul. Unii Lubelskiej 1, 71-252 Szczecin, tel/fax: (+48) 512 309 967; e-mail: elzbieta.sowinska.przepiera@pum.edu.pl
common maternal complications of Cushing syndrome are hypertension (58 to 68%), diabetes or impaired fast- ing glucose (25%), preeclampsia (14%), osteoporosis or pathologic fractures (5%), psychiatric disorders (4%), cardiac failure (3%), wound infection (2%), and mater- nal death (2%). Fetal complications include prematurity (43%), intrauterine growth retardation (21%), still birth (6%), spontaneous abortion/intrauterine death (5%), and adrenal hypoplasia (2%) [2].
For the whole population of patients with ACC the risk of recurrence in five years has been estimated at 18-47%, 36-62%, and 50-81%, respectively, for stages 1, 2, and 3. The five-year survival is approximately 63-88% for stage 1,38-73% for stage 2, 19-54% for stage 3, and 0-21% for stage 4 [3].
ACC and pregnancy
According to Abiven-Lepage et al., adrenocortical tumors diagnosed during pregnancy or in the post- partum period tend to be more often cortisol-secreting tumors and discovered at a more advanced stage compared to the group of nonpregnant women with adrenocortical tumors, although the differences did not meet statistical significance. In their series, the fetal outcome was poor. The overall survival of mothers was worse than that of matched controls even consider- ing stage of disease and age [4]. In our case, however, the fetal outcome was good. Despite being born by the emergent cesarean section in the 31st gestation week (GW) and with low birth weight, the boy was otherwise healthy.
ACC diagnostics in pregnant women
Free plasma cortisol in pregnant patients is two to three times higher than in non-pregnant women, but its circa- dian rhythm is preserved [5]. Low-dose dexamethasone suppression test (LDDST) during pregnancy more fre- quently produces false-positive results [6-8]. This could be accounted for by the following pregnancy-related changes: (1) estrogen-induced elevation in the corti- sol-binding globulin (CBG), (2) the impaired suppress- ibility of the hypothalamic-pituitary-adrenal axis, (3) placental secretion of adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH), which is not regulated by negative feedback control, (4) tissue refractoriness to glucocorticoids, and (5) pos- sible anti-glucocorticoid effects of progesterone [7]. Thus, LDDST is not recommended for the detection of hypercortisolemia in pregnancy.
Urine free cortisol (UFC) and ACTH serum levels are also higher during gestation than in non-pregnant women. Initially, UFC is within the normal range
in the first trimester but increases with time, and in the second/third trimester it can reach concentrations three times higher [6].
Moreover, it appears that during pregnancy in adre- nal Cushing’s syndrome, the ACTH level is frequently non-suppressed, which is why Lindsay et al. suggest combining adrenal ultrasound imaging, high-dose dexamethasone suppression test (HDDST), and plasma ACTH levels in differential diagnosis of pregnant pa- tients with Cushing’s syndrome. An adrenal source of cortisol is suspected in patients with borderline or low plasma ACTH followed by non-suppressed cortisol on HDDST. By this token, regardless of the ultrasonog- raphy result, MRI is required to delineate the lesion and establish tumor staging [6, 9].
There are findings showing the utility of late eve- ning salivary cortisol concentrations in pregnant wom- en [10]. Therefore, in the Polish diagnostic and thera- peutic recommendations for adrenocortical carcinoma it is recommended that late evening salivary cortisol concentrations be assessed in pregnant women with suspected hypercortisolemia. If this diagnostic method is unavailable, measuring free cortisol in daily urine is an alternative approach [8].
In our case, clinical symptoms of Cushing’s syn- drome and hirsutism combined with very high tes- tosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-SO4), and cortisol, very low ACTH with no circadian rhythm preserved, and the lesion in the adrenal gland gave the full picture of Cushing’s syndrome of adrenal origin.
Surgical treatment of ACC during pregnancy
According to ESE and ENS@T 2018 guidelines as well as the newest Polish guidelines, open surgery is the standard surgical approach for confirmed or highly suspected ACC [1, 8]. Laparoscopic adrenalectomy can be performed for tumors < 6 cm without any evidence of local invasion [1]. ESE and ENS@T 2018 guidelines recommend prompt surgical resection regardless of pregnancy trimester [1]. However, some publications indicate that the second trimester is the best time for any kind of surgery because at this point the risk of spontaneous abortion is lower than in the first trimester, organogenesis is complete, the induction of premature labor is less likely, and the uterus is not too large for surgery [11].
Although pregnancy is considered as a contraindi- cation to laparoscopy, it has been used successfully in selected cases. However, it is crucial to acknowledge the risks related to laparoscopic surgery in pregnan- cy: increased intra-abdominal pressure can disturb
placental blood flow, and absorption of insufflated carbon dioxide can induce fetal acidosis, whereas trocar placement might cause direct uterus injury [7]. During surgery, special precautions should be taken such as maintenance of pneumoperitoneum pressure below 12 mmHg and avoidance of direct contact between the surgical instruments and the uter- ine muscle [12]. In prevention of thromboembolism, compression boots can be used [7]. The unequivocal advantage of laparoscopy is a much better cosmetic result than after open surgery, which is important for young patients.
Despite the abovementioned limitations, laparos- copy is part of gynecologists’ everyday practice, with success for decades [11]. Laparoscopic cholecystectomy [13] and appendectomy have also been successfully performed during pregnancy.
Pharmacological treatment of ACC and pregnancy
According to ESE and ENSAT 2018 guidelines, adju- vant mitotane treatment is recommended in patients without macroscopic residual tumor after surgery who are considered high risk of recurrence (stage III or R1 resection or proliferation index Ki-67 > 10%). However, it should also be discussed individually with patients at low/moderate risk of recurrence (stage I-II, RO resection, and Ki-67 ≤ 10%) [1]. Mitotane is in drug category C, so it is relatively contraindicated during pregnancy due to its potential of teratogenic effects.
However, the observation of four children who had fetal exposure to sub-therapeutic mitotane concentra- tions has shown no teratogenic effect, neurological abnormality or cortisol deficiency [14]. Due to the small sample size, generalizability of the drug safety is limited.
Other anti-steroidogenic drugs can be used in patients with ACC to control hypercortisolism in the preoperative period. One such drug is metyrapone, which can be used during pregnancy, but it may ag- gravate hypertension because of deoxycorticosterone accumulation leading ultimately to preeclampsia. This drug also passes through the placental barrier, which can affect fetal adrenal steroid synthesis [15]. Metyra- pone was administered to our patient preoperatively with no adverse effects.
Ketoconazole is an anti-steroidogenic agent as well, but there is reported teratogenicity and an increased rate of abortion in animal studies. As an alternative op- tion, cabergoline was used in the treatment of Cushing’s syndrome. There were two reported cases of conceived and maintained pregnancy while on high-dose caber- goline with complete remission [9].
Chemotherapy and radiotherapy during pregnancy
Both chemotherapy and radiotherapy are strictly contraindicated during pregnancy. If the patient has an indication and such treatment cannot be deferred, the pregnancy must be terminated prior to therapy commencement.
Material and methods
We conducted an extensive search via MEDLINE us- ing the following phrases: “Adrenocortical carcinoma”, “ACC”, and “Pregnancy” without temporal or language restrictions. We took into consideration only cases with ACC diagnosed during pregnancy. Ten papers were found, with 12 described cases. We analyzed the management and outcome both for the mother and the child. We also included a case of a woman treated in our department. Taking into consideration the tumor ENSAT stage, there were two patients with stage I, four cases with stage II, four cases with stage III, and one case with stage IV. In eight cases the surgery was performed in the second trimester, and in four cases in the third trimester. In two cases a laparoscopic technique was used. In 10 cases an open surgery was performed. Details regarding the previously published cases of ACC diagnosed during pregnancy are pre- sented in Table 1.
A case of a pregnant woman diagnosed with ACC in our department
A 29-year-old woman was admitted to the Department of Endocrinology, Metabolic and Internal Diseases of Pomeranian Medical University Hospital No.1 in the 20th/21st GW with hirsutism, red abdominal striae, round face with thin limbs, weight gain, and hyperten- sion with heart palpitations (Fig. 1). In the six months prior to pregnancy, amenorrhea occurred. In abdomi- nal ultrasonography, there was a huge mass of 9.5 cm diameter with calcifications, located in the region of the left adrenal gland. Laboratory test results were as follows: low plasma ACTH accompanied by high cortisol with no circadian rhythm preserved (Tab. 2), and very high testosterone, DHEA-SO4, androstene- dione, 24-hour urinary free cortisol, and hypokalemia (Tab. 3). In the abdominal magnetic resonance without contrast enhancement, there was a mass measured as 92 × 104 × 99 mm (anteroposterior, right-left, and craniocaudal, respectively) in the left adrenal gland. It caused compression of the upper pole of the left kidney, left renal artery and vein, splenic vein, and inferior mesenteric vein, without evidence of
| No | Publication | Age | Gestational age at surgery (s) or at presentation (p) | Hormonal secretion | Tumor ENS@T 2018 stage | Surgical approach | Fetal outcome | Maternal outcome |
|---|---|---|---|---|---|---|---|---|
| 1. | Klepinowska et al. 2024* | 29 | 21 st GW (s) | Cortisol, androgens | II | Open | Child born in 31th GW in good condition with caesarian section due to risk of fetal hypoxia, IUGR (BW: 1250 g), healthy after a year | Radiotherapy, mitotane therapy, subsequently chemotherapy, unstoppable progression, the patient died 14 months after the diagnosis |
| 2. | Puglisi et al. 2023 [16] | 26 | 20th GW (s) | Cortisol, androgens | I | Laparoscopy | Caesarian section in 36th GW, newborn in good condition | After 1 year no evident recurrence |
| 3. | Marino and Webster 2023 [17] | 28 | 15th GW (p) | Cortisol, androgens | IV | No surgery | Spontaneous abortion at 17th GW | Died 3 months after presentation |
| 4. | Zhang et al. 2020 [18] | 22 | 31st GW (s) | Cortisol | III | Open | Vaginal spontaneous labor after 5 days after surgery (APGAR 10), baby died after a week (intestinal perforation) | Mother started chemotherapy after delivery; after next 6 months no evident recurrence |
| 5. | Jairath and Aulakh 2014 [2] | 31 | 4,5 months (p) | Cortisol, androgens | II | Open | Spontaneous abortion after 1 day | After 6 months no recurrence |
| 6. | Jarvis and Morton 2014 [19] | 27 | 26th GW (p) | Cortisol, androgens | III | Open (after caesarian section) | Planned caesarian section in 27th GW, healthy female newborn (BW: 990 g) | After 5 months pulmonary metastasies revealed; chemotherapy; 14 months postpartum with stable metastatic disease radiologically |
| 7. | Kotteas et al. 2012 [20] | 28 | 24th GW (s) | Cortisol | II | Open | Caesarian section in 38th GW, male newborn (BW: 1800 g) | Relapse after 7 months, reoperation, mitotane therapy, progression, chemotherapy, died 27 months after diagnosis |
| 8. | Abiven-Lepage et al. 2010 [4] | 32 | 29th GW (s) | Cortisol, androgens | ǁ | Open | Spontaneous membrane rupture and premature delivery in 31st GW, IUGR (BW: 1680 g), hypoglycemia | NA |
| 9. | Abiven-Lepage et al. 2010 [4] | 32 | 33th GW (s) | Cortisol | III | Open (after preterm labor) | Preterm birth with stillborn shortly after diagnosis | NA |
| 10. | Abiven-Lepage et al. 2010 [4] | 27 | 27th GW (s) | Cortisol, androgens | III | Open | The surgery was combined with caesarian section, IUGR (BW: 1500 g) | NA |
| 11. | Klibanski et al. 2006 [7 | 35 | 22th GW (s) | Cortisol | I | Laparoscopy | CC in 36th GW, small weight but APGAR 9 | After 7 months liver metastasis revealed, chemotherapy |
| 12. | White 1994 [21] | 27 | 24th GW (p) | Cortisol | NA | Open | Spontaneous labor 3 days after the surgery, APGAR 8 | Progression, mitotane therapy and chemotherapy, died 19 months after diagnosis |
| 13. | Bank et al. 1965 [22] | 28 | Beginning of 3rd trimester (p) | Cortisol | NA | Open transthoracic route (12 days after caesarian section) | Planned caesarian section in the end of 8th month, healthy male newborn (BW: 2850 g) | It was a recurrence in tumor bed 4 years after primary treatment; the surgery was followed by radiotherapy; after 4 years patient with no biochemical signs of recurrence |
*This article; ENS@T - European Network for the Study of Adrenal Tumors; GW - gestation week; BW - birth weight; IUGR - intrauterine growth retardation; NA - not available
obvious infiltration of these structures (Fig. 2). Fetal ultrasound identified no abnormalities. The case was discussed by the multidisciplinary team at the tumor board involving experienced endocrinologists, gyne- cologists, and surgeons, and an open surgery was pro- posed to the patient. She was informed about the risk of hypercortisolism in pregnancy, risk of surgery for the fetus, and the possibility of malignancy. The pa- tient, after having discussion with her family, gave
informed consent for the procedure. Metyrapone was administered in the preoperative period. The surgery was performed in the 21st GW with no perioperative complications. Hydrocortisone was administered orally in the postoperative period to prevent adrenal crisis. The pathology report established the diagnosis of ACC with extensive areas of necrosis, presence of atypical mitotic figures, and mitotic activity of 26 per 50 high-power fields (HPF), and focal tumor architec- ture was noted within the surgical margins. Secondary consultation confirmed diagnosis of ACC with MIB-1 index equal to 22.8%. The tumor board along with the patient decided to defer the adjuvant therapy until the 32nd GW to increase the odds for the fetus to survive. The patient was informed about the poor prognosis for her. The pregnancy was continued with very strict supervision and proper management of the post-surgery adrenal insufficiency. There were no complications until the 31st GW when dimin- ished fetal movements were observed. Due to risk of fetal hypoxia a caesarian section was performed urgently. The male newborn weighted 1250 g and was otherwise healthy with no congenital defects. After de- livery, the patient immediately had chest, abdominal, and pelvic computed tomography (CT) scans, which showed local recurrence in the tumor bed with size of the malignancy 35 x 55 x 55mm (anteroposterior, right-left, and craniocaudal, respectively). At this point, the lesion infiltrated the left renal artery and vein and the splenic vein, spleen, left kidney, pancreas, jeju- num, and descending colon. No spread to lungs, liver, or bones was seen. The next tumor board recommend- ed mitotane treatment and tumor bed radiotherapy, which were applied over the following two months. Afterwards, the CT scan revealed reduction in size of the lesion in the tumor bed. However, it also indi- cated two new metastases in the liver and numerous lesions within the abdominal adipose tissue, mes- entery, abdominal subcutaneous tissue, and parietal and diaphragmatic pleura. The patient was qualified to chemotherapy. She underwent two cycles of treat- ment and then the patient ceased the chemotherapy to initiate unconventional treatment abroad. When she appeared again three months later the disease was ad- vanced and disseminated. She was pronounced dead the next month (14 months after diagnosis). Her child was sound and healthy at that time.
| 8:00 a.m. | 12:00 p.m. | 5:00 p.m. | 11:00 p.m. | |
|---|---|---|---|---|
| ACTH [pg/mL] | < 1 | < 1 | < 1 | < 1 |
| Cortisol [ug/dL] | 52.99 | 57.47 | 57.81 | 58.32 |
| Laboratory test | Preoperative results | Postoperative results | Reference range |
|---|---|---|---|
| Sodium [mmol/L] | 144 | 142 | N: 135-145 |
| Potassium [mmol/L] | 2.95 | 3,58 | N: 3.50-5.50 |
| Testosterone [ng/ml] | 5.150 | 0,660 | N: 0.06-0.82 |
| DHEA-S04 [ug/dL] | 757.30 | 13.59 | N: 78.8-340 |
| Androstenedione [ng/ml] | > 10 | 0,87 | N: 0.75-3.89 |
| SHBG [nmol/L] | 166.50 | 145,30 | N: 19.8-122 |
| Cortisol at 8 a.m. [ug/dL] | 52.99 | 1,24 | N: 6.2-19.4 |
| ACTH at 8 a.m. [pg/mL] | < 1 | 5.18 | N: 7.20-63.30 |
| 24-hour urinary free cortisol [ug/24 h] | 2276.56 2080.00 | 540.20 | N: 36.00-137.00 |
| 24-hour urinary 17-ketosteroids [mg/24 h] | 20.0 75.8 | – | N: 10.00-25.00 |
| 24-hour urinary metanephrine [ug/24 h] | 83.03 50.42 | – | N: 0.00-350.00 |
DHEA-S04 - dehydroepiandrosterone sulfate; SHBG - sex hormone binding globulin; ACTH - adrenocorticotropic hormone
Conclusions
ACC in pregnancy remains a huge challenge for prac- titioners. Acknowledging differences in hormonal tests in pregnant women such as higher free plasma cortisol, ACTH, UFC, and high rate of false-positive results of LDDST in comparison to non-pregnant patients, is criti- cal. Therapeutical options are scarce and pose an ethical
dilemma. In many cases, the multidisciplinary tumor board together with the patient need to decide whether to take the most aggressive therapeutic approach risk- ing poor fetal outcome or try to delay the most toxic treatment risking progression and poor maternal out- come. The patient needs to be well informed and psy- chologically supported throughout the process.
Author contributions
M.K .: investigation, data curation, writing-original draft, final ap- proval of the version to be published; E.S .- P .: design, supervision, validation, writing- critical review, final approval of the version to be published; E.A .- M .: resources, writing- critical review, final approval of the version to be published; B.K .: resources, writing - critical review, final approval of the version to be published; K.S .: resources, writing- critical review, final approval of the version to be published; A.S .: design, supervision, validation, writing - critical review and editing, final approval of the version to be published.
Funding
This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.
Conflict of interest
Authors declare no conflict of interest.
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