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Pregnancy in patients with adrenocortical carcinoma: a case-based discussion
Soraya Puglisi1 · Vittoria Basile1 · Paola Sperone2 · Massimo Terzolo1
Accepted: 24 October 2022 / Published online: 22 November 2022 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Although adrenocortical carcinoma (ACC) during pregnancy is rare, a retrospective review of a case series at our hospital revealed that almost one third of our patients were women in childbearing age. Given that the age of maternity is increasing, dealing with a tumor diagnosis during pregnancy and the need for fertility planning in cancer survivors is likely to become more frequent.
We thus carried out a case-based discussion regarding: i) diagnosing and treating an ACC during pregnancy; ii) patients conceiving while on mitotane; iii) ACC survivors with a maternal desire.
In each of these cases, it is important to provide patients with sufficient information, to offer medical advice and psychologi- cal support, to personalize treatments in accordance with the wishes of the patient and her relatives, and to collaborate with other specialists since a multidisciplinary expert team is required to manage each case individually.
Keywords Pregnancy . Adrenocortical cancer . Mitotane . Fetal outcome . Prognosis . Fertility
1 Background
Adrenocortical carcinoma (ACC) is a rare endocrine tumor affecting around two cases per million inhabitants per year [1, 2]. Although generally considered as an aggressive tumor associated with a poor outcome, the survival chances vary considerably, and the tumor stage is the main determinant of prognosis. A five-year survival ranges from 13% at stage IV ACC (tumors with distant metastases), to 50% at stage III (tumors with positive lymph nodes or infiltrating neigh- boring organs/veins, but without distant metastases), 61% for stage II (tumors confined to the adrenal gland and with a size> 5 cm), up to 80% for stage I (tumors confined to the adrenal gland and size ≤5 cm) [3]. Moreover, prognosis is highly influenced by whether the tumor was removed com- pletely and by other molecular and clinical factors, which are still not completely understood [4].
ACC can occur at any age and is more frequently found in women (54-59%) [1, 2, 5, 6].
A retrospective analysis of 261 consecutive patients with ACC referred to our tertiary center (San Luigi Gonzaga Hos- pital, Orbassano, Turin, northern Italy), from 1 January 1988 to 31 December 2018, confirmed that women are mostly affected: 164 patients were women (62.8%) (unpublished data). The median age of female patients was 44 (interquar- tile range, IQR, 33-57) years. Women of potential child- bearing age (from 14 to 45 years) accounted for 32.2% of the total cohort (84 out of 261 patients) (Fig. 1).
Given this background, both the diagnosis of ACC during pregnancy and in women with a maternal desire with the subsequent need for fertility planning in patients with ACC, particularly in long-term survivors, could represent different clinical scenarios.
Pregnancy-associated cancer is defined as a malignant tumor diagnosed during pregnancy and up to one year after delivery, a condition occurring in approximately 1 out of 1000 pregnancies [7, 8]. However, there has been an increas- ing incidence of pregnancy-associated cancer in the last few decades [9], probably due to women wishing to postpone childbirth.
The most common tumor types associated with preg- nancy are breast, cervical, hematological and skin cancers,
☒ Massimo Terzolo massimo.terzolo@unito.it
1 Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
2 Medical Oncology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
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14-19 yrs
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20-24 yrs
25-29 yrs
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and although large-scale studies on the oncological man- agement during pregnancy have not specifically considered ACC [10, 11], some general considerations may be applica- ble to this rare tumor.
When cancer is detected during pregnancy, the effects of cancer and its treatment involve both the mother and the fetus, thus it is often difficult to decide the most appropri- ate therapeutical strategy. It is of paramount importance to provide patients with sufficient information, to offer medical advice and psychological support, to personalize treatment in accordance with the wishes of the patient and her rela- tives, and to collaborate with obstetrics and gynecologists.
Another issue is pregnancy planning in cancer survivors. Nowadays, it is more common for patients to deal with cancer before having children. Moreover, some patients that have survived cancer may wish to have a child, even if their life expectancy has been compromised. Consequently, in women with ACC at a reproductive age who are con- templating having children, the impact of the tumor and its treatment on fertility and pregnancy outcomes needs to be discussed.
This review describes possible clinical scenarios in which the management of ACC is burdened by an ongoing or desired pregnancy.
2 Diagnosis of ACC during pregnancy
2.1 Case 1
A 26-year-old primigravid woman at the 16th gestational week (GW) presented with the results of an abdominal ultrasound (US) reporting a left adrenal mass of 5 cm. She had abdominal swelling, with no other symptoms. The physical examination did not show typical signs of steroid excess. An abdominal magnetic resonance imaging (MRI)
without contrast showed an heterogenous left adrenal mass (50×42 × 49 mm), without loss of signal intensity on out-of- phase images. Plasma renin and aldosterone concentrations, aldosterone/renin ratio (ARR), and levels of 24-h urinary free cortisol and 24-h urinary fractionated metanephrines were in the normal range for the trimester of pregnancy. Lev- els of adrenocorticotropic hormone (ACTH) were 20 pg/ml (normal range, 5-50 pg/ml), testosterone 0.5 ng/ml (normal range, 0.3-1.0 ng/ml), while dehydroepiandrosterone sulfate (DHEAS) was 936 µg/dl (normal range, 60-260 µg/dl).
The fetal ultrasound showed a fetus without abnormality and with a normal gestational age. The case was discussed at the tumor board, involving endocrinologists, gynecologists, urologists, and anesthesiologists, to identify the ideal timing and best surgical approach. The board concluded that adre- nalectomy with a laparoscopy approach should be performed by the urological team as soon as possible.
The patient and her partner were informed of the possible malignancy and the risk of ACC progression during preg- nancy, and they gave consent to remove the tumor. At the 20th GW the patient underwent laparoscopic surgery, with complete tumor removal. The pathology report concluded for stage I ACC with an R0 resection (microscopically free- margins), and a Weiss score of 3, Ki67 of 5%. At the 36th GW, the patient underwent a caesarian section and the new- born was in a good clinical condition. After one year, the abdominal/chest computerized tomography (CT) scan was negative for ACC recurrence.
2.2 Diagnostic considerations
During pregnancy, an adrenal tumor needs to be identified as soon as possible particularly if it is suspected to be malig- nant. In fact, without prompt treatment, the consequences for both the mother and the fetus could be serious.
In almost all series, more than half of patients with ACC present with signs and symptoms of adrenal steroid hormone excess, in most cases hypercortisolism [12]. The excess cortisol may cause several cardiometabolic altera- tions, such as arterial hypertension, impairment of glucose metabolism (with impaired glucose tolerance or diabetes mellitus), weight gain, deep venous thrombosis or pulmo- nary embolism. These are all conditions that pregnancy itself may induce or worsen.
A cortisol secreting tumor should be highly suspected in patients with specific manifestations of hypercortisolism, including proximal myopathy, easy bruising, and striae rubrae i.e. hyperpigmented violaceous striae, totally differ- ent from the skin-colored striae of normal pregnancies. It should also be considered in pregnant women with sudden appearance/worsening of acne and hirsutism.
These characteristics are typical of Cushing syndrome (CS), however signs of virilization could be the expression
of androgen excess, which is often concomitant with hypercortisolism, and the coexistence of different types of secretions is virtually pathognomonic of a malignant adrenal tumor. Patients with non-secreting ACC may pre- sent with cancer-related symptoms, including cachexia, anorexia, abdominal pain due to the mass effect, particu- larly in the case of tumors with rapid growth.
Finally, in some cases the tumors could be clinically unapparent and incidentally found at radiological exams, particularly in the second and third trimesters of preg- nancy when abdominal ultrasounds are usually performed. Interestingly, a study including 12 patients diagnosed with ACC during pregnancy or in the first six months after delivery, reported endocrine and endocrine-related fea- tures in 75% of patients (hypertension, diabetes, morpho- logical alterations, virilization, mood impairment) [13]; however, the hormonal assessment demonstrated that all 12 patients secreted cortisol (alone or with androgens). Therefore, in pregnant women with suspected ACC, a hormonal work-up must be always performed preopera- tively, regardless of the presentation modality. In fact, a slight autonomous cortisol secretion could be present even in patients without apparent clinical manifestations, potentially causing a postoperative life-threatening adrenal insufficiency [12].
This is not an easy scenario because the clinical picture of pregnancy, characterized by weight gain, possible appear- ance of striae, mood disturbances, and metabolic complica- tions confuse the recognition of a Cushing phenotype.
Moreover, the biochemical evaluation of a suspected hyper- cortisolism in pregnancy should take into account the hormonal changes that occur physiologically during gestation. Pregnancy has a profound impact on the hypothalamic-pituitary-adrenal axis which is characterized by a rise in cortisol levels, mainly due to: i) a massive increase in the placental corticotropin releasing hormone (CRH), which considerably increases the maternal ACTH and cortisol levels as pregnancy advances; interestingly, as the placental CRH production is induced by glucocorticoids, a positive feed-forward mechanism is gen- erated until delivery [14]; ii) production of ACTH from the fetoplacental unit, which further stimulates cortisol production from the maternal adrenal glands; iii) rise in cortisol binding globulin (CBG) levels induced by the hyperestrogenism, which leads to an increase in total cortisol levels, but also an increase in free cortisol levels because cortisol is displaced from CBG by progesterone [15]. As a result of all these changes, the excretion of urinary free cortisol (UFC) increases progressively during pregnancy by 1.7, 2.4, and 3.1 times more than normal values in non-pregnant women in the first, second, and third gestational trimesters, respectively [16]. In contrast, the circadian rhythm of cortisol seems to be maintained throughout pregnancy.
Finally, there is evidence of a lack of cortisol suppression with the low-dose dexamethasone suppression test (1-mg
DST) in healthy pregnant women, with a high number of false-positives and an increasing loss of suppressibility as pregnancy progresses [17]. This is possibly caused by the estrogen-induced increase in CBG levels during pregnancy, similarly to what occurs in women taking oral contraceptives [18]. Other hypotheses are tissue refractoriness to cortisol and feedback regulation of the hypothalamic-pituitary-adrenal axis being reset during pregnancy [19]. For these reasons, 1-mg DST is not recommended for the initial diagnosis of CS in pregnant women. Instead, UFC levels should be assessed, although in the second or third trimesters only UFC values more than three times the upper limit of normal can be con- sidered as predictive of disease [20, 21]. This is a substantial difference from the general recommendations for securing a diagnosis of CS sustained by ACC, which put great value on 1-mg DST for the initial evaluation [22] (Table 1).
Similar considerations are valid for the post-partum period, as there is evidence that total plasma cortisol and CBG levels remain elevated until 2-3 months after deliv- ery, while plasma free cortisol and UFC rapidly return to concentrations not significantly different from nonpregnant women [16].
In the last decade the use of the midnight salivary cortisol in pregnancy has been reconsidered. Although the preservation of the cortisol circadian rhythm in physiological pregnancy sug- gested the use of the midnight salivary cortisol for the diagnosis of hypercortisolism, the 2008 Endocrine Society guidelines did not recommend it, due to the lack of specific diagnostic thresh- olds in this subset of patients [20]. However, a recent study has defined new cut-offs according to the trimester of pregnancy (6.9, 7.2 and 9.1 nmol/L for the first, second, and third trimes- ters, respectively) [23]. The current recommendation is to con- sider values higher than two to three times the upper limit of the normal range as predictive of disease [21, 24].
The evaluation of androgens and steroid precursors should take into account that their levels change according to the gestational age. For example, testosterone concentrations increase up to three times in the third trimester compared with non-pregnant women [25, 26], while DHEAS levels decrease as pregnancy progresses, with a 50% reduction in the second trimester [26]. The trimester-specific reference intervals for 17-hydroxyprogesterone (17-OHP), androsten- edione, and DHEAS were reported by Soldin et al. [27]. Using the isotope dilution tandem mass spectrometry, the authors demonstrated that 17-OHP levels rose through- out pregnancy, whereas by GW 12 androstenedione levels increased by 80% and remained constant in the second and third trimesters [27]. It is important to identify any exces- sive sex steroid secretion in pregnant women with ACC, because androgens could affect fetal sex differentiation, as demonstrated by the case report of a partially virilized 46, XX female newborn with ambiguous genitalia from a mother affected by an androgen-secreting ACC [28].
| PREGNANT WOMEN | NONPREGNANT WOMEN | |
|---|---|---|
| BIOCHEMICAL ASSESSMENT | ||
| Cortisol excess | - 24-h UFC (to consider pathological in the second or third trimester only if> 3 ULN) | Serum cortisol following 1-mg DST If in doubt: - 24-h UFC - Plasma ACTH (8.00 a.m.) |
| - Midnight salivary cortisol (to consider pathological if>2-3 ULN) | ||
| Avoid 1-mg DST (high number of false positive results) | - Midnight salivary cortisol | |
| Aldosterone excess | Potassium; plasma aldosterone and DRC (or PRA) to calculate ARR* F | Potassium If hypokalemia and/or arterial hypertension: Plasma aldosterone and DRC (or PRA) to calculate ARR |
| Sex steroid excess | Testosterone | Testosterone |
| ** Androstenedione | Androstenedione | |
| DHEAS ** | DHEAS | |
| 17OH-progesterone ** | 17OH-progesterone | |
| Cathecolamine excess (for differential diagnosis with pheochromocytoma) | 24 h-urinary fractionated metanephrines or free plasma metanephrines *** | 24 h-urinary fractionated metanephrines or free plasma metanephrines |
| IMAGING | ||
| Abdominal US Abdominal MRI (without CM) | Abdominal/chest CT scan (with CM) Abdominal MRI (with CM) If in doubt: 18FDG-PET / CT |
ARR aldosterone to renin ratio, CM contrast medium, CT computed tomography, DRC direct renin concentration, DHEAS dehydroepiandroster- one sulfate, DST dexamethasone suppression test, 18FDG-PET positron emission tomography with 18F-2-deoxy-d-glucose, MRI magnetic reso- nance imaging, PRA plasma renin activity, UFC urinary free cortisol, ULN upper limit number, US ultrasound
* for the reference ranges according to the gestation week, see Sanga et al. [29]
** for the reference ranges according to the trimester, see Soldin et al. [27]
the reference ranges for metanephrines are the same as for nonpregnant women since there is no evidence that they change during pregnancy
Although aldosterone excess is less frequent than hyper- cortisolism in patients with ACC, aldosterone and renin levels should be evaluated and the ARR should be calculated, taking into account the physiological increase in pregnancy of both these hormones. A recent review reported that until GW 32, the ARR cut-off values suggesting the presence of aldoster- one excess were lower than the usual cut-off of 20.6 ng/mIU for the diagnosis of primary aldosteronism [29]. Sanga and colleagues illustrated with a nomogram the range of values suggestive of aldosterone excess according to the GW [29]. Although moderate/severe hypertension and hypokalemia must raise the suspicion of aldosterone excess, these features can be hidden in pregnancy by the anti-mineralocorticoid and anti-kaliuretic effects of progesterone.
The guidelines of the European Society of Endocrinology (ESE) / European Network for the Study of Adrenal Tumors (ENSAT) recommend adrenal-focused imaging in all patients with suspected ACC, including abdominal CT or abdominal MRI to differentiate malignant from benign masses, in addi- tion to a chest CT to identify metastases. On the other hand, positron emission tomography with 18F-2-deoxy-d-glucose,
usually combined with CT (18FDG-PET/CT) should be used as a second-line test for indeterminate masses [22].
Although US is generally not considered as a specific imaging for ACC, there are advantages (noninvasive, rapid, inexpensive, readily available and without effects on the fetus) that make it suitable for pregnant women, and US has a reported sensitivity of 89% to 97% for the identification of adrenal masses [30]. After a first evaluation with US, abdominal MRI is a better option than CT in order to prevent the damage from ionizing radiation exposure for the fetus (Table 1). As the MRI contrast medium gadolinium may cross the placenta, it should be avoided during pregnancy [31].
Although no one type of imaging is able to definitively prove the diagnosis of ACC, there are radiological charac- teristics that guide the diagnosis towards malignancy: intra- tumoral hemorrhage or necrosis, irregular tumor margins, large tumor size (usually>4 cm), and lack of signal intensity loss on out-of-phase MRI images (due to the scarce lipid content, while the loss of signal is typical of benign adeno- mas with abundant intra-cytoplasmatic fat) [22, 32].
2.3 Treatments
Since only case reports and case series have been reported in the literature, the optimal management of ACC dur- ing pregnancy is not well defined and each case should be addressed individually, preferably in specialized centers and with a multidisciplinary team involving experienced endocrinologists, oncologists, gynecologists, psychologists, surgeons and anesthesiologists. The treatment in pregnant women should consider both the disease presentation (stage and metastatic spread) and the issues related to pregnancy (gestational age and maternal desire). However, given the dismal prognosis of unoperated ACC, radical surgery is rec- ommended regardless of the GW [22, 33].
The second trimester is considered as the safest period to undergo surgery during pregnancy, while doing surgery in the first trimester is burdened by an increased risk of abor- tion in the first trimester and an increased risk of preterm labor in the third one. The risk of ACC progression when- ever surgery is postponed, however, demands for immediate action and surgery should be done as soon as possible. It is reassuring that a recent study shows that adrenalectomy can be performed safely during any trimester, if necessary, as long as expert management is offered [34].
If an intervention is planned, especially in the third tri- mester, the patient and her partner must be informed of the risk of a preterm delivery. The antenatal corticosteroid administration is recommended at 24-25 GW and should be considered at 22-23 GW to improve the newborn outcomes [35]. Medically induced abortion followed by standard treat- ment of ACC is a potential option, especially in the first tri- mester [13, 22]. In any case, a multidisciplinary team should clearly inform the couple about the cancer prognosis, the therapeutic options, and the potential short-term and long- term risks for the child.
For localized ACC, the only curative approach is radical surgery, which can be performed with open surgery or with laparoscopy. Although open surgery is considered the stand- ard surgical technique, the ESE/ENSAT guidelines state that laparoscopic adrenalectomy is a reasonable option for an adrenal mass with a diameter of less than 6 cm without evi- dence of local invasion, if the surgeon has sufficient experi- ence in this type of surgery [22]. In pregnancy, laparoscopy is the preferred surgical approach for adrenal masses, due to the short duration of the intervention and limited bleed- ing, and the insufflation pressures used in the procedure (10-15 mmHg) are safe in pregnant patients [34]. However, as only a few cases of surgery in pregnant women with ACC have been reported in the literature since the 1990s (Table 2), it is impossible to reach certain conclusions on the best surgical approach. Therefore, the treatment plan must be individualized on the basis of the disease characteristics (e.g. tumor diameter and stage) and pregnancy conditions.
Moreover, the moral and religious beliefs of the patient and her partner must be respected. A shared decision-making process is the only possible way to manage this difficult scenario.
3 Occurrence of pregnancy during mitotane treatment
3.1 Case 2
A 27-year-old patient was found with a cortisol and andro- gen secreting ACC in February 2012, diagnosed after one year of oligomenorrhea, hirsutism, acne and weight gain. The right adrenal mass (92×92 × 88 mm) was removed with laparoscopy in March 2012. The pathology report was R0, Ki67 14%, stage II, and adjuvant treatment with mitotane was initiated in May 2012. Menses returned after surgery and the patient was informed of the need for non-hormonal contraception. In the following months, plasma mitotane lev- els increased, with a peak of 18.8 mg/L in November 2012 (mitotane dose was 5 g/die). Surveillance with thoracic and abdominal CT every three months did not reveal disease recurrence.
In June 2013, the patient presented with self-reported pregnancy (GW 7) and mitotane was immediately discontin- ued. The patient and her husband were informed of the pos- sible teratogenic effects of mitotane, and the risk of tumor recurrence was discussed. In July 2013, the couple decided on a therapeutical abortion. In August 2013, mitotane ther- apy was re-started and continued until July 2014, when the patient decided to discontinue the treatment definitively. In November 2015, the patient moved to another city and was followed at another center. She informed us that she had given birth in 2016 with an uneventful delivery and the child was growing normally and the ACC had not reappeared.
3.2 Case 2 discussion
Given that ACC recurs frequently after primary surgery, with a rate of post-operative relapses ranging from 30 to 80% [42-44], adjuvant treatment with mitotane following tumor removal is recommended at least for high-risk patients. Despite some controversy remaining on how to define this category, high-risk patients typically have at least one of the following characteristics: stage III, or Ki-67> 10%, or Rx (unknown margin resection) / R1 (microscopically positive margin resection) [22, 45].
Mitotane is an adrenolytic drug, available in 500-mg tablets for oral administration. It is a parent compound of the insecticide dichlorodiphenyltrichloroethane, DDT, and is able to destroy the cells of the adrenal cortex and to inhibit steroidogenesis, through the depolarization
| Reference | Age (yrs) GW at surgery | Tumor ENSAT stage | Tumor diameter (mm) | Hormonal secretion | Surgical approach | Surgical complication | Fetal outcome | Maternal outcome |
|---|---|---|---|---|---|---|---|---|
| White, 1994 [36] | 27 29 | NA | NA | Cortisol, androgens | Open | No | Spontaneous labor and delivery 3 days after surgery Apgar score 8 | Patient died 19 months after surgery, due to ACC progression |
| Klibanski et al. 2006 [37] | 35 22 | I | 50 | Cortisol | Laparoscopy | No | Caesarian section at 36 GW Apgar score 9 | ACC progression (hepatic metastases) |
| Abiven-Lapage et al. 2010 [13] | 32 29 | II | 100 | Cortisol, androgens | Open | No | At 31 GW premature rupture of the fetal membranes and vaginal delivery Low BW (1.680 g) | NA |
| Abiven-Lapage et al. 2010 [13] | 27 27 | III | 180 | Cortisol, androgens | Open | Abdominal lymphedema | Caesarian section at 27 GW | NA |
| (concomitant with adrenal surgery) Low BW (1.500 g) | ||||||||
| Kotteas et al. 2012 [38] | 28 24 | II | 55 | Cortisol | Open | No | Caesarian section at 36 GW Low BW (1.800 g) | Patient died 27 months after diagnosis, due to ACC progression |
| Homer et al. 2012 [39] | 28 29 | II | 90 | Cortisol, androgens | Open | No | Caesarian section at 30 GW due to fetal distress | After 9 months, no evidence of ACC recurrence |
| Jairath and Aulakh 2014 [40] | 31 20 | II | 77 | Cortisol, androgens | Open | No | One day after surgery, spontaneous abortion | After 6 months, no evidence of ACC recurrence |
| Zhang et al. 2020 [41] | 22 31 | III | 150 | Cortisol | Open | No | At 32 GW premature rupture of the fetal membranes and vaginal delivery. The newborn (Apgar Score 10) died one week after birth due to intestinal perforation | After 6 months, patient had completed chemotherapy, without evidence of ACC recurrence |
BW birth weight, GW gestational week, NA not available
of mitochondrial membranes and the deregulation of cytochrome P450-enzymes. The exact mechanism of action of mitotane at the molecular level, however, has not been completely clarified [46]. The drug is used in the adjuvant context because it has been demonstrated as being able to reduce the risk of recurrence, thus prolong- ing recurrence-free survival (RFS) [47-49]. It is common practice to regularly monitor plasma mitotane concentra- tions during treatment in order to maintain mitotane levels above 14 mg/L, a threshold associated with drug activity [50-53], but under 20 mg/L, to avoid severe neurologi- cal toxicity (cerebellar symptoms and disturbed cognitive performance).
However, even when plasma mitotane levels stay within the therapeutic range (14-20 mg/L) there are many side effects. The most common ones are gastrointestinal symp- toms (diarrhea, nausea), which occur early during treatment regardless of the amount of mitotane levels [54]. Moreover, mitotane use is associated with a wide range of unwanted endocrine and metabolic effects, including adrenal insuf- ficiency in all patients, which require adequate replacement therapies [55-57].
On the other hand, the impact of mitotane on sexual func- tion in women seems to be limited, and the menstrual cyclic- ity is maintained in most patients. We recently reported that menstrual irregularities were observed in less than one third of 26 fertile women treated adjuvantly with mitotane: spot- ting was reported in four patients, metrorrhagia in two and oligomenorrhea in two [55]. In the same study, new ovarian cysts (of at least 2 cm) occurred during mitotane therapy in 17 out of 26 patients (65.4%) [55], which confirms previous observations [58, 59]. Although imaging follow-up of only the ovarian cysts was sufficient in most cases, with no need for any treatment, it is important to understand this conse- quence of mitotane treatment in order to prevent a misdiag- nosis of ACC progression when a growing ovarian mass is detected in a young woman.
The optimal duration of mitotane treatment is unclear. A recent multicentric ENSAT study showed the lack of benefit in prolonging treatment for more than two years in patients with low risk of recurrence [60]. The treatment-related toxicity and the desire to have children are additional fac- tors to consider when discussing the possibility of stopping treatment.
ESE/ENSAT guidelines recommend avoiding pregnancy whilst on mitotane treatment, due to its potential teratogenic effects [22]. Although the lack of a large series hampers a final judgment, it has been suggested that mitotane may be able to cross the placenta and exert its adrenolytic and anti-androgenic activity on the fetus. Unfortunately, only a few reports on pregnancy in women on mitotane are avail- able [61-64]. Two cases in which mitotane was continued during pregnancy had different outcomes. In the first case,
a spontaneous abortion occurred at the 10th GW and the mother remained free of disease after 6 months [61]. In the second case, a caesarian section was performed at the 31st GW due to a maternal HELLP (Hemolytic anemia, Elevated Liver enzymes and Low Platelet count) syndrome and the newborn showed normal growth, at least until 1 year of age, while the mother experienced ACC recurrence [62]. Tripto-Shkolnik et al. [63] reported the case of a 33 year- old women with metastatic ACC treated with mitotane for 4 years, who discontinued mitotane at GW 6. At GW 16, the fetus was morphologically normal, without intrauter- ine growth retardation, despite a measurable concentration of mitotane in the maternal blood. At GW 21 an abortion was performed (due to ACC recurrence with liver and lung metastases), with undetectable mitotane levels in the fetal cord blood and amniotic fluid, which suggested limited placental transfer of the drug. The patient responded par- tially to chemotherapy and died during surgery performed to remove the liver lesion [63].
Recently, a case series of four children (from three women, one with twins) exposed to mitotane during their intrauterine life was published [64]. Interestingly, despite detectable levels of mitotane in the maternal blood (0.9, 2.4 and 6.7 mg/L, respectively), no fetal malformations were observed. The children presented at birth with intact adrenal function and normal genitalia, suggesting that fetal steroido- genesis and, in the male child, testosterone secretion, were not affected by the mitotane dose used in these cases. The follow-up (up to 7 years of age for the twins) revealed no neurological abnormalities. Although mitotane seemed to have no teratogenic effect in these cases, the authors con- cluded that, considering the low mitotane concentrations observed in their cases and the lack of long-term follow-up, the recommendation to avoid pregnancy during mitotane treatment was still valid [64].
Although specific studies in women using mitotane dur- ing breastfeeding are not available, given the lipophilic nature of the drug, is reasonable to argue that it is excreted in breast milk. Therefore, breast-feeding should be avoided during mitotane treatment and after its discontinuation until mitotane concentrations are detectable in the mater- nal blood.
In conclusion, it is impossible to express a definitive opin- ion regarding the safety of mitotane in pregnancy given the scarce evidence available. For this reason, in women with ACC who are of fertile age and treated with mitotane, effec- tive contraception to prevent pregnancy is recommended [22]. The patient and her partner should also be informed that mitotane levels may remain measurable in blood for many months after treatment discontinuation, and before considering parenthood, it is recommended that the patient waits until plasma mitotane levels become undetectable, which usually takes many months [65].
Whether a patient conceives during active treatment with mitotane involves ethical, religious, personal and familial issues. In our opinion physicians need first to take into account the wishes of the patient, her ethical and religious beliefs, and to try to assess the potential risks for the mother and the fetus, and to present and discuss all possibilities (including therapeutical abortion). This is a challenging scenario and a careful assessment of the risk of recurrence including the time elapsed since surgery (duration of RFS) should be part of the decision-making process. In addition, whether or not the patient is disease-free at the time of con- ception and the type of treatment should also be considered (Table 3). If the decision to continue pregnancy is taken, in our opinion mitotane should be discontinued and a close fetal US monitoring be recommended.
4 Pregnancy planning in patients with history of acc
4.1 Case 3
In the diagnostic work-up of a 33-year-old woman with regular menses and a history of two years of unsuccessful attempts to conceive, an abdominal ultrasound found a solid mass close to the right kidney pole, with a size of 4 cm. An abdominal CT scan showed that it was an adrenal tumor characterized by high density (40 Hounsfield Units) that showed a bright uptake at the 18FDG-PET/TC (Standard- ized Uptake Value, SUV, max 10). The hormonal assessment was normal. The patient underwent laparoscopic surgery and the pathological report confirmed an ACC (Weiss 5, Ki67 20%, R0, Stage I). Due to the notable risk of recurrence due to the high proliferation activity of the tumor [45], adjuvant mitotane treatment was initiated, and after three months, the
patient’s plasma mitotane levels were on target. The patient maintained plasma mitotane levels in the therapeutic range (14-20 mg/L) for two years, although she occasionally com- plained of nausea and diarrhea which required titration of the mitotane dose.
At the start of mitotane treatment, the possibility of a future pregnancy was discussed, and oocyte cryopreservation was proposed in consideration of the patient’s age and the pre- sumed duration of the mitotane therapy. However, the patient was unwilling to accept this procedure. After two years of treatment, mitotane was discontinued and plasma mitotane levels decreased in the following months and were undetecta- ble after six months. Since then, the patient has been trying to conceive, still unsuccessfully after one year. As the radiologi- cal follow-up for ACC recurrence is to date negative, in vitro fertilization (IVF) has been proposed by the gynecologists. We thus looked for the presence of estrogen and progestin receptors on tumor specimens, since some ACCs are able to express these receptors in varying degrees [66, 67], and the search was negative. After we knew the tumor did not express estrogen or progesterone receptors, we agreed on IVF.
4.2 Case 3 discussion
Due to the rarity and aggressiveness of ACC, there a few data on patients with a history of ACC who become preg- nant, and many questions regarding appropriate pregnancy planning remain unanswered. The bottom line is that we are currently unable to quantify the risk of an ACC recurring if a woman becomes pregnant.
The influence of the gonadal axis on adrenal cell prolif- eration has been proven by several in vitro studies. Bielinska et al. demonstrated that the development of adrenocorti- cal tumors in some strains of mice after gonadectomy was
| IN FAVOR OF CONTINUING PREGNANCY | IN FAVOR OF INTERRUPTING PREGNANCY | |
|---|---|---|
| MOTHER/COUPLE-RELATED FACTORS | ||
| Strong maternal desire | X ☒ | |
| Religious belief forbidding abortion | X ☒ | |
| FETUS-RELATED FACTORS | ||
| Detection of malformations at US fetal monitoring | X ☒ | |
| DISEASE/TREATMENT-RELATED FACTORS | ||
| No evidence of disease after surgical tumor removal | X ☒ | |
| In adjuvant setting, ACC with low risk of recurrence | X ☒ | |
| In adjuvant setting, long RFS | X ☒ | |
| In adjuvant setting, low mitotane levels at the time of pregnancy discovery | X ☒ | |
| Stage IV ACC | X ☒ | |
| Severe steroid secretion | X ☒ |
correlated with the expression of luteinizing hormone (LH) receptors in the adrenal cells, in response to continuous gon- adotropin stimulation [68]. Mazzucco et al. demonstrated that the increased expression of LH receptor genes in adrenocorti- cal cells was associated with the development of adrenocorti- cal hyperplasia, adrenocortical tumor and cushingoid phe- notype in transplanted mice [69]. Moreover, De Cremoux et al. reported the overexpression of progesterone receptors in certain adrenocortical tumors, in a context of very low levels of estradiol receptors (ER) a and high levels of ERß expres- sion [70]. This was in accordance with a previous observation that the H295R ACC cell line produces more mRNA for ER than for ER& [71].
Taken together, these findings suggest that pregnancy could adversely influence the prognosis of ACC. In clinical practice there are contrasting reports, however, with reports of worse survival outcomes in patients with past or cur- rent ACC in pregnancy [13] which were not confirmed by other authors [65]. Abiven-Lepage G et al. retrospectively analyzed a cohort of 110 women with ACC aged between 16-49 years, and compared 12 women diagnosed with ACC during pregnancy or in the postpartum period (up to six months after the delivery) with non-pregnant ACC patients. They reported larger tumor volumes and more advanced stages in the first subgroup, although the differences were not statistically significant. The one-year and 5-year survival rate of patients with ACC diagnosed during pregnancy were 50% and 13%, respectively, significantly worse than that of the matched controls [13].
De Corbiere et al. reported that the overall survival of 17 women with ACC who became pregnant at least three months after the initial treatment was not significantly dif- ferent from that of the matched controls [65]. Given this scarce and conflicting information, ESE/ENSAT guidelines suggest informing the patient that it may be prudent to avoid pregnancy in the initial years following a diagnosis of ACC. This is when the rate of recurrence is higher, despite there being no evidence on how long a patient should wait after treatment of ACC to safely consider pregnancy [22]. The regular imaging surveillance should be continued until con- ception, then the timing of imaging (MRI) during pregnancy should be evaluated on an individual basis.
In patients with advanced ACC, which has a high mor- tality rate, avoiding conception is usually recommended until a long-term remission has been demonstrated. The guidelines also suggest using contraceptives other than estrogen-containing preparations, due to the possibility that estrogens may facilitate the progression of tumors that express estrogen receptors [22, 72]. Due to the recent evi- dence that the activation of the progesterone receptor may reduce proliferation of ACC cell lines in preclinical models [66, 67], we feel confident in using progesterone derivative for contraception.
Given that the drugs used to treat ACC (e.g., mitotane, chemotherapy), can impact on fertility, patients should be informed about the relevant options, in order to help the patient’s maternal desire when permitted by the clinical conditions.
Although IVF and embryo preservation are important options for cancer survivors, there are also associated risks, which should be discussed with the patient [73]. The hormo- nal stimulation used to induce the oocyte maturation could promote ACC growth, for the reasons previously reported. In the case of a patient without a partner providing the sperm needed for the embryo cryopreservation, oocyte cryopreser- vation could be proposed [73].
Lastly, a case was recently published of a 33-year-old woman with ACC and impaired ovarian function that per- sisted five years after mitotane withdrawal. After the impos- sibility of obtaining follicular growth with ovarian stimu- lation, an in-vitro maturation (IVM) of immature oocytes aspirated from the antral follicles was successfully carried out [74]. After microinjection of the partner’s spermatozoa and the transfer of a two-day old embryo, the patient deliv- ered a healthy newborn at GW 37. In this patient, mitotane seemed to have induced persistent damage of the thecal cells, while the granulosa cells and antral follicles were relatively preserved [74]. This case suggests the need to evaluate fertil- ity conservation options before starting mitotane in patients with ACC of childbearing age.
In summary, clinicians should aim primarily to ensure patient survival and the maternal desires of the patients should be considered carefully. An informed discussion on pregnancy planning and counseling for fertility protection (especially for patients who are candidates for mitotane or chemotherapy) should therefore become part of the manage- ment of patients in reproductive age who have ACC.
5 Conclusions
In the rare case of ACC occurrence during pregnancy, physi- cians have to guide patients toward informed treatment deci- sions, weighing the risks to both the mother and the fetus, and taking into account the oncological circumstances and the patient’s wishes. The paucity of data regarding the safety of treatment during pregnancy means that is it essential that all cases (case reports, case series) are reported with their outcomes. In the meantime, a multidisciplinary and expert team is required to manage these challenging cases on an individual basis.
For women in reproductive age, fertility planning should be discussed with the patient and her partner, and counseling for fertility protection should be considered, especially in patients who will be undergoing cytotoxic chemotherapy and/or mitotane therapy.
Author’s contribution MT received research grants from HRA Pharma, and advisory board honoraria from HRA Pharma and Cor- cept Therapeutics.
Funding This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), grant number IG2019-23069 to Prof. Massimo Terzolo.
Declarations
Conflict of interest The other authors have no conflicts of interest to declare.
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