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d’Endocrinologie Annals of Endocrinology
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Letter to the Editor
Ectopic adrenocortical carcinoma of the ovary: An unex- pected outcome
Un corticosurrénalome ovarien au devenir exceptionnel
ARTICLE INFO
Keywords: Adrenocortical carcinoma Ovary Pregnancy Mitotane Prognosis
Mots clés : Corticosurrénalome Ovaire Grossesse Mitotane Prognostique
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Steroid cell tumours are a rare subgroup of sex cord-stromal tumours of the ovary. First described by Scully RE [1], this cate- gory traditionally included Leydig cell tumour, stromal luteoma and steroid cell tumour, not otherwise specified (NOS) [2]. Steroid cell tumours are often androgenic and can be associated with Cushing’s syndrome, mimicking an adrenocortical carcinoma. Indeed, the ovary may contain ectopic adrenal cells originating from gonadal and adrenal tissues of the genital ridge [1]. Adrenocortical neo- plasms of the ovary are exceptionally rare; their prevalence and prognosis, and the optimal follow-up, are poorly documented. We report the case of a young girl with a metastatic, ectopic ovarian adrenocortical neoplasm. In 1991, when she was 4 years of age, the patient rapidly (within 1 month) developed signs of early puberty (breasts plus pubic and armpit hair); this prompted her parents to consult. Laboratory investigation showed increased levels of the sex hormones estrone, 17-OH-progesterone, and testosterone. Low levels of pituitary gonadotropins suggested autonomous secretion of sex hormones from ovarian and/or adrenal origin. At that time, no pelvic imaging was performed. Triptorelin (a gonadotropin releas- ing hormone analogue) was prescribed and maintained between the ages of 4 and 8 years. Menarche occurred at 9 years of age. Genetic investigations did not identify TP53 gene mutation rulling out a Li-Fraumeni syndrome. At 15 years of age, the patient reported abdominal pain and, since a computed tomography (CT) revealed a mass in the right ovary, aright salpingo-oophorectomy was performed. Hormonal investigation was not considered. Anato- mopathological examination revealed a tumour 20 cm in diameter with large cells, pale and oxyphilic granular cytoplasm, rounded dystrophic nuclei, and rare mitotic figures. Spans, cords, and mas- sifs were evident within a vessel-rich endocrinoid stroma. These structures were in contact with, but did not penetrate, the capsule.
Haemorrhagic foci were observed. Expert analysis by a referral cen- tre identified an ovarian steroid tumour. There were > 2 mitoses/10 high-power fields but data on Ki67 and the Weiss score were lack- ing. The patient was regularly examined; no notable event occurred prior to the age of 17 years, at which time she was started on oral contraceptives (cyproterone acetate and ethynylestradiol) because the left ovary was multicystic. Appropriate follow-up was sched- uled; there was no evidence of malignant transformation.
At 21 years of age, the patient was admitted to our unit for the first time, with a persistent cough; CT revealed multiple pulmonary tumours and positron emission tomography (PET) con- firmed that the tumours were active (Fig. 1A). Biopsy revealed pulmonary metastasis of the right ovarian carcinoma that was diagnosed 17 years earlier. Following a multidisciplinary consul- tation, the decision was made to prescribe adrenolytic medication (mitotane at an initial dose of 2 g/day). As this was relatively well tolerated, the dose was rapidly increased to 6g/day to achieve a serum level of 14-20 mg/L. Some clinical features were sug- gestive of Cushing’s syndrome, including obesity (weight: 119 kg, height: 154 cm, body mass index 50 kg/m2), acanthosis nigricans, and a “buffalo neck”. Plasma cortisol analysis was inappropriate due to the use of oestroprogestative contraception; unfortunately, urinary free cortisol data were unavailable. A few months later, a regular menstrual cycle returned, with notable loss of body hair. Her weight fell from 119 to 87 kg. Testosterone was unde- tectable, which remains the case at the time of this report. Dehydroepiandrosterone-sulfate (DHEAS) serum level remained normal over the next 10 years. Serum dehydroepiandrosterone- sulfate (DHEAS) level remained normal over the next ten years. PET showed that the lung metastases progressively declined; no other metastasis was identified during regular check-ups (Fig. 1B). Complete remission was achieved in 2014, 5 years after mitotane initiation; pulmonary metastasis radiologically disappeared. Over the years, mitotane was less tolerated with side effects associating asthenia, gastrointestinal complaints (nausea, diarrhoea), together with many episodes of acute adrenal insufficiency despite high- dose of hydrocortisone. The patient expressed a strong desire to become pregnant and wished to stop treatment. After consider- ing the risks and benefits, mitotane was discontinued in July 2019. At the time, her testosterone and (DHEAS) levels remained low, and there was no sign of disease recurrence on the last PET scan performed in January 2020 (Fig. 1).
To the best of our knowledge, only six cases of ectopic ovarian adrenocortical neoplasms have been reported [3-7]. Most patients died between 2 days and 17 months after initial diagnosis. One 73-year-old woman developed recurrence and peritoneal metas- tases 12 months after laparoscopic ovariectomy; she had not been prescribed adjuvant treatment. Given the lack of valid data, the treatment for ectopic adrenocortical carcinomas follows similar recommendations to that for eutopic tumours. The European Society of Endocrinology considers surgery mandatory, and mitotane is approved both in an adjuvant setting and for patients
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with advanced disease [8]. A combination of etoposide, doxoru- bicin, cisplatin, and mitotane is among the therapeutic options for patients with residual, advanced adrenocortical carcinomas after first-line therapy. One patient with an ectopic adrenocortical carcinoma, who did not respond to conventional chemotherapy, was unsuccessfully treated with ketoconazole [5] and received, as the first case report, mitotane monotherapy. The follow-up duration was 10 years and she exhibited a complete response. Similarly, in our case, the medical history is suggestive of a slowly progressive tumour. Despite the initial misdiagnosis, 17 years passed between first symptoms and metastases occurrence.
When evaluating prognostic factors, current recommendations by the European Network for the Study of Adrenal Tumors (ENSAT) suggest considering classification of the tumour at initial diagno- sis with evaluation of tumour stage, resection status, Ki67 index, as well as autonomous cortisol secretion [8]. Ki67 index is miss- ing in our case report. In addition, although, the patient lacked the specific features of Cushing’s syndrome, weight loss during mitotane treatment suggested that the drug might have controlled a likely hypercortisolism. It has been reported that, mitotane con- trols hypercortisolism over the long term but that the antisecretory effects requires several months to appear; they are sustained there- after because the drug is stored in adipose tissue. Mitotane has demonstrated efficacy in adrenocortical carcinoma and it is used to treat all forms of hypercortisolism [8]. Data on mitotane monother- apy in advanced disease are scarce. Megerle et al. studied a large cohort (127 patients) with advanced adrenocortical carcinomas, of whom 20.5% showed an objective response (complete or partial response, or stable disease). Only three patients (2.4%) exhibited complete remission [9], emphasizing the exceptional clinical evo- lution of our case. Interestingly, mitotane blood levels were found to be correlated with the objective response rate, progression- free survival and overall survival [9,10]. The European Society of Endocrinology Guidelines recommend that the mitotane blood level should remain over 14mg/L [8]; this was always the case for our patient. A complete response was achieved 5 years after mitotane initiation, emphasising the long-lasting effects of the drug. In the study of Megerle et al., long-term disease control (> 180 days) was achieved in 40.9% of patients; long-term benefits (>12 months) were seen in 22% of patients. Mitotane treatment was stopped 5 years after our patient achieved a complete response. The
future course of our patient is not predictable and indeed there are no guidelines pertaining to the optimal time for mitotane discon- tinuation. Hermsen et al. reported extremely long survival (12-28 years) after initial diagnosis of adrenal carcinoma in six patients, despite recurrences and metastases; their patients had been off mitotane for many years prior to the study [11]. Our patient wished to become pregnant; thus, mitotane treatment was discontinued because the drug is teratogenic. Pregnancy should be avoided until mitotane becomes undetectable in the plasma, which usually takes 1 to 3 years. Long-term remission is advisable before attempt- ing pregnancy, but the optimal duration of remission remains to be determined. Pregnancy after monitoring the evolution of an adrenocortical carcinoma must be monitored cautiously. Indeed, adrenal carcinogenesis is affected by the hormonal milieu of preg- nancy. An adrenocortical carcinoma diagnosed during pregnancy or the immediate postpartum period may be associated with a poorer prognosis than other such carcinomas, because the tumours are more advanced and often associated with hypercortisolism with a poor overall maternal survival [12]. However, in a study on 17 pregnancies patients previously treated for adrenocortical carcino- mas, pregnancy did not seem to be associated with poorer clinical outcomes, similarly to breast cancer, another hormone-dependent cancer ([13]. Interestingly, according to the largest relevant study to date, since adrenocortical carcinomahas been localized in all patients,a “healthy mother effect” is suggested, women in good health beeing more willing to attempt pregnancy [14]. There has been no report of pregnancy after development of an ectopic ovar- ian adrenocortical carcinoma. Regarding the foetal outcome, De Corbière et al. reported no adverse effects when mitotane has been discontinued for at least one year before the time of conception, but data on mitotane plasma levels were missing [14].
In conclusion, the survival of our patient (who is now aged 33 years) was unexpected; this is an extraordinary outcome of an exceptional disease and the first case of ectopic ovarian adreno- cortical carcinoma with a survival exceeding 10 years.
Patient consent
Informed consent has been obtained from the patient for publi- cation of the case report and accompanying images.
Disclosure of interest
The authors declare that they have no competing interest.
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Data sharing is not applicable to this article as no new data were created or analyzed in this case study.
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References
[1] Scully RE. Sex cord-stromal tumors. In: Blaustein A, editor. Pathology of the female genital tract. New York, NY: Springer; 1982. p. 581-601, http://dx.doi.org/10.1007/978-1-4757-1767-9.23.
[2] Hayes MC, Scully RE. Ovarian steroid cell tumors (not otherwise specified). A clinicopathological analysis of 63 cases. Am J Surg Pathol 1987;11:835-45, http://dx.doi.org/10.1097/00000478-198711000-00002.
[3] Marieb NJ, Spangler S, Kashgarian M, Heimann A, Schwartz ML, Schwartz PE. Cushing’s syndrome secondary to ectopic cortisol produc- tion by an ovarian carcinoma. J Clin Endocrinol Metab 1983;57:737-40, http://dx.doi.org/10.1210/jcem-57-4-737.
[4] Young RH, Scully RE. Ovarian steroid cell tumors associated with cush- ing’s syndrome: a report of three cases. Int J Gynecol Pathol 1987;6:40-8, http://dx.doi.org/10.1097/00004347-198703000-00005.
[5] Donovan JT, Otis CN, Powell JL, Cathcart HK. Cushing’s syndrome secondary to malignant lipoid cell tumor of the ovary. Gynecol Oncol 1993;50:249-53, http://dx.doi.org/10.1006/gyno.1993.1202.
[6] Elhadd TA, Connolly V, Cruickshank D, Kelly WF. An ovarian lipid cell tumour causing virilization and Cushing’s syndrome. Clin Endocrinol 1996;44:723-5, http://dx.doi.org/10.1046/j.1365-2265.1996.693515.x.
[7] Chentli F, Terki N, Azzoug S. Ectopic adrenocortical carci- noma located in the ovary. Eur J Endocrinol 2016;175:K17-23, http://dx.doi.org/10.1530/EJE-16-0224.
[8] Fassnacht M, Dekkers O, Else T, Baudin E, Berruti A, de Krijger R, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Net- work for the Study of Adrenal Tumors. Eur J Endocrinol 2018;179:G1-46, http://dx.doi.org/10.1530/EJE-18-0608.
[9] Megerle F, Herrmann W, Schloetelburg W, Ronchi CL, Pulzer A, Quin- kler M, et al. Mitotane monotherapy in patients with advanced adrenocortical carcinoma. J Clin Endocrinol Metab 2018;103:1686-95, http://dx.doi.org/10.1210/jc.2017-02591.
[10] Gonzalez RJ, Tamm EP, Ng C, Phan AT, Vassilopoulou-Sellin R, Per- rier ND, et al. Response to mitotane predicts outcome in patients with recurrent adrenal cortical carcinoma. Surgery 2007;142:867-75, http://dx.doi.org/10.1016/j.surg.2007.09.006 [discussion 867-875].
[11] Hermsen IGC, Gelderblom H, Kievit J, Romijn JA, Haak HR. Extremely long sur- vival in six patients despite recurrent and metastatic adrenal carcinoma. Eur J Endocrinol 2008; 158:911-9, http://dx.doi.org/10.1530/EJE-07-0723.
[12] Abiven-Lepage G, Coste J, Tissier F, Groussin L, Billaud L, Dousset B, et al. Adrenocortical carcinoma and pregnancy: clinical and bio- logical features and prognosis. Eur J Endocrinol 2010;163:793-800, http://dx.doi.org/10.1530/EJE-10-0412.
[13] de Simone V, Pagani O. Pregnancy after breast cancer: hope after the storm. Minerva Ginecol 2017;69:597-607, http://dx.doi.org/10.23736/S0026-4784.17.04113-2.
[14] de Corbière P, Ritzel K, Cazabat L, Ropers J, Schott M, Libé R, et al. Pregnancy in women previously treated for an adrenocortical carcinoma. J Clin Endocrinol Metab 2015;100:4604-11, http://dx.doi.org/10.1210/jc.2015-2341.
Laurence Salle * Robin Mas Marie-Pierre Teissier-Clément Department of Endocrinology, Diabetology and Nutrition, University Hospital of Limoges, 2, avenue Martin-Luther-King, 87042 Limoges, France
* Corresponding author.
E-mail address: laurence.teyssieres@orange.fr (L. Salle)
Recurrent hypothyroidism and thrombopenic throm- botic purpura
Hypothyroïdie et purpura thrombotique thrombocytopénique
ARTICLE INFO
Keywords: Hypothyroidism Thrombotic microangiopathy
Mots clés : Hypothyroïdie Microangiopathie thrombotique
Thrombotic thrombocytopenia purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia linked to disseminated microvascular platelet rich-thrombi [1]. TTP is caused by deficiency of a plasma metallo- protease, ADAMTS13. When exposed to high shear stress in the microcirculation, von Willebrand factor (VWF) and platelets are prone to form aggregates. This propensity of VWF and platelet to form microvascular thrombosis is mitigated by ADAMTS13, which cleaves VWF before it is activated by shear stress to cause platelet aggregation in the circulation. Deficiency of ADAMTS13, due to autoimmune inhibitors in patients with acquired TTP and mutations of the ADAMTS13 gene in hereditary cases, leads to VWF - platelet aggregation and microvascular thrombosis. TTP shows striking involvement of myocardial arteries and variable degrees of vascular involvement in kidney, pancreas, brain, and adrenal glands [2]. We have previously reported the case of a patient in which reversible hypothyroidism was observed in the course of TTP [3]. A second episode of hypothyroidism is reported in the same patient during a relapse of thrombotic microangiopathy.
A 42-year-old man was admitted to the hospital in Novem- ber 1997 because of headache, lethargy, fatigue and mild right arm weakness. During the preceding 10 days, he had had five transient neurologic ischemic attacks. Laboratory findings were as following: thrombocytopenia (platelet count 27 giga/L); mechani- cal hemolytic anemia (hemoglobin 9.7 g/dL, schizocytes 2%, lactate dehydrogenase (LDH) 842 U/L), glycaemia 4,8 mmol/L, serum crea- tinine 104 mol/L. Head CT injected with iodine did not show any acute or subacute infarction or hemorrhage. TTP was diagnosed and after five plasma exchanges and 2 mg vincristine injection, remis- sion was achieved and the patient was discharged from the hospital. There was no evidence of an underlying disorder. Thyroid function tests performed because of unusual asthenia at presentation before plasma exchange and head CT disclosed mild hypothyroidism (TSH 17 mIU/mL, normal range < 5 mIU/mL). Thyroid gland was clinically normal. Serum was negative for thyroid autoantibodies. Because the clinical presentation of hypothyroidism was poor, we kept watch without specific therapy. Thyroid function returned to nor- mal value after 6 months.
The patient remained in remission for 20 years and then pre- sented to our department with paresthesia in upper right limb and dysarthria related to a limited ischemic stroke on magnetic resonance imaging. Biological findings showed mild hemolytic ane- mia (hemoglobin: 10.5 g/dL, thrombocytopenia (platelet count: 60 giga/L, and schistocytes (4%) at blood film examination. The LDH level was 450 U/L (N 135-325 U/L), haptoglobin was <0.1 g/L, cre- atinine 84 pmom/L. On admission, TSH was slightly increased, 7.4 mIU/mL, (normal range 0.270-4.20), T4 was normal.
A diagnosis of relapsing autoimmune TTP was rapidly estab- lished, based on the presence of microangiopathic hemolytic