Case Report
Jersy Cárdenas-Salas, Beatriz Castelo, Rita María Regojo, Juan Antonio González-Sanchez and Cristina Álvarez-Escola*
Long-term complete remission of metastatic adrenocortical carcinoma
https://doi.org/10.1515/hmbci-2022-0017 Received February 6, 2022; accepted July 20, 2022; published online September 8, 2022
Abstract
Objectives: To report a rare case of a metastatic adreno- cortical carcinoma (ACC) that achieve a complete and a long-term remission.
Case presentation: AAC is a rare and aggressive tumor, with a high risk of recurrence and that present metastases in 21% of cases at diagnosis. Treatment of advanced ACC is challenging, mitotane is the only available adrenolytic treatment, with modest and unpredictable responses. Response rates to systemic chemotherapy are not encour- aging. We describe the case of a 39-year-old woman with a metastatic ACC, that achieve a complete and long-term remission after chemotherapy, mitotane treatment and surgery of primary tumor and liver metastases.
Conclusions: A complete remission of a metastatic adre- nocortical carcinoma is possible in some rare cases after a multimodal treatment.
Keywords: adrenocortical carcinoma; metastatic; remission.
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive tumor with an annual incidence of 0.5-2.0 cases per
*Corresponding author: Cristina Álvarez-Escolá, Department of Endocrinology, “La Paz” University Hospital, Paseo de la Castellana, 261, 28046, Madrid, Spain, Phone: +34-917277209, E-mail: escola.cristina@gmail.com
Jersy Cárdenas-Salas, Department of Endocrinology, “Fundación Jiménez-Diaz” University Hospital, Madrid, Spain
Beatriz Castelo, Department of Oncology, “La Paz” University Hospital, Madrid, Spain
Rita María Regojo, Department of Pathology, “La Paz” University Hospital, Madrid, Spain
Juan Antonio González-Sanchez, Department of Surgery, “La Paz” University Hospital, Madrid, Spain
million individuals. It follows a bimodal age distribution with peaks incidence in childhood and at the age of 55. Complete surgical removal is the only therapy able to achieve healing. At the time of diagnosis 21% has metas- tasis, however, surgery of the primary tumor can bring benefit even in these patients when it is feasible. Impor- tantly, even after complete surgical removal, patients are at risk of recurrence as late as 10-12 years. [1] The 5 year survival rate of Stage I to IV (ENSAT 2008) is 82, 61, 50 and 13% respectively [2]. Treatment options for advanced ACC are limited. Mitotane is the only available adrenolytic treatment, with modest and unpredictable responses. Response rates to systemic chemotherapy are not encour- aging and only a few randomized controlled studies are available. Herein, we report a very rare case of complete and long-term remission of a metastatic ACC that was achieved after an unexpected excellent-response to mito- tane treatment, that allowed us to perform a surgical approach to the primary tumor and subsequently to liver metastases. The patient remains without recurrence after 19 years of diagnosis.
Case presentation
In March 2003, a 39-year-old Caucasian female consulted for a six-month-evolution hirsutism. She also reported new-onset acne, asthenia, face oedema, amenorrhea and increase of 5 kg in weight. She was diagnosed of epilepsy in childhood, her menarche age was 13 years and she had four pregnancies and one spontaneous abortion. Her mother had colon and bladder cancer. On examination the blood pressure, weight and body mass index were 150/90 mm Hg, 74.5 kg and 29.10 kg/m2 respectively. She also had a full- moon complexion; face, neck and chest acne; and terminal hair on the face, breast areola and peri-umbilical region (Ferrimang- Gallway scale: 12 points). No goiter, lymph- adenopathies, megalies neither clitoromegaly were found.
Laboratory tests revealed hemoglobin 15.9 g/dL, hematocrit 48.7%, platelets 200,000/uL, lactate dehydro- genase 350 IU/L (normal value: 100-190), sodium
141 mEq/L (135-145), potassium 3.1 mEq/L (3.5-5.1), normal renal and liver function tests and no disturbances in acid-base balance. Testosterone levels were 3.36 ng/ml (0.00-1.00), androstendione 2,100 ng/dL (46-371), DHEA-sulfate 898 µg/dL (82-300), urine cortisol 541 µg/ 24 h (20-90), ACTH <4 pg/mL (5-46) and serum nocturnal cortisol 24 mg/dL. Serum-cortisol after 8 mg-dexa- methasone suppression test was 17 mg/dL. An abdom- inal ultrasound found an intra-abdominal mass. Computed tomography (CT) reported a left adrenal mass (16 × 10 x 15 cm) with left renal vein invasion and collat- eral venous drainage, a left renal-hiliar and para-aortic lymphadenopathy and multiple pulmonary and multiple liver metastases (3 cm in the largest diameter within the right liver lobe) (Figure 1A-C). Although not recom- mended for localized or potentially resectable adrenal masses, because of its metastatic condition, a fine needle aspiration was performed and cytology of the adrenal mass was suggestive of ACC (Figure 2A). No lesions on bone scan were found. Our diagnosis was ACTH-independent Cushing
syndrome and virilization syndrome secondary to a left STAGE-IV ACC (ENSAT 2008) and secondary hypertension.
Ketoconazole 100 mg bid, enalapril 25 mg/daily, amlodipine 10 mg/daily and a cisplatin-epirrubicine- cyclophosphamide based chemotherapy (6 cycles) were prescribed. A CT scan performed 8 months later, showed discreet progression of the adrenal mass (Increase of 2 cm in the largest diameter), so ketoconazole was withdrew; and mitotane (initial dose 2.5 gr/daily, maximum dose 4 gr/daily) and hidrocortisone (40-60 mg/daily) were prescribed. A few admissions because of mitotane related adrenal insufficiency symptoms were reported. The dis- ease remained stable for two years when a CT scan showed a complete disappearance of pulmonary metas- tases (Figure 1D), but progression of liver metastases (greater than 9 cm in maximum diameter located in the VI and VII liver segments) (Figure 1E). The adrenal mass had decreased in size (7 x 10 cm) but seemed to invade the left kidney (Figure 1F). Three months later a left adrenalec- tomy, left nephrectomy and splenectomy were performed.
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The pathologist reported an ACC that infiltrated the renal capsule and perirrenal fat tissue, without invading the renal parenchyma. The neoplasm met Weiss ACC criteria with presence of all the negative histologic prognostic factors: high nuclear grade [3, 4], mitotic rate >5 (45 mitosis/50HPF), presence of atypical mitotic figures, >75% of eosinophilic tumor cells, diffusse architecture, necrosis, venous invasión and invasion of adjacent soft tissue (Weiss score: 9) (Figure 2B and C). Three months later a right hepatectomy and cholecystectomy were performed. The pathology reported an ACC metastasis with areas of central necrosis that reached the surgical margin in some areas (Figure 2D).
Since then (37 months after diagnosis) the levels of testosterone, DHEAs and cortisol remain suppressed and no evidence of structural recurrence has been identified in the imaging tests performed. Her overall survival is 19 years and her recurrence-free survival (RFS) is 16 years. She is currently being treated with Mitotane 1 gr/day (levels under therapeutic range), hidroaltesone 40 mg/day, 9-fluoralphahidrocortisone: 1 mg/day, Cal- cium 2 gr/daily, simvastatine 40 mg/daily and ezetimibe 10 mg/daily.
Discussion
ACC is a rare tumor with very poor prognosis. The one-year overall survival of patients within Stage IV is 15%. The majority of individuals with ACC who achieve more than 5 year survival are not cured and it is expected to find a
recurrence or distant metastases in 85% of cases when surgery is performed with curative intention [1].
Mitotane causes selective cytotoxic atrophy of the ad- renal cortex and it has a long half-life (18-159 days). A 38%- objective response in metastatic disease has been observed when plasma levels are between 14 and 20 mg/dL; there is no response if they are less than 14 mg/dL and neurotoxicity is present if levels are more than 20 mg/dL [1, 3]. Retro- spective analysis found that as an adjuvant therapy it is associated with an improvement in RFS and recent meta- analysis have concluded that it is associated with a signifi- cant prolongation of overall survival and RFS [4]. Moreover, higher response rate and increased progression free-survival (PFS) has been documented in patients with advanced dis- ease who received the combination of mitotane, etoposide, doxorubicin and cisplatin compared to mitotane and streptozotocin. However there was no difference in overall survival [5].
To our knowledge, 11 cases of complete remission of Stage-IV ACC have been reported (Table 1). In all of them surgery of primary tumor was performed at diagnosis and mitotane was prescribed in 9 cases. Following mitotane administration, a complete remission of pulmonary, liver and both metastases were observed in two, and one case respectively. In the other cases surgery, radiotherapy or radio-frequency were performed for metastases treatment. In our case, surgery of the primary tumor was performed almost three years after the initial diagnosis and right hepatectomy was necessary in a second time. Due to the poor response to systemic treatments, some authors recommend surgery as the best treatment for ACC and
| Gender/ age | Hormone production | Metastases | Surgical treatment | Medical treatment | Survivall | |
|---|---|---|---|---|---|---|
| Becker | ở 3.5 y | Androgen | Liver | Adrenalectomy, | Mitotane 1 gr/daily (31 months). Liver me- | OS: 4 years |
| et al. [10] | and cortisol | nephrectomy | tastases complete remission. | RFS: | ||
| 17 months | ||||||
| Becker et al. [10] | ở 69 y | Non functioning | Liver | Adrenalectomy | Mitotane 1-10 gr/daily | OS: NA |
| RFS: 6 years | ||||||
| and | ||||||
| 4 months | ||||||
| Kornely | ₡ 53 y | Androgen | Liver | Adrenalectomy, local | Mitotane 1.5-12 gr/daily. Liver metastases | OS: NA |
| et al. [ ] | recurrence surgery, liver metastasectomy | complete remission. | RFS: 4 years | |||
| Sakamoto et al. [12] | ֏ 53 y | Non | Liver + lung | Adrenalectomy, nephrec- | No treatment | OS: NA |
| functioning | tomy, liver enucleation, | RFS: | ||||
| lung lobectomy, colectomy | 18 years | |||||
| Godil et al. | _ | Non | Lung | Adrenalectomy, lung | Mitotane 0.25-2 gr/daily (12 months). Lung | OS: |
| [13] | congenital | functioning | lobectomy | metastases complete remission. | 3.5 years | |
| RFS: 2 years | ||||||
| Ilias et al. [14] | ₡ 24 y | Androgen | Liver | Adrenalectomy, | Cisplatin ( year) | OS: 17 years |
| and cortisol | nephrectomy | Mitotane 1-2.4 gr/daily (16 years). Liver | RFS: | |||
| metastases complete remission. | 16 years | |||||
| De Leon et al. [15] | ở 2 m | Androgen and cortisol | Lung | Adrenalectomy, lung lobectomy | Mitotane 2-2.5 gr/daily (16 months) | OS: 14 years and |
| 10 months RFS: | ||||||
| 14 years and 4 months | ||||||
| De Ramirez | ở 29 y | Non functioning | Liver | Adrenalectomy, nephrec- | Cisplatin + etoposide ( courses). Liver | OS: 7 years |
| [16] | tomy, splenectomy, distal | metastases partial remission. | and 3 months RFS: 9 months | |||
| pancreatectomy, liver lobectomy | ||||||
| Arai et al. [17] | ở 10 y | Androgen | Lung | Adrenalectomy, nephrec- tomy, liver lobectomy, | Carboplatin + etoposide + doxorubicin (9 courses) | OS: NA |
| bilateral lung lobectomy | Mitotane 1-3 gr/daily. No response. | RFS: NA | ||||
| Chalasani et al. [18] | 9 57 y | Androgen | Liver + lung | Adrenalectomy, | Mitotane 3-6 gr/daily (5 months) lung and | OS: 25 years |
| nephrectomy | liver metastases complete remission. | RFS: | ||||
| 24.5 years | ||||||
| Pal et al. | ₡ 55 y | Non | Liver + lung | Adrenalectomy, nephrec- | Mitotane 4-10 gr/daily (3 years). Lung me- | OS: 12 years |
| [19] | functioning | tomy, liver radio- frequency, lung lobectomy | tastases complete remission. | RFS: 7 years |
y, years; m, months; OS, overall survival; RFS, recurrence-free survival; 0, duration of treatment; NA, not available.
claims that complete resection offers the best chance for long term survival [6]. In the studied cases, the largest disease-free survival (DFS) was 24.5 years in a 57 year-old woman with lung and liver metastases treated with mito- tane for 5 months; and a more than 10 years DFS was re- ported in only three other cases, as in our case. In our case, the ACC was a cortisol and androgen secreting tumor. Else et al. concluded that the stage, the tumor grade and the cortisol production were associated with poor prognosis
[7]. Cortisol production has also been associated with increased likelihood of metastasis at early stages [8, 9] In our case metastases were present at diagnosis, but cortisol production did not imply a poor prognosis. Other factors associated with poor prognosis are size larger than 12 cm, high mitosis rate, the presence of necrosis, high Ki67 expression and TP53 mutation.
In our case the patient was rejected for surgery at diagnosis, however due to the dramatic response
experienced after Mitotane administration, it was possible to perform radical surgery and resection of hepatic me- tastases. We conclude that even in Stage IV ACC, and in the presence of poor risk factors, it is possible to achieve complete remission in some cases. More studies must be conducted in order to identify which patients would respond the most to mitotane therapy.
Conclusions
Although its aggressive condition and high recurrence risk, a complete remission of a metastatic adrenocortical carci- noma is possible in some rare cases after a multimodal treatment.
Research funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contributions: CAA & JJCS were the main writers of the manuscript. CAA is the named physician of the patient. All the team members reviewed the manuscript and helped in the patient care, diagnosis and follow-up. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest. Informed consent: Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Ethical approval: Not applicable. Approval by an ethics committee was not obtained nor sought after due to the current manuscript representing a single-patient case report, describing what is known to be standard of care involving minimal risk.
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