Onkologie 2012;35:517-519 DOI: 10.1159/000341830
A Pregnant Patient with Adrenocortical Carcinoma: Case Report
Elias Kotteasa Eli loachimb Nicholas Pavlidisª
ªDepartment of Medical Oncology, School of Medicine, University of loannina, bPathology Department, General Hospital of loannina ‘G. Hatzikosta’, Ioannina, Greece
Keywords
Pregnancy · Adrenal cancer . Adrenalectomy
Summary
Background: Coexistence of an adrenocortical carcinoma and pregnancy is extremely rare with only 25 described cases so far, and has a poor prognosis. Case Report: We report the case of a 28-year-old patient with adreno- cortical carcinoma initially presenting with Cushing’s syndrome and pre-eclampsia in the 22nd week of gesta- tion, treated in our department. She underwent adre- nalectomy, but eventually died from metastatic disease. We focus on existing treatment options and concerns for this rare malignancy during pregnancy. Conclusion: Early diagnosis and surgery are the cornerstones for bet- ter outcome.
Introduction
Cancer in pregnancy is a rare phenomenon with enormous impact on the lives of both the patient and the fetus, as well as their family. Malignancies most often encountered during pregnancy are breast cancer, cervical cancer, and hematologi- cal conditions [1]. The development of primary carcinoma of the adrenal cortex or ‘adrenocortical carcinoma’ (ACC) dur- ing pregnancy is an extraordinarily rare condition with about 25 cases described worldwide. This is no surprise if we con- sider that the annual incidence of ACC among the general population is estimated at 1/1,000,000 adults and that approxi- mately 1/1,000 pregnancies is complicated by cancer. The
Schlüsselwörter
Schwangerschaft · Nebennierentumor · Adrenalektomie
Zusammenfassung
Hintergrund: Adrenokortikale Karzinome während der Schwangerschaft sind mit bisher nur 25 berichteten Fällen extrem selten und von einer schlechten Prognose gekennzeichnet. Fallbericht: Wir berichten von einer 28-jährigen Patientin mit adrenokortikalem Karzinom, die zunächst mit Morbus Cushing und Präeklampsie in der 22. Schwangerschaftswoche vorstellig wurde und in unserer Abteilung behandelt wurde. Trotz Durchführung einer Adrenalektomie verstarb die Patientin schließlich an den Folgen ihrer metastasierten Erkrankung. Existie-
rende Behandlungsoptionen und Bedenken bezüglich dieser seltenen Tumorerkrankung während der Schwan- gerschaft werden diskutiert. Schlussfolgerung: Eine frühe Diagnose und chirurgische Behandlung sind die Voraussetzung für ein besseres Outcome.
prognosis is very grim. At the time of diagnosis 20-30% of patients already present with metastases with an overall 5-year survival of < 35%. Only surgical excision, when possi- ble, provides curative potential since response to systemic therapy is limited [1-3]. This article presents the case of a pregnant woman with ACC treated in our department.
Case Report
A 28-year-old woman was admitted to hospital at 22 weeks of gestation because of a recent onset of Cushing’s syndrome (CS) and pre-eclampsia- related hypertension. The patient had been well until 6 weeks earlier
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Elias A. Kotteas, MD Department of Medical Oncology Ioannina School of Medicine Stavros Niarchos Avenue, 45500, Ioannina, Greece Tel. +30 265109939-1, Fax -4 ilkotteas@hotmail.com
when her family noticed upper body obesity and striae on the skin of her abdomen; besides, she complained of headaches and fatigue. Initial laboratory examinations showed proteinuria, high serum and urine free cortisol levels (49.7 mg/dl and 2,060 nmol/24 h, respectively; normal ranges during pregnancy 20-35 mg/dl and 230-680 nmol/24 h, respec- tively) while plasma adrenocorticotropin hormone (ACTH) was low (5.2 pg/ml; normal range during pregnancy 20-120 pg/ml). No cortisol suppression was observed upon dexamethasone administration. Non- ACTH-dependent CS was indicated, and additional tests excluded the occurrence of pheochromocytoma. Abdominal ultrasonography disclosed a solid 5.5-cm mass in the left adrenal gland. An open kidney-sparing left adrenalectomy was performed during the 24th week of gestation. Under the microscope, a highly cellular tumor was observed with capsular invasion and malignant mononuclear and multinuclear cells forming cellular beams separated by fibrous tissue, without vascular involvement. There were areas of confluent or comedo necrosis, cellularity with nuclear pleomorphism, and a small number of atypical mitotic figures (fig. 1). Immunohistochemically the tumor cells showed positivity for vimentin, inhibin, melan-A, calretinin, synaptophysin, and CD56 with a high ratio of MIB1-positive cells. These morphological parameters met 4 of the 9 criteria of the Weiss scoring system for diagnosing ACC (3 cri- teria required). Taking into account the increased MIB1 staining, a clear histological documentation of ACC was made. After surgical excision, serum cortisol levels dropped, hypertension declined, and the patient was put on replacement treatment with hydrocortisone. At the 36th week of gestation she delivered a low birth weight (1,800 g) baby boy by caesar- ean section. The patient visited our department with CS relapse after 7 months. A new solid mass of 5.4 cm with heterogeneous enrichment of the left renal vein extending into the renal pelvis was revealed. There- upon, the patient underwent left radical nephrectomy and complete tumor ablation. Disease recurrence with vascular and renal pelvis inva- sion was confirmed. Adjuvant mitotane administration was initiated, concurrent with hydrocortisone. After 11 months of treatment she experi- enced CS and ascites. Peritoneal metastases were found in her abdominal computed tomography scan. Cytological analysis of the ascitic fluid confirmed the spread of the disease. Chemotherapy with cisplatin, doxo- rubicin, and etoposide on a 28-day cycle was initiated. Oral ketoconazole was also administered in an attempt to control the hypercortisolemic state. The patient received 3 cycles of chemotherapy with no objective response, and finally, after 2 months, she succumbed to her disease. Over- all survival was 27 months.
Discussion
ACC among non-pregnant women usually appears as a hormone-secreting tumor in 75% of cases and seldom as an inactive tumor. On the other hand, almost all pregnant women with ACC present symptoms of hypercortisolemia due to rapidly developing CS. ACC during pregnancy is mostly a cortisol/androgen-secreting tumor. The appearance of CS during pregnancy is uncommon (150 reported cases to date). About 10% are complicated by ACC. Therefore, physi- cians must be particularly suspicious of ACC in a pregnant woman with CS manifestation [4]. As in our case, CS often goes undetected until 12-26 weeks of gestation, partially be- cause changes in physical appearance are ascribed to preg- nancy [5, 6]. A key examination is abdominal ultrasound. When a mass is detected, magnetic resonance imaging is a safe and excellent tool at differentiating between adenomas and non-adenomatous lesions of the adrenal glands, and sheds more light on tumor extension and vascular invasion [7]. The European Network for Studying Adrenal Tumors (ENSAT) has adapted a revised TNM classification for ACC. Tumors strictly located within the adrenal gland are defined as stage I and II, depending on tumor size (> 5 cm for stage II). Stage III means the neoplasm infiltrates the surrounding tissue or lymph nodes or blood vessels, and stage IV is determined by the presence of distant metastases. Tumor stage at diagnosis is the best prognostic factor for overall survival [8]. The avail- able literature shows that at the time of diagnosis 33% of pregnant patients had stage II disease, 42% had stage III, and 25% had stage IV [9]. Our patient was considered as stage II ACC (5.9-cm mass), although lymph node sampling was not available.
Fine-needle biopsy is a contradictory diagnostic tool due to the risk of implantation metastasis. Adrenalectomy aiming at R0 resection is the standard treatment; even after radical surgery, up to 85% of patients develop recurrent disease. Historically, laparoscopic adrenalectomy (LA) was not rec- ommended for ACC because it is a high-risk intervention for tumor fragmentation, local recurrence, and peritoneal carci- nomatosis. However, recent data from non-pregnant patients show that open adrenalectomy (OA) and LA have similar recurrence rates (77% for LA and 69% for OA, follow-up 39 months) when performed by a qualified oncologic surgeon. A study from the German ACC Study Group suggests that locoregional lymphadenectomy provides additional benefit and reduces the recurrence risk for patients when compared to those who do not undergo such treatment [10-12]. LA is a safe procedure during pregnancy without increased risk for intra- or postoperative complications (3%) for both the mother and the fetus, as compared to non-pregnant patients [13, 14]. After tumor resection, cortisol replacement therapy must be immediately initiated, and the mother and the neo- nate should be monitored closely for cortisol withdrawal signs.
In our case, neither the mother nor the fetus had complica- tions during or after surgery. Abortion is an option in early pregnancies and advanced disease [15]. Metyrapone and keto- conazole at high doses are potent steroidogenesis inhibitors which can significantly reduce cortisol levels. Metyrapone may exacerbate or worsen hypertension and pre-eclampsia, while ketoconazole has been shown to be teratogenic in rats. Mitotane, an antineoplastic-adrenolytic agent approved for the treatment of ACC, may be administered when the tumor cannot be removed or in the adjuvant setting if there is a high likeli- hood of recurrence (stage III disease). However, its use is not recommended for pregnant patients. With no adequate, well- controlled studies on pregnant patients, serious consideration should be given prior to the administration of these drugs [15- 18]. Pregnancy outcomes for a mother with ACC and her fetus may be complicated by hypertension and diabetes mellitus in the former and by preterm birth and low birth weight, stillbirth, or abortion in the latter [9]. Despite preterm birth, the young boy in our case has shown no long-term prob- lems to date.
An ACC diagnosis during pregnancy is correlated with worse survival rates in comparison to non-pregnant adults. These are the remarks of a recent study evaluating the overall survival rates of 12 patients with ACC during either preg-
nancy or in the post-partum period compared to 98 non-preg- nant controls (95% confidence interval 1.34-11.85; p = 0.013). Survival rates for pregnant women were 50% at 1 year, 28% at 3 years, and 13% at 5 years (5-year survival for non-preg- nant patients is 35%). This could be partially explained by the fact that pregnant women with ACC are diagnosed at a more advanced stage of the disease. Hypercortisolemia cannot be considered a factor affecting the results since survival re- mained grim even after tumor excision. As already men- tioned, 10% of pregnant women with CS are found to have ACC. Hence, one may well speculate that pregnancy is a risk factor for ACC, or, in other words, pregnancy probably creates an environment in which ACC behaves more aggres- sively [9]. The care of a pregnant woman with ACC involves evaluation of competing maternal and fetal risks and benefits, which must be undertaken by a multidisciplinary team includ- ing oncologists, endocrinologists, surgeons, and gynecologists. Early diagnosis and surgery are essential so that better out- comes may be achieved.
Disclosure Statement
None of the authors declare any conflict of interest.
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