Adrenal metastatic melanoma first identified during pregnancy: a diagnostic challenge
Tal Schillera,b, Edi Vaisbuchb,c, Taiba Zornitzkia,b and Alena Kirzhnerb,d
Adrenal nonadenomatous tumors (NAT) first identified during pregnancy are very rare and pose a diagnostic and therapeutic dilemma with significant risks for the mother and fetus. The aim of this study is to report a case of a large adrenal NAT identified in pregnancy and literature review. A literature search was conducted, and data were summarized. A 37-year-old primigravida woman, with a history of melanoma, excised 12 years before presentation without recurrence, presented at 35 weeks gestation due to intractable right flank pain. MRI demonstrated an eight cm, heterogeneous, septate, right adrenal mass suspected to be either pheochromocytoma/paraganglioma (PPGL), adrenocortical carcinoma or metastasis. Blood metanephrines were sent urgently to enable a safe delivery and were within normal range, as were cortisol and androgen levels. A biopsy was taken from a palpable breast mass as well as from an ovarian mass during the operation. At 36 weeks gestation, she was delivered by cesarean section. PET computed tomography performed
after delivery revealed the extensive metastatic spread of recurring melanoma including the right adrenal gland. Timely diagnosis and management by a multidisciplinary team are important to avoid a catastrophic outcome. There is no consensus on optimal management and timing of delivery. PPGL should be ruled out before delivery. Melanoma Res 32: 488-491 Copyright @ 2022 Wolters Kluwer Health, Inc. All rights reserved.
Melanoma Research 2022, 32:488-491
Keywords: melanoma in pregnancy, metastatic melanoma, metastasis to adrenal
ªDepartment of Diabetes, Endocrinology and Metabolic Disease Institute, Kaplan Medical Center, Rehovot, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, “Department of Obstetrics and Gynecology and “Department of Internal Medicine, Kaplan Medical Center, Rehovot, Israel
Correspondence to Alena Kirzhner, MD, Department of Internal Medicine, Kaplan Medical Center, Pasternak St., POB 1, Rehovot 76100, Israel Tel: +972 08 9441300; e-mail: ide.elena@gmail.com
Received 2 May 2022 Accepted 11 July 2022
Introduction
Adrenal tumors first identified during pregnancy are a rare occurrence. Nonetheless, they should be diagnosed correctly and treated in a timely manner, as delays and suboptimal management can be lethal to both mother and fetus. The differential diagnosis includes primary adrenal tumors such as pheochromocytoma/paragangli- oma (PPGL), adrenocortical carcinoma (ACC) or meta- static disease. Their rarity precludes formal guidelines, and the management is decided in each case individu- ally preferably by a multidisciplinary team including an endocrinologist, maternal-fetal medicine specialist and any other discipline deemed necessary [1]. Treatment may be either medical or surgical depending on the final diagnosis. There are no clear guidelines on the optimal timing or mode of delivery. Here we present a case high- lighting the clinical dilemmas.
Case presentation
A 37-year-old primigravida presented to our hospital at 35 weeks’ gestation due to intractable right flank pain. Her medical history was notable for a hypoplastic right kidney with reduced function and mild hydronephrosis. Additionally, melanoma was excised from her lower back 12 years before presentation without a known recurrence. She did not smoke and took only multivitamins for her pregnancy. Her gynecological history was unremarkable
with regular menses until a spontaneous pregnancy. Family history was negative for hypertension.
On physical examination, blood pressure was normal, without tachycardia. No signs of hypercortisolism or hyperandrogenism were noted.
Laboratory evaluation included normal chemistry and specifically creatinine and serum electrolytes, and a nor- mal complete blood count.
Due to the severe pain, an abdominal ultrasound was performed that demonstrated an 80 mm heterogenous mass above the right kidney. An MRI of the abdomen and pelvis without gadolinium contrast revealed an 80×80×75mm, heterogeneous, septate, right adre- nal mass located in the right adrenal gland, and inva- sion to the inferior vena cava could not been ruled out (Fig. 1a,b). Fetal assessments with ultrasound and cardi- otocography were normal.
Given the intractable pain and the gestational age, it was decided to proceed to delivery after PPGL was ruled out. Plasma fractionated metanephrines were sent urgently and were within the normal range. Other test results included aldosterone (231 pmol/l, normal range 48-643 pmol/l), morning plasma cortisol (852 nmol/L, nor- mal for the third trimester), dehydroepiandrosterone-sul- fate (1.27 µmol/l, normal range 0.94-10.80 pmol/l), total
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MRI image (a) T2 weighted image (sagittal) and (b) T1 weighted image (transverse) demonstrates an 80× 80× 75 mm mass (arrow) in the right adrenal; PET CT revealed adrenal mass of the right adrenal (c,d). CT, computed tomography.
testosterone (1.2 nmol/l, normal range 0.4-2.1 nmol/l) and chromogranin-A (55 ng/ml, normal range 19.4-98.1 ng/ml).
During admission, a breast mass measuring approxi- mately 30 mm was palpated and a biopsy was taken.
At 36 weeks gestation, after a course of betamethasone, a cesarean delivery due to the patient’s preference was performed, and a female newborn weighing 2986g was delivered with an APGAR score of 9/9. Intraoperative findings were notable for a right ovarian mass and mul- tiple omental masses, biopsies were taken, and a right oophorectomy was performed. The histological examina- tion confirmed a metastatic malignant melanoma from all biopsies taken. The placenta was sent to pathology and was not metastasized.
PET computed tomography (CT) performed after delivery revealed extensive metastatic spread to lymph nodes above and below the diaphragm, bone, breast, omentum and the
right adrenal (Fig. 1c,d). A brain MRI was performed and revealed small lesions, located on the frontoparietal right side of the brain without mass effect. After delivery, the patient was referred to the oncology unit at another hos- pital. Results of mutational status showed the melanoma was positive for a BRAFV600E mutation. The patient is currently receiving treatment with dabrafenib/trametinib.
Discussion
Adrenal tumors first identified during pregnancy are extremely rare and antenatal diagnosis is difficult and often missed. Here, we report a case of a large unilateral adrenal mass suspected to be either PPGL, ACC or metastasis. The final diagnosis was advanced metastatic melanoma.
A literature search conducted focusing on adrenal masses first identified in pregnancy, larger than 4 cm, with non- adenomatous features on MRI revealed that the most common masses in pregnancy were PPGL.
PPGL is rare during pregnancy and reported in only 0.007% of all pregnancies [2]. Uncontrolled catecho- lamine release by these tumors can lead to pregnancy complications and increase the risk of maternal and fetal morbidity and mortality. Although considerable advances were made over the last decade in the management of PPGL, the diagnosis in pregnancy can be challenging because symptoms of catecholamine excess are nonspe- cific and can overlap with symptoms of normal pregnancy.
The largest series to date was recently published by Bancos et al. [2] and included 249 pregnancies in 232 women with PPGL identified from the International Pheochromocytoma and Pregnancy Registry between 1 Jan 1980 and 31 Dec 2019. They also conducted a system- atic review of studies published between 1 Jan 2005 and 27 Dec 2019 [2]. In this cohort 54% of PPGL were diag- nosed during pregnancy at a median of 24 weeks gesta- tion (range 2-38 weeks), 15% were diagnosed before and 31% within 12 months after delivery. Of the 249 pregnan- cies 206 (83%) were symptomatic and the most common symptoms were hypertension (93%), palpitations (57%), headaches (50%) and diaphoresis (42%). A correct diag- nosis before delivery is crucial to improve maternal and fetal outcomes. PPGL left untreated or diagnosed after delivery has been associated with a 27-fold increased risk of maternal or fetal complications. Complications of catecholamine excess occurred in 33 pregnancies (all in PPGLs diagnosed during or after pregnancy) including fetal death in 15 pregnancies, severe maternal complica- tions or death in 13 pregnancies and both maternal and fetal complications in five pregnancies. Major risk factors for adverse outcomes include an unrecognized PPGL, a tumor located in the abdomen or pelvic and catechola- mine excess above 10 times the upper limit of the nor- mal range. However, diagnosis of PPGL before or during pregnancy and timely medical treatment with adrenergic blockade were associated with good outcomes [2].
ACC is a rare and aggressive tumor with an annual inci- dence of 1-2 per million, more frequent in women, and may be diagnosed in their childbearing years [3]. We found a few case reports with ACC first recognized dur- ing pregnancy. The leading presentation was Cushing’s syndrome. The largest series was published by Abiven- Lepage et al. [3] and described the outcome of 12 women diagnosed with ACC, three during pregnancy and nine immediately after delivery. They were compared to women with ACC, not in proximity to pregnancy [3]. Patients diagnosed during pregnancy or postpartum had larger tumors, tended to be discovered at a more advanced stage and had a poor survival rate of 50% at 1 year and only 13% at 5 years. Out of the 12 pregnancies one was terminated, one resulted in intrauterine fetal death and five delivered prematurely before 37 weeks gestation.
The most common cancers diagnosed during pregnancy are breast (1 in every 1000 pregnancies), cervical (1 per
1200-10000 pregnancies), lymphoma (1 per 1000-6000 pregnancies) and leukemia (1 in 75 000 pregnancies) [4]. Pregnancy-associated melanoma (PAM) is reported between 2.8 and 5.0 per 100000 pregnancies and mela- noma accounts for eight percent of all malignant tumors arising during pregnancy [5]. It is unclear whether the pregnancy is an independent risk factor for the devel- opment of melanoma or aggravates its progression dur- ing pregnancy. Current understanding is that melanoma in pregnant women does not carry a significantly poorer prognosis than in the nonpregnant state [6].
Melanoma has the potential to metastasize to the pla- centa and fetus and is the most common neoplasm to do so (about 30% of all reported cases) [7]. The risk of metastasis to the placenta and fetus is higher in patients with widely metastatic melanoma. The placentas of women with the suspected or known disseminated dis- ease should be examined thoroughly [6].
For patients with advanced disease, there are few con- clusive data to support the use of either immunotherapy or BRAF-directed treatments during pregnancy due to the possibility of teratogenic and embryotoxic effects [6]. A few case reports have been published and consist of patients who wished to continue their pregnancy, or who became pregnant while on treatment [8-11].
Out of the four cases of BRAF-directed treatment during pregnancy, all four infants were born prematurely, prior 37 weeks gestation, and one case of fetal growth restric- tion was reported. Like BRAF-directed therapy, immu- notherapy is not recommended for use in pregnancy, especially given uncertainty over the role that immune checkpoint molecules have on immune homeostasis dur- ing pregnancy [12]. Although data are lacking, the gen- eral recommendation for women with PAM stage IV is the termination of pregnancy or early induction to facili- tate optimal management of the mother [6].
A retrospective series of 22 women diagnosed with stage III/IV melanoma (according to the updated American Joint Committee on Cancer sixth edition of cancer staging) during pregnancy demonstrated metastases in descending order to the inguinal area (70%), lungs, liver, brain, ovary, bone and spleen [13]. No cases of adrenal metastasis were reported.
Metastatic disease to the adrenal first discovered in preg- nancy is extremely rare. We identified three case reports originating from the pancreas, lung and trophoblastic disease. All are typically discovered late in pregnancy with widespread metastatic disease and poor prognosis [14-16].
Conclusion
Management of an adrenal tumor during pregnancy should include a multidisciplinary approach involv- ing endocrinologists and maternal-fetal experts. PPGL
should be ruled out before delivery to avoid a cata- strophic outcome.
Acknowledgements
Conflicts of interest There are no conflicts of interest.
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