Brain Metastasis in Patients With Adrenocortical Carcinoma: A Clinical Series
Mauricio Burotto, Nishant Tageja, Avi Rosenberg, Sowmya Mahalingam, Martha Quezado, Margarita Velarde, Maureen Edgerly, and Tito Fojo
Center for Cancer Research (M.B., N.T., M.V., M.E., T.F.) and National Laboratory of Pathology (A.R., M.Q.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and The George Washington University (S.M.), Rockville, Maryland 20852
Introduction: Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases.
Objective: The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute.
Methods: We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available.
Results: The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, be- tween 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up.
Conclusion: Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario. (J Clin Endocrinol Metab 100: 331-336, 2015)
A drenocortical carcinoma (ACC) is a rare and heter- ogeneous malignancy that affects between 1 and 2 persons per 1 million population. Although the disease oc- curs mainly in adults, children can be affected as well. The median age at diagnosis is 46-55 years (1). Historically only about 30% of these malignancies are confined to the adrenal gland at the time of diagnosis. In these cases, an open resec- tion performed by a specialized surgeon to achieve a state of no residual disease offers the best chance for cure (2). Reop- eration in case of a recurrence has been suggested to improve survival, but those studies are retrospective and may suffer from a selection bias with inclusion of patients with more indolent clinical presentations (3, 4).
Metastatic ACC has a dismal prognosis with an overall survival of less than 1 year (5). The most common sites of metastases are the lung, liver, lymph nodes, and less com- monly, the bones (2, 6). Palliation of functioning tumors may be achieved by resection of both the primary tumor and met- astatic lesions. Unresectable or widely disseminated tumors may be palliated by adrenolytic therapy with mitotane and other antihormonal drugs (ie, ketoconazole and metyrap- one), and less frequently by systemic chemotherapy, and/or radiation therapy (7, 8). However, 5-year survival for pa- tients with stage IV tumors is less than 20% (9, 10). In the present communication, we describe the largest clinical series of intracranial metastases in adult ACC patients.
Abbreviations: ACC, adrenocortical carcinoma; CNS, central nervous system; CT, com- puted tomography; MRI, magnetic resonance imaging; NCI, National Cancer Institute.
Copyright @ 2015 by the Endocrine Society
Subjects and Methods
Patient 1
A 38-year-old woman was first seen in March 1995 because of amenorrhea, hirsutism, weight gain, and the deepening of her voice. A computed tomography (CT) scan revealed an adrenal mass and two liver nodules, and these were resected surgically. Pathology established the diagnosis of ACC with extracapsular extension and metastasis to the liver. Two years later, her symp- toms recurred, and imaging revealed a 2-cm mass in the adrenal bed and lung metastases. She was referred to the National Cancer Institute (NCI) where after signing consent she enrolled on an institutional review board-approved treatment protocol of daily oral mitotane and monthly combination chemotherapy with doxorubicin, vincristine, and etoposide. She received seven cy- cles of therapy, achieving a partial response. In December 1997 the residual mass in the adrenal bed was resected and in January 1998, bilateral pulmonary metastasectomies were performed. She remained free of detectable disease for nearly 2 years suf- fering a relapse in September 1999. Then in January 2000 she was treated with the experimental agent tariquidar, a P-glyco- protein inhibitor, plus vinorelbine, but after two cycles her dis- ease progressed and she began a clinical trial with ixabepilone, an epothilone B analog, receiving seven cycles of treatment without major adverse events. In the third week of the eighth cycle, nearly 6 years after her original diagnosis, the patient experienced a sudden onset of weakness in the right leg, difficulty with her right hand and arm coordination, with numbness, tingling, and dys- esthesias in her right leg. Neurological examination revealed four fifths motor strength in the right lower extremity. Proprioception was impaired in the right hand. Cerebellar examination revealed adiadochokinesia. Deep tendon reflexes were absent in the right lower extremity. Laboratory results were normal with the ex- ception of a serum lactate dehydrogenase of 1273. A magnetic resonance imaging (MRI) of the brain revealed a 5-cm left pos- terior parietal lobe mass with edema and midline shift. She was admitted, started on iv corticosteroids, and subsequently under- went a surgical resection. In the first week after the resection, the patient regained function in her right arm as well the right leg and continued to improve clinically with physical therapy and reha- bilitation without evidence of intracranial recurrence. She died 12 months after her surgery of systemic disease. Figure 1 shows photomicrographs of the brain metastasis in this case.
Patient 2
A 29-year-old woman presented with abdominal discomfort and had a diagnosis of ACC after undergoing a right adrenalec- tomy in January 2001. Over the next 3 years, she developed lung and liver metastases and was treated with paclitaxel, streptozo- cin, and gemcitabine for widespread systemic disease as well as radio-frequency ablation for liver metastases. She was referred to the NCI 3 years after her diagnosis. After signing consent to enroll on an institutional review board-approved study, she un- derwent a pretreatment positron emission tomography scan, which revealed three metastatic lesions in the left frontal and parietal lobes. These lesions were also confirmed on MRI. She had no neurological signs or symptoms. A craniotomy with tu- mor resections was performed, and she recovered well but un- fortunately died 2 months later in June 2004 with widespread systemic disease. Figure 1 shows photomicrographs of the brain metastasis in this case.
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Patient 3
A 37-year-old male was diagnosed with ACC in July 2010 after a workup for hypertension revealed a 28- × 21-cm ab- dominal mass and surgery established a diagnosis of ACC. Eight months later he underwent a second resection for re- currence at the tumor bed and was noted to have pulmonary metastases. Over the next 2 years, he had multiple lines of chemotherapy for metastatic disease in the lungs, liver, and lymph nodes, with increasing disease burden. He was referred to the NCI and signed an institutional review board-approved screening consent but was not eligible for enrollment into the ongoing clinical trials and was referred back to his oncologist
Retroperitoneal
Endobronchial
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for continued care. In October 2013, more than 3 years after the initial diagnosis, he developed a headache followed by tonic-clonic seizures. A CT scan revealed two bleeding me- tastases in the frontal and parietal lobes with a midline shift. An emergent metastasectomy was performed followed by 3 weeks of rehabilitation with a remarkable recovery. A repeat MRI scan did not reveal any other parenchymal lesions. The patient died in May 2014 from systemic disease 8 months after presenting with brain metastasis.
Patient 4
A 44-year-old male first sought medical attention in Septem- ber 2007 for acute onset of abdominal pain and was found to have an 8- × 10-cm right suprarenal mass diagnosed as ACC after an open resection with partial hepatectomy. He was re- ferred to the NCI, signed an IRB-approved screening consent, and began continuous follow-up with both his referring oncol- ogist and physicians at the NCI. After treatment with mitotane for close to a year, he developed recurrence at his tumor bed and underwent a re-resection. Subsequently he developed metastases to the liver, bone, and pleura that were managed with multiple chemotherapy regimens. In November 2013, 6 years after his original diagnosis, he developed an unsteady gait, and a CT scan revealed metastasis to the cerebellum with no other parenchymal lesions. Resection was successful with full functional recovery, and this was followed by radiation. Seven months after resection,
the patient is doing well on no active treatment and is being followed up on an institutional review board-approved natural history study. Figure 1 shows photomicrographs of the brain metasta- sis in this case.
Patient 5
A 60-year-old Caucasian male was evaluated in June 2004 for a history of early satiety, fatigue, and abdominal dis- comfort. Surgery removed a 15- × 20- X 17-cm ACC. Four months later, routine restaging CT scans revealed pulmonary nodules. He underwent multiple lines of chemotherapy over the next 2 years. During an attempt to perform laser ab- lation of his endobronchial tumors in August 2006, he developed left-sided hemiparesis. A CT scan revealed an in- traparenchymal hemorrhage in the right parietal and occipital lobes, with signif- icant mass effect. After signing an insti- tutional review board-approved con- sent, the patient was taken to surgery emergently for evacuation of hemor- rhage and metastasectomy. Figure 2 shows the histological characterization of this case. Except for a decreased plan- tar flexion on the left 1 week after sur- gery, the patient’s neurological examina- tion was normal. The patient returned to Mexico and was lost to follow-up.
Patient 6
A 48-year-old Caucasian female was found to have an incidental adrenal mass measuring 2.4- × 2.2-cm in September 2002. This mass was followed with routine CT scans by the patient’s endocrinologist. In August 2013, she sought medical attention for abdominal pain, and CT scans revealed enlargement of the adrenal mass to 4.8 by 5.3 cm along with evidence of innumerable pulmonary me- tastases. Biopsies of the lung and the adrenal mass established the diagnosis of ACC, and she began therapy with a cisplatin- based chemotherapy regimen plus mitotane. Two cycles into the treatment, a CT scan revealed a solitary hemorrhagic brain metastasis in the right parietal lobe that was treated with y-knife surgery. The patient was referred to the NCI but did not enroll in a treatment protocol, enrolling instead on an institutional review board-approved natural history study. The patient is alive and presently receiving therapy with strep- tozocin plus mitotane.
Discussion
We report six patients with a diagnosis of ACC who developed brain metastases and were managed with sur- gery and/or radiation (Table 1). The median time from the diagnosis of ACC to the presentation of brain me-
| Patient | Age, y | Stageª | Prior Chemotherapy Regimens, n | Time From Original Presentation to Brain Metastases, mo | Clinical Presentation | Number and Location of Metastases | Treatment | Time From Brain Metastases to Death |
|---|---|---|---|---|---|---|---|---|
| 1 | 38 | IV | 3 | 70 | Hemiparesis; cerebellar symptoms | 1 left parietal | Surgical resection | 12 mo |
| 2 | 29 | II | 4 | 47 | Hemiparesis | 3 (1 frontal, 2 left parietal) | Surgical resection | 2 mo |
| 3 | 37 | III | 5 | 39 | Seizures | 2 (1 frontal, 1 right parietal) | Surgical resection | 7 mo |
| 4 | 44 | III | 3 | 75 | Unsteady gait | 1 cerebellum (+ right orbital metastasis) | Surgical resection + cyberknife | Alive at 7 mo |
| 5 | 60 | II | 2 | 26 | Hemiparesis | Occipital hemorrhagic | Surgical resection | Lost to follow-up |
| 6 | 48 | IV | 1 | 3b | Headache | Right parietal hemorrhagic | y-Knife | Alive at 9 mo |
Abbreviations: UICC, Union for International Cancer Control; WHO, World Health Organization.
a UICC/WHO staging.
b Three months from the initial diagnosis of ACC, but an abnormal adrenal gland had been noted more than a decade earlier.
tastases was 43 months (range 3-75 mo). Five of the six patients had received chemotherapy (median of three lines of chemotherapy; range 1-5) and had undergone additional surgical and ablation procedures prior to presenting with intracranial metastases. As shown in
A
B
C
D
E
F
Figure 3, one to three lesions were found with vasogenic edema and hemorrhagic features in three of the cases. Five of the six patients underwent neurosurgical resec- tion of the metastasis, and two patients were managed with focalized radiation. A detailed analysis of the tissue from one pa- tient (case 5) illustrates the chal- lenges a pathologist faces in con- firming a histological diagnosis (Figure 2).
A review of the published Eng- lish literature reveals few reports describing brain metastases at the time of the initial presentation or at progression in adults with a diag- nosis of ACC (11, 12). Kubota et al (11) reported the case of a 47-year- old man with intracranial metasta- sis that developed 9 months after the initial diagnosis of ACC. The patient died 7 months later with widespread lung metastases. While Ohwada et al (12) reported the case of a patient with metastases to the lung, liver, and bone that devel- oped intracranial metastasis and died 27 months later due to wide- spread systemic disease burden. Brain metastases have also been re- ported in children with ACC (13, 14).
Brain metastases are reported in 8.5%-9.6% of patients with solid tumors, with lung cancer, melanoma, renal cancer, and breast cancer com- prising most cases (15). An increase in the incidence of brain metastasis in the last decade may be explained by the
increased use of advanced imaging (CT, MRI, and positron emission tomography) and an increase in cancer incidence (16). The natural history of intracranial metastases in pa- tients with solid tumors varies with histology. Brain metas- tases in patients with malignant melanoma tend to be mul- tiple and can present at any time in the course of the disease but are most frequently noted at the time of presentation (17). Similarly, in patients with small-cell carcinoma of the lung, brain metastases occur frequently at the time of diag- nosis or shortly thereafter. This finding has led to the wide- spread use of prophylactic cranial irradiation in these pa- tients, with favorable results (18). However, in other solid tumors, most notably breast carcinoma, brain metastases tend to present late in the course of the disease, which is likely reflective of better treatments, longer survival, and improved surveillance (19). It is worth noting that although the use of the antibody trastuzumab has improved progression-free and overall survival in patients with a diagnosis of HER-2- positive breast cancer, it cannot cross the blood-brain bar- rier, and hence, late central nervous system (CNS) relapses continue to be seen (20). This latter paradigm of metastases occurring late in the course of disease may be more similar to what we report. Indeed, in this clinical series, the only patient with an early diagnosis of a brain metastasis (3 mo after the original diagnosis), had been noted more than a decade ear- lier to have an abnormal adrenal gland, suggesting the brain metastases did not occur early in the evolution of her disease.
We would stress that despite these six case reports, the incidence of brain metastases remains low. How- ever, clinicians managing patients with ACC should be aware of the possibility of brain metastasis as a site of progression, particularly in cases with a prolonged dis- ease course and multiple systemic treatments. In such patients the occurrence of CNS symptoms consistent with metastatic disease can support the use of radio- logical imaging to clarify the origin of these symptoms. However, we would also note that in patients with ACC the occurrence of CNS symptoms will most likely be due to mitotane toxicity than to CNS metastases. Symptoms referable to the CNS include lethargy, sedation, ataxia, confusion, and dizziness (21, 22). Temporarily halting mitotane administration and then resuming at a lower dose is recommended in the management of such symp- toms. These six cases derive from nearly 350 cases we have followed up closely and about 500 in all that have been seen at the National Cancer Institute in the last 2 decades, meaning the incidence of this complication is about 1%-2%. The outcomes of the patients reported here with intracranial metastases, survival greater than 6 months in five of the six with death due to systemic
disease without intracranial recurrence or complica- tions, argue for an aggressive treatment approach using a multidisciplinary team to discuss treatment options including surgery and radiation when feasible.
Acknowledgments
Address all correspondence and requests for reprints to: Mauricio Burotto, MD, Center for Cancer Research, National Cancer Institute, 10 Center Drive 12N226, Bethesda, MD 20892. E-mail: mauricio.burottopichun@nih.gov.
Disclosure Summary: The authors have nothing to disclose.
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