Clinical Study
Pediatric adrenal cortical carcinoma: brain metastases and relationship to NF-1, case reports and review of the literature
Aaron Scott Wagner1, Julie M. Fleitz2 and B.K. Kleinschmidt-DeMasters1,3,4
“Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA; 2 Division of Neuro-oncology, The Children’s Hospital, Denver, CO, USA; 3 Department of Neurology; 4Department of Neurosurgery, University of Colorado Health Sciences Center, Denver, CO, USA
Key words: adrenal cortical carcinoma, adrenal gland, brain, central nervous system, metastasis, neurofibromatosis, type 1
Summary
Adrenal cortical carcinoma (ACC) is a rare childhood neoplasm that seldom manifests brain metastases; hence few papers in the literature focus on neurological manifestations associated with ACC. Although ACC is known to be a signature tumor type in several inherited cancer predisposition syndromes, particularly Li Fraumeni, ACC has not been previously associated with neurofibromatosis, type 1 (NF-1), an inherited disorder with frequent CNS lesions that might prompt concern for metastatic disease by neuroimaging studies. We present two pediatric patients with ACC and unusual CNS findings. The first child developed metastasis to the brain 4 years after resection of his adrenal primary and 2 and 1 years, respectively, after metastases to the liver and lungs. Soon after our experience with this patient, a girl with known NF-1 presented with virilization; adrenalectomy disclosed an ACC and systemic metastases were found within months. Disseminated disease prompted concern that her complex intracranial lesions identified by neuroimaging studies might represent brain metastases, but this proved to be NF1-related hamartomatous lesions. We review the literature on ACCs in pediatric patients regarding brain metastases and previous associations with NF-1.
Introduction
Adrenal cortical carcinoma (ACC) is a rare tumor type, with a reported annual incidence of 1/2 to 2 cases per million. A bimodal occurrence has been observed, with peaks in children less than 5 years and a second peak in mid-adult life in individuals 30-50 years of age. In the pediatric population, these tumors are known to be associated with the following cancer syndromes: Beckwith-Wiedemann syndrome, multiple endocrine neoplasia type 1, and especially Li Fraumeni syndrome [1]. ACCs are most strongly associated with the latter cancer predisposing condition, where they occur almost exclusively in childhood and account for 3.1% of tu- mors in families with a TP53 germline mutation, the mutation that is responsible for the majority of families with classic Li-Fraumeni syndrome [2,3].
In addition to the known association of childhood ACCs with various inherited cancer disorders, they are also distinct from ACCs in adults in that pediatric pa- tients are more likely to manifest excess hormone secretion than adults [4]. Pure virilization is particularly characteristic of childhood cases, but mixed virilization- Cushing’s syndrome may also occur [4]. Although up to 25% of patients with ACC present with advanced dis- ease, distant metastases are more frequent in adults than children [4,5]. Common metastatic sites are liver and lung, followed by lymph nodes, bone, omentum/peri- toneum/pleura, kidney, vena cava, and diaphragm [5,6]. Brain metastases from ACCs are decidedly uncommon
and only limited numbers of case reports have appeared in the literature. Nevertheless, on review of large series of ACCs, most record one or two patients with brain involvement, suggesting that this site for spread should be anticipated by oncologists and surgeons [6-9].
We describe two pediatric patients with ACC and unusual CNS features. The first is a boy presented with precocious puberty, was diagnosed with ACC, and then developed brain metastases several years later. Family history and the finding of a signature tumor met criteria for Li Fraumeni Syndrome. The second patient had known neurofibromatosis, type I (NF-1), a condition not typically listed as one of the cancer syndromes associated with adrenal cortical neoplasms. This girl presented with a virilization syndrome soon after our experience with the first patient, and she was found to have ACC. The presence of this tumor, in conjunction with multiple intracranial lesions by magnetic resonance imaging (MRI), raised concerns regarding possible metastases to the brain. Brain lesions were followed by neuroimaging studies over time and proved to be man- ifestations of her NF-1, not metastases.
Case reports
Case #1
The patient is a 10-year old boy who presented orig- inally in November 2000 with signs of precocious
puberty. A large right sided suprarenal mass was discovered, sub-totally resected, and was found to have invaded the inferior vena cava and right atrium. Pathology revealed adrenal cortical carcinoma, a diagnosis which coupled with his mother’s develop- ment of breast cancer at age 20, met published criteria for Li Fraumeni syndrome [3]. However, this could not be genetically confirmed because of privacy restrictions. After 7 courses of chemotherapy with etoposide, doxorubicin, and cisplatin he developed metastatic disease to the lungs and liver. In August 2001 he developed two lung metastases, documented by wedge biopsies to be metastatic adrenal cortical carcinoma. Then, in March 2002, 60% of his liver was resected due to liver metastases. By August of 2003, he was known to have nearly two dozen small, slowly enlarging lung metastases. At that time he was found to have cognitive deficits, with difficulty in naming and repetition. MRI scans showed an approximately 5 x 4 cm., heterogeneously enhancing, left parietal lobe mass for which he underwent gross total surgical resection on August 23, 2003 (Figure 1a, b). The intracranial tumor was metastatic adrenal cortical carcinoma histologically identical to his primary and to his previous liver and lung metastases. After resection, his neurological symptoms quickly resolved. He did well until the spring of 2004 when he devel- oped widespread metastatic lung disease; he suc- cumbed in May of 2004, 31/2 years after disease onset.
Case #2
The patient is a 3-year-old girl who was diagnosed with NF-1 at age 11/2 years in February 2004 when she pre- sented with seizures and was found to have Lisch nod- ules in her left eye and extensive café au lait spots. Seizures were eventually controlled with levetiracetam (Keppra). MRI revealed several changes consistent with NF-1, including an ill-defined area of increased T2 and FLAIR signal in the right temporal lobe, adjacent external capsule and posterior limb of the internal cap- sule (Figure 2a). This was felt to be consistent with either hamartoma or a low grade lesion; additional abnormalities consistent with NF-1 were noted in the cerebellar peduncles, pons (Figure 2b), medulla, and
bilateral posterior caudate heads. None of these areas showed enhancement with administration of gadolin- ium. The lesions were followed by serial neuroimaging studies and on subsequent scans the area in the right temporal lobe decreased in size and intensity and the remaining spots were unchanged. She then began to develop pubic hair, clitoral enlargement, rapid weight gain and Cushingoid features. Androgens were drawn revealing testosterone of 443 ng/dl, androstenedione of 481 ng/dl, and dehydroepiandrosterone of 706 ng/dl. By ultrasound, a 6.4 cm diameter retroperitoneal suprare- nal mass was visualized. Sub-total surgical resection of the mass was performed on March 19, 2004, and was diagnosed as adrenal cortical carcinoma. After a post surgical course which included prolonged intubation and pneumonia, she recovered sufficiently to begin chemotherapy with etoposide, cisplatin, doxorubicin, and concurrent mitotane. Her first course was compli- cated by the development of a chylothorax. This was treated with thoracostomy and promptly resolved allowing completion of her course. Additionally, a pal- pable mass in the left neck was discovered. CT revealed a large thoracic inlet mass displacing midline structures and impinging the left internal jugular vein. By her third course of chemotherapy the mass in her neck had become slightly smaller by CT scan and softer by exam. However, a new small paraspinous mass emerged in the retroaortic region. Chemotherapy was continued and most recent lab values were testosterone of 35 ng/dl, androstenedione of 142 ng/dl, and DHEA of 187 ng/dl. Most recent scans show possible pneumonia but no definite lung metastases.
Pathological findings
Case 1: The original adrenal tumor from 2000 measured 13.0 × 9.0×6.5 cm and weighed 525 g. Grossly, the tumor showed a tan to red mottled surface, focal yellow, necrotic areas, calcification, and hemorrhage. Micro- scopically, the highly cellular, necrotic tumor was com- posed of trabeculae and nests of polygonal cells. Cells variably manifested uniform, round nuclei or hyper- chromatic, enlarged, pleomorphic nuclei; cytoplasm was abundant and eosinophilic. Mitotic rate was high, with
(a)
(b)
(a)
(b)
40 per 50 high power microscopic fields. Surgical mar- gins were positive. Tumor cells showed no immunore- activity for chromogranin or TP53, although focal cells stained for neuron specific enolase. Cytogenetically, the tumor cells showed loss of portions of chromosome 3, addition of material on 17p and 21q, and loss of entire copies of chromosome 15 and Y, abnormalities consis- tent with adrenal cortical carcinoma. The lung metas- tases from 2002 showed similar histological features to the original tumor and additionally showed positive immunoreactivity for epidermal growth factor receptor and negative immunostaining for CD117.
The brain metastasis from 2003 demonstrated a mass sharply demarcated from the surrounding brain (Figure 3a) with histological similarity to the other two masses with numerous, and atypical, mitotic figures (Figure 3b). Additional immunohistochemical staining conducted on the brain metastasis was negative for glial fibrillary acidic protein and cytokeratins AE1/AE3; again there was weak positive cytoplasmic immunore- activity for neuron specific enolase.
Case 2: The adrenal tumor had a maximal diameter of 23 cm and weighed 328 g. Grossly, necrosis and hem- orrhage was observed. Microscopically, the tumor showed marked nuclear pleomorphism, variation in nuclear size, multinucleated tumor cells, and greater than 17 mitoses per 20 high power microscopic fields, with atypical mitotic figures. Tumor involved the sur- gical margins and invasion of lympho-vascular spaces was identified. Immunohistochemical staining showed reactivity for vimentin, but not for cytokeratins AE1/ AE3, chromogranin, synaptophysin, S100 protein, or epithelial membrane antigen. Immunostaining for Inhibin-alpha and Melan-A (Mart-1) was variably positive. MIB-1 revealed a proliferation rate in excess of 20-30% of tumor cell nuclei. TP53 immunostaining revealed immunoreactivity in 100% of tumor nuclei (Figure 4). Electron microscopy showed an abundance of mitochondria and smooth endoplasmic reticulum, as well as lysosomal granules, lipid inclusions and stacked rough endoplasmic reticulum. Dense core granules typical of pheochromocytoma were not found.
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(b)
Discussion
Adrenal cortical carcinomas (ACCs) are uncommon pediatric tumors that are known to have metastatic
potential. Although older series emphasized a poor prognosis for these tumors, a recent review of pediatric series published in the 1990s suggests that children with ACCs may do better than adults, with 43-91% overall survival rates [4]. Although in some series children are less likely to present at higher stages of disease, survival is significantly reduced in those with metastases [10].
Surgical excision remains the mainstay of treatment. In both of our patients, it was known at the time of surgery that a total surgical resection was not achieved in the primary site in the adrenal gland. Extent of sur- gical resection is the single most important prognostic factor for long-term survival in patients with ACC [4,6, 7,10-13]. For patients with metastatic disease it appears that total resection of the metastatic lesion, where pos- sible, may be the most effective treatment to extend survival and quality of life [5, 11].
A role for radiation therapy has not been definitively established, and as noted by Liou and Kay, given the limited efficacy of this therapy, the known risk for development of second primary tumors in children with ACC within the radiation portals may not be worth the risk [4]. The need for efficacious chemotherapy for met- astatic ACC is obvious, especially given the rarity of the tumor, controversies regarding efficacy of mitotane, and the relatively few published clinical trials (reviewed by Liou and Kay). Ayass et al. have advocated a regimen of high-dose carboplatinum and VP-16, but the patient they treated was very young, 17 months [14]. It would appear that some very young children with ACCs may even have spontaneous regression of their tumors, based on the report by Saracco et al. [15]. Hence the behavior of ACCs in very young children may be relatively unique and differ from that in adults and older children. More information needs to be gathered regarded efficacy of various chemotherapy regimens in children with ACC.
Our patients both received etoposide, doxorubicin, and cisplatin, with Patient 2 additionally receiving mitotane. Patient 1 survived 31/2 years after diagnosis with relatively good quality of life, albeit several
documented metastases. He had no recurrence of neurological findings after excision of his brain metas- tases and death was presumed to be due to systemic disease. Patient 2 is alive on this regimen, with meta- static disease that is partially responsive to the regimen, 10 months after presentation.
Brain metastases are rare in ACC. When we encountered Patient #1, a MEDLINE search identified only isolated examples of children or adults with ACC and metastases to the brain. Further in-depth review of older series on ACC disclosed a few additional instances of this occurrence, as listed in Table 1. These large ser- ies, collectively involving 257 patients, showed that 0-11% (mean 4.9%) of all patients with ACCs develop brain metastases [6-10, 16-17]. To our knowledge, our report represents the fifth example of brain metastases in pediatric (non-congenital) patients with ACC and the most thorough literature review on the subject. When studied collectively, we conclude that, although rare, metastases to brain from ACC occur often enough that oncologists, internists, pediatricians, and surgeons need to be cognizant of the pattern.
From our literature review, it appears that patients who develop brain metastases with ACCs first have antecedent lung metastases, implying that a secondary metastasis to brain, or so-called ‘metastasis from a metastasis’, is responsible for the CNS lesion. Indeed, of the literature cases that we identified, 5 of the 8 patients for whom the data was provided had prior disease in the lungs. The literature is unclear regarding the typical time course between the development of the lung metastasis and the brain metastases from ACC. A 47-year old re- ported by Kubota et al. presented with both brain and lung metastases 9 months after adrenalectomy [18]. In contrast, Romaguera et al. reported a brain metastasis in a 9-year old girl who had been free of symptoms for 5 years [19]. Saracco et al. reported a unique congenital patient with simultaneous brain and cutaneous metas- tases from ACC [15] Seabold et al. reported 2 patients with brain metastases: a 35-year old female developed lung metastases 3 years after presentation with ACC and brain metastases 4 years after the first lung metas- tasis was found [20]. A 54-year old male was found to have metastatic disease in both liver and brain 18 months after resection of a markedly hemorrhagic ACC and 3 years after the occurrence of a retroperito- neal hematoma in the same area [20]. In our Patient 1, the time interval between lung and brain metastases was slightly in excess of 2 years. The few other cases we identified were reported in the context of large case series and the exact course of the disease was not detailed in the reports [5,6,8,9,16,17]. These literature examples, however, would suggest that the time course for developing brain metastases after lung lesions is unpredictable and hence clinicians need to be vigilant for this uncommon occurrence. Similar to the situation with soft tissue sarcomas and brain metastases, better therapy for local disease may prolong survival in patients with ACC and enhance the possibility for late development of metastases to sites formerly considered unusual for this tumor type, including brain. It would, therefore, seem advisable to be vigilant in observing
| Author, date | Pt age, sex | History | Other metastases | Li Fraumeni or NF-1 |
|---|---|---|---|---|
| Harrison et al., 1973 [17] | No specific patient demographics given to match metastases listed | Two instances of brain metastasis in series of 18 patients with ACC | No data given as to other concurrent or antecedent metastases. | No mention |
| Hajjar et al., 1975 [9] | No specific patient demographics given to match metastases listed | Three instances of brain metastasis in series of 30 patients with ACC | No data given as to other concurrent or antecedent metastases. | No mention |
| Seabold et al., 1977 [20] | 35 y/o female | ACC with brain metastasis | Liver, lung, pelvis, vertebrae, contralateral adrenal | No mention |
| Seabold et al., 1977 [20] | 54 y/o male | ACC with brain metastasis | Liver | No mention |
| Lefevre et al., 1984 [13] | 4 y/o male | ACC with brain metastasis | None | Presumed neither (specific mention was made of Li Fraumeni in other cases in this series) |
| Lefevre et al., 1984 [13] | 17 months male | ACC with brain metastasis | Lung | Presumed neither (specific mention was made of Li Fraumeni in other cases in this series) |
| Saracco et al., 1988 [15] | 1 day old male | ACC with brain metastasis which resolved completely after resection of primary | Skin | No mention |
| Bodie et al., 1989 [6] | No specific patient demographics given to match metastases listed | 2 patients out of total of 82 with ACC with metastases to brain | No data given as to other concurrent or antecedent metastases. | No mention |
| Ayass, 1991 [14] | 17 month old male | ACC with metastasis to brain | Lung, paraspinal | No mention |
| Lack et al., 1992 [7] | 10 y/o male | ACC with brain metastasis | Lung, liver, kidneys | No mention |
| Pommier and Brennan 1992 [5] | No specific patient demographics | Brain metastases listed under | No data available for concurrent | No mention |
| miscellaneous sites of metastases but no exact number | of antecedent mets. | |||
| Tartour et al., 1993 [8] | 60 y/o female | ACC with brain metastasis | Liver, bone | No mention |
| Evans and Vassilopoulou- Sellin 1996 [16] | No specific patient demographics | 1 of 48 patients with ACC with metastasis to the brain | No data available for concurrent of antecedent mets. | No mention |
| Kubota et al., 1997 [18] | 47 y/o male | ACC with brain metastasis | Lung | No mention |
| Bartley, George et al., 2001 [28] | 27 y/o male | ACC with metastases to lung, | Lung, vertebrae, pelvis | No mention |
| vertebrae and bony orbit with extension into cranial vault | ||||
| Patient 1, this report 2004 | 10 y/o male | ACC with brain metastases | Lung, liver | Li Fraumeni |
patients with ACC, especially those known to have metastases in the lungs. Alterations in neurological status should prompt consideration of CNS metastatic disease.
The diagnosis of ACC in Patient 2 in the setting of neurologic symptoms closely followed chronologically our experience with Patient 1. Not surprisingly, increased emphasis was placed in this second patient with ACC on excluding metastasis to the CNS. Her seizure manifestations preceded development of her ACC and can be attributed to her NF-1. Close follow up by serial MRI scans showed that her CNS abnormalities were unchanging and not due to metastatic disease. This patient was diagnosed with NF-1 at age 11/2 years when she was found to have Lisch nodules in her left eye, coupled with extensive café au lait spots. Classically the adrenal tumor associated with NF-1 is pheochromocy- toma and not adrenal cortical adenomas or carcinomas.
Pheochromocytomas are tumors of the adrenal me- dulla that show somewhat similar histological features to ACCs on light microscopy but can be readily distin- guished by their positive immunoreactivity for chro- mogranin A in contrast to negative staining in ACC. Electron microscopy further shows dense core granules in pheochromocytoma, but not ACC. Extensive immu- nohistochemical and electron microscopy investigations in both cases, but particularly Patient 2, clarified the correct diagnosis of ACC.
MEDLINE search of the literature revealed even fewer examples of ACC in patients with NF-1 than was the case for brain metastases with ACC [21,22]. Our investigation of the older literature, however, suggests that there may be other examples of this association. Fraumeni himself reported two cases of ACC in patients with extensive, large café au lait spots [23]. There is no information given about the subsequent history of these 2 patients, or whether they had other features that would have made the diagnosis of NF-1 such as Lisch Nodules, axillary freckling or other features of the disease that were recognized as part of the diagnosis after these patients were reported. If these patients are considered to meet criteria for NF-1, our Patient 2 would bring the total cases of ACC associated with NF-1 in the literature to six, as outlined in Table 2. However, since we have no other information, the features that they did have do not
meet criteria for NF-1 and the confirmed total of ACC associated with NF-1 is now four. Sartori et al. first postulated an increased risk of adrenal cortical adenomas in NF-1 in his case report from 1989 [24]. However, thus far only two benign, functional adrenal cortical adeno- mas (including the one by Sartori et al.) have been identified in NF-1 patients [24,25], in contrast to four (and possibly six) ACCs. Thus, by our literature review, although both are rare, more ACCs have been associated with NF-1 than functional adrenal adenomas.
A final interesting point is that although TP53 immu- nostaining was conducted on both patients’ tumors, only the second child, without Li-Fraumeni syndrome, showed strong diffuse nuclear immunoreactivity. The incidence of somatic TP53 mutations in sporadic (non-Li- Fraumeni associated) ACCs is 23% [3]. When strong immunostaining is seen in 100% of tumor nuclei the correlation is strong that the patient’s tumor will have a point mutation [26]. Hence, it can reasonably be con- cluded that Patient 2 harbored a somatic p53 mutation in her ACC, but not necessarily a germ line mutation. Extensive questioning of the patient’s family did not disclose relatives with early onset cancers that might suggest she belonged to a Li-Fraumeni family. Charac- teristic organ-specific mean ages of cancer onset are found for the signature tumor types seen in Li-Fraumeni syn- drome [27]. These include a mean age of 5 years for ACCs, 16 years for sarcomas, 25 years for brain tumors, 37 years for breast cancers, and almost 50 years for lung cancers [27]. Our patient 2 had sufficient numbers of rel- atives spanning these ages to confidently exclude a family history of Li-Fraumeni syndrome.
In contrast, in the ACC from Patient 1, whose mother had breast cancer at age 20 years, well below the mean age for Li-Fraumeni patients, we did not identify strong TP53 immunostaining in tumor nuclei. This suggests that the family may be a Li-Fraumeni like kindred. Although germline p53 mutations are responsible for the vast majority of classic Li-Fraumeni families, small subsets have other mutations. Recently germline hChk2 mutations have been identified in some families [2]. At this time the scarcity of such families precludes the ability to draw conclusions regarding any possible phe- notypic/clinical differences between the two types of germline mutations [2].
| Author, date | Pt age, sex | History | Other metastases | Li Fraumeni or NF-1 |
|---|---|---|---|---|
| Fraumeni and Miller, 1967 [23] | 16 y/o female | ACC | No mention | Possibly NF-1; patient is reported to have a single very large café au lait spot on abdomen, thorax and umbilicus |
| Fraumeni and Miller, 1967 [23] | 17 y/o female | ACC | No mention | Possibly NF-1; mention of large multiple café au lait spots |
| Fraumeni and Miller, 1970 [23] | 41/2 y/o female | ACC with brain metastases | None | NF-1 |
| Sorensen et al., 1986 [21] | No specific patient demographics | 2 pts listed with ACC out of 212 malignant tumors | No mention | NF-1 |
| Sorensen, S. et al., 1986 [21] | 46 y/o female | ACC as a second primary tumor in a series of 212 malignant tumors in pts with NF-1 | No mention | NF-1 |
| Patient 2, this report 2004 | 3 y/o female | ACC | Neck, paraspinous mass | NF-1 |
In conclusion, ACC is an uncommon tumor with an acknowledged increased incidence of occurrence in the Li-Fraumeni syndrome, as well as other cancer syn- dromes. Traditionally, it has not been associated with patients with NF-1. Few reports have detailed pediatric patients with brain metastases from ACC or provided extensive literature review on the subject. Although we report our experience with only two patients, more information is needed on efficacy of various chemo- therapy regimens specifically in children with ACCs. Our recent experience with the two pediatric patients presented here illustrates the possible range of CNS manifestations associated with ACCs.
Acknowledgements
The authors thank Ms. Lisa Litzenberger for photo- graphic expertise and Dr Josh Seinfeld for his assistance with study of the neuroimaging scans.
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Address for offprints: B.K. Kleinschmidt-DeMasters, M.D., University of Colorado Health Sciences Center, Department of Pathology, B-216, Denver, Colorado 80262, USA; Tel .: + 1-303-315-7298; Fax: + 1-303- 315-6721; E-mail: bk.demasters@uchsc.edu