Adrenal Ganglioneuroblastoma in Adults: A Case Report and Review of the Literature.
One of the most common unexpected findings revealed by imaging studies is an adrenal mass, called incidentaloma, which occurs in about 2-4% of the radiological studies performed for other reasons . The preliminary evaluation of the mass is aimed to distinguish benign from malign lesions and to exclude hormonal hypersecretion. Most adrenal masses are small nonfunctioning adrenocortical adenomas, which do not require treatment or follow-up. Nevertheless, if the mass shows hormonal hypersecretion or malignancy is suspected, surgery is recommended .
Ganglioneuroblastoma (GNB) represents a rare cause of adrenal tumor in adults. Preoperative suspicion is challenging and the final diagnosis is often made by the pathologist after surgical removal.
2. Case Presentation
A 20-year-old Caucasian woman was admitted through the Emergency Department for right flank pain. Abdominal ultrasound examination was performed and a contralateral adrenal mass was incidentally found. Subsequently, the patient underwent computed tomography (CT) to confirm the finding. The mass in left adrenal lodge was solid and measured 11 x 10 x 7 cm, showing heterogeneous density (varying 17-40 HU) and calcifications (Figure 1). Dynamic analysis revealed a progressive and modest contrast enhancement in venous phase.
The patient was addressed to the Endocrine Unit for biochemical evaluation of the adrenal mass.
She was in good clinical conditions and the complete physical examination was negative; in particular, no Cushing stigmata or hirsutism was present. Her height was 153 cm, weight 48.5 kg (BMI 20.7 Kg/[m.sup.2]), blood pressure was 110/ 70 mmHg, pulse rate 64beats/min, andSp[O.sub.2] 99% (room air). There was no family history of relevant morbidities. She was active smoker and suffered from patent foramen ovale of the heart and focal nodular hyperplasia of the liver.
Results of the complete blood count, plasma levels of electrolytes, tests of coagulation, kidney, liver, and thyroid function were normal. Adrenal function evaluation revealed that urinary metanephrines and normetanephrines in the normal range, DHEA-S 1500ng/ml (350-4300), aldosterone 457.2pg/ml (37-150), renin 1.5ng/ml/h (1.0-2.4), aldosterone-renin ratio 30.48, basal cortisol, and17-OH-progesterone were normal both in basal condition and after stimulation with ACTH 250 mcg. Regrettably the patient was on contraceptive estroprogestinic therapy at the time of hormonal evaluation.
Considering the size and the undetermined radiological features, the adrenal mass met the criteria for surgical removal according the most recent international guidelines .
The patient was admitted to the Department of Urology where she underwent transabdominal adrenalectomy. The adrenal mass incorporated the renal hilum, aorta, and superior mesenteric arteria; therefore intraoperative decision to perform additional left nephrectomy was taken. There were no complications after surgery.
The surgical sample sent for pathological examination included left kidney, left adrenal gland, and two lymph nodes (celiac and paraaortic). The tumor grossly was grey and multilobulated, replaced the entire adrenal gland, measured 11 x 10 x 7 cm, weighed 195 g, and incorporated arterial and venous vessels of renal hilum and sparing renal parenchyma. The histological report described a spindle cell stroma in a fibrillary matrix interspersed with scattered nests of primitive neuroblasts and high proportion of differentiating elements (ganglion cells) (Figure 2), placing the tumor in a favorable subgroup (ganglioneuroblastoma intermixed). Localization was found in both lymph nodes. These findings were consistent with intermixed stroma-rich ganglioneuroblastoma (GNB) according to Shimada et al., arising from the adrenal and with metastatic extension to ipsilateral lymph nodes . The mitosis-karyorrhexis index (MKI) was <2%. In this case, any N-MYC amplification was detected and any deletion of the short arm of the chromosome 1. Chemotherapy was not proposed based on the favorable histology. Any disease recurrence occurred in the 21-month follow-up from surgery.
Incidentally discovered adrenal masses are becoming more common with the imaging technological advances and the increased number of imaging studies performed. Nowadays the prevalence of adrenal incidentalomas in radiological studies has come close to the autoptic data: approximately 2-4% in adult age, increasing up to 10% in elderly population. Their differential diagnosis must consider a wide range of pathologies (Table 1). The prevalence of different etiologies varies among the studies; however, it is likely that the majority consists in nonfunctioning adenomas. Other frequently reported lesions are cortisol secreting adenomas, pheochromocytomas, primitive carcinomas, and distant metastatic lesions. In a study including 1111 adult patients with adrenal incidentalomas, GNB was diagnosed in only one case . It is important to point out that the majority of adrenal lesions do not come to surgery; therefore pathological diagnoses of most adrenal incidentalomas remain unknown .
Peripheral neuroblastic tumors (PNTs) are a group of tumors arising from sympathetic ganglion cells. In two-thirds of the cases, PNTs arise in the adrenal gland or the retroperitoneal paravertebral ganglia. PNTs represent one of the most frequent solid tumors in children, while the occurrence in adults is very rare. Overall survival in infants is very high (91%) and progressively declines parallel to the increased age at diagnosis. In a study performed on RARECAREnet and involving very few cases, 5-year survival was reported to be 48% in adolescents (15-24 years) and 40% in adults (25-64 years) . The vast majority of PNTs are sporadic and family history is reported only in a small percentage of cases . Conditions such as Hirschsprung's disease and central hypoventilation, Turner syndrome, and Neurofibromatosis 1 seem to confer an increased risk of developing neuroblastic tumors, according to the literature [7-9]. No association with patent foramen ovale or focal nodular hyperplasia has been reported. PNTs are made up of two components: neuroblastic cells, with different degrees of differentiation, and Schwannian cells. The International Neuroblastoma Pathology Classification (INPC) distinguishes four pathological groups according to the different proportion of ganglion and Schwann cells: neuroblastoma (Schwannian stroma-poor, undifferentiated/poorly, differentiated/differentiating), ganglioneuroblastoma intermixed (Schwannian stroma-rich), ganglioneuroma (Schwannian stroma-dominant), and ganglioneuroblastoma nodular (composite Schwannian stromarich/stroma-dominant/stroma-poor) . Clinic presentation is variable and the most common symptoms include pain or compression of the abdominal viscera. Metastatic dissemination occurs in about 40% of patients and involves more frequently bone and bone marrow. Catecholamines secretion is documented in more than 70% of cases . The International Neuroblastoma Risk Group Consensus Pretreatment Classification Scheme defines prognosis and design treatment programs based on the stage of the tumor (according to the International Neuroblastoma Risk Group Staging System, INRGSS), age at diagnosis, pathology (INPC), and gene expression abnormalities (MYCN gene amplification, 11q aberration, and ploidy) (Table 2) . Therapeutic modalities include surgery, radiotherapy, and chemotherapy combined on the basis of the individual patient. Very low risk group is treated only with surgery, followed by observation. Radiotherapy and chemotherapy are reserved for the higher risk groups, combined in different protocols .
Revision of the published literature in PubMed retrieved 15 cases of adult-onset adrenal GNB (Table 3) [12, 13]. The majority of patients were male and mean age at diagnosis was 38.9 years (21-67 years). Clinic was not specific and often represented by pain or other symptoms due to compression. Catecholamines secretion was documented only in 4 cases. Left adrenal gland was more frequently involved, and in one case bilateral tumors were reported. Imaging features of GNB varied from oval and homogeneous masses to heterogeneous, infiltrating, and calcified lesions. Because most of the lesions grew silently, at time of diagnosis big masses were found (mean size 10.44 cm). In locally advanced PNTs with potentially associated surgery-related complications, presurgical chemotherapy should be administered in order to shrink the tumor and enable safe resection saving other abdominal viscera involved . Neuroblastic origin of the tumor was suspected preoperatively in just few cases, suggesting that though the radiological appearances of adrenal GNB have been described in detail , the preoperative diagnosis remains challenging and may be misleading. Consequently patients were addressed straight to surgery and the definitive etiology was histologically defined. Metastases were found at diagnosis in half of the patient and occurred in lymph nodes, liver, or bone marrow. The presence of metastases does not seem to correlate with the size or the histopathological subtype of the tumor. Most of the patients were treated only with surgery, showing no recurrence during follow-up (mean follow-up duration 20.9 months). Metastases were detected after 2.5 years in a patient who refused radio- and chemotherapy after surgical removal. One patient died 3 months after diagnosis due to heart failure.
No long-term data in adults have been reported due to the small series of patients.
There is no evidence about the most appropriate follow-up for adrenal GNB in adults.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
 G. Arnaldi and M. Boscaro, "Adrenal incidentaloma," Best Practice & Research: Clinical Endocrinology & Metabolism, vol. 26, no. 4, pp. 405-419, 2012.
 M. Fassnacht, W. Arlt, I. Bancos et al., "Management of adrenal incidentalomas: European society of endocrinology clinical practice guideline in collaboration with the european network for the study of adrenal tumors," European Journal of Endocrinology, vol. 175, no. 2, pp. G1-G34, 2016.
 H. Shimada, I. M. Ambros, L. P. Dehner et al., "The International Neuroblastoma Pathology Classification (the Shimada system)," Cancer, vol. 86, no. 2, pp. 364-372,1999.
 A. A. Kasperlik-Zaluska, E. Roslonowska, J. Slowinska-Srzednicka et al., "1,111 Patients with adrenal incidentalomas observed at a single endocrinological center: incidence of chromaffin tumors," Annals of the New York Academy of Sciences, vol. 1073, pp. 38-46, 2006.
 R. Luksch, M. R. Castellani, P. Collini et al., "Neuroblastoma (Peripheral neuroblastic tumours)," Critical Reviews in Oncology/Hematology, vol. 107, pp. 163-181, 2016.
 A. Claviez, M. Lakomek, J. Ritter et al., "Low occurrence of familial neuroblastomas and ganglioneuromas in five consecutive GPOH neuroblastoma treatment studies," European Journal ofCancer, vol. 40, no. 18, pp. 2760-2765, 2004.
 D. E. Weese-Mayer, C. M. Rand, A. Zhou, M. S. Carroll, and C. E. Hunt, "Congenital central hypoventilation syndrome: a bedside-to-bench success story for advancing early diagnosis and treatment and improved survival and quality of life," Pediatric Research, vol. 81, no. 1-2, pp. 192-201, 2016.
 J. Blatt, A. F. Olshan, P. A. Lee, and J. L. Ross, "Neuroblastoma and related tumors in Turner's syndrome," The Journal of Pediatrics, vol. 131, no. 5, pp. 666-670, 1997.
 P. Origone, R. Defferrari, K. Mazzocco, C. Lo Cunsolo, B. De Bernardi, and G. P. Tonini, "Homozygous inactivation of NF1 gene in a patient with familial NF1 and disseminated neuroblastoma," American Journal of Medical Genetics, vol. 118, no. 4, pp. 309-313, 2003.
 E. H. LaBrosse, C. Com-Nougue, J. M. Zucker et al., "Urinary excretion of 3-methoxy-4-hydroxymandelic acid and 3-methoxy-4-hydroxyphenylacetic acid by 288 patients with neuroblastoma and related neural crest tumors," Cancer Res, vol. 40, no. 6, pp. 1995-2001, 1980.
 S. L. Cohn, A. D. J. Pearson, W. B. London et al., "The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report," Journal of Clinical Oncology, vol. 27, no. 2, pp. 289-297, 2009.
 E. Bolzacchini, B. Martinelli, and G. Pinotti, Adult onset of ganglioneuroblastoma of the adrenal gland: case report and review of the literature. Surg Case Rep, 1, 79, 2015.
 W. Qiu, T. Li, X. D. Sun, and G. Y. Lv, "Onset of adrenal ganglioneuroblastoma in an adult after delivery," Annals of Surgical Treatment and Research, vol. 89, no. 4, pp. 220-223, 2015.
 G. Cecchetto, V Mosseri, B. De Bernardi et al., "Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European international society of pediatric oncology neuroblastoma group," Journal of Clinical Oncology, vol. 23, no. 33, pp. 8483-8489, 2005.
 Y.-K. Guo, Z.-G. Yang, Y. Li et al., "Uncommon adrenal masses: CT and MRI features with histopathologic correlation," European Journal of Radiology, vol. 62, no. 3, pp. 359-370, 2007.
Stefano Benedini, (1,2) Giorgia Grassi, (1,2) Carmen Aresta, (1,2) Antonietta Tufano, (2) Luca Fabio Carmignani, (3) Barbara Rubino, (4) Livio Luzi, (1,2) and Sabrina Corbetta (5)
(1) Department of Biomedical Sciences for Health, Universita degli Studi di Milano, Milan, Italy
(2) Endocrinology Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
(3) Urology Department, IRCCS Policlinico San Donato, San Donato Milanese, Italy
(4) Pathology Department, IRCCS Policlinico San Donato, San Donato Milanese, Italy
(5) Endocrinology Service, Department of Biomedical Sciences for Health, University of Milan, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
Correspondence should be addressed to Stefano Benedini; firstname.lastname@example.org
Received 19 April 2017; Revised 19 May 2017; Accepted 24 May 2017; Published 21 June 2017
Academic Editor: Carlo Capella
Caption: Figure 1: Abdominal CT scan with and without contrast enhancement: presence of a big and heterogeneous mass with calcification in left adrenal lodge (b). Dynamic analysis revealed a progressive and modest contrast enhancement in venous phase (a).
Caption: Figure 2: Histological examination (hematoxylin and eosin stain, 10x): high proportion of ganglion cells (black arrow) in spindle stroma and dystrophic calcification (white arrow).
Table 1: Causes of adrenal masses. (i) Cystic masses: endothelial cyst, pseudocyst, and hydatid cyst (ii) Solid masses: adenoma, nodular hyperplasia, carcinoma, metastases, pheochromocytoma, neuroblastic tumors, neurofibroma, schwannoma, leiomyoma, angiosarcoma, hamartoma, tuberculoma, and amyloidosis (iii) Fat-containing masses: lipoma and myelolipoma Modified from Arnaldi and Boscaro . Table 2: International Neuroblastoma Risk Group Consensus Pretreatment Classification Scheme. INRG Stage Age (months) INPC group L1/L2 GN maturing; GNB intermixed L1 Any, except GN Localized tumor confined to maturing or GNB with absence of image-defined intermixed one body compartment and risk factors <18 Any, except GN maturing or GNB L2 intermixed Locoregional tumor with presence of one or more image- [greater than or GNB nodular; NB defined risk factor equal to]18 <18 M Distant metastatic disease <12 (except MS) 12-18 <18 [greater than or equal to]18 MS Metastatic disease confined to marrow in children <18 months skin, liver, and/or bone INRG Stage Grade of MYCN gene differentiation L1/L2 LI NA Localized tumor confined to Amplified with absence of image-defined one body compartment and risk factors NA L2 Differentiating NA Locoregional tumor with presence of one or more image- Poorly defined risk factor differentiated or NA undifferentiated NA M Distant metastatic disease NA (except MS) NA Amplified MS Metastatic disease confined to NA marrow in children <18 months Amplified skin, liver, and/or bone INRG Stage 11q Ploidy aberration L1/L2 L1 Localized tumor confined to with absence of image-defined one body compartment and risk factors No Yes L2 No Locoregional tumor with presence of one or more image- defined risk factor Hyperploid M Distant metastatic disease Diploid (except MS) Diploid MS no Metastatic disease confined to yes marrow in children <18 months skin, liver, and/or bone INRG Stage Pretreatment risk group L1/L2 Very low L1 Very low Localized tumor confined to High with absence of image-defined one body compartment and risk factors Low Intermediate L2 Low Locoregional tumor with presence of one or more image- Intermediate defined risk factor Low M Distant metastatic disease Intermediate (except MS) Intermediate High High MS Very low Metastatic disease confined to High marrow in children <18 months High skin, liver, and/or bone INRG: International Neuroblastoma Risk Group; INCP: International Neuroblastoma Pathology Classification; GN = ganglioneuroma; GNB = ganglioneuroblastoma; NB = neuroblastoma; NA: not amplified; modified from Cohn et al. . Table 3: Reported cases of adult-onset adrenal GNB in literature. First Age Gender Symptoms Size Author (years) (cm) (year) Butz 25 M (1940) Cameron (1967) 58 F Diarrhea Takahashi 21 M Asymptomatic 8,8 (1988) Fatigue, low Koizumi 47 F back pain 9 (1992) Higuchi 29 M 11 (1993) Hiroshige (1995) 35 M Asymptomatic 10 Mehta (1997) 22 M 9 Rousseau F (1998) Headache, Fujiwara 25 M palpitations, 9 (2000) hypertension, weight loss Slapa Asymptomatic (2002) 20 F 18 Koike 50 M Asymptomatic 4,5 (2003) Right flank and epigastric pain, Gunlusoy 59 M malaise, anemia, 12 (2004) weight loss, microscopic hematuria Increased Mizuno 53 M frequency of 11 (2010) urination Bolzacchini 63 M Asymptomatic 5 (2015) Qiu 27 F Pain 11 (2015) Present 21 F Asymptomatic 11 case (2015) First Side Imaging Hormonal activity Author (year) Butz (1940) [up arrow] urinary catecholamines, Cameron vanilmandelic (1967) Right acid and homovanilman- delic acid Takahashi Left [up arrow] urinary (1988) vanilmandelic acid [up arrow] urinary catecholamines, vanilmandelic acid and homovanilman- Koizumi Right Heterogeneous delic (1992) acid Higuchi [up arrow] urinary (1993) catecholamines Hiroshige (1995) Left Heterogeneous and None calcifications Mehta (1997) Bilateral Rousseau Left (1998) Ovalar, Fujiwara Left heterogeneous, None (2000) calcifications Slapa (2002) None Koike Right Ovalar, necrotic None (2003) central area Gunlusoy Right Lobulated, None (2004) necrotic areas Smooth margins, homogeneous Mizuno Right None (2010) Bolzacchini Left Irregular margins, None (2015) heterogeneous Qiu Left Ovalar, None (2015) cystic-solid Present Left Lobulated, None case (2015) heterogeneous, calcifications First Metastases Preliminary Author diagnosis (year) Butz Liver (1940) Cameron (1967) Absent Pheochromocytoma Takahashi Lymph nodes Neuroblastoma (1988) Koizumi Bone marrow None (1992) Higuchi Bone (1993) marrow Hiroshige (1995) Absent Carcinoma, m Mehta (1997) Rousseau Liver (1998) Fujiwara Absent Pheochromocytoma (2000) Slapa (2002) Absent Koike Pheochromocytoma, (2003) adrenal malignancy, neuroblastic tumor Gunlusoy Lymph nodes None (2004) Lumbar spine Mizuno None (2010) Bolzacchini Absent None (2015) Qiu Absent Pheochromocytoma (2015) Present Lymph nodes Adrenal carcinoma, case (2015) leiomyosarcoma First Histopathology Treatment Follow-up Author (year) Butz (1940) Cameron 3.5 years, (1967) Surgery no recurrence Takahashi Surgery + 8 months, no (1988) RT + CT recurrence 3 months, dead Koizumi None (1992) Higuchi Surgery 10 months, no (1993) recurrence Hiroshige (1995) suroblastoma Surgery 2 years, no recurrence Mehta (1997) Surgery Rousseau Surgery + (1998) RT + CT Fujiwara GNB intermixed + Surgery 5 years, (2000) pheochromocytoma no recurrence Slapa 1 year, (2002) no recurrence Surgery Koike Surgery 2.5 years, (2003) no recurrence Gunlusoy Surgery (2004) Recurrence after 2.5 years Mizuno GNB nodular Surgery (2010) Bolzacchini GNB nodular Surgery 6 months, (2015) no recurrence 5 months, Qiu GNB intermixed Surgery no recurrence (2015) Present GNB intermixed Surgery 21 months, case (2015) no recurrence Modified from Bolzacchini et al. [12,13].
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Case Report|
|Author:||Benedini, Stefano; Grassi, Giorgia; Aresta, Carmen; Tufano, Antonietta; Carmignani, Luca Fabio; Rubi|
|Publication:||Case Reports in Endocrinology|
|Article Type:||Clinical report|
|Date:||Jan 1, 2017|
|Previous Article:||A Case of Hyperparathyroidism due to a Large Intrathyroid Parathyroid Adenoma with Recurrent Episodes of Acute Pancreatitis.|
|Next Article:||Atypical Complications of Graves' Disease: A Case Report and Literature Review.|