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Adrenal Ganglioneuroblastoma in Adults: A Case Report and Review of the Literature.

1. Introduction

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 [1]. 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 [2].

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 [2].

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 [3]. 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.

3. Discussion

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 [4]. 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 [1].

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) [5]. The vast majority of PNTs are sporadic and family history is reported only in a small percentage of cases [6]. 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) [3]. 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 [10]. 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) [11]. 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 [5].

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 [14]. 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 [15], 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.


[1] G. Arnaldi and M. Boscaro, "Adrenal incidentaloma," Best Practice & Research: Clinical Endocrinology & Metabolism, vol. 26, no. 4, pp. 405-419, 2012.

[2] 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.

[3] 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.

[4] 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.

[5] R. Luksch, M. R. Castellani, P. Collini et al., "Neuroblastoma (Peripheral neuroblastic tumours)," Critical Reviews in Oncology/Hematology, vol. 107, pp. 163-181, 2016.

[6] 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.

[7] 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.

[8] 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.

[9] 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.

[10] 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.

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[12] 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.

[13] 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.

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[15] 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;

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 [1].

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

                                          <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

M Distant metastatic disease              <12
(except MS)                              12-18
                                   [greater than or
                                      equal to]18
Metastatic disease confined to
  marrow in children <18 months
  skin, liver, and/or bone

INRG Stage                             Grade of        MYCN gene


LI                                                        NA
Localized tumor confined to                            Amplified
with absence of image-defined
one body compartment and risk


L2                                  Differentiating       NA
Locoregional tumor with
  presence of one or more image-        Poorly
  defined risk factor              differentiated or      NA

M Distant metastatic disease                              NA
(except MS)                                               NA

Metastatic disease confined to                            NA
  marrow in children <18 months                        Amplified
  skin, liver, and/or bone

INRG Stage                            11q         Ploidy


Localized tumor confined to
with absence of image-defined
one body compartment and risk

L2                                     No
Locoregional tumor with
  presence of one or more image-
  defined risk factor

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

L2                                      Low
Locoregional tumor with
  presence of one or more image-   Intermediate
  defined risk factor

M Distant metastatic disease       Intermediate
(except MS)                        Intermediate

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. [11].

Table 3: Reported cases of adult-onset adrenal GNB in literature.

First               Age      Gender       Symptoms       Size
Author             (years)                                (cm)

Butz                 25        M

(1967)               58        F          Diarrhea

Takahashi            21        M        Asymptomatic      8,8

                                        Fatigue, low

Koizumi              47        F          back pain        9

Higuchi              29        M                          11

Hiroshige (1995)     35        M        Asymptomatic      10

Mehta (1997)         22        M                           9

Rousseau                       F
Fujiwara             25        M       palpitations,       9
(2000)                                  hypertension,
                                        weight loss

Slapa                                   Asymptomatic
                     20        F                          18
Koike                50        M        Asymptomatic      4,5
(2003)                                Right flank and
                                      epigastric pain,

Gunlusoy             59        M      malaise, anemia,    12
(2004)                                  weight loss,

Mizuno               53        M        frequency of      11
(2010)                                    urination

Bolzacchini          63        M        Asymptomatic       5

Qiu                  27        F            Pain          11

Present              21        F        Asymptomatic      11
case (2015)

First                Side           Imaging          Hormonal activity

(1940)                                              [up arrow] urinary
Cameron                                                vanilmandelic
(1967)               Right                               acid and

Takahashi            Left                           [up arrow] urinary
(1988)                                               vanilmandelic acid

                                                    [up arrow] urinary
                                                    vanilmandelic acid
                                                     and homovanilman-
Koizumi              Right       Heterogeneous             delic
(1992)                                                     acid

Higuchi                                             [up arrow] urinary
(1993)                                                catecholamines

Hiroshige (1995)     Left      Heterogeneous and           None
Mehta (1997)       Bilateral

Rousseau             Left
Fujiwara             Left        heterogeneous,            None
(2000)                           calcifications

Koike                Right      Ovalar, necrotic           None
(2003)                            central area

Gunlusoy             Right         Lobulated,              None
(2004)                           necrotic areas

                                Smooth margins,
Mizuno               Right                                 None

Bolzacchini          Left      Irregular margins,          None
(2015)                           heterogeneous

Qiu                  Left           Ovalar,                None
(2015)                            cystic-solid

Present              Left         Lobulated,               None
case (2015)                     heterogeneous,

First               Metastases       Preliminary
Author                                 diagnosis

Butz                  Liver

(1967)                Absent       Pheochromocytoma

Takahashi          Lymph nodes       Neuroblastoma

Koizumi            Bone marrow           None

Higuchi                Bone
(1993)                marrow

Hiroshige (1995)      Absent         Carcinoma, m

Mehta (1997)

Rousseau              Liver

Fujiwara              Absent       Pheochromocytoma

Koike                             Pheochromocytoma,
(2003)                            adrenal malignancy,
                                   neuroblastic tumor

Gunlusoy           Lymph nodes           None

                   Lumbar spine

Mizuno                                   None

Bolzacchini           Absent             None

Qiu                   Absent       Pheochromocytoma

Present            Lymph nodes    Adrenal carcinoma,
case (2015)                         leiomyosarcoma

First               Histopathology     Treatment      Follow-up


Cameron                                              3.5 years,
(1967)                                  Surgery     no recurrence

Takahashi                              Surgery +    8 months, no
                                        RT + CT      recurrence

                                                   3 months, dead

Koizumi                                  None

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
Koike                                   Surgery      2.5 years,
(2003)                                              no recurrence

Gunlusoy                                Surgery

                                                   after 2.5 years
Mizuno                GNB nodular       Surgery

Bolzacchini           GNB nodular       Surgery       6 months,
(2015)                                              no recurrence
                                                      5 months,

Qiu                 GNB intermixed      Surgery     no recurrence

Present             GNB intermixed      Surgery      21 months,
case (2015)                                         no recurrence

Modified from Bolzacchini et al. [12,13].
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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
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