1
UNIVERSITÀ DI PISA
DIPARTIMENTO DI PATOLOGIA CHIRURGICA, MEDICA, MOLECOLARE E DELL’AREA CRITICA
Corso di Laurea Specialistica in Medicina e Chirurgia
Tesi di laurea
Surgical management of ganglioneuroma: our experience and
literature review.
Relatore: Candidato: Prof. Claudio Spinelli Leonardo Rossi
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Index
Abstract--- 3
Aim of the study--- 5
1 Introduction --- 5 1.1 Phatophysiology--- 5 1.2 Istological features--- 6 1.3 Epidemiology--- 7 1.4 Risk group--- 7 1.5 Clinical features--- 11 1.6 Diagnosis--- 12 1.7 Treatment--- 14
2 Materials and methods--- 16
3 Results--- 17
4 Discussion--- 27
5 Conclusions--- 41
6 References--- 42
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Abstract
Background and aims: ganglioneuromas are benign tumors which origin from
the neural crest. This tumor affects mainly young patients rather than adult ones, and its most frequent localizations are mediastinum, retroperitoneal tissue (non-adrenal), adrenal glands and cervical region. Usually, ganglioneuromas are discovered as incidentalomas since they are often asymptomatic, even if they could present sympathetic or mass-related symptoms. To obtain a definitive diagnosis, histological exam is necessary. The surgical excision is the chosen treatment and it offers an excellent prognosis.
Methods: we conducted a retrospective analysis of our cases of ganglioneuroma
from 2004 to 2014; this study aims to compare our experience’s data with
literature review (2000-2014). Data about patients’ features, tumors’ localization, symptoms, treatment and follow-up were analyzed and reported in detailed tables.
Results: between 2004-2014 we treated 12 patients affected by ganglioneuroma.
For all of them the diagnosis was incidental; 7 out of 12 (58.3%) patients presented an adrenal mass; in 2 patients (16.7%) the tumor was localized in cervical region; in other 2 patients (16.7%) the tumor was in the retroperitoneal
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tissue (non-adrenal) and one patient (8.3%) presents a ganglioneuroma in the costo-vertebral space. All our patients underwent surgical removal and none of them present surgery-related complications or recurrences to date.
Conclusions: our data widen the knowledge about ganglioneuroma and confirm
that the surgical approach has an excellent prognosis with very low incidence of surgery-related complications and recurrences.
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Aim of the study
This thesis purposes of describing our cases of ganglioneuroma and comparing them with the literature to extend the knowledge about this tumor.
1 Introduction
1.1 Pathophysiology: ganglioneuroma is a benign tumor and it arises from sympathetic ganglion cells, which are cells of neural crest origin [1]. It belongs to neuroblastoma group, as ganglioneuroblastoma and neuroblastoma [2]. The histologic difference between ganglioneuroma, ganglioneuroblastoma and neuroblastoma is their stage of neuroblast maturation [3]. A tumor composed primarily of neuroblasts is referred to as neuroblastoma (NB); a tumor composed entirely of mature ganglion cells and other mature tissue is a ganglioneuroma (GN); a tumor with both immature and mature cell types is a ganglioneuroblastoma (GNB) [4]. GN can arise de novo in any sympathetic tissue [5], or result from the maturation of a ganglioneuroblastoma or neuroblastoma into a ganglioneuroma. They may also develop within a neuroblastoma treated with chemotherapy [4]. These benign tumors may occur in any part of the mediastinum, the retroperitoneal tissue and the adrenal gland; few GNs occur in the cervical region [6]. Ganglioneuromas have also been
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reported to occur rarely in other locations, such as the tongue, bladder, uterus, bone and skin [7]; other unusual locations reported are heart, bone and intestine. Central nervous system location is rare [4]. Most GN are sporadic, but they can also be associated with neurofibromatosis type II, multiple endocrinologic neoplasia type II, Hirschprung disease, central failure of ventilation and Di George syndrome [5]. Metastases in these tumors are exceedingly rare and are thought to be the end result of matured ganglioneuroblastoma or neuroblastoma metastases rather then true ganglioneuroma metastases [4].
1.2 Istological features: GNs are rare, benign, fully differentiated tumors
that contain mature Schwann cells, ganglion cells, fibrous tissue and nerve fibers. These tumors have no immature elements (such as neuroblasts), atypia, mitotic figures, intermediate cells or necrosis. The presence of any these tissue characteristics excludes the diagnosis of ganglioneuroma [4]. Ganglioneuroma are considered to be mature tumors and do not have immature elements. Ganglioneuroma average 8cm in size and have a pseudocapsule. They are firm to the touch and have a light color ranging from white to yellow. Internally, the tumor may have a whorled appearance with trabeculae [4].
Bruce et al [8] have analyzed ganglioneuroma’s tissue: at light microscopy the tumor was composed primarily of tangled masses of neurites in bundles. Large (up to 20 u) ganglion cells with abundant cytoplasm and a large, usually round, nucleus with a single prominent nucleolus were frequent. Many of them were surrounded by satellite cells with a thin encircling rim of
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cytoplasm and a flattened nucleus. Rare groups of lymphocytes were present. Lightly eosinophilic, Bodian positive, amorphous inclusions resembling Pick's bodies were found in the cytoplasm of many ganglion cells. They were frequently as large as the nucleus.
The ganglion cell bodies were easily recognized at the electron microscopy [8] by their characteristic cytoplasm and nucleus. The cytoplasm contained prominent vesiculated rough endoplasmic reticulum, and a moderate number of mitochondria and lysosomes. The nucleus was large and oval with a prominent nucleolus. Most cells contained scattered dense core neurosecretory granules 50-100 nm in diameter, typical of catecholamine granules.
1.3 Epidemiology: GN is a rare tumor that appears mainly in childhood
[1]: the median age at the diagnosis is approximately 7 years [5]. The reported incidence of GN is one per million in general population. The data in the literature vary from a preference of the female gender to no gender difference [9].
1.4 Risk groups: two histologic classification systems are commonly
used in the United States to stratify neuroblastic tumors into risk groups: the
Shimada classification and the Pediatric Oncology Group (POG) classification
[4]. Both systems assess histologic features such as cellular differentiation, to arrive at a prognostic classification.
The POG system is based on the degree of differentiation of the different histologic elements. GN shows completely differentiated stromal and cellular
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components. NB contains less than 50% differentiated elements and GNB is intermediate. NB may be further subclassified as undifferentiated (the most immature NB), poorly differentiated or differentiating(the most mature NB) [4]. The Shimada classification combines histologic features and patient age at diagnosis. The histologic features consist of stroma, grade and architecture. The age groups of the Shimada classification system are less than 1,5 years, 1,5-5 years and more than 5 years age. Children with favorable histologic characteristics are either less than 1,5 years of age with a low or intermediate MKI (mitosis-karyorrhexis index) and differentiating or partially differentiating tumor or 1,5-5 years old with a low MKI and differentiating tumor. All other combinations are considered unfavorable histologic characteristics [4].
Table 1: Prognostic Evaluation of Neuroblastic Tumors According to the International Neuroblastoma Pathology Classification.
International Neuroblastoma Pathology classification Original Shimada classification Prognostic group Neuroblastoma (Schwannian stroma-poor) Stroma-poor
Favorable Favorable Favorable
<1.5 yrs Poorly
differentiated or differentiating & low or intermediate
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MKI tumor
1.5–5 yrs Differentiating & low MKI tumor
Unfavorable Unfavorable Unfavorable
<1.5 yrs a) undifferentiated tumorc
b) high MKI tumor 1.5–5 yrs a) undifferentiated
or poorly differentiated tumor b) intermediate or high MKI tumor ≥5 yrs All tumors Ganglioneuroblastoma, intermixed (Schwannian stroma-rich) Stroma-rich Intermixed (favorable) Favorable Ganglioneuroma (Schwannian stroma-dominant) Maturing Well differentiated (favorable) Favorable Mature Ganglioneuroma Ganglioneuroblastoma, nodular (composite Schwannian stroma- rich/stroma-dominate and stroma-poor) Stroma-rich nodular (unfavorable) Unfavorable
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In 1986, an international consensus group devised the International Neuroblastoma Staging System (INSS) , based on clinical, radiologic and surgical feature [4].
Table 2: International Neuroblastoma Staging System (INSS.) STAGE DESCRIPTION
1 Localised Tumour with complete gross excision, with or
without microscopic residual disease; representative ipsilateral
lymph nodes negative for Tumour microscopically (nodes
attached to and removed with the primary Tumour may be
positive).
2° Localised Tumour with incomplete gross excision;
representative ipsilateral nonadherent lymph nodes negative for Tumour microscopically.
2B Localised Tumour with or without complete gross excision,
with ipsilateral nonadherent lymph nodes positive for Tumour.
Enlarged contralateral lymph nodes must be negative microscopically.
3 Unresectable unilateral Tumour infiltrating across the midline,
with or without regional lymph node involvement; or localized
unilateral Tumour with contralateral regional lymph node
involvement; or midline Tumour with bilateral extension by
infiltration (unresectable) or by lymph node involvement. The
midline is defined as the vertebral
column. Tumours originating on 1 side and crossing the
midline must infiltrate to or beyond the opposite side of the vertebral column.
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4 Any primary Tumour with dissemination to distant lymph
nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S).
4S Localized primary Tumour (as defined for stage 1, 2A, or 2B),
with dissemination limited to skin, liver, and/or bone marrow (limited to infants younger than 1 year). Marrow involvement should be minimal (<10% of total nucleated cells identified as
malignant by bone Biopsy or by bone marrow aspirate). More
extensive bone marrow involvement would be considered to be stage 4 disease. The results of the MIBG (Meta-ldo-Benzyl-Guanidine) scan (if performed) should be negative for disease in the bone marrow.
1.5 Clinical features: The symptoms of this neoplasia are usually related
to the mass effects, nerve dysfunction or sympathetic activity due to secretory cells within the tumor [1]. If the tumor is in the mediastinum, it may cause chest pain, cough, difficulty breathing or compression of the trachea; if the tumor is in the retroperitoneal space, it may result in abdominal pain or discomfort and distension; if the tumor is in near the spinal cord, it may cause spine deformity and possible compression of the spinal cord [4]. However, it is often asymptomatic regardless of the size with an incidental diagnosis, as experienced in the majority of our cases (they are typically discovered on a routine radiograph o CT-scan). This aspect depends on its slow growth, as well as it often does not induce alterations of laboratory test results. Levels of urinary and blood metanephrines and catecholamines are often normal or slightly elevated
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[10], even if GNs may be hormonally active and hypertension, diarrhea, flushing and virilization may occur as a result the secretion of cathecolamine, vasoactive intestinal polypeptide, or androgenic hormone. In rare cases, GN secretes sufficient quantities of VMA (vanillylmandelic acid) or HVA (homovanillic acid). Cathecolamine production by GN was previously believed to be unusual, because it was theorized that more mature tumors have more mature biologic behavior [4]; to date, it has been reported that ganglioneuroma are secretory in up to 39% of patients releasing cathecolamines [9]. 1. 6 Diagnosis: Imaging techniques used to characterize the lesion are CT and MRI above all. Although GN tends to be relatively homogeneous, the imaging characteristics of GN are similar to those of GNB and NB; hence, they cannot be discriminated at imaging evaluation save for the presence of metastases, which are quite rare in GN.
Plain radiographs may show a posterior mediastinal mass, which may cause rib spreading and foraminal erosion. A mass may also be noted in the retroperitoneum, pelvis or neck [4].
CT- Scanning is the imaging modality that is commonly used to evaluate neuroblastic tumors. It is the superior imaging technique when it comes to identifying tumor size, organ of origin, tissue invasion, adenopathy and calcification. Newly diagnosed cases are evaluated with standard chest, abdominal and pelvic CT. Retroperitoneal and adrenal GNs appear well defined. Their shape ranges from round to lobulated, they show discrete and punctate
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calcification in 42-60% of cases, and they tend to grow around major blood vessels, which are not compressed by the tumor [4].
MRI creates images with better tissue discrimination than CT. Ganglioneuromas appear homogeneous on MRI and have relatively low signal intensity on T1-weighted images. On T2-T1-weighted MRI, the signal intensity is proportional to the ratio of myxoid stroma to cellularity and also to amount of collagen present in the tumor. Tumors with intermediate to high signal intensity on T2-weighted images have a higher degree of cellularity and more collagen. Markedly high T2 intensity signifies a high myxoid stroma component and low cellularity and collagen amount [11].
MRI imaging enhancement varies considerably because GNs typically do not demonstrate early enhancement on dynamic RMI imaging. However, these tumors accumulate contrast material over time, observable on delay imaging. On T1- and/or T2-weighted images, the capsule is theoretically identified as a low intensity ring around the tumor [12].
Ultrasound of GN shows a homogeneous, hypoechoic, well circumscribed mass. Scintigraphy with Iodine-tagged medaiodobenzylguanidine (MIBG) - a cathecolamine analog - is used to identify cathecolamine-producing tumors. MIBG has 88% sensitivity and 99% specificity for tumors containing sympathetic tissue such as GNB, GN, NB, pheochromocytomas and carcinoids. The disadvantage is that there is no way to discriminate the type of tumor in which the uptake occurs [4]. GN, like GNB and NB, may accumulate MIBG;
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this has been reported in up to 57% of GNs in one study [9]. In this study, most of the tumors that were MIBG-avid also produced increased amounts of catecholamines.
However, these techniques are not sufficient for final diagnosis, and both CT and MRI do not allow to distinguish this benign lesion carefully. In order to obtain definitive diagnosis, histological exam of the lesion is necessary [13]. For this reason, and for the rarity of this neoplasia, the diagnosis can be very challenging [1, 5, 10].
The differential diagnosis should take into consideration above all adrenal adenoma, adrenal carcinoma, neuroblastoma, ganglioneuroblastoma and
pheochromocytoma [4].
1.7 Treatment: the recommended treatment is a surgical resection and the prognosis seems to be excellent [14]. Further, Retrosi et al [15] reported that even with incomplete tumor resection the prognosis is good.
Complete surgical resection is important because it allows for good tissue sampling and a thorough pathology examination of the specimen to ensure correct diagnosis of ganglioneuroma [4]. Complications may occur as a result of surgery, since GN can tightly adhere to, or encase major vascular structures [16]. De Bernardi et al [17] reported that the surgery-related complication’s rate was 17.8%; However, Retrosi et al [15] reported a higher rate of complications (30%). If the tumor has been present for a long time and is causing symptoms
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(such as spinal cord compression), removal of the tumor may not necessarily reverse the deficit.
Rarely, a GN may recur or become malignant and metastasize: this last situation is possible for the capacity of de-differentiation of ganglion cells in a ganglioneuroma or for the presence of a long-term, quiescent form of neuroblastoma [18]. Due to the benign nature of GN, patients are not indicated to receive adjuvant chemotherapy or radiotherapy [2]. In case of complete resection authors propose different follow-up protocol: Cerullo et al [19] recomend yearly intensive clinical examination and MRI imaging to ensure no local recurrence and Modha et al [20] suggest an intensive one-year follow-up as well. Differently, in case of incomplete resection, a longer follow-up is needed since malignant transformation have rarely been described [18, 21-23] decades after the diagnosis of GN [17].
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2 Materials and methods
The authors conduced a retrospective analysis about patients suffering from ganglioneuroma between 2004 and 2014, treated in Department of Surgical, Medical, Pathological, Molecular and Critic Area, University of Pisa, Italy. Written informed consent was obtained from the patients or from their relatives,
according to the ethical guidelines.
Symptoms, localization, laboratory data, therapy and complications were evaluated for a detailed analysis. A median follow-up of 4.3 years (range from 1 to 10 years) was taken to verify the current status of the patients and to investigate any possible recurrence.
A literature review (2000-2014) using the search terms “ganglioneuroma”, “incidentaloma”, “surgical resection” was performed and the cases were
reviewed. Data regarding signs, symptoms, lesion areas, treatment and follow-up were reported into tables for description and analysis.
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3 Results
Between 2004 and 2014 we performed in our department 12 surgical resection for GN (Table 3, Table 4). The patients were 4 male adults, 5 female adults and 3 female children. Median age at diagnosis was 27 years (range 4 - 41 years): 3 out of 12 patients (25%) were under 20 years at diagnosis. For all patients (100%) the diagnosis was incidental. The patients underwent instrumental exams for different reasons and a non-specific mass was found. In all cases the first view of the tumor occurred during an US exam, but only in one case the US exam was performed due to a cervical visible and palpable mass. Seven patients (58,3%) presented an adrenal mass, whereas the others five patients (41.7%) presented different localizations (2 GNs (16.7%) in cervical region, 2 GNs (16.7%) in retroperitoneal tissue (specifically, one paravertebral tumor and one tumor behind the head of the pancreas), 1 GN (8.3%) in costo-vertebral space).
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Only one patient (8.3%) presented a non-specific visible and palpable mass, while in the other eleven patients the disease was asymptomatic (91.7%). Accordingly, all patients were submitted to more accurate exams like CT and MRI [figure 1, figure 2(a), 2(b)].
Localization
Adrenal gland (58,3%)
Retroperitoneal tissue (16,7%) Cervical region (16,7%) Costovertebral space (8,3%)
19 Figure 1: coronal T2-weighted MRI reveals a well-defined right adrenal mass in our thirteen female patient (arrow).
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Figure 2(a)
Figure 2(b)
Figure 2(a: coronal) (b: axial):T1-weighted MRI reveals a well-defined right adrenal mass in our thirteen female patient (arrows).
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Due to the low specificity of the imaging for this tumor, the definitive diagnosis was based on histological exams [figure 3(a), 3(b), 3(c), 3(d)].
Figure 3(a) Figure 3(b)
Figure 3(c) Figure 3(d)
Figure 3 (a)(b)(c)(d): histological exam of our twenty-nine male patient’s ganglioneuroma: note the presence of mature ganglion cell (bold type arrows) – sometimes with dismosfism – on a background of mature Schwann cell (dotted arrows).
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The size of the tumors varies from 1,2x1x0,4 cm to 14,5x8x3,5 cm (on average 5,5x3,7x2,5).
Immunohistochemical tests showed lesional cells strongly positive to S-100 in 9 specimens (75%); NSE expression was positive in 4 cases (33,3%). The research of desmine, myogenin and CD99 were negative in one case; chromogranin and synaptophysin were focally positive in one case. Ki67 labeling index was <5% in four cases (33,3%). In all patients the levels of LDH were normal, as well as the electrolytes and the aldosterone levels. None of VMA/ HVA test identified any abnormalities and normal value was found for
blood level of adrenalina.
0% 20% 40% 60% 80% 100% S-100 + NSE + Ki 67 < 5% LDH abnormalities VMA/HVA abnormalities positive negative
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All patients underwent a surgical resection and the mass was completely excised. The chosen approach has depended on the mass localization: laparoscopic surgery for adrenal GNs, open surgery for retroperitoneal tumors (non-adrenal), cervicotomy for masses of the neck and toracotomic approach for GN of the costo-vertebral space. No intraoperative or post-operative complications occurred. All patients are alive, with no recurrence of disease to
date (Table 3, Table 4).
Treatment
• surgical excision: 100%
Surgery-related complications
• no complications: 100%
Follow-up
• no recurrence: 100%
24 Table 3: Description of our patient’s features.
Age Sex Localization LDH,
VMA/HVA, NSE, S-100 alterations Proliferative activity Ki-67 < 5%
Symptoms Therapy Complications
Follow-up
4 F Retroperitoneal
tissue
NSE +, S-100 +
None None Surgical
removal None No tumor recurrence (4 years) 5 F Retroperitoneal tissue
None None None Surgical
removal
None No tumor
recurrence (1 year)
13 F Adrenal gland NSE +,
S-100 + + None Surgical removal None No tumor recurrence (2 years) 21 M Costovertebral space
None None None Surgical
removal
None No tumor
recurrence (10 years)
26 F Cervical region S-100 + None Visible
mass Surgical removal None No tumor recurrence (8 years)
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29 M Adrenal gland S-100 + None None Surgical
removal
None No tumor
recurrence (2 years)
33 M Adrenal gland S-100 + None None Surgical
removal
None No tumor
recurrence (2 years)
37 F Adrenal gland S-100 + + None Surgical
removal
None No tumor
recurrence (1 year)
37 F Cervical region None None None Surgical
removal
None No tumor
recurrence (7 years)
37 F Adrenal gland NSE +,
S-100 + + None Surgical removal None No tumor recurrence (5 years)
41 F Adrenal gland S-100 + None None Surgical
removal
None No tumor
recurrence (5 years)
41 M Adrenal gland NSE +,
S-100 + + None Surgical removal None No tumor recurrence (5 years)
26 Table 4: Brief table describing our patients’ features.
Sex Age Localization Symptoms
Follow-up Male 4 (33.3%) Under 20 3 (25%) Adrenal gland 7 (58.3%) No related symptoms 11 (91.7%) No recurrence 12(100%) Female 8 (66.7%) Over 20 9 (75%) Costovertebral space 1 (8.3%) Related symptoms 0 (0%) Recurrence 0 (0%) Retroperitoneal tissue 2 (16.7%) Palpable mass 1 (8.3%) Progression 0 (0%) Cervical region 2 (16.7%)
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4 Discussion
GNs were first described by Lorentz in 1870 and first reported as occurring in the neck by De Quervain in 1899 [24]. The gender incidence varies in the literature [9]. Our literature review displays 105 (57.4%) female patients and 78 (42.6%) male patients (Table 5; Table 6). Our casuistry, instead, shows 8 out of 12 of female patients (66.7%). Although GNs usually develop in childhood, they are often detected in adults since they grow slowly. Two-third of patients is under the age of 20 years, and GNs are rarely observed over 60 years [63]. These data are confirmed by our literature review, in which 91.3 % of the patients are under 20 years. On the other hand, only 25% of our cases are under
20 years.
Hypothesis for the pathogenesis of benign GNs include the spontaneously or artificially induced maturation of neuroblasts in a neuroblastoma into distinct ganglion cells, the separation of the remaining cells from embryonic neural crest and the necrosis of neuroblasts at an early stage of tumor development [9]. In accordance to literature, also our GN cases can be defined as incidentalomas. These benign tumors may occur in any part of the mediastinum, the retroperitoneal tissue and the adrenal gland; few GNs occur in the cervical region [6]. Ganglioneuromas have also been reported to occur rarely in other locations, such as the tongue, bladder, uterus, bone and skin [7]. In our literature
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review - considering only cases with specified localization - the most involved localizations are confirmed: 29.7% of GNs are situated in adrenal glands, 21.8% in mediastinum, 20.8% in retroperitoneal tissue and 10.9% in cervical region. Even though with different percentages, our casuistry reports the same involved areas: 58.3% of GNs are located in adrenal glands, 16.7% of GNs are located in the retroperitoneal tissue, 16.7% of GNs are located in the cervical region and 8.3% of GNs are located in the costo-vertebral space.
The site and the size of the mass affect the symptomatology even if, in almost all the cases we experienced, the mass did not give any signs or symptoms. Cough, back pain and dyspnea may be observed in patients with
Localization
Adrenal gland (29,7%) Retroperitoneal tissue (21,8%) Mediastinum (20,8%) Cervical region (10,9%) Other localization (16,8%)29
tumors located in the mediastinum, whereas palpable abdominal mass, as well as sub-abdominal or back pain, may be observed in patients with tumor located in the retroperitoneum [63]; dysphagia is the most common presenting symptom for patient with retropharyngeal GN [64]. Even in our casuistry 91.7% of the patients did not report any related symptoms; one (8.3%) patient presents a visible and palpable cervical mass. Differently, our literature review reports 58,2% of the GNs with related symptoms, whereas 36.3% of GNs are asymptomatic and 5.5% of GNs presented a palpable mass.
These tumors are most commonly non-functional lesions [65]. According to this, none of our cases release cathecolamines, as the normal values of
Clinical data
Symptomatic (58,2%) Asymptomatic (36,3%) Visible/palpable mass (5,5%)
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VMA/HVA demonstrate. It has been reported that ganglioneuroma are secretory in up to 39% of patients releasing cathecolamines [9]. The elevated catecholamine increase the levels of VMA or HVA in the plasma or in urine, causing hypertension, diarrhea, sweating, flushing and renal acidosis [6]. When the mass was discovered, RMI or CT was usually performed to define the size, location, composition of the mass and its relationship to adjacent structures; specifically, this last aspect is important for the surgical approach [66]. On CT, adrenal ganglioneuroma appears as well-defined mass that is oval, crescentic, or lobulated with a fibrous capsule [67, 68]. Ganglioneuromas present low, homogeneous attenuation on unenhanced CT scan, and demonstrate slight to moderate enhancement, which may be heterogeneous or homogeneous
[67, 69].
There are described some features to MRI of adrenal gland with a ganglioneuroma: it has low signal intensity on T1-weighted images and heterogeneous, high signal intensity on T2-weighted images [68]. Nevertheless remains difficult to discriminate a benign lesion like ganglioneuroma from other kind of lesions: without a pathological exam of the lesion, it’s hard to reach a definitive diagnosis. Thus, histopatological exam of the surgical specimen has a central role [13]. Even for our patients MRI and CT-scan did not give any information about the biological behavior, but rather showed us extension and
exact localization of the mass.
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definitive diagnosis [15]. This is confirmed by our literature review, in which in 168 out of 175 (96%) patients a surgical excision was performed, while 5 (2.9%) patients were not surgically treated due to too extensive involvement of the tumor; only 2 (1.1%) patients underwent debulking treatment.
Considering only cases with a reported follow-up, 118 out of 119 (99.2%) of them did not presented recurrences. Our experience strengthens these data since all our patients underwent surgical resection and none of them present any recurrence to date. Since GN can tightly adhere to, or encase major vascular structures [16], attempting resection may lead to severe, sometimes life-threatening complications [17]. Although the potential risks of operating on a GN are well known, reports on surgery-related complications, including blindness and neurological dysfunctions, are limited to few single case reports; De Bernardi et al [17] reported that the surgery-related complication’s rate was 17.8%: specifically, 10% deals with moderate and sometimes persistent complications and 7% deals with severe complications. However, Retrosi et al [15] reported a higher rate of complications (30%), which occur more frequently in thoracic tumors, which includes Horner's syndrome, chylothorax, pneumothorax and arm pain. When the resection is near complete, the tumor may remain stable or grow slowly [10], even though four occurrences of late malignant changes have been reported [18, 21-23]: this last situation is possible for the capacity of de-differentiation of ganglion cells in a ganglioneuroma or for the presence of a long-term, quiescent form of neuroblastoma [18]. Retrosi et
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al [15] reported that the survival rate in children with this tumor is good despite incomplete tumor resection; even Sànchez-Galàn et al [70] asserted no regrowth or malignant behavior in a 4-cases casuistry with a residual mass after surgery. According to this, in our literature review only one case (0.8%) presented progression of tumor after incomplete surgery [17]. Adjuvant chemotherapy or radiotherapy are not indicated due to the benign nature of the disease [2]. In case of complete resection there is not a clear follow-up protocol in place: Cerullo et al [19] suggest yearly intensive clinical examination and MRI imaging to ensure no local recurrence and Modha et al [20] agree with them recommending an intensive one-year follow-up. Understandably, in case of incomplete resection a longer follow-up is requested since malignant transformation have occasionally been reported [18, 21-23] decades after the diagnosis of GN [17].
Table 5: Description of cases’ details reported in literature (2000-2014).
Study Case Age Sex Localization Symptoms/
tumefaction Therapy Follow-up Skaggs DL et al., 2000 [25] 1 5 M Sympathetic spinal cord symptoms Surgical removal Not reported
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et al.,
2001 [26]
4F tissue (5) (3), none (2) reported
(5) recurrence (5) Califano L et al., 2001 [27]
1 11 F Cervical region palpable
mass Surgical removal No recurrence Geoerger B et al., 2001 [9] 49 1-26 24 M, 25F Mediastinum (18), Thorax-abdomen (2), abdomen (18), adrenal glands (10), not specified (1) symptoms (34), none (13), palpable mass (2) Surgical removal (46) [complete (34), incomplet e (12)]; not reported (3) No recurrence (40), not reported (9) Kaufman MR et al., 2001 [24]
1 2 F Cervical region symptoms Surgical
removal Not reported Otal P et al., 2001 [28] 1 12 F Retroperitoneal tissue
not reported Surgical removal
Not reported
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D et al.,
2002 [29]
tissue removal reported
Chang CY et al., 2003 [30] 1 3 F Mediastinum and retroperitoneal tissue
none None Not
reported
Stàrek I
et al.,
2004 [31]
1 2 F Cervical region palpable
mass Surgical removal No recurrence Cannon TC et al., 2004 [32] 1 12 M Orbit palpable mass Debulkin g Not reported Yavascao glu I et al., 2004 [33]
1 9 M Adrenal Gland symptoms Surgical
removal No recurrence Przkora R et al., 2006 [34]
1 17 F Sacral region symptoms Surgical
removal No recurrence Cannady SB et al., 2006 [35] 5 6-7 2M, 3F Cervical region (5) symptoms (2), none (3) Surgical removal (5) No recurrence (5)
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Shome D
et al.,
2006 [36]
1 11 M Eye symptoms Surgical
removal Not reported Pratap A et al., 2007 [37]
1 12 M Left mesentery symptoms Surgical
removal Not reported Qureshi SS et al., 2008 [38]
1 3 F Adrenal glands palpable
mass Surgical removal Not reported De Bernardi B et al., 2008 [17] 45 2-17 15 M, 30F Cervical region (2), Thorax (20), Abdomen (20), Pelvis (3) [not well specified] symptoms (25), none (20) Surgical removal (42)(com plete [27], near complete [8], incomplet e [7]), none (3) No recurrence (27), local progressio n in 1 patient with incomplet e resection, not reported (17)
36 Patterson AR et al., 2008 [39] 1 12 F Mandible palpable mass Surgical removal No recurrence Zhang WQ et al., 2009 [40] 1 3 F Paravertebral, in
the lower thorax
symptoms Surgical removal No recurrence Soccorso G et al., 2009 [41]
1 5 F Sigmoid colon symptoms Surgical
removal Not reported Zugor V et al., 2009 [42] 2 5-8 1M, 1F Retroperitoneal tissue (2) none (2) Surgical removal No recurrence (2) Dimou J et al., 2009 [43]
1 19 F Sacral region symptoms Surgical
removal Not reported Shah SR et al., 2010 [44]
1 12 F Adrenal gland symptoms Surgical
removal Not reported Kattepura S et al., 2010 [45] 1 8 F Presacral and mediastinum none Surgical removal No recurrence
37 Cai J et al., 2010 [46] 17 2-16 10 M, 7F Adrenal glands (11), retroperitoneal tissue (6) symptoms (2), none (13), palpable mass (2) Surgical removal (17) Not reported (17) Lin PC et al., 2010 [47]
1 6 F Mediastinum symptoms Surgical
removal No recurrence Al-Khiary H et al., 2010 [48]
1 2 M Orbit symptoms Debulkin
g No recurrence Jawaid W et al., 2010 [49]
1 2 F Nasopharynx symptoms Surgical
removal Not reported Do SI et al., 2011 [50]
1 65 F Uterine cervix symptoms Surgical
removal No recurrence Retrosi G et al., 2011 [15] 24 3-10 11 M, 13F Thorax (14), abdomen (7), pelvis (3) [not well specified] symptoms (15), none (9) Surgical removal (24)(com plete [17], near No recurrence (24)
38 complete [6]); none (1) Eassa W et al., 2012 [51]
1 8 M Adrenal gland none Surgical
removal Not reported Demir HA et al., 2012 [52]
1 13 F Adrenal gland symptoms Surgical
removal Not reported Vasiliadis K et al., 2012 [53] 1 23 F Retroperitoneal tissue symptoms Surgical removal Not reported Carmelo M et al., 2012 [54]
1 15 F Adrenal gland symptoms Surgical
removal Not reported Elkaoui H et al., 2012 [55]
1 69 M Sacral region none Surgical
removal No recurrence Urata S et al., 2013 [56]
1 18 M Cervical region palpable
mass
Surgical removal
Not reported
39
Kara T et
al., 2013
[57]
1 28 M Mediastinum symptoms Surgical
removal Recurrenc e Lynch WP et al., 2013 [2] 1 42 F Retroperitoneal tissue symptoms Surgical removal No recurrence Meng QD et al., 2013 [58] 1 44 M Retroperitoneal tissue symptoms Surgical removal No recurrence Nasseh H et al., 2013 [59] 1 56 M Retroperitoneal tissue symptoms Surgical removal Not reported Kagacan C et al., 2014 [60]
1 53 F Adrenal Gland symptoms Surgical
removal Not reported Adas M et al., 2014 [61]
1 18 M Adrenal Gland symptoms Surgical
removal No recurrence Koktener A et al., 2014 [62] 1 35 F Retroperitoneal tissue symptoms Surgical removal Not reported
40 Table 6: Brief table describing the literature review (2000-2014) [2, 9, 15, 17,
24-62].
Sex Age Localization Symptoms
Follow-up Male 78 (42.6%) Under 20 167 (91.3%) Adrenal gland 29 (28.7%) No related symptoms 66 (36.3%) No recurrence 117 (98.3%) Female 105 (57.4%) Over 20 16 (8.7%) Mediastinum 22 (21.8%) Related symptoms 106 (58.2%) Recurrence 1 (0.8%) Retroperitoneal tissue 21 (20.8%) Palpable mass 10 (5.5%) Progression 1 (0.8%) Cervical region 11 (10.9%)
41
5 Conclusions
In conclusion, GN is a benign and rare tumor, with low or no metabolic activity, which most often occurs in mediastinum, retroperitoneal tissue and adrenal glands. The large part of patients affected by GN are under 20 years old. It is usually asymptomatic and for this reason it is often diagnosed as incidentaloma – as our experience confirmed - even if it may become symptomatic for the
releasing of cathecolamines or for the mass-effect.
Imaging does not allow a final diagnosis, but CT-scan and MRI are important for leading the surgical approach.
For an exact diagnosis, histological exam is always necessary. Mass excision is the chosen therapy, even if this treatment may lead to surgery-related complications since GNs may adhere to, or encase, vascular structures: to our experience, these events are infrequent. GN has an excellent prognosis and recurrences or malignant transformation are rare after surgical resection: in fact, none of our patients present recurrence or malignant transformation to date.
42
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Conflict of interest and Informed consent
The authors report no conflict of interest. This work was prepared after written informed consent was obtained from the patients or their relatives.
