Neonatal suprarenal mass: differential diagnosis and treatment

Abstract

Purpose

To develop better diagnosis of and treatment strategy for suprarenal masses in the neonates.

Methods

A total of 28 neonates with suprarenal mass were treated in the Department of Pediatric Surgery, Children’s Hospital of Fudan University, between May 2003 and August 2010. The medical records of these patients were reviewed. The clinical, radiological, surgical and pathological data were collected.

Results

Six cases were diagnosed as having adrenal tumors, including 1 adrenal teratoma and 5 adrenal neuroblastomas (NB), and 22 cases were diagnosed as having adrenal hemorrhages. Ultrasound showed that the hematoma started to regress after 7 days to 6 months. Among the NBs, 2 cases were of stage I, 2 cases were of stage IV, and 1 case was of stage III. While 1 stage III patient and 1 stage IV patient underwent adjuvant chemotherapy after the surgery, other cases were cured by surgery alone and currently have no evidence of disease. The suprarenal mass presented cystoids or solid masses detected by ultrasound and CT both in adrenal hemorrhages and in tumors.

Conclusions

The accurate diagnosis of neonatal suprarenal mass depends on prenatal ultrasonography, clinical manifestations, urine VMA test, CT and ultrasound, but dynamic observation of suprarenal mass by CT and ultrasound is an important means of differential diagnosis. While conservative therapy is suitable for adrenal hemorrhage, adrenal tumors need surgical excision. In addition, adrenal mass that is difficult to diagnose can be followed up for 1 month without any adverse effects on the therapy and prognosis of the tumor.

Introduction

Suprarenal mass is a relatively uncommon clinical problem of the newborn period. During the past two decades, most of these tumors have been diagnosed antenatally due to the increasing use of third-trimester obstetrical ultrasound (Nadler and Barksdale 2000). Fetal suprarenal masses usually prove to be congenital neuroblastomas (CNB) developing from the adrenal gland. However, benign lesions such as an adrenal hemorrhage or subdiaphragmatic extralobar pulmonary sequestration (SEPS) also have been reported (Rubenstein et al. 1995). The optimal diagnosis of and treatment for these masses still remain a challenge for clinicians. The features of suprarenal mass on the antenatal ultrasound are variable and range from cystic, mixed solid and cystic, to a completely solid mass, with or without calcifications; most of these masses are proved to be congenital neuroblastomas (CNB) developing from the adrenal gland (Gurney et al. 1997). So it is virtually impossible to differentiate these lesions based on the antenatal ultrasound findings alone. CT is the modality of choice for patients with NB; it accurately depicts all primary tumors and metastatic lesions. Congenital adrenal cystic lesions such as adrenal cysts or adrenal hemorrhages are, although rare compared with CNB, truly benign lesions, and treatment strategies for them differ from those used to treat CNB (Chen et al. 1997; Acharya et al. 1997). Thus, the correct diagnosis is essential for optimal postnatal treatment, but the optimal diagnosis of and treatment for these masses still remain a challenge for clinicians. In this study, we aimed to investigate the diagnosis of and treatment strategy for suprarenal masses in neonates based on a retrospective study of 28 cases of suprarenal masses in the neonates.

Materials and methods

Patients

We reviewed the files of 30 neonate patients with suprarenal masses who were hospitalized at the Children’s Hospital of Fudan University (Shanghai, China) between May 2004 and August 2010. Two cases were excluded from this study because they gave up the therapy.

Criterion for diagnosis

Suprarenal masses in neonates were diagnosed based on prenatal examinations and postnatal ultrasonography and CT of abdomen. Diagnosis of adrenal hemorrhage was mainly based on imaging examinations such as ultrasonography and CT. Tumors were confirmed by pathological analysis after the surgery or biopsy. The neuroblastoma stage was evaluated according to International Neuroblastoma Staging System (INSS) criteria. Pathology classification was based on Shimada system and classified as FH (favorable histology) and UH (unfavorable histology).

Statistical analysis

Statistical analysis was performed with SPSS15.0 software. The differences between groups were tested for significance using α² test or Fisher’s exact test, and P values <0.05 were considered statistically significant.

Results

Basic data of patients

From May 2004 to August 2010, 28 neonates diagnosed as having suprarenal masses were hospitalized at the Children’s Hospital of Fudan University. They included 17 males and 11 females. Their age ranged from 2 h to 24 days (medium age: 3.5 days). Five cases were on the left adrenal, and 23 cases were on the right. All children were delivered in full term, including 20 cases of spontaneous delivery, 7 cases of Caesarian section and 1 case of dystocia. Five cases were born with weight more than 4 kg, 18 cases were born with weight less than 4 kg, and the birth weight of the remaining was unclear. Notably, 7 cases were diagnosed as having suprarenal masses based on prenatal ultrasonography 4–30 days before the delivery, accounting for 25 % of all cases.

Clinical features of patients

Except the 7 cases diagnosed prenatally, 8 cases had jaundice, 3 cases had asphyxia after birth, 3 cases had vomiting, 2 cases had scrotal hematoma, 2 cases had abdominal mass, and the remaining 3 cases had birth trauma, postnatal trauma and coughing, respectively. All 28 cases were subjected to routine blood test, liver and kidney function test, blood coagulation test and ultrasonography examination. In addition, 25 cases were examined by abdominal enhanced CT. Nineteen cases were subjected to 24-h urinary VMA test, and only 3 cases had values higher than normal and were pathologically confirmed as having neuroblastoma. The tumor size (maximum diameter) ranged from 2.35 to 6.00 cm with the mean as 4.28 cm.

Diagnosis and therapy of patients

Three cases of adrenal hemorrhage were discharged after finishing part of the examinations. The remaining 14 cases of adrenal hemorrhage were discharged after symptomatic treatment and followed up afterward. Among them, 7 cases were reexamined by ultrasonography 3–12 days after the treatment and discharged because the tumor size was reduced. Three cases were diagnosed as having adrenal neuroblastoma, including 1 case at clinical stage III and 2 cases at clinical stage IV. Surgery was performed in the 3 cases of adrenal neuroblastoma, with 1 case undergoing routine mass biopsy and 2 cases undergoing excision. All cases were pathologically confirmed as neuroblastoma. After the operation, one case of stage IV did not undergo chemotherapy, while other 2 cases at stage III and stage IV were treated by chemotherapy. For other 8 cases, it was very difficult to distinguish between adrenal hemorrhage and tumor; thus, they were discharged from the hospital and were followed up. Three cases developed increased mass and were hospitalized again to excise the masses, which were pathologically confirmed as neuroblastoma (clinical stage I) in 2 cases and mature teratoma in 1 case. One case exhibited no change of tumor mass and was diagnosed as having adrenal hemorrhage based on mass biopsy. The mass reduced or disappeared in the remaining 4 cases when followed up (Fig. 1).

Fig. 1.

Flowchart for the diagnosis and therapy of suprarenal masses

Follow-up of patients

Twenty-five cases were followed up till December 2010. The remaining 3 cases were of adrenal hemorrhage and not followed up. The follow-up rate was 89.3 %, and the follow-up time ranged from 4 to 78 months, with a median follow-up time of 36.4 months. All cases survived; especially, 1 case of adrenal neuroblastoma at stage IV survived despite the presence of the tumor. For the cases of adrenal hemorrhage, the mass gradually reduced about 1 week after the onset of mass, and most of them disappeared in 1–2 months, no later than 6 months. Till the end of the follow-up, suprarenal masses disappeared in all cases that were followed up, and no calcification or residual mass was observed.

Comparison analysis of patients in groups

The patients were classified into 2 groups: adrenal tumor and adrenal hemorrhage. These 2 groups were compared according to prenatal examinations, clinical manifestations, CT and ultrasonography, treatment and follow-up.

Tumor group

The group of adrenal tumor included 6 cases (2 males and 4 females). The birth weight of 1 case was more than 4 kg. Two cases were on the left side and 4 cases on the right side. The tumor size (maximum diameter) was 4.30–6.00 cm (mean 5.17 cm). Five cases were diagnosed based on prenatal examination, accounting for 83.3 % of the cases in this group. Only 1 case was hospitalized because of abdominal mass. One case was teratoma, and the other 5 cases were neuroblastoma. All cases underwent ultrasonography and enhanced CT examinations, the solid mass was detected in 4 cases, and cystic mass was detected in 1 case. Based on ultrasonography, blood-flow signals were detected in 3 cases but not in other 2 cases. Enhanced CT showed that all 5 cases of neuroblastoma had enhancement, but calcification was only detected in 2 cases. In 3 cases (50 % of the group), 24-h VMA in the urine was abnormally high. Tumor stage, treatment and follow-up results are listed in Table 1. Cases 4, 5 and 6 were difficult to diagnose and thus were followed up closely. They developed expanded mass during the follow-up and were re-hospitalized for surgery.

Table 1.

Clinical data on adrenal tumor patients

Case no.	Time of diagnosis	Side	Tumor size (cm)	Ultrasonography examination	24-h urine VMA (ng/ml)	Pathology	INSS stage	N-myc amplification	Treatment	Outcomes	Follow-up (month)
1	Pregnant 40 weeks	Right	5.6	Solid	High (7.5)	NB, FH	III	Negative	Chemotherapy after biopsy and excision	Survive without tumor	55
2	Pregnant 39 weeks	Right	5.6	Solid	High (6.6)	NB, FH	IVs liver metastasis	Negative	Excision, no chemotherapy	Survive with tumor	5
3	Pregnant 37 weeks	Left	4.3	Cystic	High (14)	NB, FH	IVs liver metastasis	Negative	Excision and chemotherapy	Survive without tumor	43
4	Not during pregnancy	Left	6.0	Solid	Normal (0.5)	NB, FH	I	Negative	Excision after follow-up, no chemotherapy	Survive without tumor	39
5	Pregnant 38 weeks	Right	4.8	Solid	Normal (2.5)	NB, FH	I	Negative	Excision after follow-up, no chemotherapy	Survive without tumor	12
6	Pregnant 40 weeks	Right	4.7	Solid and cystic	Normal (0.4)	Teratoma	–	–	Excision after follow-up	Survive without tumor	67

NB neuroblastoma; urine VMA <4.5 ng/ml was regarded as normal; pathology classification was based on Shimada system

Non-tumor group

The group of adrenal hemorrhage included 22 cases (15 males and 7 females). The birth weight of 3 cases was more than 4 kg. Three cases were on the left side and 19 cases on the right side. The tumor size (maximum diameter) was 2.35–5.88 cm (mean 4.04 cm). Two cases were diagnosed based on prenatal examination, accounting for 9.1 % of the cases in this group. All cases underwent ultrasonography, the solid mass was detected in 15 cases, and cystic mass was detected in 7 cases. In addition, blood-flow signals were detected in 2 cases but not in other 20 cases. Nineteen cases underwent enhanced CT, and only 7 cases had enhancement at the edge of the tumor. In all 13 cases tested, 24-h VMA in the urine was normal. One month after the follow-up, the tumor reduced or disappeared in 16 cases. One case exhibited no change in tumor mass and was diagnosed as having adrenal hemorrhage based on mass biopsy, and the mass disappeared 3 months after the surgery (Table 2).

Table 2.

Clinical data on adrenal hemorrhage patients

Case no.	Diagnosis before the delivery	Side	Tumor size (cm)	Ultrasonography examination	24-h urine VMA (ng/ml)	When the tumor disappeared (month)	Follow-up (month)
1	No	Right	4.9	Cystic	0.9	2	78
2	No	Right	3.6	Solid	–	3	78
3	No	Right	3.8	Cystic	–	1	71
4	No	Right	4.6	Solid	–	2	65
5	No	Right	3.1	Solid	–	–	Not followed
6	No	Right	4.0	Cystic	0.8	1	52
7	No	Left	2.5	Cystic	–	2	51
8	No	Right	4.0	Solid	–	1	51
9	No	Right	4.1	Solid	0.6	1	51
10	No	Right	5.6	Solid	0.7	2	49
11	No	Right	4.7	Solid	1.8	3	44
12	No	Right	3.5	Cystic	–	–	Not followed
13	No	Right	4.3	Solid	0.8	2	40
14	Pregnant 38 weeks	Right	3.6	Solid	0.76	6	37
15	No	Right	2.35	Cystic	–	1	35
16	No	Right	4.22	Solid	1.871	2	33
17	No	Right	4.26	Solid	0.3	–	Not followed
18	Pregnant 34 weeks	Left	2.67	Cystic	–	2	21
19	No	Right	4.49	Solid	–	1	9
20	No	Left	5.88	Solid	0.9	1	11
21	No	Right	4.34	Solid	0.6	2	11
22	No	Right	4.4	Solid	1.9	1	4

Statistical analysis showed that there were no statistically significant differences between adrenal tumor group and adrenal hemorrhage group in the tumor size (P = 0.72), the proportion of children with birth weight >4 kg (P = 0.263) and urinary VMA value (P = 0.289). However, statistically significant differences between adrenal tumor group and adrenal hemorrhage group were observed in the blood-flow signals in the tumor detected by ultrasonography (P = 0.02) and the enhancement within the tumor detected by enhance CT (P = 0.007).

Discussion

The wide application of abdominal ultrasonography during the pregnancy and in the postnatal period has led to increased rate of detection of suprarenal masses (Nadler and Barksdale 2000). Among the suprarenal masses, neuroblastoma is the predominant neonatal malignancy, but suprarenal masses can be additionally ascribed to adrenal hemorrhage and subdiaphragmatic extralobar pulmonary sequestration (SEPS) (Rubenstein et al. 1995). Suprarenal masses are predominantly in the right side (Chen et al. 1997; Acharya et al. 1997). The clinical manifestations of suprarenal masses vary, and common symptoms include jaundice, abdominal mass, anemia and scrotal hematoma. Our study showed similar results, and the clinical manifestations of jaundice, asphyxia and scrotal hematoma in neonates may help the clinical diagnosis of adrenal hemorrhage.

The accurate diagnosis of suprarenal masses in neonates still remains a challenge for clinicians (Lin et al. 1999), especially to distinguish neuroblastoma and adrenal hemorrhage. The incidence of suprarenal masses in neonates is about 1.9/1,000 (Lack 1997), much higher than that of neuroblastoma in neonates (0.058/1,000), and is related to perinatal asphyxia, stress response, birth trauma and clotting disruption. Prenatal ultrasonography is effective in the diagnosis of suprarenal masses. The rate of accurate diagnosis for neuroblastoma in neonates is 81–85 % (Sun et al. 2000; Sauvat et al. 2002), but is very low for adrenal hemorrhage (Mittelstaedt et al. 1979). In this study, our data showed that the rate of prenatal diagnosis of suprarenal masses was 25 %, among which adrenal tumor accounted for 71.4 %, much higher than adrenal hemorrhage. Our findings are in agreement with previous studies and suggest that prenatal diagnosis of suprarenal masses should be preferentially focused on neuroblastoma (Shao et al. 1999).

Imaging examinations such as ultrasonography and CT are highly contributory to the diagnosis of suprarenal masses. There are three basic morphologies on ultrasound. Half of the adrenal masses were solid isoechoic masses, and the remaining cases were either purely cystic hypoechoic masses or complex structures containing both cystic hypoechoic fluid and echogenic solid material (Fang et al. 1999; Erbil et al. 2008). The ultrasonography of adrenal hematoma is related to the time when the hematoma is formed. On the other hand, color Doppler ultrasonography could detect blood-flow signals in neuroblastoma (Kozakewich et al. 1998; Hamada et al. 1999). Based on CT examination, both hemorrhage and neuroblastoma are represented as mass with uneven density, but the former appears as round cystic lesion within the non-enhanced mass only slightly enhanced in the edge, while the latter demonstrates as tumors with irregular morphology and generally enhanced inside (Lee et al. 1998). In this study, by ultrasonography we found statistically significant difference between adrenal tumor group and adrenal hemorrhage group in the blood-flow signals in the tumor. In addition, by enhanced CT, significant difference between the two groups in the enhancement within the tumor was observed. Taken together, these data strongly suggest that CT and ultrasonography are important methods for the diagnosis and distinction of adrenal tumor and adrenal hemorrhage, and moreover, dynamic observation of suprarenal mass by CT and ultrasound were most important for differential diagnosis.

Urinary catecholamine metabolites including VMA and HVA have been proposed as a sign of neuroblastoma. However, increased urinary VMA and HVA levels were only detected in about 50 % neuroblastoma neonates (Stevens 1988). Our data show that only 3 cases had abnormal high level of urinary VMA. Notably, these 3 cases were of advanced neuroblastoma (stage III and IV), while cases of stage I neuroblastoma demonstrated normal urinary VMA level. Thus, we propose that urinary VMA level is not a valuable index for the diagnosis of adrenal masses. We also compared the tumor size between adrenal tumor group and adrenal hemorrhage group and found no statistically significant difference (P = 0.72 > 0.05). Therefore, it appears that tumor size is not useful for the diagnosis of adrenal masses.

Neonatal adrenal hemorrhage is mainly treated by conservative therapy (Sauvat et al. 2002; Hero et al. 2008). However, surgery is the main option for neuroblastoma treatment (Bianchi et al. 2000; Woodward et al. 2005). Chemotherapy is not necessary for stage I and II neuroblastoma, but stage III, IV and some stage IV neuroblastoma should be treated with postoperative adjuvant chemotherapy. In recent years, given that neonatal neuroblastoma may undergo spontaneous regression and stage IVs neuroblastoma has a good prognosis, alternative therapy has been proposed to avoid the high risk of surgery and chemotherapy for the neonates, but this treatment strategy remains controversial (Nuchtern 2006; Sklair-Levy et al. 2001). In this study, we treated adrenal hemorrhage by stopping the bleeding or follow-up and treated neuroblastoma with surgery and/or chemotherapy. All treated cases survived till the end of the follow-up. Three cases with no clear nature of the mass were followed up for 1 month till the tumor mass increased, which were then excised and still diagnosed as stage I neuroblastoma. The prognosis of this case was good, and the patient survived with no tumor, similar to the patients who underwent surgery before the follow-up. It is a big challenge for a pediatric surgeon to choose the treatment strategy for the adrenal mass with no clear nature. Based on our results, we think that these cases can be followed up and examined within 1 month after the onset of the mass. If the mass increases or shows no tendency to reduce, further imaging, urinary catecholamines, tumor histopathology and cytogenetics should be given to confirm diagnosis and staging. Otherwise, follow-up can be continued. This strategy will not significantly delay the diagnosis and effective treatment, but also will avoid unnecessary surgery and the associated risks in the neonates.

The accurate diagnosis of neonatal suprarenal mass depends on prenatal ultrasonography, clinical manifestations, urine VMA test, CT and ultrasound, but dynamic observation of suprarenal mass by CT and ultrasound is important means of differential diagnosis; especially, detection of tumor enhancement and blood-flow signal by enhanced CT and ultrasonography are important for the differential diagnosis of adrenal tumor and adrenal hemorrhage. While conservative therapy is suitable for adrenal hemorrhage, adrenal tumors need surgical excision. In addition, adrenal mass that is difficult to diagnose can be followed up for 1 month without any adverse effects on the therapy and prognosis of the tumor.