Keywords
renal neuroblastoma - Wilms tumor - diagnostic dilemma - mimicked
Introduction
Neuroblastoma (NB) is the most common malignant abdominal neoplasm in infancy and
early childhood, and it constitutes 8 to 10% of childhood cancers.[1] It is well known for its varied clinical presentations. Around 65% of primary tumors
are found in adrenals, and the remaining originate anywhere in the body along the
sympathetic chain.[1] Renal NB is believed to originate from either sequestration of adrenal medullary
tissue in the kidney during fetal development or intrarenal sympathetic ganglion or
a spread of aggressive NB infiltrating into the kidney.[2] NB is rightly known as a great masquerader of Wilms tumor clinically and radiologically.
NB arising from the kidney or large tumor that completely replaces the kidney may
also resemble Wilms tumor and cause diagnostic dilemma and improper management. Both
the tumors occur in the early pediatric age group, with Wilms tumor having a little
older peak incidence at between 3 to 4 years. Pathologically, they are different diseases,
with NB originating from the primordial neural crest and Wilms tumor arising from
mesodermal tumors.[3] Although NB, compared with Wilms tumor, is an aggressive malignancy, it usually
presents with metastasis at the time of presentation in around 75% of cases. Hereby,
we discuss three cases who presented with renal masses and posed a diagnostic dilemma
and delayed management.
Clinical Details of Patients
Case 1
A 6-year-old girl presented to our hospital with a complaint of left-sided mild abdomen
pain and abdomen lump for 1 month. There was a history of low-grade fever and weight
loss of ~10% over 1.5 months. She denied any history of hematuria. At presentation,
she had a large, hard, and nontender mass occupying the left half of the abdomen with
rounded discrete margins. She did not have hypertension.
Baseline complete blood counts, liver function tests, and kidney function tests were
normal. Serum lactate dehydrogenase (LDH) was 1311 U/L. Urine VMA (vanillylmandelic
acid)/creatinine ratio was 1.0 mg/g of creatinine (not elevated). The serum ferritin
was 1375 ng/ml. The bone marrow examination did not reveal any tumor cells. Contrast-enhanced
computerized tomography (CECT) scan of the chest and abdomen revealed a large heterogeneous
mass of 11.5 × 9.5 cm with large areas of central necrosis arising from the left kidney.
The mass appeared to displace and insinuate between the abdominal aorta and inferior
vena cava (IVC) without any vascular invasion. The chest CT scan showed multiple nodules,
1.07 cm × 0.7 cm in the right upper lobe and another in the right middle and lower
lobe. Overall, the CT findings were suggestive of Wilms tumor with lung metastasis
([Fig. 1]). Metaiodobenzylguanidine (MIBG) scan did not show any MIBG avid lesion.
Fig. 1 Contrast-enhanced computed tomography (CECT) abdomen showing left renal mass with
necrosis (A and B) and right lung metastasis (C).
With the initial possibility of Wilms tumor, she was started on chemotherapy as per
International Society of Pediatric Oncology (SIOP) protocol (weekly vincristine, actinomycin-D,
and doxorubicin) after taking a biopsy from the mass. After two cycles of the above
chemotherapy, the NMYC amplification report came out to be amplified. The patient
was then switched to the Vincristine, Cisplatin, Etoposide, Cyclophosphamide (OPEC)/Vincristine,
Carboplatin, Etoposide, Cyclophosphamide (OJEC) regimen. The biopsy tumor cells were
diffusely immunopositive for chromogranin and synaptophysin, while negative for Wilms
tumor-1. The final impression was NB.
After four cycles of OPEC/OJEC, the tumor was not amenable to surgery. After 7 months
from the presentation to us, she lost to follow-up.
Case 2
A 3-year-old male child presented to us with fever, abdominal distension, and fast
breathing for the last 2 months. He also had abdominal pain. There was a history of
blood transfusion in this child. He had hypertension. His abdomen was distended. There
was an immobile, nontender mass palpable in the left hypochondrium. Serum ferritin
was 3,432 ng/mL, and the urinary VMA was elevated.
The CECT abdomen and chest suggested left renal mass with intrathoracic extension
with left pleural effusion and pleural based mass. The possibility of Wilms tumor
was considered, and the child was started on chemotherapy for Wilms tumor (SIOP protocol:
vincristine and actinomycin-D) in another hospital, and the patient was referred to
our hospital. In view of inadequate response to chemotherapy, he was planned for re-evaluation.
A biopsy was done, which was suggestive of NB. Cytogenetic analysis showed the amplification
of MYCN. The bone marrow aspiration and biopsy did not show the presence of metastases.
He was started on the CDCE cycle (cisplatin, cyclophosphamide, doxorubicin, and etoposide).
For hypertension, he was started on amlodipine, enalapril, and labetalol. However,
there was no response in size of mass or respiratory distress. Subsequently, he was
started on OJEC chemotherapy, to which he had a suboptimal response. Parents were
counseled regarding poor prognosis in view of high-risk disease and no response to
first-line chemotherapy. After a discussion with his parents, he was planned for salvage
chemotherapy. He was started on salvage chemotherapy consisting of irinotecan and
temozolomide. Even after salvage chemotherapy, there was no response. Finally, we
decided on palliative care for him and discharged him on home-based oxygen.
Case 3
A 5-year-old male child presented with fever, pallor, and progressive abdominal distension
for the last 10 days. He had bilateral cervical lymphadenopathy (maximum size 3 cm).
The abdomen was distended, and he had a hard lump in the right hypochondriac and iliac
fossa, not moving with respiration, and it was nontender.
The CECT abdomen showed a large heterogeneously enhancing mass with renal claw sign;
the mass was encasing the aorta, IVC, and celiac trunk. A provisional diagnosis of
Wilms tumor or NB was considered. Urine VMA was not elevated (9.3 mg). Serum ferritin
(761 ng/mL) and LDH (5823 U/L) were elevated. The NMYC was not amplified. Bone marrow
examination showed the presence of metastatic infiltration by the tumor. The histopathology
report confirmed the diagnosis of NB. He was staged as high-risk (stage-IV) NB. The
child was given cytoreductive chemotherapy followed by definitive chemotherapy in
the form of an OPEC-OJEC regimen. After the fourth cycle of chemotherapy, he had progressive
disease.
Discussion
The treatment and prognosis for NB and Wilms tumors are very diverse. Primary renal
NB carries a worse prognosis and requires intensive chemotherapy. It is important
to make the distinction between these two at the earliest. In more than 90% of cases,
NB is MIBG avid, and it is associated with elevated urine VMA.[4] Compared with Wilms tumor, hypertension is more common, and pulmonary metastasis
is uncommon, and the patient is generally sicker in NB.[3] However, 5 to 10% of cases of NB may present with diagnostic ambiguity.[2] A diagnostic dilemma and inadequate management happen in children with cancer when
a relatively stable child presents with renal mass with normal blood pressure and
pulmonary metastasis and negative MIBG and normal urine VMA levels. Our first patient
presented with renal mass, normal blood pressure, pulmonary metastasis, and normal
urine VMA. Case 2 presented with renal mass with high blood pressure, pulmonary metastasis,
and elevated VMA. Case 3 presented with normal blood pressure, without pulmonary metastasis,
and normal VMA.
Renal NB is of two types. It may result from primary intrarenal NB (IRNB) or renal
invasion by NB. The IRNB may result from either sequestered adrenal rests during the
fetal life or intrarenal sympathetic ganglia.[2] Complete renal invasion by NB may also masquerade as Wilms tumor.[5] Moreover, primary IRNB is usually associated with a poor prognosis as the tumor
presents with secondary metastasis at the time presentation of. Our first case responded
to chemotherapy (pulmonary metastasis disappeared), but the tumor was not amenable
to surgery after four cycles of chemotherapy (tumor was encasing to renal vessels).
Case 2 also did not respond to chemotherapy, including salvage therapy, and case 3
progressed after four cycles of chemotherapy.
The primary renal involvement by NB is reported in 5.2 to 25% of cases.[6] The renal involvement correlates with large size of the primary tumor, lymph node
involvement, undifferentiated histology, and NMYC status.[5] In a series of 868 NB cases by Shamberger et al, 1 to 2% cases were presented as
IRNB, and they suggested that preoperative chemotherapy may reduce the number of nephrectomies
for an initial impression of Wilms tumor.[6] In the German NB trial of 1,603 NB patients, 29 patients (1.8%) were those who were
initially diagnosed and treated as Wilms tumor. In this study, the postchemotherapy
surgery of mass revealed NB. These were mostly advanced-stage disease (stage-III or
stage-IV), older age at diagnosis with higher levels of LDH, ferritin, and higher
incidence of NMYC amplification than those upfront managed as NB. In this study, the
prognosis of patients with NB was reported inferior compared with tumors that have
been radiologically classified as Wilms tumor.[7] All three cases of ours had a high LDH level and high ferritin. Our cases 1 and
2 had NMYC amplification and inadequate response to therapy. However, case 3 was NMYC
nonamplified but had progressive disease after four cycles of chemotherapy.
Lung metastasis in NB is very rare, and patients with lung metastasis are sicker,
and the prognosis of these patients is worse. Lung metastasis at the initial diagnosis
of NB was associated with NMYC amplification, metastasis to central nervous system,
elevated LDH levels, and poor outcome.[8] It was associated with an inferior outcome but not independent of tumor biology.
The same parameters were also present in our cases 1 and 2. The summary of NB cases
mimicked Wilms tumor is depicted in [Table 1].
Table 1
Summary of neuroblastoma cases mimicked Wilms tumor reported in the literature
|
Author
|
Reference
|
No of cases
|
Age
|
Gender
|
Blood pressure
|
Site
|
LDH
|
Ferritin
|
VMA
|
NMYC
|
Pulmonary metastasis
|
Bone marrow
|
MIBG
|
CT/RT
|
Surgery
|
Outcome
|
|
Abbreviations: CT, chemotherapy; Lt, left; LTFU, lost to follow-up; MIBG, meta iodobenzyl
guanidine; NA, not available; PD, progressive disease; RT, radiotherapy; Rt, right;
SCT, stem cell transplant; VMA, vanillylmandelic acid.
|
|
Fan
|
9
|
8
|
3–39 mo
|
M: 7
F: 1
|
High: 6
|
Rt:4
Lt:4
|
NA
|
NA
|
Elevated: 6
|
Not amplified: 6
NA: 2
|
NA
|
Involved: 1
|
–
|
CT: 6
SCT: 2
RT: 1
Observation: 2
|
–
|
Died: 1
|
|
Kessler et al
|
3
|
5
|
11mo–5 y
|
M: 3
F: 2
|
High: 5
|
Rt:3
Lt:2
|
NA
|
High: 1
Normal: 1
NA:3
|
Elevated: 4
|
Amplified: 2
|
None
|
Involved: 3
|
Nonavid: 1
NA: 4
|
CT: 3
RT: 3
|
Nephrectomy: 3
Tumor resection: 1
|
Died: 3
|
|
Lall et al
|
2
|
3
|
2mo–4 y
|
M: 3
|
High: 2
|
Lt:2
Rt:1
|
NA
|
NA
|
Elevated: 3
|
NA
|
None
|
Involved: 3
|
NA
|
Chemotherapy: 2
|
Nephrectomy: 2
|
Died: 1
|
|
Sarin et al
|
10
|
1
|
3.5 y
|
M
|
NA
|
Lt
|
NA
|
NA
|
Elevated
|
NA
|
None
|
Not involved
|
NA
|
CT
|
Surgical excision
|
Survived
|
|
Sellaturay
et al
|
11
|
1
|
9mo
|
M
|
High
|
Rt
|
NA
|
NA
|
Normal
|
Not amplified
|
None
|
Not involved
|
Nonavid
|
CT
|
Nephrectomy
|
Survived
|
|
Treetipsatit et al
|
12
|
1
|
5 y
|
F
|
|
Rt
|
NA
|
NA
|
NA
|
NA
|
None
|
Not involved
|
NA
|
CT
RT
|
Nephrectomy
|
Survived
|
|
Farmakis and Siegel
|
13
|
1
|
14mo
|
M
|
High
|
Lt
|
High
|
NA
|
Elevated
|
Amplified
|
Yes
|
Involved
|
Avid
|
CT
SCT
|
Nephrectomy
|
Survived
|
|
Telli et al
|
14
|
1
|
13mo
|
F
|
Normal
|
Lt
|
NA
|
NA
|
Normal
|
NA
|
Yes
|
Not involved
|
Nonavid
|
CT
SCT
|
Nephrectomy
|
Survived
|
|
Index report
|
Index cases
|
3
|
3–6y
|
M: 1
F: 1
|
High: 2
Normal: 1
|
Lt: 2
Rt: 1
|
High: 3
|
High:3
|
Elevated: 2
Normal: 1
|
Amplified: 2
|
Yes: 2
None: 1
|
Involved: 1
|
Nonavid: 1
NA:2
|
CT: 3
|
None: 2
|
LTFU: 1
Palliative care: 1
PD: 1
|
The incidence of hypertension (66–100%) is more in IRNB compared with extrarenal NB
(27%).[3] However, this finding is not specific, and it also occurs in 20% of patients with
Wilms tumor.[13] Testing of urine catecholamines (VMA and HVA) is crucial to further make the diagnosis
of NB.[9] If any patient presents with renal mass and hypertension with high catecholamines,
one should strongly suspect NB because these levels are elevated in around 90% of
cases with NB.[15]
Renal NB presents with the high stage at diagnosis as all our cases had advanced stages,
and this entity portrays poor outcomes. Primary renal NB carries a poor prognosis,
and it requires rigorous adjuvant therapy and close surveillance postoperatively.
It is very important to make the distinction between NB and Wilms tumor as treatment
and prognosis have differed in these two.[9] All three cases were initially diagnosed as Wilms tumor and later diagnosed to have
NB. All three cases in our series had a poor prognosis.
Conclusion
It is a diagnostic challenge to distinguish renal NB and Wilms tumor preoperatively.
Proper histopathological diagnosis of a renal tumor is important as the management
and prognosis of Wilms tumor and NB are different. IRNB should be considered with
the combination of renal mass with hypertension and elevated catecholamines. Primary
renal NB is associated with unfavorable biology and outcome. Besides, upfront nephrectomy
in IRNB may lead to unnecessary loss of the kidney. In doubtful cases of Wilms tumor,
the biopsy should always be performed to prevent such errors in judgments.
