Keywords neuroblastoma - pulmonary metastases - tumor thrombosis
Case Presentation
A 4-year-old girl presented with pain abdomen for 4 months and a lumpy feeling in
left upper abdomen for 2 months. On physical examination, a vague mass was palpable
at the left hypochondriac and lumbar regions. The mass was nontender, firm in consistency,
and was not ballotable. A few prominent abdominal veins were also seen. Blood workup
revealed elevated serum lactate dehydrogenases levels (763 IU, normal range: 120–220
IU). The adrenal cortical hormonal levels were within normal limits. Early morning
serum cortisol level was 80 ng/mL (normal less than 200 ng/mL). The serum catecholamine
levels were also within normal limits. Serum normetanephrine was 4 pg/mL (normal < 100
pg/mL) and serum metanephrine was 2 pg/mL (normal < 60 pg/mL). The hemogram was also
within normal limits.
Investigations and Imaging Findings
Investigations and Imaging Findings
Contrast-Enhanced Computed Tomography of Abdomen and Pelvis
A contrast-enhanced computed tomography (CT) scan of abdomen and pelvis was performed
on a 16-slice multidetector CT scanner (Siemens Somatom Sensation 16, Seimens Healthineers,
Erlangen, Germany) after administration of 40 mL intravenous nonionic contrast medium
with automated exposure control. Contrast medium used was iohexol of strength 300
mg/mL (Omnipaque, GE Healthcare, Marlborough, Massachusetts, United States). The CT
showed a large heterogeneously and mildly enhancing left suprarenal mass (as shown
in [Fig. 1 ]) with coarse calcifications within. The mass was indenting the spleen and the left
kidney was displaced in inferior direction. No definite renal or splenic infiltration
was seen. In addition, multiple conglomerate and discrete retroperitoneal nodes were
seen, encasing the abdominal aorta. Multiple bilobar hypodense hepatic lesions, suggestive
of metastases were also seen ([Fig. 2 ]). In addition, a large filling defect was seen involving the left renal vein, extending
into the inferior vena cava (IVC), reaching up to the retrohepatic IVC, up to the
level of hepatic venous confluence. It showed similar morphology and enhancement pattern
as the left suprarenal mass and was causing expansion of the involved vessels, suggestive
of tumor thrombus. Basal cuts of thorax showed multiple nodules in bilateral lower
pulmonary lobes, suggestive of metastases ([Fig. 2 ]).
Fig. 1 Axial (A ) and coronal (B ) images show a large left suprarenal mass (*) showing heterogeneous enhancement and
displacing the kidney inferiorly. The fat planes with spleen and kidney appear maintained.
Coronal CT (C ) shows multiple conglomerate and discrete retroperitoneal nodes, encasing the abdominal
aorta. Bone window (D ) demonstrates coarse calcifications within (shown by arrows). CT, computed tomography.
Fig. 2 Coronal (A ) and Sagittal (B ) images show multiple bilobar hepatic metastases. In addition, a large filling defect
was seen involving the inferior vena cava (marked by arrows), reaching up to the retrohepatic
IVC, up to the level of hepatic vein confluence. CT axial cut in lung window (C ) shows multiple varying sized pulmonary nodules and masses, scattered randomly in
both lungs with a basal predominance, suggestive of metastases. CT, computed tomography;
IVC, inferior vena cava.
Histopathology
Biopsy of the left suprarenal mass was performed under ultrasound guidance which showed
stroma poor poorly differentiated neuroblastoma with low Mitosis–Karyorrhexis index
(MKI). Histology was of unfavorable category as per the International Neuroblastoma
Pathology Classification system.[1 ] Further, evaluation with immunohistochemistry showed the tumor to be positive for
synaptophysin. Molecular studies showed N-MYC amplification. As per staging requirement
for neuroblastoma, bilateral bone marrow biopsies were done which showed normocellular
uninvolved marrow.
18-Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography
A further staging work-up with fluorodeoxyglucose positron emission tomography–computed
tomography (FDG PET-CT) was done. MIBG (metaiodobenzylguanidine) scan was not performed
after discussion at multidisciplinary meet as the tumor was poorly differentiated.
PET-CT showed hypermetabolic left suprarenal mass with hypermetabolic tumor thrombus
within the left renal vein and IVC, as well as multiple metastatic hypermetabolic
retroperitoneal nodes, and bilobar hepatic metastases. In addition, multiple metastatic
and hypermetabolic marrow lesions were seen ([Fig. 3 ]). Multiple bilateral pulmonary metastases were also seen distributed randomly in
both lungs with a basal predominance ([Fig. 2 ]).
Fig. 3 FDG PET CT of the patient showed conglomerate hypermetabolic retroperitoneal nodes
(arrows in A ). It also shows metabolically active
and inactive hepatic deposits. Hypermetabolic metastatic deposit involving left acetabulum
is shown by * in B . Maximum intensity projection
(MIP) images shows disseminated disease with multiple metabolically active nodules
in both lungs (C ). No FDG avid lesions were seen in brain.
FDG PET-CT, fluorodeoxyglucose positron emission tomography-computed tomography.
Differential Diagnosis
The main differential based on initial CT scan of abdomen was adrenocortical carcinoma
as the tumor was arising from the suprarenal region. Adrenocortical carcinoma has
a bimodal distribution of age with peaks in first and fourth decades. These can show
coarse calcification in up to 33% of cases[2 ] and lungs are the most common sites of metastases.[3 ] Intravascular tumor thrombosis can be found in up to 20% cases of adrenocortical
carcinoma.[4 ] Up to 40% cases of adrenocortical carcinomas can be nonfunctional.[5 ]
A pediatric lumbar region mass with IVC thrombus points toward a possible Wilm’s tumor.
However, in our case, fat planes with left kidney were maintained throughout with
the kidney displaced inferiorly. Hence, Wilm’s tumor was not in our list of possible
differentials.
Treatment, Outcome, and Follow-up
Treatment, Outcome, and Follow-up
As the patient had high-risk features, she was put on rapid COJEC chemotherapy regimen
(C, cisplatin; O, vincristine; J, carboplatin; E, etoposide; and C, cyclophosphamide).
She was scheduled for postchemotherapy FDG PET-CT for reassessment for surgery. After
the fifth cycle of chemotherapy, the child developed febrile neutropenia with tachycardia,
tachypnoea, and hypotension. Subsequently, the patient developed cardiac arrest and
unfortunately succumbed to same.
Discussion
Neuroblastoma spectrum comprises the most common extracranial solid neoplasm in pediatric
population[6 ] arising from neural crest cells and can show a wide range of clinical and imaging
presentation.[7 ] Bone and bone marrow metastases are the most common sites of metastases in neuroblastoma.[8 ] Unlike other pediatric extra cranial neoplasms, where lungs are usually most common
site of metastases, pulmonary metastases are very unusual in neuroblastoma even in
stage 4.[8 ]
[9 ]
[10 ] Stigall et al[11 ] described the following three types of pulmonary involvement: (1) direct extension,
(2) hematogenous spread, and (3) lymphatic spread. Our patient likely had hematogenous
spread, as they were distributed randomly in both lungs with a basal predominance
and also probably due to existing large volume tumor thrombus within the IVC.
A recent large retrospective study by International Neuroblastoma Risk Group (INRG)
showed overall incidence of pulmonary metastases to be 3.6%[12 ] which further bolstered the current clinical practice of not performing chest imaging
in suspected case of neuroblastoma. It has been postulated that this may be due hostile
environment within the lungs, inhibiting the growth of distant hematogenous seedlings
in neuroblastoma.[11 ] Even in published case reports of neuroblastomas with tumor thrombus within the
inferior vena cava, detection of pulmonary metastases was uncommon.[13 ]
[14 ]
[15 ] A study found that neuroblastoma cells do not passively travel along the direction
of blood flow.[16 ]
As it has been postulated that the pulmonary environment is relatively hostile for
the growth of neuroblastoma metastases, histologically and biologically aggressive
tumors tend to show higher incidence of pulmonary metastases.[12 ] The pathological, serological, and molecular features of such unfavorable histology
are poor differentiation, elevated lactate dehydrogenease (LDH) levels, and N-MYC
amplification, respectively.[12 ] All these findings were present in our study. The elevated LDH levels can reflect
higher proliferation of the tumor with higher cell turnover or could be due to injury
to the pulmonary tissue by the growing deposit.[12 ] Our patient did not show any evidence of neuroparenchymal metastases. While the
calvarium is a common site of neuroblastoma metastases, neuroparenchymal metastases
are rare.[8 ] Patients presenting with pulmonary metastases have been shown to have a higher incidence
of neuroparenchymal metastases well.[12 ] It is important to note that INRG study showed that while the lung metastases are
seen in association with disseminated disease to other site, these are not independent
prognostic marker of a poor outcome.
In addition, our patient showed a large tumor thrombus extending from left renal vein
into the IVC up to the hepatic venous confluence. Presence of IVC tumor thrombosis
is a rare occurrence in neuroblastoma and is an imaging feature more commonly associated
with Wilms’ tumor with only few case reports published.[17 ] As with the case of pulmonary metastases, presence of tumor thrombosis in a case
of neuroblastoma indicated an aggressive tumor and, hence, a poor prognosis and requiring
intensive chemotherapy.[18 ]
Conclusion
In conclusion, this was a unique presentation of pediatric adrenal neuroblastoma with
simultaneous presence of two rare manifestations, presence of pulmonary metastases
and tumor thrombus within the IVC. Due to this atypical presentation, the tumor was
suspected to be an adrenocortical carcinoma. Consistent with the literature, the presence
of these rare features was associated with aggressive histology, elevated LDH, and
N-MYC mutation.
Learning Points
Pediatric neuroblastomas may show extensive hematogenous metastases but surprisingly
have very low incidence of pulmonary metastases even in advanced disease. Also, these
tumors usually encase and compress the adjacent vascular structures and very rarely
cause infiltration of vessels with extension along them as a tumor thrombus.
Presence of a tumor thrombus does not imply a higher chance of pulmonary metastasis
as it has been postulated than pulmonary environment is not very conducive for growth
of these seedlings. Hence, presence of these two features simultaneously makes this
a rare presentation.
Presence of either of these (tumor thrombus and pulmonary metastases) imply aggressive
tumor as seen by unfavorable histology, elevated LDH levels, and N-MYC amplification
in this case.
Presence of pulmonary metastases is not an independent poor prognostic marker in these
patients but these patients have a poor clinical outcome due to aggressive underlying
tumor per se.
A suprarenal mass with multiple bilateral pulmonary metastases in a pediatric patient
should arouse the suspicion of an adrenocortical carcinoma which can also show coarse
calcification within. A histopathological examination is hence essential as the management
of the two tumors varies greatly.
