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Original Study

Renal Primitive Neuroectodermal Tumor With

Inferior Vena Cava Thrombus: Case Series and
Literature Review of a Rare but Challenging
Entity
Chuxiao Xu, Zhenghui Sun, Ruotao Xiao, Wei He, Lulin Ma
Abstract
Renal primitive neuroectodermal tumors with inferior vena cava (IVC) tumor thrombus is an extremely
rare entity that poses a massive challenge to diagnosis and treatments. Histopathology remains the gold
standard for definite diagnosis. Radical nephrectomy with IVC tumor thrombectomy is a challenging procedure
requiring vascular management techniques and experience. Adjuvant chemotherapy contributes to improved
progression-free, but not overall, survival.
Objective: To investigate the clinicopathological characteristics, treatments, and prognosis of patients with renal
primitive neuroectodermal ectodermal tumors (rPNETs) with inferior vena cava (IVC) tumor thrombus. Patients and
Methods: We retrospectively reviewed 6 patients with rPNETs and IVC tumor thrombus between January 2005 and
December 2019, and identified 39 published cases through a literature review. The clinicopathological characteris-
tics, treatments, and survival data were analyzed. Results: The median patient age patients was 26 years, and the
male to female ratio was approximately 1:1. The average tumor diameter was 12.5 cm. Seventeen patients (37.8%)
showed metastasis at diagnosis. Forty-three cases (95.6%) were managed with surgical resection, and 35 (77.8%)
received adjuvant chemotherapy after surgery. Follow-up data were available for 41 patients (median follow-up, 10
months; range, 4.5-13.0). The median overall survival (OS) and median progression-free survival (PFS) were both 30.0
months. Patients who received adjuvant chemotherapy had better PFS than those who underwent surgery only (30.0
months [95% confidence interval [CI], 4.3-55.7] vs 5.0 months [95% CI, 1.0-9.0]; P = .036). In terms of OS, however, the
difference between the 2 groups was not significant (30.0 months [95% CI, 8.4-52.6] vs 7.0 months [95% CI, 4.5-9.5];
P = .244). Conclusions: rPNET with IVCTT is an extremely rare entity that mostly occurs in young adults. Although
multidisciplinary treatment is used, the prognosis of this disease remains unclear. RN with IVC tumor thrombectomy is a
challenging procedure requiring vascular management techniques and experience. Adjuvant chemotherapy contributes
to improved PFS, but not OS. Thus, early diagnosis and treatment play a key role in improving prognosis.

Clinical Genitourinary Cancer, Vol. 000, No.xxx, 1–7 © 2021 Elsevier Inc. All rights reserved.
Keywords: Chemotherapy, Diagnosis, IVC tumor thrombus, Surgical procedure

Introduction Renal PNETs (rPNETs), accounting for only 1% of sarcomas,

Primitive neuroectodermal tumor (PNET) is a rare, primitive,
biologically invasive small round cell tumor derived from the
neuroectoderm.1 Based on the involved site, PNETs can be divided
into central PNETs and peripheral PNETs. Peripheral PNETs,
which are rarer than central PNETs, frequently occur in the bone,
limbs, and soft tissues of adolescents and young adults.2
Department of Urology, Peking University Third Hospital, No. 49 North Garden
Road, Beijing, PR China
Submitted: Oct 14, 2020; Revised: Mar 23, 2021; Accepted: Mar 27, 2021; Epub: xxx
Address for correspondence: Lulin Ma, Department of Urology, Peking University Third
Hospital, No. 49 North Garden Road, Beijing, 100191, PR China.
E-mail contact: malulin@medmail.com.cn
were first reported by Seemayer et al in 1975.3 To date, fewer than
150 rPNETs have been reported in the literature. Invasion into
neighboring organs and distant metastasis frequently occur as the
first manifestation owing to the aggressive biological behavior of
this tumor. The classic clinical manifestations, such as hematuria,
pain, and palpable abdominal masses, of rPNETs are similar to
those of other renal neoplasms.4 There is no specific radiological
finding to diagnose rPNETs preoperatively. The definite diagnosis
is based upon histopathology, immunohistochemistry, and cytoge-
netic studies.5 Because of the rarity of these tumors, there is no
standard treatment strategy. Radical surgery combined with postop-
erative focal radiotherapy and adjuvant chemotherapy are recom-
mended.

1558-7673/$ - see front matter © 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.clgc.2021.03.017 Clinical Genitourinary Cancer 2021 1
Please cite this article as: Chuxiao Xu et al, Renal Primitive Neuroectodermal Tumor With Inferior Vena Cava Thrombus: Case Series and Literature Review
of a Rare but Challenging Entity, Clinical Genitourinary Cancer, https://doi.org/10.1016/j.clgc.2021.03.017
 JID: CLGC
ARTICLE IN PRESS [mNS;April 30, 2021;10:4]
Renal Primitive Neuroectodermal Tumor With Inferior Vena Cava Thrombus
Nearly 50% of patients with rPNET have inferior vena cava
(IVC) tumor thrombus at the time of presentation.4 Radical
nephrectomy (RN) and IVC tumor thrombectomy (IVCTT) are
fundamental but challenging procedures. In addition, surgical
resection of the involved organs and vasculature are occasionally
indicated.6 rPNETs seem to be more aggressive than PNETs at other
sites, and the prognosis for patients with IVC tumor thrombus is
very poor.6 , 7 To the best of our knowledge, patients with rPNET
with IVC tumor thrombus have been reported rarely, and previous
studies have seldom made efforts to introduce complicated surgi-
cal procedures. In our study, we conducted a retrospective analysis
of 6 patients diagnosed with rPNETs with IVC tumor thrombus in
our institution between January 2005 and December 2019. Further-
more, we performed a systematic literature review to investigate the
clinical characteristics and histopathological features and summa-
rized the surgical experience in treating rPNET with IVCTT.
Patients and Methods
This study was approved by the Medical Ethics Committee of
Peking University Third Hospital. From January 2005 to Decem-
ber 2019, 6 patients were treated for rPNETs with IVC tumor
thrombus at our hospital. Confirmed diagnoses were obtained via
histopathology of surgical specimens. IVC tumor thrombus was
graded according to the Mayo clinical IVC tumor thrombus classifi-
cation system. A modified Clavien classification system was used to
evaluate perioperative complications. Follow-up time was calculated
from the date of diagnosis to the date of death from the disease
or the last follow-up. Data on clinical characteristics, laboratory
tests, imaging features, treatment protocols, surgical details, compli-
cations, pathological results, and outcomes were collected.
To identify published cases of rPNETs with IVC tumor throm-
bus, we thoroughly searched the PubMed and Embase databases
using the terms “PNET kidney,” “renal Ewing’s sarcoma,” “kidney
Ewing’s sarcoma,” and “inferior vena cava tumor thrombus.” All
articles, case reports, or case series in English published from April
1996 to October 2019 were considered.
Data that focused on clinicopathologic characteristics, surgi-
cal approaches, postoperative adjuvant treatments, and follow-up
outcomes were extracted. Clinicopathologic characteristics included
age, sex, tumor laterality, greatest tumor dimension, tumor throm-
bus level, sites of metastasis, and immunohistochemistry staining
and fluorescence in situ hybridization results. Surgical treatment
data included surgical methods (RN plus IVCTT or RN only)
and surgical strategies (open or laparoscopic surgery). Postoperative
adjuvant treatment including adjuvant chemotherapy and adjuvant
radiotherapy. Follow-up outcomes of enrolled cases were evaluated
by overall survival (OS) and progression-free survival (PFS). All data
were summarized in a database for final analysis.
Categorical variables are presented as percentages and frequencies.
Continuous variables are expressed as the median and interquar-
tile range. OS and PFS were estimated using the Kaplan-Meier
method and compared across groups using the log-rank test. A 2-
sided P value of less than .05 was considered to indicate a statisti-
cally significant difference. Statistical analysis was performed using
SPSS software version 22 (IBM SPSS, Chicago, IL) and GraphPad
Prism 7 (GraphPad Software, San Diego, CA).
2 Clinical Genitourinary Cancer 2021
Please cite this article as: Chuxiao Xu et al, Renal Primitive Neuroectodermal Tumor With Inferior Vena Cava Thrombus: Case Series and Literature Review
of a Rare but Challenging Entity, Clinical Genitourinary Cancer, https://doi.org/10.1016/j.clgc.2021.03.017
Results
Institutional Cases
During the selected period, a total of 6 patients were enrolled
in our study. The median age at diagnosis was 26 years (18-32
years). The clinical features of our series are summarized in Table 1.
The median tumor size was 14.5 cm (9.2-17.8 cm). Contrast-
enhanced computed tomography scans revealed solid, ill-defined
nodular masses with a mixed density in the affected kidneys on
plain scans. In the enhanced phase, the primary tumors displayed
mild inhomogeneous enhancement. Contrast-enhanced magnetic
resonance angiography demonstrated enhanced soft tissue masses in
the renal veins and IVC. One patient underwent ultrasound-guided
tumor biopsy (patient 5). All 6 tumors were positive for CD99 by
immunohistochemical staining, and the EWSR-FLI1 fusion gene
was identified in 4 samples that were subjected to fluorescence in
situ hybridization analysis. The representative imaging, pathological
and molecular features are presented in Figure 1.
Regarding the initial surgical treatment, 5 patients underwent
radical resection of the affected kidney and IVC tumor throm-
bus. One patient only underwent palliative nephrectomy. Partial
IVC resection and IVC plasty were performed in 3 cases. For all
enrolled cases, the median surgery time was 391.5 minutes (294.5-
526.5 minutes), the median estimated blood loss was 625.0 mL
(425.0-4125.0 mL), and the median postoperative hospitalization
duration was 9.0 days (8.0-15.0 days). Three patients (patients 3,
5, and 6) suffered from postoperative complications. One patient
suffered from moderate anemia classified as Clavien grade II (patient
6). One patient suffered from a small intestinal obstruction and
pulmonary embolism classified as Clavien grade II (patient 5).
One patient suffered from deep venous thrombosis classified as
Clavien grade IIIb, and he underwent transvenous catheter embolec-
tomy 1 month after the initial surgery (patient 3). All 6 patients
were managed with adjuvant therapy, 4 patients (patients 3, 4,
5 and 6) received ifosfamide and etoposide/cyclophosphamide,
adriamycin and vincristine intermittent adjuvant chemotherapy, 2
patients were managed with targeted adjuvant therapy (patients 2
and 3), and 1 patient received adjuvant focal radiotherapy for the
residual IVC tumor thrombus (patient 6).
Follow-up data were available for all 6 patients. The median
postoperative follow-up duration was 9.0 months (4.8-18.0
months). Three patients survived without recurrence or metastasis
(patients 4, 5, and 6). Two patients developed a relapse in distant
sites and died of the disease (patients 1 and 3). Patient 2 developed
lung metastases, hepatic metastases, and retroperitoneal recurrence,
and she was managed with targeted adjuvant therapy. Twenty-five
months after the initial surgery, she underwent open resection of
the recurrent retroperitoneal foci, and she was still alive at the last
follow-up. The perioperative outcomes, adjuvant treatment proto-
cols, and follow-up data are summarized in Table 2.
Systemic Review
One hundred twelve studies were identified in the PubMed and
Embase search. Eighty-seven titles and abstracts were screened for
potential inclusion after removing duplicates. Articles not written
in English, unrelated to rPNETs with IVC tumor thrombus, or
without full texts and descriptions of the clinicopathologic features
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Chuxiao Xu et al

Table 1 Clinical Characteristics of the 6 Patients in our Institute

Case Age/ Presentation Clinical Laterality Largest IVC Tumor Clinical CD99 EWS/FLI-1
No. Sex Suspicion Dimension Thrombus Stage (IHC) (FISH)
(cm) Level
1 18/F Lumbago, hematuria RCC Right 8.1 III T3b N0 M0 Positive Not done
2 17/F Lumbago RCC Right 17.0 III T 4 N0 M0 Positive Not done
3 24/M Lower limb edema RCC Right 2.1 II T3b N1 M0 Positive Positive
4 39/F Lumbago RCC Left 17.8 III T3b N1 M0 Positive Positive
5 28/F Hematuria rPNET Left 9.6 II T3b N0 M0 Positive Positive
6 29/F Lumbago RCC Left 17.8 III T 4 N1 M0 Positive Positive

Abbreviations: F = female; FISH = fluorescent in situ hybridization; FLI-1 = Friend leukemia virus integration 1; IHC = immunohistochemistry; IVC = inferior vena cava; M = male; RCC = renal
cell carcinoma; rPNET = renal primitive neuroectodermal tumor.

Figure 1 Radiologic presentation, pathological characteristics, and molecular features of case 6 in our institution. (A)
Abdominal computed tomography (CT) plain scan demonstrating a mixed solid and cystic tumor located in the upper
pole of the left kidney (red arrow). (B) Enhanced CT scan showing mild enhancement of the tumor (red arrow). (C)
Coronal contrast-enhanced magnetic resonance angiography (CEMRA), suggesting tumor invasion into the left renal
pelvis (red arrow) and a tumor thrombus in the inferior vena cava (blue arrow). (D) Hematoxylin and eosin staining of a
renal primitive neuroectodermal tumor (original magnification ×200). (E) Immunohistochemical staining for CD99
(original magnification ×200). (F) Immunohistochemical staining for Nkx2.2 (original magnification ×200). (G)
Fluorescence in situ hybridization testing indicating EWSR1 gene rearrangement.

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Please cite this article as: Chuxiao Xu et al, Renal Primitive Neuroectodermal Tumor With Inferior Vena Cava Thrombus: Case Series and Literature Review
of a Rare but Challenging Entity, Clinical Genitourinary Cancer, https://doi.org/10.1016/j.clgc.2021.03.017
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Renal Primitive Neuroectodermal Tumor With Inferior Vena Cava Thrombus

Table 2 Perioperative Outcomes, Adjuvant Treatments, and Follow-up Data of the 6 Patients in our Institution

Case Surgery for Surgery Estimated Postoperative Adjuvant Recurrence/ Follow-up

No. Primary Tumor Time (min) Blood Loss Complications Treatments Metastasis (month,
(mL) status)
1 LRN + IVCTT 278 200 None None Metastasis 1, DOD
(lung)
2 LE + ORN + IVCTT 517 650 None Pazopanib Metastasis (lung, 30, AWD
liver)
3 ORN + IVCTT 388 500 Clavien IIIb IE/CAV; Metastasis (liver, 11, DOD
irinotecan; bone)
temozolomide;
anlotinib;
pazopanib
4 ORN + IVCTT 395 4500 None IE/CAV None 14, AWOD
5 LE + ORN + IVCTT 300 600 Clavien II IE/CAV None 7, AWOD
6 OCN + LND 555 4000 Clavien II IE/CAV; SBRT None 6, AWD

Abbreviations: AWD = alive with disease; AWOD = alive without disease; CAV = cyclophosphamide, adriamycin and vincristine; DOD = died of disease; IE = ifosfamide and etoposide;
IVCTT = inferior vena cava tumor thrombectomy; LE = laparoscopic exploration; LND = lymph node dissection; LRN = laparoscopic radical nephrectomy; OCN = open cytoreductive nephrectomy;
ORN = open radical nephrectomy; SBRT = stereotactic body radiotherapy.

or treatments for the tumor were excluded. Thirty-nine patients
with rPNETs with IVC tumor thrombus were enrolled. The final
cohort encompassed a total of 45 cases (including 6 cases from our
institution).
The median age of the whole cohort was 26.0 years (19.5-
31.5 years), and the male to female ratio was approximately 1:1
(23 vs 22). The average tumor diameter was 12.5 cm. Data on
the IVC tumor thrombus level were available in 43 cases, includ-
ing 10 thrombi (29.4%) that extended above the diaphragm and
24 (70.6%) that were below the diaphragm. Seventeen patients
(37.8%) showed metastasis at the time of diagnosis. Among these
patients, 14 (82.4%) showed metastasis in the lung, 3 (17.6%) in
the liver, 2 (11.8%) in the bone, 1 (5.9%) in the adrenal gland, and
1 (5.9%) in the pancreas. Four patients (23.5%) had metastases in
more than 2 organs.
Forty-three patients underwent surgical resection. Among these
patients, 42 (97.7%) were managed with open surgeries; only
1 (2.3%) underwent totally laparoscopic surgery. In terms of
surgical methods, 35 (81.4%) underwent nephrectomy together
with IVCTT, and the other 8 (18.6%) underwent nephrec-
tomy only. Histopathologically, all 45 tumors were positive for
CD99, vimentin, and Nkx2.2. The EWS/Friend leukemia virus
integration 1 (FLI-1) fusion gene was identified in 18 patients
(40.0%) who underwent molecular diagnosis. Regarding adjuvant
therapy, 35 patients (77.8%) received adjuvant chemotherapy,
and only 6 patients (13.3%) received adjuvant radiotherapy
(Table 3).
Follow-up data were available for 41 patients (91.1%), and the
median follow-up time was 10.0 months (4.5-13.0). The median
OS time and median PFS time were both 30 months. After
removing 2 patients who had not undergone surgical treatment, a
Kaplan-Meier analysis was performed for 39 individuals with defini-
tive outcomes. Factors including sex, age, tumor diameter, IVC
tumor level, metastases at diagnosis, surgical strategies, adjuvant
chemotherapy, and adjuvant radiotherapy were used for grouping.
Survival curves among different groups were compared (Table 4).
Patients managed with adjuvant chemotherapy had a significantly
better outcome in terms of PFS than those managed with surgery
alone (30.0 months [95% confidence interval (CI), 4.3-55.7] vs 5.0
months [95% CI, 1.0-9.0]; P = .036). Nevertheless, the difference
in OS between the 2 groups was not significant (Figure 2).
Discussion
Physicians should rise to the challenge of preoperatively diagnos-
ing this scarce neoplasm. The clinical characteristics of rPNETs with
IVC tumor thrombus are similar to those described in previous
studies.8-13 Efforts have been made to investigate the radiological
characteristics of rPNETs. In a study conducted by Kumar et al,14
renal vein invasion, IVC involvement, and 9 other parameters were
significant in the univariate analysis for differentiating rPNETs
from clear cell renal cell carcinoma. Akkaya et al15 concluded that
isointensity or hypointensity on T1-weighted images and heteroge-
neous intermediate to high signal intensity on T2-weighted images
can serve as representative magnetic resonance imaging features
of rPNETs. An accurate diagnosis should be made according to
histopathology. Microscopically, rPNETs are composed of small
round cells arranged in solid sheets and lobules with both pushing
and finger-like infiltration into the surrounding renal parenchyma.
Homer-Wright rosette formation may provide clues for the diagno-
sis of rPNET. However, these findings can also be present in other
tumors; thus, immunohistochemistry sections should be carefully
selected for the differential diagnosis.5 , 6 CD99 was positive in more
than 90% of the patients with rPNET. A majority of patients were
also found to have high expression of vimentin, neuron-specific
enolase, and FLI-1.5 , 16 Although these markers are considered to be
specific to rPNET, approximately 40% of the patients were misdiag-
nosed.9 Molecular studies were used to obtain a confirmed diagno-
sis. The most common genetic alteration seen in rPNETs is the
reciprocal translocation between the genes EWS (22q12) and FLI-1
(11q24). The EWS/FLI-1 fusion transcript has been shown to be
expressed in 72% of cases.5

4 Clinical Genitourinary Cancer 2021

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JID: CLGC
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Figure 2 Survival estimates calculated by the Kaplan–Meier method. (A) Overall survival curves of patients who received
adjuvant chemotherapy and who did not. (B) Progression-free survival curves of patients who received adjuvant
chemotherapy and who did not.
There is no standardized treatment strategy for this rare entity,
and a surgery-based multidisciplinary treatment is frequently used.
However, RN with IVCTT seems to be challenging for urolo-
gists, and previous studies have made few efforts to investigate
the techniques of this complicated procedure. We thus concluded
several key points regarding surgical treatment based on our clini-
cal experience. First, optimizing the appropriate surgical strategy
(open surgery or laparoscopic surgery) needs systemic considera-
tion. Patients with larger tumors tend to undergo open RN with
IVCTT owing to its advantages in tumor dissection. Patients with
higher IVC tumor thrombus levels (Mayo III-IV) are more likely
to undergo open RN with IVCTT than those with lower levels
(Mayo I-II). The surgical treatment of Mayo III or IV tumor throm-
bus probably requires extra complicated steps. For instance, liver
mobilization is necessary to dissect the retrohepatic IVC, hepatic
artery and vein, portal vein, and hepatic short vein in cases of
Mayo III tumor thrombus. Patients with Mayo IV thrombus tend
to undergo open thoracoabdominal procedures based on cardiopul-
monary bypass. Other factors, such as the extent of adhesions, IVC
wall invasion, patient status, and experience of the operators, may
also influence the choice of surgical strategy. Accordingly, most of
the patients diagnosed with rPNETs with IVC tumor thrombus in
our series were managed with open surgery owing to the large tumor
size, severe adhesions, and fragile texture of the tumor thrombus.
Second, an accurate evaluation of the IVC tumor thrombus level
plays an important role in surgical treatment. Contrast-enhanced
magnetic resonance angiography is used commonly for tumor
thrombus evaluations preoperatively, and its diagnostic sensitivity
and specificity for IVC wall invasion are 100% and 89%, respec-
tively.17 rPNETs are a highly aggressive entity and have the poten-
tial to progress rapidly; thus, we recommend that contrast-enhanced
magnetic resonance angiography should be completed within 2
weeks before surgery. Intraoperatively, transesophageal echocardiog-
Please cite this article as: Chuxiao Xu et al, Renal Primitive Neuroectodermal Tumor With Inferior Vena Cava Thrombus: Case Series and Literature Review
of a Rare but Challenging Entity, Clinical Genitourinary Cancer, https://doi.org/10.1016/j.clgc.2021.03.017
[mNS;April 30, 2021;10:4]
Chuxiao Xu et al
raphy is a powerful tool for surveilling the tumor thrombus location
promptly. A missed embolus can be detected by transesophageal
echocardiography immediately during the procedure. After resec-
tion of the IVC tumor thrombus, transesophageal echocardiography
should be used to confirm the complete removal of the whole IVC
tumor thrombus. Third, a tumor thrombus with IVC wall invasion
is a clinical situation that needs special consideration. Several radio-
logical features may provide clues for the diagnosis of IVC wall
invasion. Gohji et al18 and Zini et al19 concluded that IVC diame-
ter is one of the risk factors for IVC wall invasion. Based on our
experience, spiculation of the IVC wall, an edema zone outside the
IVC wall, and irregular tumor thrombus shape also have high value
in the evaluation of IVC wall invasion preoperatively. Nevertheless,
the most accurate method for identifying IVC wall invasion relies on
intraoperative exploration and histopathological examination. If less
than one-third of the circumference is involved and thus resected,
the IVC wall could be sutured with 4-0 Prolene thread. Otherwise,
IVC segmental resection is preferred.
In this study, we analyzed the prognostic factors of patients
with rPNET and IVC tumor thrombus. We demonstrated that
postoperative adjuvant chemotherapy was the only factor associ-
ated with better survival outcomes. Adjuvant therapy should be
considered after surgery owing to the highly aggressive behavior
of rPNETs. Chemotherapeutic agents encompass vincristine, dacti-
nomycin, adriamycin, cyclophosphamide, ifosfamide, and etopo-
side.3 Despite the high response rate of rPNETs to chemotherapy,
the efficiency of this commonly used protocol remains controver-
sial, and previous studies have seldomly focused on patients with
rPNET with IVC tumor thrombus. A study performed by Risi
et al9 found that the 12-month OS rate of patients with rPNET
treated with adjuvant or neoadjuvant therapy was 93%, compared
with 75% for untreated patients (P = .092). However, the sample
size of this study was small, and the survival rate was calculated
Clinical Genitourinary Cancer 2021 5
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Renal Primitive Neuroectodermal Tumor With Inferior Vena Cava Thrombus

Table 3 Summary of the Clinicopathological Characteristics Table 4 Kaplan-Meier Analysis Results of the Factors
and Treatment Strategies of the 45 Cases Associated With OS and PFS

Variables Value, n(%) Variables OS PFS

Age at diagnosis, years (Log-rank (Log-rank
P Value) P Value)
Median 26
Male sex .376 .678
Range 5-78
Age ≤18 years .533 .469
Sex
Largest tumor dimension ≤12 cm .441 .829
Male 23 (51.1) Infradiaphragmatic IVC tumor thrombus .205 .713
Female 22 (48.9) Metastases at diagnosis .607 .837
Laterality RN + IVCTT .289 .978
Left 15 (33.3) Adjuvant chemotherapy .244 .036
Right 30 (66.7) Adjuvant radiotherapy .357 .377
Largest tumor dimension, cm
Abbreviations: IVCTT = inferior vena cava tumor thrombectomy; OS = overall survival;
Mean ± SD 12.5 ± 4.8 PFS = progression-free survival; RN = radical nephrectomy.
Range 4.3-30.0
Tumor thrombus level
Infradiaphragmatic 35 (77.8) Radiation therapy is used when surgical resection is impossible or
Supradiaphragmatic 10 (22.2) residual disease is present.10 One patient in our review underwent
Metastasis at diagnosis palliative nephrectomy, and she had a residual tumor thrombus
Yes 17 (37.8) in the IVC. Stereotactic body radiotherapy was used as adjuvant
No 28 (62.2) therapy, and she was alive without any evidence of progression 6
months after the initial surgery. Previous literature supported larger
CD99
tumor size and clinical M1 disease at diagnosis were poor prognostic
Positive 40 (88.9)
factors.9 , 10 , 20 , 21 However, our study suggested no significant differ-
NA 5 (11.1)
ence in OS or PFS between the patients with tumors greater than 12
ESW/FLI-1
cm and patients with tumors less than 12 cm, or between patients
Positive 18 (40.0) with metastases and patients without. The inconsistency of results
NA 27 (60.0) could be explained by heterogeneity of the patient cohort. Our
Surgical approach study focused on patients with rPNET and IVC tumor thrombus,
Open surgery 42 (93.4) which had been seldomly addressed. Moreover, we only enrolled
Laparoscopic surgery 1 (2.2) patients managed with surgical treatments in the survival analysis.
None 2 (4.4) Different disease status and treatment strategies may result in the
Surgical method difference in oncological outcomes and results of survival analy-
RN 8 (17.8) sis. According to the existing literature, IVC thrombus level was
not associated with prognosis in patients with renal cell carcinoma
RN + IVCTT 35 (77.8)
and IVC tumor thrombus after surgical resection.22-24 However, the
None 2 (4.4)
relationship between IVC thrombus level and oncological outcomes
Adjuvant therapy
in patients with rPNETs and IVC tumor thrombus had not been
Chemotherapy 35 (77.8)
investigated. Our study suggested that the level of IVC thrombus
Radiotherapy 7 (15.6) was not the prognostic factor of OS or PFS, which was similar to
None 10 (22.2) the results of previous studies concerning patients with renal cell
carcinoma and IVC tumor thrombus.
Abbreviations: IVCTT = inferior vena cava tumor thrombectomy; FLI-1 = Friend leukemia virus
integration 1; NA = not available; RN = radical nephrectomy. Although a multidisciplinary treatment protocol is used, the
prognosis of rPNETs remains poor. The 5-year disease-free survival
rate of well-defined extraskeletal PNETs is approximately 45% to
with patients without metastasis. According to the data from our 55%, and patients with the advanced stage disease have a relapse-free
literature review, adjuvant chemotherapy significantly improved the survival of only 2 years.6 More than 40% of patients who presented
PFS of patients with rPNET with IVC tumor thrombus, but it with no metastasis eventually developed metastasis after surgery.9
failed to improve OS. This finding can be partly explained by the The most common metastasis sites include the lung, liver, bone,
highly aggressive biological behavior of rPNETs and the limited and lymph nodes. Thus, strict follow-up after surgery is necessary.
response to applied chemotherapy protocols. Adjuvant chemother- The findings of this study have to be seen in the light of some
apy may prolong the time between the initial treatments and tumor limitations. The first is the retrospective nature of our study. Cases
progression and thus improve the quality of life to some extent. enrolled might have heterogeneity and some of the data were not
Once the tumor progresses, however, patients will die soon after. available in early literature reports. The second is the short follow-

6 Clinical Genitourinary Cancer 2021

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of a Rare but Challenging Entity, Clinical Genitourinary Cancer, https://doi.org/10.1016/j.clgc.2021.03.017
JID: CLGC
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up period of our cohort. We could only evaluate the short-term
oncological outcomes of patients with rPNET and IVC tumor
thrombus. The third is the limited sample size. Patients with rPNET
and IVC tumor thrombus are extremely scarce in clinical practice.
Only 45 cases were analyzed through systemic review and this factor
probably contributes to the nonsignificant difference in survival
outcomes between subgroups with or without potential prognostic
factors.
Conclusions
rPNETs with IVC tumor thrombus is an extremely scarce entity
that typically occurs in young adults. The clinical manifestations
and radiological characteristics of rPNETs are quite similar to
those of common renal neoplasms with IVC tumor thrombus.
Confirmed diagnosis relies on histopathology. There are no guide-
lines for this disease, and multidisciplinary treatment protocols are
recommended. RN with IVCTT is a challenging procedure requir-
ing vascular management techniques and experience. Adjuvant
chemotherapy contributes to improved PFS, but not OS. Although
systemic therapy is used, the prognosis of rPNETs with IVC tumor
thrombus remains unclear. Thus, early diagnosis and treatment play
a key role in improving prognosis.
Clinical Practice Points
• An rPNET with IVC tumor thrombus is an extremely rare entity
that poses a massive challenge to diagnosis and treatments.
• Owing to atypical clinical manifestations and radiological charac-
teristics, histopathology serves as the gold standard for diagnosis.
• RN and IVCTT is a challenging procedure requiring vascular
management techniques and experience. Laparoscopic surgery
can be conducted in selected patients with Mayo I or II tumor
thrombus.
• Adjuvant chemotherapy can improve the prognosis of patients
with rPNET to some extent and it should be recommended.
• Although systemic therapy is used, the prognosis of rPNETs with
IVC tumor thrombus remains unclear. Thus, early diagnosis and
treatment play a key role in improving prognosis.
Disclosure
The authors have stated that they have conflicts of interest.
Acknowledgments
None.
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