2.3 Statistical analysis
We used descriptive statistical analyses as appropriate. We summarized
continuous data using means and standard deviations, and categorical
data using counts and percentages. Diagnostic yield was defined as the
proportion of PCNB specimens sufficient for pathologists to make
confident diagnoses among all biopsies performed. The final diagnosis in
all cases was defined as the results of histological examinations of
excised specimens. Accuracy was calculated as the proportion of biopsies
resulting accurate diagnoses among those being diagnostic. Comparisons
between diagnostic accuracies in diagnosing benign and malignant lesions
were assessed by Fisher’s exact test. P value < 0.05 was
considered statistically significant.
RESULTS
A total of 169 children aged 1 to 190 months (mean age±SD = 48.7 ± 40.9
months) who underwent both PCNB and surgery in our department from June
2009 to January 2019 were included in this study. All biopsies were
performed under ultrasound guidance. Patients demographics is shown in
table 1. Over half of all the patients underwent PCNB for abdominal and
pelvic masses. And retroperitoneal and liver masses constituted a large
portion. Local anesthesia was well tolerated in the majority.
Final surgical diagnoses are listed in table 2. Neuroblastoma is the
most common malignancy, followed by nephroblastoma, rhabdomyosarcoma,
hepatoblastoma and malignant germ cell tumor. There was more variety in
the benign conditions confirmed by postoperative pathology. Fibromatosis
and ganglioneuroma, mesenchymal hamartoma of the liver constituted
nearly half of the benign cases.
In 5 cases the quality of PCNB specimen was too poor for pathologists
and in another 5 cases the specimens were not sufficient for confident
diagnoses. The diagnostic yield was 94.1% (159/169). In the remaining 159 cases,
PCNB was successful in determining benign and malignant conditions in
150 cases, giving a success rate of 94.3% (150/159). In 33 cases who
were diagnosed of benign diseases by PCNB at first, only 24 were proven
to have benign conditions by postoperative pathology. And in all 126
cases whose PCNB pathology indicated malignancies, surgical pathology
confirmed malignant diagnoses. Consistency between PCNB and final
diagnoses was found in 143 cases, resulting a total accuracy of 89.9%.
In 3 benign cases, PCNB pathology was different from the final
diagnoses, and the accuracy was 87.5% (21/24). Meanwhile, among the 126
malignant cases, the difference in diagnoses was found in just 4 children.
The accuracy for diagnosing malignancies was 96.8% (122/126). Fisher’s
exact test showed that the difference was not statistically significant
(p=0.0818).
All the patients whose PCNB results were not consistent with surgical
results were listed in table 3, including those with non-diagnostic PCNB
samples. Neuroblastoma (6), immature teratomas (3), and tumors of
angiogenesis (4) were more likely to be misdiagnosed. Necrosis was the
main cause of failure to diagnose.
There were 6 complications in this 7-year study (3.5%). In general, the
procedure was well tolerated by majority of patients and all patients
were discharged within 24 hours. Only 6 severe complications occurred
within 2 weeks after PCNB. Their information was listed in table 4. It
should be noticed that patient 4 was also diagnosed of horseshoe kidney.
Patient 5 experienced the tumor rupture during neoadjuvant chemotherapy
shortly following the biopsy. And patient 6 accidentally fell to the
ground before the rupture occurred. All recovered with conservative
treatment including blood transfusion, sedation, close monitoring, and
other supportive therapy.
During follow-ups, no evidence of needle tract dissemination was found.
DISCUSSION
Although there have been more options in the imaging mode for PCNB, such
as CT (used more in bone lesions) and MRI, ultrasound is the dominant as
it spares patients from additional radiation exposure. This is of more
significance in pediatric populations than in adults. Besides, Michael
Accord et al show that the addition of CT and 3D fluoroscopy in imaging guide does not increase the overall diagnostic yield6.
Final diagnoses are crucial in evaluating the reliability of PCNB
technique. We think the most accurate diagnoses are surgical pathology.
In previous studies, it was impossible to obtain surgical pathology of
every patient. Their final diagnoses were based on resection pathology,
reaction to treatment, and follow-ups, which might be less reassuring.
In our study we only enrolled patients with postoperative pathology to
ensure the accuracy of the final diagnosis and the related statistics,
adding more confidence and credibility to our results.
The choice of needles was controversial. In previous studies, some
researchers found that needle sizes were unrelated to the
accuracy8,12,13 while some argued that larger needles
were better as more samples were more likely to be of diagnostic
value14,15. Unfortunately, the size of the needle used
was not routinely recorded in every medical record in our center, so we
could not analyze the relation between needle sizes and biopsy accuracy.
In our cohort, larger needles were preferred whenever possible and safe.
Before the year 2018 14G needles were the only option in our center. In
recent 2 years we used 16G and 18G needles. We assumed that 18G needles
might cause less damage so in obtaining pancreatic tumor tissues they
are the only choices. In our study, no clinically significant pancreatic
damage was found after biopsies. And for lesions close to intestines we
also preferred the smaller needles. However, in one case the tumor was
rich in calcification, and it was difficult to take out the 18G needle.
When the needle was finally pulled out with more force than usual, it
bent. Thus, we concluded that in tumors rich in calcification, larger
needles such as 14G and 16G ones should be recommended if possible, to
reduce the risk of fracture and difficulties to remove the instrument.
In previous studies, reported complications included pain,
intra-abdominal infection, pneumothorax, hematuria, and
hemorrhage8,9,13,16–20. Post-biopsy bleeding
including intra-tumoral hematoma is the most common. However, the
complication rate is generally low and nearly all were managed
successfully with conservative therapy such as oral analgesics and blood
transfusion. In our series, there were 6 major complications in our
cohort. All were tumor ruptures within 2 weeks after biopsies. From
table 4 no relation could be found between the tumor type and this
serious complication except that these lesions were all located in the
abdomen. It should be noted that one of the patients also had the
congenital condition of horseshoe kidney which might increase the
rupture risk. Another rupture occurred during neoadjuvant chemotherapy.
Therefore, this incidence might be the result of biopsy and tumor lysis
induced by chemotherapy combined. And the girl who received a biopsy in
the pancreas fell onto the ground, which might partly explain the
rupture. In our cohort, we required all patients to be closely monitored
for 4-6 hours before discharges. From our experience, although major
complications are rare, we suggest more care should be directed onto
patients with congenital defects and those receiving chemotherapy.
Another concern about PCNB is needle track seeding. In our cohort, no
tumor dissemination along the needle track is found. It is also quite
rare in previous studies9,13,19 and almost all the
reports are related with nephroblastoma18,21,22 and
the prognosis is generally quite good after chemotherapy and excision.
Another earlier research on biopsy of renal tumors suggested posterolateral entries to confine tumor soilage instead of peritoneal
dissemination. We suggest marking the biopsy site on the skin during
renal tumor biopsy and excising the needle track if possible.
In our study, the accuracy of PCNB in diagnosing malignant tumors is
higher than that in benign tumors, although the difference was not
significant (P=0.08, slightly over 0.05). This finding is consistent
with previous researches 7–9,17,23. It might be due
to the high heterogeneity of pediatric solid tumors. Our studies also
showed that for differentiating different teratomas PCNB was not
reliable. Some researchers also reported higher diagnostic accuracy
and/or diagnostic yield in homologous tumors12,24,25.
Necrosis, missing tumor tissues, and crushed samples are common problems
encountered in PCNB, and impact pathological diagnoses including genetic
testing. Possible measures to improve PCNB reliability include standby
sample assessment, more comprehensive imaging evaluation, and new
diagnostic techniques. Standby sample assessment by onsite pathologists
and cytologists could improve the accuracy of PCNB in histology diagnoses and
genetic examinations26,27. And new imaging modality
for prebiopsy evaluation and/or guidance during biopsy may lead to a more
precise location of viable tissues, therefore improving diagnostic yield
and accuracy. PET-CT28,29, MRI25,30and contrast ultrasound31 have
shown promising utility. Moreover, the augmented reality-assisted biopsy
technique may facilitate more accurate passages towards targeted
tissue32. Also, improvements in diagnostic techniques
could improve the reliability of PCNB13,24. Recently,
liquid biopsy has been studied a lot as it may reflect the whole picture
of the tumor. MYCN status is critical for staging neuroblastoma and
guiding treatment33. Traditionally
MYCN amplification (MNA) is measured
by fluorescence in situ hybridization (FISH). As MNA is categorized into
homologous and heterogeneous amplifications, theoretically PCNB may fail
to obtain tissue with MNA in tumors with heterogeneous MNA which means
MNA is unequally distributed in tumor cells and may not be present in
certain clusters of cells. Droplet digital polymerase chain reaction
(ddPCR) as a novel technique of liquid biopsy has been shown to replace
FISH technique to overcome sampling insufficiency or
inadequacy34,35.
For diagnosing benign neoplasms PCNB is not as reliable as for
malignancies, especially in tumors of angiogenesis, which is consistent
with previous studies7–9,12,17,23. Some researchers
suggest incisional biopsy on suspicion of benign tumors as a second core
needle biopsy may not provide additional valuable information for
diagnoses17.
There are several limitations in our study.
First, our cohort is from a single academic third-tertiary children’s
hospital with an abundant ultrasound experience in pediatric
populations. Ultrasound diagnoses are heavily dependent on personal
experience. Our radiologists might be more experienced in evaluating the
surrounding tissues and tumor compositions. Decisions of more
appropriate and safe biopsy entry sites might be made more easily.
Therefore, our results might not be replicated in other institutions.
Second, pediatric solid tumors are rare
diseases36–41. Currently, the diagnoses are mainly
made based on pathology, morphology, immunohistology, and molecular
biomarkers in some tumors41. The diagnoses are heavily
dependent on pathologists’ experience, and central pathology review may
reduce mistakes. However, up to now there has been no census on central
pathology review for pediatric solid tumors in China. Although in some
cases in our study the slides were reviewed by pathologists from other
institutions, the accuracy of pathological diagnoses cannot be
guaranteed.
Third, in our research few samples were stored for future research
purposes. Although biological information has been more and more
important in both diagnoses and guiding treatment of pediatric
tumors33, no fresh samples were reserved for genetic
testing and other biological molecular assessment. Besides, currently
there has been no central biobank for pediatric tumors and no standard
for handling those biological samples. And clinical trials for pediatric
solid tumors have just found their way into China. Collaboration between
different hospitals is just taking the first step. We plan to store more
samples for future research and look forwards to establishing a national
central biobank for childhood solid tumors. More work will be done in
the future.
In summary, ultrasound guided PCNB is generally safe and effective for
diagnosing pediatric solid tumors, especially for malignancies. However,
its reliability in diagnosing benign conditions is still in question.
More comprehensive prebiopsy imaging evaluation, closer follow-ups, and
new techniques might prevent misdiagnoses and/or failures to diagnose.