Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03849482 |
| Other study ID # |
MultiParotid |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 24, 2019 |
| Est. completion date |
December 31, 2021 |
Study information
| Verified date |
February 2019 |
| Source |
IRCCS San Raffaele |
| Contact |
Davide Di Santo, MD |
| Phone |
+390226432172 |
| Email |
disanto.davide[@]hsr.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Parotid gland tumors are mostly treated surgically, but the extent of parotidectomy is
decided upon preoperative work-up information. Preoperative management generally includes
clinical evaluation, collection of a pathological sample, most often through fine-needle
aspiration cytology (FNAC), and imaging. FNAC, despite its high sensitivity and specificity,
has the drawback of an approximately 20 per cent rate of nondiagnostic or indeterminate
result. Magnetic Resonance Imaging (MRI) provides the best morphological description of the
lesion, which is helpful to the surgeon for the planning of the intervention. Recently,
advanced functional techniques have been introduced, in association to the conventional
morphologic ones: diffusion-weighted imaging (DWI) and dynamic contrast-enhanced imaging
(DCEI) demonstrated the ability to provide information about the possible histological origin
of parotid lesions. Multiparametric MRI (mp-MRI) comes from the combination of anatomical and
functional sequences.
The Authors postulate that mp-MRI evaluation may be able to provide information not only
about the extension of the lesion, but also about histology, with a high accuracy, at least
comparable to ultrasound-guided FNAC.
In the present study, the Authors aim to define the value of FNAC and mp-MRI in the
preoperative management of parotid gland tumors, comparing their success intended as the
capability of the exam to be both diagnostic and accurate in formulating the correct
histological suspect of malignancy.
Participants are patients affected by parotid gland neoplasms, candidates for surgical
resection. The lesion will preoperatively be assessed with both clinical evaluation,
ultrasound-guided FNAC and mp-MRI in our Institution. Mp-MRI includes conventional sequences,
DWI and DCEI; its interpretation will allow the definition of the suspect histology. FNAC and
mp-MRI suspects will be compared to the final histopathological report after surgical removal
of the neoplasm.
The study considers a total of 100 patients, of whom 50 are analyzed retrospectively (being
already operated after obtaining both FNAC and mp-MRI preoperatively) and the remaining 50 to
be enrolled prospectively.
Description:
Participants affected by parotid gland neoplasms are evaluated by an ear, nose and throat
surgeon in our hospital, who defines the indication to surgical removal.
Preoperative management includes:
- Clinical Evaluation: participant's history and physical examination are collected.
Participants are asked for the presence of pain, facial nerve weakness, fixation to skin
and surrounding tissues, trismus, skin ulceration, lymphadenopathy, numbness, B
symptoms.
- FNAC: it is always performed under US guidance in our Department of Radiology, and
subsequently analyzed by a cytopathologist in our Department of Pathology. The same
sampling technique is always employed. After skin disinfection, a 23-gauge needle
attached to a syringe is inserted into the lesion and moved inside it to obtain enough
cytological material. The material is subsequently expelled onto a glass slide, and the
smear is prepared between two glass slides and fixed. The procedure is repeated two to
three times to reduce the probability of nondiagnostic results.
- mp-MRI: MRI scans are conducted using a 1.5-T imager (Philips Health-care, DA Best, The
Netherlands) with a head and neck array coil. The MRI study protocol consists of
localizer sequences in transversal, sagittal and coronal planes followed by two axial T2
weighted images: a T2 Turbo Spin-Echo (repetition time -TR-: 4465, echo time -TE-: 80,
section thickness: 3mm, intersection gap: 0.3mm) centered on parotid glands and a T2 MV
sequence for lymph nodes identification (TR: 3000, TE: 83, section thickness: 4mm,
intersection gap: 0.4mm). Then axial T1 weighted images are obtained (TR: 571, TE: 16,
section thickness: 3 mm, intersection gap: 0.3mm). Coronal T1, T2 and STIR images are
subsequently obtained. Thereafter, DWI is performed by using a multisection spin-echo
singleshot echoplanar sequence in the transverse plane (TR: 2800, TE: 160, 20 - 25cm
field of view, 92 x 90 matrix, 3mm section thickness). Sensitizing diffusion gradients
are applied sequentially in the x, y, and z directions with b values of 0, 500, and 1000
sec/mm2. ADC maps are generated. After detecting the mass in the morphological images,
The Radiologist identifies corresponding slice position for a T1 weighted FLASH sequence
(TR: 30, TE: 4.6) in the transversal plane, used for DCEI. Each patient receives
intravenous contrast injection (weight-adapted dosage, 0.1ml Gadolinium per Kilogram
body weight) with a flow rate of 2ml/second using a power injector, followed by a 20ml
saline flush. The contrast agent application and the T1-weighted FLASH sequence are
started simultaneously. MR images are sequentially obtained at 5sec intervals for
360sec. After DCEI, postcontrast T1 weighted spin echo images are obtained, with the
parameters similar to those of the pre-contrast imaging. A region of interest (ROI) for
signal intensity measurement is drawn manually avoiding the vessels and necrotic or
cystic portions of the tumors. Thereafter, the Radiologist plots the average signal
intensity within the ROI against time, and a Time Intensity Curve (TIC) is constructed,
using a dedicated software (Philips Intellispace Portal). The ROI can be identified with
an adequate accuracy only for tumors with a minimum diameter of 1cm; therefore for
smaller lesions a mp-MRI analysis is not possible. TICs are constructed as follows: Time
to peak (Tpeak) is manually positioned by the Radiologist in the first value of the
curve in which the signal intensity (SI) reached the 90% of the difference between the
maximum (SImax) and the starting (SIpre) signals: Tpeak > 0.9 (SImax - SIpre) + SIpre.
Washout Ratio (WR) is calculated at 300sec (SIend) and expressed as a percentage, using
the following equation: WR = [(SImax - SIend) / (SImax - SIpre)] x 100 (%). TICs are
defined as follows: Type A: Tpeak > 120sec (gradual enhancement, ascending plateau);
Type B: Tpeak ≤ 120sec and WR ≥ 30% (early enhancement, early washout); Type C: Tpeak ≤
120sec and WR < 30% (early enhancement, late washout); Type D: flat curve (vacillation
of the curve around the low signal level may be observed due to imaging artifacts).
Interpretation of preoperative management findings aims to label each case as "benign" or
"malignant", and is performed as follows:
- Clinical Evaluation: malignancy is suspected if any of pain, facial nerve weakness,
fixation to skin and surrounding tissues, trismus, skin ulceration, lymphadenopathy,
numbness, B symptoms is present.
- FNAC results were classified as: "benign" if a specific histologically benign diagnosis
was made, if the report stated "no evidence of malignancy", or if only benign diagnoses
were listed in the differential; "malignant" if a specific histologically malignant
diagnosis was made, if malignant cells were identified, if the report stated "suspicious
for malignancy" or "suspicious for lymphoproliferative disorder". The decision to
consider as malignant also reports stating "suspicious for" comes from the observation
that surgeons would manage these lesions as malignant anyway; "indeterminate" if,
despite the presence of a cytologically adequate sample, the pathologist was not able to
define the benign or malignant nature of the lesion; "nondiagnostic" if the pathological
sample was insufficient or did not contain enough meaningful material.
- Conventional MRI results are classified as "malignant" if: presence of infiltration of
surrounding non-glandular structures (including the facial nerve) is identified;
presence of suspect metastatic lymph nodes is identified; the tumor is characterized by
low signal on T2-weighted images and displays ill-defined borders. All other cases were
classified as "benign".
- Multiparametric MRI results are recorded, and interpreted according to a stepwise
approach. The first step of mp-MRI interpretation is the evaluation of conventional MRI
findings. If the tumor presented features undoubtedly indicating a malignant origin
(infiltration of contiguous non-glandular structures - including the facial nerve - or
evidence of lymph node metastases), the lesion is immediately labeled as "malignant" at
mp-MRI. The third category used to define malignant nature at conventional MRI
evaluation, such as low signal on T2-weighted images and ill-defined borders is not
considered as undoubtedly indicating malignancy, and further steps of mp-MRI evaluation
are performed. After conventional MRI evaluation, advanced MRI techniques are used. The
second step includes DWI with ADC maps generation and measurement. Depending on the ADC
value, three main categories are identified: 1. tumors with extremely low ADC value (<
0.6 x 10^-3 mm2/sec); 2. tumors with low or intermediate ADC value (≥ 0.6 x 10^-3
mm2/sec and ≤ 1.4 x 10^-3 mm2/sec);
- tumors with high ADC value (> 1.4 x 10^-3 mm2/sec). The third step is the construction
of a TIC using DCEI. Findings obtained with both DWI and DCEI are combined and
interpreted as follows: A. high ADC value (> 1.4 x 10^-3 mm2/sec) and TIC type A, B (not
plausible) or C are most often suggestive of a Pleomorphic Adenoma (PA), but also of
myoepithelioma. Due to the rarity of myoepithelioma and to the fact that its surgical
treatment is essentially the same of PA, this eventuality is not considered. TIC type B
is not considered a plausible possibility, as this finding is very rarely reported in
PAs. In such cases, a hemorrhagic complication after a recently performed FNAC in a
Warthin Tumor (WT) should be considered. Tumors in this category are labeled as
"benign", with suspected histology of PA; B. high ADC value (> 1.4 x 10^-3 mm2/sec) and
TIC type D can be referred to cystic lesions. Cysts are characterized by very high ADC
values, being composed of fluid or mucinous content. Tumors in this category are labeled
as "benign", with suspected histology of cystic lesion; C. low or intermediate ADC value
(≥ 0.6 x 10^-3 mm2/sec and ≤ 1.4 x 10^-3 mm2/sec) and TIC type A or C are typical of
malignant epithelial tumors, but also of some atypical adenomas (cellular adenomas,
basal cell adenomas). In an attempt to reduce the number of false negative results,
tumors in this category are labeled as "malignant". No specific tumor histology can be
suspected, due to the large overlap of findings and the high number of parotid gland
malignant histotypes; D. low or intermediate ADC value (≥ 0.6 x 10^-3 mm2/sec and ≤ 1.4
x 10^-3 mm2/sec) and TIC type B are typical of WTs. Tumors in this category are labeled
as "benign", with suspected histology of WT; low or intermediate ADC value (≥ 0.6 x
10^-3 mm2/sec and ≤ 1.4 x 10-3^mm2/sec) and TIC type D are not plausible, as TIC type D
is typical of cysts, which are characterized by very high ADC values. In such cases, one
should consider the possibility of repositioning the ROI, as this finding may be related
to positioning of the ROI in a necrotic or cystic portion (therefore not informative) of
a parotid tumors; E. extremely low ADC value (< 0.6 x 10^-3 mm2/sec) and TIC type A (not
plausible), B or C are suggestive of parotid gland lymphomas. Tumors in this category
are labeled as "malignant", with suspected histology of lymphoma; F. extremely low ADC
value (< 0.6 x 10^-3 mm2/sec) and TIC type D are suggestive of lipomas. Lipomas display
typical very low ADC values. Tumors in this category are labeled as "benign", with
suspected histology of lipoma; G. mp-MRI IS considered "indeterminate" if the exam is
unable to reliably measure ADC or construct a TIC, due to a very recently performed FNAC
(less than two weeks) with reported complications (clinical evidence of infection or
conventional MRI evidence of intralesional hemorrhage), or intense movement artifacts.
Study power analysis:
The number of participants to be treated is decided taking into account the paired design of
the study, to detect any difference in the percentage of success (intended as the capability
of the diagnostic test to be diagnostic and to correctly identify malignant tumors) between
the two tests (FNAC and mp-MRI), assuming a percentage of participants for whom mp-MRI has
success while FNAC does not of 20%, a percentage of participants for whom FNAC has success
while mp-MRI does not of 5%, a power of 80% and an alfa error of 5%. These percentage
strictly depend on the expected rate of non success due to indeterminate or nondiagnostic
results of the tests. Therefore, we defined to be 100 participants the number to be treated.
Statistical analysis:
Number of indeterminate and nondiagnostic results, sensitivity, specificity, positive
predictive value, negative predictive value and accuracy of Clinical Evaluation, FNAC,
conventional MRI and mp-MRI will be reported. The comparison between success of respectively
FNAC and mp-MRI will be investigated with the McNemar test. SPSS software (IBM Corporate, US)
will be used. P will be considered to be significant if < 0.05.
