CT signs suggesting malignancy in Branch duct type IPMN's

1

UNIVERSITÀ DI PISA

Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in

Medicina e Chirurgia

Scuola di specializzazione in Radiodiagnostica

Direttore: Prof. Davide Caramella

TESI DI SPECIALIZZAZIONE

CT suggesting maligancy in branch duct type IPMN’s

Relatore: Candidata:

Chiar.mo Prof. Davide Caramella Dr.ssa Gloria Zingoni

3

INDEX

METHODS AND MATERIALS 5

RESULTS 9

DISCUSSION 12

CONCLUSION 15

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ABSTRACT

Background. Management of branch duct type IPMNs (BD-IPMNs) largely relies on imaging

finding. In particular Sendai guidelines propose surgical treatment in symptomatic BD- IPMNs or asymptomatic lesions with a diameter >3cm, in presence of mural nodules or Wirsung caliber >6mm. The International Consensus guidelines published in 2012 still suggest a conservative approach, even for lesion larger than 3cm, without other imaging findings of malignancy, removing the recommendation for surgical resection based on size alone. However, these indications have been strongly challenged by recent studies showing that small BD-IPMNs could be associated with malignancy; moreover surgical BD-IPMN treatment is confined to lesions evolved to invasive cancer, losing the possibility of a preventive therapeutic approach, especially in younger patients (<65 years). Our study aims to recognize CT signs predictive of evolution to malignancy in BD-IPMN.

Our study aims to recognize CT signs predictive of evolution to malignancy in BD-IPMN.

Methods and materials. We included 43 patients affected by BD-IPMN. For each patient we

evaluated the first and the last CT exams performed in the follow-up (mean follow-up period: 37months, range: 18 months-7 years). Post-contrastographic CT study included the pancreatic (35”), venous (70”) and late (180”) phases. The following CT parameters were examined: localization, morfology (unilocular/multilocular), Wirsung caliber, baseline attenuation, parietal and septal enhancement, neural plexus (celiac and AMS) and celiac ganglia involvement, size of the main cystic lesion.

Results. In 26 patients no significant changes in CT findings were found (confirmed by imaging

follow-up). Other 17 were submitted to surgical resection because of clinical symptoms or CT signs suggestive for malignant degeneration, that was confirmed at pathology in 16 cases (10/16 with a diameter <3cm). Malignancy was statistically related to baseline attenuation (p<0.0001), enhancement behaviour (<0,0001), Wirsung caliber >5mm (p<0,0001), perineural plexus and celiac ganglia involvement (p<0,0001). No correlation was found considering lesion dimension (p=0.4644).

Conclusions. Even if current guidelines propose follow-up in asymptomatic BD-IPMNs less than

3cm (or 4cm) in diameter, the event of malignant degeneration in small lesion has been described, suggesting the need of considering further imaging parameters predictive of malignancy.

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INTRODUCTION

The malignancy risk of branch-duct type IPMN, main-duct type IPMN (MD-IPMN) and mixed type IPMN is 24.4%, 62.2% and 57.6%, respectively [1].Due to the higher malignant potential, surgical resection is strongly recommended for MD- IPMN and mixed type IPMN patients. However, the treatment strategies for BD-IPMN are more complicated, and the concepts of “high-risk stigmata of malignancy” and “worrisome features” were proposed by Sendai Consensus Guidelines (SCG) [2].

Presently, the safety of the SCG for BD-IPMNs remains debatable. Although the SCG have been well-validated by several large retrospective studies by reporting a negative predictive value (NPV) and sensitivity of about 100% [3], more recently, several investigators have reported a sensitivity ranging from 75% to 97% and, as a consequence, several malignant BD-IPMNs could be missed [4].

The aim of our study to recognize CT signs predictive of evolution to malignancy in BD-IPMN.

MATERIALS AND METHODS

This retrospective study involved 43 patients (21 females, 22 males; mean age 74 years, ranging from 60 to 91 years) with IPMN Branch-Duct Type diagnosis, performed by MRI exam. All patients underwent pancreatico-biliary MDCT evaluation, with a protocol aimed at studying the pancreas [5], between April 2008 and February 2015 at our institution.

After the MDCT exam, the management of each patient was individualized based on cyst characteristics, patient’s age and comorbidity.

All patients were monitored throught a period ranging from 18 months to 5 years and our analysis was performed comparing their first and the last MDCT exams.

Imaging technique

All patients underwent preoperative MDCT using a 64-row scanner (Light Speed Plus VCT, GE Medical System, Milwaukee USA) in accordance with the standardized evaluation protocol.

After basal scanning, high-concentration iodinated contrast medium (370-400) was injected intravenously at a flow rate of 4 mL/sec, using a dual-head pump injector. A post-contrastographic

6 study included 3 phases: pancreatic phase (at 35-40 sec), venous phase (at 70 sec) and late phase (at 180 sec). The following scanning parameters were used: section reconstruction 2.5-1.25mm; section interval 1.25-0.625 mm; pitch 6 (High Speed-HS modality) or beam pitch 0.984:1; anode voltage 100-120 kV; 300-350 mA or automatic tube current modulation (smart mA, noise index 21); 0.6/0.8-second rotation speed; 512 matrix size.

Evaluation parameters

Two observers (01-02), with respectively 5 and 15 years radiological experience in abdominal imaging, analysed all the CT images separately, without knowing the clinical, laboratory patients’ data and the histopathological outcome of the resected lesions.

All lesions were classified as unifocal or multifocal, and unilocular or multilobular cysts. The dimension (absolute values with millimetre accuracy) of the largest cyst of each patient was used for the analysis. The following parameters were identified in the largest cyst: pancreatic side, intracystic attenuation assessed in basal acquisition, presence of wall thickening and/or intracystic septa. The post-contrastographic behaviour was evaluated and classified as grade 0, no enhancement; grade 1, asymmetric parietal and septal enhancement; grade 2, parietal and septal circumferential enhancement (Figure 1 and 2).

Figure 1. Parietal and septal asymmetrical enhancement (A pancreatic phase, late phase B)

7 Figure 2. Circumferential parietal and the septal enhancement (A pancreatic phase, late phase B)

The Wirsung calibre, the presence of pancreatic lithiasis and the appearence of celiac ganglia and perineural plexus involvement (comprehensive of both the celiac and the superior mesenteric artery plexi) were evaluated. The perineural plexus involvement was classified in a scale from 1 to 3 as: regular (1), minor (2) or gross (3) thickening of the plexus fibers (Fig.3).

Figure 3. A, slight thickening of nerve fibers (celiac plexus); B, slight thickening of nerve fibers (mesenteric artery superior plexus); C, grossly thickening of nerve fibers (celiac plexus); D, grossly thickening of nerve fibers

(mesenteric artery superior plexus).

The celiac ganglia appearance was identifies as “normal” or “pathological” (when it presented a thickened-nodular appearance or gross enlargement) (Fig.4).

8 Figure 4. Celiac ganglia A:normal appearance, B:pathological aspect

Statistical analysis

Data statistical analysis was performed using JMP version 7.0 (SAS) statistics software.

Statistical correlation was carried out using one-way ANOVA analysis of variance; χ-squared test was used when appropriate to compare the distribution of individual variables between groups. Statistical comparisons of different factors were performed with the bivariate test.

A p value of .05 or less was considered significant.

For analysis of inter-observer variability, kappa statistics were used (Cohen’s and Fleiss’ kappa coefficient).

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RESULTS

Ninety-two MDCT exams (the first and the last exams of the 43 patients enrolled) were evaluated in order to investigate the 43 selected cysts and the changes of the pancreatic features during the follow-up.

Twenty-six out of 43 patients, whose lesions presented a stable CT imaging during an instrumental mean follow-up of 53 months (range 36-86 months), did not undergo surgical treatment, but were still monitored every six months (US and MRI or CT exams). Surgery was performed in 17 patients (after a mean follow-up of 21 months): 8/17 presented clinical worsening (recurrent acute pancreatitis in 5 patients, jaundice in 3 cases); lesion warning features were recognized in 9 patients. The CT parameters referred to suspect degeneration, including: increase in size; basal attenuation change from water to solid value; enhancement behaviour modification (Table 1).

Not degenerate lesions n=27

Degenerate lesions n=16 Basal density attenuation values

<20HU >20HU 25 2 6 10

Increase in size Range 5-45mm

Average:20,6±9,3mm Range 15-55mm Average:26,6±11,2mm Pattern enhancement No enhancement Asymmetric enhancement Circumferential enhancement 16 4 7 1 1 14 Table 1

On the basis of the lesions behaviour and histology the patients were subdivided into two groups: Group A, with a lesion without modification during instrumental follow-up or with a benign BD-IPMN diagnosis; Group B, patients with histological confirmation of lesion degeneration (histological lesions’ patterns are summarized in Table 2)

10 Epithelial thype of IPMN

pancreatobiliary 3

gastric 8

intestinal 5

Table 2

Twenty out of 27 lesions in Group A were greater than 30mm (33.9±3.6mm; range 31-40mm); 7/27 presented a diameter ≤ 3cm (16.9±5.9mm; range 5-30mm). In Group B 6/16 lesions were greater than 30mm (42.4±8.0mm; range 35-55mm), while 10/16 (63%) resulted ≤ 3cm (21.2±5.1mm; range 15-30mm). However, no significant differences about dimensions (p=0,46) were identified between the two groups analysed.

The baseline attenuation of the cysts was subdivided based on a 20 HU cut-off. A <20HU value was recorded in 25/27 lesions in Group A, and in 6/16 ones in Group B; the attenuation parameter significantly correlated with the degeneration of the lesions (p<0.0001).

Seexteen out of 27 lesions in Group A showed no enhancement (grade 0) in the post contrastographic phases, 4 and 7 lesions presented grade 1 and grade 2 of enhancement, respectively. In Group B only one lesion was classified as grade 0 of enhancement, while 14/16 showed grade 2. Grade 2 of enhancement was strictly correlated with the degenerated lesion (p<0.0001).

About the pancreatic tissue features, a dilatation (≥ 5mm) of the Wirsung duct was detected in 2/27 and 9/16 patients in Group A and B, respectively; a significant correlation between the Wirsung dilatation and the degenerated lesions was identified (p<0,0001).

In 13/27 patients of Group A the perineural plexus involvement was classified as class 1, in 12 patients as class 2 and in only two patients as class 3. In Group B one only patient presented a class 1, 10 and 5 patients presented a class 2 and a class 3, respectively.

In 16 patients of the Group A a normal appearance of the celiac ganglia was identified; while in Group B 13 out of 16 patients presented a pathological appearance of the celiac ganglia.

Both the perineural plexus involvement and the celiac ganglia apperence were statistically correlated with the degenerated lesions (p=0.0020 and p=0.0078, respectively).

The pancreatic side, the presence of multiple lesions and of lithiasis were not correlated with BD-IPMN degeneration. On the contrary the morphology of the lesion was related with BD-BD-IPMN

11 degeneration, in fact a p value of 0,0068 was determined between uniloculated cysts and not-degenerated lesions.

Analysis of the subset of lesions with diameter <3 cm

In order to evaluate the Fukuoka statment about the high risk stigmata related to lesion dimension major than 3 cm, all lesions were subdividen into two subset: “large lesions”, lesions diameter ≥ 3cm, and “small lesions”, the ones with a diameter less than 3 cm.

All the parameters were analysed by selecting exclusively the patients with “small lesions” (n = 33; 23 in Group A and 10 in Group B).

Between patients in Group B (with degenerated lesions) and the presence of internal septa (p=0.0047), the enhancement grade (p<0.0001), the basal attenuation (p<0.0001), a significant correlation was detected.

About the basal attenuation, the area under the curve (AUC) of the ROC analysis was 0.9114. Nine out of the 10 degenerated lesions with a diameter less than 3cm presented a altered plexus; the perineural plexi involvement was related with degenerated lesions.

The celiac ganglia appearance and the degeneration of the lesion were not correlated (p=0.1040).

Inter-observer accordance

An observer agreement of 100% was reported for dimension, pancreatic side and morphology of the cystic lesion as for Wirsung calibre.

The overall concordance on intra-cystic attenuation of the cyst was 92% (sensitivity, 92%; specificity, 92%). The overall accuracy of differentiation among the post-contrastographic behaviour was 85% (sensitivity, 100 %; specificity, 78 %) with good inter-observer agreement (κ, 0.84–0.95). The overall accuracy of the classification of the perineural plexus involvement and the celiac ganglia appearance was respectively 87% (sensibility 93%, specificity 83%) and 91% (sensibility 92%, specificity 89%).

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DISCUSSION

Due to an increasing clinic awareness in regards to the possibility of a malignant degeneration of the IPMN pathology and thanks to the improving imaging technologies, the impact on the number of patients diagnosed with IPMN main (IPMN-MD) and branch duct type (IPMN-BD) has been increased dramatically [6].

There is a general consensus regarding fact that the IPMN-MD should be surgically removed, because they have a high frequency of turning towards malignancy (variable in between the 60% and the 92%) [6,7].

The definition of a way of managing a IPMN-BD therapy is still controversial and it represents the main topic of this study.

The incidence of malignant transformation in this group of neoplasm in fact, varies between the 6% and the 46% with a frequency of histological diagnosis of invasive cancer between 11% and 31% [7].

In 2006 with the preparation of the first guidelines proposed by Sendai, knowing the low frequency of IPMN-BD malignant degeneration, a surgical treatment planning has been proposed only for the patients showing clinical symptoms. The asymptomatic patients were divided into two different groups (high and low risk) based on the characteristics of the imaging lesions. Opposite to the low risk patients, that led to a simple instrumental and laboratory follow-up, the high risk ones could be addressed to surgery when the dimensions of the lesion were greater or equal to 3 cm; or when the diameter of the lesion was less than 3 cm but associated with other characteristics, like intramural nodules and / or main pancreatic duct dilation greater or equal to 5 mm [8].

The IAP (International Association of Pancreatology) has been called again in 2010 to update the 2006 International Guidelines for IPMN management, after the renewed state of the art. The new guidelines were published in 2012 and they showed substantial differences in BD-IPMN management. In specific, according to the new Fukuoka’s guidelines, the 3 cm cyst dimensional limit has been downgraded as a “warning characteristics” therefore a stricter follow-up is needed; this suggests that the dimension of the cystic duttulectasia can be a “weaker indicator of malignancy” than other characteristics like the presence of wall nodules as an example [9].

Many studies conducted after the Consensus Conference, observed that the 2012 guidelines showed a positive predictive value (VPP) greater than the 2006 guidelines (88% versus 67%) and also a

13 higher negative predictive value (VPN: 92.5% versus 88%) [10].

However, Sahora et al. [11] have recently demonstrated, by evaluating different cases of 240 patients, that the cystic dimensions greater or equal to 3 cm were significantly associated with the presence of high-grade dysplasia or invasive carcinoma; the thesis has been further supported by a meta-analysis conducted by Anand et al., which highlighted that the 3 cm dimensional cut-off was considerably increasing the risk of being malignant, with an odds ratio pool of 62,4 (95%; CI of 30,8-126,3) [12].

In this study, the dimensional criteria (>3cm) did not result as a sign of malignancy (p=0.5635); we have also experienced an unusual event in the acquisition of an abdominal TC during the post-contrastographic phases. During the portal and late phase it has been observed the progressive ejection of mucin from a secondary duttulectasia of the pancreatic head towards the main duct; the lesion, which in the pre-contrastographic acquisition had the dimensions of 2,8x1,2cm, after 3 minutes (late phase) appeared with a diameter of 1,7x0,7 cm.

Therefore, the dimension of a cystic dilatation of a secondary duct is likely to depend on the amount of intralesional mucin and its variation with time determines the dimensional variation of the lesion. In the cases presented, 1/3 of the patients with a cystic lesion > 4 cm did not experience further evolutions during the next 3 years of clinic- instrumental follow-up.

The dimensional criteria arises another issue raised by a recent study conducted by Fritz et al. [13]. The author examined a group of “Negative-Sendai” patients who presented cystic dimensions lower than 2 cm, without intramural nodules or wall thickening: over 69 patients included in the casuistry with IPMN-BD “Negative Sendai, 24.6% (17/69) were showing malignant characteristics (invasive carcinoma or carcinoma in situ) at the histologic post-surgical resection.

In addition to that, the study conducted by Nguyen AH et al. [14] demonstrated the presence of high-grade dysplasia or invasive carcinoma in IPMN-BD dimensionally lower than 2 cm with fine needle aspiration (FNA) under endoscopic ultrasound.

The acknowledgment of pre-invasive lesions should be considered fundamental as the prognosis and the rate of recurrence of the IPMN lesions depends on the characteristics of tumour invasiveness rather than on the size of the lesion or the involvement of the primary or secondary duct. It has been also demonstrated that the rate of recurrence is higher for the IPMN-BD, therefore these are the lesions that should go first through surgical resection [15].

The utilization of eco-endoscopy, since it is an invasive diagnostic method, has been identified as potential investigation to be used to only in case of clinical suspicions of degeneration at the evaluation with a second level method like acquired TC with protocol aiming at the study of pancreas or the RM associated with cholangiographic sequences [16]. Following this statement, the

14 eco-endoscopy with FNA is not a routine exam; therefore it appears invalidating looking for imaging characteristics with a high positive predictive value to adequately select the patients that need a deeper cytological study.

Also our study confirmed the data of potential malignity for the small lesions, in fact 11 over 16 of the cystic degenerated lesions presented a diameter lower than 3 cm and on 5 out of the 26 (20.0%) duttulectasie with diameter smaller or equal to 2.5 cm, areas of ductal carcinoma have been identified at the post-surgical histologic exam.

These data suggest that some small cyst have the potential to be malignant and that the prediction of malignancy based on the only dimensional criteria is strongly not recommended.

We therefore tried to identify imaging TC parameters that could address the diagnostic / therapeutic procedure for patients affected by IPMN-BD, by mainly identifying two characteristics not described in literature before which correlated in a statistically significant way the malignancy of the cystic lesion: the intra-cystic lesion evaluated in basal conditions by considering a cut-off > 20 HU which reflects the percentage of solid content of the cystic lesion (with a p<0.0001; VPP of neoplastic degeneration of 80.0%) and the interest of the perineural plexuses (sensibility 96.0% and specificity 60.2%). The interest of the perineural plexus has been assessed with the current developments on the state of the art which highlight how the cellular mutation is responsible for carcinogenesis and how the cancerous micro environment contributes to the formation and progression of neoplasia. The invasion of the extra-pancreatic perineural plexus (celiac and mesenteric) shows off frequently at the anatomo-pathologic evaluation of the surgical specimen after resection of ductal adenocarcinoma [17].

Considering that the model of histologic progression from PanIN to pancreatic ductal carcinoma on lab rats KPC has been previously demonstrated as a valid model to analyse the histologic alterations observed in the human disease [18], the rats gave us the opportunity to study the changes in the nervous system that occur during the neo-plastic phases of the degenerative pancreatic disease. Stopczynski RE’s study [19] on KPC laboratory tests highlighted how the neuroplastic changes start during the pre-neoplastic / dysplastic pancreatic ductal carcinoma, by suggesting an active role of the nervous system on the disease progression.

Based on the data given by the current state of the art, we started analysing the TC aspect of perineural plexuses by classifying them depending on their involvement as normal, slightly thickened and grossly thickened, and by evaluating the correlation between assigned classification and neoplastic degeneration.

In our case studies the only anatomic alteration of the fibres of the plexus present VPP of 44.0% with a VPN of 92.8%; the grossly thickened appearance of the plexus is characterised by a higher

15 VPP (71.4%) despite of a negative predictive value relatively lower 78.1%). This demonstrates that not having alterations in the plexus is a strongly indicative index that the lesion is benignant; on the opposite side, when the lesion starts its first cellular modifications through a neoplastic degeneration, the micro environment next to it is negatively affected and determines a progressive alteration (first simply by thickening and then progressing toward a nodular appearance until it becomes mass-like) of the extra pancreatic perineural plexus.

Our study confirmed also that the enhancement pattern, with progressive impregnation of contrast parietal or intralesional during portal and late phases was statistically correlated with the malignant degeneration of the lesion (p<0,0001), however this characteristic shows a positive predictive value of 50% so it is not invalidating in the selection of the patients to be submitted to further diagnostic invasive tests. It is interesting to know that the negative predictive value is equal to 93.7%, this identifies the missed post-contrastographic enhancement as an indication of benignity which can be used to address the patient to a management of a simple follow-up.

CONCLUSIONS

The current guidelines advice the asymptomatic patients affected by IPMN-BD with a cystic lesion with a diameter lower than 3 cm to carry a simple instrumental follow-up, considering that probabilities of malignant degeneration are very low. However, our study underlines that the cystic dilatation duct with diameter < 3 cm have been evaluated as degenerated at the histopathological analysis, by confuting the dimensional criteria as reliable diagnostic parameter in terms of therapeutic management of the patient.

The main classifications proposed in the existing literature should then be modified to reduce the importance of dimensional criteria which does not have a high positive predictive value referring to the neoplastic degeneration.

Moreover, cystic lesion dimension as criterion of possible degeneration should be revised, considering that it can reduce during the follow-up because of the reduction of the mucin content (Figure 5).

16 Figure 5

The evaluation of post-contrastographic parietal and septal enhancement and the Wirsung calibre greater than 5 mm, already proposed in Sendai guidelines, have been recognised as valid selection criteria of patients who need a deeper eco endoscopic study about neoplastic degeneration of IPMN-BD lesions.

The new imaging evaluating parameters considered in our study, regarding the basal intra-lesional density and perineural involvement in specific, due to the high positive predictive value, could be proposed as suspicious clues which deserve a deep diving through invasive methods.

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