Pancreatic head excavation for tissue diagnosis may reduce unnecessary pancreaticoduodenectomies in the setting of chronic pancreatitis

Sassari, Italy

Pancreatic head excavation for tissue diagnosis may reduce unnecessary pancreaticoduodenectomies in the setting of chronic pancreatitis

Alessandro Fancellu, Giorgio C Ginesu, Claudio F Feo, Maria L Cossu, Marco Puledda, Antonio Pinna and Alberto Porcu

Sassari, Italy

BACKGROUND: The necessity to obtain a tissue diagnosis of cancer prior to pancreatic surgery still remains an open debate. In fact, a non-negligible percentage of patients undergoing pancreaticoduodenectomy (PD) for suspected cancer has a benign lesion at final histology. We describe an approach for patients with diagnostic uncertainty between cancer and chronic pancreatitis, with the aim of minimizing the incidence of PD for suspicious malignancy finally diagnosed as benign disease.

METHODS: Eighty-eight patients (85.4%) with a clinicoradiological picture highly suggestive for malignancy received formal PD (group 1). Fifteen patients (14.6%) in whom preoperative diagnosis was uncertain between pancreatic cancer and chronic pancreatitis underwent pancreatic head excavation (PHEX) for intraoperative tissue diagnosis (group 2): those diagnosed as having cancer received PD, whereas those with chronic pancreatitis received pancreaticojejunostomy (PJ).

pancreatic carcinoma; chronic pancreatitis; pancreaticoduodenectomy; pancreatic head excavation

Introduction

Preoperative biopsy for tissue diagnosis is not usually performed before pancreaticoduodenectomy (PD) in those patients where both the clinical picture and the imaging findings are consistent with resectable carcinoma of the head of the pancreas.[1-3]Nonetheless, a continuing debate exists on whether or not patients with potentially resectable carcinomas of the pancreatic head should undergo preoperative biopsy before PD, because it is well recognized that in 4%-13% of patients undergoing a so-called “blind PD” (i.e. without a histologically-proven diagnosis of malignancy), a diagnosis of non-malignant lesion will eventually be established.[1-6]

In fact, different solid pancreatic head masses resembling ductal adenocarcinoma may ultimately be diagnosed as benign lesions, such as chronic pancreatitis, benign endocrine neoplasms, and masses of inflammatory or autoimmune etiology.[7,8]In particular, chronic pancreatitis is often indistinguishable from pancreaticcancer, mostly when enlargement of the pancreatic head is present on imaging studies. Furthermore, these two conditions may co-exist in the same patient and chronic pancreatitis is a well-known risk factor of pancreatic cancer.[9]Although PD has been considered as an acceptable option also for patients with symptomatic chronic pancreatitis, the non-negligible rates of complications associated with that surgical procedure led some clinicians to develop drainage procedures and limited pancreatic resections.[10-14]

In 2009, with the aim of minimizing the number of PD for benign pancreatic lesions mimicking malignancy of the head of the pancreas, we started an approach for those patients in whom preoperative work-up and intraoperative assessment were uncertain between cancer and chronic pancreatitis. In those cases, a pancreatic head excavation (PHEX) was carried out in order to obtain a tissue diagnosis on frozen section. This procedure allowed us to continue with either a formal PD in patients with carcinoma, or with a pancreaticojejunostomy (PJ) in those with benign lesions. The purpose of this study was twofold: to assess the surgical outcomes of PHEX for intraoperative diagnosis and to evaluate the rates of unnecessary PD since this approach was adopted.

Methods

Patient selection

Data from every patient undergoing pancreatic and biliary surgery between January 2009 and December 2013 have been prospectively collected in an institutional review board-approved database. For the present study, we queried our institutional database for any patient undergoing surgery for histologically-proven or suspicious pancreatic head carcinoma.

In general, the policy at our institution is to proceed with formal PD in presence of a clinicoradiological picture highly suggestive for pancreatic head adenocarcinoma; preoperative cytological or histological diagnosis is not usually pursued in this setting. In the study cohort, brushing for cytology examination was only obtained in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for preoperative biliary stent placement. All patients underwent total body CT-scan and transabdominal ultrasound as preoperative imaging studies. In selected cases, also endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP) were used. Patients with autoimmune pancreatitis were excluded.

We identified two groups of patients. Group 1 included patients having a clinicoradiological picture highly suspicious for malignancy; all of them received formal PD with or without pylorus preservation. Group 2 included patients with preoperative work-up that was considered uncertain between pancreatic cancer and chronic pancreatitis; in all patients of this group a PHEX and intraoperative frozen section analysis was performed with the aim of guiding the surgical strategy as described below.

MRCP was performed in 14 patients of group 1 and in all patients of group 2. In the latter group MRCP showed signs of chronic pancreatitis and enlargement of the pancreatic head, however it was challenging to differentiate mass forming chronic pancreatitis from pancreatic adenocarcinoma.

All patients of group 2 also underwent EUS, and ultrasound features were evaluated against the Rosemont criteria for diagnosis of chronic pancreatitis as described by Catalano and coworkers.[15]The demographic and clinical characteristics of the whole cohort are provided in Table 1. In patients of group 2, the preoperative diagnosis was defined as “uncertain” according to the findings resumed in Table 2, the main selection criterion being an enlargement of the pancreatic head in the setting of imaging findings indicative of chronic pancreatitis.

This study was approved by the institutional review board of our department and all patients involved in this study have given their informed consent. In particular, patients of group 2 were properly advised that the PHEX procedure was designed to permit intraoperative diagnosis and to guide surgical strategy. The patients were also informed about the risks and benefits of a PD carried out for a potential benign disease.

All patients of group 2 were operated on by the same surgeon (Porcu A). For all patients the following data were extrapolated: demographic and clinical character-istics (age, gender, presence or absence of jaundice and abdominal pain, alcohol consumption, smoking), preoperative imaging, laboratory assessment, surgical procedure, definitive histological diagnosis, postoperative complications and survival outcomes.

Table 1. Demographic and clinical characteristics of study paients (n, %)

Table 2. Characteristics of patients in whom the diagnosis was deemed unclear between cancer and chronic pancreatitis

Overall survival and disease-free survival for patients receiving PHEX and PD for cancer (group 2) was compared with survival of the control group of 88 patients (group 1) who received formal PD for carcinoma of the pancreatic head in the same time-frame at our institution.

Operative procedure in patients with uncertain diagnosis

Through a midline incision, careful exploration of the peritoneal surfaces and regional lymph nodes for metastatic disease was performed as a first step. Upon entering the lesser sac, the Kocker maneuver was performed to mobilize the duodenum and the head of the pancreas from their posterior attachments in the retroperitoneum. When an enlargement of the head of the pancreas, possibly consistent with either cancer or chronic pancreatitis was encountered at manual palpation, we performed a wide PHEX as described following. After careful division and ligation of the small anterior branches of the pancreaticoduodenal vessels, the pancreatic head along with the uncinate process was exposed. At this point, we performed a local excavation of a quite extended portion of the head of the pancreas, measuring about 3×2×2 cm, including the terminal end of both the common bile duct and the main pancreatic duct, using a cold knife. Accurate hemostasis control was established by means of electrocautery, ultrasonic coagulation shears and 3-0 mono filament absorbable sutures. This operative step reproduced previously described procedures, such as the Bern technique illustrated by Gloor and coworkers as a modi fication of the Beger and Frey procedure for treatment of chronic pancreatitis,[16]as well as the one proposed by Ho and Frey in those cases in which the chronic pancreatitis was limited to the pancreatic head.[17]

The operative specimen was then sent for frozen section examination and a decision was taken on the basis of the intraoperative histological diagnosis, as follows. When the lesion was proved to be malignant, a formal PD was carried out. When the frozen section diagnosis indicated a benign disease, a Roux-en-Y limb was constructed by dividing the jejunum approximately 15 cm distal to the ligament of Treitz to create a PJ using 3-0 or 4-0 interrupted sutures. Great care was taken to provide a complete drainage of the bile and pancreatic juice. Again, this step recalls the reconstructive stage in both the Bern and Ho and Frey operations for chronic pancreatitis located in the head of the organ.[16,17]In all cases the PHEX was performed with limited bleeding (≤60 mL).

Intraoperative histological examination

Intraoperative frozen section assessment of the pancreatic tissue obtained with PHEX was carried out in each case. At least eight 3-6 mm thick serial sections were examined. Differential diagnosis between pancreatic adenocarcinoma and chronic pancreatitis was reached through checking for the presence of nuclear size variation of at least 4:1 between ductal epithelial cells, cribriform glands, incomplete duct lumen, disorganized duct distribution, perineural in filtration by glands, single cells in filtrating the stroma, disorganized stroma, large irregular nucleoli, epithelial mitoses, and necrotic glandular debris.[18]The rest of the pancreatic tissue and the frozen tissue were fixed and embedded in paraf fin for permanent hematoxylin and eosin examination. The total procedure time for the frozen section examination was 20± 10 minutes. The operative technique is illustrated in Fig. 1.

Statistical analysis

Categorical variables were compared by the Chisquare test or the Fisher’s exact test as appropriate, and continuous variables were assessed by the Student’sttest or the Mann-WhitneyUtest. Overall survival was calculated from the time point of surgical operation to death or last patient contact for patients receiving PD for pancreatic adenocarcinoma. Overall survival and disease-free survival probabilities were estimated by the Kaplan-Meier method and compared by means of the log-rank test.APvalue of 〈0.05 was considered statistically significant. Analysis was conducted using IBM SPSS Statistics version 20 (IBM Corporation, 2011).

Fig. 1. A: Pancreatic head excavation for tissue diagnosis in patients with preoperative diagnosis unclear between cancer and chronic pancreatitis. B: A Roux-en-Y pancreaticojejunostomy was constructed in patients in which the frozen section analysis revealed chronic pancreatitis. Intraoperative photographs illustrate the technique (C and D).

Results

One hundred and seventeen patients underwent surgical exploration for either confirmed or suspected cancer of the pancreatic head during the considered time frame. Fourteen patients were deemed unresectable because of unexpected locally advanced disease identified at the time of surgery. Among 103 patients with potentially resectable disease, 88 (85.4%) had a clinicoradiological work-up highly suspicious for malignancy (group 1), whereas 15 patients (14.6%) had a preoperative diagnosis uncertain between cancer and chronic pancreatitis (group 2). Demographic and clinical characteristics (Table 1) were similar across the two groups with the exception of proportion of patients with jaundice, which was smaller in group 2 (P〈0.05). Only 14 (13.6%) patients of the whole cohort study had a preoperative diagnosis of malignancy obtained by cytologic examination at the time of endoscopic biliary stent placement. The decision to insert a biliary stent was made due to the coexistence of elevated bilirubin levels and severe cholangitis. Seven patients in group 2 (46.7%) underwent an attempt to obtain a preoperative cytology diagnosis through fineneedle aspiration cytology that was inconclusive for the surgical planning.

Fig. 2. Flowchart of 103 patients operated on for confirmed or suspected pancreatic head cancer between 2009 and 2013.

All patients of group 1 received formal PD. Patients of group 2 had PHEX as first operative step with the purpose of obtaining tissue diagnosis. Of these patients, 8 (53.3%) were diagnosed as pancreatic adenocarcinoma at frozen section analysis, therefore they received PD; 7 (46.7%) were histologically proved fibrosis and/or chronic inflammation and no features of malignancy, a Rouxen-Y PJ was performed (Fig. 2).

Globally, 96 patients underwent PD, whereas 7 received PJ according to the above described procedure. We observed an improvement of symptoms in all patients with chronic pancreatitis undergoing PJ, such as chronic pain and digestive difficulties. The categories of surgical outcomes and the grade of complications were according to the International Study Group of Pancreatic Surgery (ISGPS) and the Clavien classification[19-22]and sumarized in Table 3. There were 2 perioperative mortalities in group 1 and overall morbidity related to pancreatic surgery was 36.9%.

All patients of group 1 had pancreatic cancer at final histology. In group 2, we did not find any false positive nor false negative cases at frozen section analysis, thus 8 patients were diagnosed as having pancreatic adenocarcinoma and 7 chronic pancreatitis at final histology. Out of the 4 patients with clinical history of chronic pancreatitis (Table 1), 1 had a final diagnosis of adenocarcinoma. Regarding pathological stage of tumors of group 1, 24 (27.3%) were in stage pT1, 55 (62.5%) in stage pT2, and 9 (10.2%) in stage pT3. As for the 8 patients of group 2 with cancer, 7 (87.5%) tumors were in stage pT1, and 1 (12.5%) in stage pT2. Sixty patients of group 1 (68.2%), and 4 (50.0%) of group 2 with pancreatic adenocarcinoma had positive lymph nodes (pN1 stage).Further resection was needed to achieve clear margins in two patients of group 1, and in 1 of group 2 because of positive pancreatic transection margin at frozen section examination. At final histology, the percentages of R1 resection were 27.7% and 12.5%, respectively in the 88 patients of group 1 and in the 8 of group 2 with pancreatic adenocarcinoma. No patient had R2 resection at final histology.

Table 3. Surgical outcomes and complications

Overall, we did not observe any patients undergone PD for benign disease. Fifty-three (60.2%) patients of group 1 and 5 (62.5%) of group 2 received adjuvant chemotherapy. As for survival of patients in group 2, after a median follow-up of 42 months (range 12-71), none of the patients who underwent PJ because of frozen section analysis negative for cancer developed clinical or radiological signs of pancreatic cancer, nor metastatic disease from pancreatic adenocarcinoma. Considering the patients with final diagnosis of pancreatic carcinoma (all patients of group 1 who received formal PD and 8 patients of group 2 who received PHEX+PD) we did not observe significant difference in both median diseasefree survival (24 months in the group 1 and 18 months in the group 2,P=0.389) and median overall survival (22 months in the group 1 and 18 months in the group 2,P=0.509) (Fig. 3).

Fig. 3. Overall survival (A) and disease-free survival (B) following formal PD and PHEX+PD.

Discussion

The main result of our study is that we observed no patients undergone PD for suspicious malignancies of the head of the pancreas and ultimately diagnosed as benign disease, in spite of the fact that only a minority of patients (13.6%) had a proven diagnosis of malignancy before surgery. This figure mostly depends on the tissue diagnosis obtained from frozen section during PHEX in those patients in which the preoperative diagnosis was unclear between cancer and chronic pancreatitis.

The issue regarding pancreatic surgery before proof of cancer continues to be an open debate. In modern practice, histologic diagnosis of pancreatic carcinoma is mandatory for patients with unresectable or metastatic disease and before neo-adjuvant treatment.[1,3]However, general consensus exists that preoperative biopsy is not required before PD when the clinical and imaging workup are consistent with resectable cancer of the pancreatic head.[7]This concept has recently been reinforced by a consensus statement from the ISGPS.[1]Our policy is to proceed to formal PD when pancreatic head masses are highly suspected to be carcinomas at preoperative imaging. The described PHEX technique is used for intraoperative diagnosis only in cases in which preoperative diagnosis is considered to be uncertain.

The incidence of benign disease after PD for suspected malignancy has been reported in up to 13.6% of cases.[3]Gerritsen et al[3]found that about 7% of patientsundergone PD for suspected malignancy were ultimately diagnosed as benign disease. Interestingly, in our experience we obtained a benign frozen section analysis in 7 of 103 patients undergone surgery for documented or suspicious pancreatic head carcinoma; this accounts for a proportion of 6.8% of cases in which a possibly unnecessary PD would have been carried out for a benign condition.

Despite significant advances in imaging techniques, preoperative differential diagnosis between pancreatic cancer and chronic pancreatitis is difficult, especially when preoperative assessment only detects alterations in the head of the organ.[4,8]Furthermore, both conditions may co-exist. van Gulik et al[23]demonstrated that 6% of patients who underwent PD for suspected pancreatic head carcinoma were ultimately diagnosed as chronic pancreatitis. Strate et al[24]found that 6 out of 80 patients candidates to either the Beger or Frey procedure for chronic pancreatitis were diagnosed pancreatic carcinoma at frozen section. Although many patients with chronic pancreatitis complain of typical long case history of recurring episodes of severe upper abdominal pain irradiated to the back and weight loss, it should be recognized that the disease may also occur in asymptomatic or pauci-symptomatic forms.[25]For example, in the study from Smith et al,[26]none of the 22 patients with histologically proven chronic pancreatitis was reported to have neither chronic pain or other symptoms. Only 4 patients in our series had an ascertained preoperative diagnosis consistent with chronic pancreatitis.

Many pancreatic surgeons argue that confirmatory biopsy has become less important than in the past, due to the fact that the mortality rates associated to PD have strongly decreased in high-volume centers.[1]We do not completely share this point of view and believe that PD represents an overtreatment for chronic pancreatitis except in presence of selected cases. Although perioperative mortality for PD occurs in less than 2% of cases in highvolume centers, this figure is by no means negligible. Moreover, morbidity associated to PD remains relatively high with rates approaching 40% even in high-volume centers.[7,10,11,27-29]However, we would highlight that the PHEX technique as described herein may be used in selected cases in which the diagnosis is uncertain and PD is expected to be an overtreatment in presence of chronic pancreatitis localized in the head of the organ. Indeed, in patients with chronic pancreatitis in whom PD is planned on the basis of preoperative work-up, PHEX should not to be considered an option.

Several reports[10,30-32]in the literature have highlighted the advantages of derivative procedures and the so-called “organ-sparing” resections for treatment of chronic pancreatitis, such as local resection of the pancreatic head with or without duct drainage, and duodenum-preserving resections. When compared to PD, the“organ-sparing” resections bear the advantages of lowest cost and morbidity and early prevention of postoperative diabetes, as well as a general improvement of the quality of life.[10,33,34]

Frozen section analysis is routinely performed on the common bile duct and pancreatic duct/pancreatic face margin during PD for cancer, whereas its use for proof of malignancy has been less commonly used and still remains controversial.[35,36]Intraoperative biopsy for tissue diagnosis via needle and wedge biopsies has been proposed by some authors with the aim of guiding surgical decision.[37,38]However, it is not clear how much tissue was available for diagnostic purposes in the different studies. Nelson et al[37]reported an accuracy of 83% in six patients in which frozen section analysis was performed for tissue diagnosis. Garcea et al[4]reported a specificity of 100% and a sensitivity of 90% for intraoperative histology in a cohort of 128 patients with possible periampullary malignancy undergoing PD. However, some authors reported lower accuracy;[1]in general, the incidence of false negative results ranges widely in the literature between 1% and 75%. An important issue is the quantity of tissue available for frozen section: this information is not specifically addressed in the different studies on this topic. False negative rates at frozen section may result both from the scarce amount of tissue sample, and the difficulties in differentiating between chronic inflammation and cancer at microscopic examination. In the method described herein, we used a substantial quantity of pancreatic tissue (about 3×2×2 cm) which was sufficient for an accurate diagnosis. In our study we found no discordance between frozen section and final pathology.

PHEX is a procedure used in different surgical operations for chronic pancreatitis.[16,17,39]Andersen and Topazian[40]described PHEX, using ultrasonic dissection, as a variation on the theme of duodenum-preserving pancreatic head resection for benign lesions. The technique described in the present study is also similar to organ-preserving pancreatic head resection proposed by Farkas and colleagues in 2003; however, they performed intraoperative needle biopsies and frozen section in a setting of chronic pancreatitis.[11]The same authors reported the organ-preserving pancreatic head resection as a safe and effective procedure for chronic pancreatitis in their analysis of the 10-year results of the technique.[39]In a recent review from Andersen and Frey,[10]PHEX has been considered as effective as PD for the surgical treatment of chronic pancreatitis, with lower mortality andmorbidity.

However, PHEX has never been described as a diagnostic step during pancreatic surgery for suspected malignancy, to the best of our knowledge. We recognize that our approach might raise some concerns. First, there was the theoretic risk of leaving undetected a small carcinoma, deeply located in the pancreatic head. After a median follow-up of 42 months, none of the 7 patients in which the intraoperative diagnosis was chronic pancreatitis died of pancreatic cancer nor did any develop metastases from pancreatic cancer. In our opinion, this finding might corroborate the safety of our approach even if the follow-up is short, assuming that symptoms, as well as radiological signs, of pancreatic cancer are usually detectable early in the course of the disease. Another issue is that performing a two-step operation might compromise the oncologic safety of formal PD when cancer is encountered during PHEX. In fact, the PHEX approach may theoretically lead to disruption of tumor planes. In this regard, we did not observe a significant difference in median survival of patients undergone formal PD and those undergone PHEX prior to PD. We are aware that the technique described herein might seem to go against the principles of the “no touch technique” advocated for pancreatic cancer, which still remains a tumor with a dismal prognosis. However, no oncological disadvantages have been shown in our cohort. Moreover, the PHEX for tissue diagnosis has been used in a very selected group.

The main limitations of our study are its retrospective design and the relatively small cohort of patients. However, a recent multicenter study from 11 institutions (1629 cases) evaluated the preoperative characteristics of patients in the time frame 2003-2010, and found that nearly 7% of patients undergoing PD for suspected malignancy were ultimately diagnosed with benign disease; only 19% of patients with benign disease were correctly predicted with the model the authors used.[3]Thus, our single-institution study including 103 patients in a 5-year time frame (accounting for a mean of 20.5 cases per year) probably reflects the rates of resectable pancreatic head cancers in medium-volume centers. Indeed, it is commonly known that only 15% to 20% of patients with pancreatic cancer are candidates for resection surgery. In this scenario, the occurrence of clinicoradiological uncertainty before surgery is even rare. In spite of the relatively small cohort of patients, it should be taken into account that the PHEX approach for intraoperative diagnosis might be reserved to a very select group of challenging cases in which the preoperative diagnosis is uncertain.

In conclusion, the ongoing debate on misinterpretation of benign lesions in patients with suspected malignancy is a part of the general discussion regarding the optimal management of carcinoma of the pancreatic head. At present, treatment of pancreatic carcinoma is a field lacking solid level I evidence and where the decision-making process in front of suspected pancreatic head mass depends on the surgeons’ judgment of the preoperative work-up. The role of intraoperative biopsy will likely become better defined as accuracy of predictive models based on laboratory tests and imaging will improve in the future. Our results suggest that PHEX and frozen section evaluation are accurate for tissue diagnosis and may reduce the occurrence of unnecessary PD for benign lesions, when the clinicoradiologic picture is uncertain between cancer and chronic pancreatitis.

Contributors:FA and Porcu A performed manuscript preparation and revision. FA also performed statistical analysis. GGC, FCF and CML reviewed the data and wrote manuscript. PM and Pinna A collected the data. FA is the guarantor.

Funding:None.

Ethical approval:This study was approved by the Institutional Review Board of the Department of Clinical and Experimental Medicine of the University of Sassari, Italy.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received October 21, 2016

Accepted after revision February 8, 2017

No patient

PD for benign disease. All patients in group 1 had adenocarcinoma on final histology. Eight patients of group 2 (53.3%) received PD after intraoperative diagnosis of cancer, whereas 7 (46.7%) received PJ because no malignancy was found at introperative frozen sections. No signs of cancer were encountered in patients receiving PHEX and PJ after a median follow-up of 42 months. Overall sur-vival did not differ between patients receiving PD for cancer in the group 1 and those receiving PD for cancer after PHEX in the group 2 (P=0.509).

(Hepatobiliary Pancreat Dis Int 2017;16:315-322)

Author Affiliations: Department of Clinical and Experimental Medicine, Unit of General Surgery 2 - Clinica Chirurgica, University of Sassari, V.le San Pietro 43, 07100 Sassari, Italy (Fancellu A, Ginesu GC, Feo CF, Cossu ML, Puledda M, Pinna A and Porcu A)

Prof. Alessandro Fancellu, Department of Clinical and Experimental Medicine, Unit of General Surgery 2 - Clinica Chirurgica, University of Sassari, V.le San Pietro 43, 07100 Sassari, Italy (Tel: +39-079-228432; Fax: +39-079-228394; Email: afancel@uniss.it)

? 2017, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(17)60015-8

Published online May 3, 2017.

CONCLUSION: Although the described technique has been used in a very selected group of patients, our results suggest that PHEX for tissue diagnosis may reduce rates of unnecessary PD, when the preoperative diagnosis is uncertain between cancer and chronic pancreatitis.