Is pancreatic calculus treatment of AIP different from that of ordinary CP?
The present study uncovered the following observations regarding ESWL treatment of pancreatic calculi in patients with chronic stage AIP or ordinary CP: (1) the AIP group was significantly older than the CP group and displayed fewer clinical symptoms requiring ESWL therapy, (2) the AIP group showed frequent pancreatic duct stenosis proximal to pancreatic calculi, (3) the rate of complete stone extraction from the MPD was slightly lower in the AIP group, and (4) there were no significant differences in the rates of subsequent surgical treatment, adverse effects, or pancreatic stone recurrence after ESWL between the groups.
In this investigation, we enrolled 100 patients with chronic calcified pancreatitis who had undergone ESWL. The indications for ESWL were: (1) obstructing stone in the MPD whose volume was deemed too large for endoscopic therapy and (2) chronic pain or repeated pancreatitis attacks, as well as (3) preservation of pancreatic function by pancreatic juice release. All patients provided informed consent for this treatment.
Of the 73 patients with AIP who were registered at our hospital, 15 (20%) later experienced calculi formation that met the Japanese diagnostic criteria for ordinary CP. Among them, several patients who fulfilled the indications for ESWL did not consent to treatment, which was a limitation of this study. As we aimed to evaluate pancreatic stone treatment, we selected only the 8 patients with chronic stage AIP who had met the requirements for ESWL and had provided consent after being explained all possible complications, such as acute pancreatitis, and the risk of non-preservation of pancreatic function. Larger prospective comparisons of chronic stage AIP and ordinary CP are required.
Many patients with calcified ordinary CP complain of epigastralgia and back pain due to increased pancreatic duct pressure caused by intraductal pancreatic stones [
38]. However, this study revealed that only 12% of AIP patients who were treated with ESWL displayed these symptoms. We earlier identified severe inflammation of the pancreatic head and non-narrowing of the pancreatic duct in the body region, both of which indicated that severe pancreatic juice stagnation had induced pancreatic calcification, to be risk factors for extensive pancreatic stone formation in AIP [
27,
29]. Accordingly, we had expected that AIP complicated with numerous pancreatic calculi would be accompanied by epigastralgia similarly to ordinary CP, but the present study showed that most AIP patients were asymptomatic. Although AIP and ordinary CP both displayed the imaging findings of severe pancreatic calculi and pancreatic atrophy that were characteristic of a chronic stage of pancreatitis, there was a discrepancy in the occurrence of abdominal pain between the two conditions. The reason for this difference may be pathophysiological differences that require further study.
In our cohort, ESWL was performed on AIP patients mainly to preserve pancreas function. Previous reports have examined the efficacy of pancreatic calculus treatment by endoscopy and ESWL on pancreatic exocrine and endocrine function in ordinary CP. In terms of exocrine function, a BT-PABA test showed improvement in 60-77% of cases [
32,
33], although several studies found no significant differences before and after therapy. Concerning endocrine function, few reports have been able to demonstrate a clear improvement in glucose tolerance or insulin secretion capacity following treatment [
34,
39]. In patients with chronic calcified pancreatitis who receive treatment for the purpose of function preservation, it will be of merit to evaluate whether pancreatic condition is affected by relevant therapy. However, as this study focused primarily on pancreatic stone treatment approaches, detailed pancreatic function readings were not obtained before and after intervention. The BT-PABA test is the standard pancreatic exocrine function examination in Japan, but it is affected by various factors, such as liver and renal dysfunction, and is somewhat complex for patients to understand. It will be important to perform precise assessment of exocrine and endocrine dysfunction in chronic stage AIP over a long-term period that includes the presence or absence of pancreatic stone treatment. We have also been considering new alternative approaches to the BT-PABA test.
We previously proposed that AIP could exhibit severe pancreatic stone formation over a long-term period due to disease recurrence [
17,
20] and pancreatic juice stasis preceded by pancreatic head swelling, narrowing of both Wirsung’s and Santorini’s ducts in the affected region, and MPD non-narrowing in the pancreatic body [
27,
29,
30]. Another risk factor for pancreatic calculus formation in AIP is excessive alcohol intake of pure ethanol of >50 g/day [
40]. There was 1 alcoholic subject among the 8 AIP patients who received calculus treatment with ESWL. In this patient, both pancreatic juice stagnation due to AIP-specific inflammation [
27,
29] and pancreatic juice denaturation from alcohol abuse might have been associated with the calculi. Further examination is required on alcohol consumption and the clinical background of pancreatic stone formation in AIP.
When assessing the suitability of ESWL treatment, it is important to identify patients having cancer of the pancreas. Subjects with pancreatic cancer were excluded from this investigation after extensive examination, although it should be noted that pancreatic stones make it challenging to detect pancreatic tumors. All ESWL patients were free from pancreatic cancer during the entire study period.
What are effective approaches for the treatment of AIP with ESWL?
The present study uncovered a tendency for increased pancreatic duct stenosis proximal to pancreatic stones in AIP that was unlike the widely distributed duct stenosis encountered in ordinary CP. In such AIP patients, the stones fragmented by ESWL may sometimes have difficulty passing through the narrowed duct in the head region, which might diminish the efficacy of endoscopic treatment. Pancreatic duct dilation is a useful technique to remove crushed calculi pieces following ESWL in ordinary CP with pancreatic duct stenosis. Here, duct stenosis proximal to pancreatic calculi was present in 4 of 8 AIP patients (50%). Endoscopic pancreatic duct dilation was performed on 1 patient, which resulted in complete stone extraction. Thus, similarly to ordinary CP, combination therapy of endoscopic pancreatic duct dilation and ESWL in AIP may constitute an effective procedure to remove pancreatic stones in the presence of proximal duct stenosis.
We observed that pancreatic calculus treatment in AIP was significantly more common in elderly people who exhibited fewer symptoms in the present study. Accordingly, intensive ESWL and endoscopic treatment may be avoided or postponed in patients with the factors of: (1) advanced age, (2) mild or no chronic pain or pancreatitis, and (3) pancreatic duct stenosis proximal to pancreatic calculi. For such cases, we suggest conservative follow-up that includes periodic blood tests and imaging studies. Regular evaluation of exocrine and endocrine function during long-term follow-up will also help assess the need and timing of ESWL and endoscopic treatment in chronic AIP patients with pancreatic stones.
In ordinary CP, the most important factor in preventing calculus recurrence is avoidance of alcohol. However, treatment for pancreatic duct stenosis is thought to be another important step [
41]. In AIP, MPD stenosis may affect not only the efficacy of pancreatic stone treatment, but also pancreatic stone recurrence afterwards. Furthermore, previous studies have reported that smoking status (not smoking or cessation) was related to the efficacy of ESWL and pain relief after ESWL for CP [
36,
42]. Although this investigation did not evaluate smoking habits, further examination is needed in comparisons between ordinary CP and chronic stage AIP. Careful follow-up to evaluate calculus recurrence and exacerbation is also required for AIP with pancreatic stones, regardless of any ESWL or endoscopic treatment.
Is the histopathology of chronic stage AIP different from that of ordinary CP?
Although ordinary CP and chronic stage AIP exhibit similar imaging findings, including pancreatic calculus formation and pancreatic atrophy, their clinical manifestations, such as chronic pain and pancreatitis attacks, appear to be different. From the viewpoint of long-term pancreatic exocrine and endocrine function, it will be of interest to clarify whether the histopathology of ordinary CP is in fact different from that of chronic stage AIP with pancreatic stones. Since there have been few reports describing this relationship, we examined the pancreatic histopathology of an AIP patient who experienced pancreatic calculus relapse after surgical treatment and compared it with that of typical ordinary CP. We observed that the nodular pancreatitis characteristic of ordinary CP was widespread in tissue samples, while LPSP, which was typical of AIP, was found in restricted areas only. From these findings, we considered the following possibilities as mechanisms of chronic stage AIP histopathology: (1) based on our previous reports that AIP could progress to CP with severe calcification over a long-term period [
27,
29], LPSP may have shifted to a histopathology similar to that of ordinary CP, (2) due to the patient’s history of alcoholism, LPSP may have been complicated with a histopathology of typical alcoholic pancreatitis, and (3) based on the findings of Fukui et al. that obstructive pancreatitis complicated with pancreatic cancer also revealed abundant IgG4-bearing plasma cell infiltration [
43], LPSP with marked IgG4-bearing plasma cell infiltration may have coexisted with obstructive pancreatitis. Although we followed the clinical outcome of a single patient, our findings suggested that AIP could shift to a clinical condition similar to that of ordinary CP not only in imaging findings, but also in pancreatic histopathology, over a long-term course. Further analysis of the pancreatic histopathology of AIP with pancreatic atrophy and calculi is needed to clarify the clinical conditions of advanced stage AIP.
In the present study, there are several limitations and future perspectives. Specifically, our investigation included a limited number of patients and was retrospective in nature. It also employed the revised JCDC for CP, which has a strong emphasis on imaging findings, and the subjects enrolled all had type 1 AIP. More detailed analyses of physical findings and exocrine and endocrine dysfunction are needed as well.