High-grade dysplasia of the cystic duct margin in the absence of malignancy after cholecystectomy

Abstract

Background

A total of 750 000 cholecystectomies are performed annually in the USA. No data exist on patients with microscopic high-grade dysplasia at the cystic duct margin and the associated incidence of cholangiocarcinoma.

Methods

Pathology reports for 1992–2010 were reviewed for patients with high-grade dysplasia of the cystic duct margin in the absence of invasive gallbladder cancer. Clinical data were obtained from chart review.

Results

Five patients with high-grade dysplasia at the cystic duct margin without evidence of malignancy were identified. Radiologic imaging was abnormal in two patients. The cystic duct stump was abnormally dilated in both patients and one patient had an enlarged portacaval lymph node. All five patients underwent exploration and resection of either the cystic duct stump or the bile duct. Specimens in four of the patients showed no evidence of malignancy or dysplasia. One patient was found to have a node-positive adenocarcinoma of the cystic duct.

Conclusions

High-grade dysplasia at the cystic duct margin without evidence of invasive gallbladder cancer is rare. Patients with this finding should undergo cross-sectional imaging and a diagnosis of an underlying cholangiocarcinoma should be considered, especially if imaging reveals any abnormalities.

Introduction

Laparoscopic cholecystectomy is a common operation performed worldwide. In the USA, approximately 750 000 cholecystectomies are performed each year. Unsuspected gallbladder cancer is found in 0.3–2.0% of cholecystectomy specimens.^1–4 The finding of dysplasia in the absence of gallbladder cancer is uncommon, but its true incidence is not well reported in the literature.⁵ The finding of high-grade dysplasia at the cystic duct margin, without associated gallbladder cancer, is therefore rare. Such a finding would raise an obvious concern for an underlying carcinoma of the cystic duct or an adenocarcinoma of the bile duct.

Bile duct cancers are frequently associated with dysplasia near the primary tumour^6–8 and can be multifocal in 10% of patients.^9–11 The majority of patients with multifocal disease have a primary tumour in the bile duct and a second tumour in the gallbladder.^9,11 This raises the possibility that the finding of high-grade dysplasia at the cystic duct margin may be associated with an underlying bile duct carcinoma. The natural history of high-grade dysplasia at the cystic duct margin, in the absence of known gallbladder cancer, is unclear, and the optimum management of a patient with this finding is unknown. The aim of this study was to report a case series of five patients with this rare finding.

Materials and methods

With the approval of the local institutional review board (IRB), a retrospective review of patients who presented with high-grade dysplasia of the cystic duct in the absence of gallbladder cancer was performed. A free text search of pathology reports for the terms ‘cholecystectomy’, ‘cystic duct’ and ‘dysplasia’ was performed; this identified 193 patients. Patients were included if they had evidence of high-grade dysplasia at the cystic duct margin. Patients were excluded if they had evidence of an invasive cancer. Of the 193 patients initially identified, seven had high-grade dysplasia at the cystic duct margin without evidence of invasive cancer. Two of these patients had been evaluated by our pathology department to provide second opinions on the histologic diagnosis. As no follow-up data for these two patients were available, they were excluded and thus the study included five patients treated at the Memorial Sloan–Kettering Cancer Center (MSKCC).

Patient, radiologic, pathologic and treatment-related variables were obtained by retrospective chart review. Patient factors evaluated included age, gender, medical comorbidities and symptoms. Pre- and post-diagnosis imaging was reviewed. Pathologic variables of the underlying malignancy (if present) were recorded. Treatment-related variables included operative and perioperative details and adjuvant therapy.

Results

Patient characteristics are summarized in Table 1. The majority of the patients underwent imaging which consisted of magnetic resonance imaging (MRI) with cholangiography. Radiologic imaging was abnormal in two of the five patients. Both of these patients had a dilated cystic duct and one had enlarged portal nodes. In four of the five patients, surgical exploration revealed no abnormalities and histologic evaluation demonstrated no evidence of carcinoma or dysplasia. A bile duct adenocarcinoma was found in one of the five patients. This patient was a 66-year-old man who presented with nausea, vomiting and abdominal pain. An ultrasound demonstrated sludge in the gallbladder and pericholecystic fluid. The patient underwent an uneventful laparoscopic cholecystectomy. Pathologic examination of the gallbladder revealed focal areas of low- and high-grade dysplasia extending to the cystic duct margin (Fig. 1). An MRI scan revealed a mildly dilated cystic duct remnant with a slightly enlarged adjacent lymph node (Fig. 2). The patient was explored and found to have a palpable mass in the cystic duct remnant and metastases in portal lymph nodes without evidence of distant metastases. He underwent a bile duct resection, portal lymphadenectomy and partial hepatectomy of segments IVb and V of the liver. Pathology revealed a margin-negative T2N1 bile duct adenocarcinoma centred at the cystic duct with four of six lymph nodes positive (Fig. 3). The patient's postoperative course was complicated by a wound infection, but otherwise he recovered well. The patient was treated with adjuvant gemcitabine, but subsequently suffered disease recurrence and died of his disease 15 months after the date of diagnosis.

Table 1.

Patient characteristics

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Age, years	66	77	61	65	57
Sex	Male	Female	Male	Male	Female
Preoperative imaging	MRCP	PET/CT (non-contrast)	MRCP	Triphasic CT	MRCP
				MRCP	ERCP
Radiographic abnormality	Mildly dilated cystic duct stump	No suspicious findings	No suspicious findings	Minimal thickening of cystic stump	No suspicious findings
	Borderline enlarged lymph node			Sub-centimetre lesions in segments III and IV
Operation	Bile duct resection	Cystic duct excision	Cystic duct excision	Bile duct resection	Cystic duct excision
	Portal lymphadenectomy	Portal lymphadenectomy	CBD exploration with removal of stone	Portal lymphadenectomy
	Partial hepatectomy segments IV and V	Partial hepatectomy segments IV and V
Operative findings	Palpable mass at cystic duct remnant	None	CBD stone	Palpable mass at cystic duct remnant	None
	Enlarged portal lymph nodes			No liver lesions identified
Pathology	Cholangiocarcinoma (T2N1)	No evidence of malignancy or dysplasia	No evidence of malignancy or dysplasia	No evidence of malignancy or dysplasia	No evidence of malignancy or dysplasia
	4/6 nodes positive
Status	DoD: 15.3 months	NED: 0.9 months	NED: 16.0 months	NED: 25.6 months	NED: 2.1 months

MRCP, magnetic resonance cholangiopancreatography; PET, positron emission tomography; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; CBD, common bile duct; DoD, died of disease; NED, no evidence of disease.

Figure 1.

Pathology shows high-grade dysplasia of the cystic duct margin in Patient 1. (Haematoxylin and eosin stain; original magnification 100×)

Figure 2.

Magnetic resonance imaging in Patient 1 shows a dilated cystic duct remnant (white arrow) and borderline enlarged lymph node tissue (black arrow)

Figure 3.

Pathology reveals invasive adenocarcinoma of the bile duct wall in Patient 1. (Haematoxylin and eosin stain; original magnification 100×)

Discussion

Dysplasia has been reported in cholecystectomy specimens in the literature, but its true incidence is unknown.⁵ Little is known about the incidence of dysplasia at the cystic duct margin. There are no data on the incidence of cholangiocarcinoma or carcinoma of the cystic duct in association with high-grade dysplasia at the cystic duct margin of a cholecystectomy specimen. This small series demonstrates that there is a small, but real, risk for underlying biliary carcinoma with this finding.

About 10% of bile duct carcinomas are multifocal,^9–11 probably as a result of either synchronous lesions or the intraepithelial spread of tumour. It is therefore possible that high-grade dysplasia at the cystic duct represents multifocal biliary neoplastic changes or the extension of an underlying malignancy. Many bile duct carcinomas involve the superficial spread of non-invasive cancer. Sakamoto et al. found that 25% of resected hilar cholangiocarcinomas involved non-invasive extensions and that these extensions might extend to 20 mm.¹² Ebata et al. demonstrated that up to 50% of patients showed a superficial extension up to 1 mm and 11% presented with extensions up to 20 mm.¹³

The natural history of high-grade dysplasia of the cystic duct margin in the absence of gallbladder carcinoma is unknown. High-grade dysplasia, also known as carcinoma in situ or biliary intraepithelial neoplasia grade 3 (BiliN3), is present at resected margins of cholangiocarcinoma in 9–13% of patients.^6–8 Survival in these patients has been shown to be equivalent to that in patients with negative surgical margins.^6,7 This most probably reflects the poor prognosis related to the invasive component in these patients. However, one series found an increased rate of local recurrence in longterm survivors with high-grade dysplasia at the surgical margins.⁶ An earlier paper by Shirai et al. demonstrated that two patients with early-stage gallbladder cancer and high-grade dysplasia of the cystic duct developed local recurrence at >5 years after resection.¹⁴ Taken together, these findings suggest that the progression of high-grade dysplasia to an invasive component probably takes years.

The finding of high-grade dysplasia at the cystic duct margin in the absence of associated gallbladder cancer is rare. A review of pathology records at MSKCC demonstrated only seven patients who fit these criteria, and only five of them had been treated at MSKCC. The small number of patients in this series makes it difficult to draw conclusions. However, based on this series, it is the authors' recommendation that after review of pathology, patients should undergo high-quality cross-sectional imaging to evaluate the cystic duct remnant, the bile duct and locoregional lymph nodes. Magnetic resonance cholangiopancreatography is an ideal imaging modality in this context. Two of the five patients in this series had abnormal imaging that revealed a dilated cystic duct stump. The one patient with a carcinoma had a dilated cystic duct as well as mildly enlarged portal lymph nodes. If imaging reveals any abnormality, exploration with excision of the cystic duct margin is recommended. Frozen-section analysis should be performed and, if positive, complete resection to negative margins and portal lymphadenectomy should be carried out. Given that one of the five patients in this series was found to have a cholangiocarcinoma, exploration and excision of the cystic duct stump should be strongly considered, regardless of the findings on imaging.

Conflicts of interest

None declared.