| Abstract|| |
Background: Intracholecystic papillary–tubular neoplasm (ICPN) is a relatively new entity which includes neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm. This study is done to evaluate the pathological features of ICPN and to find out the factors associated with invasion. Materials and Methods: This is a 5-year retrospective study in a referral pathology center. A total of 19 cases of ICPN are found. The cases are analyzed for age and sex distribution, clinical suspicion, stages, histological architecture, differentiation, and grade of dysplasia. Descriptive statistics and test of significance by Chi-square and t-test are used in the study. Results: ICPN comprises 23.5% of all gallbladder neoplasms. Two-thirds of the cases were suspected radiologically. Age range is 26–65 years with mean age of 50 years. They are 2.8 times more common in female. Approximately one-third of the cases show invasion. The most common histological pattern is papillary, followed by papillary–tubular and finally by tubular pattern. Pyloric and biliary are the most common differentiation pattern followed by oncocytic and intestinal pattern. About three-fourths of the cases are associated with high-grade dysplasia mostly diffuse high-grade dysplasia. Conclusion: We have found the younger age of presentation, less proportion of invasive tumors, fewer tumors with biliary phenotypes, and fewer tumors with high-grade dysplasia as compared to previous studies. Factors significantly associated with invasion are grade and extent of dysplasia particularly diffuse high-grade dysplasia.
Keywords: Biliary, intracholecystic papillary–tubular neoplasm, papillary, papillary-tubular, pyloric
|How to cite this article:|
Hazarika P, Sharma MK. Intracholecystic papillary–tubular neoplasm of gallbladder: A 5-year retrospective pathological study. Indian J Pathol Microbiol 2018;61:516-9
|How to cite this URL:|
Hazarika P, Sharma MK. Intracholecystic papillary–tubular neoplasm of gallbladder: A 5-year retrospective pathological study. Indian J Pathol Microbiol [serial online] 2018 [cited 2019 Jun 16];61:516-9. Available from: http://www.ijpmonline.org/text.asp?2018/61/4/516/242989
| Introduction|| |
Intracholecystic papillary–tubular neoplasm (ICPN) is a new terminology in classification of gallbladder tumor proposed by Adsay et al. in 2012. It represents intracholecystic neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm in size. They follow adenoma carcinoma sequence of progression rather than flat dysplasia to invasive carcinoma, which is more commonly seen in pancreatobiliary carcinomas. ICPN indicates a distinct subset of gallbladder neoplasms that resembles to intrabile duct papillary neoplasm and intrapancreatic mucinous neoplasm which are known to have a better prognosis than other bile duct and pancreatic malignancies., Before the term ICPN came to exist, these cases were histologically diagnosed as adenoma or papillary carcinoma with or without invasion. However, the term papillary carcinoma also included lesions with surface papillary dysplasia with or without invasion without producing a mass lesion in gallbladder. Papillary carcinomas were also found to have a lower incidence of invasive growth and better prognosis, even for those with invasion than conventional adenocarcinomas.
There are relatively few clinical and pathological studies and a few case reports of ICPN till now.,,,,,, We have done a 5-year retrospective study in a referral pathology center to study the pathological features of ICPN and to find out the factors associated with invasion in them.
| Materials and Methods|| |
This is a 5-year retrospective study in a tertiary referral center. All the records (including slides, blocks, and case record sheets) of cases diagnosed as ICPNs, papillary carcinomas, and adenomas in the past 5 years (from January 2012 to December 2016) are retrieved from the archives. Intracholecystic lesions with size <1 cm and flat papillary dysplasia with or without invasion are excluded from the study. Seven of the papillary carcinomas and three adenomas are re-reported as ICPN. A total of 19 cases of ICPNs out of 81 gallbladder neoplasms are found. They are analyzed for distribution of age, sex, invasiveness, architecture, histological differentiation, and grade of dysplasia. Approximately 15 sections were studied in noninvasive cases to rule out the possibility of invasion. Grading of dysplasia is done as like that of gastrointestinal tract adenomas. Severe cytological atypia frequently accompanies acute cholecystitis as a reactive change and so they are excluded from the diagnosis of dysplasia. Follow-up was done by periodic phone calls. However, follow-up was possible only in 11 cases and others were lost to follow-up. Hence, survival analysis is not possible. The findings are presented in tabulated form and analyzed statistically for significance by t-test and Chi-square test using SPSS version 23 to find out the histological associates of invasion.
| Results|| |
Age and sex distribution
[Table 1] shows that ICPNs have most commonly occurred in the 50–<60-year age group. Age range is 26–65 years with a mean age of 50 years. They are 2.8 times more common in female than male.
Twelve tumors were suspected clinically either preoperatively or intraoperatively and all were diagnosed as carcinoma. Rest seven were not suspected clinically.
Stages of the tumors
Out of the 19 cases, 13 are noninvasive, 5 are stage PT2, and 1 is stage PT1.
The gross appearance of an ICPN is shown in [Figure 1]. Microscopically, the cases are divided into tubular, papillary–tubular, and papillary pattern based on criteria as mentioned below. Tubular is composed exclusively of tubules and no papillary structures. Papillary is composed mostly or exclusively of papillary structures and few tubular structures if any. Papillary–tubular is composed of admixture of significant proportion of tubular and papillary structures. However, possibility of bias cannot entirely be excluded during separation of papillary from papillary–tubular architecture.
|Figure 1: Gross appearance of intracholecystic papillary–tubular neoplasm|
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[Table 2] shows that ICPNs are of mostly papillary and papillary–tubular architecture. Papillary pattern shows the highest incidence of invasion, and tubular shows lowest, but the difference is not significant (P = 0.887).
Four different histological differentiation patterns are noted – gastric pyloric, biliary, intestinal, and oncocytic [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f. Biliary type shows cuboidal to columnar cells with nonmucinous eosinophilic cytoplasm. Gastric pyloric type shows columnar mucosa containing mucin. Intestinal type shows columnar mucosa containing goblet cells or tall columnar mucosa with stratified cigar-shaped nuclei resembling intestinal adenomas. Oncocytic type shows large columnar and polygonal cells with eosinophilic granular cytoplasm and central large mostly rounded nuclei. Occasional foci of tumor show differentiation intermediate between biliary and intestinal type with tall columnar stratified nuclei. There may be some bias in subtyping lineage of differentiation in these foci. Two of the tumors show three lineages of differentiation and four show two lineages of differentiation. Rest 13 cases show single lineage of differentiation. The frequencies of all the differentiation patterns are presented in [Table 3].
|Figure 2: Histology of intracholecystic papillary–tubular neoplasms. (a) papillary biliary type, high grade (H and E, ×40), (b) papillary biliary type, low grade (H and E, ×40), (c) papillary pyloric type, high grade (H and E, ×40), (d) papillary intestinal type with tall columnar cells and stratified cigar-shaped nuclei, high grade (H and E, ×40), (e) Tubular intestinal type with pyloric type glands and intestinal goblet cells, high grade (H and E, ×40), (f) Papillary oncocytic type, high grade (H and E, ×40)|
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It is found that biliary and pyloric are the most common differentiation patterns each comprising 37% of total. Intestinal differentiation is associated with higher risk of invasion (66.7%). Two of the noninvasive cases are associated with cholesterolosis.
Grades of dysplasia
Tumors are divided into low- and high-grade dysplasia as like adenomas of the gastrointestinal tract. Five tumors are low grade, 3 are focally high grade, and 11 are diffusely high grade. It is found that all the low-grade and focally high-grade tumors are noninvasive. However, five of the diffusely high-grade tumors are noninvasive and rest six are invasive.
Follow-up is possible in five noninvasive and six invasive ICPN patients. All the followed noninvasive ICPN patients are alive (2 years 9 months, 2 years 6 months, 1 year 8 months, and 1 year and 7 months). One of the six followed invasive patients is dead after 1 year and others are alive (1 year, 2 years, 1 year 7 months, 9 months, and 4 months).
| Discussion|| |
ICPN constitutes 23.5% of all gallbladder neoplasms in our study. Almost two-third of the cases were suspected radiologically and all were diagnosed as cancer. Adsay et al. found 90% of their cases detected by radiological examination which is much higher than the present study. Variation in diagnostic facility might underlie this difference. We have found ICPN to be most common in the sixth decade with age range of 26–65 years and mean age of 50 years. Adsay et al., Isozaki et al., and Bennett et al. found a higher mean age of 61, 68, and 69 years, respectively.,, It is seen that gallbladder carcinoma in general shows an earlier mean age of presentation in South Asian countries as demonstrated by Hamdani et al. and Poudel et al., ICPN in the present study also shows similar age distribution. However, as like other studies, we have also found female dominance (female: male ratio 2.8:1 in the present study, 1.3:1 by Bennett et al., and 2:1 by Adsay et al.).,
We have found a lower prevalence of invasive growth in ICPN (31.6%) as compared to Adsay et al. (55.3%), Argon et al. (56%), and Bennettet al. (57%). This could probably be attributed to detection of ICPNs in a younger age in our study so that many of the patients have been operated before they would have progressed to invasive carcinomas.
Initial study by Adsay et al. demonstrated that histologically ICPN showed tubular, papillary, or mixed papillary–tubular architecture as like adenomas in rest of the gastrointestinal tract. They found papillary pattern in 43%, papillary–tubular in 31%, and exclusively tubular in 26% of cases. We have found almost similar distribution of architectural patterns. The corresponding figures in our study are papillary 42.1%, papillary–tubular 36.8%, and exclusively tubular 21.1%.
ICPN recapitulates the histological pattern from stomach to colon. Five different patterns such as biliary, gastric pyloric, gastric foveolar, intestinal, and oncocytic types are recognized till now. The present study shows biliary differentiation in 37% of cases, pyloric in 37%, intestinal in 11.1%, and oncocytic in 14.8%. The corresponding figures by Adsay et al. are biliary 50%, gastric 36%, intestinal 8%, and oncocytic 6% and Isozaki et al. are biliary 56%, gastric 34.8%, and intestinal 8.7%. We have found relatively less number of biliary-type as compared to other studies. This implies that metaplasia–dysplasia–carcinoma sequence is more common than de novo dysplasia–carcinoma sequence in our region as compared to Western countries. This may be due to a higher prevalence of cholelithiasis and cholecystitis in our region which is frequently associated with metaplasia.,, Two of the cases both noninvasive are associated with cholesterolosis. This could be by chance as cholesterolosis is very common or might have some pathogenetic roles.
Dysplasia particularly high-grade dysplasia is a risk factor for invasive malignancy. Adsay et al. found high-grade dysplasia in 95% of their cases. We have found high-grade dysplasia in 73.7% of cases (14 of 19). Out of the high-grade dysplasia cases, 3 show focal high grade and 11 show diffuse high-grade dysplasia. The younger age of presentation in our study could be somehow related to lower prevalence of high-grade dysplasia.
Presence or absence of invasion determines the clinical outcomes in ICPN as noninvasive tumors show excellent prognosis, but invasive tumors show less favorable prognosis. Papillary architecture, diffuse high-grade dysplasia, and biliary and foveolar differentiation are recognized to be high-risk factors associated with invasion., We have found that papillary architecture only slightly increases the risk of invasion (37.5% in papillary, 28.6% in papillary–tubular, and 25% in tubular type). Statistically, the three architectural patterns do not show significant association with invasion (P = 0.887). Adsay et al. found 68.1% of papillary carcinoma type of ICPN to harbor invasive foci. Low incidence of invasion (25% of all cases) in papillary carcinoma was reported by Wan et al. before the term ICPN was used. Of course, many of their cases were not papillary ICPNs but were papillary dysplasia with or without invasive carcinomas.
None of the differentiation subtypes are significantly associated with invasion either individually (P value ranges from 0.2048 to 0.3440) or together (P = 0.483). Intestinal differentiation, although constitutes only 11.8% of total cases in the present study, shows a high incidence of invasive growth (2 of 3 cases). This is again in contrast to the previous study who found biliary and foveolar type to be more commonly associated with invasion.
Diffuse high-grade dysplasia is associated with increased incidence of invasion in the present study (P = 0.05) as like the other two studies., All the low-grade and focally high-grade dysplastic tumors in the present study are noninvasive, but majority (54.5%) of the diffusely high-grade dysplastic tumors are invasive. Association of grade of dysplasia and invasion is statistically significant with P = 0.041.
| Conclusion|| |
ICPN encompasses a range of architectural patterns, lineages of differentiation recapitulating different parts of the gastrointestinal tract, and variable grades and extent of dysplasia. We have found earlier age of onset, lower proportion of invasive growth, and less number of tumors with biliary differentiation in ICPN in contrast to the previous studies. Only factors significantly associated with invasion are extensive high-grade dysplasia. Architectural patterns and differentiation subtypes are not significantly associated with invasion.
The authors are grateful to Anuradha H Medhi, stastitian, Jorhat Medical College, for helping in statistical analysis of the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Adsay V, Jang KT, Roa JC, Dursun N, Ohike N, Bagci P, et al.
Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are≥1.0 cm): Clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol 2012;36:1279-301.
Xiao SY. Intraductal papillary mucinous neoplasm of the pancreas: An update. Scientifica (Cairo) 2012;2012:893632.
Xue-Shuai W, Yi-Yao X, Xin-Ting S. Intraductal papillary neoplasm of the bile duct. World J Gastroenterol 2013;19:8595-604.
Albores-Saavedra J, Tuck M, McLaren BK, Carrick KS, Henson DE. Papillary carcinomas of the gallbladder: Analysis of noninvasive and invasive types. Arch Pathol Lab Med 2005;129:905-9.
Isozaki M, Ohike N, Tajiri T, Mitsuya T, Takimoto M. Clinicopathological study of intracholecystic papillary-tubular neoplasms (ICPNs) of the gallbladder. Showa Univ J Med Sci 2014;26:17-26.
Bennett S, Marginean EC, Paquin-Gobeil M, Wasserman J, Weaver J, Mimeault R, et al.
Clinical and pathological features of intraductal papillary neoplasm of the biliary tract and gallbladder. HPB (Oxford) 2015;17:811-8.
Argon A, Barbet FY, Nart D. The relationship between intracholecystic papillary-tubular neoplasms and invasive carcinoma of the gallbladder. Int J Surg Pathol 2016;24:504-11.
Hashimoto S, Horaguchi J, Fujita N, Noda Y, Kobayashi G, Ito K, et al.
Intracholecystic papillary-tubular neoplasm of the gallbladder presenting with jaundice. Intern Med 2014;53:2313-7.
Yamamoto K, Yamamoto F, Maeda A, Igimi H, Yamamoto M, Yamaguchi R, et al.
Tubulopapillary adenoma of the gallbladder accompanied by bile duct tumor thrombus. World J Gastroenterol 2014;20:8736-9.
Serdar B, Gizem A, Carlos RJ, Volkan AN. Intracholecystic papillary tubular neoplasm of the gallbladder with microinvasive carcinoma. Pathol Case Rev 2014;19:283-8.
Hamdani NH, Qadri SK, Aggarwalla R, Bhartia VK, Chaudhuri S, Debakshi S, et al.
Clinicopathological study of gall bladder carcinoma with special reference to gallstones: Our 8-year experience from Eastern India. Asian Pac J Cancer Prev 2012;13:5613-7.
Poudel R, Singh SK, Basnet S, Dev Kota H, Adhkari SK. Clinicopathological study of gall bladder cancer and its relationship with gall stones. J Soc Surg Nepal 2016;18:46. Available from: http://www.nepjol.info/index.php/JSSN/article/view/15308
. [Last assessed on 2nd
Unisa S, Jagannath P, Dhir V, Khandelwal C, Sarangi L, Roy TK, et al.
Population-based study to estimate prevalence and determine risk factors of gallbladder diseases in the rural gangetic basin of North India. HPB (Oxford) 2011;13:117-25.
Singh V, Trikha B, Nain C, Singh K, Bose S. Epidemiology of gallstone disease in Chandigarh: A community-based study. J Gastroenterol Hepatol 2001;16:560-3.
Seretis C, Lagoudianakis E, Gemenetzis G, Seretis F, Pappas A, Gourgiotis S, et al.
Metaplastic changes in chronic cholecystitis: Implications for early diagnosis and surgical intervention to prevent the gallbladder metaplasia-dysplasia-carcinoma sequence. J Clin Med Res 2014;6:26-9.
Wan X, Zhang H, Chen C, Yang X, Wang A, Zhu C, et al.
Clinicopathological features of gallbladder papillary adenocarcinoma. Medicine (Baltimore) 2014;93:e131.
Department of Pathology, Jorhat Medical College and Hospital, Jorhat - 785 001, Assam
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]