Cholelithiasis

* Context.-Although papillary carcinomas have been recognized as distinct morphologic variants of gallbladder neoplasms, they have been lumped together in a single group despite the recognition of noninvasive and invasive types. As a result, the biologic behavior of each type remains undescribed.

Objective.-To compare the biologic behavior of noninvasive and invasive papillary carcinomas of the gallbladder.

Design.-The clinical and morphologic features of 16 noninvasive papillary carcinomas (>1 cm) of the gallbladder were analyzed, and their clinical behavior was compared with that of 370 invasive papillary carcinomas recorded in the Survey Epidemiology and End Results (SEER) Program of the National Cancer Institute from 1973 through 2001. The biologic behavior of invasive papillary carcinomas was compared with that of invasive nonpapillary carcinomas of the gallbladder recorded in SEER. Hematoxylin-eosin-stained sections were available for review in the 16 noninvasive papillary carcinomas. The number of slides examined per case varied from 3 to 16, with an average of 7.

Results.-The 16 patients with noninvasive papillary carcinomas included 11 women and 5 men, aged 34 to 83 years (mean age, 61 years). Thirteen patients had cholelithiasis. Laparoscopic cholecystectomy was performed on 12 patients and open cholecystectomy on 4. The tumors measured from 1.3 to 8.6 cm and were well to moderately differentiated. Fourteen noninvasive papillary carcinomas showed biliary phenotype, and 2 showed intestinal phenotype. Follow-up was obtained in 11 patients; 6 were asymptomatic 5 to 11 years after surgery, 2 were symptom free 9 months to 4 years following cholecystectomy, and 3 died of unrelated causes 2 to 3 years after surgery. Three hundred seventy cases of invasive papillary carcinomas were recorded in SEER. The 10-year relative survival rate for 225 patients with invasive papillary carcinomas confined to the gallbladder wall was 52%, while the 10-year relative survival rate for 83 patients with papillary carcinomas that had spread to the lymph nodes was less than 10%. Of the remaining 62 invasive papillary carcinomas, 58 had distant metastases and 4 were not staged. The 10-year relative survival rate for invasive nonpapillary carcinomas confined to the gallbladder wall was 30%.

Conclusion.-Noninvasive papillary carcinomas of the gallbladder-regardless of size, cell phenotype, and degree of differentiation-do not metastasize, and a simple cholecystectomy appears to be a curative procedure. In contrast, invasive papillary carcinomas do metastasize and are associated with a poor prognosis (10-year relative survival rate for tumors confined to the gallbladder wall was 52%, while the 10-year relative survival rate for tumors with lymph node metastasis was

(Arch Pathol Lab Med. 2005;129:905-909)

Papillary carcinomas are uncommon neoplasms, representing nearly 5% of all malignant gallbladder tumors.1 Evidence accumulated in the last 20 years indicates that papillary carcinomas of the gallbladder are associated with a better prognosis than conventional nonpapillary carcinomas.2,3 This relatively favorable prognosis has been attributed to their exophytic growth, delayed invasion into the gallbladder wall, and possibly early obstructive symptoms.1,4 However, noninvasive and invasive papillary carcinomas have traditionally been lumped together in a single group, which explains the lack of information about the clinical course associated with the 2 types.1,4 We therefore believe that separation of invasive and noninvasive papillary carcinomas is crucial in determining the clinical course of these tumors and in estimating patient outcome.

In this study, we examined the clinical and morphologic features of 16 noninvasive papillary carcinomas of the gallbladder and compared their clinical behavior with that of invasive papillary carcinomas recorded in the Surveillance, Epidemiology, and End Results (seeR) Program of the National Cancer Institute from 1973 through 2001.

MATERIALS AND METHODS

The consultation files of one of the authors (J.A.S.) and the surgical pathology files of the University of Texas Southwestern Medical Center, Dallas, were searched for cases of noninvasive papillary carcinoma of the gallbladder. Of the 16 cases found, 15 were retrieved from the consultation files, and 1 had been accessioned at the University of Texas Southwestern Medical Center. Criteria for including carcinomas in the noninvasive category were (1) predominant (>80%) papillary architecture, (2) lack of infiltration into the wall of the gallbladder, and (3) tumor size greater than 1.0 cm. The latter feature, although arbitrarily chosen, allowed exclusion of in situ papillary carcinomas, which have similar histologie features but measure only a few millimeters and which are usually incidental microscopic findings. Papillary carcinomas extending along Rokitansky-Aschoff sinuses were not considered invasive, even though some tumors were able to reach the serosa by this pathway. Clinicopathologic data, such as age, sex, tumor size, presence of lymph node metastases, and follow-up data, were obtained from pathology reports, referring physicians, and medical records. Routine hematoxylin-eosin-stained sections were available in all cases. The number of slides examined per case varied from 3 to 16, with an average of 7.

Additional data on invasive papillary and nonpapillary carcinomas (adenocarcinoma, adenosquamous carcinoma, and mutinous adenocarcinoma) of the gallbladder were obtained from the SEER Program of the National Cancer Institute for the years 1973 through 2001. The SEER Program, which covers 11 geographic areas, includes 12% of the US population and represents national demographic patterns. Population-based from inception, SEER has accrued data through regional and statewide tumor registries since 1973. It contains a comprehensive record of histopathologic diagnoses for patients with cancer. Incidence rates are expressed as per 100 000 persons and are age-adjusted to the 2000 US census as standard for the population.

Histology Codes

For submission to the seeR Program, the histologie types were recorded from the pathology reports and coded according to the International Classification of Disease for Oncology. For this study, the morphologic types included adenocarcinoma, not otherwise specified (NOS) (M8140); carcinoma, NOS (M8010); mutinous carcinoma (M8480); adenosquamous carcinoma (M8560); and papillary carcinoma (M8260). Only cases that were microscopically confirmed were included. cases reported from death certificates only and autopsy cases were excluded. Survival rates were calculated according to the Relative Survival Method5 using seeR*Stat, which is available on the Internet.6 Survival rates were compared using the z test, which is a statistical procedure available in SEER*Stat for comparing the relative survival of 2 groups of cases.7 Differences in survival rates were considered significant at P

RESULTS

The study group included 11 women and 5 men, ranging in age from 34 to 83 years (mean age, 61 years). Only 1 patient was younger than 40 years. Six patients were Mexican American, 4 were Mexican, 4 were Anglo-Saxon, 1 was Native American, and 1 was African American. Chief complaints at the time of presentation included abdominal pain and weight loss. Thirteen patients had associated cholelithiasis (81%). Laparoscopic cholecystectomy was performed on 12 patients, and the 4 patients with the largest tumors were treated by traditional open cholecystectomy. Follow-up information was obtained for 11 patients. Six patients were asymptomatic for 5 to 11 years after surgery, 2 were tumor free 9 months to 4 years following cholecystectomy, and the remaining 3 died of unrelated causes (1, 2, and 3 years after surgical treatment).

SEER Data

From 1973 through 2001, there were 8773 cases of gallbladder cancer, including in situ carcinomas, reported to seeR. The 4 most common nonpapillary types and number of papillary carcinomas reported are listed in the Table. These types comprised 88.8% of all reported cases of gallbladder cancer. Of the 394 cases of papillary carcinoma (Table), 370 were invasive. Of these 370 cases, 225 were localized to the wall of the gallbladder, 83 already had regional lymph node metastases, 58 had distant metastases, and 4 were not staged.

In Figure 1, the 10-year relative survival rate of patients with invasive papillary carcinomas is compared with the survival rate of patients with the 4 most common histologie types of nonpapillary carcinomas combined into a single group for calculating outcome. According to Figure 1, there was a statistically significant survival difference between papillary carcinomas localized to the gallbladder and papillary carcinomas that had spread to regional lymph nodes. In addition, there was a significant survival difference between the localized papillary carcinoma and localized nonpapillary carcinoma and between regional papillary carcinoma and regional nonpapillary carcinoma. Similar survival differences were also seen when 10-year outcome was compared among cases of papillary carcinoma and those of adenocarcinoma, NOS only (data not shown).

Gross Findings

Eight of the noninvasive papillary carcinomas arose in the fundus, 4 in the body, and 1 in the neck of the gallbladder. Three tumors filled most of the lumen and distended the gallbladder (Figures 2 and 3). Their site of origin could not be determined with certainty. The size of the tumors was recorded in 13 cases and varied from 1.3 to 8.6 cm. The tumors were described as pedunculated or sessile polypoid nodules or as cauliflower-like masses projecting into the lumen of the gallbladder.

Histologic Findings

The tumors exhibited an exophytic, complex papillary architecture with or without gland formation (Figures 4 through 6). Thin villiform and broad papillae of variable sizes frequently branched and contained fibrovascular cores. The cell phenotype was biliary in 14 neoplasms and intestinal in 2 (Figures 7 through 13). Neoplastic glands were confined to the broad fibrovascular cores of 2 papillary carcinomas with intestinal phenotype, whereas formation of cribriform structures along the fibrovascular cores was seen in 2 neoplasms with biliary phenotype. The columnar or cuboidal biliary-type cells were pseudostratified and often contained mucin vacuoles (Figures 7 and 9). They usually showed moderate nuclear enlargement. The nuclei were vesicular or hyperchromatic and had small or prominent nucleoli. Marked nuclear pleomorphism was focal and noted in only 3 tumors (Figure 10). The columnar cells with intestinal phenotype were similar to those of colonie adenocarcinomas (Figure 13). One papillary carcinoma, intestinal type, contained numerous goblet cells admixed with the columnar cells (Figure 12). An inflammatory infiltrate rich in lymphocytes was seen in the broad fibrovascular cores of 4 tumors with biliary phenotype (Figure 11). Mitotic figures varied from 2 to 5 per 10 high-power fields. Three papillary carcinomas extended along Rokitansky-Aschoff sinuses and reached the serosa by this pathway but did not show stromal invasion. Originally, however, these tumors were misinterpreted as invasive. Three papillary carcinomas were multicentric and separated by normal gallbladder mucosa, while 2 originated in tubular adenomas, pyloric gland type.

COMMENT

Although papillary carcinomas have long been recognized as distinct morphologic variants of malignant epithelial gallbladder neoplasms, they have usually been categorized as a single group despite the recognition of noninvasive and invasive types.1,4 These tumors have the same demographic patterns as other histologic types of gallbladder carcinomas. They are most common among Mexican, Mexican American, and Native American women and are usually associated with cholelithiasis.1 Because of prognostic implications, however, it is crucial to separate papillary carcinomas into noninvasive and invasive types. To include a papillary carcinoma in the noninvasive category, we recommend extensive sampling in view of the fact that some of these tumors can be large enough to fill the entire lumen of the gallbladder, as occurred in 3 of our cases, and invasion into the wall can be a focal change. If possible, the entire tumor should be submitted for microscopic examination. Inadequate sampling can lead to an erroneous diagnosis of noninvasive papillary carcinoma. On the other hand, papillary carcinomas that extend along Rokitansky-Aschoff sinuses and reach the muscle layer or serosa by this pathway should not be misinterpreted as invasive.8

Our results indicate that noninvasive papillary carcinomas, regardless of size, cell phenotype, or extent of differentiation, do not metastasize and are cured by simple cholecystectomy. None of the 11 patients we were able to monitor during the 9 months to 11 years after surgery died as a result of the tumor. The 3 deaths that occurred in this group were unrelated to the tumor. In contrast, the SEER data based on 370 cases of invasive papillary carcinoma confirm its malignant behavior. The 10-year relative survival rate for tumors confined to the wall of the gallbladder was 52%, while the 10-year survival rate for tumors with lymph node metastases was less than 10%. Moreover, invasive papillary carcinomas of the gallbladder have a significantly better prognosis than invasive nonpapillary carcinomas (adenocarcinomas, NOS; carcinomas, NOS; mucinous adenocarcinomas; and adenosquamous carcinomas). The 10-year relative survival rate for nonpapillary carcinomas confined to the wall was 30%. The difference is statistically significant. The papillary architecture appears to reflect a more indolent course in carcinomas of gallbladder. It would be of interest to investigate the molecular abnormalities associated with the noninvasive and the invasive papillary carcinomas to try to explain the difference in biologic behavior and to study this model of neoplastic progression.

Histologically, the vast majority of noninvasive papillary carcinomas are well to moderately differentiated and show a biliary phenotype. Similar findings have been reported in noninvasive papillary carcinomas of the extrahepatic bile ducts.9 The invasive component of papillary carcinomas of the gallbladder is usually tubular and similar to conventional adenocarcinoma.1 In a small proportion of cases, the invasive component shows undifferentiated or mucinous features. Similar tubular and undifferentiated components have been described in invasive papillary carcinomas of the extrahepatic bile ducts,10 which have been compared to intraductal papillary mucinous tumors of the pancreas,11 despite major differences. For example, these pancreatic tumors commonly exhibit a gastrointestinal phenotype and less frequently a biliary phenotype.12,13 Moreover, the invasive component of the intraductal papillary mucinous tumors is usually mutinous, and less frequently tubular, and therefore similar to conventional ductal pancreatic carcinomas.12 The abundant extracellular mucin, which is the hallmark of intraductal papillary mucinous neoplasms of the pancreas, is seldom seen in the noninvasive papillary carcinomas of the gallbladder or extrahepatic bile ducts.

Papillary carcinomas of the gallbladder join the group of malignant papillary neoplasms with an indolent clinical course that arise in ductal structures or hollow viscera and which are characterized by a noninvasive component that after many years may lead to invasion. Patients with noninvasive tumors have a more favorable prognosis than those with invasive papillary carcinomas whose histologic features differ from those of the noninvasive component.

In conclusion, our study supports the idea that papillary carcinomas of the gallbladder should be divided into non-invasive and invasive types. Those that lack an invasive component behave as in situ carcinomas, regardless of size, extent of differentiation, or cell phenotype. In contrast, invasive papillary carcinomas metastasize and are associated with a less favorable outcome.

References

1. Albores-Saavedra J, Henson DE, Klimstra D. Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Ampulla ofVater. Washington, DC: Armed Forces Institute of Pathology; 2000. Atlas of Tumor Pathology, 3rd series, fascicle 27.

2. Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the gallbladder: histologic types, stage of disease and survival rates. Cancer. 1 992;70:1493-1497.

3. Henson DE, Lynn RC, Albores-Saavedra J. Extrahepatic biliary tract and the ampulla of Vater cancers. In: Cospodarowicz MK, Henson DE, Hutter RPV, et al. Prognostic Factors in Cancer. International Union Against Cancer. New York, NY: Wiley-Eiss; 2001:311-332.

4. Albores-Saavedra J, Menck HR, Scoazec JC, et al. Tumors of the gallbladder and extrahepatic bile ducts. In: Hamilton SR, Aaltonen LA, eds. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press; 2000: 203-218. World Health Organization Classification of Tumours', vol 2.

5. Cutler Sj, Axtell LM, Schottenfeld D. Adjustment of long-term survival rates for deaths due to intercurrent disease./Chronic Dis. 1969;22:485-491.

6. Surveillance, Epidemiology, and End Results (seeR) Program. seeR'Stat Database: Incidence-seeR 9 Registry Public-Use, November 2003 submission (1973-2001), released April 2004. Bethesda, Md: National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Cancer Statistics Branch. Available at: www. seer.cancer.gov.

7. Brown CC. The statistical comparison of relative survival rates. Biometrics. 1983;39:941-948.

8. Albores-Saavedra J, Shukla D, Carrick K, et al. In situ and invasive adenocarcinomas of the gallbladder extending into or arising from Rokitansky-Aschoff sinuses: a clinicopathologic study of 49 cases. Am J Surg Pathol. 2004;28:621-628.

9. Albores-Saavedra J, Murakata L, Krueger JE, Henson DE. Noninvasive and minimally invasive papillary carcinomas of the extrahepatic bile ducts. Cancer. 2000;89:508-515.

10. Hoang MP, Murakata LA, Katabi N, et al. Invasive papillary carcinomas of the extrahepatic bile ducts: a clinicopathologic and immunohistochemical study of 13 cases. Mod Pathol. 2002;15:1251-1258.

11. Abraham SC, Lee JH, Boitnott JK, et al. Microsatellite instability in intraductal papillary neoplasms of the biliary tract. Mod Pathol. 2002;! 5:1309-1317.

12. Sessa F, Solcia E, Capella C, et al. lntraductal papillary-mucinoustumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients. Wrchows Arch. 1994;425:357-367.

13. Adsay NV, Colon KS, Zee SY, et al. lntraductal mucinous neoplasms of the pancreas: an analysis of in situ and invasive carcinoma in 25 patients. Cancer. 2002;94:62-77.

Jorge Albores-Saavedra, MD; Matthew Tuck, BS; Bernadette K. McLaren, MD; Keiley S. Carrick, MD; Donald Earl Henson, MD

Accepted for publication March 8, 2005.

From the Departments of Pathology, Louisiana State University Health Sciences Center, Shreveport (Drs Albores-Saavedra and McLaren); The George Washington University Cancer Institute, Washington, DC (Drs Tuck and Henson); and the University of Texas Southwestern Medical Center, Dallas (Dr Carrick).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Jorge Albores-Saavedra, MD, Department of Pathology, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130 (e-mail: jalbor@lsuhsc.edu).

Copyright College of American Pathologists Jul 2005
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