Liver, Gallbladder, Extrahepatic Bile Ducts, and Pancreas

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1 171 Liver, Gallbladder, Extrahepatic Bile Ducts, and Pancreas Marisa T. Carriaga, M.D.,* and Donald Earl Henson, M.D.t Background. The liver, gallbladder, bile ducts, and pancreas have a common embryologic origin; cancers that arise from these sites therefore are expected to share a similar spectrum of histologic types. These cancers are known for their extremely poor prognoses. Methods. Data from the Surveillance, Epidemiology, and End Results Program regarding the incidence, distribution of histologic types, stage of disease, and survival for cancers of the gallbladder (n = 4412), extrahepatic bile ducts (n = 3486), pancreas (n = 23,116), and liver (n = 6,391) were reviewed. The most common histologic types are discussed, and the frequency of rare types is reported. Results. The incidence of biliary cancer decreased, while the incidence of hepatic and pancreatic cancer rose slightly over the 15year period from 1973 to Age and sex distributions varied by histologic type. Greater than 98% of pancreatic and biliary cancers were carcinomas, and adenocarcinoma (not otherwise specified) was the most common histologic type recorded. In the liver, hepatocellular carcinoma was the most common type, followed by intrahepatic cholangiocarcinoma. The overall 5year relative survival rates for these cancers were very low: gallbladder, 12.3%; extrahepatic bile duct, 12.7%; liver 3.1%; and pancreas 2.5% (all stages combined, ). Conclusions. This review confirmed that these carcinomas are associated with a very poor outcome; however, survival was influenced by stage of disease and histologic type. In the gallbladder and extrahepatic bile ducts, papillary adenocarcinoma was associated with the best outcome of all histologic types, and in the exocrine pancreas, mucinous cystadenocarcinoma was associated with the best prognosis. Cancer 1995;75: Key words: cancer, bile ducts, epidemiology, gallbladder, histologic type, liver, pancreas, SEER, staging, survival. From the *Department of Pathology, Georgetown University School of Medicine, Washington, DC; and the tnational Cancer Institute, Division of Cancer Prevention and Control, Bethesda, Maryland. Address for reprints: Donald Earl Henson, M.D., Program Director, Early Detection Branch, Division of Cancer Prevention and Control, National Cancer Institute, EPN Building, Room 305, 9000 Rockville Pike, Bethesda, MD Received August 22,1994; accepted September 20,1994. The liver, gallbladder, bile ducts, and pancreas have a common embryologic origin; cancers that arise from these sites therefore are expected to share a similar spectrum of histologic types. In all four sites, greater than 95% are carcinomas. Adenocarcinoma is the most common histologic type reported. The behavior of the different subtypes of adenocarcinoma often differs from that of the typical adenocarcinoma (not otherwise specified [NOS]). Differences in incidence, age and sex distribution, stage distribution, and survival can be observed among the various histologic types of hepatic, biliary, and pancreatic cancers. These cancers are known for their extremely poor prognoses. For all these sites, however, the histologic type of the tumor has an influence on outcome. In this report, we summarize the results of our review of primary cancers of the liver, gallbladder, extrahepatic bile ducts (including the ampulla of Vater), and pancreas, as recorded in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. Information regarding the incidence and distribution of histologic types, stage of disease, and survival is presented for 6391 cases of primary liver cancer, 4412 cases of gallbladder cancer, 3486 cases of extrahepatic bile duct cancers, and 23,116 cases of pancreatic cancer collected during the period Materials and Methods The general methods are described in the introduction to this supplement.' Only histologically confirmed primary cancers of the liver, gallbladder, extrahepatic bile ducts, and pancreas were included in this analysis. The microscopic confirmation rates for invasive cancers of these sites were as follows: for liver and intrahepatic bile ducts, 83%; for the gallbladder, 96%; for the extrahepatic bile ducts and ampulla of Vater, 86%; and for the pancreas, 74%. The microscopic confirmation rate is the percentage of cases recorded in SEER that were confirmed by histologic examination of the primary tumor. The stage of disease was recorded as localized, re

2 172 CANCER Supplement January 1,1995, Volume 75, No. 1 gional, or distant. Although this staging system is less precise than the tumornodemetastasis system of the American Joint Committee on Cancer and the International Union Against Cancer, the localizedregionaldistant staging was used because of its relative consistency over the 15 years covered in this study. The survival rates given for all stages combined includes the unstaged cases. When a stage distribution is presented, the percentage given for each stage is the number of cases in a particular stage divided by the total number of staged cases only. Cases of primary liver cancer were recorded as localized stage if the tumor was a single lesion confined to one lobe or had satellite nodules confined to the lobe of the primary lesion and did not involve regional lymph nodes. Cases with regional lymph node metastases were recorded as regional stage. Cases also were recorded as regional if the tumor involved two lobes by contiguous growth, involved the gallbladder from the right lobe when the right lobe was the primary site, or extended directly to major blood vessels, extrahepatic ducts, diaphragm, and/or pleura. Cases were recorded as distant if there was distant site and/or distant lymph node involvement. Cases of gallbladder cancer were recorded as localized stage if the tumor was confined to the gallbladder without nodal involvement, with or without local vessel invasion, or was listed as localized with no further detailed information. Cases were recorded as regional stage if the tumor was accompanied by regional lymph node metastases or if the tumor extended to the liver, extrahepatic bile ducts, pancreas, intestine, stomach, and/or greater omentum, with or without regional lymph node involvement. Cases were recorded as distant if there was distant site and/or distant lymph node involvement. Cases of extrahepatic bile duct cancer were recorded as localized stage if the tumor was confined to the extrahepatic bile ducts without nodal involvement, whether or not there was local vessel invasion, or was listed as localized with no additional detailed information. Cases were recorded as regional stage if the regional lymph nodes were involved or if the tumor extended to the duodenum, gallbladder, pancreas, and/ or liver, with or without regional lymph node involvement, or showed other direct extension. Cases were recorded as distant if there was distant site and/or distant lymph node involvement. Anatomic information was coded according to the International Classification of Diseases for Oncology (ICDO), which does not subdivide the extrahepatic bile ducts. Therefore, no information is available from the SEER Program on the precise location of the tumors within the biliary tree. Cancers of the ampulla of Vater were included in the analysis of the extrahepatic bile ducts. Cases of pancreatic cancer were recorded as localized stage if the tumor was confined to the pancreas without regional lymph node involvement, with or without local vessel invasion, or was listed as localized with no additional detailed information. Cases were recorded as regional stage if regional lymph nodes were involved or if the tumor extended to the bile ducts, duodenum, and/or stomach, with or without regonal lymph node involvement. Cases also were recorded as regional if the tumor involved the liver, transverse colon, omentum, and/or gallbladder, with or without regional lymph node metastases. Cases were recorded as distant stage if there was distant site and/or distant lymph node involvement. In all four sites, cases listed as papillary carcinoma NOS were combined with papillary adenocarcinoma. Cases listed as mucinproducing adenocarcinoma were combined with mucinous adenocarcinoma, except in the pancreas, where they were considered separately. The data have been grouped into three 5year periods: , , and The 5 year relative survival rates were based only on data from 1978 through The incidence rate is the number of new cases per 100,000 persons per year, ageadjusted to the 1970 U.S. population. Unless otherwise stated, the information given is for all races and for males and females combined. Liver Primary cancers of the liver are uncommon in the United States but are common in other parts of the world, especially in Africa and southeast Asia. In the United States, approximately 2% of all cancer deaths are attributed to liver ~ancer.~ Most primary liver cancers are hepatocellular carcinomas (HCCs); intrahepatic cholangiocarcinoma is the second most common, followed by hepatoblastoma and angiosarcoma. In areas of the world where hepatitis B virus (HBV) infection is endemic, HCC is the most prevalent cancer. In the United States, HCC accounts for 1% of all new cancer cases diagnosed ann~ally.~ Hepatocellular carcinoma occurs more frequently in men than in women and is more common in African Americans than in whites.485 Although HCC most often occurs in patients older than 60 years, all age groups are affected.68 Intrahepatic cholangiocarcinoma is much less common than HCC and also occurs less frequently than its extrahepatic ~ounterpart.~ Hepatoblastoma is primarily a malignant tumor of infants and young children; two patterns have been describeda pure epithelial type and a mixed epithelial mesenchymal type., In adults, most

3 Liver, Gallbladder, Bile Ducts, Pancreas/Carriaga and Henson 173 Table 1. Liver and Intrahepatic Bile Ducts (T ): Frequencies and Percent Distribution by Histology and Sex, All Races, Microscopically Confirmed* Cases, SEER Both sexes Male Female Histologyt Frequency % Frequency % Frequency % Liver and intrahepatic bile ductsinvasive 6, , , Carcinoma 6, , , "Epidermoid" carcinoma$ Adenocarcinoma 1, Cholangiocarcinoma (8140,8160,8180, 8500) 1, Other Other specific carcinomas 4, , , Hepatocellular carcinoma ( ) 4, , , Other Unspecified ("Carcinoma, NOS") Sarcoma Hemangiosarcoma ( , ) Other Other specified types Hepatoblastoma (8970) Other Unspecified Liver and intrahepatic bile ducts in situ SEER: Surveillance, Epidemiology, and End Results; ICD0: International Classification of Diseases for Oncology; NOS: not otherwise specified. * Excludes lymphohematopoietic neoplasms, Kaposi's sarcoma, neuroblastoma, chordoma and esthesioneuroblastoma (Percy C, Introduction). t Contents of groups, based on ICD0,' are as defined by Berg (Percy C, Introduction). Numbers in parentheses are ICD0 histology codes. $ Includes squamous, basal and transitional cell carcinomas. hepatic sarcomas are angiosarcomas, highly aggressive tumors similar to those found in other Results The total number of primary liver cancers recorded in SEER was 7745; of these, 6391 (83%) were confirmed histologically. The distribution of histologic types is presented in Tables 1 and 2. Approximately 95% of all primary cancers of the liver were carcinomas; 2% were sarcomas, and 1.5% were hepatoblastomas. The majority of carcinomas were hepatocellular carcinomas; the second most common type was intrahepatic cholangiocarcinoma. Combined hepatocellular carcinomas, composed of both HCC and cholangiocarcinoma, accounted for 2% of primary liver cancers. Only three cases of the fibrolamellar variant of HCC were reported. The group labeled "other adenocarcinomas" included 28 mucinproducing adenocarcinomas, 14 mucinous adenocarcinomas, 9 clear cell adenocarcinomas, 11 trabecular adenocarcinomas, 5 papillary adenocarcinomas, 3 cystadenocarcinomas, and 1 each of scirrhous, tubular, adenosquamous, and malignant mixed tumor NOS. This group represents variants of both HCC and cholangiocarcinoma: trabecular adenocarcinoma, clear cell adenocarcinoma, and malignant mixed tumor were most likely variants of HCC, whereas mucinous carci Table 2. Histologic Types of Primary Liver Cancer* Histologic type n % of total Total All invasive Carcinoma Hepatocellular carcinoma Cholangiocarcinoma Combined hepatocellular carcinoma and cholangiocarcinoma Other adenocarcinoma Carcinoma, NOS Other specified types Hepatoblastoma Sarcoma Angiosarcoma Other sarcoma Other & unspecified In situ * Microscopically confirmed cases only o 62 1.o

4 174 CANCER Supplement January 2,2995, Volume 75, No. 1 noma, papillary carcinoma, and cystadenocarcinoma were seen more commonly in cholangiocarcinoma than in HCC. Other specific carcinomas included six carcinoid tumors, two giant cell, two medullary, one spindle cell, and one small cell carcinoma. Approximately 25% of tumors listed as carcinoma NOS were recorded as poorly differentiated tumors, including 42 undiff erentiated carcinomas, 19 anaplastic, 15 large cell, and 2 pleomorphic. Only one case of primary squamous cell carcinoma was reported. Of all sarcomas, 5 1 % were angiosarcomas (hemangiosarcomas). Sixteen cases of malignant hemangioendothelioma, 1 malignant epithelioid hemangioendothelioma, and 1 Kupffer cell sarcoma were also recorded under the category "other sarcoma". The remaining sarcomas included 20 leiomyosarcomas, 7 embryonal sarcomas (malignant mesenchymomas), 2 rhabdomyosarcomas, 5 spindle cell sarcomas, 3 malignant fibrous histiocytomas, 2 fibrosarcomas, 2 mesotheliomas, 1 malignant hemangiopericytoma, and 1 neurofibrosarcoma. In addition, four carcinosarcomas and one endodermal sinus tumor were reported. Of the 6391 patients with primary liver cancer, 4262 (67%) were male and 2129 (33%) were female. Of the patients with HCC, 72% were male. Unlike cases of HCC, cases of cholangiocarcinoma and hepatoblastoma were divided almost equally among males and females. The only major histologic type seen more often in females than in males was angiosarcoma. Table 1 gives the frequency distributions of the major histologic types by sex. Hepatocellular carcinomas comprised 73% of all liver cancers in males but only 57% of those in females; cholangiocarcinoma and sarcomas therefore accounted for a higher percentage of cases in females than in males. Carcinomas of the liver and intrahepatic bile ducts occurred primarily in the elderly population. Greater than 85% of carcinomas occurred in individuals 50 years of age or older. The age distributions for HCC and cholangiocarcinoma were similar. However, 47 patients with HCC were younger than 20 years, but only one patient with cholangiocarcinoma was younger than 20. Black patients were younger at diagnosis than white patients. For HCC, the median age of white patients was 67 years, compared with 63 years in black patients; for cholangiocarcinoma, the median ages were 67 years in whites and 59.5 years in blacks, The median age of patients with sarcomas was 63 years, all races combined. As expected, the vast majority (81%) of patients with hepatoblastoma were younger than 5 years of age (median age, 1.5 years), but seven additional cases were reported in adults older than 60 years of age. Although hepatoblastoma was the most common primary liver tumor in children younger than 5 years of l l HCC, Male + * HCC, Female *CHOL, Male + CHOL, Female 61 I Age at diagnosis Figure 1. Liver and intrahepatic bile ducts: agespedc incidence rates by histologic subtype and sex according to the SEER data for HLL: hepatocellular caranoma. LHUL: cholangtocaranoma. age (86%), HCC still accounted for 9% of the tumors in this age group. Furthermore, in children older than 5 years, HCC comprised 64% of all cancers, a proportion similar to that seen in adults. In the same age group (5 19 years), 23% of all cancers were sarcomas, and the percentage of hepatoblastoma fell to 15%. The ageadjusted incidence of hepatocellular carcinoma rose slightly, from 1.3 to 1.5 per 100,000, over the three periods. Hepatocellular carcinomas was three to four times more common in males than in females (2.3 vs. 0.8 for ), andmore than twice as common in blacks than in whites (2.4 vs. 1.1). The highest rates were found in the black male population (4.1, compared with 1.7 in white males). The ageadjusted incidence of intrahepatic cholangiocarcinoma was 0.4 throughout the three periods. Like the rates for HCC, rates of intrahepatic cholangiocarcinoma were higher in males (0.6) than in females (0.3). Unlike HCC, cholangiocarcinomas occurred with almost equal frequency in both the black and white populations. The overall incidence of angiosarcoma was below 0.1 for all groups. The incidence of hepatoblastoma was 0.4 for children younger than 5 years of age ( ). Figure 1 gives the agespecific incidence of HCC and cholangiocarcinoma for males and females. In males, the peak incidence of HCC was 15.7 in the 80 84year age group, whereas in females, the peak was only 5.0, all races combined. The highest rate of cholangiocarcinoma was 4.6 in males aged 85 years and older; in females, the peak was 2.2 in the 8084year age group. I X

5 Liver, Gallbladder, Bile Ducts, Pancreas/Curriugu and Henson 175 Table 3. FiveYear Relative Survival Rates for Primary Liver Cancer by Histologic Type and Stage of Disease (197886) Histologic type n LOC REG DIST UNSTGD ALL All types Carcinoma Hepatocellular carcinoma Cholangiocarcinoma Carcinoma, NOS Angiosarcoma Heuatoblastoma * 59.2* LOC: local; REG: regional; DIST distant; UNSTGD: unstaged; ALL: survival for all stages combined (includes unstaged cases); : fewer than 25 cases; NOS: not otherwise specified. * 0 05 < SE I The peak incidence of HCC in black males was 28.5 in the 7074year age group, much higher than the peak in white males (13.5 in the 8084year age group). This racial difference was not seen with the other major histologic types. The cases of HCC were distributed fairly evenly among the three stages. More patients with cholangiocarcinoma had distant stage disease than localized (33% vs. 21%). Most cases of carcinoma NOS also were listed as distant stage. Only 18% of sarcomas were recorded as localized, but almost 50% of patients with hepatoblastoma had localized stage disease. Fiveyear survival rates for the major histologic types are listed in Table 3. The outcome for all types of carcinoma was very poor, with 5year survival rates of less than 5%, all stages combined. The 5year survival rate for angiosarcoma was also very low (approximately 10%). The histologic type with the best outcome was hepatoblastoma, with a 5year survival rate of 59%. Survival rates for both HCC and cholangiocarcinoma rose slightly over the three periods, but remained very low. The 5year rate for HCC rose from 2.8% to 4.8%, and the rate for cholangiocarcinoma rose from 1.6% to 5.1%. Discussion Primary liver cancers are uncommon in this country, but the incidence rose slightly from 1973 to This increase was seen for HCC but not for cholangiocarcinoma. The incidence of HCC rose in both male and female populations, but rates remained three times higher in men than in women. Hepatocellular carcinoma, the most common histologic type of primary liver cancer, accounted for 68% of all primary liver cancers. In SEER, 19% of primary liver cancers were intrahepatic cholangiocarcinoma, a higher percentage than those reported in other ~eries.~,'~ Cho langiocarcinoma, however, can account for up to 30% of primary liver cancers worldwide, especially in southeast Asia.I4 A combination of HCC and cholangiocarcinoma occurs infrequentlyx5; 139 combined HCCs (2%) were recorded in SEER. Patterns of HCC represented in SEER ranged from trabecular carcinomas to undifferentiated carcinomas. Nine clear cell adenocarcinomas were reported; in this uncommon variant of HCC, a major portion of the tumor is composed of cells with a high cytoplasmic lipid or glycogen content. l6,i7 The fibrolamellar variant of HCC is distinguished by its relatively favorable prognosis and the usual absence of cirrhosis.8f'820 We report no survival data for fibrolamellar HCC because only three cases were recorded in SEER. In other studies, fibrolamellar HCC accounted for up to 10% of all HCCS~,'~ and for 50% of HCCs in patients younger than 40 years.8 We cannot exclude the possibility that some cases of fibrolamellar HCC were not specifically reported as such in SEER. The second most common primary liver cancer was intrahepatic cholangiocarcinoma. This group included subtypes also seen in the gallbladder and extrahepatic bile ductspapillary carcinoma, mucinous adenocarcinoma, and cystadenocarcinoma. The 5year survival rate for intrahepatic cholangiocarcinoma was lower than that for its extrahepatic counterpart; both types had a very poor outcome. Hepatoblastoma is the most common liver cancer in infancy, but it is not restricted to the pediatric population. Rare cases have been reported in adults*l; in SEER, seven patients with hepatoblastoma were older than 60 years of age. Pure epithelial and mixed epithelial mesenchymal patterns occur; fetal, embryonal and anaplastic variants also have been de~cribed.~*~*'~~ Hepatoblastomas are rapidly fatal if not successfully resected. Long term survival has been reported for the fetal type after complete resection, but none has been reported for the anaplastic type, which is thought to have

6 176 CANCER Supplement January I, 2995, Volume 75, No. 1 the poorest However, a recent analysis of increased risk of primary liver cancer following the long 105 cases of hepatoblastoma showed no significant re term use of oral contraceptive^.^',^^ lationship between histologic subtype and progn~sis. ~ There is a well known association between angio Angiosarcomas and malignant hemangioendothel sarcoma and exposure to vinyl chloride. Thorotrast iomas comprised 65% of all sarcomas. Hepatic angio exposure, exogenous hormone use, and cirrhosis also sarcomas are often multicentric, causing widespread have been implicated in the development of angiosardestruction of the liver and death, often before the oc coma.11.12,49 Intrahepatic cholangiocarcinoma is associcurrence of distant meta~tases.~ The prognosis for ma ated with liver fluke infestation in Asia; it also has been lignant epithelioid hemangioendothelioma is much linked to ulcerative colitis, primary sclerosing cholanmore favorable than that for the typical angiosarcoma; gitis, and cystic disorders of the biliary systemrisk a few patients have survived for decades, and some pa factors also described for extrahepatic bile duct carcitients are candidates for liver transplantati~n.~~~ Leio n~ma.~o ~ myosarcoma is considered a very rare hepatic tumorz6 but was the second most common sarcoma reported in Gall bladder SEER. Intrahepatic leiomyosarcomas most likely arise from smooth muscle cells of the bile ducts or blood ves Carcinoma of the gallbladder is an uncommon but sels. One subtype that arises from the ligamentum teres highly lethal disease. In many patients, the disease is is resectable and associated with a more favorable clin not suspected clinically and is found at an advanced ical co~rse. ~ Seven cases of embryonal sarcoma (malig stage, often during surgery for cholelithiasis. The assonant mesenchymoma) were reported. Ultrastructural ciated survival rates are very low, similar to those seen and immunohistochemical studies confirm that this tu for pancreatic and lung cancer. Nevertheless, survival mor is an undifferentiated mesenchymal neopla~m.~~~~~ depends on the histologic type of gallbladder cancer Primary carcinoid tumors have been well docuand the degree of differentiation of the t~mor.~~ ~ Although gallbladder carcinoma is rare in the mented in the liver; six cases were recorded in SEER. United States, the incidence varies among different eth A single case of hepatic squamous cell carcinoma was nic groups. Gallbladder carcinoma is more common in reported. Primary squamous cell carcinoma in the liver Native Americans and some Hispanic Americans than probably develops in areas of squamous metaplasia secin whites or African Ameri~ans.~~~ In the southwestondary to chronic inflammation of the intrahepatic bile ern United States, the high incidence of gallbladder carducts3 Other rare tumors reported in SEER included cinoma in Native Americans parallels the high prevafour carcinosarcomas and one endodermal sinus tumor. lence of cholelithiasis in this p~pulation. ~~~ A strong Distinguishing among the various histologic types of primary liver cancer is important for studying their etiology. The most important risk factor for HCC is viral infection by HBV or hepatitis C virus (HCV). The association between HBV infection and the development of HCC is well kn~wn.~ ~~ The integration of HBV DNA into the cellular genome of tumors has been demonstrated in many studies, although a causal relationship between this integration and malignant transformation has not yet been firmly established. Hepatitis C virus infection, with its associated cirrhosis, is now recognized to be as important a risk factor for HCC as is HBV.3642 Cirrhosis is also a risk factor for HCC, whether from viral infection, hemochromatosis, alcoholic liver disease, or metabolic disorder^.^'^^ In addition, cirrhosis often contributes to the terminal hepatic failure in HCC patients and also hampers the response to therapy. Hepatocellular carcinomas also have been reported in association with exposure to substances such as aflatoxin,45 nitrosamines, and thorium dioxide (thorotrast). Exogenous hormone use has been studied as a possible risk factor. Two recent studies again have suggested an association long has been noted between gallbladder carcinoma and cholelithiasis, which is present in 7590% of Sustained chronic inflammation is thought to predispose to carcinoma through a dysplasia, carcinoma in situ, invasive carcinoma sequence.54,6366 In recent years, the incidence of gallbladder cancer in this country has appeared to stabilize or decline, in concert with an increase in the number of cholecystectomies performed for ch~lelithiasis.~~ Results The total number of cases of primary invasive gallbladder cancer recorded in SEER was 4435; of these, 4266 (96%) were histologically confirmed. Tables 4 and 5 list the most common histologic types recorded in SEER. Of the 4266 cases of invasive gallbladder cancer, 1181 (28%) were reported in males, and 3085 (72%) in females. All histologic types showed a similar sex distribution. Approximately 99% of all gallbladder cancers were recorded as carcinomas. Of these carcinomas, 90% were

7 Liver, Gallbladder, Bile Ducts, Pancreas/Carriaga and Henson 177 Table 4. Gallbladder (T156.0): Frequencies and Percent Distribution by Histology and Sex, All Races, Microscopically Confirmed* Cases, SEER Both sexes Male Female Histologyt Frequency % Frequency YO Frequency Yo Gallbladderinvasive Carcinoma "Epidermoid' carcinoma$ Adenocarcinoma Adenocarcinoma, NOS (8140) Papillary adenocarcinoma, NOS (8260) Mucinous adenocarcinoma and mucinproducing 4, , , , , , , , , , , adenocarcinoma ( ) Other Other specific carcinomas Unspecified ("Carcinoma, NOS") Sarcoma Other specified types Unspecified Gallbladder in situ SEER: Surveillance, Epidemiology, and End Results; ICD0: International Classification of Diseases for Oncology; NOS: not otherwise specified * Excludes lymphohematopoietic neoplasms, Kaposi's sarcoma, neuroblastoma, chordoma and esthesioneuroblastoma (Percy C, Introduction).' t Contents of groups, based on ICD0: are as defined by Berg (Percy C, Introduction).' Numbers in parentheses are ICD0' histology codes. $ Includes squamous, basal, and transitional cell carcinomas. adenocarcinomas, and adenocarcinoma NOS was the most frequent subtype reported, followed by papillary carcinoma and mucinous adenocarcinoma. The group labeled "other adenocarcinomas" included 108 cases of adenosquamous carcinoma and 22 Table 5. Histologic Types of Gallbladder Cancer* Histologic type n % of invasive Total 4412 All invasive Carcinoma Aden o c a r c i n o m a Adenocarcinoma, NOS Papillary adenocarcinomat Mucinous and mucin producing Mucinous carcinoma Mucinproducing carcinoma Other adenocarcinoma Squamous cell carcinoma Carcinoma, NOS Other specific carcinomas Sarcoma Other & unspecified In situ 146 NOS: not otherwise specified. * Microscopically confirmed cases only. t Includes papillary adenocarcinoma, NOS (8260) and papillary carcinoma, NOS (8050). cases of adenocarcinoma with squamous metaplasia. In addition, 76 cases of squamous cell carcinoma were reported. These 206 cases, representing nearly 5% of all invasive cancers, are thought to arise from metaplastic squamous epithelium. Included in the carcinoma NOS group were 40 undifferentiated carcinomas, 25 anaplastic carcinomas, 3 large cell carcinomas, and 2 pleomorphic carcinomas; this group had the lowest 5year survival (Table 6). Not shown in Table 4 are 19 signet ring cell carcinomas, 17 cases of small cell (oat cell) carcinoma, 5 cases of carcinoid tumor, and 1 spindle cell carcinoma. Seven adenocarcinomas were associated with adenomas. Thirteen carcinosarcomas and seven sarcomas also were recorded, including four leiomyosarcomas and two spindle cell sarcomas. Cancers of the gallbladder occurred primarily in elderly patients. Approximately 75% of patients were older than 65 years; most fell within the 7579year age group. The overall median age for patients with invasive carcinoma was 73 years, whereas the median age for in situ carcinomas was 69 years. Only three patients with invasive carcinoma were younger than 30 years of age. Black patients were younger at diagnosis than white patients (median age, 69 years in blacks vs. 73 in whites). For mucinous and mucinproducing adenocarcinomas, the median ages were 65 years for black patients and 72 years for white. The ageadjusted incidence of invasive gallbladder

8 178 CANCER Supplement January 2,2995, Volume 75, No. 1 Table 6. FiveYear Relative Survival Rates for Gallbladder Cancer by Histologic Type and Stage of Disease (197886) Histologic type n LOC REG DIST UNSTGD ALLt All types Carcinoma, all Adenocarcinoma Adenocarcinoma, NOS Papillary adenocarcinoma * 40.5* Mucinoust Other * Squamous cell carcinoma Carcinoma, NOS LOC: local; REG: regional; DIST distant; UNSTGD: unstaged; ALL survival for all stages combined (includes unstaged cases); : fewer than 25 cases; NOS: not otherwise specified. * 0.05 < SE I t Includes rnucinous and mucinuroducing adenocarcinomas. carcinoma decreased from 1.4 to 1.2 over the three periods, whereas the incidence of in situ carcinoma rose slightly from 0.0 to 0.1. Rates for all major histologic types were lower in blacks than in whites or all races combined. As expected, the incidence of adenocarcinoma was almost two times higher in females than in males. For the period , the incidence rates were 1.4 for white females and 0.8 for white males; the rate for black females was 1.3, compared with 0.6 for black males. The agespecific incidence of invasive adenocarcinoma increased with advancing age; for all age groups, rates were higher in females than in males. During , the peak incidence, seen in women older than 85 years of age, was 19.1, compared with 8.9 in men. In , the peak incidence was lower among women (16.1) but higher in men (12.1). Although the overall agespecific rates of invasive cancer fell over the three periods, the incidence of in situ carcinoma rose in the population over the age of 65 years (data not shown). For every histologic type except papillary adenocarcinoma, more cases were recorded as distant stage than either localized or regional. For all histologic types combined, approximately 25% of cases were localized stage disease and 40% were distant stage. Mucinous carcinomas and carcinomas NOS both showed a high percentage of distant stage disease (52% and 58%, respectively). In contrast, 64% of papillary adenocarcinomas were diagnosed as localized. The different combinations of gender and race yielded similar stage distributions. No significant changes in stage distribution were seen among the three periods. For some histologic types, a slight increase was seen in the proportion of localized stage disease over time; the corresponding decrease was seen in regional stage disease, rather than in distant. The 5year relative survival rates for the major histologic types are given i; Table 6. Papillary adenocarcinomas had the best outcome of all histologic types listed, with a 5year survival rate of 41%. The other histologic types showed significantly less favorable survival, with rates close to 109'0, all stages combined. Survival rates for squamous cell carcinoma and mucinous adenocarcinoma were lower than that for adenocarcinoma NOS. Cases recorded as carcinoma NOS showed the worst outcome; included in this group were undifferentiated, large cell, anaplastic, and pleomorphic carcinomas. Table 6 shows a sigruficant association between stage of disease and survival; localized stage disease was associated with much better survival than was regional or distant stage disease. Fiveyear survival rates were virtually zero for cases that had been staged distant at time of magnosis. Survival rates in black patients were lower than those seen in white patients. During , the 5 year survival rate for invasive gallbladder carcinoma was 12.3% for whites (n = 2052) and 5.1% for blacks (n = 125), all stages combined. This difference in survival was not associated with a shift in the distribution of stage at diagnosis and was present even within localized stage disease: the 5year survival rate for localized stage adenocarcinoma was 43% for whites and 21% for blacks. The 5year survival rate for invasive adenocarcinoma rose from 9.3% ( ) to 15.7% ( ) for white patients, but no increase in survival rates was seen for black patients. Discussion The results of this study support previous observations that cancers of the gallbladder are uncommon, occur

9 Liver, Gallbladder, Bile Ducts, Pancreas/Carriugu and Henson 179 Table 7. Extrahepatic Bile Ducts (T ): Frequencies and Percent Distribution by Histology and Sex, All Races, Microscopically Confirmed* Cases, SEER Both sexes Male Female Histologyt Frequency % Frequency Yo Frequency % Extrahepatic bile ductsinvasive Carcinoma Epidermoid carcinoma$ Adenocarcinoma Adenocarcinoma, NOS (8140) Papillary adenocarcinoma, NOS (8260) Mucinous adenocarcinoma and mucinproducing adenocarcinoma ( ) Other Other specific carcinomas Unspecified ( Carcinoma, NOS ) Sarcoma Other specified types Unspecified Extrahepatic bile ducts in situ SEER: Surveillance, Epidemiology, and End Results; ICD0: International Classification of Diseases for Oncology; NOS: not otherwise specified. * Excludes lymphohematopoietic neoplasms, Kaposi s sarcoma, neuroblastoma, chordoma and esthesioneuroblastoma (Percy C, Introduction). t Contents of groups, based on ICD0, are as defined by Berg (Percy C, Introduction). Numbers in parentheses are ICD0 histology codes. t Includes sauamous, basal, and transitional cell carcinomas most often in females and the elderly, and have a very poor prognosis. Adenocarcinoma NOS, the most frequently reported histologic type, was associated with a 5year survival rate of 11 YO. Papillary adenocarcinomas had much better survival than all other types, with a 5year rate of 41%, but papillary carcinomas represented only 6% of all gallbladder cancers. The carcinoma NOS group had the poorest outcome; 23% of these cases were recorded as poorly differentiated histologic types. Papillary carcinomas, conversely, are generally low grade. Tumor type appears to have an influence on survival, although our histologic groupings also tend to reflect the grade of the tumor. Severe chronic inflammation of the gallbladder can result in squamous metaplasia of the lining epithelium, from which squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma with squamous metaplasia might arise54*6870; these histologic types accounted for nearly 5% of all invasive cancers in SEER. Carcinomas showing neuroendocrine differentiation also might arise from metaplastic epithelium. Some investigators report that neuroendocrine tumors often contain squamous or adenocarcinomatous components, which suggests divergent differentiation from a common tumor ce11.54,7176 In this study, 22 cases were recorded as small cell, oat cell, or carcinoid tumor. Sarcomas and carcinosarcomas accounted for less than 1% of all gallbladder cancers. No cases of clear cell or intestinaltype adeno~arcinoma~~ were reported in SEER. Stage of disease is a strong prognostic fa~tor.~~,~~ As expected, survival decreased significantly with advancing stage: the 5year survival for localized disease was 42%, compared with only 4% for regional stage cases. Unfortunately, the disease was limited to the gallbladder in only 25% of the patients. The relatively high survival rate of patients with papillary adenocarcinoma was related to the stage of disease: 64% of papillary adenocarcinomas were of localized stage at diagnosis. In contrast, greater than 50% of mucinous carcinomas and carcinoma NOS were recorded as distant stage, with only 19% and 1 YO recorded as localized, respectively; these two groups had the worst outcome of all histologic types reviewed. Carcinoma is an incidental finding in approximately 1% of all patients undergoing routine cholecystectomies for ch~lelithiasis~~~~ ; however, this percentage is undoubtedly higher for older age groups. One hundred, fortysix cases of in situ carcinoma were recorded in SEER; these most likely were found incidentally in routine cholecystectomy specimens. In situ carcinomas are expected to be associated with survival rates of virtually 100%.64,65,6s In our study, however, approximately 10% of patients with in situ carcinoma died from their disease. This finding suggests that thorough examination of the entire gallbladder might reveal

10 180 CANCER Supplement January 1,1995, Volume 75, No. 1 an area of invasive cancer adjacent to or possibly far removed from the original in situ location. Despite new surgical and chemotherapeutic approaches to treatment,81*85 the overall 5year survival rate increased only slightly, from 8% in to 14% in Improved survival clearly depends on the earlier detection of gallbladder carcinoma. Carcinoma has been shown to coexist with calcified porcelain gallbladders and those showing segmental adenomyomatosis86ss; preexisting conditions such as these help to identify patients at high risk. Advances in imaging techniques, bile cytology (direct and salineirrigated), and the monitoring of serum levels of nonspecific tumor markers,53,8991 may contribute to the detection of early lesions in patients at risk for gallbladder cancer. Extrahepatic Bile Ducts Compared with cancers of the gallbladder, cancers of the extrahepatic bile ducts have differences and similarities. In both sites, greater than 99% of all cancers are carcinomas. Extrahepatic bile duct carcinomas are less common overall, slightly more common in males, have a different epidemiologic pattern, and usually are not associated with lithiasis. Similarities include corresponding histologic types, poor outcome, low rate of resectability, and occurrence in older age group~.~~~' Results The total number of invasive cancers of the extrahepatic bile ducts and ampulla of Vater recorded in SEER was 4023; of these, 3468 (86%) were confirmed histologically. Of the cancers of the extrahepatic bile ducts, 99% were carcinomas. Tables 7 and 8 list the most common histologic types. The vast majority of carcinomas were adenocarcinomas, and adenocarcinoma NOS was the most frequently reported subtype. Papillary adenocarcinomas (i.e., papillary adenocarcinomas NOS and 22 additional cases listed as papillary carcinomas NOS) accounted for 9.3% of all extrahepatic bile duct cancers; mucinous and mucinproducing adenocarcinomas comprised 4.8%. The other adenocarcinoma group included 20 cases of adenocarcinoma in villous adenoma and 6 cases of signet ring cell carcinoma. The remainder of the cases were additional cases of adenocarcinoma NOS recorded as infiltrating duct carcinomas or cholangiocarcinoma. In the carcinoma NOS group, 217 of 234 cases were not subtyped further; the remaining 17 (7%) were recorded as large cell, undifferentiated, anaplastic, or pleomorphic. In addition to the 8 squamous cell carcinomas, 14 cases of adenosquamous carcinoma and 1 Table 8. Histologic Types of Extrahepatic Bile Duct Cancer* Histoloeic tvue n % invasive Total All invasive Carcinoma Adenocarcinoma Adenocarcinoma, NOS Papillary adenocarcinomat Mucinous and mucinproducing Mucinous Mucinproducing Other adenocarcinoma Squamous cell carcinoma Carcinoma, NOS Other specific carcinomas Sarcoma Other & unspecified In situ NOS: not otherwise specified. * Includes ampulla of Vater; microscopically confirmed cases only. t Includes papillary adenocarcinoma, NOS (8260) and papillary carcinoma, NOS (8050). case of adenocarcinoma with squamous metaplasia were reported. Not shown in the tables are six cases of small cell carcinoma, seven carcinoid tumors, and seven sarcomas, including two leiomyosarcomas and three rhabdomyosarcomas. In situ carcinomas accounted for only 0.5% of all cancers. Unlike gallbladder carcinomas, which were much more common in women than in men, invasive carcinomas of the extrahepatic bile ducts showed a slight male preponderance. Of the 3468 patients with invasive extrahepatic bile duct cancers, 1808 (52%) were male. Similarly, 56% of patients with papillary carcinoma and 54% of those with mucinous carcinoma were male. Approximately 65% of all patients with extrahepatic bile duct carcinomas were older than 65 years; most patients fell within the 7074year age group. The median age was 69 years, lower than that recorded for patients with gallbladder cancer (73 years). Bile duct sarcomas affected younger patients: the median age was 44 years, but three of the seven cases were rhabdomyosarcomas, which are primarily childhood tumors.92 During , the ageadjusted incidence of extrahepatic bile duct carcinoma was 1.2 per 100,000 for males and 0.8 for females. The rates were lower in the black population (0.8) than in whites (1.0). The highest agespecific incidence was found in the population aged 8084 years (9.9 in , all races and both sexes combined). The overall 5year survival rates for adenocarci

11 Liver, Gallbladder, Bile Ducts, Pancreas/Carriaga and Henson 181 Table 9. FiveYear Relative Survival Rates for Extrahepatic Bile Duct Cancer by Histologic Type and Stage of Disease (197886) Histologic type n LOC REG DIST UNSTGD ALL All types Carcinoma, all Adenocarcinoma Adenocarcinoma, NOS Papillary adenocarcinoma * 24.2* 33.7 Mucinoust Other * 20.0* Carcinoma, NOS * 9.8 LOC: local; REG: regional; DIST distant; UNSTGD: unstaged; ALL: survival for all stages combined (includes unstaged cases); : fewer than 25 cases; NOS: not otherwise specified. * 0.05 < SE t Includes mucinous and mucinproducing adenocarcinomas. noma increased slightly over the three periods, from 11.7% to 15.1%. When separated by gender, this slight improvement over time is seen only in female patients: for males, the 5year survival rates were 14.1% in and 13.0% in , but for females the survival rate rose from 9.1% to 17.3%. In both the gallbladder and the extrahepatic bile ducts papillary adenocarcinomas were associated with the best prognosis (Table 9). The other histologic types showed very low 5year survival rates, comparable to those seen in gallbladder carcinoma. Of the major types of extrahepatic bile duct cancers, mucinous adenocarcinomas had the poorest outcome. The expected association between survival and stage of diseases is presented in Table 9: survival decreased with advancing stage. The 5year survival rate for patients with distant stage disease was essentially zero. Extrahepatic bile duct cancers were more often regional stage than either localized or distant (28% localized, 46% regional, and 26% distant, all histologic types combined). Of the major histologic types, papillary adenocarcinoma had the highest proportion of localized stage disease (43%) and the lowest percentage of distant stage disease (10%). In contrast, only 14% of mucinous carcinomas were staged as localized; this type showed the poorest outcome. Discussion Cancers of the extrahepatic bile ducts are less common than those of the gallbladder. The same major histologic types can be found in both sites, but slight differences are seen in the frequency of certain subtypes. In both sites, 99% of cases were carcinomas, and the most frequently reported subtype was adenocarcinoma NOS. Papillary carcinomas accounted for a higher percentage of carcinomas in the extrahepatic bile ducts than in the gallbladder, whereas mucinous carcinomas were slightly more common in the gallbladder than in the bile ducts. Several uncommon histologic types were represented in both sites, such as scirrhous adenocarcinoma, adenosquamous carcinoma, carcinoid tumors, signet ring cell carcinomas, small cell (oat cell) carcinomas, and adenocarcinoma in villous or tubular adenomas. In SEER, some histologic types, such as clear cell adenocarcinoma and cystadenocarcinoma, were reported in the bile ducts but not in the gallbladder. Others, such as carcinosarcoma, were reported only in the gallbladder. Adenosquamous carcinoma and squamous cell carcinoma have been described in both the gallbladder and bile d ~ ~ t s however, ~ ~ ~ adenosquamous ~ ~ ~ ~ ~ carci, ~ ~ ; noma, squamous cell carcinoma, and adenocarcinoma with squamous metaplasia were more common in the gallbladder than in the extrahepatic bile duct. Eighteen in situ carcinomas were reported (comprising 0.5% of all malignant bile duct tumors), whereas 146 (3.3%) were recorded in our review of gallbladder cancers. The higher percentage of in situ carcinoma in the gallbladder reflects the contribution of routine cholecystectomies to the detection of early lesions. An increased incidence of extrahepatic bile duct cancers has been reported in patients with ulcerative colitis, primary sclerosing cholangitis, and disorders leading to biliary stasis, such as choledochal ~ysts.~~~" Sustained chronic inflammation may contribute to the development of dysplasia and carcinoma. In both the gallbladder and extrahepatic bile ducts, areas of dysplasia and carcinoma in situ may be found adjacent to invasive carcinoma, suggesting such a sequence in the development of these t ~ m o r ~. ~ ~, ~ ~ ~ ~ ~ ~ Bile duct carcinomas also might develop from preexisting adenomas. Twentythree cases that arose in an

12 182 CANCER Supplement Juanuury 1,1995, Volume 75, No. 1 Table 10. Pancreas (T ): Frequencies and Percent Distribution by Histology and Sex, All Races, Microscopically Confirmed* Cases, SEER, Both sexes Male Female Histologyt Frequency % Frequency YO Frequency Yo Pancreasinvasive 23, , , Carcinoma 22, , , "Epidermoid' carcinoma$ Adenocarcinoma 18, , , Adenocarcinoma, NOS (8140) 15, , , Papillary adenocarcinoma, NOS (8260) o Mucinous adenocarcinoma (8480) Mucinproducing adenocarcinoma (8481)g Infiltrating duct carcinoma ( ) Other Other specific carcinomas Islet cell carcinoma ( ) Other Unspecified ("Carcinoma, NOS") 3, , , Sarcoma Other specified types Unspecified Pancreas in situ SEER Surveillance, Epidemiology, and End Results; ICD0: International Classification of Diseases for Oncology; NOS: not otherwise specified. * Excludes lymphohematopoietic neoplasms, Kaposi's sarcoma, neuroblastoma, chordoma and esthesioneuroblastoma (Percy C, Introduction).' t Contents of groups, based on ICD0: are as defined by Berg (Percy C, Introduction).' Numbers in parentheses are ICD0 histology codes. $ Includes squamous, basal and transitional cell carcinomas. 4 Before 1977, this entity was incorporated in mucinous adenocarcinoma, (8480). adenoma were reported in SEER (0.7%). In one study of 43 cases, investigators proposed that 21% of bile duct carcinomas and 47% of papillary bile duct carcinomas had arisen from adenomas.lo3 If a specific search for adenomatous components had been conducted, the number reported here may have been higher. Conversely, very well differentiated areas of papillary carcinoma might be mistaken for a benign adenomatous component.54 It is interesting to note that 20 of the 23 cases were associated with villous adenomas, 1 with a tubulovillous adenoma, and only 2 with tubular adenomas. Prognosis in patients with bile duct carcinoma has been linked to its histologic type and degree of differentiation.54,92,104, 105 In both the gallbladder and extrahepatic bile ducts, papillary adenocarcinomas were associated with the best outcome of the histologic types reviewed. Bile duct carcinomas are better differentiated overall than gallbladder carcinomas.53,54,92,105.'06 Our data showed a somewhat higher proportion of aggressive tumors (large cell, undifferentiated, anaplastic, and pleomorphic) in the gallbladder than in the bile ducts. Less than 25% of cases of extrahepatic bile duct carcinoma were staged as distant, but cases of gallbladder carcinoma were more often distant stage than either localized or regional; this can be attributed to the relatively early appearance of obstructive symptoms in ex trahepatic bile duct tumors. Nonetheless, the 5year survival rate for localized stage extrahepatic bile duct carcinoma was much lower than that for localized stage gallbladder carcinoma. Papillary adenocarcinoma, the histologic type with the best outcome, showed the highest proportion of localized stage disease. Mucinous adenocarcinoma had the lowest proportion of localized stage disease and the lowest 5year survival rate. Mucinous adenocarcinoma (colloid carcinoma) also is associated with poor outcome in colorectal Diagnosis of bile duct tumors has been improved in recent years by transhepatic and endoscopic retrograde cholangiography, in addition to ultrasonography and computed t~mography.'~' Cytologic examination of cholangiography specimens also may be useful for diagnosis, although interpretation can be difficult because many of these tumors are well differentiated.1101*2 Although bile duct carcinomas are often small and have not metastasized when detected, patient outcome remains poor. An important factor in prognosis is the location of the tumor within the biliary tree. Tumors in the lower third of the bile duct can be resected more successfully than those from other location^,'^^^"^^^^^ but the majority of tumors are located within the upper third of the bile Bile duct tumors also can be diffusely infiltrative or multifocal and therefore can

13 Liver, Gallbladder, Bile Ducts, Pancreas/Cnrringn nnd Henson 183 further complicate surgical resection. Developments in adjuvant therapy and new approaches to surgical management eventually may lead to clinically significant improvements in survival. Pancreas Pancreatic cancer is known for its extremely poor prognosis. In the United States, it accounts for approximately 2.5% of all new cancer cases ann~ally,~ but accounts for 5% of all cancer deaths4 It is the fifth leading cause of death from cancer, exceeded only by cancers of the lung, colon, breast, and prostate. Pancreatic cancer is associated with the lowest 5year survival rate of all types of cancer surveyed in SEER.4 Most cancers of the exocrine pancreas are ductal adenocarcinoma, although only approximately 5% of all pancreatic cells are ductal epithelial cell^."^ Greater than 80% of the pancreas is composed of acinar cells, but only 1% of pancreatic cancers are of acinar cell origin. Several variants of exocrine pancreatic carcinoma have been described, each with its own characteristic histologic appearance and behavior Unfortunately, however, the vast majority are typical ductal adenocarcinomas that follow an insidious and rapidly fatal course. Endocrine carcinomas are far less common than ductal adenocarcinomas but are associated with a better prognosis. I3*l4' Pancreatic sarcomas are very rare Results The total number of primary invasive pancreatic cancers recorded in SEER was 31,136; of these, 23,107 (74%) were confirmed histologically. Of all the pancreatic cancers, 98% were carcinomas. Tables 10 and 11 list the most common histologic types of pancreatic cancer recorded in SEER. Adenocarcinomas accounted for 82% of the carcinomas. Adenocarcinoma NOS was the most frequent subtype reported, followed by mucinous adenocarcinoma. The group labeled "other adenocarcinoma" included cystadenocarcinomas, acinar cell carcinomas, and adenosquamous carcinomas. Among the 122 cystadenocarcinomas reported were 4 1 mucinous variants, 15 papillary variants, and 9 papillary mucinous variants. In addition to 123 adenosquamous carcinomas and 101 squamous cell carcinomas, 14 cases of adenocarcinoma with squamous metaplasia were reported; these tumors accounted for 1 % of all pancreatic cancers. Also listed under "other adenocarcinoma" were 53 scirrhous adenocarcinomas, 43 signet ring cell carcinomas, and 12 clear cell carcinomas. The cases listed as carcinoma NOS accounted for Table 11. Histologic Types of Pancreatic Cancer* Histologic type Total Invasive Carcinoma, all Adenocarcinoma Adenocarcinoma, NOS Papillary adenocarcinomat Mucinous Mucinproducing Infiltrating duct Other adenocarcinoma Adenosquamous Cystadenocarcinoma Acinar cell Other Other carcinoma Islet cell Other Squamous cell carcinoma Carcinoma, NOS Sarcoma Other & unspecified In situ n % of invasive NOS: not otherwise specified. * Microscopically confirmed cases only. t Includes papillary adenocarcinoma, NOS (8260) and papillary carcinoma, NOS 18050). 13.5% of all invasive pancreatic cancers and included 2 14 undifferentiated carcinomas, 144 anaplastic carcinomas, 56 large cell carcinomas, and 36 pleomorphic carcinomas. The remaining 2671 cases were not subtyped further. In SEER, 402 islet cell carcinomas were reported, including 21 malignant gastrinomas, 5 malignant insulinomas, 4 malignant glucagonomas, and 1 malignant vipoma (listed under "other specific carcinomas"). Also recorded under "other specific carcinomas" were 100 small cell carcinomas NOS, 32 giant cell carcinomas, 30 carcinoid tumors, 16 neuroendocrine carcinomas, and 7 tumors listed as medullary carcinoma NOS. The 24 sarcomas included 9 leiomyosarcomas, 6 sarcomas NOS, 4 malignant fibrous histiocytomas, 1 epithelioid sarcoma, 1 liposarcoma, 1 rhabdomyosarcoma, 1 angiosarcoma, and 1 malignant epithelioid hemangioendothelioma. Three carcinosarcomas were reported. One tumor listed as giant cell tumor of bone was most likely a case of pancreatic giant cell carcinoma with osteoclastlike giant cells, a rare tumor that histologically resembles giant cell tumor of bone. Adenocarcinomas NOS and islet cell carcinomas both showed a slight male preponderance (Table 12), and two thirds of the 24 patients with sarcomas were

14 184 CANCER Supplement January 2,2995, Volume 75, No. 1 Table 12. Sex Distribution for Selected Histologic Types of Pancreatic Cancer Histologic twe Total Male Female All invasive Adenocarcinoma, NOS Papillary adenocarcinoma C ystadenocarcinoma Islet cell carcinoma 401* Squamous cell carcinoma Sarcoma NOS: not otherwise specified. * Does not include 1 viooma. male. Papillary adenocarcinomas and cystadenocarcinomas, however, were more common in females than in males. All histologic types of pancreatic cancer were rare in those younger than 40 years of age. Most patients were in the 6569year age group. The median age of patients with adenocarcinoma was 67 years, whereas the median age of patients with islet cell carcinoma was 60 years. Overall, the median age of female patients was slightly higher than that of males. For all major histologic types, black patients were younger at diagnosis than white patients. The median age of patients with islet cell carcinoma was 53 years in black patients, and that for white patients was 61 years. Similarly, the median age for sarcomas was 60 years in black patients, and it was 70 in white patients. The ageadjusted incidence of pancreatic adenocarcinoma rose from 5.5 to 6.2 ( , all races and sexes combined). The highest rate was seen in the black male population (12.8), but the greatest increase over time occurred among black females (6.4 in to 8.2 in ). The incidence of islet cell carcinoma was 0.1 per 100,000 throughout the three periods. Figure 2 gves the agespecific incidence of pancreatic adenocarcinoma and islet cell carcinoma for the period The incidence of adenocarcinoma began to climb from 1.9 at age 4044 years to a peak of 42.6 in the 7579year age group. For any given age and year group, rates remained higher in males than in females, and higher in blacks than in whites (data not shown). For the population aged 60 years and older, the incidence of pancreatic adenocarcinoma increased from 1973 to 1987, but no increase was seen in the population younger than 60 years. Islet cell carcinomas also were most common in patients older than 60 years; however, the incidence of islet cell carcinoma did not exceed 0.6 for any age group throughout the three periods. For all major histologic types, the majority of cases were recorded as distant stage at diagnosis, with fewer than 10% as localized stage. The stage distribution of islet cell carcinoma was similar to that for exocrine carcinomas. Mucinproducing adenocarcinoma showed the highest proportion of distant stage disease (77%), followed by mucinous adenocarcinoma (74%), adenocarcinoma NOS (66%), and islet cell carcinoma (63%). The proportion of distant stage disease decreased slightly over time for most types of adenocarcinoma, with a corresponding increase in localized and regional stage disease. The outcome for all types of carcinoma of the exocrine pancreas was dismal, with 5year survival rates below lo%, regardless of histologic type or stage of disease. The overall 5year survival rate for adenocarcinoma NOS was 1.3%. Papillary carcinoma again was associated with the best outcome, but the 5year survival rate was only 7.7%. The 5year survival rate for islet cell carcinoma was much higher than that for exocrine carcinomas: 67% for regonal stage disease and 36% for all stages combined. Table 13 lists the median survival and 1year observed survival rates for selected histologic types. The median survival times for islet cell carcinomas and carcinoid tumors were longer than 12 months. Of the exocrine carcinomas, mucinous cystadenocarcinoma was associated with the best outcome: median survival was also longer than 12 months, and 14 of 20 patients were alive at 1 year. Other histologic types with a more favorable outcome than the typical ductal adenocarcinoma included cystadenocarcinoma NOS, papillary adenocarcinoma, and acinar cell carcinoma: approxi Rate per 100,000 * Adenocarcinoma i Age at diagnosis Figure 2. Pancreas: agespecific incidence rates by histologic subtype for all races and both sexes according to the SEER data for

15 Liver, Gallbladder, Bile Ducts, Pancreas/Cnrriaga and Henson 185 Table 13. Median Survival and 1Year Observed Survival Rates for Selected Histologic Types of Pancreatic Cancer (198387) Median survival 1yr survival Histologic type n (mo) (%) SE Islet cell carcinoma 112 > Mucinous cystadenocarcinoma 20 > 12.0 Carcinoid 11 > 12.0 Cystadenocarcinoma, NOS Papillary carcinoma Acinar cell carcinoma Adenocarcinoma, NOS Mucinous adenocarcinoma Adenosquamous carcinoma Small cell carcinoma Giant cell carcinoma Pleomoruhic carcinoma SE: standard error; : fewer than 25 cases (survival rates cannot be reported); NOS: not otherwise specified mately 40% of patients with these tumors were alive at 1 year. Adenocarcinoma NOS was associated with a median survival of 4.1 months and a 1year survival rate of 15%, all stages combined. The median survival for small cell carcinoma, giant cell carcinoma, and pleomorphic carcinoma was less than 3 months. None of the 10 patients with pleomorphic carcinoma was alive at 6 months. Although the data are not shown, the survival rates decreased with advancing stage. For carcinomas of the exocrine pancreas, however, the 5year survival rates were so low that the differences in survival among the stages were not clinically meaningful. Similarly, the median survival rates for localized and regional stage adenocarcinoma NOS were 7.5 months and 6.8 months, respectively, whereas the median survival for distant stage disease was 2.9 months. No improvement in survival was seen over the 15year period covered in this study. Discussion Exocrine carcinomas. Of all cancers of the exocrine pancreas, 98% were carcinomas; the vast majority were ductal adenocarcinomas and less than 1% were recorded as acinar cell carcinoma. The most common subtype of adenocarcinoma listed was adenocarcinoma NOS; far less common were mucinous and papillary adenocarcinomas. Approximately 6.0% of all pancreatic cancers were recorded as mucinous or mucinproducing carcinomas, a proportion similar to that seen in the gallbladder and extrahepatic bile ducts (5.3% and 4.8%, respectively). Like mucinous carcinomas of the re~tum,'~~~'~* those of the gallbladder and extrahepatic bile ducts were associated with 5year survival rates lower than that for adenocarcinomas NOS. In the pancreas, however, no significant difference in survival was observed between mucinous carcinoma and adenocarcinoma NOS. Papillary adenocarcinomas were more common in the extrahepatic bile ducts and gallbladder than in the pancreas. In all three sites, papillary carcinomas were associated with a better outcome than adenocarcinoma NOS. Cystadenocarcinoma also had a better prognosis than the typical ductal adenocarcinoma. Greater than 70% of cases occurred in women. Mucinous cystadenocarcinoma had the best outcome of all cancers of the exocrine pancreas: survival was similar to that observed for carcinoid and islet cell carcinomas. The distinction between mucinous cystadenocarcinoma and cystadenoma is no longer made: all mucinous cystic tumors should be considered potentially malignant.'21,'22 Fifteen papillary cystadenocarcinomas were reported. The term "papillary cystadenocarcinoma" sometimes is used synonymously for "mucinous cystadenocarcinoma", but also might represent the socalled papillary cystic neoplasms, solid and papillary epithelial neoplasms, or solid and cystic neoplasms of the pancreas. These tumors have a distinctive histologic appearance, usually affect young women, and are associated with a better prognosis than adenocarcinoma NOS However, no case was reported specifically as papillary cystic neoplasm in SEER. (The term papillary cystic neoplasm was not specified in ICD01, although it is now included in 1CD02.)2 Fortynine cases of acinar cell carcinoma were reported in SEER, comprising 0.2% of all pancreatic cancers, although a somewhat higher incidence has been reported in other Almost two thirds of pa

16 186 CANCER Supplement January 2,2995, Volume 75, No. 1 Table 14. Other Digestive (T ): Frequencies and Percent Distribution by Histology and Sex, All Races, Microscopically Confirmed* Cases, SEER ~ ~~ ~ Both sexes Male Female Histologyt Frequency % Frequency % Frequency % Other digestiveinvasive Carcinoma "Epidermoid" carcinoma$ Adenocarcinoma Adenocarcinoma, NOS (8140) Other Other specific carcinomas Unspecified ("Carcinoma, NOS") Sarcoma Other specified types Unspecified Other digestive in situ SEER: Surveillance, Epidemiology, and End Results; ICD0: International Classification of Diseases for Oncology; NOS: not otherwise specified. * Excludes lymphohematopoietic neoplasms, Kaposi's sarcoma, neuroblastoma, chordoma and esthesioneuroblastoma (Percy C, Introduction).' t Contents of groups, based on ICD0,' are as defined by Berg (Percy C, Introduction).' Numbers in parentheses are ICD0 histology codes.' $ Includes squamous, basal and transitional cell carcinomas. tients with acinar cell carcinoma were men, and the median survival was approximately 5 months. All cystadenocarcinomas in this review were considered to be of ductal origin, but rare cases of acinar cell cystadenocarcinoma have been rep~rted.'~~,'~~ The majority of the cases listed as carcinoma NOS were not subtyped further, but 450 were classified as undifferentiated, anaplastic, large cell, or pleomorphic Carcinomas. Pleomorphic carcinomas in the pancreas, also called giant cell carcinomas, are associated with a more aggressive course than that seen with ductal adenocarcinomas NOS.'29,'30 Of the 10 patients described here, none was alive at 6 months after diagnosis. Adenosquamous carcinomas, adenocarcinomas with squamous metaplasia, and squamous cell carcinomas accounted for approximately 1% of all pancreatic cancers. The existence of pure squamous cell carcinoma is questioned by some investigators, who suggest that these tumors are adenosquamous carcinomas whose adenocarcinomatous component would be revealed by extensive sampling.'31j32 Tumors of uncertain histogenesis include papillary cystic neoplasms, clear cell ~arcinorna,'~~ small cell car ~inoma,'~~ and pancreatic giant cell tumor with osteoclastlike giant cell^.'^^'^^ Twelve cases of clear cell carcinoma were recorded in SEER. Foci of cells with clear cytoplasm have been described in benign pancreatic centroductular cell hyperpla~ia"~; clear cell carcinomas might arise from these cells. Pancreatic pant cell tumor with osteoclastlike giant cells, which resembles giant cell tumor of bone, is another extremely rare tumor: fewer than 20 cases have been reported in the literature and only 1 case was reported in SEER between 1973 and Only 23 of the 23,116 cases of pancreatic cancer in SEER were sarcomas (0.1%). The most common sarcoma was leiomyosarcoma, followed by malignant fibrous histiocytoma. Endocrine carcinomas. Endocrine carcinomas of the pancreas are associated with a much better outcome than is their exocrine counterpart. Patients with carcinoid tumors had the best outcome of the histologic types reviewed; median survival was greater than 12 months, and 84% of patients were alive 1 year after diagnosis. Unfortunately, carcinoid tumors comprised only 0.1 % of all pancreatic cancers. Islet cell carcinomas accounted for 1.7% of all pancreatic cancers in this review and affected males and females almost equally. These tumors are subclassified by their clinical, immunohistochemical, and ultrastructural feature^.'^^'^' In SEER, malignant gastrinoma was the most frequently reported subtype; malignant insulinomas, malignant glucagonomas, and a single malignant vipoma also were reported. The majority of islet cell carcinomas (92%) were not classified further. Like carcinomas of the exocrine pancreas, the majority of islet cell carcinomas are detected at an advanced stage, because these tumors are diagnosed as malignant based on the presence of distant metastases or invasion of contiguous structures. Greater than 62% of our cases had distant metastases at diagnosis. Although the stage distributions for islet cell carcinoma and ductal adenocarcinoma NOS were essentially the

17 Liver, Gallbladder, Bile Ducts, Pancreas/Carriaga and Henson 187 same, islet cell carcinoma was associated with much higher survival rates. The Annual Cancer Statistics Review4 reported a 6% decrease in incidence over the period The present analysis, which includes only histologically confirmed cases, showed a small increase in the overall ageadjusted incidence, from 7.0 to 7.4. This was due primarily to an increase in the female population; the rate for males remained relatively unchanged over the three periods. The greatest increase occurred in black females, where the incidence rose to exceed that for white males during the years Overall, however, pancreatic cancer remained more common in men than in women, and more common in blacks than in whites. Histologic Type Pancreatic carcinomas have some features in common with biliary carcinomas. The same spectrum of histologic types is observed for cancers of the pancreas, gallbladder, and extrahepatic bile ducts, with only subtle differences in the proportion of each type. In all three sites, adenocarcinoma NOS was the most common subtype reported. Squamous cell carcinomas and adenosquamous carcinomas were more common in the gallbladder than in the pancreas or extrahepatic bile ducts. Papillary adenocarcinomas were most common in the extrahepatic bile ducts. In the pancreas and gallbladder, papillary adenocarcinoma showed a female preponderance. For all three sites, papillary adenocarcinoma was associated with significantly higher survival rates than those for adenocarcinoma NOS. Mucinous carcinomas accounted for roughly 3% of all cancers in the pancreas and biliary tract. In the gallbladder and pancreas, mucinous carcinoma showed the highest proportion of distant stage disease, suggesting a more aggressive course for this histologic type, similar to that seen in mucinous carcinoma of the colon and rectum. Although the majority of these tumors are typical adenocarcinomas with very poor prognoses, this review has shown that histologic type is a useful prognostic factor in pancreatic and biliary cancers. Other Digestive System In the SEER Program, 671 cases of gastrointestinal cancer were classified to the very general site of gastrointestinal tract NOS. Nearly all were carcinomas (96%) and 83% were adenocarcinomas (Table 14). References 1. Percy C. Introduction. Cancer 1995; 75: International Classification of Diseases for Oncology. 2nd ed. Geneva: World Health Organization, American Cancer Society. Cancer facts and figures. Atlanta, (GA): The American Cancer Society, Ries LAG, Hankey BF, Miller BA, Hartman AM, Edwards BK. 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