Obstructive Jaundice Secondary to Metastatic Cancer: · PDF fileObstructive Jaundice Secondary to Metastatic Cancer (continued from page 27) A B C Figure 2. Squamous cell carcinoma

PRACTICAL GASTROENTEROLOGY • SEPTEMBER 200424

GASTRIC CANCER

Despite its decline in incidence over the past fewdecades, gastric cancer is still the second most com-mon cancer worldwide. Approximately one-half of

patients with gastric cancer are not surgical resectioncandidates due to advanced disease at presentation.Those who undergo potentially curative resections havea high rate of both local and distant recurrence.

Gastric cancer spreads locally within the gastric wallinfiltrating into the submucosa early in their develop-ment. The presence of nodal metastases is very closelyrelated to depth of local invasion. With mucosal inva-

Obstructive Jaundice Secondaryto Metastatic Cancer: A Review

A SPECIAL ARTICLE

S. Patel, M.D., N. Kheterpal, M.D., R. Patwardhan, M.D.,J. Levey, M.D., Division of Digestive Disease and Nutri-tion, University of Massachusetts Medical Center andWorcester Medical Center, Fallon Clinic, Worcester MA.

by S. Patel, N. Kheterpal, R. Patwardhan, and J. Levey

Jaundice due to metastatic cancer is much more common than originally appre-ciated. Studies have shown that up to 21% of malignant biliary obstructions area result of distant primary malignancies metastatic to the pancreaticobiliary sys-tem(1). Jaundice due to biliary stasis occurs from either the diffuse hepaticparenchymal infiltration of malignant cells causing obstruction of the smallintrahepatic biliary ducts or by compression of the larger extrahepatic ducts.The latter form of obstruction can be due to intraluminal invasion within thesubmucosal layer of the bile duct or from external compression secondary toenlarged tumor-infiltrated periportal lymph nodes and masses or pancreaticparenchymal lesions. The clinical differentiation of primary and secondary pan-creatico-biliary tumors can be difficult. In fact many of these patients who pre-sent with jaundice are initially misdiagnosed with primary cholangiocarcinomaor pancreatic carcinoma. It is important to make this distinction due to the ther-apeutic implications. Some authors have actually shown improved survival inpatients with metastatic disease compared to those with primary pancreatic orbile duct cancers. The most common primary cancers to metastasize to the pan-creatico-biliary system are stomach, colon, breast, kidney, and lung (2–5). Otherreported primary tumors causing metastatic biliary obstruction include malig-nant melanoma, lymphoma,gallbladder, ovary, duodenum, esophagus, liver,cervix, uterus, muscle, prostate, bone, and brain.

The possibility of metastatic tumor should be considered in all patients withobstructive jaundice, especially if a previous malignant lesion has been identi-fied. Improved imaging (MRI)and biopsy techniques (EUS with FNA) should behelpful in distinguishing primary and metastatic biliary cancer. In this article wewill review the characteristics of the common primary tumors causing metasta-tic biliary obstruction.

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sion, lymph nodes are involvedin 0% to 7% and in 15% to 30%of lesions involving the submu-cosa (6). Gastric cancer thatinvades the muscular propria iscalled advanced carcinoma.Once it reaches the serosa of thestomach it also spreads via theperitoneal cavity. The progres-sion of lymph node spread canbe categorized into three tiers.The first level, N1 nodes, areperigastric nodes (Figure 3A,groups 1–6) followed by N2nodes (Figure 3B, groups 7–11 )which are found along the celiacaxis and finally to the N3 nodes,which include the hepatoduode-nal ligament nodes, paraaorticnodes, and those around the origin of the middle colicand superior mesenteric arteries. This staging is the logicbehind the extensive local resections that have beendeveloped for surgical excision.

Obstructive jaundice is frequently present inpatients with advanced gastric carcinoma and is amongthe more common causes of malignant biliary obstruc-tion by metastatic cancer (4–7). Bile duct obstructionin advanced gastric carcinoma is predominantly due tometastatic lymphadenopathy in the hepatoduodenalligament around the level of the cystic duct(4). Stan-dard gastric surgery with lymph node dissection forgastric carcinoma does not remove N3 lymph nodesalong the hepatoduodenal ligament. Despite this,malignant obstruction after gastrectomy is rare occur-ring in only 1.4%–2.3 % of patients (4,6). Obstructivejaundice in these patients also can be due to benignpost-surgical causes. Imaging via endoscopic retro-grade cholangiography can be challenging, however,due to sugeries such as Billroth II reconstruction.

The treatment goal in patients with jaundice due toadvanced gastric carcinoma is palliation. Biliarydrainage can be accomplished with the placement ofplastic or expandable metallic stents with patency rates of three and eight months respectively. Themedian survival in these patients after biliary drainageis approximately two months (7). Anecdotal reports

PRACTICAL GASTROENTEROLOGY • SEPTEMBER 2004 27

A SPECIAL ARTICLE

Obstructive Jaundice Secondary to Metastatic Cancer

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Table 1Primary and secondary tumors associated with biliary tract obstruction.

Tumor Frequency %

PrimaryPancreas 80Bile Duct 5Ampullary 1Duodenum 1

Secondary (porta hepatis)Gastric 10–50Colon 20–40Melanoma 15Breast 10Lung 1Lymphoma 1

Secondary (pancreas)KidneyLung

Figure 1. Breast carcinoma metatatic to the duodenal wallresulting in biliary obstruction was diagnosed at ERCP. Thispatient survived over 4 years after endoscopic biliarydrainage, radiation therapy, and chemotherapy.


have shown some prolongation of survival with exter-nal and intraluminal radiation therapy in comparison tobiliary drainage alone (8). Hemoglobin and total serumbilirubin levels on admission have been shown to beindependent risk factors predicting survival (7). Someauthors therefore advocate reserving the use of metal-lic stents with radiation therapy for patients with a nor-mal hemoglobin level and a lesser degree of jaundice.

COLON CANCERColorectal cancer is the second leading cause of cancerdeaths in the United States. Over the past few years ourunderstanding regarding the genetics of colorectal cancerhas improved immeasurably. This has led to improve-ments in screening techniques as well as medical and sur-

gical therapy. Despite these advances, the overall five yearmortality from colorectal cancer remains around 40%.

The liver is the most common organ of distantmetastases from colorectal cancer. Patients withhepatic metastases have a median survival of six to 12months. Chemotherapy improves survival to 12 to 18months (9). Surgical resection of isolated liver metas-tases can offer long term survival and potentially acure in patients with disease limited to the liver.Repeat liver resection has been shown to be safe andeffective in the management of recurrent disease.

Jaundice is a common late feature of advanced coloncancer and usually signifies extensive hepatic metastasis.In this setting the onset of jaundice carries a grave prog-nosis with a median survival of approximately onemonth (10). There exists, however, a small subgroup of

A SPECIAL ARTICLE



A B C

Figure 2. Squamous cell carcinoma of the cervix metastatic to the porta hepatis. A) extrinsic compression of the biliary tree atthe porta hepatis. (B) endoscopic biliary drainage with a metallic stent. (C) histopathology of mass at porta hepatis confirmingmetastatic cervical carcinoma.

Figure 3A and 3B. N1 nodes and N2 nodes.

A B

patients whose jaundice is due to extrahepatic biliaryobstruction. Obstruction generally occurs from metasta-tic lymphadenopathy at the level of the common bileduct or higher in the porta hepatic compressing the com-mon hepatic duct. These periportal nodal metastases canoccur frequently without tumor in the liver. In this settingthe prognosis is more favorable with a median survivalof 23 months. Biliary bypass with gastrojejunostomy inpatients with extrahepatic obstruction from metastaticcolon cancer offers palliation of symptoms and prolongslife (3). This compares favorably to obstruction sec-ondary to pancreatic and periampullary cancer in whichthe survival rates are three to five months and are notlengthened by biliary drainage procedures.

Studies have shown that colorectal cancer canspread along intact basement membranes of biliaryepithelial cells (11). Metastatic colon cancer has the abil-ity to replace normal biliary mucosa making its diff e r e n-tiation from primary cholangiocarcinoma challenging.The clinical and radiographic findings of these two enti-ties can mimic one another. Distinction is made gener-ally by careful histologic examination. The clinical man-ifestation of this process is slow generally occurring 45months from the resection of the primary colonic carci-noma. Distinguishing metastatic colon cancer with intra-biliary growth from primary cholangiocarcinoma isimportant as it can have significant treatment implica-tions. Intrabiliary extension of metastatic colon cancerinto the hepatic ducts can be an unexpected obstacle forthe surgeon and may prohibit curative resection.

BREAST CANCERInvasive breast cancer is the most common malignancyin women and accounts for 15% of all cancer deaths.Improved screening has led to earlier detection withonly 1%–5% of patients having metastatic disease atpresentation. This coupled with improved treatment reg-imens have reduced overall breast cancer mortality.H o w e v e r, the rate of recurrence after initial therapyremains substantial. In patients treated for early stagedisease, the recurrence rate is the highest within the firstfive years but can occur up to thirty years after the diag-nosis. Although 15% to 40% of reoccurrences involvethe chest wall and axillary or supraclavicular nodes,breast cancer can metastasize to any organ in the body.

Breast cancer is generally thought to be a systemicdisease even at the time when initial treatment is started.Jaundice in patients with breast cancer is usually a resultof metastatic disease replacing liver parenchyma. Theonset of jaundice in this setting is an ominous sign witha mean survival of only one month (12). However, whileliver metastases can be a cause of jaundice in a breastcancer patient, there exists a largely unrecognized groupof patients whose jaundice is caused by obstruction ofextra-hepatic bile ducts by nodal metastases. The timeinterval between initial diagnosis and jaundice due toextrahepatic obstruction tends to be longer at a mean of16 months (2). Obstruction of the biliary tree has beenshown to occur anywhere between the porta hepatis andthe duodenal wall (2,12,13,14). This fact is importantbecause in these patients with normal liver function,relief of biliary obstruction using surgical bypass or bil-iary stenting extends survival to over a year (2,14). Fur-thermore, since breast cancer reduces with irradiation, itis preferable in this situation to achieve immediate reliefof jaundice by transhepatic intubation of the biliary treefollowed by radiation to the portal nodes (13).

Patients with extra-hepatic metastatic obstructionfrom breast cancer are being recognized increasingly andshould be treated vigorously, especially since patientswithout liver parenchymal involvement have a greatersurvival (median six months) than those with liverinvolvement (median 1.8 month) (2). The use of novelc h e m o t h e r a p y, hormonal therapy and irradiation in con-junction with biliary decompression may lead to evenmore prolonged survival and requires further study.

KIDNEYThe appearance of metastases many years afternephrectomy is a well-known feature of renal cell car-cinoma (RCC). Most recurrences appear two to threeyears after surgery, but late recurrences have beencommonly reported. In a study by McNichols, et al,11% of patients who survived 10 years or more afternephrectomy developed metastases(14). These clinicalobservations have led to the development of long-termsurveillance protocols for patients who have under-gone nephrectomy for RCC.

Renal cell carcinoma is the most common primaryneoplasm to metastasize to the pancreas, accounting


A SPECIAL ARTICLE



for 2% to 3% of all pancreatic malignancies(16). Pan-creatic metastasis of renal cell carcinoma is sympto-matic in only 50% of cases. These patients presentwith jaundice generally due to compression of theintrapancreatic portion of the common bile duct by ametastatic lesion in the head of the pancreas. The meaninterval between diagnosis of the primary RCC anddiscovery of pancreatic metastases has been shown tobe 9.7 years (17) This long disease-free interval sug-gests a slow biological tumor growth pattern.

The mode of spread of renal cell carcinoma to thepancreas is unclear. The possible routes discussed inthe literature include lymphatogenous and hematoge-nous spread. Lymphatogenous spread may occur by ret-

rograde lymph flow sec-ondary to infiltration of theretroperitoneal lymph nodesby the tumor. It also appearsthat there are some lym-phatic routes from the headof the pancreas to the dorsalside of the renal artery (18).Hematogenous spread mayoccur via portacaval shunts.

Diagnosis is generallyaided by the use of contrast-enhancing computed tomog-r a p h y. Due to their hypervas-cularity, metastatic RCClesions appear well-definedand hyperattenuated relativeto pancreatic tissue. This vas-cular appearance differs fromprimary pancreatic carci-noma which tend to be hypo-vascular lesions and there-fore non-enhancing on CT.The most reliable method ofdiagnosis remains pancreaticb i o p s y, however it carries ahigher risk of hemorrhage inRCC.

Survival of patients withmetastatic RCC in general isusually poor with a five-yearsurvival rate of 2.7% (19).

This suggests that RCC has both a rapid and slow type ofgrowth pattern. Growth is slow in most cases of RCC withlate metastases, particularly those with pancreatic metas-tases. Chemotherapy, hormonal therapy, and radiotherapyhave generally proved ineffective for primary renal cellcarcinoma or metastatic deposits. Despite the earlypromising results of immunotherapy, a complete responseoccurs in less than 15%, emphasizing that this is a diseasebest treated with complete resection of the primary andmetastatic lesions where possible. When metastatic dis-ease is limited to the pancreas, surgical resection hasimproved the five-year survival rate to 29%–35% (19,20).These results are better than the survival rates for those

A SPECIAL ARTICLE



Table 2

Interval Survival between 1° with

Study N dx and jaundice Treatment Treatment

GastricChu, et al 41 21.8 months (38) Biliary drainage: 70 days

(36) with PTC(1) with operative t-tube(1) with endoprosthesis

ColonWarshaw, et al 8 13 months (8) Biliary drainage: 18 months

(4) with surgical bypass(1) with t–tube(1) with PTC(2) with XRT

Riopel, et al 8 45 months (7) Surgical resection —BreastPopp, et al 7 40 months (1) Surgical bypass alone 17 months

(1) Surg + chemotherapy(1) Surg + radiation therapy(1) PTC + radiation therapy(3) Radiation therapy alone

Kopelson, et al 26 16 months (6) Radiation therapy alone 6 months(3) XRT + surgical bypass

+ chemo(7) Chemo + surgical bypass

KidneyGhavamian, et al 11 9.7 years Surgical resection 4.6 yearsHirota, et al 49 11 years Surgical resection 13 monthsLungJohnson, et al 5 — (5) Chemotherapy alone >12 months

with primary pancreatic cancers. For these reasons,aggressive surgical management of pancreatic metastasesdue to renal cell carcinoma is warranted. Excision of allmetastases evident on radiographs and during surg i c a lexploration should be attempted while preserving as muchfunction of the pancreas as possible.

LUNGLung cancer is currently the most common cause ofcancer mortality in the United States and throughoutthe world. Small cell lung cancer (SCLC) represents15% to 25% of all lung cancers and occurs almostexclusively in smokers. It is distinguished from non-small cell lung cancer by its rapid doubling time, highgrowth fraction, and the early development of metas-tases. Approximately 70 percent of patients presentwith overt metastatic disease at the time of diagnosis.Despite the relative chemosensitivity of SCLC,patients with extensive stage disease rarely enjoy pro-longed relapse-free survival.

Patients with metastatic small-cell lung cancer canpresent with jaundice. Jaundice is usually due to dif-fuse hepatic parenchymal involvement, but can also bea result of extrahepatic biliary obstruction from a pan-creatic metastasis. The former is associated with apoor prognosis with a mean survival of three months,while the latter has been shown to be chemosensitiveoffering rapid palliation and an improved survival ofover a year (21). The use of novel combinationchemotherapy and irradiation in conjunction with bil-iary decompression may lead to even more prolongedsurvival and requires further study.

CONCLUSIONMetastatic carcinoma is a recognized cause of malig-nant biliary obstruction. If obstructive jaundice occursin the setting of a previous malignancy, one muststrongly consider the cause as secondary to metastases.Biliary obstruction can be a result of a wide array ofmetastatic malignancies and can present at any level of the biliary tree. Interestingly, some groups ofpatients with metastatic biliary obstruction may have asurvival advantage when compared to patients withprimary malignant biliary obstruction. Although the

approach to biliary drainage is largely the same,metastatic biliary obstruction should be identifiedbecause of the impact on subsequent medical and sur-gical therapies. ■

References1. Stellato T, Zollinger R, Shuck J. Metastatic malignant biliary

obstruction. Am Surg, 1987;53:385.2. Kopelson G, Chu A, Doucette J, Gunderson L. Extra-hepatic bil-

iary tract metastases from breast cancer. Int J Radiat Oncol BiolPhys, 1980;6:497-504.

3. Warshaw A, Welch J. Extrahepatic biliary obstruction bymetastatic colon carcinoma. Ann Surg, 1978;188:593-597.

4. Papachristou D, Fortner J. Biliary obstruction after gastrectomyfor carcinoma of the stomach. Surg Gynecol Obstet,1978;147:401-404.

5. Lokich J, Kane R, Harrison D, McDermott W. Biliary tractobstruction secondary to cancer. J Clin Oncol, 1987;5:969-981.

6. Torii A, Sakai M, Inoue K, Yamabe H, Ueda S, Okuma M. Aclinicopathological analysis of early gastric cancer: retrospectivestudy with special reference to lymph node metastasis. CancerDetect Prev, 1994;18(6):437-441.

7. Chu K, Law S, Branicki F, Wong J. Extrahepatic biliary obstruc-tion by metastatic gastric carcinoma. J Clin Gastro, 1998;27(1):63-66.

8. Kim G, Shin H, Seong J, et al. The role of radiation treatment onthe management of extrahepatic biliary tract metastases from gas-tric carcinoma. Int J Radiat Oncol Biol Phys, 1994;28:711-717.

9. Silverman D, Murray J, Smart C, et al. Estimated median survivaltimes of patients with colorectal cancer based on experienceswith 9,745 patients. Am J Surg, 1977;133:289.

10. Jaffe B, Donegan W, Watson F, Spratt J. Factors influencing sur-vival in patients with untreated hepatic metastases. Surg GynecolObstet, 1968;127:1.

11. Riopel M, Klimstra D, Godellas C, Blumgart L, Westra W. Intra-biliary growth of metastatic colonic adenocarcinoma. Am J SurgPath, 1997;21(9):1030-1036.

12. Pappo I, Feigin E, Uziely B. Biliary and pancreatic metastases ofbreast carcinoma: is surgical palliation indicated? J Surg Oncol,1991;46:211-214.

13. Popp J, Schapiro R, Warshaw A. Extrahepatic biliary obstructioncaused by metastatic breast carcinoma. Ann Intern Med,1979;91:568-571.

14. Ellis M, Levey J, Endoscopic biliary drainage for breast carci-noma metastatic to the duodenum. American Journal of Gas -troenterology, 2003;98:S167.

15. McNichols D, Segura J, DeWeerd J. Renal cell carcinoma: long-term survival and recurrence. J Urol, 1981;126:17.

16. Roland C, van Heerden J. Nonpancreatic primary tumors withmetastasis to the pancreas. Surg Gynecol Obstet, 1989;168:345.

17. Ghavamain R, Klein K, Stephens D, et al. Renal cell carcinomametastatic to the pancreas: clinical and radiographic features.Mayo Clin Proc, 2000;75:581-585.

18. Nagakawa T, Konishi I, Ueno K, et al. A clinical study of lym-phatic flow in carcinoma of the pancreatic head area – peripan-creatic regional lymph node grouping. Hepatogastroenterology,1993;40:457.

19. Riches. Natural history of tumours of the unrinary tract. Can MedAssoc J, 1966;95:256.

20. Z’graggen K, Fernandez-del Castillo C, Rattner D, Sigala H,Warshaw A. Metastases to the pancreas and their extiration. ArchSurg, 1998;133:413-418.

21. Johnson D, Hainsworth J, Greco F. Extrahepatic biliary obstruc-tion caused by small-cell lung cancer. Ann Int Med, 1985;102:487-490.


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Obstructive Jaundice Secondary to Metastatic Cancer: · PDF fileObstructive Jaundice Secondary to Metastatic Cancer (continued from page 27) A B C Figure 2. Squamous cell carcinoma