Tumors In The Liver - Diagnostic Problems
Case 8 -
Intraductal Cholangiocarcinoma (Biliary Papillomatosis)
Linda D. Ferrell, M.D.
Wendy L. Frankel, M.D.
54 year old woman with cirrhosis and a history of
ulcerative colitis. She presented for pre-liver transplant evaluation and abdominal CT demonstrated
marked hepatomegaly and severe dilation of biliary tree, suggestive of obstruction of the common hepatic
duct. At gross examination, multiple ducts were found to contain papillary excrescences.
Case 8 - Figure 1 - Intraductal paillary proliferation of columnar epithelium and adjacent fibrotic liver, low power
Case 8 - Figure 2 - Intraductal papillary proliferation (arrow), medium power
Case 8 - Figure 3 - Severely dysplastic columnar epithelium (carcinoma in-situ) with mitotic figures (arrow), high power
Intraductular papillary proliferation of columnar
epithelium within the liver, low power.Severely dysplastic columnar epithelium (carcinoma in-situ), high
Diagnosis- Intraductal Cholangiocarcinoma (Biliary Papillomatosis)
Clinical features. Cholangiocarcinoma typically occurs in the elderly, with both
sexes affected equally. There is no association with cirrhosis in general, although patients with
primary sclerosing cholangitis do have a significantly increased risk for developing this tumor. The
tumor is most prevalent in Southeast Asia, where liver fluke infestation with Clonorchis and Opisthorchis is high. Other possible
risk factors include congenital anomalies of the biliary tree such as von Meyenberg complexes,
choledochol cyst, Caroli's disease, and anomalous arrangements of the pancreatic and common bile ducts;
hepatolithiasis, and thorotrast. The presenting systems depend on the location of the tumor, with four
locations often designated separately as peripheral (intrahepatic), hilar, extrahepatic, or intraductal.
The peripheral type usually remains asymptomatic until the tumor is in a late stage; the hilar,
extrahepatic, and intraductal types present with signs of obstruction. Prognosis for the peripheral,
hilar, and extrahepatic types is dismal, usually because the disease has reached an advanced stage by the
time it is diagnosed rendering surgical removal difficult if not impossible; however, the length of
survival may be increased when tumor-free surgical margins can be attained.
The intraductal papillary type, also known as intraductal papillomatosis, biliary
papillomatosis, or intraductal papillary tumor generally involves extensive areas of the intrahepatic
and/or the extrahepatic bile ducts, with preference for the latter. Men are more affected than woman at
about a 2.4 to 1 ratio, and patients are usually middle to older age (mean age 60). Although
histologically benign in most cases, the lesion is generally considered in the clinical setting as a
borderline or low grade malignant tumor due to its tendency to recur, its multicentricity, its ability to
undergo malignant transformation and metastasize (although only rarely), and its significant morbidity
and mortality due to its intraductal growth pattern and subsequent complications such as recurrent bouts
of cholangitis and obstructive jaundice, as well as episodes of sepsis and hemobilia. Even with invasion
present, the incidence of metastases is still much less than the other forms of cholangiocarcinoma. In
spite of the fact that most of these intraductal papillary tumors may not become invasive or metastasize,
due to the multicentric nature of the lesions, the possibility of a cure is unlikely without liver
transplantation. Even then, the lesion may possibly recur in the extrahepatic ducts.
Gross features. The peripheral, hilar, and extrahepatic variants of
cholangiocarcinoma are usually firm, white-tan lesions due to dense fibrous stroma within the lesions.
In contrast, the intraductal papillomatous variants are soft, polypoid or cauliflower-like lesions that
protrude into the large ducts and cause ductal dilatation; these lesions are typically multifocal.
Microscropic features. The peripheral, hilar, and extrahepatic variants are
adenocarcinomas that typically have a significant component of dense fibrous stroma. The tumors often
are well-differentiated, with tubular gland formation and minimal cytologic changes; however, foci of
atypia with increased nuclear:cytoplasmic ratios, prominent nucleoli, variation in nuclear size, and loss
of polarity will often be seen. Features that have been noted to support the diagnosis of carcinoma over
a benign hyperplastic or reactive process include the formation of intracytoplasmic lumina or a focal
cribriform pattern. In addition, multilayering of nuclei and intraluminal cellular debris can also be
helpful features to suggest the possibility of malignancy.
Intraductal papillomatosis, or biliary papillomatosis (and its invasive form, papillary
adenocarcinoma) grows into the duct lumina as a multifocal, papillary lesion. The architecture consists
of papillae lined by columnar epithelial cells supported by a delicate fibrovascular stroma. The nuclei
are round to oval, and basally located, without significant multilayering. The cytoplasm is generally
abundant and mucinous, but clear, or oncocytic differentiation as well as intestinal metaplasia with
goblet cell change can also be present. Mitotic figures are infrequent. Frank invasion of the stalk and
underlying periductular tissues must be seen for a diagnosis of adenocarcinoma.
Special studies. Immunoperoxidase and mucin staining can be used to differentiate
cholangiocarcinoma from HCC as described previously (see above). However, differentiation from
metastatic adenocarcinoma can be very problematic if there is no known primary at another site. An
adenocarcinoma composed of tall columnar cells with an adenomatous pattern, focal cribriform pattern,
lack of intraepithelial mucin, and luminal necrotic debris is more suggestive of metastatic colonic
carcinoma than primary cholangiocarcinoma. The latter usually shows more intraepithelial mucinous
differentiation or is composed of glands lined by low-columnar to cuboidal cells. Cytokeratin profiles
for types 7, 19, and 20 have also shown to be helpful in differentiating primary from metastatic
leisons. The cholangiocarcinoma is generally CK7 and 19 positive, 20 negative, while metastatic
colorectal adenocarcinoma is CK7 negative in about 90% of cases, but usually positive for either 19 or 20
30,31. Another marker that could be helpful is Lex, which often shows cytoplasmic and
membranous reactivity in cholangiocarcinoma but only cytoplasmic reactivity in metastatic carcinoma. In
contrast, Leu-M1 and B72.3 are more likely to show the opposite pattern with cytoplasmic staining in
cholangiocarcinoma and cytoplasmic and membranous staining in metastatic adenocarcinoma.
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TABLE 5: Bile Duct Lesions
| ||BDA ||VMC ||BDP ||Cystadenoma ||Cholangiocarcinoma ||Metastatic adeno|
|Incidental ||yes ||yes ||no ||no ||no ||no|
|Location ||subcap ||subcap || || || |
|Multiple ||no ||yes ||yes ||no ||no ||yes|
|Size ||<0.5 cm ||<0.5 cm || || || |
|Border ||regular ||regular ||irregular || ||irregular ||irregular|
|Cytoplasm ||mucin ||bile || || ||mucin ||mucin|
|Mitosis ||no ||no ||rare ||no ||yes ||yes|
|Atypia ||no ||no ||rare ||no ||yes ||yes|
|Shape ||round ||ectatic ||round ||multicystic || |
|Lymphs ||yes ||no ||no,neuts ||no ||no ||no|
BDA=bile duct adenoma, VMC=von Meyenberg's complex, BDP=bile duct proliferation