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Year : 2014  |  Volume : 57  |  Issue : 1  |  Page : 105-108
Clear cell papillary cholangiocarcinoma: A case report with review of literature

Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra Pradesh, India

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Date of Web Publication17-Apr-2014


Clear cell papillary cholangiocarcinoma is a rare variant of intrahepatic cholangiocarcinoma with only nine reported cases in the literature. This tumor needs to be differentiated from clear cell variant of hepatocellular carcinoma and other metastatic clear cell carcinomas. This tumor is known to have better prognosis compared to conventional intrahepatic cholangiocarcinoma. Hence, it is important to correctly diagnose this entity and differentiate it from other histologic mimics. We describe clinical, histopathological, and immunohistochemical findings of one such rare case in a 66-year-old gentleman who was incidentally detected to have an intrahepatic tumor at routine ultrasound examination.A review of all the similar cases reported so far in the literature is also provided.

Keywords: Cholangiocarcinoma, clear cell variant, IHC

How to cite this article:
Khera R, Uppin SG, Uppin MS, Sundaram C. Clear cell papillary cholangiocarcinoma: A case report with review of literature. Indian J Pathol Microbiol 2014;57:105-8

How to cite this URL:
Khera R, Uppin SG, Uppin MS, Sundaram C. Clear cell papillary cholangiocarcinoma: A case report with review of literature. Indian J Pathol Microbiol [serial online] 2014 [cited 2021 Oct 25];57:105-8. Available from: https://www.ijpmonline.org/text.asp?2014/57/1/105/130914

   Introduction Top

Intrahepatic cholangiocarcinoma (ICC) represents about15% of primary liver cancers. The usual morphologic variants are adenosquamous, sarcomatoid, mucinous, mucoepidermoid, signet-ring cell, and squamous cell carcinoma. [1] Clear cell cholangiocarcinoma is a rare variant with only nine such cases reported in the literature so far. [2],[3],[4],[5],[6],[7],[8] The background and risk factors of the ICC clear cell variant are unknown. Unlike typical ICC, there is no report on the relevance of hepatitis and the prognosis is relatively good. Wehere report a case of clear cell type of ICC with special emphasis on immunohistochemical differentiation from other clear cell tumors and the importance of recognizing this rare entity. Extensive review of literature is also presented.

   Case Report Top

A 66-year-old asymptomatic man was incidentally found to have a mass in the liver at routine ultrasound examination.Contrast enhanced CT scan (CECT) of the abdomen showed a heterogeneously enhancing mass lesion in segment 6 of the liver [Figure 1]a-c. The alpha feto protein (AFP)level was 5.6 U/L. Patient received two cycles of chemoembolization with clinical diagnosis of hepatocellular carcinoma. The tumor did not respond to chemotherapy and a non-anatomic resection of liver with the tumor was carried out.On gross examination, the mass was measuring 12 × 7 × 5 cm.The cut surface of the mass was firm grey-pink with a central area of necrosis. The borders were infiltrative and the tumor was close to the capsule [Figure 1]d. Microscopic examination revealed a tumor comprised predominantly of papillary structures with thin fibrovascular cores [Figure 2]a. The cells lining these papillae were cuboidal to columnar with majority having clear cytoplasm and bland nuclei with focal stratification [Figure 2]b. Focal areas within the tumor showed tubular structures lined by similar clear cells [Figure 2]c and d. Areas of necrosis were also seen. Immunohistochemistry showed the tumor cells to be positive for Pan-CK, CK 7, CK 20, CK 19, and EMA [Figure 3]a-e. These cells were negative for AFP,CD10, HMB-45,Hepatocyte specific antigen (HSA), vimentin, CD56, alpha-inhibin, and CA19-9 [Figure 4]a-h. Based on the histopathologic and immunohistochemical findings, the tumor was diagnosed as intrahepatic cholangiocarcinoma, clear cell variant.
Figure 1: (a-c) CECT Abdomen showing persistent delayed enhancing lesion in right lobe of liver and (d) Cut surface of resected specimen showing greyish-pink colored tumor central yellowish area of necrosis

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Figure 2: (a and b) Sections showing papillary formations with fibrovascular cores lined by cuboidal to columnar cells with clear cytoplasm. The nuclei of these cells are fairly uniform. (H and E; AX40, BX100) (c and d) tubular structures lined by clear cells (H and E; CX40, DX100)

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Figure 3: Immunohistochemical findings of the tumor. The tumor cells are positive for (a) Pan CK, (b) CK 7, (c) CK 20, (d) CK 19, and (e) EMA (luminal aspect)

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Figure 4: Immunohistochemical findings of the tumor. The tumor cells are negative for (a) AFP, (b) CD10, (c) HMB45, (d) HSA, (e) vimentin (positive in stromal core but negative in tumor cells), (f) CD56, (g) alpha-inhibin, and (h) CA19-9

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   Discussion Top

Intrahepatic cholangiocarcinoma is an epithelial malignancy that originates in the intrahepatic bile duct epithelium. Most ICCs are adenocarcinomas showing a tubular pattern, while some show cords or papillary structures. [1] Clear cell variant is very rare with very few reported cases in the literature [Table 1]. There is no clear definition of histology and background disease for this rare entity. [8]

The clear cell variant of ICC is characterized by tubular structures, solid nests, and papillary structure comprised of cells with copious clear cytoplasm. [2],[6] This case showed predominantly papillary pattern with focal tubular pattern.

The clear cell change has been attributed to the presence of intracytoplasmic glycogen,mucin, or lipid based on electron microscopy or histochemistry. [4],[5],[6],[7] The clear cells in this case showed positivity for PAS that was lost after diastase pretreatment indicating the presence of intracellular glycogen.
Table 1: Reported cases of intrahepaticcholangiocarcinoma clear cell variant

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Papillary and clear cell features have been described in carcinomas of the thyroid, [9] female genital tract, [10],[11] breast, [12] urinary tract, [13] and lungs. [14] However, in most of the reported cases, exclusion of a metastatic renal cell carcinoma or carcinoma from another site was a crucial element in the diagnosis. A meticulous workup and sufficient follow-up are necessary before diagnosing an extra-renal primary clear cell carcinoma. For clear cell carcinomas involving the liver, it is necessary to differentiate whether the tumor is primary or metastatic,and if primary, whether it can be classified as HCC or ICC.

Immunohistochemistry is useful in such cases to rule out the other clear cell tumors. Hepatocellular carcinomas are usually negative for both CK7 and CK20. Moreover negativity for AFP and HSA ruled out the possibility of hepatocellular carcinoma in the present case.One of the diagnostically helpful and characteristic feature of clear cell renal cell carcinoma (RCC) is the presence of network of small thin-walled blood vessels, [15] which was absent in the present case. Negativity for CD10, vimentin and positivity for CK 7 and 20 ruled out the possibility of a metastatic renal cell carcinoma. In addition, radiological examination did not show any mass within the kidney.

Clear cell carcinoma has been described in pancreas as a very rare entity.Immunohistochemical findings of such tumors are currently unclear with variable expression of CK 7 and CK 20 and also of CK 8, 18, 19 in the reported cases. [16] Kim et al. [17] in their series of pancreatic carcinomas with clear cell features suggested that HNF1B was a useful biomarker to identify clear cell carcinomas, which could not be performed in the present case.

Metastasis from adrenocortical carcinoma which can also show clear cells should be considered in differential diagnosis.Immunohistochemically, the cells of adrenocortical neoplasms are immunoreactive for vimentin, synaptophysin, inhibin, and Melan-A (Mart-1; A103) and keratin. They are negative for epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), B72.3, and Lewis blood group antigens.The present case showed positivity for EMA and was negative for alpha-inhibin.

Clear cell carcinomas can also be seen in urinary tract, which is a very rare variant of urothelial carcinomas and also include clear cell adenocarcinoma of urinary bladder.Immunohistochemically, they show positivity for CK 7, CK 20, CK 8, CK 18, and CK 19. [18]

Above discussed possible primaries were excluded by radiological examination that did not reveal any mass in kidney, pancreas, adrenal, or bladder.

Haas et al. [7] described three such tumors with clear cell morphology and demonstrated expression of CD 56. In addition to cholangiocarcinomas, an association of CD 56 expression and clear cell phenotype has also been previously described for a minority of clear cell renal carcinomas and benign clear cell tumors of the lung (sugar tumor). This case showed negative staining with CD 56.

Clear cell change in the benign bile duct tumors has seldom been reported except for three cases of atypical bile duct adenomas, described by Albores. [6] Immunohistochemically, they showed similar reactivity to their malignant counterpart; the only reported difference was low Ki-67 (MIB-1) labeling (<10%) for bile duct adenomas compared to high labeling in ICCs (>50%). However, the clear cell variant of ICC has also been reported to show positivity of less than 5%. [7]

All the cases of clear cell variant of ICC reported in the literature so far showed CK 7+/CK 20- profile. Our case differed from the previously reported cases in that tumor cells were positive for both CK 7 and CK 20. Expression of both CK 7 and CK 20 has been reported in 43% cases of cholangiocarcinoma. [19] Rullier, et al. [20] studied 48 cases of cholangiocarcinoma and CK 20 was found to be positive in 70% of their cases.

ICC is said to have a poor prognosis because of its tendency to be diagnosed at a late stage and the absence of effective treatment. [21],[22] Clear cell variant ICC has been reported to have a good prognosis, except for one death with metastasis after hepatic resection, and one case that had not been operated on because of underlying diseases and died 14 months later. [4],[5],[6],[7] Our patient is free of disease at 18 months post-surgery.

   Conclusion Top

Recognition of clear cell variant of ICC is important both for pathologists and clinicians as this variant has been reported to have better prognosis as compared to conventional cholangiocarcinoma. However, further studies with longer follow-up are needed to reach to a definite conclusion in this regard.

   Acknowledgements Top

The authors would like to acknowledge Dr. N Bheerappa and Dr.Vijay Bada for their inputs.

   References Top

1.Nakanuma Y, Sripa B, Vatanasapt V, Leong AS, Ponchon T, Ishak KG. Intrahepatic cholangiocarcinoma. In: Hamilton SR, Aaltonen LA, editors. World Health Organization Classification of Tumours, Pathology and Genetics: Tumours of the Digestive System. Lyon: IARC Press; 2000. p. 173-80.  Back to cited text no. 1
2.Logani S, Adsay V. Clear cell cholangiocarcinoma of the liver is a morphologically distinctive entity. Hum Pathol 1998;29:1548-9.  Back to cited text no. 2
3.Adamek HE, Spiethoff A, Kaufmann V, Jakobs R, Riemann JF. Primary clear cell carcinoma of noncirrhotic liver: Immunohistochemical discrimination of hepatocellular and cholangiocellular origin. Dig Dis Sci 1998;43:33-8.  Back to cited text no. 3
4.Tihan T, Blumgart L, Klimstra DS. Clear cell papillary carcinoma of the liver: An unusual variantof peripheral cholangiocarcinoma. Hum Pathol 1998;29:196-200.  Back to cited text no. 4
5.Falta EM, Rubin AD, Harris JA. Peripheral clear cell cholangiocarcinoma: A rare histologic variant. Am Surg 1999;65:592-5.  Back to cited text no. 5
6.Albores-Saavedra J, Hoang MP, Murakata LA, Sinkre P, Yaziji H. Atypical bile duct adenoma, clear cell type: A previously undescribed tumor of the liver. Am J SurgPathol 2001;25:956-60.  Back to cited text no. 6
7.Haas S, Gütgemann I, Wolff M, Fischer HP. Intrahepatic clear cell cholangiocarcinoma: Immunohistochemicalaspectsin a very rare type of cholangiocarcinoma. Am J SurgPathol 2007;31:902-6.  Back to cited text no. 7
8.Toriyama E, Nanashima A, Hayashi H, Abe K, Kinoshita N, Yuge S, et al. A case of intrahepatic clear cell cholangiocarcinoma. World J Gastroenterol 2010;16:2571-6.  Back to cited text no. 8
9.Dickersin GR, Vickery AL, Smith SB. Papillary carcinoma of the thyroid,oxyphil cell type. "clear-cell" variant: A light- and electron-microscopic study. Am J Surg Pathol 1980;4:501-9.  Back to cited text no. 9
10.Doshi N, Tobon H. Primary clearcell carcinomas of the ovary. An analysis of 15 cases with review of the literature. Cancer 1977;39:2658-64.  Back to cited text no. 10
11.Nordqvist SR, Fidler WJ, Woodruff J M, Lewis JL. Clearcell adenocarcinoma of the cervix and vagina. A clinicopathologic study of 21 cases with and without a history of maternal ingestion of estrogens. Cancer 1976;37:858-71.  Back to cited text no. 11
12.Hull MT, Warfel KA. Glycogen-rich clear cell carcinomas of the breast. A clinicopathologic and ultrastructural study. Am J Surg Patho1986;10:553-9.  Back to cited text no. 12
13.Cantrell BB, Leifer G, DeKlerk DP, Eggleston JC. Papillary adenocarcinoma of the prostatic urethra with clear-cell appearance. Cancer 1981;48:2661-7.  Back to cited text no. 13
14.Gaffey MJ, Mills SE, Askin FB, Ross GW, Sale GE, Kulander BG, et al. Clear cell tumor of the lung. Aclinicopathologic, immunohistochemical, and ultrastructural study of eight cases. Am J Surg Pathol 1990;14:248-59.  Back to cited text no. 14
15.Grignon DJ, Eble JN, Bonsib SM, Moch H. Clear cell renal cell carinoma. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. World Health Organization Classification of Tumours. Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press; 2004. p. 23-5.  Back to cited text no. 15
16.Lee HY, Lee DG, Chun K, Lee S, Song SY. Clear cell carcinoma of the pancreas-a case report and review of the literature. Cancer Res Treat 2009;41:175-81.  Back to cited text no. 16
17.Kim L, Liao J, Zhang M, Talamonti M, Bentrem D, Rao S, et al. Clear cell carcinoma of thepancreas: Histopathologic features and a unique biomarker: Hepatocyte nuclear factor-1 beta. Mod Pathol 2008;21:1075-83.  Back to cited text no. 17
18.Kramer MW, Abbas M, Pertschy S, Becker JU, Kreipe HH, Kuczyk MA, et al. Clear-cell variant urothelial carcinoma of the bladder: A case report and review of the literature. Rare Tumors 2012;4:e48.  Back to cited text no. 18
19.Chu P, Wu E, Weiss LM.Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: A survey of 435 cases. Mod Pathol 2000;13:962-72.  Back to cited text no. 19
20.Rullier A, Le Bail B, Fawaz R, Blanc JF, Saric J, Bioulac-Sage P. Cytokeratin 7 and 20 expression in cholangiocarcinomas varies along the biliary tract but still differs from that in colorectal carcinoma metastasis. Am J Surg Pathol 2000;24:870-6.  Back to cited text no. 20
21.Nakanuma Y, Sasaki M, Ikeda H, Sato Y, Zen Y, Kosaka K, et al. Pathology of peripheral intrahepatic cholangiocarcinoma with reference to tumorigenesis. Hepatol Res 2008;38:325-34.  Back to cited text no. 21
22.Kitajima K, Shiba H, Nojiri T, Uwagawa T, Ishida Y, Ichiba N, et al. Intrahepatic cholangiocarcinoma mimicking hepatic inflammatory pseudotumor. J Gastrointest Surg 2007;11:398-402.  Back to cited text no. 22

Correspondence Address:
Megha S Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Andhra Pradesh - 500 082
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.130914

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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