Intrahepatic Cholangiocarcinoma With Sarcomatous Transformation: Demonstrating the Transition Zone

ABSTRACT

Intrahepatic cholangiocarcinoma with sarcomatous transformation (ICC-S) is a rare, aggressive neoplasm with epithelial and sarcomatous elements. We report a rapid progression of ICC-S in a 66-year-old woman. Initially, a seemingly benign 8-cm mass was observed. However, the tumor doubled to 16 cm within 3 months during follow-up. Partial hepatectomy confirmed ICC-S and histopathological examination showed cytokeratin 7 and vimentin positivity in epithelial and sarcomatous components, respectively. An analysis of transition zone indicated epithelial–mesenchymal transition as a mechanism for sarcomatous transformation. We provide the first detailed immunohistochemical analysis of the transition zone in ICC-S, highlighting epithelial–mesenchymal transition's role in pathogenesis.

INTRODUCTION

Intrahepatic cholangiocarcinoma (ICC) is the second most prevalent primary liver cancer.¹ ICC with sarcomatous transformation (ICC-S) is a rare variant with unclear pathogenesis, differing from sarcomatous transformation of hepatocellular carcinoma associated with transcatheter arterial chemoembolization.^2,3

There are 3 hypotheses regarding the ICC-S development (Figure 1). First, there is sarcomatous transdifferentiation, referred to as epithelial–mesenchymal transition (EMT).⁴ In this theory, direct transformation of the epithelial component into a sarcomatous form is responsible for ICC-S formation. Second, there is biphasic transdifferentiation, where malignant pluripotent stem cells concurrently differentiate into epithelial and sarcomatous components.⁴ Finally, sarcomatous redifferentiation is considered, wherein sarcomatous components arise from redifferentiation multipotent, undifferentiated cells derived from the epithelial carcinoma cells.⁴ Despite these theories, few studies have investigated the pathogenesis of this rare tumor.

Figure 1.

Three proposed mechanisms of sarcomatous transformation of intrahepatic cholangiocarcinoma. (A) Epithelial–mesenchymal transformation, (B) biphasic transdifferentiation, and (C) sarcomatous redifferentiation.

We present a rapidly progressing case of ICC-S with the first immunohistochemical analysis of the transition zone.

CASE REPORT

A 66-year-old woman presented with an unpleasant upper abdominal sensation. Ultrasonography demonstrated a large mass in the left hepatic lobe (S3). Contrast-enhanced computed tomography revealed an ovoid 8.5-cm mass suggestive of hepatic hemangioma. During the arterial phase, peripheral contrast enhancement was present, with an additional finding suggestive of hemorrhage (Figure 2). She had no significant medical or family history of hepatic disorders and was referred to our department.

Figure 2.

Computed tomography findings during the arterial phase (A) at initial presentation, (B and C) at revisitation 3 months later.

On admission, a physical examination revealed a well-appearing woman in no acute distress. Laboratory examinations were unremarkable with negative serologic testing for hepatitis B and C. Tumor markers (alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 19-9) were normal. The patient was classified as Child-Pugh B, and hemangioma with intratumor bleeding was suspected (Figure 2). Partial hepatectomy was scheduled 3 months later upon the patient's request.

Three months later, the patient presented with malaise, abdominal tension, and lower extremity edema. The contrast-enhanced computed tomography revealed that the tumor had increased to 16 cm (Figure 2). Although the initially discovered segment of the tumor demonstrated contrast enhancement during the arterial phase, the newly formed tumor segments were hypovascular without enhancement (Figure 2), with the lateral segmental artery in middle of the tumor (Figure 2). While the tumor protruded outside of the liver capsule, there was no sign of metastases or peritoneal seeding. Partial hepatectomy was performed as planned, resulting in complete tumor resection with clear surgical margins.

Macroscopically, the specimen was cream-white and 160 × 120 × 170 mm in size (Figure 3). The cut plane was smooth and glossy. Microscopically, the tumor comprised both sarcomatous and epithelial components with a transition zone between the 2 components (Figure 3). The epithelial component exhibited differentiated ductal structures (Figure 3). The transition zone contained poorly differentiated epithelial cells with clear vacuoles (Figures 3 and 4). The sarcomatous component was densely populated with pleomorphic, spindle-shaped cells with eosinophilic vacuoles and nuclei with prominent irregularities (Figure 3).

Figure 3.

Macroscopic and microscopic findings of the tumor demonstrating (A) macroscopic specimen, (B) epithelial component of the tumor, (C) undifferentiated epithelial component with clear cells, and (D) sarcomatous component.

Figure 4.

The transition area between epithelial and sarcomatous components. The left portion demonstrates the undifferentiated epithelial cells, and the right portion demonstrates the sarcomatous region. The samples were stained using (A) hematoxylin and eosin staining, (B) cytokeratin 7, and (C) vimentin.

Immunohistochemically, highly differentiated epithelial cells were diffusely positive for pan-cytokeratin, cytokeratin (CK) 7, and CK19 and negative for vimentin. The undifferentiated epithelial cells in the transition zone were positive for both CK7 and vimentin (Figure 4). The spindle-shaped cells were diffusely positive for vimentin but negative for CK7. All components of the tumor tested negative for AFP, CD34, CD68, CDK4, hepatocyte, HMB45, HNFIβ, MDM2, PAX8, and TTF1.

Despite an uneventful postoperative course, the patient returned 2 months later with lower abdominal fullness. Computed tomography scans revealed a 15.5-cm hypodense peritoneal mass and multiple lung nodules, indicating metastases. Needle biopsy confirmed ICC-S. Despite chemotherapy with doxorubicin and ifosfamide, the patient died 4 months postoperatively.

DISCUSSION

ICC-S is a rare variant of ICC with a poor prognosis. Despite several existing reports on this rare tumor, its pathogenesis has not been elucidated, with little attention to the transition zone. We report the first detailed immunohistochemical analyses of the transition zone with compelling evidence of EMT as a cause of sarcomatous transformation.

EMT is a mechanism of sarcomatous changes in epithelial tumor components, often associated with increased tumor cell motility, invasiveness, and resistance to apoptosis.^4,5 In our case, an undifferentiated transition zone bridged the cholangiocarcinoma and sarcomatous regions, supporting EMT as the underlying pathogenesis (Figure 1). Morphologically, the transition zone displayed dedifferentiated clear cells, which transitioned into the sarcomatous component. Immunohistochemistry revealed coexpression of epithelial and mesenchymal markers within the transition zone, congruent with the morphological characteristics. On the other hand, the biphasic differentiation theory proposes formation of ICC-S from a common precursor cell, such as a hepatic progenitor cell or mesenchymal stem cell. However, the presence of a transition zone with coexpressed markers argues against a separate origin for the epithelial and sarcomatous elements. Furthermore, the absence of CD34 expression, a marker of precursor cells, argues against the biphasic differentiation theory.⁶

Although limited to cell lines, a few studies have investigated the EMT in ICC-S.^7,8 One study demonstrated upregulation of EMT-associated antigens (VIM, TWIST1) in ICC-S cell lines compared with ICC cell lines, suggesting EMT as a likely mechanism of ICC-S formation.⁷ In addition, ICC-S cell lines exhibited higher rates of p53 mutations and reduced Fas/FasL expression compared with ICC cell lines.⁸ However, such findings have not been validated clinically, and no genetic analyses were performed in our case.

A systematic PubMed search revealed a paucity of literature on this rare tumor, with many reports overlooking the transition zone. Three case reports presented immunohistochemical samples of the border between the epithelial and sarcomatous components.^9–11 Yugawa et al reported the border of 2 components without a transition zone, suggesting biphasic transdifferentiation (Figure 1).¹⁰ Two other reports reported intermingling of 2 components without detailed pathological analysis.^9,11 In addition, 4 studies reported the transition zone with hematoxylin–eosin staining, although no immunohistochemical data were available.^12–15 Specifically, 2 reports illustrated areas of direct transition between the 2 components suggestive of EMT (Figure 1).^14,15 The 2 other reports did not provide detailed description of the border.^12,13 The lacking literature on the transition zone highlights a significant gap in our understanding of the pathogenesis of ICC-S.

Future studies on the transition zone are warranted to further elucidate the pathogenesis of this rare tumor type.

DISCLOSURES

Author contributions: Conception and design of the study: T. Shimoda, K. Takahashi, Acquisition and analysis of data: K. Takahashi, K. Asayama, R. Matsuoka, T. Oda, Drafting the manuscript or figures: T. Shimoda, K. Takahashi, K. Asayama. Article guarantor: K. Takahashi.

Financial disclosure: None to report.

Previous presentation: This work was presented at the 78th General Meeting of the Japanese Society of Gastroenterological Surgery; July 14, 2023; Hakodate, Japan.

Informed consent was obtained for this case report.