Intrahepatic sarcomatoid cholangiocarcinoma

Abstract

Sarcomatoid carcinoma is a rare tumour composed of intermingled malignant epithelial and mesenchymal cells, and it has been reported in various organs including the liver. Sarcomatoid cholangiocarcinoma (CCC) is an extremely rare liver primary tumour. Here, we report a case of an elderly man who was admitted to our hospital after head trauma. He performed a head CT that diagnosed cerebral metastasis. On abdominal CT, he presented a 10×8×9 cm-sized hypodense liver mass in the VII and VIII segments, with peripheral enhancement. Histological and immunohistochemical examination of the tumour showed a malignant neoplasm with both carcinomatous and sarcomatous components and positive expression of cytokeratin and vimentin antibodies. The patient was diagnosed with intrahepatic sarcomatoid CCC at an advanced stage and died 45 days after the diagnosis. We emphasise the importance of immunohistochemistry which may provide a clue to proper diagnosis.

Background

Epithelial tumours with sarcomatoid changes are unusual neoplasms and have been reported in various sites including the upper digestive tract, lung, pancreas, skin, breast, thyroid, uterus, urinary tract and gallbladder.^{1 2} The WHO Classification has applied this term to all tumours showing morphological and/or immunological evidence of both malignant epithelial and mesenchymal differentiation.³

Sarcomatoid cholangiocarcinoma (CCC) is an extremely rare primary liver tumour, and its pathogenesis has not yet been thoroughly clarified. Several hypotheses have been proposed to explain the intermingling of epithelial and mesenchymal malignancies namely biphasic differentiation from pluripotent stem cells and redifferentiation of immature multipotent carcinoma cells transformed from carcinoma cells.⁴ Extremely rare cases of alpha-fetoprotein (AFP)-producing CCC reinforce these complex pathogeneses.⁵ The prevalence of sarcomatoid transformation was observed in about 4.5% of surgical and autopsied cases of intrahepatic CCC.^{1 6} Another sarcomatoid carcinoma primarily occurring in the liver is sarcomatoid hepatocellular carcinoma (HCC), which was reported in about 3.9% to 9.4% of HCC autopsy cases and may be associated with preoperative anticancer treatment such as transcatheter arterial chemoembolisation, radiofrequency ablation or percutaneous ethanol injection.^{1 6 7}

Intrahepatic sarcomatoid CCC should be distinguished from carcinosarcoma and CCC with sarcomatoid transformation, even if they all share the expression of both epithelial and mesenchymal features.⁸ In fact, the first one has epithelial and mesenchymal features expressed in the sarcomatous component of the tumour, whereas the second one has only mesenchymal features and the latter one only epithelial features expressed in the sarcomatous component.⁸

The diagnostic difficulty should be kept in mind especially in needle biopsy specimens. Immunohistochemistry may then provide a clue to proper diagnosis.

We report a case of intrahepatic sarcomatoid CCC and illustrate the difficulties in diagnosing this type of tumour.

Case presentation

An elderly man was admitted to the hospital with head trauma, due to a fall. A head CT was performed and demonstrated an enlarged left parieto-occipital mass of 35 mm in diameter with perilesional brain oedema, characterised as metastasis. On admission, the patient was fully awake, mobile and oriented to place and time. He did not have any previous symptoms. On physical examination, there were no abnormal findings. He had a history of arterial hypertension, hypercholesterolaemia, heavy cigarette smoking and inactive hepatitis B. No relevant family history was known.

The laboratory data were as follows: haemoglobin 12.4 g/dL (normal, 13–17 g/dL), international normalised ratio 1.21, total protein 6.5 g/dL (normal, 6.6–8.3 g/dL), albumin 3.7 g/dL (normal, 3.5–5.2 g/dL), total bilirubin 0.4 mg/dL (normal, 0.3–1.2 mg/dL), glutamic oxaloacetate transaminase 20 U/L (normal, <35 U/I), glutamic pyruvic transaminase 15 U/L (normal, <45 U/L), alkaline phosphatase 113 U/L (normal, 40–150 U/L) and AFP 1753 ng/mL (normal, <8.6 ng/mL). Serum carbohydrate antigen (CA) 19.9, CA 125 and carcinoembryonic antigen were within normal limits. Antibodies to both the core and surface antigens of hepatitis B virus were positive; hepatitis C antibody was negative. Thoracic, abdominal and pelvic CT were performed, being the liver studied without contrast, in arterial, portal and late phase. Upper abdominal CT examination revealed a 10×8×9 cm-sized heterogeneous and hypodense liver mass in the VII and VIII segments, with peripheral enhancement on the arterial phase and a slightly progressive contrast enhancement from the periphery to centre in portal and late phase (figure 1). The large area in the centre of the lesion that showed no contrast enhancement is compatible with necrotic changes. Thoracic CT demonstrated multiple bilateral lung nodules compatible with metastatic lesions (the largest one with 14 mm of diameter) and right hilar adenopathies.

Figure 1.

Axial CT images: on precontrast images (A), the lesion presents as a bulky hypodense mass in the right liver lobe; arterial phase (B) reveals peripheral areas of enhancement, and slight progressive centripetal enhancement in portal (C) and late (D) phases. The large area in the centre of the lesion that showed no contrast enhancement is compatible with necrotic changes.

A percutaneous needle biopsy of the tumour was performed. Histological examination showed a malignant tumour with a carcinomatous and a sarcomatous component, without cirrhosis. The latter was composed of pleomorphic spindle cells with prominent nucleoli (figure 2). The tumour cells reacted positively with cytokeratin 7 (CK7) (figure 3) and vimentin and reacted negatively with cytokeratin 20 (CK20) and hepatocyte paraffin 1 (Hep Par 1). It was then classified as sarcomatoid CCC, based on histological and immunohistochemical findings.

Figure 2.

Microscopic examination revealed spindle-shaped cells with round pleomorphic nuclei (black arrow), with invasion of the adjacent liver parenchyma (blue arrow). This microscopic section was photographed at x100 magnification and stained with H&E.

Figure 3.

Immunohistochemistry with the antibody to CK7 shows strong reactivity with all spindle tumour cells (black arrow) and negativity in the adjacent liver parenchyma (blue arrow). This microscopic section was photographed at x100 magnification.

Outcome and follow-up

The patient was categorised on stage IVB (T2b N1 M1) and was given dexamethasone for brain metastasis with oedema. As prognosis was extremely poor, he was not eligible for chemotherapy or radiation therapy and received palliative care. He died of hospital-acquired pneumonia 45 days after diagnosis.

Discussion

Intrahepatic sarcomatoid CCC is a rare but aggressive malignancy with a very poor prognosis.⁸ To the best of our knowledge, only 27 cases of sarcomatoid CCC have been described in the English language literature as case reports or series.^6–15 Three of them were reported in patients from Europe.^{1 9 10} The majority of the tumours are diagnosed in an advanced stage, mostly accompanied with abdominal pain as the only presenting symptom.^{1 6} It affects mostly adults in the seventh decade of age, with a slightly male predominance (55.6% of the cases).^6–15

Regarding our case report, the patient had no previous symptoms and had normal liver biochemistry with high serum AFP levels. The laboratory data were normal and not disease specific. This was consistent with previous reports, except for the serum AFP level which is usually negative or low.^{2 6} According to one study, only 6.4% of CCC patients show serum AFP elevation of more than 1000 ng/mL leading to the suggestion that CCC may originate from hepatic stem cells that underwent malignant transformation.^{5 16} An increased serum CA 19.9 level was present in 51.8% of the patients.^6–15 Positivity for the hepatitis C antibody and the hepatitis B surface antigen was confirmed in 14.8% and 7.4% of the cases, respectively.^6–15 3.7% of the cases had cirrhosis.^6–15

Abdominal CT revealed a bulky liver mass with enhancement of the periphery, which is difficult to differentiate from ordinary CCC.^{8 10} The same CT features were described in previous reports with a mean tumour diameter of 9.5 cm.^{2 6–15}

On transcutaneous needle biopsy of our case, we could sample the carcinomatous and sarcomatous components of the tumour. These findings combined with the immunohistochemical study confirmed the diagnosis. Vimentin, a specific marker for cells of mesenchymal origin, can be coexpressed with cytokeratin in a number of epithelial cell types and their corresponding tumours (endometrium, thyroid, gonadal epithelial cells, renal tubules, adrenal cortex, lung, salivary gland, hepatocytes and bile duct).¹⁷ It had been suggested that a variety of high-grade epithelial tumours may acquire the expression of vimentin.¹⁷ The immunoreaction to vimentin in the epithelium-derived tumour may reflect a sarcomatous transformation process and the cytokeratin staining suggests that transformed sarcomatous carcinoma cells retain some phenotype of carcinoma cells.^{13 14 17} When used in a panel of antibodies, Hep Par 1, a marker of hepatocytes, increases diagnostic yield.¹⁷ It provides useful diagnostic information in distinguishing HCC from CCC and metastatic carcinoma in the liver.¹⁷ In this case, the negative staining for Hep Par 1 combined with CK7 immunoexpression, specific for biliary epithelium, was in favour of a cholangiocellular rather than a hepatocellular origin.¹⁷ The negative staining for CK20 excluded the diagnosis of metastasis from the gastrointestinal tract.¹⁷ Other markers to distinguish HCC from CCC and metastatic carcinoma, such as AFP, are of limited use.¹⁷ Some authors reported also cases of combined HCC and CCC which retain features of both tumours and their characteristic immunophenotype.¹⁸

This case illustrates the difficulty in establishing an early diagnosis of this rare entity with silent and aggressive nature. Caution should be used in interpretation of the immunohistochemical staining as small biopsies such as needle cores may produce false negative results.¹⁷ Such diagnostic fallacy can happen in case the specimens only contain the sarcomatous portion of the tumour, thus interpreting it wrongly as primary sarcoma.⁹ In this case, the immunohistochemistry plays an important role by helping in the recognition of the cholangiocarcinomatous nature of the tumour.

The poor prognosis can be attributed to aggressive intrahepatic spreading and frequent metastasis of sarcomatous cells, as identified in our case report.²

In 14 of the 27 patients (51.8%), by the time of diagnosis, the tumour had invaded the adjacent organs or metastasised to distant organs.^6–15 Patients achieved a 40% survival of only 6 months.^6–15 Mean survival time after diagnosis was 1.9 months without surgery (ranging from 0 to 3.8 months) and 11.3 months with surgery (ranging from 1.1 to 48 months).^6–15 In two cases, there was no information about the outcome.^6–15 These poor results suggest early microscopic metastatic seedlings prior to surgery. Compared with ordinary CCC, prognosis was reportedly worse.¹³

The effectiveness of radio and chemotherapy remains unclear.^{2 8} Early detection and radical surgery with careful follow-up would be necessary for patients of CCC with sarcomatous changes to help improve the prognosis.^{6 8}

In conclusion, intrahepatic sarcomatoid CCC is a rare and aggressive tumour. Since clinical, laboratorial and imagiological findings are not disease specific, diagnosis should be done with careful interpretation of histopathological examination. Because of its higher incidence of metastasis, the prognosis is much poorer compared with other malignant solid liver lesions.¹³ Radical surgery at an early disease stage is the only chance for long-term survival. Furthermore, we emphasise the importance of molecular genetic studies to provide insight into the histogenesis of this tumour that might have implications for new treatment options.

Learning points.

• Intrahepatic sarcomatoid cholangiocarcinoma is a rare but aggressive malignancy.

• The diagnosis is based on histological and immunohistochemical findings.

• The cytokeratin immunoexpression, specific for biliary epithelium, is diagnostically the most important finding.

• Early detection and radical surgery would be necessary to help improve the very poor prognosis.