J Gastrointest Canc (2012) 43 (Suppl 1):S139–S144 DOI 10.1007/s12029-011-9326-5
CASE REPORT
Hepatoid Adenocarcinoma of the Gallbladder Case Report and Literature Review Anastasios J. Karayiannakis & Stylianos Kakolyris & Alexandra Giatromanolaki & Nikos Courcoutsakis & Helen Bolanaki & Leonidas Chelis & Efthimios Sivridis & Constantinos Simopoulos
Published online: 22 September 2011 # Springer Science+Business Media, LLC 2011
Introduction
Case Report
Hepatoid adenocarcinoma (HAC) is a rare tumor consisting of three distinct patters, solid, tubular and trabecular, with morphological and functional features resembling hepatocellular carcinoma (HCC). The tumor is found most frequently in the stomach [1, 2], where it was originally described by Ishikura et al. [3] as a specific subtype of primary gastric carcinoma, with occasional reports describing locations in other organs such as the lung [4, 5], kidney [6], female reproductive tract [7–11], pancreas [12–14], and gallbladder [15, 16]. In this report, we present a case of HAC of the gallbladder.
A 60-year-old woman was admitted because of low-grade fever (37.7–38°C) present mostly in the afternoon, nonproductive cough, general fatigue, loss of appetite and mild epigastric pain. Conjunctival, palmar and nailbed pallor was evident on general examination. Abdominal examination revealed mild tenderness over the right upper abdominal quadrant but no mass was palpable. There were no enlarged neck, axillary or inguinal lymph nodes. Pulmonary auscultation was unremarkable. Laboratory tests revealed hypochromic anemia. Liver and renal function tests were all normal. Hepatitis B and C serology tests were negative. Serum levels of alphafetoprotein (α-FP) and carcinoembryonic antigen (CEA) were increased at 62 ng/ml (reference range, 0–7 ng/ml) and 10.4 ng/ml (reference range, 0.9–5.4 ng/ml), respectively, but the carbohydrate antigen 19–9 (CA19-9) level was normal at 17.2 U/ml (reference range, 0–37 U/ml). The patient was evaluated for her anemia. Total colonoscopy and gastroscopy were normal. Bone marrow biopsy and myelogram were unremarkable. She was also thoroughly investigated for microbial, viral or parasitic infection or inflammatory disease. Repeated blood, urine and bronchial secretion cultures were all negative. Abdominal ultrasonography (Fig. 1) and computed tomography (CT) revealed a distended gallbladder containing large stones and intraluminal mass (Fig. 2), and enlarged regional lymph nodes. Thoracic CT and bone scintigraphy were unremarkable. The patient underwent an exploratory laparotomy. At surgery, the gallbladder was found enlarged, full and distended. Grossly enlarged lymph nodes were present at
A. J. Karayiannakis (*) : H. Bolanaki : C. Simopoulos Second Department of Surgery, Democritus University of Thrace, Medical School, 68 100, Alexandroupolis, Greece e-mail:
[email protected] S. Kakolyris : L. Chelis Department of Clinical Oncology, Democritus University of Thrace, Medical School, 68 100, Alexandroupolis, Greece A. Giatromanolaki : E. Sivridis Department of Pathology, Democritus University of Thrace, Medical School, 68 100, Alexandroupolis, Greece N. Courcoutsakis Department of Radiology and Medical Imaging, Democritus University of Thrace, Medical School, 68 100, Alexandroupolis, Greece
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Fig. 3 Macroscopic appearance of the resected gallbladder showing a yellowish-white polypoid tumor occupying its lumen. The contained gallstones are also seen Fig. 1 Abdominal ultrasonography revealing a tumor mass within the gallbladder lumen
the hepatic hilus, along the hepatoduodenal ligament and the celiac artery. There were no other pathologic findings. Cholecystectomy and resection of the hepatic bed of the gallbladder were performed along with selective lymph node sampling. The macroscopic inspection of the resected gallbladder revealed a yellowish-white, well-circumscribed, polypoid tumor in the body of the gallbladder, measuring 6×5×3 cm and occupying the entire lumen without obvious invasion of the gallbladder bed (Fig. 3). Microscopically, the tumor had a morphological appearance resembling HCC. It was composed of polygonal cells with enlarged vesicular nuclei having prominent nucleoli and abundant eosinophilic cytoplasm (Fig. 4). The neoplastic cells, arranged in solid sheets or groups and exceptionally in a trabecular pattern,
Fig. 2 Abdominal computed tomography showing a mass of the same density as liver parenchyma within the lumen of the gallbladder
were invading the three fourths of the muscle layer sparing the remaining portion and the serosa. No identification of bile in the cytoplasm of tumor cells was observed, but intracellular PAS-positive hyaline globules were occasionally seen. There were extensive areas of necrosis but there was no lymphatic–vascular space invasion or extension to the adjacent liver. Immunohistochemistry showed that the tumor cells were positive for EMA, pankeratins, cytokeratins 8, 18 and 19, and for CEA. Focal α-FP expression was also present. The histological and immunophenotypic findings of the examined lymph nodes were consistent with those of the gallbladder lesion. Based on these findings, the diagnosis of HAC of the gallbladder with metastasis to regional lymph nodes was made.
Fig. 4 Microscopic appearance of the hepatoid carcinoma of the gallbladder (arrows). Note the solid pattern of growth and the nuclear atypicality of tumor cells (H&E, original magnification ×200)
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One month after surgery, serum α-FP levels returned to normal (5.1 ng/ml) but CEA level remained elevated at 11.3 ng/ml. An abdominal CT scan was performed before chemotherapy commencement showing enlarged regional lymph nodes as the only evidence of disease. The patient was treated with oral administration of sorafenib at a dose of 400 mg twice daily for 4 consecutive weeks followed by 2-week rest. Clinical evaluation and laboratory tests were performed every 2 weeks whilst abdominal CT and chest radiographs were performed every 2 months or earlier, if clinically indicated. The treatment was well tolerated without serious side effects apart of mild (grade I/II) nausea and the patient remained well with stable disease for 15 months. At that time, her serum α-FP level elevated to 28.45 ng/ml. Abdominal and thoracic CT showed disease progression with multiple, enlarged lymph nodes in the abdomen and mediastinum. Treatment with sorafenib was interrupted and the patient received a combination of paclitaxel plus gemcitabine at the doses of 100 and 900 mg/m2, respectively, administered every 2 weeks. Serum α-FP levels decreased slightly (19.83 ng/ml) but 4 months later, they increased again (46.3 ng/ml) along with deterioration of patient’s performance status. A CT scan of the abdomen showed multiple liver metastases. Chemotherapy was stopped and the patient died 1 month later due to liver insufficiency thus succeeding an overall survival of 20 months after surgery.
Discussion HAC is a very rare entity originally identified as a specific type of gastric carcinoma [3] followed by reports of other localizations such as the gallbladder by Watanabe et al. [15] in 1993 who reported an α-FP producing gallbladder carcinoma and by Vardaman and Albores-Saavedra in 1995 [16], who described a clear cell carcinoma of the gallbladder, immunohistochemically positive for α-FP and CEA, containing areas of hepatoid differentiation with formation of bile canaliculi. Since then, seven more cases of gallbladder HAC have been described in the English literature as shown in Table 1 [17–22]. The histogenesis of HAC is attributed to either endodermal cells with bipotential differentiation into cells with tubular and hepatoid features or by acquisition of hepatic differentiation during the progression of an adenocarcinoma. The latter view is supported by the finding of foci of well-differentiated adenocarcinoma adjacent to or intermingled with the hepatoid areas of the tumor [18]. HAC of the gallbladder has hepatocellular histopathological features and should, therefore, be distinguished from HCC of the liver invading the gallbladder or α-FP-producing adenocarcinomas. Immunohistochemical cytokeratin (CK)
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profiling for CK7, CK8, CK18, CK19 and CK20 along with the expression of liver-specific proteins such as α-FP, albumin, transferrin, and α1-antitrypsin may be helpful. An immunophenotype consisting of positive staining for CK 8, 18, 19, and 20 and negative for CK7 suggests hepatoid carcinoma and distinguishes it from HCC (CK 8 and 18 positive but usually negative for CK 7 or 19) or adenocarcinoma of the biliary tract which is commonly CK 7, 8, 18, and 19 positive [17–21]. The expression of α-FP is suggestive but no conclusive for the diagnosis of hepatoid carcinomas given that it is expressed in only one fourth of the cases [23]. This is clinically important since hepatoid carcinomas irrespective of α-FP expression have a more aggressive behavior compared with α-FP-producing tumors lacking hepatoid features [24]. A bile canalicular staining pattern with polyclonal antibodies against CEA (pCEA) or absence of immunostaining with monoclonal antibodies (mCEA) is highly specific for HCC. Hepatocyte paraffin 1 (Hep Par 1), a monoclonal antibody reactive with a hepatocyte-specific epitope, has been suggested as a useful marker for diagnosing hepatoid carcinoma but despite its high specificity it is not absolutely sensitive for the detection of a hepatocellular phenotype [23] and the diagnosis of hepatoid carcinomas should be based primarily on their histopathological features [17, 18]. In our case, the patient was a 60-year-old woman presenting with mild epigastric pain, fatigue, loss of appetite and fever (38°C). Previous reports have shown that most patients are females (five females versus two males) in their seventies, complaining of right upper quadrant abdominal pain (four patients) [18, 20–22], general fatigue, loss of appetite or weight loss in two cases [17, 21] and high fever (from 38°C to 39°C) in one case [17] as in our patient. Cholelithiasis was diagnosed in four patients including this case [19, 20], two patients were described as having cholecystitis [20, 21] and in two other patients the tumor was found incidentally at a regular medical check-up [19]. Interestingly, serum levels of tumor markers have been evaluated in only two previous reports with the concentrations of α-FP, CEA and CA19-9 being normal in one patient [17] while the second patient was found to have abnormally elevated α-FP at 511 μg/ml with normal values being less than 20 μg/ml [22] whereas in our case both α-FP and CEA levels were markedly elevated. Ultrasonography and/or computed tomography revealed a nodular mass with a heterogeneous echogenecity within the gallbladder [17] or an irregularly thickened gallbladder wall [18, 21], whereas two patients were reported as having “gallbladder cancer” detected by abdominal ultrasonography [19]. Other imaging examinations included a magnetic resonance cholangiopancreatography revealing a defect at the fundus of the gallbladder [17] and magnetic resonance imaging (MRI) in another patient with findings (irregular
Fatigue, appetite and weight loss, fever (38–39°C)
Abdominal pain
Incidental finding
Incidental finding
Abdominal pain
Abdominal pain general fatigue, loss of appetite
Abdominal pain in the right upper quadrant
M/77
M/72
F/74
F/74
F/71
F/76
F/55
Cholecystectomy and lymphadenectomy
US: “gallbladder cancer”
US: hepatic mass
α-FP: 511 μg/ml
MRI: tumor in the gallbladder fossa, liver metastases
US and CT: thickened gallbladder wall (cholecystitis)
Liver biopsy. Palliative chemotherapy
Cholecystectomy
Cholecystectomy and biopsies of the pancreas and liver
Cholecystectomy and lymphadenectomy
US: gallstones, “gallbladder cancer”
US: gallstones, acute cholecystitis
Cholecystectomy and partial hepatectomy
Not reported
Not reported
Not reported
Not reported
CA19-9: 42.0 U/ml
Cholecystectomy, resection of segments V and IVa. No adjuvant chemotherapy
Treatment
US and CT: thickened gallbladder wall, liver metastases
US and CT: heterogenous gallbladder mass, metastases in liver segments V and IVa
α-FP: 3.5 ng/ml
CEA: 0.8 ng/ml CA19-9: 0.00 U/ml
Imaging findings
Serum tumor markers
A 7-cm tumor in the gallbladder fossa
A 2.5×1.5×0.5 cm, whitish, solid tumor in the neck of the gallbladder
A white tumor in the lumen of the gallbladder. Metastases in the pancreas.
A 6.5×4×3.5 cm, nodule in the gallbladder
A 5×4.5×1.8 cm, nodule in the gallbladder
A 6×3×3 cm, yellow, solid tumor in the body of the gallbladder
A 4.5×4×3.7 cm, yellowish nodule in the fundus of the gallbladder
Gross features
Tumor cells with eosinophilic cytoplasm and enlarged nuclei arranged in nests and trabeculae Polygonal tumor cells with eosinophilic cytoplasm, round nuclei and prominent nucleoli arranged in trabeculae Polygonal tumor cells with clear cytoplasm, enlarged nuclei, and prominent nucleoli arranged in nests and trabeculae Hepatocyte-like adenostructures
Tumor cells with eosinophilic cytoplasm and enlarged nuclei arranged in nests and trabeculae
Tumor cells with eosinophilic cytoplasm, enlarged nuclei and prominent nucleoli arranged in trabeculae
Tumor cells with eosinophilic cytoplasm, enlarged nuclei and prominent nucleoli arranged in nests
Microscopic appearance
Alive 8 months after surgery
Hep Par1, α-FP and pCEA: positive CK7: negative
Not defined
Survival of 1 month. Generalized disease
α-FP, Victoria blue, Stein, and PAS: positive
CK7, CK19, α-FP, CD10 and CD56: positive CK20: negative
Not reported
Not reported
Survival of 5 months. Intraperitoneal recurrence 2 months after surgery
Survival of 15 months without any recurrence
Patient status
CK8, CK19, Hep Par1 and CD10: positive CK7 and α-FP: negative
CK8, CK19, Hep Par1 and α-FP, CD10 and pCEA: positive CK7: negative
CK8, CK19 and Hep Par1: positive CK7, α-FP and CEA: negative
CK7, CK8 and CK18: positive CK19, α-FP, CEA and CA19-9: negative
Immuno-histochemistry
[22]
[21]
[20]
[19]
[19]
[18]
[17]
Ref.
US ultrasonography, CT computed tomography, MRI magnetic resonance imaging, α-FP alpha-fetoprotein, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19–9, CK cytokeratin, Hep Par 1 hepatocyte paraffin 1, pCEA polyclonal CEA antibody
Symptoms
Sex/age (years)
Table 1 Clinicopathological characteristics of patients with hepatoid adenocarcinoma of the gallbladder in previous reports
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borders and abnormal enhancement) suggestive of malignant lesion of the gallbladder [22]. MRI has been suggested as particularly useful for the diagnosis of gallbladder hepatoid carcinoma. On contrast-enhanced MRI scans, the tumor has imaging characteristics and enhancement patterns similar to intrahepatic cholangiocarcinoma with typical hypointense center due to desmoplasia and peripheral enhancement [22]. Specific contrast media such as superparamagnetic iron oxide (SPIO) may show lack of Kupffer cells. The MRI features of a tumor located within the gallbladder in a non-cirrhotic patient of advanced age with high serum α-FP levels render the diagnosis of HAC of the gallbladder very likely. Correct preoperative diagnosis is very important since hepatoid carcinomas have a dismal prognosis because of extensive hematogenous metastasis to the liver and early lymph node involvement and should be treated aggressively. Nevertheless, the correct diagnosis has never been made preoperatively and all tumors diagnosed so far were of large dimensions usually 5–8 cm in diameter [17–20, 22] and of advanced stage with multiple liver metastases and/or regional lymph node involvement [17, 18]. Cholecystectomy, atypical liver resections and regional lymph node resection [17–19] have been performed but the results were poor with only a few months of survival [18, 20], the longest being 15 months [17]. Our patient had also a large tumor measuring 6 cm in maximal dimension, without direct invasion or metastases to the liver but with extensive regional lymph node metastases and was treated by simple cholecystectomy as there was extensive lymph node involvement. Nevertheless, her serum α-FP level decreased rapidly after surgery, suggesting that it was tumor-derived and reflecting the tumor burden. Data concerning the systemic treatment of the HAC of the gallbladder are lacking in the literature apart from one report where palliative chemotherapy was given in a patient with HAC of the gallbladder and liver metastases but the medications or regimen used, treatment response and patient survival were not reported [22]. Apparently, surgical resection is indicated, if feasible. Adjuvant or palliative chemotherapy may be given in inoperable or metastatic cases as suggested by reports of treatment of HACs of the stomach where medications such as etoposide, adriamycin, cisplatin, 5-fluorouracil and more recently irinotecan and paclitaxel either alone or in combinations, have been used [2, 25]. Since HAC has both morphological and functional features of HCC, we used sorafenib based on our previous experience and literature data on its effectiveness in inoperable HCC patients. Sorafenib is an inhibitor of several receptor tyrosine kinases involved in neovascularization and tumor progression, with remarkable responses and/or prolonged disease stability and survival benefit for patients with advanced HCC by blocking tumor prolifera-
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tion and angiogenesis and inducing apoptosis [26–29]. To the best of our knowledge this is the first case of a patient with gallbladder HAC treated with sorafenib. Under this regimen the disease remained stable for 15 months along with normal serum α-FP levels. Upon disease progression, we selected the combination of paclitaxel and gemcitabine although with a modest success. Paclitaxel either alone or in combination with 5-FU has shown efficacy in the treatment of metastatic gastric HAC [25] suggesting that paclitaxel may represent a useful drug also for the treatment of HAC of the gallbladder. Interestingly, the kinetics of serum α-FP level after surgery and its time course during chemotherapy, where an elevation was observed before the appearance of any symptoms or imaging detection of disease progression, were in accordance with the extent of the disease. A similar observation has been made previously in patients with HACs of the stomach [25, 30]. These findings suggest that serum α-FP measurement is useful for the follow-up of patients with HAC of the gallbladder under chemotherapy as a marker of treatment response and/or disease relapse.
Conclusions HAC of the gallbladder is very rare but it should be considered in older patients with a gallbladder tumor and elevated serum α-FP levels in the absence of risk factors of HCC. Awareness of this entity is important for correct preoperative diagnosis and differential diagnosis between gallbladder carcinoma and HCC allowing employment of an aggressive surgical treatment. Sorafenib and probably other tyrosine kinase inhibitors may be useful for the treatment of inoperable or metastatic cases of HAC of the gallbladder.
Conflict of interest The authors declare that they have no conflict of interest.
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