Correspondence and requests for reprints : Dr. Jing-Houng Wang
Address : Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center.
123 Ta-Pei Rd, Niao-Sung, Kaohsiung County, 83301 Taiwan
Primary Hepatocellular Carcinoma in Ectopic Liver and Later Metastasis
to Mother Liver Ĉ A Case Report and Review of the Literature
Yuan-Hung Kuo
1, Jing-Houng Wang
1,2, Tsung-Hui Hu
1,2, and Chuan-Mo Lee
1,2Abstract
We are presenting a case of primary ectopic hepatocellular carcinoma (HCC) that later developed HCC in the mother liver during long-term follow-up. A 64-year-old woman presented with a sudden on- set of abdominal pain and internal bleeding. Ectopic HCC was diagnosed by the surgical resection of 2 tumors during laparotomy, which were found near the triangular ligament and lesser curvature of the stomach. Imaging studies revealed no intrahepatic lesion or peritoneal tumors during follow-up.
However, 2 small HCCs in the mother liver were detected two years after surgery without peritoneal re- currence. Progressive alpha-fetoprotein elevation was noted despite the complete ablation of the moth- er liver HCC by image study. Recurrent peritoneal HCC carcinomatosis was detected and confirmed by exploratory laparotomy two years later. The patient died because of disease progression seven years after the peritoneal tumors resection without HCC recurrence in the mother liver. A literature review dis- closed 7 ectopic HCC cases, including the present one, who developed mother liver HCC during the follow-up period. Regular serum AFP level monitoring and image studies are recommended for de- tecting recurrent or metastatic HCC after tumor resection. ( J Intern Med Taiwan 2008; 19: 422-427 )
Key Words Ĉ Adjuvant chemotherapy, Ectopic hepatocellular carcinoma, Tumor rupture
1
Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital -Kaohsiung Medical Center;
2
Chang Gung University College of Medicine, Taiwan
Introduction
Ectopic livers are islands of normal liver parenchyma that have become separated from the main lobes of the liver and are found incidentally by peritoneoscopy, laparotomy, and autopsy. They can occur in various sites near the liver, such as the gall- bladder, hepatic ligaments, omentum, retroperi- toneum and thorax
1-3.
Of the approximately 100 cases of ectopic liver that have been reported, hepatocellular carcinoma (HCC) was detected in 34, with the mother liver free of tumor originally
4. The carcinogenic factors in- volved in neoplastic change in the ectopic liver but not the mother liver are not well understood. Of these reported ectopic liver with HCC, 6 patients developed HCC in the mother liver during post-resection fol- low-up
5-10. A case of ectopic HCC post-surgical re- section with a delayed HCC development in the moth- er liver during long-term follow-up is presented.
Case report
A 64-year-old woman was sent to the emergen- cy department in April 1999 due to a sudden onset of dull abdominal pain and hypovolemic shock. Her medical history was unremarkable except for a cholecystectomy 4 years previously for gall stones.
No regular medication or alcohol abuse was noted. A physical examination revealed a slightly pale con- junctiva and diffused dull abdominal pain without re- bounding tenderness. Laboratory studies revealed the following: alanine transaminase (ALT): 50 U/L (nor- mal range: 0-40 U/L), aspartate transaminase (AST):
67 U/L (normal range: 0-37 U/L), hemoglobin : 9.8 g/dl (normal range: M:13.5-17.5, F:14-16 g/dl), platelet count: 280x10
3/mm
3(normal range: 150-400 x10
3/mm
3), and white blood count: 27.5x10
3/mm
3(normal range: M:3.9-10.6, F:3.5-11 x10
3/mm
3). The computed tomography (CT) of the abdomen revealed massive ascites, in which the hemoperitoneum was impressed. Urgent surgical intervention was arranged
immediately due to hypovolemic shock, upon which two small bleeding tumors were found incidentally.
One tumor, measuring approximately 4x2x2cm was found on the triangular ligament between the left lobe of the liver and the spleen. Another smaller tumor of about 2x1x1cm was found close to the lesser curva- ture of the stomach. A complete tumor resection was performed. The histology revealed well-differentiat- ed HCC with a trabecular architecture (Fig. 1).
Neither intrahepatic lesion nor hepatic cirrhosis was detected during the operation. The immediate post- operative serum Alpha-fetoprotein (AFP) level was 20.9ng/ml (normal range: Ŵ 5 ng/ml). Negative vi- ral markers, including the hepatitis B virus surface antigen (HBsAg) and antibody to the hepatitis C virus (anti-HCV), were found. The final diagnosis for this patient was ectopic HCC.
However, the progressive elevation of the serum
AFP level was detected a year after the tumor resec-
tion. No definite peritoneal or liver lesion was demon-
strated by the image studies, including liver ultra-
sonography (US), helical CT, magnetic resonance
(MR) imaging and hepatic angiography. At the 28
month-follow-up, a liver US detected 2 small hypoe-
Fig.1.Histological examination (hematoxylin and eosin
stain, magnification x100), showing well-differen-
tiated hepatocellular carcinoma with trabecular ar-
chitecture (white arrow) and high nucleocytoplas-
mic (N/C) ratio.
choic nodules, measuring 0.9 cm and 1.2 cm on seg- ments 6 and 7, respectively, and a hepatic angiogra- phy demonstrated a small hypervascular nodule over segment 7 of the liver (Fig. 2). Fine needle aspiration was performed and the cytology revealed HCC. HCC in mother liver was diagnosed. The patient received a percutaneous ethanol injection and transarterial em- bolization for HCC in mother liver. Follow-up imag- ing studies including liver ultrasonography, helical CT, magnetic resonance imaging, and positron emis- Fig.2.a.Ultrasonography(US) of the abdomen showed a hypoechoic nodule about 0.9 cm at segment 6 (white arrow). b. Another hypoechoic nodule about 1.2 cm at segment 7 (white arrow). c.
Celiac angiography showed one hypervascular lesion at segment 7 (white arrow).
sion tomography were performed and revealed com- plete ablation of HCC in the mother liver.
However, the progressive elevation of the serum AFP level to 6062 ng/ml was noted (Fig. 3). A liver US and helical CT revealed a nodule below the left diaphragm. An exploratory laparotomy was per- formed in September 2003, which was 53 months af- ter the initial tumor resection. Unfortunately, peri- toneal carcinomatosis was found with multiple small nodules in the omentum, mesentery and pelvic cavi- ty, although no HCC recurrence was noted in the mother liver. The pathology of the resected nodule once again revealed HCC. Hence, primary ectopic HCC with later metastasis in the mother liver and peritoneal carcinomatosis was the preferred diagno- sis according to the clinical course. Supportive treat- ment was offered because of the poor prognosis. The patient died due to disease progression in May 2006, 7 years after the first tumor resection.
Discussion
We are reporting a case of primary ectopic HCC
within the abdominal cavity. The presentation of this
ectopic HCC was dull abdominal pain and hypov-
olemic shock due to tumor bleeding. Although intra-
abdominal bleeding with obscured origin usually re-
quired further investigation, such as an abdominal an-
giography to confirm the bleeding site, our patient re-
ceived direct surgical intervention due to hemody- namic instability. An ectopic HCC rupture was found accidentally. Most ectopic HCC is detected acciden- tally, with presentations such as a high AFP level, ab- dominal pain, or abdominal mass. However, 12% of
reported ectopic HCC present with tumor rupture and bleeding
4. This specific diagnosis should be consid- ered for patients with internal bleeding and an ob- scured bleeding site.
The prevalence of ectopic liver was very low, at 0.47% in the laparoscopic series
2. The ectopic livers appeared to be more prone to hepatocarcinogenesis than the mother liver. Arakawa et al. proposed that ectopic livers are more susceptible to carcinogenesis because they lack the complete functional architec- ture, such as venous and biliary drainage, which are necessary for excreting viruses or chemical carcino- gens. This property enabled far earlier HCC devel- opment in the ectopic liver than in the mother liver
5. Kubota et al. reviewed 34 reported cases of ectopic HCC and showed that the affected patients were old- er (mean age, 62.5 years) and male predominant (79.4%)
4. Most patients did not have HCC in the mother liver initially. Cirrhotic liver was found in on- ly 7 patients (20.6%)
4, while 8% of the patients test- ed positive for HBsAg and 13.3% tested positive for anti-HCV
4. Based on the above-mentioned data, it is likely that non-viral factors played a major role in the hepatocarcinogenesis of the ectopic liver.
Fig.3.Series of serum AFP level and management. Point a: Apr-00, AFP: 52 ng/ml. Point b: Aug-01, AFP:
547 ng/ml Ɩ Liver HCC detection and received TAE & PEI. Point c: Nov-01,AFP: 998 ng/ml Ɩ Received TAE; May-02,AFP: 1500 ng/ml Ɩ Received TAE; Aug-02,AFP: 2400 ng/ml Ɩ Received PEI. Point d: Sep-03, AFP: 6062 ng/ml Ɩ Received exploratory laparotomy and carcino- matosis was confirmed.
Table. Review of primary HCC in ectopic liver and later metastasis to mother liver
Author/Year Age/Sex Ectopic HCC
LC AFP HBsAg/ Liver HCC FU/
Size(cm) Location Presentation (ng/ml) HCV Ab No/FU prognosis Kawahara
6/ 64/ Small, Abdominal Massive (-) 117000 NA/NA Mul/ 40m/
1988 M Autopsy cavity ascites 40m expired
Kawabata
7/ 74/ 12, Rec Left chest Left chest (-) 4116 NA/(+) Mul/ 36m/
1996 M wall pain 36m alive
Arawaka
5/ 64/ 4, Rec, Gastic Occasional (-) 4900 (-)/NA Mul/ 15m/
1999 M serosa finding 12m expired
Kim
8/ 43/ 10, Rec Between Occasional (-) NA (+)/NA Mul/ 23m/
2003 F spleen, diaphragm finding 7m alive
Leone
9/ 34/ 10, Rec Between Intraab- (-) NA (-)/(-) 3/ 55m/
2004 F spleen, dominal 55m alive
diaphragm bleeding
Shigemori
10/ 72/ 14, Rec Jejunum Occasional (-) NA (-)/(-) Mul/ 12m/
2006 M finding 2m alive
Current case 64/ 4, Rec Between left Intra- (-) NA (-)/(-) 2/ 85m/
F 2, Rec lobe, spleen, abdominal 28m expired
stomach bleeding
HCC, hepatocellular carcinoma; LC, liver cirrhosis AFP, alpha-fetoprotein; HBsAg, hepatitis B surface antigen; HCV Ab, antibody to hepatitis C virus; No: number; FU: follow up.
AFP Level (ng/ml)
The majority of patients who reported with pri- mary ectopic HCC had good outcomes following the resection of the extrahepatic tumor
5. However, the de- velopment of delayed HCC in the mother liver dur- ing post-operative follow-up were reported in 7 cas- es, including our case
5-10. (Table) No primary liver tu- mor was noted for all these 7 cases originally. HCCs were detected in mother livers in 3 patients within the first year during follow-up. One patient presented by Arawaka et al. was found to have multiple pulmonary tumors together with hepatic lesions during the first year follow-up
5. Leone et al. also described a 34 year- old patient with ovarian and uterus metastasis of HCC within two years after the resection of ectopic HCC
9. Although a hysteroannessiectomy was performed, 3 small tumors were diagnosed in the mother liver 55 months postoperatively. Two other patients had mul- tiple HCCs in mother livers after 3-years' follow-up.
The remnant ectopic HCC may have resulted from i- nadequate resection, and local metastasis might have been the cause of a delayed distant metastasis to the lung. Therefore, recurrent peritoneal HCCs with in- vasion to mother liver may have the potential to ex- plain the presentation of tumor in mother liver dur- ing long-term follow-up.
In our case report, two small HCCs were found in the mother liver 2 years after surgery and were com- pletely ablated by local treatment. Peritoneal carci- nomatosis of HCC was demonstrated 4 years after the initial ectopic tumor excision. However, after re- viewing all 7 cases, the resection of the extrahepatic tumor alone does not guarantee promising outcomes.
There is a possibility that ectopic liver does not nec- essarily develop in one site. When the visible ectopic tumors were excised, the hepatocarcinogenic process may still progress gradually in some obscure extra- hepatic liver tissue. These slowly developed ectopic tumors might invade the local and surrounding tis- sue, such as the peritoneum, or distantly metastasize to the mother liver and other major organs over time.
Surgical resection is currently the main treat-
ment method for ectopic HCC due to the benign na- ture of the extrahepatic nodules following resection, as stated in previous studies
5. However, no report was found regarding the long-term prognosis of patients with ectopic HCC after resection
11. Based on our case report, recurrent ectopic HCC could still develop even 3 years after the treatment of the initial lesion
5-10. Hence, radical wide excision of ectopic HCC, in- cluding the adjacent organs, might yield a more promising outcome in these patients.
Huang et al. reported one diaphragmatic ectopic HCC patient receiving 2 courses of chemotherapy 1 month after tumor resection due to the persistent high serum AFP level postoperatively
12. The serum AFP level decreased gradually and the image studies re- vealed no local recurrence or distal metastasis eight months later. Long-term follow-up is necessary to confirm the effectiveness of postoperative adjuvant chemotherapy.
In conclusion, patients with ectopic HCC do not always have good prognosis after tumor resection.
Regular serum AFP level monitoring and image studies are recommended for detecting recurrent or metastatic HCC after initial ectopic HCC resection.
If a persistent elevation of serum AFP is detected without the definite finding of a tumor, further man- agement, such as adjuvant chemotherapy, might be considered.
References
1.Watanabe M, Matsuura T, Takatori K, et al. Five cases of ectopic liver and a case of accessory lobe of the liver. Endoscopy 1989;
21: 39-42.
2.Asada J, Onji S, Yamashita Y, et al. Ectopic liver observed by peritoneoscopy: report of a case. Gastroenterol Endosc 1982;
24: 309-12.
3.Clearfield HR. Embryology, malformation, and malposition of the liver. In: Kaiser MH, Roth JLA, Schaffner F,eds. Bockus Gastroenterology, 4th ed. Philadelphia: Saunders, 1985; 2659- 65.
4.Keiichi K, Junji K, Kyu R, et al. Ectopic hepatocellular carci- noma arising from pancreas: a case report and review of the lit- erature. World J Gastroenterol 2007; 13: 4270-3.
5.Arakawa M, Kimura Y, Sakata K, et al. Propensity of ectopic
liver to hepatocarcinogenesis: case reports and a review of the literature. Hepatology 1999; 29: 57-61.
6.Kawahara E, Kitamura T, Ueda H, et al. Hepatocellular carci- noma arising in the abdominal cavity. An autopsy case of ec- topic liver origin. Acta Pathol Jpn 1988; 38: 1575-81.
7.Kawabata K, Adachi Y, Ito T, et al. Occurrence of hepatocellu- lar carcinoma 3 years after resection of a left chest wall tumor which was suspected as ectopic hepatocellular carcinoma. Kan- Tan-Sui 1996;32:93-8. [In Japanese]
8.Kim KA, Park CM, Kim CH, et al. Hepatocellular carcinoma in an ectopic liver: CT findings. Eur Radiol 2003; 13(Suppl 4):
L45-7.
9.Leone N, Carrera M, Carucci P, et al. Ectopic liver and hepato- carcinogenesis: report of three cases with four years follow-up.
Eur J Gastroenterol Hepatol 2004; 16: 731-5.
10.Shigemori M, Kondo M, Azechi H, et al. A case of ectopic hep- atocellular carcinoma in the jejunum. J Gastroenterol 2006; 41:
913-8.
11.Takaaki T, Tadahiko E, Eijirou H, et al. Ectopic hepatocellular carcinoma arising in the bile duct. J Hepatobiliary Pancreat Surg 2005; 12: 266-8.
12.Huang TW, Chan DC, Lee HS, et al. Ectopic Hepatocellular car- cinoma of the diaphragm. Dig Dis Sci 2007; 52: 1118-20.
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