Hepatocellular carcinoma presenting as an extrahepatic mass: A case report and review of literature

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is a primary liver tumor generally diagnosed based on radiographic findings. Metastatic disease is typically associated with increased tumor diameter, multifocality, and vascular invasion. We report a case of a patient who presented with extrahepatic HCC metastasis to a portocaval lymph node with occult hepatic primary on computed tomography (CT). We review the literature for cases of extrahepatic HCC presentation without known hepatic lesions and discuss strategies to differentiate between metastatic and ectopic HCC.

CASE SUMMARY

A 67-year-old male with remotely treated hepatis C was referred for evaluation of an enlarging portocaval, mixed cystic-solid mass. Serial CT evaluations demonstrated steatosis, but no cirrhosis or liver lesions. Endoscopic ultrasound demonstrated a normal-appearing pancreas, biliary tree, and liver. Fine needle aspiration yielded atypical cells. The differential diagnosis included duodenal or pancreatic cyst, lymphoproliferative cyst, stromal or mesenchymal lesions, nodal involvement from gastrointestinal or hematologic malignancy, or duodenal gastro-intestinal stromal tumor. After review by a multidisciplinary tumor board, the patient underwent open surgical resection of a 5.2 cm × 5.5 cm retroperitoneal mass with pathology consistent with moderately-differentiated HCC. Magnetic resonance imaging (MRI) subsequently demonstrated a 1.2 cm segment VIII hepatic lesion with late arterial enhancement, fatty sparing, and intrinsic T1 hyperintensity. Alpha fetoprotein was 23.3 ng/mL. The patient was diagnosed with HCC with portocaval nodal involvement. Review: We surveyed the literature for HCC presenting as extrahepatic masses without history of concurrent or prior intrahepatic HCC. We identified 18 cases of extrahepatic HCC ultimately found to represent metastatic lesions, and 30 cases of extrahepatic HCC found to be primary, ectopic HCC.

CONCLUSION

Hepatocellular carcinoma can seldomly present with extrahepatic metastasis in the setting of occult primary. In patients with risk factors for HCC and lesions suspicious for metastatic disease, MRI may be integral to identifying small hepatic lesions and differentiating from ectopic HCC. Tumor markers may also have utility in establishing the diagnosis.

Key Words: Extrahepatic, Metastasis, Portocaval, Lymph node, Case report

Core Tip: Hepatocellular carcinoma (HCC) metastases are typically associated with increased tumor diameter, multifocality, and vascular invasion. We report a rare case of HCC metastasis to a portocaval lymph node with initially occult hepatic primary. Our case illustrates that multimodal evaluation including alpha fetoprotein and contrast-enhanced magnetic resonance imaging may improve the sensitivity of identification of primary HCC lesions. We also reviewed the literature for HCC presenting as extrahepatic masses (18 cases: Metastatic lesions; 30 cases: Primary ectopic HCC), and discuss that, in patients with extrahepatic sites of HCC, thorough assessment for intrahepatic lesions is critical to classifying disease as metastatic HCC or ectopic HCC.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths in the United States[1]. The majority of HCC cases in the western hemisphere occur in patients with chronic liver disease, and surveillance in at-risk patients with abdominal ultrasound every six months is recommended[2,3]. Implementation of surveillance strategies has enabled early-stage detection of HCC, and thus, many patients are asymptomatic at the time of diagnosis, or have symptoms and findings associated with underlying cirrhosis rather than the tumor itself.

HCC diagnosed in patients outside of surveillance protocols are associated with metastatic disease at the time of diagnosis in 10%-15% of cases[4-6]. Metastases are typically found in patients with advanced local disease (size > 5 cm, macrovascular invasion)[7], with the most common sites of metastasis being lung, peritoneal lymph nodes, bone, and adrenal gland. Median survival in patients with metastatic disease is between 7 and 15 months[8].

HCC presenting as an extrahepatic lesion without known intrahepatic disease is extremely rare. Metastases from occult hepatic lesions and HCC arising from ectopic liver tissue have both been described[9,10]. We report the case of a patient who presented with an enlarging portocaval mass in the absence of known hepatic lesions, who was found to have metastatic HCC upon surgical resection and follow-up imaging. We review other cases reported in the literature of extrahepatic HCC presentation without evidence of primary hepatic lesion and discuss strategies for diagnostic differentiation between metastatic and ectopic HCC.

CASE PRESENTATION

Chief complaints

A 67-year-old male was referred to the surgical oncology clinic for abdominal pain and a growing portocaval mass.

History of present illness

He reported a one-year history of aching abdominal discomfort, nausea, and 10-pound weight loss. His review of systems was unremarkable other than abdominal pain and weight loss.

Personal and family history

His medical history was notable for hepatitis C treated with pegylated interferon and ribavirin two decades prior and poorly controlled hypertension. He did not carry a diagnosis of cirrhosis and had never had pancreatitis. He had previously undergone an exploratory laparotomy and appendectomy four decades prior under circumstances the patient could not recall, as well as a remote laparoscopic cholecystectomy. He was a one pack per week smoker. He had no prior family history of gastrointestinal malignancy.

Physical examination

On physical exam, he was a well-appearing, overweight (body mass index 28.6) male with well-healed midline laparotomy and laparoscopic scars, no abdominal distension or tenderness, and no scleral icterus or jaundice.

Laboratory examinations

His complete blood count was notable for a hemoglobin of 10.4 g/dL, metabolic panel was notable for a creatinine of 1.36 mg/dL (estimated glomerular filtration rate of 57 mL/min), aspartate aminotransferase of 61 U/L (but normal alanine aminotransferase, alkaline phosphatase, and bilirubin levels), and tumor markers were notable for a carcinoembryonic antigen level of 2.9 ng/mL and carbohydrate antigen 19-9 level of 52 U/mL.

Imaging examinations

He had undergone serial intravenous-contrasted computed tomography (CT) scans of the abdomen and pelvis leading up to surgical referral, which demonstrated an enlarging portocaval lesion from 3.6 cm × 2 cm eight months prior (Figure 1A) to 5.2 cm × 3.2 cm (Figure 1B). CT also demonstrated hepatic steatosis, but no abnormal pancreatic, biliary, hepatic, or duodenal lesions.

Figure 1 Lesion growth on computed tomography. Serial intravenous-contrasted Computed tomography scans of the abdomen and pelvis demonstrated increase in size of the patient’s portocaval mass (arrows). A: 3.6 cm × 2 cm, 8 months prior to presentation; B: 5.2 cm × 3.2 cm, time of presentation.

MULTIDISCIPLINARY EXPERT CONSULTATION

He had undergone an upper endoscopy that demonstrated duodenal erythema, ulceration, and a possible submucosal mass. An endoscopic ultrasound demonstrated a mixed cystic-solid mass between the pancreas and inferior vena cava, as well as a normal-appearing pancreas, biliary system, and liver. Fine needle aspiration demonstrated rare fragments of cytokeratin 8/18 and arginase-1 positive atypical cells with hepatoid differentiation, negative for CD34, SOX10, synaptophysin and chromogranin immunohistochemical stains. Although suspicious, the scant nature of the specimen precluded a definitive diagnosis of malignancy.

FINAL DIAGNOSIS

Differential diagnosis for a portocaval, retroduodenal, peripancreatic, mixed cystic-solid lesion includes a duodenal or pancreatic cyst, lymphoproliferative cyst, stromal or mesenchymal lesions, nodal involvement from gastrointestinal or hematologic malignancy, or duodenal gastro-intestinal stromal tumor. Given an enlarging lesion with symptomatic mass effect and histologic features of atypia concerning for malignancy, surgical resection was recommended after review at our multidisciplinary tumor board.

TREATMENT

The patient underwent open surgical resection of a 5.2 cm × 5.5 cm encapsulated retroperitoneal mass via a right subcostal incision. He had dense right upper quadrant adhesions between the omentum, colon, small bowel, and the gallbladder fossa that was able to be safely dissected free. No evidence of metastatic foci was present. The liver appeared steatotic but was without evidence of cirrhosis. After mobilization of the hepatic flexure and duodenum, the portocaval mass was exposed, mobilized, and resected from adjacent duodenum, pancreatic head, portal structures, and inferior vena cava. Post-operatively, the patient recovered well and was discharged on post-operative day (POD) 6.

OUTCOME AND FOLLOW-UP

He re-presented on POD 9 with bilious emesis and was found to have a leukocytosis of 15.9 × 10³/µL with a 5.1 cm × 5.0 cm × 8.4 cm rim-enhancing collection in the resection bed associated with compressive mass effect on the duodenum. CT-guided aspiration of the fluid yielded hematoma with no organisms on gram stain or culture. The patient had marked symptomatic improvement and was discharged home on hospital day 4 of his readmission.

Pathologic evaluation revealed vague nodules of large polygonal cells with eosinophilic granular to clear vacuolated cytoplasm, steatotic and clear-cell changes, increased mitosis, necrosis and rare hyaline bodies (Figure 2A), positive for cytokeratin 8/18, pancytokeratin, HepPar1, arginase-1, glypican-3 (Figure 2B), and CA-9, and negative for cytokeratin 7/20, synaptophysin, chromogranin, DOG-1, CD117, PAX-8, SF-1, SOX-10, and Melan-A. Morphology and immunophenotype were consistent with moderately-differentiated HCC. A thin rim of peri-lesional lymphoid and fibrous tissue suggested a near-completely replaced lymph node.

Figure 2 Histopathologic evaluation of the resected mass. A: Hematoxylin and eosin staining at low and high magnification reveals vague nodules of large polygonal cells with eosinophilic granular to clear vacuolated cytoplasm, steatotic and clear-cell changes, increased mitosis, necrosis and rare hyaline bodies; B: Immunohistochemistry demonstrates positive staining for HepPar1, arginase-1, and glypican-3.

A gadobutrol-contrasted magnetic resonance imaging (MRI) abdomen was obtained, which demonstrated a 1.2 cm lesion in segment VIII with late arterial enhancement, fatty sparing, and intrinsic T1 hyperintensity, but no washout on delayed images (Figure 3), and two 1.2 cm lesions in segments II and VII with late arterial enhancement and no washout or pseudocapsule. Alpha fetoprotein (AFP) was 23.3 ng/mL. The patient was diagnosed with HCC with portocaval nodal involvement. He was referred to medical oncology for consideration of systemic therapy for his advanced HCC and was initiated on durvalumab and tremelimumab. At 8-month follow-up after surgical resection, he remained clinically well with minimal enlargement of his hepatic lesions (segment VIII, 1.9 cm; segment II, 1.5 cm; segment VII, 1.3 cm).

Figure 3 Magnetic resonance imaging of the liver. Magnetic resonance imaging abdomen demonstrated a 1.2 cm lesion in segment VIII with late arterial enhancement, fatty sparing, and intrinsic T1 hyperintensity. A: T1-weighted, pre-contrast; B: T1-weighted immediate post-contrast; C: T1-weighted, 5 min post-contrast.

DISCUSSION

We report a case of a patient who presented with extrahepatic nodal metastasis of HCC with occult hepatic primary. Diagnosis was achieved upon resection of the mass and histopathologic evaluation, which was consistent with HCC invasion of a portocaval lymph node. Subsequent MRI evaluation demonstrated several small intrahepatic lesions consistent with HCC and an elevated AFP. This case report includes longitudinal workup, evaluation, treatment, and follow-up of this patient. Our limitations, mostly inherent to the nature of case reports, include the single-subject data used and thus the generalizability of our findings. We thus also include a literature review of relevant cases to corroborate our observations.

HCC is the most common primary liver tumor that typically arises in the setting of chronic liver disease. HCC presenting as an extrahepatic lesion is a rare but nevertheless previously described occurrence. Intra-abdominal metastases have previously been reported with initial presentations as retrogastric, peripancreatic, adrenal, omental, or ovarian masses[9,11]. Seldomly, extrahepatic HCC has also presented as chest wall and mediastinal metastases with occult hepatic lesions[12,13]. In cases of occult primary, definitive pathologic diagnoses were made with surgical resection or tissue sampling of metastatic foci prior to identification of primary lesions later.

Ectopic HCC, a distinct entity where malignant degeneration occurs in normal hepatic parenchyma found outside the liver, has also been reported in gallbladder, perihepatic ligaments, omentum, retroperitoneum, and thoracic locations–and can be difficult to distinguish from foci of metastatic HCC[14]. Ectopic liver tissue is postulated to have increased neoplastic potential over the orthotopic liver due to compromised vascular supply or biliary drainage[15,16]. In cases of ectopic HCC, the orthotopic liver is typically uninvolved, and resection of the ectopic focus can be curative and associated with good prognosis[17]. A list of previously reported sites of extrahepatic HCC presentation (1) as metastases from occult hepatic lesion; and (2) deriving from ectopic hepatic parenchyma is shown in Table 1.

Table 1 Previously reported cases of extrahepatic hepatocellular carcinoma presentation without known primary hepatic lesion¹.

Center (number of cases)	Country	Report year	Site of extrahepatic HCC presentation	Largest dimension (cm)	AFP (ng/mL)	Diagnosis achieved by	Liver imaging at time of resection or biopsy	Follow-up duration (months)	Status at follow-up	Ref.
Metastatic HCC
Brigham and Women’s Hospital, Deaconess Hospital, Cardinal Cushing Hospital (7)	United States	1986	Retrogastric (1), ovarian (1), adrenal (1), omental (1), peripancreatic (3)	Not reported	Not reported	Resection (6), autopsy (1)	Not reported	Not reported	Not reported	Longmaid et al[9]
Centre Régional de Lutte Contre le Cancer	France	1995	Skull	8	66000	Resection	CT	35	Alive, recurrence-free	Raoul et al[29]
Universita Degli Studi Di Parma	Italy	1998	Left iliac bone	10	“Normal”	Resection	CT	45	Alive, recurrence-free	Iosca et al[30]
Ankara University Medical School	Turkey	2004	Left chest wall	7	60000	Biopsy	CT, ultrasound	< 1	Palliative, deceased	Coban et al[31]
Tata Memorial Hospital	India	2005	Umbilical, lung	6.5	63235	Biopsy	CT	Not reported	Not reported	Shah et al[32]
Tata Memorial Hospital	India	2005	Sternum	9	18303	Biopsy	CT	5	Disease progression, deceased	Qureshi et al[33]
Aristotle University of Thessaloniki	Greece	2005	Adrenal	10	75.6	Resection	CT, Ultrasound	10	Disease progression, deceased	Tsalis et al[34]
Mayo Clinic	United States	2005	Mesentery	Not reported	“Normal”	Biopsy	CT, Ultrasound	8	Disease progression, deceased	Batsis et al[35]
Hanyang Medical Center	South Korea	2006	Left chest wall	12	308	Resection	CT, Ultrasound, MRI	12	Vertebral metastasis, no hepatic lesions	Hyun et al[36]
University of Pittsburgh	United States	2007	Left chest wall	15	16125	Resection	CT, MRI	Not reported	Not reported	Khalbuss et al[12]
Nara Medical University	Japan	2010	Left iliac bone	20	115	Biopsy	CT, MRI, angiography	120	Alive, recurrence-free after TACE	Takahama et al[37]
Yonsei University College of Medicine	South Korea	2012	Right iliac bone	13	15	Biopsy	CT, MRI, angiography, PET	12	Disease progression, alive	Jung et al[38]
University of Malaya	Malaysia	2014	Mediastinum	Not reported	709	Biopsy	CT	1	Deceased	Koh et al[13]
College of Medicine, the Catholic University of Korea	South Korea	2015	Cervical vertebrae, right iliac bone	7.6	5013	Debulking	CT, MRI	6	Lung metastases, alive	Hwang et al[39]
Changi General Hospital	Singapore	2015	Adrenal	14	33127	Biopsy	CT	2	Disease progression, deceased	Mundada et al[40]
Khyber Teaching Hospital	Pakistan	2015	Right ilium, vertebrae	20	108795	Biopsy	CT, MRI	Not reported	Not reported	Abbas et al[41]
KMCT Medical College	India	2016	Adrenal	7.6	“Normal”	Resection	CT	7	Disease progression, alive	Pradeep et al[11]
Saiseikai Kanazawa Hospital	Japan	2022	Thoracic vertebrae	Not reported	3.1	Biopsy	CT	8	Disease progression, deceased	Shirota et al[42]
HCC arising from ectopic liver tissue2
Center for Adult Diseases, Osaka	Japan	1973	Lesser sac	24	Not reported	Autopsy	Autopsy	N/A	N/A	Horiuchi
Kanazawa University	Japan	1988	Multifocal peritoneum, diaphragm	Not reported	117000	Resection	CT, ultrasound, angiography	39	Multifocal metastases in liver, deceased	Kawahara et al[43]
National Cancer Center Institute	Japan	1994	Left diaphragm	3	2207	Resection	CT, angiography	96	Alive, recurrence-free	Takayasu et al[44]
Università di Udine	Italy	1994	Left subphrenic	6.5	2325	Resection	CT, angiography	12	Alive, recurrence-free	Basile et al[16]
Ohmuta Municipal Hospital, Chiba University School of Medicine	Japan	1999	Gastric	4	4900	Resection	CT, ultrasound, angiography	12	Multifocal hepatic and pulmonary metastases, deceased	Arakawa et al[10]
Université Bordeaux	France	1999	Left subphrenic	Not reported	Not reported	Resection	MRI	Not reported	Not reported	Le Bail et al[45]
Hôpital Beaujon	France	2000	Chest wall	11	“Normal range”	Resection	CT, ultrasound, MRI, angiography	36	Alive, recurrence-free	Asselah et al[46]
Korea University College of Medicine	South Korea	2003	Left subphrenic	9	Not measured	Resection	CT	23	Multifocal hepatic metastases, alive	Kim et al[47]
Molinette Hospital (3)	Italy	2003	Gallbladder (1), perisplenic (2),	9 (2), 10 (1)	4000 in one	Resection	CT	48-alive, recurrence-free; 4-multifocal hepatic recurrence; 48-alive, recurrence-free		Leone et al[48]
Otsu Red Cross Hospital	Japan	2006	Lower abdomen / small bowel	7	99100	Resection	CT, MRI, angiography	18	Alive, single hepatic recurrence	Shigemori et al[49]
National Defense Medical Center	Taiwan	2007	Left diaphragm	10	45000	Resection	CT, ultrasound	8	Alive, recurrence-free	Huang et al[50]
University of Florida College of Medicine	United States	2007	Pancreatic	3.7	Not reported	Resection	CT	15	Alive, recurrence-free	Cardona et al[51]
National Taiwan University College of Medicine	Taiwan	2007	Lower abdomen / small bowel	15	87500	Resection	CT, ultrasound, MRI	Not provided	Not provided	Liu et al[52]
Dokkyo University Hospital	Japan	2007	Pancreatic	6.5	Not measured	Resection	CT, MRI, angiography	36	Alive, recurrence-free	Kubota et al[53]
Korea University College of Medicine	South Korea	2008	Left subphrenic	4.1	“Within normal limits”	Resection	CT	Not reported	Not reported	Seo et al[17]
Chhatrapati Shahuji Maharaj Medical University	India	2010	Left suprarenal	8	“Strongly positive”	Resection	CT	6	Multifocal metastasis, deceased	Singh et al[54]
Oita University Faculty of Medicine	Japan	2011	Left subphrenic	Not provided	84865	Biopsy	CT	Not provided	Not provided	Nishikawa et al[55]
Hekinan Municipal Hospital	Japan	2011	Perisplenic	6	Not reported	Autopsy	CT	33	Deceased	Matsuyama et al[56]
Fukuoka University	Japan	2012	Diffuse peritoneal	1	241	Biopsy	CT, PET	Not provided	Systemic treatment for disseminated disease	Miyake et al[57]
Recep Tayyip Erdogan University Training and Research Hospital	Turkey	2014	Para-aortic / adrenal	6.4	20000	Biopsy	CT, Ultrasound	Not provided	Not provided	Yuce et al[58]
University of Oslo	Norway	2015	Left subphrenic	3.5	200	Resection	CT, ultrasound, MRI	48	Alive, 3 focal recurrences resected	Aarås et al[59]
Inje University College of Medicine	South Korea	2015	Left subphrenic	3.8	Not provided	Resection	CT	17	Alive, recurrence-free	Lee et al[60]
Third Military Medical University, Chongqing	China	2016	Multifocal (perigastric, paraortic, pulmonary)	6.4	24793	Biopsy	CT, MRI, PET	15	Alive, on systemic therapy	Cui et al[61]
Medical University of Lodz	Poland	2017	Pancreatic	2.5	“Not elevated”	Resection	CT	24	Alive, recurrence-free	Braun et al[62]
West China Hospital, Sichuan University	China	2017	Pancreatic	5	1200	Resection	CT, ultrasound, MRI, PET	21	Alive, recurrence-free	Li et al[63]
Zhejiang University School of Medicine	China	2017	Multifocal (gastrohepatic ligament, perisplenic, pelvic)	30	8.0	Resection	CT, MRI	22	Multifocal recurrences, deceased	Jin et al[64]
University of Arkansas for Medical Sciences	United States	2017	Within choledochal cyst	Not provided	2.9	Biopsy	CT	Not provided	Not provided	George et al[65]
Complejo Hospitalario de Navarra	Spain	2019	Mesentery	8	651	Resection	CT, ultrasound	24	Alive, recurrence-free	Martínez-Acitore et al[66]
Kumamoto University	Japan	2020	Peripancreatic	7.5	1.7	Resection	CT, MRI, PET	8	Alive, recurrence-free	Adachi et al[14]
New York Medical College	United States	2021	Adrenal	9.1	1.9	Resection	CT, MRI	10	Alive, multifocal recurrence	Wei et al[67]

¹Cases of extrahepatic hepatocellular carcinoma (HCC) presentation with workup identifying concurrent hepatic tumors and cases of pedunculated HCC with extrahepatic growth were excluded.

²Of 17 additional cases of ectopic hepatocellular carcinoma were identified in the review by Arakawa et al[10] with reports only available in Japanese.

AFP: Alpha-fetoprotein; CT: Computed tomography; MRI: Magnetic resonance imaging; PET: Positron emission tomography; TACE: Trans-arterial chemoembolization; HCC: Hepatocellular carcinoma.

These aforementioned cases represent a minority of patients with HCC, as most patients with extrahepatic disease also have locally advanced primary tumors[7]. Several staging systems have been created to predict the prognosis for patients with HCC. Primary tumors < 2 cm in diameter are considered early-stage local disease under the American Joint Committee on Cancer[18], Barcelona Clinic Liver Cancer[19], and Hong Kong Liver Cancer staging systems[20]. Macrovascular invasion, large tumor size, multifocality, and high AFP level have been previously reported to be risk factors for extrahepatic metastasis[21-23]. Despite having few of these features associated with risk for extrahepatic disease, our patient atypically developed nodal metastasis with small hepatic tumors and moderately differentiated tumor histology.

Additionally, hepatic lesions were not noted on serial contrast enhanced CTs prior to surgical resection of the portocaval mass, and gadobutrol-contrasted MRI was ultimately used post-operatively to detect the primary hepatic lesions. Historically, studies evaluating the sensitivity of CT and MRI in diagnosing HCC have been equivocal[24,25], likely reflecting the unique features and advantages of each modality; CT has greater spatial resolution and is less prone to artifact, while MRI has superior soft tissue contrast[26]. However, several recent studies have reported higher sensitivity of MRI over CT in the detection of HCC lesions under 2 cm[2,27,28]. Use of hepatobiliary agent gadoxetate with MRI additionally increases sensitivity and positive predictive value over CT and MRI with other contrast agents[26,27]. In our patient, MRI identification of hepatic lesions after resection of his extrahepatic HCC was critical in classifying his disease as metastatic HCC[9,12,13,29-42], which requires adjuvant treatment, rather than ectopic HCC for which resection would be curative[10,14,16,17,43-67].

CONCLUSION

Our case illustrates that, although uncommon, early-stage HCC can seldomly present with extrahepatic metastasis in a patient without prior diagnosis of HCC. Contrast-enhanced CT may not identify small hepatic lesions. In the workup of undifferentiated masses in patients with risk factors for HCC (such as hepatitis C in our patient), multimodal evaluation that includes AFP and contrast-enhanced MRI may improve the sensitivity of the diagnostic algorithm in identifying primary HCC lesions. In patients found to have extrahepatic HCC without apparent hepatic lesion on CT, additional evaluation with MRI should be considered to exclude primary intrahepatic HCC and distinguish metastatic disease from ectopic HCC.