Hepatic Sarcoidosis Mimicking a Metastatic Tumor

Abstract

Although the liver is often involved in sarcoidosis, the majority of patients are asymptomatic and have a normal liver function; therefore, hepatic sarcoidosis may sometimes not be recognized in clinical practice. Radiologically, most hepatic nodules show hypoenhancement on contrast-enhanced computed tomography or magnetic resonance imaging (MRI) and they are hypointense across all sequences of MRI. In this case, hepatic nodules were slightly hyperintense on T2-weighted images and contrasted from the early phases on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid. We faced difficulties in distinguishing hepatic sarcoidosis from metastatic liver tumors with concurrent duodenal adenocarcinomas. Consequently, this case was diagnosed based on the pathological findings from a laparoscopic lateral segment hepatectomy.

Introduction

Sarcoidosis is a multisystem inflammatory disease characterized by the formation of non-caseating granulomas. The pulmonary system is the most commonly involved organ, accounting for 90% of all cases (1). Liver involvement is found in approximately 50-65% of cases (2), but the majority of patients are asymptomatic with normal liver enzyme tests. Radiologically, most cases of hepatic sarcoidosis are hypodense nodules relative to the adjacent normal parenchyma without peripheral enhancement on contrast-enhanced computer tomography (CE-CT) (3). On magnetic resonance imaging (MRI), nodules appear as hypointense in all sequences (4,5). Furthermore, nodules are most conspicuous on T2-weighted fat-saturated and early phase gadolinium-enhanced T1-weighted images (5). We herein report a case of hepatic sarcoidosis that was difficult to distinguish from metastatic liver tumors due to atypical CT and MRI findings with concurrent duodenal adenocarcinoma. The patient was finally diagnosed based on the pathological findings obtained from a laparoscopic lateral segment hepatectomy.

Case Report

A 68-year-old woman presented to our clinic with suspected liver tumors detected on non-contrast CT. The CT one year earlier showed no liver tumors. She received prednisolone 2 mg per day for suspected systemic lupus erythematosus and underwent mitral annuloplasty at the age of 59 years. The patient had no history of drinking or smoking.

At the time of the visit, her blood pressure was 143/80 mmHg and her pulse was 71 beats per minute. Laboratory findings showed that liver function tests, angiotensin-converting enzyme (ACE), immunoglobulin G4, and tumor markerssuch as carcinoembryonic antigen, carbohydrate antigen19-9, α-fetoprotein (AFP), and protein induced by vitamin K absence or antagonist-2 were within normal ranges. The soluble form of interleukin-2 receptor (sIL-2R) was elevated. Hepatitis B surface antigen and hepatitis C antibody tests were negative (Table).

Table.

The Laboratory Findings.

WBC	7,000	/μL		Na	142	mEq/L		HBsAg	(-）
RBC	434×104	/μL		K	3.9	mEq/L		HCV Ab	（-）
Hb	12.3	g/dL		Cl	103	mEq/L		CEA	<1.0	ng/mL
Hct	37.6	%		Ca	9.1	mg/dL		CA19-9	5.9	U/mL
Plt	253.6	×104/μL		BUN	12	mg/dL		AFP	4.1	ng/mL
				Cre	0.63	mg/dL		PIVKA-2	20	mAU/mL
				AST	22	U/L		IgG4	48	mg/dL
				ALT	15	U/L		ACE	14.9	IU/mL
				ALP	95	U/L		sIL-2R	822	U/mL
				γ-GTP	26	U/L
				T-Bil	0.4	mg/dL
				LDH	154	U/L
				TP	8.2	g/dL
				Alb	3.8	g/dL
				CK	30	U/L
				CRP	1.74	mg/dL

WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Ht: hematocrit, Plt: platelet, BUN: blood urea nitrogen, Cre: creatinine, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T-Bil: total bilirubin, LDH: lactate dehydrogenase, TP: total protein, Alb: albumin, CK: creatine kinase, CRP: C-reactive protein, HBsAg: hepatitis B surface antigen, HCV Ab: hepatitis C antibody, CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen19-9, AFP: α-fetoprotein, PIVKA-2: protein induced by vitamin K absence or antagonist-2, IgG: immunoglobulin G, ACE: angiotensin-converting enzyme, sIL-2R: soluble form of the interleukin-2 receptor

CE-CT revealed multiple hepatic nodules with peripheral enhancement and swelling of the para-aortic lymph nodes (Fig. 1). No hepatomegaly or splenomegaly was observed. On MRI, hepatic nodules were hypointense on T1-weighted images, slightly hyperintense on T2-weighted images, and hyperintense on diffusion-weighted images. On gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI), the nodules showed contrast from the early phases and were hypointense compared to the surrounding area in the hepatobiliary phase (Fig. 2). Sonazoid-enhanced ultrasound showed oval-shaped nodules that were hypoechoic in the early vascular, late vascular, and Kupffer phases (Fig. 3).

Figure 1.

Plain (a, d), arterial phase (b, e) and portal phase (c, f) of contrast-enhanced computer tomography (CE-CT) images revealed that multiple hepatic nodules (red arrows), which peripherally enhanced, and para-aortic lymph nodes swelling (g, h) (green arrows).

Figure 2.

T1-weighted (a, h), T2-weighted (b, i), diffusion-weighted (c, j), arterial phase (d, k), portal phase (e, l), late phase (f, m), and hepatobiliary phase (g, n) of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) images. Red arrows indicate hepatic nodules.

Figure 3.

Sonazoid-enhanced ultrasound (US) images. The nodules showed oval-shaped nodules, which were hypoechoic in the early vascular (a), late vascular (b) and Kupffer phase (c). Red arrows indicate hepatic nodules.

Based on these findings, the hepatic nodules were suspected to be metastatic tumors; therefore, esophagogastroduodenoscopy (EGD) was performed. A highly elevated and erythematous lesion measuring approximately 25 mm in size was found in the second portion of the duodenum (Fig. 4). Biopsies of the lesion revealed a pathological suspicion of adenocarcinoma. However, colonoscopy revealed no tumor lesions.

Figure 4.

Initial esophagogastroduodenoscopy (EGD) images of a tumor in the second portion of duodenum.

We then performed ¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT). FDG accumulation was observed in the hepatic nodules (SUVmax 4.5 early→4.9 delayed), duodenal tumors (SUVmax 3.6 early→5.6 delayed), and para-aortic lymph nodes (SUVmax 4.8 early→6.8 delayed) (Fig. 5).

Figure 5.

¹⁸F-fluorodeoxyglucose positron emission tomography-CT (FDG-PET/CT) images. FDG accumulation was observed in the hepatic nodules (SUVmax 4.5 early→4.9 delayed), duodenal tumor (SUVmax 3.6 early→5.6 delayed), and the para-aortic lymph nodes (SUVmax 4.8 early→6.8 delayed). Maximum intensity projection (a) and fused images (b-f).

Based on the radiological and endoscopic findings, metastatic liver tumors from duodenal adenocarcinomas were suspected. However, this case was atypical because of the absence of swollen lymph nodes in the duodenum. To establish a definitive diagnosis, ultrasound-guided liver biopsies of hepatic nodules were performed. Two biopsies were performed, and a histological examination showed fibrosis (F1-2) and inflammation (A2-3) according to the new Inuyama classification, with lymphocyte predominance in the perilobular regions. Interface hepatitis and bile duct hyperplasia were also observed. However, no evidence of destructive cholangitis or biliary stasis was found. As the findings were nonspecific, with no granulomas or malignancy, a definitive diagnosis could not be made (Fig. 6a, b). Therefore, laparoscopic lateral segment hepatectomy and para-aortic lymph node sampling were performed with sufficient informed consent. A histological examination revealed non-necrotizing granulomas with Langhans giant cells in the periportal area (Fig. 6c-g). Focal inflammation, predominantly composed of lymphocytes, was observed surrounding the granulomas (Fig. 6h, i). Acid-fast and Grocott staining results were negative. Additionally, non-necrotizing granulomas with Langhans giant cells were confirmed in the para-aortic lymph nodes.

Figure 6.

Histological images of liver of biopsy specimens (a, b) and resected laparoscopic lateral segment hepatectomy (c-i). Non-necrotizing granulomas with Langhans giant cells (yellow arrows) were found in the periportal area.

Consequently, the patient was diagnosed with hepatic sarcoidosis concurrent with duodenal adenocarcinoma. In this case, there was no involvement of the pulmonary, cardiac, central nervous, ocular, or skin systems. For hepatic sarcoidosis, the prednisolone dose was increased and then tapered off, and the patient is currently under observation without any steroid therapy.

Although the duodenal tumor had grown since the initial EGD (Fig. 7a-c), laparoscopic-endoscopic cooperative surgery was performed (Fig. 7d, e). A histological examination revealed superficial duodenal adenocarcinoma, and a successful endoscopic and histological resection was achieved (Fig. 7f).

Figure 7.

Esophagogastroduodenoscopy images of the duodenal tumor before laparoscopic-endoscopic cooperative surgery (a-c) and the resected specimen (d, e). Pathohistological findings; Adenocarcinoma, tub1, pT1a (M), 45×31 mm, Type 0-IIa, Ly0, V0, pUL0, pHM0, pVM0 (f).

Discussion

We report a case of hepatic sarcoidosis that was difficult to distinguish from metastatic tumors due to preoperative atypical CT and MRI findings. In this case, the surgical pathology revealed non-necrotizing granulomas with Langhans giant cells, thus leading to a definitive diagnosis of hepatic sarcoidosis.

Regarding the radiological findings of hepatic sarcoidosis, CT and MRI are useful for determining liver involvement and evaluating hepatomegaly. Hepatomegaly is a common finding on CT (6), while focal nodules are reported in only 0-19% of patients (7-9), which show hypoattenuating nodules on CE-CT (10). On MRI, nodules are hypointense across all sequences, particularly on T2-weighted fat-saturated images (5,6). On gadolinium-enhanced images, hypoenhanced nodules relative to the background of the liver help to differentiate them from metastases and lymphomas (11). In this case, the hepatic nodules were peripherally enhanced on CE-CT and EOB-MRI, raising suspicion of metastatic tumors (11). Additionally, the hepatic nodules were slightly hyperintense on T2-weighted images, which reflected the degree of activity and indicated the presence of inflammation, lymphoid cell infiltration, and edema (12,13). Therefore, the hepatic nodules in this case were considered to be highly active. The findings from FDG-PET/CT were helpful in evaluating the involved organs, including the liver and lymph nodes, but did not contribute to the differentiation of metastatic liver tumors.

Radiological findings alone were not the only reason why it was difficult to distinguish from metastatic liver tumors, as summarized below. First, the patient had concurrent duodenal adenocarcinoma. In cases of duodenal adenocarcinoma, the incidence of lymph node metastasis from submucosal (SM) -invasive tumors is approximately 5% (14,15). The tumor was approximately 25 mm in size and had a highly elevated lesion. Therefore, SM invasion could not be ruled out. Second, the ACE levels were within the normal range. Third, pulmonary involvement, which is the most common manifestation of sarcoidosis, was not observed. Finally, a total of two liver biopsies did not provide a definitive diagnosis. Therefore, it was difficult to distinguish hepatic sarcoidosis from metastatic liver tumors. Consequently, the patient underwent surgical resection after obtaining sufficient informed consent, and the pathological findings confirmed the diagnosis of hepatic sarcoidosis. Similar to our case, hepatic sarcoidosis has been reported to mimic metastatic lesions (16-18) and cholangiocellular carcinoma (19), which require either a biopsy or surgery in order to make a definitive diagnosis.

A histopathological examination is usually necessary to confirm the diagnosis and distinguish it from other hepatic granulomatous diseases, especially primary biliary cirrhosis (PBC) (20) and infectious disorders. Sarcoid granulomas are most commonly found within the portal tracts and periportal zone, which contrasts with the findings in PBC and infectious disorders (1). In this case, sarcoid granulomas were found within the periportal zone and non-necrotizing granulomas with Langhans giant cells were confirmed in the hepatic nodules. Surrounding the granulomas, focal inflammation predominantly composed of lymphocytes was observed, which is consistent with the high intensity observed on T2-weighted images. Additionally, a histopathological examination of the para-aortic lymph nodes revealed findings similar to those of the hepatic nodules. Enlarged abdominal lymph nodes are detected in approximately 30% of patients with sarcoidosis, particularly in the porta hepatis, para-aortic region, and celiac axis (6). In our case, the abdominal lymph nodes affected by sarcoidosis were typically smaller and less confluent than those observed in lymphomas (6,21).

In sarcoidosis, hepatic involvement is found in approximately 50-65% of all cases (2). Additionally, postmortem studies have indicated that hepatic granulomas are found in as many as 70% of sarcoidosis cases (22). Because the majority of patients are asymptomatic and have normal liver enzyme test results, liver involvement may not be well recognized in clinical practice. Specific symptoms of hepatic sarcoidosis include jaundice, pruritus, right upper abdominal pain, and hepatomegaly (23,24). These symptoms are most likely due to chronic bile stasis caused by intrahepatic granulomas in the portal area (1). Some patients with hepatic sarcoidosis can develop serious complications, such as portal hypertension (25), cirrhosis (23,26), and Budd-Chiari syndrome (27). Furthermore, other studies have reported a correlation between hepatic sarcoidosis and hepatocellular carcinoma (28,29). In this case, granulomas were found in the periportal area, which could lead to cholestasis and potential complications in the future. Therefore, a careful follow-up is required.

In conclusion, this case demonstrated some of the challenges in distinguishing hepatic sarcoidosis from metastatic tumors in the context of concurrent duodenal adenocarcinoma. Even with atypical radiographic images, such as slightly hyperintense T2-weighted MR images and peripherally enhanced nodules on CE-CT and EOB-MRI, hepatic sarcoidosis should be included in the differential diagnosis, and liver biopsies are recommended.

The authors state that they have no Conflict of Interest (COI).