Unusual presentation of synchronous double primary gallbladder and hepatic malignancies: A case report

Abstract

BACKGROUND

Synchronous double primary malignancies of the gallbladder and liver are exceedingly rare clinically and prone to misdiagnosis as metastatic lesions. Due to anatomic contiguity and overlapping imaging characteristics, distinguishing primary carcinomas from metastatic disease is challenging, often delaying curative-intent treatment. Current lack of consensus on management underscores the imperative to investigate their pathologic features and individualized strategies for improved prognostication.

CASE SUMMARY

This study presents a rare case of synchronous double primary malignancies involving both gallbladder adenocarcinoma and hepatocellular carcinoma. Following a comprehensive analysis of the patient’s diagnostic workup, therapeutic interventions, and 12-month follow-up outcome, the clinicopathological characteristics and prognostic determinants of such synchronous malignancies are described. These findings offer valuable guidance for clinicians in optimizing diagnostic strategies and treatment decision-making for complex presentations of multiple primary cancers.

CONCLUSION

The critical insights obtained from this case, integrated with a review of current literature, identify the key diagnostic challenges in differentiating primary vs metastatic lesions and propose a multidisciplinary management framework.

Key Words: Multiple primary cancers; Metastatic cancer; Multidisciplinary team; Diagnosis and treatment; Prognosis; Case report

Core Tip: The synchronous double primary malignancies of the gallbladder and liver represent an exceedingly rare clinical entity with no established management consensus. We present a distinctive case of a 70-year-old patient who achieved no evidence of disease status following multidisciplinary intervention. This case highlights the diagnostic challenges in distinguishing synchronous primaries from metastatic disease, underscores the critical role of histopathological confirmation, and demonstrates the potential for favorable outcomes through aggressive surgical intervention. Our experience provides valuable insights for managing such complex cases.

INTRODUCTION

Synchronous multiple primary cancers (MPCs) refer to the occurrence of two or more independently originating malignant tumors diagnosed in the same patient within a 6-month interval, posing significant challenges in clinical diagnosis and management. Synchronous double primary carcinomas of the gallbladder and liver are exceptionally rare and are frequently misdiagnosed as metastatic disease, leading to inappropriate therapeutic strategies. Studies indicate that synchronous MPCs account for approximately 2%-8% of all cancer cases, with a notable predominance in the digestive system; however, reports of synchronous gallbladder and hepatocellular carcinoma (HCC) remain exceedingly scarce[1]. This article presents a case of a 70-year-old female with moderately differentiated gallbladder adenocarcinoma coexisting with HCC, highlighting the diagnostic pitfalls and therapeutic approaches through multidisciplinary collaboration, radiological and pathological evaluation, aiming to provide valuable insights for clinical practice.

CASE PRESENTATION

Chief complaints

A 70-year-old female patient was admitted on July 1, 2024, with a 20-day history of abdominal distension and incidentally discovered gallbladder space-occupying lesions identified 9 days previously.

History of present illness

Initial symptoms included intermittent epigastric and dorsal pain without fever, chills, nausea, or vomiting. Previous ultrasound at an external hospital revealed gallbladder occupation, hepatic space-occupying lesions, cholelithiasis, and liver cirrhosis. Notable clinical features included reduced appetite, mild fatigue, a 5 kg weight loss, and normal bowel/bladder function.

History of past illness

The patient’s medical history included a 40-year chronic hepatitis B virus (HBV) infection without regular monitoring or antiviral therapy, 15 years of untreated cholelithiasis, and a remote hysterectomy for uterine fibroids.

Personal and family history

The patient denies any history of tobacco use or alcohol consumption. There is no family history of similar conditions.

Physical examination

The patient has an Eastern Cooperative Oncology Group performance status of 1 and a numerical rating scale score of 2, with mild icterus noted in the skin and sclera. The abdomen is flat and symmetrical without abdominal wall varicosities, visible peristalsis, or intestinal patterns. On palpation, the abdomen is soft and non-tender with no rebound tenderness or palpable masses. The liver and spleen are non-palpable below the costal margin with negative Murphy’s sign. Percussion reveals the upper liver border at the 5^th intercostal space on the right midclavicular line without hepatorenal tenderness or shifting dullness. Bowel sounds are normal at 4/minute with no vascular bruits auscultated.

Laboratory examinations

Liver function tests showed no abnormalities: Albumin (36 g/L), total bilirubin (12.55 μmol/L), alanine aminotransferase (25 U/L), aspartate aminotransferase (33 U/L), alanine aminotransferase/aspartate aminotransferase (0.76), prothrombin time (12.0 seconds), international normalized ratio (1.11), and Child-Pugh grade A. Results of tests for tumor markers were as follows: Cancer antigen-199 227.3 U/mL (elevated), alpha-fetoprotein 5.8 ng/mL (normal), and protein induced by vitamin K absence-II 42.39 mAU/mL (elevated). Serology showed positive hepatitis B surface antigen and HBV DNA of 7.513 × 10⁵ IU/mL.

Imaging examinations

Dynamic contrast-enhanced abdominal computed tomography (CT) demonstrated irregular gallbladder wall thickening, enlarged porta hepatis lymph nodes (suspected metastasis), and multiple hypodense hepatic lesions (Figure 1). Magnetic resonance imaging with contrast revealed T1-short/T2-long nodular lesions with diffusion restriction and enhancement, strongly suggestive of gallbladder carcinoma (Figure 2A). Additional hepatic lesions showed variable enhancement patterns (Figure 2B-D), warranting differentiation between HCC and metastasis. Positron emission tomography (PET)-CT confirmed metabolically active gallbladder lesions [maximum standardized uptake value (SUVmax): 8.0] and suspicious lymph nodes (SUVmax: 5.3). A left hepatic lobe nodule (SUVmax: 3.5) remained indeterminate.

Figure 1 Abdominal computed tomography. A: Abdominal computed tomography showing a 2.0 cm × 1.0 cm mass in the gallbladder. Arrow: Gallbladder mass (axial view); B: Abdominal computed tomography showing a 1.6 cm × 1.5 cm lesion in the left lateral lobe of the liver. Arrow: Liver lesion (axial view).

Figure 2 Abdominal magnetic resonance imaging scan. A: Abdominal magnetic resonance imaging (MRI) scan showing a 2.0 cm × 1.0 cm mass in the gallbladder. Arrow: Gallbladder mass (axial view); B: Abdominal MRI scan showing a 1.6 cm × 1.5 cm lesion in the left lateral lobe of the liver. Arrow: Liver lesion (axial view); C: Abdominal MRI showing a 1.6 cm × 1.5 cm lesion in the left lateral lobe of the liver. Arrow: Liver lesion (coronal view); D: Abdominal MRI scan showing a 1.0 cm × 0.8 cm lesion in segment VI of the liver. Arrow: Liver lesion (axial view).

MULTIDISCIPLINARY EXPERT CONSULTATION

Two ultrasound-guided liver biopsies (July 5 and 9) revealed chronic active hepatitis with cirrhotic changes but no definitive malignancy. Multidisciplinary consensus recommended laparoscopic excision for histopathological confirmation. Laparoscopic exploration identified cirrhotic liver morphology with a 1.5 cm left lobe mass and a segment VI hyperechoic nodule. Severe gallbladder adhesions were noted.

FINAL DIAGNOSIS

Gallbladder adenocarcinoma and HCC.

TREATMENT

Cholecystectomy and lesion resections were performed, and the pathology of intraoperative frozen sections showed the following: Moderately differentiated adenocarcinoma in the gallbladder (T1b, Figure 3A); HCC in the left liver mass (grade II, Figure 3B); and a dysplastic nodule in the segment VI nodule. Radical resection involving pericholecystic hepatic parenchyma (2 cm margin) and lymphadenectomy (stations 8, 9, 12, 13) showed no metastasis.

Figure 3 Microscopic view. A: Microscopic view of gallbladder adenocarcinoma (with invasion into the muscular layer, 10 ×); B: Microscopic view of hepatocellular carcinoma (hematoxylin and eosin staining, 40 ×).

OUTCOME AND FOLLOW-UP

The patient had an uneventful recovery and was discharged on postoperative day 5. The current surveillance protocol (imaging and tumor marker monitoring every 3 months in the first year, and 6 months thereafter) showed no evidence of disease status and no recurrence or metastasis. The patient also received regular postoperative oral antiviral therapy with entecavir (0.5 mg orally once daily).

DISCUSSION

According to the diagnostic criteria established by Warren and Gates[2], this case represents a rare instance of MPCs. MPCs refer to the occurrence of two or more independent primary malignancies in the same individual, either synchronously or metachronously. Based on the diagnostic interval between tumors (< 6 months), this case qualifies as synchronous MPCs. The incidence of MPCs among cancer patients ranges from 2% to 8%, with gastrointestinal tumors being particularly common[1]. MPC cases primarily involve the digestive system, with initial tumors predominantly occurring in the stomach and colorectum, while synchronous dual primary cancers in the liver and gallbladder are exceptionally rare[3].

The diagnostic challenge in this case was differentiating MPCs from “gallbladder cancer with hepatic metastasis”. Despite the patient’s history of chronic HBV infection and liver cirrhosis suggesting a potential secondary primary malignancy, the absence of elevated alpha-fetoprotein levels, lack of typical HCC “rapid wash-in and wash-out” enhancement patterns on CT, and the inherent rarity of dual primary cancers complicated preoperative diagnosis. Previous studies have demonstrated statistically significant differences in SUVmax values (18 fluorine-fluorodeoxyglucose PET/CT) between primary and metastatic liver cancers, with primary HCC typically showing SUVmax ≈ 8.657 ± 1.169[4]. However, in the present study, the patient’s SUVmax of 3.5 deviated from these findings, highlighting both the limitations of PET/CT in MPC diagnosis and the irreplaceable “gold standard” status of pathological confirmation.

No standardized treatment protocol exists for MPC patients, with limited literature guidance. Current approaches follow general oncological principles, prioritizing management of tumors with poorer prognosis, immediate life-threatening potential, or symptomatic burden[5]. In this case, both primary cancers demonstrated early-stage features on intraoperative frozen section pathology, enabling successful R0 resection. Lyu et al[3] demonstrated through clinical analysis that radical treatment for all cancer foci significantly improves median survival (168 months vs 68 months in incomplete treatment groups). Kourie et al[6] emphasized surgical intervention and chemotherapy for synchronous MPCs, advocating R0 resection when feasible and dual-effective chemotherapeutic regimens for inoperable cases. When clinically permissible, aggressive radical treatments (including surgically manageable procedures and tolerable systemic therapies) should be implemented to optimize outcomes. Determining optimal intervention timing, treatment sequencing, and therapeutic combinations requires case-specific analysis and ongoing clinical exploration. With regard to the prognosis of MPCs, numerous studies suggest comparable survival outcomes between MPCs and single primary malignancies[7-9]. Li et al[10] reported comparable long-term survival in 14 cases of hepatogastric MPCs following radical resection to single-cancer counterparts. Notably, literature data indicate that MPC patient survival depends on the most aggressive tumor focus rather than tumor multiplicity[11]. Numerous studies have confirmed improved outcomes with radical MPC treatment[12-15].

This study has several limitations. First, the single-case design employed in this research indicates that our findings may not be representative of a wider population. While single-case designs facilitate in-depth analysis of individual cases, the results may be influenced by the specific characteristics of the patient, thereby limiting the generalizability of the findings. Therefore, we recommend that future studies adopt a multicenter design with larger sample sizes to enhance the representativeness and external validity of the results. Second, our study only included a short-term follow-up, which may restrict our understanding of the long-term treatment effects and potential delayed complications. To more comprehensively evaluate therapeutic outcomes, future research should incorporate long-term follow-up to monitor patients’ prolonged prognosis and quality of life.

In the present case, the patient underwent surgical resection of the tumor, resulting in the resolution of abdominal discomfort and significant improvement in nutritional status. At the six-month postoperative follow-up, the patient’s weight had increased by 5 kg. Based on our follow-up observations, the patient currently exhibits no evidence of disease and has experienced substantial improvement in quality of life. Since its establishment, our center has collected postoperative patients’ subjective perceptions of treatment efficacy through telephone interviews and questionnaires, including symptom relief, daily activity capacity, and psychosocial support. Preliminary assessments indicate that, despite some challenges during treatment, most patients experienced an overall improvement in quality of life post-treatment, particularly in physical function and psychological well-being. However, these findings require further validation in future studies with larger sample sizes and extended follow-up periods.

CONCLUSION

Key clinical insights from this case include the following: (1) Maintain diagnostic suspicion: Clinicians must maintain awareness of MPCs when evaluating multi-organ malignancies, rigorously clarifying tumor relationships rather than defaulting to “Occam’s razor” assumptions of metastasis that may delay appropriate treatment; (2) Standardized management: Implement comprehensive protocols encompassing preoperative multidisciplinary team discussions, intraoperative pathology-guided decision-making, and guideline-compliant postoperative surveillance; and (3) MPC ≠ advanced disease: As demonstrated by this case and a literature review, favorable prognoses remain achievable in MPC patients, warranting active therapeutic approaches. The exceptional rarity of synchronous hepatobiliary MPCs (both being aggressive gastrointestinal malignancies) underscores the need for multicenter studies to elucidate risk factors and prognostic patterns. The authors have compiled relevant data from national and international studies on such dual-primary cases (Table 1) for reference.

Table 1 Relevant data from national and international studies on dual-primary cases.

Patient number	Age (years)	Gallbladder lesion	Liver lesion	Treatment modalities	Prognosis of patients (not lost) (OS)
1	65	3 cm × 3 cm, highly differentiated adenocarcinoma	6.2 cm × 4.5 cm, hepatocellular carcinoma complicated with cholangiocarcinoma	Surgical treatment	8 months, dead
2	7	3.5 cm × 3 cm, moderately differentiated adenocarcinoma	2.8 cm × 2.4 cm, hepatocellular carcinoma complicated with cholangiocarcinoma	N/A	10 months, dead
3	56	1.9 cm × 1.5 cm, moderately differentiated adenocarcinoma	5 cm × 3 cm, hepatocellular carcinoma	N/A	28 months, dead
4	81	The cavity was full of moderately differentiated adenocarcinoma	7.8 cm × 6.5 cm, hepatocellular carcinoma	N/A	24 months, alive
5	54	Invasion of the whole layer, moderately differentiated adenocarcinoma	11 cm × 10 cm, hepatocellular carcinoma	N/A	2 months, dead
6	57	Invasion of the whole layer, moderately differentiated adenocarcinoma	5 cm × 5 cm, hepatocellular carcinoma	N/A	3 months, dead
7	63	5 cm × 3 cm, moderately differentiated adenocarcinoma	2.2 cm × 1.5 cm, hepatocellular carcinoma	Surgical treatment	17 months, alive
8	70	0.7 cm × 0.7 cm, highly differentiated adenocarcinoma	4.5 cm × 5.5 cm, hepatocellular carcinoma	Conservative treatment	4 months, dead
9	70	2 cm × 1 cm, moderately differentiated adenocarcinoma	1.6 cm × 1.5 cm, hepatocellular carcinoma	Surgical treatment	13 months, alive

OS: Overall survival; N/A: Not applicable.