Primary Hepatic Lymphoma with Hepatocellular Carcinoma: A Case Report

Summary

It is important to be alert for primary hepatic lymphoma (PHL) in patients with hepatocellular carcinoma (HCC) who display atypical clinical features and multiple lymphadenopathies. If lesions exhibit unexpected indocyanine green (ICG) enhancement during surgery, resection should be considered following a thorough evaluation.

Abstract

This case report highlights the diagnostic challenges associated with PHL and outlines corresponding diagnostic strategies, underscoring the importance of clinicians being vigilant for PHL in patients with HCC, particularly when clinical presentations and imaging features are atypical. Instead of making a decision based only on a positive ICG result, it is advised that clinicians thoroughly assess the features of the newly discovered lesions found through ICG imaging during the procedure, the patient's general condition, and the surgical risks before deciding whether to resect them. We conducted a retrospective analysis of a confirmed case of PHL complicated by HCC. indicates that even when HCC is suspected, the possibility of PHL should not be ruled out when diagnosing liver lesions; therefore, active screening is necessary. ICG imaging can serve as an adjunctive tool to improve the detection rate of lesions during surgery; however, its clinical value is limited for small-volume lesions that are not considered for surgical resection.

Introduction

Primary hepatic lymphoma (PHL) is an extremely rare extranodal lymphoma originating from hepatic lymphoid tissue or residual hematopoietic tissue¹, accounting for less than 0.016% of all non-Hodgkin lymphomas². Due to its diverse imaging manifestations and the lack of specific clinical symptoms, PHL is often misdiagnosed as hepatocellular carcinoma (HCC) or other liver mass lesions^2,3. Most patients present with non-specific symptoms such as upper abdominal pain, fever, and weight loss, and common laboratory findings include elevated lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels^4,5.

The differential diagnosis between PHL and HCC has important clinical implications. HCC is the most common primary liver cancer worldwide. Both HCC and PHL may present on imaging as solitary liver lesions with arterial enhancement, but their treatment regimens are vastly different: HCC is primarily treated with surgical resection, interventional therapy, or targeted therapy, whereas PHL requires systemic chemotherapy^6,7. A misdiagnosis can lead to unnecessary invasive treatments or delay the optimal treatment window. Although cases of coexisting PHL and HCC have been reported occasionally, the existing literature primarily focuses on pathological diagnosis, and there remains limited discussion regarding preoperative differential diagnosis strategies, comparisons of imaging features, and clinical decision-making pathways^7,8,9.

In recent years, indocyanine green (ICG) fluorescence imaging has become increasingly widespread in liver surgery¹⁰. The principle behind this technique is that normal liver cells rapidly excrete ICG via the bile ducts after uptake through the organic anion transport polypeptide (OATP8), whereas tumor tissue retains ICG due to impaired bile excretion, creating a fluorescent contrast¹¹. In HCC, well-differentiated cancer cells partially retain OATP8-mediated uptake but exhibit impaired excretion, resulting in “neoplastic fluorescence”; in contrast, PHL, as a tumor of the lymphohematopoietic system, lacks the hepatocyte-specific ability to take up ICG. Its imaging mechanism may rely on tumor compression of surrounding liver tissue, leading to delayed ICG excretion and the formation of characteristic “ring-shaped fluorescence”^12,13.

The core value of ICG technology lies in its ability to detect occult lesions not identified by preoperative imaging. Studies have shown that ICG fluorescence imaging can detect microscopic lesions on the liver surface as small as 2 mm in diameter¹⁴. In this study, intraoperative ICG fluorescence imaging successfully identified a PHL lesion missed by conventional imaging, confirming its unique value in detecting rare liver tumors. Although ICG fluorescence imaging is highly sensitive, decisions regarding the resection of fluorescence-positive lesions during surgery should be based on a comprehensive assessment. Resection of typical fluorescence lesions may be considered, whereas the decision to resect atypical fluorescence lesions should be made only after careful evaluation. Additionally, in patients with liver masses accompanied by multiple enlarged lymph nodes, PHL should be included in the differential diagnosis.

This report presents a pathologically confirmed case of HCC coexisting with PHL, focusing on the value of ICG fluorescence imaging in detecting occult lesions and key points for differential diagnosis, to guide the diagnosis and management of similar rare cases.

Case Presentation:

This case analysis involves a 57-year-old male patient admitted to our hospital in July 2024 after a hepatic lesion was identified during routine physical examination. The patient remained asymptomatic, with no fever, chills, cardiovascular symptoms, or gastrointestinal complaints such as nausea, vomiting, or abdominal discomfort. The patient's medical history was notable for primary aldosteronism with secondary hypertension lasting one month, along with a 40-year history of heavy smoking (20 cigarettes/day) and chronic alcohol intake (60 g/day of ethanol).

Diagnosis, Assessment, and Plan:

Enhanced MRI (Figure 1A,B) shows a mass in the V/VIII sector of the liver, measuring approximately 45 mm × 42 mm × 50 mm; its morphological features are consistent with HCC. In addition, there is a mass in the left lateral lobe that does not show significant enhancement on the contrast-enhanced images; enhanced CT scan (Figure 2A,B) shows that the mass in the left lobe of the liver appeared identical to the liver parenchyma during both the venous and arterial phases, with no significant enhancement observed. This confirms the findings of the MRI examination and strongly suggests that the mass located in segments V/VIII of the liver is hepatocellular carcinoma. On physical examinations, the patient’s primary positive finding was mild tenderness in the right upper abdomen; no other significant abnormalities were observed. Laboratory examination results showed tumor markers: carcinoembryonic antigen (CEA) at 6.83 ng/mL and alpha-fetoprotein (AFP) at 6.89 ng/mL. Among liver function markers, alanine aminotransferase (ALT) was 23.9 IU/L, ALP was 110.3 IU/L, and LDH was within normal limits. Renal function parameters showed serum creatinine at 64 µmol/L and an estimated glomerular filtration rate (eGFR) of 119.59 mL/min/1.73 m²; all eight items in the infectious disease screening were negative. (Supplementary Table 1 summarizes the results of the above ancillary tests.)

Based on the above evidence, imaging examinations demonstrated a space-occupying lesion in segments V and VIII of the liver consistent with the characteristics of hepatocellular carcinoma (HCC). Given the patient’s good liver and kidney function, overall good health, and absence of contraindications for surgery, the patient underwent the surgery on August 21, 2024.

Protocol

The operation followed standard procedures and received ethics approval. This study was permitted by the Ethics Committee of Third Affiliated Hospital of Guangzhou Medical University (Approval No. of the Medical Ethics Committee: [2025] No. 038). Informed written consent was obtained from the patient. The research content and methods adhered to medical ethics norms and requirements. The reagents and equipment used in the study are listed in the Table of Materials.

1. Preoperative Preparation:

1. Fasting and fluid restriction: Solid food was withheld for 8 h and clear liquids for 2 h before induction to reduce the risk of aspiration pneumonitis¹⁵.
2. Mechanical bowel preparation: Beginning at 14:00 the day before surgery, 2000 mL of polyethylene glycol-electrolyte solution was ingested until the effluent was clear.
3. Skin degreasing and disinfection: Two full-body showers were taken on the evening before surgery and again on the morning of surgery, with particular attention to the umbilicus; a sterile gown was donned in the morning.
4. Fluorescent-contrast administration: Two days before surgery, 0.2 mg/kg of indocyanine green was injected intravenously by the ward nurse to ensure adequate near-infrared fluorescence imaging, with emergency resuscitation equipment readily available due to the risk of anaphylaxis¹⁶.
5. Informed consent: The attending surgeon reiterated the extent of resection, risks of fluorescence navigation, and management of additional lesions; the patient or legal representative then signed the operative consent.
6. Pre-entry checks: Removable dentures, watches, necklaces, earrings, and eyeglasses were removed; the bladder was emptied, and the patient was escorted into the restricted surgical zone.

2. Surgical Procedure:

1. Anesthesia and positioning.
   1. General anesthesia with endotracheal intubation.
   2. Supine, legs apart, 20° reverse-Trendelenburg, 15° left tilt, no kidney bridge.
2. Pneumoperitoneum and trocar placement.
   1. A 12 mm Hg pneumoperitoneum was created via a 1 cm supra-umbilical Veress needle, with intraperitoneal placement confirmed before insufflation to prevent extraperitoneal insufflation¹⁷.
   2. Five ports (5/12 mm) were inserted using a five-trocar technique and connected to a three-way stopcock and insufflation tubing.
3. Fluorescence mapping and verification checkpoints: Both intraoperative verification checkpoints (segments V/VIII and segment IV) were prospectively defined prior to surgery based on preoperative imaging findings and were consistently applied during the procedure.
   1. First verification point (segments V/VIII): a 55 mm × 40 mm area of hypoechoic tissue was identified, consistent with the intense ICG fluorescence typical of HCC. The tissue was firm in consistency. This area was marked with an ultrasonic scalpel for subsequent resection.
   2. Second verification point (segment IV): a 20 mm × 30 mm area of abnormal fluorescence was incidentally detected, with signal intensity higher than that of the surrounding liver parenchyma, suggesting that the nature of this lesion differs from that of the primary lesion; during surgery, the area was found to be firm and hard to the touch, and it was marked with an ultrasonic scalpel for subsequent resection.
   3. Visibility criteria: Lesions must be clearly visible to the naked eye in fluorescence mode, with a minimum detectable lesion diameter of ≥20 mm.
4. Hepatic inflow control.
   1. The hepatoduodenal ligament was dissected and encircled with a tape.
   2. Intermittent Pringle maneuver: 15 min clamp / 5 min release cycles.
5. Parenchymal transection.
   1. Liver parenchyma was sequentially divided with an ultrasonic scalpel plus bipolar cautery, and the liver parenchyma and intrahepatic vessels were transected using a stapler (staple size: 35 mm × 2.5 mm).
   2. Structures ≥ 2 mm were clamped and ligated with 3-0 suture; those < 2 mm were clipped.
6. Specimen retrieval.
   1. The segment 5/8 specimen was placed in a 130 mL bag, the segment 4 specimen in a 60 mL bag.
   2. Both were extracted intact through the 12 mm port to avoid wound seeding.
7. Raw surface management: Active bleeding was controlled with bipolar electrocautery; larger breaches were closed with barbed sutures and sealed with fibrin glue and absorbable vascular sealing medical adhesive (model: 2 mL).
8. Drainage and closure.
   1. A drainage tube was positioned in the right subhepatic space, and a drainage tube at the segment 4 bed; both exited the right lateral abdominal wall and were secured with 7-0 silk.
   2. After the instrument and sponge were counted to confirm accuracy, the fascial defects were closed, and the skin was approximated subcutaneously.
9. Surgical Parameters Record.
   1. Total operative time: 300 min.
   2. Intraoperative blood loss: 200 mL.
   3. Blood transfusion status: None.

3. Postoperative Care:

1. Recovery monitoring.
   1. 1 h observation in the PACU; returned to the ward when the Steward score ≥4.
   2. Continuous ECG and SpO₂ monitored for 24 h.
2. Drain management.
   1. Both drains were connected to sterile closed bags; daily output and characteristics were recorded.
   2. Removal criteria: < 20 mL/day of non-bilious fluid. The 22-Fr drain was removed on POD 5, the 14-Fr drain on POD 6.
3. Early mobilization and diet.
   1. Turned in bed at 6 h; ambulated within 24 h.
   2. Diet was advanced from clear to full liquids to regular food within 48 h, supplemented with 500 kcal/day of enteral nutrition.
4. Laboratory follow-up.
   1. CBC and liver/renal panels were checked on POD 1, 3, and 5.
   2. If ALT/AST < 100 U/L, TBil normal, and no infection, discharge work-up began.
5. Discharge criteria.
   1. Afebrile ≥ 72 h, dry incisions, both drains were removed, independent ambulation.
   2. Discharged on POD 10; sutures removed in the outpatient clinic 7 days later, with medical oncology referral for adjuvant chemotherapy.

4. Postoperative Chemotherapy Regimen:

1. First cycle of chemotherapy.
   1. Day 1: Prior to chemotherapy, verify baseline complete blood count and liver function, as severe neutropenia and diarrhea are dose-limiting toxicities requiring treatment withholding¹⁸; then initial catheter-guided peritoneal and hepatic artery angiography + transcatheter arterial chemoembolization (TACE) + hepatic artery catheterization to establish a hepatic artery access route; On the same day, 130 mg of oxaliplatin, 0.65 g of fluorouracil, and 400 mg of calcium folinate were infused via the hepatic artery catheter, and a 48 h continuous infusion of 3.6 g of fluorouracil was initiated.
   2. Day 2: Continued infusion of fluorouracil via the hepatic artery catheter, completing the total 48 h infusion volume.
   3. Day 3: Systemic chemotherapy with irinotecan 275 mg administered via peripheral vein.
   4. Day 4: Sintilimab was administered via a peripheral vein. The interval between cycles was approximately 1 month.
2. Second chemotherapy cycle: The complete regimen of the first chemotherapy cycle was repeated.

5. Postoperative CT Follow-up: A CT scan was performed 8 months after surgery.

Results

The protocol was executed as planned. The following results correspond to each major protocol step. Intraoperative fluorescence imaging identified a firm mass measuring 20 x 30 mm at the periphery of the left outer lobe of the liver (Figure 3A,B; see Supplementary Video 1 for the intraoperative procedure). Additionally, a tumor lesion was identified in liver segment V/VIII and was also resected using intraoperative fluorescence guidance. Pathology proved the...

Discussion

PHL is extremely rare². The diagnosis of PHL requires the fulfillment of three criteria: (1) clinical manifestations of liver dysfunction; (2) absence of palpable lymphadenopathy and radiological evidence of distant lymphadenopathy; (3) absence of leukemia in the peripheral blood smear¹⁹. It can occur at any age, with a male-to-female ratio of approximately 2–3:1. The pathogenesis of PHL remains elusive, but it is associated with infections including EBV (Epstein...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Absorbable, regenerated oxidized cellulose hemostatic nonwoven fabric	Ethicon LLC	2082
bipolar coagulation	Covidien Ltd.	LF1537
connecting needle	Zhejiang Sujia Medical Devices Co., Ltd.	Not applicable
connecting pipe	Zhejiang Sujia Medical Devices Co., Ltd.	VL-1.4×500
endoscope clip	Micro-Tech (Nanjing) Co., Ltd.	ROCC-D-26-195
fluorescent yarn	Not applicable	Not applicable
drainage tube	Hubei Kangquan Medical Technology Co., Ltd.; Ethicon Endo-Surqery, LLC	F22, F14
ligating clip	Guona Technology	J10-5
retrieval bag 130ml	Qingdao Zhonghui Shengxi Bioengineering Co., Ltd.	ZHQWDB-130
retrieval bag 60ml	Qingdao Zhonghui Shengxi Bioengineering Co., Ltd.	ZHQWDB-60
absorbable vascular sealing medical adhesive	Saixes Biotechnology Co., Ltd.	2 mL
stapler35/nail warehouse35*2.5	Ethicon Endo-Surqery, LLC	CDH35A / VASECR35
suture	Ethicon, LLC; Covidien LP	PDP148, VCP1603, W8761, VLOCL,CL923
three-way connector	Hangzhou Jingling Medical Equipment Co., Ltd.	ST02
ultrasound knife	Houkai (Tianjin) Medical Technology Co., Ltd.	USE36