“WBC-HBP Dissociation” Unveils Occult Xanthogranulomatous Inflammation Mimicking Hepatocellular Carcinoma in Diabetic Patients

Introduction

The non-invasive diagnosis of hepatocellular carcinoma (HCC) primarily relies on the LI-RADS 5 imaging criteria: Arterial Phase Hyperenhancement (APHE) followed by washout.¹ While HCC pathogenesis involves complex cell signaling pathways,^2,3 clinical diagnosis is largely morphological. However, the specificity of these imaging features can be compromised in patients with background liver fibrosis. In such cases, benign inflammatory lesions may exhibit a “pseudo-washout” appearance due to differential contrast kinetics.⁴ This occurs when contrast clears rapidly from the lesion while being retained in the surrounding fibrotic parenchyma due to expanded extracellular volume (ECV).⁵ False-positive diagnoses of LI-RADS 5 are clinically significant as they can lead to unnecessary major hepatic resections and increased patient morbidity.⁶ Among the mimics of malignancy, hepatic Xanthogranulomatous Inflammation (XGI) is a rare entity that is frequently overlooked in the differential diagnosis of HCC.⁷

The diagnostic difficulty is further increased in patients with metabolic comorbidities, particularly diabetes. In patients with uncontrolled diabetes, “diabetic immunoparesis” impairs neutrophil mobilization from the bone marrow,⁸ often resulting in normal White Blood Cell (WBC) counts even during active infection.⁹ This normal WBC count can mislead clinical decision-making by obscuring the infectious etiology of a hepatic mass. Clinicians currently face a blind spot: distinguishing these “radiologically aggressive” but “hematologically silent” lesions from HCC without invasive biopsies.¹⁰ Standard biomarkers often fail in this context.

In this report, we analyze a case of solitary hepatic XGI in a patient with concurrent liver fibrosis and diabetes. We propose a novel clinical sign: “WBC-HBP Dissociation.” Our data suggests that Heparin-Binding Protein (HBP), a pre-formed granule protein, provides superior sensitivity over routine leukocyte counts for detecting localized inflammation in this specific demographic.^11,12

Case Presentation

Clinical History and Laboratory Findings

A 50-year-old male was admitted for the management of uncontrolled Type 2 Diabetes Mellitus (T2DM). His medical history included chronic Hepatitis B virus (HBV) infection of 10 years’ duration. On admission, glycemic control was poor, with a Glycated Hemoglobin (HbA1c) level of 12.00%.

Routine preoperative laboratory tests were performed. Hematological parameters showed a normal White Blood Cell (WBC) count of 5.83 × 10^9/L (Reference range: 3.5−9.5 × 10^9/L). Liver function tests revealed 14.6 IU/L for Alanine Aminotransferase (ALT) (Reference: 9–50 IU/L), 13.3 IU/L for Aspartate Aminotransferase (AST) (Reference: 15–40 IU/L), and 13.4 μmol/L for Total Bilirubin (Reference: 0–26.0 μmol/L).Additionally, Alkaline Phosphatase (ALP) was 93 IU/L (Reference: 45–125 IU/L), Gamma-Glutamyl Transferase (GGT) was 46.3 IU/L (Reference: 10–60 IU/L), and Albumin was 36.5 g/L (Reference: 40–55 g/L).

The patient presented with severe hyperglycemia (HbA1c 12.00%). We suspected “diabetic immunoparesis,” a state where normal WBC counts fail to signal active inflammation. To investigate, we assessed Heparin-Binding Protein (HBP) as a direct marker of neutrophil activation. The results were significant: HBP levels were elevated at 16.7 ng/mL (Reference: 0–11.4 ng/mL), and C-reactive protein (CRP) measured 13.90 mg/L. These values confirmed neutrophil degranulation, even though systemic leukocytosis was absent.

The tumor marker panel was negative. Alpha-fetoprotein (AFP) was <2.00 ng/mL (Reference: 0–7 ng/mL), Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) was 8.38 ng/mL (Reference: 0–40 ng/mL), Carcinoembryonic Antigen (CEA) was 1.75 ng/mL (Reference: 0–5 ng/mL), and Carbohydrate Antigen 19–9 (CA19-9) was 9.89 U/mL (Reference: 0–30 U/mL). Transient elastography (FibroScan) indicated a Liver Stiffness Measurement (LSM) of 11.6 kPa, consistent with advanced hepatic fibrosis (F3-F4).

Imaging Assessment

Gray-scale ultrasound identified a hypoechoic nodule measuring approximately 34 mm × 29 mm in Segment V. The lesion exhibited indistinct boundaries and abutted the gallbladder wall (Figure 1A). Contrast-Enhanced Ultrasound (CEUS) demonstrated a “fast-in, fast-out” vascular pattern: rapid, homogeneous hyperenhancement in the arterial phase (19 s) (Figure 1B) followed by washout in the portal venous phase (60 s) (Figure 1C). This profile was consistent with hepatocellular carcinoma.

Figure 1 Contrast-enhanced ultrasound (CEUS) findings. (A) Conventional B-mode ultrasound reveals a hypoechoic nodule (arrow) in liver Segment V with indistinct boundaries adjacent to the gallbladder. (B) Arterial phase image (19 s) shows rapid hyperenhancement of the nodule (arrow). (C) Portal venous phase image (60 s) demonstrates washout (hypo-enhancement) of the lesion (arrow) compared to the surrounding liver parenchyma.

Dynamic CT scan findings were concordant with ultrasound. The non-contrast phase revealed a hypoattenuating nodule in Segment V (Figure 2A). The lesion displayed arterial phase enhancement (Figure 2B) and washout in the portal venous phase relative to the liver parenchyma (Figure 2C). This vascular profile met the LI-RADS 5 criteria for malignancy.

Figure 2 Dynamic Contrast-Enhanced CT (CECT) findings. (A) Non-contrast CT showing a hypoattenuating nodule (arrow) in Segment V. (B) Arterial phase imaging reveals intense enhancement of the lesion (arrow). (C) Portal venous phase imaging demonstrates distinct washout (hypo-attenuation) of the lesion (arrow) relative to the liver parenchyma, consistent with the LI-RADS 5 vascular profile.

Magnetic Resonance Imaging (MRI) showed a mass measuring 4.7 cm × 3.5 cm spanning segments IVb/V. Diffusion-Weighted Imaging (DWI) demonstrated marked hyperintensity (Figure 3A), indicating restricted diffusion. On axial T1-weighted imaging, the mass appeared hypointense (Figure 3B). These findings supported a preoperative diagnosis of neoplasm.

Figure 3 Magnetic Resonance Imaging (MRI) features. (A) Diffusion-weighted imaging (DWI) demonstrates marked hyperintensity (arrow), indicating restricted diffusion. (B) Axial T1-weighted imaging reveals a hypointense lesion (arrow) in Segment V.

Surgical Intervention and Pathological Diagnosis

Despite negative tumor markers, the lesion was classified as LI-RADS 5 based on arterial phase hyperenhancement and washout in a high-risk patient. In accordance with AASLD guidelines, the vascular pattern was considered diagnostic for HCC, and biopsy was deferred. Given the subcapsular location, a laparoscopic anatomical liver resection (Segment 5) combined with cholecystectomy was performed.

Postoperative histopathology diagnosed Xanthogranulomatous Inflammation (XGI). Microscopically, the hepatic parenchyma was replaced by inflammatory infiltrates (Figure 4A). The lesion consisted predominantly of sheets of lipid-laden foamy histiocytes with clear cytoplasm (Figure 4B), intermingled with lymphocytes, plasma cells, and occasional multinucleated giant cells.

Figure 4 Histopathological and immunohistochemical characterization. (A) Low-power Hematoxylin and Eosin (H&E) staining (×200) demonstrates inflammatory infiltrates replacing the hepatic parenchyma (arrow). (B) High-power H&E staining (×400) reveals sheets of lipid-laden foamy histiocytes (arrow) with abundant clear cytoplasm. (C) Immunohistochemistry (IHC) for CD68 shows strong cytoplasmic positivity (arrow). (D) IHC for Smooth Muscle Actin (SMA) highlights spindle-shaped myofibroblasts (arrow) within the stroma. (E) IHC for Anaplastic Lymphoma Kinase (ALK) is negative. (F) IHC for IgG4 reveals only scattered positive plasma cells (arrows).

Immunohistochemical staining was performed to exclude malignancy and other inflammatory lesions. Foamy histiocytes were positive for CD68 (Figure 4C), and stromal spindle cells were positive for Smooth Muscle Actin (SMA) (Figure 4D). Anaplastic Lymphoma Kinase (ALK) was negative (Figure 4E), excluding Inflammatory Myofibroblastic Tumor (IMT). IgG4 staining revealed only scattered positive cells (Figure 4F), ruling out IgG4-related disease. Masson’s trichrome staining confirmed background bridging fibrosis.

Discussion

Imaging Characteristics and Diagnostic Challenges

The primary diagnostic challenge in this case was the vascular profile observed on CEUS and CECT, which mimicked the classic “fast-in, fast-out” pattern of HCC. In patients with advanced fibrosis (LSM 11.6 kPa), the specificity of this pattern is reduced. The “washout” appearance observed in this case of XGI likely represents “pseudo-washout”.¹³ This phenomenon occurs when rapid contrast clearance from the hypervascular inflammatory lesion is contrasted against prolonged retention in the fibrotic parenchyma.¹⁴ While arterial hyperenhancement in XGI is caused by inflammatory hyperemia, the relative hypodensity in the venous phase can easily be mistaken for malignancy. Other inflammatory lesions, such as inflammatory pseudotumors and hepatic tuberculosis, can also present with similar imaging features, complicating the differential diagnosis.¹⁵

Mechanism of WBC-HBP Dissociation The discrepancy between normal WBC counts and elevated HBP levels (“WBC-HBP Dissociation”) reflects differences in their release kinetics. Systemic leukocytosis relies on a delayed bone marrow response, which is often impaired in diabetic patients due to “diabetic immunoparesis”.^16,17 Hyperglycemia can blunt neutrophil chemotaxis and mobilization, resulting in normal cell counts despite active infection. In contrast, HBP is a pre-formed protein stored in neutrophil granules and is released immediately upon activation.^18,19 Crucially, HBP is released by activated neutrophils regardless of the inflammation site. It is not specific to hepatic pathology but serves as a systemic indicator of neutrophil degranulation. In this patient, HBP leaked into the circulation from the localized hepatic inflammation, providing a sensitive marker that was detectable even when the systemic cellular response was suppressed.²⁰

Clinical Implications Strict adherence to LI-RADS criteria without considering clinical context can lead to misdiagnosis and overtreatment. Major hepatic resections for benign lesions carry significant risks of morbidity, emphasizing the need for accurate preoperative differentiation.^21,22 We suggest that in high-risk patients (eg., those with diabetes) presenting with “radiologically aggressive” but “hematologically silent” (normal WBC) lesions, HBP should be assessed. An elevated HBP level in the absence of leukocytosis may warrant a deviation from the standard resection algorithm. In such cases, 18F-FDG PET-CT or targeted biopsy should be considered before surgery, as XGI typically demonstrates intense FDG uptake distinct from many well-differentiated HCCs.²³ Based on these clinical implications, we propose a diagnostic algorithm to guide the preoperative evaluation of indeterminate hepatic masses in high-risk patients (Figure 5).

Figure 5 Proposed diagnostic algorithm. The flowchart illustrates the clinical decision-making pathway. Patients with LI-RADS 5 imaging features but negative tumor markers and normal WBC counts (Steps 1–3) represent a diagnostic challenge. In patients with metabolic comorbidities like diabetes (Step 4), assessing Heparin-Binding Protein (HBP) is recommended. An elevated HBP level (>11.4 ng/mL) despite normocytosis (“WBC-HBP Dissociation”) suggests occult inflammation, justifying the use of functional imaging (18F-FDG PET-CT) or targeted biopsy (Step 5) to avoid unnecessary hepatectomy. Abbreviations: APHE, Arterial Phase Hyperenhancement; HCC, Hepatocellular Carcinoma; XGI, Xanthogranulomatous Inflammation.

Limitations

This study has several limitations. First, as a single case report, the findings require validation in larger cohorts to establish the diagnostic accuracy of HBP for hepatic inflammatory mimics. Second, HBP is a non-specific marker of inflammation; its elevation can be caused by infections in other organs, which must be ruled out clinically. Third, preoperative PET-CT and biopsy were not performed in this case. Their inclusion might have altered the surgical management and avoided anatomical resection.

Conclusion

This case underscores a critical diagnostic pitfall: Heparin-Binding Protein (HBP) levels can reveal inflammation when standard counts fail. Hepatic Xanthogranulomatous Inflammation (XGI) can indistinguishably mimic the hemodynamic profile of Hepatocellular Carcinoma, especially in fibrotic livers. For diabetic patients, “diabetic immunoparesis” further complicates diagnosis by masking serological signs of infection. We identified that elevated HBP combined with normal WBC counts—the “WBC-HBP Dissociation”—serves as a robust indicator of occult inflammation. Integrating HBP assessment into the diagnostic algorithm for indeterminate hepatic masses provides a crucial filter. This strategy helps identify inflammatory mimics, justifying the use of PET-CT or biopsy, and ultimately spares high-risk patients from unnecessary hepatic resections.