Hepatocyte syncytial formation in feline leukemia virus infected young cats

Formação de sincícios em hepatócitos de gatos jovens infectados pelo vírus da leucemia felina

ABSTRACT:

Giant cell hepatitis (GCH) is an uncommon hepatic lesion in mammals, and rarely reported in domestic cats. This study described the anatomopathological features and immunoexpression of HepPar-1 and feline leukemia virus glycoprotein 70 (FeLV gp70) in three FeLV-positive domestic cats with hepatocyte syncytial formation resembled GCH. The cats did not present any clinical sign of hepatic failure; however, one of the patients exhibited elevated alanine aminotransferase activity. Grossly, the livers were moderately enlarged, slightly pale, and exhibited mild lobular pattern accentuation. Histologically, lesions included hepatocyte dissociation, hepatocellular necrosis, multinucleated and/or enlarged hepatocytes displaying karyomegaly. Normal and altered hepatocytes showed immunolabeling for HepPar-1 and FeLV gp70. The findings reinforce the need to consider GCH as a differential diagnosis in cats with unexplained elevations in liver enzymes, particularly when infected with FeLV.

Key words:
megalocytosis; karyomegaly; multinucleation; syncytial; liver; hepatic; feline

RESUMO:

A hepatite de células gigantes (HCG) é uma lesão hepática incomum em mamíferos e raramente relatada em gatos domésticos. Este estudo teve como objetivo descrever as características anatomopatológicas e a imunomarcação de HepPar-1 e glicoproteína 70 do vírus da leucemia felina (FeLV gp70) em três gatos domésticos FeLV-positivos com formação de células sinciciais em hepatócitos, se assemelhando à HCG. Os animais descritos não apresentaram sinais clínicos de insuficiência hepática. Entretanto, um dos gatos exibiu atividade aumentada de alanina aminotransferase. Além disso, macroscopicamente, os fígados dos animais estavam moderadamente aumentados, discretamente pálidos e com leve acentuação do padrão lobular. Histologicamente, as lesões incluíam dissociação hepatocelular, necrose de hepatócitos, hepatócitos multinucleados e/ou aumentados exibindo cariomegalia. Ao mesmo tempo, Hepatócitos normais e alterados demonstraram imunomarcação para HepPar-1 e FeLV gp70. Os achados reforçam a necessidade de considerar a HCG como diagnóstico diferencial em gatos com elevações inexplicadas de enzimas hepáticas, especialmente quando infectados pelo FeLV.

Palavras-chave:
megalocitose; cariomegalia; multinucleação; sincicial; fígado; hepático; felino

Giant cell hepatitis (GCH) is characterized by inflammation, karyomegaly, loss of acinar strucutre and numerous multinucleated hepatocytes scattered throughout the hepatic parenchyma (JIAO et al., 2023). This condition accounts for approximately 0.1-0.2% of all liver diseases in humans, where most cases are idiopathic, although associations with Human Hepatitis B Virus (HBV), Human Hepatitis C Virus (HCV), Human Hepatitis D Virus (HDV), and Human Immunodeficiency Virus (HIV) have been reported (JIAO et al., 2023; TORBENSON et al., 2010). In animals, GCH is rare, with only a few cases described in cats, calves, and foals (CULLEN & STALKER, 2016). In felines, this lesion has been reported in two FeLV-positive individuals with mediastinal lymphoma (SUZUKI et al., 2001) and in one FeLV-negative cat infected with Platynosomum illiciens (KOBAYASHI et al., 2025).

Feline Leukemia Virus (FeLV) is a gammaretrovirus associated with a wide spectrum of diseases in cats, including neoplastic and inflammatory disorders (HARTMANN & HOFMANN-LEHMANN, 2020). Hepatocellular dissociation, focal hepatic necrosis, and cirrhosis have been associated with FeLV infection (REINACHER, 1989). Based on these findings, FeLV has recently been recognized as an emerging hepatotropic virus in domestic cats (CAPOZZA et al., 2021).

Reports of GCH in cats are exceedingly rare, which makes it difficult to establish associations between the lesion and potential risk factors, as well as to elucidate its pathogenesis. The first description involved two FeLV-positive cats in which no viral particles were identified within hepatocytes by electron microscopy (SUZUKI et al., 2001). Nevertheless, a definitive association between the lesion and FeLV infection could not be established. This study described the anatomopathological features to assess the immunoexpression of HepPar-1 and FeLV gp70 in the livers of three domestic cats with hepatocyte syncytial formation resembled GCH.

Three cats from a cohort of 559 domestic cats submitted for routine necropsy between 2020 and 2022 at a Brazilian veterinary anatomic pathology service (Laboratório de Patologia Veterinária, Universidade Federal de Santa Maria) were diagnosed postmortem with hepatitis exhibiting the following histologic features: varying degrees of hepatic inflammation, marked megalocytosis, marked karyomegaly, and frequent multinucleation (hepatocytes containing three or more nuclei). All cats originated from Santa Maria, Rio Grande do Sul, Brazil. Data regarding sex, breed, age, and cause of death were obtained from necropsy reports.

Cats underwent complete necropsy, and tissue samples (including liver, kidneys, spleen, myocardium, lungs, bone marrow, lymph nodes, brain, adrenal glands, and thyroid glands) were fixed in 10% neutral buffered formalin and routinely processed for histopathological evaluation. New 3-μm paraffin-embedded liver sections were prepared for immunohistochemistry (IHC). Multinucleation was defined as the presence of three or more nuclei within a single hepatocyte. Karyomegaly was defined when hepatocyte nuclei measured more than twice the diameter of a normal hepatocyte nucleus (JAGER et al., 2024). Megalocytosis was defined when hepatocytes were more than three times the size of a normal hepatocyte (JAGER et al., 2024).

IHC was performed on liver and bone marrow using a mouse monoclonal antibody against FeLV gp70 (clone C11D8, 1:1000) to evaluate the presence or not of the viral antigens, and on liver using a mouse monoclonal anti-Hep Par 1 antibody (1:80) to confirm that these giant and multinucleated cells are hepatocytes. Endogenous peroxidase activity was blocked with 3% hydrogen peroxide. Antigen retrieval was performed in a microwave oven for 10 minutes using citrate buffer (pH 6.0) (FeLV gp70) or with proteinase K at 25 °C (HepPar-1). Nonspecific binding was blocked with 5% nonfat dry milk. Tissue sections were incubated with the primary antibody overnight (16 hours) at 4 °C. Detection was performed using a polymer-HRP system (EasyLinkOne-HRP, EP-12-20502, EasyPath), followed by chromogen development with 3,3′-diaminobenzidine (DAB, EasyPath). Slides were counterstained with Harris hematoxylin. As a positive control for FeLV gp70, bone marrow from a FeLV-positive domestic cat (confirmed by commercial PCR for both RNA and proviral DNA) was used. Two negative controls were included: one normal liver from a FeLV-negative cat and one normal liver from a FeLV-positive cat, both previously tested using a commercial serological assay (SNAP FIV/FeLV Combo Test; IDEXX Laboratories, Inc., Westbrook, Maine, USA). For Hep Par 1, normal hepatocytes within the same histologic sections (internal control) and a normal liver section from an adult cat fixed in 10% formalin were used.

Case 1 was a one-year-old spayed female mixed-breed cat that died spontaneously after developing severe neurologic signs secondary to encephalic and spinal cord diffuse small cell lymphoma. It also had markedly increased alanine aminotransferase (ALT) activity (1,600 IU/L). Case 2 was a two-year-old spayed male mixed-breed cat with acute erythroid leukemia and metastatic spread to the spleen and liver, which resulted in spontaneous death. Case 3 involved a two-year-old neutered male mixed-breed cat with intestinal large cell lymphoma and metastatic involvement of the liver. Information regarding whether this animal died spontaneously or was euthanized was not available. No laboratory data were available for cats nº2 or nº3. All three cats were FeLV-positive (SNAP FIV/FeLV Combo Test; IDEXX Laboratories, Inc., Westbrook, Maine, USA) prior to the death.

On gross examination, all three livers were moderately enlarged (the edges were rounded, with the parenchyma projecting beyond the costal arch), slightly pale, and exhibited mild lobular pattern accentuation (Figure 1A). Histologically, varying degrees of hepatocyte dissociation, centrilobular necrosis (restricted to cases 1 and 3), hepatocyte loss, sinusoidal distension, lymphoplasmacytic inflammation (Figure 1B) and hemorrhage were observed, predominantly in periportal areas but occasionally extending across the lobule (Table 1). Multinucleated hepatocytes were present throughout the parenchyma and occurred in association with karyomegaly-characterized by enlarged nuclei with vesicular to coarsely granular chromatin and prominent nucleoli-and megalocytosis (Figure 1C). Multinucleated and enlarged hepatocytes often contained cytoplasmic lipid vacuoles, typically accentuated near the plasma membrane (Figures 1D). Intracanalicular bile plugs were identified, and Kupffer cells frequently exhibited intracytoplasmic brown granular pigment. Adjacent to these lesions, mild lymphoplasmacytic infiltrates and moderate bile duct hyperplasia was observed. Additionally, in cases 2 and 3, disseminated metastases from the primary neoplasms permeated the hepatic parenchyma, typically with a periportal distribution.

Figure 1
Hepatocyte syncytial formation in feline leukemia virus infected young cats resembling giant cell hepatitis. A, Case 2, Liver, natural surface: the liver is slightly pale and enlarged, with mild lobular pattern accentuation; B, Case 1, liver, hepatocyte multinucleation is a prominent feature, accompanied by loss of acinar structure and lymphoplasmacytic inflammation, Hematoxylin & eosin (H&E), 40x. C, Case 2, liver, multiple multinucleated hepatocytes are observed with loss of acinar structure, H&E, 40x. D, Case 1, liver, karyomegaly and a multinucleated hepatocyte is accompanied by cytoplasmic vacuolation, H&E, 100x. E, Case 3, liver, normal and multinucleated hepatocyte exhibited strong cytoplasmic Hep Par 1 immunolabeling, immunohistochemistry, 40x. F, Case 1, liver, membranous FeLV gp70 protein expression in hepatocytes with one or more nuclei, immunohistochemistry, 100x.

Table 1
Histologic features and injury degree of three cases of hepatocyte syncytial formation resembling giant cell hepatitis.

Histological feature	Case 1	Case 2	Case 3
Hepatocyte dissociation	Moderate	Mild	Severe
Hepatocellular necrosis	Mild	Absent	Mild
Hepatocyte loss	Moderate	Absent	Mild
Sinusoidal distension	Mild	Absent	Mild
Hemorrhage	Moderate	Absent	Absent
Karyomegaly	Severe	Severe	Severe
Megalocytosis	Severe	Severe	Severe
Multinucleated cell counta	17	21	34
Number of nuclei per multinucleated cellb	3-9	3-8	3-12
Hepatocyte cytoplasmic vacuolation	Moderate	Mild	Severe
Bile plugs	Mild	Absent	Mild
Hemosiderin	Mild	Mild	Absent
Inflammation	Moderate	Mild	Mild
Bile duct hyperplasia	Mild	Mild	Mild

• ^aCount of multinucleated cells in 10 fields of 0.237-mm²; ^bVariation of nucleus number per multinucleated cells.

HepPar-1 immunoexpression was detected in all three cases as a granular cytoplasmic pattern in normal hepatocytes, as well in giant and multinucleated cells confirming that these cells are hepatocytes (Figure 1E). FeLV gp70 expression (Table 2) was present in all livers, generally in a patchy distribution throughout the parenchyma, with membranous labeling observed in both normal (particularly near affected areas) and altered hepatocytes (Figure 1F), either in clusters or as isolated cells. Cytoplasmic FeLV gp70 labeling was also detected in some leukocytes and megakaryocytes, as well as in metastatic cells within the liver. Evaluation of bone marrow revealed diffuse cytoplasmic labeling in hematopoietic cells in all cases.

Table 2
Immunohistochemical expression of feline leukemia virus glycoprotein 70 (FeLV gp70) in the liver of three cats hepatocyte syncytial formation resembling giant cell hepatitis.

Cat	Staining intensity	Immunostaining pattern (hepatocytes)	gp70-positive cells
Negative control 01	-	-	-
Case 01	++	Patchy, detected in groups or individual hepatocytes, in both normal and altered hepatocytes	Hepatocytes, leucocytes, megakaryocytes
Case 02	++	Patchy, detected in groups or individual hepatocytes, in both normal and altered hepatocytes	Hepatocytes, leucocytes, metastatic cells
Case 03	+	Patchy, detected in individual hepatocytes, in both normal and altered hepatocytes	Hepatocytes, leucocytes, metastatic cells
Negative control 02	+	-	Leucocytes

• +, mild immunostaining; ++, moderate immunostaining; +++ intense immunostaining; -, no immunostaining.

GCH is an uncommon to rare hepatic lesion in mammals characterized by enlarged, syncytial hepatocytes that may contain more than ten nuclei, accompanied by loss of acinar architecture (JIAO et al., 2023; TORBENSON et al., 2010). All cases described in this study exhibited these histologic features that resembling this condition. Immunohistochemical labeling for HepPar-1 confirms that the syncytial cells are indeed hepatocytes rather than multinucleated giant cells, showing the characteristic granular cytoplasmic staining pattern described for HepPar-1 (PANG et al., 2006; WENNERBERG et al., 1993). Reports of GCH are more frequent in humans, and several etiologies have been identified (JIAO et al., 2023). In animals, the condition is rare, and risk factors remain unclear (CULLEN & STALKER, 2016).

In humans, the disease spectrum ranges from acute to chronic hepatitis, with potential progression to cirrhosis, with mild clinical signs and complete recovery to those with liver failure (JIAO et al., 2023). GCH is more prevalent in newborns, in whom nearly half of the cases are idiopathic, followed by those associated with hypopituitarism and, less commonly, viral infections (TORBENSON et al., 2010). In adults, there is a greater variety of etiologies associated with the occurrence of GCH. Most cases are diagnosed as autoimmune (40% to 32%), followed by drug reactions (12% to 7%), infectious agents (11%) such as HCV, HIV, HBV, and HDV respectively, as well as hematopoietic disorders (6%) such as leukemia and lymphoma. (JIAO et al., 2023; MATTA et al., 2019).

A study analyzing 70 cases of GCH in adults revealed that not all patients exhibited altered liver enzymes (JIAO et al., 2023). Among these cases, 81% exhibited elevated alanine aminotransferase, followed by elevated aspartate aminotransferase (70%), alkaline phosphatase (70%), and total bilirubin (63%). Additionally, histologically approximately 33% of cases had fewer than 5 multinucleated giant cells per field (40x), which is comparable to the cases described here, which have 1.7 to 3.4 multinucleated giant cells per field.

In veterinary medicine, horses have the greatest number of reported GCH cases, with multiple risk factors described, including leptospiral infection (WILKIE et al., 1988), neonatal isoerythrolysis (BOYLE et al., 2005), and serum hepatitis (Theiler’s disease) (CULLEN, 2019). In a previous study, 48% of Equine Parvovirus-Hepatitis Virus (EqPV-H) positive horses exhibited multinucleated hepatocytes, megalocytosis, and karyomegaly (JAGER et al., 2024). Only two prior descriptions of GCH in cats exist: one in two FeLV-positive young cats with concurrent mediastinal lymphoma, and another in a cat infected with Platynosomum illiciens (KOBAYASHI et al., 2025; SUZUKI et al., 2001).

The three cats from previous reports had concurrent hepatic lesions in addition to GCH: the FeLV-positive animals exhibited infiltrates of neoplastic lymphoblasts in centrilobular and periportal areas, and the FeLV-negative feline had P. illiciens within bile ducts (KOBAYASHI et al., 2025; SUZUKI et al., 2001). Although, all animals exhibited elevated liver enzymes (Alanine aminotransferase, aspartate aminostranferase and total bilirubin), it is difficult to determine whether these alterations were attributable solely to GCH, to other hepatic lesions, or to a combination of both (KOBAYASHI et al., 2025; SUZUKI et al., 2001). Cat nº1 from this study showed elevated ALT in the absence of additional hepatic lesions, suggesting that the enzyme elevation was secondary to GCH, although clinical signs of hepatic failure were absent.

Liver sections from the two FeLV-positive cats with GCH in a previous report were negative for feline immunodeficiency virus (FIV), feline syncytial virus (FeSV), feline herpesvirus (FHV), FeLV, and feline parvovirus (FPV) on IHC (SUZUKI et al., 2001). Electron microscopy revealed no viral particles within hepatocytes, including in multinucleated giant cells (SUZUKI et al., 2001). In our study, immunohistochemistry demonstrated viral antigen expression along the membranes of affected and morphologically normal hepatocytes. Similar immunolabeling has been reported in cutaneous keratinocytes of cats with giant cell dermatosis (GROSS et al., 1993). This cutaneous lesion has been described in FeLV-positive cats and is likewise characterized by multinucleated cells (FAVROT et al., 2005; GROSS et al., 1993). Although, this condition may be induced by FeLV, its rarity remains unexplained given the high prevalence of FeLV infection (PANDOLFO et al., 2024). Some authors propose that an atypical form of FeLV infection may underlie this condition (FAVROT et al., 2005), which could also explain the development of GCH in certain FeLV-positive cats.

FeLV gp70 immunostaining in hepatocytes was restricted to the cell membrane, with no cytoplasmic labeling, suggesting the presence of viral protein or antigen at the plasma membrane. This pattern contrasts with the cytoplasmic FeLV gp70 immunolabeling observed in leukocytes. Based on previous studies, this hepatocytic immunolabeling pattern was expected. Electron microscopy studies have demonstrated the absence of cytoplasmic viral particles in multinucleated hepatocytes, supporting the notion that FeLV does not replicate within hepatocytes (SUZUKI et al., 2001). Among the membrane receptors used by FeLV, thiamine transporter 1 (THTR1) and the feline leukemia virus subgroup C receptor (FLVCR) are widely expressed in hepatocytes (DONEGAN et al., 2019; MENDOZA et al., 2006). Therefore, it is plausible that FeLV interacts with these receptors in hepatocytes but lacks the capacity for productive replication, instead disrupting receptor function and inducing metabolic alterations that ultimately contribute to the development of these lesions (QUIGLEY et al., 2004; SHANGARI et al., 2007).

The pathogenesis of GHC remains poorly understood in humans, cats and other mammals. To some authors, the lesion seems to be a response to hepatic injury/stress rather than a primary hepatic lesion (MATTA et al., 2019). When the three cases reported herein are considered together with the three previously published cases, it is noted that five of the six cats were FeLV-positive (KOBAYASHI et al., 2025; SUZUKI et al., 2001); although, only the cats from this study exhibited FeLV gp70 immunolabeling on hepatocytes. It is also noteworthy that among these six cases, five cats had concurrent hepatic lesions: one had P. illiciens infestation, and the others exhibited infiltration of neoplastic lymphocytes within the liver parenchyma (KOBAYASHI et al., 2025; SUZUKI et al., 2001). The only GCH case without concomitant hepatic lesions was cat nº 1 from the current study. These findings suggested that feline GCH may be triggered by multiple distinct risk factors, similar to what has been described in humans and horses. Based on previous reports and the present cases, chronic inflammation or neoplastic infiltration of the liver may provide sufficient hepatic injury to induce this lesion (KOBAYASHI et al., 2025; SUZUKI et al., 2001). Furthermore, indirect effects of hematopoietic neoplasms should be considered, particularly increased cytokine production leading to systemic hyperinflammation (MELLGREN et al., 2012).

The mechanism by which hepatocytes become multinucleated in GCH remains unknown. Two main hypotheses have been proposed: nuclear proliferation without cytokinesis and/or fusion of mature hepatocytes leading to syncytium formation (SHETTY et al., 2016). Distinguishing between these mechanisms is challenging. Hepatocyte fusion may occur in severe steatosis, and syncytial multinucleation has been reported in several degenerative and regenerative hepatic conditions (CULLEN & STALKER, 2016). In addition, some morbilliviruses are known to induce syncytia in other tissues, such as measles virus in humans, respiratory syncytial virus in cattle, and canine distemper virus in dogs (ADER et al., 2013). Pyrrolizidine alkaloid toxicosis and aflatoxicosis are well-recognized causes of hepatic megalocytosis and karyomegaly, and aflatoxins can occasionally induce multinucleation (NEWMAN et al., 2007; CULLEN & STALKER, 2016).

Some infectious hepatic diseases should be considered as differential diagnoses in cats with hepatic lesions, particularly feline calicivirus (FCV) and feline herpesvirus-1 (FeHV-1) (SLAVIERO et al., 2022). However, despite some differences in the pattern of hepatic injury, these infections typically present with additional lesions in other organs, such as pneumonia or dermatologic lesions (SLAVIERO et al., 2025).

This study described the anatomopathological features of the livers of three FeLV-positive cats with hepatocyte syncytial formation, resembling GCH. Although, all livers showed FeLV gp70 immunoexpression, based on the available data, there is still not enough evidence to support a definitive causal or association relationship between the observed lesion and FeLV infection. Further investigation is warranted, including the addition of new cases and more systematic studies, to determine whether such an association exists. Based on the current literature, it is probable that GCH is a multifactorial disease in cats, representing a response of hepatic injury or stress, similar to humans.

ACKNOWLEDGMENTS

This research was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES), <http://www.capes.gov.br/> - Finance Code 001 ,and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), <http://www.cnpq. br/>.

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• CR-2025-0618.R1
• BIOETHICS AND BIOSECURITY COMMITTEE APPROVAL
  The authors confirm that the journal’s ethical policies, as noted on the journal’s author guidelines page, have been adhered to. In this study we did no performed animal experimentation, as all sample came from the diagnostic routine from the Laboratório de Patologia Veterinária.
• DATA AVAILABILITY STATEMENT
  All data suporting this study are included within the article.
• DECLARATION OF USE OF ARTIFICIAL INTELLIGENCE
  Artificial intelligence was used in a careful manner for the revision and improvement of the manuscript’s quality without any alteration to the scientific content.

Edited by

• ASSOCIATE EDITOR
  Rudi Weiblen (0000-0002-1737-9817)

Data availability

All data suporting this study are included within the article.

Publication Dates

• Publication in this collection
  31 July 2026
• Date of issue
  2026

History

• Received
  03 Dec 2025
• Accepted
  25 Jan 2026
• Reviewed
  05 May 2026