Fournier's Gangrene in the Course of Treatment of Advanced Hepatocellular Carcinoma with Molecular-targeted Therapy

Abstract

Lenvatinib is a molecular-targeted agent with proven efficacy against hepatocellular carcinoma (HCC). We herein report a case of lenvatinib-associated Fournier gangrene. A 66-year-old man with advanced HCC presented with a high fever 4 weeks after switching to lenvatinib. He had severe erythema in the inguinal region, and abdominal computed tomography revealed extensive emphysema and scrotal abscesses. He was diagnosed with Fournier's gangrene, and his symptoms were successfully treated with local debridement and antimicrobial therapy. Although reports of lenvatinib-associated Fournier's gangrene are rare, they should be kept in mind, as the condition could progress rapidly and have poor outcomes.

Introduction

In recent years, several molecular-targeted drugs and immunoconjugate therapies have been approved and made available in Japan and overseas for the treatment of patients with advanced hepatocellular carcinoma (HCC) who have a sufficient hepatic functional reserve but cannot undergo curative resection. Among these approaches, drugs with inhibitory activity against vascular endothelial growth factor (VEGF) receptors are used as either monotherapy or immunoconjugate therapy and play an important role in the treatment of advanced HCC.

Lenvatinib is an orally administered receptor tyrosine kinase inhibitor that inhibits VEGF, fibroblast growth factor, and other signaling proteins. In Japan, clinical trials involving patients with advanced HCC demonstrated the non-inferiority of lenvatinib to sorafenib in terms of the overall survival and reported a significantly superior progression-free survival and response rates (1,2). Based on these results, lenvatinib was approved in 2018 as the primary treatment for unresectable advanced hepatocellular carcinoma.

Side effects of this drug are generally known to include hypertension, skin disorders, and proteinuria. In addition, delayed wound healing and gastrointestinal perforation have been reported as serious side effects, albeit at a low frequency (1,2). There have been reports of gastrointestinal perforation with bevacizumab, which also inhibits VEGF (3-5). Furthermore, there have been several reports of Fournier's gangrene, possibly related to delayed wound healing and gastrointestinal perforation, during bevacizumab administration (6-9). However, reports of this condition during lenvatinib administration are extremely rare.

We herein report a rare case of a patient who developed Fournier's gangrene during lenvatinib treatment. This case will help clinicians be aware of the possibility of Fournier's gangrene during lenvatinib administration.

Case Report

A 66-year-old man with obesity, hypertension, type 2 diabetes mellitus, dyslipidemia, and advanced HCC presented to our emergency clinic with a fever, redness, and perineal swelling. His height, body weight, and body mass index were 170 cm, 85 kg, and 29.4, respectively. Diabetes had first been noted 10 years ago but was well controlled with diet and exercise therapy alone, with his HbA1c ranging from 6.0-6.5%. Therefore, there were no findings suggestive of peripheral neuropathy or microvascular disease.

Abdominal computed tomography (CT) performed six months earlier had shown multiple hepatocellular carcinomas in both lobes of the liver, along with complete paralysis of the lower half of the body and cystorectal disturbances due to multiple bone metastases, mainly in the 6th thoracic vertebra (Fig. 1A, B). He had been receiving atezolizumab and bevacizumab combination therapy for advanced HCC for five months. However, this treatment approach became ineffective after approximately four months, and the patient was switched to lenvatinib therapy four weeks earlier. He did not have a regular drinking habit and was negative for hepatitis viruses, such as hepatitis B virus and hepatitis C virus. In addition, autoimmune liver diseases, such as autoimmune hepatitis and primary biliary cholangitis, were serologically ruled out. Therefore, cirrhosis evolving from nonalcoholic steatohepatitis was the most strongly suspected liver pathology.

Figure 1.

Radiographic images of the upper abdomen. Contrast-enhanced computed tomography shows hepatocellular carcinoma (A) with multiple bone metastases (B).

His medications included oxycodone, vonoprazan, polaprezinc, pioglitazone, mirogabalin, branched-chain amino acid preparations and lenvatinib. In addition, the patient had an external hemorrhoidal fistula after spontaneous drainage, which had already been identified at the initial visit, and the fistula was under observation. At the time of the emergency room visit, the patient was obese (body mass index of 29.4 kg/m²) and had clear consciousness. Furthermore, his blood pressure was 118/80 mmHg, heart rate was 142/minute, SpO₂ value was 96% (room air), and body temperature was 38.5°C. Chest auscultation revealed no significant abnormal findings, but a snowgrip sensation was observed from the anterior neck to the anterior aspect of the chest. Abdominal palpation revealed increased intestinal peristalsis, feeling of fullness and gripping snow in the lower abdomen and inguinal region, along with marked erythematous edema from the scrotum to the anus. Blood test results showed a definite increase in the white blood cell count (12,700 /μL) and an extremely high serum C-related protein level (36.6 mg/dL), indicating severe inflammation (Table). Contrast-enhanced CT showed generalized subcutaneous emphysema, mediastinal and intestinal membrane emphysema (Fig. 2A-C), and obvious abscesses in the perineum (Fig. 3). Based on these findings, the patient was diagnosed with Fournier's gangrene, which had been rapidly exacerbated by the infected hemorrhoids.

Table.

Laboratory Data on Admission.

Peripheral blood cell counts
	White blood cell	12,700	/μL
	Neutrophil	83.3	%
	Red blood cell	516	×104/μL
	Hemoglobin	15.4	g/dL
	Hematocrit	46.4	%
	Platelet	21.7	×104/μL
Biochemistry
	Sodium	136	mEq/L
	Chloride	95	mEq/L
	Potassium	5.2	mEq/L
	AST	27	U/L
	ALT	29	U/L
	Lactate dehydrogenase	251	U/L
	Alkaline phosphatase	196	U/L
	Gamma-GT	199	U/L
	Creatine kinase	49	U/L
	Blood urea nitrogen	20.7	mg/dL
	Creatinine	0.36	mg/dL
	Total protein	6.7	g/dL
	Albumin	2.5	g/dL
	Total Bilirubin	0.52	mg/dL
	C-reactive protein	36.6	mg/dL
Coagulation
	PT-INR	1.14
	APTT	45.6	s
Immunology
	AFP	981	U/L
	DCP	105,343	U/L
	HBS-antigen	Negative
	HCV-antibody	Negative
	ANA	40	times
	AMA	Negative
	IgG	1,367	mg/dL

AST: aspartate aminotransferase, ALT: alanine aminotransferase, gamma-GT: gamma-glutamyl transpeptidase, PT-INR: prothrombin time international normalized ratio, APTT: activated partial thromboplastin time, AFP: alpha- fetoprotein, DCP: des-gamma-carboxy prothrombin, HBS: hepatitis B surface, HCV: hepatitis C virus, ANA: anti- nuclear antibody, AMA: anti-mitochondria antibody

Figure 2.

Radiographic images of the systemic body. Contrast-enhanced computed tomography shows generalized subcutaneous emphysema in the chest (A), mediastinal and intestinal membrane emphysema (B), and surrounding abscess tissues along the anus and perianal area (C).

Figure 3.

Macro image of a perineal lesion. Necrotic wounds with marked redness overlying from the scrotum to the anus are recognized.

The patient immediately received broad-spectrum antibacterial treatment with meropenem and vancomycin and underwent local debridement (Fig. 4), experiencing rapid improvement after treatment. Enterococcus faecium and Escherichia coli were detected in the bacterial culture of a pus sample, and based on the results of drug susceptibility testing, ceftriaxone, clindamycin, and minomycin were administered after day 7 of illness. Thoracoabdominal CT performed on day 19 showed that the subcutaneous emphysema had decreased, and the intra-abdominal and mediastinal emphysema had disappeared (Fig. 5A-C).

Figure 4.

Macro image of a perineal lesion. Necrotic tissue spreading to the perineum has been properly removed, and the wound infection has been controlled with antibiotic administration, allowing tissue repair.

Figure 5.

Radiographic images of the systemic body. Computed tomography shows improved subcutaneous emphysema (A) and intraabdominal and mediastinal emphysema (B), as well as disappearance of abscess tissue around the perianal lesion after antibiotic treatment and local debridement (C).

The patient was discharged from the hospital after approximately two months. The treatment was changed to minomycin monotherapy, and there was no flare-up of inflammation. Palliative care for advanced HCC was implemented after obtaining his informed consent (Fig. 6).

Figure 6.

Clinical course of the present case. Solid and dotted lines indicate the changes in white blood cell counts and serum C-reactive protein levels, respectively. ATZ: atezolizumab, BEV: bevacizumab

Discussion

Necrotizing soft tissue infections (NSTIs) include soft tissue infections, such as Fournier's gangrene and necrotizing fasciitis. Among them, Fournier's gangrene is widely known to occur in the perineal area, causing abscess formation and gas production, and often has a steep course that leads to septic shock, disseminated intravascular coagulation syndrome, and multiple organ failure, with a poor prognosis and mortality rate of 20-40% (10-12).

NSTIs can be classified according to the site of infection and depth of infection, but the classification system based on the causative organism (type 1, mixed infection with anaerobes and various bacteria; type 2, mixed infection with group A streptococci alone or with staphylococci; and type 3, infection with gram-negative bacteria such as Vibrio vulnificus) is clinically useful (13). Anaerobic enteric bacteria were detected in the present case; therefore, the infection in this case was classified as Type I. Fournier's gangrene is a characteristic NSTI that occurs in the perineal area and requires attention because it can easily progress to necrotizing fasciitis. Risk factors for the development and exacerbation of Fournier's gangrene include trauma, malnutrition, obesity, diabetes, cirrhosis, neutropenia, surgical invasion, and a history of sodium-glucose cotransporter-2 inhibitor use (14).

In the present case, we believe that the combination of diabetes mellitus and obesity in our patient with advanced cancer contributed to the development and exacerbation of Fournier's gangrene. The most likely cause was rapid expansion of an infected lesion originating from a hemorrhoidal fistula, as abnormal gas accumulation and abscess formation were observed around the perineal area. The patient's symptoms were detected late, owing to complete paralysis of the lower half of the body associated with metastatic bone lesions. In the present case, oxycodone was prescribed after the start of hospitalization, suggesting that spinal cord neuropathy due to bone metastatic lesions was a more likely cause of the onset of cystorectal and sensory deficits than drug-induced neuropathy.

Apart from the aforementioned factors, we cannot ignore the possibility that the continuous use of lenvatinib, an inhibitor of the VEGF signaling pathway, contributed significantly to the development of this disease. Lenvatinib inhibits normal vascular endothelial cell homeostasis in endothelial and perivascular cells via VEGF inhibition. This results in interruption of the proper wound healing process, causing spontaneous bleeding and gastrointestinal perforation (15). From a molecular biology perspective, delayed wound healing is thought to be caused by an impaired platelet function and decreased expression of vascular endothelial tissue factors. As VEGF is involved in the coagulation cascade by inducing endothelial cells to express these tissue factors, inhibition of tissue factor expression is thought to cause delayed wound healing (16-18).

Several cases of NSTI occurring after VEGF inhibitor administration have been reported in patients receiving bevacizumab (6-9), but there has only been one report involving lenvatinib (15). The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) contains more than 20,000 adverse event reports related to lenvatinib use between 2005 and January 2024. However, only four cases of Fournier's gangrene have been reported, including the present case, and two of these cases were in patients with HCC.

There have also been a small number of reports regarding necrotizing fasciitis, an NSTI, in 11 cases. A search of the FAERS database revealed a limited number of cases of Fournier's gangrene (78 cases) in patients treated with bevacizumab, which has similar inhibitory activity against VEGF to lenvatinib. The incidence of NSTIs reported in the FAERS database through 2012 was calculated by Shamloo et al. to be 0.18% (3). Thus, the incidence of Fournier gangrene associated with lenvatinib use was assumed to be very low.

In the present case, a regimen including bevacizumab was administered before lenvatinib therapy, and the possibility that bevacizumab had an effect could not be ruled out. The onset of gastrointestinal perforation in patients receiving bevacizumab has been reported to occur within 6 months in more than 80% of cases (26 of 32 patients) (4), at a median of 71 days after the start of bevacizumab therapy and 14 days after the last dose (5). In the present case, the hemorrhoidal fistula was already present prior to treatment for HCC, but after confirming that they had fistula drained spontaneously, the patient was cautiously started on atezolizumab and bevacizumab combination therapy. As no apparent exacerbation of the hemorrhoidal fistula occurred in the subsequent course, and given that eight weeks had passed since the last date of bevacizumab administration, the possibility that bevacizumab contributed to fistula exacerbation could not be completely ruled out, but it was at least very limited. However, lenvatinib appeared to have a more significant effect.

In conclusion, we encountered a rare case of Fournier's gangrene that developed during lenvatinib treatment. Given the current use of a variety of molecular-targeted therapies and immunoconjugate therapies for HCC, clinicians should be aware of the possibility of Fournier's gangrene as a serious adverse event of VEGF inhibitors, which may threaten the life of patients, even if it occurs at a low frequency.

On behalf of the patient, his family kindly provided their written consent to report his case in an internationally published medical journal, including clinical details and images.

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