Peritoneal metastasis is a rare form of recurrence in hepatocellular carcinoma (HCC). Reports suggest that implantation of tumor cells by rupture of the primary tumor,1 needle biopsy, or radiofrequency ablation (RFA)2 may cause peritoneal dissemination of HCC. Peritoneal metastasis is a sign of advanced HCC, and the treatment of choice is systemic therapy.3 Additionally, surgical resection has been reported to improve prognosis.4 Nakayama et al.5 reported that surgical resection is particularly beneficial for patients with less than four metastatic nodules, metachronous metastases, and an alpha-fetoprotein value <200 ng/mL. However, it is ambiguous whether peritoneal HCC metastases have the same biologic and prognostic value as other extrahepatic metastases: dissemination and growth of viable cells outside the liver.6-8 Peritoneal seeding is often studied in conjunction with other extrahepatic localizations.9,10 Aggressive tumor biology is often observed in patients with peritoneal localizations caused by seeding following spontaneous rupture of HCC. Furthermore, there is a lack of research comparing treatments for the peritoneal seeding of HCC.

In this study, we present a novel case of peritoneal seeding in a patient with HCC who received radiotherapy and atezolizumab plus bevacizumab combination treatment followed by successful surgical treatment for seeding nodules.

A 68-year-old man was initially diagnosed with a 3.5 cm single nodular HCC at the tip of segment 3 (Fig. 1A, B). The patient had alcoholic liver cirrhosis with Child-Pugh class A5 liver function. Surgical resection was performed for single nodular HCC. 16 months later, a 1.5 cm-sized single nodular HCC recurred at the tip of segment 6 (Fig. 1C). The patient’s alpha-fetoprotein (AFP) level was 133.76 ng/mL, and the prothrombin induced by vitamin K absence (PIVKA-II) was 75 mAU/mL. The patient underwent conventional transarterial chemoembolization for the recurrent tumor (Fig. 1D). Three months later, a 1 cm nodule increasing in size was observed on the rectovesical pouch (Fig. 2A). Radiation therapy for pelvic nodules was performed at a dose of 4,500 cGy in 10 fractions. Eight months after radiotherapy, the pelvic nodule size decreased to approximately 5 mm (Fig. 2B), and 2 years after radiotherapy, the pelvic nodule on the rectovesical pouch stabilized. However, a new 2.7 cm sized peritoneal nodule developed in the right upper quadrant omentum (Fig. 3A) 3.5 years after radiotherapy. Additionally, the size of the pelvic nodule on the rectovesical pouch had increased to 1.5 cm (Fig. 3B). The standard uptake value (SUV) of the 2.7 cm sized peritoneal nodule in the right upper quadrant omentum was 4.0 and the SUV of the rectovesical pouch was 3.1 upon ¹⁸F-fluorodeoxyglucose positron emission tomography scan (Fig. 3C, D). AFP and PIVKA-II levels were 2.7 ng/mL, and 58 mAU/mL, respectively. Hence, omental and small bowel mesentery mass excision were performed to remove the pelvic nodules (Fig. 3E, F), and the histology of the resected nodules was compatible with metastatic HCC. Three years after surgical resection, recurrent peritoneal metastases in the right upper quadrant (RUQ) omentum (Fig. 4A) and the rectovesical pouch (Fig. 4B) were noted. The patient then started systemic therapy with atezolizumab and bevacizumab. After 15 cycles of atezolizumab and bevacizumab combination therapy, the peritoneal nodule on the RUQ omentum had decreased to 2 mm in size (Fig. 4C). However, the recurrent peritoneal metastatic nodule on the rectovesical pouch remained unchanged with a size of 4 cm (Fig. 4D). The patient received 33 cycles of atezolizumab and bevacizumab as systemic therapy. Finally, laparoscopic left pelvic peritonectomy was performed to remove the remaining pelvic nodule in the rectovesical pouch (Fig. 5). Histology revealed a clear cell neoplasm with necrosis, which was compatible with steatohepatitic-type metastatic HCC. Six months after surgical treatment, there was no evidence of tumor recurrence in the peritoneum. The level of AFP was 2.1 ng/mL, and the PIVKA-II level was 31 AU/mL at the time of the final follow-up visit (Fig. 6).

Peritoneal recurrence is a rare form of HCC. According to the report of the 22nd Nationwide Survey of Primary Liver Cancer in Japan (2012–2013),11 of 7,494 resected HCC cases, only 28 (0.4%) had peritoneal dissemination. Implantation of tumor cells during needle biopsy, RFA, surgical resection, and tumor rupture are the main causes of peritoneal dissemination. However, research on treatment strategies for peritoneal HCC recurrence is severely lacking. While peritoneal seeding in other types of cancer is usually widespread and not effectively managed with surgery, peritoneal metastasis of HCC is often localized. In fact, several reports have indicated that resection for peritoneal recurrence improves the prognosis of patients with HCC.12,13

The mechanisms that drive peritoneal metastasis remain unclear. One theory is that exophytic HCC rupture in the peritoneal cavity contributes to metastasis. Several studies have revealed that ruptured HCC can lead to peritoneal seeding.7,14,15 However, in most patients, including this case, there is no evidence of overt HCC rupture. These patients probably had microscopic peritoneal metastases while the main tumors were treated. The diagnosis of HCC with peritoneal seeding after surgical resection was based on clinical suspicion. Rising serum AFP levels with no radiologic evidence of intrahepatic tumor recurrence suggest the possibility of extrahepatic recurrence.16 Typical radiologic manifestations of peritoneal seeding include peritoneal thickening with enhancing nodules, ascites, and omental cakes.17

A recent retrospective cohort study18 analyzed 11 patients with HCC peritoneal metastasis. Seven patients received systemic therapy with sorafenib, and four were treated with upfront peritonectomy followed by systemic therapy with sorafenib at recurrence. The median overall survival was 60 months for patients with peritoneal metastasis who were treated with immediate surgery, whereas the overall survival of the systemic therapy group was 11.8 months. Hence, this study highlights early surgical intervention as an effective strategy for peritoneal seeding in HCC.

In this case, when recurrence developed in the rectovesical pouch for the first time, radiotherapy was the first choice of treatment. Few reports have described the successful application of radiotherapy for the treatment of peritoneal seeding in patients with HCC. However, HCC is sensitive to radiotherapy. A recent case report from Japan also supports radiotherapy as a viable strategy for treating peritoneal seeding masses of HCC.19

In addition, recent advances in systemic therapy for HCC might play a key role in managing peritoneal metastasis. A recent case report from Japan suggested that peritoneal recurrence after surgical resection was effectively treated with first-line lenvatinib, second-line sorafenib, and third-line atezolizumab in addition to bevacizumab combination therapy.20 The patient was treated with atezolizumab plus bevacizumab combination therapy again and maintained partial remission as an outpatient.

In conclusion, peritoneal seeding of HCC is rare and may occur synchronously or metachronously. We encountered a patient who successfully underwent curative surgical treatment for peritoneal seeding of HCC after radiotherapy and atezolizumab and bevacizumab combination treatment. However, further studies are needed to support the role of surgery combined with radiotherapy and systemic therapy for peritoneal seeding in HCC.