Malignant rhabdoid tumor of the liver in a middle-aged woman: a case report and literature review

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive tumor characterized by high metastatic risk, poor prognosis and high mortality. It’s most commonly encountered in the kidney, and has a low extrarenal incidence. Extrarenal malignant rhabdoid tumors (EMRTs) tend to occur in the body's central axis, mainly in infants and early childhood. Currently, only a few cases of adult primary liver MRT have been reported. In this paper, we describe a case of liver MRT in a 40-year-old woman for the first time.

A 40-year-old woman was admitted to the hospital with the chief complaint of right upper abdominal pain for more than 4 months.

The histologic morphology of liver MRT, a rare subtype that portends a grim prognosis, is consistent with that of rhabdoid tumor in the kidney, and its histological origin is unclear [1]. Infants and young children are the main population of liver MRT. To date, a total of 55 cases of liver MRT have been reported on PubMed, including 51 pediatric patients and 4 adult patients, with a child-to-adult ratio of approximately 12:1. The median age of all pediatric patients was 7 months, and there was no sex difference. The 4 adult patients were male with ages of 27, 27, 50, and 51 [2‐5] (Table 1). Liver MRT lacks specific symptoms and signs. Common symptoms and signs include fever, abdominal discomfort, abdominal mass, anorexia/vomiting and fatigue, with systemic symptoms predominating. Patients with severe symptoms are mostly associated with spontaneous rupture of the tumor.

Imaging plays an indispensable role in disease diagnosis. Due to its rarity, there is no summative imaging feature of liver MRT. Reviewing the previous cases, liver MRT mostly manifests as solid or cystic masses with a heterogeneous echo by ultrasonography. CT usually exhibits single or multiple heterogeneous low-density masses, while the tumor exhibits heterogeneous enhancement after enhancement, possibly accompanied by calcification, necrosis and hemorrhage. The MRI findings have been described as hypointense on T1WI and heterogeneous hyperintense on T2WI, with mild enhancement or peripheral enhancement during enhancement.

The diagnosis of liver MRT still relies on the pathology. Microscopically, the tumor cells are round or polygonal, and composed of frequent mitosis, prominent nucleoli and abundant eosinophilic cytoplasm [6]. In immunohistochemical analysis, most tumors show high expression of vimentin, cytokeratin and smooth muscle actin (SMA), but negative expression of AFP, CD34 and myoglobin [6, 7]. However, several tumors, such as rhabdomyosarcoma, rhabdoid melanoma and epithelioid sarcoma, are similar to MRT in histopathology [8]. Thus, if only relying on microscopic cell morphology and common immunohistochemical markers, the final diagnosis must be established by carefully excluding other similar tumors. If possible, the expression of INI1 can be detected, which is of great value in the diagnosis of MRT. In the past, all 31 cases tested for INI1 were negative.

Currently, there are still no standard treatments for liver MRT. In previous cases, surgery, chemotherapy, radiotherapy and combinations of the three methods were used, and nearly all patients were treated with commonly used chemotherapy drugs such as vincristine, doxorubicin, etoposide, cyclophosphamide, carboplatin, cisplatin and ifosfamide. Although multimodal therapies were adopted, the survival time of most patients was very short; 82% of patients died within 6 months and 94% died within 1 year of diagnosis. The targeted drug bevacizumab has also been used to treat MRT but ended in failure [9]. One patient survived more than 3 years after liver transplantation and chemotherapy [10]. For those satisfying the criteria, liver transplantation may be an alternative approach. Nevertheless, up to 58% of patients displayed metastases at their first visit, and the application of liver transplantation is extremely limited.

To the best of our knowledge, this is the first report of liver MRT in an adult female, mainly manifesting as rupture and hemorrhage. The imaging and pathological findings of the patient were basically consistent with those that were previously reported. Unfortunately, one year after surgery, the patient developed abdominal and pelvic metastasis, suggesting that the tumor was highly aggressive. Moreover, gene detection failed to screen for sensitive chemotherapeutic drugs. Therefore, there is an urgent need to develop an effective treatment for liver MRT.

Genetic and epigenetic alterations play crucial roles in the initiation and progression of tumors. As a product of genetic and epigenetic dysregulation, gene and epigenetic therapy may provide new directions for MRT treatment. Deletion of the SMARCB1 locus (alias INI1, SNF5, BAF47) in chromosome 22q11.2 is the most specific change in MRT [11]. SMARCB1 encodes the core subunit of the SWI/SNF chromatin remodelling complex, which can directly recruit histone deacetylase activity to the cyclin D1 promoter and mediate cell-cycle arrest, and is presumed to function as a tumor suppressor [12]. Exogenous introduction of the SMARCB1 gene may restore its function for biallelic inactivation of SMARCB1. Simultaneously, loss of SMARCB1 function can activate Wnt/catenin, PI3K/Akt, hedgehog(Hh)/GLI, PRC2/H3K27 and other signalling pathways, promote the high expression of HDAC and Aurora A, and lead to changes in epigenetic regulation of the cell cycle, proliferation and differentiation (Fig. 4) [13, 14]. In addition, loss of SMARCB1 function contributes to transcriptional activation of the antiapoptotic protein MCL-1, inhibits the proapoptotic protein Noxa and induces resistance of MRT cells to topoisomerase II inhibitors (such as doxorubicin, etoposide and doxorubicin) [15]. Thus, regulation of these pathways may also play a role in the treatment of MRT.

Several inhibitors of histone modifiers have been shown to sensitize MRT cells to radiotherapy and chemotherapy, such as enhancer of zeste homolog 2 (EZH2) and histone deacetylase (HDAC) [16]. The MCL-1 inhibitor TW-37 was also shown to enhance the ability of doxorubicin to induce MRT cell death [15]. Additionally, loss of SMARCB1 is accompanied by the upregulation of cyclin D1 and cyclin-dependent kinases (CDKs) [17]. All of these factors may become potential targets for the clinical treatment of MRT in the future.

Notably, approximately 5% of MRTs do not have SMARCB1 deletions but lack SMARCA4 gene expression, and its function is still unclear [18]. The absence of SMARCB1 occurs not only in MRT, but also in some nonrhabdomyoid tumors [19]. Therefore, we need to perform an increasing number of in-depth studies to further explore the occurrence and development mechanism of MRT.

In conclusion, liver MRT is a rare tumor but also one of the most lethal malignancies. Despite the existence of intensive multimodal therapy currently, the curative effect is fairly dismal. The SMARCB1 deficiency, along with the changes in various signaling pathways, may offer new research directions for cancer therapeutics. Nevertheless, the mechanisms of the occurrence and development of liver MRT are still unclear, and we are obliged to carry out more in-depth researches to elucidate it. With the progress of medicine, we have faith that more patients will receive efficacious treatment and better prognosis.