Adult liver rhabdomyosarcoma complicated with sarcomatoid carcinoma: A case report

Abstract

BACKGROUND

Rhabdomyosarcoma (RMS) is a type of malignant tumor originating from rhabdomyocytes or mesenchymal cells differentiating into rhabdomyocytes. Hepatic pleomorphic RMS is a rare malignant liver tumor. Hepatic sarcomatoid carcinoma is also a rare epithelial malignant tumor originating from the liver; it is characterized by the coexistence of both carcinomatous and sarcomatoid spindle cell components.

CASE SUMMARY

This paper reports a special case of an elderly woman whose initial liver puncture biopsy showed pleomorphic RMS. After chemotherapy with the vincristine + doxorubicin + cyclophosphamide regimen, the alpha-fetoprotein level increased significantly. Therefore, a second liver puncture was performed, the pathological result of which was hepatic sarcomatoid carcinoma. Next-generation sequencing revealed MET gene amplification with an average copy number of 9 in the tumor tissue; however, both fluorescence in situ hybridization and immunohistochemical tests were negative for MET amplification. The treatment regimen was adjusted to chemotherapy combined with immunotherapy; however, the disease progressed rapidly, and the overall survival was only 6 months.

CONCLUSION

By sharing the diagnosis and treatment process of this patient and reviewing the relevant literature, we aim to help clinicians enhance their understanding of two rare diseases, namely pleomorphic RMS and sarcomatoid carcinoma of the liver.

Key Words: Hepatic malignant neoplasm; Pleomorphic rhabdomyosarcoma; Sarcomatoid carcinoma; Alpha-fetoprotein; MET amplification; Case report

Core Tip: Pleomorphic rhabdomyosarcoma and hepatic sarcomatoid carcinoma are both rare malignant liver tumors. This case report highlights the diagnostic and therapeutic challenges of rare hepatic malignancies, particularly, the critical importance of re-biopsy when pathological and clinical diagnoses diverge, illustrating the remarkable histopathological heterogeneity that can occur within hepatic malignancies.

INTRODUCTION

Rhabdomyosarcoma (RMS) is a type of malignant tumor originating from rhabdomyocytes or mesenchymal cells differentiating into rhabdomyocytes. According to the 2020 World Health Organization classification, RMS is divided into four major categories on the basis of pathological and morphological features: Embryonal RMS, alveolar RMS, pleomorphic RMS, and spindle cell/sclerosing RMS[1]. Embryonal and alveolar RMS account for 70%-80% of all RMS, whereas pleomorphic RMS is relatively rare. Embryonal RMS mainly occurs in children under 10 years of age; alveolar RMS is common in adolescents, and pleomorphic RMS predominantly occurs in adults over 40 years of age. RMS primarily occurs in the head and neck, followed by the genitourinary system, trunk, and extremities[2,3]. Primary RMS of the liver is extremely rare, accounting for less than 0.1% of all primary liver malignancies[4]. Hepatic sarcomatoid carcinoma (HSC) is also a rare epithelial malignant tumor originating from the liver; it is characterized by the coexistence of both carcinomatous and sarcomatoid spindle cell components. HSC accounts for 0.5%-3.9% of primary liver malignancies[5]. Therefore, an in-depth understanding of the clinical features of these diseases is essential for early diagnosis and timely treatment.

CASE PRESENTATION

Chief complaints

A 68-year-old woman presented to our hospital on February 27, 2023 with a complaint of upper abdominal distending pain for 2 months.

History of present illness

For over 2 months before her visit, the patient experienced upper abdominal distending pain without an obvious triggering factor, accompanied by decreased appetite and aversion to greasy food. She did not report symptoms such as fever, hematemesis, or melena.

History of past illness

In 2003, she was infected with hepatitis C due to a blood transfusion and took antiviral drugs for half a year.

Personal and family history

The patient denied having any personal or family history pertinent to her current presentation.

Physical examination

Physical examination at the time of admission revealed no evident positive signs.

Laboratory examinations

The pre-transfusion test was positive for hepatitis B e-antibody, hepatitis B core antibody, and hepatitis C virus antibody. The liver function test showed the following: Alanine transaminase (ALT), 88 U/L; aspartate transaminase (AST), 167 U/L; albumin, 31.2 g/L; total bilirubin, 51.8 μmol/L; direct bilirubin, 18.8 μmol/L; and indirect bilirubin, 33 μmol/L. The tumor marker alpha-fetoprotein (AFP) was 4850 IU/mL.

Imaging examinations

Plain and contrast-enhanced computed tomography: The liver capsule was smooth and morphology was normal. Multiple low-density nodules and masses were seen in the liver, with the largest one measuring approximately 5.1 cm in diameter and having unclear boundaries. After contrast medium injection, they showed heterogeneous enhancement, and some lesions had calcification. The intrahepatic bile ducts were not dilated. Low-density shadows were seen in the main portal vein and its branches. The esophageal-gastric fundus veins and splenic veins were tortuously dilated. The gallbladder was normal in size with a smooth wall, and the spleen was normal (Figure 1).

Figure 1 Contrast-enhanced abdominal computed tomography (portal venous phase). A: Thrombus in the left and right branches of the portal vein; B: Thrombus within the main portal vein; C: A mass of approximately 5.1 cm × 5.0 cm in the right lobe of the liver.

First liver puncture pathology: Histologically, the tumor cells showed evident atypia, with large cell volume, round or polygonal shape, deeply eosinophilic cytoplasm, deformed large cells resembling rhabdomyoblasts, and focal tumor giant cells. Immunohistochemistry showed Ki67 (60%), cytokeratin pan (CKpan) (-), CK8 (-), hepatocyte paraffin 1 (-), S-100 (-), HMB45 (-), desmin (+), and myogenic differentiation 1 (MyoD1) (+). The structure in the “liver” section combined with immunohistochemistry was consistent with pleomorphic RMS (Figure 2).

Figure 2 Immunohistochemical examination of the first liver puncture pathology. A: Hematoxylin and eosin staining; B: Negative expression of cytokeratin pan; C: Immunohistochemical staining showing Ki-67 (60%); D: Positive expression of desmin; E: Positive expression of myogenic differentiation 1. Magnification, × 100.

Second liver puncture pathology: Pathological findings showed that most of the tumor cells were spindle-shaped and diffusely arranged, and some local cells were epithelioid. Immunohistochemistry revealed the following: Hepatocyte paraffin 1 (-), glypican-3 (-), Ki-67 (80%), CK7 (-), vimentin (focal +), CK8 (focal +), CK19 (focal +), SMARCA4/BRG1 (+), integrase interactor-1 (+), calretinin-B (membrane +), glutamine synthetase (+), desmin (-), smooth muscle actin (-), MyoD1 (-), and CD34 (vascular +). The structure in the “liver” section, combined with immunohistochemistry, was consistent with a sarcomatoid tumor (Figure 3).

Figure 3 Immunohistochemical examination of second liver puncture pathology. A: Hematoxylin and eosin staining; B: Negative expression of glypican-3; C: Negative expression of desmin; D: Focal positive expression of cytokeratin pan. Magnification, × 100.

Next-generation sequencing: The result of tissue next-generation sequencing (NGS) showed that the patient had MET amplification (copy number 9), TP53 mutation (L252P, mutation abundance 81%), PDGFRA amplification, RET amplification, ARID1A mutation, and TSC2 mutation. The tumor mutation burden (TMB-H) was 23.33 Muts/Mb, indicating a high TMB-H. The programmed death-ligand 1 (PD-L1) combined positive score was < 1; the PD-L1 tumor proportion score was < 1%, and the microsatellite was stable. Further immunohistochemical and fluorescence in situ hybridization (FISH) verification was performed for the tissue NGS-detected MET amplification, and both the MET immunohistochemistry and FISH results were negative.

FINAL DIAGNOSIS

The patient was diagnosed as having a malignant liver tumor (pleomorphic RMS combined with sarcomatoid carcinoma, stage IV) complicated with secondary malignant liver tumors, portal vein cancer emboli, esophageal-gastric fundus varicose veins, and splenic varicose veins. Liver function was classified as Child-Pugh grade B.

TREATMENT

After a multidisciplinary consultation, the general surgery and radiotherapy departments found the current liver tumors to be too extensive to be resolved with surgical treatment or local radiotherapy. The interventional department determined that the patient had cancer emboli in the main portal vein and its branches; the emboli in the main portal vein were > 90% occlusive, making them a contraindication for transcatheter arterial chemoembolization; however, hepatic arterial infusion chemotherapy could be considered. The oncology department recommended systemic chemotherapy with the VAC regimen. After elaborate discussions, it was finally decided to administer vincristine 2 mg + liposomal doxorubicin 40 mg + cyclophosphamide 1.2 g by intravenous drip for 2 cycles. After treatment, the contrast-enhanced computed tomography (CT) re-examination on April 19, 2023, showed multiple liver masses, with some slightly smaller than before. The curative effect was evaluated as stable disease. Laboratory tests showed that ALT, AST, albumin, and total bilirubin returned to normal, but the AFP level increased from 4850 IU/mL to 10150 IU/mL.

To clarify whether the patient had a hepatocellular carcinoma component, a second liver puncture was performed. According to the pathological findings of the second liver puncture and the NGS detection result, the treatment regimen was adjusted to liposomal doxorubicin 40 mg + cisplatin 90 mg + sintilimab 200 mg by intravenous drip for 2 cycles. The AFP level declined from 10150 IU/mL to 3810 IU/mL. The contrast-enhanced CT re-examination performed on July 19, 2024, showed multiple liver masses, and the range of emboli in the main portal vein and its branches was larger than before. The curative effect was evaluated as progressive disease.

OUTCOME AND FOLLOW-UP

The patient died on August 23, 2023, with an overall survival (OS) of 6 months.

DISCUSSION

Liver RMS is an extremely rare primary malignant tumor of the liver. From 1956 to date, only 34 cases of hepatic RMS have been reported abroad. Since 1995 in China, a total of 13 cases of hepatic RMS have been reported. Table 1 summarizes 27 cases with detailed data available on PubMed since 1956. Upon a review of these cases, the author summarized the clinical features of the above cases. The age of patients with hepatic RMS was found to range from 1.4 years to 76 years, with middle-aged and elderly patients being more commonly affected. The median age is 53 years. Male patients outnumber female patients, with a male-to-female ratio of 1.5:1. The most common pathological type is embryonal RMS, followed by pleomorphic RMS, and the two account for 70% of the pathological types of hepatic RMS. Alveolar RMS is rarely reported[6], and currently, only 1 case of hepatic spindle cell/sclerosing RMS has been reported globally[7].

Table 1 Summary of cases with hepatic rhabdomyosarcoma reported in literature.

Case number	Age/sex	Tumor size	Histopathology	Treatment	Follow-up (month)	Outcome
1	14/Female	15.5 cm × 9.5 cm × 12 cm	NA	Heavy dose of X-ray therapy and radiation therapy + total right hepatic lobectomy	NA	NA
2	65/Female	35 cm × 15 cm × 10 cm	Embryonal/alveolar	Untreated	3	Death
3	76/Male	NA	Embryonal	Untreated	2	Death
4	70/Male	Multinodular liver tumors	Pleomorphic	Untreated	8	Death
5	62/Male	14 cm × 9 cm × 9 cm	NA	Operation + trans-arterial embolisation therapy + chemotherapy	3	Death
6	1.4/Male	NA	NA	Palliative CA/VD chemotherapy	15	Death
	2.4/Male	NA	NA	Left hepatectomy + adjuvant CA/VD chemotherapy + radiotherapy	76 +	Survival
	7/Male	NA	NA	Palliative CA/VD chemotherapy	8	Death
7	68/Male	NA	Alveolar	NA	NA	NA
8	53/Male	20 cm	Embryonal	Surgical resection	3	Death
9	34/Female	12 cm × 12 cm × 6 cm	NA	Surgery	NA	NA
10	69/Male	NA	Pleomorphic	NA	NA	NA
11	63/Female	10 cm × 8 cm × 7 cm	Pleomorphic	Left hepatectomy	108	Survival
	29/Female	11 cm	Pleomorphic	Right hepatectomy + adjuvant AI chemotherapy	180	Survival
12	52/Male	19 cm × 12 cm × 11 cm	NA	Untreated	2	Death
13	8/Male	NA	Pleomorphic	Extended right hepatectomy	2	Death
14	14/Male	NA	Embryonal	Induction CEV chemotherapy	NA	NA
15	59/Female	6 cm	Alveolar	Left hemi-hepatectomy + palliative AI chemotherapy	31	Death
16	17/Male	20 cm × 13 cm	Embryonal	Palliative VCD, MAID, gemcitabine-paclitaxel chemotherapy	31	Death
17	67/Male	14.5 cm × 12.3 cm × 9.1 cm	Embryonal	Left hepatectomy + adjuvant AIV chemotherapy	24	Survival
18	40/Male	4.5 cm × 4 cm × 4 cm	Embryonal	Hepatic left lateral lobectomy	NA	NA
19	66/Female	20 cm × 15 cm	Pleomorphic	Right hepatectomy	5	Death
20	57/Female	18.5 cm	Spindle cell/sclerosing	Partial hepatectomy + adjuvant VCD/IE chemotherapy	12	Survival
21	73/Female	12 cm × 10 cm	Pleomorphic	Right hepatectomy + palliative trabectedin chemotherapy	6	Death
22	5/Female	Diffuse lesions	Embryonal	Induction VCD/VI chemotherapy + SIRT with yttrium-90 + EBRT + palliative VIE chemotherapy	29	Death
23	7/Male	7.5 cm × 7.3 cm × 7.7 cm	Embryonal	Neoadjuvant VIE chemotherapy + left hepatectomy + prophylactic radiotherapy + adjuvant VIE chemotherapy	38	Survival
24	71/Male	5.6 cm	Epithelioid	Untreated	12	Death
25	60/Female	8 cm × 7 cm × 6 cm	Pleomorphic	Neoadjuvant IVAD chemotherapy + right hepatectomy + adjuvant IVAD chemotherapy	12	Survival
26	15/Male	15.3 cm × 15.6 cm × 16 cm	Embryonal	Neoadjuvant AI chemotherapy + right extended hepatectomy + adjuvant AI chemotherapy	36	Survival
27	1.4/Female	9.4 cm × 9 cm × 11 cm	NA	Neoadjuvant VCD chemotherapy + left hepatectomy + IMRT + adjuvant VCD chemotherapy	48	Survival

NA: Not available; SIRT: Selective internal radiation therapy; EBRT: External beam radiation therapy; IMRT: Intensity modulated radiation therapy; CA: Cyclophosphamide + adriamycin; VD: Vincristine + dactinomycin; AI: Adriamycin + iosfamide; CEV: Cyclophosphamide + etoposide + vincristine; VCD: Vincristine + cyclophosphamide + dactinomycin; MAID: Mesna + adriamycin + iosfamide + dacarbazine; AIV: Adriamycin + iosfamide + vincristin; IE: Iosfamide + etoposide; VI: Vincristine + iosfamide; VIE: Vincristine + iosfamide + etoposide; IVAD: Iosfamide + vincristine + adriamycin + dactinomycin.

The imaging findings of hepatic RMS are non-specific. The tumor is typically solitary, with a diameter of 4.5-35 cm (average diameter, 14 cm). It is round or oval; its interior is prone to bleeding and necrosis, and it typically shows uneven enhancement on enhanced CT scans[8]. Owing to its large size, the most common symptom is upper abdominal pain or discomfort, which may be accompanied by abdominal distension, fatigue, poor appetite, nausea, and fever. Since primary hepatic RMS does not invade the biliary tract, jaundice does not usually occur. Laboratory tests may show a mild increase in lactate dehydrogenase, and liver function indicators are generally within the normal range, as is the AFP level.

Given the non-specificity of imaging, symptoms, and laboratory tests, pathological diagnosis is the gold standard for hepatic RMS. Under the microscope, the tumor cells of hepatic pleomorphic RMS appear polygonal, round, and spindle-shaped, showing skeletal muscle differentiation without embryonic or alveolar components. In most cases, varying numbers of pleomorphic rhabdomyoblasts can be seen, which are large cells with significant atypia, abundant and deeply eosinophilic cytoplasm, no cross-striations, and large pleomorphic nuclei. Immunohistochemistry shows diffuse expression of desmin, whereas myogenin and MyoD1 are expressed locally[9]. Using immunohistochemistry, hepatic pleomorphic RMS needs to be differentiated from undifferentiated pleomorphic sarcoma, pleomorphic leiomyosarcoma, and epithelial and mesenchymal malignant tumors with rhabdoid differentiation.

Surgical resection is the most preferred treatment method to improve the prognosis of patients with hepatic RMS[10,11]. The average survival time of patients who undergo surgery is 16.7 months, whereas that of those who do not receive surgical treatment is only 9.5 months[12]. Surgical methods include anatomical hepatectomy (left/right hemi-hepatectomy or extended hemi-hepatectomy). At the same time, with the wide application of multidisciplinary comprehensive treatment for tumors, the combination of surgery and chemotherapy has shown better efficacy in hepatic RMS. Since 2022, three hepatic RMS patients (one case of RMS and two cases of embryonal RMS, all reported abroad) who received neoadjuvant chemotherapy combined with surgery and then adjuvant chemotherapy after surgery had disease-free survival (DFS) times of 36 months[13], 38 months[12], and 48 months[14], respectively. Chemotherapeutic drugs mainly include vincristine, cyclophosphamide, actinomycin D, doxorubicin, cisplatin, etoposide, and ifosfamide. Chemotherapy regimens can be selected from VAC, IVAD, AI, VCD, and IE, among others. The role of radiotherapy in hepatic RMS is not yet completely clear[15]. Most patients with hepatic RMS are middle-aged and elderly, and the proportion of the pleomorphic RMS subtype is relatively high. Different from the high sensitivity of childhood RMS to radiotherapy, the role of radiotherapy in hepatic RMS requires more case reports.

In our case, the patient was an elderly woman with a complaint of upper abdominal pain. The first puncture biopsy showed rhabdomyoblasts under the microscope, characterized by evident atypia, large cell volume, round or polygonal shape, deeply eosinophilic cytoplasm, and deformed large cells. The immunohistochemistry was positive for the skeletal muscle differentiation markers desmin and MyoD1 but negative for the epithelial markers CKpan, CK8, and Hepa. Based on the morphological features and immunohistochemical markers, the diagnosis of PRMS was clear. Following multidisciplinary discussion, the VAC chemotherapy regimen was selected. Post-treatment imaging revealed a reduction in a portion of the tumor. However, some clinical manifestations were not entirely consistent with the pathological diagnosis. First, the patient presented with a high-risk factor of previous hepatitis C infection. A history of hepatitis C infection was identified as a high-risk factor for primary liver cancer, rather than for PRMS. Second, the patient had a diffuse liver mass accompanied by portal vein tumor thrombosis, whereas PRMS typically presents as a solitary large lesion without thrombus formation. Most notably, AFP levels are generally within the normal range in PRMS; however, the patient’s baseline AFP was 4850 IU/mL, which increased significantly to 10150 IU/mL after VAC regimen chemotherapy. The above conditions required high-level consideration of whether there was concurrent hepatocellular carcinoma, and thus, a second puncture was performed to clarify the pathology, which revealed HSC.

HSC is also a rare epithelial malignant tumor originating from the liver. Its biological behavior is highly invasive and its prognosis is extremely poor. HSC predominantly occurs in middle-aged and elderly people and is more common in males, and it has an average onset age of approximately 50 years. Currently, the pathogenesis of HSC is not fully understood, and there are multiple theories, such as the embryonic residue theory, collision theory, totipotent stem cell theory, stromal induction theory, and metaplasia theory. HSC may be related to viral infection, liver cirrhosis, preoperative radiotherapy and chemotherapy, and interventional therapy. The common mutation type is the TP53 mutation[16].

The clinical manifestations and imaging findings of HSC also lack characteristic features. Patients may present with symptoms like abdominal pain, abdominal distension discomfort, jaundice, and fever[17]. The levels of serum tumor markers, such as AFP, CEA, and CA125, may be mildly elevated. Enhanced CT scanning shows a massive mass with a peripheral-to-central filling enhancement pattern or continuous enhancement of the peripheral solid component[18].

The pathological characteristic of HSC is the presence of varying degrees of trabecular pattern transition between the sarcomatoid and ordinary hepatocellular carcinoma areas. The hepatocellular carcinoma area can present a trabecular, nested, or pseudo-glandular structure, and the sarcomatoid area is typically composed of spindle cells arranged in an interlacing bundle pattern. Immunohistochemistry shows positive expression of both epithelial tumor markers (CKpan, keratin, and epithelial membrane antigen) and mesenchymal tumor markers (vimentin and smooth muscle actin). Intermediate keratins, namely CAM5.2, CK8, CK18, and CK19, may also be positively expressed[19]. In our patient, the second puncture biopsy showed spindle-shaped and diffusely arranged tumor cells, with some local epithelioid cells. These cells were positive for both the mesenchymal marker vimentin and epithelial markers CK8 and CK19 but negative for the skeletal muscle differentiation markers desmin and MyoD1. Therefore, the diagnosis of HSC was made.

The main treatment method for HSC is surgical resection[20], and postoperative adjuvant therapy significantly prolongs DFS in patients with HSC[21]. However, due to the rapid growth of the tumor, it is often in the advanced stage at the time of discovery, and the postoperative recurrence rate is relatively high. The efficacy of radiotherapy, chemotherapy, and interventional embolization treatment remains unknown. Therefore, the prognosis of HSC is worse than that of hepatocellular carcinoma[22,23], and the median OS of advanced patients is 4.8 months. Currently, immunotherapy has shown good efficacy in HSC[24,25]. The patient’s tumor tissue was negative for PD-L1 expression but had a high tumor mutation burden. Based on the KEYNOTE-158 trial, TMB-H serves as a predictive biomarker for selecting patients who are most likely to benefit from immunotherapy. Therefore, according to the pathological findings of the second liver puncture and NGS detection results, the treatment regimen was adjusted to AC chemotherapy combined with the immune checkpoint inhibitor sintilimab. Unfortunately, the OS time was not prolonged by administering chemotherapy in combination with immunotherapy.

This case reflects the high heterogeneity of tumors, and based on the pathogenesis, we postulate two potential scenarios. The first proposed pathological mechanism is hepatic carcinosarcoma. Carcinosarcoma is a malignant tumor characterized by intimate admixture of carcinomatous and sarcomatous components. The carcinomatous element may be hepatocellular, cholangiocellular, or mixed, whereas the sarcomatous component can include chondrosarcoma or osteosarcoma, leiomyosarcoma or RMS, or fibrosarcoma, among others[26]. Distinct transitional zones may be observed between the two components. The histogenesis of hepatic carcinosarcoma remains incompletely understood. One prevailing theory posits that it originates from the bidirectional differentiation of pluripotent hepatic stem cells into both carcinomatous and sarcomatous components. Liu et al[27] documented a case of carcinosarcoma comprising hepatocellular carcinoma, cholangiocarcinoma, osteosarcoma, and RMS, wherein the serum AFP level was recorded at 7406 ng/mL. In our case, although the AFP level reached 10150 ng/mL, no typical hepatocellular or cholangiocellular epithelial structures were identified in two separate biopsy procedures. The second proposed pathological mechanism was HSC with rhabdomyosarcomatous differentiation. Although relatively rare, HSC is inherently a poorly differentiated carcinoma that has the potential for heterologous differentiation into RMS[28].

At the same time, this case reflects the high heterogeneity of tumor genes. The patient’s tissue NGS showed MET gene amplification, with an average copy number of 9; however, FISH was negative for MET amplification. Previous studies by Zhang et al[29] have shown that MET gene amplification is an independent prognostic factor for HSC, and MET gene amplification in HSC is more common in the sarcomatoid area than in the epithelial area. Although this patient’s NGS testing indicated MET amplification, the MET FISH was negative. Given that FISH is the gold standard for detecting MET amplification, we were uncertain about using a MET-TKI, and thus, we did not use it.

CONCLUSION

In conclusion, both hepatic RMS and HSC are rare hepatic malignant tumors, and their pathogenesis, molecular characteristics, and optimal treatment strategies need further exploration.

ACKNOWLEDGEMENTS

The authors sincerely thank the patient for her consent to participate in this study.