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23 May 2024: Articles  China (mainland)

Duodenal Soft Tissue Sarcoma with GLI1 Gene Rearrangement: A Case Report and Literature Review

Rare disease

Jinghe Li ORCID logo1ABCDEF, Ling Zuo1BCF, Li Tang1BCF, Xiaochu Yan2ACDF, Shengkai Chen1ABCDG*

DOI: 10.12659/AJCR.943271

Am J Case Rep 2024; 25:e943271

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Abstract

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BACKGROUND: Soft tissue tumors have various subtypes, among which sarcomas exhibit high malignant potential and poor prognosis. Malignant epithelioid tumor with GLI1 alterations was originally found in myopericytoma with t(7;12) translocation. However, recent studies indicated that it is a distinct tumor type characterized by multiple nodular distributions of oval or round epithelioid cells with a rich capillary network and a lack of specific immunophenotype. There are only a few cases reported worldwide and the optimal treatment is still being explored.

CASE REPORT: We report the case of a 31-year-old patient who presented with severe anemia and a large soft tissue mass in the duodenum. The patient underwent surgical resection with a negative margin, and none of the 15 lymph nodes tested positive for the tumor. Postoperative pathology and FISH testing further confirmed the presence of GLI1 disruption and S-100 and SMA negativity. Genetic testing revealed the ACTB-GLI1 fusion. No specific medication was offered after the surgery. No tumor recurrence was found during the 23-month follow-up period. The patient’s quality of life is currently satisfactory.

CONCLUSIONS: Soft tissue sarcomas characterized by GLI1 gene rearrangement have a relatively less aggressive and metastatic nature, with the solid mass spreading minimally even as it grows. Patients can benefit from surgical resection, resulting in a relatively long period of tumor-free survival.

Keywords: Carcinosarcoma, case reports, Gene Rearrangement

Introduction

Soft tissue sarcomas with GLI1 gene rearrangement are a newly identified subtype of malignant epithelioid tumors. Previous studies have demonstrated that their morphological, immunophenotypic, and molecular features overlap with those of gastroblastoma [1,2]. However, recent literature has demonstrated that tumors with similar genetic alterations can develop in peripheral soft tissue, bones, and hollow organs. Consequently, these tumors are now collectively classified as soft tissue sarcomas with GLI1 gene rearrangement, which is characterized by multiple nodular distributions of oval or round epithelioid cells with a rich capillary network and a lack of specific immunophenotype [3,4]. These tumors also have a uniform spindle cell cytomorphology with a scant clear cytoplasm and ovoid-to-tapered nuclei, with a distinct perivascular distribution around thin-walled arborizing vessels [5]. Although reports of this tumor type are currently limited, there is a general consensus regarding their malignant potential. Surgical resection is the primary treatment approach, while the management and postoperative adjuvant treatment for inoperable patients requires further evidence [2]. Here, we report a case of a duodenal tumor with ACTB-GLI1 gene fusion, analyze its molecular and immunophenotypic characteristics, and review the existing literature, aiming to enhance our understanding of this special tumor type.

Case Report

IMAGING EXAMINATION AND SURGERY:

Contrast-enhanced CT and three-dimensional imaging of the abdomen revealed an irregular soft tissue mass (7.2×6.0 cm) spanning from the gastric antrum to the duodenal bulb and pancreatic head, suggestive of a tumor. The feeding artery of the tumor was the gastroduodenal artery. The duodenal bulb exhibited localized luminal stenosis (Figure 1).

After this work-up, he presented to our hospital for definitive treatment in January 2022. Laboratory tests showed anemia (96 g/L for hemoglobin) and the results were negative for tumor markers (Table 1). Considering that the previously provided conservative treatment was ineffective for his recurrent anemia and the biopsies obtained on gastroscopy showed dysplasia, an open pancreaticoduodenectomy was performed under general anesthesia after consultation with the patient. Intraoperative frozen pathological examination of the duodenal mass suggested a borderline or low-grade malignant soft tissue tumor. Regional lymph node dissection was then carried out.

PATHOLOGICAL FINDINGS AND GENETIC TESTING RESULTS:

The patient experienced a smooth recovery following the surgery. Postoperative pathological examination revealed the presence of a malignant tumor composed of epithelioid soft tissue. Along with the formation of duodenal surface ulcers, the tumor had invaded the entire duodenal wall, pancreas, and gastric pylorus, No intravascular tumor thrombus or nerve invasion was observed. All resection margins were negative (R0 resection). There was no evidence of lymph node invasion in the 15 nodes examined (0/15).

Immunohistochemistry analysis demonstrated the following results: CD10 (+), CD56 (++), S-100 (-), MDM2 (-), and SMA (-) (Table 2). FISH (Leica APERIO VERSA 8) demonstrated a GIL1 gene break. No break was found in EWSR1 (Figure 2). Genetic testing showed ACTB-GIL1 fusion (transcript: NM_001101.3/NM_005269.2; function domain: EX3: EX6). Based on the findings of immunohistochemistry, FISH, and genetic testing, the tumor was determined to be a soft tissue sarcoma with rearrangement of the GLI1 gene.

POSTOPERATIVE TREATMENT AND FOLLOW-UP:

The patient was discharged 3weeks after the operation. As there is currently no standard postoperative treatment plan for soft tissue sarcomas with altered GLI1 gene arrangement, regular imaging (CT every 3 months) follow-up was recommended. After 23 months of follow-up, the patient returned to his baseline function and the anemia had resolved. There was no evidence of tumor recurrence on imaging.

Written informed consent was obtained from the patient prior to publication of this case report and all procedures performed were in accordance with the ethical standards of the institutional research committee.

Discussion

GLI1 is a transcriptional effector downstream of the Hedgehog signaling pathway with roles in cell cycle regulation, DNA replication, and DNA damage repair [6,7]. Studies have shown that GLI1 is expressed at a low level in normally differentiated tissue. In tumor tissue, abnormal activation of GLI1 is associated with various features of malignancy, such as proliferation, angiogenesis, and chemotherapy resistance [8,9]. GLI1-rearrangement soft tissue sarcoma is a special type of sarcoma that occurs with a wide age range at diagnosis (4–65 years old) but is more common in young adults. The tumor can be found in multiple various locations, including the extremities, trunk, head and neck, cavities, and solid organs [10].

There are only a few cases reported worldwide. These cases involve GLI1 amplification, as well as the fusion of GLI1 with ACTB, MALAT1, and PTCH1 [11]. The expression of the GLI gene product due to gene amplification may be linked to tumori-genesis in some cases of childhood sarcoma with primitive or multipotent histological features [12]. A study by Agaram et al showed that GLI1 amplification was found in <1% of approximately 30 000 tumors analyzed. Among the different subgroups, GLI1 amplification was most commonly seen in soft tissue sarcomas (6%), followed by glioma (4%), melanoma (2%), and lung adenocarcinoma (1%). Among GLI1-amplified soft tissue sarcomas, liposarcoma was the most common (85%), followed by endometrial sarcoma (5%) [5]. GLI1 gene fusion tumors were first reported by Dahlén et al [13]. Currently, the most frequently reported subtype contains ACTB-GLI1 gene fusion, which was initially identified in a particular type of tumor, a t(7: 12) translocation pericytoma. This was previously considered to be a special soft tissue tumor type with a benign clinical course; however, recent studies suggest that metastatic potential does exist. Documented sites of disease metastasis include the liver, lymph nodes, and peritoneum [1,2,14]. These tumors have a homogeneous spindle cell morphology with little cytoplasm and ovoid-to-cone-shaped nuclei, prominent perivascular distribution around thin-walled tree-like vessels, and characteristic monomorphic nested epithelioid morphology. They are typically S100-negative.

Tumors with GLI1 alterations from various anatomical locations do not display consistent immune characteristics. Studies have shown t(7;12)-positive pericytomas are also positive for SMA and have no expression of S-100 or CD34 [4,13]. MALAT1-GLI1-positive gastric plexiform fibromyxomas only show positivity for SMA and are negative for S-100 [15]. In contrast, gastroblastomas are positive for cytokeratin and CD56, as well as being focally SMA-positive but lacking S-100 expression [1]. Lopez-Nunez et al reported a case with APOD-GLI1 gene fusion [16]. The tumor cells were strongly positive for S100 and negative for actin and calpain. Agaram et al reported 4 cases with GLI1 gene amplification, which occurred in the shoulder, back, neck, and elbow [5]. These tumors showed focal positivity for S100.

Regarding treatment, in view of its malignant potential, surgical resection is still the main approach at present. However, there is still controversy regarding the necessity of adjuvant therapy following surgery. Most studies have focused on follow-up observations, which have demonstrated a significantly prolonged tumor-free survival period (Table 3). Patients diagnosed with GLI1 fusion-associated neoplasms have been documented to have survival histories ranging from 6 to 15 years [17,18]. Surgery is clearly not a good therapeutic option for multiple lesions. Smoothened (SMO) protein plays a crucial role in the Hedgehog signaling pathway transduction process. Interfering with SMO to halt Hedgehog signaling pathway activity may offer therapeutic advantages. However, several studies have indicated that GLI1 protein may not be responsive to SMO inhibitors [19–21]. Targeting GLI1 activity would be ideal, but anti-GLI therapies are currently experimental [22]. Based on the PD-I/PD-L1 expression level, immunotherapy can be considered as a treatment option [3]. Follow-up treatments still need to be studied.

Conclusions

Soft tissue sarcomas characterized by GLI1 gene rearrangement tend to occur in young individuals. While some cases occurring on the body surface exhibit early symptoms and can be detected at an early stage, those located in hollow or abdominal organs often lack typical symptoms and are challenging to identify early on. Fortunately, this tumor type demonstrates a relatively less aggressive and metastatic nature, with the solid mass spreading minimally even as it grows. Patients can benefit from surgical resection, resulting in a relatively long period of tumor-free survival; however, there is currently no standardized approach for postoperative adjuvant therapy. The prevailing practice is to conduct follow-up observation.

Figures

(A–D) Preoperative CT imaging and 3D reconstruction. There is an irregular soft tissue mass shadow within unclear margins in the antrum-duodenum-pancreatic head and neck region. CT value is 33Hu. Obvious heterogeneous enhancement in the arterial phase is observed. Contrast agent filling in the portal venous phase becomes larger and more uniform. There is narrowing of the lumen of the duodenal bulb. Computed tomography angiography shows the lesion is supplied by the gastroduodenal artery.Figure 1.. (A–D) Preoperative CT imaging and 3D reconstruction. There is an irregular soft tissue mass shadow within unclear margins in the antrum-duodenum-pancreatic head and neck region. CT value is 33Hu. Obvious heterogeneous enhancement in the arterial phase is observed. Contrast agent filling in the portal venous phase becomes larger and more uniform. There is narrowing of the lumen of the duodenal bulb. Computed tomography angiography shows the lesion is supplied by the gastroduodenal artery. Pathology and FISH test results. Microscopic image demonstrating tumor cells distributed in nests with glassy degeneration of septal collagen fibers and surrounding tissue infiltration. The tumor cells are round or fusiform in shape and epithelioid-like. The cytoplasm shows eosinophilic staining. The shapes of the nuclei are relatively homogeneous. The chromatin is fine. The nucleoli are inconspicuous. Cytoplasmic clear cells can be observed locally. Arborized blood vessels are abundant in the stroma and some areas show a myxoid matrix (A–D). FISH shows the break of GLI1 gene. Among 100 counted cells, there are 17 wild-type cells and 83 (83%) cells with GLI1 break, accounting for 83% (E). The EWSR1 gene does not show an apparent break. Among 100 counted cells, there are 99 wild-type cells and 1 (1%) cell with an EWSR1 break (F). Interpretation of FISH testing results is: 1) Normal cells (2 yellow fusion signals) indicating that the gene is not broken, and 2) Typical abnormal cells (1 yellow fusion signal, 1 red signal, and 1 green signal) indicating that the gene is broken.Figure 2.. Pathology and FISH test results. Microscopic image demonstrating tumor cells distributed in nests with glassy degeneration of septal collagen fibers and surrounding tissue infiltration. The tumor cells are round or fusiform in shape and epithelioid-like. The cytoplasm shows eosinophilic staining. The shapes of the nuclei are relatively homogeneous. The chromatin is fine. The nucleoli are inconspicuous. Cytoplasmic clear cells can be observed locally. Arborized blood vessels are abundant in the stroma and some areas show a myxoid matrix (A–D). FISH shows the break of GLI1 gene. Among 100 counted cells, there are 17 wild-type cells and 83 (83%) cells with GLI1 break, accounting for 83% (E). The EWSR1 gene does not show an apparent break. Among 100 counted cells, there are 99 wild-type cells and 1 (1%) cell with an EWSR1 break (F). Interpretation of FISH testing results is: 1) Normal cells (2 yellow fusion signals) indicating that the gene is not broken, and 2) Typical abnormal cells (1 yellow fusion signal, 1 red signal, and 1 green signal) indicating that the gene is broken.

References:

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3.. Prall OWJ, McEvoy CRE, Byrne DJ, A malignant neoplasm from the jejunum with a MALAT1-GLI1 fusion and 26-year survival history: Int J Surg Pathol, 2020; 28(5); 553-62

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6.. Mastrangelo E, Milani M, Role and inhibition of GLI1 protein in cancer: Lung Cancer (Auckl), 2018; 27; 35-43

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13.. Dahlén A, Fletcher CD, Mertens F, Activation of the GLI oncogene through fusion with the beta-actin gene (ACTB) in a group of distinctive pericytic neoplasms: Pericytoma with t(7;12): Am J Pathol, 2004; 164(5); 1645-53

14.. Antonescu CR, Agaram NP, Sung YS, A distinct malignant epithelioid neoplasm with GLI1 gene rearrangements, frequent S100 protein expression, and metastatic potential: expanding the spectrum of pathologic entities with ACTB/MALAT1/PTCH1-GLI1 fusions: Am J Surg Pathol, 2018; 42(4); 553-60

15.. Spans L, Fletcher CD, Antonescu CR, Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 up-regulation define a subset of plexiform fibromyxoma: J Pathol, 2016; 239(3); 335-43

16.. Lopez-Nunez O, Surrey LF, Alaggio R, Novel APOD-GLI1 rearrangement in a sarcoma of unknown lineage: Histopathology, 2021; 78(2); 338-40

17.. Koh NWC, Seow WY, Lee YT, Pericytoma with t(7;12): The first ovarian case reported and a review of the literature: Int J Gynecol Pathol, 2019; 38(5); 479-84

18.. Kerr DA, Pinto A, Subhawong TK, Pericytoma with t(7;12) and ACTB-GLI1 fusion: Reevaluation of an unusual entity and its relationship to the spectrum of GLI1 fusion-related neoplasms: Am J Surg Pathol, 2019; 43(12); 1682-92

19.. Niewiadomski P, Niedziółka SM, Markiewicz Ł, GLI proteins: Regulation in develop-ment and cancer: Cells, 2019; 8(2); 147

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Figures

Figure 1.. (A–D) Preoperative CT imaging and 3D reconstruction. There is an irregular soft tissue mass shadow within unclear margins in the antrum-duodenum-pancreatic head and neck region. CT value is 33Hu. Obvious heterogeneous enhancement in the arterial phase is observed. Contrast agent filling in the portal venous phase becomes larger and more uniform. There is narrowing of the lumen of the duodenal bulb. Computed tomography angiography shows the lesion is supplied by the gastroduodenal artery.Figure 2.. Pathology and FISH test results. Microscopic image demonstrating tumor cells distributed in nests with glassy degeneration of septal collagen fibers and surrounding tissue infiltration. The tumor cells are round or fusiform in shape and epithelioid-like. The cytoplasm shows eosinophilic staining. The shapes of the nuclei are relatively homogeneous. The chromatin is fine. The nucleoli are inconspicuous. Cytoplasmic clear cells can be observed locally. Arborized blood vessels are abundant in the stroma and some areas show a myxoid matrix (A–D). FISH shows the break of GLI1 gene. Among 100 counted cells, there are 17 wild-type cells and 83 (83%) cells with GLI1 break, accounting for 83% (E). The EWSR1 gene does not show an apparent break. Among 100 counted cells, there are 99 wild-type cells and 1 (1%) cell with an EWSR1 break (F). Interpretation of FISH testing results is: 1) Normal cells (2 yellow fusion signals) indicating that the gene is not broken, and 2) Typical abnormal cells (1 yellow fusion signal, 1 red signal, and 1 green signal) indicating that the gene is broken.

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923