Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal neoplasms of the gastrointestinal tract. They are categorized into different subtypes based on the different genetic mutations and various clinicopathological characteristics (1). Approximately 85% of the GISTs harbor active mutations of the KIT or PDGFRA oncogene. Among the remaining wildtype GISTs, succinate dehydrogenase (SDH)-deficient GISTs are the most frequently found neoplasms, accounting for about 5-10% of the overall occurrence. The SDH-deficient GISTs have a predilection for children and young adult populations and have gastric involvement, multinodular growth pattern, epithelioid cytology, lymphovascular invasion, and a greater risk of metastasis to the regional lymph nodes or liver when compared to the classical GISTs. Immunophenotypically, most GISTs, including SDH-deficient GISTs, show strong and diffuse expression of KIT (CD117) and DOG1. However, in an extremely rare circumstance, tumor cells with morphologically high-grade progression, such as undifferentiated pleomorphic sarcoma (2), or heterologous epithelial (3), myogenic (4), or angiosarcomatous differentiation (3), could lose the GIST immunohistochemical characteristics. This was described as dedifferentiated GISTs, which can occur under the pressure of the tyrosine kinase inhibitor (TKI) treatment or develop de novo. The previous findings suggested that the genetic instability, such as loss of heterozygosity (LOH) or low-level KIT amplification, might have correlations with the dedifferentiation after therapy. On the other hand, alternative escape mechanisms for the KIT-independent signaling pathway might play a role in the de novo dedifferentiation (5). However, more cases are needed to investigate the underlying mechanisms. Herein, we described a case of SDH-deficient GIST with the heterologous epithelial dedifferentiation that occurred de novo with additional MDM2 gene amplification in the dedifferentiated area, which has not been reported previously.

Dedifferentiation, a cellular process reverting the cells to a less differentiated stage, has been described in various neoplasms, including soft tissue tumors such as well-differentiated liposarcoma, solitary fibrous tumor, chondrosarcoma, osteosarcoma, and chordoma. The term “dedifferentiation” or “transdifferentiation” was initially used for the GISTs to define three cases of morphological and phenotypical transition from the conventional KIT-positive GISTs to the high-grade KIT-negative neoplasms following the imatinib (IM) treatment (6). To date, at least 26 cases of dedifferentiation GIST have been reported in the currently published literature (2–14). We summarize its clinicopathological characteristics in Supplementary Table 1 as follows.

There were 20 males and 6 females, with a wide age distribution at the diagnosis, ranging from 18-75 years (median, 53 years old). Seventeen cases occurred as tumor progression after a short or long time (ranging from 3 m to 8 y) treatment with tyrosine kinase inhibitor (TKI). Most of them presented as metastatic or recurrent (involving the liver, peritoneum, mesentery, and omentum) after surgical removal of the primary tumor (in the stomach, duodenum, intestine, and rectum) and the TKI treatment. Few cases were diagnosed by biopsy and experienced progression as nodules within a mass or regrowth of a preexisting tumor under the TKI therapy. The de novo differentiated GISTs are extremely rare, with only 9 cases reported, including ours. Among them, 5 cases occurred in the stomach, 1 in the small intestine, 1 in the rectum, and 2 in the metastatic locations, which had the metastatic implants at the diagnosis.

Histologically, two components, the well-differentiated GISTs, and the anaplastic/dedifferentiated components were observed synchronously or heterochronously. Normally, the dedifferentiated component loses the usual morphological features of the GISTs, whereas they appear in various histological patterns, presenting with heterogenous phenotype, and accompanied by highly cellular, marked pleomorphism, and frequent mitoses and necrosis. Among the available data from the reported cases, 10 morphologically exhibited rhabdomyoblastic differentiation, mimicking embryonal or pleomorphic rhabdomyosarcoma (4), with the aberrant expression of desmin, myoD1, and myogenin, although the original GIST was completely negative for them. Nine dedifferentiated GISTs exhibited epithelioid or epithelial differentiation, with one showing large round and epithelioid cells, one demonstrating tubular papillary growth pattern, and seven expressing cytokeratin. Three cases were illustrated as undifferentiated pleomorphic sarcoma, one resembled angiosarcoma, and there was still one case displaying bone and cartilage formation in the recurrent lesion after the IM therapy. In the previous studies, remarkable morphologic differences between the dedifferentiated components occurring de novo or after therapy have not been elucidated. However, we noticed a possible relationship between the rhabdomyosarcomatous GIST progression and the TKI therapy. Interestingly, all the above 10 cases with the rhabdomyoblastic differentiation had undergone long or short TKI treatment. Conversely, none of the de novo GISTs showed desmin expression. In one particular case with the shortest IM treatment for only 3 months, the expression of myogenic markers was weak and focal (13), compared with the strong and diffuse immunoreactivity observed in other cases after a long-term therapy (4, 6, 9, 11). We find it worthy of further discussion that the pressure of the TKI might have a certain effect on the phenotypic transformation and/or subclone selection of the GIST tumor cells.

Immunohistochemically, the dedifferentiated component completely lost or markedly decreased the expression of the CD117 and DOG1. The anaplastic area usually expressed P53 and showed an elevated ki-67 index. Therefore, the dedifferentiated GISTs often developed a diagnostic pitfall due to their unusual histological feature, confusing immunophenotype and rarity. Clinically, the GISTs may coexist with other malignancies. Thus, the dedifferentiated area, which juxtaposed with the classical GISTs, might be misinterpreted as carcinoma, rhabdomyosarcoma, or leiomyosarcoma (15) that collided with the GISTs. However, the molecular profile of the tumor might provide more valuable diagnostic information. If the driver mutations identified in the dedifferentiated area were consistent with those in the classic area, we could be more confident to infer the common origin of these lesions and draw the diagnosis of the dedifferentiated GIST.

Genetically, the mutation analysis revealed the dedifferentiation that could occur in the GISTs with the KIT mutation, PDGFRA mutation, or wild phenotype, which included the SDH-deficient subtype. The reported cases showed that the dedifferentiated GISTs, especially those after the therapy, were often accompanied by the deletion or mutation in the KIT exon 11, which we think might be due to the mutational frequency and prognostic significance of the driver gene alterations in the GISTs.

Notably, although the dedifferentiation after therapy correlates with the disease progression and treatment failure, it is quite different from the IM-resistant, which accounts for the majority of those events. Firstly, the dedifferentiation occurs after therapy or arises de novo, while the resistance only occurs under the pressure of TKI treatment. Secondly, the dedifferentiation and resistance might represent the different evolution of the cell clones. The dedifferentiation presents with the transdifferentiation into various histological patterns and loses immunopositivity for the CD117 and DOG1, while the resistance maintains the features of the GIST cells, both morphologically and phenotypically. In one reported case, the dedifferentiated nodules were observed against the background of the IM responsive tumor cell clones, indicating the existence of the distinct subclones within the tumor (8). Thirdly, the molecular mechanisms of the two were divergent. To our knowledge, the secondary KIT/PDGFRA mutations, which are the main reason for TKI resistance (16), rarely occur in the dedifferentiated GISTs (4). On the other hand, the genetic instability, such as loss of the heterozygosity (LOH) or the low-level KIT amplification, or the alternative escape mechanisms for the KIT-independent signaling pathways might play a role in the dedifferentiation (5). Previously, inactive mutations in the CDKN2A, TP53, and RB1 have been established as the secondary genetic events that correlated with the tumor progression and malignant behavior in the GISTs (17, 18). Recently, Du et al. found that the genetic alterations involving the RB1, SMARCB1, and MAX were the most common except the secondary KIT/PDGFRA mutations accounting for the IM resistance, whereas the P53 mutation was rarely involved (19). However, the strong and diffuse P53 protein expression and additional P53 gene mutation were reported in the dedifferentiated GISTs (3). In our case report, although the P53 mutation was not detected, the MDM2 amplification was displayed in the dedifferentiated component. The MDM2 proto-oncogene is a well-known inhibitor of the tumor suppressor P53. When amplified, the MDM2 facilitates the proteasomal degradation of the P53 and inhibits the P53-mediated transactivation. Hence, we speculated that the P53 and its associated genes, or other related signaling pathways, might affect the survival and proliferation of tumor cells, and play a role in the progression of the dedifferentiated GIST, as it has been demonstrated in the dedifferentiated liposarcoma, dedifferentiated solitary fibrous tumor (20), and dedifferentiated chordoma (21).

Among the 14 reported dedifferentiated GISTs with the available follow-ups, 3 patients died of the tumor dissemination. It seems that surgical resection or debulking might be the most effective option under the current existing treatment strategies. Few cases even had long time survival with the evidence of stable disease after surgery, and some even restarted with the TKI treatment based on other new lesions (9, 11, 13). Therefore, the dedifferentiation in these cases tended to be a local event instead of the systemic progress, although it transitioned into an aggressive morphology. In our case, the metastases to the regional lymph nodes were verified to be the conventional SDH-deficient GIST component, rather than the dedifferentiated cell group. Although it is consistent with the behavior of the SDH-deficient GISTs, the biologic behavior of the dedifferentiated GISTs remains to be elucidated and more cases are to be investigated.

In conclusion, we provided a case of the dedifferentiated SDH-deficient GIST in a young woman, which was accompanied by the MDM2 amplification in the dedifferentiated area. We summarized the clinicopathological features of the reported dedifferentiated GISTs and proposed that the P53 associated genetic changes might be responsible for the occurrence of dedifferentiation. Future studies to identify the mechanisms of dedifferentiation are required for a better understanding of the clinical significance of the dedifferentiated GISTs and optimize the individual treatment.

The original contributions presented in the study are included in the article/ Supplementary Materials , further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

Q-XG made the diagnosis and wrote the manuscript. YD carried out the molecular experiments and analyzed the data. W-MZ performed immunohistochemical staining. J-WZ collected the clinicopathological materials. Z-HZ reviewed the slides and offered financial support. All authors contributed to the article and approved the submitted version.