Malignant transformation of white sponge nevus: a case report of a novel keratin 4 mutation

In this study, we report a one-year follow-up case of WSN with malignant transformation. Exome sequencing revealed a novel insertion mutation in exon 1 of KRT4, leading to a deletion-insertion mutation affecting glycine residues. Single-cell RNA sequencing further demonstrated altered epithelial proliferation and differentiation in the lesion.

Traditionally, WSN has been considered a benign genetic disorder with no malignant potential [10]. However, recent case reports challenge this view. A 2022 study in Oral Oncology found that the histomorphological features of oral squamous cell carcinoma (OSCC) closely resembled WSN, suggesting a potential malignant transformation [4, 11]. Additionally, Haseth et al. reported that 2 of 12 patients in a four-generation family with WSN developed OSCC [5]. Similarly, Downham et al. described a 59-year-old woman diagnosed with WSN who developed OSCC two years post-diagnosis [6]. This case report uniquely documents the complete progression of a WSN lesion from benign status to moderate-to-severe epithelial dysplasia within the same lesion site over a one-year observational period. This detailed account provides direct, sequential visual and histological evidence of the transformation process, illustrating the progression at regular intervals. Furthermore, our genetic analysis adds a significant dimension to the existing literature on WSN. By identifying a novel KRT4 gene mutation associated with this case of WSN, we provide evidence that not all genetic mutations linked to WSN are benign. Contrary to mutations that have been previously reported to only lead to benign presentations, the mutation identified in this study appears to significantly increase the risk of malignant transformation. In light of these findings, we advocate for regular clinical follow-up to monitor WSN lesions, especially in patients with known risk factors such as a history of smoking, alcohol consumption, or personal or familial tumor history. This is particularly crucial for lesions located in high-risk areas of the oral mucosa, where early detection and timely intervention can potentially mitigate the progression to malignancy.

Previous research has established that WSN is commonly caused by pathogenic mutations in either KRT4 or KRT13 [6, 12]. Figure 6 presents a summary of case reports involving KRT4 mutations in WSN. In the present case, exome sequencing identified a novel mutation in KRT4 (exon 1:c.259_260insCCGGCGGCTTCGGAGCTGGTTTCGGCACTGGTGGCTTTGGTG), leading to a deletion-insertion amino acid mutation (p.G87delinsAGGFGAGFGTGGFGG).

Fig. 6figure 6

Summary of pathogenic mutations in the KRT4 associated with WSN. The novel KRT4 mutation identified in this study is highlighted within a red box

This discovery broadens the known genetic spectrum of KRT4 mutations associated with WSN. The primary roles of KRT include maintaining cellular integrity, facilitating intercellular adhesion, and participating in intracellular signal transmission, material transport, and cell differentiation [13, 14]. Altered expression patterns of KRT during and post-malignant transformation have been reported to influence various signaling pathways implicated in tumor progression [15]. Given these findings, we hypothesize that the novel KRT4 mutation identified in this study may be a critical factor in the malignant transformation of WSN.

Single-cell RNA sequencing in our study indicated altered epithelial proliferation and differentiation, potentially contributing to epithelial dysplasia [15]. Literature also suggests that signaling pathways between epithelial cells and fibroblasts may promote esophageal squamous cell carcinoma [16]. Our data revealed enhanced communication between these cell types, warranting further investigation into the specific signaling pathways involved in WSN’s potential malignant transformation.

In conclusion, this case report significantly broadens the known spectrum of genetic mutations associated with WSN by documenting a novel mutation in the KRT4 gene. Our findings elucidate the role of this mutation in promoting epithelial proliferation, differentiation, and enhanced intercellular communication, thereby advancing our understanding of the molecular mechanisms underlying WSN. These insights have crucial clinical implications for both the diagnosis and therapeutic management of WSN, suggesting that specific genetic profiles may require distinct clinical approaches.

However, this study does have its limitations. The single-case nature limits the generalizability of our findings, while the rarity of WSN complicates the accumulation of a large sample size. Additionally, follow-up challenges due to patient noncompliance and potential biases inherent in observational case studies further constrain our conclusions. Recognizing these limitations, we emphasize the need for future research to encompass a wider array of cases and employ a more systematic approach to follow-up. This will enhance the robustness of the findings and improve their applicability to a broader patient population.

Moreover, there is a pressing need for advancements in genetic and molecular diagnostic tools, which could enable more comprehensive and precise studies of malignant potential. Continued improvements in patient follow-up and detailed observation of oral lesions over extended periods will be crucial in uncovering more about the disease’s progression and potential malignancy.

Moving forward, our focus will remain on enhancing the longitudinal monitoring of WSN patients and adapting our clinical strategies based on evolving insights into the genetic and phenotypic characteristics of the disease.

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