Plexiform Fibromyxoma with MALAT1–GLI1 Fusion with Limited Myxoid Stroma, Aberrant KIT Expression, and Diffuse D2-40 Expression: A Case Report
, Hidetaka Yamamoto 4, Yasuhito Tanaka 3, Masaaki Iwatsuki 2 and Yoshiki Mikami 1
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsPlexiform fibromyxoma with MALAT1–GLI1 fusion with limited myxoid stroma, aberrant KIT expression, and diffuse D2-40 expression: A case report
This manuscript presents a case of plexiform fibromyxoma (PFM) with atypical morphologic and immunophenotypic features, including cellular areas of limited myxoid stroma, focal KIT expression, and diffuse D2-40 positivity. The tumor was later confirmed to harbor MALAT1::GLI1 fusion. The topic is relevant, given the expanding molecular understanding of GLI1-altered mesenchymal tumors and the diagnostic overlap with gastrointestinal stromal tumor (GIST). However, the following require attention/clarification:
Comments
- While the diffuse D2-40 expression observed in this case is an intriguing finding, the assertion that D2-40 “might be a surrogate for MALAT1::GLI1 fusion” (line 165) appears overstated when based on a single case and very limited published data. Although the authors appropriately acknowledge the scarcity of existing literature, the language in both the Discussion and Conclusions requires moderation, particularly as this represents a central message of the manuscript. It is best to regard D2-40 expression as a potential diagnostic pitfall rather than a surrogate marker, given its well-recognized lack of specificity and the absence of established mechanistic or correlative evidence linking D2-40 expression to MALAT1::GLI1 fusion status.
- There is an inconsistency in the reported follow-up duration requiring correction: the Case Presentation section states a follow-up of 8 months (line 62), whereas the Discussion refers to a follow-up of 3 months (line 140).
- Given the relatively high mitotic count (11/50 HPF), it would be beneficial to clarify whether mitoses were confined to cellular hot spots or more diffusely distributed, and whether atypical mitotic figures were present.
- The differential diagnosis is comprehensive; however, it would benefit from greater prioritization. Some entities (e.g., mesothelioma and follicular dendritic cell sarcoma) appear less plausible in a gastric submucosal context, whereas greater emphasis on gastroblastoma would improve clarity. Rephrasing in lines 130–139 to explicitly explain why gastroblastoma was excluded would be helpful.
- Minor (line 100): “PMF” should be corrected to “PFM” for consistency in “Finally, because the diagnosis of PMF remained a serious diagnostic consideration …..”
Author Response
Reviewer 1
Comment: While the diffuse D2-40 expression observed in this case is an intriguing finding, the assertion that D2-40 “might be a surrogate for MALAT1::GLI1 fusion” appears overstated ...
Response: We agree and have moderated the language throughout the Discussion and Conclusions. We now emphasize that D2-40 is non-specific and, based on current evidence, should be regarded as a potential diagnostic pitfall rather than a surrogate marker for MALAT1::GLI1 fusion. We have also deleted the sentence of “therefore, it might be useful for the diagnosis of PFM” at Discussion (Revised Discussion/Conclusions)
Comment: There is an inconsistency in the reported follow-up duration ... 8 months vs 3 months.
Response: We corrected this inconsistency. The follow-up period is 8 months after resection throughout the manuscript. (Revised Discussion)
Comment: Given the relatively high mitotic count (11/50 HPF), clarify whether mitoses were confined to cellular hot spots ... and whether atypical mitotic figures were present.
Response: We added clarification that mitoses were predominantly observed in the hypercellular areas and that no atypical mitotic figures were identified. (Revised Pathological Findings)
Comment: The differential diagnosis is comprehensive; however, it would benefit from greater prioritization ... greater emphasis on gastroblastoma ...
Response: We have added an explicit explanation for excluding gastroblastoma (absence of a biphasic epithelial component and cytokeratin negativity), despite the shared MALAT1::GLI1 fusion reported in gastroblastoma. (Revised Pathological Findings)
Comment: Minor: “PMF” should be corrected to “PFM”.
Response: Corrected. (Revised Pathological Findings) We would like to thank reviewer for careful reviewing.
Reviewer 2 Report
Comments and Suggestions for AuthorsWatanabe et al. reported a diagnostically challenging case characterized by a limited myxoid matrix and diffuse D2-40 expression, and concluded the diagnosis to be PFM
Major Comments
- In Figure 3, the authors present positive staining results for several markers. However, several markers described as negative in the text (e.g., DOG1) are not shown. It would be helpful to include representative images of these negative markers, either in the main figures or as supplementary material.
- The MALAT1::GLI1 fusion result is not currently shown in the figures. The quantitative analysis should be included.
Author Response
Reviewer 2
Comment: In Figure 3 ... several markers described as negative in the text (e.g., DOG1) are not shown.
Response: We added representative images of key negative markers (DOG1, CD34, and S100 protein) in revised version of Figure 3 and added labels to each image to make it easier for readers to understand.
Comment: The MALAT1::GLI1 fusion result is not currently shown in the figures. The quantitative analysis should be included.
Response: Unfortunately, because the analysis was performed by the consultation system of the National Cancer Center, images and quantitative analysis results that can be used to create figures are not available. Instead, we have provided detailed data such as breakpoints described in the consultation report. (Revised Pathological Findings)
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors present a rare and diagnostically challenging case of a cellular variant of plexiform fibromyxoma (PFM). The topic is interesting and highly relevant for diagnostic pathologists, particularly due to the unusual immunophenotype and morphology that mimic more common mesenchymal tumors like GIST. The manuscript is well-written and clearly illustrated; however, I have the following concerns that should be addressed prior to publication.
- Autors state “Immunohistochemical analysis indicated the tumor cells were focally positive for KIT (Figure 3a), but negative for DOG1, making a diagnosis of GIST unlikely”. However, in the presented image (Fig. 3) CD117 expression seems to be diffuse and not focal. Therefore authors should present additional high quality images to clearly appreciate CD117 stain.
- The differential diagnosis with GIST should be explained more in detail since a CD117 positive/dog1 negative tumor can be still called GIST therefore the statement “tumor cells were focally positive for KIT (Figure 3a), but negative for DOG1, making a diagnosis of GIST unlikely” in not 100% correct.
Author Response
Reviewer 3
Comment: In Fig. 3 CD117 expression seems to be diffuse and not focal. Present additional high quality images.
Response: We have revised the description to ‘patchy (multifocal)’ KIT (CD117) expression and updated the figure legend accordingly. We have added loupe image of KIT (CD117) as inset in the revised Figure 3 panel to better demonstrate the staining distribution.
Comment: The differential diagnosis with GIST should be explained more in detail since a CD117 positive/DOG1 negative tumor can be still called GIST ...
Response: As the reviewer noted, a negative DOG1 result alone is not sufficient to exclude a GIST, and this represents an important diagnostic pitfall highlighted by the present case and one of the reasons for reporting it. Accordingly, we considered a broad differential diagnosis, including succinate dehydrogenase (SDH)-deficient GIST. Ultimately, we diagnosed plexiform fibromyxoma (PFM) based on the characteristic plexiform growth pattern and molecular confirmation of a MALAT1::GLI1 fusion. We believe our diagnostic reasoning is adequately conveyed in the Pathological Findings and Discussion sections.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe newly added CD34 image in Figure 3 does not appear negative.
Author Response
Reviewer 2
Comment: The newly added CD34 image in Figure 3 does not appear negative.
Response: CD34 is negative for tumor cells but positive for stromal vessels. We have added this in legend of Figure 3 to avoid any misunderstandings.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe revised version of this manuscript still leaves unanswered my original questions.
1) CD117 IHC positivity is unclear since the poor quality of the presented pictures (patchy, artifact, diffuse?)
2) If authors state that CD117 is positive, explain why KIT or PDGFRA mutational testing was not performed and why only Archer panel was performed. This seems no standard clinical practice.
3) Plexiform architecture is barely visible from the provided picture. Since the morphology has an important role in the diagnostic process, authors should provide better images of high quality where morphological details could be appreciated.
4) In conclusion section CD117 IHC is reported as focal.
Author Response
Reviewer 3
Comment: CD117 IHC positivity is unclear since the poor quality of the presented pictures (patchy, artifact, diffuse?)
Response: We have further revised Figure 3 panel, enlarged lope image of KIT immunohistochemistry to better demonstrate the staining distribution.
Comment: If authors state that CD117 is positive, explain why KIT or PDGFRA mutational testing was not performed and why only Archer panel was performed. This seems no standard clinical practice.
Response: The reviewer’s opinion is quite reasonable. In the diagnostic workup of GIST, KIT immunohistochemistry is reported to have a sensitivity exceeding 90% when used alone, whereas its specificity is approximately 80%. By contrast, DOG1 immunohistochemistry is considered to encompass PDGFRA-mutant GIST and has been reported to achieve both sensitivity and specificity of greater than 95% as a single marker. In the present case, DOG1 was negative; accordingly, we considered the possibility that the KIT immunoreactivity might be nonspecific. Given this concern, an SDH-deficient GIST was considered and SDHB immunohistochemistry was performed; however, SDHB expression was retained. Because the case remained diagnostically challenging, we consulted this case to recognized pathologist in Japan (H.Y.). Notably, two members of the WHO editorial board (H.Y. and M.Y.) are included among the co-authors of this manuscript. Based on the low-power finding of plexiform architecture, H.Y. raised the possibility of PFM and recommended proceeding with targeted molecular testing using the Archer panel alone. To communicate this diagnostic pathway more clearly to readers, we have added clarifying text to the “Pathological Findings” section and incorporated additional reference.
Comment: Plexiform architecture is barely visible from the provided picture. Since the morphology has an important role in the diagnostic process, authors should provide better images of high quality where morphological details could be appreciated.
Response: We believe that the low-power panoramic (loupe) image shown in Figure 2a allows appreciation of the plexiform architecture suggestive of PFM. This feature is also described in figure legend.
Comment: In conclusion section CD117 IHC is reported as focal.
Response: We appreciate the reviewer’s comment. We have revised the wording to ‘patchy’.
Round 3
Reviewer 2 Report
Comments and Suggestions for AuthorsI have no further comments.
