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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Oncol.</journal-id>
<journal-title-group>
<journal-title>Frontiers in Oncology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Oncol.</abbrev-journal-title>
</journal-title-group>
<issn pub-type="epub">2234-943X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fonc.2025.1746988</article-id>
<article-version article-version-type="Version of Record" vocab="NISO-RP-8-2008"/>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Case Report</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Primary malignant Brenner tumor of the ovary: a case report</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Hao</surname><given-names>Kun</given-names></name>
<uri xlink:href="https://loop.frontiersin.org/people/3281207/overview"/>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Writing &#x2013; original draft" vocab-term-identifier="https://credit.niso.org/contributor-roles/writing-original-draft/">Writing &#x2013; original draft</role>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Gao</surname><given-names>Feng</given-names></name>
<xref ref-type="corresp" rid="c001"><sup>*</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2617586/overview"/>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Writing &#x2013; review &amp; editing" vocab-term-identifier="https://credit.niso.org/contributor-roles/writing-review-editing/">Writing &#x2013; review &amp; editing</role>
</contrib>
</contrib-group>
<aff id="aff1"><institution>Department of Pathology, Hebei Medical University Third Hospital</institution>, <city>Shijiazhuang</city>,&#xa0;<country country="cn">China</country></aff>
<author-notes>
<corresp id="c001"><label>*</label>Correspondence: Feng Gao, <email xlink:href="mailto:fenggao@hebmu.edu.cn">fenggao@hebmu.edu.cn</email></corresp>
</author-notes>
<pub-date publication-format="electronic" date-type="pub" iso-8601-date="2026-01-14">
<day>14</day>
<month>01</month>
<year>2026</year>
</pub-date>
<pub-date publication-format="electronic" date-type="collection">
<year>2025</year>
</pub-date>
<volume>15</volume>
<elocation-id>1746988</elocation-id>
<history>
<date date-type="received">
<day>15</day>
<month>11</month>
<year>2025</year>
</date>
<date date-type="accepted">
<day>29</day>
<month>12</month>
<year>2025</year>
</date>
<date date-type="rev-recd">
<day>21</day>
<month>12</month>
<year>2025</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2026 Hao and Gao.</copyright-statement>
<copyright-year>2026</copyright-year>
<copyright-holder>Hao and Gao</copyright-holder>
<license>
<ali:license_ref start_date="2026-01-14">https://creativecommons.org/licenses/by/4.0/</ali:license_ref>
<license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License (CC BY)</ext-link>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p>
</license>
</permissions>
<abstract>
<p>Ovarian Brenner tumor is a rare type of ovarian epithelial neoplasm, predominantly benign, with only a minority exhibiting borderline or malignant characteristics. Malignant Brenner tumors (MBTs) resemble invasive urothelial carcinoma and often coexist with benign or borderline Brenner tumors. Clinically, they frequently present with non-specific symptoms, including abdominal pain and weight loss. We report the case of a 53-year-old female who presented with a mixed echoic mass in the left adnexa identified by gynecological ultrasound. Histopathological and immunohistochemical analyses of the resected specimens confirmed the diagnosis of ovarian MBT. The patient was subsequently referred for adjuvant treatment. This case highlights the diagnostic challenge of MBT and underscores the critical role of immunohistochemistry (positive for GATA3 and p63, negative for Pax-8) in confirming the diagnosis and distinguishing MBT from its histological mimics.</p>
</abstract>
<kwd-group>
<kwd>cancer</kwd>
<kwd>immunohistochemistry</kwd>
<kwd>malignant Brenner tumor</kwd>
<kwd>ovary</kwd>
<kwd>pathology</kwd>
</kwd-group>
<funding-group>
<funding-statement>The author(s) declared that financial support was not received for this work and/or its publication.</funding-statement>
</funding-group>
<counts>
<fig-count count="4"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="16"/>
<page-count count="7"/>
<word-count count="2297"/>
</counts>
<custom-meta-group>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Gynecological Oncology</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<label>1</label>
<title>Introduction</title>
<p>Ovarian Brenner tumor represents an uncommon type of ovarian epithelial neoplasm, predominantly benign, with malignant variants constituting approximately 1&#x2013;5% of cases (<xref ref-type="bibr" rid="B1">1</xref>). These tumors typically arise from metaplasia of the ovarian surface epithelium and may occur at any age, although they are more prevalent in perimenopausal women aged 50 to 70 years (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B2">2</xref>). Most patients are asymptomatic, and the tumors are often incidentally discovered following ovarian surgery performed for unrelated conditions. However, larger tumors may elicit symptoms such as abdominal distension or pain. Due to their rarity and subtle or atypical clinical presentations, Brenner tumors are commonly identified during routine physical examinations or surgical interventions for other pelvic disorders (<xref ref-type="bibr" rid="B1">1</xref>).</p>
<p>This report describes a rare case of ovarian MBT in a postmenopausal patient who presented with abnormal uterine bleeding without associated endometrial pathology. The imaging, histomorphological, and immunohistochemical features are discussed to enhance understanding of this entity.</p>
</sec>
<sec id="s2">
<label>2</label>
<title>Case presentation</title>
<p>A 53-year-old woman presented with a six-month history of intermittent vaginal bleeding occurring two years after natural menopause. An initial transvaginal ultrasound performed at a local hospital revealed a 4.48 &#xd7; 3.40 cm hypoechoic mass in the left adnexal region, exhibiting a heterogeneous internal echotexture and punctate hyperechoic foci. The patient subsequently consulted an external medicine department, where surgical intervention was recommended but declined. On September 28, 2025, she experienced recurrent minor vaginal bleeding and was evaluated at the gynecology outpatient clinic of the Third Hospital of Hebei Medical University (<xref ref-type="fig" rid="f1"><bold>Figure&#xa0;1</bold></xref>).</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>Representative timelines of patient&#x2019;s relevant data history.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-15-1746988-g001.tif">
<alt-text content-type="machine-generated">Timeline graphic detailing medical events from March to September 2025. On March 25, postmenopausal abnormal uterine bleeding occurs. June 4 notes a negative gynecological exfoliated cell test. September 25 shows an ultrasound detecting a mixed echo mass on the uterus's left side. September 26 finds no tumor marker abnormalities, yet September 30 reveals an intraoperative frozen-section analysis identifying a malignant Brenner tumor.</alt-text>
</graphic></fig>
<p>A follow-up transvaginal ultrasound demonstrated a 7.8 &#xd7; 5.6 cm mass of mixed echogenicity adjacent to the left uterus. The cystic component contained multiple linear hyperechoic structures, while the local echoes in the solid area appeared uneven, with scattered punctate hyperechoic foci. The capsule was incomplete, with relatively clear boundaries. Doppler ultrasound indicated point-like linear blood flow signals within the solid region (<xref ref-type="fig" rid="f2"><bold>Figure&#xa0;2</bold></xref>).</p>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>Ultrasound imaging demonstrating a mixed echogenic mass in the left adnexal region.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-15-1746988-g002.tif">
<alt-text content-type="machine-generated">Two ultrasound images showing a section of tissue in a gynecological examination. The left image includes color Doppler highlighting blood flow in red and blue. Both images display internal measurements and technical information, along with anatomical markers.</alt-text>
</graphic></fig>
<p>Upon admission, the physical examination revealed mild uterine enlargement. A non-tender, moderately mobile mass greater than 7 cm in diameter was palpated in the left adnexal region; the right adnexa was unremarkable. Laboratory investigations, including tumor markers (AFP, CEA, CA19-9, CA-125, CA15-3), reproductive hormones (LH, FSH, PRL, progesterone, estradiol, testosterone), complete blood count, and hepatic and renal function profiles, revealed no significant abnormalities. The patient was admitted for further diagnostic evaluation and management.</p>
<sec id="s2_1">
<label>2.1</label>
<title>Therapeutic intervention</title>
<p>After admission, the patient underwent an endometrial biopsy. The biopsy result was negative. A laparoscopic procedure was performed on September 30, 2025, to evaluate the left adnexal mass of uncertain origin.</p>
<p>During the surgical procedure, a mass approximately 7 cm in diameter was observed encasing the left ovary. Subsequently, the mass, along with the entire uterus and bilateral fallopian tubes, was removed. Intraoperative frozen-section histopathology revealed a malignant mass in the left adnexa, suggesting a possible diagnosis of MBT. After communicating the findings to the patient&#x2019;s family, comprehensive staging surgery for ovarian cancer was performed. This included right salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, omentectomy, and multiple biopsies from pelvic, abdominal, and peritoneal sites. The patient recovered uneventfully post-surgery, experienced no significant complications, and was discharged in stable condition.</p>
</sec>
<sec id="s2_2">
<label>2.2</label>
<title>Histopathological and immunohistochemical findings</title>
<p>Macroscopic examination revealed a mass measuring 7.0 cm &#xd7; 5.5 cm &#xd7; 5.0 cm, characterized by cystic and solid components. The solid portion measured 5.0 cm &#xd7; 4.0 cm and exhibited a grayish-white, fibrous appearance. In contrast, the cystic area featured a relatively smooth wall with a localized protrusion, and its thickness ranged from 0.2 to 0.3 cm.</p>
<p>Histologically, MBT resembled urothelial carcinoma, consisting of irregularly shaped and cytologically atypical transitional epithelial cells. Tumor margins were indistinct, and interstitial infiltration was noted. Tumor cells exhibited marked cellular atypia, variable nucleolar prominence, and abundant eosinophilic cytoplasm. The cystic regions were lined by multilayered epithelium, presenting features reminiscent of invasive urothelial carcinoma. Additionally, both benign and borderline Brenner cell nests were observed within the tumor tissue, along with intravascular tumor thrombi.</p>
<p>Tumors were also identified on the uterine serosa and bilateral fallopian tubes, and atrophic endometrium was present. No evidence of tumor metastasis was detected in parametrial tissues, omentum, peritoneum, or lymph nodes (<xref ref-type="fig" rid="f3"><bold>Figure&#xa0;3</bold></xref>).</p>
<fig id="f3" position="float">
<label>Figure&#xa0;3</label>
<caption>
<p><bold>(A)</bold> Frozen section of MBT (&#xd7;200; black arrow indicates malignant cells). <bold>(B&#x2013;D)</bold> Hematoxylin and eosin (H&amp;E) staining illustrating malignant cells in MBT (&#xd7;200; black arrows indicate malignant cells). <bold>(E)</bold> H&amp;E staining showing tumor thrombus (&#xd7;200; black arrow indicates tumor thrombus). <bold>(F)</bold> H&amp;E staining of borderline Brenner tumor areas (&#xd7;200). <bold>(G)</bold> H&amp;E staining of benign Brenner tumor areas (&#xd7;200). <bold>(H, I)</bold> H&amp;E staining of cystic tumor regions (&#xd7;200). <bold>(J)</bold> Tumor metastasis in the left fallopian tube (H&amp;E staining,&#xd7;200). <bold>(K)</bold> Tumor metastasis in the right fallopian tube (H&amp;E staining,&#xd7;200). <bold>(L)</bold> H&amp;E staining of endometrial tissue (&#xd7;100).</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-15-1746988-g003.tif">
<alt-text content-type="machine-generated">Histological images showing various tissue samples under a microscope. Panels A to L display different cellular and structural patterns. Some images highlight specific features such as fibroblastic tissue, glandular structures, and cellular morphology with annotations. Sections exhibit a range of colors indicating different staining results, providing insights into tissue composition and pathology.</alt-text>
</graphic></fig>
<p>Immunohistochemical analysis demonstrated that Ki-67 was positive in hotspots (&#x2265;40%), CK7 (approximately 80%+), CR (approximately 40%+), EMA (approximately 20%+), GATA3(+), CAM5.2(+), and p63(+), whereas inhibin-&#x3b1;(-), p16(-), WT1(-), Pax-8(-), CK20(-), and Vimentin(-), and p53 was wild type (<xref ref-type="fig" rid="f4"><bold>Figure&#xa0;4</bold></xref>).</p>
<fig id="f4" position="float">
<label>Figure&#xa0;4</label>
<caption>
<p><bold>(A)</bold> Immunostaining demonstrating positive GATA3 expression (&#xd7;200). <bold>(B)</bold> Immunostaining showing partial CK7 positivity (&#xd7;200). <bold>(C)</bold> Immunostaining demonstrating positive p63 expression (&#xd7;200). <bold>(D)</bold> Immunostaining for Ki-67 (hotspot area shows 40% positivity,&#xd7;200). <bold>(E)</bold> Immunostaining for Pax-8 (negative,&#xd7;200). <bold>(F)</bold> Immunostaining for inhibin-&#x3b1; (negative,&#xd7;200). <bold>(G)</bold> Immunostaining for CK20 (negative,&#xd7;200).</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-15-1746988-g004.tif">
<alt-text content-type="machine-generated">Microscopic images labeled A to G display various tissue samples stained for analysis. Images A to D show areas with dense brown staining indicating the presence of target proteins, while images E to G exhibit lighter staining suggesting lower protein expression. The background is light blue, representing the tissue matrix, and contrasts the stained regions.</alt-text>
</graphic></fig>
</sec>
<sec id="s2_3">
<label>2.3</label>
<title>Follow-up</title>
<p>The patient recovered well postoperatively without significant complications. The patient was diagnosed with FIGO stage IIA disease and is currently receiving adjuvant chemotherapy consisting of paclitaxel and carboplatin. Currently, there is no evidence of disease recurrence.</p>
</sec>
</sec>
<sec id="s3" sec-type="discussion">
<label>3</label>
<title>Discussion</title>
<p>The World Health Organization (WHO) classifies Brenner tumors into three categories: benign, borderline, and malignant. MBT of the ovary is a rare malignancy, representing a distinct subtype of ovarian cancer that resembles invasive urothelial carcinoma. It is commonly associated with benign or borderline Brenner tumors. Clinical manifestations commonly include abdominal mass or pain, and some patients report abnormal vaginal bleeding. Tumors are predominantly unilateral (&gt;80%), although bilateral cases have been reported (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B2">2</xref>).</p>
<p>In the present case, the patient&#x2019;s chief complaint was postmenopausal abnormal uterine bleeding lasting six months. Previous studies indicate that approximately 4&#x2013;14% of Brenner tumors are associated with endometrial hyperplasia, often linked to stromal luteinization and estrogen secretion, which may explain abnormal bleeding in some patients (<xref ref-type="bibr" rid="B3">3</xref>&#x2013;<xref ref-type="bibr" rid="B5">5</xref>). Nevertheless, transvaginal ultrasound showed an endometrial thickness of 0.5 cm, and preoperative curettage revealed only blood clots with minimal endometrial tissue. Postoperative pathology confirmed an atrophic endometrium, and serum estrogen and progesterone levels were within normal ranges. These findings do not support estrogen-driven endometrial hyperplasia as the cause of bleeding. Further consideration of alternative mechanisms suggests a potential role for tumor-related factors. Vascular endothelial growth factor (VEGF) is known to promote angiogenesis, invasion, metastasis, and chemotherapy resistance in ovarian cancer (<xref ref-type="bibr" rid="B6">6</xref>), and elevated VEGF can increase vascular permeability. It is therefore conceivable that MBT may produce low levels of bioactive substances or growth factors that are not detectable by routine hormone assays. Such substances could be locally converted to active estrogen within endometrial tissue or induce bleeding by altering vascular permeability. Routine hormonal testing may not capture these tumor-derived mediators. Furthermore, atrophic endometrium itself is a well-recognized cause of postmenopausal bleeding (<xref ref-type="bibr" rid="B7">7</xref>). In postmenopausal women, marked estrogen deficiency leads to a thin endometrium with fragile vessels prone to rupture. Thus, abnormal bleeding may occur even when circulating hormone levels are within normal limits. This mechanism offers an additional plausible explanation for the bleeding observed in this patient.</p>
<p>Preoperative diagnosis of Brenner tumor remains challenging because its histological features closely resemble transitional epithelium. Morphologically, benign Brenner tumor cells show mild cytological atypia, with lightly stained cytoplasm, oval nuclei, and well-defined boundaries between cell nests and surrounding stroma. In contrast, MBT demonstrates indistinct nest boundaries with stromal invasion. Residual benign or borderline Brenner components are often present, which is consistent with the characteristic histopathological features of MBT.</p>
<p>Angel Yordanov et&#xa0;al. reviewed the literature and identified 10 reported cases of MBT, including ovarian and extra-ovarian types. Their results indicated that urothelial differentiation markers, such as GATA3, p63, and CK7, were predominantly positive, while Pax-8 was typically negative (<xref ref-type="bibr" rid="B8">8</xref>). The immunohistochemical results in our patient are consistent with their findings. Positive staining was observed for GATA3, CK7, and p63, with a Ki-67 labeling index exceeding 40% in hotspot areas. Postoperative pathological examination demonstrated metastatic lesions involving bilateral fallopian tubes and uterine serosa, further supporting the diagnosis of ovarian MBT. Histopathological and immunohistochemical analyses confirmed the diagnosis of MBT, and the differential diagnosis included the following entities:</p>
<sec id="s3_1">
<label>3.1</label>
<title>M&#xfc;llerian-derived tumors</title>
<p>Tumors arising from the M&#xfc;llerian duct commonly present with abnormal uterine bleeding. Histologically, they are composed of large atypical cells with eosinophilic cytoplasm and frequently exhibit focal necrosis. PAX-8, a transcription factor typically observed in tumors of renal, thyroid, and M&#xfc;llerian origin, is usually positive (<xref ref-type="bibr" rid="B9">9</xref>). The negative expression of PAX-8 in this case supports exclusion of M&#xfc;llerian-derived tumors (<xref ref-type="bibr" rid="B8">8</xref>).</p>
</sec>
<sec id="s3_2">
<label>3.2</label>
<title>Urothelial-derived tumors</title>
<p>Histologically, malignant urothelial tumors can resemble MBT. CK20, an epithelial intermediate filament normally expressed in gastrointestinal and urothelial tissues, is detected in more than 90% of urothelial carcinomas (<xref ref-type="bibr" rid="B10">10</xref>). Negative CK20 staining and the coexistence of benign and borderline Brenner tumor components argue against urothelial origin in this case.</p>
</sec>
<sec id="s3_3">
<label>3.3</label>
<title>Metastatic gastrointestinal tumors</title>
<p>Ovarian metastases from gastrointestinal malignancies typically present at advanced disease stages and exhibit symptoms related to the primary gastrointestinal site. Microscopically, these tumors frequently display glandular or tubular formations with variable and irregular sizes. Tumor cells often exhibit diffuse infiltration and intracellular mucin production. CK20 is widely utilized as a marker for gastrointestinal tumors (<xref ref-type="bibr" rid="B11">11</xref>). In the present case, the absence of CK20 expression and lack of gastrointestinal symptoms exclude this diagnosis.</p>
</sec>
<sec id="s3_4">
<label>3.4</label>
<title>Sex cord-stromal tumors</title>
<p>These ovarian epithelial tumors consist of various subtypes and typically occur in younger patients. They often present with hormonal symptoms, such as hirsutism, virilization, menstrual irregularities, or precocious puberty (<xref ref-type="bibr" rid="B12">12</xref>). Inhibin-&#x3b1;, a member of the TGF-&#x3b2; family, is a key immunohistochemical marker used to identify sex cord-stromal tumors (<xref ref-type="bibr" rid="B13">13</xref>). The patient was postmenopausal without hormonal abnormalities, and negative inhibin-&#x3b1; staining supports exclusion of this tumor type.</p>
<p>For MBT, surgery remains the principal therapeutic approach. The surgical method selected depends primarily on tumor grade and clinical staging. Suitable procedures for appropriate patients include total hysterectomy, bilateral salpingo-oophorectomy, pelvic and/or para-aortic lymphadenectomy, random biopsies of peritoneal surfaces, and omentectomy (<xref ref-type="bibr" rid="B14">14</xref>). In the present case, comprehensive staging surgery for ovarian cancer was performed due to intraoperative frozen section results suggesting malignancy. Postoperative pathology showed no evidence of metastasis in lymph nodes or peritoneal tissues. However, owing to the rarity of MBT, chemotherapy regimens remain undefined, lacking well-established clinical guidelines. Previous studies have indicated potential therapeutic effects of paclitaxel combined with platinum-based chemotherapy, although recurrence rates appear relatively high (<xref ref-type="bibr" rid="B15">15</xref>). Nasioudis et&#xa0;al. analyzed clinical data from 202 MBT patients, demonstrating a five-year disease-specific survival of 94.5% in stage I patients, decreasing to 51.3% in patients at stage II or higher (<xref ref-type="bibr" rid="B16">16</xref>). In the present case, metastasis to the fallopian tubes and uterine serosa was identified, indicating a worse prognosis.</p>
<p>Thus, given the unique nature and rarity of this tumor, establishing comprehensive diagnostic and therapeutic protocols is crucial. These guidelines would facilitate early diagnosis, timely treatment, and individualized patient care, thereby improving patient outcomes and overall survival.</p>
</sec>
</sec>
<sec id="s4" sec-type="conclusions">
<label>4</label>
<title>Conclusion</title>
<p>MBT is a rare tumor morphologically resembling urothelial carcinoma. This report described a patient with atypical symptoms preoperatively, and no significant abnormalities detected through tumor markers or conventional hormone assays. Although abnormal uterine bleeding is occasionally observed in Brenner tumor patients, the underlying causes remain uncertain. The present case proposes two possible mechanisms for such bleeding, both requiring further investigation.</p>
<p>In summary, this case highlights the necessity of further research into MBTs, particularly regarding pathogenesis, clinical features, and optimal therapeutic regimens. We emphasize the importance for clinicians to maintain a high index of suspicion for MBT, recommend regular health evaluations to patients, and ensure early diagnosis and management to enhance long-term patient survival.</p>
</sec>
</body>
<back>
<sec id="s5" sec-type="data-availability">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.</p></sec>
<sec id="s6" sec-type="ethics-statement">
<title>Ethics statement</title>
<p>The studies involving humans were approved by The Third Hospital of Hebei Medical University, Shijiazhuang, China. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.</p></sec>
<sec id="s7" sec-type="author-contributions">
<title>Author contributions</title>
<p>KH: Writing &#x2013; original draft. FG: Writing &#x2013; review &amp; editing.</p></sec>
<sec id="s9" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></sec>
<sec id="s10" sec-type="ai-statement">
<title>Generative AI statement</title>
<p>The author(s) declared that generative AI was not used in the creation of this manuscript.</p>
<p>Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.</p></sec>
<sec id="s11" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p></sec>
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<p>Edited by: <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/680387">Anthony Taylor</ext-link>, University of Leicester, United Kingdom</p></fn>
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<p><ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/3254905">Ahmad Al-Bitar</ext-link>, Faculty of Medicine of Damascus University, Syria</p></fn>
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