A Mimic in the Frontal Lobe: CNS Histiocytosis Masquerading as a Glial Neoplasm in a Young Adult

A Mimic in the Frontal Lobe: CNS Histiocytosis Masquerading as a Glial Neoplasm in a Young Adult | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A Mimic in the Frontal Lobe: CNS Histiocytosis Masquerading as a Glial Neoplasm in a Young Adult Emil Hasanov, Parviz Samadov, Ruslan Esedov, Cavid Isayev This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7188864/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose This case describes an unusual presentation of central nervous system (CNS) histiocytosis in a 19-year-old male, presenting with imaging features initially suggestive of a glial tumor, but further work-up redirected the diagnosis toward a condition of non-glial origin. Also it highlights how evolving clinical and radiologic data can uncover an unexpected diagnosis. Methods A 19-year-old male presented with acute neurological symptoms. Serial MRI examinations with contrast administration were performed to this patient. Imaging characteristics were reviewed in correlation with clinical progression and histopathological findings. Results Initial MRI revealed a T2/FLAIR hyperintense mass in the right frontal operculum with associated perilesional leptomeningeal enhancement in the adjacent sulci. No diffusion restriction was seen. Over two weeks, the lesion nearly doubled in size, with increased patchy enhancement, leptomeningeal spread to temporal and parietal regions, and new infundibular thickening. Mild midline shift developed. Biopsy confirmed CNS histiocytosis. Partial regression was noted after steroid treatment. Conclusion This case emphasizes the possible radiologic overlap between glial tumors and rare mass like presentation with parenchimal involvement of CNS histiocytosis. Recognition of leptomeningeal involvement, infundibular thickening and steroid responsiveness can aid differentiation and prompt biopsy. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Introduction Parenchimal mass lesions are the least common CNS manifestation of hystiocytosis after diabetes insipidus (infundibulum involvement) and neurodegenerative changes. It typically manifests as a non-mass-like process, often involving the meninges, skull or the hypothalamic–pituitary axis. When parenchymal mass presents, such lesions may mimic glial processes, especially radiologically. Isolated infundibular involvement or calvarial bone lesions are more common presentations, while parenchymal mass-like lesions remain diagnostically challenging. Primary histiocytic disorders of the CNS are rare and occurs especially in young patients. These disorders, including Langerhans cell histiocytosis (LCH) and other non-Langerhans variants, can involve brain parenchyma, meninges and the hypothalamic–pituitary axis. Differentiating these from gliomas poses a diagnostic challenging, particularly when initial imaging shows mass-like lesions with enhancement and local mass effect. Case Presentation A 19-year-old previously healthy male presented with sudden loss of consciousness, followed by a generalized seizure and persistent headaches. Neurologic exam revealed no focal deficits. Routine blood tests were unremarkable. Initial Imaging Brain MRI demonstrated a T2/FLAIR hyperintense lesion in the right frontal operculum, involved both the cortex and underlying white matter, with no diffusion restriction and mild but clearly discernible contrast enhancement. Notably, there was adjacent leptomeningeal enhancement, limited to the surrounding frontal sulci. No intralesional hemorrhage or calcification was seen. Given the appearance, an diffuse glial tumor was considered the leading diagnosis. The absence of restricted diffusion reduced suspicion for lymphoma. Nonetheless, the presence of leptomeningeal enhancement raised concern, as it is an atypical feature for glial tumors, which generally do not exhibit leptomeningeal involvement. No abnormalities were detected in the calvarium or extracranial tissues. Follow-Up Imaging Two weeks later, the patient experienced clinical deterioration, with worsening headache and confusion. Repeat MRI showed significant increase in lesion size (almost twofold) and more pronounced, patchy intralesional enhancement. Also leptomeningeal enhancement markedly increased, now extending into the right temporal and parietal lobes. Thickening and enhancement of the pituitary stalk (infundibulum) was noted as a new finding. A T2 hypointense focus within the lesion, more likely consistent with internal hemorrhage. Mild midline shift, suggestive of mass effect was observed in contrast to the initial imaging. Histopathology results Microscopic examination of the biopsy material revealed fragments of a poorly differentiated small round cell tumor with a solid architectural pattern and high cellular density. Numerous mitotic figures and foci of necrosis were present. Immunohistochemical analysis demonstrated strong positivity for CD45, CD68, CD163 and CD4, supporting a diagnosis of a neoplasm of histiocytic origin. The tumor showed nuclear expression of MUM1, which is associated with activated histiocytes or lymphoid cells. Stromal elements were diffusely positive for CD3 (T-lymphocytes) and S100 expression was also noted in the background tissue. There was residual GFAP expression, suggesting the presence of glial components, although not within the tumor cells. Focal positivity for CD20, CD79a and BCL2 was restricted to reactive lymphoid infiltrates, not to the tumor itself. Importantly, the tumor was negative for CD1a, excluding Langerhans cell histiocytosis and negative for cytokeratin AE1/3, excluding epithelial malignancy. BCL6 expression was also absent. The Ki-67 proliferation index was approximately 90%, indicating a highly proliferative and aggressive tumor. Unfortunately, molecular-genetic analysis for the BRAF V600E mutation was not performed, which limits further subclassification. Nevertheless, based on the morphological and immunophenotypic findings, a histiocytic neoplasm was favored. The possibility of Erdheim–Chester disease was not excluded. Discussion Leptomeningeal enhancement is generally considered an uncommon feature in glial neoplasms, but it has been reported, particularly in the context of high-grade gliomas [ 9 , 10 ]. The presence of leptomeningeal enhancement at initial presentation, as in our case, is unusual and raises diagnostic uncertainty. While this finding does not exclude a glial origin, it necessitates careful consideration of alternative diagnoses - such as CNS histiocytosis, lymphoma or granulomatous meningoencephalitis . After the second MRI, our diagnostic criteria expanded beyond a primary glial tumor. The lesion exhibited a notable increase in size over a short period, with more heterogeneous enhancement and a strikingly wider distribution of leptomeningeal enhancement, now involving the right temporal and parietal lobes. Most importantly, a new finding of infundibular thickening and enhancement raised suspicion for infectious-inflammatory, lymphoid or histiocytic involvement and cell infiltration, given the known tropism of such entities for the hypothalamic–pituitary axis. These evolving features prompted initiation of steroid therapy. Following administration steroids, the patient demonstrated modest clinical improvement and radiological regression. At this stage, the differential diagnosis included several possibilities. Rapid lesion progression and leptomeningeal dissemination could be seen in primary CNS lymphoma , especially in immunocompromised patients, although the absence of diffusion restriction and the patient’s immunocompetent status made this less likely. Infectious or granulomatous meningoencephalitis (e.g., tuberculosis or neurosarcoidosis) was considered, particularly given the meningeal spread. However, lack of systemic findings, subsequent normal CSF studies, the absence of basal cisternal and cranial nerves enhancement reduced this likelihood (cranial nerve enhancement can be seen in histiocytosis, although it is more commonly associated with infections). Although IgG4-related disease with CNS involvement may affect the infundibulum - a key radiological distinction from histiocytosis is its frequently pachymeningeal involvement rather than an intraparenchymal mass lesion. CNS parenchymal lesions in IgG4RD remain exceedingly rare, with describing masslike brain involvement in young patients. IgG4-related disorder often demonstrates meningeal enhancement, especially around the cavernous sinus or middle cranial fossa [ 6 , 7 , 8 ]. Taken together, the rapid evolution of the lesion, widespread leptomeningeal enhancement, new hypothalamic–infundibular involvement, and the absence of findings more typical of the alternative differential diagnoses supported a diagnosis of CNS histiocytosis, which was ultimately confirmed histologically. This case underscores the potential of CNS histiocytosis to mimic glial neoplasm on initial imaging, especially radiologically. However, the appearance of leptomeningeal enhancement and infundibular involvement broadened the differential. This case is notable for the exclusive involvement of the central nervous system by histiocytosis, with no evidence of systemic disease. In the realm of CNS histiocytosis, a Mayo Clinic–based study of 377 adults reported that neurologic-only manifestations occurred in approximately 5%, underscoring the rarity of isolated parenchymal or meningeal disease [ 1 ]. Additionally, distinctive radiologic features of ALK-positive histiocytosis - such as focal parenchymal nodules with leptomeningeal enhancement - have been characterized in recent case series [ 2 ]. Conclusion CNS histiocytosis, though rare, should be considered in young patients with rapidly progressive brain lesions, especially when accompanied by meningeal spread and infundibular involvement. Biopsy remains the gold standard for diagnosis. Awareness of its radiologic mimics is essential for timely management. Declarations Ethics and Consent to Participate Declaration Not applicable. Patient data were anonymized and used in accordance with institutional standards for case reporting. Funding Declaration No external funding was received for this study. Consent for Publication Written informed consent for publication of this case and associated images was obtained from the patient. Competing Interests The authors declare that they have no competing interests. References Nathoo N, Fan X, Biegel JA, et al. Clinical features and outcomes in primary nervous system histiocytic neoplasms . Blood Cancer J. 2024;14:101. doi:10.1038/s41408-024-01083-x. Wang J, Gao X, Zhang K, et al. Imaging features of ALK‑positive histiocytosis with central nervous system involvement . Radiol Case Rep. 2024;19(3):3867–70. doi:10.1016/j.radcr.2022.07.072. Terrim S et al. Clinical presentation, investigation findings, and outcomes of IgG4‑related pachymeningitis: a systematic review. JAMA Neurol. 2024; online Nov 18. doi:10.1001/jamaneurol.2024.3947. Qing P et al. IgG4‑related intracranial lesions mimicking multiple sclerosis in a 14‑year‑old girl. Front. Neurol. 2022;13:1007153. doi:10.3389/fneur.2022.1007153. Mitani K et al. Detecting immunoglobulin G4‑related intracranial arteriopathy with MR vessel wall imaging: preliminary experience. BMC Neurol. 2022;22:476. doi:10.1186/s12883‑022‑03010‑8. Diaz M, Reiner AS, Lin A, et al. Leptomeningeal disease in histone‑mutant gliomas: clinical characteristics and prognostic insights. Neuro‑Oncology . 2023; Advance access. doi:10.1093/noajnl/vdad068 Andersen BM, Hadjipanayis CG, Cahill DP, et al. The Memorial Sloan Kettering Cancer Center experience with leptomeningeal disease in adult gliomas (2001–2016). Neurology . 2019;92(9):e982–e991. doi:10.1212/WNL.0000000000007056 Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage–dendritic cell lineages. Blood. 2016;127(22):2672–2681. doi:10.1182/blood-2016-01-690636. PMID: PMC6221469 Yoon SO. Pathologic characteristics of histiocytic and dendritic cell neoplasms. Blood Res. 2024 May 7;59(1):18. doi:10.1007/s44313-024-00015-9. PMID: 38713245; PMCID: PMC11076448. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7188864","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":490207385,"identity":"ec1d974e-1698-4c5e-8b98-3f2c58a417a8","order_by":0,"name":"Emil 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demonstrate a hyperintense mass involving the cortex and subcortical white matter of the right frontal operculum\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/0f5c25d1625348304815474e.jpg"},{"id":87825417,"identity":"382f4b8c-5c6b-40e6-969c-8cfb34a1cac4","added_by":"auto","created_at":"2025-07-29 11:41:48","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":48951,"visible":true,"origin":"","legend":"\u003cp\u003eInitial T2-weighted and FLAIR images demonstrate a hyperintense mass involving the cortex and subcortical white matter of the right frontal operculum\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/2719378e2d5457f88c2321a5.jpg"},{"id":87825422,"identity":"7214384d-1541-414f-b15f-25946ac5dd00","added_by":"auto","created_at":"2025-07-29 11:41:48","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69890,"visible":true,"origin":"","legend":"\u003cp\u003ePost-contrast T1-weighted images show mild intralesional enhancement and associated leptomeningeal enhancement surrounding the frontal lobe sulci\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/3a3e9fc3c0698fff1af28627.jpg"},{"id":87827579,"identity":"0b0e1df7-14ea-49e5-b2c5-0d65f03dd8b1","added_by":"auto","created_at":"2025-07-29 11:57:48","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":112245,"visible":true,"origin":"","legend":"\u003cp\u003ePost-contrast T1-weighted images show mild intralesional enhancement and associated leptomeningeal enhancement surrounding the frontal lobe sulci\u003c/p\u003e","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/d08ce9bfc88d760d43c7d16e.jpg"},{"id":87827578,"identity":"28abe88c-0e7e-45f9-aa4e-3e343d8f217d","added_by":"auto","created_at":"2025-07-29 11:57:48","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":77731,"visible":true,"origin":"","legend":"\u003cp\u003eFollow-up T2, FLAIR and post-contrast T1-weighted images obtained two weeks later reveal an increase in lesion size with the appearance of a new hemorrhagic focus and newly developed mild midline shift due to mass effect\u003c/p\u003e","description":"","filename":"Fig.5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/491a3f2c9e0cf2285531b8c6.jpg"},{"id":87827577,"identity":"24e6efa4-204d-496f-9178-ff46bda836d4","added_by":"auto","created_at":"2025-07-29 11:57:48","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":68567,"visible":true,"origin":"","legend":"\u003cp\u003eFollow-up T2, FLAIR and post-contrast T1-weighted images obtained two weeks later reveal an increase in lesion size with the appearance of a new hemorrhagic focus and newly developed mild midline shift due to mass effect\u003c/p\u003e","description":"","filename":"Fig.6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/1fd85bae343322899bc8e1c2.jpg"},{"id":87825424,"identity":"4181d4af-9796-4e2c-a1ff-393f79ec5c8d","added_by":"auto","created_at":"2025-07-29 11:41:48","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":59121,"visible":true,"origin":"","legend":"\u003cp\u003eFollow-up T2, FLAIR and post-contrast T1-weighted images obtained two weeks later reveal an increase in lesion size with the appearance of a new hemorrhagic focus and newly developed mild midline shift due to mass effect\u003c/p\u003e","description":"","filename":"Fig.7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/48ad8cbce7201ce232b28cce.jpg"},{"id":87825796,"identity":"aeac65de-adfa-48a8-9285-a6dab41e8e9e","added_by":"auto","created_at":"2025-07-29 11:49:48","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":96113,"visible":true,"origin":"","legend":"\u003cp\u003eThere is also progression of leptomeningeal enhancement, now involving the temporal and parietal sulci in addition to the frontal region\u003c/p\u003e","description":"","filename":"Fig.8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/950ad5a051e20558c261c9ed.jpg"},{"id":87827581,"identity":"a7bc81ab-b5f0-42de-b459-3a1ba9f8afb7","added_by":"auto","created_at":"2025-07-29 11:57:48","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":73756,"visible":true,"origin":"","legend":"\u003cp\u003eExtension of the T2 hyperintensity into the right insular cortex is observed in follow up images\u003c/p\u003e","description":"","filename":"Fig.9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/8f38a17528b32095902235be.jpg"},{"id":87825799,"identity":"a527f97b-7db5-4b09-96a8-1dc337252a36","added_by":"auto","created_at":"2025-07-29 11:49:48","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":152669,"visible":true,"origin":"","legend":"\u003cp\u003eSagittal post-contrast T1-weighted images further demonstrate new involvement of the infundibulum, showing thickening and increased contrast enhancement compared to the initial imaging\u003c/p\u003e","description":"","filename":"Fig.10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/e48d28ca9bc5128d7d7e5a69.jpg"},{"id":92367986,"identity":"e6a32fde-a178-441a-ba0a-fea8bcae8caa","added_by":"auto","created_at":"2025-09-29 00:46:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1202310,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7188864/v1/62e45aac-a5d1-42d0-ba0c-adbee9ace8eb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Mimic in the Frontal Lobe: CNS Histiocytosis Masquerading as a Glial Neoplasm in a Young Adult","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003c/p\u003e\u003cp\u003eParenchimal mass lesions are the least common CNS manifestation of hystiocytosis after \u003cem\u003ediabetes insipidus (infundibulum involvement)\u003c/em\u003e and \u003cem\u003eneurodegenerative changes.\u003c/em\u003e It typically manifests as a non-mass-like process, often involving the meninges, skull or the hypothalamic–pituitary axis. When parenchymal mass presents, such lesions may mimic glial processes, especially radiologically. Isolated infundibular involvement or calvarial bone lesions are more common presentations, while parenchymal mass-like lesions remain diagnostically challenging.\u003c/p\u003e\u003cp\u003ePrimary histiocytic disorders of the CNS are rare and occurs especially in young patients. These disorders, including Langerhans cell histiocytosis (LCH) and other non-Langerhans variants, can involve brain parenchyma, meninges and the hypothalamic–pituitary axis. Differentiating these from gliomas poses a diagnostic challenging, particularly when initial imaging shows mass-like lesions with enhancement and local mass effect.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 19-year-old previously healthy male presented with sudden loss of consciousness, followed by a generalized seizure and persistent headaches. Neurologic exam revealed no focal deficits. Routine blood tests were unremarkable.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInitial Imaging\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBrain MRI demonstrated a T2/FLAIR hyperintense lesion in the right frontal operculum, involved both the cortex and underlying white matter, with no diffusion restriction and mild but clearly discernible contrast enhancement. Notably, there was adjacent leptomeningeal enhancement, limited to the surrounding frontal sulci. No intralesional hemorrhage or calcification was seen. Given the appearance, an diffuse glial tumor was considered the leading diagnosis. The absence of restricted diffusion reduced suspicion for lymphoma. Nonetheless, the presence of leptomeningeal enhancement raised concern, as it is an atypical feature for glial tumors, which generally do not exhibit leptomeningeal involvement. No abnormalities were detected in the calvarium or extracranial tissues.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFollow-Up Imaging\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTwo weeks later, the patient experienced clinical deterioration, with worsening headache and confusion. Repeat MRI showed significant increase in lesion size (almost twofold) and more pronounced, patchy intralesional enhancement. Also leptomeningeal enhancement markedly increased, now extending into the right temporal and parietal lobes. Thickening and enhancement of the pituitary stalk (infundibulum) was noted as a new finding. A T2 hypointense focus within the lesion, more likely consistent with internal hemorrhage. Mild midline shift, suggestive of mass effect was observed in contrast to the initial imaging.\u003c/p\u003e\u003cp\u003e\u003cb\u003eHistopathology results\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMicroscopic examination of the biopsy material revealed fragments of a poorly differentiated small round cell tumor with a solid architectural pattern and high cellular density. Numerous mitotic figures and foci of necrosis were present.\u003c/p\u003e\u003cp\u003eImmunohistochemical analysis demonstrated strong positivity for CD45, CD68, CD163 and CD4, supporting a diagnosis of a neoplasm of histiocytic origin. The tumor showed nuclear expression of MUM1, which is associated with activated histiocytes or lymphoid cells. Stromal elements were diffusely positive for CD3 (T-lymphocytes) and S100 expression was also noted in the background tissue. There was residual GFAP expression, suggesting the presence of glial components, although not within the tumor cells.\u003c/p\u003e\u003cp\u003eFocal positivity for CD20, CD79a and BCL2 was restricted to reactive lymphoid infiltrates, not to the tumor itself. Importantly, the tumor was negative for CD1a, excluding Langerhans cell histiocytosis and negative for cytokeratin AE1/3, excluding epithelial malignancy. BCL6 expression was also absent.\u003c/p\u003e\u003cp\u003eThe Ki-67 proliferation index was approximately 90%, indicating a highly proliferative and aggressive tumor.\u003c/p\u003e\u003cp\u003eUnfortunately, molecular-genetic analysis for the BRAF V600E mutation was not performed, which limits further subclassification. Nevertheless, based on the morphological and immunophenotypic findings, a histiocytic neoplasm was favored. The possibility of Erdheim–Chester disease was not excluded.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003c/p\u003e\u003cp\u003eLeptomeningeal enhancement is generally considered an uncommon feature in glial neoplasms, but it has been reported, particularly in the context of \u003cem\u003ehigh-grade gliomas\u003c/em\u003e [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The presence of leptomeningeal enhancement at initial presentation, as in our case, is unusual and raises diagnostic uncertainty. While this finding does not exclude a glial origin, it necessitates careful consideration of alternative diagnoses - such as \u003cem\u003eCNS histiocytosis, lymphoma\u003c/em\u003e or \u003cem\u003egranulomatous meningoencephalitis\u003c/em\u003e.\u003c/p\u003e\u003cp\u003eAfter the second MRI, our diagnostic criteria expanded beyond a primary glial tumor. The lesion exhibited a notable increase in size over a short period, with more heterogeneous enhancement and a strikingly wider distribution of leptomeningeal enhancement, now involving the right temporal and parietal lobes. Most importantly, a new finding of infundibular thickening and enhancement raised suspicion for infectious-inflammatory, lymphoid or histiocytic involvement and cell infiltration, given the known tropism of such entities for the hypothalamic\u0026ndash;pituitary axis. These evolving features prompted initiation of steroid therapy. Following administration steroids, the patient demonstrated modest clinical improvement and radiological regression.\u003c/p\u003e\u003cp\u003eAt this stage, the differential diagnosis included several possibilities. Rapid lesion progression and leptomeningeal dissemination could be seen in \u003cem\u003eprimary CNS lymphoma\u003c/em\u003e, especially in immunocompromised patients, although the absence of diffusion restriction and the patient\u0026rsquo;s immunocompetent status made this less likely. \u003cem\u003eInfectious\u003c/em\u003e or \u003cem\u003egranulomatous meningoencephalitis\u003c/em\u003e (e.g., tuberculosis or neurosarcoidosis) was considered, particularly given the meningeal spread. However, lack of systemic findings, subsequent normal CSF studies, the absence of basal cisternal and cranial nerves enhancement reduced this likelihood (cranial nerve enhancement can be seen in histiocytosis, although it is more commonly associated with infections).\u003c/p\u003e\u003cp\u003eAlthough IgG4-related disease with CNS involvement may affect the infundibulum - a key radiological distinction from histiocytosis is its frequently pachymeningeal involvement rather than an intraparenchymal mass lesion. CNS parenchymal lesions in IgG4RD remain exceedingly rare, with describing masslike brain involvement in young patients. \u003cem\u003eIgG4-related disorder\u003c/em\u003e often demonstrates meningeal enhancement, especially around the cavernous sinus or middle cranial fossa [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTaken together, the rapid evolution of the lesion, widespread leptomeningeal enhancement, new hypothalamic\u0026ndash;infundibular involvement, and the absence of findings more typical of the alternative differential diagnoses supported a diagnosis of CNS histiocytosis, which was ultimately confirmed histologically.\u003c/p\u003e\u003cp\u003eThis case underscores the potential of CNS histiocytosis to mimic glial neoplasm on initial imaging, especially radiologically. However, the appearance of leptomeningeal enhancement and infundibular involvement broadened the differential.\u003c/p\u003e\u003cp\u003eThis case is notable for the exclusive involvement of the central nervous system by histiocytosis, with no evidence of systemic disease. In the realm of CNS histiocytosis, a Mayo Clinic\u0026ndash;based study of 377 adults reported that neurologic-only manifestations occurred in approximately 5%, underscoring the rarity of isolated parenchymal or meningeal disease [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdditionally, distinctive radiologic features of \u003cem\u003eALK-positive histiocytosis\u003c/em\u003e - such as focal parenchymal nodules with leptomeningeal enhancement - have been characterized in recent case series [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e\u003c/p\u003e\u003cp\u003eCNS histiocytosis, though rare, should be considered in young patients with rapidly progressive brain lesions, especially when accompanied by meningeal spread and infundibular involvement. Biopsy remains the gold standard for diagnosis. Awareness of its radiologic mimics is essential for timely management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics and Consent to Participate Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. Patient data were anonymized and used in accordance with institutional standards for case reporting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo external funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of this case and associated images was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNathoo N, Fan X, Biegel JA, et al. \u003cem\u003eClinical features and outcomes in primary nervous system histiocytic neoplasms\u003c/em\u003e\u003cem\u003e.\u003c/em\u003e\u003cem\u003eBlood Cancer J.\u003c/em\u003e 2024;14:101. doi:10.1038/s41408-024-01083-x.\u003c/li\u003e\n\u003cli\u003eWang J, Gao X, Zhang K, et al. \u003cem\u003eImaging features of ALK‑positive histiocytosis with central nervous system involvement\u003c/em\u003e\u003cem\u003e.\u003c/em\u003e\u003cem\u003eRadiol Case Rep.\u003c/em\u003e 2024;19(3):3867\u0026ndash;70. doi:10.1016/j.radcr.2022.07.072.\u003c/li\u003e\n\u003cli\u003eTerrim S et al. \u003cem\u003eClinical presentation, investigation findings, and outcomes of IgG4‑related pachymeningitis: a systematic review. JAMA Neurol.\u003c/em\u003e 2024; online Nov 18. doi:10.1001/jamaneurol.2024.3947.\u003c/li\u003e\n\u003cli\u003eQing P et al. \u003cem\u003eIgG4‑related intracranial lesions mimicking multiple sclerosis in a 14‑year‑old girl. Front. Neurol.\u003c/em\u003e 2022;13:1007153. doi:10.3389/fneur.2022.1007153.\u003c/li\u003e\n\u003cli\u003eMitani K et al. \u003cem\u003eDetecting immunoglobulin G4‑related intracranial arteriopathy with MR vessel wall imaging: preliminary experience. BMC Neurol.\u003c/em\u003e 2022;22:476. doi:10.1186/s12883‑022‑03010‑8.\u003c/li\u003e\n\u003cli\u003eDiaz M, Reiner AS, Lin A, et al. Leptomeningeal disease in histone‑mutant gliomas: clinical characteristics and prognostic insights. \u003cem\u003eNeuro‑Oncology\u003c/em\u003e. 2023; Advance access. doi:10.1093/noajnl/vdad068\u003c/li\u003e\n\u003cli\u003eAndersen BM, Hadjipanayis CG, Cahill DP, et al. The Memorial Sloan Kettering Cancer Center experience with leptomeningeal disease in adult gliomas (2001\u0026ndash;2016). \u003cem\u003eNeurology\u003c/em\u003e. 2019;92(9):e982\u0026ndash;e991. doi:10.1212/WNL.0000000000007056\u003c/li\u003e\n\u003cli\u003eEmile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage\u0026ndash;dendritic cell lineages. \u003cem\u003eBlood.\u003c/em\u003e 2016;127(22):2672\u0026ndash;2681. doi:10.1182/blood-2016-01-690636. PMID: PMC6221469\u003c/li\u003e\n\u003cli\u003eYoon SO. Pathologic characteristics of histiocytic and dendritic cell neoplasms. \u003cem\u003eBlood Res.\u003c/em\u003e 2024 May 7;59(1):18. doi:10.1007/s44313-024-00015-9. PMID: 38713245; PMCID: PMC11076448.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7188864/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7188864/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003cbr\u003e\nThis case describes an unusual presentation of central nervous system (CNS) histiocytosis in a 19-year-old male, presenting with imaging features initially suggestive of a glial tumor, but further work-up redirected the diagnosis toward a condition of non-glial origin. Also it highlights how evolving clinical and radiologic data can uncover an unexpected diagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003cbr\u003e\nA 19-year-old male presented with acute neurological symptoms. Serial MRI examinations with contrast administration were performed to this patient. Imaging characteristics were reviewed in correlation with clinical progression and histopathological findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003cbr\u003e\nInitial MRI revealed a T2/FLAIR hyperintense mass in the right frontal operculum with associated perilesional leptomeningeal enhancement in the adjacent sulci. No diffusion restriction was seen. Over two weeks, the lesion nearly doubled in size, with increased patchy enhancement, leptomeningeal spread to temporal and parietal regions, and new infundibular thickening. Mild midline shift developed. Biopsy confirmed CNS histiocytosis. Partial regression was noted after steroid treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003cbr\u003e\nThis case emphasizes the possible radiologic overlap between glial tumors and rare mass like presentation with parenchimal involvement of CNS histiocytosis. Recognition of leptomeningeal involvement, infundibular thickening and steroid responsiveness can aid differentiation and prompt biopsy.\u003c/p\u003e","manuscriptTitle":"A Mimic in the Frontal Lobe: CNS Histiocytosis Masquerading as a Glial Neoplasm in a Young Adult","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-29 11:41:43","doi":"10.21203/rs.3.rs-7188864/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5ed71713-8b2c-41dd-ab86-522009d39e1f","owner":[],"postedDate":"July 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-29T00:38:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-29 11:41:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7188864","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7188864","identity":"rs-7188864","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}