Sinonasal Tract Osteochondromyxoma: An Underrecognized Tumor Easily Mistaken for Nasal Chondromesenchymal Hamartoma

Sinonasal Tract Osteochondromyxoma: An Underrecognized Tumor Easily Mistaken for Nasal Chondromesenchymal Hamartoma | 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 Research Article Sinonasal Tract Osteochondromyxoma: An Underrecognized Tumor Easily Mistaken for Nasal Chondromesenchymal Hamartoma Justin A. Bishop, Ali Alani, Igor Lima Fernandes, Carlos E. Bacchi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7594659/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Matrix-producing tumors of the sinonasal region are diagnostically challenging, with a large number of similar-appearing neoplasms having different prognoses, treatment strategies, and genetic syndrome associations. Osteochondromyxoma (OCM) is a very rare tumor known to be associated with Carney complex. Since its initial description in 2001, fewer than 20 cases have been reported, with the sinonasal tract being an apparently favored site. Herein we describe 6 new cases of sinonasal OCM. OCM cases with available slides were retrieved from the surgical pathology files of the authors’ practices. The tumors arose in 4 boys and 2 girls, ranging from 4 to 17 years (mean, 9.5 years). All presented with nasal obstruction and a mass. Radiologically the tumors presented as indolent-appearing, heterogeneous, calcified, expansile masses. Histologically the tumors all consisted of bland, normochromatic spindled to stellate cells in a myxoid to collagenized stroma, with variable amounts of cartilage and bone formation. Mitotic activity was very low and necrosis was absent. All demonstrated complete loss of PRKAR1A expression by immunohistochemistry. Of these 6 cases, 3 had been originally diagnosed as nasal chondromesenchymal hamartomas, and one as osteosarcoma. Treatment and follow up information were available for 5 patients: all were treated with surgery, with one also receiving chemotherapy after an initial osteosarcoma diagnosis. At the time of last clinical follow-up, all 5 patients were alive, one with residual disease. No patient was known to have other stigmata of Carney complex. Although rare, OCM preferentially occurs in the sinonasal tract, and therefore may be encountered by head and neck pathologists. Given their predilection for young patients and overlapping morphologic features, OCM are easily misdiagnosed as other matrix-forming sinonasal tumors, especially nasal chondromesenchymal hamartoma. Immunohistochemical demonstration of PRKAR1A loss is valuable for confirming an OCM diagnosis, which should prompt clinical investigation for the possibility of Carney complex. Osteochondromyxoma PRKAR1A Carney complex nasal chondromesenchymal hamartoma Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Mesenchymal tumors of the sinonasal tract are notoriously difficult to diagnose, with an ever-growing list of often similar-looking neoplasms.( 1 ) Among this group is a subgroup of matrix-producing mesenchymal tumors, characterized by the formation of myxoid, chondroid, and/or osteoid matrix. Matrix-producing sinonasal tract tumors may be central (arising in the maxillary bone) or peripheral, and include chondromyxoid fibroma, chondroblastoma, ossifying fibromyxoid tumor, phosphaturic mesenchymal tumor, nasal chondromesenchymal hamartoma, osteosarcoma, and chondrosarcoma, among others. Distinguishing between these different entities is important due to different prognoses, treatment strategies, and genetic syndrome associations, but it is difficult even for the most experienced pathologists. Osteochondromyxoma (OCM) is a very rare tumor which was described initially as one of the least common manifestations of the Carney complex, an autosomal dominant tumor syndrome driven by germline inactivating mutations of the tumor suppressor gene PRKAR1A .( 2 ) Since its initial description in 2001, fewer than 20 cases of OCM have been reported, with and without a clear association with underlying Carney complex.( 2 – 6 ) Although the sinonasal tract is one of the most common anatomic locations for OCM, our anecdotal experience suggests that it is underrecognized by head and neck pathologists. Herein we describe 6 new cases of sinonasal OCM to draw attention to this rare neoplasm. Materials and Methods Following Institutional Research Ethics Board approval, cases of sinonasal tract OCM were retrieved from the authors’ consultation archives. All tumors were submitted entirely for histological evaluation. None of the cases have been previously published. Clinical information including follow-up was obtained from the contributing pathologists. Using standard techniques, immunohistochemistry was performed for PRKAR1A clone 6C7 (Origene, Rockville, MD).( 7 ) Clinical next-generation sequencing was performed on one case on the Foundation Medicine platform. Results The demographic and clinical findings of the 6 studied cases are summarized in Table 1 . The tumors occurred in 4 boys and 2 girls, ranging from 4 to 17 years of age (mean, 9.5 years). All presented as masses in the nasal cavity. Imaging studies were available for all cases, and consistently demonstrated large, expansile, variably mineralized lesions with associated bone erosion and peripheral sclerosis, features consistent with a slow-growing process (Fig. 1 ). Table 1 Clinical characteristics of patients with sinonasal osteochondromyxoma. Case Age (years) at initial presentation Sex Location Original diagnosis Clinical course 1 6 Female Midline nasal cavity/ skull base Nasal chondromesenchymal hamartoma Treated surgically, recurrences at 4 years, 11 years, and 12 years following original presentation 2 12 Male Left nasal cavity Nasal chondromesenchymal hamartoma Treated surgically, currently no disease 3 years after treatment 3 6 Male Left nasal cavity/ethmoid Osteochondromyxoma Treated surgically, local recurrence at 7 months 4 12 Male Right nasal cavity Osteochondromyxoma Not available 5 17 Male Right nasal cavity Osteochondromyxoma Treated surgically, currently no disease 4 years after treatment 6 4 Female Midline nasal cavity Osteosarcoma, then nasal chondromesenchymal hamartoma Received one cycle chemotherapy initially, then surgery after revised diagnosis. Alive with residual disease 4 years after treatment Morphologically, the tumors were quite consistent from case to case. Most grew in a generally circumscribed manner, although the unusual admixture of bone, cartilage and myxoid stroma seen in these tumors (see below) could at times mimic permeative growth through pre-existing bone (“pseudoinfiltrative”); two cases showed small foci of infiltrative growth within native bone (Fig. 4 ). Diffuse, permeative growth and/or destruction of native bone were not present. As their name would suggest, all produced a variable admixture of bone, cartilage, and myxoid stroma. Thin trabeculae of mature bone were typically found at the periphery of a variably cellular, somewhat lobular proliferation of stellate to spindled stromal cells in a myxoid stroma (Fig. 2 ). Within this myxoid stroma, a variable degree of cartilaginous differentiation was present, ranging from vaguely chondroid foci to areas with overt formation of mature appearing hyaline cartilage (Fig. 2 ). A distinctive feature of OCM was the presence of multiple small islands of variably calcified chondroid matrix, in which each ‘island” is surrounded by bland fibroblastic spindled cells (Fig. 3 ), creating a “frondlike” or “cotyledonoid” appearance when seen in cross section (Fig. 3 D). The tumor cells typically contained uniform, normochromatic nuclei, although two cases exhibited focal nuclear enlargement and hyperchromasia (Fig. 4 ). The mitotic rates were very low (0–1 per 10 high power fields), even in these latter two cases. PRKAR1A immunohistochemistry, performed on all cases, showed complete loss of expression in the tumor cells, with retained internal controls (Fig. 5 ). Clinical follow-up was available for 5 patients, ranging from 7-144 months (mean 56.6 months). Case 1 carried a diagnosis of NCMH for 12 years (including 3 local recurrences) before Foundation Medicine next generation sequencing was performed, which identified homozygous deletion of PRKAR1A , resulting in a revised diagnosis of OCM. This patient is currently free of disease and has not yet been evaluated for other features of Carney complex. Case 2 was treated surgically and is currently free of disease. This tumor was also originally diagnosed as NCMH, and the patient has not been evaluated for Carney complex to our knowledge. Case 3 was initially correctly diagnosed with an OCM; he experienced a local recurrence at 7 months following surgery and was subsequently lost to follow up. Case 4 was also originally diagnosed with an OCM; treatment and follow up information was unavailable. Case 5 is free of disease 4 years after surgery and the diagnosis of OCM. The patient has no other features of Carney complex. Case 6 was initially diagnosed with an osteosarcoma and treated with one cycle of chemotherapy; this was discontinued when the diagnosis of osteosarcoma was revised (incorrectly) to NCMH. This patient was alive with radiologic evidence of residual disease 4 years after surgery. Discussion OCM is perhaps the rarest member of the family of tumors defined by PRKAR1A loss and associated with Carney complex.( 6 ) Other members of this tumor family include cardiac myxomas, superficial angiomyxomas, large cell calcifying Sertoli cell tumors, pigmented nodular adrenocortical disease, and malignant melanotic nerve sheath tumors (previously “melanotic schwannoma”).( 8 ) Although published examples are scarce, OCM appears to have a predilection for the sinonasal tract, although cases involving the tibia and radius have also been reported.( 2 , 6 ) It is thus important for head and neck pathologists to be aware of this unusual and easily misdiagnosed neoplasm. To that end, we have described 6 new cases of OCM involving the sinonasal tract, the largest series of OCM to date. In our series, all 6 OCMs occurred in the nasal cavities of children ranging from 4 to 17 years, older than most previously reported patients. We do not think that the exclusively nasal location of these tumors represents referral bias, as half of these cases were referred in consultation to one of us (ALF) whose practice encompasses soft tissue and bone tumors more generally. The tumors presented as large masses with imaging characteristics of indolent, slow-growing bone neoplasms. They were treated surgically, and of the 5 with clinical follow up, 2 recurred locally with another case showing persistent disease. No patient with follow-up developed metastatic disease or aggressive local recurrence, and none were known to have any other stigmata of Carney complex. Although we cannot entirely exclude the possibility that some of these patients may have Carney complex, given the relatively limited clinical histories available to us, it is well known that a significant majority of patients with tumors originally described as being tightly associated with Carney complex (e.g., malignant melanotic nerve sheath tumor, superficial angiomyxoma) lack other features of this complex.( 9 , 10 ) Morphologically, the tumors comprising the present series were identically to previously described OCM, with a vaguely lobular proliferation of bland spindled to stellate cells in a variably myxoid, chondroid and bone-forming background. The arrangement of multiple small islands of variably calcified chondroid matrix, surrounded by bland fibroblastic spindled cells, was particularly distinctive. To the best of our knowledge, this is the first study to evaluate immunohistochemistry for PRKAR1A in the diagnosis of OCM. PRKAR1A is the protein product of the Carney complex–associated tumor suppressor gene PRKAR1A ( protein kinase A regulatory subunit 1α ), which is located on chromosome 17p23-24, and has been shown to be mutated in approximately 40% of familial and sporadic Carney complex cases.( 11 – 14 ) Loss of heterozygosity and mutations of PRKAR1A have been demonstrated in various Carney complex–associated neoplasms, including malignant melanotic nerve sheath tumors,( 15 ) pancreatic tumors,( 16 ) and pigmented epithelioid melanocytomas.( 17 ) Loss of PRKAR1A expression by immunohistochemistry has been demonstrated in several different Carney complex-associated neoplasms, including malignant melanotic nerve sheath tumors, cardiac myxomas, pigmented epithelioid melanocytomas, superficial angiomyxomas, and large cell calcifying Sertoli cell tumors ( 7 , 9 , 17 – 19 ). In agreement with these prior studies, we have found loss of PRKAR1A expression also to be a consistent feature of OCM. Given the young age of most patients with OCM, the most important differential diagnostic consideration is with NCMH, a rare but well-described sinonasal tumor closely associated with DICER1 predisposition syndrome.( 20 , 21 ) Indeed, half of the tumors in the present series had been originally diagnosed as NCMH. While both OCM and NCMH are benign and treated surgically, their respective syndromic associations make an accurate diagnosis important. While both OCM and NCMH contain myxoid and chondroid areas, NCMH usually contains more hypercellular, immature cartilage as well as admixed invaginations of sinonasal surface epithelium (Fig. 6 A). Immature woven bone formation, partly derived from enchondral ossification of the lesional cartilage, can occur in both lesions. Lastly, although there are no established diagnostic immunohistochemical markers for DICER1-associated neoplasms, we have never observed loss of PRKAR1A in those NCMH seen in our consultation practices (Fig. 6 B). Given the overlapping clinical and histological features of these two neoplasms, PRKAR1A immunohistochemistry may thus be of considerable value in this differential diagnosis. The differential diagnosis of OCM also includes chondromyxoid fibroma (CMF), which often occurs in the sinonasal area and consists of a distinctly lobular proliferation of moderately variable spindled to stellate cells, often with associated osteoclast-like giant cells, in association with a chondromyxoid matrix. Unlike OCM, however, true cartilage formation is not a feature of CMF.( 22 , 23 ) In challenging cases, immunohistochemistry for GRM1, reflecting underlying GRM1 rearrangements with various partners,( 24 ) may be quite helpful in substantiating the diagnosis of CMF.( 25 ) OCM must also be distinguished from chondroblastic osteosarcoma and chondrosarcoma. Chondroblastic osteosarcomas typically have much more aggressive imaging features than OCM, are composed of overtly malignant spindled to epithelioid cells, and contain areas of immature and “lace-like” osteoid. Additionally, the chondroblastic component is usually much more cellular and atypical compared with OCM. Chondrosarcoma is exceptionally rare in the pediatric age group, usually presents less heterogeneously on imaging, and displays permeative growth into surround host bone, not seen in OCM. Neither chondroblastic osteosarcoma nor chondrosarcoma would be expected to demonstrate loss of PRKAR1A expression. In summary, we have reported 6 new cases of OCM, an exceptionally rare, Carney complex-associated, benign neoplasm with an apparent predilection for the sinonasal tract. Given the differences in syndromic association and clinical behavior, OCM should be distinguished from NCHM and other matrix-forming tumors of the sinonasal region. Loss of PRKAR1A expression by immunohistochemistry is a valuable tool for confirming an OCM diagnosis and should prompt clinical investigation for the possibility of Carney complex. Declarations Declarations and Compliance with Ethical Standards Funding : This study was partially funded by the Jane B. and Edwin P. Jenevein M.D Endowment for Pathology at UT Southwestern Medical Center. No external funding was obtained for this study. Conflicts of interest/Competing interests : All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. Availability of data and material : All data generated or analyzed during this study are included in this published article. Code availability : Not applicable. Authors’ contributions: ALF and JAB designed the study, performed data collection and interpretation, and prepared the manuscript. All authors read and approved the final paper. Ethics approval: All procedures performed in this retrospective data analysis involving human participants were in accordance with the ethical standards of the institutional review board (UT Southwestern IRB 112017-073). Consent to participate/publication : The IRB-approved study did not require informed consent. References Thompson LDR, Fanburg-Smith JC. Update on Select Benign Mesenchymal and Meningothelial Sinonasal Tract Lesions. Head Neck Pathol. 2016;10(1):95-108. Carney JA, Boccon-Gibod L, Jarka DE, et al. Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders. Am J Surg Pathol. 2001;25(2):164-176. Alahmari MS, Alshahrani AM, Alharbi SM, et al. Nasal Osteochondromyxoma Without Carney Complex: A Case Report and a Literature Review. Cureus. 2024;16(7):e64223. Peng S, Behbahani M, Sharma S, et al. 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De La Pena NM, Yekzaman BR, Patra DP, et al. Craniofacial Chondromyxoid Fibromas: A Systematic Review and Analysis Based on Anatomic Locations. World Neurosurg. 2022;162(21-28. Meredith DM, Fletcher CDM, Jo VY. Chondromyxoid Fibroma Arising in Craniofacial Sites: A Clinicopathologic Analysis of 25 Cases. Am J Surg Pathol. 2018;42(3):392-400. Nord KH, Lilljebjorn H, Vezzi F, et al. GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma. Nat Genet. 2014;46(5):474-477. Toland AMS, Lam SW, Varma S, et al. GRM1 Immunohistochemistry Distinguishes Chondromyxoid Fibroma From its Histologic Mimics. Am J Surg Pathol. 2022;46(10):1407-1414. Additional Declarations No competing interests reported. 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15:43:46","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":160062,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure1imaging.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/cf1b17ed4994e285f8a25794.png"},{"id":92194856,"identity":"af55487c-68a2-44d8-b53e-3f1f081130df","added_by":"auto","created_at":"2025-09-25 15:43:46","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3936000,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/2f678d30ca76e9111d5f37c4.png"},{"id":92194852,"identity":"b06d34d9-7a30-44a5-9938-2bba35a6ab41","added_by":"auto","created_at":"2025-09-25 15:43:46","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1080898,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/99c45601945fd9300decec4e.png"},{"id":92194843,"identity":"55d16d6c-7be4-40eb-bdcb-dc2d88b2aadd","added_by":"auto","created_at":"2025-09-25 15:43:46","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":441710,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure5PRKAR1A.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/be22e9be0b7a4d1cdfc8ce37.png"},{"id":92196558,"identity":"bbf81ec1-b756-4fee-b0d5-294a84130983","added_by":"auto","created_at":"2025-09-25 15:59:46","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1843147,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure6NCMH.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/9f58f42d76579a74b02d0265.png"},{"id":92194846,"identity":"eaa409b0-d81f-4eb7-bc0f-9e0afa560973","added_by":"auto","created_at":"2025-09-25 15:43:46","extension":"xml","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67094,"visible":true,"origin":"","legend":"","description":"","filename":"aef6959e82e848adadf16274aeb8c8dd1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/ff23dbd4eea35a847308f50f.xml"},{"id":92195546,"identity":"a5ae5875-295e-4045-85b2-4b82ff037aea","added_by":"auto","created_at":"2025-09-25 15:51:46","extension":"html","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":74877,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/218bf5a39f219e81c6ac33c1.html"},{"id":92196556,"identity":"2ef172c4-3147-43a4-8749-62dc7df90a01","added_by":"auto","created_at":"2025-09-25 15:59:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":382100,"visible":true,"origin":"","legend":"\u003cp\u003e(A-B)\u003cstrong\u003e \u003c/strong\u003eRadiologically, the osteochondromyxomas were large, circumscribed mixed radiopaque/radiodense lesions with a sclerotic rim.\u003c/p\u003e","description":"","filename":"Figure1imaging.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/6076c0def0af229c36c9ca02.png"},{"id":92194854,"identity":"0a3224b5-ea2f-4c70-8413-6bd506adabc5","added_by":"auto","created_at":"2025-09-25 15:43:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51889488,"visible":true,"origin":"","legend":"\u003cp\u003e(A-D) The sinonasal osteochondromyxomas grew in the sinonasal subepithelial tissues as variably cellular mixtures of myxoid and cartilaginous tissue, with frequent spicules of mature lamellar bone.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/9a9cca4755b45b3a29bcb6ae.png"},{"id":92195534,"identity":"8ac3c7d4-6bf6-47dd-b5c8-0bb5065a00f5","added_by":"auto","created_at":"2025-09-25 15:51:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":13411035,"visible":true,"origin":"","legend":"\u003cp\u003e(A-B) A characteristic feature seen in all of the sinonasal osteochondromyxomas was coalescing trabeculae of hyalinized collagen, sometimes showing partial ossification (C-D).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/6dcdc7c8aec14e327d0044e2.png"},{"id":92194842,"identity":"819b0616-aa9b-4509-a353-8475aac5544b","added_by":"auto","created_at":"2025-09-25 15:43:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":25763465,"visible":true,"origin":"","legend":"\u003cp\u003e(A) A subset of sinonasal osteochondromas showed an infiltrative-appearing pattern with native bone. (B) Occasional cases exhibited mild cellular atypia, but mitotic activity was minimal.\u003c/p\u003e","description":"","filename":"FIgure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/98d6a28c6ec60bb85362aefe.png"},{"id":92194836,"identity":"9fad9951-8b93-4790-92e5-5b1f316c386b","added_by":"auto","created_at":"2025-09-25 15:43:45","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":12132429,"visible":true,"origin":"","legend":"\u003cp\u003eAll cases demonstrated complete loss of tumor expression of PRKAR1A, with retained staining in normal tissues.\u003c/p\u003e","description":"","filename":"Figure5PRKAR1A.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/ef88d09adfaae846dcae9481.png"},{"id":92194839,"identity":"7f0614a2-7ffa-4595-8d25-fff07dcae7ff","added_by":"auto","created_at":"2025-09-25 15:43:46","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":26325082,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Nasal chondromesenchymal hamartoma with lobules of variable cellular cartilage with myxoid to hyaline features, and admixed invaginations of surface epithelium. (B) Retained PRKAR1A immunoexpression was observed in this case.\u003c/p\u003e","description":"","filename":"Figure6NCMH.png","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/c8abd4613a3ff99aa9aa5090.png"},{"id":92197166,"identity":"8af40664-88f3-46ce-9365-a30db8c8ed1e","added_by":"auto","created_at":"2025-09-25 16:08:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":115680292,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7594659/v1/d897d2a5-bf23-44ab-a759-3514acdc214e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sinonasal Tract Osteochondromyxoma: An Underrecognized Tumor Easily Mistaken for Nasal Chondromesenchymal Hamartoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMesenchymal tumors of the sinonasal tract are notoriously difficult to diagnose, with an ever-growing list of often similar-looking neoplasms.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Among this group is a subgroup of matrix-producing mesenchymal tumors, characterized by the formation of myxoid, chondroid, and/or osteoid matrix. Matrix-producing sinonasal tract tumors may be central (arising in the maxillary bone) or peripheral, and include chondromyxoid fibroma, chondroblastoma, ossifying fibromyxoid tumor, phosphaturic mesenchymal tumor, nasal chondromesenchymal hamartoma, osteosarcoma, and chondrosarcoma, among others. Distinguishing between these different entities is important due to different prognoses, treatment strategies, and genetic syndrome associations, but it is difficult even for the most experienced pathologists.\u003c/p\u003e\u003cp\u003eOsteochondromyxoma (OCM) is a very rare tumor which was described initially as one of the least common manifestations of the Carney complex, an autosomal dominant tumor syndrome driven by germline inactivating mutations of the tumor suppressor gene \u003cem\u003ePRKAR1A\u003c/em\u003e.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Since its initial description in 2001, fewer than 20 cases of OCM have been reported, with and without a clear association with underlying Carney complex.(\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Although the sinonasal tract is one of the most common anatomic locations for OCM, our anecdotal experience suggests that it is underrecognized by head and neck pathologists. Herein we describe 6 new cases of sinonasal OCM to draw attention to this rare neoplasm.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eFollowing Institutional Research Ethics Board approval, cases of sinonasal tract OCM were retrieved from the authors\u0026rsquo; consultation archives. All tumors were submitted entirely for histological evaluation. None of the cases have been previously published. Clinical information including follow-up was obtained from the contributing pathologists.\u003c/p\u003e\u003cp\u003eUsing standard techniques, immunohistochemistry was performed for PRKAR1A clone 6C7 (Origene, Rockville, MD).(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Clinical next-generation sequencing was performed on one case on the Foundation Medicine platform.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe demographic and clinical findings of the 6 studied cases are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The tumors occurred in 4 boys and 2 girls, ranging from 4 to 17 years of age (mean, 9.5 years). All presented as masses in the nasal cavity. Imaging studies were available for all cases, and consistently demonstrated large, expansile, variably mineralized lesions with associated bone erosion and peripheral sclerosis, features consistent with a slow-growing process (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of patients with sinonasal osteochondromyxoma.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge (years) at initial presentation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLocation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOriginal diagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eClinical course\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMidline nasal cavity/\u003c/p\u003e\u003cp\u003eskull base\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNasal chondromesenchymal hamartoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTreated surgically, recurrences at 4 years, 11 years, and 12 years following original presentation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLeft nasal cavity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNasal chondromesenchymal hamartoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTreated surgically, currently no disease 3 years after treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLeft nasal cavity/ethmoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOsteochondromyxoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTreated surgically, local recurrence at 7 months\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRight nasal cavity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOsteochondromyxoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot available\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRight nasal cavity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOsteochondromyxoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTreated surgically, currently no disease 4 years after treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMidline nasal cavity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOsteosarcoma, then nasal chondromesenchymal hamartoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReceived one cycle chemotherapy initially, then surgery after revised diagnosis. Alive with residual disease 4 years after treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eMorphologically, the tumors were quite consistent from case to case. Most grew in a generally circumscribed manner, although the unusual admixture of bone, cartilage and myxoid stroma seen in these tumors (see below) could at times mimic permeative growth through pre-existing bone (\u0026ldquo;pseudoinfiltrative\u0026rdquo;); two cases showed small foci of infiltrative growth within native bone (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Diffuse, permeative growth and/or destruction of native bone were not present.\u003c/p\u003e\u003cp\u003eAs their name would suggest, all produced a variable admixture of bone, cartilage, and myxoid stroma. Thin trabeculae of mature bone were typically found at the periphery of a variably cellular, somewhat lobular proliferation of stellate to spindled stromal cells in a myxoid stroma (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Within this myxoid stroma, a variable degree of cartilaginous differentiation was present, ranging from vaguely chondroid foci to areas with overt formation of mature appearing hyaline cartilage (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A distinctive feature of OCM was the presence of multiple small islands of variably calcified chondroid matrix, in which each \u0026lsquo;island\u0026rdquo; is surrounded by bland fibroblastic spindled cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e), creating a \u0026ldquo;frondlike\u0026rdquo; or \u0026ldquo;cotyledonoid\u0026rdquo; appearance when seen in cross section (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). The tumor cells typically contained uniform, normochromatic nuclei, although two cases exhibited focal nuclear enlargement and hyperchromasia (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The mitotic rates were very low (0\u0026ndash;1 per 10 high power fields), even in these latter two cases. PRKAR1A immunohistochemistry, performed on all cases, showed complete loss of expression in the tumor cells, with retained internal controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eClinical follow-up was available for 5 patients, ranging from 7-144 months (mean 56.6 months). Case 1 carried a diagnosis of NCMH for 12 years (including 3 local recurrences) before Foundation Medicine next generation sequencing was performed, which identified homozygous deletion of \u003cem\u003ePRKAR1A\u003c/em\u003e, resulting in a revised diagnosis of OCM. This patient is currently free of disease and has not yet been evaluated for other features of Carney complex. Case 2 was treated surgically and is currently free of disease. This tumor was also originally diagnosed as NCMH, and the patient has not been evaluated for Carney complex to our knowledge. Case 3 was initially correctly diagnosed with an OCM; he experienced a local recurrence at 7 months following surgery and was subsequently lost to follow up. Case 4 was also originally diagnosed with an OCM; treatment and follow up information was unavailable. Case 5 is free of disease 4 years after surgery and the diagnosis of OCM. The patient has no other features of Carney complex. Case 6 was initially diagnosed with an osteosarcoma and treated with one cycle of chemotherapy; this was discontinued when the diagnosis of osteosarcoma was revised (incorrectly) to NCMH. This patient was alive with radiologic evidence of residual disease 4 years after surgery.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOCM is perhaps the rarest member of the family of tumors defined by \u003cem\u003ePRKAR1A\u003c/em\u003e loss and associated with Carney complex.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Other members of this tumor family include cardiac myxomas, superficial angiomyxomas, large cell calcifying Sertoli cell tumors, pigmented nodular adrenocortical disease, and malignant melanotic nerve sheath tumors (previously \u0026ldquo;melanotic schwannoma\u0026rdquo;).(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Although published examples are scarce, OCM appears to have a predilection for the sinonasal tract, although cases involving the tibia and radius have also been reported.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) It is thus important for head and neck pathologists to be aware of this unusual and easily misdiagnosed neoplasm. To that end, we have described 6 new cases of OCM involving the sinonasal tract, the largest series of OCM to date.\u003c/p\u003e\u003cp\u003eIn our series, all 6 OCMs occurred in the nasal cavities of children ranging from 4 to 17 years, older than most previously reported patients. We do not think that the exclusively nasal location of these tumors represents referral bias, as half of these cases were referred in consultation to one of us (ALF) whose practice encompasses soft tissue and bone tumors more generally. The tumors presented as large masses with imaging characteristics of indolent, slow-growing bone neoplasms. They were treated surgically, and of the 5 with clinical follow up, 2 recurred locally with another case showing persistent disease. No patient with follow-up developed metastatic disease or aggressive local recurrence, and none were known to have any other stigmata of Carney complex. Although we cannot entirely exclude the possibility that some of these patients may have Carney complex, given the relatively limited clinical histories available to us, it is well known that a significant majority of patients with tumors originally described as being tightly associated with Carney complex (e.g., malignant melanotic nerve sheath tumor, superficial angiomyxoma) lack other features of this complex.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) Morphologically, the tumors comprising the present series were identically to previously described OCM, with a vaguely lobular proliferation of bland spindled to stellate cells in a variably myxoid, chondroid and bone-forming background. The arrangement of multiple small islands of variably calcified chondroid matrix, surrounded by bland fibroblastic spindled cells, was particularly distinctive.\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, this is the first study to evaluate immunohistochemistry for PRKAR1A in the diagnosis of OCM. PRKAR1A is the protein product of the Carney complex\u0026ndash;associated tumor suppressor gene \u003cem\u003ePRKAR1A\u003c/em\u003e (\u003cem\u003eprotein kinase A regulatory subunit 1α\u003c/em\u003e), which is located on chromosome 17p23-24, and has been shown to be mutated in approximately 40% of familial and sporadic Carney complex cases.(\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) Loss of heterozygosity and mutations of \u003cem\u003ePRKAR1A\u003c/em\u003e have been demonstrated in various Carney complex\u0026ndash;associated neoplasms, including malignant melanotic nerve sheath tumors,(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) pancreatic tumors,(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and pigmented epithelioid melanocytomas.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) Loss of PRKAR1A expression by immunohistochemistry has been demonstrated in several different Carney complex-associated neoplasms, including malignant melanotic nerve sheath tumors, cardiac myxomas, pigmented epithelioid melanocytomas, superficial angiomyxomas, and large cell calcifying Sertoli cell tumors (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In agreement with these prior studies, we have found loss of PRKAR1A expression also to be a consistent feature of OCM.\u003c/p\u003e\u003cp\u003eGiven the young age of most patients with OCM, the most important differential diagnostic consideration is with NCMH, a rare but well-described sinonasal tumor closely associated with DICER1 predisposition syndrome.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Indeed, half of the tumors in the present series had been originally diagnosed as NCMH. While both OCM and NCMH are benign and treated surgically, their respective syndromic associations make an accurate diagnosis important. While both OCM and NCMH contain myxoid and chondroid areas, NCMH usually contains more hypercellular, immature cartilage as well as admixed invaginations of sinonasal surface epithelium (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA). Immature woven bone formation, partly derived from enchondral ossification of the lesional cartilage, can occur in both lesions. Lastly, although there are no established diagnostic immunohistochemical markers for DICER1-associated neoplasms, we have never observed loss of PRKAR1A in those NCMH seen in our consultation practices (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB). Given the overlapping clinical and histological features of these two neoplasms, PRKAR1A immunohistochemistry may thus be of considerable value in this differential diagnosis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe differential diagnosis of OCM also includes chondromyxoid fibroma (CMF), which often occurs in the sinonasal area and consists of a distinctly lobular proliferation of moderately variable spindled to stellate cells, often with associated osteoclast-like giant cells, in association with a chondromyxoid matrix. Unlike OCM, however, true cartilage formation is not a feature of CMF.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) In challenging cases, immunohistochemistry for GRM1, reflecting underlying \u003cem\u003eGRM1\u003c/em\u003e rearrangements with various partners,(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) may be quite helpful in substantiating the diagnosis of CMF.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eOCM must also be distinguished from chondroblastic osteosarcoma and chondrosarcoma. Chondroblastic osteosarcomas typically have much more aggressive imaging features than OCM, are composed of overtly malignant spindled to epithelioid cells, and contain areas of immature and \u0026ldquo;lace-like\u0026rdquo; osteoid. Additionally, the chondroblastic component is usually much more cellular and atypical compared with OCM. Chondrosarcoma is exceptionally rare in the pediatric age group, usually presents less heterogeneously on imaging, and displays permeative growth into surround host bone, not seen in OCM. Neither chondroblastic osteosarcoma nor chondrosarcoma would be expected to demonstrate loss of PRKAR1A expression.\u003c/p\u003e\u003cp\u003eIn summary, we have reported 6 new cases of OCM, an exceptionally rare, Carney complex-associated, benign neoplasm with an apparent predilection for the sinonasal tract. Given the differences in syndromic association and clinical behavior, OCM should be distinguished from NCHM and other matrix-forming tumors of the sinonasal region. Loss of PRKAR1A expression by immunohistochemistry is a valuable tool for confirming an OCM diagnosis and should prompt clinical investigation for the possibility of Carney complex.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclarations and Compliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eThis study was partially funded by the Jane B. and Edwin P. Jenevein M.D Endowment for Pathology at UT Southwestern Medical Center. No external funding was obtained for this study.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConflicts of interest/Competing interests\u003c/em\u003e: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and material\u003c/em\u003e: All data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCode availability\u003c/em\u003e: Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026rsquo; contributions:\u003c/em\u003e ALF and JAB designed the study, performed data collection and interpretation, and prepared the manuscript. All authors read and approved the final paper.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics approval:\u003c/em\u003e All procedures performed in this retrospective data analysis involving human participants were in accordance with the ethical standards of the institutional review board (UT Southwestern IRB 112017-073).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent to participate/publication\u003c/em\u003e: The IRB-approved study did not require informed consent.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eThompson LDR, Fanburg-Smith JC. Update on Select Benign Mesenchymal and Meningothelial Sinonasal Tract Lesions. \u003cem\u003eHead Neck Pathol. \u003c/em\u003e2016;10(1):95-108.\u003c/li\u003e\n\u003cli\u003eCarney JA, Boccon-Gibod L, Jarka DE, et al. 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Large cell calcifying Sertoli cell tumour: molecular and immunohistochemical assessment of a series comprising non-metastasising and metastasising neoplasms. \u003cem\u003eHistopathology. \u003c/em\u003e2023;82(7):1079-1088.\u003c/li\u003e\n\u003cli\u003eNeumann NM, LeBoit PE, Cohen JN. Superficial Angiomyxomas Frequently Demonstrate Loss of Protein Kinase A Regulatory Subunit 1 Alpha Expression: Immunohistochemical Analysis of 29 Cases and Cutaneous Myxoid Neoplasms With Histopathologic Overlap. \u003cem\u003eAm J Surg Pathol. \u003c/em\u003e2022;46(2):226-232.\u003c/li\u003e\n\u003cli\u003eSchultz KA, Yang J, Doros L, et al. DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions. \u003cem\u003ePathol Case Rev. \u003c/em\u003e2014;19(2):90-100.\u003c/li\u003e\n\u003cli\u003ePriest JR, Williams GM, Mize WA, et al. Nasal chondromesenchymal hamartoma in children with pleuropulmonary blastoma--A report from the International Pleuropulmonary Blastoma Registry registry. \u003cem\u003eInt J Pediatr Otorhinolaryngol. \u003c/em\u003e2010;74(11):1240-1244.\u003c/li\u003e\n\u003cli\u003eDe La Pena NM, Yekzaman BR, Patra DP, et al. Craniofacial Chondromyxoid Fibromas: A Systematic Review and Analysis Based on Anatomic Locations. \u003cem\u003eWorld Neurosurg. \u003c/em\u003e2022;162(21-28.\u003c/li\u003e\n\u003cli\u003eMeredith DM, Fletcher CDM, Jo VY. Chondromyxoid Fibroma Arising in Craniofacial Sites: A Clinicopathologic Analysis of 25 Cases. \u003cem\u003eAm J Surg Pathol. \u003c/em\u003e2018;42(3):392-400.\u003c/li\u003e\n\u003cli\u003eNord KH, Lilljebjorn H, Vezzi F, et al. GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma. \u003cem\u003eNat Genet. \u003c/em\u003e2014;46(5):474-477.\u003c/li\u003e\n\u003cli\u003eToland AMS, Lam SW, Varma S, et al. GRM1 Immunohistochemistry Distinguishes Chondromyxoid Fibroma From its Histologic Mimics. \u003cem\u003eAm J Surg Pathol. \u003c/em\u003e2022;46(10):1407-1414.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"head-and-neck-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Head and Neck Pathology](https://www.springer.com/journal/12105)","snPcode":"12105","submissionUrl":"https://submission.springernature.com/new-submission/12105/3","title":"Head and Neck Pathology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Osteochondromyxoma, PRKAR1A, Carney complex, nasal chondromesenchymal hamartoma","lastPublishedDoi":"10.21203/rs.3.rs-7594659/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7594659/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMatrix-producing tumors of the sinonasal region are diagnostically challenging, with a large number of similar-appearing neoplasms having different prognoses, treatment strategies, and genetic syndrome associations. Osteochondromyxoma (OCM) is a very rare tumor known to be associated with Carney complex. Since its initial description in 2001, fewer than 20 cases have been reported, with the sinonasal tract being an apparently favored site. Herein we describe 6 new cases of sinonasal OCM.\u003c/p\u003e\u003cp\u003eOCM cases with available slides were retrieved from the surgical pathology files of the authors\u0026rsquo; practices. The tumors arose in 4 boys and 2 girls, ranging from 4 to 17 years (mean, 9.5 years). All presented with nasal obstruction and a mass. Radiologically the tumors presented as indolent-appearing, heterogeneous, calcified, expansile masses. Histologically the tumors all consisted of bland, normochromatic spindled to stellate cells in a myxoid to collagenized stroma, with variable amounts of cartilage and bone formation. Mitotic activity was very low and necrosis was absent. All demonstrated complete loss of PRKAR1A expression by immunohistochemistry. Of these 6 cases, 3 had been originally diagnosed as nasal chondromesenchymal hamartomas, and one as osteosarcoma. Treatment and follow up information were available for 5 patients: all were treated with surgery, with one also receiving chemotherapy after an initial osteosarcoma diagnosis. At the time of last clinical follow-up, all 5 patients were alive, one with residual disease. No patient was known to have other stigmata of Carney complex.\u003c/p\u003e\u003cp\u003eAlthough rare, OCM preferentially occurs in the sinonasal tract, and therefore may be encountered by head and neck pathologists. Given their predilection for young patients and overlapping morphologic features, OCM are easily misdiagnosed as other matrix-forming sinonasal tumors, especially nasal chondromesenchymal hamartoma. Immunohistochemical demonstration of PRKAR1A loss is valuable for confirming an OCM diagnosis, which should prompt clinical investigation for the possibility of Carney complex.\u003c/p\u003e","manuscriptTitle":"Sinonasal Tract Osteochondromyxoma: An Underrecognized Tumor Easily Mistaken for Nasal Chondromesenchymal Hamartoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-25 15:43:40","doi":"10.21203/rs.3.rs-7594659/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-21T21:35:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-21T21:30:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-18T15:57:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"256121807200098577687867257546498563431","date":"2025-09-17T14:31:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294138575988792251696992117109560916375","date":"2025-09-17T11:20:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-17T00:16:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-16T20:52:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-16T13:14:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Head and Neck Pathology","date":"2025-09-11T19:50:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"head-and-neck-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Head and Neck Pathology](https://www.springer.com/journal/12105)","snPcode":"12105","submissionUrl":"https://submission.springernature.com/new-submission/12105/3","title":"Head and Neck Pathology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"62914ecd-de4e-4f77-a4da-f2835c5252cf","owner":[],"postedDate":"September 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-25T15:43:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-25 15:43:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7594659","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7594659","identity":"rs-7594659","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}