Angiomatoid fibrous histiocytoma of the adrenal gland: A clinical and pathological observation of two cases

Angiomatoid fibrous histiocytoma of the adrenal gland: A clinical and pathological observation of two cases | 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 Angiomatoid fibrous histiocytoma of the adrenal gland: A clinical and pathological observation of two cases Li Yang, Li Xiao, Jiandi Li, Kanglai Wei, Lin Shi, Jun Chen, Gang Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6253095/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Nov, 2025 Read the published version in World Journal of Surgical Oncology → Version 1 posted 11 You are reading this latest preprint version Abstract Background Angiomatoid fibrous histiocytoma (AFH) is a rare low-grade neoplasm, typically arising in pediatric/adolescent extremity subcutaneous tissues. Adrenal AFH is extremely uncommon, with limited reported cases. Elucidating clinicopathologic/molecular profiles of adrenal AFH is critical for accurate diagnosis and management. Case presentation Two adrenal AFH cases (18-year-old male, 50-year-old female) from Guangxi Medical University Second Hospital were retrospectively analyzed, focusing on clinical features, histopathology, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and follow-up. Case 1: Classic AFH morphology with unique features: diffuse intratumoral lymphoid tissue (with follicles) instead of capsular lymphoid cuffs, and lymphangioma-like cystic spaces (lacking angiomatoid hemorrhage).Case 2: Cystic tumor misdiagnosed as "adrenal pseudocyst"; true parenchyma resided in the cyst wall, with nodular lymphoid aggregates (no lymphoid cuff) and erythrocyte/hemosiderin-filled vascular clefts. Marked hyaline fibrosis was noted.Molecular: Both cases showed EWSR1 break-apart (FISH+), negative for EWSR1::CREB1/ATF1 fusions. IHC revealed desmin positivity (both), ALK-D5F3 expression (Case 2). Conclusions Atypical-location AFH (e.g., adrenal) exhibits divergent pathologic phenotypes. Diagnosis requires integrated IHC/molecular analysis (e.g., EWSR1 status). Prognostic implications of genetic alterations (e.g., ALK expression) highlight the need for molecular profiling to guide therapy and prognosis. angiomatoid fibrous histiocytoma (AFH) adrenal gland Figures Figure 1 Figure 2 Background Angiomatoid fibrous histiocytoma (AFH) was first described by Enzinger [ 1 ] in 1979 and represents an uncommon intermediate-grade soft tissue neoplasm, accounting for approximately 0.3% of all soft tissue tumors [ 2 ]. It exhibits low to intermediate malignant potential. Although AFH has a local recurrence rate of up to 12%, its metastatic rate is less than 1%, with distant lymph node metastasis being extremely rare and an overall low mortality rate [ 3 ]. The tumor predominantly arises in the subcutaneous soft tissues of the extremities, with the trunk and head and neck regions being secondary sites [ 4 ]. In contrast, adrenal involvement is exceptionally rare, with no cases found in the domestic literature and only a single case documented internationally [ 5 ].Given its rarity and unique clinical presentation, investigating the clinicopathological and molecular characteristics of adrenal AFH is of significant importance.Herein, we report two cases of adrenal AFH from the Second Affiliated Hospital of Guangxi Medical University. In conjunction with a review of the literature, we analyze the clinicopathological features, immunohistochemical profiles, and molecular genetic findings of these tumors. This study aims to enhance the understanding of this uncommon tumour and inform diagnostic and therapeutic approaches. Case report Case 1 An 18-year-old male presented with recurrent abdominal pain and vomiting persisting for over 2 weeks. Contrast-enhanced computed tomography (CT) revealed a hypodense mass in the right adrenal region, measuring approximately 5.7 cm × 5.1 cm × 4.5 cm(Figure 1A), The mass showed distinct margins and enhanced visibility of the solid component upon contrast scanning. The imaging differential diagnosis included pheochromocytoma and ganglioneuroma. Postoperative whole-body positron emission tomography-computed tomography (PET-CT) imaging showed no evidence of tumour. Gross examination: The tumor measured 7 cm × 5.1 cm × 3.7 cm, was encapsulated, and had a smooth surface. The cut surface appeared grayish-white, of intermediate consistency, and solid, with irregular cystic spaces present. A small amount of adrenal tissue was identified around the tumor (Figure 1B). Microscopic examination: The tumor was characterized by a thick fibrous capsule, well-demarcated from the surrounding adrenal tissue in most areas, with focal involvement of the adrenal gland (Figure 1C). Beneath the fibrous capsule, there was extensive lymphocytic and plasma cell proliferation, with the formation of lymphoid follicles creating a 'lymphoid cuff' structure. Significant fibroproliferation was observed, with fibrous tissue extending into the tumor parenchyma and forming a multinodular architecture by encircling and separating the tumor cells. The tumor exhibited a mixed cystic and solid pattern, with tumor cells arranged in nodular or sheet-like formations predominantly surrounding areas of cystic degeneration. The tumor cells had a histiocytoid appearance, with round or oval nuclei, small nucleoli, and occasional nuclear grooves. The cytoplasm was lightly eosinophilic, with indistinct borders, and no mitotic figures were identified. Notably, within the cystic spaces of the tumor, most were empty or contained a small amount of eosinophilic fluid, with only a few containing a small number of red blood cells. Importantly, none of the cystic spaces were lined by epithelial or endothelial cells. Immunophenotyping demonstrated dendritic positivity for desmin (Figure 1D), in addition to the expression of EMA, CD99, and SMA. Immunostaining was negative for CD68, ALK, CD31, CD34, CD21, and CD35. The Ki-67 proliferation index was 5%. Fluorescence in situ hybridization (FISH) demonstrated positivity for the EWSR1 break-apart probe (Figure 1E), whereas probes for EWSR1::CREB1 and EWSR1::ATF1 gene fusions were negative. Case 2 A 50-year-old female presented without significant clinical symptoms but was found to have a right adrenal mass on examination. She visited a local hospital after detecting the mass 6 days prior. CT at the local hospital revealed an irregular soft tissue density mass in the right adrenal region, with heterogeneous internal density, and a maximum size of approximately 6.4 cm × 7.5 cm × 7.6 cm. Contrast-enhanced scanning showed heterogeneous enhancement of the mass, with a lobulated appearance. The boundary between the lesion and the diaphragm was indistinct, and the adjacent right diaphragm was slightly thickened. The surrounding fat planes were blurred, with patchy areas of infiltration, and enlarged lymph nodes were visible around the mass (Figure 2A). The imaging findings indicated a malignant adrenal tumor with right diaphragm invasion and metastasis to adjacent lymph nodes. The patient underwent right adrenal tumor resection and partial right adrenalectomy. The postoperative pathological diagnosis was “adrenal pseudocyst.” Over a year postoperatively, the patient experienced recurrent fever for half a year and presented to our hospital. CT at our institution revealed a mass-like area of abnormal density in the right adrenal region, measuring approximately 3.2 cm × 2.4 cm × 3.0 cm. Contrast-enhanced scanning showed heterogeneous mild enhancement, with unclear boundaries. The lesion was indistinguishable from the adjacent right kidney, inferior vena cava, and right diaphragm (Figure 2B). Imaging diagnosis considered: postoperative recurrence of the tumor with possible metastasis to the para-aortic lymph nodes and left iliac bone. Involvement of the right kidney, inferior vena cava, right diaphragm, right peritoneum, liver, left iliac vessels, gluteus maximus, and quadratus femoris muscles could not be excluded. Metastasis to the intermuscular lymph nodes remained to be ruled out. Consequently, a consultation of the patient's original pathology slides was conducted, and a biopsy of the left iliac bone was performed. The corrected pathological diagnosis was angiomatoid fibrous histiocytoma (AFH) of the adrenal gland with metastasis to the iliac bone. Gross examination: The tumor measured 9.5 cm × 6 cm × 5 cm. The surface was partially encapsulated. The cut surface appeared grayish-brown, with a cystic and solid appearance, and showed evidence of hemorrhage and necrosis. Microscopic examination: The tumor exhibited a cystic architecture with a thick fibrous cyst wall. The cyst wall exhibited extensive lymphocyte and plasma cell proliferation, with occasional lymphoid follicle formation. Vascular cleft-like structures were present within the cyst wall, containing numerous red blood cells and hemosiderin deposits, none of which were lined by epithelial or endothelial cells (Figure 2C). Tumor cells were arranged in small clusters or nests, with some areas extending beyond the fibrous cyst wall. The tumor cells had a histiocytoid appearance with visible mitotic figures (approximately 3/10high-power fields [HPF]). Significant interstitial fibrosis with hyaline degeneration was also observed. In the iliac bone metastasis, the tumor cells exhibited a histiocytoid morphology with minimal cytologic atypia (Figure 2D). Immunophenotyping analysis revealed dendritic positivity for desmin (Figure 2E), with expression of ALK-D5F3 (Figure 2F), epithelial membrane antigen (EMA), and CD99. The tumour was negative for CD68, S-100, CD31, CD34, CD21, and CD35. The Ki-67 proliferation index was 10%. FISH demonstrated positivity for the EWSR1 break-apart probe, whereas probes for EWSR1::CREB1 and EWSR1::ATF1 gene fusions were negative. Discussion Clinical Features AFH predominantly affects children and adolescents, with a mean age of approximately 20 years. The two cases reported herein include an 18-year-old patient (Case 1), which aligns with the previously reported age distribution, and a 50-year-old patient (Case 2), suggesting that adrenal AFH may have a broader age range and is not exclusive to children and adolescents. AFH typically occurs in superficial locations of the extremities; however, both cases in this report originated in the adrenal glands, an exceedingly rare site for this tumor. To date, no similar cases have been reported domestically, with only one case documented internationally [5]. Clinically, Case 1 presented with recurrent abdominal pain and vomiting, while Case 2 was largely asymptomatic initially, later developing unexplained recurrent fever following tumor recurrence, which is consistent with the clinical manifestations of adrenal AFH reported in the literature [5]. In terms of biological behavior, AFH is generally considered to have low malignant potential or intermediate characteristics. Due to the uncertain differentiation of tumor cells, the WHO classification groups AFH under the category of “tumors of uncertain differentiation” [6]. The clinical behavior of the two cases in this study varied significantly: Case 1 exhibited benign features with no recurrence postoperatively, whereas Case 2 demonstrated aggressive behavior, with local invasion into surrounding soft tissues and metastasis to bone, a manifestation that is highly unusual for AFH. Pathological Characteristics Gross Features AFH typically presents as well-circumscribed tumours with diameters ranging from 0.7 to 12 cm. Upon sectioning, they appear greyish-brown with a firm texture and exhibit irregular haemorrhagic cystic spaces. The two cases reported herein had relatively large tumours, with diameters of 7 cm and 9 cm, respectively. Case 1 exhibited a cystic-solid appearance with inconspicuous intra-cystic haemorrhage, whereas Case 2 presented as a cystic tumour accompanied by prominent haemorrhage. Morphological Features Classical AFH displays the following three characteristic pathological morphologies:(1) The tumor periphery is encircled by a substantial infiltrate of lymphocytes and plasma cells, often forming a "lymphatic cuff" that fuses with a fibrous pseudocapsule; (2) The central neoplastic parenchyma comprises nodular, irregularly sheet-like, and nest-like spindle-to-oval histiocyte-like cells. The nuclei exhibit a round or oval morphology, with small nucleoli and prominent nuclear grooves. (3) The tumor contains multifocal hemorrhagic cystic spaces devoid of endothelial lining. Case 1 in this study exhibits morphological concordance with classical AFH, yet it possesses unique features that differentiate it. Notably, the lymphatic tissue is not confined to the periphery of the capsule but is diffusely distributed within the tumour parenchyma, accompanied by the formation of numerous lymph follicles. In the literature, the presence of a "lymphatic cuff" is considered a significant diagnostic clue for solid-variant AFH, observed in approximately 80% of cases [7]. However, Case 1 lacks a prominent "lymphatic cuff" structure. Although cystic spaces are formed within the tumor, intra-cystic hemorrhage is inconspicuous, lacking the typical "angiogenic" features and resembling more of a "lymphangioma-like" appearance. Case 2 presents as a cystic tumor with a relatively thick fibrous capsule, initially misdiagnosed as an "adrenal pseudocyst" by the original institution. In reality, the capsule wall represents the true tumor parenchyma. In this case, the lymphatic tissue does not form a "lymphatic cuff"-like structure but is instead scattered in nodular fashion, with only a few lymph follicles visible. Cyst formation is not prominent, manifesting more as vascular lumen-like fissures containing abundant red blood cells and hemosiderin. Marked interstitial fibrosis with hyalinization is also noted, inconsistent with the mucinous features commonly reported in intracranial AFH in the literature [8]. The two cases reported herein do not fully conform morphologically to classical AFH, solid-variant AFH, or AFH located in other special sites, thereby providing additional morphological characteristics for AFH. Of particular note is Case 2, where the tumor cells showed minimal atypia and only a few mitotic figures both at the time of surgery and upon recurrence. Nevertheless, the tumor demonstrated malignant behavior with surrounding tissue infiltration and metastasis. Therefore, it is speculated that the biological behavior of AFH occurring in the adrenal gland is not directly related to cellular atypia and mitotic figures but may be more associated with specific genetic alterations. Immunophenotypic Characteristics The tumor cells in both patients expressed EMA, CD99, and Desmin, with Desmin demonstrating a dendritic positivity. The tumor cells in Case 2 expressed ALK-D5F3, while both cases were negative for CD34, CD21, and CD35. The negativity for CD34 suggests the absence of endothelial cell lining within the vascular lacunae of the tumor. Approximately 90% of cases express the ALK protein [9], however, current studies indicate that cases expressing ALK protein do not have amplification or mutation of the ALK gene, and the mechanism of ALK expression remains unclear. Molecular Pathological Features Studies have demonstrated that over 80%–90% of angiomatoid fibrous histiocytoma (AFH) cases harbor the EWSR1::CREB1 fusion gene, with a minority of cases also showing EWSR1::ATF1 or FUS::ATF1 fusion genes [10-][11]. In the present study, fluorescence in situ hybridization (FISH) analysis revealed EWSR1 gene rearrangement in both cases, yet further testing for EWSR1::CREB1 and EWSR1::ATF1 fusions was negative. Similar findings have been reported in a subset of AFH cases, where only EWSR1 gene rearrangement was detected without the common fusion partners CREB1 or ATF1[9].Similar observations have also been reported in pediatric AFH cases [12].Unfortunately, due to financial constraints, next-generation sequencing (NGS) could not be performed to identify additional fusion genes, which represents a significant limitation, especially in Case 2. We hypothesize that the observed aggressive biological behavior in this case could be linked to an EWSR1-related fusion gene alteration. Differential Diagnosis Hematoma and Hemangioma：The majority of AFH tumors are often accompanied by the formation of irregular cystic cavities, which can easily be confused with hematoma or hemangioma. Case 2 in this study was initially misdiagnosed as a pseudocyst due to its cystic tumor wall with sparse tumor cells and no lining cells. However, AFH is negative for endothelial cell markers (such as CD31, CD34, etc.), indicating that the cells within the cyst wall are not endothelial cells, and the irregular hemorrhagic clefts are not true vascular lumens. This distinction can be made to differentiate AFH from hematoma or hemangioma [13]. Lymph Node Metastasis of Tumor: AFH is surrounded by a fibrous pseudocapsule with a large number of lymphocytes subcapsularly and may form germinal centers, which can lead to misdiagnosis as lymph node metastasis of a tumor. However, AFH lacks lymphatic sinus structures, and the germinal centers do not distribute subcapsularly. These features are helpful in differentiation. Aneurysmal Fibrous Histiocytoma (AFH-like in name but distinct pathologically): While the name is somewhat similar to AFH, aneurysmal fibrous histiocytoma belongs to an entirely different pathology. The former is located in the dermis, lacks a pseudocapsule, and is characterized by the presence of abundant cleft-like or blood sinus-like capillaries within the tumor. The solid areas surrounding the blood vessels exhibit the classic morphology of fibrous histiocytoma, and the stroma commonly contains abundant hemosiderin deposition and aggregations of hemosiderin-laden macrophages. Treatment and Prognosis The primary treatment for angiomatoid fibrous histiocytoma (AFH) is wide surgical excision, with negative margins being crucial. The local recurrence rate after complete resection ranges from 2% to 10%. Costa et al. reported that irregular tumor borders and head and neck locations are associated with local recurrence, while tumor depth is correlated with subsequent local and distant metastasis. However, the associations between mitotic activity, nuclear pleomorphism, inflammatory response, tumor size, patient age, and adjuvant therapy with clinical behavior remain unclear [14]. To date, no reports have demonstrated a correlation between genetic factors or immunohistochemical profiles and clinical behavior. Therefore, for surgical treatment of AFH, ensuring wide excision and negative margins is essential. Radiotherapy or chemotherapy is typically considered for large tumors, those with distant metastasis, or those located near major vessels [15], and long-term close follow-up is required. In this study, Case 2 developed metastasis to the iliac bone and underwent AI chemotherapy, which showed suboptimal efficacy. Recent studies have shown that the ALK inhibitor crizotinib can provide a cure or remission in recurrent AFH cases with ALK protein expression [16], suggesting that targeted therapy may represent a future direction for treatment. Conclusion In conclusion, pathologists should enhance their ability to recognise the morphology of angiomatoid fibrous histiocytoma (AFH), particularly when it occurs in rare locations, as these tumours may exhibit unique histological features. The key morphological characteristics of adrenal AFH include nests of histiocytoid cells, widespread proliferation of lymphoid tissue with lymphoid follicle formation, various cleft-like structures, and marked interstitial fibrosis. These features are highly suggestive of the diagnosis. Definitive diagnosis requires integration of immunophenotypic analysis and molecular testing, as studies have shown that the prognosis of the tumour is closely related to genetic alterations. In-depth investigation into the molecular biology of AFH not only optimises diagnostic protocols and therapeutic strategies but also provides a reliable basis for prognostic assessment. Overall, the case reports presented herein further expand the spectrum of adrenal tumours and offer new insights into the diagnosis and study of AFH in rare locations. Declarations Acknowledgements Not applicable. Author contributions Yang Li and Xiao Li contributed equally to this work. Yang Li: Responsible for the conception and design of the case report, collection and analysis of patient data. Xiao Li: Involved in the collection and interpretation of patient data, and drafting of the manuscript. Li Jiandi: Contributed to the collection of relevant case materials and literature review. Wei Kanglai: Participated in the literature review and modification of the manuscript. Shi Lin: Provided professional advice and assistance in the diagnosis and treatment process of the patient. Chen Gang and Chen Jun: As corresponding authors, they supervised the entire study, provided critical feedback on the manuscript, and approved the final version for submission. All authors have read and approved the final manuscript. Funding This research received no external funding. Data availability No datasets were generated or analysed during the current study Ethics approval and consent to participate At our institution, Institutional Review Board approval is not required for case reports. Written informed consent was obtained from the patient to publish this paper. Consent for publication Written informed consent was obtained from the patient to publish this paper. Competing interests The authors declare no competing interests. References Enzinger FM. Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm. Cancer. 1979;44(6):2147–57. WHO Classification of Tumours Editorial. Board.WHO classification of tumours editorial board [M]. 5th ed. Lyon: IARC; 2020. Wilk M, Zelger BG, Debiec-Rychter M, Sciot R, Zelger B. Angiomatoid fibrous histiocytoma - case series with emphasis on a late fibrotic variant. J Dtsch Dermatol Ges. 2015;13(5):441–8. Zhang Z. Angiomatoid fibrous histiocytoma in the right elbow: A case report. Asian J Surg. 2024;47(1):588–9. Khan IS, Kuick CH, Jain S, et al. Primary Adrenal Angiomatoid Fibrous Histiocytoma With Novel EWSR1-ATF1 Gene Fusion Exon-Exon Breakpoint. Pediatr Dev Pathol. 2019;22(5):472–4. Saito K, Kobayashi E, Yoshida A, et al. Angiomatoid fibrous histiocytoma: a series of seven cases including genetically confirmed aggressive cases and a literature review. BMC Musculoskelet Disord. 2017;18(1):31. Thway K, Fisher C. Angiomatoid fibrous histiocytoma: the current status of pathology and genetics. Arch Pathol Lab Med. 2015;139(5):674–82. Ballester LY, Meis JM, Lazar AJ, et al. Intracranial Myxoid Mesenchymal Tumor With EWSR1-ATF1 Fusion. J Neuropathol Exp Neurol. 2020;79(3):347–51. Cheah AL, Zou Y, Lanigan C, et al. ALK Expression in Angiomatoid Fibrous Histiocytoma: A Potential Diagnostic Pitfall. Am J Surg Pathol. 2019;43(1):93–101. Berklite L, John I, Ranganathan S, et al. SOX9 Immunohistochemistry in the Distinction of Angiomatoid Fibrous Histiocytoma From Histologic Mimics: Diagnostic Utility and Pitfalls. Appl Immunohistochem Mol Morphol. 2020;28(8):635–40. Schaefer IM, Fletcher CD. Myxoid variant of so-called angiomatoid malignant fibrous histiocytoma: clinicopathologic characterization in a series of 21 cases. Am J Surg Pathol. 2014;38(6):816–23. Feng X, Tao J, Wang Y, Long AY, He LJ, Zhang N. [Clinicopathological and molecular characteristics of angiomatoid fibrous histiocytoma in children]. Zhonghua Bing Li Xue Za Zhi. 2024;53(5):483–5. Chinese. Pasricha S, Durga G, Sharma A, et al. Angiomatoid fibrous histiocytoma: Report of two cases, initially construed as sarcoma with unusual clinico-pathological features. Indian J Pathol Microbiol. 2022;65(4):921–4. Saito K, Kobayashi E, Yoshida A, et al. Angiomatoid fibrous histiocytoma: a series of seven cases including genetically confirmed aggressive cases and a literature review. BMC Musculoskelet Disord. 2017;18(1):31. Yu DP, Xu ZX, Wu J. Intracranial angiomatoid fibrous histiocytoma: A case report. Asian J Surg. 2023;46(11):5086–7. Ngo C, Grinda T, Boilève A, et al. Durable response to crizotinib in metastatic angiomatoid fibrous histiocytoma with EWSR1-CREB1 fusion and ALK overexpression. Ann Oncol. 2022;33(8):848–50. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Nov, 2025 Read the published version in World Journal of Surgical Oncology → Version 1 posted Editorial decision: Revision requested 08 Jul, 2025 Reviews received at journal 07 Jul, 2025 Reviewers agreed at journal 30 Jun, 2025 Reviews received at journal 05 Apr, 2025 Reviewers agreed at journal 03 Apr, 2025 Reviewers agreed at journal 26 Mar, 2025 Reviewers agreed at journal 25 Mar, 2025 Reviewers invited by journal 24 Mar, 2025 Editor assigned by journal 23 Mar, 2025 Submission checks completed at journal 19 Mar, 2025 First submitted to journal 18 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6253095","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":435754657,"identity":"8c021001-cd97-4d13-9092-de5abe5222b5","order_by":0,"name":"Li Yang","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Yang","suffix":""},{"id":435754658,"identity":"3e5c837e-c801-428b-95a6-d7e5516f8dc1","order_by":1,"name":"Li Xiao","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Xiao","suffix":""},{"id":435754659,"identity":"5dbd6d7b-c82e-476f-94b9-94213bcd4b2a","order_by":2,"name":"Jiandi Li","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiandi","middleName":"","lastName":"Li","suffix":""},{"id":435754660,"identity":"ff97d5c3-a513-42d4-8f1e-504f7afd2841","order_by":3,"name":"Kanglai Wei","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kanglai","middleName":"","lastName":"Wei","suffix":""},{"id":435754661,"identity":"2fa47ace-946f-43dc-810a-8277ccda2600","order_by":4,"name":"Lin Shi","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Shi","suffix":""},{"id":435754662,"identity":"47a2d4d7-2216-49ad-8aec-4d80a27c39f9","order_by":5,"name":"Jun Chen","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Chen","suffix":""},{"id":435754663,"identity":"00b02e6a-394f-4c8a-8b38-cca18baae2a7","order_by":6,"name":"Gang Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYDACCSjND6UZG4jWItlAshaDA8Rq4Z/dfOzhl5o7dpvPrzHdzMNgI7vhAPOzB3gtuXMs3Vjm2LPkbTeepd3mYUgz3nCAzdwAnxYDiRwzaQm2w8lmNw4fA2o5nLjhAA+bBH4t+d+kJf4dTjaecbANqOU/MVpy2CQ/th22M+BvBtlygLAWiRtpZtKMfYcTJG6wpd2cY5BsPPMwmxleLfwzkp9J/vh22J6//4zZjTcVdrJ9x5uf4dUCAsw8DAyJDRIJIHeCuITUAwHjDwYGewb+A0QoHQWjYBSMghEJAAJhTWVgRz0UAAAAAElFTkSuQmCC","orcid":"","institution":"The First Affiliated Hospital of Guangxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Gang","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2025-03-18 12:23:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6253095/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6253095/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12957-025-03971-3","type":"published","date":"2025-11-26T15:58:48+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79757438,"identity":"1e20b268-aec7-4f56-9e89-6ae2a9d8efd7","added_by":"auto","created_at":"2025-04-02 10:39:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":84811,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(1A) \u003c/strong\u003eCT revealed a hypodense mass in the right adrenal region, with clear margins and measuring approximately 5.7 cm × 5.1 cm × 4.5 cm (red arrow). Contrast-enhanced scanning showed enhancement of the solid portion. (\u003cstrong\u003e1B\u003c/strong\u003e) Gross examination showed the tumour with well-defined margins and a greyish-white, solid cut surface. Irregular cystic spaces were present, and scattered adrenal tissue was visible around the tumour (red arrow). (\u003cstrong\u003e1C\u003c/strong\u003e) Microscopically, the tumour was encapsulated by fibrous tissue with focal involvement of the adrenal gland (red arrow). Tumour cells were arranged in nodular patterns with a histiocytoid appearance. Central cystic spaces or clefts were present without lining by epithelial or endothelial cells. Lymphoid tissue beneath the capsule formed a “lymphoid cuff” structure. (\u003cstrong\u003e1D\u003c/strong\u003e) mmunohistochemical analysis revealed dendritic positivity for desmin.1E: FISH demonstrated positivity for the EWSR1 break-apart probe.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253095/v1/204add98df818a3fc3a619cc.jpg"},{"id":79758490,"identity":"39756e56-9530-4a1b-b356-3aa959f922d8","added_by":"auto","created_at":"2025-04-02 10:47:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":60934,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(2A) \u003c/strong\u003eCT at the local hospital revealed an irregular soft tissue density mass in the right adrenal region, with heterogeneous internal density and a maximum size of approximately 6.4 cm × 7.5 cm × 7.6 cm (red arrow). (\u003cstrong\u003e2B\u003c/strong\u003e) CT plain scan and contrast-enhanced imaging at our institution revealed a mass-like area of abnormal density in the right adrenal region, measuring approximately 3.2 cm × 2.4 cm × 3.0 cm (red arrow). (\u003cstrong\u003e2C\u003c/strong\u003e) The tumor is cystic with a thick fibrous cyst wall. The inner cyst wall is infiltrated by numerous lymphocytes and plasma cells. Focal areas demonstrate a vascular cleft-like appearance containing large numbers of red blood cells and hemosiderin deposits. Focal clusters of histiocytoid cells are present (red arrow). (\u003cstrong\u003e2D\u003c/strong\u003e) Metastatic tumor focus in the iliac bone.2E: Dendritic positivity for desmin.2F: Positivity for ALK-D5F3.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253095/v1/dfe663d0790457ad10fc8ef1.jpg"},{"id":97178647,"identity":"2bb73f19-7d41-447b-be33-fc96b05e44a2","added_by":"auto","created_at":"2025-12-01 16:12:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":626443,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6253095/v1/aa9c2489-741c-44d7-8f43-d0a39c418551.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Angiomatoid fibrous histiocytoma of the adrenal gland: A clinical and pathological observation of two cases","fulltext":[{"header":"Background","content":"\u003cp\u003eAngiomatoid fibrous histiocytoma (AFH) was first described by Enzinger [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] in 1979 and represents an uncommon intermediate-grade soft tissue neoplasm, accounting for approximately 0.3% of all soft tissue tumors [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. It exhibits low to intermediate malignant potential. Although AFH has a local recurrence rate of up to 12%, its metastatic rate is less than 1%, with distant lymph node metastasis being extremely rare and an overall low mortality rate [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The tumor predominantly arises in the subcutaneous soft tissues of the extremities, with the trunk and head and neck regions being secondary sites [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In contrast, adrenal involvement is exceptionally rare, with no cases found in the domestic literature and only a single case documented internationally [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].Given its rarity and unique clinical presentation, investigating the clinicopathological and molecular characteristics of adrenal AFH is of significant importance.Herein, we report two cases of adrenal AFH from the Second Affiliated Hospital of Guangxi Medical University. In conjunction with a review of the literature, we analyze the clinicopathological features, immunohistochemical profiles, and molecular genetic findings of these tumors. This study aims to enhance the understanding of this uncommon tumour and inform diagnostic and therapeutic approaches.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn 18-year-old male presented with recurrent abdominal pain and vomiting persisting for over 2 weeks. Contrast-enhanced computed tomography (CT) revealed a hypodense mass in the right adrenal region, measuring approximately 5.7 cm \u0026times; 5.1 cm \u0026times; 4.5 cm(Figure 1A),\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mass showed distinct margins and enhanced visibility of the solid component upon contrast scanning. The imaging differential diagnosis included pheochromocytoma and ganglioneuroma. Postoperative whole-body positron emission tomography-computed tomography (PET-CT) imaging showed no evidence of tumour.\u003c/p\u003e\n\u003cp\u003eGross examination: The tumor measured 7 cm \u0026times; 5.1 cm \u0026times; 3.7 cm, was encapsulated, and had a smooth surface. The cut surface appeared grayish-white, of intermediate consistency, and solid, with irregular cystic spaces present. A small amount of adrenal tissue was identified around the tumor (Figure 1B).\u003c/p\u003e\n\u003cp\u003eMicroscopic examination: The tumor was characterized by a thick fibrous capsule, well-demarcated from the surrounding adrenal tissue in most areas, with focal involvement of the adrenal gland (Figure 1C). Beneath the fibrous capsule, there was extensive lymphocytic and plasma cell proliferation, with the formation of lymphoid follicles creating a \u0026apos;lymphoid cuff\u0026apos; structure. Significant fibroproliferation was observed, with fibrous tissue extending into the tumor parenchyma and forming a multinodular architecture by encircling and separating the tumor cells. The tumor exhibited a mixed cystic and solid pattern, with tumor cells arranged in nodular or sheet-like formations predominantly surrounding areas of cystic degeneration. The tumor cells had a histiocytoid appearance, with round or oval nuclei, small nucleoli, and occasional nuclear grooves. The cytoplasm was lightly eosinophilic, with indistinct borders, and no mitotic figures were identified. Notably, within the cystic spaces of the tumor, most were empty or contained a small amount of eosinophilic fluid, with only a few containing a small number of red blood cells. Importantly, none of the cystic spaces were lined by epithelial or endothelial cells.\u003c/p\u003e\n\u003cp\u003eImmunophenotyping demonstrated dendritic positivity for desmin (Figure 1D), in addition to the expression of EMA, CD99, and SMA. Immunostaining was negative for CD68, ALK, CD31, CD34, CD21, and CD35. The Ki-67 proliferation index was 5%.\u003c/p\u003e\n\u003cp\u003eFluorescence in situ hybridization (FISH) demonstrated positivity for the EWSR1 break-apart probe (Figure 1E), whereas probes for EWSR1::CREB1 and EWSR1::ATF1 gene fusions were negative.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 50-year-old female presented without significant clinical symptoms but was found to have a right adrenal mass on examination. She visited a local hospital after detecting the mass 6 days prior. CT at the local hospital revealed an irregular soft tissue density mass in the right adrenal region, with heterogeneous internal density, and a maximum size of approximately 6.4 cm \u0026times; 7.5 cm \u0026times; 7.6 cm. Contrast-enhanced scanning showed heterogeneous enhancement of the mass, with a lobulated appearance. The boundary between the lesion and the diaphragm was indistinct, and the adjacent right diaphragm was slightly thickened. The surrounding fat planes were blurred, with patchy areas of infiltration, and enlarged lymph nodes were visible around the mass (Figure 2A). The imaging findings indicated a malignant adrenal tumor with right diaphragm invasion and metastasis to adjacent lymph nodes. The patient underwent right adrenal tumor resection and partial right adrenalectomy. The postoperative pathological diagnosis was \u0026ldquo;adrenal pseudocyst.\u0026rdquo;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOver a year postoperatively, the patient experienced recurrent fever for half a year and presented to our hospital. CT at our institution revealed a mass-like area of abnormal density in the right adrenal region, measuring approximately 3.2 cm \u0026times; 2.4 cm \u0026times; 3.0 cm. Contrast-enhanced scanning showed heterogeneous mild enhancement, with unclear boundaries. The lesion was indistinguishable from the adjacent right kidney, inferior vena cava, and right diaphragm (Figure 2B). Imaging diagnosis considered: postoperative recurrence of the tumor with possible metastasis to the para-aortic lymph nodes and left iliac bone. Involvement of the right kidney, inferior vena cava, right diaphragm, right peritoneum, liver, left iliac vessels, gluteus maximus, and quadratus femoris muscles could not be excluded. Metastasis to the intermuscular lymph nodes remained to be ruled out. Consequently, a consultation of the patient\u0026apos;s original pathology slides was conducted, and a biopsy of the left iliac bone was performed. The corrected pathological diagnosis was angiomatoid fibrous histiocytoma (AFH) of the adrenal gland with metastasis to the iliac bone.\u003c/p\u003e\n\u003cp\u003eGross examination: The tumor measured 9.5 cm \u0026times; 6 cm \u0026times; 5 cm. The surface was partially encapsulated. The cut surface appeared grayish-brown, with a cystic and solid appearance, and showed evidence of hemorrhage and necrosis.\u003c/p\u003e\n\u003cp\u003eMicroscopic examination: The tumor exhibited a cystic architecture with a thick fibrous cyst wall. The cyst wall exhibited extensive lymphocyte and plasma cell proliferation, with occasional lymphoid follicle formation. Vascular cleft-like structures were present within the cyst wall, containing numerous red blood cells and hemosiderin deposits, none of which were lined by epithelial or endothelial cells (Figure 2C). Tumor cells were arranged in small clusters or nests, with some areas extending beyond the fibrous cyst wall. The tumor cells had a histiocytoid appearance with visible mitotic figures (approximately 3/10high-power fields [HPF]). Significant interstitial fibrosis with hyaline degeneration was also observed. In the iliac bone metastasis, the tumor cells exhibited a histiocytoid morphology with minimal cytologic atypia (Figure 2D).\u003c/p\u003e\n\u003cp\u003eImmunophenotyping analysis revealed dendritic positivity for desmin (Figure 2E), with expression of ALK-D5F3 (Figure 2F), epithelial membrane antigen (EMA), and CD99. The tumour was negative for CD68, S-100, CD31, CD34, CD21, and CD35. The Ki-67 proliferation index was 10%.\u003c/p\u003e\n\u003cp\u003eFISH demonstrated positivity for the EWSR1 break-apart probe, whereas probes for EWSR1::CREB1 and EWSR1::ATF1 gene fusions were negative.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003eClinical Features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AFH predominantly affects children and adolescents, with a mean age of approximately 20 years. The two cases reported herein include an 18-year-old patient (Case 1), which aligns with the previously reported age distribution, and a 50-year-old patient (Case 2), suggesting that adrenal AFH may have a broader age range and is not exclusive to children and adolescents. AFH typically occurs in superficial locations of the extremities; however, both cases in this report originated in the adrenal glands, an exceedingly rare site for this tumor. To date, no similar cases have been reported domestically, with only one case documented internationally [5].\u003c/p\u003e\n\u003cp\u003eClinically, Case 1 presented with recurrent abdominal pain and vomiting, while Case 2 was largely asymptomatic initially, later developing unexplained recurrent fever following tumor recurrence, which is consistent with the clinical manifestations of adrenal AFH reported in the literature [5]. In terms of biological behavior, AFH is generally considered to have low malignant potential or intermediate characteristics. Due to the uncertain differentiation of tumor cells, the WHO classification groups AFH under the category of “tumors of uncertain differentiation” [6]. The clinical behavior of the two cases in this study varied significantly: Case 1 exhibited benign features with no recurrence postoperatively, whereas Case 2 demonstrated aggressive behavior, with local invasion into surrounding soft tissues and metastasis to bone, a manifestation that is highly unusual for AFH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathological Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGross Features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAFH typically presents as well-circumscribed tumours with diameters ranging from 0.7 to 12 cm. Upon sectioning, they appear greyish-brown with a firm texture and exhibit irregular haemorrhagic cystic spaces. The two cases reported herein had relatively large tumours, with diameters of 7 cm and 9 cm, respectively. Case 1 exhibited a cystic-solid appearance with inconspicuous intra-cystic haemorrhage, whereas Case 2 presented as a cystic tumour accompanied by prominent haemorrhage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMorphological Features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Classical AFH displays the following three characteristic pathological morphologies:(1) The tumor periphery is encircled by a substantial infiltrate of lymphocytes and plasma cells, often forming a \"lymphatic cuff\" that fuses with a fibrous pseudocapsule; (2) The central neoplastic parenchyma comprises nodular, irregularly sheet-like, and nest-like spindle-to-oval histiocyte-like cells. The nuclei exhibit a round or oval morphology, with small nucleoli and prominent nuclear grooves. (3) The tumor contains multifocal hemorrhagic cystic spaces devoid of endothelial lining.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCase 1 in this study exhibits morphological concordance with classical AFH, yet it possesses unique features that differentiate it. Notably, the lymphatic tissue is not confined to the periphery of the capsule but is diffusely distributed within the tumour parenchyma, accompanied by the formation of numerous lymph follicles. In the literature, the presence of a \"lymphatic cuff\" is considered a significant diagnostic clue for solid-variant AFH, observed in approximately 80% of cases [7]. However, Case 1 lacks a prominent \"lymphatic cuff\" structure. Although cystic spaces are formed within the tumor, intra-cystic hemorrhage is inconspicuous, lacking the typical \"angiogenic\" features and resembling more of a \"lymphangioma-like\" appearance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCase 2 presents as a cystic tumor with a relatively thick fibrous capsule, initially misdiagnosed as an \"adrenal pseudocyst\" by the original institution. In reality, the capsule wall represents the true tumor parenchyma. In this case, the lymphatic tissue does not form a \"lymphatic cuff\"-like structure but is instead scattered in nodular fashion, with only a few lymph follicles visible. Cyst formation is not prominent, manifesting more as vascular lumen-like fissures containing abundant red blood cells and hemosiderin. Marked interstitial fibrosis with hyalinization is also noted, inconsistent with the mucinous features commonly reported in intracranial AFH in the literature [8].\u003c/p\u003e\n\u003cp\u003eThe two cases reported herein do not fully conform morphologically to classical AFH, solid-variant AFH, or AFH located in other special sites, thereby providing additional morphological characteristics for AFH. Of particular note is Case 2, where the tumor cells showed minimal atypia and only a few mitotic figures both at the time of surgery and upon recurrence. Nevertheless, the tumor demonstrated malignant behavior with surrounding tissue infiltration and metastasis. Therefore, it is speculated that the biological behavior of AFH occurring in the adrenal gland is not directly related to cellular atypia and mitotic figures but may be more associated with specific genetic alterations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmunophenotypic Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The tumor cells in both patients expressed EMA, CD99, and Desmin, with Desmin demonstrating a dendritic positivity. The tumor cells in Case 2 expressed ALK-D5F3, while both cases were negative for CD34, CD21, and CD35. The negativity for CD34 suggests the absence of endothelial cell lining within the vascular lacunae of the tumor. Approximately 90% of cases express the ALK protein [9], however, current studies indicate that cases expressing ALK protein do not have amplification or mutation of the ALK gene, and the mechanism of ALK expression remains unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMolecular Pathological Features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Studies have demonstrated that over 80%–90% of angiomatoid fibrous histiocytoma (AFH) cases harbor the EWSR1::CREB1 fusion gene, with a minority of cases also showing EWSR1::ATF1 or FUS::ATF1 fusion genes [10-][11]. In the present study, fluorescence in situ hybridization (FISH) analysis revealed EWSR1 gene rearrangement in both cases, yet further testing for EWSR1::CREB1 and EWSR1::ATF1 fusions was negative. Similar findings have been reported in a subset of AFH cases, where only EWSR1 gene rearrangement was detected without the common fusion partners CREB1 or ATF1[9].Similar observations have also been reported in pediatric AFH cases [12].Unfortunately, due to financial constraints, next-generation sequencing (NGS) could not be performed to identify additional fusion genes, which represents a significant limitation, especially in Case 2. We hypothesize that the observed aggressive biological behavior in this case could be linked to an EWSR1-related fusion gene alteration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDifferential Diagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHematoma and Hemangioma：The majority of AFH tumors are often accompanied by the formation of irregular cystic cavities, which can easily be confused with hematoma or hemangioma. Case 2 in this study was initially misdiagnosed as a pseudocyst due to its cystic tumor wall with sparse tumor cells and no lining cells. However, AFH is negative for endothelial cell markers (such as CD31, CD34, etc.), indicating that the cells within the cyst wall are not endothelial cells, and the irregular hemorrhagic clefts are not true vascular lumens. This distinction can be made to differentiate AFH from hematoma or hemangioma [13].\u003c/p\u003e\n\u003cp\u003eLymph Node Metastasis of Tumor: AFH is surrounded by a fibrous pseudocapsule with a large number of lymphocytes subcapsularly and may form germinal centers, which can lead to misdiagnosis as lymph node metastasis of a tumor. However, AFH lacks lymphatic sinus structures, and the germinal centers do not distribute subcapsularly. These features are helpful in differentiation.\u003c/p\u003e\n\u003cp\u003eAneurysmal Fibrous Histiocytoma (AFH-like in name but distinct pathologically): While the name is somewhat similar to AFH, aneurysmal fibrous histiocytoma belongs to an entirely different pathology. The former is located in the dermis, lacks a pseudocapsule, and is characterized by the presence of abundant cleft-like or blood sinus-like capillaries within the tumor. The solid areas surrounding the blood vessels exhibit the classic morphology of fibrous histiocytoma, and the stroma commonly contains abundant hemosiderin deposition and aggregations of hemosiderin-laden macrophages.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment and Prognosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The primary treatment for angiomatoid fibrous histiocytoma (AFH) is wide surgical excision, with negative margins being crucial. The local recurrence rate after complete resection ranges from 2% to 10%. Costa et al. reported that irregular tumor borders and head and neck locations are associated with local recurrence, while tumor depth is correlated with subsequent local and distant metastasis. However, the associations between mitotic activity, nuclear pleomorphism, inflammatory response, tumor size, patient age, and adjuvant therapy with clinical behavior remain unclear [14]. To date, no reports have demonstrated a correlation between genetic factors or immunohistochemical profiles and clinical behavior. Therefore, for surgical treatment of AFH, ensuring wide excision and negative margins is essential. Radiotherapy or chemotherapy is typically considered for large tumors, those with distant metastasis, or those located near major vessels [15], and long-term close follow-up is required. In this study, Case 2 developed metastasis to the iliac bone and underwent AI chemotherapy, which showed suboptimal efficacy. Recent studies have shown that the ALK inhibitor crizotinib can provide a cure or remission in recurrent AFH cases with ALK protein expression [16], suggesting that targeted therapy may represent a future direction for treatment.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, pathologists should enhance their ability to recognise the morphology of angiomatoid fibrous histiocytoma (AFH), particularly when it occurs in rare locations, as these tumours may exhibit unique histological features. The key morphological characteristics of adrenal AFH include nests of histiocytoid cells, widespread proliferation of lymphoid tissue with lymphoid follicle formation, various cleft-like structures, and marked interstitial fibrosis. These features are highly suggestive of the diagnosis. Definitive diagnosis requires integration of immunophenotypic analysis and molecular testing, as studies have shown that the prognosis of the tumour is closely related to genetic alterations. In-depth investigation into the molecular biology of AFH not only optimises diagnostic protocols and therapeutic strategies but also provides a reliable basis for prognostic assessment. Overall, the case reports presented herein further expand the spectrum of adrenal tumours and offer new insights into the diagnosis and study of AFH in rare locations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYang Li and Xiao Li contributed equally to this work.\u003c/p\u003e\n\u003cp\u003eYang Li: Responsible for the conception and design of the case report, collection and analysis of patient data.\u003c/p\u003e\n\u003cp\u003eXiao Li: Involved in the collection and interpretation of patient data, and drafting of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLi Jiandi: Contributed to the collection of relevant case materials and literature review.\u003c/p\u003e\n\u003cp\u003eWei Kanglai: Participated in the literature review and modification of the manuscript.\u003c/p\u003e\n\u003cp\u003eShi Lin: Provided professional advice and assistance in the diagnosis and treatment process of the patient.\u003c/p\u003e\n\u003cp\u003eChen Gang and Chen Jun: As corresponding authors, they supervised the entire study, provided critical feedback on the manuscript, and approved the final version for submission.\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt our institution, Institutional Review Board approval is not required for case reports. Written informed consent was obtained from the patient to publish this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient to publish this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEnzinger FM. Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm. Cancer. 1979;44(6):2147\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWHO Classification of Tumours Editorial. Board.WHO classification of tumours editorial board [M]. 5th ed. Lyon: IARC; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilk M, Zelger BG, Debiec-Rychter M, Sciot R, Zelger B. Angiomatoid fibrous histiocytoma - case series with emphasis on a late fibrotic variant. J Dtsch Dermatol Ges. 2015;13(5):441\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Z. Angiomatoid fibrous histiocytoma in the right elbow: A case report. Asian J Surg. 2024;47(1):588\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan IS, Kuick CH, Jain S, et al. Primary Adrenal Angiomatoid Fibrous Histiocytoma With Novel EWSR1-ATF1 Gene Fusion Exon-Exon Breakpoint. Pediatr Dev Pathol. 2019;22(5):472\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaito K, Kobayashi E, Yoshida A, et al. Angiomatoid fibrous histiocytoma: a series of seven cases including genetically confirmed aggressive cases and a literature review. BMC Musculoskelet Disord. 2017;18(1):31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThway K, Fisher C. Angiomatoid fibrous histiocytoma: the current status of pathology and genetics. Arch Pathol Lab Med. 2015;139(5):674\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBallester LY, Meis JM, Lazar AJ, et al. Intracranial Myxoid Mesenchymal Tumor With EWSR1-ATF1 Fusion. J Neuropathol Exp Neurol. 2020;79(3):347\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheah AL, Zou Y, Lanigan C, et al. ALK Expression in Angiomatoid Fibrous Histiocytoma: A Potential Diagnostic Pitfall. Am J Surg Pathol. 2019;43(1):93\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerklite L, John I, Ranganathan S, et al. SOX9 Immunohistochemistry in the Distinction of Angiomatoid Fibrous Histiocytoma From Histologic Mimics: Diagnostic Utility and Pitfalls. Appl Immunohistochem Mol Morphol. 2020;28(8):635\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchaefer IM, Fletcher CD. Myxoid variant of so-called angiomatoid malignant fibrous histiocytoma: clinicopathologic characterization in a series of 21 cases. Am J Surg Pathol. 2014;38(6):816\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeng X, Tao J, Wang Y, Long AY, He LJ, Zhang N. [Clinicopathological and molecular characteristics of angiomatoid fibrous histiocytoma in children]. Zhonghua Bing Li Xue Za Zhi. 2024;53(5):483\u0026ndash;5. Chinese.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePasricha S, Durga G, Sharma A, et al. Angiomatoid fibrous histiocytoma: Report of two cases, initially construed as sarcoma with unusual clinico-pathological features. Indian J Pathol Microbiol. 2022;65(4):921\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaito K, Kobayashi E, Yoshida A, et al. Angiomatoid fibrous histiocytoma: a series of seven cases including genetically confirmed aggressive cases and a literature review. BMC Musculoskelet Disord. 2017;18(1):31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu DP, Xu ZX, Wu J. Intracranial angiomatoid fibrous histiocytoma: A case report. Asian J Surg. 2023;46(11):5086\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNgo C, Grinda T, Boil\u0026egrave;ve A, et al. Durable response to crizotinib in metastatic angiomatoid fibrous histiocytoma with EWSR1-CREB1 fusion and ALK overexpression. Ann Oncol. 2022;33(8):848\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"angiomatoid fibrous histiocytoma (AFH), adrenal gland","lastPublishedDoi":"10.21203/rs.3.rs-6253095/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6253095/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eAngiomatoid fibrous histiocytoma (AFH) is a rare low-grade neoplasm, typically arising in pediatric/adolescent extremity subcutaneous tissues. Adrenal AFH is extremely uncommon, with limited reported cases. Elucidating clinicopathologic/molecular profiles of adrenal AFH is critical for accurate diagnosis and management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation \u003c/strong\u003eTwo adrenal AFH cases (18-year-old male, 50-year-old female) from Guangxi Medical University Second Hospital were retrospectively analyzed, focusing on clinical features, histopathology, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and follow-up. Case 1: Classic AFH morphology with unique features: diffuse intratumoral lymphoid tissue (with follicles) instead of capsular lymphoid cuffs, and lymphangioma-like cystic spaces (lacking angiomatoid hemorrhage).Case 2: Cystic tumor misdiagnosed as \"adrenal pseudocyst\"; true parenchyma resided in the cyst wall, with nodular lymphoid aggregates (no lymphoid cuff) and erythrocyte/hemosiderin-filled vascular clefts. Marked hyaline fibrosis was noted.Molecular: Both cases showed EWSR1 break-apart (FISH+), negative for EWSR1::CREB1/ATF1 fusions. IHC revealed desmin positivity (both), ALK-D5F3 expression (Case 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eAtypical-location AFH (e.g., adrenal) exhibits divergent pathologic phenotypes. Diagnosis requires integrated IHC/molecular analysis (e.g., EWSR1 status). Prognostic implications of genetic alterations (e.g., ALK expression) highlight the need for molecular profiling to guide therapy and prognosis.\u003c/p\u003e","manuscriptTitle":"Angiomatoid fibrous histiocytoma of the adrenal gland: A clinical and pathological observation of two cases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-02 10:39:20","doi":"10.21203/rs.3.rs-6253095/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-08T15:05:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-07T23:27:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"229853778661969048988070442856896556240","date":"2025-06-30T23:00:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-05T10:29:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"12036612826115973071325943094728839786","date":"2025-04-03T04:34:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85130172389939060807048047743259991049","date":"2025-03-27T03:10:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"116449569691788127258498377201564199987","date":"2025-03-25T06:17:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-24T15:21:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-23T13:45:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-20T00:23:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Surgical Oncology","date":"2025-03-18T12:18:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a41ec95-5015-45f4-9b24-f06a87c60765","owner":[],"postedDate":"April 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T16:05:29+00:00","versionOfRecord":{"articleIdentity":"rs-6253095","link":"https://doi.org/10.1186/s12957-025-03971-3","journal":{"identity":"world-journal-of-surgical-oncology","isVorOnly":false,"title":"World Journal of Surgical Oncology"},"publishedOn":"2025-11-26 15:58:48","publishedOnDateReadable":"November 26th, 2025"},"versionCreatedAt":"2025-04-02 10:39:20","video":"","vorDoi":"10.1186/s12957-025-03971-3","vorDoiUrl":"https://doi.org/10.1186/s12957-025-03971-3","workflowStages":[]},"version":"v1","identity":"rs-6253095","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6253095","identity":"rs-6253095","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}