Atypical Nodal Kaposi Sarcoma in HIV Infection. A case report and literature review

Atypical Nodal Kaposi Sarcoma in HIV Infection. 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A case report and literature review María Dioselina Ruiz Barrera, Luis Ernesto Heredia Santos, María Alaciel Galván Merlos, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9363985/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Kaposi sarcoma is an angioproliferative neoplasm driven by human herpesvirus 8 (HHV-8), most commonly observed in immunocompromised individuals, particularly those with untreated human immunodeficiency virus infection. It classically presents with cutaneous and mucocutaneous lesions; however, atypical forms without skin involvement, especially those with predominant lymph node disease, are rare and frequently lead to diagnostic uncertainty. We report the case of a 26-year-old male with recently diagnosed HIV infection and no prior antiretroviral therapy, who presented with a two-week history of persistent fever, constitutional symptoms, abdominal pain, and progressive intolerance to oral intake. On admission, he exhibited hemodynamic instability, severe anemia, thrombocytopenia, and progressive renal dysfunction. Imaging studies revealed generalized lymphadenopathy involving multiple nodal chains, bilateral pleural effusion, hepatosplenomegaly, and free abdominal fluid, suggesting a systemic process. Initial diagnostic considerations included lymphoma, disseminated infection, and other HIV-associated malignancies. An excisional inguinal lymph node biopsy demonstrated a vascular mesenchymal neoplasm composed of spindle cells, and immunohistochemical analysis confirmed Kaposi sarcoma with nuclear positivity for HHV-8. Notably, no cutaneous or mucosal lesions were identified throughout the clinical course. Nodal Kaposi sarcoma without cutaneous involvement represents an uncommon and underrecognized presentation, particularly in young patients with untreated HIV infection. Its clinical features frequently overlap with lymphoproliferative disorders and opportunistic infections, contributing to diagnostic delays. The pathogenesis is driven by the interplay between HIV-induced immunosuppression, chronic immune activation, and HHV-8–mediated oncogenesis. In this context, early histopathological evaluation remains essential for definitive diagnosis, as imaging findings lack specificity. This case highlights the importance of including Kaposi sarcoma in the differential diagnosis of unexplained lymphadenopathy in patients with HIV, even in the absence of cutaneous lesions. Recognition of atypical presentations is critical to ensure timely diagnosis and appropriate management, ultimately improving patient outcomes. Kaposi Sarcoma HIV Infection Acquired Immunodeficiency Syndrome Human Herpesvirus 8 Lymphadenopathy Nodal Kaposi Sarcoma Angioproliferative Neoplasms Immunosuppression AIDS-Related Malignancies Differential Diagnosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 INTRODUCTION HIV Infection: Epidemiological, Immunopathogenic Basis and Oncologic Complications Human immunodeficiency virus (HIV) infection continues to be a relevant global public health problem, despite advances in antiretroviral therapy (ART), which have transformed its clinical course into a controllable chronic disease with a significant increase in survival [1]. However, important challenges persist, including late diagnosis, sustained transmission in vulnerable populations, and difficulties in therapeutic adherence, which condition progression to advanced immunosuppression [2]. The current epidemiological profile shows a shift toward younger populations and groups with specific risk behaviors, which maintains the incidence of HIV-associated complications, particularly in contexts where access to ART is limited or initiated late. In this scenario, opportunistic diseases and neoplasms continue to represent important causes of morbidity and mortality in patients with HIV [3]. The pathophysiology of HIV is characterized by progressive depletion of CD4+ T lymphocytes, as well as a complex dysfunction of the immune system involving both innate and adaptive immunity. This process implies not only cellular loss but also functional alterations, such as T-cell exhaustion, dysfunction of antigen-presenting cells, and persistent activation of macrophages [1]. A key element in immunopathogenesis is early damage to gut-associated lymphoid tissue (GALT), which favors microbial translocation into systemic circulation. This phenomenon perpetuates chronic immune activation and generates a persistent inflammatory state that contributes to the development of systemic comorbidities, including cardiovascular, metabolic, and neoplastic diseases [2]. Even in patients on ART, residual inflammation and persistent immune activation condition a pro-inflammatory and pro-oncogenic environment, in which residual viral replication is favored and the immune system is unable to control oncogenic infections [1]. People living with HIV have a significantly higher risk of developing neoplasms compared to the general population, due to the interaction between immunosuppression, chronic inflammation, and coinfections with oncogenic viruses [3,4]. AIDS-defining cancers include Kaposi sarcoma, non-Hodgkin lymphoma, and invasive cervical cancer, all closely related to viral infections such as HHV-8, Epstein–Barr virus (EBV), and human papillomavirus (HPV) [3]. In the ART era, a decrease in the incidence of these tumors has been observed; however, a relative increase in non-AIDS-defining neoplasms has emerged, such as Hodgkin lymphoma, anal cancer, hepatocellular carcinoma, and lung cancer [5]. This epidemiological change is associated with aging of the HIV population, persistence of chronic inflammation, and prolonged exposure to additional risk factors. Kaposi sarcoma is an angioproliferative neoplasm associated with human herpesvirus type 8 (HHV-8), whose pathogenesis involves proliferation of infected endothelial cells in a context of immunosuppression and angiogenic stimulation mediated by proinflammatory cytokines. Although its classic presentation is cutaneous, it may manifest with visceral or nodal involvement, particularly in patients with advanced immunodeficiency, which represents an important diagnostic challenge [6]. The current approach to HIV infection includes not only virological control through ART but also strategies aimed at prevention and early detection of neoplasms. Immune restoration through ART has been shown to significantly reduce the incidence of AIDS-defining cancers; however, it does not completely eliminate oncologic risk [3]. In this context, targeted screening strategies have been developed, particularly for neoplasms associated with oncogenic viruses, such as cervical cancer and anal cancer, especially in high-risk populations. Likewise, control of modifiable risk factors, early detection of viral coinfections, and close clinical follow-up form an integral part of patient management. Therefore, the contemporary approach to HIV requires a comprehensive vision that includes oncologic surveillance, control of chronic inflammation, and early identification of atypical manifestations, with the aim of improving clinical outcomes and reducing disease burden [7]. Kaposi Sarcoma: Pathophysiology, Role of HHV-8, and Relationship with Immunosuppression Kaposi sarcoma (KS) is a low- to intermediate-grade vascular neoplasm, characterized by proliferation of spindle cells, formation of irregular vascular slits, extravasation of erythrocytes, and variable inflammatory infiltrate. In biological terms, it does not behave as a purely mesenchymal conventional sarcoma, but rather as an angioproliferative proliferation strongly influenced by inflammatory, viral, and immunological signals. In practice, this explains its tendency to be multifocal, its association with states of immunosuppression, and the possibility of affecting not only skin but also mucosae, lymph nodes, and visceral organs. Currently, four main clinical-epidemiological variants are recognized: classic, endemic, iatrogenic, and epidemic or HIV-associated. Although they share a viral etiological basis, they differ in age of presentation, clinical aggressiveness, anatomical distribution, and immunological context. The HIV-associated variant usually presents a more aggressive behavior, greater tumor burden, and more frequent extracutaneous involvement, particularly when advanced immunosuppression or absence of antiretroviral treatment exists [8,9]. Human herpesvirus type 8 (HHV-8), also called Kaposi sarcoma-associated herpesvirus (KSHV), is the indispensable etiologic agent of KS. Without HHV-8 infection, the disease does not develop; however, viral presence alone is not sufficient, as a permissive biological context is also required, especially one of immunoderegulation. HHV-8 also participates in other lymphoproliferative and inflammatory entities, such as primary effusion lymphoma, KSHV-associated multicentric Castleman disease, and KSHV-related cytokine inflammatory syndrome, which underscores its oncogenic and proinflammatory capacity [10,11]. Following primary infection, HHV-8 establishes latency in host cells, with restricted expression of viral genes oriented toward maintaining the episome, promoting cellular survival, and avoiding immune elimination. Under certain conditions, the virus can reactivate and enter the lytic phase, with expression of genes that enhance inflammation, angiogenesis, and proliferation. The alternation between latency and lysis is central to KS oncogenesis, as both phases contribute distinct elements to the tumor microenvironment [8,11]. HHV-8 promotes tumorigenesis through several viral proteins with functions analogous to cellular regulators. Among the most important are LANA-1, which contributes to maintenance of the viral genome and blocks suppressor pathways such as p53 and Rb; vIL-6, which promotes cellular proliferation and inflammation; vBcl-2, which inhibits apoptosis; and vGPCR, which stimulates proangiogenic signaling. Together, these mechanisms generate an environment of abnormal cellular survival, resistance to apoptosis, and sustained proliferative activation. At the microenvironment level, KS depends on a network of cytokines and growth factors, including IL-6, TNF-α, IFN-γ, PDGF, and VEGF, which stimulate angiogenesis, inflammation, and expansion of spindle cells. This “cytokine-dependent” nature helps explain why the tumor may coexist with systemic inflammatory syndromes and why some clinical manifestations exceed the simple tumor mass. The KS lesion is predominantly composed of spindle cells with an aberrant endothelial/lymphatic phenotype. Immunohistochemically, they usually express markers such as CD34 and frequently podoplanin (D2-40), while nuclear positivity for HHV-8 LNA-1 is the most useful confirmatory finding. This profile supports that neoplastic cells derive from an endothelial population reprogrammed by the virus and the inflammatory environment. From a histopathological standpoint, KS shows a stepwise evolution from patch to plaque to nodular lesions, with progressive increase in spindle cell proliferation, greater vascular complexity, and more evident erythrocyte extravasation. In nodal or visceral disease, these features may be preserved, although the anatomical pattern of infiltration modifies the macroscopic appearance and clinical suspicion [8]. Although HHV-8 is necessary, immunosuppression is the factor that most strongly determines the clinical expression of KS. This is demonstrated both in people with HIV and in solid organ transplant recipients and patients under iatrogenic immunosuppression. A recent meta-analysis showed that the risk of cancers related to viral infections increases markedly in people with HIV and also in transplant recipients, with KS being one of the tumors with the highest relative increase in both groups. In people with HIV, the meta-risk for KS was extraordinarily high [12]. In HIV infection, the loss of immune control over HHV-8 does not depend solely on the numerical decrease of CD4 cells, but also on qualitative dysfunction of cellular and humoral immunity, persistent immune activation, and a proangiogenic cytokine environment. Therefore, HIV not only facilitates persistent HHV-8 infection but also creates a biological setting that favors tumor expansion. This phenomenon helps explain why HIV-associated KS may be more aggressive and disseminated than other variants [9,13]. HIV–HHV-8 Interaction and Development of Angioproliferative Neoplasms The interaction between human immunodeficiency virus (HIV) and human herpesvirus type 8 (HHV-8) constitutes a paradigmatic model of viral oncogenesis in the context of immunosuppression. This interaction not only increases the risk of developing Kaposi sarcoma (KS), but also modulates its clinical behavior, favoring more aggressive, multifocal forms with greater systemic involvement [14]. The interaction between HIV and HHV-8 constitutes a central element in the pathophysiology of Kaposi sarcoma and other angioproliferative neoplasms. Under normal conditions, HHV-8 infection remains in a latent state under immune system control, particularly mediated by cellular immunity. However, in the context of HIV infection, the progressive depletion of CD4+ T lymphocytes and global immune dysfunction compromise this control, allowing viral reactivation and proliferation of infected cells. In addition to quantitative CD4 reduction, HIV induces functional alterations such as T-cell exhaustion and decreased cytotoxic response, which favor viral persistence and oncogenesis [3,14]. HIV infection is associated with a state of persistent chronic immune activation, characterized by sustained elevation of proinflammatory cytokines and activation of intracellular pathways that promote cellular proliferation. This inflammatory environment generates a proangiogenic microenvironment in which HHV-8 finds ideal conditions to enhance its oncogenic activity. Overexpression of factors such as vascular endothelial growth factor (VEGF), as well as cytokines such as IL-6 and TNF-α, contributes to the proliferation of infected endothelial cells and the formation of aberrant vascular structures. This phenomenon is key to explaining the angioproliferative nature of Kaposi sarcoma and its tendency toward multifocal dissemination [1,14]. Beyond immunosuppression, HIV may exert direct effects on HHV-8 replication. It has been demonstrated that HIV viral proteins, particularly the Tat protein, have the capacity to induce activation of HHV-8 genes, promoting its transition from latent to lytic phase. This shift increases the expression of viral genes involved in cellular proliferation, angiogenesis, and immune evasion. Likewise, the Tat protein exerts direct proangiogenic effects on endothelial cells, stimulating their migration and proliferation, thereby contributing to tumor expansion [6]. HHV-8 primarily infects endothelial cells, inducing their transformation into a proliferative phenotype characteristic of Kaposi sarcoma. In the context of HIV infection, endothelial dysfunction is exacerbated by systemic inflammation and oxidative stress, favoring cellular reprogramming. Infected cells acquire spindle-shaped morphology and express endothelial markers such as CD34 and podoplanin, reflecting their vascular origin. This transformation process is mediated both by viral gene expression and by the influence of the inflammatory microenvironment, consolidating a cellular phenotype resistant to apoptosis and with high proliferative capacity [14]. A distinctive feature of Kaposi sarcoma is its multifocal behavior, which does not follow the classical model of single clonal expansion. Instead, multiple foci of infection and cellular transformation may develop simultaneously in different anatomical territories, favored by HHV-8 dissemination and persistent immunosuppression. This pattern explains the frequent simultaneous involvement of skin, mucosae, lymph nodes, and visceral organs, as well as the clinical variability of the disease. In patients with HIV, this dissemination tends to be more aggressive and rapidly progressive [3]. The HIV–HHV-8 interaction has relevant clinical implications, as it determines the presentation, evolution, and prognosis of Kaposi sarcoma. In patients with untreated HIV infection, KS typically presents with greater aggressiveness, higher tumor burden, and early systemic involvement, including nodal or visceral forms. These atypical presentations may hinder diagnosis, especially in the absence of characteristic cutaneous lesions, requiring a high index of clinical suspicion. Timely initiation of antiretroviral therapy has been shown to significantly reduce the incidence and severity of KS by improving immune function and limiting viral replication. Therefore, understanding the interaction between both viruses is essential for the diagnostic and therapeutic approach in these patients [3]. Clinical Spectrum of Kaposi Sarcoma: From Cutaneous Disease to Visceral Forms Kaposi sarcoma (KS) presents a broad clinical spectrum, with cutaneous involvement being the most frequent manifestation. Classic cutaneous lesions are characterized by violaceous, erythematous, or brown macules, papules, or nodules, which may be located on the lower extremities, face, oral cavity, or trunk. Histologically, these lesions correspond to vascular proliferations with erythrocyte extravasation and hemosiderin deposition, explaining their characteristic coloration [14]. Clinical progression typically follows a staged evolution, from patch to plaque to nodular lesions, with progressive increase in dermal infiltration and spindle cell proliferation. In immunocompetent patients, as in the classic form, the disease is usually indolent; however, in the context of immunosuppression, especially in patients with HIV, progression may be more rapid and aggressive. In addition to the skin, KS may involve mucosae, particularly the oral cavity, where lesions may localize to the palate, gums, or tongue. These manifestations are especially frequent in patients with HIV and are usually associated with more advanced disease. Clinically, they may present as violaceous nodular lesions that can ulcerate or bleed, compromising swallowing or oral function [15]. Lymph node involvement represents a less frequent but clinically relevant form. It may present as isolated or generalized lymphadenopathy and, in some cases, as the predominant or initial manifestation of the disease, especially in patients with significant immunosuppression. This pattern may mimic lymphoproliferative disorders, making diagnosis difficult and delaying timely treatment [14]. In its more advanced forms, KS may involve visceral organs, including the lungs, gastrointestinal tract, liver, and lymphatic system. Pulmonary involvement may present with dyspnea, cough, hemoptysis, and radiological findings such as interstitial infiltrates, nodules, or pleural effusion. In the gastrointestinal tract, lesions may be asymptomatic or present with bleeding, abdominal pain, or anemia [16]. Visceral disease is usually associated with high tumor burden and worse prognosis, particularly in patients with uncontrolled HIV infection. In these cases, presentation may be nonspecific and may coexist with other opportunistic infections, making early identification of KS more difficult [3]. The clinical spectrum of KS is closely influenced by the patient’s immune status. In immunocompetent individuals, the disease is usually localized and slowly progressive. In contrast, in immunosuppressed patients, particularly those with untreated HIV infection, KS tends to be more aggressive, with extensive cutaneous involvement, lymph node disease, and visceral dissemination [15]. Immune restoration through antiretroviral therapy has been shown to significantly modify the clinical presentation of KS, reducing its incidence, limiting its progression, and, in some cases, inducing partial regression of lesions [16]. Atypical forms of KS, such as primary nodal involvement without evident cutaneous lesions, represent an important diagnostic challenge. These presentations may be confused with lymphomas, disseminated infections, or inflammatory diseases, delaying diagnosis and treatment initiation. In this context, biopsy of the affected tissue, together with histopathological and immunohistochemical evaluation, is essential to establish a definitive diagnosis. Identification of HHV-8 positivity in tumor cells is the most important confirmatory criterion [14]. Nodal Involvement in Kaposi Sarcoma: Atypical Presentation and Clinical Relevance Kaposi sarcoma (KS) is characterized by marked clinical heterogeneity, with the skin being the most frequently affected site. Cutaneous lesions represent the initial presentation in most patients and manifest as violaceous or erythematous macules that progress to infiltrated plaques and eventually to tumor nodules. This evolution reflects progressive histopathological changes, including increased spindle cell proliferation, disorganized neovascularization, and erythrocyte extravasation [14]. From a pathophysiological perspective, these lesions are not solely the result of tumor proliferation but also of an intense interaction between angiogenesis, inflammation, and viral factors. The characteristic coloration of the lesions is related to hemosiderin accumulation and erythrocyte extravasation, while their nodular consistency reflects expansion of the spindle cell component [15]. In patients with HIV infection, the cutaneous presentation may be extensive, with multiple lesions distributed on the face, trunk, extremities, and mucosae. Unlike the classic form, the epidemic variant tends to have a more aggressive course, with rapid progression and greater tendency for systemic dissemination [3]. Mucosal involvement is a frequent manifestation in immunosuppressed patients, particularly those with HIV infection. The oral cavity is the most common site, especially the hard palate, although the gums, tongue, and oropharynx may also be affected. These lesions are usually nodular, highly vascularized, and prone to bleeding, which may result in significant functional complications such as dysphagia or pain [15]. On the other hand, involvement of the lymphatic system represents a key component in the progression of KS. Nodal involvement may present as localized or generalized lymphadenopathy and, in some cases, as the predominant or even initial manifestation of the disease. This pattern is particularly relevant in patients with HIV, where KS may mimic lymphoproliferative diseases such as non-Hodgkin lymphoma, due to the presence of multiple adenopathies, constitutional symptoms, and hematological abnormalities [14]. Lymph node infiltration reflects not only tumor dissemination but also the active participation of the lymphatic system as a reservoir for HHV-8 and as a site of altered immune interaction [6]. In advanced stages, KS may affect multiple visceral organs, resulting in a complex clinical presentation with greater prognostic impact. Pulmonary involvement is one of the most relevant forms and may present with progressive dyspnea, cough, hemoptysis, and pleural effusion. Radiologically, it may appear as interstitial infiltrates, nodules, septal thickening, or peribronchovascular lesions, which often necessitates differentiation from opportunistic infections such as Pneumocystis jirovecii pneumonia or tuberculosis [16]. The gastrointestinal tract is another frequent site of involvement, where lesions may be subclinical or present with bleeding, abdominal pain, anemia, or even obstruction. Endoscopically, nodular or violaceous plaque-like lesions are observed, similar to cutaneous lesions, and may involve any segment of the digestive tract. Hepatic, splenic, and diffuse nodal involvement usually reflect disseminated disease. In these cases, clinical presentation may include constitutional syndrome, weight loss, persistent fever, and signs of systemic inflammation, which may mimic disseminated infections or hematologic neoplastic processes [3,14]. The clinical spectrum of KS is directly influenced by the degree of host immunosuppression. In immunocompetent patients, the disease is usually localized, slowly progressive, and predominantly cutaneous. In contrast, in patients with untreated HIV infection, KS tends to present with extensive disease, visceral involvement, and rapid progression. Immune restoration through ART significantly modifies this clinical spectrum, reducing the incidence of new lesions and, in some cases, inducing tumor regression. However, immune reconstitution inflammatory syndrome (IRIS) may also occur, in which KS lesions may transiently worsen after initiation of therapy [3,16]. Atypical presentations of KS, such as primary nodal involvement without evident cutaneous lesions, are uncommon but clinically relevant. These forms may delay diagnosis due to their similarity to other entities, especially lymphomas, disseminated infections, or inflammatory diseases. In these scenarios, clinical suspicion must remain high, particularly in patients with HIV and systemic manifestations. Diagnostic confirmation requires biopsy of the affected tissue, with histopathological and immunohistochemical evaluation demonstrating HHV-8 positivity, which constitutes the diagnostic gold standard. These non-classical forms, such as predominant nodal presentation, represent a diagnostic challenge and justify the importance of case reports that contribute to expanding clinical knowledge of the disease [14]. Differential Diagnosis of Lymphadenopathy in Patients with HIV Lymphadenopathy in patients with HIV infection represents a frequent clinical finding of great diagnostic relevance, as it may appear at any stage of infection and may be due to reactive, infectious, or neoplastic causes. In practical terms, the approach should consider three major etiological groups: reactive/inflammatory lymphadenopathy related to HIV itself or immune reconstitution, lymphadenopathy secondary to opportunistic infections or coinfections, and lymphadenopathy due to malignant processes, especially lymphoma, Kaposi sarcoma, and HHV-8–associated Castleman disease. This classification is particularly useful because it guides both clinical interpretation and the selection of imaging studies and the need for lymph node biopsy [17,18]. In early or intermediate stages of infection, HIV itself may produce reactive lymphoid hyperplasia and persistent generalized lymphadenopathy. In these cases, lymph nodes are usually multiple, mobile, and not always painful, and may coexist with mild constitutional symptoms or even be an incidental finding. Histopathologically, these lymph nodes show reactive changes rather than neoplastic infiltration, although their clinical appearance may overlap with more severe entities. Therefore, the mere presence of lymphadenopathy in a patient with HIV should not be assumed to be benign if alarm features are present, such as progressive enlargement, nodal conglomerates, B symptoms, cytopenias, hepatosplenomegaly, or systemic deterioration [17,19]. In patients with HIV, a significant proportion of lymphadenopathies have an infectious origin. Among the most relevant causes are tuberculous lymphadenitis, nontuberculous mycobacterial infections, histoplasmosis, cryptococcosis, toxoplasmosis, syphilis, and other concomitant viral infections. Suspicion increases when lymphadenopathy is accompanied by persistent fever, weight loss, night sweats, elevated acute-phase reactants, or evidence of disseminated disease. In endemic areas or in patients with advanced immunosuppression, granulomatous and fungal infections must be prioritized, as they can closely mimic both clinically and radiologically lymphoproliferative disorders. Among malignant causes, HIV-associated non-Hodgkin lymphoma constitutes one of the most important differential diagnoses in the presence of multiple or generalized lymphadenopathy. Clinically, it is usually accompanied by B symptoms, rapid progression, hepatosplenomegaly, cytopenias, and marked elevation of lactate dehydrogenase, although these findings are not exclusive. In practice, lymphoma is often the primary diagnostic consideration when lymphadenopathy in multiple regions coexists with constitutional syndrome and organ dysfunction, especially in patients with untreated HIV infection or advanced immunosuppression. This clinical overlap is precisely what leads entities such as nodal Kaposi sarcoma to be initially interpreted as lymphoproliferative disease [17,18]. Although Kaposi sarcoma is classically associated with cutaneous and mucosal lesions, it may also involve lymph nodes as part of disseminated disease or, less frequently, as the predominant manifestation. In patients with HIV, this possibility should be considered especially when lymphadenopathy is accompanied by findings consistent with systemic disease, cytopenias, or visceral involvement. The diagnostic difficulty lies in the fact that nodal Kaposi sarcoma may lack evident cutaneous lesions and mimic both lymphoma and disseminated infections. Therefore, in the presence of persistent or progressive lymphadenopathy, excisional biopsy remains essential to distinguish between infectious, reactive, and neoplastic processes [18]. HHV-8–associated multicentric Castleman disease occupies a fundamental place in the differential diagnosis of lymphadenopathy in patients with HIV, particularly when fever, intense systemic inflammation, hepatosplenomegaly, edema, organ dysfunction, or coexistence with Kaposi sarcoma are present. Its clinical relevance lies in the fact that it may present with generalized lymphadenopathy and florid systemic symptoms, mimicking sepsis, lymphoma, or tumor progression. Moreover, it may biologically overlap with other HHV-8–related diseases, requiring an integrated interpretation of histopathology, clinical presentation, and disease course. In patients with uncontrolled HIV and diffuse lymphadenopathy, Castleman disease must always be considered, particularly if there is a disproportionate inflammatory response [20–22]. Imaging studies are useful for defining the distribution, accessibility, and pattern of lymphadenopathy, but they rarely establish the etiological diagnosis on their own. Computed tomography may show localized or generalized lymphadenopathy, central necrosis, nodal conglomerates, mediastinal, abdominal, or inguinal involvement, as well as associated visceral disease. However, there is significant radiological overlap between infectious and neoplastic causes. Therefore, imaging should be understood as a tool to stratify risk and select the optimal biopsy site, rather than as a confirmatory method. In particular, the presence of lymphadenopathy in multiple chains, visceromegaly, and systemic findings should prompt early histological evaluation [18]. In patients with HIV, lymph node biopsy should be considered early when lymphadenopathy is persistent, progressive, large, deeply located, or accompanied by constitutional symptoms, cytopenias, organomegaly, or unexplained clinical deterioration. It is also indicated when suspicion of lymphoma, nodal Kaposi sarcoma, or Castleman disease is high, or when infectious etiologies cannot be demonstrated by less invasive methods. Excisional biopsy remains the procedure with the highest diagnostic yield, as it allows assessment of nodal architecture, infiltration patterns, special stains, and immunohistochemistry. In this context, it is the decisive tool to differentiate reactive, infectious, lymphoproliferative, and HIV-associated neoplastic processes [17,18]. In a young patient with HIV, febrile syndrome, cytopenias, multiple lymphadenopathy, and systemic deterioration, the initial differential diagnosis usually leans toward disseminated opportunistic infection or lymphoma. However, the presence of nodal Kaposi sarcoma as an initial or predominant manifestation requires broadening the diagnostic perspective. This type of presentation underscores that, in HIV, lymphadenopathy should not be interpreted in isolation but rather in conjunction with immune status, imaging findings, clinical evolution, and histopathological evaluation. Precisely due to this syndromic overlap, nodal Kaposi sarcoma constitutes an entity of high clinical and academic interest within the spectrum of lymphadenopathies in patients with HIV [18,22]. Diagnostic Limitations and Clinical Challenges in Young Patients In young patients, the diagnosis of immunosuppression-associated neoplasms, such as Kaposi sarcoma, represents a significant clinical challenge due to lower initial suspicion. Unlike populations with classical risk factors or long-standing known immunosuppression, young patients may present with nonspecific clinical manifestations that are initially interpreted as acute infectious or inflammatory processes. This low clinical suspicion is further accentuated when the diagnosis of HIV infection is recent or even unknown at the time of initial evaluation, delaying appropriate syndromic integration [3]. Additionally, initial clinical manifestations are usually nonspecific, including constitutional syndrome, fever, malaise, and gastrointestinal symptoms, which contributes to an initial diagnostic approach oriented toward common infections. In this context, HIV-associated neoplasms may go unnoticed during the early stages of clinical evaluation [15]. One of the main diagnostic challenges in young patients with HIV is the clinical overlap between infectious and neoplastic processes. Opportunistic infections, particularly in advanced stages of immunosuppression, may present with persistent fever, weight loss, lymphadenopathy, hematological abnormalities, and multiorgan involvement, which is clinically indistinguishable from entities such as lymphoma or disseminated Kaposi sarcoma. In regions with high prevalence of tuberculosis or other granulomatous infections, the initial tendency is usually to prioritize infectious etiologies, which may delay the performance of biopsies or histopathological studies. This diagnostic delay is critical, as HIV-associated neoplasms may progress rapidly if not identified in a timely manner [4]. Imaging studies, particularly computed tomography, are fundamental tools in the evaluation of lymphadenopathy and systemic disease; however, they have important limitations in differentiating between infectious and neoplastic etiologies. Findings such as multiple lymphadenopathy, hepatosplenomegaly, pleural effusion, or pulmonary infiltrates may be observed in both disseminated infections and malignant processes, including lymphoma and Kaposi sarcoma. This radiological overlap limits the ability of imaging to establish a definitive diagnosis; therefore, its utility lies mainly in characterizing disease extent and identifying the optimal biopsy site. In young patients, where initial suspicion of neoplasia is low, this limitation may contribute to additional diagnostic delays [16]. Lymph node or affected tissue biopsy constitutes the gold standard for the diagnosis of neoplasms in patients with HIV. However, in young patients, the indication for invasive procedures may be deferred due to initial suspicion of infectious or self-limited processes. This delay in obtaining tissue may significantly prolong the time to definitive diagnosis. In the case of nodal Kaposi sarcoma, where evident cutaneous lesions may be absent, biopsy becomes even more relevant. Confirmation through histopathology and immunohistochemistry, with positivity for HHV-8, is essential to differentiate it from lymphomas or other lymphoproliferative diseases [14]. Diagnostic delay in young patients with HIV-associated neoplasms has significant clinical implications, as it allows disease progression toward more advanced and disseminated forms. In Kaposi sarcoma, this may translate into visceral involvement, higher tumor burden, and accelerated clinical deterioration. Likewise, delayed initiation of antiretroviral therapy and oncologic treatment is associated with poorer therapeutic response and higher morbidity and mortality. This highlights the importance of maintaining a high index of diagnostic suspicion, even in young patients, particularly when clinical features suggest systemic disease [3]. The management of young patients with HIV and suspected neoplasia involves multiple clinical challenges, including the need to integrate clinical, laboratory, imaging, and histopathological information in a context of high diagnostic uncertainty. The coexistence of multiple processes, such as opportunistic infections, systemic inflammation, and neoplasms, further complicates the interpretation of findings. In addition, social and behavioral factors, such as recent HIV diagnosis, associated stigma, and lack of prior medical follow-up, may influence delayed presentation and treatment adherence. These elements must be considered within the comprehensive approach to patient care [15]. Overall, diagnostic limitations in young patients with HIV underscore the need to adopt a systematic clinical approach based on early identification of warning signs, appropriate use of diagnostic studies, and timely performance of biopsy when indicated. In particular, the presence of persistent lymphadenopathy, cytopenias, constitutional syndrome, or organ dysfunction should prompt a thorough evaluation that includes the possibility of immunosuppression-associated neoplasms [17]. Justification of the Systematic Review of the Literature Kaposi sarcoma (KS) is a well-characterized neoplasm in its cutaneous form; however, presentations with predominant or primary nodal involvement are uncommon and poorly described in the literature. This low incidence limits early clinical recognition and hinders the development of clear diagnostic patterns, particularly in young patients with HIV infection. In this context, a systematic review of the literature allows consolidation of available evidence, identification of common clinical characteristics, and establishment of correlations between presentation, diagnosis, and evolution of these atypical cases. Furthermore, variability in the clinical expression of KS, influenced by immune status and interaction with HHV-8, generates a heterogeneous spectrum of manifestations that requires structured analysis to improve clinical understanding [14,15]. The diagnosis of nodal Kaposi sarcoma, especially in the absence of cutaneous lesions, represents a considerable clinical challenge due to overlap with other common entities in patients with HIV, such as non-Hodgkin lymphoma, disseminated opportunistic infections, and Castleman disease. This diagnostic ambiguity is further aggravated by the lack of specific guidelines for the approach to these atypical presentations. In this scenario, a systematic review allows integration of information from case reports, clinical series, and observational studies in order to identify diagnostic patterns, suspicion criteria, and more effective management strategies. Systematization of evidence is particularly relevant in rare diseases or those with unusual presentation, where clinical trials are limited or nonexistent [3]. HIV-associated Kaposi sarcoma presents a distinct clinical behavior compared to other variants, with a greater tendency toward dissemination and systemic involvement. However, within this group, significant variations exist in presentation, especially in young patients or those with recent HIV diagnosis. A systematic review of the literature allows evaluation of how factors such as degree of immunosuppression, viral load, absence of antiretroviral therapy, and HHV-8 coinfection influence the clinical presentation of KS. This information is fundamental for improving risk stratification and guiding diagnostic suspicion in clinical practice [16]. Integration of evidence through a systematic review has direct implications in clinical practice, as it enhances the clinician’s diagnostic capacity when faced with atypical presentations. In the case of nodal KS, identification of recurrent clinical features, laboratory findings, and imaging patterns may facilitate early suspicion and accelerate the indication for biopsy, thereby reducing diagnostic delays. Additionally, literature review allows evaluation of therapeutic strategies used in similar cases, including the impact of antiretroviral therapy and available oncologic options, contributing to optimization of patient management [15]. Despite advances in knowledge of Kaposi sarcoma, important gaps persist regarding its atypical presentations, particularly those with primary nodal involvement. Most available evidence derives from case reports or small series, limiting generalizability and hindering development of specific clinical guidelines. In this sense, systematic review not only allows synthesis of existing evidence but also identification of areas of uncertainty that require further research, such as prognostic factors, treatment response in nodal forms, and the relationship between HHV-8 viral load and disease extent [14]. Synthesis of Available Evidence on Nodal Kaposi Sarcoma Kaposi sarcoma (KS) is a predominantly cutaneous neoplasm; however, nodal involvement represents a less frequent but clinically significant form within its spectrum of presentation. Available evidence suggests that nodal involvement usually occurs as part of disseminated disease, particularly in patients with HIV infection and advanced immunosuppression. However, cases of predominant or primary nodal involvement without evident cutaneous lesions are rare and are mainly described in case reports and small clinical series, limiting understanding of their clinical behavior. This low frequency contributes to nodal KS being underdiagnosed or identified late, especially in young patients, where initial suspicion is often directed toward infectious or lymphoproliferative etiologies [14,15]. Analysis of published cases shows that nodal KS may present with localized or generalized lymphadenopathy, with predilection for inguinal, axillary, and cervical regions. In many cases, these lymphadenopathies are accompanied by constitutional symptoms such as fever, weight loss, and night sweats, generating a strong initial suspicion of lymphoma or disseminated infection. In patients with HIV, presentation is usually more aggressive, with rapid progression and frequent association with hematological abnormalities such as anemia and thrombocytopenia. Additionally, coexistence of visceral involvement, such as hepatosplenomegaly or pleural effusion, is common in reported cases, reinforcing the systemic nature of the disease in this context [3,16]. Imaging studies described in the literature show that nodal KS is frequently associated with multiple lymphadenopathies in different nodal chains, without specific radiological characteristics that clearly differentiate it from lymphoma or infections. Computed tomography usually demonstrates lymph nodes of variable size, with or without necrosis, as well as concomitant findings such as pleural effusion, pulmonary infiltrates, or visceromegaly. This lack of radiological specificity constitutes an important limitation, as it complicates differential diagnosis based solely on imaging, underscoring the need for histopathological confirmation in all suspected cases [14,16]. Definitive diagnosis of nodal KS is based on histopathological study, which reveals proliferation of spindle cells, formation of irregular vascular spaces, and erythrocyte extravasation. However, since these findings may overlap with other vascular neoplasms or reactive processes, immunohistochemistry is essential to confirm the diagnosis. Nuclear positivity for HHV-8 (LANA-1) constitutes the most specific diagnostic marker, allowing differentiation of KS from other lymphoproliferative or infectious entities. Other markers, such as CD34 and podoplanin, support the endothelial origin of tumor cells [14]. Available evidence consistently shows that nodal KS occurs predominantly in patients with significant immunosuppression, especially those with untreated HIV infection. Low CD4 count and high viral load are associated with increased risk of disseminated disease and atypical presentations. Likewise, some studies suggest that active HHV-8 coinfection and systemic inflammatory state contribute to disease progression and aggressive behavior, although the exact relationship between HHV-8 viral load and clinical extent is not yet fully defined [3,14]. Treatment of nodal KS in patients with HIV includes antiretroviral therapy as the cornerstone of management, since immune restoration may induce partial or complete regression of lesions. However, in cases with extensive disease or visceral involvement, additional systemic treatment such as chemotherapy is usually required. Reported clinical evolution is variable and depends on the degree of immunosuppression, disease extent, and response to treatment. In general, cases diagnosed late have worse prognosis, highlighting the importance of early recognition of these atypical presentations [15,16]. One of the main findings in the literature is the scarcity of systematic studies on nodal KS. Most data come from case reports or small series, limiting the ability to establish definitive conclusions regarding its epidemiology, prognostic factors, and optimal therapeutic strategies. This limitation highlights the importance of documenting and reporting well-characterized clinical cases that contribute to expanding knowledge of this entity and improving its recognition in clinical practice [14]. Knowledge Gaps in Non-Classical Presentations One of the main knowledge gaps in Kaposi sarcoma (KS) is the underrepresentation of its non-classical forms in the biomedical literature. Most of the available knowledge derives from the typical cutaneous form, particularly in the context of HIV infection, whereas predominantly nodal, visceral, or mucosal presentations without evident cutaneous lesions remain mainly described in isolated reports or small series. This imbalance results in the conceptual framework of KS remaining centered on its dermatological phenotype, leaving relatively poorly characterized those variants that present as lymphadenopathy, gastrointestinal disease, pulmonary involvement, or systemic disease without apparent cutaneous involvement [10,23,24]. This limitation has direct consequences in clinical practice. When an entity is primarily defined by its classical form, atypical variants fall outside the initial reasoning of both the clinician and the radiologist, favoring diagnostic delays, inefficient stepwise investigations, and a greater likelihood of attributing the presentation to more common conditions such as lymphoma or disseminated opportunistic infections [23–25]. Another important gap is the limited systematic characterization of patients with nodal or visceral KS. Although it is recognized that KS may affect virtually any organ, there is still limited information regarding the true frequency of nodal involvement as an initial manifestation, its patterns of anatomical distribution, its clinical correlates, and its relationship with systemic disease burden. Recent studies continue to indicate that visceral or nodal involvement may present with nonspecific symptoms and without concomitant cutaneous lesions, which hinders early recognition [23,25,26]. Similarly, gaps persist regarding the natural history of these presentations. It is not well defined whether nodal forms simply represent a variant of advanced disseminated disease or whether, in some cases, they constitute a particular biological phenotype with distinct immunological or viral determinants. This uncertainty limits the ability to stratify risk and anticipate clinical outcomes [10,23]. Non-classical presentations of KS share manifestations with multiple common diseases in immunosuppressed patients, especially in individuals with HIV. Fever, weight loss, lymphadenopathy, pleural effusion, hepatosplenomegaly, cytopenias, and inflammatory alterations may also be observed in HIV-associated lymphoma, disseminated tuberculosis, systemic mycoses, HHV-8–associated multicentric Castleman disease, and other lymphoproliferative disorders. Despite this overlap, there remains a lack of specifically validated diagnostic algorithms to guide the evaluation of lymphadenopathy or visceral disease when cutaneous KS is absent [10,23,25]. The practical consequence is that diagnosis continues to depend largely on individual clinical suspicion and the timely decision to perform a biopsy. This introduces considerable variability between centers and professionals and may significantly affect time to definitive diagnosis [24,25]. Available evidence also shows an important gap in the utility of imaging methods to distinguish non-classical KS from other etiologies. Computed tomography may reveal multiple lymphadenopathies, pleural effusion, gastrointestinal lesions, or visceral involvement; however, these findings lack specificity and may be indistinguishable from opportunistic infections or lymphoproliferative disease. Even in recent reviews, the value of imaging is described more as a tool for disease extension rather than for etiological differentiation. This leaves a gap in the development of useful radiological criteria for suspicion of nodal or visceral KS. There are still no sufficiently robust patterns that allow the radiologist to confidently suggest this possibility in the absence of accompanying cutaneous lesions. Therefore, imaging remains complementary but not definitive in many of these presentations [23,25]. Although HHV-8 is indispensable for the development of KS, there are still areas of uncertainty regarding how to integrate viral biology into everyday clinical practice. In particular, it is not fully clarified what prognostic role viral activity, coinfection with other HHV-8–related entities, and inflammatory biomarkers play in patients with non-classical disease. Recent reviews on HHV-8–associated disorders emphasize that there remains significant biological overlap between KS, multicentric Castleman disease, and other related syndromes, which complicates both classification and clinical interpretation of complex cases [10]. Consequently, a gap persists between molecular knowledge of HHV-8 and its clinical application in predicting disease extent, response to treatment, or risk of relapse, especially in patients with predominant nodal or visceral involvement [10,23]. Another important limitation is the absence of prospective studies specifically focused on non-classical nodal or visceral KS. Most therapeutic evidence comes from heterogeneous cohorts of HIV-associated KS, where cases with cutaneous or mucocutaneous disease predominate. This makes it difficult to determine whether current therapeutic recommendations, such as initiation of ART or use of liposomal anthracyclines or paclitaxel in advanced disease, have the same prognostic behavior in non-classical presentations, particularly when onset is nodal or visceral. In other words, although general treatment principles exist, more detailed data are still lacking regarding optimal therapeutic sequence, response criteria, and specific prognosis in patients without predominant cutaneous lesions. This gap is especially relevant in atypical cases, where diagnostic delay may modify tumor burden at the time of treatment initiation [23,27]. Non-classical presentations in young patients constitute an even less studied area. In these cases, low initial oncologic suspicion and the tendency to prioritize infectious or inflammatory causes may further delay histological confirmation. Recent literature on atypical presentations emphasizes that young age or even absence of apparent risk factors may contribute to diagnostic anchoring errors, especially when the initial presentation does not include cutaneous lesions [24,25]. This is particularly important in patients with recently diagnosed HIV, in whom lymphadenopathy, cytopenias, and systemic symptoms usually first suggest lymphoma or opportunistic infection. Consequently, studies evaluating specifically how age influences diagnostic bias, time to biopsy, and clinical outcomes in non-classical KS are lacking [23,25]. Overall, knowledge gaps in non-classical presentations of KS point to several specific needs: improving clinical characterization of nodal and visceral involvement, developing specific diagnostic algorithms for patients with HIV and lymphadenopathy without cutaneous lesions, better defining the role of imaging and HHV-8–related biomarkers, and generating prospective cohorts to evaluate prognosis and therapeutic response in these atypical phenotypes [10,23,25]. Justification and Objective of the Case Report Kaposi sarcoma (KS) continues to be one of the most representative neoplasms associated with HIV infection, particularly in scenarios of late diagnosis or absence of antiretroviral treatment. Despite the decrease in its incidence in the era of combination antiretroviral therapy, KS remains a clinically relevant entity due to its capacity to present in aggressive forms with systemic involvement, especially in patients with advanced immunosuppression. In recent years, the literature has emphasized that the clinical behavior of KS has changed, showing greater heterogeneity in its presentation, including non-classical forms affecting lymph nodes and visceral organs without evident cutaneous manifestations. These atypical variants represent an important diagnostic challenge and highlight the need to expand clinical understanding of the disease spectrum [3,14,15]. Non-classical presentations of KS, particularly those with predominant nodal involvement or without cutaneous lesions, are poorly described in the literature and mostly correspond to isolated case reports. This limitation hinders identification of reproducible clinical patterns and contributes to low diagnostic suspicion in clinical practice [28]. The value of case reports in this context lies in their ability to document unusual manifestations, expand clinical knowledge, and generate hypotheses that can be explored in subsequent studies. In rare diseases or those with atypical variants, such as nodal KS, this type of evidence acquires particular relevance for the medical community [29]. In patients with HIV infection, the presence of generalized lymphadenopathy constitutes a frequent finding with a broad differential diagnosis that includes opportunistic infections, inflammatory diseases, and neoplasms. In this context, nodal Kaposi sarcoma may go unnoticed due to its clinical similarity to non-Hodgkin lymphoma, multicentric Castleman disease, or disseminated infections such as tuberculosis or systemic mycoses. The absence of characteristic cutaneous lesions in some cases contributes to delayed diagnosis, which may lead to progression toward advanced disease. Therefore, documentation of cases with atypical presentations is essential to increase clinical awareness and promote a broader and more timely diagnostic evaluation [15,16]. Early diagnosis of KS is a determining factor in patient prognosis, as it allows timely initiation of antiretroviral therapy and, when necessary, specific oncologic treatment. Immune restoration through ART has been shown to reduce disease progression and improve clinical outcomes, even in cases with systemic involvement. In contrast, diagnostic delay, frequent in non-classical presentations, is associated with higher tumor burden, visceral involvement, and poorer therapeutic response. This underscores the importance of recognizing these clinical variants and integrating KS into the differential diagnosis in patients with HIV and persistent lymphadenopathy [3,14]. The present case report gains relevance by documenting an unusual presentation of Kaposi sarcoma with predominant nodal involvement in a young patient with recently diagnosed HIV. This type of presentation is not only uncommon but also represents a significant diagnostic challenge due to the absence of typical cutaneous manifestations. The detailed description of the case, including clinical course, laboratory findings, imaging studies, and histopathological confirmation, provides valuable evidence that contributes to expanding the known clinical spectrum of KS. It also facilitates comparison with previously reported cases and reinforces the importance of considering this entity in complex clinical scenarios [15]. Objective of the Case Report The objective of this report is to describe an atypical presentation of Kaposi sarcoma with predominant nodal involvement in a young patient with HIV infection, highlighting the associated diagnostic challenges, relevant clinical characteristics, and the importance of histopathological confirmation. Additionally, this case is intended to be integrated with the available evidence in the literature in order to contribute to a better understanding of the clinical spectrum of KS and to promote a broader diagnostic approach in patients with HIV who present with lymphadenopathy and systemic manifestations. CASE PRESENTATION This is a 26-year-old male patient, previously without known chronic diseases, who was admitted for evaluation by the Internal Medicine service in the context of a febrile syndrome under investigation associated with significant hematological abnormalities. His past medical history is notable for a recent diagnosis of human immunodeficiency virus (HIV) infection, confirmed a few days prior to hospital admission, without having initiated antiretroviral therapy at the time of initial evaluation. From a hematological standpoint, the patient had a history of severe microcytic hypochromic anemia, classified as grade III according to the World Health Organization criteria, as well as thrombocytopenia under investigation, suggesting the presence of an underlying systemic process. These hematological abnormalities constitute frequent clinical findings in patients with HIV infection and may be related to multiple pathophysiological mechanisms, including bone marrow suppression, infiltration by neoplastic processes, autoimmune phenomena, or opportunistic infections. HIV infection represents a major risk factor for the development of various immunosuppression-associated neoplasms, particularly those related to oncogenic viral infections. Among these, Kaposi sarcoma constitutes one of the AIDS-defining neoplasms and is closely associated with infection by human herpesvirus type 8 (HHV-8). Although this neoplasm classically manifests through characteristic violaceous cutaneous lesions on the skin and mucosae, it may also present with visceral or nodal involvement, especially in patients with advanced immunosuppression. In the context of Internal Medicine practice, the concomitant presence of febrile syndrome, cytopenias, and recent diagnosis of HIV infection requires consideration of a broad diagnostic spectrum that includes opportunistic infections, malignant hematological diseases, lymphoproliferative processes, and neoplasms associated with immunodeficiency. This clinical scenario requires a systematic and comprehensive diagnostic approach aimed at identifying the etiology of the clinical presentation and establishing timely treatment. Therefore, from the initial moment of hospital evaluation, the case represented a relevant diagnostic challenge for the Internal Medicine service, as it involved a young patient with recently documented immunosuppression and systemic manifestations potentially related to infectious or neoplastic processes associated with HIV infection. Onset of Clinical Presentation The current illness began approximately two weeks prior to hospital admission, with the onset of abdominal pain of nonspecific characteristics, without radiation or clear quadrant predominance. This symptom was accompanied by systemic manifestations such as arthralgias and generalized myalgias, as well as progressive deterioration of general condition. As the clinical course evolved, the patient developed intolerance to oral intake characterized by persistent nausea that progressed to vomiting of gastrointestinal contents. Subsequently, non-quantified fever developed, predominantly nocturnal, accompanied by profuse diaphoresis and subjective malaise, which motivated his first evaluation at the primary care level. During this initial evaluation, symptomatic management with analgesics and antipyretics was initiated, without documentation of significant clinical improvement in the following days. Due to persistence of the febrile syndrome and progressive deterioration of general condition, the patient sought medical evaluation again and was referred to the hospital emergency department for further study and management. Upon admission to the emergency department, systemic compromise was documented, characterized by arterial hypotension with blood pressure of 85/51 mmHg, tachycardia with heart rate of 131 beats per minute, respiratory rate of 23 breaths per minute, and body temperature of 39.3 °C. Oxygen saturation was 95% on room air. In the epidemiological context of the SARS-CoV-2 pandemic, and given the presence of fever and signs of systemic inflammatory response, a diagnostic protocol for COVID-19 infection was initiated using a rapid test, which resulted negative. However, as part of the institutional measures in place at that time, the patient was initially admitted to the area designated for suspected COVID-19 cases, despite the absence of clinical or paraclinical evidence confirming this etiology. During the first hours of hospital observation, respiratory manifestations suggestive of viral respiratory infection were ruled out, and the patient was subsequently transferred to the Internal Medicine service to continue the diagnostic approach to a febrile syndrome of undetermined etiology. This change of setting allowed initiation of a broader clinical evaluation aimed at identifying the cause of the underlying systemic process, considering both infectious processes and hematological or neoplastic diseases associated with the context of recent immunosuppression due to HIV infection. Thus, the onset of the clinical presentation was characterized by a progressive constitutional syndrome accompanied by gastrointestinal manifestations and persistent fever, whose evolution prompted hospitalization and initiation of a comprehensive diagnostic approach under the perspective of the Internal Medicine service. The chronological evolution of the patient’s clinical course is summarized in Table 1. Clinical Event Description Two weeks prior to hospital admission Onset of clinical presentation with abdominal pain, arthralgias, myalgias, intolerance to oral intake, nausea, and vomiting. Subsequently, predominantly nocturnal fever and diaphoresis developed. One week prior to hospital admission Diagnosis of HIV infection, without initiation of antiretroviral therapy. Day 1 Presentation to emergency department due to persistent febrile syndrome and deterioration of general condition. Initial vital signs: BP 85/51 mmHg, HR 131 bpm, RR 23 rpm, T 39.3 °C, SpO₂ 95% on room air. Day 1 Diagnostic protocol for SARS-CoV-2 initiated, with negative rapid test. Day 2 Admission to Internal Medicine service for evaluation of febrile syndrome of undetermined etiology. Day 3 First chest computed tomography, showing mediastinal and bilateral axillary lymphadenopathy without significant pulmonary infiltrates. Day 5 Initial laboratory tests showing severe anemia (Hb 5.9 g/dL), thrombocytopenia (28,000/µL), elevated C-reactive protein and D-dimer, and onset of renal function deterioration. Day 6 Excisional biopsy of inguinal lymph node performed for diagnostic purposes. Day 6 Arterial blood gas compatible with metabolic acidosis with respiratory compensation. Day 9 Follow-up laboratory tests showing worsening renal function, persistence of cytopenias, and elevated inflammatory markers. Day 11 Persistence of severe thrombocytopenia and progression of renal insufficiency. Day 12 Second computed tomography showing multiple lymphadenopathies in different nodal chains, bilateral pleural effusion, hepatosplenomegaly, and free abdominal fluid. Subsequently Histopathological and immunohistochemical study confirmed nodal Kaposi sarcoma with HHV-8 positivity. Final Diagnosis Nodal Kaposi sarcoma associated with HIV infection. Table 1. Clinical timeline of the patient. The timeline summarizes the main clinical, diagnostic, and evolutionary events during the patient’s hospitalization, from symptom onset to histopathological confirmation of diagnosis. Abbreviations: BP, blood pressure; HR, heart rate; RR, respiratory rate; SpO₂, oxygen saturation by pulse oximetry; Hb, hemoglobin; HIV, human immunodeficiency virus; CRP, C-reactive protein. Hospital Admission and Initial Clinical Evaluation After transfer to the Internal Medicine service, the patient underwent a comprehensive clinical evaluation aimed at identifying the etiology of the febrile syndrome and previously documented hematological abnormalities. At the time of admission to the hospital ward, apparent hemodynamic stabilization was observed compared to parameters recorded during initial evaluation in the emergency department. Vital signs at admission were as follows: blood pressure 130/75 mmHg, heart rate 75 beats per minute, respiratory rate 20 breaths per minute, body temperature 36.5 °C, and oxygen saturation 92% on room air. Despite relative improvement of the initial systemic inflammatory response, the prior persistence of fever and presence of significant cytopenias justified a detailed clinical evaluation. During general physical examination, the patient was conscious, alert, and oriented, without evidence of focal neurological deficit. Mucocutaneous inspection revealed marked pallor, consistent with previously documented severe anemia, although hydration status was adequate. No cutaneous lesions suggestive of Kaposi sarcoma, such as violaceous macules, plaques, or nodules on skin or visible mucosae, were identified at the time of evaluation. Examination of the head and neck showed a cylindrical neck without signs of jugular venous distention or vascular bruits, and without palpable cervical lymphadenopathy. The oral cavity showed no ulcerative lesions or vascular proliferations suggestive of mucosal involvement by immunosuppression-associated neoplasms. Cardiopulmonary evaluation revealed symmetric thoracic movements with adequate expansion. Pulmonary auscultation demonstrated vesicular breath sounds present in both hemithoraces without added sounds, while cardiac auscultation revealed rhythmic heart sounds of good intensity, without murmurs or gallop, not suggesting acute cardiopulmonary involvement. Abdominal examination revealed a soft, depressible abdomen, non-tender to superficial and deep palpation, with preserved peristalsis on auscultation. Percussion was tympanic over the colonic frame, and no palpable visceromegaly or evident intra-abdominal masses were identified during initial evaluation. However, during examination of the inguinal region, a palpable lymph node was identified in the left inguinal region measuring approximately 3 × 3 cm, of firm consistency, mobile relative to deep planes, and non-tender to palpation. This finding constituted a relevant clinical datum within the context of febrile syndrome and immunosuppressed state. Examination of the extremities showed symmetric limbs, without edema or peripheral vascular alterations, with palpable distal pulses and capillary refill time of approximately two seconds. From the perspective of the Internal Medicine clinical approach, the combination of febrile syndrome of undetermined origin, severe cytopenias, recently diagnosed HIV infection, and presence of peripheral lymphadenopathy raised a broad differential diagnosis. Among the main diagnostic possibilities considered were opportunistic infections, lymphoproliferative diseases such as lymphoma, disseminated infections including mycobacteriosis, as well as neoplasms associated with immunosuppression, including Kaposi sarcoma with atypical presentation. Consequently, after the initial clinical evaluation, it was decided to initiate a comprehensive diagnostic protocol, which included laboratory studies, imaging studies, and targeted evaluation of the inguinal lymphadenopathy with the aim of establishing its etiology and reaching a definitive diagnosis. Diagnostic Evaluation and Clinical Course Following the initial clinical evaluation in the Internal Medicine service, a comprehensive diagnostic protocol was initiated with the aim of identifying the etiology of the febrile syndrome, documented cytopenias, and presence of lymphadenopathy. Given the context of recently diagnosed HIV infection and the presence of systemic manifestations, the diagnostic approach was oriented toward ruling out opportunistic infections, hematological diseases, and neoplastic processes associated with immunosuppression. Initial laboratory studies demonstrated severe hematological abnormalities, particularly anemia and significant thrombocytopenia. Hemoglobin levels of 5.9 g/dL were documented, with hematocrit of 20.1%, findings consistent with severe anemia, as shown in Figure 1. Concomitantly, platelet count was markedly decreased, with initial values around 28,000/µL, confirming the presence of significant thrombocytopenia. Leukocyte count remained within relatively preserved ranges, with neutrophil predominance as represented in Figure 2. These hematological abnormalities raised the possibility of an underlying systemic process that could involve bone marrow suppression or infiltration, systemic inflammation, or neoplastic processes. Inflammatory markers were found to be elevated, highlighting C-reactive protein levels above 19 mg/dL, supporting the presence of an active systemic inflammatory process. Likewise, markedly elevated D-dimer levels were documented, suggesting activation of the coagulation cascade and endothelial dysfunction, findings that may be observed in severe inflammatory processes, systemic infections, or neoplastic diseases as shown in Figure 3. Biochemical studies additionally demonstrated progressive deterioration of renal function during hospitalization. Serum creatinine levels showed an increase from 1.23 mg/dL at initial evaluation to 3.77 mg/dL and subsequently 4.80 mg/dL, accompanied by a parallel rise in urea and blood urea nitrogen levels. These findings were consistent with the development of acute kidney injury, likely of multifactorial etiology, associated with systemic inflammatory response, hemodynamic alterations, and the underlying disease as represented in Figure 4. Concomitantly, electrolyte abnormalities were documented, including hyponatremia, hyperkalemia, hypocalcemia, and hyperphosphatemia, changes that reinforced the suspicion of significant renal involvement. Serum albumin levels were markedly decreased, with values around 1.33 g/dL, suggesting a significant systemic inflammatory state, as well as possible nutritional compromise or alterations in protein synthesis, as represented in Figure 5. Liver function tests showed mild alterations, with transaminases within near-normal ranges and minimal elevation of bilirubin levels. Tumor markers, including alpha-fetoprotein (AFP), CA 19-9, and carcinoembryonic antigen (CEA), were within normal limits, making the presence of primary neoplasms of gastrointestinal or hepatobiliary origin less likely. During the hospital course, an arterial blood gas analysis was also performed, which documented a pH of 7.45, with decreased bicarbonate levels and a negative base excess, findings consistent with metabolic acidosis with respiratory compensation, likely related to progressive deterioration of renal function. In parallel with laboratory evaluation, imaging studies were performed with the aim of identifying possible infectious foci or neoplastic processes. Chest computed tomography revealed the presence of bilateral axillary and mediastinal lymphadenopathy, without pulmonary infiltrates suggestive of acute infectious processes. The lungs showed preserved architecture, with only mild left basal laminar atelectasis identified. No space-occupying lesions were identified in the mediastinum as described in Figure 6. The presence of lymphadenopathy in multiple nodal chains, including mediastinal, axillary, and inguinal regions, raised suspicion of a lymphoproliferative or systemic neoplastic process. In the context of HIV infection, the differential diagnosis primarily included HIV-associated non-Hodgkin lymphoma, disseminated infections such as tuberculosis or systemic mycoses, multicentric Castleman disease, and Kaposi sarcoma with atypical nodal presentation. Given these findings, histopathological study of the affected lymph node through lymph node biopsy was considered essential in order to establish a definitive diagnosis and guide subsequent therapeutic management. Diagnostic Confirmation Given the persistence of the febrile syndrome, the presence of significant cytopenias, and the identification of lymphadenopathy in multiple nodal territories, it was decided to advance the diagnostic approach by obtaining tissue for histopathological study. In this context, an excisional biopsy of the inguinal lymph node was performed, a procedure considered fundamental to establish a definitive diagnosis, particularly in the setting of suspected lymphoproliferative or neoplastic processes associated with HIV infection. Histopathological analysis of the lymph node revealed a neoplastic proliferation of mesenchymal origin with a vascular pattern, characterized by the presence of spindle-shaped cells arranged in irregular fascicles, associated with the formation of irregular, narrow vascular channels. Areas with erythrocyte extravasation were also identified, a phenomenon frequently observed in vascular tumors and particularly characteristic of Kaposi sarcoma. The normal nodal architecture was partially replaced by this cellular proliferation, suggesting tumor infiltration of the lymphatic tissue. Because these morphological characteristics may be observed in various vascular tumors, immunohistochemical studies were performed in order to confirm the nature of the neoplasm. In the immunohistochemical panel, nuclear positivity for the latent antigen of human herpesvirus type 8 (HHV-8 LNA-1) was observed, a finding considered highly specific for Kaposi sarcoma. Likewise, positivity for CD34, an endothelial marker, was documented, demonstrating cytoplasmic staining in spindle cells and in the endothelium of capillaries present in the lesion. Additionally, the marker podoplanin (D2-40) showed cytoplasmic and membranous positivity, supporting the vascular origin of the neoplastic proliferation. The combination of morphological findings observed in histopathology together with the immunohistochemical profile allowed the establishment of a definitive diagnosis of Kaposi sarcoma with nodal involvement. This finding was particularly relevant, given that the patient did not present evident cutaneous lesions at the time of initial evaluation, suggesting an atypical presentation of the disease with predominant nodal involvement. In the context of recently diagnosed HIV infection, Kaposi sarcoma represents an AIDS-defining neoplasm associated with HHV-8 infection and favored by the state of cellular immunosuppression. Histopathological confirmation of Kaposi sarcoma explained the presence of multiple lymphadenopathies and contributed to orienting the diagnostic approach toward a vascular neoplasm associated with immunodeficiency. Therefore, lymph node biopsy and immunohistochemical analysis were determinant in clarifying the etiology of the clinical presentation, allowing the diagnosis of nodal Kaposi sarcoma in the context of HIV infection, a rare entity when it presents as an initial manifestation without evident cutaneous lesions. Clinical Interpretation and Relevance of the Case The presented case illustrates an atypical form of presentation of Kaposi sarcoma associated with HIV infection, characterized by predominant nodal involvement in the absence of evident cutaneous lesions at the time of initial evaluation. Although Kaposi sarcoma classically manifests with violaceous cutaneous lesions on the skin and mucosae, particularly in the lower extremities or oral cavity, primary or predominant involvement of lymph nodes is uncommon and may represent a significant diagnostic challenge in clinical practice. From the perspective of the Internal Medicine approach, this case acquired particular complexity due to the coexistence of febrile syndrome of undetermined origin, severe cytopenias, progressive deterioration of renal function, and multiple lymphadenopathies in a young patient with recently diagnosed HIV infection and without antiretroviral therapy. In this context, the initial differential diagnosis was broad and included several entities, among them HIV-associated non-Hodgkin lymphoma, disseminated opportunistic infections such as tuberculosis or systemic mycoses, multicentric Castleman disease, and other neoplasms related to immunosuppression. In parallel with clinical and laboratory evaluation, imaging studies were performed with the aim of identifying possible infectious foci or neoplastic processes. Initial chest computed tomography demonstrated the presence of bilateral axillary and mediastinal lymphadenopathy, without pulmonary infiltrates suggestive of acute infectious processes. The lungs showed preserved architecture, with only mild left basal laminar atelectasis, without mediastinal space-occupying lesions. Subsequently, a follow-up chest computed tomography was performed, in which progression of findings was documented, with an increase in the number and size of lymphadenopathies in multiple nodal territories, as well as the appearance of bilateral pleural effusion, hepatosplenomegaly, and free fluid in the abdominal cavity, which oriented toward a systemic process of infiltrative or neoplastic nature as described in Figure 7. The presence of severe cytopenias, particularly anemia and thrombocytopenia, contributed to increasing the initial suspicion of malignant or infiltrative hematological processes. Likewise, the identification of lymphadenopathy in multiple nodal territories on imaging studies reinforced the diagnostic possibility of a lymphoproliferative disease. However, histopathological study of the lymph node allowed identification of a vascular neoplasm compatible with Kaposi sarcoma, as shown in Figure 8, and was subsequently confirmed by immunohistochemistry with positivity for HHV-8, as shown in Table 2. Antibody Clone Staining pattern Interpretation Human herpesvirus 8 (HHV-8) 13B10 Nuclear Positive CD34 QBEND10 Cytoplasmic and membranous Positive Podoplanin (D2-40) D2-40 Cytoplasmic and membranous Positive Table 2. Immunohistochemical findings. Immunohistochemical analysis demonstrated nuclear positivity for HHV-8 (LNA-1), confirming the diagnosis of Kaposi sarcoma. CD34 and podoplanin (D2-40) positivity support the endothelial origin of the spindle cell proliferation. Abbreviations: HHV-8, human herpesvirus 8. Kaposi sarcoma associated with HIV is characterized as an angioproliferative neoplasm induced by infection with human herpesvirus type 8, whose development is favored by impairment of cellular immunity mediated by CD4 T lymphocytes. In patients with HIV infection without antiretroviral treatment, persistent viral replication and immunological dysfunction favor proliferation of endothelial cells infected by HHV-8, leading to the formation of tumor lesions. Nodal involvement may occur as part of disseminated disease; however, when it presents as an initial manifestation without evident cutaneous lesions, it may delay diagnosis due to its clinical similarity to other entities, particularly HIV-associated lymphomas. In this sense, lymph node biopsy constitutes a fundamental diagnostic tool, as it allows differentiation between infectious, inflammatory, and neoplastic processes through histopathological analysis and the application of immunohistochemical techniques. This case highlights the importance of maintaining a high index of diagnostic suspicion in patients with HIV infection who present with lymphadenopathy and systemic manifestations, even in the absence of the cutaneous lesions classically described for Kaposi sarcoma. It also emphasizes the relevance of performing a systematic and timely diagnostic approach in patients with febrile syndrome and cytopenias, in order to identify early neoplastic diseases associated with immunosuppression. Finally, the identification of Kaposi sarcoma in this clinical context emphasizes the need to consider this entity within the differential diagnosis of lymphadenopathy in patients with HIV, particularly in those without antiretroviral treatment, as its timely recognition directly impacts prognosis and the initiation of appropriate therapeutic management. DISCUSSION The presented case illustrates an atypical form of Kaposi sarcoma (KS) associated with HIV infection, characterized by predominant nodal involvement in the absence of evident cutaneous lesions at the time of initial evaluation. Although KS classically manifests with violaceous cutaneous lesions, its clinical spectrum is broad and may include mucosal, visceral, and lymphatic involvement, particularly in patients with advanced immunosuppression [ 14 , 15 ]. In the context of HIV infection, the development of KS is closely related to the interaction between immunosuppression, chronic inflammation, and coinfection with human herpesvirus type 8 (HHV-8). Depletion of CD4 + lymphocytes and global immune dysfunction favor viral reactivation and proliferation of infected endothelial cells, leading to the formation of angioproliferative lesions [ 3 ]. One of the most relevant aspects of this case is the predominant nodal presentation, which is uncommon and represents a significant diagnostic challenge. Available evidence indicates that nodal involvement in KS usually occurs as part of disseminated disease; however, cases with nodal involvement as the initial or main manifestation are rare and poorly described in the literature [ 15 , 16 ]. This presentation may mimic other more frequent entities in patients with HIV, particularly non-Hodgkin lymphoma, disseminated opportunistic infections, or HHV-8–associated multicentric Castleman disease, contributing to diagnostic delays [ 16 ]. In the described case, the presence of multiple lymphadenopathies, febrile syndrome, cytopenias, and deterioration of renal function initially suggested an infectious or lymphoproliferative process. This approach is consistent with what is reported in the literature, where the initial differential diagnosis in patients with HIV and generalized lymphadenopathy usually includes granulomatous infections, systemic mycoses, and immunosuppression-associated lymphomas [ 4 ]. The absence of characteristic cutaneous lesions in this patient contributed to lower suspicion of KS, delaying consideration of this entity within the differential diagnosis. Imaging studies, although useful for evaluating disease extent, have important limitations in etiological differentiation. In this case, computed tomography demonstrated multiple lymphadenopathies and systemic involvement, findings that may be observed in both infectious and neoplastic processes. This lack of radiological specificity has been widely described and underscores the need for histopathological confirmation in all suspected cases [ 14 , 16 ]. Lymph node biopsy was decisive in establishing the definitive diagnosis, demonstrating a vascular neoplasm with histological features compatible with KS, confirmed by immunohistochemistry with HHV-8 positivity. This finding highlights the importance of early histopathological evaluation in patients with persistent lymphadenopathy, especially when the diagnosis remains unclear after initial studies [ 14 ]. From a clinical standpoint, this case highlights several gaps in the recognition of non-classical presentations of KS. In particular, recent literature indicates that nodal or visceral forms without cutaneous lesions are underrepresented and may go unnoticed in clinical practice, contributing to diagnostic delays and worse prognosis [ 15 ]. Likewise, the lack of specific diagnostic algorithms for these presentations complicates clinical decision-making in early stages. Timely initiation of antiretroviral therapy constitutes a fundamental pillar in the management of HIV-associated KS, as immune restoration may induce tumor regression and improve clinical outcomes. However, in cases with disseminated disease or visceral involvement, additional systemic oncologic treatment may be required [ 3 ]. In this sense, early diagnosis is crucial to optimize treatment and improve prognosis. Finally, this case highlights the importance of maintaining a high index of diagnostic suspicion in patients with HIV who present with lymphadenopathy and systemic manifestations, even in the absence of cutaneous lesions. Inclusion of KS within the differential diagnosis in these scenarios is essential to avoid diagnostic delays and allow timely management. CONCLUSIONS Kaposi sarcoma associated with HIV infection continues to represent an entity of high clinical relevance, particularly in patients with recent diagnosis or without antiretroviral treatment, in whom immunosuppression favors more aggressive, disseminated, and atypical presentations. This case highlights the heterogeneity of the clinical spectrum of the disease and the need to recognize non-classical variants that may deviate from its usual cutaneous presentation. Presentation with predominant nodal involvement in the absence of evident cutaneous lesions constitutes an uncommon form that represents a significant diagnostic challenge. In these scenarios, clinical overlap with more prevalent entities in patients with HIV, such as non-Hodgkin lymphoma, disseminated opportunistic infections, and HHV-8–associated Castleman disease, may lead to delays in diagnostic suspicion and in the initiation of appropriate management. This case emphasizes the importance of a comprehensive and systematic diagnostic approach in patients with HIV who present with persistent lymphadenopathy and systemic manifestations. Integration of clinical data, laboratory findings, imaging studies, and, fundamentally, histopathological evaluation with immunohistochemistry, is essential to establish the definitive diagnosis. In particular, identification of HHV-8 positivity constitutes a key element to confirm Kaposi sarcoma in atypical presentations. Likewise, it is emphasized that imaging studies, although useful for evaluating disease extent, have limitations in etiological differentiation, and therefore should not delay biopsy in cases with persistent diagnostic suspicion. The timely decision to obtain tissue for histological study is determinant in avoiding diagnostic delays and improving clinical outcomes. From a therapeutic standpoint, early initiation of antiretroviral therapy is fundamental, as restoration of immune function may modify disease progression and improve prognosis. In cases with systemic involvement or advanced disease, an additional therapeutic approach with specific oncologic treatment may be required, reinforcing the importance of early and accurate diagnosis. Finally, this case contributes to expanding knowledge regarding non-classical presentations of Kaposi sarcoma, particularly in young patients with HIV infection. Documentation of these clinical variants is essential to improve diagnostic suspicion, reduce diagnostic delays, and optimize clinical management. In this sense, it is indispensable to maintain a high index of suspicion and to include Kaposi sarcoma within the differential diagnosis of lymphadenopathy in patients with HIV, even in the absence of cutaneous manifestations, thereby promoting a broader, timely, and outcome-oriented clinical approach in this population. Declarations ACKNOWLEDGMENTS The authors would like to acknowledge the healthcare personnel of the Mexican Social Security Institute (IMSS) for their commitment, professionalism, and dedication to patient care. Their continuous efforts play a fundamental role in the diagnosis and management of complex clinical conditions. We also extend our gratitude to the pathology department for their invaluable contribution to the diagnostic process, particularly in the histopathological and immunohistochemical evaluation that was essential for establishing the final diagnosis. The authors wish to express their sincere appreciation to each member of the team whose contributions made this work possible. María Dioselina Ruiz Barrera is acknowledged for her leadership, clinical dedication, and commitment to academic excellence. Luis Ernesto Heredia Santos is recognized for his clinical insight and contribution to patient care and case analysis. María Alaciel Galván Merlos is appreciated for her guidance, supervision, and support in the clinical management of the case. Leticia Guerrero Navarrete is acknowledged for her collaboration and commitment to patient-centered care. Lissette Haydee García Mena is recognized for her academic support and contribution to the organization and interpretation of information. María Jose Hernández Cruz is appreciated for her assistance in data collection and clinical documentation. Liliana Antonio Revuelta is acknowledged for her contribution to data analysis and critical review of the manuscript. We also recognize the value of collaboration, mentorship, and friendship that transcends time and borders, enriching both the academic and human dimensions of this work. Finally, we dedicate this work to all patients living with HIV. Through this report, we aim to contribute to greater awareness, earlier diagnosis, and improved clinical care, reaffirming that they are not alone and that ongoing efforts in research and medicine remain essential to improving their outcomes and quality of life. Conflicts of Interest / Competing Interests The authors declare that they have no competing interests, either financial or non-financial, related to this work. FUNDING This study received no external funding. ETHICAL APPROVAL This case report was conducted in accordance with institutional ethical standards, as well as with the principles outlined in the Declaration of Helsinki for research involving human subjects. The clinical management and documentation of this case were performed within the framework of standard medical care at the Mexican Social Security Institute (IMSS). Institutional procedures and patient care were carried out in compliance with national regulations, including the Mexican Official Standard NOM-004-SSA3-2012 for clinical records and the applicable provisions of the General Health Law regarding medical care services. CONSENT TO PARTICIPATE AND FOR PUBLICATION Written informed consent for hospitalization and medical care was obtained from the patient prior to admission. Additionally, informed consent for the use of clinical information for academic and publication purposes was obtained from the patient. Supporting documentation is available, including the institutional informed consent form issued by the Mexican Social Security Institute. All identifying patient information has been anonymized to protect confidentiality. Data Availability The data supporting the findings of this study are available from the corresponding author upon reasonable request. All data are de-identified in accordance with institutional and ethical regulations. Code Availability No custom code or software was developed or used in this study. All relevant data supporting the findings are included within the manuscript. AUTHOR CONTRIBUTIONS STATEMENT M.D.R.B. conceptualized the study, led the clinical management of the patient, and wrote the main manuscript. L.E.H.S. contributed to patient care, data acquisition, and manuscript drafting. M.A.G.M. supervised the clinical management and critically revised the manuscript for important intellectual content. L.G.N. contributed to clinical data interpretation and manuscript review. L.H.G.M. conducted the literature review and contributed to manuscript editing. M.J.H.C. participated in data collection and clinical documentation. 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HIV lymphadenopathy: Differential diagnosis and important imaging features. American Journal of Roentgenology 2021;216:526–33. https://doi.org/10.2214/AJR.19.22334. Barrionuevo-Cornejo C, Dueñas-Hancco D. Lymphadenopathies in human immunodeficiency virus infection. Semin Diagn Pathol 2018;35:84–91. https://doi.org/10.1053/j.semdp.2017.12.001. Ground M, Veenendaal T, Chiluzi D, Nkhonjera G, Glas A, Glas-van Dijk L. HHV8-Associated Multicentric Castleman Disease: A Case Report on a Rare Complication of HIV in a Low-Income Setting. Res Rep Trop Med 2024;Volume 15:91–7. https://doi.org/10.2147/RRTM.S483426. Hoffmann C, Oksenhendler E, Littler S, Grant L, Kanhai K, Fajgenbaum DC. The clinical picture of Castleman disease: a systematic review and meta-analysis. Blood Adv 2024;8:4924–35. https://doi.org/10.1182/bloodadvances.2024013548. Ocampo-Gonzalez FA, Bhagat G. KSHV/HHV-8-associated multicentric Castleman disease and nodal Kaposi sarcoma displaying a lymphangiectatic pattern. Blood 2024;144:587. https://doi.org/10.1182/blood.2024024839. Htet KZ, Bahrani E, Leslie KS. Updates on Kaposi sarcoma. Clin Dermatol 2025. https://doi.org/10.1016/j.clindermatol.2025.09.013. Jebrini NEM, Natsheh MA, Jaber M, Muhtaseb R, Qunaibi Y, Hidri H, et al. Atypical presentation of Kaposi sarcoma in an HIV-negative patient: a case report and comprehensive literature review. Annals of Medicine & Surgery 2024;86:7325–9. https://doi.org/10.1097/ms9.0000000000002553. Guimarães A, Azevedo R, Lopes S, Soares J. Atypical Presentation of Kaposi Sarcoma. ACG Case Rep J 2026;13:e01963. https://doi.org/10.14309/crj.0000000000001963. Cao E, Saad M, Deisch J, Barbosa M, Fakhouri Y, Sutjita M. Noncutaneous Visceral Kaposi Sarcoma of the Stomach and Liver: A Case Report. Case Rep Oncol 2025;18:1–13. https://doi.org/10.1159/000550013. Rojek NW, Worswick S, Shinkai K, Fox LP. Diagnóstico clínico y tratamiento 2025. In: Papadakis MA, Rabow MW, McQuaid KR, Gandhi Monica, editors. Diagnóstico clínico y tratamiento 2025. 64 a edición, New York, NY: 2025. Dittmer DP, Damania B. Kaposi’s sarcoma-associated herpesvirus (KSHV)-associated disease in the AIDS Patient: An update. Cancer Treat Res 2019;177:63–80. https://doi.org/10.1007/978-3-030-03502-0_3. Nissen T, Wynn R. The clinical case report: a review of its merits and limitations. London: 2014. https://doi.org/10.1186/1756-0500-7-264. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9363985","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":622611956,"identity":"924d6510-f545-4152-b017-36897fda6ea7","order_by":0,"name":"María Dioselina Ruiz Barrera","email":"data:image/png;base64,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","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":true,"prefix":"","firstName":"María","middleName":"Dioselina Ruiz","lastName":"Barrera","suffix":""},{"id":622611958,"identity":"ec55142b-16ec-4ef4-a8b3-1440d3799ecb","order_by":1,"name":"Luis Ernesto Heredia Santos","email":"","orcid":"","institution":"Mexican Social Security Institute","correspondingAuthor":false,"prefix":"","firstName":"Luis","middleName":"Ernesto Heredia","lastName":"Santos","suffix":""},{"id":622611960,"identity":"1d222c51-4ae8-4ea2-82f4-6bdd2627cdca","order_by":2,"name":"María Alaciel Galván Merlos","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"Alaciel Galván","lastName":"Merlos","suffix":""},{"id":622611962,"identity":"40a68a7a-6360-4186-ab9d-8abad89c4800","order_by":3,"name":"Leticia Guerrero Navarrete","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"Leticia","middleName":"Guerrero","lastName":"Navarrete","suffix":""},{"id":622611964,"identity":"16980467-8002-40e8-b9fb-40ad12bdcdda","order_by":4,"name":"Lissette Haydee García Mena","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"Lissette","middleName":"Haydee García","lastName":"Mena","suffix":""},{"id":622611967,"identity":"d1b849bc-477e-4524-ba14-d36420fb5b07","order_by":5,"name":"María Jose Hernandez Cruz","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"Jose Hernandez","lastName":"Cruz","suffix":""},{"id":622611968,"identity":"e11bcb89-8d72-420e-b77f-f9641e5d3fe0","order_by":6,"name":"Liliana Antonio Revuelta","email":"","orcid":"","institution":"Instituto Politécnico Nacional","correspondingAuthor":false,"prefix":"","firstName":"Liliana","middleName":"Antonio","lastName":"Revuelta","suffix":""}],"badges":[],"createdAt":"2026-04-09 06:23:58","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9363985/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9363985/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106903458,"identity":"d15ec0f2-6250-45dc-a2e0-82152b413261","added_by":"auto","created_at":"2026-04-14 15:11:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":407716,"visible":true,"origin":"","legend":"\u003cp\u003eHematological parameters during hospitalization. This figure shows the evolution of hemoglobin levels and platelet counts during hospitalization (days 5, 9, and 11). Hemoglobin values remained markedly decreased throughout the observation period, reflecting persistent severe anemia. Platelet counts demonstrated a progressive decline over time, indicating worsening thrombocytopenia during the clinical course.\u003c/p\u003e","description":"","filename":"FIGURE1.Hematologicalparametersduringhospitalization.png","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/515598903bf9b93d6b1ee8e2.png"},{"id":106903381,"identity":"b21a30f4-f663-4819-ad7c-a158a39fd95e","added_by":"auto","created_at":"2026-04-14 15:11:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":529726,"visible":true,"origin":"","legend":"\u003cp\u003eLeukocyte differential and neutrophil-to-lymphocyte ratio (NLR). This figure illustrates the trends in total leukocyte count, absolute neutrophil and lymphocyte counts, and the neutrophil-to-lymphocyte ratio during hospitalization. Leukocyte and neutrophil counts progressively increased, while lymphocyte levels remained relatively low. The neutrophil-to-lymphocyte ratio peaked around day 9, reflecting an intensified systemic inflammatory response.\u003c/p\u003e","description":"","filename":"FIGURE2.LeukocytedifferentialandneutrophiltolymphocyteratioNLR.png","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/4d0d16f8f4a6163be859ce72.png"},{"id":106903366,"identity":"2d58da32-9fda-4cef-948e-a8544ef44d87","added_by":"auto","created_at":"2026-04-14 15:11:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":238252,"visible":true,"origin":"","legend":"\u003cp\u003eD-dimer levels during hospitalization. This figure shows the progression of D-dimer levels during hospitalization. Markedly elevated values were observed throughout the clinical course, with a progressive increase from day 5 to day 11, suggesting ongoing systemic inflammation and activation of the coagulation cascade.\u003c/p\u003e","description":"","filename":"FIGURE3.Ddimerlevelsduringhospitalization.png","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/4e69a04a2a7167d55151696d.png"},{"id":106903367,"identity":"b93ba061-3318-4718-a94c-b035f19d7dc0","added_by":"auto","created_at":"2026-04-14 15:11:39","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":509750,"visible":true,"origin":"","legend":"\u003cp\u003eRenal function tests during hospitalization. This figure presents the temporal changes in renal function markers, including urea, blood urea nitrogen (BUN), and serum creatinine levels. All parameters showed a progressive increase from day 5 to day 11, indicating worsening renal dysfunction during hospitalization.\u003c/p\u003e","description":"","filename":"FIGURE4.Renalfunctiontestsduringhospitalization.png","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/b447392c4c3c0ab47329bd56.png"},{"id":106903364,"identity":"4a5666f2-25c0-4128-b8fb-c1b8a40ed37d","added_by":"auto","created_at":"2026-04-14 15:11:39","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":430643,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in serum electrolytes during hospitalization. This figure illustrates the evolution of serum sodium, potassium, and chloride concentrations during hospitalization. Sodium and chloride levels remained relatively stable throughout the observation period, whereas potassium levels showed a gradual increase, consistent with impaired renal function.\u003c/p\u003e","description":"","filename":"FIGURE5.Trendsinserumelectrolytesduringhospitalization.png","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/b7da75687f664a6915df6e96.png"},{"id":106903374,"identity":"0604c3ce-e076-4dd9-99d2-fa4b26b1add5","added_by":"auto","created_at":"2026-04-14 15:11:42","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1264531,"visible":true,"origin":"","legend":"\u003cp\u003eChest imaging findings during hospitalization. Panel A. Chest radiograph. Frontal chest radiograph showing preserved cardiomediastinal silhouette and bilateral perihilar interstitial markings without evidence of focal consolidation. No pleural effusion or pneumothorax is identified. Panels B–E. Chest computed tomography (CT) scans (axial lung window). Axial CT images demonstrate preserved pulmonary architecture without evidence of focal consolidation or radiological findings suggestive of acute infectious processes. A mild left basal laminar atelectasis is observed. Additionally, bilateral axillary and mediastinal lymphadenopathy are identified, without evidence of mediastinal space-occupying lesions. Overall, these findings are consistent with the absence of acute pulmonary infection, with associated lymphadenopathy suggestive of an underlying systemic or neoplastic process, as described in the clinical context.\u003c/p\u003e","description":"","filename":"FIGURE6.Chestimagingfindingsduringhospitalization.png","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/7d3d77f2dbeea6dd2876898a.png"},{"id":106903358,"identity":"1fe4117f-c46c-47ef-895e-9e4e048b230a","added_by":"auto","created_at":"2026-04-14 15:11:37","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1447866,"visible":true,"origin":"","legend":"\u003cp\u003eFollow-up computed tomography showing progression of thoracic involvement. Panel A–C. Coronal CT reconstructions. Coronal images demonstrate extensive bilateral pulmonary involvement characterized by patchy consolidations with a predominantly perihilar and basal distribution. There is evidence of associated bilateral pleural effusion occupying a significant portion of the thoracic cavity, contributing to partial compression of the underlying lung parenchyma. Additionally, findings suggest increased soft tissue density consistent with generalized lymphadenopathy and possible associated systemic involvement. Panels D–F. Axial CT images (lung window). Axial sections confirm the presence of bilateral pleural effusions with compressive atelectasis of adjacent lung segments. Patchy areas of consolidation and interstitial involvement are observed, without well-defined cavitary lesions. The distribution and extent of findings are suggestive of a progressive systemic process rather than a localized pulmonary infection. Overall, the imaging findings demonstrate clear radiological progression compared to prior studies, with development of pleural effusions, worsening parenchymal involvement, and features consistent with systemic disease, correlating with the patient’s clinical deterioration.\u003c/p\u003e","description":"","filename":"FIGURE7.Followupcomputedtomographyshowingprogressionofthoracicinvolvement..png","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/db3a8e462fdade22cc218a39.png"},{"id":106903376,"identity":"409bd04d-c467-48d7-ba81-ab23d19dce56","added_by":"auto","created_at":"2026-04-14 15:11:42","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":4070793,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological and immunohistochemical findings of nodal Kaposi sarcoma. A–B. Hematoxylin and eosin (H\u0026amp;E) staining. Microscopic examination shows a mesenchymal vascular neoplasm characterized by a proliferation of spindle-shaped cells arranged in interlacing fascicles. Irregular, slit-like vascular spaces are observed, containing extravasated erythrocytes. The background demonstrates a mixed inflammatory infiltrate. These findings are consistent with Kaposi sarcoma. C. CD34 immunohistochemistry. Immunostaining reveals cytoplasmic positivity in spindle cells as well as in endothelial cells lining vascular channels, supporting the endothelial origin of the neoplastic proliferation. D. HHV-8 (LNA-1) immunohistochemistry. Nuclear positivity for human herpesvirus 8 (HHV-8) latent nuclear antigen-1 (LNA-1) is demonstrated, confirming the diagnosis of Kaposi sarcoma.\u003c/p\u003e","description":"","filename":"FIGURE8.HistopathologicalandimmunohistochemicalfindingsofnodalKaposisarcoma.png","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/21d248f2c82ac5de72e03656.png"},{"id":107681596,"identity":"85118f30-4bf9-4e6d-bf5c-1c5797f0ab34","added_by":"auto","created_at":"2026-04-24 02:55:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10456587,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9363985/v1/25d683d7-57b5-450b-b55c-d5ea85a5c8ae.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Atypical Nodal Kaposi Sarcoma in HIV Infection. A case report and literature review","fulltext":[{"header":"INTRODUCTION","content":"\u003ch2\u003eHIV Infection: Epidemiological, Immunopathogenic Basis and Oncologic Complications\u003c/h2\u003e\n\u003cp\u003eHuman immunodeficiency virus (HIV) infection continues to be a relevant global public health problem, despite advances in antiretroviral therapy (ART), which have transformed its clinical course into a controllable chronic disease with a significant increase in survival [1]. However, important challenges persist, including late diagnosis, sustained transmission in vulnerable populations, and difficulties in therapeutic adherence, which condition progression to advanced immunosuppression [2].\u003c/p\u003e\n\u003cp\u003eThe current epidemiological profile shows a shift toward younger populations and groups with specific risk behaviors, which maintains the incidence of HIV-associated complications, particularly in contexts where access to ART is limited or initiated late. In this scenario, opportunistic diseases and neoplasms continue to represent important causes of morbidity and mortality in patients with HIV [3].\u003c/p\u003e\n\u003cp\u003eThe pathophysiology of HIV is characterized by progressive depletion of CD4+ T lymphocytes, as well as a complex dysfunction of the immune system involving both innate and adaptive immunity. This process implies not only cellular loss but also functional alterations, such as T-cell exhaustion, dysfunction of antigen-presenting cells, and persistent activation of macrophages [1].\u003c/p\u003e\n\u003cp\u003eA key element in immunopathogenesis is early damage to gut-associated lymphoid tissue (GALT), which favors microbial translocation into systemic circulation. This phenomenon perpetuates chronic immune activation and generates a persistent inflammatory state that contributes to the development of systemic comorbidities, including cardiovascular, metabolic, and neoplastic diseases [2].\u003c/p\u003e\n\u003cp\u003eEven in patients on ART, residual inflammation and persistent immune activation condition a pro-inflammatory and pro-oncogenic environment, in which residual viral replication is favored and the immune system is unable to control oncogenic infections [1].\u003c/p\u003e\n\u003cp\u003ePeople living with HIV have a significantly higher risk of developing neoplasms compared to the general population, due to the interaction between immunosuppression, chronic inflammation, and coinfections with oncogenic viruses [3,4].\u003c/p\u003e\n\u003cp\u003eAIDS-defining cancers include Kaposi sarcoma, non-Hodgkin lymphoma, and invasive cervical cancer, all closely related to viral infections such as HHV-8, Epstein\u0026ndash;Barr virus (EBV), and human papillomavirus (HPV) [3].\u003c/p\u003e\n\u003cp\u003eIn the ART era, a decrease in the incidence of these tumors has been observed; however, a relative increase in non-AIDS-defining neoplasms has emerged, such as Hodgkin lymphoma, anal cancer, hepatocellular carcinoma, and lung cancer [5]. This epidemiological change is associated with aging of the HIV population, persistence of chronic inflammation, and prolonged exposure to additional risk factors.\u003c/p\u003e\n\u003cp\u003eKaposi sarcoma is an angioproliferative neoplasm associated with human herpesvirus type 8 (HHV-8), whose pathogenesis involves proliferation of infected endothelial cells in a context of immunosuppression and angiogenic stimulation mediated by proinflammatory cytokines. Although its classic presentation is cutaneous, it may manifest with visceral or nodal involvement, particularly in patients with advanced immunodeficiency, which represents an important diagnostic challenge [6].\u003c/p\u003e\n\u003cp\u003eThe current approach to HIV infection includes not only virological control through ART but also strategies aimed at prevention and early detection of neoplasms. Immune restoration through ART has been shown to significantly reduce the incidence of AIDS-defining cancers; however, it does not completely eliminate oncologic risk [3].\u003c/p\u003e\n\u003cp\u003eIn this context, targeted screening strategies have been developed, particularly for neoplasms associated with oncogenic viruses, such as cervical cancer and anal cancer, especially in high-risk populations. Likewise, control of modifiable risk factors, early detection of viral coinfections, and close clinical follow-up form an integral part of patient management. Therefore, the contemporary approach to HIV requires a comprehensive vision that includes oncologic surveillance, control of chronic inflammation, and early identification of atypical manifestations, with the aim of improving clinical outcomes and reducing disease burden [7].\u003c/p\u003e\n\u003ch2\u003eKaposi Sarcoma: Pathophysiology, Role of HHV-8, and Relationship with Immunosuppression\u003c/h2\u003e\n\u003cp\u003eKaposi sarcoma (KS) is a low- to intermediate-grade vascular neoplasm, characterized by proliferation of spindle cells, formation of irregular vascular slits, extravasation of erythrocytes, and variable inflammatory infiltrate. In biological terms, it does not behave as a purely mesenchymal conventional sarcoma, but rather as an angioproliferative proliferation strongly influenced by inflammatory, viral, and immunological signals. In practice, this explains its tendency to be multifocal, its association with states of immunosuppression, and the possibility of affecting not only skin but also mucosae, lymph nodes, and visceral organs.\u003c/p\u003e\n\u003cp\u003eCurrently, four main clinical-epidemiological variants are recognized: classic, endemic, iatrogenic, and epidemic or HIV-associated. Although they share a viral etiological basis, they differ in age of presentation, clinical aggressiveness, anatomical distribution, and immunological context. The HIV-associated variant usually presents a more aggressive behavior, greater tumor burden, and more frequent extracutaneous involvement, particularly when advanced immunosuppression or absence of antiretroviral treatment exists [8,9].\u003c/p\u003e\n\u003cp\u003eHuman herpesvirus type 8 (HHV-8), also called Kaposi sarcoma-associated herpesvirus (KSHV), is the indispensable etiologic agent of KS. Without HHV-8 infection, the disease does not develop; however, viral presence alone is not sufficient, as a permissive biological context is also required, especially one of immunoderegulation. HHV-8 also participates in other lymphoproliferative and inflammatory entities, such as primary effusion lymphoma, KSHV-associated multicentric Castleman disease, and KSHV-related cytokine inflammatory syndrome, which underscores its oncogenic and proinflammatory capacity [10,11].\u003c/p\u003e\n\u003cp\u003eFollowing primary infection, HHV-8 establishes latency in host cells, with restricted expression of viral genes oriented toward maintaining the episome, promoting cellular survival, and avoiding immune elimination. Under certain conditions, the virus can reactivate and enter the lytic phase, with expression of genes that enhance inflammation, angiogenesis, and proliferation. The alternation between latency and lysis is central to KS oncogenesis, as both phases contribute distinct elements to the tumor microenvironment [8,11].\u003c/p\u003e\n\u003cp\u003eHHV-8 promotes tumorigenesis through several viral proteins with functions analogous to cellular regulators. Among the most important are LANA-1, which contributes to maintenance of the viral genome and blocks suppressor pathways such as p53 and Rb; vIL-6, which promotes cellular proliferation and inflammation; vBcl-2, which inhibits apoptosis; and vGPCR, which stimulates proangiogenic signaling. Together, these mechanisms generate an environment of abnormal cellular survival, resistance to apoptosis, and sustained proliferative activation.\u003c/p\u003e\n\u003cp\u003eAt the microenvironment level, KS depends on a network of cytokines and growth factors, including IL-6, TNF-\u0026alpha;, IFN-\u0026gamma;, PDGF, and VEGF, which stimulate angiogenesis, inflammation, and expansion of spindle cells. This \u0026ldquo;cytokine-dependent\u0026rdquo; nature helps explain why the tumor may coexist with systemic inflammatory syndromes and why some clinical manifestations exceed the simple tumor mass.\u003c/p\u003e\n\u003cp\u003eThe KS lesion is predominantly composed of spindle cells with an aberrant endothelial/lymphatic phenotype. Immunohistochemically, they usually express markers such as CD34 and frequently podoplanin (D2-40), while nuclear positivity for HHV-8 LNA-1 is the most useful confirmatory finding. This profile supports that neoplastic cells derive from an endothelial population reprogrammed by the virus and the inflammatory environment. From a histopathological standpoint, KS shows a stepwise evolution from patch to plaque to nodular lesions, with progressive increase in spindle cell proliferation, greater vascular complexity, and more evident erythrocyte extravasation. In nodal or visceral disease, these features may be preserved, although the anatomical pattern of infiltration modifies the macroscopic appearance and clinical suspicion [8].\u003c/p\u003e\n\u003cp\u003eAlthough HHV-8 is necessary, immunosuppression is the factor that most strongly determines the clinical expression of KS. This is demonstrated both in people with HIV and in solid organ transplant recipients and patients under iatrogenic immunosuppression. A recent meta-analysis showed that the risk of cancers related to viral infections increases markedly in people with HIV and also in transplant recipients, with KS being one of the tumors with the highest relative increase in both groups. In people with HIV, the meta-risk for KS was extraordinarily high [12].\u003c/p\u003e\n\u003cp\u003eIn HIV infection, the loss of immune control over HHV-8 does not depend solely on the numerical decrease of CD4 cells, but also on qualitative dysfunction of cellular and humoral immunity, persistent immune activation, and a proangiogenic cytokine environment. Therefore, HIV not only facilitates persistent HHV-8 infection but also creates a biological setting that favors tumor expansion. This phenomenon helps explain why HIV-associated KS may be more aggressive and disseminated than other variants [9,13].\u003c/p\u003e\n\u003ch2\u003eHIV\u0026ndash;HHV-8 Interaction and Development of Angioproliferative Neoplasms\u003c/h2\u003e\n\u003cp\u003eThe interaction between human immunodeficiency virus (HIV) and human herpesvirus type 8 (HHV-8) constitutes a paradigmatic model of viral oncogenesis in the context of immunosuppression. This interaction not only increases the risk of developing Kaposi sarcoma (KS), but also modulates its clinical behavior, favoring more aggressive, multifocal forms with greater systemic involvement [14].\u003c/p\u003e\n\u003cp\u003eThe interaction between HIV and HHV-8 constitutes a central element in the pathophysiology of Kaposi sarcoma and other angioproliferative neoplasms. Under normal conditions, HHV-8 infection remains in a latent state under immune system control, particularly mediated by cellular immunity. However, in the context of HIV infection, the progressive depletion of CD4+ T lymphocytes and global immune dysfunction compromise this control, allowing viral reactivation and proliferation of infected cells. In addition to quantitative CD4 reduction, HIV induces functional alterations such as T-cell exhaustion and decreased cytotoxic response, which favor viral persistence and oncogenesis [3,14].\u003c/p\u003e\n\u003cp\u003eHIV infection is associated with a state of persistent chronic immune activation, characterized by sustained elevation of proinflammatory cytokines and activation of intracellular pathways that promote cellular proliferation. This inflammatory environment generates a proangiogenic microenvironment in which HHV-8 finds ideal conditions to enhance its oncogenic activity. Overexpression of factors such as vascular endothelial growth factor (VEGF), as well as cytokines such as IL-6 and TNF-\u0026alpha;, contributes to the proliferation of infected endothelial cells and the formation of aberrant vascular structures. This phenomenon is key to explaining the angioproliferative nature of Kaposi sarcoma and its tendency toward multifocal dissemination [1,14].\u003c/p\u003e\n\u003cp\u003eBeyond immunosuppression, HIV may exert direct effects on HHV-8 replication. It has been demonstrated that HIV viral proteins, particularly the Tat protein, have the capacity to induce activation of HHV-8 genes, promoting its transition from latent to lytic phase. This shift increases the expression of viral genes involved in cellular proliferation, angiogenesis, and immune evasion. Likewise, the Tat protein exerts direct proangiogenic effects on endothelial cells, stimulating their migration and proliferation, thereby contributing to tumor expansion [6].\u003c/p\u003e\n\u003cp\u003eHHV-8 primarily infects endothelial cells, inducing their transformation into a proliferative phenotype characteristic of Kaposi sarcoma. In the context of HIV infection, endothelial dysfunction is exacerbated by systemic inflammation and oxidative stress, favoring cellular reprogramming. Infected cells acquire spindle-shaped morphology and express endothelial markers such as CD34 and podoplanin, reflecting their vascular origin. This transformation process is mediated both by viral gene expression and by the influence of the inflammatory microenvironment, consolidating a cellular phenotype resistant to apoptosis and with high proliferative capacity [14].\u003c/p\u003e\n\u003cp\u003eA distinctive feature of Kaposi sarcoma is its multifocal behavior, which does not follow the classical model of single clonal expansion. Instead, multiple foci of infection and cellular transformation may develop simultaneously in different anatomical territories, favored by HHV-8 dissemination and persistent immunosuppression. This pattern explains the frequent simultaneous involvement of skin, mucosae, lymph nodes, and visceral organs, as well as the clinical variability of the disease. In patients with HIV, this dissemination tends to be more aggressive and rapidly progressive [3].\u003c/p\u003e\n\u003cp\u003eThe HIV\u0026ndash;HHV-8 interaction has relevant clinical implications, as it determines the presentation, evolution, and prognosis of Kaposi sarcoma. In patients with untreated HIV infection, KS typically presents with greater aggressiveness, higher tumor burden, and early systemic involvement, including nodal or visceral forms. These atypical presentations may hinder diagnosis, especially in the absence of characteristic cutaneous lesions, requiring a high index of clinical suspicion. Timely initiation of antiretroviral therapy has been shown to significantly reduce the incidence and severity of KS by improving immune function and limiting viral replication. Therefore, understanding the interaction between both viruses is essential for the diagnostic and therapeutic approach in these patients [3].\u003c/p\u003e\n\u003ch2\u003eClinical Spectrum of Kaposi Sarcoma: From Cutaneous Disease to Visceral Forms\u003c/h2\u003e\n\u003cp\u003eKaposi sarcoma (KS) presents a broad clinical spectrum, with cutaneous involvement being the most frequent manifestation. Classic cutaneous lesions are characterized by violaceous, erythematous, or brown macules, papules, or nodules, which may be located on the lower extremities, face, oral cavity, or trunk. Histologically, these lesions correspond to vascular proliferations with erythrocyte extravasation and hemosiderin deposition, explaining their characteristic coloration [14].\u003c/p\u003e\n\u003cp\u003eClinical progression typically follows a staged evolution, from patch to plaque to nodular lesions, with progressive increase in dermal infiltration and spindle cell proliferation. In immunocompetent patients, as in the classic form, the disease is usually indolent; however, in the context of immunosuppression, especially in patients with HIV, progression may be more rapid and aggressive. In addition to the skin, KS may involve mucosae, particularly the oral cavity, where lesions may localize to the palate, gums, or tongue. These manifestations are especially frequent in patients with HIV and are usually associated with more advanced disease. Clinically, they may present as violaceous nodular lesions that can ulcerate or bleed, compromising swallowing or oral function [15].\u003c/p\u003e\n\u003cp\u003eLymph node involvement represents a less frequent but clinically relevant form. It may present as isolated or generalized lymphadenopathy and, in some cases, as the predominant or initial manifestation of the disease, especially in patients with significant immunosuppression. This pattern may mimic lymphoproliferative disorders, making diagnosis difficult and delaying timely treatment [14].\u003c/p\u003e\n\u003cp\u003eIn its more advanced forms, KS may involve visceral organs, including the lungs, gastrointestinal tract, liver, and lymphatic system. Pulmonary involvement may present with dyspnea, cough, hemoptysis, and radiological findings such as interstitial infiltrates, nodules, or pleural effusion. In the gastrointestinal tract, lesions may be asymptomatic or present with bleeding, abdominal pain, or anemia [16].\u003c/p\u003e\n\u003cp\u003eVisceral disease is usually associated with high tumor burden and worse prognosis, particularly in patients with uncontrolled HIV infection. In these cases, presentation may be nonspecific and may coexist with other opportunistic infections, making early identification of KS more difficult [3].\u003c/p\u003e\n\u003cp\u003eThe clinical spectrum of KS is closely influenced by the patient\u0026rsquo;s immune status. In immunocompetent individuals, the disease is usually localized and slowly progressive. In contrast, in immunosuppressed patients, particularly those with untreated HIV infection, KS tends to be more aggressive, with extensive cutaneous involvement, lymph node disease, and visceral dissemination [15].\u003c/p\u003e\n\u003cp\u003eImmune restoration through antiretroviral therapy has been shown to significantly modify the clinical presentation of KS, reducing its incidence, limiting its progression, and, in some cases, inducing partial regression of lesions [16].\u003c/p\u003e\n\u003cp\u003eAtypical forms of KS, such as primary nodal involvement without evident cutaneous lesions, represent an important diagnostic challenge. These presentations may be confused with lymphomas, disseminated infections, or inflammatory diseases, delaying diagnosis and treatment initiation. In this context, biopsy of the affected tissue, together with histopathological and immunohistochemical evaluation, is essential to establish a definitive diagnosis. Identification of HHV-8 positivity in tumor cells is the most important confirmatory criterion [14].\u003c/p\u003e\n\u003ch2\u003eNodal Involvement in Kaposi Sarcoma: Atypical Presentation and Clinical Relevance\u003c/h2\u003e\n\u003cp\u003eKaposi sarcoma (KS) is characterized by marked clinical heterogeneity, with the skin being the most frequently affected site. Cutaneous lesions represent the initial presentation in most patients and manifest as violaceous or erythematous macules that progress to infiltrated plaques and eventually to tumor nodules. This evolution reflects progressive histopathological changes, including increased spindle cell proliferation, disorganized neovascularization, and erythrocyte extravasation [14].\u003c/p\u003e\n\u003cp\u003eFrom a pathophysiological perspective, these lesions are not solely the result of tumor proliferation but also of an intense interaction between angiogenesis, inflammation, and viral factors. The characteristic coloration of the lesions is related to hemosiderin accumulation and erythrocyte extravasation, while their nodular consistency reflects expansion of the spindle cell component [15].\u003c/p\u003e\n\u003cp\u003eIn patients with HIV infection, the cutaneous presentation may be extensive, with multiple lesions distributed on the face, trunk, extremities, and mucosae. Unlike the classic form, the epidemic variant tends to have a more aggressive course, with rapid progression and greater tendency for systemic dissemination [3].\u003c/p\u003e\n\u003cp\u003eMucosal involvement is a frequent manifestation in immunosuppressed patients, particularly those with HIV infection. The oral cavity is the most common site, especially the hard palate, although the gums, tongue, and oropharynx may also be affected. These lesions are usually nodular, highly vascularized, and prone to bleeding, which may result in significant functional complications such as dysphagia or pain [15].\u003c/p\u003e\n\u003cp\u003eOn the other hand, involvement of the lymphatic system represents a key component in the progression of KS. Nodal involvement may present as localized or generalized lymphadenopathy and, in some cases, as the predominant or even initial manifestation of the disease. This pattern is particularly relevant in patients with HIV, where KS may mimic lymphoproliferative diseases such as non-Hodgkin lymphoma, due to the presence of multiple adenopathies, constitutional symptoms, and hematological abnormalities [14].\u003c/p\u003e\n\u003cp\u003eLymph node infiltration reflects not only tumor dissemination but also the active participation of the lymphatic system as a reservoir for HHV-8 and as a site of altered immune interaction [6].\u003c/p\u003e\n\u003cp\u003eIn advanced stages, KS may affect multiple visceral organs, resulting in a complex clinical presentation with greater prognostic impact. Pulmonary involvement is one of the most relevant forms and may present with progressive dyspnea, cough, hemoptysis, and pleural effusion. Radiologically, it may appear as interstitial infiltrates, nodules, septal thickening, or peribronchovascular lesions, which often necessitates differentiation from opportunistic infections such as Pneumocystis jirovecii pneumonia or tuberculosis [16].\u003c/p\u003e\n\u003cp\u003eThe gastrointestinal tract is another frequent site of involvement, where lesions may be subclinical or present with bleeding, abdominal pain, anemia, or even obstruction. Endoscopically, nodular or violaceous plaque-like lesions are observed, similar to cutaneous lesions, and may involve any segment of the digestive tract. Hepatic, splenic, and diffuse nodal involvement usually reflect disseminated disease. In these cases, clinical presentation may include constitutional syndrome, weight loss, persistent fever, and signs of systemic inflammation, which may mimic disseminated infections or hematologic neoplastic processes [3,14].\u003c/p\u003e\n\u003cp\u003eThe clinical spectrum of KS is directly influenced by the degree of host immunosuppression. In immunocompetent patients, the disease is usually localized, slowly progressive, and predominantly cutaneous. In contrast, in patients with untreated HIV infection, KS tends to present with extensive disease, visceral involvement, and rapid progression. Immune restoration through ART significantly modifies this clinical spectrum, reducing the incidence of new lesions and, in some cases, inducing tumor regression. However, immune reconstitution inflammatory syndrome (IRIS) may also occur, in which KS lesions may transiently worsen after initiation of therapy [3,16].\u003c/p\u003e\n\u003cp\u003eAtypical presentations of KS, such as primary nodal involvement without evident cutaneous lesions, are uncommon but clinically relevant. These forms may delay diagnosis due to their similarity to other entities, especially lymphomas, disseminated infections, or inflammatory diseases. In these scenarios, clinical suspicion must remain high, particularly in patients with HIV and systemic manifestations. Diagnostic confirmation requires biopsy of the affected tissue, with histopathological and immunohistochemical evaluation demonstrating HHV-8 positivity, which constitutes the diagnostic gold standard. These non-classical forms, such as predominant nodal presentation, represent a diagnostic challenge and justify the importance of case reports that contribute to expanding clinical knowledge of the disease [14].\u003c/p\u003e\n\u003ch2\u003eDifferential Diagnosis of Lymphadenopathy in Patients with HIV\u003c/h2\u003e\n\u003cp\u003eLymphadenopathy in patients with HIV infection represents a frequent clinical finding of great diagnostic relevance, as it may appear at any stage of infection and may be due to reactive, infectious, or neoplastic causes. In practical terms, the approach should consider three major etiological groups: reactive/inflammatory lymphadenopathy related to HIV itself or immune reconstitution, lymphadenopathy secondary to opportunistic infections or coinfections, and lymphadenopathy due to malignant processes, especially lymphoma, Kaposi sarcoma, and HHV-8\u0026ndash;associated Castleman disease. This classification is particularly useful because it guides both clinical interpretation and the selection of imaging studies and the need for lymph node biopsy [17,18].\u003c/p\u003e\n\u003cp\u003eIn early or intermediate stages of infection, HIV itself may produce reactive lymphoid hyperplasia and persistent generalized lymphadenopathy. In these cases, lymph nodes are usually multiple, mobile, and not always painful, and may coexist with mild constitutional symptoms or even be an incidental finding. Histopathologically, these lymph nodes show reactive changes rather than neoplastic infiltration, although their clinical appearance may overlap with more severe entities. Therefore, the mere presence of lymphadenopathy in a patient with HIV should not be assumed to be benign if alarm features are present, such as progressive enlargement, nodal conglomerates, B symptoms, cytopenias, hepatosplenomegaly, or systemic deterioration [17,19].\u003c/p\u003e\n\u003cp\u003eIn patients with HIV, a significant proportion of lymphadenopathies have an infectious origin. Among the most relevant causes are tuberculous lymphadenitis, nontuberculous mycobacterial infections, histoplasmosis, cryptococcosis, toxoplasmosis, syphilis, and other concomitant viral infections. Suspicion increases when lymphadenopathy is accompanied by persistent fever, weight loss, night sweats, elevated acute-phase reactants, or evidence of disseminated disease. In endemic areas or in patients with advanced immunosuppression, granulomatous and fungal infections must be prioritized, as they can closely mimic both clinically and radiologically lymphoproliferative disorders.\u003c/p\u003e\n\u003cp\u003eAmong malignant causes, HIV-associated non-Hodgkin lymphoma constitutes one of the most important differential diagnoses in the presence of multiple or generalized lymphadenopathy. Clinically, it is usually accompanied by B symptoms, rapid progression, hepatosplenomegaly, cytopenias, and marked elevation of lactate dehydrogenase, although these findings are not exclusive. In practice, lymphoma is often the primary diagnostic consideration when lymphadenopathy in multiple regions coexists with constitutional syndrome and organ dysfunction, especially in patients with untreated HIV infection or advanced immunosuppression. This clinical overlap is precisely what leads entities such as nodal Kaposi sarcoma to be initially interpreted as lymphoproliferative disease [17,18].\u003c/p\u003e\n\u003cp\u003eAlthough Kaposi sarcoma is classically associated with cutaneous and mucosal lesions, it may also involve lymph nodes as part of disseminated disease or, less frequently, as the predominant manifestation. In patients with HIV, this possibility should be considered especially when lymphadenopathy is accompanied by findings consistent with systemic disease, cytopenias, or visceral involvement. The diagnostic difficulty lies in the fact that nodal Kaposi sarcoma may lack evident cutaneous lesions and mimic both lymphoma and disseminated infections. Therefore, in the presence of persistent or progressive lymphadenopathy, excisional biopsy remains essential to distinguish between infectious, reactive, and neoplastic processes [18].\u003c/p\u003e\n\u003cp\u003eHHV-8\u0026ndash;associated multicentric Castleman disease occupies a fundamental place in the differential diagnosis of lymphadenopathy in patients with HIV, particularly when fever, intense systemic inflammation, hepatosplenomegaly, edema, organ dysfunction, or coexistence with Kaposi sarcoma are present. Its clinical relevance lies in the fact that it may present with generalized lymphadenopathy and florid systemic symptoms, mimicking sepsis, lymphoma, or tumor progression. Moreover, it may biologically overlap with other HHV-8\u0026ndash;related diseases, requiring an integrated interpretation of histopathology, clinical presentation, and disease course. In patients with uncontrolled HIV and diffuse lymphadenopathy, Castleman disease must always be considered, particularly if there is a disproportionate inflammatory response [20\u0026ndash;22].\u003c/p\u003e\n\u003cp\u003eImaging studies are useful for defining the distribution, accessibility, and pattern of lymphadenopathy, but they rarely establish the etiological diagnosis on their own. Computed tomography may show localized or generalized lymphadenopathy, central necrosis, nodal conglomerates, mediastinal, abdominal, or inguinal involvement, as well as associated visceral disease. However, there is significant radiological overlap between infectious and neoplastic causes. Therefore, imaging should be understood as a tool to stratify risk and select the optimal biopsy site, rather than as a confirmatory method. In particular, the presence of lymphadenopathy in multiple chains, visceromegaly, and systemic findings should prompt early histological evaluation [18].\u003c/p\u003e\n\u003cp\u003eIn patients with HIV, lymph node biopsy should be considered early when lymphadenopathy is persistent, progressive, large, deeply located, or accompanied by constitutional symptoms, cytopenias, organomegaly, or unexplained clinical deterioration. It is also indicated when suspicion of lymphoma, nodal Kaposi sarcoma, or Castleman disease is high, or when infectious etiologies cannot be demonstrated by less invasive methods. Excisional biopsy remains the procedure with the highest diagnostic yield, as it allows assessment of nodal architecture, infiltration patterns, special stains, and immunohistochemistry. In this context, it is the decisive tool to differentiate reactive, infectious, lymphoproliferative, and HIV-associated neoplastic processes [17,18].\u003c/p\u003e\n\u003cp\u003eIn a young patient with HIV, febrile syndrome, cytopenias, multiple lymphadenopathy, and systemic deterioration, the initial differential diagnosis usually leans toward disseminated opportunistic infection or lymphoma. However, the presence of nodal Kaposi sarcoma as an initial or predominant manifestation requires broadening the diagnostic perspective. This type of presentation underscores that, in HIV, lymphadenopathy should not be interpreted in isolation but rather in conjunction with immune status, imaging findings, clinical evolution, and histopathological evaluation. Precisely due to this syndromic overlap, nodal Kaposi sarcoma constitutes an entity of high clinical and academic interest within the spectrum of lymphadenopathies in patients with HIV [18,22].\u003c/p\u003e\n\u003ch2\u003eDiagnostic Limitations and Clinical Challenges in Young Patients\u003c/h2\u003e\n\u003cp\u003eIn young patients, the diagnosis of immunosuppression-associated neoplasms, such as Kaposi sarcoma, represents a significant clinical challenge due to lower initial suspicion. Unlike populations with classical risk factors or long-standing known immunosuppression, young patients may present with nonspecific clinical manifestations that are initially interpreted as acute infectious or inflammatory processes. This low clinical suspicion is further accentuated when the diagnosis of HIV infection is recent or even unknown at the time of initial evaluation, delaying appropriate syndromic integration [3].\u003c/p\u003e\n\u003cp\u003eAdditionally, initial clinical manifestations are usually nonspecific, including constitutional syndrome, fever, malaise, and gastrointestinal symptoms, which contributes to an initial diagnostic approach oriented toward common infections. In this context, HIV-associated neoplasms may go unnoticed during the early stages of clinical evaluation [15].\u003c/p\u003e\n\u003cp\u003eOne of the main diagnostic challenges in young patients with HIV is the clinical overlap between infectious and neoplastic processes. Opportunistic infections, particularly in advanced stages of immunosuppression, may present with persistent fever, weight loss, lymphadenopathy, hematological abnormalities, and multiorgan involvement, which is clinically indistinguishable from entities such as lymphoma or disseminated Kaposi sarcoma. In regions with high prevalence of tuberculosis or other granulomatous infections, the initial tendency is usually to prioritize infectious etiologies, which may delay the performance of biopsies or histopathological studies. This diagnostic delay is critical, as HIV-associated neoplasms may progress rapidly if not identified in a timely manner [4].\u003c/p\u003e\n\u003cp\u003eImaging studies, particularly computed tomography, are fundamental tools in the evaluation of lymphadenopathy and systemic disease; however, they have important limitations in differentiating between infectious and neoplastic etiologies. Findings such as multiple lymphadenopathy, hepatosplenomegaly, pleural effusion, or pulmonary infiltrates may be observed in both disseminated infections and malignant processes, including lymphoma and Kaposi sarcoma. This radiological overlap limits the ability of imaging to establish a definitive diagnosis; therefore, its utility lies mainly in characterizing disease extent and identifying the optimal biopsy site. In young patients, where initial suspicion of neoplasia is low, this limitation may contribute to additional diagnostic delays [16].\u003c/p\u003e\n\u003cp\u003eLymph node or affected tissue biopsy constitutes the gold standard for the diagnosis of neoplasms in patients with HIV. However, in young patients, the indication for invasive procedures may be deferred due to initial suspicion of infectious or self-limited processes. This delay in obtaining tissue may significantly prolong the time to definitive diagnosis. In the case of nodal Kaposi sarcoma, where evident cutaneous lesions may be absent, biopsy becomes even more relevant. Confirmation through histopathology and immunohistochemistry, with positivity for HHV-8, is essential to differentiate it from lymphomas or other lymphoproliferative diseases [14].\u003c/p\u003e\n\u003cp\u003eDiagnostic delay in young patients with HIV-associated neoplasms has significant clinical implications, as it allows disease progression toward more advanced and disseminated forms. In Kaposi sarcoma, this may translate into visceral involvement, higher tumor burden, and accelerated clinical deterioration.\u003c/p\u003e\n\u003cp\u003eLikewise, delayed initiation of antiretroviral therapy and oncologic treatment is associated with poorer therapeutic response and higher morbidity and mortality. This highlights the importance of maintaining a high index of diagnostic suspicion, even in young patients, particularly when clinical features suggest systemic disease [3].\u003c/p\u003e\n\u003cp\u003eThe management of young patients with HIV and suspected neoplasia involves multiple clinical challenges, including the need to integrate clinical, laboratory, imaging, and histopathological information in a context of high diagnostic uncertainty. The coexistence of multiple processes, such as opportunistic infections, systemic inflammation, and neoplasms, further complicates the interpretation of findings. In addition, social and behavioral factors, such as recent HIV diagnosis, associated stigma, and lack of prior medical follow-up, may influence delayed presentation and treatment adherence. These elements must be considered within the comprehensive approach to patient care [15].\u003c/p\u003e\n\u003cp\u003eOverall, diagnostic limitations in young patients with HIV underscore the need to adopt a systematic clinical approach based on early identification of warning signs, appropriate use of diagnostic studies, and timely performance of biopsy when indicated. In particular, the presence of persistent lymphadenopathy, cytopenias, constitutional syndrome, or organ dysfunction should prompt a thorough evaluation that includes the possibility of immunosuppression-associated neoplasms [17].\u003c/p\u003e\n\u003ch2\u003eJustification of the Systematic Review of the Literature\u003c/h2\u003e\n\u003cp\u003eKaposi sarcoma (KS) is a well-characterized neoplasm in its cutaneous form; however, presentations with predominant or primary nodal involvement are uncommon and poorly described in the literature. This low incidence limits early clinical recognition and hinders the development of clear diagnostic patterns, particularly in young patients with HIV infection. In this context, a systematic review of the literature allows consolidation of available evidence, identification of common clinical characteristics, and establishment of correlations between presentation, diagnosis, and evolution of these atypical cases. Furthermore, variability in the clinical expression of KS, influenced by immune status and interaction with HHV-8, generates a heterogeneous spectrum of manifestations that requires structured analysis to improve clinical understanding [14,15].\u003c/p\u003e\n\u003cp\u003eThe diagnosis of nodal Kaposi sarcoma, especially in the absence of cutaneous lesions, represents a considerable clinical challenge due to overlap with other common entities in patients with HIV, such as non-Hodgkin lymphoma, disseminated opportunistic infections, and Castleman disease. This diagnostic ambiguity is further aggravated by the lack of specific guidelines for the approach to these atypical presentations. In this scenario, a systematic review allows integration of information from case reports, clinical series, and observational studies in order to identify diagnostic patterns, suspicion criteria, and more effective management strategies. Systematization of evidence is particularly relevant in rare diseases or those with unusual presentation, where clinical trials are limited or nonexistent [3].\u003c/p\u003e\n\u003cp\u003eHIV-associated Kaposi sarcoma presents a distinct clinical behavior compared to other variants, with a greater tendency toward dissemination and systemic involvement. However, within this group, significant variations exist in presentation, especially in young patients or those with recent HIV diagnosis. A systematic review of the literature allows evaluation of how factors such as degree of immunosuppression, viral load, absence of antiretroviral therapy, and HHV-8 coinfection influence the clinical presentation of KS. This information is fundamental for improving risk stratification and guiding diagnostic suspicion in clinical practice [16].\u003c/p\u003e\n\u003cp\u003eIntegration of evidence through a systematic review has direct implications in clinical practice, as it enhances the clinician\u0026rsquo;s diagnostic capacity when faced with atypical presentations. In the case of nodal KS, identification of recurrent clinical features, laboratory findings, and imaging patterns may facilitate early suspicion and accelerate the indication for biopsy, thereby reducing diagnostic delays. Additionally, literature review allows evaluation of therapeutic strategies used in similar cases, including the impact of antiretroviral therapy and available oncologic options, contributing to optimization of patient management [15].\u003c/p\u003e\n\u003cp\u003eDespite advances in knowledge of Kaposi sarcoma, important gaps persist regarding its atypical presentations, particularly those with primary nodal involvement. Most available evidence derives from case reports or small series, limiting generalizability and hindering development of specific clinical guidelines. In this sense, systematic review not only allows synthesis of existing evidence but also identification of areas of uncertainty that require further research, such as prognostic factors, treatment response in nodal forms, and the relationship between HHV-8 viral load and disease extent [14].\u003c/p\u003e\n\u003ch2\u003eSynthesis of Available Evidence on Nodal Kaposi Sarcoma\u003c/h2\u003e\n\u003cp\u003eKaposi sarcoma (KS) is a predominantly cutaneous neoplasm; however, nodal involvement represents a less frequent but clinically significant form within its spectrum of presentation. Available evidence suggests that nodal involvement usually occurs as part of disseminated disease, particularly in patients with HIV infection and advanced immunosuppression. However, cases of predominant or primary nodal involvement without evident cutaneous lesions are rare and are mainly described in case reports and small clinical series, limiting understanding of their clinical behavior. This low frequency contributes to nodal KS being underdiagnosed or identified late, especially in young patients, where initial suspicion is often directed toward infectious or lymphoproliferative etiologies [14,15].\u003c/p\u003e\n\u003cp\u003eAnalysis of published cases shows that nodal KS may present with localized or generalized lymphadenopathy, with predilection for inguinal, axillary, and cervical regions. In many cases, these lymphadenopathies are accompanied by constitutional symptoms such as fever, weight loss, and night sweats, generating a strong initial suspicion of lymphoma or disseminated infection. In patients with HIV, presentation is usually more aggressive, with rapid progression and frequent association with hematological abnormalities such as anemia and thrombocytopenia. Additionally, coexistence of visceral involvement, such as hepatosplenomegaly or pleural effusion, is common in reported cases, reinforcing the systemic nature of the disease in this context [3,16].\u003c/p\u003e\n\u003cp\u003eImaging studies described in the literature show that nodal KS is frequently associated with multiple lymphadenopathies in different nodal chains, without specific radiological characteristics that clearly differentiate it from lymphoma or infections. Computed tomography usually demonstrates lymph nodes of variable size, with or without necrosis, as well as concomitant findings such as pleural effusion, pulmonary infiltrates, or visceromegaly. This lack of radiological specificity constitutes an important limitation, as it complicates differential diagnosis based solely on imaging, underscoring the need for histopathological confirmation in all suspected cases [14,16].\u003c/p\u003e\n\u003cp\u003eDefinitive diagnosis of nodal KS is based on histopathological study, which reveals proliferation of spindle cells, formation of irregular vascular spaces, and erythrocyte extravasation. However, since these findings may overlap with other vascular neoplasms or reactive processes, immunohistochemistry is essential to confirm the diagnosis. Nuclear positivity for HHV-8 (LANA-1) constitutes the most specific diagnostic marker, allowing differentiation of KS from other lymphoproliferative or infectious entities. Other markers, such as CD34 and podoplanin, support the endothelial origin of tumor cells [14].\u003c/p\u003e\n\u003cp\u003eAvailable evidence consistently shows that nodal KS occurs predominantly in patients with significant immunosuppression, especially those with untreated HIV infection. Low CD4 count and high viral load are associated with increased risk of disseminated disease and atypical presentations. Likewise, some studies suggest that active HHV-8 coinfection and systemic inflammatory state contribute to disease progression and aggressive behavior, although the exact relationship between HHV-8 viral load and clinical extent is not yet fully defined [3,14].\u003c/p\u003e\n\u003cp\u003eTreatment of nodal KS in patients with HIV includes antiretroviral therapy as the cornerstone of management, since immune restoration may induce partial or complete regression of lesions. However, in cases with extensive disease or visceral involvement, additional systemic treatment such as chemotherapy is usually required. Reported clinical evolution is variable and depends on the degree of immunosuppression, disease extent, and response to treatment. In general, cases diagnosed late have worse prognosis, highlighting the importance of early recognition of these atypical presentations [15,16].\u003c/p\u003e\n\u003cp\u003eOne of the main findings in the literature is the scarcity of systematic studies on nodal KS. Most data come from case reports or small series, limiting the ability to establish definitive conclusions regarding its epidemiology, prognostic factors, and optimal therapeutic strategies.\u003c/p\u003e\n\u003cp\u003eThis limitation highlights the importance of documenting and reporting well-characterized clinical cases that contribute to expanding knowledge of this entity and improving its recognition in clinical practice [14].\u003c/p\u003e\n\u003ch2\u003eKnowledge Gaps in Non-Classical Presentations\u003c/h2\u003e\n\u003cp\u003eOne of the main knowledge gaps in Kaposi sarcoma (KS) is the underrepresentation of its non-classical forms in the biomedical literature. Most of the available knowledge derives from the typical cutaneous form, particularly in the context of HIV infection, whereas predominantly nodal, visceral, or mucosal presentations without evident cutaneous lesions remain mainly described in isolated reports or small series. This imbalance results in the conceptual framework of KS remaining centered on its dermatological phenotype, leaving relatively poorly characterized those variants that present as lymphadenopathy, gastrointestinal disease, pulmonary involvement, or systemic disease without apparent cutaneous involvement [10,23,24].\u003c/p\u003e\n\u003cp\u003eThis limitation has direct consequences in clinical practice. When an entity is primarily defined by its classical form, atypical variants fall outside the initial reasoning of both the clinician and the radiologist, favoring diagnostic delays, inefficient stepwise investigations, and a greater likelihood of attributing the presentation to more common conditions such as lymphoma or disseminated opportunistic infections [23\u0026ndash;25].\u003c/p\u003e\n\u003cp\u003eAnother important gap is the limited systematic characterization of patients with nodal or visceral KS. Although it is recognized that KS may affect virtually any organ, there is still limited information regarding the true frequency of nodal involvement as an initial manifestation, its patterns of anatomical distribution, its clinical correlates, and its relationship with systemic disease burden. Recent studies continue to indicate that visceral or nodal involvement may present with nonspecific symptoms and without concomitant cutaneous lesions, which hinders early recognition [23,25,26].\u003c/p\u003e\n\u003cp\u003eSimilarly, gaps persist regarding the natural history of these presentations. It is not well defined whether nodal forms simply represent a variant of advanced disseminated disease or whether, in some cases, they constitute a particular biological phenotype with distinct immunological or viral determinants. This uncertainty limits the ability to stratify risk and anticipate clinical outcomes [10,23].\u003c/p\u003e\n\u003cp\u003eNon-classical presentations of KS share manifestations with multiple common diseases in immunosuppressed patients, especially in individuals with HIV. Fever, weight loss, lymphadenopathy, pleural effusion, hepatosplenomegaly, cytopenias, and inflammatory alterations may also be observed in HIV-associated lymphoma, disseminated tuberculosis, systemic mycoses, HHV-8\u0026ndash;associated multicentric Castleman disease, and other lymphoproliferative disorders. Despite this overlap, there remains a lack of specifically validated diagnostic algorithms to guide the evaluation of lymphadenopathy or visceral disease when cutaneous KS is absent [10,23,25].\u003c/p\u003e\n\u003cp\u003eThe practical consequence is that diagnosis continues to depend largely on individual clinical suspicion and the timely decision to perform a biopsy. This introduces considerable variability between centers and professionals and may significantly affect time to definitive diagnosis [24,25].\u003c/p\u003e\n\u003cp\u003eAvailable evidence also shows an important gap in the utility of imaging methods to distinguish non-classical KS from other etiologies. Computed tomography may reveal multiple lymphadenopathies, pleural effusion, gastrointestinal lesions, or visceral involvement; however, these findings lack specificity and may be indistinguishable from opportunistic infections or lymphoproliferative disease. Even in recent reviews, the value of imaging is described more as a tool for disease extension rather than for etiological differentiation. This leaves a gap in the development of useful radiological criteria for suspicion of nodal or visceral KS. There are still no sufficiently robust patterns that allow the radiologist to confidently suggest this possibility in the absence of accompanying cutaneous lesions. Therefore, imaging remains complementary but not definitive in many of these presentations [23,25].\u003c/p\u003e\n\u003cp\u003eAlthough HHV-8 is indispensable for the development of KS, there are still areas of uncertainty regarding how to integrate viral biology into everyday clinical practice. In particular, it is not fully clarified what prognostic role viral activity, coinfection with other HHV-8\u0026ndash;related entities, and inflammatory biomarkers play in patients with non-classical disease. Recent reviews on HHV-8\u0026ndash;associated disorders emphasize that there remains significant biological overlap between KS, multicentric Castleman disease, and other related syndromes, which complicates both classification and clinical interpretation of complex cases [10].\u003c/p\u003e\n\u003cp\u003eConsequently, a gap persists between molecular knowledge of HHV-8 and its clinical application in predicting disease extent, response to treatment, or risk of relapse, especially in patients with predominant nodal or visceral involvement [10,23].\u003c/p\u003e\n\u003cp\u003eAnother important limitation is the absence of prospective studies specifically focused on non-classical nodal or visceral KS. Most therapeutic evidence comes from heterogeneous cohorts of HIV-associated KS, where cases with cutaneous or mucocutaneous disease predominate. This makes it difficult to determine whether current therapeutic recommendations, such as initiation of ART or use of liposomal anthracyclines or paclitaxel in advanced disease, have the same prognostic behavior in non-classical presentations, particularly when onset is nodal or visceral. In other words, although general treatment principles exist, more detailed data are still lacking regarding optimal therapeutic sequence, response criteria, and specific prognosis in patients without predominant cutaneous lesions. This gap is especially relevant in atypical cases, where diagnostic delay may modify tumor burden at the time of treatment initiation [23,27].\u003c/p\u003e\n\u003cp\u003eNon-classical presentations in young patients constitute an even less studied area. In these cases, low initial oncologic suspicion and the tendency to prioritize infectious or inflammatory causes may further delay histological confirmation. Recent literature on atypical presentations emphasizes that young age or even absence of apparent risk factors may contribute to diagnostic anchoring errors, especially when the initial presentation does not include cutaneous lesions [24,25].\u003c/p\u003e\n\u003cp\u003eThis is particularly important in patients with recently diagnosed HIV, in whom lymphadenopathy, cytopenias, and systemic symptoms usually first suggest lymphoma or opportunistic infection. Consequently, studies evaluating specifically how age influences diagnostic bias, time to biopsy, and clinical outcomes in non-classical KS are lacking [23,25].\u003c/p\u003e\n\u003cp\u003eOverall, knowledge gaps in non-classical presentations of KS point to several specific needs: improving clinical characterization of nodal and visceral involvement, developing specific diagnostic algorithms for patients with HIV and lymphadenopathy without cutaneous lesions, better defining the role of imaging and HHV-8\u0026ndash;related biomarkers, and generating prospective cohorts to evaluate prognosis and therapeutic response in these atypical phenotypes [10,23,25].\u003c/p\u003e\n\u003ch2\u003eJustification and Objective of the Case Report\u003c/h2\u003e\n\u003cp\u003eKaposi sarcoma (KS) continues to be one of the most representative neoplasms associated with HIV infection, particularly in scenarios of late diagnosis or absence of antiretroviral treatment. Despite the decrease in its incidence in the era of combination antiretroviral therapy, KS remains a clinically relevant entity due to its capacity to present in aggressive forms with systemic involvement, especially in patients with advanced immunosuppression. In recent years, the literature has emphasized that the clinical behavior of KS has changed, showing greater heterogeneity in its presentation, including non-classical forms affecting lymph nodes and visceral organs without evident cutaneous manifestations. These atypical variants represent an important diagnostic challenge and highlight the need to expand clinical understanding of the disease spectrum [3,14,15].\u003c/p\u003e\n\u003cp\u003eNon-classical presentations of KS, particularly those with predominant nodal involvement or without cutaneous lesions, are poorly described in the literature and mostly correspond to isolated case reports. This limitation hinders identification of reproducible clinical patterns and contributes to low diagnostic suspicion in clinical practice [28].\u003c/p\u003e\n\u003cp\u003eThe value of case reports in this context lies in their ability to document unusual manifestations, expand clinical knowledge, and generate hypotheses that can be explored in subsequent studies. In rare diseases or those with atypical variants, such as nodal KS, this type of evidence acquires particular relevance for the medical community [29].\u003c/p\u003e\n\u003cp\u003eIn patients with HIV infection, the presence of generalized lymphadenopathy constitutes a frequent finding with a broad differential diagnosis that includes opportunistic infections, inflammatory diseases, and neoplasms. In this context, nodal Kaposi sarcoma may go unnoticed due to its clinical similarity to non-Hodgkin lymphoma, multicentric Castleman disease, or disseminated infections such as tuberculosis or systemic mycoses. The absence of characteristic cutaneous lesions in some cases contributes to delayed diagnosis, which may lead to progression toward advanced disease. Therefore, documentation of cases with atypical presentations is essential to increase clinical awareness and promote a broader and more timely diagnostic evaluation [15,16].\u003c/p\u003e\n\u003cp\u003eEarly diagnosis of KS is a determining factor in patient prognosis, as it allows timely initiation of antiretroviral therapy and, when necessary, specific oncologic treatment. Immune restoration through ART has been shown to reduce disease progression and improve clinical outcomes, even in cases with systemic involvement. In contrast, diagnostic delay, frequent in non-classical presentations, is associated with higher tumor burden, visceral involvement, and poorer therapeutic response. This underscores the importance of recognizing these clinical variants and integrating KS into the differential diagnosis in patients with HIV and persistent lymphadenopathy [3,14].\u003c/p\u003e\n\u003cp\u003eThe present case report gains relevance by documenting an unusual presentation of Kaposi sarcoma with predominant nodal involvement in a young patient with recently diagnosed HIV. This type of presentation is not only uncommon but also represents a significant diagnostic challenge due to the absence of typical cutaneous manifestations. The detailed description of the case, including clinical course, laboratory findings, imaging studies, and histopathological confirmation, provides valuable evidence that contributes to expanding the known clinical spectrum of KS. It also facilitates comparison with previously reported cases and reinforces the importance of considering this entity in complex clinical scenarios [15].\u003c/p\u003e\n\u003ch2\u003eObjective of the Case Report\u003c/h2\u003e\n\u003cp\u003eThe objective of this report is to describe an atypical presentation of Kaposi sarcoma with predominant nodal involvement in a young patient with HIV infection, highlighting the associated diagnostic challenges, relevant clinical characteristics, and the importance of histopathological confirmation. Additionally, this case is intended to be integrated with the available evidence in the literature in order to contribute to a better understanding of the clinical spectrum of KS and to promote a broader diagnostic approach in patients with HIV who present with lymphadenopathy and systemic manifestations.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eThis is a 26-year-old male patient, previously without known chronic diseases, who was admitted for evaluation by the Internal Medicine service in the context of a febrile syndrome under investigation associated with significant hematological abnormalities. His past medical history is notable for a recent diagnosis of human immunodeficiency virus (HIV) infection, confirmed a few days prior to hospital admission, without having initiated antiretroviral therapy at the time of initial evaluation.\u003c/p\u003e\n\u003cp\u003eFrom a hematological standpoint, the patient had a history of severe microcytic hypochromic anemia, classified as grade III according to the World Health Organization criteria, as well as thrombocytopenia under investigation, suggesting the presence of an underlying systemic process. These hematological abnormalities constitute frequent clinical findings in patients with HIV infection and may be related to multiple pathophysiological mechanisms, including bone marrow suppression, infiltration by neoplastic processes, autoimmune phenomena, or opportunistic infections.\u003c/p\u003e\n\u003cp\u003eHIV infection represents a major risk factor for the development of various immunosuppression-associated neoplasms, particularly those related to oncogenic viral infections. Among these, Kaposi sarcoma constitutes one of the AIDS-defining neoplasms and is closely associated with infection by human herpesvirus type 8 (HHV-8). Although this neoplasm classically manifests through characteristic violaceous cutaneous lesions on the skin and mucosae, it may also present with visceral or nodal involvement, especially in patients with advanced immunosuppression.\u003c/p\u003e\n\u003cp\u003eIn the context of Internal Medicine practice, the concomitant presence of febrile syndrome, cytopenias, and recent diagnosis of HIV infection requires consideration of a broad diagnostic spectrum that includes opportunistic infections, malignant hematological diseases, lymphoproliferative processes, and neoplasms associated with immunodeficiency. This clinical scenario requires a systematic and comprehensive diagnostic approach aimed at identifying the etiology of the clinical presentation and establishing timely treatment.\u003c/p\u003e\n\u003cp\u003eTherefore, from the initial moment of hospital evaluation, the case represented a relevant diagnostic challenge for the Internal Medicine service, as it involved a young patient with recently documented immunosuppression and systemic manifestations potentially related to infectious or neoplastic processes associated with HIV infection.\u003c/p\u003e\n\u003ch2\u003eOnset of Clinical Presentation\u003c/h2\u003e\n\u003cp\u003eThe current illness began approximately two weeks prior to hospital admission, with the onset of abdominal pain of nonspecific characteristics, without radiation or clear quadrant predominance. This symptom was accompanied by systemic manifestations such as arthralgias and generalized myalgias, as well as progressive deterioration of general condition. As the clinical course evolved, the patient developed intolerance to oral intake characterized by persistent nausea that progressed to vomiting of gastrointestinal contents.\u003c/p\u003e\n\u003cp\u003eSubsequently, non-quantified fever developed, predominantly nocturnal, accompanied by profuse diaphoresis and subjective malaise, which motivated his first evaluation at the primary care level. During this initial evaluation, symptomatic management with analgesics and antipyretics was initiated, without documentation of significant clinical improvement in the following days.\u003c/p\u003e\n\u003cp\u003eDue to persistence of the febrile syndrome and progressive deterioration of general condition, the patient sought medical evaluation again and was referred to the hospital emergency department for further study and management. Upon admission to the emergency department, systemic compromise was documented, characterized by arterial hypotension with blood pressure of 85/51 mmHg, tachycardia with heart rate of 131 beats per minute, respiratory rate of 23 breaths per minute, and body temperature of 39.3 \u0026deg;C. Oxygen saturation was 95% on room air.\u003c/p\u003e\n\u003cp\u003eIn the epidemiological context of the SARS-CoV-2 pandemic, and given the presence of fever and signs of systemic inflammatory response, a diagnostic protocol for COVID-19 infection was initiated using a rapid test, which resulted negative. However, as part of the institutional measures in place at that time, the patient was initially admitted to the area designated for suspected COVID-19 cases, despite the absence of clinical or paraclinical evidence confirming this etiology.\u003c/p\u003e\n\u003cp\u003eDuring the first hours of hospital observation, respiratory manifestations suggestive of viral respiratory infection were ruled out, and the patient was subsequently transferred to the Internal Medicine service to continue the diagnostic approach to a febrile syndrome of undetermined etiology. This change of setting allowed initiation of a broader clinical evaluation aimed at identifying the cause of the underlying systemic process, considering both infectious processes and hematological or neoplastic diseases associated with the context of recent immunosuppression due to HIV infection.\u003c/p\u003e\n\u003cp\u003eThus, the onset of the clinical presentation was characterized by a progressive constitutional syndrome accompanied by gastrointestinal manifestations and persistent fever, whose evolution prompted hospitalization and initiation of a comprehensive diagnostic approach under the perspective of the Internal Medicine service.\u003c/p\u003e\n\u003cp\u003eThe chronological evolution of the patient\u0026rsquo;s clinical course is summarized in Table 1.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDescription\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTwo weeks prior to hospital admission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eOnset of clinical presentation with abdominal pain, arthralgias, myalgias, intolerance to oral intake, nausea, and vomiting. Subsequently, predominantly nocturnal fever and diaphoresis developed.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOne week prior to hospital admission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eDiagnosis of HIV infection, without initiation of antiretroviral therapy.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003ePresentation to emergency department due to persistent febrile syndrome and deterioration of general condition. Initial vital signs: BP 85/51 mmHg, HR 131 bpm, RR 23 rpm, T 39.3 \u0026deg;C, SpO₂ 95% on room air.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eDiagnostic protocol for SARS-CoV-2 initiated, with negative rapid test.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eAdmission to Internal Medicine service for evaluation of febrile syndrome of undetermined etiology.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eFirst chest computed tomography, showing mediastinal and bilateral axillary lymphadenopathy without significant pulmonary infiltrates.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eInitial laboratory tests showing severe anemia (Hb 5.9 g/dL), thrombocytopenia (28,000/\u0026micro;L), elevated C-reactive protein and D-dimer, and onset of renal function deterioration.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eExcisional biopsy of inguinal lymph node performed for diagnostic purposes.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eArterial blood gas compatible with metabolic acidosis with respiratory compensation.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eFollow-up laboratory tests showing worsening renal function, persistence of cytopenias, and elevated inflammatory markers.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003ePersistence of severe thrombocytopenia and progression of renal insufficiency.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eSecond computed tomography showing multiple lymphadenopathies in different nodal chains, bilateral pleural effusion, hepatosplenomegaly, and free abdominal fluid.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubsequently\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eHistopathological and immunohistochemical study confirmed nodal Kaposi sarcoma with HHV-8 positivity.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28.0672%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFinal Diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.9328%;\"\u003e\n \u003cp\u003eNodal Kaposi sarcoma associated with HIV infection.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp id=\"_Toc226412375\"\u003eTable\u0026nbsp;1. Clinical timeline of the patient. The timeline summarizes the main clinical, diagnostic, and evolutionary events during the patient\u0026rsquo;s hospitalization, from symptom onset to histopathological confirmation of diagnosis. Abbreviations: BP, blood pressure; HR, heart rate; RR, respiratory rate; SpO₂, oxygen saturation by pulse oximetry; Hb, hemoglobin; HIV, human immunodeficiency virus; CRP, C-reactive protein.\u003c/p\u003e\n\u003ch2\u003eHospital Admission and Initial Clinical Evaluation\u003c/h2\u003e\n\u003cp\u003eAfter transfer to the Internal Medicine service, the patient underwent a comprehensive clinical evaluation aimed at identifying the etiology of the febrile syndrome and previously documented hematological abnormalities. At the time of admission to the hospital ward, apparent hemodynamic stabilization was observed compared to parameters recorded during initial evaluation in the emergency department.\u003c/p\u003e\n\u003cp\u003eVital signs at admission were as follows: blood pressure 130/75 mmHg, heart rate 75 beats per minute, respiratory rate 20 breaths per minute, body temperature 36.5 \u0026deg;C, and oxygen saturation 92% on room air. Despite relative improvement of the initial systemic inflammatory response, the prior persistence of fever and presence of significant cytopenias justified a detailed clinical evaluation.\u003c/p\u003e\n\u003cp\u003eDuring general physical examination, the patient was conscious, alert, and oriented, without evidence of focal neurological deficit. Mucocutaneous inspection revealed marked pallor, consistent with previously documented severe anemia, although hydration status was adequate. No cutaneous lesions suggestive of Kaposi sarcoma, such as violaceous macules, plaques, or nodules on skin or visible mucosae, were identified at the time of evaluation.\u003c/p\u003e\n\u003cp\u003eExamination of the head and neck showed a cylindrical neck without signs of jugular venous distention or vascular bruits, and without palpable cervical lymphadenopathy. The oral cavity showed no ulcerative lesions or vascular proliferations suggestive of mucosal involvement by immunosuppression-associated neoplasms.\u003c/p\u003e\n\u003cp\u003eCardiopulmonary evaluation revealed symmetric thoracic movements with adequate expansion. Pulmonary auscultation demonstrated vesicular breath sounds present in both hemithoraces without added sounds, while cardiac auscultation revealed rhythmic heart sounds of good intensity, without murmurs or gallop, not suggesting acute cardiopulmonary involvement.\u003c/p\u003e\n\u003cp\u003eAbdominal examination revealed a soft, depressible abdomen, non-tender to superficial and deep palpation, with preserved peristalsis on auscultation. Percussion was tympanic over the colonic frame, and no palpable visceromegaly or evident intra-abdominal masses were identified during initial evaluation.\u003c/p\u003e\n\u003cp\u003eHowever, during examination of the inguinal region, a palpable lymph node was identified in the left inguinal region measuring approximately 3 \u0026times; 3 cm, of firm consistency, mobile relative to deep planes, and non-tender to palpation. This finding constituted a relevant clinical datum within the context of febrile syndrome and immunosuppressed state.\u003c/p\u003e\n\u003cp\u003eExamination of the extremities showed symmetric limbs, without edema or peripheral vascular alterations, with palpable distal pulses and capillary refill time of approximately two seconds.\u003c/p\u003e\n\u003cp\u003eFrom the perspective of the Internal Medicine clinical approach, the combination of febrile syndrome of undetermined origin, severe cytopenias, recently diagnosed HIV infection, and presence of peripheral lymphadenopathy raised a broad differential diagnosis. Among the main diagnostic possibilities considered were opportunistic infections, lymphoproliferative diseases such as lymphoma, disseminated infections including mycobacteriosis, as well as neoplasms associated with immunosuppression, including Kaposi sarcoma with atypical presentation.\u003c/p\u003e\n\u003cp\u003eConsequently, after the initial clinical evaluation, it was decided to initiate a comprehensive diagnostic protocol, which included laboratory studies, imaging studies, and targeted evaluation of the inguinal lymphadenopathy with the aim of establishing its etiology and reaching a definitive diagnosis.\u003c/p\u003e\n\u003ch2\u003eDiagnostic Evaluation and Clinical Course\u003c/h2\u003e\n\u003cp\u003eFollowing the initial clinical evaluation in the Internal Medicine service, a comprehensive diagnostic protocol was initiated with the aim of identifying the etiology of the febrile syndrome, documented cytopenias, and presence of lymphadenopathy. Given the context of recently diagnosed HIV infection and the presence of systemic manifestations, the diagnostic approach was oriented toward ruling out opportunistic infections, hematological diseases, and neoplastic processes associated with immunosuppression.\u003c/p\u003e\n\u003cp\u003eInitial laboratory studies demonstrated severe hematological abnormalities, particularly anemia and significant thrombocytopenia. Hemoglobin levels of 5.9 g/dL were documented, with hematocrit of 20.1%, findings consistent with severe anemia, as shown in Figure 1. Concomitantly, platelet count was markedly decreased, with initial values around 28,000/\u0026micro;L, confirming the presence of significant thrombocytopenia. Leukocyte count remained within relatively preserved ranges, with neutrophil predominance as represented in Figure 2. These hematological abnormalities raised the possibility of an underlying systemic process that could involve bone marrow suppression or infiltration, systemic inflammation, or neoplastic processes.\u003c/p\u003e\n\u003cp\u003eInflammatory markers were found to be elevated, highlighting C-reactive protein levels above 19 mg/dL, supporting the presence of an active systemic inflammatory process. Likewise, markedly elevated D-dimer levels were documented, suggesting activation of the coagulation cascade and endothelial dysfunction, findings that may be observed in severe inflammatory processes, systemic infections, or neoplastic diseases as shown in Figure 3.\u003c/p\u003e\n\u003cp\u003eBiochemical studies additionally demonstrated progressive deterioration of renal function during hospitalization. Serum creatinine levels showed an increase from 1.23 mg/dL at initial evaluation to 3.77 mg/dL and subsequently 4.80 mg/dL, accompanied by a parallel rise in urea and blood urea nitrogen levels. These findings were consistent with the development of acute kidney injury, likely of multifactorial etiology, associated with systemic inflammatory response, hemodynamic alterations, and the underlying disease as represented in Figure 4.\u003c/p\u003e\n\u003cp\u003eConcomitantly, electrolyte abnormalities were documented, including hyponatremia, hyperkalemia, hypocalcemia, and hyperphosphatemia, changes that reinforced the suspicion of significant renal involvement. Serum albumin levels were markedly decreased, with values around 1.33 g/dL, suggesting a significant systemic inflammatory state, as well as possible nutritional compromise or alterations in protein synthesis, as represented in Figure 5.\u003c/p\u003e\n\u003cp\u003eLiver function tests showed mild alterations, with transaminases within near-normal ranges and minimal elevation of bilirubin levels. Tumor markers, including alpha-fetoprotein (AFP), CA 19-9, and carcinoembryonic antigen (CEA), were within normal limits, making the presence of primary neoplasms of gastrointestinal or hepatobiliary origin less likely.\u003c/p\u003e\n\u003cp\u003eDuring the hospital course, an arterial blood gas analysis was also performed, which documented a pH of 7.45, with decreased bicarbonate levels and a negative base excess, findings consistent with metabolic acidosis with respiratory compensation, likely related to progressive deterioration of renal function.\u003c/p\u003e\n\u003cp\u003eIn parallel with laboratory evaluation, imaging studies were performed with the aim of identifying possible infectious foci or neoplastic processes. Chest computed tomography revealed the presence of bilateral axillary and mediastinal lymphadenopathy, without pulmonary infiltrates suggestive of acute infectious processes. The lungs showed preserved architecture, with only mild left basal laminar atelectasis identified. No space-occupying lesions were identified in the mediastinum as described in Figure 6.\u003c/p\u003e\n\u003cp\u003eThe presence of lymphadenopathy in multiple nodal chains, including mediastinal, axillary, and inguinal regions, raised suspicion of a lymphoproliferative or systemic neoplastic process. In the context of HIV infection, the differential diagnosis primarily included HIV-associated non-Hodgkin lymphoma, disseminated infections such as tuberculosis or systemic mycoses, multicentric Castleman disease, and Kaposi sarcoma with atypical nodal presentation.\u003c/p\u003e\n\u003cp\u003eGiven these findings, histopathological study of the affected lymph node through lymph node biopsy was considered essential in order to establish a definitive diagnosis and guide subsequent therapeutic management.\u003c/p\u003e\n\u003ch2\u003eDiagnostic Confirmation\u003c/h2\u003e\n\u003cp\u003eGiven the persistence of the febrile syndrome, the presence of significant cytopenias, and the identification of lymphadenopathy in multiple nodal territories, it was decided to advance the diagnostic approach by obtaining tissue for histopathological study. In this context, an excisional biopsy of the inguinal lymph node was performed, a procedure considered fundamental to establish a definitive diagnosis, particularly in the setting of suspected lymphoproliferative or neoplastic processes associated with HIV infection.\u003c/p\u003e\n\u003cp\u003eHistopathological analysis of the lymph node revealed a neoplastic proliferation of mesenchymal origin with a vascular pattern, characterized by the presence of spindle-shaped cells arranged in irregular fascicles, associated with the formation of irregular, narrow vascular channels. Areas with erythrocyte extravasation were also identified, a phenomenon frequently observed in vascular tumors and particularly characteristic of Kaposi sarcoma. The normal nodal architecture was partially replaced by this cellular proliferation, suggesting tumor infiltration of the lymphatic tissue.\u003c/p\u003e\n\u003cp\u003eBecause these morphological characteristics may be observed in various vascular tumors, immunohistochemical studies were performed in order to confirm the nature of the neoplasm. In the immunohistochemical panel, nuclear positivity for the latent antigen of human herpesvirus type 8 (HHV-8 LNA-1) was observed, a finding considered highly specific for Kaposi sarcoma. Likewise, positivity for CD34, an endothelial marker, was documented, demonstrating cytoplasmic staining in spindle cells and in the endothelium of capillaries present in the lesion. Additionally, the marker podoplanin (D2-40) showed cytoplasmic and membranous positivity, supporting the vascular origin of the neoplastic proliferation.\u003c/p\u003e\n\u003cp\u003eThe combination of morphological findings observed in histopathology together with the immunohistochemical profile allowed the establishment of a definitive diagnosis of Kaposi sarcoma with nodal involvement. This finding was particularly relevant, given that the patient did not present evident cutaneous lesions at the time of initial evaluation, suggesting an atypical presentation of the disease with predominant nodal involvement.\u003c/p\u003e\n\u003cp\u003eIn the context of recently diagnosed HIV infection, Kaposi sarcoma represents an AIDS-defining neoplasm associated with HHV-8 infection and favored by the state of cellular immunosuppression. Histopathological confirmation of Kaposi sarcoma explained the presence of multiple lymphadenopathies and contributed to orienting the diagnostic approach toward a vascular neoplasm associated with immunodeficiency.\u003c/p\u003e\n\u003cp\u003eTherefore, lymph node biopsy and immunohistochemical analysis were determinant in clarifying the etiology of the clinical presentation, allowing the diagnosis of nodal Kaposi sarcoma in the context of HIV infection, a rare entity when it presents as an initial manifestation without evident cutaneous lesions.\u003c/p\u003e\n\u003ch2\u003eClinical Interpretation and Relevance of the Case\u003c/h2\u003e\n\u003cp\u003eThe presented case illustrates an atypical form of presentation of Kaposi sarcoma associated with HIV infection, characterized by predominant nodal involvement in the absence of evident cutaneous lesions at the time of initial evaluation. Although Kaposi sarcoma classically manifests with violaceous cutaneous lesions on the skin and mucosae, particularly in the lower extremities or oral cavity, primary or predominant involvement of lymph nodes is uncommon and may represent a significant diagnostic challenge in clinical practice.\u003c/p\u003e\n\u003cp\u003eFrom the perspective of the Internal Medicine approach, this case acquired particular complexity due to the coexistence of febrile syndrome of undetermined origin, severe cytopenias, progressive deterioration of renal function, and multiple lymphadenopathies in a young patient with recently diagnosed HIV infection and without antiretroviral therapy. In this context, the initial differential diagnosis was broad and included several entities, among them HIV-associated non-Hodgkin lymphoma, disseminated opportunistic infections such as tuberculosis or systemic mycoses, multicentric Castleman disease, and other neoplasms related to immunosuppression.\u003c/p\u003e\n\u003cp\u003eIn parallel with clinical and laboratory evaluation, imaging studies were performed with the aim of identifying possible infectious foci or neoplastic processes. Initial chest computed tomography demonstrated the presence of bilateral axillary and mediastinal lymphadenopathy, without pulmonary infiltrates suggestive of acute infectious processes. The lungs showed preserved architecture, with only mild left basal laminar atelectasis, without mediastinal space-occupying lesions. Subsequently, a follow-up chest computed tomography was performed, in which progression of findings was documented, with an increase in the number and size of lymphadenopathies in multiple nodal territories, as well as the appearance of bilateral pleural effusion, hepatosplenomegaly, and free fluid in the abdominal cavity, which oriented toward a systemic process of infiltrative or neoplastic nature as described in Figure 7.\u003c/p\u003e\n\u003cp\u003eThe presence of severe cytopenias, particularly anemia and thrombocytopenia, contributed to increasing the initial suspicion of malignant or infiltrative hematological processes. Likewise, the identification of lymphadenopathy in multiple nodal territories on imaging studies reinforced the diagnostic possibility of a lymphoproliferative disease. However, histopathological study of the lymph node allowed identification of a vascular neoplasm compatible with Kaposi sarcoma, as shown in Figure 8, and was subsequently confirmed by immunohistochemistry with positivity for HHV-8, as shown in Table 2.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"588\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 30.7301%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntibody\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.7895%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.6367%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStaining pattern\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27.8438%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInterpretation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 30.7301%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHuman herpesvirus 8 (HHV-8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.7895%;\"\u003e\n \u003cp\u003e13B10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.6367%;\"\u003e\n \u003cp\u003eNuclear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27.8438%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 30.7301%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD34\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.7895%;\"\u003e\n \u003cp\u003eQBEND10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.6367%;\"\u003e\n \u003cp\u003eCytoplasmic and membranous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27.8438%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 30.7301%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePodoplanin (D2-40)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.7895%;\"\u003e\n \u003cp\u003eD2-40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.6367%;\"\u003e\n \u003cp\u003eCytoplasmic and membranous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27.8438%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp id=\"_Toc226412376\"\u003eTable\u0026nbsp;2. Immunohistochemical findings. Immunohistochemical analysis demonstrated nuclear positivity for HHV-8 (LNA-1), confirming the diagnosis of Kaposi sarcoma. CD34 and podoplanin (D2-40) positivity support the endothelial origin of the spindle cell proliferation. Abbreviations: HHV-8, human herpesvirus 8.\u003c/p\u003e\n\u003cp\u003eKaposi sarcoma associated with HIV is characterized as an angioproliferative neoplasm induced by infection with human herpesvirus type 8, whose development is favored by impairment of cellular immunity mediated by CD4 T lymphocytes. In patients with HIV infection without antiretroviral treatment, persistent viral replication and immunological dysfunction favor proliferation of endothelial cells infected by HHV-8, leading to the formation of tumor lesions.\u003c/p\u003e\n\u003cp\u003eNodal involvement may occur as part of disseminated disease; however, when it presents as an initial manifestation without evident cutaneous lesions, it may delay diagnosis due to its clinical similarity to other entities, particularly HIV-associated lymphomas. In this sense, lymph node biopsy constitutes a fundamental diagnostic tool, as it allows differentiation between infectious, inflammatory, and neoplastic processes through histopathological analysis and the application of immunohistochemical techniques.\u003c/p\u003e\n\u003cp\u003eThis case highlights the importance of maintaining a high index of diagnostic suspicion in patients with HIV infection who present with lymphadenopathy and systemic manifestations, even in the absence of the cutaneous lesions classically described for Kaposi sarcoma. It also emphasizes the relevance of performing a systematic and timely diagnostic approach in patients with febrile syndrome and cytopenias, in order to identify early neoplastic diseases associated with immunosuppression.\u003c/p\u003e\n\u003cp\u003eFinally, the identification of Kaposi sarcoma in this clinical context emphasizes the need to consider this entity within the differential diagnosis of lymphadenopathy in patients with HIV, particularly in those without antiretroviral treatment, as its timely recognition directly impacts prognosis and the initiation of appropriate therapeutic management.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe presented case illustrates an atypical form of Kaposi sarcoma (KS) associated with HIV infection, characterized by predominant nodal involvement in the absence of evident cutaneous lesions at the time of initial evaluation. Although KS classically manifests with violaceous cutaneous lesions, its clinical spectrum is broad and may include mucosal, visceral, and lymphatic involvement, particularly in patients with advanced immunosuppression [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the context of HIV infection, the development of KS is closely related to the interaction between immunosuppression, chronic inflammation, and coinfection with human herpesvirus type 8 (HHV-8). Depletion of CD4\u0026thinsp;+\u0026thinsp;lymphocytes and global immune dysfunction favor viral reactivation and proliferation of infected endothelial cells, leading to the formation of angioproliferative lesions [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne of the most relevant aspects of this case is the predominant nodal presentation, which is uncommon and represents a significant diagnostic challenge. Available evidence indicates that nodal involvement in KS usually occurs as part of disseminated disease; however, cases with nodal involvement as the initial or main manifestation are rare and poorly described in the literature [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This presentation may mimic other more frequent entities in patients with HIV, particularly non-Hodgkin lymphoma, disseminated opportunistic infections, or HHV-8\u0026ndash;associated multicentric Castleman disease, contributing to diagnostic delays [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the described case, the presence of multiple lymphadenopathies, febrile syndrome, cytopenias, and deterioration of renal function initially suggested an infectious or lymphoproliferative process. This approach is consistent with what is reported in the literature, where the initial differential diagnosis in patients with HIV and generalized lymphadenopathy usually includes granulomatous infections, systemic mycoses, and immunosuppression-associated lymphomas [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The absence of characteristic cutaneous lesions in this patient contributed to lower suspicion of KS, delaying consideration of this entity within the differential diagnosis.\u003c/p\u003e \u003cp\u003eImaging studies, although useful for evaluating disease extent, have important limitations in etiological differentiation. In this case, computed tomography demonstrated multiple lymphadenopathies and systemic involvement, findings that may be observed in both infectious and neoplastic processes. This lack of radiological specificity has been widely described and underscores the need for histopathological confirmation in all suspected cases [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLymph node biopsy was decisive in establishing the definitive diagnosis, demonstrating a vascular neoplasm with histological features compatible with KS, confirmed by immunohistochemistry with HHV-8 positivity. This finding highlights the importance of early histopathological evaluation in patients with persistent lymphadenopathy, especially when the diagnosis remains unclear after initial studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom a clinical standpoint, this case highlights several gaps in the recognition of non-classical presentations of KS. In particular, recent literature indicates that nodal or visceral forms without cutaneous lesions are underrepresented and may go unnoticed in clinical practice, contributing to diagnostic delays and worse prognosis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Likewise, the lack of specific diagnostic algorithms for these presentations complicates clinical decision-making in early stages.\u003c/p\u003e \u003cp\u003eTimely initiation of antiretroviral therapy constitutes a fundamental pillar in the management of HIV-associated KS, as immune restoration may induce tumor regression and improve clinical outcomes. However, in cases with disseminated disease or visceral involvement, additional systemic oncologic treatment may be required [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In this sense, early diagnosis is crucial to optimize treatment and improve prognosis.\u003c/p\u003e \u003cp\u003eFinally, this case highlights the importance of maintaining a high index of diagnostic suspicion in patients with HIV who present with lymphadenopathy and systemic manifestations, even in the absence of cutaneous lesions. Inclusion of KS within the differential diagnosis in these scenarios is essential to avoid diagnostic delays and allow timely management.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eKaposi sarcoma associated with HIV infection continues to represent an entity of high clinical relevance, particularly in patients with recent diagnosis or without antiretroviral treatment, in whom immunosuppression favors more aggressive, disseminated, and atypical presentations. This case highlights the heterogeneity of the clinical spectrum of the disease and the need to recognize non-classical variants that may deviate from its usual cutaneous presentation.\u003c/p\u003e \u003cp\u003ePresentation with predominant nodal involvement in the absence of evident cutaneous lesions constitutes an uncommon form that represents a significant diagnostic challenge. In these scenarios, clinical overlap with more prevalent entities in patients with HIV, such as non-Hodgkin lymphoma, disseminated opportunistic infections, and HHV-8\u0026ndash;associated Castleman disease, may lead to delays in diagnostic suspicion and in the initiation of appropriate management.\u003c/p\u003e \u003cp\u003eThis case emphasizes the importance of a comprehensive and systematic diagnostic approach in patients with HIV who present with persistent lymphadenopathy and systemic manifestations. Integration of clinical data, laboratory findings, imaging studies, and, fundamentally, histopathological evaluation with immunohistochemistry, is essential to establish the definitive diagnosis. In particular, identification of HHV-8 positivity constitutes a key element to confirm Kaposi sarcoma in atypical presentations.\u003c/p\u003e \u003cp\u003eLikewise, it is emphasized that imaging studies, although useful for evaluating disease extent, have limitations in etiological differentiation, and therefore should not delay biopsy in cases with persistent diagnostic suspicion. The timely decision to obtain tissue for histological study is determinant in avoiding diagnostic delays and improving clinical outcomes.\u003c/p\u003e \u003cp\u003eFrom a therapeutic standpoint, early initiation of antiretroviral therapy is fundamental, as restoration of immune function may modify disease progression and improve prognosis. In cases with systemic involvement or advanced disease, an additional therapeutic approach with specific oncologic treatment may be required, reinforcing the importance of early and accurate diagnosis.\u003c/p\u003e \u003cp\u003eFinally, this case contributes to expanding knowledge regarding non-classical presentations of Kaposi sarcoma, particularly in young patients with HIV infection. Documentation of these clinical variants is essential to improve diagnostic suspicion, reduce diagnostic delays, and optimize clinical management. In this sense, it is indispensable to maintain a high index of suspicion and to include Kaposi sarcoma within the differential diagnosis of lymphadenopathy in patients with HIV, even in the absence of cutaneous manifestations, thereby promoting a broader, timely, and outcome-oriented clinical approach in this population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eACKNOWLEDGMENTS\u003c/h2\u003e\n\u003cp\u003eThe authors would like to acknowledge the healthcare personnel of the Mexican Social Security Institute (IMSS) for their commitment, professionalism, and dedication to patient care. Their continuous efforts play a fundamental role in the diagnosis and management of complex clinical conditions.\u003c/p\u003e\n\u003cp\u003eWe also extend our gratitude to the pathology department for their invaluable contribution to the diagnostic process, particularly in the histopathological and immunohistochemical evaluation that was essential for establishing the final diagnosis.\u003c/p\u003e\n\u003cp\u003eThe authors wish to express their sincere appreciation to each member of the team whose contributions made this work possible. Mar\u0026iacute;a Dioselina Ruiz Barrera is acknowledged for her leadership, clinical dedication, and commitment to academic excellence. Luis Ernesto Heredia Santos is recognized for his clinical insight and contribution to patient care and case analysis. Mar\u0026iacute;a Alaciel Galv\u0026aacute;n Merlos is appreciated for her guidance, supervision, and support in the clinical management of the case. Leticia Guerrero Navarrete is acknowledged for her collaboration and commitment to patient-centered care. Lissette Haydee Garc\u0026iacute;a Mena is recognized for her academic support and contribution to the organization and interpretation of information. Mar\u0026iacute;a Jose Hern\u0026aacute;ndez Cruz is appreciated for her assistance in data collection and clinical documentation. Liliana Antonio Revuelta is acknowledged for her contribution to data analysis and critical review of the manuscript.\u003c/p\u003e\n\u003cp\u003eWe also recognize the value of collaboration, mentorship, and friendship that transcends time and borders, enriching both the academic and human dimensions of this work.\u003c/p\u003e\n\u003cp\u003eFinally, we dedicate this work to all patients living with HIV. Through this report, we aim to contribute to greater awareness, earlier diagnosis, and improved clinical care, reaffirming that they are not alone and that ongoing efforts in research and medicine remain essential to improving their outcomes and quality of life.\u003c/p\u003e\n\u003ch2\u003eConflicts of Interest / Competing Interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests, either financial or non-financial, related to this work.\u003c/p\u003e\n\u003ch2\u003eFUNDING\u003c/h2\u003e\n\u003cp\u003eThis study received no external funding.\u003c/p\u003e\n\u003ch2\u003eETHICAL APPROVAL\u003c/h2\u003e\n\u003cp\u003eThis case report was conducted in accordance with institutional ethical standards, as well as with the principles outlined in the Declaration of Helsinki for research involving human subjects. The clinical management and documentation of this case were performed within the framework of standard medical care at the Mexican Social Security Institute (IMSS).\u003c/p\u003e\n\u003cp\u003eInstitutional procedures and patient care were carried out in compliance with national regulations, including the Mexican Official Standard NOM-004-SSA3-2012 for clinical records and the applicable provisions of the General Health Law regarding medical care services.\u003c/p\u003e\n\u003ch2\u003eCONSENT TO PARTICIPATE AND FOR PUBLICATION\u003c/h2\u003e\n\u003cp\u003eWritten informed consent for hospitalization and medical care was obtained from the patient prior to admission. Additionally, informed consent for the use of clinical information for academic and publication purposes was obtained from the patient. Supporting documentation is available, including the institutional informed consent form issued by the Mexican Social Security Institute.\u003c/p\u003e\n\u003cp\u003eAll identifying patient information has been anonymized to protect confidentiality.\u003c/p\u003e\n\u003cp\u003eData Availability\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request. All data are de-identified in accordance with institutional and ethical regulations.\u003c/p\u003e\n\u003cp\u003eCode Availability\u003c/p\u003e\n\u003cp\u003eNo custom code or software was developed or used in this study. All relevant data supporting the findings are included within the manuscript.\u003c/p\u003e\n\u003ch2\u003eAUTHOR CONTRIBUTIONS STATEMENT\u003c/h2\u003e\n\u003cp\u003eM.D.R.B. conceptualized the study, led the clinical management of the patient, and wrote the main manuscript.\u003c/p\u003e\n\u003cp\u003eL.E.H.S. contributed to patient care, data acquisition, and manuscript drafting.\u003c/p\u003e\n\u003cp\u003eM.A.G.M. supervised the clinical management and critically revised the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eL.G.N. contributed to clinical data interpretation and manuscript review.\u003c/p\u003e\n\u003cp\u003eL.H.G.M. conducted the literature review and contributed to manuscript editing.\u003c/p\u003e\n\u003cp\u003eM.J.H.C. participated in data collection and clinical documentation.\u003c/p\u003e\n\u003cp\u003eL.A.R. contributed to data analysis and critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDeeks SG, Lewin SR, Havlir D V. The end of AIDS: HIV infection as a chronic disease. The Lancet 2013;382:1525\u0026ndash;33. https://doi.org/10.1016/S0140-6736(13)61809-7.\u003c/li\u003e\n\u003cli\u003eGuaraldi G, Palella FJ. Clinical implications of aging with HIV infection: Perspectives and the future medical care agenda. AIDS 2017;31:S129\u0026ndash;35. https://doi.org/10.1097/QAD.0000000000001478.\u003c/li\u003e\n\u003cli\u003eYarchoan R, Uldrick TS. HIV-Associated Cancers and Related Diseases. New England Journal of Medicine 2018;378:1029\u0026ndash;41. https://doi.org/10.1056/NEJMra1615896.\u003c/li\u003e\n\u003cli\u003eGrulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007;370:59\u0026ndash;67. https://doi.org/10.1016/S0140-6736(07)61050-2.\u003c/li\u003e\n\u003cli\u003eSilverberg MJ, Lau B, Achenbach CJ, Jing Y, Althoff KN, D\u0026rsquo;Souza G, et al. Cumulative incidence of cancer among persons with HIV in North America: A cohort study. Ann Intern Med 2015;163:507\u0026ndash;18. https://doi.org/10.7326/M14-2768.\u003c/li\u003e\n\u003cli\u003eMesri EA, Cesarman E, Boshoff C. Kaposi\u0026rsquo;s sarcoma and its associated herpesvirus. Nat Rev Cancer 2010;10:707\u0026ndash;19. https://doi.org/10.1038/nrc2888.\u003c/li\u003e\n\u003cli\u003eBettuzzi T, Lebbe C, Grolleau C. Modern Approach to Manage Patients With Kaposi Sarcoma. J Med Virol 2025;97:e70294. https://doi.org/10.1002/jmv.70294.\u003c/li\u003e\n\u003cli\u003eBagratee TJ, Ramsuran V, Msimang M, Ramdial PK. Recent Advances in the Histopathology, Molecular Biology, and Treatment of Kaposi Sarcoma: A Contemporary Review. Int J Mol Sci 2025;26:10058. https://doi.org/10.3390/ijms262010058.\u003c/li\u003e\n\u003cli\u003eRusso I, Marino D, Cozzolino C, Del Fiore P, Nerjaku F, Finotto S, et al. Kaposi\u0026rsquo;s Sarcoma: Evaluation of Clinical Features, Treatment Outcomes, and Prognosis in a Single-Center Retrospective Case Series. Cancers (Basel) 2024;16. https://doi.org/10.3390/cancers16040691.\u003c/li\u003e\n\u003cli\u003eDenaro N, Brambilla L, Scarf\u0026igrave; F, Tourlaki A, Muscatello A, Solinas C, et al. Castleman Disease and Kaposi Sarcoma: A Review of the Literature and a Case Series. J Clin Med 2025;14. https://doi.org/10.3390/jcm14186563.\u003c/li\u003e\n\u003cli\u003ePagtalunan CJ, Zhang I, Turley A, Liu F. Recent Studies on Kaposi\u0026rsquo;s Sarcoma-Associated Herpesvirus Circular RNAs. Cancers (Basel) 2025;17:3743. https://doi.org/10.3390/cancers17233743.\u003c/li\u003e\n\u003cli\u003eJin F, Vajdic CM, Poynten IM, McGee-Avila JK, Castle PE, Grulich AE. Cancer risk in people living with HIV and solid organ transplant recipients: a systematic review and meta-analysis. Lancet Oncol 2024;25:933\u0026ndash;44. https://doi.org/10.1016/S1470-2045(24)00189-X.\u003c/li\u003e\n\u003cli\u003eMa S, Chen X, Lai Y. Global research landscape of HIV and Kaposi\u0026rsquo;s sarcoma: a visualized bibliometric analysis. Front Microbiol 2025;16:1601245. https://doi.org/10.3389/fmicb.2025.1601245.\u003c/li\u003e\n\u003cli\u003eCesarman E, Damania B, Krown SE, Martin J, Bower M, Whitby D. Kaposi sarcoma. Nat Rev Dis Primers 2019;5:5. https://doi.org/10.1038/s41572-019-0060-9.\u003c/li\u003e\n\u003cli\u003eLebbe C, Garbe C, Stratigos AJ, Harwood C, Peris K, Marmol V del, et al. Diagnosis and treatment of Kaposi\u0026rsquo;s sarcoma: European consensus-based interdisciplinary guideline (EDF/EADO/EORTC). Eur J Cancer 2019;114:117\u0026ndash;27. https://doi.org/10.1016/j.ejca.2018.12.036.\u003c/li\u003e\n\u003cli\u003eBower M, Dalla Pria A, Coyle C, Andrews E, Tittle V, Dhoot S, et al. Prospective stage-stratified approach to AIDS-related Kaposi\u0026rsquo;s sarcoma. Journal of Clinical Oncology 2014;32:409\u0026ndash;14. https://doi.org/10.1200/JCO.2013.51.6757.\u003c/li\u003e\n\u003cli\u003eBourne-Watrin M, Fran\u0026ccedil;oise U, Baron SA, Adenis AA, Louis DP, Epelboin L, et al. Etiological spectrum and diagnostic features of lymphadenopathy in People Living with HIV in French Guiana: A 17-years multicenter retrospective case series. PLoS Negl Trop Dis 2025;19:e0013558. https://doi.org/10.1371/journal.pntd.0013558.\u003c/li\u003e\n\u003cli\u003eGlushko T, He L, McNamee W, Babu AS, Simpson SA. HIV lymphadenopathy: Differential diagnosis and important imaging features. American Journal of Roentgenology 2021;216:526\u0026ndash;33. https://doi.org/10.2214/AJR.19.22334.\u003c/li\u003e\n\u003cli\u003eBarrionuevo-Cornejo C, Due\u0026ntilde;as-Hancco D. Lymphadenopathies in human immunodeficiency virus infection. Semin Diagn Pathol 2018;35:84\u0026ndash;91. https://doi.org/10.1053/j.semdp.2017.12.001.\u003c/li\u003e\n\u003cli\u003eGround M, Veenendaal T, Chiluzi D, Nkhonjera G, Glas A, Glas-van Dijk L. HHV8-Associated Multicentric Castleman Disease: A Case Report on a Rare Complication of HIV in a Low-Income Setting. Res Rep Trop Med 2024;Volume 15:91\u0026ndash;7. https://doi.org/10.2147/RRTM.S483426.\u003c/li\u003e\n\u003cli\u003eHoffmann C, Oksenhendler E, Littler S, Grant L, Kanhai K, Fajgenbaum DC. The clinical picture of Castleman disease: a systematic review and meta-analysis. Blood Adv 2024;8:4924\u0026ndash;35. https://doi.org/10.1182/bloodadvances.2024013548.\u003c/li\u003e\n\u003cli\u003eOcampo-Gonzalez FA, Bhagat G. KSHV/HHV-8-associated multicentric Castleman disease and nodal Kaposi sarcoma displaying a lymphangiectatic pattern. Blood 2024;144:587. https://doi.org/10.1182/blood.2024024839.\u003c/li\u003e\n\u003cli\u003eHtet KZ, Bahrani E, Leslie KS. Updates on Kaposi sarcoma. Clin Dermatol 2025. https://doi.org/10.1016/j.clindermatol.2025.09.013.\u003c/li\u003e\n\u003cli\u003eJebrini NEM, Natsheh MA, Jaber M, Muhtaseb R, Qunaibi Y, Hidri H, et al. Atypical presentation of Kaposi sarcoma in an HIV-negative patient: a case report and comprehensive literature review. Annals of Medicine \u0026amp; Surgery 2024;86:7325\u0026ndash;9. https://doi.org/10.1097/ms9.0000000000002553.\u003c/li\u003e\n\u003cli\u003eGuimar\u0026atilde;es A, Azevedo R, Lopes S, Soares J. Atypical Presentation of Kaposi Sarcoma. ACG Case Rep J 2026;13:e01963. https://doi.org/10.14309/crj.0000000000001963.\u003c/li\u003e\n\u003cli\u003eCao E, Saad M, Deisch J, Barbosa M, Fakhouri Y, Sutjita M. Noncutaneous Visceral Kaposi Sarcoma of the Stomach and Liver: A Case Report. Case Rep Oncol 2025;18:1\u0026ndash;13. https://doi.org/10.1159/000550013.\u003c/li\u003e\n\u003cli\u003eRojek NW, Worswick S, Shinkai K, Fox LP. Diagn\u0026oacute;stico cl\u0026iacute;nico y tratamiento 2025. In: Papadakis MA, Rabow MW, McQuaid KR, Gandhi Monica, editors. Diagn\u0026oacute;stico cl\u0026iacute;nico y tratamiento 2025. 64\u003csup\u003ea\u003c/sup\u003e edici\u0026oacute;n, New York, NY: 2025.\u003c/li\u003e\n\u003cli\u003eDittmer DP, Damania B. Kaposi\u0026rsquo;s sarcoma-associated herpesvirus (KSHV)-associated disease in the AIDS Patient: An update. Cancer Treat Res 2019;177:63\u0026ndash;80. https://doi.org/10.1007/978-3-030-03502-0_3.\u003c/li\u003e\n\u003cli\u003eNissen T, Wynn R. The clinical case report: a review of its merits and limitations. London: 2014. https://doi.org/10.1186/1756-0500-7-264.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Kaposi Sarcoma, HIV Infection, Acquired Immunodeficiency Syndrome, Human Herpesvirus 8, Lymphadenopathy, Nodal Kaposi Sarcoma, Angioproliferative Neoplasms, Immunosuppression, AIDS-Related Malignancies, Differential Diagnosis","lastPublishedDoi":"10.21203/rs.3.rs-9363985/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9363985/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eKaposi sarcoma is an angioproliferative neoplasm driven by human herpesvirus 8 (HHV-8), most commonly observed in immunocompromised individuals, particularly those with untreated human immunodeficiency virus infection. It classically presents with cutaneous and mucocutaneous lesions; however, atypical forms without skin involvement, especially those with predominant lymph node disease, are rare and frequently lead to diagnostic uncertainty.\u003c/p\u003e \u003cp\u003eWe report the case of a 26-year-old male with recently diagnosed HIV infection and no prior antiretroviral therapy, who presented with a two-week history of persistent fever, constitutional symptoms, abdominal pain, and progressive intolerance to oral intake. On admission, he exhibited hemodynamic instability, severe anemia, thrombocytopenia, and progressive renal dysfunction. Imaging studies revealed generalized lymphadenopathy involving multiple nodal chains, bilateral pleural effusion, hepatosplenomegaly, and free abdominal fluid, suggesting a systemic process. Initial diagnostic considerations included lymphoma, disseminated infection, and other HIV-associated malignancies. An excisional inguinal lymph node biopsy demonstrated a vascular mesenchymal neoplasm composed of spindle cells, and immunohistochemical analysis confirmed Kaposi sarcoma with nuclear positivity for HHV-8. Notably, no cutaneous or mucosal lesions were identified throughout the clinical course.\u003c/p\u003e \u003cp\u003eNodal Kaposi sarcoma without cutaneous involvement represents an uncommon and underrecognized presentation, particularly in young patients with untreated HIV infection. Its clinical features frequently overlap with lymphoproliferative disorders and opportunistic infections, contributing to diagnostic delays. The pathogenesis is driven by the interplay between HIV-induced immunosuppression, chronic immune activation, and HHV-8\u0026ndash;mediated oncogenesis. In this context, early histopathological evaluation remains essential for definitive diagnosis, as imaging findings lack specificity.\u003c/p\u003e \u003cp\u003eThis case highlights the importance of including Kaposi sarcoma in the differential diagnosis of unexplained lymphadenopathy in patients with HIV, even in the absence of cutaneous lesions. Recognition of atypical presentations is critical to ensure timely diagnosis and appropriate management, ultimately improving patient outcomes.\u003c/p\u003e","manuscriptTitle":"Atypical Nodal Kaposi Sarcoma in HIV Infection. A case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-14 15:10:15","doi":"10.21203/rs.3.rs-9363985/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fa33599d-8577-45c9-a3d8-c63bb66eccca","owner":[],"postedDate":"April 14th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-24T02:54:15+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-14 15:10:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9363985","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9363985","identity":"rs-9363985","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}