Potential utilization of lymphoscintigraphy in patients with kaposiform hemangioendothelioma

Introduction

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor characterized by locally aggressive behavior, most commonly diagnosed in infancy or early childhood. Its occurrence is exceptionally low, with an estimated incidence of approximately 0.71 cases per 1,000,000 individuals in North America (1). The most frequently involved sites are the extremities, followed by the trunk and the head and neck region (2). KHE exhibits a highly variable clinical presentation, largely dictated by lesion location, size, and associated complications. Accordingly, its management should be individualized, with current options including observation, surgical resection, topical medical therapy, systemic pharmacotherapy, and interventional embolization (2,3).

Lymphedema, a chronic condition characterized by localized swelling due to impaired lymphatic drainage, can lead to a range of physical, functional, and psychosocial complications, such as recurrent infections, functional impairment, chronic pain, or discomfort (4,5). In KHE, dysregulated lymphangiogenesis has been implicated in the development of secondary lymphedema, as reported in several previous studies (6-10). Once established, lymphedema is often difficult to reverse, despite various therapeutic interventions including physiotherapy, surgery, and sirolimus treatment (2,8). Monitoring the status of this lymphatic disorder is therefore crucial for the comprehensive management of patients with KHE. Lymphoscintigraphy is widely regarded as the first-line imaging modality for assessing lymphatic system function and has demonstrated significant utility in guiding clinical decision-making, particularly in rare lymphatic disorders (11,12). However, lymphoscintigraphy remains underutilized in the evaluation of KHE patients. This retrospective study sought to characterize lymphoscintigraphic imaging features of KHE and to evaluate its potential utility in clinical management. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-0739/rc).

Methods

Patients

Patients with a confirmed diagnosis KHE who underwent lymphoscintigraphy between January 2019 and December 2025 at West China Hospital were retrospectively enrolled in this study. The diagnosis of KHE was established through a comprehensive evaluation integrating clinical presentation, imaging findings, and histopathological confirmation. This single-center, retrospective study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of West China Hospital, Sichuan University (approval No. 392/2026). Informed consent was waived in this retrospective study.

Patients were excluded if they had coexisting venous or lymphatic malformations, underwent lymphoscintigraphy using non-standardized protocols, had poor-quality imaging studies, or lacked sufficient clinical documentation. Medical records were systematically reviewed to extract demographic information and relevant clinical characteristics.

Imaging acquisition and image analysis

Lymphoscintigraphy was performed using a standardized protocol for all patients. A dose of 2 mCi/0.5 mL of filtered ^99mTc sulfur colloid (Chengdu Xinke Pharmaceutical Co., Ltd., Chengdu, China) was injected subcutaneously into the first and second web spaces of the hands for upper extremity evaluations and the corresponding web spaces of the feet for lower extremity assessments. Whole-body images were acquired using a dual-head single-photon emission computed tomography (SPECT) system equipped with a low-energy, high-resolution collimator (Discovery NM/CT 670 CZT, GE Healthcare, Chicago, IL, USA). Imaging sessions were conducted at 10 minutes, 1 hour, and 3 hours post-injection. The acquisition parameters included an energy peak of 141 keV, a window width of 20%, a scan speed of 15 cm/min, an acquisition matrix of 256×1,024, and a zoom factor of 1.0.

Two board-certified nuclear medicine physicians interpreted the images by consensus. The size and anatomical location of lesions were documented. In patients with involvement of both the upper and lower extremities, key lymphoscintigraphic features were evaluated, including the extent of dermal backflow, lymphatic flow pattern, visualization of lymphatic stasis, regional lymph nodes, and presence of collateral lymphatic vessels (13). In accordance with previously published criteria, the imaging findings were classified into three categories: (I) normal lymphatic drainage (grade L); (II) partial lymphatic obstruction (grade P); and (III) total lymphatic obstruction (grade T) (14,15). Partial obstruction was further subdivided into three stages: P-1, distal linear lymphatic ducts without dermal backflow; P-2, engorged distal linear lymphatic ducts with dermal backflow in the proximal or distal lymphedematous limb; P-3, engorged lymphatic ducts with entire dermal backflow. Total obstruction consisted of three subgroups: T-4, engorged or absent lymphatic ducts with distal dermal backflow; T-5, engorged or absent lymphatic ducts with dermal backflow in the entire limb; T-6, absent lymphatic ducts without dermal backflow. For patients who underwent post-treatment or follow-up lymphoscintigraphy, changes between baseline and subsequent scans were systematically described.

Some patients additionally underwent magnetic resonance (MR) scans using either 1.5 T or 3.0 T MR scanners, with a slice thickness of 4 mm and an inter-slice gap of 1 mm. Axial, coronal, or sagittal T1- and T2-weighted sequences were acquired, with fat-suppression techniques applied as part of the protocol. All the images were reviewed by a radiologist with more than 5 years of experience in musculoskeletal and vascular imaging.

Patient management

Patients in this study received a range of therapeutic interventions, including systemic pharmacotherapy, surgical excision, and physiotherapy. Although surgical resection is considered the most effective treatment for KHE, it is feasible only in a select subset of patients due to factors such as lesion location, size, and invasiveness. All patients in this cohort received systemic pharmacotherapy with sirolimus. Physiotherapy was employed as an adjunctive modality and included the use of compression garments, multilayer compression bandages, and manual lymphatic drainage to manage associated symptoms, particularly lymphedema or tissue swelling.

Statistical analysis

Statistical analyses were performed using SPSS software (version 27.0; IBM Corp., Armonk, NY, USA). Descriptive statistics were used to summarize the demographic and clinical characteristics of the study population. Continuous variables are presented as mean ± standard deviation (SD) or median [interquartile range (IQR)], while categorical variables are reported as frequencies and percentages. The association between clinical findings and lymphoscintigraphic features was also explored.

Results

Baseline characteristics

Between January 2019 and December 2025, a total of 25 patients (15 male, 10 female) diagnosed with KHE underwent lymphoscintigraphy. The median age at the time of imaging was 21 months (range, 3 to 84 months). Nearly all patients had extremity involvement, with only one case exhibiting truncal involvement. All patients presented with a solitary, mixed-type lesion. Regarding previous treatments, twenty-four patients received systemic pharmacotherapy, 22 received physiotherapy, and nine patients underwent surgical excision. Detailed demographic and clinical characteristics are summarized in Table 1.

Lymphoscintigraphy findings

The single patient with truncal involvement who received injection in the first and second web spaces of the feet presented with solitary abnormal accumulation in the right anterior chest wall (Figure 1). Among 24 patients with extremity involvement, two patients who have lesions in the knees achieved complete surgical resection, and exhibited normal lymphatic drainage on the lymphoscintigraphy while the remaining 22 patients have abnormal lymphoscintigraphic findings (Table 2). Seventeen (77.3%) and 5 (22.7%) patients had lymphedema of the upper and lower extremities, respectively. Remarkably, lymphatic stasis was revealed in all patients. About 68% (15/22) of patients demonstrated a restricted pattern without visible regional lymph nodes (Figure 2), while the remaining 32% (7/22) showed a trunk flow pattern (Figure 3). Collateral lymphatic vessels were rarely found (1/22).

Figure 1 Lymphoscintigraphy and MRI findings in a 2-year-old girl with KHE of the right anterior chest wall. Anterior and posterior views at 1 hour (A; arrows) demonstrate abnormal radiotracer accumulation in the right chest region. Progressive tracer uptake is observed on delayed images (B; arrows). Corresponding axial T1WI and T2WI reveal heterogeneous signal intensity, consistent with associated lymphatic malformations (C,D; arrows). KHE, kaposiform hemangioendothelioma; MRI, magnetic resonance imaging; T1WI, T1-weighted image; T2WI, T2-weighted image.

Figure 2 Restricted lymphatic flow patterns in lower extremity KHE. A 3-year-old boy with right thigh KHE showed focal intense uptake at the lesion (A; arrow) but no visible ipsilateral inguinal or lumbar lymph nodes (A; red circle). T2WI revealed heterogeneous hyperintensity within the mass (B,C). In a 7-year-old with right knee KHE, focal uptake (D; arrow) was accompanied by distal dermal backflow, with non-visualization of regional nodes (D; red circle). Heterogeneous hyperintense signals were noted within the knee joint on T2WI (E,F). A 3-month-old infant with left lower limb KHE similarly demonstrated intense focal uptake (G; arrow) and absent regional lymph nodes (G; red circle), with corresponding heterogeneous hyperintensity on T2WI (H,I). KHE, kaposiform hemangioendothelioma; T2WI, T2-weighted image.

Figure 3 Trunk flow patterns in lower and upper extremity KHE. In a 15-month-old boy with right thigh KHE, the lesion showed intense radiotracer uptake with visible ipsilateral lumbar lymph nodes (A; arrows). Axial T1WI demonstrated a signal isointense to muscle (B; arrow), whereas axial and sagittal T2WI revealed a heterogeneous hyperintense signal (C,D; arrows). In a 7-month-old boy, the KHE lesion in the right hand exhibited intense radiotracer accumulation with presence of ipsilateral axillary lymph nodes (E; arrows). It appears isointense to muscle on axial T1WI (F; arrow) and heterogeneously hyperintense on axial and sagittal T2WI (G,H; arrows). KHE, kaposiform hemangioendothelioma; T1WI, T1-weighted image; T2WI, T2-weighted image.

As illustrated in Figure 4, the distribution of lymphatic staging among the patients was as follows: grade L, 8.3% (2/24); grade P, 29.2% (7/24); and grade T, 62.5% (15/24). Notably, more than half of the cohort exhibited total obstruction, with grade T-6 emerging as the predominant subtype for both upper and lower extremity involvement. We further explored the correlation between clinical features and the severity of lymphatic obstruction (Table 3). Patients with large lesions (≥10 cm) were more likely to present with total obstruction. In contrast, no statistically significant differences were observed between partial and total obstruction groups regarding gender, age, anatomical location of involvement, or the presence of dermal backflow.

Figure 4 Lymphatic staging lower and upper extremity KHE using the TLS system. Grade L: normal lymphatic drainage; grade P: partial lymphatic obstruction; grade T: total lymphatic obstruction. L, normal lymphatic drainage. P-1, distal linear lymphatic ducts without dermal backflow; P-2, engorged distal linear lymphatic ducts with dermal backflow in the proximal or distal lymphedematous limb; P-3, engorged lymphatic ducts with entire dermal backflow. T-4, engorged or absent lymphatic ducts with distal dermal backflow; T-6, absent lymphatic ducts without dermal backflow. KHE, kaposiform hemangioendothelioma; TLS, Taiwan Lymphoscintigraphy Staging.

Lymphoscintigraphy follow-up

A total of six patients underwent follow-up lymphoscintigraphy between 14 and 36 months after initial imaging. All of these patients received systemic pharmacotherapy and physiotherapy, with no surgical interventions during the follow-up period. Five patients demonstrated no significant improvement in lymphatic drainage; specifically, abnormal drainage persisted in two patients with partial obstruction and three with total obstruction (Figure 5). In contrast, one patient, initially presenting with partial obstruction, achieved normal drainage (Figure 6) (9). Furthermore, among the remaining 16 patients restricted to clinical follow-up, none exhibited complete resolution of lymphedema.

Figure 5 Lymphoscintigraphy follow-up in cases of partial and total lymphatic obstruction. A 15-month-old boy with right thigh KHE had partial lymphatic obstruction. Initial imaging showed focal intense uptake within the lesion (A; arrow) and heterogeneous hyperintensity on axial and sagittal T2WI (B,C; arrows). After systemic pharmacotherapy and physiotherapy, lymphoscintigraphy demonstrated persistent obstruction (D; arrow), with no significant change in lesion size or signal intensity on T2WI (E,F; arrows). In a 6-year-old girl with left leg KHE, baseline imaging revealed total obstruction (G; arrow) and heterogeneous hyperintensity on T2WI (H,I; arrows). Follow-up after treatment showed no significant improvement in lymphatic drainage on lymphoscintigraphy (J; arrow) or in signal characteristics on T2WI (K,L; arrows). KHE, kaposiform hemangioendothelioma; T2WI, T2-weighted image.

Figure 6 Response to therapy in a 19-month-old boy with KHE in the right upper extremity. Initial lymphoscintigraphy showed focal uptake in the right forearm with visible regional lymph nodes, indicating partial obstruction (A; arrows). Axial and sagittal T2WI demonstrated extensive heterogeneous hyperintensity within the lesion (B,C; arrows). Following treatment with compression therapy and pharmacotherapy, follow-up lymphoscintigraphy showed normalized lymphatic drainage (D). T2WI revealed only minimal residual hyperintensity within the lesion (E,F). Adapted from (9). Licensed under CC BY 4.0. KHE, kaposiform hemangioendothelioma; T2WI, T2-weighted image.

Discussion

Secondary lymphedema is a recognized, albeit less common, complication of KHE, with a reported incidence of 11.0% (13/118) (8). Several mechanisms underlying the development of lymphedema in KHE patients have been proposed. Fundamentally, KHE is increasingly characterized as a mixed vascular-lymphatic anomaly, evidenced by the co-expression of vascular markers (CD31, CD34) and specific lymphangiogenic markers (D2-40, LYVE-1, PROX1, and VEGFR-3) within tumor cells (16,17). Consequently, the structurally aberrant and functionally incompetent lymphatic vessels inherent to the lesion fail to adequately drain lymph fluid. Aggravating this intrinsic dysfunction, KHE typically displays an infiltrative growth pattern lacking a distinct capsule, extending deeply into subcutaneous tissues, muscle, and bone. Such invasion mechanically compromises surrounding lymphatic networks through disruption, compression, or occlusion, blocking drainage and triggering severe, frequently refractory lymphedema (18). Moreover, lesion-associated chronic inflammation and fibrosis drive sclerosing lymphangitis, resulting in wall thickening, luminal narrowing, and obliteration that further aggravates lymphatic obstruction (19).

Lymphoscintigraphy remains the primary imaging modality for evaluating secondary lymphedema associated with KHE. Our study identified distinct lymphoscintigraphic features specific to this entity. Notably, lymphedema was confined to the unilateral extremity ipsilateral to the KHE lesion in all cases (100%, 22/22). Remarkably, solitary focal tracer accumulation was observed within the affected extremity in every patient (100%, 22/22), indicating the presence of malformed lymphatic vessels within the tumor mass. This imaging signature is critical for distinguishing KHE-associated lymphedema from primary lymphedema (5,9). Indeed, these findings align with the clinicopathological characteristics of KHE. Two patients who underwent complete surgical resection while preserving normal lymphatic pathways demonstrated normalized lymphoscintigraphy postoperatively. Although curative radical surgery that spares function and prevents mutilation is ideal, it is achievable in only a minority of patients due to extensive, discontinuous tumor spread, involvement of critical structures, and severe coagulopathy (2,3). In our cohort, 68% (15/22) of patients exhibited complete lymphatic obstruction, evidenced by the absence of visible lymphatic vessels or regional lymph nodes on both early and delayed scans. Conversely, 32% (7/22) presented with partial obstruction, characterized by delayed lymphatic drainage and reduced tracer accumulation in regional lymph nodes. Although MR imaging (MRI) offers superior soft-tissue contrast for delineating KHE mass size, extension, and lymphatic anatomy, lymphoscintigraphy provides a more accurate functional evaluation of lymphatic flow, especially regarding the severity of the obstruction (20). We found that a large lesion size (≥10 cm) was not only significantly associated with the presence of secondary lymphedema (8), but also correlated strongly with total obstruction. This association likely reflects the more extensive and severe disruption of lymphatic vessels caused by larger tumors. Conversely, no significant associations were found with gender, age, lesion location, or dermal backflow. Given these findings, early lymphoscintigraphy is advised for patients with large extremity lesions to detect potential abnormalities in lymphatic drainage.

In contrast to primary lymphedema, KHE-associated lymphedema is notably resistant to reversal once established, regardless of the therapeutic approach. In our cohort, only 1 out of 22 patients achieved complete remission by the final follow-up. Follow-up lymphoscintigraphy corroborated these clinical findings, revealing no significant improvement in abnormal lymphatic drainage in the majority of evaluated cases (5/6). Consequently, for most patients, sustained long-term management with sirolimus and physiotherapy is essential to preserve quality of life by alleviating pain and mitigating functional impairment. For the cured patient with restored lymphatic drainage, routine surveillance is enough. Therefore, serial lymphoscintigraphy proved invaluable for monitoring disease status and tailoring individualized management strategies (21).

In addition to lymphoscintigraphy, MR lymphangiography (MRL) has emerged as a vital complementary modality for evaluating lymphatic vessels in both primary and secondary lymphedema. Owing to its superior spatial resolution, MRL provides exquisite delineation of lymphatic anatomy, flow dynamics, and surrounding structures (e.g., the venous system), which is particularly advantageous for preoperative surgical planning (22). Furthermore, the near-isotropic voxels in MRL allow for high-quality multiplanar reconstructions, thereby facilitating microsurgical interventions in ways that lymphoscintigraphy cannot (23). Additionally, MRL eliminates the risk of ionizing radiation. However, contrast-enhanced MRL necessitates the interstitial injection of gadolinium-based contrast agents, which currently constitutes an off-label use (22). Consequently, the tolerability and long-term safety of this technique warrant further validation through well-designed clinical trials.

Limitations

Our study has several inherent limitations. First, as a retrospective, single-center study with a limited sample size, our findings require validation in larger, multicenter cohorts. Second, a range of previous therapeutic interventions may introduce heterogeneity, as prior treatments, particularly surgery, may have altered lymphatic drainage patterns. Third, while follow-up lymphoscintigraphy was performed in a subset of patients (n=6) and yielded preliminary insights, its definitive clinical utility warrants further investigation in larger series. Finally, the absence of SPECT/computed tomography (CT), which offers superior anatomical localization and functional data, represents a missed opportunity for more comprehensive characterization (24).

Conclusions

In the context of KHE, lymphoscintigraphy emerges as a pivotal modality for assessing lymphatic transport, serving critical roles in both initial diagnosis and the longitudinal monitoring of secondary lymphedema. However, these promising findings warrant validation in larger, prospective studies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-0739/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-0739/dss

Funding: This work was supported by the Qimingxing Research Fund for Young Talents (No. HXQMX0166).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-0739/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of West China Hospital, Sichuan University (approval No. 392/2026). Informed consent was waived in this retrospective study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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