Synovial Sarcoma in the Setting of Klippel–Trenaunay Syndrome: A Rare Case

INTRODUCTION

Maurice Klippel and Paul Trenaunay, two French doctors, were the first to describe Klippel–Trenaunay syndrome (KTS) in 1900. The clinical diagnosis is defined by the presence of at least two elements of the classical triad: capillary malformations (port-wine stains), venous malformations or varicosities, and hypertrophy of the affected limb’s soft tissues and/or bones. As a result, it is also known as capillary-lymphatic-venous malformation (CLVM).^[1]

KTS occurs mainly as a sporadic disease and arises from somatic mutations. Genetic studies have linked KTS to post-zygotic mutations in genes such as PIK3CA, resulting in dysregulated activation of the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, which is involved in the regulation of cellular proliferation and angiogenesis. Activating mutations lead to abnormal tissue overgrowth and vascular malformations. Clinically, patients experience chronic pain, limb length discrepancy, risk of thromboembolic events, bleeding complications, lymphedema, and functional impairment related to the underlying vascular and overgrowth anomalies.^[2]

Although KTS is primarily considered a benign vascular malformation syndrome, existing clonal mutations in PIK3CA can increase the risk of tumourigenesis.^[3] compared to the general population.^[3] Carcinoma risk in KTS is associated with hemihypertrophy, and reports of association with Wilm’s tumour, rhabdomyosarcoma, angiosarcoma, and squamous cell carcinoma have been reported.

Synovial sarcoma (SS) is an uncommon but highly aggressive soft tissue cancer, representing approximately 5%–10% of all sarcomas. Despite its name, it does not arise from synovial tissue but from primitive mesenchymal cells capable of dual epithelial and spindle-cell differentiation.^[4] It commonly presents as a slow-growing deep soft-tissue mass near joints, often in the lower extremities.^[5]

In patients with KTS, preexisting vascular and lymphatic malformations may obscure newly developing masses, leading to diagnostic difficulty or delay. New lesions can be misinterpreted as part of the underlying anomaly rather than a separate neoplasm, as reported in cases of malignancies such as rhabdomyosarcoma.^[6]

We report a rare case of synovial sarcoma arising in the affected limb of a patient with KTS, highlighting the importance of careful evaluation of new or rapidly evolving lesions in individuals with underlying vascular malformations.

CASE REPORT

A 23-year-old male presented with complaints of swelling in the left lumbar region, which developed 2 years ago and was gradually increasing in size, not associated with pain. On inspection, the swelling appeared diffuse and ill-defined, with overlying skin that was thickened, without ulceration, redness, or prominent dilated veins. On palpation, the swelling measured approximately 5 x 4 cm, and margins were ill-defined and blended with the surrounding tissues. It was firm, non-tender, non-pulsatile, and showed no local rise in temperature [Fig 1a]. The patient developed left foot drop with a high-stepping gait approximately six months ago. The patient had a history of progressive diffuse swelling of the left thigh along with thickened skin over the left gluteal and lumbar regions for approximately 13 years [Fig 1b]. A diagnosis of KTS had been established in 2022 based on imaging findings [computed tomography (CT) angiography demonstrated extensive slow-flow vascular malformations involving the left gluteal region and lower limb]. No other comorbidities were noted

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Fig 1: (a and b) Clinical photograph of a 23-year-old male presenting with left lumbar swelling (white arrow in a) showing asymmetric limb hypertrophy of the left lower limb with associated cutaneous vascular malformations and hyperpigmentation, consistent with underlying KTS syndrome. KTS: Klippel–Trenaunay syndrome

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He was evaluated with an MRI of the lumbar spine (plain and contrast), which revealed an altered signal intensity lesion in the left lower lumbar and upper gluteal region, measuring 6.5 x 11.4 cm. The lesion demonstrated heterogeneous post-contrast enhancement and was centred in the left hemipelvis, extending medially into the L4–L5 and L5–S1 neural foramina with involvement of the sacrum. Laterally, it caused widening of the left greater sciatic notch and extended into the left gluteal region, with infiltration of the gluteal muscles. Additional heterogeneous enhancement of the subcutaneous tissue in the left upper thigh was also noted, suggestive of tumour infiltration [Fig 2].

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Fig 2: (a and b) Axial and (c) Coronal post-contrast T1 fat saturation MRI images at the level of the pelvis showing a heterogeneously enhancing altered signal intensity lesion in the left side of the pelvis, which is seen causing expansion of the left greater sciatic notch (green arrows in a and c) and is seen extending into the left gluteal region (orange arrows in a-c) with infiltration of gluteal muscles. Medially, it is noted extending into L4-L5, L5-S1 vertebral foramina and is noted involving the sacrum, representing the lumbar lesion (white arrows in a and c). MRI: Magnetic resonance imaging.

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Subsequently, a core needle biopsy from the left lumbar lesion was suggestive of a malignant spindle cell neoplasm. Immunohistochemistry demonstrated strong nuclear positivity for TLE-1 (transducin-like enhancer of split 1) and membranous positivity for CD99 (cluster of differentiation 99) with a high Ki-67 (Ki-67 proliferation index) index of 70–90%, while tumour cells were negative for CD34 (cluster of differentiation 34), S100 (S100 calcium-binding protein), SMA (smooth muscle actin), STAT6 (signal transducer and activator of transcription 6), CK, synaptophysin, and NKX2.2 (NK2 homeobox 2) [Fig 3]. A diagnosis of monophasic synovial sarcoma was made. As part of the metastatic workup, contrast-enhanced CT of the chest was performed, and the scan revealed sub-centimetre-sized bilateral pleural-based and parenchymal lung nodules, the largest measuring 9 mm, suspicious for metastatic disease. The patient subsequently received chemotherapy with six cycles of Ifosfamide– Adriamycin (IA), which was completed in December 2025.

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Fig 3: (a) H&E x40, microscopic image showing monophasic tumour composed of spindle cells arranged as fascicles, sheets with hyperchromatic nuclei and indistinct bipolar cytoplasm. Focal mitotic activity noted. (b) CD99 IHC x400, intense membranous positivity seen in the lesional cells; (c) Ki-67 IHC x400, Nuclear positivity in >90% of lesional cells; (d))TLE 1 IHC x400, Intense nuclear positivity seen in the majority of the lesional cells. IHC: Immunohistochemistry; H&E: Haematoxylin and eosin ; CD99: Cluster of differentiation 99; Ki-67: Ki-67 Proliferation index; TLE-1: Transducin-like enhancer of split 1

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A follow-up MRI scan performed showed no significant change in the size of the lesion. Consequently, a whole-body ¹⁸F FDG PET/CT was performed, which showed an intense FDG-avid soft tissue density lesion with calcific foci in the left lumbar region measuring 4.9 (AP) x 5.6 (T) x 5.8 (CC) cm with a max SUV of 30. Another FDG avid ill-defined heterogeneous density lesion was noted in the left pelvic region, with extension into the acetabular foramen and involving the left gluteal muscles. Involvement of the neural foramina of L5 - S4 vertebrae was noted. Multiple heterogeneous FDG-avid soft tissue density lesions were noted in the posterior compartment of the left thigh and left leg, the largest measuring 10.5 (AP) x 11.9 (T) x 19.1 (CC) cm with a max SUV of 4.5. The lesions are associated with central areas of necrosis. Multiple non-FDG avid vascular dilatations (SUVmax similar to mediastinal blood pool) were noted in the intermuscular and subcutaneous planes of the left lower limb. Mild FDG avidity was noted in the periarticular region of the left intertarsal bone with surrounding subcutaneous fat stranding, likely due to stress-related changes related to foot drop. Non-FDG avid sub-centimetre-sized multiple pulmonary nodules and an FDG-avid lytic left iliac bone metastasis (with a max SUV of 7.9) were noted [Fig 4]. With the help of ¹⁸F FDG PET/CT, additional lytic bone metastasis in the left ilium was diagnosed apart from lung metastases (documented in the previous CECT chest). As the patient was already diagnosed with metastatic disease [lung metastases], the same treatment regimen was continued even after an ¹⁸F FDG PET/CT scan. The first maintenance dose was administered on 12 March 2026.

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Fig 4: ¹⁸F FDG PET/CT images showing (a) Maximum intensity projection (MIP) image showing foci of increased FDG uptake in the left lumbar, left pelvis and left thigh region; (b and c) Sagittal fused PET/CT and CT images showing a soft tissue density lesion in the left lumbar region (blue arrows) and a lytic lesion involving the left ilium (white arrows). (d) Sagittal fused PET/CT image showing a heterogeneous density lesion in the posterior aspect of the left thigh; (e) Coronal fused PET/CT image showing vascular dilatations in the subcutaneous plane of the left leg; (f and g) Axial fused PET/CT and CT images in lung window showing non-FDG avid sub-centimetre-sized bilateral lung nodules (white arrow in f and blue arrow in g). FDG: Fluorodeoxyglucose; PET/CT: Positron emission tomography/computed tomography; CT: Computed tomography

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DISCUSSION

About 2 to 3 people per 100,000 live births are affected by KTS, which usually manifests at birth, in early infancy, or in childhood, with no preference for sex or ethnicity.^[7] Unilateral lower limb manifestation is most common; however, upper limb and truncal involvement have been reported.^[1] Our patient presented with unilateral left lower limb involvement at 10 years of age with a clinical triad consistent with KTS.

KTS is predominantly a sporadic condition arising from somatic mutations in the PIK3CA gene, though rare familial cases have been described. It belongs to the PIK3CA-related overgrowth spectrum (PROS), a group of clinical conditions characterised by somatic or mosaic mutations of this gene. Overgrowth syndromes such as Beckwith–Wiedemann syndrome, Cowden syndrome, and PTEN hamartoma tumour syndrome involve mutations in the PTEN gene as well as the PI3K–AKT pathway, and consequently carry a significantly elevated risk of malignancy, warranting cancer surveillance from childhood. In contrast, KTS is associated with a comparatively lower malignancy risk; however, this risk remains elevated relative to the general population, underscoring the importance of regular clinical follow-up and careful evaluation of new or regressive lesions.^[8]

Fay et al.^[6] described a case where rhabdomyosarcoma initially mimicked a benign vascular malformation, while Simas et al.^[9] reported a case of epithelioid angiosarcoma arising in a patient with KTS. In both instances, the presence of underlying vascular malformations contributed to diagnostic delay, as the malignant lesions were initially attributed to the existing vascular pathology. Our patient had features consistent with KTS since the age of 10 years but was lost to follow-up, later presenting with a gradually enlarging lumbar swelling, which on further evaluation was confirmed as synovial sarcoma. This highlights the importance of regular surveillance in patients with KTS to facilitate early detection of malignancy.

Friedrichs et al. (2011) demonstrated that aberrant PI3K/ AKT pathway activation is integral to synovial sarcoma cell proliferation and survival.^[10] While an association between synovial sarcoma and KTS has not been previously described, a shared mutation may lead to an increased susceptibility to malignant transformation. This is further supported by Xu et al. (2022), who reported an association between KTS and angiosarcoma, both PIK3CA-related conditions, which further supports the hypothesis that the dysregulated signalling underlies malignant susceptibility in KTS.^[11]

In anatomically distorted regions, such as KTS affected limbs, multimodality imaging helps to identify the full disease burden. MRI provides excellent anatomical detail and soft tissue contrast, helpful in the assessment of locoregional disease extent. ¹⁸F FDG PET/CT offers whole-body functional imaging, where metabolic activity provides information on viable tumour tissue, occult metastatic lesions, differentiates active tumour from necrosis, and assesses the biological aggressiveness of the tumour. It also aids in accurate staging, treatment planning, and early evaluation of treatment response, and has been shown to add value over CT/MRI in staging and restaging of sarcomas.^[12]

In our case, ¹⁸F FDG PET/CT aided in identifying additional iliac bone metastasis. Metser et al. (2023) demonstrated that ¹⁸F FDG PET/CT identified occult metastatic disease in 16.2% of patients with no evidence of metastases on conventional imaging, and confirmed metastatic involvement in 47.8% of patients with equivocal findings on standard workup.^[13] Annovazzi A et al (2020) observed that ¹⁸F FDG PET/ CT led to a change in treatment strategy in 23.2% patients. Additional diagnostic information provided by PET/CT beyond conventional imaging, contributing to both disease upstaging (58.8%) and downstaging (41.2%).^[14]

In addition, the lumbar lesion demonstrated markedly elevated FDG uptake on PET/CT, which correlates with a high Ki-67 index of > 90% on histopathology, indicative of a highly aggressive tumour. These findings are consistent with Macpherson et al.(2018), who demonstrated a statistically significant association between SUVmax and tumour grade in bone and soft-tissue sarcomas, with high-grade sarcomas exhibiting a mean SUVmax greater than 10.^[15]

CONCLUSION

Synovial sarcoma arising in the background of Klippel– Trenaunay syndrome is extremely rare. It highlights the need for careful clinical follow-up in patients with vascular overgrowth syndromes, as new or enlarging lesions may represent malignant transformation. 18F FDG PET/CT proved instrumental in enabling whole-body metabolic staging, detection of occult metastases, and assessment of tumour aggressiveness. This information is critical for multidisciplinary management and prognostication. The incorporation of ¹⁸F FDG PET/CT alongside regular clinical surveillance for early detection of malignancy is integral in KTS patients presenting with new or progressive lesions.