Blue rubber bleb nevus syndrome complicated with esophageal squamous carcinoma: A case report with robotic-assisted resection and literature review

Introduction

Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital vascular disorder characterized by the presence of multiple venous malformations in the skin and gastrointestinal (GI) tract. ¹ These lesions can result in a variety of clinical manifestations, including chronic gastrointestinal bleeding, anemia, and abdominal pain. ² The pathophysiology of BRBNS is associated with genetic mutations in the TEK gene, which disrupt normal angiogenesis and vascular development. ³ Despite its rarity, BRBNS has been well documented in case series and clinical reports, highlighting its significant impact on patient health and quality of life.

In contrast, esophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy, particularly prevalent in certain geographical regions. ⁴ Risk factors for ESCC include smoking, alcohol consumption, dietary habits, and chronic esophageal inflammation. ⁵ This condition often presents at an advanced stage, resulting in poor prognosis and limited treatment options. Management of ESCC typically involves a multimodal approach, including surgery, chemotherapy, and radiotherapy. ⁶

Although both BRBNS and ESCC have been extensively studied individually, the co-occurrence of these two conditions is extremely rare, with only a limited number of cases reported in the medical literature. This combination of a congenital vascular anomaly and a primary malignancy poses unique diagnostic and therapeutic challenges, as the clinical manifestations of BRBNS may obscure or mimic symptoms of ESCC, potentially leading to delayed diagnosis. Understanding the interplay between these two distinct pathological entities is crucial for early detection, appropriate management, and improved patient outcomes. In this case report, we describe a patient with BRBNS who subsequently developed ESCC, with the aim of contributing to the limited knowledge on the coexistence of these two conditions and providing insights into diagnostic and treatment strategies. We report this case in compliance with the Case Report (CARE) reporting checklist. ⁷

Case report

A male in his early 50s was admitted to Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China, in April 2025 with a history of dysphagia for more than 1 month and scattered blue-purple blisters over the whole body for more than 40 years, which faded when pressed. Gastroscopy revealed strip-shaped dark purple mucosal elevations in the middle and lower esophagus and scattered dark purple submucosal ecchymoses of varying sizes in the gastric angle, gastric antrum, and duodenum, without a clear diagnosis. Over the past 8 years, stool tests were repeatedly positive for occult blood, with recurrent anemia. Colonoscopy revealed extensive hemangiomas in the terminal ileum and entire colon. In the past month, the patient developed dysphagia, particularly for solid foods. On admission, physical examination showed multiple scattered blue-purple blisters over the whole body, with a diameter of 0.5–2 cm, which faded when pressed (Figure 1). After admission, auxiliary examinations showed a hemoglobin level of 120 g/L and fecal occult blood 2+. To confirm the diagnosis, a biopsy was performed on a tissue from the back. The histopathological examination revealed epidermal capillary expansion and thin walls with blood sinus formation, along with vascular hyperplasia and dilated, congested vascular lumens in the dermis, accompanied by vascular endothelial cell hyperplasia. These findings were consistent with BRBNS. Gastroscopy showed multiple blue-purple hemangiomas in the esophagus, stomach, and duodenum with esophageal stenosis. Some surface vessels showed grape-like tortuous changes. Additionally, a large ulcerated area was visible in the esophagus approximately 27–32 cm from the incisors, involving one-third of the circumference, with granulation hyperplasia on the surface and a tendency to bleed on contact. Pathological examination of the endoscopic biopsy suggested ESCC. Immunohistochemistry showed Ki67 (about 70%+), cytokeratin pan (CKpan; AE1/AE3) (+), P63 (+), P40 (+), cytokeratin 7 (CK7) (−), and P53 (approximately 75% weak to strong positive). Endoscopic ultrasonography showed diffuse multiple blue-purple hemangiomas in the esophagus, predominantly located in the submucosa, with moderate- to low-echo changes at the lesion sites. A large ulcerated area was observed in the esophagus 27–32 cm from the incisors, with mucosal thickening of approximately 8 mm at the lesion site. These lesions exhibited low-echo changes with relatively uniform internal echo, an unclear boundary, and indistinct demarcation from the submucosa. The muscular layer was mostly intact, with local involvement, and the adventitia appeared faintly intact (Figure 2). Colonoscopy revealed multiple blue hemangiomas in the terminal ileum and colon (Figure 3). Positron emission tomography–computed tomography (PET–CT) showed thickening of the middle thoracic esophageal wall with increased metabolism, suggestive of a malignant lesion. The remaining esophageal wall showed circumferential irregular thickening with slightly increased fluorine-18 fluorodeoxyglucose (FDG) metabolism, consistent with BRBNS. Based on the patient’s medical history, imaging findings, and gastroenteroscopy results, he was diagnosed with BRBNS complicated with ESCC. Following multidisciplinary team (MDT) consultation and comprehensive evaluation, robot-assisted McKeown minimally invasive esophagectomy was performed. During the procedure, an ulcerative tumor was identified in the mid-esophagus, with invasion into the esophageal adventitia. Additionally, diffuse hemangioma-like dilatations were observed throughout the esophageal lumen, presenting as spongy lesions containing abundant blood. The spongy septa of these lesions were found to involve the main bronchus (Figure 4). The intraoperative blood loss was 1500 mL, and the patient received 5 U of red blood cells and 800 mL of plasma during the procedure. On postoperative day 1, the hemoglobin level was 62 g/L, and blood transfusion support was provided. Postoperative pathology showed moderately differentiated keratinizing squamous cell carcinoma. The tumor invaded the adventitia layer, the resection margins were negative, and no lymph node metastasis was detected. The final pathologic tumor stage was pT3N0M0 (tumor–node–metastasis (TNM), eighth edition). The patient was discharged 2 weeks following surgery, with good anastomotic healing and no complications, such as recurrent laryngeal nerve injury or thoracic duct injury. The timeline of the case is presented in Figure 5. Ten months after the procedure, follow-up chest CT showed no residual tumor or recurrence.

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Figure 1.

An asymptomatic cutaneous hemangioma visible on the chest skin.

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Figure 2.

Gastroscopy revealing an esophageal tumor and gastrointestinal venous malformations.

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Figure 3.

Colonoscopy revealing multiple venous malformations in the colon.

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Figure 4.

Vascular malformations enveloping tumor tissue under the endoscopic field.

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Figure 5.

The clinical course timeline of the patient.

Discussion

BRBNS is a rare congenital venous developmental malformation, and its pathogenesis remains unclear. Literature reports suggest that it may be associated with mutations in genes located on the short arm of chromosome 9 and mutations in TEK (encoding the TIE2 gene).^3,8 We conducted an extensive literature review of similar published case reports. To the best of our knowledge, this is the first reported case of BRBNS with esophageal cancer. BRBNS can occur in childhood, and it shows a male predominance. Vascular malformations in BRBNS can involve various parts of the body, predominantly the skin and digestive tract as well as the nervous system, liver, muscles, and nasopharynx. Lesions in the digestive tract can result in varying degrees of hematemesis, melena, or anemia and may also lead to serious complications, including hemangioma rupture, intestinal volvulus, and intussusception. Currently, there is no curative treatment for BRBNS, and symptomatic management is mainly adopted according to the location and severity of the lesions. Skin lesions are usually asymptomatic and generally do not require treatment. Patients with serious complications, such as intestinal rupture, intestinal volvulus, and intussusception, should undergo surgical treatment as soon as possible.^9,10 In 2012, Yuksekkaya et al. ¹¹ reported a case of a patient with BRBNS treated with sirolimus, in whom gastrointestinal and skin hemangiomas were significantly reduced, gastrointestinal bleeding resolved, anemia was corrected, and no adverse drug reactions were observed during 20 months of follow-up. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, exerts immunosuppressive, antivascular endothelial cell proliferation, and antiangiogenic effects. In recent years, multiple studies have reported favorable therapeutic efficacy of sirolimus in patients with BRBNS. It not only significantly improves gastrointestinal bleeding but also reduces and shrinks hemangioma lesions^12–14 and improves patients’ quality of life. In the present case, preoperative medication reduced the risk of intraoperative bleeding, consistent with the findings of Zhou et al. ¹⁵ Sirolimus was administered orally to patients with BRBNS at an initial dose of 1.0 mg/m² of body surface area once daily, with the dosage titrated to maintain a therapeutic trough plasma concentration of 3–10 ng/mL. ¹⁶ The treatment duration for the 11 enrolled patients ranged from 3 to 17 months, with a median follow-up of 15 months. Nine patients received the drug for more than 6 months and 7 for more than 12 months, with all patients remaining on treatment at the study’s conclusion. For monitoring, trough plasma sirolimus concentrations were measured at 1, 3, 6, and 12 months post-initiation to guide dosage adjustments. ¹⁷ Laboratory tests (complete blood count, hemoglobin, biochemistry, D-dimer, coagulation indices, and fecal occult blood) and whole-body magnetic resonance imaging (MRI; to quantify venous malformation lesion size) were conducted at baseline and at 3, 6, and 12 months. Additionally, adverse events were recorded via monthly telephone follow-up, and clinical indicators were assessed at the same time points. Esophageal cancer is a common malignant tumor in China, with both incidence and mortality ranking among the highest. It is classified into squamous cell carcinoma and adenocarcinoma, with squamous cell carcinoma accounting for the majority of cases. This condition often remains asymptomatic during early development, and patients frequently present at an advanced stage, resulting in a poor prognosis. ¹⁸ Surgery remains the primary treatment of choice for patients with esophageal cancer. However, in the present case, the patient had BRBNS with diffuse, multiple blue-purple hemangiomas in the esophagus, which increased the risk of surgical bleeding. ¹⁹ The concurrent presence of BRBNS and esophageal cancer presents a significant challenge in surgical oncology, requiring a balance between achieving oncological radicality and managing the inherent risks associated with vascular malformations. The application of the da Vinci robotic surgical system in our case demonstrated several key advantages that were pivotal in optimizing patient outcomes. One of the major challenges in treating patients with BRBNS is the high risk of intraoperative bleeding due to diffuse vascular malformations in the gastrointestinal tract. The da Vinci system’s three-dimensional (3D) high-definition vision system provides a 10–15 fold magnified stereoscopic view of the surgical field, enabling clear differentiation between abnormal blood vessels and normal tissues. ²⁰ This enhanced visualization was particularly important during esophageal dissection, where the risk of inadvertent injury to the intricate network of vascular lesions was high. ²¹ The robotic arms, with seven degrees of freedom, mimic the dexterity of human hands with greater precision (accuracy within 0.1 mm). This allows meticulous blunt and sharp dissection around major vessels such as the aorta and azygos vein, thereby minimizing the risk of vascular injury. ²² The ability to perform precise bipolar electrocoagulation under direct 3D vision further enhances hemostasis and reduces the need for blind clamping or suturing, which are common sources of complications in traditional open surgery.

Despite its minimally invasive nature, the da Vinci system did not compromise the principles of oncological resection. The enhanced visualization and precision allowed for more comprehensive lymph node dissection, including the mediastinal and left gastric artery lymph nodes. The surgical team achieved clear surgical margins with confidence, ensuring that the oncological integrity of the procedure was maintained. This is particularly important in patients with esophageal cancer, where the extent of lymph node dissection and margin status are critical prognostic factors. However, despite the notable advantages of the da Vinci robotic surgical system demonstrated in this complex case, its inherent limitations constrain its widespread adoption and universal application in treating patients with BRBNS complicated with ESCC. First, the high economic cost of robotic surgery, including substantial upfront investment, ongoing maintenance fees, disposable surgical instruments, and associated facility upgrades, poses a significant financial burden on healthcare institutions. This limits its availability to well-resourced medical centers and creating disparities in access for patients across different healthcare settings. ²³ Second, the technology entails a steep learning curve for surgical teams. Achieving proficiency in operating the robotic arms, interpreting the 3D magnified surgical view, and coordinating the system’s mechanical movements with real-time surgical decision-making requires extensive specialized training and a high volume of case experience. ²⁴ This learning phase may delay the translation of the technology’s benefits into clinical practice and increase procedural risks for early adopters, particularly in the context of ultra-rare and complex conditions such as BRBNS with ESCC that offer few opportunities for hands-on practice. ²⁵ Third, high-quality clinical data remain limited regarding the long-term efficacy and comparative outcomes of robotic-assisted esophagectomy in patients with concurrent vascular malformations and esophageal cancer. Most existing evidence for robotic thoracic surgery focuses on uncomplicated esophageal cancer or other thoracic malignancies, and there is a paucity of prospective cohort studies, randomized controlled trials, or large case series examining robotic surgery in BRBNS complicated with ESCC. Consequently, the perceived benefits of the system in this patient population remain largely anecdotal, and definitive conclusions regarding superiority over open or video-assisted thoracoscopic surgery (VATS) in terms of oncologic outcomes, bleeding reduction, and long-term complication rates cannot yet be established. ²⁶ Collectively, these limitations highlight that robotic surgery is not a universally accessible or evidence-based solution for this rare dual pathology, and its use should be weighed against institutional resources, surgical team expertise, and the individual patient’s clinical context.

The successful management of patients with BRBNS and esophageal cancer often requires a multidisciplinary approach, involving collaboration among thoracic surgery, anesthesiology, and gastroenterology. The minimally invasive approach of the da Vinci system expedited the patient’s recovery, enabling earlier initiation of adjuvant therapies such as chemotherapy and radiotherapy.

In the present case, no postoperative complications, including recurrent laryngeal nerve injury or thoracic duct leakage, were observed. The patient recovered uneventfully and was discharged 2 weeks following surgery.

Conclusion

BRBNS is a rare disease, and cases complicated with esophageal cancer are exceedingly uncommon. To date, no previous reports have documented BRBNS complicated with esophageal cancer. In this context, the present report underscores the distinct advantages of the da Vinci robotic surgical system, including its ability to provide precise vascular management, enable minimally invasive yet oncologically sound surgery, and facilitate multidisciplinary care, in the management of BRBNS and esophageal cancer. These features suggest that the robotic-assisted surgery offers promising approach for improving outcomes in patients with complex and rare conditions.