Novel Combination Therapy with Sorafenib and Propranolol for Refractory Lymphangioma Circumscriptum

Dear Editor,

Lymphangioma circumscriptum (LC) represents a superficial lymphatic malformation classified under the broader category of lymphangiomas, which are congenital hamartomatous proliferations of the lymphatic system. According to the International Society for the Study of Vascular Anomalies (ISSVA) classification, LC is categorized as a common (cystic) lymphangioma within the microcystic subtype (diameter <1 cm).[1] Despite various therapeutic approaches, including surgical excision, sclerotherapy, cryotherapy, laser ablation, and radiotherapy, the condition frequently recurs due to the persistence of deep lymphatic cisterns that communicate with superficial vessels. This case report presents a novel therapeutic approach targeting the molecular pathways implicated in lymphangiogenesis.

A 33-year-old man presented with a 12-year history of progressive lingual lesions in the form of pinhead-sized vesicles on the anterior third of his tongue, which were diagnosed as lymphangioma circumscriptum. The lesions were characterized by episodic bleeding, pain, and serous discharge following minor trauma, significantly impacting his quality of life. The patient had previously undergone multiple therapeutic interventions, including sirolimus, sclerotherapy, CO₂ laser ablation, radiotherapy, and intralesional bleomycin injections, all providing only temporary symptomatic relief followed by recurrence. Dermatological examination revealed multiple discrete to confluent erythematous and hyperpigmented vesicles distributed on the dorsal, ventral, and lateral aspects of the anterior third of the tongue [Figure 1a and b]. These vesicles exuded serous fluid and blood upon trauma. Dermoscopy revealed multiple grouped vesicles with translucent fluid inside, along with a few vesicles with blood fluid levels [Figure 1c]. Microscopic evaluation demonstrated dilated, thin-walled lymphovascular channels in the subepithelial tissue, extending into skeletal muscle bundles. These channels were lined by bland endothelium and contained fibrin, lymphocytes, and erythrocytes. Focal lymphocytic aggregates were observed in the intervening stroma [Figure 2a]. Immunohistochemically, the endothelial cells exhibited strong and diffuse expression of D2-40 (podoplanin) and CD31, while CD34 expression was focal [Figure 2b-d]. These findings confirmed the diagnosis of recurrent/residual lymphangioma circumscriptum.

Figure 1.

(a and b) Dermatological examination revealed multiple discrete to confluent erythematous and hyperpigmented vesicles distributed on the dorsal, ventral, and lateral aspects of the anterior third of the tongue, (c) Dermoscopy revealed multiple grouped vesicles with translucent fluid inside along with few vesicles having blood fluid levels (Dermlite DL4, 10×, contact)

Figure 2.

(a) Dilated, thin-walled lymphovascular channels in the subepithelial tissue extending into skeletal muscle bundles. These channels were lined by bland endothelium and contained fibrin, lymphocytes, and erythrocytes. Focal lymphocytic aggregates were observed in the intervening stroma (Hematoxylin and eosin, 10×) (b-d) - Immunohistochemistry (10×), the endothelial cells exhibited strong and diffuse expression of D2-40 (podoplanin) and CD31, focal expression of CD34

After informed consent, the patient was initiated on a combination regimen of sorafenib and propranolol. The dose of sorafenib was up-titrated from 50 mg once a day to 200 mg twice a day, and propranolol from 10 mg once a day to 40 mg once a day in two weeks’ time. This approach was based on the role of VEGF-C (Vascular endothelial growth factor-C) and the Ras (Rat sarcoma)/Raf (Rapidly accelerated fibrosarcoma kinase)/MEK (Mitogen-activated protein kinase)/ERK (Extracellular signal regulated kinase) signaling pathway in lymphangiogenesis. The patient had significant clinical improvement, characterized by resolution of the vesicular lesions, and complete cessation of symptomatic episodes within two months of initiation of therapy [Figure 3a and b] Medications were stopped at six months without tapering. No side effects were noted in the patient, and lesions resolved without any remnant structural defect or scar formation. At two-year follow-up, no recurrence was observed, and the patient remained asymptomatic with excellent functional outcomes.

Figure 3.

(a and b) Complete resolution of vesicular lesions in two-month after initiation of therapy

Lymphangioma circumscriptum represents a persistent therapeutic challenge due to its high recurrence rate with conventional interventions. The deep-seated communicating channels lead to limited efficacy of superficial treatments, and the propensity for recurrence.[2] Sirolimus (rapamycin), an inhibitor of the mammalian target of rapamycin (mTOR), was among the first molecular therapies explored for complicated vascular anomalies, including lymphatic malformations. The mechanistic basis for this effect lies in the mTOR pathway’s central role in lymphangiogenesis through regulation of cellular proliferation, survival, and metabolism. While sirolimus has shown promising results, particularly for macrocystic lymphatic malformations, its efficacy for microcystic lesions like lymphangioma circumscriptum has been less consistent, with response rates ranging from 30–60% in various studies.[3] The molecular studies have revealed that lymphatic vessel development and homeostasis is tightly regulated by several signaling pathways, with the VEGF-C/VEGFR-3 axis playing a central role, with VEGF-C being essential for lymphatic development.[4] Propranolol, initially recognized for its efficacy in infantile hemangiomas, has also been repurposed for lymphatic malformations with a success rate up to 36%.[5] The RAS/RAF/MEK/ERK signaling cascade has emerged as a critical regulator of lymphangiogenesis, independent of VEGF-C signaling. Our therapeutic strategy employed a dual approach targeting both the VEGF signaling axis and the RAS/RAF/MEK/ERK pathway. Sorafenib is indicated for treatment of advanced renal cell carcinoma, hepatocellular carcinoma and differentiated thyroid cancer. It acts by inhibiting Raf-1 and B-Raf kinases in the RAS/RAF/MEK/ERK signaling pathway and multiple receptor tyrosine kinases involved in lymphangiogenesis, including VEGFR-2, VEGFR-3 and PDGFR (platelet derived growth factor receptor)-β. Propranolol acts by downregulating VEGF expression (including VEGF-A, VEGF-C and VEGF-D) and attenuating the mitogen-activated protein kinase cascade necessary for lymphangiogenesis as well as potentially inducing vasoconstriction and reducing blood flow to lymphatic endothelial cell. This approach has a few theoretical advantages, such as broader pathway coverage by simultaneously targeting multiple components of the VEGF and RAS/RAF/MEK/ERK pathways, which potentially circumvent compensatory mechanisms that might lead to treatment resistance. The combination allows for reduced dosing of each agent (sorafenib 200 mg twice a day instead of the standard 400 mg twice a day), potentially mitigating adverse effects like nausea, vomiting, diarrhea, abdominal pain, and derangement of liver enzymes, while maintaining efficacy and mechanistic synergy. Inhibition of both pathways may have synergistic rather than merely additive effects, as cross-talk between VEGF signaling and the RAS/RAF/MEK/ERK cascade has been demonstrated in lymphatic endothelial cells.[6] Given the recalcitrant nature of this patient’s condition, having failed multiple conventional treatments, the robust and durable response to this combination therapy is particularly noteworthy. The absence of recurrence at two-year follow-up is especially significant, considering the high recurrence rates typically observed with lymphangioma circumscriptum.

This combination represents a novel approach that has not been previously reported for lymphangioma circumscriptum.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)

We have not used artificial intelligence.

Funding Statement

Nil.