Unexpected development of tongue squamous cell carcinoma after sclerotherapy for the venous malformation: a unique case report and literature review
© Chen et al.; licensee BioMed Central Ltd. 2013
Received: 21 September 2013
Accepted: 20 October 2013
Published: 4 November 2013
Sclerotherapy is a common and effective treatment for venous diseases, including venous malformations (VMs), which are common vascular anomalies in the oral and maxillofacial regions. However, the safety of sclerotherapy has not been fully elucidated. Occasionally, patients who underwent sclerotherapy may present diverse but minor side effects such as erythema, swelling, pain, tenderness, hyperpigmentation, skin ulceration and necrosis.
Here we report a unique case of a 65-year-old female patient presented with an original VM lesion on the right side of the tongue. Intralesional sclerotherapy and followed surgical resection resulted in major remission of the original lesion, without recurrence during a 3-year follow-up. However, two years later, the patient was again referred to us for a painful mass on the right side of the tongue that gradually enlarged for 1 month. The mass was biopsied under local anesthesia after complete systematic examination, and the result indicated a well-differentiated squamous cell carcinoma (SCC). Then, the patient underwent right neck dissection, extensive resection of the SCC, reconstruction of the defect with forearm flap, microvascular anastomosis, and repair of the forearm defect with free abdomen skin graft.
To the best of our knowledge, this is the first study to document the development of oral SCC after sclerotherapy for VM, underscoring the need for long-term follow-up.
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1897394831087742.
KeywordsVenous malformation Sclerotherapy Squamous cell carcinoma
Venous malformations (VMs), formerly known as “cavernous hemangiomas”, are the most common slow-flow vascular malformations that have a propensity to form in the oral maxillofacial regions. VMs have an estimated incidence of 1 to 2 in 10,000 births and a prevalence of 1% . Unlike infantile hemangiomas, VMs never regress and most of them are sporadic and unifocal. They have no sex preponderance, but they have an age-dependent variation in penetrance, which peaks at approximately 20 years old . Clinically, VMs located in the oral region often cause serious problems in speech and swallowing, and they may even be life threatening because of bleeding, expansion, or obstruction of vital structures. Given the anatomic and histologic characteristics of the oral and facial regions, sclerotherapy is the preferable treatment option to reduce the volume of the lesions. However, the safety of sclerotherapy has not been fully elucidated. This case report describes a 65-year-old female patient who suffered squamous cell carcinoma (SCC) of the tongue after sclerotherapy for VM.
Pathological and immunohistochemical findings
Sclerotherapy is a common treatment method for venous diseases. In most cases, the treatment is effective, with a low frequency of complications. Previous studies have shown that the complications of sclerotherapy could be classified as local or systemic. Local complications include any transient adverse effects, such as peripheral nerve palsy, skin blistering, tissue fibrosis, or skin necrosis. Systemic complications include death and permanent adverse effects, such as deep venous thrombosis, pulmonary embolism, and other cardiovascular or pulmonary events .
Information of patients who suffered carcinoma development after sclerotherapy
Duration of carcinoma development (months)
54.7 ± 6/M
58.3 ± 5.0/Unknown
51.0 ± 18.9 ml
Simple renal cyst
Minocycline and Ethanol
Pingyangmycin and Sodium morrhuate
Pingyangmycin and sodium morrhuate were the sclerosants used in this case. Pingyangmycin is a bleomycin A5 derivative. Given its rare side effects, low cost, and easy availability, it is widely used in China for over 20 years. Zheng et al. used pingyangmycin to treat VMs in the oral and maxillofacial regions, and showed that 134 of 179 patients (74.9%) were improved or cured . Pulmonary fibrosis is the most serious complication of pingyangmycin, but the risk is minimal when the dose per treatment is less than 1 mg/kg per session, with a total dose of 5 mg/kg. Our previous study also found that alternating injections of pingyangmycin and sodium morrhuate is more effective for VMs than using them alone . However, the safety of this therapeutic modality has not been fully elucidated yet. Here, we report a 65-year-old female patient who suffered SCC of the tongue after sclerotherapy with pingyangmycin and sodium morrhuate. This case is unique because it presents an oral mucosal carcinoma developed from a VM after sclerotherapy, and no ulceration occurred before the carcinoma development. Also, this is the first report to link the sclerosant pingyangmycin with carcinogenesis. Nevertheless, there are still several puzzles to be solved for their potential relationship.
In that regard, the post-operation pathological examination result have showed that the well-differenced SCC was surrounded by residual VMs and phlebolith, and meanwhile revealed that a large amount of mesenchymal-like cells were located in the boundary area between SCC and residual VMs. These observations suggested a potential relationship between SCC development and sclerotherapy, and also promoted us to hypothesize that whether the carcinoma development after sclerotherapy was associated with the increased mesenchymal components, because a plenty of previous studies have indicated the promotive roles of stromal microenvironment during carcinogenesis .
Based on the above concerns, we then performed the immunohistochemical analysis for several mesenchymal markers. Firstly, we found that N-Cadherin and vimentin were strongly expressed in almost the entire specimen, including the invasive front of SCC, the boundary area between SCC and residual VMs, as well as the perivascular walls of VMs, which suggested the significantly increased mesenchymal components. Then, by comparison with those surgical VMs without sclerotherapy, we confirmed the increased expression of α-SMA around or invaded across the vessels of residual VMs in the present case. Importantly, nuclear location of slug, a key member of the EMT-related transcription factors, was also frequently found in the inner layer of the vessels, while positive nuclear location of slug was nearly undetectable in the VM samples without sclerotherapy. All these results indicated an occurrence of EndoMT-like process in this case after sclerotherapy with pingyangmycin. Notably, previous studies also indicated the truth that sclerotherapy could significantly increase the mesenchymal components (mainly fibroblasts) through an EndoMT-like process [14, 15]. More specifically, our very recent study revealed that sclerotherapy-induced EndoMT might be associated with the activation of mTOR pathway . Taken all the above findings into consideration, we suspected that EndoMT might be an important mechanism contributing to the sclerotherapy of venous diseases, but might be also a possible link between sclerotherapy and carcinoma development. Besides, we speculated that sclerotherapy could lead the lesions and adjacent tissues to become harden and constrict, so that the mechanical force and heat stimulation may also play a potential role during the process of carcinogenesis. Also, it has been widely accepted that carcinoma development involves the progressive accumulation of genetic abnormalities as well as the alteration of local environment [16–18]. Thus, further study will be required to determine whether sclerotherapy could lead to genetic abnormalities or environmental alteration.
We herein described an unusual case of 65-year-old female patient who suffered SCC of the tongue after sclerotherapy for VM, and meanwhile provided some underlying clues for the possible link between sclerotherapy and carcinoma development. Therefore, we emphasize that long-term routine follow-up after sclerotherapy is necessary, and the side effects and complications of sclerosants should not be overlooked, especially any neoplasm in oral and facial regions.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Squamous cell carcinoma
Alpha-smooth muscle actin
Sodium tetradecyl sulfate
This work was supported by grant from the National Natural Science Foundation of China (81300895) to Dr. G Chen. We thank Prof. XM Chen in Department of Oral Pathology, School and Hospital of Stomatology, Wuhan University for pathological diagnosis.
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