Acta Otorrinolaringológica Gallega

Caso Clínico:

ANGIOSARCOMA CERVICAL APÓS RADIOTERAPIA: UM RARO TUMOR

Cervical angiosarcoma after radiation therapy: a rare tumour

Ana Margarida Machado;

Bruno Pombo; Carlos Faria;

Joana Gonçalves; Nuno Silva;

Jorge Miguéis;

João Casalta, Luís Silva

Otorhinolaryngology Department,

Centro Hospitalar Universitário de Coimbra,

Coimbra, Portugal

Contacto:

Ana Margarida Machado.

Centro Hospitalar e Universitário de Coimbra

Email: amargaridasmachado@gmail.com

Recibido: 14/9/2020 Aceptado: 18/11/2021

ISSN:
2340-3438

Edita:
Sociedad Gallega de Otorrinolaringología

Periodicidad:
continuada.

Web:
www.sgorl.org/revista

Correo electrónico:
actaorlgallega@gmail.com

Resumo

Introdução:

O surgimento de um angiosarcoma na região cervical após radioterapia por carcinoma das cordas vocais é raro mas tem um impacto significativo na sobrevida. Este é um tumor maligno agressivo derivado de células mesenquimatosas com diferenciação endotelial. O diagnóstico precoce requer uma alta suspeição clínica para uma orientação adequada do doente. Os autores apresentam uma revisão da apresentação clínica, diagnóstico e tratamento do angiosarcoma induzido por radiação.

Caso Clínico:

Homem, de 51 anos de idade, de raça caucasiana, desenvolve um angiosarcoma após irradiação da região cervical direita para tratamento de carcinoma epidermóide das cordas vocais. A tomografia computorizada revelou lesão multifocal centrada no músculo esternocleidomastoideu com invasão da artéria carótida direita e metástases ganglionares regionais. A biópsia da lesão foi efetuada e o exame histológico revelou positividade para ERG e CD31. O doente foi submetido a quimioterapia paliativa. Dois meses depois, o doente faleceu após pneumonia bacteriana resultante de complicação da quimioterapia.

Discussão:

O angiosarcoma induzido por radiação é um sarcoma de tecidos moles com origem nas células endoteliais e com mau prognóstico. Frequentemente estes sarcomas surgem na região cervical de forma multifocal, em homens caucasianos idosos, vários anos após a exposição à radiação. O surgimento precoce, meses após radioterapia, é incomum colocando em questão a possibilidade de mutação nos genes BRCA1 ou BRCA 2. O tratamento envolve cirurgia, radioterapia e quimioterapia. Contudo, a sobrevida é reduzida e dependente da localização, tamanho, ressecabilidade, tipo tumoral e complicações.

Palavras-Chave

Angiosarcoma induzido por radiação; Sarcoma; Tecidos moles; Pescoço; Complicações

Abstract

Introduction:

The development of a cervical angiosarcoma after radiation therapy for the treatment of vocal cord cancer is rare but has a significant impact on survival. It is an aggressive malignant vascular tumour derived from mesenchymal cells with endothelial differentiation. Early detection requires a high index of suspicion and is important for optimal management of this aggressive disease. The authors present a review of the clinical presentation, diagnostic methods, and treatment options.

Clinical Case:

A 51-year-old white male developed an angiosarcoma of the right cervical region after adjuvant radiation therapy for epidermoid carcinoma of the vocal cord. The computed tomography (CT) scan revealed a multifocal lesion centred on the right sternocleidomastoid muscle invading the right carotid artery as well as regional lymph nodes metastases. Open surgical biopsy of the lesion was performed, and the histological examination was positive for Ets-related gene (ERG) and cluster of differentiation 31 (CD31). The patient underwent palliative chemotherapy. Two months later, the patient died after a bacterial pneumonia which resulted of chemotherapy treatment.

Discussion:

Radiation-induced angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin that have a poor prognosis. Frequently, such sarcomas appear as multifocal cervical diseases in elderly white men, several years after radiation therapy. However, early occurrence, months after previous radiation therapy, is very uncommon, creating the suspicion of BRCA 1 or BRCA 2 genes mutations. The treatment usually involves surgery, radiation therapy and chemotherapy, but outcomes vary widely and are impacted by location, size, resectability, tumour type and complications.

Keywords

Radiation-induced angiosarcoma; Sarcoma; Soft-tissue; Neck; Complications

Introduction

Radiation-induced angiosarcoma is an aggressive malignant vascular tumour derived from mesenchymal cells with endothelial differentiation¹. It can occur in any body region exposed to radiation². The occurrence in a high vascularized neck region, after radiotherapy for vocal cord cancer is rare but has a significant impact on survival. Its early detection requires a high index of suspicion and is important for optimal management of this aggressive disease³. The authors present a review of the clinical presentation, diagnostic methods, and treatment options.

Clinical Case

A 51-year-old white man was referred to the Department of Otorhinolaryngology with a complaint of hoarseness and throat irritation in the preceding 6 months. He had previous history of tobacco use (30 pack-year), cardiovascular disease and depression. There was no history of familial syndromes, cancer, chronic lymphoedema, exposure to exogenous toxins or presence of foreign bodies. He did not complaint of breathing difficulty, dysphagia, voice misuse or previous radiation history. Indirect laryngoscopy revealed a tumor in the right vocal cord. Fiberoptic nasopharyngolaryngoscopy showed an irregular growth in the right vocal cord with normal cord mobility. A biopsy-proven epidermoid carcinoma was diagnosed in the hystopathologic analysis. Computed tomography (CT) scan of the neck showed enhancement in the right vocal cord. Both supraglottic and subglottic extension of the growth as well as swollen lymph node in neck were not detected. The clinical staging was defined as cT1aN0M0⁴. Given the early stage of this disease and temporary unavailability of laser surgery, the patient was proposed for radical radiotherapy (66Gy) on the glottic plane (33 fractions).

In follow-up outpatient evaluation, 2 months after the end of radiotherapy, the physical examination of the patient detected multiple swollen lymph nodes in the right levels II, III, IV and V. A CT scan of the neck showed that the lesion was centred in the medial aspect of the right sternocleidomastoid muscle (Fig. 1), anterior to the carotid space (Fig. 1 and 2), causing compression and partial thrombosis of the right internal jugular vein (Fig. 2 and 3). A large compressing of the trachea by multiple necrotic adenopathies was identified, the largest one on the supraclavicular region with 30 x 50 mm dimension. The PET/CT scan (¹⁸FDG) did not reveal any new suspicious lesions on vocal cords. The suspension microlaryngoscopy was negative. The conventional fine needle aspiration of adenopathies was inconclusive. The histopathologic analyses by cell block technique and immunohistochemical investigation identified many neoplastic cells positive for Ets-related gene (ERG) and cluster of differentiation 31 (CD31). According to the histological and immunohistochemical findings, the diagnosis was that of a high-grade angiosarcoma of neck (Fig. 4 and 5). The clinical staging was defined as cT4bN1M0⁵. The patient required tracheostomy due to airway obstruction. He was proposed for palliative chemotherapy treatment in a regimen of doxorrubicin and dacarbazin (90/900 mg/m²). The patient died after initiated palliative chemotherapy complicated with pneumoniae and septic shock.

Discussion

An angiosarcoma is a rare vascular malignant tumour with an incidence < 2% of all sarcomas⁶. It arises more commonly in elderly white males, with particularly tendency to occur in head and neck (60%), in a multifocal presentation². The risk factors for angiosarcoma involve radiation, chronic lymphoedema (Stewart-Treves Syndrome), exogenous toxins (vinyl chloride, thorium dioxide, arsenic, anabolic steroids), foreign bodies and familial syndromes (Neurofibromatosis NF1, Mutated BRCA 1 or BRCA 2, Mafucci Syndrome, Klippel-Trenaunay Syndrome)^1,7.

In the head or neck, an angiosarcoma presents itself as an enlarging bruise, a discoloured nodule or ulceration. The differential diagnosis includes haemangioblastoma, Kaposi sarcoma, metastatic cancer, squamous-cell cancer and Merkel cell carcinoma⁸. Moreover, these lesions should be differentiated from benign entities such as cellulitis, infection or skin injuries².

Angiosarcomas are defined into different groups: cutaneous, lymphoedema-associated, radiation-induced, primary-breast, and soft-tissue angiosarcomas⁷. Radiotherapy is the independent risk factor best described but not exclusive of breast cancer therapy. The criteria commonly used to diagnose a radiation-induced sarcoma involve: sarcoma arising within the previous irradiated field (in the area encompassed by the 5% isodose line); a latency of several years between radiation therapy and the development of the sarcoma; and a histological distinction between the secondary sarcoma and the index lesion. New radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) do not seem to change the incidence of radiation-induced sarcomas^9-12.

The diagnosis involves CT, MRI, and histopathologic analysis. CT offers the advantage of three-dimensional information about local invasion, vascularity, fatness, directing biopsies for histopathologic analysis and surgical radiotherapy planning⁹. MRI has several advantages over CT because of high resolution, better definition of cortical bone erosion and marrow infiltration⁹. Confirmation diagnosis is based on the microscopic findings of the biopsy and immunohistochemical methods. Angiosarcomas may express ERG¹³ and CD31¹⁴, making the diagnosis reliable and possible to differentiate this pathology from another sarcoma, carcinoma or melanoma.

As in this patient, the most common location is the neck⁷, with a multifocal presentation². A radiation-induced angiosarcoma is a subtype more prevalent after adjuvant radiotherapy⁷. However, the short timing appearance without other risk factors takes in question the possible association with an unknown familial syndrome or previous exposure to radiation. Several studies have demonstrated a mutational pattern associated with genes involved in DNA repair. Angiosarcoma have been associated with radiation-induced gene mutations¹⁵ as MYC, FLT4, PTPRB and PLCG1 genes^1,6,16. Mutations of BRCA 1 and BRCA 2 genes are well-known risk factors for radiation-induced breast angiosarcoma. Particularly, the BRCA1 damage response pathway was highly enriched with genetic variation in one study¹⁷. Moreover, while important in revealing the biology behind radiation-induced breast angiosarcoma, it may suggest the same genetic background as a risk factor in this patient.

Angiosarcomas have a poor prognosis with reported low 5-year survival rate of 10-50%^3,18-20. Treatment options include surgery, radiotherapy and chemotherapy⁹. Surgical resection with clear margins seems to offer the best outcomes for such sarcomas²⁰. However, in this clinical case, the carotid artery invasion made traditional margin-driven therapy challenging. Radiotherapy could have been an option if the amount of prior radiation delivered in the same field was not overcome⁹. The benefit of chemotherapy for neck soft tissue sarcomas is uncertain. Innovative therapies have been developing²¹. The outcomes are influenced accordingly to location, size, resectability, tumour type and complications²².

We report a case of a cervical angiosarcoma after radiation therapy, a possible complication of neck radiotherapy for vocal cord carcinoma. Histopathologic markers reported in the literature, such as ERG and CD31, helped confirm the diagnosis. Cytogenetic analysis can stratify and define treatment methods accordingly to gene amplification or mutations. Radiation-induced cervical angiosarcomas can develop many years after radiotherapy. In this clinical case, the early development should arouse the suspicion for mutations or amplifications of genes involved in DNA repair. Therefore, it is important to remain vigilant to any soft tissues changes after any exposure to radiotherapy. Surgery is the main curative treatment. The evidence for adjuvant radiotherapy or chemotherapy is weak. Chemotherapy is given mainly in a palliative context. Antiangiogenic therapies could improve the outcomes, but further prospective studies are needed.

Declaration of conflict of interest

The authors declare that they have no conflict of interest in connection with the submitted manuscript.

Informed consent

The authors declare that the written and informed consent for publication was obtained.

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Figures

Figure 1: Axial CT slice at the hyoid level.

Description: The lesion invades the carotid artery with about 120º encasement (straight arrow) and the sternocleidomastoid muscle medial border (dashed arrow).

Figure 2: Axial CT slice at the base of tongue.

Description: The lesion is located anterior to the carotid space (arrow heads). It displays hiper-enhancement and necrotic areas. Necrotic lymphadenopathy with rim enhancement (straight arrows). There is partial thrombosis of the right internal jugular vein (dashed arrow).

Figure 3: Sagital CT slice at the vascular space plane.

Description: The lesion is located anterior to the right internal jugular vein (arrow heads). Partial thrombosis of the right internal jugular vein can be identified (straight arrow).

Figure 4: Histopathological picture of high grade angiosarcoma (A. H&E x200; B. H&E x400)

A

B

Description: Histopathologic analyses by cell block technique of the tumour showing pleomorphic cells with high mitotic rate, hyperchromatic vesicular nuclei, abundant eosinophilic cytoplasm and intracytoplasmic lumina.

Figure 5: Immunohistochemical picture of high grade angiosarcoma (A. ERG x400; B. CD31 x400)

A

B

Description: Immunohistochemical analyses by cell block technique of the tumour showing tumour cells expressing ERG and CD31