Abstract
Soft tissue sarcomas are uncommon in the head and neck. Primary angiosarcomas of the oral cavity area are extremely rare, and have mostly been presented as case reports. This paper presents the clinical and histological features of three such cases. All patients were diagnosed based on the presence of rapidly extending masses involving the tongue, maxillary gingiva, or mandibular gingiva; bone destruction was present in two cases. The resected specimens revealed clustered large, pleomorphic, and spindle-shaped cells with a markedly haemorrhagic background. Tumour cells showed expression of vascular endothelial markers, such a CD31, CD34, and factor VIII-related antigen. Despite undergoing radical surgery, distant metastases developed in all three cases. We also studied the clinicopathological features of a series of oral angiosarcomas. This article therefore reports the clinicopathological features of the three new cases and provides a review of the cases of primary oral angiosarcoma reported during the past 20 years.
Angiosarcomas are malignant tumours of the vascular endothelium, comprising only 2% of soft tissue sarcomas. The occurrence of these tumours in the oral cavity is extremely rare. Primary angiosarcoma of the oral cavity and salivary gland area represents only 1% of all angiosarcomas.
Angiosarcoma manifests an aggressive clinical course and a poor prognosis, even in cases in which surgical removal of the tumour is possible, and affected patients do not usually benefit from chemoradiotherapy. Approximately half of the patients die within 15 months of the diagnosis, and only 12% survive for 5 years or longer. Generally, better differentiated tumours have been associated with better survival rates. Tumour-related death is usually due to uncontrolled local progression and/or distant metastases to the lungs, liver, and bone. Early detection and treatment are essential to control this highly malignant soft tissue cancer.
Naka et al. have reported the diagnostic criteria for angiosarcoma to be as follows: (1) varying degrees of a vasoformative pattern of growth, well developed vascular channels, slit-like irregular spaces covered by large cells with hyperchromatic nuclei, or ill-defined vascular lumens with occasional vacuolization in the cytoplasm of proliferating cells; and (2) positive reactions of proliferating cells for endothelial cell markers including factor VIII-related antigen (FVIII-RAg), UEA-1, and/or CD31, but negative reactions for HMB45. However, a variety of cellular types or patterns have been seen, and there has usually been an admixture of cell types and patterns within a given tumour, rather than a single type or pattern. Poorly differentiated areas devoid of vessel formation or intracytoplasmic lumina and consisting of sheets of polygonal cells containing abundant amphophilic or basophilic cytoplasm and vesicular nuclei have been seen in some cases.
The aim of the present study was to describe the clinicopathological and immunohistochemical features of three new cases of primary intraoral angiosarcoma and also to provide a review of the cases of primary oral angiosarcoma reported during the last 20 years.
Materials and methods
Three well-documented cases of angiosarcoma with intraoral presentation were obtained from a review of the hospital files. All samples had been formalin-fixed and paraffin-embedded, and the corresponding paraffin blocks were available for further examination. Sections 4 μm thick were cut and stained with haematoxylin–eosin and for endothelial markers. Consecutive sections, collected on positively charged slides, were used for immunohistochemical studies that were carried out with a conventional avidin–biotin–peroxidase complex (ABC) technique. All cases were evaluated and diagnosed by pathologists.
The histological grade was assessed according to the updated version of the FNCLCC system (French National Federation of Cancer Centres) based on tumour differentiation, mitotic count, and necrosis (Supplementary Material, Table S1). The clinical staging was evaluated according to the soft tissue sarcoma classification system jointly produced by the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC). In short, there were four categories: primary tumour size (T), regional lymph nodes (N), distant metastasis (M), and the histological grade (G).
The classifications of margins were evaluated according to the guidelines for the management of soft tissue sarcomas. There are four categories of margins that have been described histologically: intra-lesional, marginal, wide, and radical.
Results
Clinical findings
The conspicuous clinical features of the three cases obtained from the hospital files are reported in Table 1 , and representative photographs and imaging findings are shown in Fig. 1 . The current series comprises three patients (two males, one female) with oral angiosarcoma. At the time of diagnosis, the patients ranged in age from 55 to 78 years (mean 65.6 years). Clinically, all exhibited rapidly expanding masses that were red to bluish in colour and of a soft to fibrous consistency, which bled easily. The tumour size ranged from 25 to 60 mm.
| Case no. | Age, years | Gender | Primary site | Clinical findings | TNM classification a | Stage a | Treatment | Surgical margins | Recurrence or metastasis | Clinical course |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 55 | M | Mandibular gingiva | Symptom: Rapidly expanding mass Colour: Bluish Size:25 mm × 20 mm Characteristics: Haemorrhagic and fragile mass |
T1aN0M0G4 | II | Segmental mandibular resection + Lt RND | Radical | Thoracic vertebrae metastasis | DOD (3 months) |
| 2 | 64 | M | Maxillary gingiva | Symptom: Expanding mass Colour: Dark red Size: 42 mm × 20 mm Characteristics: Haemorrhagic and fragile mass |
T1bN1M0G2 | IV | Maxillectomy + Bil. RND → CT (CDDP + ADM) | Radical | Lung metastasis → lobectomy | NED (30 months) |
| 3 | 78 | F | Tongue | Symptom: Rapidly expanding mass Colour: Normal pink Size: 60 mm × 50 mm Characteristics: Haemorrhagic and painful mass |
T2bN1M0G3 | IV | Subtotal glossectomy + Rt RND | Wide | Lung metastasis | DOD (6 months) |
Radiologically, there was erosion of the adjacent (maxillary or mandibular) cortical bone in two cases, and a tumour with extension beyond half of the tongue and right anterior floor of the mouth in the other case. In two cases, both computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated enlarged lymph nodes in the laterocervical chain and retromandibular region, which were suspected to be lymph node metastasis.
Pathological findings
The broad pathological features of the cases are reported in Table 2 , and representative photomicrographs (haematoxylin–eosin, magnification 50× and 200×) are shown in Fig. 2 . All cases underwent an incisional biopsy, followed by surgical resection. In case 1, the resected tumour was found to be composed of solid sheets of mitotically active (30 per 10 high-power fields) pleomorphic cells with large nuclei containing multiple nucleoli. The tumour cells were intensely eosinophilic and showed distinct cell borders and intracytoplasmic vacuoles containing intact or fragmented red blood cells. Very rarely, the latter were contained within slit-like spaces. The morphological features of this case resembled those of epithelioid angiosarcoma.
| Case no. | Histology | Differentiation a | Necrosis b | Mitosis c | FNCLCC histological grades | Vascular endothelial marker(s) | Mesenchymal marker(s) | Epithelial marker(s) | Neural marker(s) | Muscular marker(s) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Epithelioid angiosarcoma with rare slit-like spaces | 3 | 1 | 3 | Grade 3 | CD34 (+) | NA | EMA (+) AE1/AE3 (−) |
NA | NA |
| 2 | Spindle cells, intercellular haemorrhage, slit-like spaces | 1 | 1 | 3 | Grade 2 | FVIII-RAg (+) CD31 (+) CD34 (+) |
Vimentin (+) | AE1/AE3 (−) | S100 (−) | SMA (−) |
| 3 | Abortive vessels and pleomorphic spindle cells | 3 | 1 | 3 | Grade 3 | FVIII-RAg (−) CD31 (+) CD34 (−) |
Vimentin (+) | AE1/AE3 (+) | S100 (−) | SMA (−) Desmin (−) |
a 1 = well differentiated; 2 = moderately differentiated; 3 = poorly differentiated.
In case 2, the specimen was made up of pleomorphic spindle cells with an indistinct luminal formation lined by endothelial-like cells showing prominent nuclear pleomorphism, and papillary outpouchings projecting into the lumens of the vascular channels. In case 3, vascular formation was only detectable as slit-like spaces containing minimal amounts of red blood cells, which were surrounded by a homogeneous population of spindle cells. The endothelial-like cells progressively merged into the surrounding spindle cell population.
In all three cases, the tumours showed extensive necrosis, invaded the adjacent tissues extensively, and reached the surface epithelium; nevertheless, the latter was never directly invaded by the tumour. The histological grade was classified as grade 3 in two cases and as grade 2 in the other case.
Staging
According to the AJCC clinical staging system, the tumours were classified T1a, T1b, and T2b. There were two N1 cases. The total overall stage assigned one case as stage II and two cases as stage IV.
Immunohistochemistry
The immunohistochemical findings of the three cases are listed in Table 2 and representative images are shown in Fig. 3 . Overall, all three tumours were immunoreactive for CD31 or CD34, whereas only one of the tumours displayed FVIII-RAg positivity. In one case, anti-cytokeratin wide spectrum (AE1/AE3) antibodies stained a subpopulation of neoplastic cells in the epithelioid angiosarcoma. All cases studied were negative for the S100 protein, HMB45, and desmin, and positive for vimentin. One case showed a Ki-67 index of only 20%, while the other two cases had values higher than 50%.
Treatment and follow-up
Following the pathological diagnosis of angiosarcoma, all patients underwent surgical excision. In all three cases, the tumours were excised completely, and all of the surgical margins were free of the lesion. In the maxillary case (case 2), postoperative chemotherapy was started 30 days after surgery. The chemotherapy regimen consisted of three cycles of cisplatin and doxorubicin. After the three cycles of chemotherapy, we administered cancer immunotherapy with peptide-based vaccines as adjuvant treatment for 1 year. Twenty-four months after surgery, the patient was diagnosed with a solitary lung metastasis, however this was controlled with surgery. Ten months after the lobectomy, the patient remains well, without any obvious recurrence or metastatic disease. The other two cases did not receive postoperative treatment due to the detection of early distant metastases (lung and thoracic vertebra). They both died within 6 months of the initial treatment. Loco-regional control was achieved up to their deaths.
Results
Clinical findings
The conspicuous clinical features of the three cases obtained from the hospital files are reported in Table 1 , and representative photographs and imaging findings are shown in Fig. 1 . The current series comprises three patients (two males, one female) with oral angiosarcoma. At the time of diagnosis, the patients ranged in age from 55 to 78 years (mean 65.6 years). Clinically, all exhibited rapidly expanding masses that were red to bluish in colour and of a soft to fibrous consistency, which bled easily. The tumour size ranged from 25 to 60 mm.
| Case no. | Age, years | Gender | Primary site | Clinical findings | TNM classification a | Stage a | Treatment | Surgical margins | Recurrence or metastasis | Clinical course |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 55 | M | Mandibular gingiva | Symptom: Rapidly expanding mass Colour: Bluish Size:25 mm × 20 mm Characteristics: Haemorrhagic and fragile mass |
T1aN0M0G4 | II | Segmental mandibular resection + Lt RND | Radical | Thoracic vertebrae metastasis | DOD (3 months) |
| 2 | 64 | M | Maxillary gingiva | Symptom: Expanding mass Colour: Dark red Size: 42 mm × 20 mm Characteristics: Haemorrhagic and fragile mass |
T1bN1M0G2 | IV | Maxillectomy + Bil. RND → CT (CDDP + ADM) | Radical | Lung metastasis → lobectomy | NED (30 months) |
| 3 | 78 | F | Tongue | Symptom: Rapidly expanding mass Colour: Normal pink Size: 60 mm × 50 mm Characteristics: Haemorrhagic and painful mass |
T2bN1M0G3 | IV | Subtotal glossectomy + Rt RND | Wide | Lung metastasis | DOD (6 months) |
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