Keywords
hemangioendothelioma - surgery - radiotherapy - pazopanib - outcomes - case report
Introduction
Sarcomas are malignant tumors of the skeletal and extraskeletal connective tissue
that can arise from mesenchymal tissue at any body site. Uncommon subtypes of sarcoma
together account for 5% of sarcoma tumours.[1] They are especially challenging to diagnose and treat. Epithelioid hemangioendothelioma
(EHE) is an uncommon vascular sarcoma that accounts for less than 1% of all vascular
tumors.[2] The World Health Organization describes malignant EHE as an intermediate malignant
neoplasm.[2] The risk of recurrence at the local site and failures distantly are high with EHEs;
however, tumor-specific mortality rates may rely on their anatomic site of origin.
There are only limited cases reported of EHE in the face–neck region, with an appearance
in the oral cavity being extremely rare.[3] The frequently reported oral cavity site for EHE is the tongue, which accounts for
26% of cases. This is followed by the mandibular and maxillary gingiva involvement,
contributing to 22 and 19% of cases, respectively.[4]
[5] The present study describes a rare case of mandibular EHE, its management, and a
summary of the literature available.
Case Presentation
A 56-year-old lady, with no comorbidities and no habits presented with right submandibular
swelling which gradually increased over 2 years. On clinical examination, the submandibular
mass was lobulated and soft in consistency measuring 3 × 4 cm and not fixed to the
overlying skin. There were no signs of inflammation and the swelling was not tender
to touch. There was a palpable left level Ib neck node of 1.5 × 2 cm in size in the
contralateral neck. The rest of the head and neck area examination was noncontributory.
Computed tomography (CT) imaging ([Fig. 1A]) done was suggestive of a 28 × 27 × 39 mm sized ill-defined soft tissue lesion seen
in the hemimandible along the right lower alveolus which was causing destructive cortical
erosion. The adjacent enhancing soft tissue component showed loss of fat planes with
the right submandibular gland inferiorly. A peripherally enhancing centrally necrotic
left submandibular lymphadenopathy was present measuring 18 × 17 mm in size. Whole-body
positron emission tomography-CT (PET-CT) scan done was suggestive of 3 × 2.4 cm sized
fluorodeoxyglucose (FDG) avid spiculated lesion in the right submandibular region,
eroding overlying angle and adjacent posterior body of the right hemimandible and
infiltrating the right anterior belly of the digastric and closely abutting platysma.
A 1.7 × 2.2 cm sized FDG avid left cervical level Ib lymph node was also noted. Heterogeneously,
FDG avid discrete cervical level Ia and bilateral level II lymph nodes were also present.
Mild FDG avid multiple subpleural and parenchymal nodules were noted in bilateral
lung fields suggestive of metastasis ([Fig. 1C]). Biopsy from the right submandibular region was suggestive of EHE. In view of rare
disease and asymptomatic suspicious lung metastasis, the case was discussed in a multidisciplinary
tumor board following which the patient was taken up for wide local excision with
right segmental mandibulectomy with bilateral supraomohyoid neck dissection. Histopathology
of the resected specimen was suggestive of EHE involving the right submandibular gland
and underlying bone ([Fig. 2A]) with maximum tumor size of 2.8 cm, medial and lateral soft tissue margins were
involved by the tumor, perineural invasion was present ([Fig. 2B]), and lymphovascular invasion was not seen. Federation Nationale des Centres de
Lutte Contre Le Cancer (FNCLCC) grade 4, mitotic rate was < 1/50 high-power field
(HPF), and necrosis 10% ([Fig. 2C]). One lymph node in the left level Ib was positive (out of 5), while the right-sided
nodes were negative. Tumor cells were immunoreactive for CD34 ([Fig. 2D]). In view of positive margin and lymph node involvement, the patient was planned
for adjuvant radiation to a dose of 60 Gy in 30 fractions to postoperative bed and
involved the lymph node region by image-guided external beam radiotherapy (RT) technique.
In phase 1, 50 Gy in 25 fractions was delivered to the tumor bed and bilateral neck
region, and in phase 2 (boost), 10 Gy in 5 fractions was delivered to the tumor bed
and involved the nodal region, Therefore, a total of 60 Gy in 30 fractions, 2 Gy per
fraction, one fraction daily, over 6 weeks along with cisplatin chemotherapy (40 mg/m2) concurrently was given once a week, which she tolerated well with grade 1 dermatitis
and grade 2 mucositis. The patient recovered from acute toxicities 2 weeks after completion
of RT and was started on targeted therapy tablet pazopanib (dose 400 mg) twice a day
to control systemic disease and reduce the risk of locoregional failure. PET-CT scan
repeated after 3 months was suggestive of postoperative fibrosis of the right submandibular
region with stable pulmonary metastasis. At 2-year follow-up, the patient is asymptomatic
and on tablet pazopanib dose reduced to 200 mg twice a day due to oral mucositis.
Latest PET-CT showed local-regional control and metabolically inactive pulmonary metastatic
diseases.
Fig. 1 Contrast-enhanced computed tomography (CT) (A) and positron emission tomography (PET) images (B) showing soft tissue lesion seen in the right hemimandible causing cortical erosion
and involving the submandibular gland inferiorly with an enhancing centrally necrotic
left submandibular lymphadenopathy and (C) mild fluorodeoxyglucose (FDG) avid multiple parenchymal nodules were noted in bilateral
lung fields suggestive of metastasis.
Fig. 2 Histopathological findings. (A) Cords of cells infiltrating and destroying bone and embedded in a myxohyaline matrix,
hematoxylin and eosin (H&E) stain, 10 × . (B) Perineural invasion, H&E stain, 10 × . (C) Partly viable tumor and partly coagulative necrosis (in the upper half of image),
H&E stain, 10 × . (D) Immunohistochemistry for CD34, showing positivity for tumor cells and interspersed
vessels within the tumor, DAB-H, 10 × . H&E, hematoxylin and eosin stain; DAB-H, diaminobenzidine-hematoxylin.
Discussion
Hemangioendothelioma (HE) is a rare vascular neoplasm with an equivocal biological
behavior, intermediate between highly malignant angiosarcoma and completely benign
hemangiomas. HE involving the skin and soft tissue includes papillary, retiform, kaposiform,
epithelioid, pseudomyogenic, and composite type.[6]
EHE is distinguished by epithelioid or histiocytoid cells with endothelial features,
accounting for less than 1% of all vascular tumors. In 1975, HE was reported initially
by Dail and Liebow as pulmonary in origin.[7] Earlier, it was described as an bronchoalveolar cell carcinoma with vascular invasion
with an aggressive behavior, hence, the name given was an intravascular bronchioloalveolar
tumour.[8]
[9] In 1982, the name EHE was coined by Weiss and Enzinger to define a vascular tumor
of soft tissue and bone with characteristic features intermediate between hemangioma
and angiosarcoma.[10]
[11]
EHE has been considered to be the most aggressive among all types of HEs with a high
risk of distant metastasis and mortality, accounting for 20 to 30% and 10 to 20% cases,
respectively.[12] One of the largest series[6]
[13] of EHE reported, recurrences at local site in 13% of cases and regional-distant
failure in approximately 31% sites such as regional lymph nodes, lungs, liver, and
bone. The authors concluded in a study with 49 patients of soft tissue EHE, that the
risk of metastasis was greater in lesions > 3 cm and those showing ≥ 3 mitotic figures
per 50 HPF.[14]
The etiology of EHE up to this time is unclear. At the molecular front, various angiogenic
stimulators may act as promoters of endothelial cell proliferation.[15] A study suggests that for proliferation of EHE, monocyte chemoattractant protein-1
is needed and by stimulation the angiogenic nature of endothelial cell, it might promote
lesions to proliferate.[16]
EHE is diagnosed predominately in female population, usually between the age group
of 20 and 60 years.[17] The frequently reported symptom is pain. Cutaneous and soft tissue EHE often present
as a painful mass and may cause thrombosis or occlusion in the affected vessel. Although
in the present case, the mass was painless and nontender on palpation. In the majority
of cases, EHE is multifocal or metastatic at diagnosis.
EHE cases show noticeable nuclear atypia with prominent nucleoli, focal and solid
growth patterns, necrotic foci, and higher mitotic activity (> 2 mitoses per10 HPF)
in approximately 10% of cases. These characteristics are valuable diagnostic hints
and also suggestive of the aggressive nature of the disease.[18] EHE has numerous morphological features that are indistinguishable from melanomas,
carcinomas, and epithelioid sarcomas but the important differential diagnosis is with
primary or metastatic carcinomas. CD31, CD34, ERG, and FLI-1 are endothelial differentiation
markers frequently expressed in EHE.[19]
[20] Less than 30% of cases showed focal cytokeratin immunopositivity.[21]
EHE at a molecular level is represented by YAP1-TFE3 (10%) or WWTR1-CAMTA1 (90%) gene
fusions.[22]
[23]
[24] The molecular characterization of EHE is highly recommended for diagnostic confirmation
and rule out the differential diagnosis, like angiosarcoma and epithelioid hemangioma.
Unlike EHE with WWTR1-CAMTA1 fusion, EHE with YAP1-TFE3 consist of epithelioid neoplastic
cells with bright copious eosinophilic cytoplasm and focally unequivocal vasoformative
features.[23]
[24] Although, currently molecular study has no predictive or prognostic value, neither
can it be utilized for treatment stratification purposes.
Surgical excision with regional nodal resection is the standard treatment for EHE.
The main purpose of surgery is to ensure R0 resection, that is, complete resection
of the tumor with microscopic negative margins. The expected cure rate in EHE after
R0 resection is 70 to 80%.[25]
The risk of recurrence at the local site is approximately 10 to 15% following complete
surgical resection.[10] Although EHE is assumed to be a moderately radiosensitive tumor, the role of adjuvant
RT is not well established. Indications of adjuvant RT can be extrapolated from the
principles and management of soft tissue sarcomas (STS) of the extremity. Adjuvant
RT can be considered in cases of close or positive margin to optimize the treatment
outcome. Adjuvant RT is advisable to a dose of 60 Gy in patients with positive or
close margins or cases where there is a higher risk of local recurrence. Local irradiation
after resection of bone EHE up to 60 Gy showed no locoregional failures on 2 years'
follow- up.[26] In the present case study, adjuvant RT was planned for the patient as medial and
lateral inked margins were positive for tumor cells.
The role of preoperative RT is unclear, as there are no cases published so far for
EHE. But for cases where positive or close surgical margins is expected following
surgery, preoperative RT to a dose of 50 Gy in 25 fractions may be considered as per
standard STS protocols. In cases where the disease is unresectable, definitive RT
to a total dose of 60 Gy, 1.8 to 2 Gy/fraction has been recommended. However, depending
on the clinical burden, distant metastasis, and symptoms, RT can also be delivered
in a palliative setting.[17] Moreover, in neoadjuvant or adjuvant settings, none of the literature supports the
use of systemic treatment in patients with resectable EHE.
Cytotoxic chemotherapy and tyrosine kinase inhibitors are the different options for
systemic therapy. Although cytotoxic chemotherapy, such as single-agent gemcitabine,
can be considered, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase
inhibitors pazopanib, an antiangiogenic drug in phase III trial of STS, showed successful
results.[27] Pazopanib resulted in clinical improvement and control of liver and lung metastasis
for almost 8 years in a young female with EHE with distant metstatsis.[28] It was well tolerated with no major side effects compared to cytotoxic therapies.
Pazopanib therapy was considered postsurgery and radiochemotherapy in the present
study to target lung metastasis and reduce the risk of locoregional recurrence.
The efficacy of other targeted agents such as VEGFR inhibitors (bevacizumab, sorafenib),
mammalian target of rapamycin (mTOR) inhibitors (sirolimus), and immunomodulatory
drugs (lenalidomide) in the treatment of EHE is limited, and further studies are required
to determine treatment strategies. However, mTOR inhibitors have been marked with
the highest clinical activity, with progression-free survival (PFS) and overall survival
of approximately 1 and 2 years, respectively. An even longer PFS has been reported
in 10% of patients.[24] The systemic approach is preferred treatment option for advanced, metastatic, and
progressive EHE. Owing to the rarity of the disease, no standard treatment protocols
for EHE exist. To assess clinical outcomes in EHE, a case-by-case treatment approach
and follow-up strategies are needed ([Table 1]).
Table 1
Literature review of epithelioid hemangioendotheliomas in the intraoral region and
treatment outcomes
|
No.
|
Study
|
Year
|
No. of cases
|
Age
|
Site
|
Treatment
|
Follow-up
|
|
1.
|
Wesley et al[29]
|
1975
|
1
|
18
|
Mandibular gingiva
|
Surgical excision
|
NED, 2 years
|
|
2.
|
Mentzel et al[30]
|
1997
|
5
|
30-65
|
Soft tissue, cheek and neck
|
Surgical excision
|
NED, 42–60 months
|
|
3.
|
Ebo et al[31]
|
1986
|
1
|
NA
|
Gingiva
|
Surgical excision
|
NED, 36 months
|
|
4.
|
Ellis and Kratochvil[32]
|
1986
|
12
|
4-67
|
Neck, gingiva
|
WLE and surgical excision
|
LN metastases 2 cases
Recurrence: 1 case
|
|
5.
|
Moran et al[33]
|
1987
|
1
|
25
|
Palate
|
Surgical excision
|
NED, 21 months
|
|
6.
|
de Araújo et al[34]
|
1987
|
1
|
4
|
Gingiva
|
Surgical excision
|
NA
|
|
7.
|
Marrogi et al[5]
|
1991
|
2
|
36-45
|
Tongue, gingiva
|
Surgical excision
|
Recurrence: 1 case
|
|
8.
|
Flaitz et al[35]
|
1995
|
1
|
7
|
Gingiva
|
WLE
|
NED, 48 months
|
|
9.
|
Kiryu et al[36]
|
1996
|
1
|
46
|
Soft tissue, cheek
|
Surgical excision
|
NED, 36 months
|
|
10.
|
Orsini et al[37]
|
2001
|
1
|
18
|
Buccal mucosa
|
Surgical excision
|
Recurrence: 9 months
|
|
11.
|
Chi et al[38]
|
2005
|
1
|
28
|
Gingiva
|
Surgical excision
|
NED, 8 months
|
|
12.
|
Rigby et al[39]
|
2006
|
1
|
34
|
Soft tissue, neck
|
Surgical excision
|
NED, 84 months
|
|
13.
|
Yoruk et al[40]
|
2008
|
1
|
44
|
Submandibular region
|
Surgical excision
|
NED, 6 months
|
|
14.
|
Sun et al[41]
|
2007
|
9
|
6-53
|
Tongue (n = 4), lip (n = 1), gingiva and alveoli of the maxilla/mandible(n = 2),
buccal mucosa (n = 1),
FOM (n = 1).
|
Surgical excision
|
NED, 6 months–8 years
Recurrence in 3 cases
|
|
15.
|
Mohtasham et al[42]
|
2008
|
1
|
9
|
Maxillary gingiva
|
Surgical excision
|
Recurrence, 1-year
|
|
16.
|
Gordón-Núñez et al[43]
|
2010
|
1
|
17
|
Mandibular gingiva
|
Surgical excision
|
NED, 21 months
|
|
17.
|
Salgarelli et al[3]
|
2016
|
1
|
32
|
Mandibular gingiva
|
Surgical excision
|
Node metastases after 4 years
|
|
18
|
Ranjit et al[44]
|
2015
|
1
|
25
|
Submandibular region
|
Surgical excision
|
NA
|
|
19
|
Present case
|
2021
|
1
|
56
|
Mandible and submandibular region with lung metastasis
|
Surgical excision → chemoradiation → pazopanib
|
On follow-up
disease free
|
Abbreviations: FOM, floor of mouth; LN, lymph node; NA, not available; NED, no evidence
of disease; WLE, wide local excision.
Conclusion
EHE is a rare tumor with a borderline behavior between hemangiomas and malignant angiosarcomas.
The surgical excision of tumor is the standard approach for localized disease and
adjuvant RT use can be extrapolated from the management of STS guidelines. Considering
its aggressive behavior and high propensity for distant metastasis and with no standard
treatment guidelines, an individual case-based multimodality approach should be considered
to get the best treatment outcomes.
