# Radiation Oncology/Sarcoma/Angiosarcoma

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## Overview

* Rare malignancy of vascular origin
** Soft tissue sarcoma ~1% of all malignancies
** Angiosarcoma ~2% of soft tissue sarcomas
* Clinically heterogenous, and can occur anywhere in the body
** ~1/3 cutaneous
** ~1/4 soft tissue
** Rest miscellaneous locations
* Thought to arise from vascular endothelium
* Unlike other sarcomas, may present as multifocal disease, and spread to LNs and distantly
* Typically have an aggressive course, with difficulty clearing surgical margins, and with frequent local and distant failure
* Treatment is challenging, and requires multidisciplinary approach

## Pathogenesis

* Thought to originate from vascular endothelium
** Cell marker studies are consistent with lymphocyte differentiation but ultrastructural characteristics are consistent with blood vessel differentiation (PMID 3104187)
* Vascular endothelial factor D (VEGF-D) (PMID 14746640) and angiopoietin 2 (PMID 15149523) significantly elevated compared to controls
* Fas ligand (w:Fas_ligand|Fas-L) is detected in >70% tumors (PMID 11549589), and number of Fas-L positive cells correlates inversely with survival. This suggests that Fas-L positive tumor cells may induce apoptosis in tumor-infiltrating lymphocytes (TILs) and thus blunt immune response
* Frequently develops in areas previously treated with radiation (e.g. breast) or with chronic lymphedema Stewart-Treves syndrome
** Median time from RT 8.6 years in one series (PMID 15166970), and risk increases with dose
* Pathology
** Distinguished from hemangioma by presence of "collagen dissection patterns", anastomoses, and papillary formation
** Early lesions may in fact present as benign hemangiomas
** Most present as intermediate or high grade lesions, but typically have an aggressive course
** Well differentiated tumors are composed of well-formed, irregular vascular channels (sinusoids) anastomosing together, lined by atypical cells (64%)
** Poorly differentatied tumors may contain only pleomorphic spindle cells with subtle vascular lumens, or may still contain vaso-formative areas
** Grade is not a prognostic factor

## Treatment

* Mass General Hospital; 2007 (1980-2006) PMID 17356953 -- "Treatment and outcome of 82 patients with angiosarcoma." (Abraham JA, Ann Surg Oncol. 2007 Jun;14(6):1953-67.)
** Retrospective. 82 patients (32 cutaneous, 22 deep tissue/organs, 10 RT or lymphedema, 8 bone, 7 non-RT breast).
** Primary disease: 46 patients, all treated with surgery, 67% RT and 27% chemo. 5-year DSS 60%. Negative prognosis: intermediate/high grade, RT- or lymphedema-related
** Advanced disease: 36 patients, 36 palliative surgery, 78% RT, 58% chemo. Median survival 7 months. Cutaneous tumors better prognosis
** Conclusion: Aggressive surgical resection with RT for close margins or worrisome pathology can result in long-term survival. Advanced disease poor prognosis
* UCLA; 1996 (1955-1990) PMID 8635113 -- "Angiosarcoma. A report of 67 patients and a review of the literature." (Mark RJ, Cancer. 1996 Jun 1;77(11):2400-6.)
** Retrospective. 67 patients. Median F/U 2.5 years)
** Outcome: 2-year DFS 44% and 5-year DFS 24%. 81% LR component
** 5-year DFS: surgery + RT 43% vs. surgery +/- CT 17% (SS)
** Conclusion: Surgery + RT offers best chance for long term control; chemo undefined

## Cutaneous Angiosarcoma
### Overview

* Typically presents on scalp or face
* Optimal treatment has not been defined due to rarity, but probably includes primary resection with wide margins, followed by adjuvant RT
* RT recommendations from PMID 17023791
** Consider dose 45-50 Gy subclinical disease, 60-65 Gy for adjuvant treatment, and 70-75 Gy for gross disease
** Risk of LN mets is probably 10-20%, therefore consider elective nodal RT
** Consider total scalp irradiation due to need for very wide margins
* Docetaxel and paclitaxel appear to have some activity in palliative setting

### Presentation

* Patients tend to be older, white, and male
* Lesion that resembles a "spreading bruise", variable color from blue, purple, to red
* May be gravity dependent, and be brought on for example by washing hair in a sink
* Nodular component often develops with time
* Usually asymptomatic, but may develop bleeding or ulceration
* Typically more extensive than suggested by physical findings

### Diagnosis

* "Head-Tilt" maneuver, where patient is asked to place his/her head below the level of the heart for 10 seconds. The involved area becomes markedly violaceous and engorged (PMID 17224545)
* MRI to define extent of primary tumor
* Consider CT to detect regional node mets
* Biopsy necessary to obtain diagnosis, but grading may be difficult (PMID 16359536)
* There is no specific AJCC Staging; please see Staging for soft tissue sarcoma, with understanding that angiosarcoma grade is not prognostic
* Hamamatsu; 2005 (Japan) PMID 16272865 -- "Magnetic resonance imaging findings of angiosarcoma of the scalp." (Isoda H, J Comput Assist Tomogr. 2005 Nov-Dec;29(6):858-62.)
** 8 patients with angiosarcoma of the scalp.
** Outcome: tumors well enhanced on both contrast T1 with fat saturation and T2 with fat saturation. In 4/8 patients tumors were larger than on inspection
** Conclusion: MRI useful for determining extent
* Institut Curie; 2003 (France) PMID 12951681 -- "Cytohistologic correlations in angiosarcoma including classic and epithelioid variants: Institut Curie's experience." (Klinanienko J, Diagn Cytopathol. 2003 Sep;29(3):140-5.)
** Retrospective. FNA and histology review of 29 tumors in 23 patients
** Conclusion: Accurate tumor typing difficult, particularly in low-grade angiosarcoma

### Outcomes

* Japan; 2005 (1988-2002) PMID 15817349 -- "Angiosarcoma of the scalp treated with curative radiotherapy plus recombinant interleukin-2 immunotherapy." (Ohguri T, Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1446-53.)
** Retrospective. 20 patients treated with RT and recombinant IL-2. RT dose median 70 Gy
** Outcome: median OS 3 years, 5-year DSS 40%; 70% developed recurrence, 50% local component
** IL-2 resulted in significantly less DM
** Conclusion: RT + rIL-2 is effective, need additional studies
* Multi-institutional; 2004 PMID 15153886 -- "Cutaneous angiosarcoma: a case series with prognostic correlation." (Morgan MR, J Am Acad Dermatol. 2004 Jun;50(6):867-74.)
** Retrospective. 4 institutions. 47 patients with cutaneous angiosarcoma (breast, prior-RT, or prior lymphedema excluded). Average age 75 years, men 3:1, 96% head and neck. Follow up range 0.5-5 years
** Histology: anastomosing dissecting sinusois lined by atypical cells (64%), diffuse epithelioid/spindle cell proliferation (15%), mixed (21%). Average depth of invasion 2.9 mm (1.8-6 mm), average size 5.3 cm (1-9 cm)
** 5-year outcome: LR 84%, OS 34%; most patients died with widespread pulmonary, cardiac, and/or brain mets.
** Negative predictors: large diameter (>5 cm), depth (>3 mm), high mitotic rate, SM+
** Conclusion: poor prognosis
* Michigan; 2003 (1975-2002) PMID 14534889 -- "Cutaneous angiosarcoma of the scalp: a multidisciplinary approach." (Pawlik TM, Cancer. 2003 Oct 15;98(8):1716-26.)
** Retrospective. 29 patients with scalp lesions only. 75% pT2, 76% high grade. 97% surgery but only 21% SM-. RT given as wide-field in 79% including all patients with SM-. Median F/U 1.5 years
** Outcome: median OS 2.4 years; negative prognosis: older patients and T2 disease. RT prolonged time to local recurrence
** Conclusion: surgery first option, post-op RT should be employed routinely
* MD Anderson; 1995 (1970-1989) PMID 8625109 -- "Cutaneous angiosarcoma of the head and neck. A therapeutic dilemma." (Morrison WH, Cancer. 1995 Jul 15;76(2):319-27.)
** Retrospective. 14 patients with scalp (n=11) and upper face (n=3). Surgery in 7, chemo in 10. Median RT dose 60 Gy (50-66) microscopic and 55-75 Gy macroscopic
** 5-year outcome: LR control microscopic 40% vs. 24% macroscopic; infield control 80% vs. 55%; 5-year OS 50% vs. 13% (overall 29%)
** Conclusion: RT effective for local disease, especially if R0/R1 disease
* St. John's Hospital; 1987 (London, UK) PMID 3104187 -- "Angiosarcoma of the face and scalp, prognosis and treatment." (Holden CA, Cancer. 1987 Mar 1;59(5):1046-57.)
** Retrospective. 72 patients with angiosarcoma of face and scalp.
** 5-year OS: 12%; half died within 15 months of presentation
** Prognostic factors: larger lesions (>10cm); location, age, gender, appearance not significant
** Radical RT (wide-field electrons) resulted in good local control; 2 patients developed pulmonary disease 10 years later

### Chemotherapy

* Kobe; 2007 (2003-2006) PMID 17582627 -- "Docetaxel: A therapeutic option in the treatment of cutaneous angiosarcoma: report of 9 patients." (Nagano T, Cancer. 2007 Aug 1;110(3):648-51.)
** Retrospective. 9 patients given docetaxel 25 mg/m2 QW x8 weeks. 6 had RT, 4 surgery, and IL-2
** Outcome: 2 CR, 4 PR. Severe radiation dermatitis in 3/9
** Conclusion: docetaxel has activity and may suppress lung mets
* MSKCC; 1999 (1992-1998) PMID 10570428 -- "Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face." (Fata F, Cancer. 1999 Nov 15;86(10):2034-7.)
** Prospective. 9 patients with AS of scalp or face. 6 prior RT. 3 metastatic, 6 unresectable or recurrent. paclitaxel 175 mg/m2 (also 90 and 250) Q3W
** Outcome: 4 CR, 4 PR. Median duration of response 5 months
** Toxicity: neutropenia and peripheral neuropathy
** Conclusion: paclitaxel as single agent has substantial activity

### Review

* Univ Florida; 2006 PMID 17023791 -- "Cutaneous angiosarcoma." (Mendenhall WM, Am J Clin Oncol. 2006 Oct;29(5):524-8.)