Breast Sarcoma 

Cancer / By

Breast Sarcoma – Introduction

  • Breast sarcomas are rare, nonepithelial, mesenchymal-derived malignancies reported to comprise < 1% of all breast malignancies and < 5% of all sarcomas(1,2,3)

Types

  • types by history of previous cancer
    • primary breast sarcoma originates de novo from mesenchymal tissue of breast(1,2,3)
    • secondary breast sarcoma (more common than primary breast sarcoma) includes
      • radiation-associated breast sarcoma (most commonly secondary angiosarcoma) caused by previous radiation therapy, most commonly for invasive breast carcinoma, ductal carcinoma in situ, and Hodgkin and non-Hodgkin lymphoma(1,2,3)
      • Stewart-Treves syndrome, a lymphangiosarcoma caused by chronic lymphedema from previous axillary lymphadenectomy(1,2)
  • histologic subtypes include
    • angiosarcoma (most common)(1,3)
    • pleomorphic sarcoma (malignant histiocytoma)(1,3)
    • fibrosarcoma(1,3)
    • leiomyosarcoma(1,3)
    • osteosarcoma(1,3)
    • liposarcoma(1,3)
    • chondrosarcoma(1)
    • Kaposi sarcoma(1)

Epidemiology

Who Is Most Affected

  • overall, breast sarcomas most commonly affect women aged 30-59 years (median age 50 years)(1,2,3)
    • primary angiosarcomas most common in women aged 30-40 years(1)
    • radiation-associated secondary breast sarcomas usually occur at older age compared to primary breast sarcoma(1,2,3)

Incidence/Prevalence

  • reported incidence of any breast sarcoma 4.5-4.6 cases per million women per year(1,2)
  • reported incidence of breast angiosarcoma 0.002%-0.05% per year (reported secondary breast angiosarcoma incidence 0.01%-0.02% per year)(1)
  • incidence of breast sarcoma increased from 1.52 per 1,000,000 persons per year in 1993-1998 to 2.04 per 1,000,000 persons per year in 2009-2013 in Sweden
    •  based on population-based surveillance
    • 344 adults with breast sarcoma (including phyllodes tumors) from Swedish Cancer Register from 1993 to 2013 were compared to general population from Swedish Population Register
    • 46 adults (13%, median age 70.5 years) had angiosarcoma
    • incidence of breast sarcoma
      • 1.52 cases per 1,000,000 persons per year in 1993-1998
      • 2.04 cases per 1,000,000 persons per year in 2009-2013 (relative risk [RR] 1.1, 95% CI 1.05-1.16 vs. 1993-1998)
    • overall incidence of angiosarcoma
      • 0.09 cases per 1,000,000 persons per year in 1993-1998
      • 0.14 cases per 1,000,000 persons per year in 1999-2003 (not significant vs. 1993-1998)
      • 0.34 cases per 1,000,000 persons per year in 2004-2008 (RR 3.59, 95% CI 1.3-9.88 vs. 1993-1998)
      • 0.42 cases per 1,000,000 persons per year in 2009-2013 (RR 4.47, 95% CI 1.68-11.9 vs. 1993-1998)
    • Reference – Breast Cancer Res Treat 2020 Oct;183(3):669full-text
  • 0.1% prevalence of radiation-associated secondary breast angiosarcoma in retrospective population-based cohort study of 184,823 patients from the Netherlands Cancer Registry after radiation therapy for stage I-III primary breast cancer (JAMA Oncol 2019 Feb 1;5(2):267full-text)
  • reported prevalence of secondary breast sarcoma about 0.2% in patients with breast cancer after radiation therapy(2,3)

Risk Factors

  • risk factors of breast sarcoma include
    • hereditary syndromes(2)
      • Li-Fraumeni syndrome, especially if associated with TP53 mutation
      • familial adenomatous polyposis
      • neurofibromatosis type 1
    • previous exposure to arsenic compounds, vinyl chloride, and alkylators(2)
    • HIV or human herpes virus infection, which may be associated with increased risk of Kaposi sarcoma(2)
  • risk factors for secondary breast angiosarcoma include
    • previous radiation therapy (highest risk at 5-10 years after irradiation), with higher risk with(2,3)
      • higher radiation doses(1,2)
      • concurrent chemoradiation(1,2)
      • childhood exposure to radiation therapy(1,2)
    • genetic risk factors
      • ataxia-telangiectasia(2)
      • BRCA1 mutation(1,2)
    • older age and prior breast-conserving therapy each associated with increased risk of radiation-associated secondary angiosarcoma in patients from the Netherlands who were treated for stage I-III primary breast cancer
      •  based on retrospective population-based cohort study
      • 296,577 patients (median age 58 years) with stage I-III primary breast cancer from the Netherlands Cancer Registry between 1989 and 2015 were evaluated
        • median follow-up of 7.7 years
        • 184,823 patients (62%) received radiation therapy for breast cancer
      • secondary angiosarcoma developed in 209 patients (0.1%) who received radiation therapy vs. 0 patients (0%) who did not receive radiation therapy (p value not estimable)
      • median time from radiation therapy to radiation-associated secondary angiosarcoma 8 years (range 3-20 years)
      • increased risk of radiation-associated secondary angiosarcoma associated with
        • older age (hazard ratio 1.05, 95% CI 1.04-1.06)
        • breast-conserving therapy (hazard ratio for mastectomy 0.22, 95% CI 0.1-0.49)
      • Reference – JAMA Oncol 2019 Feb 1;5(2):267full-text
    • use of radiation therapy and chemotherapy for nonmetastatic breast cancer each associated with increased risk of secondary sarcoma (at any location) in women
      •  based on cohort study
      • 17,745 women with nonmetastatic breast cancer treated between 1981 and 2000 in Paris, France, were evaluated
        • 14,512 women (81.8%) received radiation therapy
        • 4,679 women (26.4%) received chemotherapy
      • median follow-up of 13.4 years
      • 2,370 women (13.4%) developed secondary malignancies, including 49 women with sarcomas (0.3%)
      • compared to women who received neither radiation therapy nor chemotherapy, increased risk of secondary sarcoma associated with
        • radiation therapy (risk ratio 5.59, 95% CI 1.35-23.17)
        • chemotherapy (risk ratio 2.87, 95% CI 1.61-5.12)
      • Reference – Cancer Radiother 2017 Feb;21(1):10
    • higher dose of previous radiation therapy associated with increased risk of bone or soft tissue sarcoma at any location in women with breast cancer
      •  based on nested case-control study
      • 6,597 women (mean age 55 years) with breast cancer in France were followed for mean 8 years and evaluated for development of bone and soft tissue sarcomas
        • breast cancer treatment between 1954 and 1983
        • 1,755 women (26.6%) did not receive radiation therapy
      • 15-year cumulative incidence of sarcoma at any location (no p value reported)
        • 0.28% in entire cohort
        • 0.4% in women who received radiation therapy
        • 0% in women who did not receive radiation therapy
      • compared to general population, radiation therapy associated with
        • increased risk of bone and soft tissue sarcoma at any location
          • during entire period of follow-up (standardized incidence ratio 10.5, 95% CI 5.6-17.6)
          • during follow-up of ≥ 5 years (standardized incidence ratio 14.6, 95% CI 7.3-25.7)
        • no significant difference in risk of bone and soft tissue sarcoma at any location during follow-up of < 5 years
      • 14 women (mean age 55 years) who developed bone or soft tissue sarcoma ≥ 1 year after breast cancer diagnosis were matched to 98 controls (mean age 55 years) by age at diagnosis of breast cancer, initial treatment period, and length of follow-up
        • mean dose of radiation to breast 57.9 Gy in women with bone or soft tissue sarcoma and 49.9 Gy in controls (p = 0.03)
        • mean dose of radiation at site of bone or soft tissue sarcoma 38.8 Gy in women with bone or soft tissue sarcoma and 18.9 Gy in controls (no p value reported)
      • Reference – Breast Cancer Res Treat 2005 Feb;89(3):277

Etiology and Pathogenesis

Causes

  • cause of primary breast sarcoma unknown(2)
  • secondary angiosarcoma
    • radiation-associated sarcoma (most common) caused by previous radiation therapy (most commonly for invasive breast carcinoma, ductal carcinoma in situ, and Hodgkin and non-Hodgkin lymphoma)(1,2,3)
    • Stewart-Treves syndrome (lymphangiosarcoma in breast, upper extremities, and axilla) caused by chronic lymphedema from previous axillary lymphadenectomy(1,2)

Pathogenesis

  • primary angiosarcoma
    • originates from breast stroma(1)
    • pathogenesis unclear but may be associated with increased risk of hereditary syndromes and environmental exposures(1,2)
  • pathogenesis of secondary breast sarcoma
    • radiation-associated secondary breast sarcoma
      • radiation therapy damage to double-stranded DNA causes genome instability(1)
      • sarcoma cells usually associated with increased MYC and FLT4 gene amplification(2)
    • Stewart-Treves syndrome(2)
      • previous mastectomy, axillary lymphadenectomy, and radiation therapy can lead to chronic lymphedema
      • lymphatic obstruction results in impaired immune responsiveness that is postulated to lead to lymphangiosarcoma development
  • disease progression of breast sarcoma usually involves hematologic metastases(1,2)
    • common sites of metastases include lungs, bones, and liver
    • lymphatic metastases are rare

History and Physical

History

Chief Concern (CC)

  • painless breast mass(1,2,3)
  • multifocal red, blue, or purple discolored macules for angiosarcoma arising from dermis(1,2)
  • other rare symptoms may include(1)
    • nipple discharge
    • nipple inversion
    • skin retraction or dimpling (excluding angiosarcoma)
  • may be incidentally detected on routine mammography screening(3)

History of Present Illness (HPI)

  • ask about duration of mass and changes over time, as sarcoma grows rapidly over a few months(1,2,3)
  • ask about dates of any prior radiation therapy, as radiation-associated secondary breast sarcoma reported to have highest risk 5-10 years after previous radiation therapy(1,2,3)

Past Medical History (PMH)

  • ask about history of radiation therapy, especially for
    • invasive breast carcinoma(1,2,3)
    • ductal carcinoma in situ(1)
    • Hodgkin lymphoma(1)
    • non-Hodgkin lymphoma(2,3)
  • ask about history of HIV or human herpes virus infection (may be associated with increased risk of Kaposi sarcoma)(2)

Family History (FH)

  • ask about hereditary syndromes, including(2)
    • Li-Fraumeni syndrome, especially if associated with TP53 mutation
    • familial adenomatous polyposis
    • neurofibromatosis type 1
  • ask about known genetic risk factors, including
    • ataxia-telangiectasia(2)
    • BRCA1 mutation(1,2)

Social History (SH)

  • ask about exposure to(2)
    • arsenic compounds
    • vinyl chloride
    • alkylators

Physical

Breast

  • general sarcoma mass characteristics
    • unilateral, large, firm, well-circumscribed, painless, and solitary mass(1,2,3)
    • median size of mass 3-5 cm (range 1-20 cm)(1,2,3)
    • usually no overlying skin changes (except for angiosarcoma)(2)
    • no predisposition for laterality or quadrant of breast more affected(1)
    • thickening of skin possible(2)
  • breast changes characteristic of angiosarcoma
    •  ill-defined mass(1)
    • multifocal red, blue, or purple discolored macules if arising from dermis(1,2)
    • skin thickening(2,3)
  • breast mass characteristics of Stewart-Treves syndrome (lymphangiosarcoma of upper extremities, breast, and axilla) include multifocal purple maculopapular rash, with ulceration if disease progresses in the setting of lymphedema(1,2)

Lymphatics

  • palpable axillary lymphadenopathy is rare (reactive lymphadenopathy reported in 25% of patients)(1,2,3)

Diagnosis

Making the Diagnosis

  • suspect breast sarcoma in women presenting with unilateral, large, firm, well-circumscribed, painless, and solitary mass rapidly growing in size
  • initial evaluation involves imaging with any of the following
    • mammography
    • ultrasound
    • magnetic resonance imaging
  • definitive diagnosis requires histologic confirmation, commonly from core needle biopsy

Differential Diagnosis

Testing Overview

  • diagnosis and preoperative planning should involve multidisciplinary consultation, including surgical oncologists, reconstructive surgeons, medical oncologists, pathologists, radiologists, radiation oncologists, and nuclear medicine and organ-based specialists(2,3,5)
  • initial evaluation generally includes any of the following
    • mammography
    • ultrasound
    • magnetic resonance imaging (MRI)
    • x-ray or computed tomography (CT) of chest
  • definitive diagnosis requires histologic confirmation, commonly from core needle biopsy
  • staging evaluation
    • local staging generally involves
      • contrast-enhanced CT
      • MRI
    • detection of distant metastases
      • CT can detect metastases in lungs, bones, and liver
      • chest x-ray may be alternative option for detection of lung metastases if CT not performed(1,4)
      • MRI or CT (if MRI contraindicated) is necessary to detect central nervous system involvement in patients with angiosarcoma(2,4,5)
    • positron emission tomography may provide information on staging, prognosis, tumor grading, and response to neoadjuvant therapy, but its role in breast sarcoma is unclear(2,3,4)

Recommendations From Professional Organizations

National Comprehensive Cancer Network (NCCN)

  • NCCN recommendations on evaluation of soft tissue sarcomas in extremity, body wall, head, or neck(4)
    • evaluation and management should involve multidisciplinary approach with expertise in sarcoma (NCCN Category 2A)
    • workup includes
      • history and physical (NCCN Category 2A)
      • imaging studies
        • imaging of primary tumor (NCCN Category 2A)
          • primarily with contrast-enhanced or noncontrast magnetic resonance imaging (MRI) with or without contrast-enhanced computed tomography (CT)
          • other imaging studies with angiogram or x-ray may be necessary
        • chest imaging (NCCN Category 2A) with noncontrast CT (preferred) or x-ray
      • core needle (preferred) or incisional biopsy after adequate imaging (NCCN Category 2A), with
        • incorporation of biopsy pathway along future resection axis with minimal dissection and careful monitoring of hemostasis (NCCN Category 2A)
        • determination of histologic grade and subtype (NCCN Category 2A)
        • inclusion of immunohistochemistry, molecular genetics, cytogenetics, and electron microscopy if necessary (NCCN Category 2A)

European Society for Medical Oncology (ESMO)-European Reference Network on Rare Adult Cancers (EURACAN)

  • diagnostic approach should involve multidisciplinary team including pathologists, radiologists, surgeons, radiation therapists, medical oncologists, and nuclear medicine and organ-based specialists, as appropriate(5)
  • for primary soft tissue and visceral sarcomas at any location, initial evaluation includes(5)
    • ultrasound, which may be used initially but requires subsequent imaging with MRI and/or CT
    • MRI as main imaging modality
    • CT for calcified lesions and ruling out myositis ossificans
    • x-ray to rule out bone tumor, to detect bone erosion (if risk of fracture), and to detect calcifications
  • to confirm diagnosis, histologic confirmation with biopsy is necessary(5)
    • choice of biopsy
      • multiple core needle biopsies with ≥ 14- to 16-guage needles are the standard procedure
      • excisional biopsy may be appropriate for < 3-cm superficial lesions
      • open biopsy may be appropriate in select patients
      • fine-needle aspiration generally not recommended
    • technical considerations
      • consider immediate evaluation of tissue viability to ensure adequacy of biopsy
      • do not use frozen-section technique for immediate diagnosis because it does not allow complete diagnosis, especially if neoadjuvant therapy planned
      • plan biopsy such that biopsy pathway and scar can be removed by definitive resection
      • tumor grade may be underestimated by biopsy
      • consider collecting fresh frozen tissue and tumor imprints (touch preparations) for molecular genetics
  • consider combining information from positron emission tomography and pathology to estimate tumor grade if neoadjuvant therapy planned(5)

Imaging Studies

Mammography

  • initial diagnostic imaging for patients with breast mass(1,2,3)
  • most common finding is opaque round, oval, or lobular mass(1,2,3)
  • other possible findings include
    • architectural distortion without discrete mass reported in 30% of patients(1,3)
    • normal appearance (even with palpable mass and skin involvement)(1,2)
    • spiculation and calcification (rare)(2,3)
    • skin thickening(2,3)
  • may mimic fibroadenoma(2)

Ultrasound

  • initial diagnostic imaging for patients with breast mass, but findings are often nonspecific(1,2,3)
  • irregular, hypoechoic mass with indistinct edges or spiculated margins and no shadowing or attenuation(1,2,3)

Magnetic Resonance Imaging (MRI)

  • initial diagnostic imaging option for patients with breast mass depending on age and history(1,2,3)
  • shows lesions with irregular or spiculated margins and heterogeneous internal enhancement(1)
  • contrast enhancement rapid with washout kinetics(2,3)
  • usual findings of angiosarcoma
    • heterogeneously hypointense on T1-weighted images(2,3)
    •  high signal intensity on T2-weighted images(2,3)
  • contrast-enhanced MRI is an imaging option for local staging of sarcoma extent(3)

Computed Tomography (CT)

  • contrast-enhanced CT is an option for local staging (reported to have similar performance as MRI)(2,3)
  • CT also useful for detection of distant metastases to lungs, bones, and liver(1,2,3)

Biopsy and Pathology

  • definitive diagnosis of breast sarcoma and subtype differentiation require histologic confirmation with morphologic analysis from microscopic examination; immunohistochemical analysis, cytogenetics, electron microscopy, and molecular genetic testing may be useful(1,2,3,4)
  • sentinel lymph node biopsy may be appropriate for particular histologies known to involve lymph nodes, particularly if positive lymph nodes would change treatment(4)
  • choice of biopsy procedure
    • core needle biopsy (usually with image guidance) preferred; open incisional biopsy may be considered by experienced surgeon(4,5)
    • if initial core needle biopsy not diagnostic
      • consider repeating image-guided core needle biopsy if initial biopsy not diagnostic due to limited sampling size(4)
      • surgical biopsy can be used(3)
    • fine-needle aspiration usually not useful, as it is inadequate to determine subtype or grade of tumor except in select centers(4,5)
  • pathologic and histologic findings
    • gross inspection of sarcomas typically shows fleshy, firm tumor with some hemorrhage or necrosis(1)
    • immunohistochemistry
      • useful to differentiate sarcomas and carcinomas and histologic subtypes of sarcomas(4,5)
      • sarcomas do not show diffuse or significant reactivity for cytokeratin and myoepithelial markers found in epithelial carcinoma(1,2)
      • angiosarcomas are positive for(2)
        • factor VIII-related antigen
        • Ulex europaeus I lectin
        • CD31
        • CD34
      • osteosarcomas with chondroid components are positive for(2)
        • epithelial membrane antigen
        • S100
    • findings from other analysis, such as electron microscopy, molecular genetics, and cytogenetics, may be helpful for diagnosis of some subtypes of sarcomas
    • histologic subtypes include
      • angiosarcoma (most common)(1,3)
      • pleomorphic sarcoma (malignant histiocytoma)(1,3)
      • fibrosarcoma(1,3)
      • leiomyosarcoma(1,3)
      • osteosarcoma(1,3)
      • liposarcoma(1,3)
      • chondrosarcoma(1)
      • Kaposi sarcoma(1)
  • minimizing risk of tumor dissemination
    • biopsy tract should be planned such that it is incorporated into definitive resection, due to potential risk of tumor seeding(5)
    • surgical biopsy should be planned such that biopsy scar can be removed at subsequent definitive resection(5)
  • principles of pathologic assessment of soft tissue sarcoma at any location from professional organizations
    • National Comprehensive Cancer Network principles suggest including following evaluation in pathology report(4)
      • organ, site, and operative procedures
      • primary diagnosis using standardized nomenclature
      • depth of tumor (deep vs. superficial [no involvement of superficial fascia])
      • size of tumor
      • histologic grade using standardized system such as the French Federation of Cancer Sarcoma Group (FNCLCC) grading system
      • necrosis
        • presence vs. absence
        • microscopic vs. macroscopic
        • approximate extent in percentage
      • status of margins of excision (if involved, state which margins; if close, measure distance and state which margins)
      • quality of margins (fascia vs. soft tissue)
      • status of lymph nodes, including location, number examined, and number positive
      • results of immunohistochemistry, electron microscopy, and molecular genetic studies
      • other tumor features of potential clinical value
        • mitotic rate per 10 high-power fields
        • vascular invasion status
        • tumor margin characteristics (well-circumscribed vs. infiltrative)
        • type and extent of inflammatory infiltrate
      • TNM staging
    • European Society for Medical Oncology (ESMO)-European Reference Network on Rare Adult Cancers (EURACAN)(5)
      • diagnosis should use 2013 World Health Organization classification
      • pathologic assessment should include the following evaluation in pathology report
        • tumor site
        • tumor size
        • tumor depth (relationship with superficial fascia)
        •  histologic grade (if feasible) using standardized system such as the FNCLCC grading system
      • pathologic assessment of specimens from definitive resection should include the following evaluation in pathology report
        • tumor intactness
        • tumor margin status, including distance from closest inked margins
        • pathologic response to preoperative therapy, if given

Staging

  • American Joint Committee on Cancer staging for soft tissue sarcoma of trunk and extremitiesView full sizeTable 1: Clinical StagingStageTNMGradeIAT1N0M0G1, GXIBT2, T3, T4N0M0G1, GXIIT1N0M0G2, G3IIIAT2N0M0G2, G3IIIBT3, T4N0M0G2, G3IVAny TN1M0Any GAny NM1
  • definitions of staging abbreviations
    • primary tumor (T)
      • TX – primary tumor cannot be assessed
      • T0 – no evidence of primary tumor
      • T1 – tumor ≤ 5 cm in greatest dimension
      • T2 – tumor > 5 cm and ≤ 10 cm in greatest dimension
      • T3 – tumor > 10 cm and ≤ 15 cm in greatest dimension
      • T4 – tumor > 15 cm in greatest dimension
    • regional lymph nodes (N)
      • N0 – no regional lymph node metastasis or unknown lymph node status
      • N1 – regional lymph node metastasis
    • distant metastasis (M)
      • M0 – no distant metastasis
      • M1 – distant metastasis
    • grade (G)
      • GX – grade cannot be assessed
      • G1 – total differentiation, mitotic count, and necrosis score of 2 or 3
      • G2 – total differentiation, mitotic count, and necrosis score of 4 or 5
      • G3 – total differentiation, mitotic count, and necrosis score of 6, 7, or 8
  • French Federation of Cancer Sarcoma Group grading system
    • histologic grade (G) (sum of differentiation score plus mitotic count score plus tumor necrosis score, with score range 2-8)
      •  grade 1 (G1) – total score 2-3
      •  grade 2 (G2) – total score 4-5
      •  grade 3 (G3) – total score 6-8
    • tumor differentiation
      •  score 1 – sarcomas closely resembling normal adult mesenchymal tissue and potentially difficult to distinguish from the counterpart benign tumour (for example, well-differentiated liposarcoma and well-differentiated leiomyosarcoma)
      •  score 2 – sarcomas for which histologic typing is certain (for example, myxoid liposarcoma, conventional leiomyosarcoma, and conventional malignant peripheral nerve sheath tumor)
      •  score 3 – embryonal and undifferentiated sarcomas, synovial sarcomas, or sarcomas of uncertain type, including high-grade myxoid liposarcoma, pleomorphic liposarcoma, poorly differentiated/pleomorphic leiomyosarcoma, poorly differentiated malignant nerve sheath tumor, and undifferentiated pleomorphic sarcoma
    • mitotic count per high-power field (HPF) (1 HPF = 0.1734 mm2)
      •  score 1 – 0-9 mitoses/10 HPF
      •  score 2 – 10-19 mitoses/10 HPF
      •  score 3 – > 19 mitoses/10 HPF
    • tumor necrosis
      •  score 0 – no necrosis
      •  score 1 – < 50% tumor necrosis
      •  score 2 – ≥ 50% tumor necrosis
    •  Reference – Pathology 2014 Feb;46(2):113

Management

Management Overview

  • management should involve multidisciplinary consultation (NCCN Category 2A), including surgical, medical, and radiation oncologists; reconstructive surgeons; pathologists; radiologists; and nuclear medicine and organ-based specialists(4,5)
  • for patients with localized, initially resectable disease (stage I-III disease and select stage IV [N1, M0] disease), offer wide surgical resection with negative margins as primary definitive management modality (NCCN Category 2A; ESMO/EURACAN Grade A, Level II for stage I disease; ESMO/EURACAN Grade A, Level IV for stage II-IV disease)(4,5)
    • if incomplete resection, re-resection appropriate if complete (R0) resection achievable
    • consider neoadjuvant radiation therapy and/or systemic chemotherapy before surgical resection for patients with
      • stage IA/IB disease if wide margins are difficult or if possible high surgical morbidity
      • stage II-IV disease (especially if deep tumor, tumor > 5 cm, or select high-risk tumor site after multidisciplinary risk assessment)
    • consider adjuvant radiation therapy and/or systemic chemotherapy for patients with
      • unacceptable surgical margins
      • stage II-IV disease (especially if deep tumor or tumor > 5 cm)
  • for patients with localized, initially unresectable disease or resectable disease with adverse functional outcomes (stage I-III disease and select stage IV [N1, M0] disease)
    • offer initial radiation therapy and/or systemic chemotherapy to facilitate surgical resection (NCCN Category 2A; ESMO/EURACAN Grade A, Level III)(4,5)
    • if disease becomes resectable, offer surgical resection with negative margins as primary definitive management modality (NCCN Category 2A; ESMO/EURACAN Grade A, Level V) with or without neoadjuvant and/or adjuvant therapy similar to management in localized, initially resectable disease(4,5)
    • if disease remains resectable with adverse functional outcomes, management options include(4)
      • radical resection (NCCN Category 2A)
      • definitive radiation therapy (initial dose typically 50 Gy with boost to ≥ 63 Gy, but higher doses [70-80 Gy] may be considered) (NCCN Category 2A)
    • if disease remains unresectable, management options include(4)
      • definitive radiation therapy if not previously irradiated (NCCN Category 2A)
      • systemic chemotherapy (NCCN Category 2A)
      • palliative surgery (NCCN Category 2A)
      • if asymptomatic disease, observation (NCCN Category 2A)
      • best supportive care (NCCN Category 2A)
  • for distant metastatic disease (stage IV [M1] disease)
    • for isolated metastases
      • management of primary tumor follows that of localized, initially resectable disease(4)
      • regardless of location of metastases, systemic chemotherapy (generally anthracycline-based) is management option (NCCN Category 2A; ESMO/EURACAN Grade A, Level I)(4,5)
      • for management of pulmonary metastases
        • metastasectomy is preferred management if complete resection (R0) of all lesions is possible (NCCN Category 2A; ESMO/EURACAN Grade B, Level IV) with optional neoadjuvant chemotherapy for synchronous and/or multiple and/or bilateral pulmonary metastases (ESMO/EURACAN Grade B, Level III)(4,5)
        • other management option is stereotactic body radiation therapy (SBRT) (NCCN Category 2A)(4)
      • for management of extrapulmonary metastases, management options other than systemic chemotherapy include(4)
        • metastasectomy (with lymphadenectomy if lymph node involved) with or without radiation therapy (NCCN Category 2A)
        • SBRT (NCCN Category 2A)
        • ablative procedures (NCCN Category 2A)
        • embolization (NCCN Category 2A)
        • observation (NCCN Category 2A)
    • for disseminated metastases, management is palliative and options include
      • systemic chemotherapy (generally anthracycline-based) (NCCN Category 2A; ESMO/EURACAN Grade A, Level I)(4,5)
      • radiation therapy or SBRT (NCCN Category 2A)(4)
      • surgery (NCCN Category 2A)(4)
      • if asymptomatic, observation (NCCN Category 2A)(4)
      • best supportive care (NCCN Category 2A)(4)
      • ablative procedures (NCCN Category 2A)(4)
      • for nonpulmonary metastases, embolization (NCCN Category 2A)(4)

Recommendations From Professional Organizations

National Comprehensive Cancer Network (NCCN) Recommendations on Management of Soft Tissue Sarcoma in Extremity, Body Wall, Head, or Neck

  • for stage IA/IB (low grade) disease, perform wide surgical resection (NCCN Category 2A)(4)
    • consider neoadjuvant radiation therapy if wide margins are difficult or if possible high surgical morbidity
    • after resection
      • if appropriate margins, proceed to surveillance (NCCN Category 2A)
      • if margins not acceptable
        • for presence of gross residual disease (R2 resection), repeat imaging before additional management (NCCN Category 2A)
        • additional management options include
          • re-resection (NCCN Category 2A) (for R2 margin, consider radiation therapy before re-resection)
          •  for stage IA disease, observation (NCCN Category 2A)
          • adjuvant radiation therapy (NCCN Category 2B for stage IA disease; NCCN Category 1 for stage IB disease)
        • after treatment, proceed to surveillance
  • for stage II-III and select stage IV (N1, M0) resectable disease with acceptable functional outcomes(4)
    • for stage II disease, management options include
      • surgical resection with appropriate margins followed by (NCCN Category 2A)
        • adjuvant radiation therapy (NCCN Category 1)
        • observation if negative margins and risk of radiation therapy are unacceptable (NCCN Category 2A)
      • neoadjuvant radiation therapy (NCCN Category 1) followed by surgical resection with appropriate margins (NCCN Category 2A)
    • for stage III or select stage IV (N1, M0), management options include
      • surgical resection with appropriate margins (NCCN Category 2A) followed by either
        • adjuvant radiation therapy (NCCN Category 1)
        • adjuvant radiation therapy plus adjuvant systemic therapy (NCCN Category 2A)
      • neoadjuvant radiation therapy (NCCN Category 1) followed by surgical resection with appropriate margins (NCCN Category 2A), and then consider adjuvant systemic therapy (NCCN Category 2A)
      • neoadjuvant radiation therapy plus systemic therapy, followed by surgical resection with appropriate margins, and then consider adjuvant systemic therapy (NCCN Category 2A)
      • neoadjuvant systemic therapy, followed by surgical resection with appropriate margins (NCCN Category 2A), and then adjuvant therapy with either
        • radiation therapy (NCCN Category 2A)
        • radiation therapy plus systemic therapy (NCCN Category 2A)
      • for tumor < 5 cm (and sufficient surrounding tissue for future re-resection if recurrence), may consider omitting radiation therapy
    • after treatment, proceed to surveillance
  • for stage II-III or select stage IV (any T, N1, M0) resectable disease with adverse functional outcomes or unresectable primary disease, management options include(4)
    • initial therapy to facilitate surgical resection
      • options of initial therapy include (NCCN Category 2A)
        • radiation therapy
        • chemoradiation
        • systemic therapy
      • if disease becomes resectable with acceptable functional outcomes, follow management options as resectable disease with acceptable functional outcomes
      • if disease remains resectable with adverse functional outcomes, management options include either
        • radical resection (NCCN Category 2A)
        • definitive radiation therapy (NCCN Category 2A)
      • if disease remains unresectable, management options include
        • definitive radiation therapy if not previously irradiated (NCCN Category 2A)
        • systemic therapy (NCCN Category 2A)
        • palliative surgery (NCCN Category 2A)
        • if asymptomatic disease, observation (NCCN Category 2A)
        • best supportive care (NCCN Category 2A)
    • radical resection with consideration of adjuvant systemic therapy (NCCN Category 2A)
    • after treatment, proceed to follow-up
  • for synchronous stage IV (M1) disease with(4)
    • metastases in single organ with limited tumor bulk amenable to local therapy
      • management of primary tumor follows management options as resectable disease with acceptable functional outcomes
      • management options for metastases include
        • regardless of location of metastases, systemic therapy (NCCN Category 2A)
        • for lung metastases, either
          • resection (preferred) (NCCN Category 2A)
          • stereotactic body radiation therapy (SBRT) (NCCN Category 2A)
        • for metastases at other locations
          • metastasectomy (with lymphadenectomy if lymph node involved) with or without radiation therapy (NCCN Category 2A)
          • SBRT (NCCN Category 2A)
          • ablative procedures (NCCN Category 2A)
          • embolization (NCCN Category 2A)
          • observation (NCCN Category 2A)
    • disseminated metastases, palliative management options include
    • after treatment, proceed to follow-up
  • for locally recurrent disease, follow management option similar to de novo disease based on disease stage as above (NCCN Category 2A)(4)
  • for metastatic recurrence(4)

European Society of Medical Oncology (ESMO)-European Reference Network on Rare Adult Cancers (EURACAN) Recommendations on Management of Soft Tissue and Visceral Sarcoma at Any Location

Surgery and Procedures

Definitive Resection

  • surgical management requires multidisciplinary approach involving expertise in surgical oncology and plastic and vascular surgery(2,4)
  • surgical management of primary tumor
    • complete resection of primary tumor with wide and negative margins is primary definitive management for breast sarcoma(1,2,3,4)
    • choice of breast conservation vs. mastectomy
      • breast-conserving surgery for primary breast sarcoma is an option based on tumor size, breast size, adequate margins, and feasibility of radiation(5)
        • CLINICIANS’ PRACTICE POINT: It is the topic editor’s opinion that breast-conserving surgery is not commonly utilized.
      • total mastectomy may be necessary for
        • large tumors extending close to chest wall, with possible resection of pectoralis muscles and ribs if involved(2,3)
        • primary angiosarcoma (even if small size)
          • reported to have poor cosmetic outcomes from breast-conserving excision (due to need of wide margins)(2)
          •  reported to have 30% local recurrence rate with breast-conserving excision(1)
          • mastectomy with removal of muscle fascia recommended for most cases, even when radiation therapy planned(5)
        • radiation-associated secondary angiosarcoma, with removal of all previously radiated skin (including skin outside breast borders)(1)
    • procedural considerations for resection of primary tumor
      • resection should include previous biopsy tract due to risk of tumor seeding(4,5)
      • resection may require reconstruction(2,3)
      • skin incisions typically performed along longest axis of tumor(3)
      • considerations for planning adjuvant radiation therapy
        • surgical clips should be placed marking boundary of resection bed and any margins of concern to help plan radiation portals(4)
        • if closed suction drainage used, drains should exit skin close to edge of surgical margin, as drain tract should be included in radiation portal or further reexcision(4)
      • considerations for margins(4)
        • surgeon should mark margins
        • if positive margins on final pathology, reexcision should be strongly considered unless it would strongly impact function
        • if close margin (or positive margin where reexcision not advisable), radiation therapy should be considered unless histology is atypical lipomatous tumor or well-differentiated liposarcoma
  • axillary lymphadenectomy and sentinel lymph node sampling
    • not performed in absence of clinically evident lymph node involvement(5)
    • reported to be associated with risk of surgery-related morbidity, such as lymphedema(3)
    • lymphadenectomy may be necessary only if clinically evident lymph node involvement(4,5)
  • re-resection (with or without adjuvant therapy) is management option for local recurrence(4,5)
  • metastasectomy is possible management option for distant metastases (mostly pulmonary metastases)(4,5)

Reconstruction

  • CLINICIANS’ PRACTICE POINT: Breast-conserving surgery with oncoplastic surgery is not usually considered in breast sarcoma.
  • early consultation with reconstructive surgeons necessary for management of breast sarcoma(3)
  • goal of reconstruction is primarily wound closure(3)
  • for wound closure without breast reconstruction following large resections, reconstructions involve(1,2)
    • partial thickness skin graft
    • tissue flap

Efficacy of Definitive Resection

  • surgery may improve event-free survival in women with localized radiation-associated secondary breast sarcoma (level 2 [mid-level] evidence)
    •  based on retrospective cohort study
    • 176 patients (median age 51 years, 79% female) with localized radiation-associated sarcoma at any location were evaluated
    • median follow-up of 3.2 years
    • histologic subtypes of radiation-associated sarcomas included
      • angiosarcoma (41%)
      • undifferentiated pleomorphic/spindle cell sarcoma (40%)
      • leiomyosarcoma (8%)
      • malignant peripheral nerve sheath tumor (6%)
      • osteosarcoma (2%)
    • 67 adult women (38.1%) had radiation-associated secondary breast angiosarcoma after primary breast cancer (invasive and ductal carcinoma in situ)
      • 5-year overall survival 75%
      • 3-year event-free survival 43%
      • 63 women (94%) treated with surgery, and 3 women (4%) treated with radiation
      • in multivariate analysis, compared to surgery with negative margins, no surgery associated with worse event-free survival (hazard ratio for local recurrence, distant metastasis, or death 6.8, 95% CI 1.4-33.7)
    • Reference – Int J Radiat Oncol Biol Phys 2019 Jun 1;104(2):425
  • lumpectomy and mastectomy may be associated with similar overall survival in women with nonmetastatic breast angiosarcoma (level 2 [mid-level] evidence)
    •  based on cohort study
    • 808 women (median age 69 years) with nonmetastatic breast angiosarcoma who received lumpectomy (13%) or mastectomy (87%) between 2004 and 2015 identified from the National Cancer Database
    • 606 women (75%) had secondary angiosarcoma, and 202 women (25%) had de novo angiosarcoma
    • propensity score for likelihood of receiving lumpectomy or mastectomy calculated for each patient based on clinical, demographic, treatment-specific, and disease-specific factors
    • in propensity-matched analysis, 5-year overall survival 46.1% with lumpectomy vs. 39.4% with mastectomy (not significant); results consistent in multivariate analysis
    • in multivariate analysis, positive surgical margin was the only treatment-related factor associated with decreased overall survival (adjusted hazard ratio for death 2.33, 95% CI 1.61-3.36); type of surgery not associated with survival
    • Reference – Breast J 2019 Nov;25(6):1230
  • radical resection with complete removal of all previously irradiated skin may improve overall and disease-specific survival compared to partial resection in women with cutaneous radiation therapy-associated secondary breast angiosarcoma (level 2 [mid-level] evidence)
    •  based on retrospective cohort study
    • 76 women (median age 62 years) with cutaneous radiation-associated breast angiosarcoma after radiation therapy for primary invasive breast carcinoma or ductal carcinoma in situ received radical (50%) or partial/conservative (50%) resection from 1993 to 2015
      • radical resection defined as mastectomy with removal of all or nearly all previously irradiated skin
      • partial resection defined as mastectomy without removal of all previously irradiated skin
    • median follow-up of 27 months
    • comparing radical vs. partial/conservative resection
      • median overall survival 110 vs. 35 months (p < 0.01)
      • 5-year disease-specific survival 86% vs. 46% (p < 0.01), results remained significant in multivariate analysis
      • 5-year cumulative incidence of local recurrence 23% vs. 76% (p < 0.01)
      • 5-year cumulative incidence of distant metastases 18% vs. 47% (p = 0.02)
      • margin-negative resection 100% vs. 73% (p < 0.01)
    • in multivariate analysis, positive margin associated with decreased disease-specific survival (hazard ratio for death 4.09, 95% CI 1.43-11.75) and radical resection associated with improved disease-specific survival (hazard ratio for death 0.16, 95% CI 0.03-0.75)
    • Reference – Ann Surg 2017 Apr;265(4):814
  • definitive resection reported to have 5-year overall survival of 74% in women with radiation-associated breast angiosarcoma (level 3 [lacking direct] evidence)
    •  based on case series
    • 50 women (mean age 70 years) with nonmetastatic radiation-associated breast angiosarcoma between 1989 and 2014 were identified from the Finnish Cancer Registry
    • 47 women received definitive surgery
      • median follow-up of 5.4 years
      • 10 patients (21%) had re-resection for insufficient surgical margins
      • 24 patients (51%) had reconstruction
      • adjuvant therapy
        • 5 patients (11%) had adjuvant chemotherapy
        • 1 patient (2%) had adjuvant radiation therapy
      • 5-year overall survival 74%
      • 5-year local recurrence-free survival 62%
      • 5-year distant recurrence-free survival 75%
      • in multivariate analysis, larger planned surgical margin associated with increased overall survival (adjusted hazard ratio for death 0.42, 95% CI 0.24-0.74)
    • Reference – Ann Surg Oncol 2020 Apr;27(4):1002full-text

Radiation Therapy

Principles of Radiation Therapy

  • radiation therapy (neoadjuvant or adjuvant)
    • recommended for stage II and III breast sarcomas(4,5)
    • considered for stage I breast sarcoma with positive margins following resection when re-resection to negative margins not possible(4,5)
    • considered for stage IV breast sarcoma following metastasectomy(4)
    • considered for definitive treatment of limited single-organ metastases using stereotactic body radiation therapy (SBRT)(4)
    • considered for palliation of disseminated metastases using external beam radiation therapy (EBRT) or SBRT(4)
  • decision on timing of radiation, before or after surgery, should be made in multidisciplinary setting with considerations to balance neoadjuvant benefits of reduced long-term complications (fibrosis, edema, and joint stiffness) with risk of increased short-term wound complications(3)
    • benefits of radiation before surgery include
      • lower total radiation dose(4)
      • shorter course of treatment(4)
      • smaller radiation field, which is reported to be associated with lower rate of late complications(4)
      • ability to optimize target localization for radiation planning(3,4)
      • radiation delivery not affected by postoperative wound healing(4)
      • ability to restage patients before resection, as distant metastases may preclude definitive resection(4)
    • benefits of radiation after surgery include(4)
      • more definitive pathology assessment when decision for preoperative radiation not definitive
      • lower risk of wound healing complications
  • radiation therapy for primary breast sarcoma
    • neoadjuvant radiation therapy
      • may be used for large or inoperable tumor to improve resectability(3)
      • may be preferred over adjuvant radiation therapy(4)
    • radiation dosing
      • generally 50 Gy of EBRT(3,4)
      • for positive margins following neoadjuvant radiation therapy and surgical resection, consider radiation boost of 14-20 Gy with fractionated EBRT or brachytherapy(4)
  • for radiation-associated angiosarcoma, role of radiation therapy is evolving
    • reirradiation should be considered(5)
    • use requires consideration in multidisciplinary setting(1)
    • balance risk of complications associated with high cumulative radiation dose, including(2)
      • rib fractures
      • lung fibrosis
      • cardiomyopathy
    • adjuvant radiation therapy considerations
      • radiation dose
        • EBRT 50 Gy to wider field, with tumor bed boost of 10-20 Gy depending on margins(4)
        • brachytherapy with or without EBRT(4)
          • for positive margins, brachytherapy low dose rate of 16-20 Gy or high dose rate equivalent of 14-16 Gy plus EBRT 50 Gy
          • for negative margins, brachytherapy low dose rate of 45 Gy or high dose rate equivalent such as 36 Gy in 3.6-Gy fractions twice daily for 10 fractions
      • radiation field should include(3)
        • anatomic breast, including surgical bed, with similar principles for radiation therapy in epithelial breast cancer
        • axillary surgical bed if axillary lymphadenectomy performed and involved
  • definitive radiation therapy may be an option for resectable disease with adverse functional outcomes or unresectable disease(4)
    • initial radiation dose typically 50 Gy (with boost to ≥ 63 Gy)
    • higher radiation doses (70-80 Gy) may be considered depending on tolerance of normal tissues
  • hyperthermia may be added to radiation therapy in high-risk disease(2)

Addition of Hyperthermia to Radiation Therapy

  • hyperthermia may be added to radiation therapy in high-risk disease(2)
    • noninvasive selective heating of tumor area to 40-43 degrees C (104-109.4 degrees F) by electromagnetic heating device
    • mechanism of action includes
      • direct cytotoxicity
      • improving chemotherapy effect by increasing chemical reaction and intratumoral drug absorption
    • hyperthermia plus reirradiation with or without surgery reported to have 1-year overall survival of 45% and complete response rate of 56% in case series of 24 adults with radiation-associated angiosarcoma of chest wall (Strahlenther Onkol 2013 May;189(5):387)

Efficacy of Radiation Therapy

  • addition of radiation therapy to surgery may decrease local recurrence but may not improve overall survival in patients with radiation-associated breast angiosarcoma (level 2 [mid-level] evidence)
    •  based on individual patient data meta-analysis of observational studies
    • systematic review and individual patient data meta-analysis of 12 retrospective cohort studies and 62 case series or case reports evaluating efficacy of management modalities in 222 patients (median age 69 years in 208 patients) with radiation-associated breast angiosarcoma after primary breast cancer
    • management modalities
      • surgery alone in 68%
      • surgery plus radiation therapy (with or without hyperthermia) in 17%
      • surgery plus chemotherapy in 6%
      • radiation therapy plus hyperthermia alone in 6%
      • chemotherapy alone in 3%
      • surgery plus chemotherapy plus radiation therapy in 0.5%
    • median follow-up for surviving patients
      • 24 months for surgery alone group
      • 52 months for surgery plus radiation therapy group
      • 16 months for surgery plus chemotherapy group
    • 5-year overall survival 43%
    • 5-year local recurrence-free interval 32%
    • comparing surgery plus radiation therapy to surgery alone
      • no significant difference in overall survival
      • 5-year local recurrence-free interval 57% with surgery plus radiation therapy vs. 34% with surgery alone (hazard ratio for local recurrence or death 0.46, 95% CI 0.26-0.84)
    • Reference – Eur J Cancer 2014 Jul;50(10):1779
  • adjuvant radiation therapy after surgical resection may not improve survival in women with nonmetastatic breast angiosarcoma (level 2 [mid-level] evidence)
    •  based on cohort study
    • 826 women (mean age 66 years) with nonmetastatic breast angiosarcoma from 2004 to 2014 who underwent surgical resection were identified from the National Cancer Database
      • 220 women (27%) had primary angiosarcoma, and 606 women (73%) had secondary angiosarcoma
      • 93 women (11.3%) received adjuvant radiation therapy alone, and 46 women (5.6%) received adjuvant radiation therapy plus chemotherapy
    • 600 women had ≥ 3 years of follow-up and were included in analysis
    • nonsignificantly higher (p = 0.086) use of radiation therapy in women with positive margins (25.4%) than in women with negative margins (16.3%)
    • in multivariate analysis, no significant differences in overall survival
      • comparing adjuvant radiation therapy alone to no adjuvant therapy in overall analysis or in subgroup analysis stratified by surgical margins
      • comparing adjuvant radiation therapy plus chemotherapy to no adjuvant therapy in overall analysis
    • Reference – Breast Cancer Res Treat 2019 Jun;175(2):409

Chemotherapy

Principles of Chemotherapy

  • roles of neoadjuvant and adjuvant chemotherapy are unclear(1,2,3)
  • neoadjuvant chemotherapy
    • may be useful for
      •  high-grade tumors ≥ 5 cm in size(3)
      • angiosarcoma(3)
    • possible benefit includes decreasing tumor size to facilitate definitive resection with negative margins(1)
    • possible risk includes delaying time to surgery, which can result in disease progression to unresectable disease, as chemotherapy response is highly variable(1,2,3)
  • adjuvant chemotherapy
    •  may be useful for high-grade tumors > 5 cm in size(2)
    • factors to consider for decision regarding adjuvant chemotherapy include(3)
      • age
      • comorbidities
  • for recommendations on when systemic therapy should be offered or considered, see Recommendations from Professional Organizations

Systemic Therapy Regimens

Efficacy of Chemotherapy in Localized Disease

  •  evidence for benefit of adjuvant chemotherapy in soft tissue sarcoma at any location is conflicting
  • addition of chemotherapy to surgery may not improve overall survival or reduce local recurrence in patients with radiation-associated breast angiosarcoma (level 2 [mid-level] evidence)
    •  based on individual patient data meta-analysis of observational studies
    • systematic review and individual patient data meta-analysis of 12 retrospective cohort studies and 62 case series or case reports evaluating efficacy of management modalities in 222 patients (median age 69 years in 208 patients) with radiation-associated breast angiosarcoma after primary breast cancer
    • management modalities
      • surgery alone in 68%
      • surgery plus radiation therapy (with or without hyperthermia) in 17%
      • surgery plus chemotherapy in 6%
      • radiation therapy plus hyperthermia alone in 6%
      • chemotherapy alone in 3%
      • surgery plus chemotherapy plus radiation therapy in 0.5%
    • median follow-up for surviving patients
      • 24 months for surgery alone group
      • 52 months for surgery plus radiation therapy group
      • 16 months for surgery plus chemotherapy group
    • 5-year overall survival 43%
    • 5-year local recurrence-free interval 32%
    • comparing surgery plus chemotherapy to surgery alone, no significant differences in
      • overall survival
      • local recurrence-free interval
    • Reference – Eur J Cancer 2014 Jul;50(10):1779
  • neoadjuvant or adjuvant chemotherapy might improve overall survival in adults with nonmetastatic radiation-associated breast angiosarcoma but not nonmetastatic primary angiosarcoma (level 2 [mid-level] evidence)
    •  based on retrospective cohort study
    • 58 adults (median age 58 years) with nonmetastatic breast angiosarcoma were evaluated
      • 24 adults (41%) had primary angiosarcoma, and 34 adults (59%) had radiation-associated angiosarcoma
      • 53 adults (91%) had definitive resection, 1 adult (2%) had palliative resection, and surgical status unknown in 4 adults (7%)
      • 28 adults (48%) received chemotherapy (20 adults had adjuvant chemotherapy, and 8 adults had neoadjuvant chemotherapy); regimens included
        • gemcitabine with or without taxane
        •  ifosfamide plus anthracycline
        • doxorubicin plus taxane
        • paclitaxel alone
        • doxorubicin plus cyclophosphamide
        • liposomal doxorubicin alone
    • median follow-up of 43.4 months
    • in adults with radiation-associated angiosarcoma, 50-month overall survival 100% with neoadjuvant or adjuvant chemotherapy vs. 50% with no chemotherapy (p = 0.043, survival rate estimated from graph)
    • comparing neoadjuvant or adjuvant chemotherapy vs. no chemotherapy, no significant differences in
      • overall survival in adults with primary angiosarcoma
      • recurrence-free survival in adults with primary or secondary angiosarcoma
    • Reference – Am J Clin Oncol 2020 Nov;43(11):820
  • adjuvant chemotherapy might improve overall survival in women with nonmetastatic breast angiosarcoma that is > 5 cm in size (level 2 [mid-level] evidence)
    •  based on cohort study
    • 826 women (mean age 66 years) with nonmetastatic breast angiosarcoma from 2004 to 2014 who underwent surgical resection were identified from the National Cancer Database
      • 220 women (27%) had primary angiosarcoma, and 606 women (73%) had secondary angiosarcoma
      • 116 women (14%) underwent lumpectomy, and 710 women (86%) underwent mastectomy
      • 147 women (17.8%) received adjuvant chemotherapy alone, and 46 women (5.6%) received adjuvant chemotherapy plus radiation therapy
    • 600 women had ≥ 3 years of follow-up and were included in analysis
    • in multivariate analysis
      • compared to no adjuvant chemotherapy, adjuvant chemotherapy alone associated with
        • nonsignificant increase in overall survival in overall analysis (adjusted hazard ratio for death 0.74, 95% CI 0.53-1.03)
        • increased overall survival in subgroup analysis of women with tumor > 5 cm (adjusted p = 0.016)
      • comparing adjuvant chemotherapy plus radiation therapy to no adjuvant therapy, no significant difference in overall survival
    • Reference – Breast Cancer Res Treat 2019 Jun;175(2):409

Efficacy of Chemotherapy in Advanced or Metastatic Disease

  • addition of bevacizumab to paclitaxel might not improve overall or progression-free survival in adults with advanced or metastatic unresectable angiosarcoma at any location (level 2 [mid-level] evidence)
    •  based on small randomized trial without blinding
    • 50 adults (median age 56 years) with advanced or metastatic unresectable angiosarcoma with ≤ 2 lines of prior systemic chemotherapy were randomized to paclitaxel 90 mg/m2 IV on days 1, 8, and 15 plus bevacizumab 10 mg/kg IV once every 2 weeks vs. paclitaxel alone for 6 cycles (28-day cycles)
    • upon completion of 6 cycles, adults in paclitaxel plus bevacizumab group were given maintenance bevacizumab 15 mg/kg once every 3 weeks until unacceptable toxicity or progression
    • 49 adults (median age 66 years, 78% female) eligible for trial after randomization
      • breast was most common primary site of angiosarcoma in 24 adults (49%)
      • median follow-up of 21 months
      • comparing paclitaxel plus bevacizumab vs. paclitaxel alone (no p value reported for any analyses)
        • median overall survival 15.9 vs. 19.5 months
        • median progression-free survival 6.6 months vs. 6.6 months
        • overall response rate 28% vs. 45.8%
        • grade 3-4 adverse events in 44% vs. 21.7%
      • most common grade ≥ 3 adverse events in 48 adults with ≥ 1 dose of treatments
        • for paclitaxel plus bevacizumab include neutropenia (12%), neuropathy (8%), diarrhea (8%), dyspnea (8%), and arterial hypertension (8%)
        • for paclitaxel alone include neutropenia (8.7%) and anemia (4.8%)
    • Reference – J Clin Oncol 2015 Sep 1;33(25):2797, commentary can be found in J Clin Oncol 2016 Mar 1;34(7):764

Other Management

Surveillance

  • National Comprehensive Cancer Network (NCCN) recommendations on follow-up of soft tissue sarcoma in extremity, body wall, head, or neck(4)
    • for stage IA/IB (low grade)
      • history and physical every 3-6 months for first 2-3 years and then annually thereafter (NCCN Category 2A)
      • imaging follow-up includes
        • following neoadjuvant therapy and surgery, baseline uncontrasted and contrast-enhanced magnetic resonance imaging (MRI) and/or contrast-enhanced computed tomography (CT) (NCCN Category 2A)
        • imaging of primary location of sarcoma (with uncontrasted and contrast-enhanced MRI and/or contrast-enhanced CT) based on estimated risk of locoregional recurrence every 3-6 months for first 2-3 years, then every 6 months for next 2 years, and then annually thereafter if no evidence of radiologic disease (NCCN Category 2A)
        • chest CT (contrast-enhanced if combined with abdominal/pelvic imaging) or x-ray (NCCN Category 2A); obtain every 6-12 months if low risk for metastatic recurrence (NCCN Category 2A); obtain every 3-6 months for 2-3 years, then every 6 months for 2 years, and then annually if intermediate or high risk for metastatic recurrence (NCCN Category 2A)
    • for stage II/III disease or stage IV (N1, M0) disease
      • history and physical every 3-6 months for first 2-3 years, then every 6 months for next 2 years, and then annually thereafter (NCCN Category 2A)
      • imaging follow-up includes
        • postoperative baseline and periodic imaging of primary location of sarcoma (with uncontrasted and contrast-enhanced MRI and/or contrast-enhanced CT) based on estimated risk of locoregional recurrence every 3-6 months for first 2-3 years, then every 6 months for next 2 years, and then annually thereafter if no evidence of radiologic disease (NCCN Category 2A)
        • chest x-ray or CT (contrast-enhanced if combined with abdominal/pelvic imaging) (NCCN Category 2A); obtain every 6-12 months if low risk for metastatic recurrence (NCCN Category 2A); obtain every 3-6 months for first 2-3 years, then every 6 months for next 2 years, and then annually if intermediate or high risk for metastatic recurrence (NCCN Category 2A)
    • for synchronous stage IV (M1) disease
      • history and physical every 2-6 months for first 2-3 years, then every 6 months for next 2 years, and then annually thereafter if free of disease recurrence (NCCN Category 2A)
      • imaging follow-up includes
        • consideration of postoperative baseline and periodic imaging of primary location of sarcoma (with uncontrasted and contrast-enhanced MRI and/or contrast-enhanced CT) based on estimated risk of locoregional recurrence (NCCN Category 2A)
          • every 3-6 months for first 2-3 years, then every 6 months for next 2 years, and then annually thereafter if no evidence of radiologic disease (NCCN Category 2A)
          • consider ultrasound for small superficial lesions (NCCN Category 2A)
        • chest x-ray or CT (contrast-enhanced if combined with abdominal/pelvic imaging) (NCCN Category 2A) every 3-6 months for first 2-3 years, then every 6 months for next 2 years, and then annually
        • imaging of chest and known sites of metastatic disease (with uncontrasted and contrast-enhanced MRI and/or contrast-enhanced CT) (NCCN Category 2A) with follow-up frequency depending on radiographic evidence of disease
          • if no known radiographic evidence of disease, every 3-6 months for first 2-3 years, then every 6 months for next 2 years, and then annually thereafter (NCCN Category 2A)
          • if known radiographic evidence of disease, every 2-3 months (NCCN Category 2A)
    • after 10 years, likelihood of recurrence is small and continued follow-up frequency may be individualized
  • European Society of Medical Oncology (ESMO)-European Reference Network on Rare Adult Cancers (EURACAN) guidelines on follow-up of soft tissue and visceral sarcoma at any location after surgical resection(5)
    • frequency for clinical assessment of local recurrence
      • for patients with low-grade sarcoma, every 4-6 months for first 3-5 years and then annually thereafter
      • for patients with intermediate and high-grade sarcoma, every 3-4 months for first 2-3 years, then twice a year up to year 5, and then annually thereafter
    • chest x-ray or chest CT
      • for patients with low-grade sarcoma, every ≥ 4-6 months for first 3-5 years and then annually thereafter
      • for patients with intermediate and high-grade sarcoma, every 3-4 months for first 2-3 years, then twice a year up to year 5, and then annually thereafter

Complications

  • untreated soft tissue sarcoma may lead to mass effects such as pain or pressure due to compression or displacement of adjacent nerves, vessels, tissue, or organs
  • radiation therapy-associated long-term complications may include
    • for primary breast sarcoma
      • fibrosis(3)
      • edema(3)
      • joint stiffness(3)
    • for reirradiation of radiation-associated secondary breast sarcoma
      • rib fractures(2)
      • fibrosis(2,3)
      • cardiomyopathy(2)
  • systemic therapy complications may include
    • long-term effects of doxorubicin
      • effects on fertility
        •  in women of reproductive potential, may cause infertility, amenorrhea, or premature menopause (recovery of menses and ovulation related to age at treatment)
        •  in men, may result in oligospermia, azoospermia, and/or permanent loss of fertility (sperm counts reportedly return to normal in some men and may occur several years after therapy ends)
      • secondary malignancies
        •  increased risk reported for development of secondary acute myeloid leukemia and myelodysplastic syndrome after anthracycline treatment, including doxorubicin
        •  reported cumulative incidence 0.2% at 5 years and 1.5% at 10 years
      • Reference – FDA DailyMed 2019 Dec 31
    • long-term effects of ifosfamide
      • cumulative nephrotoxicity
        •  potentially irreversible
        •  may lead to renal insufficiency and/or renal failure
        •  may be partly prevented by aggressive hydration during treatment
      • effects on fertility
        •  ifosfamide interferes with gametogenesis (oogenesis and spermatogenesis)
        •  amenorrhea, azoospermia, and sterility reported in both sexes
        •  sterility may be irreversible
        •  sterility reported to depend on dose, duration of therapy, and patient’s gonadal function at time of treatment
        • Reference – FDA DailyMed 2019 Oct 18
      •  secondary malignancies including acute leukemias, lymphoma, thyroid cancer, and other sarcomas; may develop several years after chemotherapy has been discontinued (FDA DailyMed 2019 Oct 18)

Prognosis

  • breast sarcoma typically has worse prognosis than breast carcinoma(2)
  • prognosis of radiation-associated secondary breast sarcoma
    • may be poorer than primary breast sarcoma due to delayed diagnosis and genetic features(1,3)
    • 5-year overall survival 43% in systematic review of observational studies with 222 patients with radiation-associated secondary breast angiosarcoma
  • local recurrence reported to be more common than metastatic recurrence(2)
  • adverse prognostic factors may include
    • tumor size > 5 cm(1,2,3)
    • high tumor histologic grade(1,2,3)
    • positive resection margins(1,2,3)
    • angiosarcoma (compared to other histologic subtypes)(1,3)
  • high-grade tumor, distant recurrence, and age > 60 years each associated with poorer overall survival in patients with primary breast angiosarcoma, while high-grade tumor and tumor size > 5 cm both associated with poorer overall survival in patients with secondary breast angiosarcoma
    •  based on systematic review of observational studies
    • systematic review of 47 observational studies evaluating patients with primary or secondary breast angiosarcoma
    • 10 observational studies (including 1 de novo retrospective cohort study with 22 patients) included in meta-analysis evaluating prognosis in 380 patients with primary angiosarcoma and 595 patients with secondary angiosarcoma
    • in analysis of patients with primary angiosarcoma
      • decreased overall survival associated with
        • high-grade tumor (G3) (hazard ratio [HR] for death 3.57, 95% CI 1.93-6.6) compared to low-grade tumor (≤ G2)
        • distant recurrence (HR for death 2.64, 95% CI 1.69-4.12) compared to local recurrence
        • age > 60 years (HR for death 1.54, 95% CI 1.06-2.22) compared to ≤ 60 years
      • no significant differences in overall survival comparing
        • use of adjuvant radiation therapy to no adjuvant radiation therapy
        • tumor size > 5 cm to ≤ 5 cm
      • no significant differences in recurrence-free survival associated with tumor grade, tumor size, use of adjuvant chemotherapy, or age
    • in analysis of patients with secondary angiosarcoma
      • decreased overall survival associated with
        • high-grade tumor (G3) (HR 2.23, 95% CI 1.27-3.91) compared to low-grade tumor (≤ G2)
        • tumor size > 5 cm (HR 2.94, 95% CI 1.1-7.88) compared to ≤ 5 cm
      • no significant differences in overall survival comparing
        • age > 60 years to ≤ 60 years
        • receipt of mastectomy to breast-conserving surgery
        • use of adjuvant radiation therapy to no adjuvant radiation therapy
        • use of adjuvant chemotherapy to no adjuvant chemotherapy
        • multifocal tumor to unifocal tumor
      • decreased recurrence-free survival associated with increasing size as a continuous variable (HR 1.09, 95% CI 1.06-1.12), and nonsignificant decrease associated with increasing age as a continuous variable (HR 1.06, 95% CI 0.99-1.13)
      • no significant difference in recurrence-free survival associated with adjuvant chemotherapy or tumor grade
    • in analysis of all patients
      • decreased overall survival associated with
        • high-grade tumor (G3) (HR 2.71, 95% CI 1.82-4.05) compared to low-grade tumor (≤ G2)
        • tumor size > 5 cm (HR 2.66, 95% CI 1.23-5.77) compared to ≤ 5 cm
        • distant recurrence (HR 2.15, 95% CI 1.60-2.89) compared to local recurrence
        • age > 60 years (HR 1.54, 95% CI 1.15-2.06) compared to ≤ 60 years
      • no significant differences in overall survival associated with race, type of surgery (mastectomy vs. breast-conserving therapy), or use of adjuvant radiation therapy or chemotherapy
      • decreased recurrence-free survival associated with
        •  tumor size > 5 cm (HR for death or recurrence 2.49, 95% CI 1.21-5.1) compared to ≤ 5 cm
        • high-grade tumor (G3) (HR 1.68, 95% CI 1.02-2.76) compared to low-grade tumor (≤ G2)
      • no significant differences in recurrence-free survival associated with use of adjuvant radiation therapy or chemotherapy or age
    • Reference – Breast Cancer Res Treat 2019 Dec;178(3):523full-text, commentary can be found in Breast Cancer Res Treat 2020 Feb;179(3):765
  • larger tumor size and age associated with poorer overall survival in patients with radiation-associated breast angiosarcoma
    •  based on systematic review of observational studies
    • systematic review of 12 retrospective cohort studies and 62 case series or case reports evaluating prognostic factors in 222 patients (median age 69 years in 208 patients) with radiation-associated breast angiosarcoma after primary breast cancer
    • 5-year overall survival 43%
    • 5-year local recurrence-free interval 32%
    • in multivariate analysis
      • decreased overall survival associated with
        • larger tumor size (adjusted hazard ratio [HR] for death 1.07, 95% CI 1.03-1.11) in analysis of 121 patients
        • older age (adjusted HR for death 1.03, 95% CI 1-1.07) in analysis of 121 patients
      • increased local recurrence associated with larger tumor size (HR for local recurrence 1.07, 95% CI 1.04-1.11) in analysis of 128 patients
    • Reference – Eur J Cancer 2014 Jul;50(10):1779

Prevention and Screening

  • not applicable

Guidelines and Resources

Guidelines

United States Guidelines

  • National Comprehensive Cancer Network (NCCN) statement on mitigating the impacts of anticancer drug shortages can be found at NCCN 2023 Jun 7 PDF
  • National Comprehensive Cancer Network (NCCN) clinical practice guidelines on soft tissue sarcoma can be found at NCCN website (free registration required)
  • American Society of Clinical Oncology (ASCO) position on prioritization of antineoplastic agents in limited supply for first intervention can be found at ASCO, accessed 2023 Jun 13

European Guidelines

Review Articles

National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

  • The CTCAE provides the definitions of terminology used for reporting of adverse events that occur during medical therapies or procedures, depending on their severity.
  • The CTCAE grading system for the severity of adverse events:
    • Grade 1 describes mild adverse events which fulfill ≥ 1 of the following criteria:
      • No symptoms or have mild symptoms
      • Clinical or diagnostic findings only
      • Not requiring interventions for management
    • Grade 2 describes moderate adverse events which fulfill ≥ 1 of the following criteria:
      • Requiring only minimal, local, or noninvasive intervention for management
      • Limiting age-appropriate instrumental activities of daily living (ADL)
    • Grade 3 describes adverse events that are severe or medically significant but not immediately life-threatening which fulfill ≥ 1 of the following criteria:
      • Requiring hospitalization
      • Prolonging of hospitalization
      • Disabling
      • Limiting self care ADL
    • Grade 4 describes life-threatening adverse events which require urgent interventions for management.
    • Grade 5 describes adverse events leading to death.
  • The CTCAE version 5 (November 27, 2017) table listing all the CTCAE definitions by organs or systems can be found at NCI website.

Patient Information

References

General References Used

  1. Duncan MA, Lautner MA. Sarcomas of the Breast. Surg Clin North Am. 2018 Aug;98(4):869-876.
  2. Lim SZ, Ong KW, Tan BK, Selvarajan S, Tan PH. Sarcoma of the breast: an update on a rare entity. J Clin Pathol. 2016 May;69(5):373-381.
  3. Hsu C, McCloskey SA, Peddi PF. Management of Breast Sarcoma. Surg Clin North Am. 2016 Oct;96(5):1047-1058.
  4. von Mehren M, Kane JM, Bui MM, et al. Soft Tissue Sarcoma. Version 2.2021. In: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN 2021 Apr from NCCN website (free registration required).
  5. Casali PG, Abecassis N, Aro HT, et al; ESMO Guidelines Committee and EURACAN. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv51-iv67full-text, correction can be found in Ann Oncol 2018 Oct 1;29(Suppl 4):iv268, commentary can be found in Ann Oncol 2019 Jan 1;30(1):153, eUpdates can be found at ESMO 2021.

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