Radiation-induced undifferentiated pleomorphic sarcoma of the breast

Abstract

Breast sarcoma is a rare form of malignancy that arises from connective tissue within the breast, comprising less than 5% of all sarcomas. They develop as primary tumours or as secondary following radiation therapy. Diagnosis can be challenging as breast sarcomas are often asymptomatic and resemble benign breast tissue changes. Radiation-induced breast sarcomas present in various forms with an average latency period of 10–20 years following initial radiation therapy. Angiosarcomas are the most common form, while other types such as undifferentiated pleomorphic sarcomas remain rare. Here, we report a case of radiation-induced undifferentiated pleomorphic breast sarcoma in a 75-year-old woman that developed nearly 20 years following breast conserving surgery and radiation for invasive ductal carcinoma. The patient initially noticed a mass in 2017 on self-examination. The mammogram, ultrasound and biopsy at the time showed a benign 2.2 cm nodular fasciitis without malignancy. The mass grew rapidly in the next 6 months to 5.6 cm and repeat biopsy diagnosed undifferentiated pleomorphic sarcoma. The mass abutted the pectoralis muscle but staging workup ruled out distant metastasis and the patient underwent wide local resection of the mass with clear margins. The patient subsequently underwent further postoperative radiation due to insufficient posterior margin width on wide local excision, as chest wall resection would have been required for a wider posterior margin. Prognosis for postradiation sarcomas is generally poor with 27%–36% 5-year survival, with surgical resection as the main line of treatment. The patient currently remains disease-free after 15 months of surveillance.

Background

Breast sarcoma is a group of heterogeneous non-epithelial tumours that arise from mesenchymal tissues of the breast. ¹ Subtypes include angiosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma and undifferentiated pleomorphic sarcoma (UPS), which was previously known as malignant fibrous histiocytoma.^{2 3} These sarcomas are extremely rare and account for less than 5% of all sarcomas.^{4 5} Breast sarcomas can develop as primary tumours, or more commonly, as secondary tumours following radiation therapy with, or without, chemotherapy.⁵ Adjuvant radiotherapy is the standard of care for breast cancer following breast-conserving surgery or in some cases, even after total mastectomy.⁶ Radiation therapy improves overall survival in breast cancer patients, but associated side effects include swelling, skin changes, fatigue, brachial plexopathy, difficulties with breast feeding, lymphoedema and in rare cases, sarcomas.^{7 8} Overall, radiation-induced breast sarcoma (RIBS) remains a rare entity with a cumulative incidence of 0.3% at 15 years postradiation treatment with 48% being angiosarcomas, the most common form of breast sarcoma.^8–10 UPS, on the other hand, has been reported to encompass 10.5%–24% of all primary breast sarcomas and there are few reports on its incidence among secondary breast sarcomas.¹¹ Diagnosis is difficult due to their rarity, the lack of initial symptoms and their mimicry of benign breast changes on imaging as well as pathology.^12–14 Furthermore, there are no randomised trials to guide their treatment or provide prognostic factors.^{3 15 16} Current management strategies are limited to single institution retrospective analysis, case report and extrapolation from treatment of identical sarcomas from other parts of the body.¹⁷ In this report, we present a diagnostically challenging case of radiation-induced UPS nearly 20 years following lumpectomy and radiation therapy for invasive breast cancer of the ipsilateral breast.

Case presentation

A 75-year-old woman was initially diagnosed with a 1.4 cm node-negative, strongly estrogen receptor (ER)/progesterone receptor (PR)-positive, stage IA invasive ductal and lobular carcinoma of the right breast in 1998. The patient was treated with lumpectomy, axillary dissection, radiation therapy (50.4 Gy to the breast in 28 fractions followed by a 10 Gy boost to the lumpectomy cavity in 2 Gy fractions for total dose of 60.4 Gy), four cycles of doxorubicin and cyclophosphamide, followed by 5 years of tamoxifen. The patient received routine screening mammography and remained disease-free until the summer of 2017, when she palpated a lump in the upper outer quadrant of her right breast.

Investigation

An ultrasound study revealed a 2.2×1.9 cm abnormality, which the biopsy at the time identified as benign soft tissue changes (figure 1). Six months later, the patient noticed significant growth of the mass (figure 2). A repeat mammogram, ultrasound (figure 3) and biopsy in January 2018 showed a 5.6 cm, grade II UPS. Immunohistochemical stains were positive forKi-67 (25% of the tumour), vimentin and cluster of differentiation (CD) 68, while negative for S100, desmin, actin, myogenin, Human Melanoma Black (HMB) 45, CD 34, cytokeratin AE1/AE3, CAM 5.2 and EMA, which is consistent with UPS. Subsequently, a CT scan of the chest identified a 6 cm right breast mass with no evidence of metastases (figure 4).

Figure 1.

(A) The mammogram and (B) the ultrasound of the right breast mass after the patient first palpated a lump during one of her self-breast examinations, which was shown to be benign changes on the pathology report. PALP, palpable; F, fine needle.

Figure 2.

Right breast mass presented in ipsilateral breast 20 years after lumpectomy, radiation and chemotherapy for invasive ductal carcinoma.

Figure 3.

(A) The mammogram and (B) the ultrasound of the right breast mass, which was diagnosed as radiation-induced undifferentiated pleomorphic sarcoma of the breast.

Figure 4.

CT scan of the right breast mass, measuring at 6 cm wide with no evidence of metastasis as shown in (A) the axial view and (B) the sagittal view (marked by arrow).

Treatment

The patient underwent wide local resection and negative margins were achieved, although having a narrow posterior margin of 0.1 cm, where the mass abutted the pectoralis muscle (figure 5). The decision was made to treat the patient with radiation therapy rather than chest wall resection. She received a dose of 51 Gy in 1.5 Gy increments two times a day to the tumour bed with 12 mEv electrons.

Figure 5.

Surgically resected gross tissue specimen of radiation-induced undifferentiated pleomorphic sarcoma of the breast with clear tissue margins all around.

Outcome and follow-up

The patient continues to have a 6-month clinic follow-ups and she remains disease-free after 15 months.

Discussion

UPS remains rare among breast sarcomas.^{8 18} Only a small number of case studies and single-centre retrospective studies of radiation-induced UPS are reported.^{13 19–31} Increase in the incidence of RIBS over the last decade is likely due to standard acceptance of breast conservation in 2002 with 20 years results from National Surgical Adjuvant Breast and Bowel Project.^{32 33}

Diagnosing radiation-induced UPS can be challenging. The initial evaluation of breast sarcoma follows that of any breast mass suspicious for cancer. This includes mammography, ultrasonography and occasional MRI for discordant or equivocal findings.³⁴ Breast sarcomas often resemble benign breast tissues changes as a solitary, firm, well circumscribed, painless breast mass.¹⁷ Mammography has been reported to demonstrate architectural distortion without a discrete mass in 30% of the cases. Rapid growth over several months is often the only distinguishing feature.¹ Furthermore, radiation-induced changes to the architecture of the breast tissue poses an additional challenge to the physical examination, which may explain why RIBS usually presents with more advanced disease than primary breast sarcomas.¹⁷

There are no prospective randomised trials to determine the standard of care. Currently, through extrapolation from studies of UPS in other areas of the body along with retrospective analysis of case reports and single centre retrospective studies on breast UPS, surgical resection with a clear margin of 2–4 cm is considered the only potentially curative mode of therapy, with or without radiation therapy.^{16 35 36} The natural history of breast sarcoma and their response to treatment seem to resemble sarcomas at other sites. Although total mastectomy is often required, partial mastectomy with negative margins does not necessarily compromise the outcome. It is therefore critical to diagnose these tumours early as they are usually fast growing and the two most important prognostic factors are tumour size (<2, 2–5 and >5 cm), depth and grade.4 15 36 37 Our case demonstrated that with a missed diagnosis, within 6 months, tumour size can more than double. Adjuvant radiation and chemotherapy may benefit patients with high-grade features.^{17 38} Although there have been limited studies on biological markers as prognostic factors, high Ki-67 has been shown to be a poor prognostic factor that is associated with higher risk of local recurrence, distant metastasis and poor prognosis in primary UPS of the breast.¹⁵ Overall, the 2-year and 5-year survival following treatment is reported to range from 40%–60% to 20%–35%, respectively.^{13 16} Options for treating the close posterior margin in our patient included chest wall resection versus chest wall radiation. We chose the latter, as it was felt that the increased risk of wound complications associated with repeat radiation therapy to this region would be relatively low given the long time period of 20 years from the previous treatment. This treatment regimen was used in 17% of patients in a review by Depla et al, with significant improvement in disease-free survival.³⁹ Chemotherapy was also discussed, but refused by the patient. Chemotherapy after surgical resection was used in 6% of patients in the studies reviewed by Depla et al with no definite outcome improvement.³⁹ A case report of neoadjuvant chemotherapy in inoperable malignant fibrous histiocytoma resulted in sufficient response for wide local excision.⁴⁰ Treatment for the individual patient must be determined with a multidisciplinary approach, as there are no standard treatment algorithms.

Patient’s perspective.

My second experience with another breast cancer was a challenge, given that I thought I was cured, and then you deal with another mass. Seeking medical attention is very important and looking for the right person to address this is extremely important.

Learning points.

• Radiation-induced undifferentiated pleomorphic sarcoma of the breast is a rare form of radiation-induced breast sarcomas.

• Diagnosis can be difficult due to its resemblance to benign breast tissue changes in a postirradiation field.

• There is no standardised treatment, however, wide local excision, with or without radiation and chemotherapy, is considered the only curative option.