Erythema of the skin after breast radiotherapy: It is not always recurrence

Abstract

Recurrence of breast cancer is a predominant fear for patients who were treated for breast cancer. Acute and late dermatologic effects of radiotherapy are not uncommon and could have similar characteristics to breast cancer recurrence. Thus, it is important to highlight key differences between the clinical and histologic presentations of radiation effects and recurrence. Herein, we present two patients who presented with late dermatologic effects of radiotherapy months to years after treatment, neither of whom had workup consistent with cancer recurrence. We provide clinical and microscopic descriptions of each case and provide a review to differentiate various dermatologic conditions. This report aims to outline potential late dermatologic effects of radiation treatment and emphasise that changes in the breast do not always signal breast cancer recurrence.

1. INTRODUCTION

There are currently over 3.5 million breast cancer survivors in the United States.1 The advancement of treatment options have led to more individuals living longer disease‐free lives; however, many patients report psychological distress, depression, and anxiety, sometimes many years after treatment.2 One of the most common fears for these patients is recurrence after treatment.3 Breast cancer survivors require long‐term follow‐up care to evaluate any latent physical effects of treatment, assess ongoing needs, and monitor for breast cancer recurrence.4

Despite regular mammographic screening, many survivors fear that morphological changes in the breast are evidence of a recurrence, as skin involvement may be a presenting sign of carcinoma.5 In particular, inflammatory breast cancer, the most aggressive form of breast cancer, typically presents with red, warm, and thickened skin with associated oedema, termed peau d'orange.6 However, these symptoms may also indicate late post‐treatment effects.

Although radiation therapy is an effective modality in the treatment of breast cancer, it can induce acute and chronic toxicities to irradiated areas, including the skin. Side effects involving the skin can include dermal sclerosis,7 dermatitis,8 dimpling of the skin from lymphoedema,9 and in rare cases, radiation‐induced morphea (RIM).10 Thus, it is important to distinguish between late effects of radiation and symptoms of breast cancer recurrence.

We present two women who presented with dermatologic changes several years after post‐lumpectomy radiation treatment. This report aims to highlight potential late dermatologic effects of radiation and emphasise that changes in the breast do not always signal breast cancer recurrence. Herein, we outline the differences between dermatologic changes in the breast due to radiation and changes that indicate malignancy.

2. CASE PRESENTATIONS

2.1. Patient 1

A 51‐year‐old female was diagnosed in 2005 with a 1.3‐cm high‐grade ductal carcinoma in situ (DCIS) of the left breast. She underwent lumpectomy and received accelerated partial breast irradiation (APBI) to the lumpectomy cavity plus margin using three‐dimensional conformal radiotherapy (3D‐CRT) approach with 6 mV photons to a total dose of 38.5 Gy delivered in 10 fractions over 5 days. The patient experienced mild skin erythema focally around the lumpectomy incision and mild tenderness of the breast, but otherwise tolerated the treatment well. She completed 3.5 years of tamoxifen.

In 2018, 13 years after radiation treatment, the patient presented to a routine follow‐up visit with oedema and violaceous pink erythema with telangiectatic changes circumferentially around the areola of the left breast (Figure 1A,B). She denied any trauma, bites, friction, or pressure to the area. There was no discharge of the nipple on manual expression and no discrete palpable masses; however, there was subcutaneous induration diffusely around the breast, most significant at the medial edge. Workup for breast cancer recurrence, including mammogram, breast ultrasound, breast magnetic resonance imaging (MRI), and punch biopsy of the skin was negative. Final pathology from the punch biopsy of the left superior medial breast showed mild dermal sclerosis and eccrine glands that lacked peri‐adnexal adipose tissue. The punch biopsy of the left inferior medial breast showed slightly thickened collagen bundles in the dermis with a mild decrease in CD34 expression (Figure 2). Overall, the biopsy findings were compatible with post‐radiation morphea, a rare, painful, and disfiguring late effect of radiotherapy characterised by thickening of the skin due to excessive collagen deposition.11

Figure 1.

Post‐radiation changes in the left breast in patient 1. A, Thirteen years after accelerated partial breast radiation therapy following lumpectomy for high‐grade DCIS there is periareolar erythema/purpura and induration. B, Bilateral breasts at dermatology follow‐up 2 months later showing significant improvement in erythema/purpura. C, Seven‐month follow‐up following initial presentation of dermatological symptoms

Figure 2.

A,B, Histologic sections of the left medial breast show mild dermal sclerosis with mild vascular ectasia and a mild perivascular lymphocytic infiltrate in the dermis. C, An elastic‐Van Gieson stain shows slightly fragmented elastin fibers. D, An immunohistochemical stain for CD34 highlights a mild decrease in dermal CD34 expression

One month following biopsy, the patient presented to follow up with a completely clear breast, which is unusual for morphea. At follow‐up 7 months after initial dermatological changes, the patient reported that left breast fullness and erythema would wax and wane and symptoms were at least somewhat improved with massage therapy (Figure 1C). Given the negative workup, it was concluded that her symptoms were most likely due to lymphoedema and vascular congestion.

2.2. Patient 2

A 51‐year‐old female was diagnosed in 1998 with a 1.5‐cm grade 2, ER‐positive, PR‐negative, HER2‐negative, invasive ductal carcinoma (IDC), with associated DCIS. She underwent lumpectomy and received 6 cycles of cyclophosphamide, methotrexate, and 5‐fluorouracil, followed by whole breast radiotherapy to a dose of 50.4 Gy in 1.8 Gy fractions with a 10 Gy boost to the lumpectomy cavity. She was later diagnosed at the age of 62 with a 1.3‐cm ipsilateral breast cancer with extensive dermal invasion. She underwent mastectomy and 4 cycles of taxol and carboplatin followed by letrozole. She developed recurrent disease in the chest wall and metastatic disease involving the mediastinal lymph nodes. She completed radiation treatment to the mediastinum and axilla to a dose of 30 Gy in 10 fractions. Five months after radiation, she presented with a rash on her right chest wall and lymphoedema of the arm. Biopsy showed superficial perivascular dermatitis (Figure 3).

Figure 3.

A,B, Histologic sections of the right breast show a superficial perivascular dermatitis with mild vascular ectasia of papillary dermal vessels

3. DISCUSSION

Radiation‐associated dermatologic changes can manifest several months to years after treatment and can range in severity. Radiation treatment factors that influence the development of skin abnormalities are total dose, dose per fraction and number of fractions, techniques, the use of systemic therapy, and genetic predisposition. At the macroscopic level, dermatologic changes may include rash, chest pain, swelling of the breast/chest wall, and skin induration and retraction. Thus, symptoms and signs that occur secondary to radiation therapy are similar to those communicated to patients by clinicians as consistent with signs of breast cancer recurrence. This in part contributes to panic and anxiety in patients when they experience such changes.12

Various radiation techniques can be used for the treatment of breast cancer, and side effects differ based on radiation technique. Treatment options include whole breast irradiation (WBI), typically given over 5 to 7 weeks to a total dose of 50 Gy in 25 fractions with or without a boost or using a hypofractionated approach of 40 Gy in 15 fractions, and APBI, which targets a smaller area of the breast than WBI and is often completed in 1 to 2 weeks. Prospective randomised trials indicate that APBI is a viable alternative for women undergoing breast conserving therapy,13 with lower acute and late toxicity at 5 years.14, 15 Whelan et al16 recently reported that APBI was non‐inferior to WBI in preventing ipisilateral breast tumor recurrence with less acute toxicity but increased rates of late toxicity at 8.6 years.

Although it is imperative that physicians educate patients on detecting and reporting any changes after breast cancer treatment, awareness of symptom similarity between recurrence and treatment‐related side effects should also be emphasised. Appropriate workup for disease recurrence, including mammography and ultrasound, with or without breast MRI, should be performed if a patient presents with abnormal skin changes. It is important to note several radiographic similarities and differences that exist between dermal breast cancer recurrence and cutaneous effects of radiation (Table 1).17

Table 1.

Clinical, radiographic, and histologic features of breast cancer recurrence compared with side effects of radiation

	Features
	Clinical	Radiographic	Histologic
Dermal recurrence of breast cancer	Deep red, splotchy pattern Thickened skin with associated oedema (peau d'orange) Warm May be papular	Skin thickening which enhances on breast MRI Increased trabecular thickening May have associated mass or enlarged axillary lymph node	Intravascular/intralymphatic tumor emboli Dermal deposits of pleomorphic, mitotic, and neoplastic cells in the vascular lumen Atypical cells with enlarged nuclei, prominent nucleoli Abundant eosinophilic cytoplasm
Cutaneous effects of radiation therapy
Oedema	Erythema, blush color Skin dimpling, swelling (peau d'orange) Occasional tingling or numbness Achiness, heaviness of breast Decreased flexibility or tightness of area	Irradiated breast appears denser than contralateral breast Engorgement of dermal and intramammary lymphatics (trabecular thickening) No coexisting mass	Cutaneous and subcutaneous thickening Thickened collagen bundles in dermis Negative immunohistochemical staining for cytokeratins
Radiation dermatitis	Erythema, oedema, pigment changes Dry or moist desquamation Blisters or skin ulceration	Thickening of the dermis	Keratinocyte apoptosis Vacuolisation of basal cell layer and epidermal oedema (acute) Eosinophilic sclerosis, atypical fibroblasts, vascular malformation (late) Negative immunohistochemical staining for cytokeratins
Radiation‐induced morphea	May mimic recurrent cancer or radiation dermatitis with violaceous erythema and peau d'orange	Thickening of the dermis Infiltration of subcutaneous fatty tissue	Perivascular lymphocytic infiltration Prominent fibrosis and thickened collagen fibers Sclerosis of subcutaneous fatty tissue and dermis Negative immunohistochemical staining for cytokeratins

Owing to these potential similarities on imaging, a more comprehensive workup may be required. A punch biopsy of the skin can help with the diagnosis of any dermatologic changes and a biopsy of any parenchymal changes on imaging or exam can diagnose any breast tissue changes. On biopsy, evidence for local breast cancer recurrence is evident on morphologic evaluation, with immunohistochemical stains used when additional clarification is necessary. DCIS is indicated by a monotonous, uniform population of round cells with an increase in nuclear‐cytoplasmic ratio and can architecturally form cribriform, solid, or micropapillary patterns limited to the ducts or lobules of the breast. In contrast, IDC proliferates past the ducts with stromal invasion.18 Inflammatory breast cancer is a clinical diagnosis, but histologic evaluation usually reveals intralymphatic tumor emboli.19 Radiation dermatitis is characterised as a transendothelial migration of immune cells from circulation to the skin. Acute effects are characterised by keratinocyte apoptosis, vacuolisation of the basal cell layer, and epidermal oedema, while late effects present with eosinophilic sclerosis, atypical fibroblasts, and vascular malformation.20 RIM is a largely under‐recognised dermatologic effect due to both its rarity and overlapping histological and clinical markers with other conditions. Histologically, RIM presents with perivascular lymphocytic infiltration, with prominent fibrosis and thickened collagen fibers. Clinically, RIM may mimic radiation dermatitis or recurrent breast cancer, presenting with violaceous erythema and a peau d'orange appearance.11 Thus, we emphasise the need for microscopic evaluation of suspecting dermatologic conditions, in addition to radiographic imaging, in the post‐treatment setting for breast cancer.

Of note, the risk of acute and long‐term sequelae in the setting of adjuvant systemic therapies after radiation treatment has long been characterised.21 Case reports have observed radiation recall dermatitis in patients receiving tamoxifen,22 chemotherapy,23 and trastuzumab monotherapy24 for breast cancer treatment. These agents are first‐line therapies prescribed to reduce the risk of recurrence in cancers that are hormone dependent or have amplified human epidermal growth factor receptor 2, respectively. It is important, however, to note that adverse dermatologic effects may occur in a rare subset of patients.

We present two patients who have developed late adverse effects, likely due to the prior radiation treatment for breast cancer. Though their symptoms were similar to those of patients with recurrent breast cancer, imaging and histology indicated the contrary. Although the seriousness of possible recurrence should not be trivialised, we aim to increase general awareness and outline these two cases as examples that erythema and oedema of the breast/chest wall skin do not necessarily equate to breast cancer recurrence.

CONFLICT OF INTEREST

The authors have no potential conflict of interest.

Gutkin PM, Fernandez‐Pol S, Horst KC. Erythema of the skin after breast radiotherapy: It is not always recurrence. Int Wound J. 2020;17:910–915. 10.1111/iwj.13350