Clinical manifestations and evaluation of locoregional recurrences of breast cancer

INTRODUCTION — 

Following breast-conserving therapy or mastectomy, breast cancer can recur locally, regionally, and/or at distant metastatic sites. A local recurrence is defined as reappearance of cancer in the ipsilateral preserved breast or chest wall. A regional recurrence denotes tumor involving the ipsilateral regional lymph nodes, usually the ipsilateral axillary or supraclavicular, and less commonly the infraclavicular and/or internal mammary. The term "locoregional recurrence" is used to indicate a recurrence in either the ipsilateral breast/chest wall or regional nodal basin, as opposed to a distant site.

In this topic, we discuss the epidemiology, risk factors, clinical manifestations, diagnosis, and evaluation of locoregionally recurrent breast cancer. Such cases typically require management in a multidisciplinary fashion, which is covered in other topics. (See "Surgery and radiation for locoregional recurrences of breast cancer" and "Systemic therapy for locoregionally recurrent breast cancer".)

Patients who have synchronous distant metastases with a locoregional recurrence are diagnosed as having stage IV breast cancer, the management of which is discussed elsewhere. (See "Overview of the approach to metastatic breast cancer".)

EPIDEMIOLOGY — 

The incidence of and time to local recurrence, and the pattern of recurrence, differ after breast-conserving therapy (BCT) versus mastectomy.

Local recurrence after breast-conserving therapy — The incidence of local recurrence after BCT in modern series is in the range of 2.5 to 5.5 percent [1-5]. As an example, a study which pooled data of 4404 women who underwent breast-conserving surgery and systemic therapy from five early trials reported a local recurrence rate of 4.6 (4.0 to 5.4) percent at five years, 5.2 (4.4 to 6) percent at seven years, and 6.2 (5.3 to 7.3) percent at 10 years. Recurrence was most likely in the triple-negative subtype [6]. Locoregional recurrence occurs with different patterns according to breast cancer subtypes [7]. Many studies report both true local recurrences and new primaries as ipsilateral breast tumor recurrence as it is not always possible to distinguish the two. (See 'Distinguishing a new primary from a recurrence' below.)

Breast cancer tends to recur at a median of three to four years after BCT (five to seven years after adjuvant systemic therapy [8,9]), which is typically later than after mastectomy (median two to three years) [10-15]. This may be due to the differences in biology or presentation that led to a decision for mastectomy versus breast conservation.

Local recurrence after BCT may be either invasive or in situ cancer (ductal carcinoma in situ [DCIS]). For patients who were initially treated for invasive disease, more than 80 percent of locoregional recurrences are invasive; the remainder are DCIS. For patients who recur after treatment for DCIS, 40 to 50 percent will have invasive disease, whereas the remainder will have DCIS [16].

Approximately 75 percent of local recurrences after BCT are isolated to the breast and clinically solitary; 5 to 15 percent present with a simultaneous regional nodal recurrence, and another 5 to 15 percent have distant metastases at the time of recurrence [11,14,17-20].

Local recurrence after mastectomy — Approximately 2.3 to 3.6 percent of patients undergoing mastectomy for operable breast cancer will have a chest wall or regional nodal recurrence [21-26].

The median interval to a locoregional recurrence after mastectomy is two to three years, and 90 percent arise within five years [10,27-32]. Recurrence may be delayed in patients who receive adjuvant endocrine therapy [8,9,33,34].

There is wide variability in the reported incidence of simultaneous locoregional and distant metastases (10 to 60 percent) [8,28,35-39]. However, it is generally thought that approximately one-third of patients who present with a postmastectomy locoregional recurrence also have synchronous distant disease [20,28].

About half of the locoregional recurrences occur in the supraclavicular, axillary, or internal mammary nodes, with the supraclavicular nodes being the most common site, while the other half occur in the chest wall [40,41]. Sixty to 70 percent of the chest wall recurrences are isolated; 30 to 40 percent present with simultaneous chest wall and lymph node recurrences [28,42-45].

Regional recurrence — The incidence rate for regional recurrence in breast cancer, isolated or associated with local recurrence, ranges from 1 to 10 percent [46,47].

RISK FACTORS

In those treated with breast-conserving therapy — Ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) increases with omission of radiation therapy (RT) and a positive pathologic margin, although it can also vary by molecular subtypes [7].

RT is considered a standard component of breast-conserving therapy (BCT) for the majority of women with invasive breast cancer or ductal carcinoma in situ (DCIS), the elimination of which is a major risk factor for both recurrence and, in select patients, mortality [48]. In a meta-analysis of 17 randomized trials involving 10,801 women undergoing BCS, RT to the conserved breast halved the recurrence rate [49]. However, certain subsets of women may be reasonably treated with lumpectomy alone, such as older women with estrogen receptor (ER)-positive disease.

For all patients undergoing BCS, tumor excision should be complete, such that negative margins within breast tissue are achieved. Occasionally, the surgical excision is taken to the edge of breast tissue posteriorly or anteriorly, and no more tissue can be removed in these directions. This is not considered a risk factor for recurrence. For invasive disease, the goal should be to ensure that there is no tumor at the inked border on microscopic pathologic examination; wider surgical margins are generally required for DCIS due to a greater propensity for multifocality. Positive or unknown histologic margins within breast tissue should prompt reexcision since such patients are at higher risk for local recurrence even when RT is administered. (See "Breast-conserving therapy", section on 'Margins of resection'.)

Other risk factors for local recurrence after BCT are [50-53]:

●Younger patient age

●Larger tumor size

●Higher tumor grade

●Presence of lymphovascular space invasion

●Absence of hormone receptors in the tumor (ie, ER- and progesterone receptor [PR]-negative breast cancer) [53-60]

In those treated with mastectomy — Risk for a postmastectomy local recurrence increases with the number of positive axillary lymph nodes and the size of the primary tumor [61]. The number of positive nodes is a stronger risk factor than the size of the primary tumor.

Other factors that may help to predict for locoregionally recurrent disease after mastectomy include age at diagnosis, hormone receptor status, the presence of lymphovascular invasion or extracapsular nodal extension, and positive deep margins [50,62,63]. Additionally, a higher 21-gene assay recurrence score is prognostic for locoregional recurrence (hazard ratio 2.36, 95% CI 1.02-5.45) [64]. However, postmastectomy chest wall irradiation reduces the rate of chest wall recurrence by 65 to 75 percent.

CLINICAL MANIFESTATIONS

Ipsilateral breast tumor recurrence — Ipsilateral breast tumor recurrences (IBTRs) are generally detected either by finding a palpable mass on physical examination or as a change on post-treatment surveillance mammography.

Both radiation therapy (RT) and surgery can lead to changes in the breast, such as mass-like fibrosis, that can be difficult to distinguish from a local recurrence on physical examination. Furthermore, the findings associated with a local recurrence may be subtle, particularly if the primary tumor was an infiltrating lobular cancer. In such cases, a local recurrence may be associated with only minimal thickening or retraction of the biopsy site without a mass. Any change in the examination more than one or two years after completion of RT must be viewed as suspicious for recurrence and evaluated. Since IBTRs detected on physical examination may be mammographically occult, a normal mammogram in the face of a change on physical examination does not rule out the possibility of a local recurrence.

Rarely, local recurrences after breast-conserving therapy (BCT) are inflammatory or extensively involve the skin [65-68]. Often, these are misdiagnosed as postoperative infection or breast lymphedema. Any patient with a history of breast cancer and new inflammatory-type changes in the breast (erythema, warmth, peau d'orange appearance) who does not respond readily to antibiotics should undergo a biopsy to rule out recurrent disease. In general, these patients have a poor prognosis.

Postmastectomy recurrence — A postmastectomy recurrence is usually detected clinically as a mass or multiple nodules in the chest wall or overlying skin in or near the mastectomy scar or in the skin flaps. The skin of the chest wall may also be diffusely involved with inflammatory changes without a discernible mass. The term "carcinoma en cuirasse" refers to a distinct form of local recurrence in which there is diffuse infiltration of the skin or subcutaneous tissues of the chest wall [69], with woody induration and spread of tumor often beyond the limits of standard surgical or radiation boundaries. Nodules and ulceration are often present.

Lymph node recurrence — Patients may also present with signs or symptoms of a regional recurrence: many patients present with palpable adenopathy in the axilla or supraclavicular fossa [70], although a regional recurrence may also present with pain in either location or the new onset of brachial plexopathy or lymphedema of the arm. These may occur in the absence of palpable adenopathy. Any patient who develops new-onset lymphedema following breast cancer treatment should be evaluated for the possibility of a regional recurrence.

Solitary "sternal metastases" may actually represent direct extension of involved internal mammary nodes. Such patients should be carefully imaged to adequately assess this distinction.

DIAGNOSTIC EVALUATION — 

The initial evaluation should include biopsy of all potential sites of disease (skin, chest wall, regional nodes) and staging to determine the extent of disease. Genetic testing should be considered for appropriate patients.

Breast/chest wall imaging — Any changes on physical examination should prompt imaging. (See "Approach to the patient following treatment for breast cancer", section on 'Breast imaging'.)

●For those who underwent previous breast-conserving therapy (BCT), a diagnostic mammogram and ultrasound of the lesion identified on examination are performed [71]. In cases where an abnormal finding was identified on screening mammography, a follow-up diagnostic mammogram should be performed, with ultrasound of any lesion that appears suspicious.

●For those who underwent previous mastectomy, ultrasound is usually the initial imaging study.

●Breast MRI may be performed when mammography and/or ultrasonography are inconclusive [71]. MRI is increasingly used to detect or evaluate suspected local recurrences. Although MRI may be more sensitive than mammography in detecting occult breast cancer recurrences [72-80], it is less specific, resulting in more false-positive imaging studies. (See "MRI of the breast and emerging technologies", section on 'Differentiating postoperative changes from recurrence'.)

In modern series of BCT, local recurrences are detected by mammography alone approximately 40 to 75 percent of the time, by physical examination alone in 10 to 30 percent, by a combination of mammography and physical examination in 10 to 25 percent, and by other imaging modalities (eg, magnetic resonance imaging [MRI]) in 5 percent of cases [81-85].

Axillary imaging — Given the substantial rate of simultaneous regional recurrences in patients with a locally recurrent breast cancer, axillary ultrasound of the regional nodal basins should be routinely performed, regardless of whether palpable adenopathy is appreciated on examination, and fine needle aspiration (FNA) or core biopsy can be used to confirm disease and deploy marker clips for future localization.

Biopsy — Any new clinical or radiographic finding that is suspicious for a recurrent malignancy should prompt a biopsy. FNA biopsy is a simple and accurate method for differentiating scar from recurrent carcinoma. However, tissue biopsy (core needle or excisional) may be needed not only to confirm the diagnosis of a local recurrence but also to assay the tumor tissue for hormone receptors and human epidermal growth factor receptor 2 (HER2) overexpression, as well as other factors such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations in estrogen receptor (ER)-positive cancers and programmed cell death ligand 1 (PD-L1) in triple-negative cancers, each of which is important for treatment decisions regarding adjuvant chemotherapy and/or hormonal therapy and to determine if the patient has distant metastases [86]. (See "Overview of the approach to metastatic breast cancer".)

The type of biopsy performed to diagnose a recurrence may also depend on the location of the recurrence. Internal mammary or supraclavicular recurrences are safer to sample via FNA, whereas other sites are amenable to core needle biopsy sampling. (See "Breast biopsy".)

The sites of resectable disease should be marked prior to initial therapy (regardless of whether initial surgical or systemic therapy is planned).

Evaluation for distant metastases — Patients who present with an invasive locoregional recurrent breast cancer may require complete restaging to rule out distant metastases [20]. For patients with simultaneous distant metastases, the treatment is systemic therapy, and the goal of treatment in this situation is generally palliation without intent to cure. (See "Overview of the approach to metastatic breast cancer".)

Some experts restage all patients with an invasive locoregional recurrence [87], while others only restage patients with a chest wall or regional recurrence but not always those with an in-breast recurrence after BCT.

If elected, restaging workup for metastatic diseases generally includes the following [88]:

●Radionuclide bone scan. Bone is the most common site of metastatic disease.

●Computed tomography (CT) of the chest, abdomen, and pelvis [89,90]. The most common site of unsuspected disease is in the internal mammary lymph nodes. Chest CT is also useful to differentiate recurrent tumor in the chest wall, subcutaneous fat, pectoralis muscles, and brachial plexus from postoperative and postradiation change [89,90]. MRI of the chest and abdominal imaging is a satisfactory alternative, especially of the thorax if patients cannot tolerate CT contrast dye.

●For patients with symptoms of a brachial plexopathy or arm edema without obvious adenopathy, contrast-enhanced MRI can help in the distinction between tumor recurrence versus radiation-induced fibrosis [91]. (See "Brachial plexus syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy'.)

●Positron emission tomography/CT (PET/CT) is most commonly used to survey the entire body for sites of distant metastatic spread (but not brain involvement) in patients with a documented locoregional recurrence [92]. PET scans are more sensitive than conventional imaging such as CT, and the detection of unsuspected metastatic disease may alter the therapeutic plan.

Genetic counseling — Genetic counseling and genetic testing may also be important, depending on age, personal and family history, and the biologic subtype of the cancer. The clinician should obtain an updated family history and consider genetic testing or retesting if testing was not done recently, given the more informative multigene panels available today. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)

DIAGNOSIS — 

Diagnosis is confirmed by histologic features of a biopsy specimen. (See 'Biopsy' above and "Pathology of breast cancer".)

DIFFERENTIAL DIAGNOSIS

Benign and other malignant etiologies — Differential diagnosis of a breast or chest wall lump identified radiographically or on examination in a patient previously treated for breast cancer includes a new primary breast cancer rather than a recurrence; fat necrosis, which may occur after any previous surgery to the breast; radiation fibrosis; other types of malignancies (eg, breast sarcoma, which can arise after radiation); infection; and benign breast lesions. (See "Clinical manifestations, differential diagnosis, and clinical evaluation of a palpable breast mass".)

In general, these etiologies are distinguished from a recurrent breast cancer on the basis of pathologic findings on the biopsy specimen. However, a true recurrence can be more difficult to differentiate from a new primary, as discussed below.

Distinguishing a new primary from a recurrence — The reappearance of disease in an ipsilateral preserved breast after breast-conserving therapy (BCT) can represent either a local recurrence of the initial cancer or a second primary tumor.

Whereas a chest wall recurrence after mastectomy is usually reflective of true recurrent disease, rarely, it may be an entirely new primary because the breast is not an encapsulated organ, and therefore mastectomy usually does not remove all potentially at-risk normal ductal and lobular units, which may then generate a new malignancy at a later date.

A recurrence of the original tumor can be distinguished from a new primary by its location relative to the original tumor. After BCT, 50 to 90 percent of ipsilateral breast tumor recurrences (IBTRs) occur in the same quadrant as the original tumor, representing a true recurrence (within the primary tumor site or boost volume of the treated breast) or marginal miss (near but not within the boost volume). As the interval from initial diagnosis lengthens, malignancies are more likely to arise in other quadrants of the breast, likely representing mainly new primary tumors [18,93-95].

The distinction can also be made on other grounds (eg, histologic subtype, mammographic appearance, hormone receptor status, human epidermal growth factor receptor 2 [HER2] overexpression, discordant DNA [deoxyribonucleic acid] flow cytometry) [13,95-98]. Typically, the estrogen receptor (ER)/progesterone receptor (PR) and HER2 receptor status of a true recurrence, but not necessarily a new primary, should be the same as in the original primary tumor. At least some data suggest that molecular classification is a more reliable method than receptor status for distinguishing a true (ie, genetically related) recurrence versus a genetically distinct second primary tumor [99,100].

Ipsilateral new primary breast cancers tend to develop later in the follow-up period than do true local recurrences (eg, median of 7.3 versus 3.7 years in one study [96]), and the prognosis is generally more favorable. Although ipsilateral second primary tumors are not generally treated differently from true recurrences at present, some studies suggest the potential for tailoring therapy based upon molecular classification, which may have therapeutic and prognostic implications. (See "Surgery and radiation for locoregional recurrences of breast cancer", section on 'New primary versus true recurrence' and "Systemic therapy for locoregionally recurrent breast cancer".)

TREATMENT AND PROGNOSIS — 

Locoregional recurrent breast cancers require multimodal treatments including surgery, radiation therapy, and, frequently, systemic therapy. The treatment strategies and prognosis are discussed in separate topics. (See "Surgery and radiation for locoregional recurrences of breast cancer" and "Systemic therapy for locoregionally recurrent breast cancer".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer" and "Society guideline links: Breast surgery".)

SUMMARY AND RECOMMENDATIONS

●Locoregional recurrence rate – The incidence of locoregional recurrence of breast cancer is 2.5 to 5.5 percent after breast-conserving therapy (BCT) and 2.2 to 3.6 percent after mastectomy. The median interval to recurrence is longer after BCT (three to four years) than after mastectomy (two to three years). (See 'Epidemiology' above.)

●Risk factors – The major risk factors for locoregional recurrences after BCT are lack of radiation therapy and positive pathologic margins. The locoregional recurrences after mastectomy are best predicted by the size of the primary and the number of positive lymph nodes. (See 'Risk factors' above.)

●Clinical manifestations

•Ipsilateral breast tumor recurrences after BCT are generally detected either by finding a palpable mass on physical examination or as a change on post-treatment surveillance mammography. (See 'Ipsilateral breast tumor recurrence' above.)

•A postmastectomy recurrence is usually detected clinically as a mass or multiple nodules in the chest wall or overlying skin in or near the mastectomy scar or in the skin flaps. (See 'Postmastectomy recurrence' above.)

•Lymph node recurrences are usually detected as palpable adenopathy in the axilla or supraclavicular fossa, although a regional recurrence may also present with pain in either location or the new onset of brachial plexopathy or lymphedema of the arm. (See 'Lymph node recurrence' above.)

●Diagnostic evaluation – The initial evaluation of suspected recurrent breast cancer should include biopsy of potential sites of disease (skin, chest wall, regional nodes) and breast/chest wall, axilla, and body imaging to determine the extent of recurrence and to exclude metastatic disease. Genetic testing may also be offered to appropriate patients. (See 'Diagnostic evaluation' above.)

Some experts restage all patients with an invasive locoregional recurrence, while others only restage patients with a chest wall or regional recurrence but not always those with an in-breast recurrence after BCT. (See 'Evaluation for distant metastases' above.)

●Differential diagnosis – The differential diagnosis of a breast or chest wall lump identified radiographically or on examination in a patient previously treated for breast cancer includes a new primary breast cancer; a recurrence; fat necrosis, which may occur after any previous surgery to the breast; radiation fibrosis; other types of malignancies (eg, breast sarcoma, which can arise after radiation); infection; and benign breast lesions. (See 'Differential diagnosis' above.)

●Distinguishing a true recurrence from a new primary tumor – A recurrence of the original tumor may be putatively distinguished from a new primary by its location relative to the original tumor or on other grounds (eg, histologic subtype, mammographic appearance, hormone receptor status, human epidermal growth factor receptor 2 [HER2] overexpression, discordant DNA flow cytometry). Distinguishing a true recurrence from a new primary by molecular classification may have therapeutic and prognostic implications. (See 'Distinguishing a new primary from a recurrence' above and "Surgery and radiation for locoregional recurrences of breast cancer", section on 'New primary versus true recurrence'.)