The initial search of MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO yielded a total of 722 articles. Seven other articles found separately while undergoing our initial research were added to this total. Abstracts were manually screened, with 657 articles discarded after failing to meet the predetermined inclusion criteria. After removal of 25 duplicate articles, the full text of the remaining 47 articles were reviewed, leading to the elimination of an additional 11 articles that did not meet the necessary criteria. This resulted in 36 articles (Figure 1), including 27 individual case reports (Table 1) and 9 retrospective reviews (Table 2). Approximately 13.7% of patients in the 9 retrospective reviews presented with a skin lesion before or simultaneous to the diagnosis of breast cancer (Figure 2).
Forty-one percent (17/41) of the patients with cutaneous metastasis as a presenting feature of their breast cancer fell outside the age range for breast cancer screening recommended by the US Preventive Services Task Force,42 with 24% of the patients younger than 50 years and 17% older than 74 years (Figure 3).
The most common cutaneous lesions were erythematous nodules and plaques, with a few reports of black17,21 or flesh-colored5,20,31 lesions, as well as ulceration.8,17,32 The most common location for skin lesions was on the thorax (chest or breast), accounting for 57% of the cutaneous metastases, with the arms and axillae being second most commonly involved (15%)(Figure 4). Some cases presented with skin lesions extending to multiple regions. In these cases, each location of the lesion was recorded separately when analyzing the data. An additional 5 cases, shown as “Other” in Figure 4, included the eyelids, occiput, and finger. Eight case reports described symptoms associated with the cutaneous lesions, with painful or tender lesions reported in 7 cases5,9,14,17,20,30,32 and pruritus in 2 cases.12,20 Moreover, 6 case reports presented patients denying any systemic or associated symptoms with their skin lesions.2,5,9,16,17,28 Multiple cases were initially treated as other conditions due to misdiagnosis, including herpes zoster14,30 and dermatitis.11,12
Eighteen cases reported positive immunohistochemistry from cutaneous biopsy (Table 3), given its high specificity in determining the origin of cutaneous metastases, while 8 case reports only performed hematoxylin and eosin staining. One case did not report hematoxylin and eosin or immunohistochemical staining. Table 4 lists the final breast cancer diagnosis for each case.
As per the standard of care, patients were evaluated with mammography or ultrasonography, combined with fine-needle aspiration of a suspected primary tumor, to give a definitive diagnosis of breast cancer. However, 4 cases reported negative mammography and ultrasonography.13,22,28,31 In 3 of these cases, no primary tumor was ever found.13,22,31
Our systematic review demonstrated that cutaneous lesions may be the first clinical manifestation of an undetected primary malignancy.40 These lesions often occur on the chest but may involve the face, abdomen, or extremities. Although asymptomatic erythematous nodules and plaques are the most common clinical presentations, lesions may be tender or pruritic or may even resemble benign skin conditions, including dermatitis, cellulitis, urticaria, and papulovesicular eruptions, causing them to go unrecognized.
Nevertheless, cutaneous metastasis of a visceral malignancy generally is observed late in the disease course, often following the diagnosis of a primary malignancy.14 Breast cancer is the most common internal malignancy to feature cutaneous spread, with the largest case series revealing a 23.9% rate of cutaneous metastases in females with breast carcinoma.6 Because of its proximity, the chest wall is the most common location for cutaneous lesions of metastatic breast cancer.
Malignant cells from a primary breast tumor may spread to the skin via lymphatic, hematogenous, or contiguous tissue dissemination, as well as iatrogenically through direct implantation during surgical procedures.3 The mechanism of neoplasm spread may likewise influence the clinical appearance of the resulting lesions. The localized lymphedema with a peau d’orange appearance of inflammatory metastatic breast carcinoma or the erythematous plaques of carcinoma erysipeloides are caused by embolized tumor cells obstructing dermal lymphatic vessels.3,11 On the other hand, the indurated erythematous plaques of carcinoma en cuirasse are caused by diffuse cutaneous and subcutaneous infiltration of tumor cells that also may be associated with marked reduction in breast volume.3
A primary breast cancer is classically diagnosed with a combination of clinical breast examination, radiologic imaging (ultrasound, mammogram, breast magnetic resonance imaging, or computed tomography), and fine-needle aspiration or lesional biopsy with histopathology.9 Given that in 20% of metastasized breast cancers the primary tumor may not be identified, a negative breast examination and imaging do not rule out breast cancer, especially if cutaneous biopsy reveals a primary malignancy.43 Histopathology and immunohistochemistry can thereby confirm the presence of metastatic cutaneous lesions and help characterize the breast cancer type involved, with adenocarcinomas being most commonly implicated.28 Although both ductal and lobular adenocarcinomas stain positive for cytokeratin 7, estrogen receptor, progesterone receptor, gross cystic disease fluid protein 15, carcinoembryonic antigen, and mammaglobin, only the former shows positivity for e-cadherin markers.3 Conversely, inflammatory carcinoma stains positive for CD31 and podoplanin, telangiectatic carcinoma stains positive for CD31, and mammary Paget disease stains positive for cytokeratin 7 and mucin 1, cell surface associated.3 Apart from cutaneous biopsy, fine-needle aspiration cytology can likewise provide a simple and rapid method of diagnosis with high sensitivity and specificity.14
Although cutaneous metastasis as the presenting sign of a breast malignancy is rare, a high index of suspicion should be exercised when encountering rapid-onset, out-of-place nodules or plaques in female patients, particularly nodules or plaques presenting on the chest.