Metastatic Tumors to the Eyelids
Key Points
Eyelid metastasis is very rare accounting for less than 1% of malignant eyelid lesions
Breast carcinoma is most frequent, followed by skin melanoma, gastric carcinoma, uveal melanoma, lung carcinoma, and kidney carcinoma
Clinically, metastatic lesions generally appear as a painless diffuse eyelid swelling, or solitary acutely inflamed tender nodule mimicking acute chalazion, but may show no specific clinical features that distinguish them from primary eyelid malignancies
They typically occur as a late event in the course of systemic disease, and in the case of breast cancer may appear 2 to 10 years after the initial diagnosis
The management of metastases is directed at the systemic disease with systemic chemotherapy and immunotherapy
Local eyelid treatment may include observation, excisional biopsy, and external beam radiotherapy
The prognosis of patients with eyelid metastatic tumors varies depending on the type of malignancy, primary tumor stage, and extent of systemic metastatic disease
Eyelid metastasis is a very rare condition that accounts for less than 1% of malignant eyelid lesions.1,2,3,4,5 In a survey of 892 eyelid lesions, of which 214 were malignant, only 3 cases (0.3%) were metastatic tumors.2 In another review, out of 1502 eyelid lesions evaluated histopathologically, only 1 case (0.07%) of eyelid metastasis was found.3 Up to 50% of cases are derived from a breast carcinoma, which explains why eyelid metastasis occurs more frequently in women than in men. However, no sex differences have been observed for metastases of other origins.6 Eyelid metastases predominantly occur in adulthood, although very rare cases related to sarcoma or embryonic tumors of a neural origin can occur in children.7 The majority of metastatic lesions to the eyelid are carcinomas, with the breast, gastrointestinal tract, and lung as common sites for the primary lesion.8,9 Most eyelid metastases appear in patients with a known history of systemic cancer, but eyelid metastasis can be the first symptom of systemic cancer in 7% to 45% or the first sign of metastatic recurrence from known cancer.1,6,8,10 There should be a high level of suspicion for the possibility of metastatic disease when dealing with rapidly growing lesions of the ocular adnexa, especially when there is a known history of malignancy elsewhere in the body.
Three clinical presentations of eyelid metastases have been observed. The most frequent is a painless, subcutaneous, skin-colored nodule, seen in up to 62% of all cases. These lesions are often mistaken clinically for a chalazion. The second type of presentation is a diffuse, infiltrative, inflammatory pattern seen in 30% of cases. Such lesions are characterized by a red to brown induration of the eyelids, with a morpheaform appearance. Finally, the ulcerated type (8%) results from invasion of the epidermis by neoplastic cells and may appear in conjunction with either of the aforementioned types.3,8 Zimmermann et al11 described a fourth, edematous variant of eyelid metastasis presentation, but this may just be an earlier stage of the diffuse type. This is seen more commonly with breast metastases.
Three surveys plus several later individual case descriptions totaling 76 cases have reported the distribution of eyelid metastases by primary tumor site.1,6,8,12,13,14,15,16,17 Taken together, breast carcinoma was the most common primary site (32%), followed by skin melanoma (20%), gastric carcinoma (8%), uveal melanoma (8%), lung carcinoma (5%), and kidney carcinoma (4%). Other rarely reported primary sites for eyelid metastases include salivary duct carcinoma, leiomyosarcoma, osteogenic carcinoma, Kaposi sarcoma, carcinoid tumor, neuroendocrine carcinoma, lymphoma, thyroid carcinoma, rectal carcinoma, bladder urothelial carcinoma, mediastinal teratoma with malignant transformation, hepatocellular carcinoma, prostate cancer, and uterine cervical carcinoma.18,19,20,21,22,23,24,25,26,27,28,29,30,31
Etiology and Pathogenesis
Metastasis is a complex, multistage process that requires carefully timed, diverse stages and properties acquired by cancer cells. Metastatic cells must move from the primary tumor site, enter the bloodstream and survive there, and then exit the bloodstream at the arrest organ. They then must colonize the distant tissue and grow into a macroscopic metastatic lesion.32 Circulating tumor cells represent an intermediate stage between the primary tumor and the metastatic tumor.
Specific tumor-host cell interactions facilitate the initiation of metastatic spread and determine the distribution of metastatic tumor deposits in various organs and tissues.33,34,35,36,37 Individual tumor types form metastatic tumors in specific organs, unrelated to the route of tumor cell migration.33 Studies have shown that breast cancer cells obtained from
metastasis-free organs of mice that suffer from lung and lymph node metastases are not only alive but can resume neoplastic growth and metastatic behavior if reinoculated into compatible organs. This supports the idea that metastatic tumor cells are dependent on suitable stromal environments for their growth.33 As a result, mature metastases are not just aggregations of tumor cells, but consist of a mixed population of neoplastic and non-neoplastic cells.38 Among the non-neoplastic cells are various cell lineages including fibroblasts, macrophages, and endothelial cells, among others. Over time, the architecture of the lesion becomes organized into a distorted histologic version of the original organ that produced the primary tumor.
metastasis-free organs of mice that suffer from lung and lymph node metastases are not only alive but can resume neoplastic growth and metastatic behavior if reinoculated into compatible organs. This supports the idea that metastatic tumor cells are dependent on suitable stromal environments for their growth.33 As a result, mature metastases are not just aggregations of tumor cells, but consist of a mixed population of neoplastic and non-neoplastic cells.38 Among the non-neoplastic cells are various cell lineages including fibroblasts, macrophages, and endothelial cells, among others. Over time, the architecture of the lesion becomes organized into a distorted histologic version of the original organ that produced the primary tumor.
Intrinsic properties, such as gene expression patterns in the metastasizing cells, help drive the metastatic event,33 and individual tumor cells differ in their metastatic potential.39,40,41,42 The programmed steps initiated in metastatic cells follow an orderly sequence that has been speculated to superficially resemble embryonic cell migration,33 and the orderly migration of lymphocytes as they move around the body.
Primary tumor cells that invade surrounding tissue lose E-cadherin function resulting in decreased intercellular adhesion. This is a molecule that links cells together through their actin cytoskeleton. This loss of function is caused by mutations or gene downregulation. These epithelial tumor cells can then migrate across the basement membrane to enter the tissue stroma facilitated by enzymes, such as matrix metalloproteinases, which cleave proteins.
Emerging evidence supports the concept that different stromal components in the primary tumor microenvironment also contribute to the regulation of cancer formation and promote the development of metastasis. These include cancer-associated fibroblasts, macrophages, neutrophils, myeloid-derived suppressor cells, regulatory T cells, natural killer cells, and extracellular matrix, among others.43 Certain tumor cells acquire the ability to induce epithelial-to-mesenchymal transition, which helps them to break loose from the primary tumor.44
The metastatic process begins when cells from the primary tumor separate from other cells and invade the surrounding stroma where they are directed toward blood vessels by growth factor gradients. Through the process of intravasation, they penetrate the vessel, aided by increased permeability and fragility of the vessel wall from tumor-associated dysregulation of angiogenic signaling,45 and inflammatory signaling.46 Cancer cells can also access the bloodstream indirectly via the lymphatic system.32
When the circulating tumor cells reach the bloodstream they are subjected to attack by immune cells, especially by natural killer cells.47 However, they can employ several mechanisms to avoid immune surveillance, such as coupling to reactive platelets and allowing them to imitate host cells and to be protected from shear forces.48,49 The platelets also release transforming growth factor-β, which can downregulate a surface receptor that in turn downregulates the antitumor function of CD8+ T lymphocytes and natural killer cells.50
These circulating tumor cells are also characterized by an increased ability to survive in the bloodstream,51 although over time a majority of these cells die. In one study, only 2.5% went on to form micrometastases, and far fewer (0.01%) of these cells induced macrometastases.52 They are also believed to possess stem-like properties that are capable of self-renewal and tumor formation.53,54
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
