Abstract
Breast cancer is the main site of origin of orbital metastatic disease. Although invasive lobular breast carcinoma accounts for 10–15% of all breast cancer cases, it has been noticed that it metastasizes to the orbit more often compared to breast cancer of no special type (NST). The pathogenesis of this metastasis is not entirely understood; however, it seems that the unique tissue-specific characteristics of orbital microenvironment might contribute to metastatic disease in this particular site. Given the increasing survival of breast cancer patients and the prolonged metastatic potential of invasive lobular breast carcinoma, it is possible that the incidence of this rare metastasis might increase in the future. The purpose of this review is to present clinical manifestations, immunohistochemical characteristics and therapeutic options for orbital metastases from invasive lobular carcinoma.
Introduction
Invasive lobular breast carcinoma (ILBC) is the second most common histological subtype of breast cancer after breast cancer of no special type (NST, former invasive ductal breast carcinoma). ILBC accounts for 10–15% of all breast cancer cases, and it has been observed that its incidence has remarkably increased during the last 40 years [25,26,35,56]. Risk factors for ILBC include late age at first birth, menopausal hormone replacement therapy, late age at menopause, and a first-degree relative with ILBC [3,10,48]. ILBC is associated with older age, higher stage at diagnosis and a higher percentage of positive expression of estrogen receptors (ER) and progesterone receptors (PR), while the HER2 positivity is lower compared to NST [6,9]. Contrary to NST, ILBC is related to the inactivation of the tumour suppressor gene E-cadherin [57]. ILBC metastases can emerge even 20 years after initial tumour diagnosis, and in almost one-third of the cases, there are metachronous recurrences [34]. ILBC is associated with different metastatic patterns compared to NST. Studies have shown that ILBC is more likely to metastasize to the bones, gastrointestinal tract, peritoneum, myometrium, endometrium, cervix, or ovaries compared to NST, which has a greater lungs/pleura, central nervous system, liver and distant nodes involvement [5,17,28].
Metastatic tumours of the orbit are relatively infrequent, accounting for 1% to 13% of all orbital tumours. It is also presumed that only 2–3% of patients with systemic cancer will develop an orbital metastasis [43]. However, it seems that when orbital metastasis occurs, it is more likely to come from primary breast cancer in female patients, especially in ages between 40 and 79 [55]. Other primary sites include the prostate gland, the lungs, the skin, the kidneys and the gastrointestinal tract [43]. Even though the predominance of breast cancer origin among metastatic orbital tumours has been reported in several retrospective studies, the histologic type of breast carcinoma had not been documented [13,27,43,55]. Raap et al. (2015) analyzed a case series of metastatic orbital tumours from various primary sites according to the histologic subtype of the primary tumour and observed that the lobular breast carcinoma was over-represented [36]. A higher prevalence of lobular breast cancer was also reported in a recent study of ten breast cancer metastatic orbital tumours [19]. In light of this interesting correlation, in the present article, we aim to provide an updated review of published case reports and case series of metastatic orbital tumours from lobular breast carcinomas in order to summarize patients’ characteristics, clinical manifestations of the tumours, immunohistologic features as well as management data. Possible pathogenetic mechanisms of this rare metastasis are also discussed.
Materials and methods
We searched PUBMED using combinations of the following terms: ‘invasive lobular breast cancer’, ‘orbital metastases’, ‘lobular carcinoma’, ‘eye’, ‘ocular’, and ‘orbit’. We set no geographical restrictions. Non-English literature was excluded. We excluded the cases with inadequate tumour histologic characterization. We identified 25 case reports and 2 case series published in the last 25 years. In total, we extracted information from 40 cases of patients with orbital metastasis occurred from invasive lobular breast carcinoma [2,8,12,15,16,18,20–24,29,30,32,33,36–40,47,49,50,52,53,58,59].
Results
Patients’ characteristics and clinical presentation
All 40 patients were women. We observed that the mean age ± SD of patients at diagnosis of orbital metastasis was 60.0 ± 11.8 (age range: 39–85 years) (Table 1). The mass was unilateral in 72.5% and bilateral in 27.5% of the cases. No metastatic predisposition for the left or the right orbit was observed. Regarding the location of the lesion, in the majority of the patients (80%), the mass was orbital, while the rest 8 out of 40 patients (20%) had isolated periorbital or ocular lesions. Ocular sites involved the retina, the iris, the choroid and the optic nerve and extraocular sites mainly included orbital fat, extraocular muscles and eyelids. In the cases we have studied, patients referred to the doctor mostly for reduced vision or diplopia (42.5%) and swelling (40%). Interestingly, one patient presented gaze-evoked amaurosis, a transient monocular vision loss provoked by eccentric gaze. Other common symptoms were ocular dysmotility and pain. Four patients presented blepharoptosis as the initial symptom of the metastatic tumour. The duration of the symptoms varied from a few weeks up to years, but most of the patients noted their symptoms for months before they asked for a medical consult.
Patients’ characteristics and clinical presentation of the tumours
Patients’ characteristics and clinical presentation of the tumours
Most of the patients presented to the doctor with a known history of ILBC (20/40), while the orbital metastasis was the initial presentation of the ILBC in 14/40. In one patient, a poorly differentiated uterine adenocarcinoma had been presented 11 years before the orbital and breast involvement, which was misdiagnosed at the time, and it was retrospectively identified as metastatic ILBC. For the rest of the patients (5/40), the data regarding the prior history of ILBC was not available. Among the patients with a known history of cancer, the median interval between cancer diagnosis and the orbital involvement was five years (range: 3 months-25 years) (Table 2).
Immunohistochemical features and management
Abbreviations: ER: Estrogen Receptors, PR: Progesterone Receptors, HER-2: Human Epidermal Growth Factor Receptor 2, N/A: Not Available.
Evaluation of estrogen and progesterone receptors (ER, PR) and HER2 expression by immunohistochemistry are routinely performed in breast carcinomas. It should be noted that the hormone receptor status in metastatic lesions may vary from that seen in the primary malignancy. Among the cases we studied, ER expression was documented in 32 cases, PR expression in 22 cases, and HER-2 expression in 16 cases. Results were: ER positivity in 29/32, PR positivity in 12/22 and HER-2 positivity in 3/16 (Table 2).
Regarding disease management, five patients were treated with hormone therapy only, one with systemic chemotherapy only, three with surgical treatment only, and ten patients were treated with combinations of surgery, local radiotherapy, systemic chemotherapy and hormone therapy. One patient declined any intervention. For the rest of the patients, management data was not available. Remission of the orbital tumour was reported in the majority of patients treated with local radiotherapy. In most cases, vision preservation was achieved. Follow-up data was scarce.
Discussion
In the present review, we focused on lobular breast carcinomas since it has recently been suggested that they tend to metastasize to the orbit more frequently compared to invasive breast cancer of no special type [18,19,36]. The high frequency of ILBC in orbital metastases highlights the special metastatic behavior of this tumor subtype and may have implications for the understanding of the differential organotropism between ILBC and NST. It has been suggested that the difference might be associated with the lack of intercellular cohesiveness due to the absence of E-cadherin in ILBC, which is typically expressed in many neoplastic cell types, including NST [19]. In addition, high expression of estrogen receptors in ILBC might be associated with its tendency towards sites that produce estrogens. Generally, positive ER expression has been reported in 92% of ILBC [5] while positive PR expression in 54% [54]. In our review, the immunohistochemical characteristics of the tumours from the cases we included are consistent with the aforementioned reported data.
Moreover, regarding intraocular metastatic tumors, it might be possible that unique immune characteristics of ocular microenvironment and inhibition of immune response in the eye might induce tumorigenesis in this particular site [31]. In order for cancer cells to proliferate, they must evade the immune system surveillance. The eye is considered to have an “ocular immune privilege”, which is the result of both anatomical and immunoregulatory mechanisms [31]. The endothelial cells in the retina and iris have tight junctions that create a blood: ocular barrier, which obstructs macromolecules and leukocytes from easily entering ocular tissue [7]. Additionally, the aqueous humor (AH) that fills the anterior compartment of the eye is rich in immunosuppressive and anti-inflammatory factors such as transforming growth factor-𝛽 (TGF-𝛽) and 𝛼-melanocyte-stimulating hormone (𝛼-MSH) that inhibit the complement cascade [45,46]. It also contains somatostatin, which suppresses IFN-𝛾 production, acting as an immunosuppressant [51]. Nevertheless, it should be noted that ‘ocular immune privilege’ might contribute to the pathogenesis of intraocular tumours, and not orbital tumours, which are the majority of the cases.
Metastasis to the orbit is an uncommon complication in women with invasive lobular carcinoma. Most frequently, it occurs in patients with a known history of breast cancer, even many years after diagnosis and treatment of the primary tumour. This observation is in line with epidemiological data about ILBC, which reports that it occurs in older age and can give late metastases compared to NST [44]. However, it is noteworthy that a considerable percentage of the cases we studied (14/40) presented orbital metastasis as the initial presentation of breast cancer. Patients presented ocular symptomatology that forced them to visit the ophthalmologist. Interestingly, in 27.5% of the cases, metastases were bilateral, and the symptomatology affected both eyes. The clinical presentation of orbital metastases has a progressive course with combined motor and sensory deficits. However, misdiagnosis is common because similar clinical presentation occurs in more common orbital diseases, such as idiopathic orbital inflammation, myositis, or thyroid-associated orbitopathy [52]. As a result, patients remain practically untreated, and only when the symptoms persist or worsen, radiological exams are performed, and signs of a possible metastatic disease could be detected.
Regarding radiologic evaluation, magnetic resonance imaging (MRI) is the imaging method of choice for orbital tumours. The advantages of MRI over computerized tomography (CT) include a higher soft tissue contrast and the lack of ionizing exposure. Almost all orbital metastases evaluated with MRI show some degree of enhancement with contrast agents. However, even the radiological findings can be subtle and may not differentiate between benign versus malignant lesions. Metastasis can only be confirmed by biopsy. Orbital imaging with CT or MRI helps guide the biopsy in order to determine the appropriate surgical approach and to minimize injury to vital orbital structures [18,55]. Histopathologic differential could be challenging when there is no known history of breast cancer.
The presence of such metastases suggests a systemic haematogenous spread of the disease. In fact, anatomical studies describe limited lymphatic drainage in the orbit; therefore, distant metastases to the orbit occur through the blood flow [11,43]. The treatment can be adjusted depending on the clinical presentation and the extent of the metastatic disease, as well as the immunohistochemical characteristics of the tumour. The physician should keep in mind that a potential consequence can be blindness; therefore, orbital involvement often requires local disease management. Orbital surgery is mainly used for diagnostic rather than therapeutic purposes, given that the disease is already widespread at the time of diagnosis and is not curative. An open biopsy is sometimes necessary due to the presence of fibrosis that could result in an inadequate specimen when fine-needle aspiration is used. Additionally, surgery may also be useful in the palliative management of some patients since, in selected cases, tumor resection, even if incomplete, may be beneficial to improve symptomatology [41]. In one of the cases we studied, surgical orbital decompression was used to immediately reduce pressure on the optic nerve, which resulted in visual improvement [50].
Orbital radiotherapy is the treatment of choice for controlling tumour’s size and preserving visual function. External beam radiation therapy (EBRT) is commonly used [4]. The recommended dosage is 35–40 Gy to the affected orbit in divided doses over three to five weeks. However, dosage depends on the proximity of the radiation-sensitivity of the tumour as well as on the tolerance of normal tissue and the overall prognosis of the patient. Radiation delivery in small fractions is preferred in order to maintain normal tissue [14]. Complications of ocular radiotherapy are either acute or chronic. Acute complications include self-resolved radiation blepharoconjunctivitis with a risk of infection, while chronic complications may be cutaneous and conjunctival telangiectasias, eyelash loss, cataract, dry eye, radiation retinopathy, and optic neuropathy [14]. Systemic chemotherapy is preferred mainly when other synchronous metastases are present. The expression of estrogen receptors makes it possible to treat the orbital metastases using endocrine therapy. For HER2(+) cancers apart from chemotherapy and endocrine therapy, trastuzumab is also recommended as it improves overall survival [42].
Regarding the prognosis of the patients with orbital metastasis, a study by Shields et al. including patients with metastatic orbital tumours from various primary sites, reported overall mean survival of 20 months after diagnosis of orbital involvement. In the same study, patients with breast cancer and orbital metastasis had a mean survival time of 22 months [43]. Ahmad et al. reported that the mean survival time after diagnosis of orbital metastasis was 31 months [1]. However, in our analysis, survival data was limited due to a lack of follow-up.
Conclusion
In conclusion, this review provides clinical, immunohistological and therapeutic data from the literature regarding ILBC metastases to the orbit. Given that the survival of patients with breast cancer is increasing due to improvement in breast cancer management, we could assume that the prevalence of orbital metastasis is likely to be increasing. Therefore, breast cancer metastasis should be included in the differential diagnosis of an inflammatory orbital mass, especially when there is a known history of breast carcinoma. For patients with orbital tumours as initial manifestation, ophthalmologists could be the first to suggest the diagnosis. Therefore, when metastasis is suspected, a thorough medical history must be obtained, and physical examination should be performed, including breast examination. In cases with high suspicion and absence of a prior history of breast neoplasm, mammography should be considered. Treatment should be focused on controlling tumour’s size and preserving visual function. Radiotherapy is preferred for local treatment.
Footnotes
Acknowledgements
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Conflicts of interest
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