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 Реферат RUS  Реферат ENG  Литература  Полный текст
УДК:УДК 617.7

DOI:https://doi.org/10.25276/2410-1257-2019-4-23-26

Офтальмологические проявления системных онкологических заболеваний


     We all know that many systemic diseases cause a wide range of findings in the eye examination. In our daily practice in ophthalmology, we encounter many comorbidities and play a critical role in the management of these systemic conditions such as diabetic retinopathy (DR) or thyroid-associated orbitopathy. An ophthalmologist may also play an important role in systemic cancers.

    Having sufficient knowledge about the systemic cancers and their potential ophthalmic manifestations are important for 2 reasons. First, in some patients, the disease may initially manifest with ocular signs before the diagnosis of a systemic malignant disease. Thus, considering potential systemic cancers in the etiology of the ocular manifestations and performing a diagnostic screening in these patients can help make an early diagnosis of cancer followed by appropriate treatment. Secondly, in some advanced cancer patients with relatively shorter life expectancies, several ophthalmic problems can be resolved and quality of life may be increased in the last precious days of the patient by applying simple and cheap methods, only if they are diagnosed.

    A brief review of the epidemiology is required to understand the importance of the subject. Cancer is the second leading cause of death in the world after cardiovascular system diseases. Every year, a growing number of new cases of cancer emerge, with increasing incidence and prevalence rates. Oncology authors have already predicted that cancer would be the most common cause of death in 2030. Therefore, owing to the interaction of several factors including the increase in the incidence of cancers, advances in the diagnosis and treatment, the longer survival rates of these patients, and the increased access to the physician; we encounter ocular findings of systemic cancers increasingly day by day. An important point to remember is that all eye diseases in the normal population, such as cataract, glaucoma etc., can also be seen in cancer patients with similar or different incidence rates. Therefore, linking all conditions to cancer may be as much erroneous as missing pathologies related to a malignant disease. All findings should be systematically evaluated and the differential diagnosis of each unique manifestation in every patient should be made carefully. The most common type of primary malignancies is breast cancers in women, and lung and prostate cancers in men.

    In cancer patients, ocular manifestations can develop via various mechanisms;

    Local Invasion and Metastasis: The most important group of patients with systemic cancers comprises the ones suffering from the direct effects of systemic cancers. In this group of patients, malignant cells are present in the eye tissues. The disease may manifest in the form of a local invasion as with paranasal sinus tumors, or it may present itself in the form of a hematogenous metastasis.

    Metastases can be seen in the orbit, intraocular tissues, conjunctiva, and in every type of ocular tissue except the lens. In addition, metastases in the CNS that affect the visual pathways or the cranial nerves controlling the eye movements are related to various neuro-ophthalmologic findings. There are two very important points about metastases. One of them stands for patients whose clinical findings are compatible with metastasis, but who do not have a known history of cancer. Diagnostic screening for systemic cancers will reveal the presence of a primary cancer in most of these patients. The second point stands for patients with a known history of cancer, who are considered to be cured or who are assumed to be at an early stage like stage 1, 2 cancers. Diagnosis of metastasis is highly important in these patients as it will lead to making a diagnosis of a stage 4 cancer. Naturally, this will cause changes in the systemic treatment regimens and follow-up schedules of these patients.

    Besides these two special cases, a significant proportion of patients with an ocular metastasis have also metastases in other organs, such as the liver, bones or the brain.

    In the eye, metastases may occur in all types of tissues except the lens. Obviously, uveal metastases are the most common type because the uvea is the part of the eye with the highest rate of vascularization. Uveal metastases are also the most common intraocular malignant tumors in adults. As the lymphatic system of the eye has not been clearly established yet, the hematogenous route of spread remains to be the most common mode of metastasizing to the eye for the malignant cells. Metastases to the choroid are the most common location among all types of uveal metastases.

    The origin of these metastases is usually carcinomas. Ocular metastases occur very rarely in sarcomas. The most common ocular metastases are found in women with breast cancers, and in men with lung cancers.

     The first symptom in choroidal metastases is painless vision loss, but the lesion may be asymptomatic initially until the macula is involved. Their ophthalmoscopic appearance is typically one or multiple yellow-to-cream-colored lesions initially having a flat configuration. Depending on the type of carcinoma, the color of the lesions may vary in a range from orange to coffee-like tones. Figure 1 shows early metastatic lesions. When the lesions grow or take the form of thicker infiltrates, a serous retinal detachment (RD) occurs due to subretinal fluid accumulation.

    The presence of subretinal fluid and serous RD are found in 75% of choroidal metastases. Figure 2 shows a metastatic lesion similar to central serous chorioretinopathy. The differentiating features of this detachment include a less undulating pattern in the retina and the presence of shifting fluid compared to a more common form, the rhegmatogenous RD.

    We can list many pathologic entities of the choroid and retina in the differential diagnosis of choroid metastases. Generally, it is possible to make a diagnosis based on a good anamnesis, and clinical examination and US imaging findings. A diffusion-weighted MRI can be performed in difficult-to-diagnose cases. However, in every patient with a history of cancer, it would be inappropriate to make a diagnosis of metastasis without performing an adequate clinical examination and diagnostic evaluation.

    For instance, Figure 3 shows a patient, who was considered to be in remission after receiving systemic treatment for cancer. When the patient presented with the complaint of vision loss to another center, he was mistakenly diagnosed with a metastasis to the choroid. This indicated a stage 4 cancer; therefore, chemotherapy started immediately. Surprisingly, the eye examination made after a few sessions of chemotherapy showed a large mass in the choroid accompanied by a serous detachment in the retina. The ultrasound examination findings favored a melanoma rather than a metastasis.

    This case is a good example in showing that the underlying cause can well be another type of intra-ocular cancer, as well as, all other types of ophthalmic diseases. In other words, it should always be remembered that, in patients with systemic cancers, other types of intra-ocular tumors and all other eye diseases must be included in the differential diagnosis of a metastasis to the eye.

    Metastases to the iris usually present with symptoms including pain, visual loss, IOP elevation, inflammation; or they may be asymptomatic. Figure 4 shows an iris metastasis in the form of a pink, vascular mass.

    Metastasis to the ciliary body causes dilation in the episcleral sentinel vessels, bulging of the iris, a sector cataract, lens displacement, and focal episcleral pigmentation.

    Orbital metastases can be seen in almost all types of cancer. Clinical symptoms and findings may vary widely depending on the size and location of the mass. Symptoms such as proptosis, ptosis, extraocular motility limitations, and dystopia are seen most frequently. The clinical picture may sometimes show features reflecting a primary tumor. For example, prostate cancer tends to metastasize to the bone and causes osteolytic or osteoblastic changes. In breast cancers, we can see a wide variety of clinical forms of orbital metastases, which may be located anywhere in the orbit including the muscle, fat, or bone tissue. The patient in Figure 5 has a metastasis extending from the upper part of the orbit to the cranial region.

    One little-known point about orbital metastases is that; sometimes, instead of exophthalmos, enophthalmos may develop. This is mainly due to the fact that in the case of scirro cancers, the mass is as hard as wood and it retracts the globe back. In some cases, with excessive bone resorption, enophthalmia may occur, resembling orbital decompression. We can see this situation mostly in gastric cancers and sometimes in breast cancer.

    In children, we see orbital metastases rather than intraocular ones. The most important of these is neuroblastoma. In addition, Ewing tumor and Wilms’ tumor can rarely metastasize to the orbit.

     Paraneoplastic Syndromes (PNS) result from indirect and remote effects of cancers via an autoimmune mechanism in the absence of any tumoral involvement in the ocular region. Furthermore, a definite diagnosis of a PNS requires the clinical picture not to be explained by the side effects of any modes of treatment. The main underlying reason for a PNS to develop is that the primary tumor secretes an antibody that disrupts or mimics the function of a normal protein in the circulation. These antibodies cross-react with some tissue antigens in the neural system.

    PNS can be seen before the diagnosis of the disease, in its active period and even after treatment and recovery. The most important point in making a diagnosis of PNS is the requirement to rule out all other potential clinical conditions in the differential diagnosis before reaching a final conclusion; including metastasis, infection, metabolic causes or an adverse effect of a drug.

    Although PNS has been described in the last quarter of the 20th century, many publications have emerged almost only in the form of case reports; yet the diagnostic and therapeutic difficulties have not been overcome. In order to make a definitive diagnosis, it is necessary to detect some antibodies.

    The most important PNSs of the eye are Carcinoma Associated Retinopathy (CAR), Melanoma Associated Retinopathy (MAR), Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP), Paraneoplastic Optic Neuropathy (PON), opsoclonus, and Lambert Eaton Syndrome.

    In Carcinoma Associated Retinopathy (CAR), damage to the photoreceptor layer occurs due to an antibody against a 23 kD-weighing protein, recoverin, involved in important functions of the retina. This syndrome, which initially presents with a nearly normal appearance of the fundus, is characterized by a slow but progressive visual loss. Often, 50% of patients do not have a cancer diagnosis at the time of visual loss. Retinitis pigmentosa-like findings such as narrowing in the retinal vessels, retinal pigment epithelium (RPE) atrophies, disc pallor or mild vitritis may be seen later. Diagnosis can be made by exclusion of other causes and by diagnostic tests including ERG, dark adaptation test, and antibody determination. For the treatment of CAR; several options such as steroids, intravenous immunoglobulins, and plasmapheresis have been tried, but they have not been found useful and the visual prognosis is poor.

    Melanoma Associated Retinopathy (MAR) is a rare paraneoplastic syndrome characterized by damage to the bipolar cell layer in some patients with skin melanoma. In MAR, unlike CAR, the condition is milder and regresses with the treatment of the disease. The fundus is usually normal.

    Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) is characterized by uveal thickening and melanocyte proliferation at the RPE, which causes painless vision loss.

    Side effects of cancer therapy: Undesirable effects of the chemotherapeutic or other pharmacological agents used in the treatment of primary disease and radiation therapies applied to the head and neck region can cause some ocular problems.

    The most common treatment for systemic cancers is chemotherapy with antitumor agents. These agents, while killing tumor cells, create many side effects in the normal tissue. Any eye symptom has been reported for almost all agents as a rare or frequent adverse event. Chemotherapy agents enter the lachrymal system and the tear, causing some superficial topical side effects in the eye and on the ocular surface.

    The most common chemotherapeutic agents and their untoward effects on the eye are listed in Table 1.

    Radiotherapy, which is commonly used in head and neck tumors, is associated with toxic effects in every part of the eye, from the skin to the optic nerve and the brain. For example, the development of cataract in the lens is actually the most innocent type of all these effects. The risk of developing retinopathy is related to the method and dose of the radiotherapy applied to the patient. There is a high risk of developing radiation retinopathy over a certain dose in conventional radiotherapy. However, dividing the high doses into fractions reduces the risk of retinopathy slightly. The point that should not be forgotten here is that radiation retinopathy may not occur immediately after the treatment but it emerges after a long period following the radiotherapy; for instance, it may occur after 3-4 years.

    People, who received a combination of chemotherapy and radiotherapy or who suffer from vascular diseases, have a higher risk of retinopathy; because the pathogenesis is related to vascular injuries similarly observed in diabetic retinopathy (DR). The difference from DR is the presence of more severe endothelial damage and a lower amount of microaneurysms in this type of retinopathy.

    1. The fourth group comprises the ocular findings resulting from systemic abnormalities; such as coagulation disorders, and metabolic and immune disorders caused by a primary cancer.

    2. Finally, there are some systemic cancer syndromes associated with some ocular findings; including Multiple Endocrine Neoplasia Type IIb, Gardner Syndrome, Neurofibromatosis, von Hippel–Lindau syndrome, Aniridia, Cowdens syndrome, Carney complex, Muir–Torre syndrome etc.


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