 Alright, so I'm going to be talking about a case that we were consulted on at the VA. This is a patient that was an inpatient over there. I'll talk about his case and some of the relevant pathology. I'll just kind of review some of the literature that I've found regarding other reports of his most likely diagnosis. So this was a 67-year-old male who presented with a chief complaint of nausea, weakness, and headache. On further history, except for the past several months he had had just low energy, poor appetite, and had been nauseated. Over that time period, he was an avid golfer, had been golfing every day and got to the point that he was not able to swing a club anymore. Alright, for the past three weeks he said, in association with the other symptoms, he started to have a dull headache around the left eye. And it was intermittent, came and went. He had some intermittent dyplopia along with that and some actually chest pain over the same past few weeks. His past medical history was none. He didn't know history of eye problems. Past medical history, he did have a history of coronary artery disease with bypass surgery. He had a pacemaker placed. History of atrial fibrillation, diabetes, COPD, hypertension. Unfortunately, a pretty common combination at the VA. Some medications were listed here. He was on insulin for his diabetes and some antihypertensives. Family history was not significant for any eye problems or diseases or for any cancers. He was a long time smoker, many years of smoking. Three quarters of the pack per day currently, but history of smoking more than that. No history of alcohol use, no illicit drug use. So on exam, his vision was 2025 in the right and 2030 in the left. Pupils were equally, did not have an APD. Pressure was normal in both eyes. Motility in the right eye was full. In the left eye, he did have minus half in abduction. It was otherwise full. We did find in most of that an esophorea that was worse with left gaze. And a right hyperphorea in left gaze and up gaze. Visual fields were full. Color vision was normal in both eyes. Stereo vision, he saw two out of three animals, six out of nine circles. Hurtel showed that he had just a slight amount of proptosis in the left eye compared to the right, just two millimeters. On slit lamp exam, he was found out some mild ptosis in the left eye, but otherwise no eyelid abnormalities. The remainder of his slit lamp exam, looking at the anterior segment, was normal. His funnest exam showed that he had flat corridor nevus in the left eye, but otherwise was normal. So, he had come from an outside hospital, and he had mentioned these symptoms at that point. At the outside hospital, they had gotten a CT of his orbits that we had access to. So I'll review those. So the first one, an axial view. You can see there's a pretty well circumscribed mass involving the muscle belly of the left lateral rectus muscle. Appears to be sparing the muscle tendon. Here's a coronal view. You can see, kind of at least at this section, how much of the orbit that's taking up in comparison with the other side. Then looking at a sagittal view, you can see that it's basically abutting the posterior edge of the globe and kind of taking up all that space between the globe and the orbital wall. So, based on the patient's history of these B symptoms and the CT that was obtained with the orbits, the primary team decided to pursue an oncologic workup, and so they got some more CT images. They just got a CT chest abdomen pelvis that shows more abnormalities, as you can see here. So, what we've got here is a left large pleural effusion with complete collapse of the left lower lung lobe. They also commented on multiple non-calcified pulmonary nodules in the right lung and some mediastinal adenopathy. CT abdomen shows in the left kidney, this is in the inferior pole of the left kidney, you can see this increased area of enhancement that they, the radiologist commented, appeared consistent with renal cell carcinoma. There was no apparent renal vein involvement at the time, but they did see some periaortic. It was just a sagittal and coronal view of that same renal mass. So, the differential at this point included neoplastic and non-neoplastic causes. So, as far as thinking about the orbital lesion, most common given the other lesions found elsewhere in the body were metastatic disease from a renal cell or possibly a lung carcinoma. Other metastatic considerations have been prostate and metastatic melanoma. This could have been a primary orbital tumor just that happened to occur with the other masses of hemangioma. It could have been a lymphoma or sarcoma. Then non-neoplastic things to consider would have been an idiopathic orbital inflammatory disease, specifically an orbital myositis or thyroid eye disease, although that would be a very atypical presentation for that. So, it was taken by Dr. Patel for a biopsy of this mass. So, first lateral campotomy was performed. Tarsal plate was disinserted laterally from the orbital rim. And access is gained through the orbital septum and blunt dissection is done basically in the space between the inferior and lateral rectus muscles until the tumor was visualized. So, it's a little bit of a tight space here and we don't see much of what's going on deep in the orbit. Eventually the tumor is visualized and some biopsies are taken. So, samples were fixed and H and E stain was obtained. This is a 40x magnification showing, you can kind of just see these nests of inflammatory cells. You can go closer, this is the 100x view and you can see one of these inflammatory infiltrates, a little higher magnification. 200x, you can start to see that the inflammatory infiltrate, there's a lymphocyte and a plasma cell. Then 400x you can get a little bit closer. So, we're still really just seeing inflammation, a lymphocytic and plasma cell inflammation that didn't look very specific and actually on initial read didn't look classic for carcinoma. So, it required some more staining to really come up with diagnosis. So, special stains were obtained and this was found to stain strongly positive for cytokeratin 7 and vimentin. A lot of other lung and kidney specific stains were sent and interestingly none of those came back positive. But, according to the pathologist that I talked to at the U that did these stains, that does not necessarily rule out either diagnosis. There can certainly be cases that don't stain positive for those. Melanoma markers were also sent and were negative. Because it looked so atypical for a carcinoma, some stains were sent to rule out a lymphoma and a plastic large cell lymphoma and those were also negative. And so, it was thought that given the combination of cytokeratin 7 and vimentin positivity, most likely diagnosis is poorly differentiated carcinoma. That still didn't tell us exactly what the primary site was, but given those combination of stains, renal cell carcinoma is known to stain positive for both of those in many cases. Well, as of last night, they made the meeting and said it's consistent with carcinoma cells. Oh, did they? Yeah. Okay, good. So, cytokeratin 7, this is a type 2 caratin. This is not our patient's path. I was not able to get that quickly enough. It's expressed in glandular cells and transitional epithelium in many organs including lung and kidney. It's seen in a lot of types of carcinoma including papillary, variant of clear cell carcinoma and lung, no carcinoma. It's not expressed by most GI malignancies. Again, this is just what a vimentin stain might look like, but not pathology from our patient. This is an intermediate filament protein that's expressed in mesenchymal cells. And it used to be thought that this was a very specific stain for sarcomas or mesenchymal cell tumors. But more recently it's been found to stain positive a lot more types of tumors than that including lymphoma, melanoma, and some mesoderm derived carcinomas including renal cell, some adenocarcinomas and thyroid. So looking at orbital metastatic disease, there's a good number of case series and reviews out there. The one that I found from Ferry and Fons, this one actually, this was the biggest one that I could find that they reviewed the most cases at one time. This was back in the 70s and there have been more reviews since then but none of them have been even half this large. So their review of 227 cases of metastatic carcinoma to the orbit and or the eye. They found that 196 of those or 86% had involvement just in the eye. And that's consistent with our knowledge of frequent metastases to the coroid. 28 patients had involvement in just the orbit or 12%. 20 patients or 8% had involvement of both the orbit and there was a wide range of age at onset of symptoms. A mean of 52.5 years. And contrary to teaching at the time, there was no predilection for the left eye or orbit. So it used to be thought that based on the anatomy of the aorta, metastatic disease getting to the left, basically the left side of the left orbit would have less of a tortuous path. It has more of a straight shot to get there. And so you'd expect to see more disease in the left than the right. They found that was not. As far as symptoms and signs that people presented with when they found to have orbital metastasis, exoptamos was most common. Pain, decreased vision, swelling around the eye. Patients had a visible mass and diplopia. And then looking at the sites where these tumors originated, most common overall was breast. And this is, again, this is just looking at orbital metastases. This is not including the eye or intraocular metastases. This is just for the orbit only. They found that breast was most common. Overall, in males, most common was lung. And then kidney was a pretty big player as well. Particular prostate, pancreatic, small bowel, malignancies were also found. But you'll notice too that 40% in males and 30.8% in females, they were not able to determine the primary malignancy. So this is kind of just telling you when eye symptoms developed in relation to when the primary neoplasm was diagnosed. And so in just over half of these cases, they already had a known primary neoplastic process when they developed eye symptoms. But in almost half, the eye symptoms came on first before they detected any primary source. And in a minority of cases, they found the cancer diagnosis at about the same time the patient developed eye symptoms. So the authors commented that pulmonary metastasis was often a prerequisite, which would make sense. Cells are going to have to go through the venous system, through the lung, in order to gain access to the orbit. But there are, at least at a review that these authors had looked at, there were 15% of autopsies on patients with ocular metastasis did not show any lung lesions. Of course, it is possible that they just weren't large enough lung lesions to be able to see grossly until they missed those. Prognosis. For patients, overall, that had intraocular or orbital metastasis median survival of 7.4 months, for patients with just orbital involvement, it was actually a little bit better, 15.6 months. And a little bit less in patients with anterior segment metastatic disease. Patients were followed up to 84 months with the last patient's last known status. And at that point, only 6.6 were still living, and about half of those were without any other known metastatic disease. It was unclear why there were certain primary malignancies that showed propensity to ocular orbital metastasis like breast cancer, but others like the GI tract that are rarely seen. There are several case reports and a few case series out there of discrete metastatic disease to the extraocular muscles like we saw in our patient here. I wanted to mention just one of a series of five cases that were reported by Capone and others, because it was so similar, I thought, to this patient that we had. He was a 63-year-old that presented with eye irritation and eventually developed horizontal diplopia a couple weeks later. Had a positive tensilon test, and so it was treated with periodostigmine. Then a month later, developed some subtle left proptosis, some low-grade fevers and weight loss. And further imaging, including a CT, showed focal nodular enlargement of multiple extraocular muscles, the right medial and lateral rectus. And left, I'm going to mention, there were four extraocular muscles involved in the left. They obtained a workup that showed also lytic lesions in the skull, some pulmonary nodules and a vascular lesion of the left kidney. They pursued an open skull biopsy, and that was consistent with renal cell carcinoma. There were some images of their patient that they reported on. And you see pretty similar findings. You see this rectus enlargement, multiple spots. From their literature review at the time, this was back in 1990, but there had been 31 cases reported. And similar to orbital metastatic disease, when you limit it to discrete metastasis to the extraocular muscles, breast cancer leads the pack at 51.6%. They included melanoma, whereas the fairy and font review did not. That was a high proportion of these as well. Lung cancer, renal cell carcinoma, these were certainly players as well, and carcinoma, neuroendocrine, gastric tumors, and then there were a couple that were not specified. Again, there was no predilection for either orbit. Most of these reports were since the dawn of CT, and since that gained widespread use. They noticed that horizontal rectus muscles are more frequently involved than vertical or obliques, and commented that this was likely because the horizontal rectus muscles are a lot more appreciated on axial CT. Rectus muscles are larger than obliques, and so they're likely just seeing it a lot easier. Median survival in this group was 5.5 months, but the breast cancer subgroup did better than that last. Just from my own PubMed search, besides the ones that they mentioned in their case series, there are several other cancers that have been reported to metastasis to the extraocular muscles, including prostate, gastroesophageal junction, adenocarcinoma, lymphoma, some rhabdomyosarcomas that were metastatic, pancreatic carcinoma, and neuroendocrine tumor, and a signet ring, adenocarcinoma, thyroid. Thinking about workup and treatment for these patients, oftentimes, as would make sense, if you biopsy some tissue from what's thought to be the primary lesion, compare that with tissue from the orbital lesion, that can help give you a specific diagnosis. Treatment is usually palliative because these patients are usually pretty advanced stage disease by the time they have extraocular muscle metastasis. As far as treating i-symptoms, radiotherapy can be given to the affected orbit. Systemic steroids can be given to reduce the side effects of the radiation. If patients are having intractable orbital pain and in the subset of patients that have metastatic carcinoid, surgery has been found to increase survival. So, surgery can be considered for these patients, but often it's not done. Just a quick review on renal cell carcinoma itself. 65,000 new cases and 14,000 deaths in the United States each year. Higher incidence in men compared to women comes on around age 64, it's the median age. 17% have metastatic disease at presentation. 17 have spread to lymph nodes and 62% are localized. 5-year survival rate has actually increased in the past 60 years from 34% to 71%. Treatment for localized disease, erotical nephrectomy is often curative and they might combine that with some adjuvant therapy. For advanced disease, it's usually unresectable. If patients have a good performance status measured by some kind of... I'm not sure what the measurements are. If they're found to have a good performance status, interleukin-2 has been found to induce long-term remissions in about 10%. For patients that are not candidates for interleukin-2 or that fail interleukin-2 therapy, VEGF inhibitors or M-tor inhibitors can be. Looking at ocular orbital involvement specifically from renal cell cancer, as of 2007, and there have been a few more cases since then, but as of the 71 cases of renal cell, metastatic to the higher orbit had been reported at the median age of 57. Again, more common in males, a lot more strikingly so. So renal cells, 50% more common in males, but there's a high proportion of male to female spread to the orbit or eye. Most cases are unilateral, there are a few bilateral cases. 45% had a previous history of renal cell carcinoma. Duration of symptoms had a big range prior to diagnosis. And the orbit was the most frequently involved site. So it's breaking this down into intraocular sites and extraocular sites that are listed from here down. And you'll see that the highest number of cases were in the orbit. And there were more extraocular spread cases than there were intraocular. And there were some spread to some interesting places like the lacrimal gland and the contract. 18 of these patients had other concurrent metastases at the time of diagnosis. Most of them to lung. Again, 72% were found to have lung metastases. 50% had brain, METS, 44% had bone, and 5% had liver. One patient with liver metastases and one with amyloid sinus disease. 31 of these patients underwent nephrectomy. Seven or 10% of these patients had radiotherapy or chemotherapy, and one had embolization. As far as treating the orbital lesions, 20.6% had a mass excision. 7% or 5% of the patients had a nucleation. One had an evisceration. A couple had eardectomy, and quite a few, 19% had external beam radiotherapy to treat their ocular orbital disease. Final outcome was known in 39 of the 71 cases. 33% were alive at that point. 67% deceased. So clinical course for our patient. At this point, oncology has recommended or brought up to the patient the idea of possible nephrectomy for cytoreduction, which he's declined. He's going to be following up with oncology this week to discuss more possible treatment options, which will likely be palliative. So to conclude, so metastatic carcinomas are a rare cause of orbital masses. Most common orbital metastases and discrete extraocular metastases come from breast and lung cancers, but renal cell primary, malignancy is not uncommon among these metastatic lesions. Renal cell carcinoma is more common than intraocular metastases, more common in the orbit than inside the eye, and treatment is most often palliative given the customary Q kid photo. Any questions? Yes? So excellent summary of obviously a complicated area. But just to throw a controversy in this, it turns out that there's now a fairly well accepted, although not universally accepted, concept that renal cell carcinoma fits with both breast and prostate, where you can get clearly histologically cancerous lesions that just are quiescent, stay over-tested, and that turn-catch disease. So I mean, the teaching algorithm is having, if it's renal cell carcinoma, you get it out of the dot. That's interesting. And prostate, prostate to neck at 66, and you look at it as 80%, but by the age of 80 or 90, essentially everybody has it. I would say directed prostate cancer, very controversial. That's a big, big bad on the cancer field. I didn't realize it. You know, it's interesting that you went over the results of Ray Font's study, and that study is now almost four years old, but it's still relevant. There's been a couple changes that are important. First off, it's the increase in lung carcinoma in women. And in the 70s, there were still television ads allowed for cigarettes. And it was interesting. There was one company that targeted women specifically, and so you saw this sleek, sophisticated woman with her cigarette. And their tagline was, you come a long way and baby. And that was it. So I must admit, some madmen, you know, thought this up, but what's happened since that time is, yeah, women have come a long way. They're now dying of lung cancer, similar to what men are doing. So we're seeing more and more lung cancer showing up metastatically in women. And the second thing with that study is they didn't have four years ago have decreased the number of those, you know, unknown tumors. They just said, okay, this is a tumor. We're not sure where it's from. You're after years that are staining just more and more sophisticated. We're finding that that number is really dropping down. So like this one, even when they did a whole panel that was still some controversy, they would look at all the staining and then say, well, okay, this is consistent. So, you know, in terms of that, like 20% of what was unknown, that drops everywhere. What's interesting about this one is when we looked at the biopsy, there were multifocal areas, I mean, planetary reaction, but hidden inside those inflammatory reactions were these medium-sized cells with kind of an eosinophilic, staining cytokinesis. We weren't sure what they were. And so we kind of sent it over to them. Those were the ones that were picking up the staining and eventually the specimen, and it wasn't a giant mass of tumors, and funny looking cells, and then a bunch of cytoreduction comes up every time we see it. From my limited reading, there was not, there wasn't much comment on any help from cytoreduction by an epirectomy. That's something I'd probably have to run by oncology or urology and get their thoughts. Talking about urology, they've shown a woman just to cut out a bunch of issues. Yeah. Yeah. I don't know that the patient's decision was a bad thing. I don't know that the epirectomy would have helped. I'd have to do more reading on that.