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Neuro oncology

Neuro-oncology encompasses both primary brain tumors as well as secondary tumors. In other words, tumors from systemic cancers that involve the central nervous system. It’s really much too large an area to cover in one hour, so what I thought I would do is spend the majority of time talking to you about primary brain tumors, because I think most medical oncologists are least familiar with these tumors. Yet, increasingly so, medical oncologists are going to be seeing these tumors.

When one actually looks at SIR data from the NCI one can see a bi-modal distribution in the incidence of primary brain tumors. It can peak for the first few years of life, which then falls off and then begins to rise in late adolescence, peaking around the age of 60. In fact, these tumors represent very significant problems. They are the second leading cause of cancer mortality in patients under the age of 34, and the fourth leading cause of death in patients between the ages of 34 and 54. And in fact, primary brain tumors – now that leukemia has been cured in 70-80% of children – has really become the primary oncologic problem in the pediatric population. Plus, primary brain tumors do in fact present a significant cancer problem in the United States.

Depending on the classification, there are as many as 15-30 different primary brain tumors. Meningiomas are very common but they are generally restricted to surgical management and radiation and only occasionally – for rare syndromes where we see malignant meningiomas – do medical oncologists see these patients.

When we talk about brain tumors almost regardless of the type of histology, we can group the syndromes, as far as how patients present, into the following signs and symptoms. The common presenting symptom is one of headaches. Seizures are seen in approximately half the patients, as are mental status changes and some kind of motor deficits. With the more readily available access to CAT scans and MRI scans, we are picking up patients earlier in the course of their disease, and that the number of patients who are actually presenting with significant increased intracranial pressure has significantly decreased.

Basal Cell Carcinoma

Basal cell carcinomas are among the most common cutaneous malignant tumors. Two thirds of basal cell carcinomas are associated with actinic damage; however, one third occur in areas not exposed to the sun. These lesions, although histologically malignant, only rarely metastasize. However, if neglected, they are destructive and can cause disability or death by invading adjacent soft tissue, cartilage, or bone.

A basal cell carcinoma usually presents as a dome-shaped, white to pink papule or nodule with a raised pearly border and prominent superficial vessels. There may be scaling, crusting, or ulceration. Various other clinical types of basal cell carcinoma have also been observed. The cystic variety is translucent and contains gelatinous fluid. The sclerosing variety, appearing as a fibrotic, whitish, macular plaque with indistinct borders, may easily be overlooked. Superficial multicentric lesions may resemble asymptomatic eczematous plaques, although close inspection reveals a fine, raised pearly border. The pigmented variety may be confused clinically with a malignant melanoma. A rodent ulcer is usually a painless basal cell carcinoma that has progressively enlarged, producing tissue destruction with invasion and ulceration of underlying structures.

Multiple basal cell carcinomas, ranging in number from a few to hundreds, may occur in patients with the basal cell nevus syndrome, an autosomal dominant condition. The basal cell carcinomas begin to appear after puberty on the face, the trunk, and the extremities. Many are highly invasive and involve the embryonic cleft areas of the face, especially the regions around the eyes and the nose. Other associated features of the basal cell nevus syndrome include odontogenic jaw cysts, palmar and plantar pits, ectopic calcification (particularly of the falx cerebri), and ocular and skeletal abnormalities such as hypertelorism and shortening of the fourth and fifth metacarpals. This disease complex has also been termed Gorlin’s syndrome.

Thyroid cancer. Conclusion

This is a guy looking sort of downcast and the caption reads, “Unfortunately there’s no cure. There’s not even a race for the cure.” Adrenal cancer is kind of like that. There is no cure unfortunately and it’s a rare enough cancer so it hasn’t gotten a lot of publicity. I’m not sure if there’s even a web site for adrenal cancer or not. Peak incidences is middle age, in the 40’s and 50’s, and there are two basic kinds of clinical presentations. Folks with nonfunctioning tumors; the tumors are generally going to be quite large at the time of presentation and the presentation will relate to clinical manifestations attributable to an abdominal mass.

These tumors tend to spread by direct invasion of surrounding structures as well as hematogenously. Alternately the tumors could present as a functioning syndrome. And they are about split, non-functioning tumors in most series compromise about 40-50% of the series and functioning tumors the remaining 50-60%. Among the functioning syndromes one can see Cushing’s syndrome with all the stigmata of hypercortisolism, virilization – either alone or virilization together with Cushing’s syndrome – comprise another large group of patients. Considerably less common might be patients who present with symptoms of mineral corticoid excess alone, hypertension, alkalosis, that sort of thing. Also quite common is the occasional man who presents with feminization as a result of an estrogen-secreting adrenal carcinoma.

This is a scan of a patient we saw several years ago, who presented with florid Cushing’s syndrome, had this very large mass that appeared to be arising from the adrenal gland. It was infiltrating into the vena cava, there were hepatic mets and very very extensive disease at the time of presentation. Unfortunately this patient did not do well and never really recovered from her surgery.

Indeed, surgery is the major therapeutic modality for this. The overall outlook in this disease is not good, but probably the single most important factor in terms of outcome is the resectability of the tumor. And this is just a chart of tumors that were completely resected versus those that were not. Among the chemotherapies for adrenal cancer, the agent that is used most commonly is mitotane, which has been shown to have some activity in these tumors. It’s a difficult drug to take. A couple of things to keep in mind if patients are on mitotane, since it is going to block adrenal hormone production, the patient should be on hydrocortisone to prevent adrenal insufficiency. There are some studies to suggest that monitoring serum levels is helpful and that there is sort of a fairly narrow therapeutic range. That folks who have levels less than 14 mg/L tend to have less effective tumor response, whereas side effects tend to become increasingly a problem for those with levels above 20 mg. So there is a role for monitoring, if you can do so.

Side effects for mitotane include weakness, somnolence, confusion, lethargy, headache, anorexia, nausea, diarrhea. Neurologic side effects are also seen, including ataxia and dysarthria. As I said, in general … you know, for us endocrinologists, when we have to deal with this, this is not an easy drug for patients. Frequently it will be necessary in these patients, in addition to attempting to do what one can to control the tumor, to in addition attempt some type of medical therapy to ameliorate their hypercortisolism, or perhaps their hyperandrogenism. And among the agents that can be used are ketoconazole, aminoglutethimide, metyrapone, and the RU486 steroid receptor blocking agent can also be used. But again, in general, I would say this is a disease in which the major treatment is surgical and which can be a very very difficult disease to deal with.

Management of medullary thyroid cancer

Management of medullary thyroid cancer: the disease again may present with symptoms or with a thyroid nodule. I don’t screen all my thyroid nodule patients with calcitonin levels but frequently the cytology will suggest that that’s what’s going on. If we do suspect it before surgery then certainly a pheochromocytoma should be ruled out by the appropriate urine studies. We mentioned the major treatment is total thyroidectomy with central node dissection. There’s a lot of controversy in terms of management of residual disease regarding chemotherapy or not. As far as the familial issue, a not uncommon situation now is that one has diagnosed somebody with medullary thyroid cancer, there may not be a family history, but still the question arises; maybe there is incomplete penetrance, maybe this has been a germ line mutation in an ancestor that is only now becoming apparent.

The genes for MEN IIa IIb and familial medullary thyroid cancer have been identified. They are all associated with alterations in the red oncogene and it can be screened for. So my practice in the follow-up of a patient who has presented with medullary thyroid cancer is to do the screening for red oncogene rearrangements in the presenting patient. If that is negative, then I think you can be reasonably confident that it is unlikely to be a familial case and you don’t need to go to great lengths to screen the rest of the family. On the other hand, if the screen for red oncogene rearrangements is positive, then certainly a full evaluation of the rest of the family should be followed out. Although I didn’t put the data on here, one of the significant factors in terms of cure of patients with the familial disease is early surgery. So in somebody who you have identified as having a oncogene present for this, I would recommend thyroidectomy be done as reasonably quickly as possible without waiting for the presence of either hyper-calcitonemia or certainly not for the presence of a thyroid nodule.

The multiple endocrine neoplasia syndromes, IIa: hyperparathyroidism, pheo, medullary thyroid cancer. IIb: the mucosal neuromas, pheo, and medullary thyroid cancer. And just for completion, type I is the three P’s. The important thing to remember about the P’s is that pheochromocytoma, although it begins with a P is not one of the P’s in type I but it is the combination of hyperparathyroidism, pancreatic islet cell neoplasms and pituitary neuroendocrine neoplasms. The gene for the type I syndrome was identified recently. I don’t know if there are any commercial screening kits available for it yet, but Steve Marks at the NIH has done excellent work in this area. And if you ever had a case, if you can’t find the screening test – if it’s not commercially available – I would give him a call and he would probably be able to help you out.

I’ll sort of give you a choice here which is; Bob has asked me to throw in a few slides on adrenal cancer, and I did. And the choice we have is that we can either break now and this is it, or if you are really anxious to hear about adrenal cancer, we could do that for five minutes. But … do it? Okay.

Medullary thyroid cancer

So let’s now turn to medullary thyroid cancer, which as I mentioned is really embryologically distinct from the follicular cell derived thyroid cancers. It accounts for a lesser percentage, say in the range of 5% of thyroid malignancies, and as I’m sure you remember, calcitonin is a very very sensitive tumor marker. Although these tumors, which are in effect part of the neuroendocrine tumor family, can often secrete other hormones as well. I personally think that tumors that secrete solely calcitonin, I’m not sure there is a clinical hypercalcitonemia syndrome, these patients do not become hypocalcemic or anything else.

But it’s not unusual for some patients to have some kind of an endocrine syndrome in medullary thyroid cancer, perhaps related to co-secretion of something else. The most interesting patient that I saw during the past year was referred to me with flushing, and my flushing work-ups are almost invariably negative. I can’t remember the last time I was actually able to find something in somebody who had recurrent flushing. But this patient had a thyroid nodule so I turned to my fellow and said, “Well, what do you think he’s got?” The fellow didn’t know. I said, “Well, obviously he’s got medullary thyroid cancer causing flushing.” And the fellow looked at me like I was a little crazy and of course I thought that was not very likely anyway. It turned out to be true. That’s what the man had. So these cases can present occasionally in a more symptomatic fashion.

Medullary thyroid cancer can be present either as a sporadic or in a number of different familial forms. The sporadic form tends to be unifocal in the thyroid gland, tends to present in a older middle aged population and is moderately virulent. Metastases are certainly not uncommon at the time of diagnosis, which can involve nodal spread as well as spread to lung, liver and bone. The major treatment for medullary thyroid cancer is thyroidectomy, as opposed to the follicular cell derived thyroid cancers where there is a limited role for very extensive neck dissection. Medullary thyroid cancer since it is primarily a surgical disease should have a careful central neck dissection done as part of the protocol.

There are several familial forms of medullary thyroid cancer, noted as I’m sure most of you remember, it is associated with some of the multiple endocrine neoplasia syndromes. And there is also a pure familial medullary thyroid cancer syndrome, although the genetic defect is related. This is just a survival curve for the different syndromes. MEN IIa, multiple endocrine neoplasia type II, is the combination of medullary thyroid cancer, pheochromocytoma, and hypercalcemia as a result of hyperparathyroidism. MEN IIb or also called MEN III is the combination of medullary thyroid cancer, pheochromocytoma and these mucosal neuromas. You can see that MEN IIa is a relatively indolent disorder and folks do very well with it. In comparison, MEN IIb is a much more virulent disease and as you can see the outcome in sporadic cases is kind of intermediate. I put the familial medullary cancer in sort of the same range.

The utility of thyroglobulin

This is an example of the utility of thyroglobulin. This is a patient who had surgery and 131 iodine ablation over here. The thyroglobulin level was initially around 5 at the time they were off suppression. They were started on thyroxin suppression. Their TSH was brought low and their thyroglobulin declined. A year later their thyroxin was stopped, TSH went back up, there was a slight increase in the thyroglobulin levels but the 131 iodine scan was negative, so they were put back on suppression. Several months after that their thyroglobulin, even while on suppression, started to rise and then when they were taken off suppression there was a considerably greater increment in their thyroglobulin, and the scan at that time was positive showing recurrent disease with pulmonary mets, which was treated with a second treatment with radioiodine.

Finally, as far as the other treatment issue that is available is the question of what one should do as far as thyroxine suppression. This is just some data from a recent, retrospective study, in which patients were scaled regarding the degree of thyroxine suppression. There were some patients who had essentially undetectable TSH’s and other patients whose TSH was not quite fully suppressed. What this is showing is that in patients with – this is going back to a TNM staging – TNM stage I or II disease, that there was not very much of an impact on recurrence related to the degree of thyroxin suppression but that in these higher risk patients with stage III disease, particularly, that the patients who were more fully suppressed had a lower risk of recurrence. So again, certainly in some of the patients who might be at a higher a priori risk there’s justification in treating them with sufficient thyroxine to keep their TSH suppressed, I feel that to an undetectable level at least for the first several years after treatment.

What about the patients who, in a way, I suppose you might be more likely to see, or the ones we need to call for additional help on, are those with differentiated radioiodine resistant thyroid cancer. A couple of potential treatment options; there is a role for external beam irradiation in these patients. Chemotherapy has been, I’d say, disappointing at best, but there still may be a role for it. The most commonly used drug has been Adriamycin, either by itself or in combination with cisplatin, with other agents. There are a variety of kind of interesting approaches being tried right now. In addition I believe there is a Taxol trial going on, although I haven’t seen any results on it. There has also been this interest in redifferentiation, in trying to treat the tumor in such a way as to lessen its radioiodine resistance and enable it to be more effective in taking up radioiodine. Retinoic acid and its congeners has been used and there has also been this interesting finding that occasionally in patients treated with Adriamycin as chemotherapy, that if you repeat the scan after they have gone through a couple of treatment cycles, that there have been some patients who have then been shown to take up radioiodine.

Suggesting that in some way there was some type of redifferentiation that took place. But clearly, these patients who get to a stage of radioresistant disease are a very very troubling group to treat. My approach, in terms of these patients, is; the question is whether they have progressive disease and whether they are symptomatic. If they are not symptomatic – and many many patients, even with extensive thyroid cancer, may not be – or maybe minimally symptomatic, there is certainly reason to simply continue to follow those patients. If there are significant symptoms taking place, which may frequently relate to bony metastases, then I think the important issue is to localize the disease. If the disease if very focal, if it involves an isolated or bony matter or a large soft tissue lesion, then there is certainly a role for external beam irradiation and/or surgery, depending on the locations involved. If the patient is progressing, has diffuse disease, then I think that might be the situation in which there would be a role for systemic chemotherapy, using either Adriamycin or some combination of agents. Then as I mentioned, consider at least not giving up totally on radioiodine but consider another scan maybe after a few cycles to see if there might have been some redifferentiation issue.

Radioiodine ablation

The next thing, following surgery and assuming that a total thyroidectomy has been done, the next thing is going to be radioiodine ablation. Basically what is done here is the patient is allowed to become hypothyroid, their TSH rises and they then are given a tracer dose of 131 iodine which typically will show uptake in the neck, because even a total thyroidectomy, surgically complete, is rarely complete at the level of radioiodine uptake. Assuming that there is a remnant, then that is going to be ablated with 131 iodine. There are questions in terms of dosage which I propose not to get into right now. But following ablation with radioiodine the patient would then be placed on thyroxine therapy with the goal of suppressing the TSH and now we are down to what we will call surveillance. This is the kind of findings that one might see in a patient, in terms of the benefit of adjunctive radioiodine. This is a total body metastatic scan, an anterior and posterior image, in a patient who had undergone a surgically complete thyroidectomy. This is uptake in the salivary glands, that’s normal. This is, as you can see, a lot of uptake remaining in the thyroid bed and at least some of this would appear to be metastatic in origin, going all the way down to the level of the suprasternal notch. In addition, you can see areas of uptake in the lung. This is a xiphoid marker here, some residual iodine in the lung uptake is actually this over here. So that patient was given a therapeutic dose of 131 iodine, probably in that case 200 microcuries of iodine were given. And this is a scan that was done a year or two later. At this time the patient was again withdrawn from thyroxine, the TSH was again allowed to rise and they were again given a tracer dose of radioiodine. There is still this appropriate uptake into the salivary glands, but you can see now the neck and the chest are now clear. There is still some uptake in the large colon over here. In fact, this patient has been disease free since the time of this treatment.

And this again is just some data from Masoferre’s studies on recurrence and death rate again in patients with intermediate stage II and III disease in the absence or presence of radioiodine. And you can see that there were no deaths in the radioiodine treated group and a substantial decrease in the risk of recurrence as well.

Finally, the surveillance data. We’ve already sort of alluded to that. There are two major components to surveillance. One is the measurement of thyroglobulin, the thyroglobulin which is a normal thyroid product should be undetectably low in patients who have undergone total thyroidectomy and radioiodine ablation who are disease free. So a rising thyroglobulin is a marker of a return of thyroid tissue, obviously very suspicious for thyroid cancer. The other major surveillance tool that I alluded to is the use of the whole body metastatic survey. My recommendation is, assuming that we treat the patient which might typically occur eight weeks or so after their initial surgery, assuming that we treat the patient, that there is some remnant uptake. Certainly if there is metastatic uptake, I would repeat a scan a year later and a year after that I would want to see two negative scans at yearly intervals following radioiodine therapy before I’d stop doing yearly scans. If the scans continued to show metastatic uptake then of course one might want to consider further treatment with radioiodine to eradicate recurrent or residual disease. I’ll also then continue to follow the patients by measuring their thyroglobulins periodically and using that as an additional screen.