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.

Papillary and follicular carcinomas

For the rest of the talk I’m really going to treat papillary and follicular carcinomas together as far as treatment decisions are concerned. The prognostic factors are similar for staging, and although it has traditionally been said that the outcome in follicular cancer is worse than the outcome in papillary cancer, oftentimes it’s not clear if it relates to the difference in the tumor type or if it’s more properly accounted for by these risk factors. But important prognostic risk factors, in terms of staging or particularly patient age – older being worse from a viewpoint of outcome – tumor size, multifocality within the thyroid gland may be a moderate factor for risk. Tumor histology; we’ve talked about some of the very specific variant forms already. The presence of local invasion into surrounding neck structures. Cervical node metastases in papillary thyroid cancer certainly are not a terrible risk factor, and in fact many studies would suggest that there is little difference in outcome related to the presence or absence of cervical nodes, but there may be some factor. Clearly, distant metastases are important. This just shows the importance of age. Most of the deaths from papillary thyroid cancer, from differentiated thyroid cancer, occur in patients who acquire the disease at an older age. Read more…

There have been several staging systems that have been popularized for papillary thyroid cancer. It’s sort of one of these things about standards now. Everybody likes standards so much, and that’s why they make so many different ones. I counted at least eight different papillary thyroid staging systems. I’m just going to mention two of them. Certainly a TNM staging system has been widely adopted. I think that the important thing to look at here is that it covers all different forms of thyroid cancer, including medullary and anaplastic. You’ll notice that for differentiated follicular cancer, for patients less than 45, the only differentiating factor is the presence of absence of metastases. Using the TNM patient, any patient under 45 who does not have metastatic disease is going to be classified as stage I, if they do have it stage II. For age over 45, both the presence of tumor size, local spread and nodal or metastatic involvement obviously is associated with increasing staging. This just shows that the staging system this is not quite the TNM system but it is very close to it and you can see that the staging system does fairly well in papillary, follicular, medullary and anaplastic. You know, all anaplastic cancer is stage IV, in terms of predicting survival. Another system that has been used was proposed by Masoferre who has done yeoman work in the area of the natural history of thyroid cancer, and they used four stages. I happen to like this system because clinically I find it very easy. Stage I is folks with tumors less than 15 mm in size and do not have any other features. Stage II are kind of intermediate size tumors as well as patients with metastases or patients with multifocality within the thyroid gland. Stage III are patients who have local invasion into surrounding structures of the neck, and stage IV are patients with distant metastases. Again, this staging system also works quite well in terms of predicting recurrence, which tends to rise with staging as well as death from cancer, which tends to rise from stagin with stages.

What about the treatment factors, in terms of the outcome for treatment in thyroid cancer? I think the take home message from the staging system is that we can identify a group of patients who are at fairly low risk – those at young age with small or moderate size tumors who are going to do quite well – and we can identify another higher risk group – those who are older, those who have evidence of multifocality or spread. What about frequent factors? Delay in treatment – I’m not going to talk about – but Masoferre’s document the thing about thyroid nodules is that they can be present for a long time and ignored for much of that time. But Masoferre has documented that delay in terms of treating a known thyroid nodule is associated with a worse outcome. Other treatment factors, extensive surgery, the use of 131 iodine and degree of TSH suppression. I’ve got sort of an algorithm in the notes and let’s kind of go through this very quickly. The first decision that we need to make is extensive surgery. Should one have a total thyroidectomy, or a lobectomy? The point here is that if you anticipate the need for using radioiodine then the patient should certainly have a total thyroidectomy done.

There may be a group of patients – and this is a very very controversial and debated issue among surgeons – there may be a group of patients, those who are young with small tumors, for whom lobectomy is enough. In these patients you might do a lobectomy and if the pathology confirms that the tumor is indeed small, that none of these other histologic factors are present, then for that type of a patient putting the patient on thyroxin suppression and continuing to observe them is probably sufficient. However, if they are going to need more aggressive treatment following the lobectomy then you’d want to recommend having completion of that thyroidectomy done. For those of you who cannot read, the orderly is sort of wheeling one patient out of the OR and another one in, and the caption reads, “Next”. An example of the very same procedure when done correctly.

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