Browse Month: July 2009

The pathogenesis of most primary brain tumors

For the most part we still don’t truly understand the pathogenesis of most primary brain tumors, or the epidemiology as far as predisposing risk. There are certainly several genetic disorders for which there seems to be a predilection for primary brain tumors. They include neurofibromatosis, tuberous sclerosis, Turcot syndrome. But these account for well less than 1% of all the cases of primary brain tumors. We still are somewhat in the dark, relative to the etiology of this disease.

Astrocytomas are the most common primary brain tumor in adults and represents the most significant problem in adults. When we speak of astrocytomas, we divide them into low and high-grade tumors. The high-grade tumors include tumors known as anaplastic astrocytomas, which include glioblastoma multiforme. When we talk about the grading system for astrocytomas, it is in fact somewhat complicated. There are a number of different grading systems. The oldest and original one was the Kernohan system, which was a four-tier system. With grades I and II of four being classified as low-grade astrocytomas or grades III and IV being high grade astrocytomas. A grade III of four is an anaplastic astrocytoma, while grade IV of four is a glioblastoma multiforme. The problem with the Kernohan system is that, although the system did pretty well as far as prognosticating between low- and high-grade tumors, it was not very good at separating out prognostic variables between grades I and II, versus grades III and IV. And because of this discrepancy, back in the 1980s, many people went to a simpler system, a three-tier system, originally designed by ECOG. In this system grade I of three is considered a low grade astrocytoma, grade III of three is considered a glioblastoma and grade II of three is considered an anaplastic astrocytoma. If you look at survival curves in this three-tier system, you do indeed see very nice separations of the curves. The problem is that the vast majority of the patients fall into a category of grade II of three, astrocytoma.

Although low grade astrocytomas have a long natural history, these are not benign diseases. Given that these patients are young, generally speaking, this again cannot be in any way classified as a benign tumor. In fact, these are infiltrative, slowly but progressively growing tumors. Radiographically, they appear on CT scan as low- attenuating, poorly defined, non-contrast enhancing masses. While on MRI scan one generally sees increased P2 signal and they are non gadolinium enhancing. Unfortunately there is very little randomized data to suggest optimum management for these patients. The reason for this is twofold: It’s been very difficult to conduct clinical trials secondary to both the relatively long natural history of this disease and the relative rarity. So most of our recommendations relative to low-grade gliomas are based on biases and anecdotal and/or retrospective data. Currently in most large brain tumor centers, is if a low-grade glioma can be safely resected, then all attempts are made to do so. On the other hand, as one gets to a higher-grade tumor, grade II astrocytoma, it appears as though the benefits of more full resections are less pronounced. In fact the role for surgery for lower-grade tumors.

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.

Histopathologic examination of basal cell epitheliomas

Histopathologic examination of basal cell epitheliomas reveals collections of cells with dark-staining nuclei and scant cytoplasm. The periphery of the cell masses shows cells in a palisade arrangement resembling the basal layer of the epidermis. Treatment of basal cell epitheliomas consists of complete surgical excision, destruction by curettage and electrodesiccation, or radiation therapy. Cryosurgery has been employed for selected lesions, especially superficial basal cell carcinomas. A margin of seemingly normal tissue should be removed around the tumor to prevent recurrence arising from invasion by strands of tumor cells. The clean margins must be monitored by histopathologic examination.

Recurrent basal cell carcinomas are usually difficult to cure, but Mohs’ microscopic controlled surgery, when it is performed by a specially trained physician, is effective in eradicating the entire tumor. Routine in vivo chemosurgical fixation of the tumor with zinc
chloride paste is no longer required. In the current procedure, fresh tissue is removed after local anesthesia, and frozen sections are examined microscopically. This more efficient method spares a larger amount of normal skin and reduces the discomfort associated with chemical fixation. The tumor is removed layer by layer, and all margins are carefully examined until a tumor-free plane is achieved.

Indications for microscopic controlled excision of skin cancer include recurrent basal cell epitheliomas and squamous cell carcinomas; tumors with indistinct margins, such as sclerosing basal cell epitheliomas; and lesions in such areas as the inner and outer canthus of the eye and the tip of the nose, where maximal preservation of normal skin is desirable. For certain complicated or advanced tumors, the fixed-tissue approach is considered more reliable than the fresh-tissue technique.

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.