Surgical Management of Cushing's Disease: A Personal Perspective

What about Cushing's disease differs from the other types of pituitary tumors? There are several differences, of course, but one of the principal differences is evident from inspection of Figure 1, in which this young boy's spin-echo magnetic resonance image (MRI), performed on an MR scanner with a 3-T magnet, does not demonstrate his tumor, despite the fact that he has severe clinical manifestations of Cushing's syndrome. The small tumors that cause Cushing's disease present unique challenges for diagnosis and treatment; that has been so from the very beginning.FIGURE 1: No adenoma is visible on this coronal postcontrast spin-echo pituitary MRI of a young boy with Cushing's disease, despite the fact that this MRI was performed on a 3-T MRI scanner.HISTORY OF SURGERY FOR CUSHING'S DISEASE Harvey Cushing described his first patient with what we now know as Cushing's disease, Minnie G., 100 years ago in December of 1910, and although he recognized that she had a distinct clinical syndrome, he had no way of determining what was causing it.1 The function of the pituitary gland was poorly understood at the time—cortisol was not to be isolated and identified for another 40 years—but he did recognize that the syndrome might be related to the pituitary and included her in his 1912 monograph The Pituitary Body and Its Disorders.1 Twenty years later in “The Basophil Adenomas of the Pituitary Body and Their Clinical Manifestations (Pituitary Basophilism),” he described 12 patients, including Minnie G., who had the typical features of Cushing's syndrome, the general clinical syndrome caused by long-term exposure to excess glucocorticoid levels.2 Most of the patients that he presented in his monograph had died of complications associated with the syndrome, and autopsy had demonstrated small basophilic pituitary tumors. However, very little surgery was done for patients with a diagnosis of Cushing's disease for the next 7 decades. It was not until the early 1980s that pituitary surgery became the initial treatment of choice for patients with Cushing's disease. Although surgery was rare before then, it was performed occasionally. Two of Cushing's students, Drs Pattison and Naffziger, surgically explored the pituitary in 1933, the year after Cushing's monograph was published. Dr Naffziger's strategy, and one that he attempted, was to remove the offending tumor; this was the first attempt to remove a tumor in a patient with Cushing's disease.3,4 What happened between 1930 and 1980 to persuade the medical and surgical communities that the problem was not in the pituitary? Shortly after Cushing's monograph was published, the focus of determining the presumed basis of the disease became the adrenal; this focus was stimulated by 2 reports, 1 published in 1935 by Susman5 and 1 in 1936 by Costello.6 These authors examined the pituitary glands of patients who died of other causes and found that a surprisingly large fraction of patients, 9% in Susman's article and 22% in Costello's study, had incidental pituitary adenomas at autopsy, many of which were basophilic adenomas. Thus, shortly after Cushing's contribution had been widely acclaimed for its scholarship and importance, the basophilic adenomas that he had described were considered incidental findings rather than the cause of Cushing's syndrome, and the focus shifted to the adrenal for the next 40 years. It was Jules Harding, shortly after he introduced the operating microscope for pituitary surgery in 1962, who recognized that tumors can also be small and that selective adenomectomy is an effective surgical strategy. The following year, he performed the first selective adenomectomy for Cushing's disease, and that patient is still doing well 48 years later.4 It was the series of patients presented by Hardy at a conference on the diagnosis and treatment of pituitary tumors at the National Institutes of Health in 19737 and subsequent publications of series of patients by Hardy,8 Salassa et al,9 and Tyrrell et al10 that persuaded the medical and surgical communities that the source of the disorder was the pituitary gland, and only after that did neurosurgeons become regular participants in the treatment of patients with Cushing's disease. SURGICAL TREATMENT OF CUSHING'S DISEASE For Cushing's disease, as in all other types of pituitary tumors, we endeavor to eliminate the tumor immediately and completely while preserving pituitary function and avoiding complications. These goals can be achieved in most but not all patients. In 2 large multi-institutional studies, 70% to to 80% of patients who underwent surgery for Cushing's disease had remission after selective adenomectomy (defined as resolution of hypercortisolism, including hypocortisolism and eucorticolism), and 20% to to 30% did not.11,12 What underlies the failures? Some cases have diagnostic errors, and the patient does not have Cushing's disease. In other patients, those with Cushing's disease but unsuccessful surgery, the tumor is too small to find at surgery or incomplete tumor removal occurs, often because of tumor invasion of the surrounding structures. I will not attempt to summarize all aspects of Cushing's disease in this brief report but will focus on certain aspects of it that seem to be particularly pertinent for neurosurgeons and on elements that I have learned from a personal experience of operating on > 1100 patients with Cushing's disease. SURGICAL REMOVAL OF THE ADENOMA The first is the strategy of consistent and complete removal of the tumor. Almost all of our focus in pituitary surgery for the past 30 years has been how to get to the sella, not how to remove the tumor. That is, all our focus has been on the foreplay. In my experience over the past 25 years, a specific technique for tumor removal has been rewarding: the use of the histological pseudocapsule as a surgical capsule in removal of pituitary tumors of all types.13,14 Pituitary tumors are clonal tumors.15 They originate from a single cell, and as they grow, they compress the pituitary gland adjacent to the tumor. By the time a tumor becomes large enough for us to detect it on MRI or to identify it at surgery, it has compressed the pituitary gland at its margin to the extent that it creates a thin tissue envelope, a histological pseudocapsule, a distinct tissue envelope surrounding it that permits its identification and removal by working around the edge of the pseudocapsule, using it as a surgical capsule, as shown in Figure 2. Investigation of the edge of that tumor with histology demonstrates a strong, multilayered, reticulin envelope around the edge of the tumor.FIGURE 2: The use of the histological pseudocapsule as a surgical capsule. A, coronal T1 MRI after contrast demonstrating an intrasellar macroadenoma filling the left 80% of the sella in a patient with Cushing's disease. B, the adenoma has been removed by using the histological pseudocapsule as a surgical capsule. Operative photographs show the adenoma after dissection of its margin from the surrounding normal pituitary gland. The adenoma lies within the left side of the gland. C, adrenocorticotrophic hormone (ACTH; left) and reticulin (right) immunohistology of the intact specimen demonstrates that the pseudocapsule of the pituitary adenoma is intact over the the margin of the intact adenoma is examined in the edge of the specimen in the the of compressed reticulin surrounding the margin of the tumor are the thin reticulin envelope this tumor, it was enough to intact complete removal of the tumor as an intact are certain that from using that tissue envelope, the histological pseudocapsule, as a surgical It can be to identify small adenomas that not be and by following the edge of the pseudocapsule as a surgical capsule around the of the tumor, we can use it as a distinct tissue between it and the surrounding compressed pituitary gland to identify of invasion of the pituitary capsule of the and the surrounding In tumors, I use it to in the of the normal pituitary and to complete tumor and for using the histological pseudocapsule as a surgical capsule in the removal of and I particularly in the tissue the surgery, in the and the from the capsule of the pituitary gland, first and the pituitary is rather than an the tumor, as is I an the capsule of the pituitary at the margin of the tumor so that a thin of the normal gland is before the this permits identification of the between the gland and the margin of the tumor. dissection around the margin of the tumor becomes because of the of the tissue at the tumor By using the tissue exposure and of the sella and tumor removal can be done and a tumor is removed in this and is for adrenocorticotrophic hormone it is evident despite the fact that the tissue capsule is the surgery, it is often very thin but the tumor.FIGURE A, exposure of the The initial of the of the sella is performed using a with a to with a thin is to remove the thin of of the sella in small These small of can be with a brief of which is performed by the and removal of the from the working The is removed until at 2 of the most of is removal to the a is to the from the of the sella after the of the sella has been The sella is removed with a small pituitary are with a thin of and compressed the by using of a with the of the very in the and the the technique or of small of in can be for that from the between the and at the of the this the be and the sella and most of the the of the of the surgery on a and completely of the of invasion of the or and in cases of small tumors that the of the pituitary gland, of the to the of the tumor as a or a of or of the to it to the pituitary capsule the to the while the pituitary capsule and because it a of of the pituitary capsule and the of the pituitary gland immediately it that be for a small of the or is the from this is a which the is to the The is using a with to the completely the the capsule of the pituitary gland. the the of the are to the of the and the margin of the The is often the and margin of the the of the the of the of the from this is by the with a small of in a exposure and the of the is the extent of the and is in a The is and from the pituitary capsule by using a in the tissue between the of the pituitary gland with an intact pituitary capsule in a to the the capsule of the pituitary gland is a despite its and it is visible the the capsule is to the It be dissection will not it and will only to the of the gland and to the tumor, the of the tumor and C, use of the surgical capsule for selective of small adenomas that are visible on with tumors within the gland that are visible on a is the pituitary capsule the at which the most of the tumor or to the of the gland Thus, this initial is not the tumor, as is permits a thin of normal gland to be before the surgical capsule of the adenoma identification of the surgical capsule and the of a surgical of dissection at the margin of the tumor, at the of the normal gland and the surgical capsule of the between the adenoma and gland is using the of the in a series of to the of the adenoma and in the between the gland and adenoma and and the tissue is the dissection is and the of the adenoma is and this has been dissection of the between the adenoma and gland is following the margin of the with in the capsule of the pituitary gland the tumor margin to on the tumor as the dissection small Hardy on the margin of a is to of the between the gland and the adenoma for dissection and for the small of of the of of in the surgical the while dissection at other around the tumor margin shown the most of the tumor has been the adenoma are and in a the margin of the adenoma often dissection using a and a small left and is performed very little is the tissue is and most of the that is is the gland than the the of the tumor have been completely to of the tumor, the between the pseudocapsule of the specimen and the pituitary capsule is with a small and the tumor is removed In cases of tumors to in the tumor can be of its in the as an intact and complete removal a tissue in the of a histological pseudocapsule and its use as a surgical capsule in the of pituitary tumors. with with of Almost all of are associated with a but compressed and pituitary gland at The compressed can be from the tumor by the use of the surgical capsule of the and is by preserving the capsule of the pituitary gland the the capsule of the has been from the a very fraction of a is the pituitary capsule by using the of a the of this is 2 to the most exposure of the is so that its is to the edge of the surgical capsule of the the margin of the adenoma to be with the of the as described in the for Figure the gland from the and as the dissection of the normal gland becomes of the pituitary capsule is performed to the margin of the between the compressed gland and the surgical capsule of the In this the most of the macroadenoma is from the compressed gland and this surgical has been to a of to the and left) of the tumor in that the of the adenoma is and the of the tumor is removed is performed to the of the tumor and to the to the dissection of the by using the of the and to It is not to remove too of the of the tumor the because the of the macroadenoma of the is to with a to of its capsule is left enough of the capsule to to the tumor which the of dissection It is often to the of the tumor margin by using with as described in the for Figure so as not to the surgical capsule of the macroadenoma its of a histological pseudocapsule and its use as a surgical capsule in the of pituitary tumors. with technique can be to remove tumors tumors, one by working around the edge of the tumor using the pseudocapsule as a surgical and tumor from within to the of the tumor but still 2 to to of tumor at the edge of the tumor, adjacent to the surgical capsule, and to the dissection to the tumor margin from the surrounding normal gland, remove the tumor, and the pituitary in often in Cushing's disease than with other types of pituitary tumors. In most patients with is an associated sella syndrome, in the of an normal pituitary is a to the as the and pituitary for a tumor that the demonstrates the MRI and in a patient with an tumor in the These tumors also the pituitary in the pituitary demonstrates a in the the or in the of the to the margin of the pituitary gland. The that I have to remove a series of tumors in the pituitary is in Figure These adenomas can but not be removed with of pituitary A, pituitary MRI before and after contrast the adenoma in the and that the adenoma is associated with an sella syndrome B, that the of the sella is as is also at C, the series of in from to exposure and removal of the tumor, show the intact tumor in the 2 that the tumor was the sella and are shown intact in the image from the and that the is also intact in that of the sella resonance a adenoma in the pituitary the of the and but not the tumor. of adenomas in or the pituitary with of pituitary with the exposure of the of the sella and removal to the of the In patients in MRI the of the was removed by first with a until the of was thin and using a of the to the pituitary and of the gland. The the pituitary was were to in the the the of the was to the The was while preserving the intact the the was identified and was not to The sella was in the in an to the and the tumor. small of or was in the to of the by the of the identification of the was in the with a or at the of the capsule of the tumor with the pituitary in the of the at the margin of the The adenoma was using of adenomas in or the pituitary with of pituitary with ADENOMA MRI of the for the of Cushing's and to the of the Cushing's we the patient who with the clinical features of Cushing's syndrome and pituitary MRI surgical of the pituitary it is to find an adenoma the patient does not have the initial in patients is to that the patient has Cushing's syndrome, the general syndrome of excess and to demonstrate Cushing's disease and not one of the other causes of Cushing's syndrome as or an adrenal of patients who Cushing's syndrome have pituitary adenomas. have been over the past to in Cushing of all the for the diagnosis of Cushing's syndrome is that on the normal by excess Thus, we on our of the normal and its to the of the causes of Cushing's syndrome and to and the for diagnostic of the For normal of and hormone from from the pituitary which the and the adrenal to and is by the of to and by the and and from the pituitary the for the diagnosis of Cushing's syndrome including on of the for and features of the in normal and patients with Cushing's syndrome and the of of the by other as the the of hormone adrenal of and the of and Cushing's syndrome is caused by adrenal tumors and and adrenal of are shown by thin by hormone is shown by thin by and by Cushing's syndrome. with of the The with the is that have a diagnostic of only about the are not as as we we can use of and to a specific we can in the of the of the diagnostic of the several years my and I to the of in with for the diagnosis of Cushing's What we found in a large series of patients was what we to that patients with Cushing's disease have a in at 1 with the patients with not By using the before or after the has a very diagnostic to patients with Cushing's disease with those from A, and in of the pituitary the which the B, with adrenocorticotrophic hormone from a patient with Cushing's disease and a patient with a and et of by and with C, in the diagnosis of Cushing's syndrome. of from one of the to the in patients with Cushing's syndrome in and in and hormone the was in of patients with Cushing's disease but was in all patients with syndrome or adrenal disease. patients with Cushing's disease who had of all patients with syndrome had of The patients with adrenal disease in was in the before and after et with and hormone for the diagnosis of Cushing's syndrome. with also at one time that we use this to the tumor was in patients with Cushing's in that not to be as as we it so now we to use the for the diagnosis and only use it patients have that with the other or have a Its for the side of the pituitary an adenoma is The patient have of excess before using the for the diagnosis of Cushing's syndrome. in the of an of we in that we of for the diagnosis of Cushing's syndrome in the in a patient who does not have excess to the the will a that Cushing's disease. Thus, we a patient with who does not have Cushing's syndrome with they will all a diagnosis of Cushing's disease, and we are at of the patient to surgery, not a tumor, all or a of the and or all in a patient who did not have Cushing's syndrome to Thus, the is to in that the use of all the for the diagnosis of the clinical of from Cushing's syndrome, on complete of the normal by excess can this by that the patient has been demonstrated to have Cushing's syndrome, by before the for diagnosis of a patient who has been shown to have Cushing's syndrome. MRI in Pituitary MRI In a patient with a diagnosis of Cushing's disease and a tumor so small that it be with the is the tumor; the tumor can be identified and is within the capsule of the it can be completely to The resolution of a tumors as small as in The with is than the spin-echo 80% Figure MRI typical of an adenoma in the pituitary gland in of normal and incidental adenomas are found in the pituitary gland in about to to 20% of in autopsy of patients the of MRI be by Pituitary MRI of a patient with pituitary not visible on postcontrast image of the pituitary demonstrates an of with to normal pituitary in the and margin of the on the an adrenocorticotrophic hormone which was at this image with the image in Figure 1, which was in the patient after contrast using of MRI the use of the MRI many patients still have a and we and identify the adenoma surgical find the tumors in patients by a the pituitary widely and inspection of the and the of the gland from one side to the other and then, no tumor is by inspection of the by a the pituitary gland with I have found the of a pseudocapsule to be the most of the of a in the pituitary gland of the pituitary gland in patients with an adenoma The of the is to find and identify the distinct margin of the on with a widely surgical of the and sella is the exposure and because it a on the of the gland that the of the widely the which exposure of an intact pituitary capsule the of the gland, and after exposure of the of the the are for of The adenoma to be or and can be identified the of the which is B, no tumor is the of the are For the of the sella of the is from the pituitary capsule by a between 2 from to The for dissection of the between the pituitary capsule and the with the of a is and in to until the sella has been 2 have been small of are the to the and to it the are and examined in this the of the gland is from the is the at which 2 the of the pituitary and the are most to a tumor can be identified from inspection of the it is removed as described in the and the for Figure no tumor is identified on inspection of the gland, a series of is of which 1 to 2 the edge of the pituitary exposure and is to a of only 1 and in the until the or the of the is the pituitary and the of to the pituitary are be to cause an in a of the pituitary or to the gland from its distinct tissue capsule is the of the with the of the margin of the tumor before it and its by using the surgical capsule of the adenoma and the surgical capsule of the adenoma is the tumor is removed using dissection the of the adenoma and the normal gland, as described in the for Figure and In cases of tumors in the of the a of the be removed to for dissection and removal of the of a histological pseudocapsule and its use as a surgical capsule in the of pituitary tumors. with a tumor be found surgical the of the pituitary and a series of in the gland and still not to find a tumor, the has to of the gland Cushing's disease in about of patients after a surgical of the on the side of an in my experience remission of Cushing's disease in about of or the from side and the about of the gland to the Cushing's disease in about of to and the other the of but not the patient to about a to to 20% of one of and it does not seem to in between is a CUSHING'S DISEASE or adenoma after surgery with of an adenoma is or immediately the of the adenoma at the that of Cushing's disease is from of left in at the surgery and at the by the tumor be the focus of the invasion the of the for the of patients who have or Cushing's disease. In my series of patients with surgery after the initial surgery for or Cushing's disease, the tumor was found at the or to the in all patients in an adenoma had been identified at the initial invasion by an tumor was identified surgery in of the patients after surgery and or Cushing's disease. In of adenomas were and the invasion of the was found in of and in all at The of tumor was not at all in of the patients with and in of patients was invasion evident on The of this that and Cushing's disease from tumor. surgery, the tumor can be found or immediately the at which the tumor was invasion with of tumor within the which tumor or invasion evident on and often by the surgery, is the basis of surgical in many patients with Cushing's disease. It is what underlies that the of the the very of reticulin the pituitary gland. of the to this from in the of the pituitary by in the described of the pituitary gland by pituitary that the pituitary capsule and the of the at the an of for have us that the of the tumor for this The findings that it most often because of rather than of the of Cushing's disease is that the of the of tumors what the of all types of pituitary tumors. The of the of the pseudocapsule at the margin of small adenomas to at about 2 to in the at which we can identify surgical from removal of pituitary adenomas using the histological pseudocapsule as a surgical capsule and as a tissue our focus over the next years. be we had of the very tumors, before or surgery, in patients with Cushing's disease and also for tumors that the and we to the basis of invasion in patients who have tumors. it be to the basis of the to tumors and it is to tumor still have to The has no personal or in of the or described in this