Inl. 1. Radiodon
Oncology
Biel.
Phys..
WHY FORM
1976. Vol.
1, pp. 1031-1034.
Pcrgamon
A NATIONAL GLENN
Press.
Printed
PITUITARY E.
SHELINE,
in lhe USA
TUMOR
RJZGISTRY?
M.D.
University of Califomia, Division of Radiation Oncology, San Francisco, CA 94143, U.S.A.
Until the mid 196Os, there was a widespread tendency to classify tumors of the anterior lobe of the pituitary gland simply as or chromophobic basophilic, acidophilic, adenomas. “Cushing’s syndrome”, diagnosed largely on the basis of corticosteroid production and by exclusion of an adrenal tumor, was considered by many to be the result of a smal1 basophilic adenoma. It was disquieting to learn that in lO-20% of patîents with Cushing’s syndrome, removal of the adrenals leads to the growth of an adrenocorticotrophîc (ACTH) secreting chromophobe rather than a basophilic adenoma. More recent information has shifted the emphasîs to the hypothalamicpîtuitary regulation of adrenocortîcotrophîc hormone (ACTH) production and tends to support Cushîng’s orîginal concept of ACTH secreting microadenomas. “Acromegaly” was thought to be the result of a growth hormone (GH) producîng acidophilic adenoma, usually larger than the basophilîc tumors and occasîonally accompanied by vîsual field deficits. Diagnosis was established by abnormal bone and soft tissue growth and indirect laboratory evîdence such as basal metabolîc rate, glucose tolerante, and 17 ketosteroid and hydroxyketo-steroîd levels. The “chromophobe adenoma” presented a dîfferent set of problems. Considered nonsecretory, unless biopsy was performed the dîagnosîs was made by exclusîon of a secretory adenoma, cranîopharyngioma, carotîd aneurysm, etc. The chromophobes tended to be even larger than the acidophilic adenomas, but were clînîcally silent until they produced either hypopîtuitarism or extended to învolve parasellar structures, most commonly the optîc chiasm. Whîle in most instances the diagnosis of a chromophobe adenoma was reasonably secure, it is possible that before the present precision leve1 of pneumoence-
phalography, some of the “chromophobes” treated without bîopsy were actually “empty sellae”, a condîtîon that may cause sellar enlargement and, rarely, hypopîtuitarîsm. Since Cushing’s syndrome and acromegaly could be diagnosed endocrinologîcally and the assocîated adenomas were thought to be sensitîve to îrradiation, in these diseases the pituitary often was irradiated without surgical interventîon. Surgical decompressîon was reserved for patients wîth large or changing visual field deficits or loss of visual acuity. Conventional radîation therapy with photons had certain advantages over surgery. It appeared to control 75-80% of acromegalics5.8a*1Z and around 30-50% of patîents with Cushîng’s syndrome,‘.’ and was thought not to suppress functîon of normal pîtuitary tissue or to adversely affect the optic chiasm or nerves; both concepts now requîre modifïcation. Furthermore, surgical intervention, directed toward the pîtuitary or the adrenal glands could be resorted to îf the radiatîon thereapy faîled. In the case of a suspected chromophobe adenoma, there was greater uncertainty of dîagnosîs, and 95% were accompained by significant visual acuity loss and/or visual field deficit. Those tumors presenting without visual problems usually extended înferiorly, often invading the nasopharynx. Twenty to thirty percent were cystîc and a large fluîdfilled cyst could not be expected to respond to irradîatîon. Prîmary surgery provîded certain diagnosis, evacuatîon of a cyst if present, and rapîd decompressîon of the optîc chiasm. Surgery, however, was accompanied by mortality rangîng from l-2% up to &lO% of patîents. Furthermore, with surgery alone, the recurrence rate was objectionably high in patîents who were observed over 15-20 years.13 The recurrence rate was markedly
1031
1032
Radiation Oncology ??Biology??Physics
September-Octobcr 1976,Vol. 1. Numbcr 9 and Number 10
reduced, however, with postoperative irradiation. Radiation therapy alone controlled 7080%, and had the advantage of no mortality and little morbidity;‘” but the response, as measured by visual field change, was more delayed and (possibly due to cystic elements) less certain. Therefore, disagreement on the optimum therapy was prevalent among neurosurgeons and radiotherapists. Some surgeons and radiotherapists believed in treating a selected qoup with primary radiation therapy, reserving surgical methods for radiation failure. Others relied largely on primary surgical intervention. Many who preferred primary surgery advocated postoperative radiation therapy. It should be noted that in most era under consideration, the neurosurgeons were using the transfrontal approach to the pituitary. Because of surgical the transsphenoidal complications hypophysectomy advocated by Cushing’ was not in wide usage; its resurgence in the form of transsphenoidal microdissection had not yet occurred. During the last 10-15 years many exciting new facets have combined to increase our understanding of the normal and abnormal pituitary, its physiologic control, and the treatment of its diseased states. Endocrinologie techniques now permit separate assessment of function of the hypothalamus and the pituitary, including its target organs. Pathophysiologists and histologists are providing new insight into the control of the pituitary hormone output and the correlation between function and histology. The neuroradiologist can provide information about the vascular supply that nourishes the pituitary and with computer-assisted tomographie techniques, may be able to distinguish cystic from solid tumors. Therapeutic techniques that are available to the neurosurgeon and to the radiation therapist have been refined. The result is a flood of exciting information which has produced more questions than answers. Whether Cushing’s syndrome is a result of a basophilic or of a chromophobic adenoma is now debated. The pituitary from an acromegalic patient may fail to show acidophilic cells and, by tintorial staining methods, be
replete with chromophobe cells. Other pituitaries show a mixture of cel1 types. The absente of cells with stained secretory granules in patients with either Cushing’s syndrome or acromegaly has been explained on the bases that such cells are, in fact, not present or that through overactivity, have become depleted of their granules. Recent evidente has even raised the question of whether there is such a lesion as a chromophobe adenoma, the claim being made that if fresh tissue is properly fixed and stained, al1 pituitary adenomas contain cells in which there are stainable granules. Development of the immunoperoxidase stains allows evaluation of both prolactin and growth hormone in pituitary cells of patients with hypersecretion of these hormones. The immunoenzyme method is claimed to be more sensitive, more specific, and to correlate better with plasma hormone levels of pituitary hormones than the standard tintorial methods. The importante of the recently acquired ability to measure plasma growth hormone and prolactin levels and the multitude of tests either to stimulate or black release of the various pituitary hormones hardly can be overemphasized. They have led to significant advances in understanding pituitary physiology and the interplay between plasma and hormone levels, the hypothalamus and the pituitary gland. Clinical applications, however, are not always clear and in certain instances, conclusions have been reached prematurely. For example, shortly after the growth hormone assay became available in the 1960s it was concluded by many that conventional radiation therapy did not reduce GH levels adequately, and this form of therapy was virtually abandoned. It now is known that conventional radiation therapy is essentially as effective in restoring plasma growth hormone levels to normal as are the various surgical procedures; however, with irradiation, the response is slow, requiring from several months to several years, whereas the drop following transsphenoidal hypophysectomy or microsurgery is prompt.3.‘4 Incidentally, the time required for response to high-dose heavy particle irradiation is not unlike that of conventional photon irradia-
Pituitary tumors 0 GLENN
E. SHELINE
1033
tion Further, we do not know whether rapid reversion to normal is necessary in a longstanding chromic disease like acromegaly, although one would intuitively think that to be the case. A similar dilemma regarding the proper treatment for patients with elevated prolactin secretion has arisen. What is the clinical significante of an elevated plasma prolactin leve1 in a patient with neither galactorrhea nor amenorrhea? Available information suggests that conventional irradiation is as effective as surgery in reducing prolactin levels, but an adequate study has not been reported. One study described at a recent meeting reported that of eight patients who were treated surgically and eight patients who were irradiated, there was an approximate 75% decrease in prolactin leve1 for each group, and two of each subsequently became pregnant.4 Following transsphenoidal microdissection, the prolactin leve1 does not always revert to normal. If the neurosurgeon increased the extent of his resection in an effort to obtain normal levels with greater consistency, would more harm or good result? Current data suggest that from 30 to 90% (frequency depending on the criteria accepted for “normal”) of the lesions previously termed “chromophobe adenomas” and assumed to be nonfunctional were in fact prolactin hypersecretors.‘.15 Since postoperative radiation therapy reduced the recurrence rates in those “chromophobe adenomas”, should lesions now known to be prolactin secretors receive postoperative irradiation? Such a conclusion is tempting to the radiation therapist, but it also is possible that the prolactin secretors account for some of the previous irradiation failures and that they might not be benéfited by radiation therapy. The newer diagnostic techniques, especially hormone assays associated with pituitary stimulating and blocking agents, provide a vastly improved ability to evaluate unwanted effects, as wel1 as those of a beneficial nature, for each therapeutic method. Evidente now available indicates that conventional photon
irradiation can alter hormone production by normal pituitary cells.“’ The injury may be either to the hypothalamus or to the pituitary itself. Detection may follow a substantial delay in time. In some patients, the pituitary deficiency can be uncovered only by endocrinologie studies, but in others it results in clinically evident deficiencies. It is surprising that these irradiation effects on pituitary function went unnoted for so long. There are also occasional instances of chiasma1 injury following conventional irradiation techniques; these are limited largely to patients who received greater than 5000 rad or individual dose fractions greater than 200 rad. The same precision of testing for response and damage should be applied to al1 therapeutic methods. It is suggested that attention should shift from histologie classification to a system based on function, with secondary consideration for size, extension, or damage produced by the pituitary tumor. Current sophisticated methods should be used to re-evaluate response to treatment and untoward effects of teatment; a controlled, randomized study of the various treatment modalities would be of great value. However, the infrequency of these disease entities and the fact that expertise with certain modalities is not available in every institution suggest that such a study must be of multi-institutional character and that randomization is not possible. The best approach may be the formation of a registry. The method of therapy favored at any institution then could be applied. For inclusion in the registry, certain pre-specified data would be required. These data would include pretreatment and periodic posttreatment clinical and laboratory observations. The data required should be adequate to permit later retrospective evaluation, yet not so extensive that the study would collapse of sheer magnitude. It is hoped that this discussion wil1 aid in the formulation of a meaningful study designed to compare the various treatment modalities in light of presently available methods.
1. Cushing, H.: Surgical experiences with pituitary disorders. J.A.M.A. 63: 1515-1525, 1914.
2. Edmonds, MW., Simpson, W.J.K., Meakin. J.W.: External irradiation
of the hypothysis
for
1034
Radiation Oncology 0 Biology 0 Physics
Septemk-October
Cushing’s disease. J. Can. Med. Assoc. 107: 860-862, 1972. 3. Hardy, J.: Transsphenoidal surgery of hypersecreting pituitary tumors. In Diagnosis and Treatment of Pituitary Tumors, ed. by Kohler, P.O., Ross, G.T. New York, Excerpta Medica Amsterdam, American Elsevier, 1973, pp. 179-194. 4. Kleinberg, D.: Endocrinologie aspects of pituitary adenomas. Presented at New York Roentgen Society Spring Conference, New York, 22-24 April 1976. 5. Kramer, S.: Indications for, and results of, treatment of pituitary tumors by external radiation. In Diagnosis and Treatment of Pituitary Tumors, ed. by Kohler, P.O., Ross, G.T. New York, Excerpta Medical Amsterdam, American Elsevier, 1973, pp. 217-229. 6. Lawrence, J.H., Linfoot, J.A., Bom, J.L., Tobias, C.A., Chong, C.Y., Okerlund, M.D., Manougian, E., Garcia, J.F., Connell, G.M.: Heavy particle irradiation of the pituitary. Progr. Neurol. Surg. 6: 272-294, 1975. 7. Melarkey, W.B., Johnson, J.C.: Pituitary tumors and hyperprolactinemia. Arch. Intern. Med. 136: 4044, 1976. 8. Orth, D.N.. Liddle. G.W.: Results of treatment in 108 patients with Cushing’s syndrome. N.E.J.M. 285: 243-247, 1471. 8a. Pistenma, D.A., Goffinet, D.R., Bagshaw, M.A., Hanbery, J.W., Eltringham, J.R.: Treatment of acromegaly with megavoltage radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 1: 885-893, 1976. 9. Richards, G.E., Wara, W.M., Grumbach, M.M., Kaplan, S.L., Sheline, G.E., Conte, F.A.:
1976, Vol. 1, Number 9 and Number 10
Delayed onset of hypopituitarism: sequela of therapeutic irradiation of centra1 nervous system, eye, and middle ear tumors. J. Peds. to be published. 10. Samann, N.A., Bakdash, M.M., Caderao, J.B., Cangir, A., Jesse, Jr., R.H., Ballantyne, A.J.: Hypopituitarism after external irradiationevidente for both hypothalamic and pituitary origin. Ann. Intern. Med. 83: 771-777, 1975. 11. Shalet, S.M., Beardwell, C.G., Morris-Jones, P., Bamford, F.N., Ribeiro, G.G., Pearson, D.: Cancer 37: 1144-1148, 1976. 12. Sheline, G.E., Goldberg, M.B., Feldman, R.: Pituitary irradiation for acromegaly. Radiology 76: 7&75,82, l%l. 13. Sheline, G.E.: Treatment of nonfunctioning chromophobe adenomas of the pituitary. Am. J. Roentgenol., Rad. Ther. Nucl. Med. 120: 553-561, 1974. 14. Sheline, G.E., Wara, W.M.: Radiation therapy of acromegaly and nonsecretory chromophobe adenomas of the pituitary. In Tumors of the Nerveus System, ed. by Seydel, H.G. New York, Wiley, 1975, pp. 117-131. 14a. Urdaneta, N., Chessin, H., Fischer, J.J.: Pituitary adenomas and craniopharyngiomas: analysis of 99 cases treated with radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 1: 895-902, 1976. 15. Zimmerman, E.A., Defendini, R., Frantz, A.G.: Prolactin and growth hormone in patients with pituitary adenomas: a correlative study of hormone in tumor and plasma by immunoperoxidase technique and radioimmunoassay. J. Clin. Endrocrinol. Metab. 38: 577-585, 1974.
Oncology
Biel.
Phys..
WHY FORM
1976. Vol.
1, pp. 1031-1034.
Pcrgamon
A NATIONAL GLENN
Press.
Printed
PITUITARY E.
SHELINE,
in lhe USA
TUMOR
RJZGISTRY?
M.D.
University of Califomia, Division of Radiation Oncology, San Francisco, CA 94143, U.S.A.
Until the mid 196Os, there was a widespread tendency to classify tumors of the anterior lobe of the pituitary gland simply as or chromophobic basophilic, acidophilic, adenomas. “Cushing’s syndrome”, diagnosed largely on the basis of corticosteroid production and by exclusion of an adrenal tumor, was considered by many to be the result of a smal1 basophilic adenoma. It was disquieting to learn that in lO-20% of patîents with Cushing’s syndrome, removal of the adrenals leads to the growth of an adrenocorticotrophîc (ACTH) secreting chromophobe rather than a basophilic adenoma. More recent information has shifted the emphasîs to the hypothalamicpîtuitary regulation of adrenocortîcotrophîc hormone (ACTH) production and tends to support Cushîng’s orîginal concept of ACTH secreting microadenomas. “Acromegaly” was thought to be the result of a growth hormone (GH) producîng acidophilic adenoma, usually larger than the basophilîc tumors and occasîonally accompanied by vîsual field deficits. Diagnosis was established by abnormal bone and soft tissue growth and indirect laboratory evîdence such as basal metabolîc rate, glucose tolerante, and 17 ketosteroid and hydroxyketo-steroîd levels. The “chromophobe adenoma” presented a dîfferent set of problems. Considered nonsecretory, unless biopsy was performed the dîagnosîs was made by exclusîon of a secretory adenoma, cranîopharyngioma, carotîd aneurysm, etc. The chromophobes tended to be even larger than the acidophilic adenomas, but were clînîcally silent until they produced either hypopîtuitarism or extended to învolve parasellar structures, most commonly the optîc chiasm. Whîle in most instances the diagnosis of a chromophobe adenoma was reasonably secure, it is possible that before the present precision leve1 of pneumoence-
phalography, some of the “chromophobes” treated without bîopsy were actually “empty sellae”, a condîtîon that may cause sellar enlargement and, rarely, hypopîtuitarîsm. Since Cushing’s syndrome and acromegaly could be diagnosed endocrinologîcally and the assocîated adenomas were thought to be sensitîve to îrradiation, in these diseases the pituitary often was irradiated without surgical interventîon. Surgical decompressîon was reserved for patients wîth large or changing visual field deficits or loss of visual acuity. Conventional radîation therapy with photons had certain advantages over surgery. It appeared to control 75-80% of acromegalics5.8a*1Z and around 30-50% of patîents with Cushîng’s syndrome,‘.’ and was thought not to suppress functîon of normal pîtuitary tissue or to adversely affect the optic chiasm or nerves; both concepts now requîre modifïcation. Furthermore, surgical intervention, directed toward the pîtuitary or the adrenal glands could be resorted to îf the radiatîon thereapy faîled. In the case of a suspected chromophobe adenoma, there was greater uncertainty of dîagnosîs, and 95% were accompained by significant visual acuity loss and/or visual field deficit. Those tumors presenting without visual problems usually extended înferiorly, often invading the nasopharynx. Twenty to thirty percent were cystîc and a large fluîdfilled cyst could not be expected to respond to irradîatîon. Prîmary surgery provîded certain diagnosis, evacuatîon of a cyst if present, and rapîd decompressîon of the optîc chiasm. Surgery, however, was accompanied by mortality rangîng from l-2% up to &lO% of patîents. Furthermore, with surgery alone, the recurrence rate was objectionably high in patîents who were observed over 15-20 years.13 The recurrence rate was markedly
1031
1032
Radiation Oncology ??Biology??Physics
September-Octobcr 1976,Vol. 1. Numbcr 9 and Number 10
reduced, however, with postoperative irradiation. Radiation therapy alone controlled 7080%, and had the advantage of no mortality and little morbidity;‘” but the response, as measured by visual field change, was more delayed and (possibly due to cystic elements) less certain. Therefore, disagreement on the optimum therapy was prevalent among neurosurgeons and radiotherapists. Some surgeons and radiotherapists believed in treating a selected qoup with primary radiation therapy, reserving surgical methods for radiation failure. Others relied largely on primary surgical intervention. Many who preferred primary surgery advocated postoperative radiation therapy. It should be noted that in most era under consideration, the neurosurgeons were using the transfrontal approach to the pituitary. Because of surgical the transsphenoidal complications hypophysectomy advocated by Cushing’ was not in wide usage; its resurgence in the form of transsphenoidal microdissection had not yet occurred. During the last 10-15 years many exciting new facets have combined to increase our understanding of the normal and abnormal pituitary, its physiologic control, and the treatment of its diseased states. Endocrinologie techniques now permit separate assessment of function of the hypothalamus and the pituitary, including its target organs. Pathophysiologists and histologists are providing new insight into the control of the pituitary hormone output and the correlation between function and histology. The neuroradiologist can provide information about the vascular supply that nourishes the pituitary and with computer-assisted tomographie techniques, may be able to distinguish cystic from solid tumors. Therapeutic techniques that are available to the neurosurgeon and to the radiation therapist have been refined. The result is a flood of exciting information which has produced more questions than answers. Whether Cushing’s syndrome is a result of a basophilic or of a chromophobic adenoma is now debated. The pituitary from an acromegalic patient may fail to show acidophilic cells and, by tintorial staining methods, be
replete with chromophobe cells. Other pituitaries show a mixture of cel1 types. The absente of cells with stained secretory granules in patients with either Cushing’s syndrome or acromegaly has been explained on the bases that such cells are, in fact, not present or that through overactivity, have become depleted of their granules. Recent evidente has even raised the question of whether there is such a lesion as a chromophobe adenoma, the claim being made that if fresh tissue is properly fixed and stained, al1 pituitary adenomas contain cells in which there are stainable granules. Development of the immunoperoxidase stains allows evaluation of both prolactin and growth hormone in pituitary cells of patients with hypersecretion of these hormones. The immunoenzyme method is claimed to be more sensitive, more specific, and to correlate better with plasma hormone levels of pituitary hormones than the standard tintorial methods. The importante of the recently acquired ability to measure plasma growth hormone and prolactin levels and the multitude of tests either to stimulate or black release of the various pituitary hormones hardly can be overemphasized. They have led to significant advances in understanding pituitary physiology and the interplay between plasma and hormone levels, the hypothalamus and the pituitary gland. Clinical applications, however, are not always clear and in certain instances, conclusions have been reached prematurely. For example, shortly after the growth hormone assay became available in the 1960s it was concluded by many that conventional radiation therapy did not reduce GH levels adequately, and this form of therapy was virtually abandoned. It now is known that conventional radiation therapy is essentially as effective in restoring plasma growth hormone levels to normal as are the various surgical procedures; however, with irradiation, the response is slow, requiring from several months to several years, whereas the drop following transsphenoidal hypophysectomy or microsurgery is prompt.3.‘4 Incidentally, the time required for response to high-dose heavy particle irradiation is not unlike that of conventional photon irradia-
Pituitary tumors 0 GLENN
E. SHELINE
1033
tion Further, we do not know whether rapid reversion to normal is necessary in a longstanding chromic disease like acromegaly, although one would intuitively think that to be the case. A similar dilemma regarding the proper treatment for patients with elevated prolactin secretion has arisen. What is the clinical significante of an elevated plasma prolactin leve1 in a patient with neither galactorrhea nor amenorrhea? Available information suggests that conventional irradiation is as effective as surgery in reducing prolactin levels, but an adequate study has not been reported. One study described at a recent meeting reported that of eight patients who were treated surgically and eight patients who were irradiated, there was an approximate 75% decrease in prolactin leve1 for each group, and two of each subsequently became pregnant.4 Following transsphenoidal microdissection, the prolactin leve1 does not always revert to normal. If the neurosurgeon increased the extent of his resection in an effort to obtain normal levels with greater consistency, would more harm or good result? Current data suggest that from 30 to 90% (frequency depending on the criteria accepted for “normal”) of the lesions previously termed “chromophobe adenomas” and assumed to be nonfunctional were in fact prolactin hypersecretors.‘.15 Since postoperative radiation therapy reduced the recurrence rates in those “chromophobe adenomas”, should lesions now known to be prolactin secretors receive postoperative irradiation? Such a conclusion is tempting to the radiation therapist, but it also is possible that the prolactin secretors account for some of the previous irradiation failures and that they might not be benéfited by radiation therapy. The newer diagnostic techniques, especially hormone assays associated with pituitary stimulating and blocking agents, provide a vastly improved ability to evaluate unwanted effects, as wel1 as those of a beneficial nature, for each therapeutic method. Evidente now available indicates that conventional photon
irradiation can alter hormone production by normal pituitary cells.“’ The injury may be either to the hypothalamus or to the pituitary itself. Detection may follow a substantial delay in time. In some patients, the pituitary deficiency can be uncovered only by endocrinologie studies, but in others it results in clinically evident deficiencies. It is surprising that these irradiation effects on pituitary function went unnoted for so long. There are also occasional instances of chiasma1 injury following conventional irradiation techniques; these are limited largely to patients who received greater than 5000 rad or individual dose fractions greater than 200 rad. The same precision of testing for response and damage should be applied to al1 therapeutic methods. It is suggested that attention should shift from histologie classification to a system based on function, with secondary consideration for size, extension, or damage produced by the pituitary tumor. Current sophisticated methods should be used to re-evaluate response to treatment and untoward effects of teatment; a controlled, randomized study of the various treatment modalities would be of great value. However, the infrequency of these disease entities and the fact that expertise with certain modalities is not available in every institution suggest that such a study must be of multi-institutional character and that randomization is not possible. The best approach may be the formation of a registry. The method of therapy favored at any institution then could be applied. For inclusion in the registry, certain pre-specified data would be required. These data would include pretreatment and periodic posttreatment clinical and laboratory observations. The data required should be adequate to permit later retrospective evaluation, yet not so extensive that the study would collapse of sheer magnitude. It is hoped that this discussion wil1 aid in the formulation of a meaningful study designed to compare the various treatment modalities in light of presently available methods.
1. Cushing, H.: Surgical experiences with pituitary disorders. J.A.M.A. 63: 1515-1525, 1914.
2. Edmonds, MW., Simpson, W.J.K., Meakin. J.W.: External irradiation
of the hypothysis
for
1034
Radiation Oncology 0 Biology 0 Physics
Septemk-October
Cushing’s disease. J. Can. Med. Assoc. 107: 860-862, 1972. 3. Hardy, J.: Transsphenoidal surgery of hypersecreting pituitary tumors. In Diagnosis and Treatment of Pituitary Tumors, ed. by Kohler, P.O., Ross, G.T. New York, Excerpta Medica Amsterdam, American Elsevier, 1973, pp. 179-194. 4. Kleinberg, D.: Endocrinologie aspects of pituitary adenomas. Presented at New York Roentgen Society Spring Conference, New York, 22-24 April 1976. 5. Kramer, S.: Indications for, and results of, treatment of pituitary tumors by external radiation. In Diagnosis and Treatment of Pituitary Tumors, ed. by Kohler, P.O., Ross, G.T. New York, Excerpta Medical Amsterdam, American Elsevier, 1973, pp. 217-229. 6. Lawrence, J.H., Linfoot, J.A., Bom, J.L., Tobias, C.A., Chong, C.Y., Okerlund, M.D., Manougian, E., Garcia, J.F., Connell, G.M.: Heavy particle irradiation of the pituitary. Progr. Neurol. Surg. 6: 272-294, 1975. 7. Melarkey, W.B., Johnson, J.C.: Pituitary tumors and hyperprolactinemia. Arch. Intern. Med. 136: 4044, 1976. 8. Orth, D.N.. Liddle. G.W.: Results of treatment in 108 patients with Cushing’s syndrome. N.E.J.M. 285: 243-247, 1471. 8a. Pistenma, D.A., Goffinet, D.R., Bagshaw, M.A., Hanbery, J.W., Eltringham, J.R.: Treatment of acromegaly with megavoltage radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 1: 885-893, 1976. 9. Richards, G.E., Wara, W.M., Grumbach, M.M., Kaplan, S.L., Sheline, G.E., Conte, F.A.:
1976, Vol. 1, Number 9 and Number 10
Delayed onset of hypopituitarism: sequela of therapeutic irradiation of centra1 nervous system, eye, and middle ear tumors. J. Peds. to be published. 10. Samann, N.A., Bakdash, M.M., Caderao, J.B., Cangir, A., Jesse, Jr., R.H., Ballantyne, A.J.: Hypopituitarism after external irradiationevidente for both hypothalamic and pituitary origin. Ann. Intern. Med. 83: 771-777, 1975. 11. Shalet, S.M., Beardwell, C.G., Morris-Jones, P., Bamford, F.N., Ribeiro, G.G., Pearson, D.: Cancer 37: 1144-1148, 1976. 12. Sheline, G.E., Goldberg, M.B., Feldman, R.: Pituitary irradiation for acromegaly. Radiology 76: 7&75,82, l%l. 13. Sheline, G.E.: Treatment of nonfunctioning chromophobe adenomas of the pituitary. Am. J. Roentgenol., Rad. Ther. Nucl. Med. 120: 553-561, 1974. 14. Sheline, G.E., Wara, W.M.: Radiation therapy of acromegaly and nonsecretory chromophobe adenomas of the pituitary. In Tumors of the Nerveus System, ed. by Seydel, H.G. New York, Wiley, 1975, pp. 117-131. 14a. Urdaneta, N., Chessin, H., Fischer, J.J.: Pituitary adenomas and craniopharyngiomas: analysis of 99 cases treated with radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 1: 895-902, 1976. 15. Zimmerman, E.A., Defendini, R., Frantz, A.G.: Prolactin and growth hormone in patients with pituitary adenomas: a correlative study of hormone in tumor and plasma by immunoperoxidase technique and radioimmunoassay. J. Clin. Endrocrinol. Metab. 38: 577-585, 1974.
