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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0277
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 7 2656-2664
Copyright © 2006 by The Endocrine Society

Surgical Remission of Pituitary Adenomas Confined to the Neurohypophysis in Cushing’s Disease

Robert J. Weil, Alexander O. Vortmeyer, Lynnette K. Nieman, Hetty L. DeVroom, John Wanebo and Edward H. Oldfield

Surgical Neurology Branch (R.J.W., A.O.V., H.L.D., J.W., E.H.O.), National Institutes of Neurological Disorders and Stroke, National Institutes of Health, and Reproductive Medicine and Biology Branch (L.K.N.), National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892-1414

Address all correspondence and requests for reprints to: Edward H. Oldfield, M.D., Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D37, MSC 1414, 9000 Rockville Pike, Bethesda, Maryland 20892-1414. E-mail: oldfiele{at}ninds.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Partial or total removal of the pituitary cures 60–80% of patients with Cushing’s disease (CD) in whom an adenoma cannot be identified at surgery. Many patients who fail complete or partial hypophysectomy are cured by sellar and parasellar irradiation.

Design/Patients: As part of a series of prospective studies of CD, we identified 12 patients (34.5 ± 19.9 yr; 11 females; four children) with tumors located completely within the neurohypophysis among 730 patients undergoing surgery for CD.

Setting: The study was conducted at a tertiary referral center at a clinical research hospital.

Results: All 12 patients had clinical and biochemically defined CD. Tumor was visible at surgery in 11 patients; all 12 tumors were positive for ACTH by immunohistochemistry. Two tumors were excised at repeat surgery because of persistent hypercortisolism within 14 d of negative exploration of the adenohypophysis. There were no long-term complications. At follow-up of 71.9 ± 34.2 months (range, 30–138 months), all patients are in remission of CD. Adult patients have had significant improvement in weight and body mass indices, with restoration of normal menses in all women. In the four pediatric patients, height, weight, and body mass indices have been restored toward normal by surgical remission of CD. Hypopituitarism or long-term neurohypophysial dysfunction has not occurred.

Conclusion: We report a new subset of patients with CD, ACTH-secreting adenomas that arise wholly within the posterior lobe of the pituitary gland. In cases of CD in which an adenoma is not identified in the adenohypophysis and in patients with persistent hypercortisolism after complete or partial excision of the anterior lobe, tumor within the neurohypophysis should be considered; selective adenomectomy of a neurohypophyseal, ACTH-secreting tumor can produce long-term remission.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
IN 1934, HARVEY CUSHING described a basophilic adenoma residing completely within the posterior lobe in the postmortem examination of a patient with hypertension during pregnancy as a "large, sharply defined cellular mass... its diameter being about 3 by 4 mm. It proves on higher magnification to have the architectural features of an adenoma, and its component elements are unmistakably fully ripened basophilic cells" (Fig. 1Go) (1). An additional case of a posterior lobe basophilic tumor associated with Cushing’s disease (CD) was briefly described in a surgical report by Wilson and colleagues (2, 3) in 1983, although details of this case were not given. Neither remission of CD after surgery limited to selective adenomectomy of an ACTH-secreting tumor within the posterior lobe nor the clinical features of patients with posterior lobe tumors have been described previously. We report 12 patients with CD in whom an ACTH-staining adenoma was contained entirely within the posterior lobe of the pituitary and detail their diagnostic features and treatment, including remission of Cushing’s syndrome after selective microsurgical adenomectomy.


Figure 1
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  		FIG. 1. Posterior pituitary basophilic adenoma described by Harvey Cushing in 1934. A, The tumor lies in the posterior portion of the neurohypophysis (arrow), behind the intermediate lobe (indicated by two arrowheads). The normal anterior lobe lies above the intermediate and posterior lobes. B, Low-power hematoxylin and eosin-stained view showing the basophilic tumor. C, High-power view showing typical pituitary basophilic tumor cells. Figures adapted from Harvey Cushing’s article in the American Journal of Pathology (1 ).

 
CD is a life-threatening illness caused by glucocorticoid excess due to an ACTH hormone-secreting pituitary adenoma (4). Expeditious diagnosis and treatment of CD are warranted to limit long-term morbidity (5, 6, 7). Most tumors are single and are located within the anterior lobe of the pituitary gland (4, 8). However, unusual and ectopic sites for adenomas have been identified, including the sphenoid sinus, anterior cranial fossa, interpeduncular cistern, and suprasellar space and within the dura investing the sella, cavernous sinus, or clivus, sites that must be considered when contemplating treatment options in patients with CD in whom tumors are not identified in the anterior lobe (4, 9, 10, 11).

Transsphenoidal pituitary surgery with selective adenomectomy is the primary treatment for CD (3, 5, 6, 12, 13, 14). For microadenomas (tumors ≤ 1 cm in maximum diameter), selective removal of an adenoma results in remission of CD in most patients (3, 13, 14). Similarly, identification and selective removal of ectopic parasellar adenomas results in long-term remission in the majority of patients (9, 10, 11). However, when an adenoma cannot be found at surgery and partial or complete removal of the anterior lobe is performed, remission rates are closer to 50–70% and are associated with an increased rate of recurrence, compared with selective adenomectomy (3, 6, 14, 15).

The following summarizes the clinical and operative findings in 12 patients in whom an ACTH-staining adenoma causing CD was identified entirely within the posterior lobe and selectively excised.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
The medical records of 12 patients with CD, who underwent transsphenoidal microsurgical surgery for initial or recurrent disease at the National Institutes of Health (NIH) between 1992 and 2003 and in whom an adenoma was identified that was confined totally within the posterior lobe, were reviewed. Over this period, 270 adult and pediatric patients with CD underwent surgical exploration. Patients were studied as part of Institutional Review Board-approved protocols at the NIH. Patients’ medical records, neuroimaging and reports, and specimen slides were reviewed. Pathological review included slides stained with hematoxylin and eosin, reticulin, and immunohistochemistry using antibodies for ACTH, MAK-6 (which recognizes intermediate filaments and is a marker of epithelial origin), and MIB-1, a marker of proliferation, with appropriate positive and negative controls (16). When the patient could not return to the NIH for distant postoperative follow-up, postal questionnaires were completed and confirmed by telephone communication with the patient and, in the case of minors, a parent.

Height and weight were measured before and at approximately 1 yr after surgery. At longer follow-up intervals, most patients returned to their local endocrinologist for medical care, rather than to the NIH. At more distant follow-up, patients were asked to weigh and measure themselves and report this value; previous studies (17, 18) demonstrated correlation of reported weight with measured weight. Body mass index [BMI; weight in kilograms divided by the square of the height in meters, or BMI = kilograms/(meters)2] was used as a measure of obesity because it depends on weight and is independent of height. BMI is a prognostic marker in adults for overall mortality as well as mortality from specific causes (17, 19, 20). Previously Manson and colleagues (17, 21) established that the relative risk of death in adults rises proportionally with increasing BMI, with a statistically significant increase noted with BMI of 25.0 kg/m2 or greater. For the adults, weight was adjusted for age using previously described normal values (17, 20, 21, 22). For children of both sexes, nomograms with SD values have been established, which were used for the calculations in this study (23, 24).

Biomedical evaluation

All patients were hypercortisolemic with clinically evident Cushing’s syndrome (6, 25). Standard biochemical testing was performed, as has been previously detailed (12, 25). In brief, multiple measurements of morning (0700–0800 h) and evening (2300–2400 h) cortisol, 24-h urinary free cortisol, and ACTH were obtained (detailed in Table 2Go). In addition most patients had determination of 17-hydroxysteroid levels and had challenge or stimulation tests consisting of dexamethasone suppression and CRH, as previously described (25). All patients underwent magnetic resonance imaging (MRI; 1.5 tesla), with fine cuts of the sella, without and with the administration of gadolinium (26). Eleven patients also underwent inferior petrosal sinus sampling, with determination of basal and stimulated levels and ratios of cortisol and ACTH in the periphery and left and right inferior petrosal sinuses, as previously described (12, 25). Postoperative testing with 24-h urinary free cortisol and morning serum cortisol was used to define remission (values < 10 µg/d and < 5 µg/dl, respectively; 277 and 139 SI).


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  		TABLE 2. Biochemical testing before surgery and operative findings

 
Surgical technique

Transsphenoidal microsurgery was performed essentially as described previously, with modifications to provide access to the posterior lobe (8, 9, 10, 27, 28). If the tumor was visible on MRI, it was approached at the outset of the procedure after the dura over the pituitary gland was opened widely. If the posterior lobe was to be examined in a patient with a normal MRI, the anterior surface of the posterior lobe was exposed after a complete exploration of the anterior lobe had been completed. A vertical incision in the anterior lobe was carried deeper, in stages, until the gelatinous contents of the intermediate lobe were exposed or the interface between the posterior surface of the anterior lobe and the capsule covering the anterior surface of the posterior lobe was reached (Fig. 2Go). The anterior lobe was separated with the tips of the bipolar forceps, or Wilson forceps, to gain sufficient space to examine the capsule of the glistening gray-white anterior surface of the posterior lobe. Rather than working within the limited side-to-side space of the crevice formed by an incision in the midline of the anterior lobe, a 2-mm vertical wedge of the anterior lobe can be removed between two vertical incisions carried through the anterior lobe. In some of the tumors described here, particularly the larger ones, this approach was used. The posterior lobe tumors generally had a pale gray-blue or gray-brown color visible on inspection of the posterior lobe surface, which, combined with their tendency to produce a somewhat enlarged posterior lobe with a distinct protuberance over the epicenter of the tumor, permitted recognition of them. Because there is no anterior lobe to compress and thereby to create a surgical capsule (a histological pseudocapsule) as occurs with adenomas in the anterior lobe, tumors in the posterior lobe are not encapsulated; they must be removed in a piecemeal manner using microinstruments and small cup pituitary forceps. Those described here were excised completely by removing completely the region of darker color within the stark white color of the posterior lobe tissue.


Figure 2
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  		FIG. 2. Operative findings. A, A schematic drawing of the operative approach, viewed in the sagittal plane. The anterior pituitary is red-brown in color, whereas the neurohypophysis is gray-white; a small, spherical tumor lies within the posterior lobe. B, Above and below, the superior-inferior incision made in the anterior pituitary is demonstrated. C, Initial exposure of the tumor in the white posterior lobe deep to the retracted red-brown anterior pituitary. D, Intraoperative photograph of an ACTH-secreting tumor confined to the posterior lobe of the pituitary in a 13-yr-old girl; it is indicated by a black arrow. The blue-gray tumor can be seen through the intact capsule of the anterior surface of the neurohypophysis. A small medial wedge of anterior lobe has been removed; the white arrows indicate the margins of the normal, red-brown anterior pituitary gland. E and F, Schematic representations of selective removal of the adenoma from the posterior lobe.

 

   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Twelve of 270 patients operated upon for confirmed CD over an 11-yr period were identified as having an ACTH-secreting tumor lying completely within the neurohypophysis. Eighty-five of these 270 patients (31%) had tumors with an epicenter in the midline or just off the midline, 30 of which were macroadenomas, 55 of which were microadenomas. Twelve of these 55 microadenomas were located deep within the anterior lobe, with the posterior margin of the tumor extending to the posterior edge of the anterior lobe and abutting, but not extending into, the anterior surface of the posterior lobe.

Among the 12 patients with tumors confined to the posterior lobe, 11 (92%) were women and four were children or adolescents (age < 20 yr at diagnosis); the mean age was 34.5 ± 19.9 yr (range, 7–66 yr). All patients had symptoms, signs, and confirmed biochemical evidence of CD (Tables 1Go and 2Go). Rapid weight gain, sc fat accumulation and central obesity; hirsutism, menstrual irregularities, fatigue, behavioral or memory alterations; hypertension, skin stria, and easy bruisability; and moon facies, headaches, depression, and myopathy occurred in 50% or more of patients (Table 1Go).


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  		TABLE 1. Manifestations of CD at presentation

 
The eight adult patients’ heights and weights were measured preoperatively and compared with standardized results for both sexes (Tables 3Go and 4Go). The preoperative BMI was calculated, with a value for the adults of 32.2 ± 5.5 kg/m2 (range, 24.9–42.7); seven of eight adults had BMIs greater than 25.0 kg/m2 and six of eight were classified as obese (BMI > 30 kg/m2) (20).


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  		TABLE 3. Characteristics and postoperative results for adult patients

 

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  		TABLE 4. Characteristics and postoperative results for pediatric patients (n = 4)

 
Of the four pediatric patients, age- and sex-adjusted heights were significantly reduced below normal, and weights were significantly above normal for age and sex (Table 4Go). Nonadjusted BMIs averaged 33.1 ± 6.3 kg/m2 (range, 26.5–41.4), with scores ranging several SD values above the age- and sex-adjusted norms (Table 4Go). All four pediatric patients were obese by age- and sex-adjusted BMI scores (23, 24).

All patients had biochemical hypercortisolism and lacked diurnal variation in plasma cortisol concentrations (Table 2Go). All patients were tested with high-dose dexamethasone and were suppressed. Ten of 11 patients (91%) undergoing the CRH test had an increase in ACTH greater than 34% and/or cortisol greater than 20% after administration of CRH. Basal and CRH-stimulated inferior petrosal sinus sampling (IPSS) measurements were consistent with CD in all 11 patients in whom the test was performed; there was no specific lateralization of IPSS values. MRI of the sella was performed in all patients before surgery (Fig. 3Go). A potential intrasellar tumor was identified in the posterior portion of the sella in two patients. Complete or partial empty sella syndrome occurred in four patients (25%).


Figure 3
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  		FIG. 3. Neuroimaging. A–C, MRIs from a 33-yr-old woman. A, Coronal, T1-weighted image at the level of the optic apparatus and pituitary stalk shows an enlarged gland. B, Sagittal, T1-weighted image at the same location shows a heterogeneous lesion in the posterior sella. C, Sagittal, T1-weighted, gadolinium-enhanced image seen in B, demonstrating the adenoma (arrow), which is slow to take up contrast, compared with the normal anterior pituitary gland. D, Intraoperative ultrasound image demonstrating a homogeneous, hyperintense spherical lesion at back of sella (arrow) corresponding to the tumor on MRI.

 
Transsphenoidal surgery, with selective tumor removal, was performed 3.8 ± 2.8 yr (range, 1.0–10.5 yr) from the onset of signs and symptoms of CD. Fourteen operations were performed in 12 patients; two patients underwent repeat surgery within 10 d of an initial exploration. In these latter two cases, a hemihypophysectomy had been performed at the first surgery after complete exploration had failed to identify a tumor in the adenohypophysis. During definitive exploration, a blue-gray tumor was identified within the posterior gland in 11 patients (92%), with a mean size of 6 ± 3 mm (range, 3–12 mm). One microscopic (<2 mm) tumor was identified upon inspection of a suspicious portion of the posterior lobe, which contained a small area of blue-gray discoloration and which was removed as a separate specimen. All tumors were ACTH positive, with MIB-1 staining of occasional tumor cells (Fig. 4Go). Cerebrospinal fluid leak was noted during surgery in seven operations (50%), likely related to the extensive exploration of the pituitary before a tumor was identified in the posterior lobe and was treated successfully with autologous fat graft and cerebrospinal fluid diversion for 3 d. Transient (<7 d) diabetes insipidus occurred in four patients, but no further treatment was required.


Figure 4
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  		FIG. 4. Pathological findings. A, Histology of patient illustrated in Fig. 2Go. Left, top, Hematoxylin and eosin (H&E) stain of a fragment of posterior lobe shows dense accumulation of basophil cells, which are intensely positive for ACTH by immunohistochemistry (center, top). Right top, Reticulin stain of the same fragment stains perivascular connective tissue only; there is no pseudocapsule; the submitted specimen contained no anterior pituitary tissue (magnification of upper row, x75). Lower row, Higher magnification (x150) reveals irregular interface between basophils and posterior lobe on H&E stain (left) and ACTH immunostain (center), whereas immunohistochemistry for MIB1 (right) reveals occasional immunoreactive cells. B, Basophilic adenoma in the neurohypophysis from the patient illustrated in Fig. 3Go, which shows a trabecular and acinar architecture (upper left, x75), lack of reticulin staining (upper right, x75), intense immunoreactivity with anti-ACTH (lower left, x150), and scattered cells positive for MIB1 (lower right, x300).

 
All 12 patients had clinical and biochemical remission after surgery limited to selective removal of an adenoma in the posterior lobe. Urinary free cortisols were less than 15 µg per 24 h (416 SI per 24 h) in each patient on postoperative d 3–5 and remained normal in all at distant follow-up. At an overall distant follow-up of 71.9 ± 34.2 months (range, 30–138 months), CD remains in remission in all patients. Five of seven patients with hypertension before surgery no longer require medical therapy, and three of four patients with CD-induced glucose intolerance have discontinued therapy. Average weight loss in adults (n = 8) was 8.9 ± 7.4 kg and 20.7 ± 14.8 kg at 1 yr and distant follow-up of 81.1 ± 33.8 months (range, 33–138 months), respectively (Table 3Go). BMIs demonstrated positive changes correlating with weight loss, with values of 25.3 ± 2.3 kg/m2 (range, 22.0–27.0) and 24.3 ± 1.8 kg/m2 (range, 21.3–26.5) at 1 yr and at distant follow-up; the average change in BMI was –3.3 ± 2.6 and –8.0 ± 5.5 at 1 yr and distant follow-up after surgery, respectively (Table 3Go). At final follow-up, six of eight adults had BMI scores less than 25 kg/m2 (considered the top end of normal) and none was obese (BMI > 30 kg/m2).

For children and adolescents (n = 4), average weight loss was 9.8 ± 6.0 kg at 1 yr; in these subjects, with an average, distant follow-up of 48.9 ± 22.9 months (range, 30–79 months), all four patients had nearly reached means of their age-adjusted weights (Table 4Go). Average growth rate was 7.5 ± 3.2 cm in the first year after surgery and averaged 4.5 ± 3.2 cm/yr, until last follow-up, upon reaching age 21, or after cessation of adolescent growth (Table 4Go). At final follow-up in all four subjects, average deviation from age-adjusted heights was 0.11 ± 1.09 SD values from age-adjusted heights; two patients, in whom recognition of CD took 2 yr or more during their peak growth years, failed to reach their age-adjusted height, whereas the other two children, diagnosed before the adolescent growth phase, both exceeded age-adjusted heights. BMI measurements were similarly improved with surgery, with significant improvements due to weight loss and resumption of growth, at both 1 yr (n = 4) and distant follow-up of more than 4 yr. BMI loss at final follow-up, compared with that before surgery, averaged 9.05 kg/m2, with decreases in BMI that ranged from 4.3 to 19.7 kg/m2.

All four adult, premenopausal women resumed normal menses, and both children with CD-induced primary amenorrhea assumed normal menstrual cycles. The hypothalamic-pituitary-adrenal axis resumed normal function at 10.5 ± 4.6 months (range, 6–18 months) from surgery, and 11 of 12 patients have successfully been weaned from hydrocortisone; one pediatric patient remains on physiological doses of cortisol replacement at 30 months. No patient requires supplemental pituitary hormones.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Transsphenoidal microsurgery is the therapy of choice for CD (3, 6, 13, 14, 27, 28, 29, 30). When a discrete tumor is identified, selective adenomectomy results in immediate and persistent remission in 66–95% of patients (3, 6, 13, 14, 27, 28, 29, 30). If surgical exploration fails to reveal an adenoma, partial or total removal of the anterior pituitary can lead to cure in up to two thirds of patients (3, 6, 14, 15, 26, 28). A minority of cases harbor tumors located in extrasellar or ectopic locations, including within the sphenoid sinus mucosa, clivus, or parasellar dura as well as the cavernous sinuses (9, 10, 11, 29). Adenomas in these locations suggest that ACTH-secreting tumors can arise outside the adenohypophysis and intermediate lobe, known collectively as the pars distalis, because both areas are derived by upward invagination of tissue from Rathke’s pouch (4, 31). Nonetheless, a significant number of patients who undergo total removal of the anterior lobe and who do not have imaging evidence of extrasellar or ectopic tumor fail to go into remission; many of these patients have remission of CD after fractionated radiosurgery of the sella (6, 13, 14, 15, 29, 32).

The patients identified in this report represent a new subset of patients with CD, ACTH-secreting adenomas that arise wholly within the posterior lobe of the pituitary gland. The cases of two previously described patients suggested that basophilic adenomas may be found in the neurohypophysis, although the connection between the tumor, its site of origin in the pituitary gland, and clinical symptomatology of CD was not examined in those two cases (1, 2, 33). In our series, 11 patients were women and eight were adults. All 12 patients presented with most of the common symptoms and signs of CD and had biochemical evidence of hypercortisolism in the basal and stimulated states, as occurs with ectopic ACTH-secreting pituitary adenomas at parasellar sites. A visible adenoma was removed from 11 patients and a microscopic tumor from the last patient. In all cases after surgery limited to selective removal of an adenoma, patients went immediately into remission, and all 12 are in remission at distant follow-up, without evidence of dysfunction of the anterior or posterior pituitary glands. All eight adults underwent prompt weight loss by 1 yr after surgery, a weight loss that was sustained for 3–11 yr. Whereas six of eight adults were classified as obese before surgery (BMI > 30 kg/m2), only one of eight was classified as overweight (BMI > 25 kg/m2) at distant follow-up, with the remainder having BMI 25 kg/m2 or less. Similarly, all four pediatric patients demonstrated significant alterations in growth, weight, and BMI, all of which were corrected or significantly improved by surgical excision of their tumor. In these patients, average growth in the first year after surgery averaged 7.5 ± 3.2 cm. For the three children aged 14 yr or younger at the time of surgery, growth in the first year averaged 9.6 ± 1.7 cm (8.0–11.4 cm), and growth was sustained in the years leading up to age 21 yr: overall growth over an average time period of 5 yr was 23.3 ± 4.2 cm (18.0–27.0 cm), which is similar to other reversible conditions that permit catch-up growth.

Furthermore, in children and adults, most of the symptoms, signs, and comorbid conditions associated with CD, including hypertension and glucose intolerance, were eliminated by surgical treatment. Both patients who received continued treatment for hypertension in long-term follow-up were older than 60 yr; however, the medication requirements for both were decreased after surgery. Finally, successful surgical treatment of CD reestablished normal gonadal function and did not induce new pituitary dysfunction.

Why have only two instances of CD caused by posterior lobe tumors previously been described (1, 2)? That most of these tumors are not visible on MRI is a contributing factor, for the modern era at least. The adenoma was identified by MRI in only two of our 12 patients. What might explain this high incidence of negative MRI, despite a tumor size averaging 6 ± 3 mm in diameter? Almost all pituitary microadenomas have a signal intensity on MRI that is similar to the anterior lobe and are nonenhancing lesions. We detect them chiefly because the anterior lobe of the pituitary gland enhances after the iv administration of gadolinium-containing contrast media, providing the appearance of a well-demarcated, darker region within the anterior lobe at the site of the nonenhancing microadenoma. In contrast to the circumstance of microadenomas within the anterior lobe, neither the intermediate lobe nor the posterior lobe enhances with contrast. Thus, the lack of identification of most of the microadenomas in the posterior lobe is probably related to the absence of contrast enhancement of the tissue surrounding the adenoma. An additional factor is that, unlike other types of pituitary tumors, many tumors causing CD are 5 mm or less in maximum diameter at diagnosis and treatment (33, 34, 35, 36). Thus, one of the principal challenges of successful treatment of CD is finding small tumors (14, 29). Almost all patients (90% or more) in whom a microadenoma can be identified at surgery have remission of CS, even in the presence of a negative MRI, as has been shown previously (14, 28). Finding very small tumors in the presence of a negative MRI may depend more on experience with CD than would experience emphasizing the other, much more common types of pituitary tumors because most other pituitary tumors are macroadenomas by the time of diagnosis (14, 29). The effect of experience seems to be a factor in identifying the tumors in the posterior lobe described here because the senior surgeon (E.H.O.) identified no posterior lobe tumors in the first 460 patients explored for CD (1981–1992) before the first adenoma confined to the posterior lobe was recognized but found 12 such tumors in the most recent 270 patients (4.4%) who received surgery for CD, an incidence similar to the frequency with which parasellar adenomas were found at other sites in the same surgical series (9).

In summary, ACTH-producing adenomas can arise and remain completely within the posterior lobe. At present, the developmental origin of these tumors remains unknown, although several possibilities exist (9, 11, 31, 37, 38, 39). Distribution of corticotrophs within the pituitary in the embryo and adult varies among species (31, 40). In dogs and horses, for example, CD appears to be the result of ACTH hypersecretion from the intermediate lobe, a distinct structure not identified in the normal adult human pituitary (4, 16, 41, 42). Whereas proopiomelanocortin expression occurs in corticotrophs in the anterior and posterior lobes in zebrafish, corticotrophs are typically found in high concentrations only within the central mucoid wedge of the anterior gland in man, a structure that abuts, but is distinct from, the posterior lobe (4, 5, 16, 40, 43). Although studies in human fetal autopsies have shown populations of corticotrophs (and all other anterior pituitary cell subtypes) within pharyngeal adenohypophyseal tissues that have not completely migrated to the sella, the presence of corticotrophs within neurohypophyseal tissue was not noted (44). In addition, investigation of Tpit, a transcription factor whose expression precedes that of proopiomelanocortin in the embryonic pituitary, and which is restricted to corticotrophs and melanotrophs, in murine models and humans demonstrates that complete loss of Tpit causes isolated ACTH deficiency but produces no clinical or structural abnormalities of the posterior lobe (37, 38, 45). Although two early studies raised the possibility of origin of basophilic (but not necessarily ACTH-secreting) tumors from the intermediate lobe, two larger studies, which included immunohistochemical analyses, do not support this hypothesis (33, 34, 35, 36). In our cases, as well as that illustrated in Fig. 1Go and that reported by Wilson and colleagues (1, 2), the tumors were wholly within the posterior lobe. Finally, although basophilic cell invasion of the posterior lobe may be seen occasionally at postmortem assessment, our immunohistochemical studies, as well as those of others (16, 39, 44), do not provide evidence that these cells form tumors. Thus, elucidation of the origin of these tumors requires future investigation.

Thus, in cases of CD in which an adenoma is not identified in the adenohypophysis or parasellar region and in patients with persistent hypercortisolism after complete or partial excision of the anterior lobe, tumor within the neurohypophysis should be considered (1, 2, 29). Resection of an ACTH-secreting tumor in the neurohypophysis can produce long-term remission, with significant improvements in health.


   Footnotes
 
Current address for R.J.W.: Brain Tumor Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

First Published Online April 24, 2006

Abbreviations: BMI, Body mass index; CD, Cushing’s disease; IPSS, inferior petrosal sinus sampling; MRI, magnetic resonance imaging.

Received February 8, 2006.

Accepted April 18, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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