—  SPECIALTY CONFERENCE  —

Neuropathology

Case 1 - Mixed Pituitary Adenoma-Gangliocytoma,
with Adenoma Immunoreactive for Prolactin and Growth Hormone

B.K. Kleinschmidt-DeMasters
University of Colorado Health Sciences Center
Denver, CO


Click on each slide thumbnail image for an enlarged view

Clinical History
The patient is a 23-year-old right handed female who first experienced difficulties in 05/2001 when she stopped taking her birth control pills and noted the onset of headaches. Over the next several months the headaches became progressively worse and were particularly painful around the time of her menstrual periods. She subsequently was started back on her birth control pills in 11/2002 and her headache improved, but because she wanted to try to become pregnant she once again ceased taking her birth control pills in 05/2002. Her headaches returned. After she stopped taking her birth control pills in 05/2002 she developed amenorrhea, but no galactorrhea. Her gynecologist saw her in 02/2003 and a prolactin level was found to be moderately elevated at 103 ng/ml. MRI scan demonstrated a 1.9 X 2.3 X 1.5 cm. sellar and suprasellar mass abutting the optic chiasm, with displacement of the normal gland superiorly and to the right. The patient was referred to an endocrinologist. More extensive workup verified the elevated prolactin level but showed normal levels of TSH, free T4, LH, and FSH. IGF-1 level was 426 (normal 182-780) and beta HCG was not detectible. The clinical impression was that the tumor was unlikely to be a prolactin-secreting adenoma due to its size and only modest elevation in prolactin; stalk effect was suspected.


Case 1 - Figure 1 - Pituitary adenoma component of the mixed pituitary adenoma-gangliocytoma shows a patternless sheet of monomorphic cells and demonstrates features indistinguishable from a pure pituitary adenoma.
Case 1 - Figure 2 - Prolactin immunostaining reveals an irregular distribution of staining throughout the tumor, with up to 50% of the adenoma population immunoreactive for this hormone in some areas.
Case 1 - Figure 3 - Growth hormone immunostaining was also irregularly distributed but clearly was present in a much smaller percentage of the adenoma population.


Case 1 - Figure 4 - A sharp junction was apparent between the pituitary adenoma component and the ganglion cell portions of this tumor. Note the very large numbers of ganglion cells near this junction.
Case 1 - Figure 5 - Ganglion cells, some of which are binucleate, are embedded in neuropil-like, finely fibrillar matrix.
Case 1 - Figure 6 - Prolactin immunostaining was identifiable in some of the binucleate cells within the gangliocytoma areas.

On 05/19/2003, she underwent transsphenoidal resection of her pituitary adenoma without complications. Postoperatively she did well except for persistent left-sided headaches that she described as sharp and virtually daily in occurrence, albeit of less severity than those she experienced preoperatively. Menstruation returned but again the headaches were worse during this time period.

Postoperative neuroimaging revealed good reduction in overall tumor mass, but persistent residual enhancing tissue in the left cavernous sinus. This was not felt to be resectable and was thought to be the likely source of the patient's continuing headaches.

On follow up examination in 09/2003 she complained of a low energy level, with persistent fatigue. One observer thought there was "a vague suggestion of acromegaly" due to her somewhat coarse facial features. Repeat laboratory studies showed normal FSH, LH, IGF-1, T-4, TSH, cortisol, and prolactin. On 10/16/2003, the patient was treated with stereotactic radiosurgery, with 15 gray delivered to the left cavernous sinus lesion; she tolerated the procedure well.

Diagnosis
Mixed pituitary adenoma-gangliocytoma, with adenoma immunoreactive for prolactin and growth hormone

Discussion
This case is a mixed pituitary adenoma-gangliocytoma. These tumorshave variable amounts of both classic pituitary adenoma and a ganglion cell tumor usually devoid of a conspicuous glial component (ie., gangliocytoma). The gangliocytoma portion of the tumor consists of a neuropil-like, finely fibrillar matrix in which are embedded large, uni-nucleate neurons showing a fairly normal appearance, with characteristic large nuclei, prominent nucleoli, and abundant basophilic cytoplasm with peripheral Nissl substance. Also present are binucleate, enlarged, and bizarre neurons. The background neuropil is hypocellular and is composed of the ganglion cell processes. The pituitary adenoma in this USCAP case demonstrated sheets of patternless monomorphic cells that were chromophobic on PAS-orange G stain and showed the expected disruption of the normal acinar pattern on reticulin staining. In this USCAP case, the pituitary adenoma was a mixed prolactin-growth hormone secreting tumor, with an irregular distribution of immunostaining seen for both hormones, but with the greatest numbers of cells showing staining for prolactin. In a mixed pituitary adenoma-gangliocytoma, the ganglion cells stain for neuronal markers (and in some studies for hypothalamic releasing hormones, pituitary hormones or neuropeptides) and the neuropil stains with axonal silver stains (Bielschowsky, Bodian, Sevier-Munger), synaptophysin, and neurofilaments. The fibrillar neuropil usually does not contain astrocytic or other glial elements and hence is usually negative for glial fibrillary acidic protein. Cytokeratin staining identifies the juxtanuclear fibrous bodies in cases where the adenoma is a sparsely granulated GH-secreting tumor and sometimes stains the ganglion cells (Geddes et al). In this USCAP case, as in many cases in the literature, the pituitary adenoma component is easily recognized or even the predominant element (Case 2, Scheithauer et al). The adenoma and gangliocytoma components may be sharply demarcated from each other, (this case, Case 3 Towfighi et al.), or they may be intimately admixed.

Sellar region masses that contain both pituitary adenoma cells and ganglion cells are uncommon, although probably not as rare as the numerous case reports in the literature would suggest. Although only 58+ cases have been reported in the literature, a recent report by Kurosaki et al. identified 6 examples of mixed pituitary adenoma-gangliocytoma amongst their series of 476 growth hormone (GH)-secreting pituitary adenomas, an incidence of 1.3%.

The entity has appeared in the literature under a plethora of names including gangliocytoma, pituitary adenoma with neuronal choristoma, hypothalamic neuronal hamartoma and adenohypophyseal neuronal choristoma, glioneuronal hamartoma with GH-cell pituitary adenoma, neurosecretory ganglion-cell choristoma, ganglioneuroma, and mixed gangliocytoma/pituitary adenoma. Since these tumors usually present as pituitary adenomas by clinical, laboratory, neuroimaging, and intraoperative criteria, and since the pituitary adenoma is often (as in this USCAP case) the predominant component of the lesion histologically, the pure appellation of "gangliocytoma" does not optimally represent the entity. Several other terms are also misleading, especially 'choristoma' and 'hamartoma', since they imply that the lesion is maldevelopmental in origin, occurs in very young children, and is non-neoplastic. We concur with Towfighi et al. that the best term for cases such as this is mixed pituitary adenoma-gangliocytoma. As this USCAP case clearly illustrates, mixed pituitary adenoma-gangliocytoma is a tumor that 1.) predominates in adults, 2.) grows and may invade adjacent structures such as the cavernous sinus, and 3.) requires surgical (and in this case, radiosurgical) intervention.

The USCAP case also illustrates the fact that these lesions are usually considered to be pituitary adenomas by the endocrinologist, neuroradiologist, and neurosurgeon preoperatively and the finding of the gangliocytoma component by the pathologist comes as a complete surprise. Indeed, most mixed pituitary adenoma-gangliocytomas are associated with an endocrinologically active pituitary adenoma component. The majority of reported patients have manifested acromegaly and growth hormone production, although at least six cases with Cushing's syndrome, and several with galactorrhea/amenorrhea and hyperprolactinemia have been identified. Most GH-secreting tumors reported in the literature have been sparsely granulated GH pituitary adenomas although mixed GH and prolactin cell adenomas (like this USCAP case) constituted 2 of the 6 cases identified by Kurosaki et al. Endocrinologically inactive tumors have also been reported, but in some cases (case 3 of Towfighi et al), despite the lack of preoperative endocrinopathy, modest prolactin and GH immunostaining had been identified in the resected adenoma.

In this USCAP case, one could argue that the moderate (103 ng/ml) elevation of prolactin was due to stalk interruption and not to prolactin and GH secretion by the tumor itself, since the patient's hyperprolactinemia disappeared following debulking of her tumor and removable of the stalk compression. No elevation of prolactin was found on her follow up visit, despite the presence of residual (potentially secretory) tumor in the left cavernous sinus. Hence this USCAP case may have caused an endocrinopathy (hyperprolactinemia) by its mass effect and not by excreting significant amounts of hormone product into the serum.

An important clinical question that is not addressed by most of the case reports is whether the behavior of mixed pituitary adenoma-gangliocytomas differssubstantially frompurepituitary adenomas without the gangliocytoma component. The most recent series by Geddes et al. included 6 cases that were sparsely granulated GH-producing adenomas-gangliocytomas. Follow up information suggests that most of these tumors exhibited benign behavior. Cases 1 and 5 had 9 and 19 year follow up time periods post surgery, respectively, and despite incomplete resection, no significant regrowth of the residual tumor occurred. Cases 2 and 3 were completely resected, while residual tumor was treated by re-operation in Case 4 and radiosurgery in Case 6. The review by Scheithauer et al. of older cases in the literature includes follow up information and also corroborates the impression that mixed pituitary adenoma-gangliocytomas exhibit behavior similar to pituitary adenomas devoid of the gangliocytoma component.

Most of the emphasis in the literature has not been on clinical features but on the origin of these tumors. Three different hypotheses have been offered: 1.) the ganglion cells are of hypothalamic origin and produce GH releasing or corticotropin releasing hormone that induces pituitary cell proliferation and eventual adenoma formation; 2.) both neuronal and pituitary adenoma elements of the lesion originate from (hypothetical) embryonal rests that may contain cells with intermediate features between neurons and adenohypophyseal cells; 3.) conversion and differentiation of sparsely granulated GH adenoma cells into neuronal (ganglion) cells. Horvath et al., Geddes et al., and this USCAP case favor/support the latter hypothesis.

Also favoring this idea are the very rare cases in the literature where the patient exhibits well-documented endocrinopathies preoperatively but is found to have a pure sellar gangliocytoma without adenoma elements. Case 7 of Geddes et al. had acromegaly preoperatively with elevated GH and prolactin levels; the gangliocytoma found by the pathologist was considered to be an adenoma that had "fully differentiated" into a gangliocytoma. Similarly McCowen et al. reported the case of a 38 year old man with a sellar/suprasellar mass and very high prolactin levels (997-1440 ng/ml) who responded to bromocriptine therapy preoperatively, but eventually underwent resection of what proved to be a pure gangliocytoma with focal immunoreactivity for prolactin. This may also represent a "fully differentiated" adenoma.

Finally, some cases have had a pure pituitary adenoma identified at surgery, only to have a mixed tumor or a pure gangliocytoma identified at a later date. We encountered an example of the first situation recently when a 20 year old male underwent his first transsphenoidal biopsy in 2002; a modest amount of a pure mixed PRL-GH secreting pituitary adenoma was removed. In an attempt to further reduce his GH levels and debulk his tumor, he underwent further resection via a subfrontal approach (which allowed access to more suprasellar elements of the neoplasm). Only this material showed the gangliocytoma component. Case 1 of Scheithauer et al. had acromegaly and a pituitary adenoma removed in life, but when the patient succumbed 2 months later after surgery, and an autopsy was performed, only the pure ganglion cell component was identifiable in the hypothalamus and chiasmal region. Despite careful examination no residual pituitary adenoma was found. Cases such as this suggest that in some instances, the diagnosis of mixed pituitary adenoma-gangliocytoma may be possible only when the more suprasellar/hypothalamic-chiasmal region portions of the mass are resected and available for examination by the pathologist.

References

Case series and reviews

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Case Reports
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  9. Hans VH, Urbach H, Kristof RA, Deckert M. January 2002: 59-year-old woman with an intrasellar lesion. Brain Pathol. 2002;12(3):391-2, 397.
  10. Kamel OW, Horoupian DS, Silverberg GD. Mixed gangliocytoma-adenoma: a distinct neuroendocrine tumor of the pituitary fossa. Hum Pathol. 1989;20(12):1198-203.
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Animal/Experimental Studies
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  3. Takor TT, Pearse AGE. Neuroectodermal origin of avian hypothalamo-hypophyseal complex: the role of the ventral neural ridge. J. Embryol Exp Morph 1975;34:311-325.