Case 1 -
Mixed Pituitary Adenoma-Gangliocytoma,
with Adenoma Immunoreactive for Prolactin and Growth Hormone
University of Colorado Health Sciences Center
Click on each slide thumbnail image for an enlarged view
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.
Mixed pituitary adenoma-gangliocytoma, with adenoma immunoreactive for prolactin and growth hormone
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
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
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.
Case series and reviews
- Kurosaki M, Saeger W, Ludecke DK. Intrasellar gangliocytomas associated with acromegaly. Brain Tumor Pathology 2002;19:63-7.
- Geddes JF, Jansen GH, Robinson SF, Gomori E, Holton JL, Monson JP, Besser GM, Revesz T. 'Gangliocytomas' of the pituitary: a heterogeneous group of lesions with differing histogenesis. Am J Surg Pathol. 2000;24(4):607-13.
- Horvath E, Kovacs K, Scheithauer BW, Lloyd RV, Smyth HS. Pituitary adenoma with neuronal choristoma (PANCH): composite lesion or lineage infidelity? Ultrastruct Pathol. 1994;18(6):565-74.
- Towfighi J, Salam MM, McLendon RE, Powers S, Page RB. Ganglion cell-containing tumors of the pituitary gland. Arch Pathol Lab Med. 1996;120(4):369-77.
- Puchner MJ, Ludecke DK, Saeger W, Riedel M, Asa SL. Gangliocytomas of the sellar region--a review. Exp Clin Endocrinol Diabetes. 1995;103(3):129-49.
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- Saeger W, Puchner MJ, Ludecke DK. Combined sellar gangliocytoma and pituitary adenoma in acromegaly or Cushing's disease. A report of 3 cases. Virchows Arch. 1994;425(1):93-9.
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