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The pituitary adenoma is a benign proliferation of cells arising from the anterior pituitary gland or adenohypophyses. It is surprising to find that as much as 20% of the general population may harbor these tumors. Needless to say, most are found after careful autopsy study. However, the advent of the sophistical imaging systems for the brain such as the CT and MRI scans have greatly contributed to the early detection of these tumors. These tumors were once classified upon the light microscopic findings on routine H and E stain. Today, the tumors are classified by the immunohistochemical findings and divided by the hormone content. There is also a clinicopathologic classification which combines the hormonal and histological findings.

Because the pituitary gland is located in the sella turcica, at the crossing of the optic nerves, it may present as a visual field defect. Hormonal imbalances such as acromegaly with excessive growth hormone or amennorrhea with excessive prolactin secretion may also occur. The most common hormones include the following:

Growth Hormone (GH)
Prolactin (PRL)
Thyroid stimulating hormone (TSH)
Adrenal corticotrophic hormone (ACTH)
Follicle stimulating hormone (FSH)
Luteinizing hormone (LH)


Disease Associations  
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1.85/100,000 general population

20% of general population

25% of all surgically resected intracranial neoplasms.

AGE RANGE-MEDIAN Increases with age
Only 3.5-5.8% of cases diagnosed before 20 years
30% of patients 50-60 years of age have clinically undetected tumors


Apoplexy Acute hemorrhagic necrosis of a pituitary adenoma leading to rapid tumor expansion with headache, lethargy, coma, and increased intracranial pressure
MEN syndromes Part of type MEN I syndrome
Pituitary adenomas occur in 2/3 of these patients




Role of E-Cadherin, -, ß-, and -Catenins, and p120 (Cell Adhesion Molecules) in Prolactinoma Behavior

Zhi Rong Qian, M.D., Chiun Chei Li, M.D., Ph.D., Hiroyuki Yamasaki, M.D., Noriko Mizusawa, M.Sc., Katsuhiko Yoshimoto, M.D., Ph.D., Shozo Yamada, M.D., Ph.D., Takashi Tashiro, M.D., Hidehisa Horiguchi, M.D., Ph.D., Shingo Wakatsuki, M.D., Mitsuyoshi Hirokawa, M.D., Ph.D. and Toshiaki Sano, M.D., Ph.D.

Departments of Pathology (ZRQ, TT, HH, SW, MH, TS) and Neurosurgery (HY), School of Medicine, Department of Pharmacology (NM, KY), School of Dentistry, Tokushima University, Tokushima; Department of Neurosurgery, Toranomon Hospital (SY), Tokyo, Japan; and Department of Pathology and Laboratory Medicine (CCL), Veterans General Hospital-Taipei and National Yung-Ming University, Taipei, Taiwan

Modern Pathology 2002;15:1357-1365 Abstract quote

E-cadherin/catenin complex regulates cellular adhesion and motility and is believed to function as an invasion suppressor system. In a number of cancers, abnormal and reduced expression of E-cadherin/catenin complex is associated with tumor invasion and metastasis. Prolactinomas show frequent invasion on the surrounding structures, despite their histologically benign nature. Furthermore, gender-based differences in endocrine and surgical findings are found in patients with prolactinoma.

To understand biological factors governing prolactinoma behavior, this study analyzed the expression of E-cadherin; -, ß-, and -catenins; p120; and cell proliferation marker MIB-1 labeling index in 13 invasive tumors (9 in men, 4 in women), 26 noninvasive tumors (4 in men, 22 in women), and 8 normal anterior pituitaries by immunohistochemistry. Immunostaining of E-cadherin; -, ß-, and -catenins; and p120 showed a membranous pattern of reactivity and generally stronger in normal pituitaries than in prolactinomas.

Expression of E-cadherin and ß-catenin was significantly lower in invasive than in noninvasive prolactinomas (P < .002 and P < .005, respectively), and reduced expression of E-cadherin and ß-catenin was more frequent in invasive than in noninvasive prolactinomas (P < .001 and P < .05, respectively); in contrast, -catenin expression showed higher in invasive than in noninvasive prolactinomas (P < .05). Expression of E-cadherin was significantly lower in macroprolactinomas than in microprolactinomas (P < .01), and decreased expression of E-cadherin and ß-catenin predicted high MIB-1 expression (P < .05). Moreover, the expression of E-cadherin and ß-catenin was significantly lower in macroprolactinomas in men than in those in women (P < .01 and P < .02, respectively). No statistical correlations were observed between expression of -catenin, p120, and clinicopathologic features.

In conclusion, the reduction of E-cadherin and ß-catenin expression was related to invasiveness and proliferative status of prolactinomas and correlated with the more aggressive behavior of prolactinomas in men compared with in women.

Analysis of epidermal growth factor receptor and activated epidermal growth factor receptor expression in pituitary adenomas and carcinomas.

Onguru O, Scheithauer BW, Kovacs K, Vidal S, Jin L, Zhang S, Ruebel KH, Lloyd RV.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, MN 55905, USA.
Mod Pathol. 2004 Jul;17(7):772-80. Abstract quote  

Epidermal growth factor receptor plays an important role in the pathogenesis of many malignancies. Various growth factors, including epidermal growth factor receptor, have been shown to influence pituitary tumor growth and differentiation.

To analyze the role of epidermal growth factor receptor in pituitary tumor development, we examined normal pituitaries (n=8), pituitary adenomas (n=158), and pituitary carcinomas (n=7) for expression of epidermal growth factor receptor protein and messenger RNA using tissue microarrays and RT-PCR.

We also examined (a) the expression of phospho-epidermal growth factor receptor, the activated form of epidermal growth factor receptor, in pituitary tumors and normal pituitaries by immunohistochemistry and (b) the effects on epidermal growth factor receptor expression of treating pituitary cells (HP75 cell line) with epidermal growth factor. Epidermal growth factor receptor and the phosphorylated variant expression were present in normal pituitary cells. Epidermal growth factor receptor messenger RNA was also detected in normal pituitaries, pituitary adenomas, and carcinomas by in situ hybridization and RT-PCR. Most pituitary adenomas showed expression of epidermal growth factor receptor and the phosphorylated variant. Nonfunctional adenomas showed higher levels of expression of epidermal growth factor receptor (76 vs 34%) and of phospho-epidermal growth factor receptor (26 vs 8%) as compared to functional adenomas. Five of seven pituitary carcinomas showed strong expression of both epidermal growth factor receptor and phospho-epidermal growth factor receptor.

When a human pituitary cell line (HP75) was cultured in the presence of epidermal growth factor receptor, there was an increase in the levels of both epidermal growth factor receptor and phospho-epidermal growth factor receptor after 5 h of treatment, thus confirming that epidermal growth factor receptor signaling was active in pituitary tumors.

These results indicate that activated epidermal growth factor receptor is expressed in pituitary adenomas and carcinomas. Higher levels in pituitary carcinomas suggest a role in pituitary tumor progression.

Expression of GATA-2 in Human Pituitary Adenomas

Katsuya Umeoka, Naoko Sanno, R. Yoshiyuki Osamura and Akira Teramoto

Department of Neurosurgery (KU, NS, AT), Nippon Medical School, Tokyo, Japan; and Department of Pathology (RYO), Tokai University School of Medicine, Kanagawa, Japan

Mod Pathol 2002;15:11-17 Abstract quote

Transcription factor GATA-2 contains two copies of a highly conserved zinc finger domain and plays unique roles at an early stage of hematopoietic differentiation. In the mouse pituitary gland, Pit-1-GATA-2 protein–protein interaction has been shown to lead to gene-specific actions to obtain cell-specific roles.

In this study, we investigated the expression of GATA-2 and Pit-1 in human pituitary adenomas using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical techniques. By immunohistochemical analysis, GATA-2 was detected in all of the gonadotropin-subunit (Gn-su)-positive adenomas (n = 8) and in four of five thyroid-stimulating hormone (TSH)-secreting adenomas, but its incidence was low in the other types of adenomas. Pit-1 protein was detected in 4 of 5 TSH-secreting adenomas and in 10 of 10 growth hormone (GH)-secreting adenomas. By RT-PCR analysis, GATA-2 was detected in all Gn-su-positive adenomas and TSH-secreting adenomas, and Pit-1 was detected in all TSH-secreting adenomas and GH-secreting adenomas.

These results suggested that GATA-2 contributes to the functional expression and the differentiation of Gn-su-positive adenomas and the TSH-secreting adenomas and that the interaction between GATA-2 and Pit-1 can lead to gene-specific action and differentiation of TSH-secreting adenomas. It is further speculated that GATA-2 and transcriptional interaction with Pit-1 play roles in the functional differentiation of specific pituitary adenomas.


Expression of Interleukin-6, Interleukin-6 Receptor (gp80), and the Receptor’s Signal-Transducing Subunit (gp130) in Human Normal Pituitary Glands and Pituitary Adenomas

Reiko Kurotani, Masanori Yasuda, Kenichi Oyama, Noboru Egashira, Muthumi Sugaya, Akira Teramoto and R. Yoshiyuki Osamura

Department of Pathology (RKMY, NE, MS, RYO), Tokai University School of Medicine, Kanagawa, Japan; and Department of Neurosurgery, Nippon Medical School (KO, AT), Tokyo, Japan

Mod Pathol 2001;14:791-797 Abstract quote

Interleukin-6 (IL-6) is an important cytokine in cell proliferation and differentiation in several organs. It has also been reported that IL-6 plays a role in secretion or release of pituitary hormones in pituitary hormone–secreting cells and pituitary adenomas, but convincing data in situ have not yet been reported.

In this study, we examined the participation of IL-6 in the production of pituitary hormones and the differences between human normal pituitary glands and pituitary adenomas by determination of the localization or expression of IL-6, IL-6 receptor (IL-6R, gp80), and the signal-transducing subunit (gp130) of the receptor using immunohistochemical staining and RT-PCR.

IL-6 was mainly expressed in ACTH- and FSH/LH-secreting cells in normal pituitary glands, as shown by double staining. gp 80 and gp130 were coexpressed in almost all GH- and PRL-secreting cells and in approximately 30% of FSH/LH-secreting cells. RT-PCR showed that IL-6 mRNA was expressed in only one of all the pituitary adenomas examined, whereas gp 80 and gp 130 mRNAs were detected in all these pituitary adenomas.

In conclusion, IL-6 was mainly expressed in ACTH- and FSH/LH-secreting cells, and the receptors were expressed in GH-, PRL- and FSH/LH-secreting cells in human normal pituitary glands. Furthermore, our data emphasized that the mechanism of IL-6 function in human pituitary adenoma cells is distinct from that in normal pituitary cells.


Expression of Neuro D1 in Human Normal Pituitaries and Pituitary Adenomas

Kenichi Oyama, Naoko Sanno, Akira Teramoto and R. Yoshiyuki Osamura

Department of Neurosurgery (KONS, AT), Nippon Medical School, Tokyo, Japan; and Department of Pathology, (RYO), Tokai University School of Medicine, Boseidai, Isehara-City, Knagawa, Japan

Mod Pathol 2001;14:892-899 Abstract quote

Neuro D1 is a basic helix-loop-helix transcription factor expressed in the endocrine cells of pancreas and in a subset of neurons as they undergo terminal differentiation. In the adult pituitary gland, Neuro D1 is expressed in corticotroph cells and contributes to the corticotroph-specific pro-opiomelanocortin (POMC) transcription by interacting with Pituitary homeobox 1 (Ptx 1) transcription factor.

In the present study, we investigated the expression of Neuro D1 in human normal pituitaries and different types of human pituitary adenomas using the RT-PCR and immunohistochemical techniques.

Using RT-PCR, Neuro D1 mRNA was found to be expressed in ACTH-secreting adenomas (n = 3) and 6 of 8 non-functioning adenomas. On the other hand, GH-secreting adenomas (n = 5) and PRL-secreting adenomas (n = 3) were completely negative for Neuro D1 mRNA.

Immunohistochemically, Neuro D1 was expressed in all ACTH-secreting adenomas (n = 10), and in 14 of 20 nonfunctioning adenomas. In contrast, 3 of 10 PRL-secreting adenomas and 2 of 10 GH-secreting adenomas showed positive Neuro D1 staining in the nuclei.

The above results suggest that Neuro D1 contribute to the functional expression and the differentiation of ACTH-secreting adenomas. It also appears from our study that Neuro D1 might play a role in the differentiation of non-functioning adenomas, the mechanism of which remains to be further investigated.

This is the first study on Neuro D1 in case of human pituitary adenomas.

Elevated expression of p21 (WAF1/Cip1) in hormonally active pituitary adenomas.

Neto AG, McCutcheon IE, Vang R, Spencer ML, Zhang W, Fuller GN.

Department of Pathology, Yale University, New Haven, CT, USA.
Ann Diagn Pathol. 2005 Feb;9(1):6-10. Abstract quote  

Although most pituitary adenomas arise sporadically, molecular studies show alterations of known oncogenes and/or tumor suppressor genes in a small percentage of adenomas, and the molecular pathology of most is unknown. The p21 gene is a universal inhibitor of cyclin-dependent kinases and serves as a cell-cycle blocker and cell-growth inhibitor.

Pituitary adenomas (n = 54) were immunophenotyped for hormone production (prolactin, growth hormone, adrenocorticotropin, thyrotropin, follicle-stimulating hormone, and luteinizing hormone), and expression of p21 was determined by immunohistochemistry. The percentage of cells expressing p21 for each tumor was evaluated blindly with regard to hormone status, and expression of p21 was then correlated with the results of hormone immunotyping.

Results show a striking difference in the expression of p21 between immunonegative adenomas and hormone-producing tumors. Whereas 71% (10/14) of nonfunctional adenomas exhibit p21 expression in fewer than 5% of cells, 77% (31/40) of hormone-producing adenomas show expression in more than 25% of cells, and of these, 68% (21/31) show expression in more than 75% of cells. Overexpression of p21 is particularly striking for growth hormone-producing tumors, of which 92% (11/12) show expression in more than 75% of cells. Hormone-producing pituitary adenomas express much more p21 than do immunonegative adenomas.

These high levels of p21 expression represent the most widespread molecular genetic alteration demonstrated to date in pituitary adenomas.


Radiologic Classification  
Grade I Microadenomas
Intrapituitary lesions <1 cm
Do not cause bony changes to the sellar turcica
Grade II >1 cm
Remain intrasellar or exhibit suprasellar expansion without invasion
Grade III Small or large locally invasive tumors that may be associated with diffuse sellar
Grade IV Large invasive tumors involving the extrasellar structures including bone, hypothalamus, and cavernous sinus


Adenomas causing GH excess Acromegaly or gigantism
Usually diagnosed early because of the clinical syndrome
GH and PRL Often associated with acromegaly and are the most frequent cause of gigantism
PRL Amenorrhea and galactorrhea
TH Less than 1% of adenomas

Cushing's disease-accounts for 2/3 of the cases of Cushing's syndrome

Nelson's syndrome resulted from patients who were treated with bilateral adrenalectomy-patients have hyperpigmentation with ACTH producing pituitary tumors

Gonadtropin (FSH/LH)

In general, clinical evidence of excess hormones is rare and tumors usually present with symptoms secondary to the mass effects of the tumor

In young women, may present as primary ovarian failure

Nonfunctioning tumors

25% of pituitary adenomas lack a clinical syndrome or characteristic serum hormone marker

There are also tumors which have detectable elevations of hormones in the blood but have no clinical symptoms from the hormones. These hormones are biologically inactive-these are termed silent adenomas and have been classified as:

Silent somatotroph adenomas
Silent lactotroph adenomas
Silent thyrotroph adenomas
Siletn corticotroph adenomas
SIlent gonadotroph adenomas


A Case of Cushing's Disease Caused by Pituitary Adenoma Producing Adrenocorticotropic Hormone and Growth Hormone Concomitantly: Aberrant Expression of Transcription Factors NeuroD1 and Pit-1 as a Proposed Mechanism.

Tahara S, Kurotani R, Ishii Y, Sanno N, Teramoto A, Osamura RY.

Department of Neurosurgery (ST, YI, NS, AT), Nippon Medical School, Tokyo, Japan.

Mod Pathol 2002 Oct;15(10):1102-5 Abstract quote

A 53-year-old Japanese woman was diagnosed with Cushing's disease caused by a adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma on the basis of clinical an imaging data. The surgically resected tumor tissue was investigated histopathologically using immunohistochemical analysis of pituitary hormones.

Our study revealed that the adenoma expressed not only ACTH but growth hormone (GH) in the tumor cells. Furthermore, immunohistochemical double staining showed that some adenoma cells were positive for both ACTH and GH. In situ hybridization for GH mRNA revealed that the adenoma cells produced GH as opposed to simply storing it. Although many pituitary adenomas produce multiple pituitary hormones, pituitary adenoma producing both ACTH and GH in the same adenoma cells, such as seen in this case, is extremely rare. To elucidate the molecular mechanism involved, we investigated the expression of transcription factors NeuroD1 and Pit-1 and found that both transcription factors were expressed in many tumor cells.

This case report describes a very rare case of pituitary adenoma that produced both ACTH and GH. We propose a hitherto undescribed translineage expression of transcription factors as the basic mechanism of this unique functional differentiation.

ECTOPIC Adenomas arising in the sphenoid sinus and parapharyngeal regions

Ectopic Pituitary Adenoma With Malignant Transformation

Naoki Hosaka, M.D.; Shin-Ichiro Kitajiri, M.D.; Harukazu Hiraumi, M.D.; Hidekazu Nogaki, M.D.; Junko Toki, Ph.D.; Guoxing Yang, Ph.D.; Hiroko Hisha, Ph.D.; Susumu Ikehara, M.D.

Am J Surg Pathol 2002; 26(8):1078-1082 Abstract quote

We report here a case of ectopic pituitary adenoma with malignant transformation after repeated relapses.

First, an ectopic pituitary adenoma producing follicle-stimulating hormone was found in the nasal cavity extending to the frontal cranial fossa. Despite repeated surgical resections of the tumor, it recurred three times in 2 years. The tumor gradually showed cellular atypia, mitosis, and necrosis. Immunohistochemical analyses revealed that the expressions of proliferating cell nuclear antigen and MIB-1 increased progressively. Moreover, the expression of p53 was detected at the second recurrence. Finally, at the third recurrence the tumor showed dissemination to the subarachnoid space and multiple metastases in the brain. The patient died of the tumor 10 months after the last resection. These findings indicate that the ectopic pituitary adenoma became malignant.

To our knowledge, this is the first report on malignant transformation of ectopic pituitary adenoma. It is important to know that ectopic pituitary adenomas show malignant transformation and that the above parameters (proliferating cell nuclear antigen, MIB-1, and p53) may be useful indicators of the malignant potential of both ectopic and sellar pituitary tumors.



Classic morphology divided the pituitary cells into acidophil, basophil, and chromophobic tumors-although there is a general correlation between the morphology and cell type, many chromophobic adenomas are associated with florid hormonal changes

There is a monotonous proliferation of cells, some arranged in an acinar pattern, others in sheets or trabeculae

Mild variation in the size and shape of the cells is noted associated with a capillary vasculature

GH-PRL-TSH Family These hormones share a common alpha subunit, differing in the beta subunit
GH cell adenomas  
GH cell adenomas with fibrous bodies
Tumor cells show more nuclear and cellular pleomorphism
Usually more acidophilic than usual GH adenomas and may be more aggressive with a faster growth rate
GH and PRL-cell (mammosomatroph) adenomas
GH and PRL localized to the same cell
PRL-cell adenomas  
PRL-cell adenomas with GH reactivity
TSH-cell adenomas (beta-TSH and alpha-subunit)  
GH, PRL, TSH producing adenomas  
ACTH Family  
ACTH-cell adenomas  
Gonadotropin family  
FSH/LH-cell adenomas (beta and alpha subunitis)  
Unclassified Adenomas  
Unusual plurihormonal adenomas  
Hormone-negative adenomas  

Silent corticotroph carcinoma of the adenohypophysis: a report of five cases.

Roncaroli F, Scheithauer BW, Young WF, Horvath E, Kovacs K, Kros JM, Al-Sarraj S, Lloyd RV, Faustini-Fustini M.


Am J Surg Pathol 2003 Apr;27(4):477-86 Abstract quote

We report five silent corticotroph carcinomas of the pituitary gland. They represent 0.05% of adenohypophyseal tumors surgically treated at Mayo Clinic during a 20-year period and about 5% of all reported pituitary carcinomas.

The patients (three females and two males), ranging in age from 26 to 58 years (mean 39 years, median 35 years) presented with symptoms of mass effect; none had Cushing's disease. All tumors were initially invasive macroadenomas, recurred locally, and metastasized, three outside the central nervous system. The follow-up period ranged from 2 to 23 years (mean 10.6 years). All patients died, four of disseminated tumor and one of myocardial infarction.

Histologically, three of the primary lesions were indistinguishable from an ordinary benign adenoma. Two were initially diagnosed as atypical adenomas as they featured nuclear pleomorphism, prominent nucleoli, mitotic activity, high MIB-1 labeling indices, and p53 overexpression. For the purpose of comparison, 17 silent corticotroph adenomas were also investigated. In addition, the clinicopathologic features of the silent carcinomas were compared with those of a meta-analysis of published Cushing's disease-associated pituitary carcinomas.

The silent adrenocorticotropin carcinomas showed a propensity for extraneural dissemination and an outcome similar to those of the Cushing's disease-associated carcinomas. The two patients with initial atypical tumors died with metastases outside the central nervous system at 2 and 4 years, whereas the three patients with tumors lacking atypia died 16, 18, and 23 years after initial sellar surgery.


Crooke's Cell Adenoma of the Pituitary: An Aggressive Variant of Corticotroph Adenoma.

George DH, Scheithauer BW, Kovacs K, Horvath E, Young Jr WF, Lloyd RV, Meyer FB.
Am J Surg Pathol. 2003 Oct;27(10):1330-6. Abstract quote  

SUMMARY: Cushing's disease is caused by functional corticotroph adenomas of the pituitary, mostly noninvasive microadenomas. Classic Crooke's cells are nonneoplastic corticotrophs with cytoplasmic accumulation of cytokeratin filaments in response to glucocorticoid excess. Corticotroph adenomas exhibiting Crooke's change are rare and incompletely understood.

We intend to define more clearly the clinicopathological features of Crooke's cell adenomas (CCA). Thirty-six CCAs were retrieved from the files of Mayo Clinic and from our (B.W.S., K.K.) consultation files. The number of informative cases varied for different criteria. Clinical follow-up was obtained in 31 cases. The 27 females and 9 males were 18 to 81 years of age (mean 46 years). At presentation, Cushing's disease was evident in 22/34 (65%); 81% were macroadenomas and 72% were invasive. All were initially treated by transsphenoidal resection. Twenty-five patients were followed for more than 1 year (mean 6.7 years). Of these, 15 (60%) developed recurrent tumor, and 6 (24%) had multiple recurrences. Lastly, 3 of these 25 patients (12%) died of tumor: 1 after multiple local recurrences and 2 from pituitary carcinoma. Compared with typical corticotroph adenomas, CCAs are aggressive.

Most are functional adenomas occurring in middle-aged women and are invasive macroadenomas prone to recurrence. Morbidity and mortality rates are substantial. CCAs represent a distinct entity that should be separated from corticotroph adenomas without Crooke's hyaline change.
Oncocytic transformation in pituitary adenomas: immunohistochemical analyses of 65 cases.

Niveiro M, Aranda FI, Paya A, Boix E, Peiro G, Pico A.

Department of Pathology, General Universitary Hospital of Alicante, Pintor Baeza s/n, 03010-Alicante, Spain
Arch Pathol Lab Med. 2004 Jul;128(7):776-80. Abstract quote

CONTEXT: Oncocytic change in pituitary adenomas has been evaluated by electron microscopy and more recently by immunohistochemistry. The clinical significance of this change is not well known, although some reports suggest a relationship with more aggressive behavior. OBJECTIVE: To assess the frequency of oncocytic change in pituitary adenomas and to correlate this finding with clinicopathologic factors. DESIGN: We studied oncocytic change in a series of 65 pituitary adenomas by immunohistochemistry. According to the percentage of oncocytic cells stained by antimitochondrial antibody, adenomas were classified in 3 groups: 50% or more, 10% to 49%, and 1% to 9% of oncocytic cells. RESULTS: Eight cases (12.3%) showing at least 50% of oncocytic cells were classified as oncocytic adenomas: 6 were gonadotroph adenomas and 2 were null-cell adenomas. Among the remaining cases, 9 (14%; all gonadotroph adenomas) showed 10% to 49% oncocytic cells, and in 14 cases (21.5%; 5 gonadotroph adenomas, 6 somatotroph adenomas, 2 corticotroph adenomas, and 1 thyrotroph adenoma) between 1% and 9% were shown. Patients with adenomas that showed oncocytic change presented more frequently at a higher average age (P =.05), but no relationship with extrasellar extension or proliferative activity measured by Ki-67 was observed. In somatotroph adenomas, cases with oncocytic change showed higher percentages of Ki-67 (P =.05) but no correlation with extrasellar extension or cytokeratin staining (dot pattern versus perinuclear) was found. CONCLUSION: Adenomas with oncocytic change present more frequently in older patients, but they are not clinically more aggressive. In addition, somatotroph adenomas with oncocytic cells show similar cytokeratin pattern and higher proliferative activity, which is not correlated with local aggressiveness.



`Gangliocytomas' of the Pituitary A Heterogeneous Group of Lesions With Differing Histogenesis

J. F. Geddes, F.R.C.Path.; G. H. Jansen, M.D.; S. F. D. Robinson, M.R.C.Path.; E. Gömöri, M.D.; J. L. Holton, M.R.C.Path.; J. P. Monson, F.R.C.P.; G. M. Besser, F.R.C.P.; T. Révész, F.R.C.Path.

From the Departments of Morbid Anatomy (J.F.G.) and Endocrinology (J.P.M., G.M.B), St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, U.K.; the Department of Histopathology, University of Pécs, Hungary (E.G.); the Departments of Neuropathology at Utrecht University Hospital, The Netherlands (G.H.J); Institute of Psychiatry, London, U.K. (S.F.D.R); and Institute of Neurology, London, U.K. (T.R., J.L.H.)

Am J Surg Pathol 2000;24:607-613 Abstract quote

Hamartomatous or neoplastic ganglion cells in the sella turcica are an unusual cause of symptoms. They have been reported in association with a functioning or nonfunctioning pituitary adenoma, with pituitary cell hyperplasia, and occasionally as masses unassociated with an adenoma, again with variable endocrinologic findings. Fewer than 50 cases of intrasellar ganglion cell lesions have been reported in the literature, only six of them associated with Cushing's syndrome.

We describe the clinicopathologic features of another eight patients, three of whom presented with acromegaly, four with apparently nonfunctioning adenohypophyseal masses, and one with Cushing's syndrome.

On histology, six of them were found to have sparsely granulated growth hormone (GH)-producing adenomas with ganglion cell areas, one appeared to have a gangliocytoma not associated with an adenoma, whereas the eighth had a ganglion cell lesion in the posterior pituitary. The morphologic and immunohistochemical findings suggest that the ganglion cell component of seven of these tumors has resulted from neuronal differentiation in a GH-producing adenoma, despite the lack of demonstrable adenoma in one case.

A true sellar ``gangliocytoma'' or hamartoma of ectopic hypothalamic-type neurons appears to be a rarer explanation for the presence of ganglion cells in a pituitary biopsy.

Metastatic adenocarcinoma to a pituitary adenoma

Christine Noga, MD
Richard A. Prayson, MD
Robert Kowalski, MD
Patrick J. Sweeney, MD
Marc Mayberg, MD

Ann Diagn Pathol 2001;5:354-360 Abstract quote

We report a case of a 60-year-old man who presented with a history of progressive blurred vision and an incomplete homonymous hemianopsia.

Magnetic resonance imaging showed a 5 cm heterogeneous mass which focally was contrast enhancing, involving the sella turcica and extending into the right cavernous sinus region. After worsening symptoms, repeat magnetic resonance imaging showed an increase in size of the lesion.

Histologically, the mass consisted of a metastatic adenocarcinoma to a nonsecreting pituitary adenoma. The carcinoma stained focally positive with antibodies to carcinoembryonic antigen, cytokeratin 20, and p53 (60% of tumor cells), and did not stain with antibody to cytokeratin 7. The histologic appearance and immunohistochemical profile of the metastasis suggests a colorectal primary.

Spindle Cell Oncocytoma of the Adenohypophysis: Report of Two Recurrent Cases.

Kloub O, Perry A, Tu PH, Lipper M, Lopes MB.

From the *Division of Neuropathology, Department of Pathology, and the double daggerDepartment of Radiology, University of Virginia, Charlottesville, VA; and the daggerDivision of Neuropathology, Department of Pathology, Washington University, St. Louis, MO.
Am J Surg Pathol. 2005 Feb;29(2):247-253. Abstract quote

The recently described "spindle cell oncocytoma of the adenohypophysis" is a very rare and often misdiagnosed entity. A benign biologic behavior has been suggested based on the absence of recurrences with a median follow-up of 3 years.

Herein, we present 2 cases of recurrent spindle cell oncocytomas. One patient is a 71-year-old woman (case no. 1) and the other a 76-year-old man (case no. 2). Recently, both underwent transsphenoidal reexploration for recurrent "pituitary adenoma." Patient no. 1 had initial surgery 11 years ago with a recurrence after 3 years that was initially stable. Ultimately, a partial resection was performed after compression of optic pathways by the tumor, and approximately 1 year later, re-resection was carried out. Patient no. 2 had initial surgery 10 years ago with recurrence and resection after 3 years. He recently presented with a large mass that involved the pituitary fossa and base of the skull, with extension into the nasopharynx and nasal cavity. The primary and recurrent lesions of both cases showed similar architecture with interlacing fascicles of spindle cells that alternated with areas of epithelioid-like cells that exhibited eosinophilic, granular cytoplasm. Neoplastic cells were positive for vimentin, S-100 protein, and epithelial membrane antigen, and negative for glial fibrillary acidic protein, chromogranin, and pituitary hormones. Increased mitotic activity was noted in 1 lesion (case no. 2), although both cases had high Ki-67 indices (18% and 20%, respectively). The ultrastructural features of both cases were characteristic with intracytoplasmic accumulations of large mitochondria.
The histopathologic features of these lesions are consistent with spindle cell oncocytoma of the adenohypophysis.

In summary, we are reporting 2 cases of recurrent spindle cell oncocytoma of adenohypophysis with longer follow-up than previously published cases, suggesting the possibility of a more aggressive behavior than has been initially considered.

`Spindle Cell Oncocytoma' of the Adenohypophysis: A Tumor of Folliculostellate Cells?

Federico Roncaroli; Bernd W. Scheithauer; Giovanna Cenacchi; Eva Horvath; Kalman Kovacs; Ricardo V. Lloyd; Patrice Abell-Aleff; Mariarita Santi; Allan J. Yates

Am J Surg Pathol 2002; 26(8):1048-1055 Abstract quote

We describe five primary tumors of the adenohypophysis featuring mitochondrion-rich spindle cells.

The patient ages ranged from 53 to 71 years (mean 61.6 years); two were female. All presented with panhypopituitarism. Two also had visual field defect. On neuroimaging all tumors showed suprasellar extension and were indistinguishable from pituitary adenoma. None showed imaging or operative evidence of dural involvement. All were gross totally removed: four by transsphenoidal surgery and one by frontal craniotomy. Follow-up ranged from 2 to 68 months (mean 35.4 months). No recurrences were noted. The clinical workup was noncontributory in all but two patients: one (case no. 4) with an oncocytic thyroid adenoma and another (case no. 5) with squamous carcinoma of both the uterine cervix and of vocal cord.

Histologically, the five tumors were composed mainly of fascicles of spindle cells with eosinophilic, granular cytoplasm. Mitoses were rare and necrosis was absent. Neoplastic cells were immunoreactive for vimentin, epithelial membrane antigen, S-100 protein, and galectin-3. Stains for pituitary hormones, synaptophysin, chromogranin, glial fibrillary acidic protein, cytokeratin CAM5.2, smooth muscle actin, CD34, and CD68 were negative. No thyroglobulin immunoreactivity was noted in the tumor of case no. 4. Ultrastructurally, the neoplastic cells contained numerous mitochondria with lamellar cristae. The neoplastic cells were linked by intermediate junctions and desmosomes. No secretory granules were noted.

The histologic, immunohistochemical, and fine structural features of these tumors were unlike those of pituitary adenoma or any other primary sellar tumor. A derivation from adenohypophyseal folliculostellate cells is suggested.



Immunohistochemical Analysis of RCAS1 in Human Pituitary Adenomas

Katsuya Umeoka, Naoko Sanno, Kenichi Oyama, Shigeyuki Tahara, Reiko Kurotani, Shoichiro Ikuyama, Manabu Nakashima, Takeshi Watanabe, R. Yoshiyuki Osamura and Akira Teramoto

Department of Neurosurgery (KU, NS, KO, ST, AT), Nippon Medical School, Tokyo, Japan; Department of Pathology (RK, RYO), Tokai University School of Medicine, Boseidai, Isehara-City, Kanagawa, Japan; Department of Clinical Immunology, Medical Institute of Bioregulation (SI), Kyushu University, Beppu, Japan; and Department of Molecular Immunology (MN, TW), Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

Mod Pathol 2001;14:1232-1236 Abstract quote

It has been reported that RCAS1 (receptor-binding cancer antigen expressed on SiSO cells) acts as a ligand for a receptor present on normal peripheral lymphocytes and induces apoptotic cell death. It is expressed in uterine and ovarian carcinomas, especially in invasive cancers.

This immunohistochemical study is aimed to elucidate the expression of RCAS1 in human pituitary adenomas in order to clarify its role in their proliferative regulation and invasiveness. Five normal pituitary glands, 50 human pituitary adenomas, and one malignant glioma were subjected to immunohistochemical studies.

In normal pituitary glands, immunostaining of RCAS1 and MIB-1 was not found. In malignant glioma, large numbers of cell nuclei were positive for MIB-1 (MIB-1 index: 28%), and RCAS1 was detected both in the cytoplasm and on the membrane of the tumor cells.

Expression of RCAS1 was noted in 48% of pituitary adenomas immunohistochemically (60.0% of growth hormone-secreting adenomas, 60.0% of prolactin-secreting adenomas, 42.9% of adrenocorticotrophin-secreting adenomas, 40.0% of thyroid-stimulating hormone-secreting adenomas, 33.3% of nonfunctioning adenomas, and 44.4% of gonadotropin-subunit-positive adenomas). It showed no correlation with tumor type, size, and invasiveness.

The statistically significant relationship between RCAS1 and MIB-1 positivity was identified in our study. These results suggest that expression of RCAS1 as well as MIB-1 positivity predict the growth potential of individual pituitary adenomas.


Topoisomerase IIalpha Expression in Pituitary Adenomas and Carcinomas: Relationship to Tumor Behavior.

Vidal S, Kovacs K, Horvath E, Rotondo F, Kuroki T, Lloyd RV, Scheithauer BW.

Department of Anatomy, Laboratory of Histology, University of Santiago de Compostela Lugo (SV), Spain.


Mod Pathol 2002 Nov;15(11):1205-12 Abstract quote

DNA topoisomerase IIalpha (Topo IIalpha) is a molecular and immunohistochemical marker that indicates proliferation rate and is the target for several antineoplastic agents.

The present immunohistochemical study of a large series of surgically removed pituitary tumors was designed to assess the prognostic significance of Topo IIalpha expression relative to patient age, gender, tumor type and size, invasiveness, metastasis, MIB-1-labeling index and angiogenesis. Changes of Topo IIalpha expression in the tumors treated with bromocriptine and octreotide, a long-acting somatostatin analogue were also investigated. Topo IIalpha immunopositivity was detected only in the nuclei of tumor cells. Gonadotroph adenomas, null cell adenomas, and ACTH-producing adenomas had the lowest Topo IIalpha indices, whereas primary pituitary carcinomas and silent type 3 adenomas presented the highest counts.

The statistical study demonstrated no significant correlation between Topo IIalpha expression, patient gender, and vascularity. In contrast, significant negative correlation was found between Topo IIalpha expression and patient age. Topo IIalpha expression was significantly higher in invasive than noninvasive tumors. A tendency to have higher counts was also observed in microadenomas compared with in macroadenomas. Although Topo IIalpha and MIB-1 indices were similar in most tumor types, no significant correlation between Topo IIalpha and MIB-1-labeling indices (r =.16, P =.09) was found. Only non-functioning adenomas showed positive correlation (r =.41, P =.006) between both proliferation markers. Our results demonstrated a significant decrease in Topo IIalpha index in octreotide-treated, GH-producing adenomas, compared with untreated tumors, but no significant changes were observed in bromocriptine-treated, PRL-producing adenomas.

The present study showed no significant advantage of Topo IIalpha over MIB-1 as a prognostic marker; however, Topo IIalpha may provide crucial information regarding selection of adenohypophyseal tumors responsive to antineoplastic therapy, such as invasive pituitary adenomas and pituitary carcinomas, which exhibit a high Topo IIalpha index.


Surgical removal is usually curative

PRL adenomas may respond to dopamine agonists such as bromocriptine

May be followed with postoperative radiation in larger tumors which cannot be totally removed


Radiation therapy for pituitary adenomas. A retrospective study of the University of Louisville experience.

Cornett MS, Paris KJ, Spanos WJ Jr, Lindberg RD, Jose B.

Department of Radiation Oncology, James Graham Brown Cancer Center, University of Louisville School of Medicine, KY 40202, USA.

Am J Clin Oncol 1996 Jun;19(3):292-5 Abstract quote

A retrospective analysis of treatment outcome was performed on patients treated with radiation for pituitary adenomas at the University of Louisville from January 1988 to December 1992.

The study population included 27 patients. Twenty received radiation as a component of their initial treatment while seven received radiation as part of their treatment for recurrent disease. Nineteen patients were treated with post-operative radiation, and eight were treated with radiation alone. Follow-up interval ranged from 1 month to 109 months, with a median of 28 months. All three patients with stage I disease were controlled with radiation alone (1/3) or combined surgery and postoperative radiation (2/3), whereas six of eight stage II patients had disease control following surgery and postoperative radiation. Both patients with stage III adenomas treated with radiation alone had local control, whereas local control was achieved in six of seven with post-operative radiation. Three of five patients with recurrent disease had local control with radiation alone, whereas both patients undergoing surgery and postoperative radiation had local control.

This retrospective analysis supports previous findings that radiation therapy alone or combined with transphenoidal resection is effective in long-term control of pituitary adenomas. It further suggests that immediate radiation therapy may be superior to radiation for surgical or medical failures.


Pituitary surgery: transsphenoidal approach.

Jane JA Jr, Thapar K, Kaptain GJ, Maartens N, Laws ER Jr.

Department of Neurosurgery, University of Virginia, Charlottesville, USA.

Neurosurgery 2002 Aug;51(2):435-42; discussion 442-4 Abstract quote

THE TRANSSPHENOIDAL APPROACH for sellar tumors has evolved significantly since it was described initially during the first decade of the 20th century.

The approach currently incorporates technological advancements and refinements in patient selection, operative technique, and postoperative care. Although many of these innovations are considered indispensable, the operative technique, as performed by contemporary neurosurgeons, is not standardized.

This variability is a reflection of surgeon's preference, the lessons of experience, and the bias inherent in neurosurgical training. The methods and preferences described herein embody the distillation of an experience gained from 3900 transsphenoidal operations.

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